The purpose of this review is to present the current knowledge about the diagnostic and treatment options in bladder cancer (BCa) patients with clinically positive lymph nodes (cN+). In this review compaction of CT and MRI performance in preoperative prediction of lymph node invasion (LNI) in BCa patients was presented, along with other diagnostic methods. Most scientific societies do not distinguish cN+ patients in their guidelines, recommendations concern muscle-invasive bladder cancer (MIBC) and differ between associations. Currently, the standard treatment of patients with MIBC is radical cystectomy (RC) with bilateral pelvic lymph node dis-section (PLND). The template of PLND and its therapeutic value remain debatable. Moreover, most guidelines recommend neoadjuvant chemotherapy (NAC). However, there is still lack of definitive evidence of the superiority of neoadjuvant chemotherapy over adjuvant chemotherapy. Nevertheless, the curative treatment that provides the best long-term survival in cN+ patients is a multimodal approach with a combination of chemotherapy and RC. Recent studies demonstrate the growing importance of immunotherapy. Special attention should be paid to cN+ BCa patients as the oncological outcomes are significantly worse for this group.

The current report represents a case of a 77-year-old man with Parkinson’s disease who died three weeks after receiving his third COVID-19 vaccination in January 2022. The patient was first vaccinated in May 2021 with the ChAdOx1 nCov- 19 vector vaccine, followed by two more doses with the BNT162b2 mRNA vaccine in July and December 2021. The family of the deceased requested an autopsy due to the ambivalent clinical features noted before death. The underlying illness (Parkinson’s disease) was confirmed by autopsy. However, no sign of a florid COVID-19 was discovered. Meanwhile, the immunohistochemical staining of the brain and heart revealed previously undiagnosed conditions. The brain, in distinctive, revealed multifocal necrotizing encephalitis with massive inflammatory lymphocyte infiltrates. In addition, the heart showed signs of serious myocarditis. Finally, immunohistochemical staining revealed that the SARS-CoV-2 spike protein was evident in the tissues investigated. Based on these immunohistochemical findings, it appears that the inflammatory changes in the patient's brain tissues are most likely the result of immunological processes. Concurrently, the absence of SARS-CoV-2 nucleocapsid-protein was evidenced, indicating that the detected spike-protein is unrelated to a SARS-CoV-2 infection. If such an infection was the cause of the spike protein, the SARS-CoV-2 nucleocapsid protein would also be detectable. As a consequence, the confirmed presence of the spike protein had to be attributed to the previous vaccination with the BNT162b2 mRNA vaccine that the deceased patient had received.

This article examines older physical education (PE) teachers’ wellbeing over the course of their career in Finland. The study highlights challenges to physical and mental functioning as well as how teachers respond to these challenges. The six interviewees were over 55-year-old PE teachers, whose career had lasted for more than 30 years. Qualitative methods were used in the collection, transcription and analysis of the research data. The qualitative analysis consisted of a series of interpretations that visualised the world described by the interviewees. All the research participants had physical problems that affected their teaching and make teachers consider a potential career change. To be able to teach, teachers adapted their ways of working according to the challenges brought by age and injuries. The research participants found that the challenges caused by musculoskeletal problems and ageing were an inevitable part of the profession. They emphasised the positive sides of the work: the profession permits varied workdays. In addition, the teachers noted that their work provides them with opportunities to remain physically fit. Teaching health education is a means to lighten the workload of older teachers. PE teachers enjoy their profession and are dedicated to it, despite all the challenges. The interviewed participants clearly experienced work engagement. Our development proposal for teacher education is that future PE teachers be informed about the risks involved in the profession. Such activity helps young teachers reflect proactively on the measures taken to maintain their functioning during their career and on perspectives related to the ways of working.

Cannabis has been used as an herbal remedy for thousands of years and recent research indicates promising new uses in medicine. Researchers have been particularly interested in the potential uses of cannabinoids in treating cancer due their ability to regulate cancer-related cell cycle pathways, leading to many beneficial effects such as tumor growth prevention, cell cycle obstruction, and cell death. The aim of this review is to summarize current knowledge on mechanisms of cannabinoids and their role in treating chemotherapy-induced nausea and vomiting, relieving cancer-associated pain, and obstructing tumor cell growth.

Despite a significant advance in the pathophysiological understanding of peripheral nerve damage, the successful treatment of large nerve defects remains an unmet medical need. In this article, axon growth guidance for peripheral nerve regeneration is systematically reviewed and discussed mainly from the engineering perspective. In addition, the common approach to surgery, bioengineering approaches to emerging technologies (i.e. optogenetic stimulation and magnetic stimulation) for functional recovery are discussed, with pros and cons. Alternatively, clear future perspectives of axon guidance and nerve regeneration are addressed.

Patients under immunosuppressive therapy for kidney diseases or on maintenance hemodialysis are more susceptible to infection than the general population since loss of renal function per se was an immunocompromised condition. Of relevance, CT imaging plays a crucial role in the detection and management of pulmonary infectious diseases. We hence presented diverse CT findings of pulmonary infections in the above said patients collected during our arduous work against a wide range of pathogens including klebsiella pneumoniae, staphylococcus aureus, candida parapsilosis, aspergillus, cryptococcus, mucor, pneumocystis carinii, cytomegalovirus, mycobacterium and nocardia. Notably, the pulmonary pathological changes were either primary pneumonia or secondary to the catheter-associated bloodstream infection. For a descriptive purpose, pulmonary manifestations of Wegener’s granuloma, lung cancer and diffuse alveolar hemorrhage/infection in vasculitis were also examined. As such, we retrospectively elaborated most likely CT features of each individual pathogen and briefly covered the differential diagnosis as well. Arguably, combination of pattern recognition with knowledge of the clinical setting could make a presumptive diagnosis and early treatment even more convenient. From the experience of first-line nephrologists, our work could make a substantial contribution to the expeditious and efficacious management of pulmonary infections in the pertinent patient population.

Cultural practices and development level can influence a population’s household structures and mixing patterns. Within some populations households can be organized across multiple dwellings. This likely affects the spread of infectious disease spreads through these communities, however, current demographic data collection tools do not record these data. Methods: Between June–October 2018, the Contact And Mobility Patterns in remote Aboriginal Australian communities (CAMP-remote) pilot study recruited Aboriginal mothers with infants in a remote northern Australian community to complete a monthly iPad-based contact survey. Results: Thirteen mother-infant pairs (participants) completed 69 study visits between recruitment and the end of May 2019. Participants reported they and their other children slept in 28 dwellings during the study. The median dwelling occupancy, defined as people sleeping in the same dwelling on the previous night, was nine (range: 3.5–25). Participants who completed at least three responses (n=8) slept in a median of three dwellings (range: 2–9). Each month a median of 28% (range: 0%–63%) of the participants travelled out of the community. Including these data in disease transmission models amplified estimates of infectious disease spread in the study community, compared to models parameterized using census data. Conclusions: The lack of data on mixing patterns in populations where households can be organized across dwellings may negatively impact the accuracy of infectious disease models for these communities and the efficacy of public health actions they inform.

Background: The incidence of traumatic acute subdural hematomas (ASDH) in elderly is increasing. Despite surgical evacuation, these patients have poor survival and low rate of functional outcome, and surgical timing plays a no clear role as predictor. We investigated if the timing of surgery has a major role in influencing outcome in these patients.Methods: We retrospectively retrieved clinical and radiological data of all patients ≥70 years operated on for post-traumatic ASDH in a 3 years period in 5 Italian Hospitals. Patients were divided in 3 surgical timing groups from hospital arrival: ultra-early (within 6h); early (6-24h); delayed (after 24h). Outcome was measured at discharge using two endpoints: survival (alive/dead) and functional outcome at Glasgow Outcome Scale (GOS). Univariate and multivariate predictor models were constructed.Results: We included 136 patients. About 33% died for consequences of ASDH and among the survivors only 24% were in good functional outcome at discharge. Surgical timing groups appeared different according to presenting GCS, which was on average lower in ultra-early surgery group, and radiological findings, which appeared worse in the same group. Delayed surgery was more frequent in patients with subacute clinical deterioration. Surgical timing appeared associated neither with survival nor with functional outcome also after stratification for preoperative GCS. Preoperative midline shift was the strongest outcome predictor. Conclusions: An earlier surgery was offered to patients with worse clinical-radiological findings. Also after stratification for GCS it was not associated with better outcome. Among the radiological markers, preoperative midline shift was the strongest outcome predictor.

First responders, such as police officers, paramedics, and fire-fighters are at an increased risk of experiencing negative mental health outcomes compared to the general population. This predisposition can partially be attributed to common occupational stressors, such as poor workplace culture and mistreatment from leadership, which may provoke strong feelings of betrayal and humiliation. The Workplace Assessment Scale (WAS) was developed as there is currently no appropriate measure to assess such feelings in the first responder population. The scale consists of the Betrayal Subscale and the Humiliation Subscale, each comprised of 5 Likert scale questions which ask participants to report the frequency at which they experience specific feelings associated with their workplace. This pilot validation study was conducted to assess preliminary reliability and validity of the WAS, using data which was originally collected as part of a larger first responder-based observational study. Based on 21/22 (95%) participant responses, the internal consistency appeared to be strong for both sub-scales as well as the overall questionnaire. However, item 9 will likely require modification or deletion from the scale. The validity analysis found no significant correlations between WAS and other psychiatric scales. Additional research is needed for further analysis and validation of the WAS.

ABSTRACT: Understanding the basis of osteoarthritis (OA) has seen some interesting advancements in recent years. It has been observed that cartilage degeneration is preceded by subchondral bone lesions, suggesting a key role of this mechanism within the pathogenesis and progression of OA, including the formation of ectopic bone and osteophytes. Moreover, low-grade, chronic inflammation of the synovial lining has gained a central role in the definition of OA pathophysiology, and central immunological mechanisms, innate but also adaptive, are now considered crucial in driving inflammation and tissue destruction. In addition, the role of neuroinflammation and central sensitization mechanisms has been characterized as underlying causes of pain chronicity. This has led to a renewed definition of OA, which is now intended as a complex multifactorial joint pathology caused by inflammatory and metabolic factors underlying joint damage. Since this evidence can directly affect the definition of the correct therapeutic approach to OA, an improved understanding of these pathophysiological mechanisms is fundamental. This review provides an overview of the most updated evidence on OA pathogenesis; it presents the most recent insight on the pathophysiology of OA, describing the interplay between immunological and biochemical mechanisms proposed to drive inflammation and tissue destruction, as well as central sensitization mechanisms. Moreover, although the therapeutic implications consequent to the renewed definition of OA are beyond this review scope, some suggestions for intervention have been addressed.

Background. It is well established that human milk feeding contributes in limiting lung disease among vulnerable neonates. The primary aim of this research was to compare the need for mechanical ventilation of human milk-fed sick neonates with that of formula-fed sick neonates. Methods. All late preterm and full term infants from a single center with findings of sepsis, from 2002 to 2017, were identified. Data regarding infant feeding during hospital admission were recorded. Multivariate logistic regression analyses were performed to assess the impact of the type of milk on ventilation support and main neonatal morbidities. Results. The total number of participants was 322 (human milk group = 260, exclusive formula group = 62). On bivariate analysis, 72% of human milk-fed neonates did not need oxygen therapy nor respiratory support versus 55% of their formula-fed counterparts (P<0.0001). Accordingly, invasive mechanical ventilation was required by 9.2% of human milk-fed infants versus 32% of their formula-fed counterparts (P=0.0085). These results hold true in multivariate analysis, indeed human milk-fed neonates were more likely to require less respiratory support (OR=0.44; 95% CI: 0.22, 0.89) when compared to those who were exclusively formula-fed. Conclusion. Human milk feeding might minimize exposure to mechanical ventilation.

Group B Streptococcus (GBS), a commensal in the body, causes a wide range of infectious diseases. The colonisation levels of GBS and its resistance profile to antibiotics provide important information useful for orienting prevention strategies. There is little data available on the subject with determination of resistance phenotypes in Cameroon. We therefore aimed to determine the prevalence of colonization, antibiotic resistance, including patterns of inducible resistance to clindamycin of GBS in Yaounde. To achieve this goal, a prospective cross-sectional study with an analytical component was carried out from the 28th June to the 29th August 2020 at the BIOSANTE laboratory and the Yaounde Gynaeco-Obstetrics and Paediatrics hospital. Vaginal swabs and urine were collected on 163 women. This samples were analysed using 5% defibrinated sheep blood agar and chocolate plus polyvitex agar. The isolates were identified using the morphology of the colony, Gram staining, haemolysis, catalase test and latex grouping test. Antibiotic susceptibility testing was done by disk diffusion method following the recommendations of the ACFSM 2019. The double disk diffusion method was used to identify isolates with clindamycin inducible resistance. Our data was analysed by the software SPSS version 2.1. The results obtained showed that the global prevalence of colonization by GBS was 37% (57/163), 40.35% in non-pregnant women and 59.65% in pregnant women. Pregnancy (P-value = 0.019) and gestational age (P-value = 0.025) constituted the risk factors of maternal colonization by GBS. In addition, the strains of GBS were resistant to all antibiotics tested. A D test showcased that 64.7% of GBS were resistant in a constitutive manner to clindamycin. We also note the presence of M phenotypes. As a whole, our results demonstrate that the rate of GBS colonization in this study was similar or higher than those in the previous report in Cameroon. All this indicates that attention should be paid to this bacterium in the monitoring of antimicrobial resistance and in the care of pregnant women and newborns.

Background: Some patients who have recovered from COVID-19 have experienced a range of persistent symptoms or the appearance of new ones after a SARS-CoV-2 infection. These symptoms can last from weeks to months, impacting everyday functioning to a significant number of patients. Methods: A cross-sectional analysis based on an online, self-reporting questionnaire was conducted in Ecuador from April to July 2022. Participants were invited by social media, radio, and TV to voluntarily participate in our study. A total of 2103 surveys were included in this study. We compared socio-demographic variables and long-term persisting symptoms at low (&lt; 2,500 m) and high altitude (&gt;2,500 m).Results: Overall, 1100 (52.3%) responders claimed to have long-term symptoms after SARS-CoV-2 infection. Most of these symptoms were reported by women (64.0%), the most affected group was young adults (68.5%), and the majority of long-haulers were mestizos (91.6%). We found that high altitude residents were more likely to report persisting symptoms (71.7%) versus those living at lower altitudes (29.3%). The most common symptoms were fatigue or tiredness (8.4%), hair loss (5.1%) and difficulty concentrating (5.0%). The highest proportion of persisting symptoms was observed among those who received an incomplete vaccine scheme.Conclusions: This is the first study describing post-COVID symptoms' persistence in low and high-altitude residents. Our findings demonstrate that women, especially those aging between 20-40, are more likely to describe sequalae associated with post-COVID. We also found that living at a high altitude was associated with earlier onset and longer symptom duration. Finally, we found a greater risk to report long lasting symptoms among women, those with previous comorbidities and those who had a severer acute SARS-CoV-2 infection.

Background/Aim: In clinical practice, uterine lipoleiomyomas are variants of uterine leiomyomas, often found incidentally, and do not require surgical treatment unless patient’s symptomatic. Therefore, these should be clinically differentiated from lesions that need surgical treatment. Conversely, hemangiomas, or blood vessel benign tumors, rarely develop in the uterus; however, many clinical complications such as abdominal pain and excessive vaginal bleeding result from a uterine hemangioma. Hemangiomas can occur at any age and primarily affect pregnant women. Materials and Methods: The oncological properties of uterine lipoleiomyoma and hemangioma in adults were investigated using molecular pathological examination on tissue excised from patients with uterine leiomyoma. Results: Through molecular pathological studies, which included potential biomarkers for uterine mesenchymal tumors, a differential diagnosis was established for this case of mesenchymal tumor. Herein, we report a 54-year-old non-pregnant woman who presented with vaginal bleeding and underwent hysterectomy after detection of a 140 × 100 mm intramural mass diagnosed as a concurrent uterine hemangioma and lipoleiomyoma after molecular histopathologic examinations. Conclusion: As far as we know, this case is the first patient of concurrent uterine hemangioma and lipoleiomyoma. Hence, such occurrence of several types of mesenchymal tumors must be considered in the differential diagnosis of patients with abnormal vaginal bleeding.

COVID-19 infection in the pediatric population usually leads to a mild illness, however, a rare but serious complication of MIS-C has been seen in children. MIS-C usually presents 2-4 weeks after COVID-19 infection or exposure, and rare reports have been documented in neonates. Vaccinations for COVID-19 have been approved for children 6 months and above in the United States, and recent reports suggest significantly low prevalence and risk of complications of MIS-C in vaccinated children compared to unvaccinated children. Vaccinations for COVID-19 are safe and recommended during pregnancy and prevent severe maternal morbidity and adverse birth outcomes. Evidence from other vaccine-preventable diseases suggests that through passive transplacental antibody transfer, maternal vaccinations are protective against infections in infants during the first 6 months of life. Various studies have demonstrated that maternal COVID-19 vaccination is associated with the presence of anti-spike protein antibodies in infants, persisting even at 6 months of age. Further, completion of a 2-dose primary mRNA COVID-19 vaccination series during pregnancy is associated with reduced risk for COVID-19–associated hospitalization among infants aged 6 months or less. Therefore, it can be hypothesized that maternal COVID-19 vaccination can reduce the risk of and severity of MIS-C in infants. In this article, we review the literature to support this hypothesis.

Medium-Long term impacts of Antiretroviral drugs on arterial blood pressure in people living with HIV in Malawi.SAGNO Jean Bpatiste², Loenardo Palombi¹ , Giuseppe Liotta¹, Victor T Tolno², Sangare H Mamary², Jere Haswel ².1= University of Tor vergata Roma, 2= Dream Health center MalawiKey Words: HIV, hypertension ABSTRACTIntroduction: We aimed to explore the medium-long term impacts of Anti-Retroviral Treatment (ART) on Hypertension in a sample of HIV-positive in Malawi. Methodology: This was a retrospective case control study carried out at DREAM health Centre in Blantyre/Malawi on patients who were enrolled from 2005 to 2019, Information about age, gender, blood pressure, ART regimen, BMI, CD4 count, Viral load, Biochemistry, hemoglobin, marital status, education level, survival and period on ARVs were retrieved from data base from 01/01/2006 to 31/12/2015.. In total, we enrolled (alive and on HAART)1350 patients > 18 years (mean age: 43.4 and the SD was ±10.7 with 1031 (65.9%) females and 534 (34.1%) males who were taking (or have taken) ARVs for more than 6 months at the date of enrollment and who were not affected by hypertension or potentially related diseases like Renal failure at the enrollment. The mean observation time, from the HAART initiation was 77 months per person (SD±40). Results: The sample was made up by two groups of patients, 675 who developed hypertension and 675 who did not, with similar age and gender composition. Among patients with hypertension, 30/675 (4.4%) developed a stage 3 hypertension, 154 a stage 2 (22.8%) and 491 a stage 1 (72.8%). Hypertension stages were not associated to statistic significant differences of age and/or gender ( p=0.422, p=0.281 respectively). At baseline, patients who developed hypertension showed higher hemoglobin, higher CD4 count and lower VL ( P<0.001). Patients on AZT-based regimen and TDF based regimen were at high risk to develop hypertension while PI-based regimen was protective to hypertension (P<0.001). In a multivariate analysis, factors independently associated to Hypertension were higher CD4 count and Body Mass Index at the visit date, while Baseline Viral Load and PI-Including regimes were protective factors. Education level was inversely associated with risk of hypertension, while being married was associated of risk of hypertension (p<0.001). Mortality rate among hypertensive patients was 1.6% for those treated for hypertension against the 3.6% for those not treated. Conclusion: this study shows a protective action of PI-including regimens compared with AZT based regimen that is associated to an increased risk of hypertension. Factors related to a better general health status are associated to an higher risk of hypertension as well as lower education, older age and male gender. Treatment should be started as soon as Hypertension stages 2-3 are reached and control by behavioral factors is no longer effective.

Previously, we reported that MTH1 inhibitors TH588 and TH1579 selectively induce oxidative damage and kill Ras expressing or transforming cancer cells, as compared to non-transforming immortalized or primary cells. While this explains the impressive anti-cancer properties of the compounds, the molecular mechanism remains elusive. Oncogenes induce replication stress, re-sulting in under replicated DNA and replication continuing into mitosis, where TH588 and TH1579 treatment cause toxicity and incorporation of oxidative damage. Hence, we hypothesized that oncogene-induced replication stress explains the cancer selectivity. To test this, we overex-pressed c-Myc in human epithelial kidney cells (HA1EB), resulting in increased proliferation, polyploidy and replication stress. TH588 and TH1579 selectively kill c-Myc overexpressing clones, enforcing the cancer cell selective killing of these compounds. Moreover, the toxicity of TH588 and TH1579 in c-Myc overexpressing cells is rescued by transcription, proteasome or CDK1 inhibitors, but interestingly not by nucleoside supplementation. This suggest that cancer selectivity is unrelated oncogene-induced replication stress. We conclude that the molecular toxi-cological mechanisms how TH588 and TH1579 kill c-Myc overexpressing cells have several com-ponents and involves MTH1-independent proteosomal degradation of c-Myc itself, c-Myc driven transcription and CDK activation, and is likely unrelated to oncogene-induced replication stress.

Breaking up prolonged sitting by short bouts of light physical activities including standing and walking has been shown to be beneficial for people with type 2 diabetes (T2D). This paper presents the development of an android mobile app to deliver a just-in-time adaptive intervention (JITAI) to reduce sedentary time in people with T2D. A total of six design workshops were conducted with seven experts to identify design requirements, a behavioural framework, and required contextual adaptations for the development of a bespoke mobile app (iMOVE). Moreover, a focus group was conducted among people with T2D as potential end-users (N=10) to ascertain their perceptions of the app. Feedback from the focus group was used in subsequent iterations of the iMOVE app. Data were analysed using an inductive qualitative thematic analysis. Based on workshops, key features of iMOVE were developed, including simplicity (e.g., navigation, login), colours and font sizes, push notifications, messaging algorithms and a triggering system for breaking up sitting time and moving more. Based on the user testing results, a goal setting tab was added, font sizes were made larger, the brightness of colours was reduced, and a colour indicator was used to indicate device connectivity with an activity tracker. A user-centric app was developed to support people with T2D to transition from sedentary to active lifestyles.

Mutations, especially those at the protein-protein interaction (PPI) interface, have been associated with various diseases. Meanwhile, though de novo mutations (DNMs) have been proven important in neuropsychiatric disorders, such as developmental delay (DD), the relationship between PPI interface DMNs and DD has not been well studied. Here we curated developmental delay DNM datasets from the PsyMuKB database and showed that DD patients showed a higher rate and deleteriousness in DNM missense on the PPI interface than sibling control. Next, we identified 302 DD-related PsychiPPIs, defined as PPI harboring a statistically significant number of DNM missenses at their interface, and 42 DD candidate genes from PsychiPPI. We then observed that PsychiPPIs preferentially affected hub proteins in the human protein interactome network. When analyzing DD candidate genes using gene ontology and gene spatio-expression, we found that PsychiPPI genes carrying PPI interface mutations, such as FGFR3 and ALOX5, were enriched in development-related pathways and the development of the neocortex, and cerebellar cortex, suggesting their potential involvement in the etiology of DD. Our results demonstrated that DD patients carried an excess burden of PPI-truncating DNM, which could be used to efficiently search for disease-related genes and mutations in large-scale sequencing studies. In conclusion, our comprehensive study indicated the significant role of PPI interface DNMs in developmental delay pathogenicity.

Recurrent hypoglycaemia, a common side-effect of insulin therapy in the treatment of type 1 diabetes, induces impaired glucose-sensing. Better understanding of how astrocytes, important non-neuronal cells in the brain, function in low glucose environments may improve our understanding of recurrent hypoglycaemia-induced defective counterregulation. Astrocytes contribute to glutamatergic signalling, which is required for hypoglycaemia counterregulation and is impaired by recurrent insulin-induced hypoglcyaemia. This study examined the glutamate response of astrocytes when challenged with acute and recurrent low glucose (RLG) exposure. The metabolic responses of cortical (CRTAS) and hypothalamic (HTAS) primary rat astrocytes were measured in acute and recurrent low glucose using extracellular flux analyses. RLG caused mitochondrial adaptations in both HTAS and CRTAS, many of which were attenuated by glutamate exposure during low glucose treatments. We observed an increase in capacity of HTAS to metabolise glutamine after RLG exposure. Demonstrating astrocytic heterogeneity in the response to LG, CRTAS increased cellular acidification, a marker of glycolysis in LG, whereas this decreased in HTAS. The directional change in intracellular Ca2+ levels of each cell type, correlated with the change in extracellular acidification rate (ECAR) during LG. Further examination of glutamate-induced Ca2+ responses in low glucose treated CRTAS and HTAS identified sub-populations of glucose-excited- and glucose-inhibited-like cells with differing responses to glutamate. Lastly, release of the gliotransmitter ATP by HTAS was elevated by RLG, both with and without concurrent glutamate exposure. Therefore, hypothalamic astrocytes adapt to RLG by increasing glutamate uptake and oxidation in a manner that attenuates RLG-induced mitochondrial adaptations.

Background: The number of young Japanese Brazilians, who are return migrants with Japanese ancestral roots, is increasing rapidly in Japan. However, the characteristics of their mental health and the relation between mental health and a complex ethnic identity remains unclear. Methods: This cross-sectional study compared 25 Japanese-Brazilian high school students with 62 Japanese high school students living in the same area. Research using self-report questionnaires on mental health, help-seeking behavior tendencies, and ethnic identity was conducted. The Japanese-Brazilian group was also divided into high and low ethnic identity groups, and their mental health conditions were compared. Results: The Japanese-Brazilian group had significantly poorer mental health conditions and lower ethnic identities than the Japanese group and were less likely to seek help from family members and close relatives. Among the Japanese Brazilians, those with low ethnic identity had significantly poorer mental health than those with high ethnic identity. Conclusions: Young Japanese Brazilians may face conflicts of ethnic identity that can disturb their mental health. To build an inclusive society, the establishment of community services to support mental health and to help return migrants develop their ethnic identity is essential.

Citrus flavonoids are well-known for beneficial effects at the cardiovascular and cardio-metabolic level, but often the encouraging in vitro results are not confirmed by in vivo approaches; also clinical trials are inconsistent. The limited bioavailability of them can be, at least in part, the reason of these discrepancies. Therefore many efforts were performed towards the improvement of their bioavailability. Hydrodynamic cavitation methods were successfully applied to the extraction of byproducts of the Citrus fruits industry, showing high process yields and affording stable phytocomplexes, known as IntegroPectin, endowed with great amounts of bioactive compounds and high water solubility. Cardioprotective effects of grapefruit IntegroPectin were evaluated by an ex vivo ischemia/reperfusion protocol. A further pharmacological characterization was carried out to assess the involvement of mitochondrial potassium channels. Grapefruit IntegroPectin, where naringin represented 98% of flavonoids, showed anti-ischemic cardioprotective activity, better than pure naringenin (the bioactive aglycone of naringin). On cardiac isolated mitochondria, this extract confirmed that naringenin/naringin were involved in the activation of mitochondrial potassium channels. The hydrodynamic cavitation-based extraction confirmed a valuable opportunity for the exploitation of Citrus fruits waste, with the end product presenting high levels of Citrus flavonoids and an improved bioaccessibility that enhances its nutraceutical and economic value.

Schizophrenia (SCZ) is a severe mental disorder that may result in hallucinations, delusions, and extremely disordered thinking. How each cell type in the brain contributes to SCZ occurrence is still unclear. Here, we leveraged the human dorsolateral prefrontal cortex bulk RNA-seq data, then used the RNA-seq deconvolution algorithm CIBERSORTx to generate SCZ brain single-cell RNA-seq data for a comprehensive analysis to understand SCZ-associated brain cell types and gene expression changes. Firstly, we observed that the proportions of brain cell types in SCZ differed from normal samples. Among these cell types, astrocyte, pericyte, and PAX6 cells were found to have a higher proportion in SCZ patients (astrocyte: SCZ = 0.163, Control = 0.145, P.adj = 4.9×10-4; pericyte: SCZ = 0.057, Control = 0.066, P.adj = 1.1×10-4; PAX6 : SCZ = 0.014, Control = 0.011, P.adj = 0.014), while the L5/6_IT_CAR3 cells and LAMP5 cells are the exact opposite (L5/6_IT_Car3 : SCZ = 0.102, Control = 0.108, P.adj = 0.016; LAMP5 : SCZ = 0.057, Control = 0.066, P.adj = 2.2×10-6). Next, we investigated gene expression in cell types and functional pathways in SCZ. We observed chemical synaptic transmission dysregulation in two types of GABAergic neurons (PVALB and LAMP5), and immune reaction involvement in GABAergic neurons (SST) and non-neuronal cell types (endothelial and oligodendrocyte). Furthermore, we observed that some differential expression genes from bulk RNA-seq displayed cell-type-specific abnormal in the expression of molecules in SCZ. Finally, the cell types with the SCZ-related transcriptomic changes could be considered to belong to the same module since we observed two major similar coordinated transcriptomic changes across these cell types. Together, our results offer novel insights into cellular heterogeneity and the molecular mechanisms underlying SCZ.

The traditional nomenclature system for classifying Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), based on clinical phenotype, described Granulomatosis with Polyangiitis (GPA), Eosinophilic Granulomatosis with Polyangiitis (EGPA) and Microscopic Polyangiitis (MPA) as distinct clinical entities. This classification has proved its expedience in clinical trials and every day clinical practice, yet, a substantial overlap in clinical presentation still exists, and often causes difficulties in prompt definition and clinical distinction. Additionally, new insights into the AAV pathogenesis point out that PR3 and MPO-AAV may not represent expressions of the same disease spectrum but rather two distinct disorders, as they display significant differences. Thus, it is supported that a classification based on ANCA serotype (PR3-ANCA, MPO-ANCA or ANCA-negative), could be more accurate and also closer to the nature of the disease, instead of the phenotype-based one. This review aims to elucidate the major differences between PR3 and MPO-AAV, in terms of epidemiology, pathogenesis, histological and clinical manifestations, and response to therapeutic approaches.

There is an increasing need for effective anxiety and pain reduction during medical imaging procedures in children. This is a complex issue, addressed by both non-pharmacological or pharmacological approaches. Dexmedetomidine is a fairly recently marketed, selective α2-adrenergic agonist, and can be administered intranasally. To develop an evidence-guided clinical protocol, we investigated its (side)-effects, preconditions and safety aspects following intranasal dexmedetomidine in children (1 month-5 years) for procedural sedation during medical imaging. To do so, a systematic search (PubMed, Embase, CINAHL (12/2021)) was performed to identify clinical studies on intranasal dexmedetomidine for procedural sedation for medical imaging (Computer Tomography, Magnetic Resonance Imaging). Following screening and quality assessment, 8 studies were retained. Nasal nebulization was considered the best administration method, dosing varied between 2 to 4 µg/kg (age-dependent) 30-45 minutes prior to imaging, and contra-indications or restrictions on oral intake were somewhat consistent across studies. Valid sedation scores were routinely used to assess sedation and the need for rescue dosing, while discharge was generally based on the Aldrete score (score ≥9). Heart rate, blood pressure and saturation were routinely monitored, with commonly observed bradycardia or hypotension (decrease by 20%). Based on these findings, a roadmap for evidence-guided clinical protocol was generated.

This paper presents a computational approach designed to construct and query a literature-based knowledge graph for predicting novel drug therapeutics. The main objective is to offer a platform that discovers drug combinations from FDA-approved drugs and accelerates their investigations by domain scientists. Specifically, the paper introduced the following algorithms: (1) an algorithm for constructing the knowledge graph from drug, gene, and disease mentions in the biomedical literature; (2) an algorithm for vetting the knowledge graph from drug combinations that may pose a risk of drug interaction; (3) and two querying algorithms for searching the knowledge graph by a single drug or a combination of drugs. The resulting knowledge graph had 844 drugs, 306 gene/protein features, and 19 disease mentions. The original number of drug combinations generated was 2,001. We queried the knowledge graph to eliminate noise generated from chemicals that are not drugs. This step resulted in 614 drug combinations. When vetting the knowledge graph to eliminate the potentially risky drug combinations, it resulted in predicting 200 combinations. Our domain expert manually eliminated extra 54 combinations which left only 146 combination candidates. Our three-layered knowledge graph, empowered by our algorithms, offered a tool that predicted drug combination therapeutics for scientists who can further investigate from the viewpoint of drug targets and side effects.

Background: The role played by the non-dominant parietal lobe in motor cognition, attention and spatial awareness networks has potentiated the use of awake surgery. When this is not feasible, asleep monitoring and mapping techniques should be used to achieve an onco-functional balance. Objective: This study aims to assess the feasibility of a dual-strip method to obtain direct cortical stimulation for continuous real-time cortical monitoring and subcortical mapping of motor and visual pathways simultaneously in parietal lobe tumour surgery. Methods: Single-centre prospective study between May’19-November’20 of patients with intrinsic non-dominant parietal-lobe tumours. Two subdural strips were used to simultaneously map and monitor motor and visual pathways. Results: Fifteen patients were included. With regards to motor function, a large proportion of patients had abnormal interhemispheric resting motor threshold ratio (iRMTr) (71.4%), abnormal Cortical Excitability Score (CES) (85.7%), close distance to the corticospinal tract – Lesion-To-Tract Distance (LTD) – 4.2mm, Cavity-To-Tract Distance (CTD) – 7mm and intraoperative subcortical distance - 6.4mm. Concerning visual function, the LTD and CTD for optic radiations (OR) were 0.5mm and 3.4mm, respectively; the mean intensity for positive subcortical stimulation of OR was 12mA±2.3mA and 5/6 patients with deterioration of VEPs>50% had persistent hemianopia and transgression of ORs. 12 patients remained stable, one patient had a de-novo transitory hemiparesis, and two showed improvements in motor symptoms. A higher iRMTr for lower limbs was related with a worse motor outcome (p=0.013) and a longer CTD to OR was directly related with a better visual outcome (p=0.041). At 2 weeks after hospital discharge, all patients were ambulatory at home and all proceeded to have oncological treatment. Conclusion: We propose motor and visual function boundaries for asleep surgery of intrinsic non-dominant parietal tumours. Pre-operative abnormal cortical excitability of the motor cortex, deterioration of the VEP recordings and CTD<2mm from the OR were related to poorer outcomes.

Psychiatric patients are particularly vulnerable to strong weather stimuli, such as foehn, a hot wind that occurs in the alps. However, there is a dearth of research regarding its impact on mental health. This study investigated the impact of foehn wind among patients of a psychiatric hospital located in a foehn area in the Swiss Alps. Analysis was based on anonymized datasets obtained from routine records on admission and discharge, including the Brief Symptom Checklist (BSCL) questionnaire, as well as sociodemographic parameters (age, sex, and diagnosis). Between 2013 and 2020 a total of 10,456 admission days and 10,575 discharge days were recorded. All meteorological data were extracted from the database of the Federal Office of Meteorology and Climatology of Switzerland. We estimated the effect of foehn on the BSCL items using a distributed lag model. Significant differences were found between foehn and non-foehn admissions in obsession-compulsion, Interpersonal Sensitivity, depression, Anxiety, Phobic Anxiety, Paranoid Ideation, and General Severity Index (GSI) (p &lt;.05). Our findings suggest that foehn wind events may negatively affect specific mental health parameters in patients. More research is needed to fully understand the impact of foehn’s events on mental health.

Coronary artery disease (CAD) represents a modern pandemic associated with significant morbidity and mortality. The multi-faceted pathogenesis of this entity has long been investigated, highlighting the contribution of systemic factors such as hyperlipidemia and hypertension. Nevertheless, recent research has drawn light to the importance of geometrical features of coronary vasculature on the complexity and vulnerability of coronary atherosclerosis. Various parameters have been investigated so far, including vessel-length, cross-sectional area, curvature, and tortuosity, using primarily invasive angiography and recently non-invasive cardiac computed tomography angiography (CCTA). It is clear that there is correlation between geometrical parameters and both the haemodynamic alterations augmenting the atherosclerosis-prone environment and the extent of plaque burden. The purpose of this review is to discuss the currently available literature regarding this issue and propose a potential non-invasive imaging biomarker, the geometric risk score, which could be of importance to allow early detection of individuals at increased risk of developing CAD.

BACKGROUND&AIMS: Hepatitis B virus (HBV) infection remains a major public health problem. The interaction between HBV and the host inflammatory response is an important factor contributing to liver damage and disease development. We compared the correlation between the subclinical index and PBMCs concentration in two groups of pregnant women (HBsAg positive), which are different in HBV DNA concentration in Vietnam. METHODS: The Hierarchical cluster analysis (HCA) was run with 20 different clustering methods on data collected from 80 Vietnamese pregnant women and their babies (60/80 cord blood). RESULTS: In the high viral load group (HBV DNA ≥ 5x10^7 copies/ml), a strong correlation between CBMCs with serum maternal Haemoglobin concentration and maternal platelet and maternal ALT. Their R values are: -0.88, 0.82, and 0.84 with p=8.97E-03, 2.41E-02 and 1.75E-01, respectively. CONCLUSIONS: We found a significant correlation shift of subclinical index between the two groups, which may be important in diagnosing pregnant women with chronic hepatitis B virus infection.

Hearing loss in infancy leads to preventable speech, language, and cognitive developmental delay [1, 2]. Sensorineural hearing loss (SNHL) is caused by damages, problems, or issues related to the inner ear such as the cochlea with or without the auditory nerve; cranial nerve VIII, involvement. There are three anatomic areas which include the outer ear: composed of the auricle and external auditory canal and the middle ear: which includes the tympanic membrane, ossicles, and the middle ear space, the inner ear: composed of the cochlea, semi-circular canals, and internal auditory canals. The unique anatomical shape of the auricle catches the incoming sound waves to send them down the external auditory canal. Hearing risk assessment should be part of all health visits while regular hearing screening checks are done for all children from 4 to 21 years [1, 2]. Assessment of hearing loss includes history, physical examination and specific hearing assessment tests.

Background: Young adults, particularly university students might be at greater risk of developing psychological distress, and exhibiting symptoms of anxiety and depression during the COVID-19 pandemic. Objective: The primary objective of this study was to explore and compare the determinants and predictors of mental health (anxiety and depression) during and after COVID-19 lockdown among university students. Methods: This was an observational, cross-sectional study with a sample size of 417 students. An online survey utilizing International Physical Activity Questionnaire–Short Form (IPAQ-SF), General Anxiety Disorder–7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9) was distributed to Universiti Tunku Abdul Rahman students via Google forms. Results: During lockdown, family income [χ² (1, n=124) = 5.155, p=0.023], and physical activity [χ² (1, n=134) = 6.366, p=0.012] were associated with anxiety, while depression was associated with gender [χ² (1, n=75) = 4.655, p=0.031]. After lockdown, family income was found to be associated with both anxiety [χ2 (1, n=111) = 8.089, p=0.004], and depression [χ2 (1, n=115) =9.305, p=0.002]. During lockdown, family income (OR=1.60, p=0.018), and physical activity (OR=0.59, p=0.011) were predictors for anxiety, and gender (OR=0.65, p=0.046) being the only predictor for depression. After lockdown, family income was a predictor for both anxiety (OR=1.67, p=0.011), and depression (OR=1.70, p=0.009). Conclusion: Significant negative effects attributed to the COVID-19 lockdown, and certain factors predisposed to the worsening of mental health status in university students. Family income, physical activity level, and gender were some of the major determinants that influenced the anxiety and depression.

The 2019-2020 Australian bushfires followed by the COVID-19 pandemic brought the significant mental health implications of working in healthcare to the fore. The importance of appropriate support services to ensure the resilience and recovery of healthcare workers has been highlighted. In response to healthcare staff experiences during the bushfires, the SEED Wellness Program was created in 2020 in the Illawarra Shoalhaven Local Health District, in NSW Australia. SEED used a participatory action methodology to engage and collaborate with healthcare staff teams in workplace-based restorative activities. Guided by Practice Theory, this study aimed to identify and describe SEED wellness practices that supported healthcare staff. Thirty-three healthcare workers participated in focus groups or individual interviews between June 2021 and March 2022. The analysis involved inductive thematic individual and collective exploration of SEED practices, including co-analysis with participants. Eight core practices that supported participants’ wellbeing were identified including responsive and compassionate leading, engaging staff at every stage of the recovery process, creating a sense of connection with others, and collective caring. The study found that workplace wellness initiatives are optimised when place-based and grounded in local knowledge, needs, and resources incorporating a collective and supportive team approach. Moreover, to ensure engagement in, and sustainability of these initiatives, both bottom-up and top-down commitment is required.

Objective To Identify risk factors of perinatal complications amongst macrosomic babies in a reference hospital structure. Method We conducted a case-control institutional based study. Cases and controls of singleton livebirths were extracted from the maternity registry from January 2017 to December 2019 The case population consisted of mother and child macrosomic couples with perinatal complications. The control group consisted of couples without perinatal complications. Matching was done on age and sex. The main primary end point was the risk factors for complications. Data were analyzed using R, software version3.0 in adjusted and unadjusted analysis with p<0.05 threshold considered statistically significant. Results Out of 362 couples, we had 186 cases and 176 controls. Maternal age ≥30 years (p=0.024); non-screening for gestational diabetes (p=0.027); history of caesarean section (p=0.041); weight gain ≥16 kg (p<0.001); maternal HIV (p=0.047); birth weight ≥4500g (p=0.015) and birth height ≥ 52.7 ±1.7cm (p=0.026) were risk factors. Conclusion The delivery of a macrosomic baby remains problematic in this setting. The improvement of the maternal-fetal prognosis requires quality prenatal surveillance and management by a multidisciplinary perinatal team involving obstetricians, endocrinologist, and neonatal pediatricians.

The high costs of cancer treatment and lack of investment in health care are significant obstacles to public health on the African continent. The objective of this study was to estimate the financial cost of treating children suffering from cancer in Africa. We conducted a systematic review and meta-analysis of expert opinions between March 2000 and March 2020. The key search terms included ‘cost’, ‘cancer’ and ‘child’; we selected articles that specifically addressed the financial costs of childhood cancer in African countries. Of the 103 articles found, 18 met the inclusion criteria. Cancer care was a heavy financial burden in most of the countries studied, although costs varied from country to country; the average expenditure on healthcare was US$1017.39 ± US$319.1 per year. In countries without a health insurance system, the highest proportion of cancer care costs, 46.6%, was indirect, whereas in countries with a cancer financing system, the direct cost of treatment was low, 53.4%. The cost of treating childhood cancer is high in Africa in relation to the standard of living of individuals residing in this region.

To Identify risk factors of perinatal complications amongst macrosomic babies in a reference hospital structure.We conducted a case-control institutional based study. Cases and controls of singleton livebirths were extracted from the maternity registry from January 2017 to December 2019 The case population consisted of mother and child macrosomic couples with perinatal complications. The control group consisted of couples without perinatal complications. Matching was done on age and sex. The main primary end point was the risk factors for complications. Data were analyzed using R, software version3.0 in adjusted and unadjusted analysis with p<0.05 threshold considered statistically significant.Out of 362 couples, we had 186 cases and 176 controls. Maternal age ≥30 years (p=0.024); non-screening for gestational diabetes (p=0.027); history of caesarean section (p=0.041); weight gain ≥16 kg (p<0.001); maternal HIV (p=0.047); birth weight ≥4500g (p=0.015) and birth height ≥ 52.7 ±1.7cm (p=0.026) were risk factors. The delivery of a macrosomic baby remains problematic in this setting. The improvement of the maternal-fetal prognosis requires quality prenatal surveillance and management by a multidisciplinary perinatal team involving obstetricians, endocrinologists and neonatal pediatricians.

Interprofessional collaboration between general practitioners (GPs) and community pharmacists (CPs) is central to implement antimicrobial stewardship (AMS) programs in primary care. This study aimed to design a GP-pharmacist antimicrobial stewardship (GPPAS) model in Australian primary care. A seven-component exploratory study was conducted since 2017 to 2021 to inform a GPPAS model. We generated both secondary and primary evidence through a systematic review, a scoping review, a rapid review, nationwide surveys of Australian GPs and CPs including qualitative components and a pilot study of a GPPAS model. All study evidence was synthesised, reviewed, merged and triangulated to design a prototype GPPAS model using a Systems Engineering Initiative for Patient Safety theoretical framework. Secondary evidence informed effective GPPAS interventions, and primary evidence captured interprofessional issues, challenges and future needs to implement GPPAS interventions by GPs and CPs. A GPPAS model framework involving GP-pharmacist team-based five GPPAS sub-models were successfully designed to foster AMS education, antimicrobial audits, diagnostic stewardship, delayed prescribing, and routine review of antimicrobial prescription by improved GP-CP collaboration. A GPPAS model could be used as a guide to collaboratively optimise antimicrobial use by GPs and CPs. Implementation studies on GPPAS model and sub-models are required to integrate GPPAS model into GP-pharmacist interprofessional care models in Australia.

Traumatic brain injury (TBI) is a major leading cause of death and disability. While previous studies regarding focal pathologies following TBI have been done, there is a lack of information concerning the role of analgesics and their influences on injury pathology. Buprenorphine (Bup), an opioid analgesic, is a commonly used analgesic in experimental TBI models. Our previous studies investigated the acute effects of Buprenorphine-sustained release-Lab (Bup-SR-Lab) on diffuse neuronal/glial pathology, neuroinflammation, cell damage, and systemic physiology. The current study investigated the longer-term chronic outcomes of Bup-SR-Lab treatment at 4 weeks following TBI utilizing a central fluid percussion injury (cFPI) model in adult male rats. Histological assessments of physiological changes, neuronal damage, cortical and thalamic cytokine expression, microglial and astrocyte morphological changes, and myelin alterations were done, as we had done in our acute study. In the current study the Whisker Nuisance Task (WNT) was also performed pre- and 4w post-injury to assess changes in somatosensory sensitivity following saline or Bup-SR-Lab treatment. Bup-SR-Lab treatment had no impact on overall physiology or neuronal damage at 4w post-injury regardless of region or injury, nor did it have any significant effects on somatosensory sensitivity. However, greater IL-4 cytokine expression with Bup-SR-Lab treatment was observed compared to saline treated animals. Microglia and astrocytes also demonstrated region-specific morphological alterations associated with Bup-SR-Lab treatment, in which cortical microglia and thalamic astrocytes were particularly vulnerable to Bup-mediated changes. There were discernable injury-specific and region-specific differences regarding myelin integrity and changes in specific myelin basic protein (MBP) isoform expression following Bup-SR-Lab treatment. This study indicates that use of Bup-SR-Lab could impact TBI-induced glial alterations in a region-specific manor 4w following diffuse brain injury.

Background: This study aimed to examine the course of Depression and anxiety in COVID-19 survivors with a psychiatric history compared with those without a psychiatric history. Methods: A web-based cross-sectional survey for COVID-19 survivors was conducted from July to September 2021. 6016 COVID-19 survivors, the accuracy of whose responses was determined to be assured, were included in analyses. Exposures included psychiatric history and time since COVID-19 infection, and the main outcomes and measures included severity of depression and anxiety, as assessed using the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7), respectively. Results: Mean severity of PHQ-9 and GAD-7 were significantly higher in participants with a psychiatric history than in those without a psychiatric history. Two-way analysis of covariance for PHQ-9 showed a significant main effect of the presence of psychiatric history and a significant interaction effect of psychiatric history × time since infection. Two-way analysis of covariance for the GAD-7 score revealed a significant main effect of the presence of psychiatric history and time since COVID-19 infection and the interaction effect of these factors. Conclusions: The course of depression and anxiety was more severe in COVID-19 survivors with a psychiatric history than in those without a psychiatric history.

Aim. To identify factors associated with mortality with tuberculosis diagnosis in the indigenous population in Peru 2015-2019. Methods. Case-control study nested in a retrospective cohort, using the registry of persons belonging to indigenous peoples of the National Tuberculosis Prevention and Control Strategy of the Ministry of Health of Peru. A descriptive analysis was applied, and then bivariate and multiple logistic regression was used to evaluate associations between the variables and the outcome (live-deceased), the results were presented as OR with their respective 95% confidence intervals. Results. The mortality rate of the total indigenous population of Peru was 1.75 deaths per 100,000 indigenous people diagnosed with TB. The community of Kukama kukamiria - Yagua reported 505 (28.48%) individuals. The final logistic model showed that indigenous men (OR=1.93; 95% CI: 1.001-3.7), with a history of HIV prior to TB (OR=16.7; 95% CI: 4.7-58.7) and indigenous people in old age (OR=2.95; 95% CI: 1.5-5.7), are factors associated with a greater chance of dying from TB. Conclusions. It is important to reorient health services among indigenous populations, especially those related to improving the timely diagnosis and early treatment of TB-HIV co-infection, to ensure comprehensive care for this population, considering that they are vulnerable groups.

Most existing cancer therapies negatively affect normal tissue as well as cancerous tissue. A potentially effective strategy for treating cancer that precludes off-target damage and could be an option for most patients would involve targeting one or more mutations that are ubiquitous in the given patient’s tumor(s). To effect this strategy, one would employ multi-region sequencing of a patient’s primary tumor and metastases to seek out mutations that are shared between all or at least most regions. Once the target or targets are known, one would ideally rapidly generate a molecular switch for at least one of said ubiquitous mutations that can distinguish the mutated DNA, RNA, or protein from the wild-type version and subsequently trigger a therapeutic response. I propose that the therapeutic response involve the replication of an oncolytic virus or intracellular bacterium, as any mutation can theoretically be detected by a vector that enters the cell - and automatic propagation could be very helpful. Moreover, the mutation “signal” can be easily enhanced through transcriptional and translational (if the target is an intracellular protein) enhancement. Importantly, RNA may make the best target for the molecular switches in terms of amplification of the signal and ease of targeting.

Monkeypox, once a rare zoonotic disease, was endemic to some African countries since its original identification among humans in 1970. Since then, cases in non endemic regions were linked to returning travelers or those who had contact with transported animals. The causative agent, Monkeypox virus, belongs to Orthopoxviruses, the same family as Variola; the causative organism for smallpox. Although most Monkeypox outbreaks until recently were linked to zoonotic transmission, secondary human-human transmission in smallpox unvaccinated individuals was observed in a small proportion of overall cases. Smallpox was declared eradicated in 1980 and since its eradication, monkeypox virus is the most significant poxvirus to cause human disease. The 2022 monkeypox outbreak marks a significant paradigm shift in the human and poxvirus association, with new modes of transmission, concerns of viral evolution and entrenchment as a sexually transmitted disease. Monkeypox clinically resembles smallpox but is far milder. At this time there are no approved therapies for monkeypox and antiviral agents effective against smallpox are being utilized. Additionally, preventive strategies being utilized include smallpox vaccination like JYNNEOS and ACAM2000. In this narrative review, we discuss the virology, epidemiology, transmission, clinical manifestations, diagnosis, management and prevention strategies associated with monkeypox.

Background: A novel virulent coronavirus is what causes Novel Corona-virus Disease 2019 (nCOVID 19). It results in severe respiratory distress syndrome and potentially fatal infectious pneumonia. On March 12, 2020, the World Health Organization first labeled it a pandemic, which was then followed on the same day by a community health emergency of global concern. Vaccines against this deadly virus are now being created. Many drugs with different uses have been repurposed and tested for the prevention and treatment of the infection. Objective: The purpose of this review is to provide an in-depth analysis of data on possible pharmacological targets and available coronavirus treatments. Methods: Following the review protocol, a literature search was conducted. Results: Chloroquine phosphate and hydroxychloroquine, Remdesivir, and Lopinavir-Ritonavir in combination with or without interferon and convalescent plasma therapy are the main treatment candidates, according to the World Health Organization. This review article has elaborated on the current evidence of prospective pharmacological targets and related ongoing research, including inflammatory chemicals, bioactive peptides, beta cells, platelets, and the Angiotensin I Converting Enzyme 2 Receptor. This information was gathered from published journals. In addition, stories of medications and biological products like interferons and vaccinations that are utilized or could be utilized have been provided. Conclusion: There are a variety of pharmacological targets and therapeutic strategies that need more study.

Tissue programmed death ligand-1 (PD-L1) protein expression is predictive of immune checkpoint inhibitor (ICI) benefit. However, tissue PD-L1 can be fraught with tissue acquisition and heterogeneity limitations. Plasma testing can overcome these limitations. However, the overall survival (OS) predictive benefit of plasma PD-L1 assays have not been well characterized. Patients with stage IV non-small cell lung cancer (NSCLC) and plasma cfRNA PD-L1 by PCR expression were identified and assessed for OS. 16 patients treated with front-line ICI-based regimens were assessed and represented a real-world patient population with over half with a performance status of 2 or greater. 10 contemporaneous patients at the same institution treated with chemotherapy alone were also identified and assessed. With a median follow-up of 33 months, median OS was 13 months with a 30% 3-year OS for the ICI treated patients compared to a median OS of 3 months and a 10% 3-year OS for those treated with chemotherapy alone. Comparative log-rank test p-value = 0.014 and a hazard ratio 0.376 (95%-CI 0.134-1.057). Plasma cfRNA PD-L1 was associated with a statistically significant survival benefit from ICI-based treatment compared to chemotherapy in the first line treatment of a real-world patient population of advanced NSCLC.

One of the mechanisms used in the management and cure of atherosclerosis is reverse cholesterol transfer (RCT), which plays a vital role in the export of cholesterol from peripheral cells. Cholesterol efflux from macrophages in the subintima of the vessel wall is a critical part of RCT. ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) are involved in the transfer of cholesterol from arterial macrophages to extracellular high-density lipoprotein cholesterol (HDL). The HDL then transports esterified cholesterol to the liver for elimination. An important factor in the reverse cholesterol transport and excretion of extracellular cholesterol is HDL. Atherogenesis can be prevented by altering the processes of RCT and cholesterol efflux, and this might lead to novel treatment options for cardiovascular disease. Research of novel modifying variables for RCT and cholesterol efflux is necessary. A better understanding of RCT's molecular processes has been gained via research, allowing for the creation of new treatments that make use of RCT's potential for pharmacological improvement. The purpose of this review is to provoke discussion on the potential impact of selected flavonoids on cholesterol efflux on the progression of atherosclerosis (Fig. 1.).

Scientific, technical and bioinformatics advances have made it possible to establish analytics-based molecular biosimilarity for the approval of biosimilars. If the molecular structure and other product- and process-related attributes are comparable within the limits of testing then a biosimilar candidate would have safe safety and efficacy as its reference products. The current model of animal and human testing becomes redundant since all of these studies have much lower sensitivity and reproducibility in confirming biosimilarity. The recent AI-based protein structure prediction model has confirmed that the 3D structure can be predicted from the amino acid sequence, reducing the need for structural analysis; however, the new test methods based on MS are millions of times more sensitive and accurate. While the regulatory agencies have begun waiving animal testing and, in some cases, clinical efficacy testing, removing clinical pharmacology profiling brings a dramatic paradigm shift, reducing development costs without compromising safety and efficacy. Also shared is a list of 160+ products ready to enter as biosimilars. Major actions from regulatory agencies and developers are required to make this paradigm shift.

Purpose: The study aimed to investigate if there were any links between liver function biomarkers and immunoglobulins levels in serum, and Toll-like receptors (TLRs) and neuropilin-1 (NRP1) in COVID-19 patients. The study also aimed to assess the accuracy—sensitivity, specificity, and area under the curve (AUC) by the receiver operator curve (ROC) analysis for immunoglobulins levels and TLRs expressions. Patients and Methods: This study included 150 patients (100 patients with confirmed COVID-19 and 50 healthy volunteers as a control group). Patients with COVID-19 were subdivided into two groups according to the severity of symptoms (moderate and severe, with 50 patients each). Serum C-reactive protein (CRP), alanine aminotransaminase (ALT), aspartate aminotransaminase (AST), albumin, lactate dehydrogenase (LDH), immunoglobulin (Ig) G, and IgM levels were estimated. TLRs (TLR2 and TLR4) and NRP1 gene expression in blood samples were investigated using quantitative real-time polymerase chain reaction (qRT-PCR). ROC analysis was also applied to determine the accuracy of various detected parameters in predicting the possibility of COVID-19 infection. Results: In COVID-19 patients, serum parameters related to liver function, except serum albumin, CRP, IgG, IgM, and TLR2, TLR4, and NRP1 mRNA expression levels, significantly elevated compared to controls. Severe COVID-19 patients exhibited significantly higher liver enzymes (ALT, AST and LDH), CRP, and TLR2 mRNA expression levels and lower albumin levels than the moderate group. In the moderate and severe groups, ALT, CRP, TLR2, and TLR4 had a significant positive correlation with IgM levels. ALT, AST, LDH, CRP, TLR2, and TLR4 showed a significant positive correlation with IgG levels in both groups. In both the moderate and severe groups, NRP1 expression was found to be significantly correlated with CRP, IgG, IgM, TLR2, and TLR4. In contrast, serum albumin levels exhibited a significant negative correlation with IgG and IgM levels only in the severe group, but they showed a significant negative correlation with TLR2, TLR4, and NRP1 expression in both moderate and severe groups. Serum ALT and AST activities were positively correlated with NRP1 expression in the moderate group but not in the severe group and as well as TLR2 and TLR4 expression in both the moderate and severe groups. ROC analysis indicated that AUC was higher than 0.800 for serum IgM level and TLR4 gene expression in moderate COVID-19 group. Conclusions: The increased liver function biomarkers in serum and NRP1 expression are closely correlated with sustained activations in humoral and innate immune responses during COVID-19 infection. As a result, TLR2, TLR4, and NRP1 could be targets for limiting COVID-19 infection and impairment effects on liver function. Moreover, detection of IgM level in serum and TLR4 expression in blood have a good accuracy in predicting the possibility of infection with COVID-19 in moderate cases.

Background: Anemia is one of the most frequent diseases worldwide, affecting a third of the general population. Anemia in general and in particular, iron-deficient anemia (IDA), has been associated to a higher risk of thrombotic manifestations, including ischemic stroke and cerebral venous thrombosis (CVT), as well as systemic extra cerebral arterial and venous thrombosis. Despite these data, anemia is seldom considered as an etiological factor of stroke. Methods: An individual case encompassing all known neurovascular and systemic arterial and venous thrombotic manifestations related to IDA is presented with the focus on clinical reasoning issues in the diagnostic pathways, starting from the neuroradiological signs. The main questions have been identified and addressed in a narrative review of the most relevant data in the literature from a pragmatic and clinical viewpoint. Results and Discussion: The presented case concerns a 46 years old man admitted to the Stroke Unit because of acute is-chemic stroke with multiple thrombi in large intracranial and extracranial vessels, multifocal ischemic lesions in several arterial territories and the concurrent finding of asymptomatic CVT, pulmonary embolism with lung infarction and aortic thrombosis. An extended diagnostic work-up excluded the main etiologies (arterial dissection, cardiac embolism, genetic and acquired prothrombotic disorders, as cancer and antiphospholipid syndrome), except for a severe IDA, such as to require blood transfusions followed by anticoagulant therapy for the several thrombotic manifestations. Neuroimaging and systemic vascular findings have been analyzed and the main issues proposed by the case in the diagnostic pathway have been identified and discussed in a pragmatic clinical road map reviewing the data provided by the literature. Conclusions: IDA is a common but treatable condition that, independently or synergically, may increase the risk of thrombotic events. The diagnostic and therapeutic approach has not yet defined and each case should be individually addressed in a pragmatic clinical road map.

Purpose: We assessed if a CXR AI algorithm can detect missed or mislabeled chest radiographs (CXRs) findings in radiology reports. Methods: We queried multi-institutional radiology reports search database of 13-million reports to identify all CXRs reports with addendums from 1999-2021. Of the 3469 CXR reports with an addendum, a thoracic radiologist excluded reports where addendum was created for typographic errors, wrong report template, missing sections, or uninterpreted signoffs. The remaining reports with addendum (279 patients) with errors related to side-discrepancy or missed findings such as pulmonary nodules, consolidation, pleural effusions, pneumothorax, and rib fractures. All CXRs were processed with an AI algorithm. Descriptive statistics were performed to determine the sensitivity, specificity, and accuracy of AI to detect missed or mislabeled findings. Results: AI had high sensitivity (96%), specificity (100%), and accuracy (96%) for detecting all missed and mislabeled CXR findings. The corresponding finding-specific statistics for AI were nodules (96%, 100%, 96%), pneumothorax (84%, 100%, 85%), pleural effusion (100%, 17%, 67%), consolidation (98%, 100%, 98%), and rib fractures (87%, 100%, 94%). Conclusion: The CXR AI could accurately detect mislabeled and missed findings. Clinical Relevance: The CXR AI can reduce the frequency of errors in detection and side-labeling of radiographic findings.

This paper presents a modular approach to generic exergame design that combines custom physical exercises in a meaningful and motivating story. This aims to provide a tool that can be individually tailored and adapted to people with different needs, making it applicable to different diseases and states of disease. The game is based on motion capturing and integrates four example exercises that can be configured via our therapeutic web platform "Blexer-med". To prove the feasibility for a wide range of different users, evaluation tests were performed on 14 patients with various types and degrees of neuromuscular disorders, classified into three groups based on strength and autonomy. Users were free to choose their schedule and frequency. Game scores and three surveys (before, during, and after the intervention) showed similar experiences for all groups, with the most vulnerable having the most fun and satisfaction. The players were motivated by the story and by achieving high scores. The average usage time was 2.5 times per week, 20 minutes per session. Pure exercise time was about half the game time. The concept has proven feasible and forms a reasonable basis for further developments. The full 3D exercise needs further fine-tuning to enhance fun and motivation.

Heart rate (HR) and respiratory rate (RR) are two vital parameters of the body medically used for diagnosing short/long term illness. Out-of-the-body, non-contact HR/RR measurement remains a challenge due to imprecise readings. “Invisible” wearables integrated into day-to-day garments has the potential to produce precise readings with comfortable user experience. Sleep studies and patient monitoring benefit from “Invisibles” due to longer wearability without significant discomfort. This paper suggests a novel method to reduce the footprint of sleep monitoring devices. We use a single silver-coated nylon fabric band integrated into a substrate of standard cotton/nylon garment as a resistive elastomer sensor to measure air and blood volume change across the chest. We introduce a novel event-based architecture to process data at the edge device and describe two algorithms to calculate real-time HR/RR on ARM Cortex-M3 and Cortex-M4F microcontrollers. RR estimations show a sensitivity of 99.03% and a precision of 99.03% for identifying individual respiratory peaks. The two algorithms used for HR calculation show a mean absolute error of 0.81±0.97 and 0.86±0.61 beats/minute compared to a gold standard ECG-based HR. The event-based algorithm converts the respiratory/pulse waveform into instantaneous events, therefore, reducing the data size by 40-140 times and requires 33% less power to process and transfer data. Further, we show that events hold enough information to reconstruct the original waveform, retaining pulse, and respiratory activity. We suggest fabric sensors and event-based algorithms would drastically reduce the device footprint and increase the performance for HR/RR estimations during sleep studies providing better user experience.

Cancer-related fatigue is a common, burdensome symptom of cancer and side-effect of chemotherapy. While a Mediterranean Diet (MedDiet) promotes energy metabolism and overall health, its effects on cancer-related fatigue remain unknown. In a randomized controlled trial, we evaluated a rigorous MedDiet intervention for feasibility and safety as well as preliminary effects on cancer-related fatigue and metabolism compared to usual care. Participants had stage I-III cancer and at least 6 weeks of chemotherapy scheduled. After baseline assessments, randomization occurred 2:1, MedDiet:usual care. Measures were collected at baseline, week 4, and week 8 including MedDiet adherence, dietary intake, and blood-based metabolic measures. Mitochondrial respiration from freshly isolated T cells was measured at baseline and 4 weeks. Participants (n=33) were 51.0±14.6 years old, 94% were female, and 91% were being treated for breast cancer. The study was feasible, with 100% completing the study and >70% increasing their MedDiet adherence at 4 and 8 weeks compared to baseline. Overall, the MedDiet intervention vs. usual care had a small-moderate effect on change in fatigue at weeks 4 and 8. For those with a baseline MedDiet score<5 (n=21), the MedDiet intervention had a moderate-large effect of 0.67 and 0.48 at weeks 4 and 8, respectively. The MedDiet did not affect blood-based lipids, though it had a beneficial effect on fructosamine (ES= -0.55). Fatigue was associated with mitochondrial dysfunction including lower basal respiration, maximal respiration, and spare capacity (p<0.05 for FACIT-F fatigue subscale and BFI, usual fatigue). In conclusion, the MedDiet was feasible and attenuated cancer-related fatigue among patients undergoing chemotherapy, especially those with lower MedDiet scores at baseline.

Background Nitrous Oxide (N₂O) is a dissociative anaesthetic that is sometimes used recreationally. The prevalence of N₂O use is difficult to quantify but appears to be increasing. Research on N₂O harms and application of harm reduction strategies are limited. The aim of this mixed method systematic review was to collate and synthesise the disparate body of research on recreational nitrous oxide use to inform harm reduction approaches tailored for young people. Methods To identify publications reporting recreational use of N₂O, a search of public health, psychology and social science databases was conducted. Databases included PubMed, CIHNAL, PsycINFO, Scopus and Web of Science. Gray literature and Google advanced search were also used. Due to limited published literature on the recreational use of N₂O, no limit was placed on publication date or study type. A thematic synthesis extracted descriptive and analytical themes from the selected studies. Quality appraisal was conducted using the CASP Tool for Qualitative studies and the Joanna Briggs Institute case report assessment tool Results The search retrieved 407 reports. Thirty-four were included in the final analysis including sixteen case reports. The included studies were primarily concerned with raising awareness of the apparently increasing use and subsequently increasing harms of recreational N₂O use. There was limited reference to policy or legislative responses in any published studies, no suggestions for harm reduction strategies or application of service level responses. In general, individuals lack awareness of N2O related harms. Conclusion The review found three key areas that deserve further consideration including: 1) policy, 2) service delivery, and 3) harm associated with N₂O use. We recommend a top-down (policy) and bottom-up (services delivery/services users) approach to harm reduction for N₂O use which also includes further consultation and research with both groups. Future research could explore young people’s experience of N₂O use including benefits and problems to inform contextually relevant harm reduction strategies.

At least 50% of factors predisposing to alcohol dependence (AD) are genetic and women affected with this disorder present with more psychiatric comorbidities, probably indicating different genetic factors involved. We aimed to run a genome-wide association study (GWAS) followed by a bioinformatic functional annotation of associated genomic regions in male and female patients with AD and eight related clinical measures. A genome-wide significant association of rs220677 with AD (p-value = 1.33×10^-8 calculated with the Yates-corrected Chi-square test under the assumption of dominant inheritance) was discovered in female patients. Associations of AD and related clinical measures with seven other single nucleotide polymorphisms listed in previous GWAS of psychiatric and addiction traits were differently replicated in male and female patients. The bioinformatic analysis showed that regulatory elements in the eight associated linkage disequilibrium blocks define the expression of 80 protein-coding genes. Nearly 68% of these and of 120 previously published coding genes associated with alcohol phenotypes directly interact in a single network. This study indicates that a number of genes behind the pathogenesis of AD are different in male and female patients, but implicated molecular mechanisms are functionally connected. The results also suggest the genetic basis of sex-specific psychiatric comorbidities of AD.

(1) Background: Painful nervus intermedius neuropathy (e.g., geniculate neuralgia) involves continuous or near-continuous pain affecting the distribution of the intermedius nerve(s). The diagnosis of this entity is challenging, particularly when the clinical and demographic features do not resemble the typical presentation of this condition. To the best of our knowledge, only three case reports have described the occurrence of nervus intermedius neuropathy in young patients. (2) Case Description: A 13-year-old female referred to the Orofacial Pain clinic with a complaint of pain located deep in the right ear and mastoid area. The pain was described as a constant throbbing and dull, with an intensity of 7/10 on numerical rating scale, characterized by superimposed brief paroxysms of severe sharp pain. The past treatments included ineffective pharmacological and irreversible surgical approaches. After a comprehensive evaluation, a diagnosis of idiopathic painful nervus intermedius neuropathy was given, which was successfully managed with the use of gabapentin. (3) Conclusions and Practical Implications: The diagnosis and treatment of neuropathic pain affecting the nervus intermedius can be challenging due to the complex nature of the sensory innervation of the ear. The diagnosis can be even more challenging in cases of atypical clinical and demographic presentations, which in turn may result in unsuccessful, unnecessary, and irreversible treatments. Multidisciplinary teams and constant knowledge update are fundamental to provide good quality of care to our patients and to not overlook any relevant signs or symptoms.

Nowadays molecular research is essential for the better understanding of tumor cells pathophysiology. The increasing number of neoplasms is taken under ‘the molecular magnifying glass’ therefore it is possible to discover complex relationships between cytophysiology and tumor cells. Signal transducer and activator of transcription 3 (STAT3) belongs to the family of latent cytoplasmic transcription factors called STATs which comprises seven members: STAT1, STAT2, STAT3, STAT5A, STAT5B, STAT6. Those proteins play important role in cytokine-activated gene expression by transducing signals from the cell membrane to the nucleus. Abnormal prolonged activation results in tumorigenesis, metastasis, cell proliferation, invasion, migration and angiogenesis. Inhibition of this transcription factor inhibits previously mentioned effects in cancer cells whereas normal cells are not affected. Hence STAT3 might be a viable target for cancer therapy.

Objective: The purpose of this study was to investigate the effects of Crocin on brain neuroterophins, cognition, sensory and motor dysfunction and compare to fingolimod effects in experimental model of demyelination with Ethidium Bromide EB in female Wistar rats. Methods: Animals were assigned in to 8 groups; Sham, Sham operated (ShOp), EAE, crocin treated (Cr5,10,20 mg/kg), Vehicle, Fingolompd (Fing) and fingolimod + crocin (Cr+Fing). Demyelination was induced by single dose injection of 10 μl of EB 0.1% into the fourth ventricle of the brain. Crocin and fingolimod were applied for 21 days, daily, oral gavage. BDNF, NGF1, nerve conduction velocities, tail flake latency, balance and behavioral variables were sampled and analyzed by paired t-test and ANOVA test with repeated post hoc measurements. Results: The results showed that crocin improves all studied factors, but remarkable imrovments were observed in dosage of 10 mg/kg. Crocin (10mg/kg) and fingolimod (1mg/kg) significantly improved cognition variables in open field test, sensory and motor nerve conduction velocity, tail flick latency and clinical signs (p<005). In addition, applying of crocin co-administered with fingolimod led to significant increases in all assessed factors, greater than crocin or fingolimod intervention alone (α≤0.001). Conclusion: Based on the current findings, crocin can improve the level of brain neurotrophins, exploratory behavior and nerve conduction after demyelination as close as fingolimod results. So, crocins can be considered as a neuro supportive agent in the management of degenerative diseases maybe similar to fingolimod mechanism.

Inflammatory reaction after ischemia-reperfusion contributes significantly to prognosis, and microglia activation is the main resource of inflammation in nervous system. STAT5 is proving to be a highly effective anti-inflammatory therapy with great potential, and inhibition of STAT5 has demonstrated significant anti-inflammation and therapeutic effects, but rarely focus on mechanism of neuroinflammation and brain injury from ischemia-reperfusion. It is the first time to found that the anti-inflammation of dauricine is mainly through STAT5-NF-κB pathway, might act as a STAT5 inhibitor. Dauricine suppressed the inflammation cytokines Eotaxin, KC, TNF-α, IL-1α, IL-1β, IL-6, IL-12β, IL-17α, and also inhibited the microglia activation. STAT5b mutant at Tyr-699 reversed the protective effect of dauricine on oxygen-glucose deprivation-reperfusion injury of neurons, and reactivated the suppression of dauricine on P-NF-κB of microglia. These results suggest that dauricine might suppress the neuroinflammation and protect the neuron from the injury of post-ischemia-reperfusion via mediating the microglia activation through STAT5-NF-κB pathway, and ss a potential therapeutic target for neuroinflammation, STAT5 needs to be raised concern in ischemic stroke.

Transient global amnesia (TGA) is an uncommon clinical syndrome characterized by a loss of short-term memory and disorientation that resolves in twenty-four hours. The etiology is unknown and the diagnosis is made by exclusion of other possible etiologies that may cause similar patterns and the reversibility of the condition in less than 24 hours. Here we report a 60-year-old male presented with sudden onset of disorientation and short-term memory loss early in the morning while at home and started to ask his whereabouts and what happened. He had no history of significant medical or psychiatric disease. There was no history of previous similar episodes. He had no recent history of sleep problems, head trauma, substance abuse, or loss of consciousness. He had no history of seizure disorder, or migraine. A neurologic examination revealed a normal wakefulness state with mild disorientation, and short-term memory impairment. He had score of 18/30 on mini-mental state examination (which later returned to normal baseline in 24 hours). Extensive lab investigations did not show any abnormal findings. Brain MRI did not show any acute cerebral pathology. The EEG was negative for any abnormal cerebral activity. His memory improved and returned to normal baseline over the course of a 20-hour from the onset. After exclusion of potential causes and the patient returned to normal state of memory, the diagnosis of transient global amnesia was made. At the follow-up visit, the patient was in a state of normal function without a recurrence of memory impairment. Here we presented this interesting case of transient global amnesia. TGA is diagnosis of exclusion and important to keep in mind when evaluating a patient with acute onset of short-term memory impairment, especially when etiological investigation revealed no potential cause.

This study focuses on cardiovascular effects, particularly myocarditis and pericarditis events, after BNT162b2 mRNA COVID-19 vaccine injection in Thai adolescents. This prospective cohort study enrolled students from two schools aged 13–18 years who received the second dose of the BNT162b2 mRNA COVID-19 vaccine. Data including demographics, symptoms, vital signs, ECG, echocardiography and cardiac enzymes were collected at baseline, Day 3, Day 7, and Day 14 (optional) using case record forms.We enrolled 314 participants; of these, 13 participants were lost to follow up, leaving 301 participants for analysis. The most common cardiovascular effects were tachycardia (7.64%), shortness of breath (6.64%), palpitation (4.32%), chest pain (4.32%), and hypertension (3.99%). Seven participants (2.33%) exhibited at least one elevated cardiac biomarker or positive lab assessments. Cardiovascular effects were found in 29.24% of patients, ranging from tachycardia, palpitation, and myopericarditis. Myopericarditis was confirmed in one patient after vaccination. Two patients had suspected pericarditis and four patients had suspected subclinical myocarditis. Conclusion: Cardiovascular effects in adolescents after BNT162b2 mRNA COVID-19 vaccination included tachycardia, palpitation, and myocarditis. The clinical presentation of myopericarditis after vaccination was usually mild, with all cases fully recovering within 14 days. Hence, adolescents receiving mRNA vaccines should be monitored for side effects. Clinical Trial Registration: NCT05288231

Background: Myometrial invasion (MI) is a parameter currently used in transvaginal ultrasound (TVS) in endometrial cancer (EC) to determine local staging, however, without molecular diagnostics, it is insufficient for selection of high-risk cases, i.e., those with a high risk of lymph node metastases (LNM). Methods: One hundred sixteen consecutive EC patients, who had received 2D transvaginal ultrasound examinations in their preoperative workup and final histopathology results as a reference standard, were included in this prospective study. Univariate and multivariate logistic models of analyzed TVS biomarkers (tumor [T] size, T area [AREA], T volume [SPE-VOL], MI, T-free distance to serosa [TFD], endo-myometrial irregularity, [EMIR], cervical stromal involvement, CSI) were evaluated to assess the relative accuracy of the possible LNM predictors. To avoid a potential bias in assuming linear relations between LNM and continuous predictors, spline functions were applied. Calculations were made in R with the use of libraries splines, glmulti, and pROC. Results: LNM was found in 20 out of 116 (17%) patients. In univariate analysis, only uMI, EMIR, uCSI and uTFD were significant predictors of LNM. Accuracy was 0.707 (AUC 0.684, 95% CI 0.568-0.801) for uMI (p<0.01), 0.672 (AUC 0.664, 95% CI 0.547-0.781) for EMIR (p<0.01), 0.776 (AUC 0.647, 95% CI 0.529-0.765) for uCSI (p<0.01), and 0.638 (AUC 0.683, 95% CI 0.563-0.803) for uTFD (p<0.05). The cut-off value for uTFD was 5.2 mm. However, AREA and VOL revealed significant relation by non-linear analysis as well. Among all possible multivariate models, the one comprising interactions of splines of uTFD with uMI and splines of SPE-VOL with uCSI showed most usefulness. Accuracy was 0.802 (AUC 0.791, 95% CI 0.673-0.91) Conclusions: A combination of uTFD for patients with uMI>50%, and SPE-VOL for patients with uCSI, allows for the most accurate prediction of LNM in EC, rather than uMI alone.

Generating long-lived mucosal and systemic antibodies through respiratory immunization with protective antigens encapsulated in nanoscale biodegradable particles could potentially decrease or eliminate the incidence of many infectious diseases but requires incorporation of a suitable mucosal immunostimulant. We previously found that respiratory immunization with a model protein antigen (LPS-free OVA) encapsulated in PLGA 50:50 nanoparticles (~380 nm diameter) surface modified with complement peptide-derived immunostimulant 02 (CPDI-02; formerly EP67) through 2kDa PEG linkers increases mucosal and systemic OVA-specific memory T-cells with long-lived surface phenotypes in young, naïve female C57BL/6 mice. Here, we determined if respiratory immunization with LPS-free OVA encapsulated in similar PLGA 50:50 microparticles (~1 μm diameter) surface modified with CPDI-02 (CPDI-02-MP) increases long-term OVA-specific mucosal and systemic antibodies. We found that, compared to MP surface modified with inactive, scrambled scCPDI-02 (scCPDI-02-MP), intranasal administration of CPDI-02-MP in 50 μL sterile PBS greatly increased titers of short-term (14 days post-immunization) and long-term (90 days post-immunization) antibodies against encapsulated LPS-free OVA in nasal lavage fluids, bronchoalveolar lavage fluids, and sera of young, naïve female C57BL/6 mice. Thus, surface modification of biodegradable microparticles with CPDI-02 is likely to increase long-term mucosal and systemic antibodies against encapsulated protein antigen after respiratory and possibly other routes of mucosal immunization.

Worldwide, one of the main causes of death among young adults is multiple trauma. In these pa-tients hemorrhagic shock represents the leading cause for worsening of the clinical status and for increased morbidity and mortality. This is due to a multifactorial complex involving cellular, bi-ological, and biophysical mechanisms. The most important mechanisms affecting clinical out-come are oxidative stress, the augmentation of pro-inflammatory status, immune deficiency, dis-ruptions in the coagulation cascade, imbalances in electrolyte and acid-base homeostasis. Poly-trauma patients in hemorrhagic shock need adequate fluid management to ensure hemodynamic stability that must consider not only the maintenance of adequate blood pressure, but also the ad-equate oxygenation of tissues for optimal cellular function. In the current clinical practice, fluid resuscitation in polytrauma patients uses a variety of widely studied pharmacological products, such as crystalloids, colloids, blood transfusions, and the infusion of other blood products. Alt-hough these products exist, an agreement was not reached on a standard administration protocol that could be generally applied for all patients. Moreover, numerous studies have reported a se-ries of adverse events related to fluid resuscitation and to the inadequate use of these products. This review aims at describing the impact the administration of all the solutions used in fluid re-suscitation might have on the cellular and pathophysiological mechanisms in the case of poly-trauma patients suffering from hemorrhagic shock.

Background: pathophysiological changes like low cardiac output (LCO) impact pharmacokinetics, but its extent may be different throughout pediatrics compared to adults. Physiologically based pharmacokinetic (PBPK) modelling enables further exploration. Methods: A validated propofol model was used to simulate the impact of LCO on propofol clearance across age groups using the PBPK platform, Simcyp® (version 19). The hepatic and renal extraction ratio of propofol was then determined in all age groups. Subsequently, dose explorations were conducted under LCO conditions, targeting a 3 µg/mL (80-125%) propofol concentration range. Results: Both hepatic and renal extraction ratios increased from neonates, infants, children to adolescents and adults. The relative change in clearance following CO reductions increased with age, with the least impact of LCO in neonates. The predicted concentration remained within the 3 µg/mL (80-125%) range under normal CO and LCO (up to 30%) conditions in all age groups. When CO was reduced by 40-50%, a dose reduction of 15% is warranted in neonates, infants and children, 25% in adolescents and adults. Conclusions: PBPK driven, the impact of reduced CO on propofol clearance is predicted to be age-dependent, proportionally greater in adults. Consequently, age group specific dose reductions for propofol are required in LCO conditions.

Individual differences in the responsiveness of the brain to transcranial electrical stimulation (tES) is increasingly demonstrated in large variability in the tES effects. Anatomically detailed computational brain models have been developed to address this variability; however, static brain models are not ‘realistic’ in accounting for the dynamic state of the brain. Therefore, human-in-the-loop optimization is proposed in this perspective article based on an extensive systems analysis of the tES neurovascular effects. First, modal analysis was conducted using a physiologically detailed neurovascular model that found stable modes in the 0 Hz to 0.05 Hz range for the pathway for vessel response through the smooth muscle cells, measured with functional near-infrared spectroscopy (fNIRS). tES effects in the 0 Hz to 0.05 Hz range can also be measured with functional magnetic resonance imaging (fMRI)-tDCS data with a maximum TR=10sec. Therefore, we investigated an open-source fMRI-tDCS dataset that used a TR=3.36sec. We found that both the anodal tDCS condition and sham tDCS condition had similar Finite Impulse Response at the region of interest underlying the anode and a remote location, which indicated a global hemodynamic effect of sham tDCS beyond the intended transient sensations. Here, transient sensations can have arousal effects on the hemodynamics so we conducted a healthy case series for black box modeling of fNIRS-pupillometry of short-duration tDCS effects. The block exogeneity test rejected the claim that tDCS is not a 1-step Granger-cause of the fNIRS total hemoglobin changes (HbT) and pupil dilation changes (p<0.05). Also, grey-box modeling using fNIRS of the tDCS effects in chronic stroke showed HbT response to be significantly different (paired-sample t-test, p<0.05) between the ipsilesional and the contralesional hemisphere for primary motor cortex tDCS and cerebellar tDCS which was subserved by the smooth muscle cells. Here, our perspective is that various physiological pathways subserving tES effects can lead to state-trait variability that can be challenging for clinical translation. Therefore, we conducted a case study on human-in-the-loop optimization using our reduced dimension model and a stochastic, derivative-free Covariance Matrix Adaptation Evolution Strategy. Future studies need to investigate human-in-the-loop optimization of tES for reducing inter-subject and intra-subject variability in tES effects.

ALDH+ H1975 lung adenocarcinoma stem cells (LSCs) are a rare cell population identified in lung adenocarcinoma (LUAD). LSCs can self-renew, drive tumor initiation, growth, metastasis, and recurrence, and are also the predominant cause of poor prognosis due to their intrinsic resistance to drugs and chemotherapy. Consequently, LSCs are a promising target for LUAD therapy. Noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), exert many significant regulatory functions in the pathogenesis of human cancers, showing the necessity for a comprehensive understanding of the mechanisms that underlie lung carcinogenesis. Nonetheless, research on many known transcripts and messenger RNAs (mRNAs) has already generated new information. Unknown biomarkers in ncRNAs and systematic and comprehensive interrelation with unknown ncRNAs and mRNAs may provide further insights into the biology of LUAD. Herein, a set of novel ncRNAs that include miRNAs, lncRNAs, circRNAs, were identified and differentially expressed patterns of ncRNAs and mRNAs in LSCs and ALDH- H1975 LUAD tumor cells (LTCs) were obtained using stringent bioinformatics pipelines. Through a meta-analysis of the identified landscapes, novel competitive endogenous RNA (ceRNA) networks were constructed to reveal the potential molecular mechanisms that regulate the hallmarks of LSCs and LTCs. This study presents a summary of novel ncRNAs and the fundamental roles of differentially expressed ncRNAs implicated in the activity of LSCs and LTCs. In addition, the study also provides a comprehensive resource for the future identification of diagnostic, therapeutic, and prognostic biomarkers in LUAD.

Close to half (45.4%) of 2.3 million breast cancers (BC) diagnosed in 2020 were from Asia. While the burden of breast cancer has been examined on the level of broad geographic regions, literature on more in-depth coverage of the individual countries and subregions of the Asian continent is lacking. This review examines the breast cancer burden in 47 Asian countries. Breast cancer screening guidelines and risk-based screening initiatives are discussed.

Diffuse interstitial lung diseases (DILD) are a heterogeneous group of over 200 entities, some with dramatical evolution and poor prognostic. Because of their overlapping clinical, physiopathological and imagistic nature, successful management requires early detection and proper progression evaluation. This paper tests a complex networks (CN) algorithm for imagistic aided diagnosis fitness for the possibility of achieving relevant and novel DILD management data. 65 DILD and 31 normal high resolution computer tomography (HRCT) scans were selected and analyzed with the CN model. The algorithm is showcased in two case reports and then statistical analysis on the entire lot shows that a CN algorithm quantifies progression evaluation with a very fine accuracy, surpassing functional parameters’ variations. The CN algorithm can also be successfully used for early detection, mainly on the ground glass opacity Hounsfield Units band of the scan.

This study aimed to apply different complexity-based methods to surface electromyography (EMG) in order to detect neuromuscular changes after realistic warm-up and stretching procedures. Sixteen volunteers conducted two experimental sessions. They were tested before, after a standardized warm-up, and after a stretching exercise (static or neuromuscular nerve gliding technique). Tests included measurements of the knee flexion torque and EMG of biceps femoris (BF) and semitendinosus (ST) muscles. EMG was analyzed using the root mean square (RMS), sample entropy (SampEn), percentage of recurrence and determinism following a recurrence quantification analysis (%Rec and %Det) and a scaling parameter from a detrended fluctuation analysis. Torque was significantly greater after warm-up as compared to baseline and after stretching. RMS was not affected by the experimental procedure. In contrast, SampEn was significantly greater after warm-up and stretching as compared to baseline values. %Rec was not modified but %Det for BF muscle was significantly greater after stretching as compared to baseline. The a scaling parameter was significantly lower after warm-up as compared to baseline for ST muscle. From the present results, complexity-based methods applied to the EMG give additional information than linear-based methods. They appeared sensitive to detect EMG complexity increases following warm-up.

The antibiotic tetracycline demeclocycline (DMC) was recently reported to rescue α-synuclein (α-Syn) fibril-induced pathology. However, the antimicrobial activity of DMC precludes its po-tential use in long-term neuroprotective treatments. Here, we synthesized a DMC derivative with residual antibiotic activity and improved neuroprotective effects. The molecule, called de-rivative demeclocycline (DDMC), was obtained by the removal of both dimethylamino substitu-ents at position 4 and the reduction of the hydroxyl group at position 12a on ring A of DMC. The modifications strongly diminished its antibiotic activity against Gram-positive and Gram-negative bacteria. Moreover, this compound preserved the low toxicity of DMC in dopaminergic cell lines while improving its ability to interfere with α-Syn amyloid-like aggregation, showing the highest effectiveness of all tetracyclines tested. Likewise, DDMC demonstrated the ability to reduce seeding induced by the exogenous addition of α-Syn preformed fibrils (α-SynPFF ) in ex vitro models and in SH-SY5Y-α-Syn-tRFP cells. In addition, in the presence of DDMC, α-SynPFF were less inflammogenic, as they dampened the release of tumor necrosis factor α (TNF-α) and glutamate by microglial cells compared to control fibrils. Our results suggest that DDMC may be a promising drug candidate for hit-to-lead development and preclinical studies in PD and other synucleinopathies.

Targeted therapies with antiangiogenic drugs (e.g., sunitinib) and immune checkpoint inhibitors (e.g., anti-PD-1 antibodies) are the standard of care for patients with metastatic renal cell carcinoma. Although these treatments improve patient survival, they are rarely curative. We previously hypothesized that advanced cancers might be treated without drugs by using artificial diets in which the levels of specific amino acids (AAs) are manipulated. In this work, after showing that AA manipulation induces selective anticancer activity in renal cell carcinoma cells in vitro, we evaluated the anticancer activity of 17 artificial diets in a challenging animal model of renal cell carcinoma. The model was stablished by injecting murine renal cell carcinoma (Renca) cells into the peritoneum of immunocompetent BALB/cAnNRj mice. Mice survival was markedly improved when their normal diet was replaced with our artificial diets. Mice fed a diet lacking six AAs (diet T2) lived longer than mice treated with sunitinib or anti-PD-1 immunotherapy; several animals lived very long or were cured. Controlling the levels of several AAs (e.g., cysteine, methionine and leucine) and lipids was important for the anticancer activity of the diets. Additional studies are needed to further evaluate the therapeutic potential of this simple and inexpensive anticancer strategy.

Growing interest surrounds the assessment of perivascular spaces (PVS) on magnetic resonance imaging (MRI) and their validation as a clinical biomarker of adverse brain health. Nonetheless, the limits of validity of current state-of-the-art segmentation methods are still unclear. Here, we propose an open-source three-dimensional computational framework comprising 3D digital reference objects and evaluate the performance of three PVS filtering methods under various spatiotemporal imaging considerations (including sampling, motion artefacts, and Rician noise). Specifically, we study the performance of the Frangi, Jerman and RORPO filters in enhancing PVS-like structures to facilitate segmentation. Our findings were three-fold. First, as long as voxels are isotropic, RORPO outperforms the other two filters, regardless of imaging quality. Unlike the Frangi and Jerman filters, RORPO’s performance does not deteriorate as PVS volume increases. Second, the performance of all “vesselness” filters is heavily influenced by imaging quality, with sampling and motion artefacts being the most damaging for these types of analyses. Third, none of the filters can distinguish PVS from other hyperintense structures (e.g. white matter hyperintensities, stroke lesions, or lacunes) effectively, the area under precision-recall curve dropped substantially (Frangi: from 94.21 [IQR 91.60, 96.16] to 43.76 [IQR 25.19, 63.38]; Jerman: from 94.51 [IQR 91.90, 95.37] to 58.00 [IQR 35.68, 64.87]; RORPO: from 98.72 [IQR 95.37, 98.96] to 71.87 [IQR 57.21, 76.63] without and with other hyperintense structures, respectively). The use of our computational model enables comparing segmentation methods and identifying their advantages and disadvantages, thereby providing means for testing and optimising pipelines for ongoing and future studies.

The recent approval of 177Lu PSMA-617 (Pluvicto®) by the United States Food and Drug Administration (FDA) is the culmination of decades of work in advancing the field of targeted radionuclide therapy for metastatic prostate cancer. 177Lu PSMA-617, along with the bone specific radiotherapeutic agent, 223RaCl2, are now commonly used in routine clinical care as a tertiary line of therapy for men with metastatic castrate resistant prostate cancer and for osseus metastatic disease respectively. While these radiopharmaceuticals are changing how metastatic prostate cancer is classified and treated, there is relatively little guidance to the practitioner and patient as to how best utilize these therapies, especially in conjunction with other more well-established regimens including hormonal, immunologic, and chemotherapeutic agents. This review article will go into detail about the mechanism and effectiveness of these radiopharmaceuticals and less well known classes of targeted radionuclide radiopharmaceuticals including alpha emitting prostate specific membrane antigen (PSMA) -, gastrin-releasing peptide receptor (GRPR) -, and somatostatin targeted radionuclide therapeutics. Additionally, a thorough discussion of the clinical approach of these agents is included and required futures studies.

Background: There is several challenges to solve irreversible loss of cardiomyocytes due to myocardial infarction. Cell therapy is believed as an ideal treatment for cardiac regeneration in the infarct area. Obtaining adipose-derived stem cells increases seems to be promising, however it is limited by the capacity to differentiate. Stimulation by injectable platelet-rich fibrin appears to have the beneficial effects to accelerate cardiomyocyte-like cells differentiation. Objective: To analyse the benefit of injectable platelet-rich fibrin to accelerate differentiation of adipose-derived mesenchymal stem cells into cardiomyocyte-like cells. Methods: This study is a true experimental randomized post-test design study. Adipose-derived mesenchymal stem cells were isolated from adipose tissues and cultured until 4 passages. The characteristics of adipose-derived mesenchymal stem cells were measured by the expression of CD 34-, CD 45-, and CD 105+ using flowcytometry. The samples were divided into 3 groups, i.e. negative control (α-MEM), positive control (differentiation medium) and treatment group (platelet-rich fibrin). The assessment of GATA-4 marker expression was conducted using flowcytometry on the fifth day and troponin was conducted using immunocytochemistry on the tenth day to determine the differentiation to cardiomyocyte. Data analysis was conducted using T-test and One-Way ANOVA on normally distributed data determined through Shapiro-Wilk test. Results: Flowcytometry on GATA-4 expression revealed significant difference on addition of platelet-rich fibrin compared with negative and positive controls (68.20 ± 6.82 vs 58.15 ± 1.23; p<0.05; 68.20 ± 6.82 vs 52.96 ± 2.02; p<0.05). This was supported by the results of immunocytochemistry on troponin expression which revealed significant difference between platelet-rich fibrin group compared with negative and positive controls (50.66 ± 7.2 vs 10.73 ± 2.39; p<0.05; 50.66 ± 7.2 vs 26.00 ± 0.4; p<0.05). Conclusion: Injectable platelet-rich fibrin has beneficial effect to accelerate differentiation of adipose-derived mesenchymal stem cells into cardiomyocyte-like cells.

Introduction: Studies conducted in real-life scenarios on vaccine protection against COVID-19 constitute an important global priority, but one that is currently mostly neglected in low- and middle-income countries such as Angola. Here, we analyze for the first-time vaccine protection against COVID-19 in a real-life scenario after 6 months of implementing a multi-vaccination plan in Angola, providing estimation of odds ratios in vaccinated individuals and vaccine efficacy against infection by SARS-CoV-2 in a period that coincided with the identification of the Omicron variant in the country. Methods: We used a negative test case-control design to assess the effectiveness of vaccination against confirmed SARS-CoV-2 infection. A total of 4.232 vaccinated and unvaccinated individuals with the result of a rapid antigen diagnostic test against SARS-CoV-2 performed from December 27 to 28, 2021 were included in the study. Data were extracted from the Digital Vaccination Record Platform (Rediv) of the Ministry of Health of Angola. All ethical procedures related to the authorization necessary to carry out the study were followed. Statistical analyzes were performed using version 7.5.2.0 of CDC's Epi Info. Frequency distributions and measures of central tendency were used to characterize the study universe. The general and sex-adjusted and age-adjusted odds ratios, were evaluated by comparing the chances of vaccination between cases and controls, and their associated 95% CI, which were calculated using the Mantel-Haenszel stratification method. The risk classification of Axel Kroeger, Piscoya and Alarcon was used to interpret the odds ratio. The Breslow-Day statistic was used to assess the homogeneity of the odds ratios. Vaccine efficacy was calculated using the odds ratio applying the accepted statistical vaccine efficacy formula:(1 − odds ratio) × 100. For all estimates, a P value < 0.05 was considered statistically significant. Results: The population consisted of 63.63% male and 36.37% female. The mean age was 36 years with a standard deviation of 13. 83. Regarding vaccination status, 83.27% of individuals were vaccinated and 16.73% were unvaccinated, with 21.81% positive and 78.19% negative for SARS -CoV-2. The odds of SARS-CoV-2 infection were 0.85 (95% CI 0.70 – 1.03) times lower in vaccinated compared to unvaccinated individuals, with P=0.09. The overall vaccine efficacy (VE) was 15% (95% CI -3 – 30). Conclusion: There was no statistically significant decrease in the chances of SARS-CoV-2 infection in vaccinated versus unvaccinated individuals. However, the overall vaccine efficacy was 15%.

Objectives: The present study was performed to compare between two different fixation techniques and evaluate the histopathological changes which occur in temporomandibular joint (TMJ) of the dogs after surgically induced unilateral subcondylar fracture. Methods: Twenty- One healthy beagle male dogs with a mean age of 30 months were used in the present study. One of these animals was sacrificed to study the normal histology of the dog TMJ. The rest of the animals (20 animals) were operated on to induce a displaced unilateral subcondylar fracture then, the animals were randomly equally divided into 2 groups. After surgery, 5 dogs of each group were sacrificed at 2 months after surgery (Short-Term), while the remaining 5 were sacrificed at 4 months after surgery (Long-Term). The heads were separated and fixed, oscillating saw was used to articulate the entire TMJ. Specimens were decalcified, then the specimens were washed, grossed and sectioned in a sagittal plane. Tissue sections of 4 um thick were cut and stained with Hematoxylin and Eosin to be studied microscopically. Results: In group I animals, at 2 months after surgery, there was a marked hypertrophy of the articular fibrous covering of the condylar head, while at 4 months after surgery, the articular fibrous covering appeared thinner than normal, with marked decrease in thickness of the articular cartilage layer. In group II, at 2 months after plate insertion, the articular fibrous covering became hypertrophic, and the articular cartilage was markedly reduced but it was of a uniform thickness, while at 4 months after subcondylar fracture and plate fixation, no significant changes could be detected either in thickness or structure of the articular fibrous covering. Conclusion: Based on this study, it is obvious that the plate fixation group gave the most favorable results, when compared with maxillomandibular fixation (MMF) group.

The number of people with neurodegenerative disease continues to increase every year. A new perspective is needed in overcoming this disease. In this review, researchers collected information about epigenetics and energy factors of neurodegenerative disease driven by mitochondria. Mitochondrial epigenetic dysregulation can cause damage to the neuron system. The increase in the amount and interaction of alpha-synuclein with SAMM50 in the mitochondria is one of the factors causing neurodegenerative disease. As an energy provider in the body, the existence of harmonization in the regulation of mitochondria specifically the mitochondrial outer membrane is important. Hydrogen peroxide (H₂O₂) has neuroprotective abilities to overcome the impairment function of mitochondria in neurodegenerative patients. Based on the computational simulation of this case, it can be used as the basic concept for the development of the role of H₂O₂ in neurodegenerative disease.

This research aimed to figure out the applications of HbA1c protein and HbA1 gene as the prognostic biomarkers for assessing the risks of different cancers among male T2D patients in Bangladesh considering their serological and oncoinformatic parameters. Depending on the concentrations of HbA1c (%) of the T2D patients (n=300), their individual FBS (mmol/L); THABF (mmol/L); creatinine (mg/dl); SC (mg/dl); STGs (mg/dl); HDLC (mg/dl); and LDLC (mg/dl) were estimated. The values of the patients were compared with the control (n=60) group as the serological analysis. Besides, HbA1 gene (encoding hBA1c protein) overexpression and promotor methylation responsible for BLCA, BRCA, CHOL, COAD, LUAD, LUSC, PAAD, and PRAD cancers in the male T2D patients were profiled as the oncoinformatic parameters based on the sample types; caner stages; racial footprints; gender; age; nodal metastasis; p53 methylations; pancreatitis; diabetes status; smoking behaviors; and overall/disease-free survivability. Finally, the ‘HbA1 gene strings’ responsible for genetic coexpression; endophytic vesicle regulation; antioxidant regulation; oxygen species metabolic regulation; and gene-mediated response to the reactive oxygen molecules were studied comprehensively. A strong correlation between BMI and FBS was observed in both the patients and the control (P<0.0001). Similarly, the values of FBS, THABF, and creatinine resulted in equal significance (P<0.0001) as compared to the HbA1c concentrations of all the T2D and control individuals. The SC, STGs, HDLC, and LDLC concentrations regulated ardently in both the control (P<0.0001), and patients group (P<0.0001), while HbA1c ranged from 3.8-5.8%, and 5.11-15.8% respectively. HbA1 gene is found downregulating with cancer progressed in most of the oncoinformatic parameters. According to the DA, CS, EI, CE, PC, NC, GF, H, and AT profiles; the HbA1 gene interacts with 8 other genes responsible for creating a protein cluster comprising- AHSP, HBA1, HBA2, HBB, HBD, HBE1, HBG2, RPS12, and RPS19 proteins for cancer formation. To recapitulate, HbA1c protein and HbA1 gene can be used as the prognostic serological and molecular biomarkers respectively for determining the risks of cancers among male chronic T2D patients.

Purpose: We hypothesized that a recently introduced epibulbar micro-shunt (PRESERFLO, P) produces nycthemeral (24h) intraocular pressure (IOP) profiles different from ab-interno trabeculectomy (Trabectome, T). P is a flow restrictor that drains fluid into the sub-tenon space. In contrast, T increases conventional outflow, which is limited by episcleral venous pressure. Methods: In this prospective cohort, we analyzed 68 patients (34 P and 34 T) who presented for 24-h IOP monitoring 6 to 12 months after surgery. IOP and tonographic outflow facility were measured in the habitual position using a pneumatonometer. The IOP variation was considered the primary outcome measure. Glaucoma medications were also compared. Results: P had a higher baseline IOP than T (24.8±10.0 vs. 17.3±7.9 mmHg, p=0.001). Postoperatively, P and T had similar nycthemeral IOP profiles, but IOP in P was significantly lower than in T, except at 4 pm. P had a lower absolute IOP variation than T (5.8±2.6 vs. 7.1±2.7 mmHg, p=0.049). The relative IOP variation was similar in both (34.8±13.2 vs. 37.2±13.1, p=0.45) as was the tonographic outflow facility (0.35±0.23 vs. 0.26±0.18 µl/min/mmHg, p=0.097). Conclusion: Nycthemeral IOP profiles of P and T were similar, but P had lower IOPs and less variation than T. This could reflect how T, unlike P, is more impacted by habitual, positional factors, especially at night.

A modern definition of “deep sleep” is elusive despite being ubiquitously appreciated as an important physiological state supporting health and homeostasis. In modern times, human deep sleep is identified by specific bioelectric signatures in the electroencephalogram (EEG) emerging somewhere between periods of wakefulness. However, deep sleep has been used to describe states of quiescence well before the first electrical brain recordings in the late 1800s, highlighting its own evolution in both lay and medical literature. Furthermore, EEG states are not only ill-defined in most mammals outside of humans and laboratory rodents, but non-existent in some invertebrates. Given that all organisms rest and do so with seemingly well-defined utility, it remains a challenge linguistically, scientifically, and comparatively define what “deep sleep” means—or what it should—in a research context. Here, I explore standard definitions of deep sleep from a modern, comparative perspective, and discuss potential problems of using a strict and narrow definition of such a fleeting concept that has historically undergone significant updates. Finally, I suggest a path towards resolving inconsistencies around the meaning of “deep sleep” and consider whether it is truly reflected by any one measure.

Abstract: The pathobiology of ascending aorta aneurysms (AAA) onset and progression is not well understood and only partially characterized. AAA are also complicated in case of bicuspid aorta valve (BAV) anatomy. There is emerging evidence about the crucial role of endothelium-related pathways, which show in AAA an altered expression and function. Here, we examined the involvement of ERG-related pathways in the differential progression of disease in aortic tissues from patients having a BAV or tricuspid aorta valve (TAV) with or without AAA. Our findings identified ERG as a novel endothelial-specific regulator of TGF-β-SMAD, Notch, and NO pathways, by modulating a differential fibrotic or calcified AAA progression in BAV and TAV aortas. We provided evidence that calcification is correlated to different ERG expression (as gene and protein), which appears to be under control of Notch signaling. The latter, when increased, associated with an early calcification in aortas with BAV valve and aneurysmatic, was demonstrated to favor the progression versus severe complications, i.e., dissection or rupture. In TAV aneurysmatic aortas, ERG appeared to modulate fibrosis. Therefore, we proposed that ERG may represent a sensitive tissue biomarker to monitor AAA progression and a target to develop therapeutic strategies and influence surgical procedures.

Pulmonary thromboembolism is a very common cardiovascular disease, with a still high mortality rate. Despite the clear guidelines, this disease still represents a great challenge both in diagnosis and treatment. Heterogeneous clinical picture, often without pathognomonic signs and symptoms, represents a huge differential diagnostic problem even for experienced doctors. The decision on the therapeutic regimen also represents a major dilemma in the group of patients who are hemodynamically stable at initial presentation and have signs of right ventricular (RV) dysfunction proven by echocardiography and positive biomarker values (pulmonary embolism of intermediate-high risk). Studies have shown conflicting results about the benefit of using fibrinolytic therapy in this group of patients until hemodynamic decompensation, due to the risk of major bleeding. The latest recommendations give preference to new oral anticoagulants (NOACs) compared to vitamin K antagonists (VKA), except for certain categories of patients (patients with antiphospholipid syndrome, mechanical valves, pregnancy). When using oral anticoagulant therapy, special attention should be paid to drug-drug interactions, which can lead to many complications, even to the death of the patient. Special population groups such as pregnant women, obese patients, patients with antiphospholipid syndrome and cancer represent a great therapeutic challenge in the application of anticoagulant therapy. In these patients, not only the effectiveness of the drugs must be taken into account, but great attention must be paid to their safety and possible side effects, which is why a multidisciplinary approach is emphasized in order to provide the best therapeutic option.

Oxidative stress appears to be associated with more severe disease in WNV infected patients. Our preliminary findings warrant prospective studies to investigate the correlation of oxidative stress with clinical outcomes and severity of WNV infection.

The low water solubility of any pharmacoactive molecules limits their pharmacological potential but the solubility parameter cannot compromise, so different approaches are employed to enhance their bioavailability. Pharmaceutically active molecules with low solubility convey a higher risk of failure for drug innovation and development. Pharmacokinetics, pharmacodynamics, and several other parameters, such as drug distribution, protein binding and absorption, are majorly affected by their solubility. Among all pharmaceutical dosage forms, the oral dosage forms cover more than 50 %, and the drug molecule should be water-soluble. For good therapeutic activity by the drug molecule on the target site, solubility and bioavailability are crucial factors. The pharmaceutical industry screening programs identified that around 40% of new chemical entities (N.C.E.s) face various difficulties at the formulation and development step. These pharmaceuticals are attributed to their less solubility and bioavailability. The bioavailability and drug solubility enhancement are significant challenges in the area of pharmaceutical formulations. According to the Classification of Biopharmaceutics, Class II and IV drugs (APIs) exhibits poor solubility, lower bioavailability, and less dissolution. Various technologies are discussed in this article to improve the solubility of the poorly water-soluble drug, for example, complexation of active molecules, utilization of emulsion formation, micelles, microemulsions, cosolvents, polymeric micelles preparation, particle size reduction technologies, pharmaceutical salts, prodrugs, solid-state alternation technique, soft gel technology, drug nanocrystals, solid dispersion methods, crystal engineering techniques and nanomorph technology. This review mainly describes several other advanced methodologies for solubility and bioavailability enhancement, such as crystal engineering, micronization, solid dispersions, nano sizing, use of cyclodextrins, solid lipid nanoparticles, colloidal drug delivery systems and drug conjugates, by some appropriate research reports.

Mental health and social resilience play a significant role in refugees’ adaptation during the resettlement process in the host country. Maintaining good mental wellbeing helps the refugees to respond to stressful experiences with healthy life choices. This study aimed to explore the mental wellbeing and social resilience of Eritrean refugees living in Germany and to identify social conditions and enablers to foster adaptation. This study employs a qualitative approach with a semi-structured, in-depth interview data collection method. Informants were identified among mostly young adult refugees living in Heidelberg, Germany, with a migration history of 3-6 years. In total, 15 informants were recruited through snowball sampling. Data were sorted and analyzed using the five pillars of the Adaptation and Development after Persecution and Trauma (ADAPT) model. The findings suggest that Eritrean refugees experience psychological distress after resettlement in Germany, however with time, their mental health has improved. The study revealed conditions that were experienced as hindrances, as well as ones that were considered to be resources of positive mental wellbeing and social resilience for resettled refugees. Challenges described were the language barrier, discrimination, unemployment, insecure residence status, loss of family and friends, conflict within the diaspora community, and isolation. The main sources of mental wellbeing and social resilience include the feeling of being welcomed by local communities, access to social services, adopting new relationships, and educational opportunities. These experiences encouraged refugees to have a favorable view of their lives and futures as well as also found to facilitate better integration and adaptation. Understanding refugee mental wellbeing and social resilience require a multidimensional perspective. Eritrean refugees living in Germany have experienced and still are experiencing resettlement challenges, as for example loss of family and friends, negative perception of the German system, loss of past achievements, or unemployment. But they have developed adaptive and resilience mechanisms, too, such as seeing an opportunity for a better life, adopting new roles, and accepting Germany as a “second home”. In addressing those by the refugees as hindrances reported issues, these could be turned into sources of mental well-being and resilience.

Six-Transmembrane Epithelial Antigen of the Prostate 1-4 (STEAP1-4) compose a family of metalloproteinases involved in iron and copper homeostasis and other cellular processes. Thus far, five homologs are known: STEAP1, STEAP1B, STEAP2, STEAP3, and STEAP4. In prostate cancer, STEAP1, STEAP2, and STEAP4 are overexpressed while STEAP3 expression is downregulated. Although the metalloreductase activities of STEAP1-4 are well-documented, their other biological functions are not. Furthermore, the properties and expression levels of STEAP heterotrimers, homotrimers, heterodimers, and homodimers are not well-understood. Nevertheless, studies over the last few decades have provided sufficient impetus to investigate STEAP1-4 as potential biomarkers and therapeutic targets for prostate cancer. In particular, STEAP1 is the target of many emerging immunotherapies. Herein, we give an overview of the structure, physiology, and pathophysiology of STEAP1-4 to provide context for past and current efforts to translate STEAP1-4 into the clinic.

Background: The link between nocturia and aging male symptoms (AMS) has not been scientifically established. This study aimed to measure the degree of severity of AMS that impact on the health-related quality-of-life (HRQoL) in adult males living with nocturia, and to determine the predictive values of nocturnal factors on AMS. Methods: It is an extended analysis of new data collected by using the Hong Kong Traditional AMS (HK-AMS) scale and Cantonese version of the Pittsburgh Sleep Quality Index (PSQI) in a recently published cross-sectional population-based survey. Results: Of the 781 respondents that have completed the set of questionnaires, 68% and 61% of men living with nocturia reported clinically significant (at moderate-to-severe levels) somato-vegetative and sexual AMS, whereas the prevalence and severity were increased with advancing nighttime voiding frequency. The nocturia-specific QoL (NQoL) score and nocturnal frequency were found to be significant predictive factors for composite, somato-vegetative and sexual AMS, in addition to age, global OSQI score, and certain metabolic diseases. Conclusions: Current findings suggested the inclusion of nocturia when measuring the male-specific HRQoL related to aging.

This retrospective study evaluated changes in the pharyngeal portion of the upper airway in pa-tients with constricted and normal airway treated with clear aligners (Invisalign, Align). Additionally, the paper has assessed the change of tongue position in the oral cavity from lateral view. Evaluation was performed with specialized software (Invivo 6.0, Anatomage) on pre-treatment and posttreatment pairs of cone beam computed tomography imaging (CBCT) data. The level of airway constriction, volume, cross-section minimal area, and tongue profile were evaluated. Patients with malocclusion, with pair or initial and finishing CBCT and without sig-nificant weight change between the scans, treated with Invisalign clear aligners were distributed in two groups. Group A consisted of fifty-five patients with orthodontic malocclusion and con-stricted upper airway. Control group B consisted of thirty-one patients with orthodontic malocclusions without any airway constriction. In the group with airway constriction, there was a statistically significant increase in volume during therapy (p<0.001). The surface of the most con-stricted cross-section of airway did not change significantly after treatment in any of the groups. The airway constriction was most frequently localized at the level of 2nd cervical vertebra. The final tongue position was different from initial in 62.2% of all clear aligner treatments.

Lesion studies are crucial in establishing brain-behavior relationships, and accurately segmenting the lesion represents the first step in achieving this. Manual lesion segmentation is the gold standard for chronic strokes. However, it is labor-intensive, subject to bias, and limits sample size. Therefore, our objective is to develop an automatic segmentation algorithm for chronic stroke lesions on T1-weighted MR images. Methods: To train our model, we utilized an open-source dataset: ATLAS v2.0 (Anatomical Tracings of Lesions After Stroke). We partitioned the dataset of 655 T1 images with manual segmentation labels into five subsets and performed a 5-fold cross-validation to avoid overfitting of the model. We used a deep neural network (DNN) architecture for model training. Results: To evaluate the model performance, we used three metrics that pertain to diverse aspects of volumetric segmentation including shape, location, and size. The Dice similarity coefficient (DSC) compares the spatial overlap between manual and machine segmentation. The average DSC was 0.65 (0.61- 0.67; 95% bootstrapped CI). Average symmetric surface distance (ASSD) measures contour distances between the two segmentations. ASSD between manual and automatic segmentation was 12mm. Finally, we compared the total lesion volumes and the Pearson correlation coefficient (ρ) between the manual and automatically segmented lesion volumes, which was 0.97(p-value &lt; 0.001). Conclusions: We present the first automated segmentation model trained on a large multicentric dataset. This model will enable automated on-demand processing of MRI scans and quantitative chronic stroke lesion assessment.

Background: Sleep deficiency can adversely affect the performance of resident physicians resulting in greater medical errors. However, the impact of sleep deficiency on surgical outcomes, particularly among attending surgeons is less clear. Methods: Sixty attending surgeons from academic and community departments of surgery or obstetrics and gynecology were studied prospectively using direct observation and self-report to explore the effect of sleep deprivation on patient safety, operating room communication, medical errors, and adverse events while operating under two conditions, Post-Call (defined as >2 hours of nighttime clinical duties) and Non-Post-Call. Results: Each surgeon contributed up to five surgical procedures post-call and non-post-call yielding 362 cases total (150 Post-Call and 210 Non-Post-Call). Most common were caesarian section and herniorrhaphy. Hours of sleep on the night before the operative procedure were significantly less Post-Call (4.98 ± 1.41) vs. Non-Post-Call (6.68 ± 0.88, p<0.01). Errors were infrequent and not related to hours of sleep or post-call status. However, Non-Technical Skills for Surgeons (NOTSS) ratings demonstrated poorer performance while Post-Call for Situational Awareness, Decision Making and Communication/Teamwork. Fewer hours of sleep also was related to lower ratings for Situational Awareness and Decision Making. Decreased self-reported alertness was observed to be associated with increased procedure time. Conclusions: Sleep deficiency in attending surgeons was not associated with greater errors during procedures performed during the next day. However, procedure time was increased suggesting that surgeons were able to compensate for sleep loss by working more slowly. Ratings on non-technical surgical skills were adversely affected by sleep deficiency.

Expression levels of Cav3.2, BKCa, and anoctamin 1 were previously found to be significantly elevated in patients with chronic kidney disease–associated pruritus (CKD-aP). On the other hand, the expression of TRPV1 was significantly reduced. We further compared CKD patients with and without CKD-aP in terms of the expression levels of several ion channels in the skin, including in peripheral nerve endings。Based on CKD-aP severity, subjects were divided into two groups: non-CKD-aP (no or slight pruritus; n = 16) and CKD-aP (mild, moderate, or severe pruritus; n = 16). Skin samples were obtained from the forearm or elbow during arteriovenous fistula surgery. We used quantitative real-time polymerase chain reaction to measure the skin expression levels of the following ion channels in the skin: Nav1.7, Kv7.2, TREK1, HCN2, TrkA, and Piezo2.　RT-PCR analyses showed that CKD-aP patients had significantly higher levels of TREK1 and Piezo2 transcripts and significantly lower levels of HCN2 transcripts than non–CKD-aP patients. No significant differences were noted between groups in the expression of Nav1.7 or TrkA. Moreover, Kv7.2 transcripts were not detected in either group. In skin samples collected from CKD-aP patients, ion channel expression patterns were altered to enhance hyperpolarization of pruriceptive neurons.

Despite concerns about the negative effects of social distancing and prolonged school closures on children’s lifestyle and physical activity (PA) during the COVID-19 pandemic, robust evidence is lacking on the impact of the COVID-19 pandemic on children’s wellbeing and daily life. This study aimed to examine changes in the PA levels, sleep patterns and screen time of school-aged children during the different phases of COVID-19 outbreak in Hong Kong using a repeated cross-sectional design. School students (Grades 1 to 12) were asked to report their daily electronic device usage and to fill in a sleep dairy recording their daily sleep and wake-up time. They were equipped with a PA monitor, Actigraph wGT3X-BT, to obtain objective data on their PA levels and sleep patterns. Students were recruited before the pandemic (Sep 2019 – Jan 2020; n=577), during school closures (Mar 2020 – Apr 2020; n=146), and after schools partially reopened (Oct 2020 – Jul 2021; n=227). Our results indicated lower PA levels, longer sleep duration, and longer screen time among participants recruited during school closures than those recruited before the COVID-19 outbreak. Primary school students were found to sleep on average for an extra hour during school closures. Our findings illustrate the impact of social distancing policies during the COVID-19 pandemic on the sleep pattern, screen time, and PA level in school-aged children in Hong Kong. Professionals should reinforce the importance of maintaining a physically active lifestyle, good sleep hygiene, and healthy use of electronic devices to parents and school-aged children during the COVID-19 Pandemic.

It is one of the central goals of cognitive neuroscience to understand how structure and function relate in the brain. We review how cognitive function characterization has been approached in the past. In addition, we examine the ongoing efforts, as well as the implications for the future. Clinical studies on patients with lesions have provided key insights into the relationship between brain areas and behavior over the past century. We describe cognitive function according to localization considering these early efforts for characterization. We chose a perceptual-cognitive function, namely body perception, to describe our current efforts. Using body perception as an example, we summarize contemporary techniques. Finally, we outline the trajectory of current progress into the future and discuss the implications for clinical and basic neuroscience.

Autonomic dysfunction is an increasingly recognised complication in chronic neurological conditions such as Parkinson’s disease , and other medical conditions, including diabetes mellitus, chronic fatigue syndrome, postural tachycardia syndrome with and without Ehlers-Danlos syndrome, fibromyalgia and recently Long Covid. Despite laboratory-based tests to evaluate normal and abnormal autonomic function, there are no home-based tests to record neuro-cardiovascular autonomic responses to common stimuli in daily life that are dependent on the normal functioning of the autonomic nervous system. We have developed an adapted blood pressure/heart Autonomic Profile (aAP) that can be used by an individual independently and repeatedly in a domiciliary setting to determine the physiological and symptomatic response to standing, food, and physical and mental (cognitive, emotional) activities. The aAP aids separating autonomic failure (often irreversible) from autonomic dysfunction. This helps the individual and attending healthcare professional understand the relationship between symptoms and common triggers in daily life and informs on self-management in debilitating conditions such as the postural tachycardia syndrome (PoTS) and Long Covid.

Traumatic cardiac arrest has a high mortality. We report the case of a 65 years old women who presented a cardiac arrest following traffic accident. Examinations concluded to a tension gastro thorax with a delayed diagnosis. Naso gastric tube insertion was for many authors a temporary care while waiting for surgery. We report on the diagnostic difficulties found in the literature and a recent review of published cases.

Neurotrauma continues to contribute to significant mortality and disability. The need for better protective equipment is apparent. This review focuses on improved helmet design and the necessi-ty for continued research. We start by highlighting current innovations in helmet design for sport and subsequent utilization in the lay community for construction. The current standards by sport and organization are summarized. We then address current standards within the military envi-ronment. The pathophysiology is discussed with emphasis on how helmets provide protection. As innovative designs emerge, protection against secondary injury becomes apparent. Much research is needed, but this focused paper is intended to serve as a catalyst for improvement in helmet de-sign and implementation to provide more efficient and reliable neuroprotection across broad arenas.

Objectives: This study assessed the associations between parent intent to have their child receive COVID-19 vaccination, and demographic factors and various child activities including attendance at in-person education or childcare. Methods: Persons undergoing COVID-19 testing residing in Minnesota and Los Angeles County, California with children aged <12 years completed anonymous internet-based surveys between May 10 and September 6, 2021 to assess factors associated with intention to vaccinate their child. Factors influencing parents’ decision to have their child attend in person school or childcare were examined. Estimated adjusted odds rations (AORs, 95% CI) were computed between parents’ intentions regarding children’s COVID-19 vaccination and participation in school and extra-curricular activities using multinomial logistic regression. Results: Compared to parents intending to vaccinate their children (n=4,686 [77.2%]), those undecided (n=874 [14.4%] or without intention to vaccinate (n=508 [8.4%]) tended to be younger, non-White, less educated and themselves not vaccinated against COVID-19. Their children more commonly participated in sports (aOR:1.51 1.17-1.95) and in-person faith or community activities (aOR:4.71 (3.62-6.11). They further indicated that additional information regarding vaccine safety and effectiveness would influence their decision. COVID-19 mitigation measures were the most common factors influencing parents’ decision to have their child attend in-person class or childcare. Conclusions: Several demographic and socioeconomic factors are associated with parents’ decision whether to vaccinate their <12-year-old children for COVID-19. Child participation in in-person activities was associated with parents’ intentions not to vaccinate. Tailored communications may be useful to inform parents’ decisions regarding safety and effectiveness of vaccination.

Background: Hypereosinophilic syndromes (HES) are a group of relatively rare disorders in which neurological manifestations are not uncommon including ischemic stroke. The hypothesized pathophysiological mechanisms are hypercoagulability, cardioembolism (mainly mediated by myocardial involvement) and damage to the endothelium. A variable ischemic pattern has been described, including an association of territorial and border zone ischemic stroke. Methods: Three patients who presented to our department with acute stroke were selected aiming to show these three different mechanisms inferred from the stroke pattern on brain Magnetic Resonance Imaging (MRI) and to simultaneously illustrate the three main causes of HES. Results and Discussion: The first patient is a 55-year-old man with an abrupt onset of aphasia due to an acute ischemic stroke involving the left parietal lobule and the angular gyrus; recent lab test had shown hypereosinophilia. An extensive workup excluded primary and secondary causes of hy-pereosinophilia so a diagnosis of idiopathic hypereosinophilia was formulated and he was treated with high doses of steroids. The second patient had severe hypereosinophilia and developed multiple small scattered ischemic lesions, mainly in watershed zones. The history of severe asthma and recurrent sinusitis supported the diagnosis of EGPA (Eosinophilic Granulomatosis with Polyangiitis); considering the severe clinical conditions and the presumptive role of hypereo-sinophilia in determining her symptoms, steroid treatment was promptly started, with good clinical response. The third patient also presented with multiple metachronous ischemic lesions, both in cortical and watershed distribution and marked eosinophilia; the diagnostic work-up found an ovarian cancer. She was treated with steroids and then underwent surgery and adjuvant chemotherapy. Conclusions: HES should be considered in stroke etiological evaluation, although it is a rare disorder, and border zones pattern on neuroimaging is quite suggestive. A thorough research of the sources of hypereosinophilia should be performed to select the appropriate therapy.

A clear relationship between the tau assemblies and toxicity has still to be established. To correlate the tau conformation with its proteotoxic effect in vivo we developed an innovative cell-worm-based approach. HEK293 cells expressing tau P301L under a tetracycline-inducible system (HEK T-Rex) were employed to produce different tau assemblies whose proteotoxic potential was evaluated using C. elegans. Lysates from cells induced for five days, significantly reduced the worm’s locomotor activity. This toxic effect was not related to the total amount of tau produced by cells or to its phosphorylation state but was related to the formation of multimeric tau assemblies, particularly tetrameric ones. We investigated the applicability of this approach for testing compounds acting against oligomeric tau toxicity, using doxycycline (Doxy) as prototype drug. Doxy affected the tau solubility and promoted the disassembly of already formed toxic aggregates in lysates of cells induced for five days. These effects translated into a dose-dependent protective action in C. elegans. These findings confirm the validity of the combined HEK T-Rex cells and C. elegans-based approach as a platform for pharmacological screening.

Reparative osteogenesis in the damaged vertebrae is a complex cascade of morphological and biochemical processes that result in the consolidation of the vertebral body. This research was aimed at studying the features of reparative osteogenesis in damaged thoracic and lumbar vertebral bodies at different time points after injury. We analyzed the morphological findings of the vertebral tissues harvested during surgical interventions in 43 patients with recent, subacute and long-standing injuries to thoracic and lumbar spine, and found that cell differentiation in osteogenesis is closely related to angiogenesis and the metabolic cascade. In areas with sufficient oxygenation, good partial pressure of oxygen, and active growth of microvasculature the normal cycle of development and differentiation of osteoblasts and osteocytes occurs, and hypoxia and acidosis lead to pathological osteogenesis. The reclination maneuver with dorsal tools on Day 10-12 of the injury may be ineffective due to the formation of adhesions between fragments, and reclination of the body of the damaged vertebra two weeks or more after the injury is apparently doomed to failure. Timely ventral fusion performed for objective indications is the key to successful rehabilitation of patients, on the one hand, and reduction of the surgical trauma volume in the future, on the other.