Dermal penetration is considered to mainly occur via passive diffusion. Therefore, a high concentration gradient of dissolved active ingredient between formulation and skin is needed to achieve an effective dermal penetration. The concentration gradient between formulation and skin can be changed by changing the amount of dissolved active ingredient in the formulation. In case of poorly soluble active ingredients this can be achieved by using nanosized drug material instead of larger sized material. The smaller size and the resulting larger surface increase the kinetic solubility and thus increase the concentration gradient of dissolved active ingredient between formulation and skin, which then results in an increased dermal penetration. In this study we demonstrated that the concentration gradient between formulation and skin can also be influenced by the number of particles being present in the formulation and by the dose (volume of formulation) applied to the skin. Particles of undissolved active ingredient are known to act as a reservoir by releasing dissolved molecules in the liquid phase of the formulation. It could now be demonstrated that the particles - once the liquid in which they are dispersed evaporates - can connect to the skin via an aqueous meniscus. The aqueous meniscus contains dissolved active ingredient and therefore creates a small local spot with a locally high concentration gradient and improved dermal penetration. Therefore, the dermal penetration can be increased with formulations that contain high amounts of particles. This can be achieved by applying formulations with high numbers of particles and/or by applying larger volumes of particle containing formulations to the skin.

In this study, we aimed to reveal the proinflammatory effects of serum 25-hydroxyvitamin D3 (Vit D) deficiency and insufficiency in new-onset type 2 diabetes mellitus (T2DM) and prediabe-tes. We recruited 84 prediabetes patients, 94 new-onset T2DM patients and 113 healthy partici-pants. Levels of C-reactive protein (CRP), fibrinogen, ferritin, interleukin-1β (IL-1β), interleu-kin-6 (IL-6), interleukin-8 (IL-8), tumour necrosis factor-α (TNF-α), nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) were measured in the serum of the par-ticipants. The ANOVA Bonferonni and Kruskal Wallis Dunn tests were used for the comparison of the inflammation markers and vitamin D levels between the groups. Upon covariance analy-sis with age, gender and BMI; Vit D levels of T2DM group were found to be significantly lower (p<0.003). Proinflammatory markers and CRP were found to be significantly higher in predia-betic and diabetic subjects. In the prediabetes group, IL-1β, IL-6, IL-8, TNF-α and MAPK were significantly higher in those with Vit D insufficiency and deficiency groups. In T2DM group, IL-1β, IL-6, IL-8, TNF-α, NF-κB, MAPK and CRP were significantly higher in those with Vit D insufficiency and deficiency. Our study emphasizes the proinflammatory effects of Vit D on the initiation of inflammation in both prediabetes and diabetes mellitus.

Liver is the sixth most common site of primary malignant tumors, and the third leading cause of cancer death worldwide. Hepatocellular carcinoma is the most common primary liver malignancy and lungs, abdominal lymph nodes and adrenal glands are the most common sites of its metastasis. We present a rare case of an isolated metastasis of a hepatocellular carcinoma in the left mandibular ramus, with regards to its clinical and radiological presentation and with regards to possible routes of the metastatic spread.

Background: Patients with chronic obstructive pulmonary disease (COPD) often suffer from acute exacerbations. Our objective was to describe recurrent exacerbations in a GP based Swiss COPD cohort, and develop a statistical model for predicting exacerbation. Methods: In a questionnaire-based COPD cohort, demographic and medical data were recorded for 24 months. Data set was split into training (75%) and validation (25%) datasets. A negative binomial regression model was developed using the training dataset to predict the exacerbation rate within 1 year. An exacerbation prediction model was developed, and the overall performance was validated. A nomogram was created to facilitate the clinical use of the model. Results: Of the 229 COPD patients analyzed, 77% of patients had no exacerbation during the follow-up. The best subset in the training dataset found that lower forced expiratory volume, high scores on the MRC dyspnoea scale, exacerbation history, being on combination therapy of LABA+ICS or LAMA+LABA at baseline were associated with a higher rate of exacerbation. When validated, the area-under-curve (AUC) was 0.75 for one or more exacerbations. Calibration was accurate (predicted 0.34 exacerbations vs observed 0.28 exacerbations). Conclusion: Nomograms built from these models can assist clinicians in the decision-making process of their COPD care.

Influenza virus can cause several complications during pregnancy. Therefore, we aimed to inves-tigate the effects of influenza on the development of congenital abnormalities (CAs) by analyzing the database of the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCS-CA). In our multicenter, case-control, population-based study, we processed clinician-reported outcomes and diagnoses collected in the HCCSCA. The case group included newborns with dif-ferent non-chromosomal birth defects, while controls were newborns without CAs. Maternal in-fluenza, as a risk factor for CAs, was analyzed by using a logistic regression model and odds ra-tios with 95% confidence intervals (CIs). Our results showed that maternal influenza in the first trimester was associated with increased odds of developing non-chromosomal CAs (OR: 1.41, CI: 1.28–1.55). There were increased odds of neural tube defects (OR: 2.22, CI: 1.78–2.76), orofacial clefts (OR: 2.28, CI: 1.87–2.78) and congenital heart defects (OR: 1.28, CI: 1.10–1.49) after influenza infection. In all cases, we found a protective effect of folic acid supplementation in the first tri-mester. The odds of non-chromosomal birth defects are higher after maternal influenza in the first -trimester. Folic acid or pregnancy vitamin supplementation and antipyretic therapy may reduce the effect of maternal influenza during the first trimester.

Aim of our study was to retrospectively evaluate whether the oral administration of L. crispatus (M247) could increase pregnancy and live birth rates in women undergoing assisted reproductive technology procedures. Enrolled women (N=160) were divided into two groups: treated (N=80) or untreated (N=80) with the probiotic strain. The odds ratio for a treated woman to get a positive pregnancy test (PPT) was 1.56. In women aged 30–40 years, M247 increased the probability of a PPT in correlation with the progressive rise in BMI, reaching 47% (35% in controls) with a BMI of 35 (odds ratio: 2.00). The CAID statistics showed that in a woman of the blastocyst subgroup, below 43 years, with a BMI over 18.6, treatment with M247 increased the chance of a PPT from 28.4% to 44.5% (odds ratio: 2.08; p<0.05). Considering live births, rate of probiotic group was 12.5% versus 7.5% (odds ratio=1.76). Considering only the blastocyst subgroup, the treatment increased the number of live births by 200% (odds ratio: 3.64; p=0.05). As confirmed also by statistical indices like NNT, NNH and LHH, the use of M247 demonstrated a risk-benefit ratio to the full advantage of the benefits.

Estrogens play a protective role during early life stages. However, endogenous 17β-estradiol (E2) can accelerate atherosclerosis progression in low-grade inflammatory conditions like established atherosclerosis. Our single-center cohort study assessed sex-specific associations of gonadal hormones with oxidative stress, inflammation, and myocardial injury markers in 111 patients (37% women) diagnosed with acute myocardial infarction (MI) between July 2011 and December 2013. Blood samples were collected within 48 hours of symptom onset, and we measured sex steroids (E2, total testosterone [T]), oxidized low-density lipoproteins, high-sensitive C-reactive protein (CRP), white blood cell counts (WBC), and cardiac enzymes (creatine kinase [CK], the CK Muscle-Brain fraction [CK-MB], and high-sensitive troponin T [hsTnT]). The SYNTAX score gauged coronary disease severity from coronary angiography results. In men with acute MI, peak cardiac enzyme levels were predicted by post-percutaneous coronary intervention (PCI) E2 plasma levels (OR 1.011, p=0.047 - CK; OR 1.018, p=0.013 - CK- MB; OR 1.019, p=0.005 - TnT), peak WBC count (OR 1.487, p=0.015 - CK ; OR 1,709, p=0,005 - CK- MB; OR 1.391, p=0.012 - TnT), and peak CRP plasma levels (OR 1.040, p=0.033 - CK; OR 1.024, p=0.029 - CK-MB; OR 1.063, p=0.006 - TnT). T levels and E2/T ratio were associated with post-PCI CRP in these men (OR 0.980, p = 0.024 - T, OR 1.010, p = 0.076 - CRP). For women, peak WBC was a marker of highest testosterone (OR 1.348, p = 0.062), and only WBC was a significant indicator of myocardial injury extent (OR 1.426, p=0.039 - CK; OR 1.384, p=0.036 - CK-MB; OR 1.299, p=0.048 - TnT). During acute MI, elevated endogenous estradiol levels correlate with myocardial necrosis severity in men, while in women, increased leukocyte levels indicate acute myocardial damage. Elevated plasma T is associated with increased WBC in women. In men, post-PCI plasma CRP specifically indicates endogenous T levels and E2/T ratio during the acute phase.

The metastatic disease is a complex and sequential process that involves the migration of tumor cells from the primary site to distant areas. This metastatic pathway is not always predictable. Therefore, this paper presents three rare cases of unusual metastases, due to their primary site: two metastases of a clear cell renal cell carcinoma, one gingival and one nasal, as well as a mandibular metastasis of a hepatocellular carcinoma. In all cases, an incisional biopsy was performed in order to sign out the diagnosis. After microscopical examination of morphological Hematoxylin and Eosin stained slides, for all cases, immunohistochemical reactions were performed to support the primary tumor site. Two cases had a previous histopathological diagnosis of a primary tumor, while for the third case, the metastatic lesion represented the first manifestation of the neoplastic disease, with an unfavorable prognosis.

Background: Evidence suggests that there is substantial comorbidity between fibromyalgia and Axis II pathology (i.e., personality disorders - PDs). The aim of the current study was to find out the exact cluster (A, B, C) PDs or traits that are more prominent in FM and may be predictors of FM diagnosis. Methods: Data from 86 subjects (53 with FM and 33 controls without FM) was analyzed in an observational, cross-sectional, comparative study. The assessment of categorical PDs and traits was performed independently with the Structured Clinical Interview for Personality Disorders (SCID-II). Binary logistic regression was used to determine FM predictors among PDs traits. Results. Compared with controls, FM patients had higher rate of PDs diagnoses (56.7 vs 18.2%, P&lt;.001). However, the rate was significantly higher only for borderline PD diagnosis (28.3% vs 6.1% P&lt;.05). The binary logistic regression analysis showed that schizotypal and schizoid (cluster A), borderline (cluster B), and dependent (cluster C) personality traits may be significant predictors of fibromyalgia (Nagelkerke R2 = 0.415). Conclusions: Our results may reflect association of FM with personality traits of all three PD clusters: A (eccentric), B (dramatic), C (anxious). However, the most consistent evidence seems to be for borderline PD.

Background As a major virus outbreak in the 21st century, the Coronavirus disease 2019 (COVID-19) pandemic has led to unprecedented hazards to mental health globally. Health care workers, patients with COVID-19 are experiencing post-traumatic stress disorders, anxiety, depression, and insomnia. Methods: A cross-sectional study using a questionnaire consisted of four parts: sociodemographic, current and previous health status, measures in a social isolation, and the Arabic version of Depression, Anxiety and Stress Scale (DASS-21). Results: We had 110 patients who completed the data. 89 (80.9%) of patients recovered from COVID-19. They ranged from 18-84 with a mean of 37.6 years (SD = 9.8 years). We had 33.6% of patients re-ported moderate to extremely severe depression compared to 18.2% with mild reported symptoms. The anxiety severity showed that (35.4%) out of patients had moderate to extremely severe anxiety, compared to (6.4%) who had mild anxiety. While stress severity showed that (22.7%) had moderate to extremely severe stress compared to (13.6%) who had mild stress. Conclusion: COVID-19 has caused a significant increase in the prevalence of mental health illness in the general population. Large systematic reviews are required to set the general overall of impact of this pandemic on mental health.

Developmental Coordination Disorder (DCD) is a neurodevelopmental condition characterized by non-progressive central motor impairments. Mild movement disorder features have been observed in DCD. Until now, the etiology of DCD remains unclear. Recent studies suggested a genetic substrate in some patients with DCD, but comprehensive knowledge about associated genes and underlying pathogenetic mechanisms is still lacking. In this study, we first identified genes described in literature in patients with a diagnosis of DCD according to the official diagnostic criteria. Second, we exposed the underlying pathogenetic mechanisms of DCD, by investigating tissue- and temporal gene expression patterns and brain-specific biological mech-anisms. Third, we explored putative shared pathogenetic mechanisms between DCD and frequent movement disorders with a known genetic component, including ataxia, chorea, dystonia, and myoclonus. We identified 12 genes associated with DCD in literature, which are ubiquitously expressed in the central nervous system throughout brain development. These genes are involved in cellular processes, neural signaling and nervous system development. There was a remarkable overlap (62%) in pathogenetic mechanisms between DCD-associated genes and genes linked with movement disorders. Our findings suggest that some patients might have a genetic etiology of DCD, which could be considered part of a pathogenetic movement disorder spectrum.

Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. In late-stage AMD, geographic atrophy (GA) of dry AMD or choroidal neovascularization (CNV) of neovascular AMD results in macular atrophy (MA), leading to significant visual loss. Despite the development of innovative therapies, there are currently no established effective treatments for MA. As a result, early detection of MA is critical in identifying later central macular involvement throughout time. Accurate and early diagnosis is achieved through a combination of clinical examination and imaging techniques. Our review of the literature depicted advances in retinal imaging to identify biomarkers of progression and risk factors for late AMD. Imaging methods like fundus autofluorescence (FAF), near-infrared reflectance (NIR), widefield imaging, optical coherence tomography (OCT), multicolor confocal scanning laser ophthalmoscopy (cSLO), and optical coherence tomography angiography (OCTA) can be used to detect and monitor the progression of retinal atrophy. Multifocal electroretinogram (ERG) and microperimetry are methods for quantifying visual function to map disease progression. The evolving diverse imaging modalities optimize detection of pathology anatomy and measurement of visual function; they may also contribute to the understanding of the underlying mechanistic pathways, particularly the underlying MA changes in late AMD.

Total-body PET/CT scanners provide increased sensitivity, enabling the adjustment of imaging parameters by reducing injected activity or shortening acquisition time. This study aimed to evaluate the limitations of reduced [18F]FDG activity doses on image quality, lesion detectabil-ity, and quantification of lesion uptake in the Biograph Vision Quadra, as well as to assess the benefits of the recently introduced ultra-high sensitivity mode in a clinical setting. A number of 26 patients who underwent [18F]FDG-PET/CT (3.0 MBq/kg, 5 min. scan time) were included in this analysis. PET raw data was rebinned for shorter frame durations to simulate 5 min. scans with lower activities in high sensitivity (HS) and ultra-high sensitivity (UHS) modes. Image quality, noise, and lesion detectability (n=82) were assessed using a 5-point Likert scale. The co-efficient of variation (CoV), signal-to-noise ratio (SNR), tumor-to-background ratio (TBR), and standardized uptake values (SUV) including SUVmean, SUVmax, and SUVpeak were evaluated. Sub-jective image ratings were generally superior in UHS compared to HS mode. At 0.5 MBq/kg, le-sion detectability decreased to 95% (HS) and 98% (UHS). SNR was comparable at 1.0 MBq/kg in HS (5.7±0.6) and 0.5 MBq/kg in UHS (5.5±0.5). With lower doses, there were negligible reductions in SUVmean and SUVpeak, whereas SUVmax increased steadily. Reducing [18F]FDG activity to 1.0 MBq/kg (HS/UHS) in a total-body PET/CT provides diagnostic image quality without statistical-ly significant changes in uptake parameters. UHS mode improves image quality, noise, and le-sion detectability compared to HS mode.

Potentilla nepalensis belongs to the Rosaceae family, and has numerous therapeutic applications as potent plant-based medicine. Forty phytoconstituents (PCs) from the root and stem through n-hexane (NR and NS) and methanolic (MR and MS) extracts were identified in our earlier studies. However, the PCs affecting human genes and their roles in the body are not disclosed till now. In this study, we employed network pharmacology, molecular docking, molecular dynamics simulations (MDS), and MMGBSA methodologies. SMILES format of PCs from the PubChem used as input to DIGEP-Pred, 764 identified as the inducing genes. Their enrichment studies have shown inducing genes gene ontology descriptions, involved pathways, associated diseases, and drugs. PPI networks constructed in String DB and network topological analysing parameters done in Cytoscape v3.10 revealed three biomarkers, TP53 from MS, NR, and NS induced genes; HSPCB and Nf-kB1 from MR induced genes. From 40 PCs, two PCs 1b (MR) and 2a (MS), showed better binding scores (kcal/mol) with p53 protein of -8.6, and -8.0; three PCs 3a, (NR) 4a and 4c (NS) with HSP protein of -9.6, -8.7, and -8.2. MDS and MMGBSA revealed these complexes are stable without higher deviations with better free energy values. Biomarkers identified in this study, have a prominent role in numerous cancers. Thus, further investigations such as in-vivo and in-vitro should be done to find the molecular functions and interlaying mechanism of the identified biomarkers on numerous cancer cell lines in considering the PCs of P.nepalensis.

Bloodstream infection (BSI) after pediatric liver transplantation (PLT) is a common and severe complication that affects patient survival. Children with biliary atresia (BA) are at an increased risk for clinically significant infections. This study evaluated the impact of post-PLT BSI on clinical outcomes in children with BA. A total of 67 patients with BA aged &lt;18 years who underwent PLT between April 2006 and September 2020 were analyzed and divided into two groups according to the occurrence of post-PLT BSI within 1 month (BSI vs. no BSI = 13 [19.4%] vs. 54 [80.6%]). The BSI group was significantly younger at the time of PLT and had a higher frequency of BSI at the time of PLT than the no BSI group. Early vascular complications within 3 months and reoperations were significantly more frequent in the BSI group. Univariate and multivariate analyses revealed that bacteremia within 1 month of PLT and graft-to-recipient weight ratio &gt;4% were significantly associated with vascular complications. In conclusion, BSI after PLT is associated with increased vascular complications and reoperations. Proper control of bacterial infections and early liver transplantation before uncontrolled BSI may reduce vascular complications and unexpected reoperations in children with BA.

Background: Myasthenia Gravis (MG) is a rare autoimmune disease presenting with au-to-antibodies that affect the neuromuscular junction. Aside from symptomatic treatment options, novel therapeutics include monoclonal antibodies (mAbs). IMGT®, the international ImMunoGe-neTics information system® (https://www.imgt.org), extends the characterization of therapeutic antibodies with a systematic description of their mechanisms of action (MOA) and makes them available through its database for mAbs and fusion proteins, IMGT/mAb-DB. Methods: Using the available literature data combined with the amino acid sequence analyses from mAbs managed in IMGT/2Dstructure-DB, the IMGT® protein database, biocuration allowed to define in a standardized way descriptions of MOA of mAbs that target molecules towards MG treatment. Results: New therapeutic targets include FcRn and molecules such as CD38, CD40, CD19, MS4A1 and interleukin-6 receptor. A standardized graphical representation of the MOA of selected mAbs was created and integrated within IMGT/mAb-DB. The main mechanisms involved in these mAbs are either blocking or neutralizing. Therapies directed to B cell depletion and plasma cells have a blocking MOA with an immunosuppressant effect along with Fc-effector function (MS4A1, CD38) or FcγRIIb engager effect (CD19). Monoclonal antibodies targeting the complement also have blocking MOA with a complement inhibitor effect and treatments targeting T cells have a blocking MOA with an immunosuppressant effect (CD40) and Fc-effector function (IL6R). On the other hand, FcRn antagonists present a neutralizing MOA with an FcRn inhibitor effect. Conclusion: The MOA of each new mAb needs to be considered in association with the immuno-pathogenesis of each of the subtypes of MG in order to integrate the new mAbs as a viable and safe option in the therapy decision process. In IMGT/mAb-DB, mAbs for MG are characterized by their sequence, domains, chains and their MOA is described.

Frontotemporal dementia (FTD) is the second most common form of presenile dementia; however, its diagnosis has been poorly investigated. Previous attempts to diagnose FTD using quantitative electroencephalography (qEEG) have yielded inconsistent results in both spectral and functional connectivity analyses. This study aimed to introduce an accurate qEEG marker that could be used to diagnose FTD and other neurological abnormalities. We used open-access electroencephalography data from OpenNeuro to investigate the power ratio between the frontal and temporal lobes in the resting state of 23 patients with FTD and 29 healthy controls. Spectral data were extracted using a Fast Fourier Transform in the delta (1–4 Hz), theta (4–8 Hz), alpha (8–13 Hz), beta (13–32 Hz), and gamma (32–45 Hz) bands. We found that the spectral power ratio between the frontal and temporal lobes is a promising qEEG marker of FTD. Frontal/temporal (F/T) theta/alpha, alpha/theta, al-pha/gamma, and gamma/alpha showed a consistently high discrimination score for the diagnosis of FTD for different parameters and referencing methods. The study findings can serve as reference for future research focused on diagnosing FTD and other neurological anomalies.

The objective was to compare the failure loads of glass ceramic, and polymer crowns against yttria-partially stabilized zirconia (Y-PSZ) crowns with varying yttria concentrations. Monolithic crowns of zirconia (Cercon XT, Katana UTML, BruxZir Anterior), glass ceramic (Celtra press, IPS e.max press, Lisi press), and polymeric materials (Trilor, Juvora, Pekkton) were fabricated and cemented to epoxy abutments. The total number of specimens was 135 for crowns and 135 for discs (15 specimens per material type and design). A universal testing machine was used to perform compressive loading of all crowns to failure with a steel hemisphere along the longitudinal axis of the abutments. Energy dispersive spectroscopy (EDS) was used to identify the concentration (mol% yttria-partially stabilized zirconia) for each zirconia brand. The data were analyzed using a generalized linear model and regression analysis. The results revealed significant differences (P < .05) in mean failure loads for different crown materials: Trilor (6811 ± 960 N) > Juvora (5215 ± 151 N) > Cercon (4260 ± 520 N) = BruxZir (4186 ± 269 N) = e.max (3981 ± 384 N) > Katana (3195 ± 350 N) = Lisi (3173 ± 234 N) = Pekkton (3105 ± 398 N) > Celtra (2696 ± 393 N). EDS showed that the zirconia materials contained yttria at different concentrations (BruxZir = 5Y-PSZ, Cercon = 4Y-PSZ, Katana = 3Y-PSZ). The yttria concentration had a significant effect on the failure load of the Katana (3Y-PSZ) crowns, which revealed lower failure loads than the Cercon (4Y-PSZ) and BruxZir (5Y-PSZ) crowns. New zirconia materials are provided with different yttria concentrations (3Y-, 4Y-, and 5Y-PSZ). Since a higher yttria concentration increases the translucency, clinicians should be aware that 4-5 wt% yttria-partially stabilized zirconia materials provide comparable or higher mechanical properties than e. max glass ceramic for dental application of crowns.

Objective: The objective of our study was to explore the potential benefits of combining moderate alcohol consumption with regular vigorous physical activity on HDL-cholesterol levels and its potential positive impact on cardiovascular health. Material and method: The study comprised two groups: group A (102 patients) who consumed 1 gram of alcohol per day, specifically red wine, and increased their exercise levels in addition to their standard medical treatment, and group B (108 patients) who adhered only to their standard medical treatment. The patients were monitored for a year, during which various clinical parameters were observed. Results:Our study showed that moderate alcohol consumption, particularly red wine, along with increased physical activity levels, was associated with enhancements in exercise tolerance and elevated levels of HDL-cholesterol. Our findings suggest the efficacy of the intervention in improving lipid profiles, with the group that consumed alcohol as part of their treatment scheme, generally experiencing more pronounced positive effects. Statistically significant differences between groups in terms of angina evolution, AMI recurrence, or arrhythmias evolution were not found. However, there were important differences in terms of EF improvement and quality of life, with the alcohol consuming group displaying greater improvements in both aspects. Conclusions:In conclusion, our study emphasizes the potential benefits of combining moderate alcohol consumption, specifically red wine, with increased physical activity levels for improving exercise tolerance and enhancing HDL-cholesterol levels. However, further research and clinical trials are essential to fully understand the mechanisms and optimize the integration of these lifestyle elements for improved cardiovascular health outcomes.

The complex interplay between dietary factors, inflammation, and macrophage polarization is pivotal in the pathogenesis and progression of chronic liver diseases (CLDs). Omega-3 fatty acids (FAs) have been attracted attention due to their potential to modulate inflammation and exert protective effects in various pathological conditions. This review explores the emerging role of omega-3 FAs and their specialized pro-resolving mediators (SPMs) in the context of macrophage polarization, with a focus on chronic liver diseases. Omega-3, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have promising effects in mitigating inflammation and enhancing the resolution of inflammatory responses. They influence the M1/M2 macrophage phenotype balance, promoting a shift towards the M2 anti-inflammatory phenotype. SPMs, such as resolvins (Rvs), protectins (PDs), and maresins (MaRs), have emerged as potent regulators of inflammation and macrophage polarization. They show anti-inflammatory and pro-resolving properties. These mediators modulate the expression of cytokines, facilitate the phagocytosis of apoptotic cells, and promote tissue repair. MaR1, in particular, has demonstrated significant hepatoprotective effects by promoting M2 macrophage polarization, reducing oxidative stress, and inhibiting key inflammatory pathways such as NF-κB. In the context of CLD, such as nonalcoholic fatty liver disease (NAFLD) and cirrhosis, omega-3 and their SPMs have shown promise in attenuating liver injury, promoting tissue regeneration, and modulating macrophage phenotypes. However, the mechanisms underlying their effects and their interactions with other cell types within the liver microenvironment require further investigation. Understanding the intricate relationship among SPM and macrophage polarization holds unlimited potential for the development of novel therapeutic strategies for chronic liver diseases.

CXCL14 is one of the most evolutionarily conserved members of the chemokine family and is constitutionally expressed in multiple organs, suggesting that it is involved in the homeostasis maintenance of the system. CXCL14 is highly expressed in colon epithelial cells and shows obvious gene silencing in clinical colon cancer samples, suggesting that its silencing is related to the immune escape of cancer cells. In this paper, we analyzed the expression profiles of multiple human clinical colon cancer datasets and mouse colon cancer models to reveal the variation trend of CXCL14 expression during colitis, colon polyps, primary colon cancer, and liver metastases. The relationship between CXCL14 gene silencing and promoter hypermethylation was revealed through the colorectal carcinoma methylation database. The results suggest that CXCL14 is a tumor suppressor gene in colorectal carcinoma, which is activated first and then silenced during the process of tumor occurrence and deterioration. Promoter hypermethylation is the main cause of CXCL14 silencing. The methylation level of CXCL14 is correlated with the anatomic site of tumor occurrence and positively correlated with patient age, and associated with prognosis. Reversing the hypermethylation of CXCL14 may be an epigenetic therapy for colon cancer.

One of the key pathogenetic links of type 2 diabetes mellitus (T2DM) is the formation of insulin resistance (IR). Besides a wide selection of synthetic antidiabetic drugs, various plant-origin extracts are also available to support the treatment of T2DM. This study aimed to investigate and gain knowledge of the chemical composition and potential IR correction effect of American cranberry (Vaccinium macrocarpon Aiton) leaf extracts and formulate novel 3D-printed oral dosage forms for such extracts. The bioactivity and IR of L-arginine-loaded cranberry leaf extracts were studied in vivo in rats. The cranberry leaf extracts consisted of quinic, 3-caffeoylquinic (chlorogenic), p-coumaroylquinic acids, quercetin 3-O-galactoside, quercetin-3-O-glucoside, quercetin-3-xyloside, quercetin-3-O-arabino-pyranoside, quercetin-3-O-arabinofuranoside, quercetin 3-O-rhamnoside and quercetin-O-p-coumaroyl-hexoside-2 identified by HPLC. In-vivo studies with rats showed that the oral administration of the cranberry leaf extracts had a positive effect on insulin sensitivity coefficients under ITT test, and affected HOMA-IR levels and liver lipid content with experimental IR. A novel 3D-printed immediate-release dosage form was developed for the oral administration of cranberry leaf extracts using polyethylene oxide (PEO) as a carrier gel in a semi-solid extrusion (SSE) 3D printing. In conclusion, American cranberry leaf extracts loaded with L-arginine could find uses in preventing health issues associated with IR.

Optic neuritis (ON) is the most common cause of vision loss in young adults. It manifests as acute or subacute vision loss, often accompanied by retrobulbar discomfort or pain on eye movements. Typical ON is associated with Multiple Sclerosis and is generally mild and steroid-responsive, whereas atypical forms are characterized by unusual features, such as optic disc edema, poor treatment response and bilateral involvement, and are often associated with autoantibodies against aquaporin-4 (AQP4) and Myelin Oligodendrocyte Glycoprotein (MOG). However, in rare cases AQP4 and MOG antibodies will come back negative, plunging the clinician in a diagnostic conundrum. Seronegative ON warrants a broad differential diagnosis, including autoantibody-associated, granulomatous, and systemic disorders. These rare forms need to be identified promptly, as their management and prognosis is greatly different. The scope of this review is to describe possible, rarer etiologies of ON when AQP4 and MOG antibodies are negative and discuss their diagnosis and treatment.

The patient was a 44-year-old woman with suspected Stevens-Johnson syndrome due to Baktar® (sulfamethoxazole trimethoprim) medication received at our outpatient dermatology clinic. Histopathological examination of the epidermis, dermis, and subcutaneous adipose tissue samples showed numerous necrotic keratinocytes in the epidermis. Apoptotic nuclei were visualized as diaminobenzidine brown deposits with immunoperoxidase staining for cleaved caspase-3. Cleaved-caspase3-positive findings were consistent with eosinophilic material that appeared to be necrotic cells within the epidermis. Therefore, these eosinophilic materials must be apoptotic bodies. Generally speaking, and especially in Japan, these materials are considered necrotic keratinocytes. To our best knowledge, no studies have used apoptotic immunohistochemical markers to examine whether these structures are apoptotic.

The increasing prevalence of periprosthetic femoral fractures, specifically in the vicinity of the hip, has emerged as a significant issue in recent times. Consequently, there is a need for a thorough examination to enhance the effectiveness of management and treatment approaches. The findings emphasized a significant disparity in the occurrence and characteristics of these fractures, as multiple studies have highlighted the efficacy of various treatment strategies, such as open reduction and internal fixation, as well as the utilization of cortical strut allografts. Furthermore, the research has identified potential risk factors that have an impact on the characteristics of fractures, providing valuable insights that could be crucial in the development of preventive strategies. This research provides a thorough examination of periprosthetic femoral fractures, highlighting the importance of a cohesive treatment algorithm to improve the handling of such fractures. Moreover, it promotes the need for a collaborative endeavor in conducting research in this field, cultivating a more profound comprehension that has the potential to drive progress in therapeutic approaches, ultimately enhancing patient results over an extended period of time. It is crucial that forthcoming research endeavors persist in expanding upon these discoveries, striving towards a unified methodology in tackling this substantial clinical obstacle.

Social communication skills, especially eye contact and joint attention, are highly impaired in autism spectrum disorder (ASD) and predict functional outcomes. Applied Behavior Analysis is one of the best evidence-based treatments for ASD, but it is not accessible to most families in low- and middle-income countries (LMICs) as it is a costly and intensive and needs to be delivered by highly specialized professionals. Parental training has emerged as an effective alternative. The aim of this study was to test the efficacy of a parental intervention group via video modeling to acquire eye contact and joint attention. Four graded measures of eye contact and joint attention (full physical prompt, partial physical prompt, gestural prompt, and independent) were assessed in 34 children with ASD and intellectual disability (ID). There was a progressive reduction in the level of prompt required over time to acquire eye contact and joint attention, and a positive correlation between the time of exposure to the intervention and acquisition of the abilities. This parent training using video modelling to teach eye contact and joint attention skills to children with ASD and ID is a low-cost intervention that can be applied in low- resource settings.

(1) Background: Alcohol consumption during pregnancy is a major concern, particularly in Europe and North America. Its prevalence has been so far under researched. In most of the studies the determination of this consumption may be underestimated, as it is based on the information obtained from questionnaires rather than from biomarkers, which will provide a much reliable approach. The main objective in this study was the comparison of prevalence of consumption during pregnancy assessed by a questionnaire and a hair biomarker. (2) Method: Cross-sectional study with a random sample of 425 pregnant women treated in public hospital consultations in Seville (Spain) and in the 20th week of their pregnancy, orally interviewed through a questionnaire elaborated ad hoc which evaluated sociodemographic, obstetric, and alcohol consumption variables. Additionally, the ethyl glucuronide metabolite (EtG) was tested on a hair sample in 252 pregnant women who agreed to facilitate it. Once data obtained through the questionnaire and the hair testing were analyzed, the level of metabolites and the self-reported alcohol consumption were contrasted. (3) Results: The prevalence of self-reported alcohol consumption (questionnaire) was 20.7% and real consumption (metabolite analysis) was 20.2%. In 16.8% of pregnant women who declared not consuming alcohol during their pregnancy a noticeable consumption was detected according to the metabolite testing. No relevant level of variability in estimated alcohol consumption was detected in the biomarker with respect to the studied sociodemographic and obstetric variables.

(1) Background: The stylohyoid syndrome, known as classical Eagle Syndrome (cES), is characterized by calcificatication of the stylohyoid chain with numerous nonspecific symptoms, mainly pain. This study introduces Minimally Invasive Cervical Styloidectomy (MICS). (2) Methods: MICS was performed on sixty-five patients diagnosed with classical Eagle syndrome. Patients underwent meticulous differential diagnosis. Surgical plans were established based on the findings from neck angioCT. (3) Results: The healing process was uneventful without significant complications. The overall success rate was 97.0%, with a follow-up of a minimum of six months. In one case, the surgery did not yield the desired improvement. In one case, a partial relapse of symptoms was observed. (4) Conclusions: MICS is a straightforward and efficient surgical treatment technique for stylohyoid syndrome.

New in vitro approaches for the assessment of their toxicity are crucial for creating better risk assessments given the growing use of nanoparticles (NPs) in the production of consumer goods. Humans will be exposed to nanoparticles through the inhalation route from contaminated aerosol. A promising method for evaluating the genotoxicity of NPs in vitro uses human airway epithelial cells. This study aimed to determine whether there were differences in morphology change of human bronchial/tracheal epithelial (HBTEC) cells responded to NPs in 2D and 3D spheroid models and to evaluate genotoxicity in 2D and 3D cultures after 24 hr exposure to TiO2-, Ag- and ZnO-NPs using the comet assay. Our 2D and 3D HBTEC cultures with TiO2-NPs did not show any statistically significant genotoxicity compared to controls for concentration points tested in vitro. HBTEC cells grown as 2D indicated that exposure to ZnO-NPs at low concentrations (10-50 ug/mL) for 24 hr did not cause any genotoxic effect but, at high concentrations, genotoxicity was observed. In contrast, treatment of 2D HBTEC with AgO-NPs led to an elevated in percentage of tail DNA damage from 50 ug/mL to 100 ug/mL, which was concentra-tion-dependent. Using 3D spheroid assays revealed a lower %tail length in ZnO- and AgO-NPs, thus exhibiting in vitro genotoxicity of NPs in this cell model. Spheroids (3D) rather than mono-layer cultures (2D) are believed to more precisely represent in vivo-like cell behavior when evaluating genotoxicity. Together, our findings demonstrate the genotoxic effects of NPs and point to the critical role that cell culture models play in the evaluation of toxicological risk.

In medico-administrative database, certain prognostic factors cannot be taken into account. The main objective was to estimate the performance of two models based on two databases: Epi-thor clinical and medico-administrative databases. For each of the two databases, we randomly sampled a development dataset with 70% of the data and a validation dataset with 30%. Performance of models was assessed by Brier score, the area under the receiver operating characteristic (AUC ROC) curve and the calibration of the model. For Epithor and medico-administrative databases, the development dataset included 10,516 patients (with resp. 227 (2.16%) and 283(2.7%) deaths) and the validation dataset included 4,507 patients (with resp. 93 (2%) and 119 (2.64%) deaths). 15 predictors were selected in the models (including FEV, Body Mass Index, ASA score and TNM stage for Epithor). The Brier score values were similar in the models of the two databases. For validation data, the AUC ROC curve was 0.73 [0.68-0.78] for Epithor and 0.8 [0.76-0.84] for medico-administrative databases. The slope of the calibration plot was less than 1 for the two databases. This work shows the good performances of a model developed from a medico-administrative database, despite the absence of clinical variables used in practice by surgeons, such as FEV1, ASA score or TNM stage.

The real long-term influences of in utero drug exposure in pregnant women on childhood development have yet to be fully determined and depend on the duration of in utero drug exposure and maternal drug levels. Therapeutic drug monitoring (TDM) during pregnancy may help limit fetal drug exposure while maintaining therapeutic drug levels in maternal blood. Most antibody therapies used in patients with Inflammatory Bowel Disease (IBD) are IgG molecules which are actively transported across the placenta, especially during the third trimester of the pregnancy. Here we propose an up to date clinical review to summarize the available findings of serum drug levels in maternal blood during pregnancy, in the blood cord, infants at delivery and in breast milk of patients with IBD treated with biologics. Conversely to adalimumab (ADA) levels, which are relatively stable during pregnancy, infliximab (IFX) drug clearance decreased significantly during the second and third trimesters, leading to increasing maternal IFX concentrations. As most guidelines recommend using live vaccines in infants at the age of one or earlier in case of negative serum drug levels in newborns, statistical models could help clinicians in making a decision to adjust the last dose of the biologic during pregnancy and to determine the optimal date to vaccinate. Altogether, data from the literature offers strong reassurance regarding the safety profile of anti-TNFα therapies during pregnancy not only for IBD patients who intend to conceive, but also for pregnant women and for the physicians taking care of these patients. ADA and IFX levels in breast milk are detectable but very low and therefore it is recommended to pursue breast feeding under anti-TNFα therapy. Our knowledge on ustekinumab or vedolizumab levels in pregnant women remains unclear and scarce. It is currently not recommended in patients with IBD in clinical practice. Therefore, TDM and proactive dose adjustment are not necessary during pregnancy since its impact for making a clinical decision have not yet been clearly demonstrated in routine practice. Overall, drug concentrations in the blood cord, the infant at birth and postpartum serum concentrations in infants, due to active placental drug transfer, may have a greater impact than the limited drug transfer in breast milk during lactation on the risk of infection and developmental outcomes. Ustekinumab and vedolizumab exposure during pregnancy and lactation are both considered low risk by the recent ECCO guidelines despite the limited data currently available.

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative motor neuron disease and remains misunderstood with difficult diagnosis and prognosis. The implication of the immune system is recognized in ALS pathophysiology, hence the interest in leucocytes count as lymphocytes and neutrophils. The neutrophil to lymphocyte ratio (NLR) has recently been used as a prognosis factor to assess the progression of ALS. Thus, the aim of this study was to analyze the evolution of the NLR during disease evolution in a French cohort of ALS patients and its relation with survival. Clinical parameters and NLR were collected in ALS patients followed at the University Hospital of Tours (France). ALS patients were subdivided into three groups in regard to their NLR value at inclusion: group 1 (NLR < 2); group 2 (NLR: 2-3); group 3 (NLR > 3). Comparison of qualitative and quantitative clinical and biological variables between NLR groups was performed. Then Cox-regressions were carried out to determine the association of NLR with survival. We observed a significant correlation of NLR with ALSFRS-r score (p<0.0001) and with vital forced capacity (p=0.0004) at inclusion. We observed that increased NLR at diagnosis is associated with decreased ALS patients’ survival.

Immunotherapy with stereotactic body radiotherapy (SBRT), low-dose antiangiogenics, immune adjuvants, nanomedicine, or other combinations will likely play a lead role in managing malignancies soon. Presently, its benefit extends to about 12% to 20% of patients, in the background of possible recurrence eventually and the toxicities, including in non-responders. Stereotactic body radiotherapy (SBRT) not only eliminates the indexed lesions, but recently, the evidence is accumulating about its systemic abscopal effects. It needs to be evolved to a dependable in situ therapeutic vaccine production and to activate short- and long-term memory immune lymphocytes. The in-situ immune cascade happens with the ability of SBRT to generate Tumor-specific neoantigens and neoepitopes, which enhance the activation of antigen-presenting cells, invoke and restore the competence of Tumor-infiltrating lymphocytes, resulting in cancer cell lysis. This cell lysis, in turn, can generate further neoantigens and epitopes, imparting a virtuous cycle that is the hallmark of effective vaccines. Additionally, SBRT can synergistically enhance the other in situ vaccination strategies, concurrent in vitro vaccines or nanomedicines, making it a primary tool for sensitizing even the “cold” tumors for immunotherapy. The present proposed hypotheses, primarily based on a preclinical literature review, focus on the critical aspects of the in-situ vaccination generation capability of SBRT when used in pulsed, cyclical, or intermittent endothelial-sparing single dose schedules along with immunotherapy and other supportive measures. This schedule is categorized as in situ vaccine dose (ISVD) radiotherapy (RT) (distinguishable from the standard therapeutic SBRT schedule) in metastatic cancer settings after standard /first-line therapies.

Background The workload of nurses in the intensive care unit (ICU) can affect the quality of nursing services. Aim This study aimed to determine the relationship between the nursing activity score and missed care in patients hospitalized in the ICU in Zanjan, Iran. Methods This observational and prospective study was conducted from April 3 to September 18 in 2021. In this study, the tools used included a patient and nurses' profile questionnaire, Nursing Activity Score (NAS). Missed care was observed in the 301 patients for whom the NAS was calculated. Analysis of variance (ANOVA) was used to investigate the differences in mean levels of missed care. Logistic regression models were used to assess the association between factors and missed nursing care. Results Results show that the Medical ICU's mean NAS was 76.31 (95% CI: -13.06 -14.89). In 9 dimensions of care, the extent of missed care was 40.7%. In the care dimensions of assessment, hand hygiene, and infection control, the mean NAS had a statistically significant increase at higher levels of missed care (P<.5). Furthermore, work experience was identified as a protective factor for missed care (OR =.59, 95% CI: .37–.94, χ2= =4.97, p =.026). Conclusion The study revealed a high incidence of missed care. The study revealed that the mean workload was high in certain dimensions of care such as assessment, hand hygiene, and infection control. The increase in workload for nurses results in lost care. Nonetheless, the utilization of experienced nurses can help mitigate this problem. However, utilizing experienced nurses can help reduce this problem.

Cannabinoids are prescribed to children with cerebral palsy (CP) despite limited evidence. We aimed to assess the prescription practices of cannabinoids in children with CP with a particular focus on indications, what kind of preparations are used and how well cannabinoids are tolerated. Furthermore, we investigated how physicians acquire knowledge on cannabinoid medication. We asked physicians with expertise in the care of children with CP about their prescription prac-tices of cannabinoids. Data was collected through an online survey, which was distributed by email. In addition to the demographic information of participants, we also inquired about the indications for the prescription of cannabinoids, about experiences regarding efficacy, and ob-served side effects of the therapy. Seventy physicians from Europe, North America and Australia completed the survey. Forty-seven participants were experienced in the treatment of children with CP by cannabinoids. The most common indication was epilepsy (69%), followed by spasticity (64%) and pain (63%). The pre-scribed preparations and doses varied considerably. Half of the participants evaluated the effect of the cannabinoids as moderate. Twenty-nine physicians reported side effects, most frequently drowsiness (26%), somnolence (19%), fatigue (13%), and diarrhea (13%). Despite the lack of evidence to date, cannabinoids are used to treat children with CP in a wide variety of indications. Randomized controlled trials in this vulnerable patient group are therefore of utmost importance.

3D printing technology has brought about a paradigm shift in the delivery of clinical care in medicine and dentistry. There are several different 3D printing technologies, which, along with different printable materials with unique biomechanical properties, allows for a wide range of applications for 3D printing in dentistry. The clinical use of 3D printing has created versatile applications which streamline our digital workflow. Technological advancements have also paved the way for the integration of new dental materials in dentistry. This paper provides an overview of the mechanisms of 3D printing, the dental materials relevant to each mechanism and the possible applications of these materials within different areas of dentistry. Understanding the existing spectrum of 3D printing applications in dentistry will serve to further expand its use in the dental field.

Background: Patients with allergic rhinitis (AR) have bothersome symptoms that may assess using the visual analog scale (VAS). Asthma frequently is associated with AR. The present study investigated the role of VAS in children with newly-diagnosed AR. Methods: Parameters were VAS for nasal and asthma symptoms, and doctor’s perception of these diseases, medication use, and asthma comorbidity. Results: 67% of AR children had asthma. Severity of perceived nasal symptoms was associated with more intense asthma symptoms and doctor’s perception of disease severity (p<0.001 and p=0.02, re-spectively. Conclusions: Allergic rhinitis frequently is associated with asthma in child-hood. Symptom perception assessment using VAS is a simple tool for assessing their intensity. Moreover, the severity of nasal symptoms is associated with asthma symptom severity. Therefore, asthma should be carefully considered in AR children and require appropriate symptom perception assessment.

Pre-exposure prophylaxis for COVID-19 with Tixagevimab/Cilgavimab in immunocompromised patients has reduced the risk of breakthrough infection, disease, hospitalization, and COVID-19 related mortality. However, the advent of the Kraken variant (XBB.1.5) has limited the use of this monoclonal antibody, based on poor efficacy in in vitro studies The objective of the study was to evaluate the risk of breakthrough infection, symptomatic disease, hospitalization, intensive care admission and COVID-19 related death in kidney transplanted recipients receiving pre-exposure prophylaxis with Tixagevimab/Cilgavimab for COVID-19 in the era of the Kraken variant (XBB.1.5). In a prospective, observational study, we enrolled kidney transplant patients undergoing pre-exposure prophylaxis for COVID-19 with Tixagevimab/Cilgavimab at the Division of Infectious Diseases of Federico II University of Naples between February 2023 and August 2023. Each patient subsequently underwent a six-month follow-up with symptom monitoring and surveillance nasopharyngeal swab for SARS-CoV-2 RNA detection every 30 days, regardless of symptoms. Thirty-four kidney transplant patients were enrolled and in the follow-up period, only one tested positive for the nasopharyngeal swab for SARS-CoV-2 research with asymptomatic infection and virological recovery on the eighth day from the diagnosis of infection. Therefore, no patient developed disease and no patient needed hospitalization and no death occurred. No adverse drug reaction to Tixagevimab/Cilgavimab occurred. Our data, although derived from a limited and uncontrolled sample, show the potential of Tixagevimab/Cilgavimab as a valid and viable therapeutic strategy in pre-exposure prophylaxis for immunocompromised patients. These findings highlight the importance of conducting clinical studies on this topic.

Sleep-disordered breathing affects the growth and development, mental aspect, and learning ability of affected children. Postoperative scarring causes anteroposterior and vertical develop-mental disorders of the maxilla. Obstructive apnea is likely to occur due to the influence on the maxillofacial and airway morphology. In this study, we investigated the sleep-respiratory dynamics of school-aged children with unilateral cleft lip and palate by performing a simple over-night sleep study, maxillofacial morphology and airway analysis using lateral cranial radiographs, and model analysis. Children with unilateral cleft lip and palate showed a significantly higher respiratory event index (REI) than normal children; the maxilla was located in the posterior position in terms of maxillofacial morphology, and airway morphology showed narrow values for all distance measurement items. Moreover, the width and length of the dental arch and the width of the alveolar base arch were significantly smaller. Furthermore, there was a negative correlation between REI and SNA, ANB, REI, and alveolar base arch width. Children with unilateral cleft lip and palate are more likely than normal children to develop sleep-disordered breathing due to in-creased airway resistance caused by undergrowth of the maxilla and narrowing of the upper airway and oral volume.

SARS-CoV-2 can trigger autoimmune central nervous system (CNS) diseases in genetically susceptible individuals, a mechanism poorly understood. Molecular mimicry (MM) has been identified in other viral diseases as potential triggers of autoimmune CNS events. This study investigated if MM is the process through which SARS-CoV-2 induce the breakdown of immune tolerance. The frequency of autoimmune CNS disorders was evaluated in a prospective cohort with patients admitted in the COVID-19 Intense Care Unity (ICU) in Rio de Janeiro. Then, an in silico analysis was performed to identify the conserved regions which share high identity between SARS-Cov-2 anti-gens and human proteins. The sequences with significant identity and antigenic properties were then assessed for their binding capacity to HLA subtypes. Of the 112 patients included, 3 were classified as having an autoimmune disorder. A total of eleven combinations had significant linear and three-dimensional overlap. NMDAR1, MOG and MPO were the self-antigens with more significant combinations, followed by GAD65. All sequences presented at least one epitope with strong or intermediate binding capacity to the HLA subtypes selected. This study underscores the possibility that CNS autoimmune attacks observed in COVID-19 patients, including those in our population, could be driven by MM in genetically predisposed individuals.

Angiogenesis is a process whereby new blood vessels are born from preexistent ones, which has a role in transporting oxygen and nutrients. On the other hand, inhibiting this process is a strategy used to treat some diseases, including cancers, diabetic retinopathy, and rheumatoid arthritis. This study investigates the effect of a new nutraceutical (Terasen®) on angiogenesis. Terasen® is made from a standardized extract of Euterpe oleraceae (Açaí), Myrciaria dubia (Camu-Camu), and purified oil of Bixa orellana (Annatto) and Astrocaryum aculeatum (Tucumã). The in vivo angiogenesis model used was the chorioallantoic membrane (CAM) from chicken embryos. The embryos were divided into seven groups: a vehicle control treated with ethanol solution (ETH), a naïve control treated only with saline solution (SOR), a positive control treated with dexamethasone (DEX), and four groups treated with Terasen® at different concentrations (0.5, 1, 2, and 3 mg/ml). The parameters assessed were the vessels’ area, length, and amount. The results show a statistically significant and concentration-dependent inhibition of angiogenesis caused by Terasen®. Our results suggest the nutraceutical has a high antiangiogenesis potential, possibly due to its bioactive compounds, including anthocyanins, quercetin, and tocotrienols.

The evolutionary conserved STING-cGAS pathway represents one of the most important cytosolic DNA sensing systems that is activated in response to viral invasion and/or damaged integrity of the nuclear envelope. The key outcome of this pathway is the production of IFN, which subsequently stimulates hundreds of genes. In oncology, the situation is a complex one since this pathway may serve either anti- or pro-oncogenic roles in a context-dependent fashion. The prevailing understanding is that when the innate immune response is activated by sensing cytosolic DNA, such as from ruptured micronuclei, it results in the production of interferon which attracts cytotoxic cells to destroy tumors. However, in tumor cells that have adjusted to significant chromosomal instability, particularly in relapsed, treatment-resistant cancers, the cGAS–STING pathway often supports cancer progression. In these cells, the pathway initiates a non-canonical nuclear factor κB transcriptional response, fostering the epithelial-to-mesenchymal transition (EMT). Here, we review this intricate pathway in conjunction with cancer progression and development of new treatment modalities.

Cardiovascular diseases (CVDs) and type 2 diabetes mellitus (T2DM) are two of the four major chronic non-communicable diseases (NCDs), representing the leading cause of death worldwide. Several studies demonstrate that endothelial dysfunction (ED) plays a central role in the pathogenesis of these chronic diseases. Although it is well known that systemic chronic inflammation and oxidative stress are primarily involved in the development of ED, recent studies have shown that perivascular adipose tissue (PVAT) is implicated in its pathogenesis, also contributing to the progression of atherosclerosis and to insulin resistance (IR). In this review we describe the relationship between PVAT and ED, and we also analyse the role of PVAT in the pathogenesis of CVDs and T2DM, further assessing its potential therapeutic target with the aim of restoring normal ED and reducing global cardiovascular risk.

Vitamin D status may impact acute affective symptomatology and the severity of symptoms in patients with bipolar disorder (BD). Therefore, this cross-sectional study analyzed 25(OH)D, 24,25(OH)2D, and the vitamin D metabolite ratio (VMR) in BD and correlated the results with clinical affective symptomatology and functionality. The inactive precursor 25(OH)D and its principal catabolite 24,25(OH)2D were measured simultaneously with a validated liquid chromatography tandem mass-spectrometry method in 170 BD outpatients and 138 healthy controls. VMR was calculated as follows: VMR=100*(24,25(OH)2D/25(OH)D). The psychometric assessment enclosed: Beck Depression Inventory-II, Hamilton Depression Rating Scale, Young Mania Rating Scale, Global Assessment of Functioning, and number of suicide attempts. We did not find a significant difference between patients and controls in the concentrations of 25(OH)D and 24,25(OH)2D. Additionally, the VMR was comparable in both groups. The calculations for the clinical parameters showed a negative correlation between the Young Mania Rating Scale and 24,25(OH)2D (r = -.154, p = .040). Based on the small effect size and the predominantly euthymic sample, further exploitation in individuals with manic symptoms would be needed to confirm this association. In addition, long-term clinical markers, and an assessment in different phases of the disease may provide available additional insights.

Cardiac surgery is a modern science in the history of medicine. The impact in cardiac disease, in term of treatment and prognosis, has made this discipline indispensable in the global health. In recent decades, the greatest investment has been dispensed in technological and material improvement, for increase the life expectancy. This surgery must address different epidemiological aspects dictated by the geography and economic-social conditions of the global populations. For this reason, it is progressively important to address the cardiac surgery accessibility disparity. Many scientific paper and international meetings have studied how cardiac surgery can increase accessibility in various countries around the world. In this review we analyze all the challenges, solutions and suggestions to make this surgery accessible to the entire global population, with the purpose to reducing the disparity across the all seven continents. For a long time, high-income countries have invested in technological capabilities and experimental advancement, not caring about unequal access in the rest of the world. We believe that it is time to reverse the growth trajectory, placing – as a priority – the accessibility and distribution of a surgical science, too significant for the right to health of all the people of the world. This is the real new challenge in cardiosurgery.

Abstract: Acute pancreatitis (AP) is a common gastrointestinal disease with high morbidity and mortality rate. Unfortunately, neither the etiology nor the pathophysiology of AP are fully un-derstood and causal treatment options are not available. Recently we demonstrated that Hepa-ranase (Hpa) is adversely involved in the pathogenesis of AP and inhibition of this enzyme ameliorates the manifestation of the disease. Moreover, a pioneer study demonstrated that As-pirin has inhibitory effect on Hpa. Another compound, which possesses a mild pan-creato-protective effect against AP, is Trehalose, a common disaccharide. We hypothesize that combination of Aspirin, Trehalose, PG545 (Pixatimod) and SST0001 (Roneparstat), specific inhib-itors of Hpa, may exert pancreato-protective effect better than each drug alone. Thus, the current study examines the pancreato-protective effects of Aspirin, Trehalose, PG545 and SST0001 in ex-perimental model of AP induced by Cerulein in wild-type (WT) and Hpa over-expressing (Hpa-Tg) mice. Cerulein-induced AP in WT mice was associated with significant rises in the se-rum levels of Lipase (X4) and amylase (X3) with enhancement of pancreatic edema index, inflammatory response, and autophagy. Responses to cerulein were all more profound in heparanase transgenic (Hpa-Tg) mice vs wild-type (WT) mice, evident by X7 and X5 folds increase in lipase and amylase levels, respectively. Treatment with Aspirin or Trehalose alone and even more so in combination with PG545 or SST0001 were highly effective, restoring the serum level of lipase back to the basal level. Importantly, a novel newly synthesized compound termed Aspirlose effectively ameliorated the pathogenesis of AP as a single agent. Collectively, the results strongly indicate that targeting Hpa by using anti-Hpa drug combinations constitute a novel therapy for this common orphan disease.

Cisplatin (CDDP), an important chemotherapeutic agent, could result in potential hepatotoxicity, but the precious molecular mechanisms remain unclear. In this study, the protective effect of ellagic acid (EA) on CDDP exposure-induced hepatotoxicity and underlying molecular mechanisms were investigated using a mouse model. Mice were randomly divided into control, CDDP model, EA100 (i.e., EA 100 mg/kg/day), and CDDP plus EA 25, 50, and 100 mg/kg/day. Mice in all CDDP-treated groups were intraperitoneally injected with CDDP 20 mg/kg/day for 2 days. In all EA co-treatments, mice were orally administrated with EA for 7 days. Our results found that, compared to the control group, CDDP treatment resulted in liver dysfunction, oxidative stress, and hepatocyte necrosis, which are effectively revised by EA supplementation in a dose-dependent manner. Meanwhile, EA supplementation inhibited CDDP-induced the elevation of caspases-9 and -3 activities in the liver tissues of mice. Furthermore, EA supplementation significantly downregulated CDDP exposure-induced the increases of NF-κB, IL-1β, TNF-α, and IL-6 proteins and mRNAs, while further upregulated the expression of Nrf2, and HO-1 proteins and mRNAs. Taken together, our results reveal that EA supplementation could ameliorate CCDP-induced liver injury in mice via the opposite regulation of Nrf2/HO-1 and NF-kB pathways.

Simple cysts (SCs) within the testes are rare in adults. The testicular SC lining comprises mesothelial cells. This report presents a case involving the accidental discovery of a castration-worthy SC in the right testis of a Japanese man in his 90s who was diagnosed with prostatic adenocarcinoma. Microscopic analysis revealed that the cystic wall was covered with flat to cuboidal mesothelial cells. Immunohistochemistry demonstrated mesothelial cell positivity for calretinin, Wilms tumor 1 (WT-1), Hector Battifora mesothelial epitope-1 (HBME-1), and cyclin-dependent kinase inhibitor p16 (p16INK4a). Notably, no human papillomavirus (HPV) in situ hybridization was detected. This report outlines an exceptionally rare instance of a simple cyst within the testis, suggesting the possibility of its origin from ectopic rete testis epithelium. This marks the inaugural documentation in the English literature of an SC within the testis found incidentally during castration for prostatic cancer.

Neonatal diffuse cutaneous mastocytosis (NDCM) is defined as the infiltration of the epidermis by a clonal proliferation of mast cells, observed at birth, without initial signs of systemic involvement. The typical driver mutation is located in the KIT gene. We report a rare case of a boy, born at term, presenting already at birth with generalized subcutaneous nodules, on the face, scalp, trunk, back, hands, and feet. The spleen, liver and inflammatory markers were normal at birth. Tryptase was significantly elevated. Bone marrow biopsy showed no mast cell involvement at age 2 months. A punch biopsy at age 2 months revealed CD117-positive cells diffusely infiltrating the skin, with subsequent DNA NGS sequencing for the formalin fixed paraffin embedded tissue (FFPE) identifying the pathogenic NM_000222.3:c.1504_1509dup; p.(Ala502_Tyr503dup) variant in the KIT gene previously associated with cutaneous mastocytosis. At 2 years follow-up, he had splenomegaly and multiple cervical, and inguinal adenopathy while the skin nodules persisted especially on the scalp with accompanying pruritus. He received oral and local sodium cromoglycate, oral antihistamines, antibiotic cream for skin infection, and iron supplementation, however compliance to treatment was relatively low. The prognosis is difficult to predict, as he developed systemic involvement, failure to thrive and mild psychomotor delay. A case aggregation of NDCM reported in the literature was performed to provide a comprehensive overview of this rare pathology, to better understand the prognosis. NDCM is a life-threatening disease with severe complications. Almost half had severe complications, such as mast hepatosplenomegaly, adenopathy, bacterial infections, mast cell leukaemia, and systemic involvement.

(1) Background: The typical transporter protein, P-glycoprotein (P-gp), has been proven to be associated with multidrug resistance (MDR). Pyxinol and 24S-Pyxinol amino acid ester derivatives had been demonstrated to be promising P-gp inhibitors for reversal of tumor MDR in KBV cells, however, their roles in MDR reversal in other tumor-resistant cells are still unclear. (2) Methods: In the present study, we synthesized 40 amino acid ester derivatives of Pyxinol and 24S-Pyxinol. The MDR reversal effects of these derivatives were evaluated in A549/Tax, MCF-7/ADR, and HCT-8/VCR cells using the CCK-8 assay. Subsequently, western blot assay, intracellular Rhodamine123 (Rh123) accumulation assay and P-gp ATPase activity assay were utilized to investigate the effects of active compound on P-gp. Molecular docking was used to predict the possible binding patterns of active compound to P-gp. Moreover, based on UPLC-Q/TOF-MS cellular metabolomics technology to identify endogenous differential metabolites and metabolic pathways associated with tumor MDR effects of the active compound. (3) Results: The results of the CCK-8 assay showed that compounds 8, 14, 16, 17, 18, 23, 25, 34, 36, 37 exhibited strong MDR reversal effect in A549/Tax, MCF-7/ADR and HCT-8/VCR cells, which were screened by reversal fold (RF) greater than 5. Among them, 10 μM of derivative 37 (new compound) showed the outstanding activity (RF: 15.31) in reversing MDR in A549/Tax cells. Compound 37 could act as a substrate for P-gp and inhibit the efflux function of P-gp by competitively binding to the binding site of antitumor drugs. Meanwhile, the molecular docking results confirmed that compound 37 was identified to under-go high-affinity binding to the drug binding site of P-gp. In addition, 14 endogenous differential metabolites and 6 metabolic pathways involved closely associated with the reversal of tumor MDR effects of compound 37 were identified. (4) Conclusions: Overall, a new candidate compound 37 (24S-3-L-threonyl-Pyxinol) could be provided for reversing tumor MDR by this study.

Suboptimal micronutrient intake in children remains a public health concern around the world. This study examined the relationship between a previously defined dietary carbohydrate quality index (CQI) and the risk of micronutrient intake inadequacy in a pediatric cohort of Spanish preschoolers. Children aged 4-5 years old were recruited at their medical center or at school, and information on sociodemographic, dietary, and life-style variables were collected through a self-administered online questionnaire. Dietary information was obtained from a validated 147-item semi-quantitative food frequency questionnaire. We calculated the CQI and categorized participants in quartiles according to their score. We assessed the intakes of 20 micronutrients and evaluated the probability of intake inadequacy using the Estimated Average Requirement cut-off point. Generalized estimating equations were used to adjust for potential confounders and account for the intra-cluster correlations between siblings. The adjusted proportions of children with inadequate intake of ≥3 micronutrients were 23%, 12%, 11% and 9% in the first, second, third and fourth quartiles of the CQI, respectively. Children in the highest quartile of CQI had 0.22-fold lower odds (95%CI 0.10-0.48) of having ≥3 inadequate micronutrient intakes than their peers in the lowest quartile. These findings reinforce the relevance of carbohydrate quality in children’s diets.

Sleep apnea is common in professional truck drivers. As undiagnosed and/or untreated sleep apnea is a risk factor for sleepiness-related traffic accidents, it should be recognized. We develop a new, simple tool to screen sleep apnea in this population. Altogether, 2066 professional truck drivers received a structured questionnaire. 175 drivers had a clinical examination and were invited to sleep laboratory studies, including cardiorespiratory polygraphy. We studied associations of different risk factors with the presence of sleep apnea. We established a new simple screening tool for sleep apnea that was compared to other existing screening tools. 1095 drivers filled in the questionnaire. 172 drivers had successful cardiorespiratory polygraphy. Full data was available for 160 male drivers, who were included in the analyses. The following five risk factors for sleep apnea formed the BAMSA-score (0 to 5): BMI>30 kgm-2, Age>50 years, Male gender, Snoring at least on one night per week and presence of Apneas at least sometimes. BAMSA showed a sensitivity of 85.7% and a specificity of 78.8% in detecting AHI≥15, when using a cut point of 4 and the ROC area was 0.823. BAMSA is a sensitive and easy-to-use tool in predicting sleep apnea in male professional drivers.

Background Total serum bile acids (TSBA), liver-spleen scan and dynamic liver functional tests, in our case the antipyrine clearance (Ap Cl), have been long adopted. The aim of our study was that of assessing whether some diagnostic tests, scarcely performed due to the novel techniques implementation, were reliable diagnostic tools. Methods Data extracted from records of two well-matched for age and gender populations was retrospectively analysed. Specifically, 17 patients with biopsy-proven chronic hepatitis were confronted with 17 subjects suffering from liver cirrhosis. Clinical, laboratory and instrumental findings, such as the Child-Pugh classification, the number connection test for evaluating hepatic encephalopathy, prothrombin time, serum albumin levels, TSBA concentration, Ap Cl determination, abdominal ultrasound and liver-spleen scan imaging as well as endoscopy features were evaluated. Results Cirrhotics showed a median concentration of TSBA increased respect to that of patients with chronic hepatitis, independently from gender, 20.1 versus 12.24 micromol/L, P= 0.0054. The median AP Cl value of the patients with liver cirrhosis was reduced confronted with that of patients with chronic hepatitis, specifically, 13.92 opposed to 18.3 mcg Ap/dL, P= 0.045. Furthermore, the median liver-spleen scan score was higher in cirrhotics than in chronic hepatitis patients, i.e., 3.47 versus 1.47, P= 0.000. The AUROCs of TSBA levels and of the liver-spleen scan scores for differentiating patients with liver cirrhosis from those with chronic hepatitis were 0.82 and 0.96, respectively. When was applied a new predictive model, combining the previous ones, the AUROC to discriminate patients belonging to the two populations was 0.98. The best cut-off of the new index was 26, with a sensitivity and specificity of 100.00% and 82.35%, respectively, correctly classifying 91.18% of the patients. Discussion Both TSBA and liver-spleen scan were high discriminant as well as their combination, while Ap Cl showed some limitations as reliable diagnostic tool. TSBA and liver-spleen scan have been too soon and unnecessarily overlooked.

Background: Influenza vaccine is a tool for preventing infection and reducing exacerbations in patients with asthma and chronic obstructive pulmonary disease (COPD). Purpose of this study is to investigate dynamics of CRP and serum cytokines (IL-2, IL-6, IL-10, IL-17) in patients with asthma and COPD, as well as to perform a correlation analysis with the clinical parameters of the disease manifestation. Methods: The study included 34 patients with asthma, 20 patients with COPD vaccinated against influenza during a period of remission from 2 to 4 weeks, both groups being under a basic maintenance therapy, and 26 healthy individuals vaccinated with the trivalent polymer-subunit vaccine Grippol® Plus, containing 5 µg of influenza virus strains and 500 µg of azoximer bromide. Results: Observing patients with asthma and COPD, during a year after the vaccination, has revealed a significant reduction in exacerbations frequency (p < 0.05) and duration (p < 0.05) of the bronchial obstructive syndrome (BF). Before the vaccination the IL-6 level in patients with asthma had a direct moderate correlation with duration of exacerbations of the underlying disease (p < 0.05), along with the number of systemic corticosteroids courses during exacerbations (p < 0.05). In 12 months after the vaccination, while assessing cytokine profile of all study groups, a significant reduction in the level of IL-6 was observed, compared to the baseline values (p< 0.05). Conclusion: Conducted analysis of immunological, clinical, and functional parameters of patients with asthma and COPD has proven for influenza vaccine to be effective in BF patients.

Ewing sarcoma (EWS) is an aggressive pediatric malignancy of the bone and soft tissues in need of novel therapeutic options. To identify potential therapeutic targets, we focused on essential biological pathways that are upregulated by EWS-FLI1, the primary oncogenic driver of EWS, including mitotic proteins such as Aurora Kinase A (AURKA), Kinesin Family Member 15 (KIF15) and its binding partner, targeting protein for Xklp2 (TPX2). KIF15/TPX2 cooperates with KIF11, a key mitotic kinesin essential for mitotic spindle orientation. Given the lack of clinical grade KIF15/TPX2 inhibitors, we chose to target KIF11 (using SB-743921) in combination with AURKA (using VIC-1911), given phosphorylation of KIF15S1169 by Aurora A is required for its targeting to the spindle. In vitro, the drug combination demonstrated strong synergy (Bliss score ≥10) at nanomolar doses. Colony formation assay revealed significant reduction in plating efficiency (1-3%) and increased percent accumulation of cells in G2/M phase with the combination treatment (45-52%) upon cell-cycle analysis indicating mitotic arrest. In vivo studies in EWS xenograft mouse models showed significant tumor reduction and overall effectiveness: drug combination vs vehicle control (p≤0.01), SB-743921 (p≤0.01) and VIC-1911 (p≤0.05). Kaplan-Meier curves demonstrated superior overall survival with the combination compared to vehicle or monotherapy arms (p≤0.0001).

Polycystic ovary syndrome (PCOS) is an insulin resistant state, compensated by hyperinsulinemia. More than 50% of the women with PCOS are obese, and/or have metabolic syndrome. Weight loss improves both metabolic and reproductive outcomes. Not only the energy content, but also the nutrient composition of a diet may be important. This article will present a series of studies from our research comparing effects of dietary protein vs. simple-carbohydrates (CHO). Results of the acute challenge studies demonstrate that simple-CHO intake causes reactive hypoglycemia in one third of the women with PCOS, especially among obese and insulin resistant individuals. Symptoms of hypoglycemia are associated with secretion of cortisol and adrenal androgens. Simple-CHO suppresses the hunger signal ghrelin for a shorter period. During weight loss, women who receive protein supplementation achieve larger amounts of weight- and fat-mass losses. Amino acid compositions of the protein supplements do not affect the improvements in weight and insulin resistance. It is plausible that simple-CHO intake leads to weight gain, or interferes with weight-loss, by causing reactive hypoglycemia, triggering adrenal steroid secretion, and leading to snacking. Since obese women with PCOS are more susceptible to reactive hypoglycemia, a vicious cycle establishes. Restriction of simple-CHO may break this cycle.

Recent successes in the field of evolutionary cancer cell biology (ECCB) have brought to a head two of the most important controversies regarding cancer origin. The first concerns the question of whether carcinogenesis is initiated only by genetic alterations, mutations, and driver genes, as the mutational theory teaches. The ECCB, claims that a large number of polyploidy-related cancers (PGCC cancers) are not due to mutations, but rather to inadequate ancient repair mechanisms used by DNA-damaged stem cells for their repair. Somatic mutations are merely secondary. The second controversy, described in the previous article, concerns the non-mutational theory itself: Are non-mutational polyploid cancers an atavism - as previously thought - or rather the effect of an ancient gene regulatory network aGRN that controls genome reprogramming in precancerous DNA-damaged cells as well in the transformed cells. Finally, the unicellular gene module of cancer, of which the aGRN is a part, has evolved along with the multicellular genome during the last 1000 My of evolution. and non-mutated cancer cell systems are under the control of the aGRN. The atavistic theory relies on phylostratigraphic evidence to determine the age of cancer genes. It states that most cancer-like genes arose during the transition period from unicellularity to multicellularity, but also during the early metazoan era. In our opinion, the atavistic theory is flawed and suffers from many misunderstandings. It provides little insight into the origin and coevolution of the cancer cell system and its control by the ancient gene regulatory network aGRN.

Keywords: bariatric surgery, sleeve gastrectomy, Roux-en-y gastric bypass, obesity, microbiota, gut-brain axis, beck scale, depression, diet, probiotics

The Peripheral giant cell granuloma (PGCG) is an asymptomatic, non-neoplastic and proliferative lesion of unknown etiology. Some possible pre-disposing factors such as hormonal changes dur-ing pregnancy, have been suggested. However, the association between PGCG and pregnancy is controversial. There are few reported clinical cases of pregnancy-associated PGCG in the litera-ture, and they occurred only in the lower jaw. The present report is on a 35-year-old female pa-tient at 36 weeks of gestation who presented with a PGCG in the central and lateral incisors of the upper jaw. The management consisted of surgical excision, along with curettage of the affected bony walls. The diagnosis was based on clinical results and imaging examinations, and it was histopathologically confirmed. The patient underwent postoperative follow-up evaluations at 3, 6 and 12 months, and there were no signs of recurrence.

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by isolated thrombocytopenia caused by both immune-mediated platelet destruction and impaired platelet production in the bone mar-row, in the absence of any other identifiable cause of low platelets count. ITP in adult patients is a disease that frequently relapses and/or becomes refractory to multiple treatments during its course, with only a small minority of adult patients attaining a sustained complete remission off-therapy. Treatment of refrac-tory ITP can be challenging, due to the unlikeliness of attaining complete response over time. On the other hand, isolated thrombocytopenia may be due to a misdiagnosed clonal myeloid disorder, such as myelodys-plastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML), thus mimicking ITP. We here per-form a narrative review on the association between ITP and MDS/CMML and the possibility of overlap and misdiagnosis between these conditions, while we report also the case a patient treated for a severe re-fractory thrombocytopenia which bone marrow examination led to suspect an overlap of MDS and ITP. Our clinical case describes ITP which is refractory to glucocorticoids, high-dose immunoglobulins, Rituxi-mab, splenectomy, thrombopoietin receptor agonists and Fostamatinib, that ultimately attained a short-lived response to a hypometylating agent that was initiated due to bone marrow examination that aroused the suspect of MDS.

Lymphangioleiomyomatosis (LAM) is characterized by lung cysts that cause lung deterioration, changes in the lymphatic system, and tumors in the kidneys. It mainly affects women of reproductive age and is a progressive disease. LAM can occur as an isolated disease or coexist with tuberous sclerosis (TSC). The source of LAM cells is unknown. Patients with confirmed LAM should be treated with an mTOR inhibitor, sirolimus, or everolimus. We present a case of LAM with TSC in a patient whose symptoms, including lymph nodes and chyaloperitoneum, mainly concern the abdominal cavity.

The oncogenicity of the human cytomegalovirus (CMV) is debated to this day. In recent years, mounting evidence addresses an anti-cancer effect via T cell-mediated CMV-targeted tumor de-struction. However, the data mostly comes from single-center studies and in vitro experiments. Broad geographic coverage is required to offer a global perspective. This study examined the correlation between country-specific CMV seroprevalence (n=73) and age-standardized inci-dence rates for 34 tumors using data obtained from the International Agency for Research on Cancer of the World Health Organization. The association between CMV and cancer incidences in 10-year age increments was also analyzed. The study revealed a worldwide inverse correlation between CMV seroprevalence and incidences of 88.2% tumors. Notably, this inverse link persists for all cancers combined (Spearman’s ρ= -0.732, p= 0.001). An antithetical and significant correlation is also observed in particular age groups for the vast majority of tumors. Our results corroborate the conclusions of previous studies and indicate that this phenomenon holds true on a global scale. It applies to a wide spectrum of cancer histologies, suggesting a common under-lying mechanism – CMV-stimulated T cell tumor targeting. Although these results further advance the notion of CMV-based therapies, further in-depth investigation of host-virus interactions is warranted.

Starvation of photoreceptors induced by reduced dysregulated ocular blood flow (OBF) is proposed as a common pathway for pathogenesis of retinitis pigmentosa (RP). The current study evaluated the safety and efficacy of ophthalmic nerve stimulation (ONS) as an OBF neuromodulator, combined with ascorbic acid (AA) as a potent anti-oxidant in treatment of RP. Additionally, the initial characteristics of rod responders were identified. Forty participants with simple RP, were enrolled in a prospective open-label intervention. The severity of the disease was clinically graded into five stages. Patients with established diagnosis of RP; aged ≥ 4 years, with BCVA ≥ 20/400 were included. All participants were daily treated with bilateral ONS sessions combined with systemic AA for two weeks. The primary efficiency endpoint was 6 months’ changes in scotopic vision as measured by a 10-items, 100 points, Low Luminance Questionnaire- (LLQ-10). The secondary efficiency points included best corrected visual acuity (BCVA) and contrast sensitivity (CS). Rod responders were defined by ≥ 25points increment of LLQ-10 score. The results showed that ONS combined with AA treatment significantly improved night vision, BCVA and CS in patients with RP. At 6-month visit, twenty-four (60%) patients were identified as rod responders and 16 (40%) patients were non-responders. The mean change in LLQ-10 score was (46.35 ±16.81) in rod responders versus (4.9 ± 7.6) in non-responders (P < 0.0001). A clinically significant improvement of BCVA (≥0.2 logMAR) and CS (≥0.3 log unit) were demonstrated in 44.4% and 56.1% of eyes of rod responders respectively. Collectively, this study sheds light on determinants of rod responsiveness which include patients’ age, duration of night blindness and the stage of RP. It also highlights two therapeutic scenarios; an early disease -modifying intervention that restore night vision and reverse the disease process and a late cone rescue intervention that improve/maintain central vision.

Extreme cytoreductive surgery (eCRS) may sometimes be required to achieve complete cytoreduction, which is one of the most important prognostic factors. This study investigated the impact of eCRS on survival and peri-postoperative outcomes. Malignant peritoneal mesothelioma (MPM) patients who underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) were retrospectively examined. Patients who underwent CRS-HIPEC were divided into eCRS and less extensive CRS (leCRS) groups. Resection of ≥5 organs or ≥3 small bowel anastomoses was defined as eCRS. Survival and perioperative outcomes of both groups were compared.In the study including 31 patients, eCRS-HIPEC was used in 15 patients. Complete cytore-duction (CC score 0/1) was achieved in all 31 patients. Compared with LeCRS, mean length of stay, length of stay in the intensive care unit, mean peritoneal cancer index (PCI), and intraoperative blood loss were higher in the eCRS group. Additionally, the risk of developing complications was observed to be more frequent and the duration of surgery was longer. Rates of serious complications and morbidity were similar in patients undergoing eCRS compared with leCRS. In patients with high PCI and multiple organ involvement, complete cytoreduction can be achieved by performing eCRS and equivalent survival results can be achieved with low PCI..

Cryosurgery has emerged as a promising method for harvesting veins, but the suitability of these cryostripped veins as grafts remains a subject of investigation. This study delves into uncharted territory by conducting an immunohistochemical analysis and exploring the molecular aspects of venous samples obtained through cryostripping. Existing literature lacks comprehensive data on the components of varicose veins' walls, particularly in relation to protein expression. Furthermore, little is known about the proliferation rate of endothelial cells within varicose veins, which we scrutinize alongside an assessment of CD34 endothelial reactivity. Materials and Methods: Our study encompassed 109 samples procured using the cryostripping method, which involves catheterizing veins with a specialized probe cooled to -85°C. Molecular profiling of the intima and endothelium was conducted using two key markers: CD34 and Ki67. Results: Immunoreactivity for CD34 was discernible across all three layers of the varicose vein walls that were excised using cryostripping. Notably, the endothelial cell layer exhibited intense and uniform positivity in 36 out of the 109 samples under investigation. In contrast, the results regarding Ki67 expression, whether pertaining to the intima or endothelium, remain inconclusive. Conclusions: Our findings advocate for the utilization of CD34 as a reliable marker to assess the morphological and molecular integrity of excised venous specimens. As the use of cryosurgery-harvested veins as grafts gains traction, this research contributes valuable insights into their potential viability for transplantation, opening new avenues for further exploration in the field of vascular surgery.

Objectives: In the context of COVID-19, patients with severe or critical illness may be more susceptible to developing secondary bacterial infections. This study aims to investigate the relationship between the use of prophylactic antibiotic therapy and the occurrence of bacterial or fungal isolates following the administration of tocilizumab in hospitalized COVID-19 patients who had previously received steroids during the first and second waves of the pandemic in Spain. Methods: This retrospective observational study included 70 patients hospitalized with COVID-19 who received tocilizumab and steroids between January and December 2020. Data on demographics, comorbidities, laboratory tests, microbiologic results, treatment, and outcomes were collected from electronic health records. Patients were divided into two groups based on the use of antibiotic prophylaxis, and the incidence of bacterial and fungal colonizations/infections was analyzed. Results: Among the included patients, 45 patients received antibiotic prophylaxis. No significant clinical differences were observed between patients based on prophylaxis use regarding the number of clinically diagnosed infections, ICU admissions, or mortality rates. However, patients who received antibiotic prophylaxis showed a higher incidence of colonization by multidrug-resistant germs compared to the subgroup that did not receive prophylaxis. The most commonly isolated microorganisms were Candida albicans, Enterococcus faecalis, Staphylococcus aureus, and Staphylococcus epidermidis. Conclusions: In this cohort of hospitalized COVID-19 patients treated with tocilizumab and steroids, the use of antibiotic prophylaxis did not reduce the incidence of secondary bacterial infections. However, it was associated with an increased incidence of colonization by multidrug-resistant organisms.

Qualitative comparative analysis (QCA) was developed by Charles Ragin in 1987 for the comparative analysis of small data sets. The method has become widespread in sociological and economic research. There are examples of successful use of QCA in the field of medicine and epidemiology. The purpose of this review is to describe the key stages of QCA with a discussion the application of this method to the analysis of medical and epidemiological data.

The purpose of this article is to highlight the new advancements in molecular and diagnostic genetic testing as well as properly classify all ovarian cancers. In this article we address statistics, histopathological classification, molecular pathways implicated in ovarian cancer, genetic screening panels and details about the genes, and also candidate genes. We hope to bring new information in the medical field as to better prevent and diagnose ovarian cancer.

Cystic Fibrosis is a chronic disease affecting multiple systems including the GI tract. Clinical manifestation in patients can start as early as infancy and vary across different age groups. With the advent of new highly effective modulators, the life expectancy of PwCF has improved significantly. Various GI aspects of CF care such as nutrition are linked to the overall improvement in morbidity, lung function, and quality of life of PwCF. The variable clinical presentations and management of GI diseases in pediatrics and adults CF should be recognized. Therefore, it is necessary to ensure efficient transfer of information between pediatric and adult providers for proper continuity of management and coordination of care at the time of transition. The transition of care is a challenging process for both patients and providers and currently, there are no specific tools for GI providers to help ensure smooth transition. In this review, we aim to highlight the crucial features of GI care at the time of transition and provide a checklist that can assist in ensuring an effective transition and ease the challenges associated with it.

Introduction: The objective of the study is to assess the failure of therapies with HFNO (High-Flow Nasal Oxygen), CPAP, Bilevel or combined therapy in patients with hypoxemic acute respiratory failure due to SARS-CoV-2 during their hospitalization. Methods: Retrospective and observational study of SARS-CoV-2 positive patients who required non-invasive respiratory support (NIRS), at the Reina Sofía General University Hospital of Murcia between March 2020 and May 2021. Results: Of 7355 patients, 197 (11,8%) were included. 95 of them failed this therapy (48,3%). We objectivated that during hospitalization in the ward the combined therapy with HFNO and CPAP had a lower failure rate overall and the highest treatment purely with Bilevel (p = 0,005). In the comparison of failure in therapy without two levels of airway pressure, HFNO, CPAP and combined therapy of HFNO with CPAP, (35,6% of patients) presented a 24,2% failure compared to those who did have two levels of pressure with Bilevel and combined therapy of HFNO with Bilevel (64,4% of patients) with 75,8% associated failure (OR: 0, 374; CI 95%: 0,203-0,688. p=0,001).Conclusions: The use of NIRS in conventional hospitalization is safe and effective in patients with respiratory failure secondary to SARS-CoV-2 infection. The therapeutic strategy with Bilevel increases the probability of failure, with the combined therapy strategy with CPAP and HFNO being the most promising option.

Background: Advances in additive manufacturing and the development of antimicrobial biopolymers facilitate the production of critical medical devices with strong and safe biocidal properties. The purpose of this study was to assess the antimicrobial efficacy, safety, and longevity of a polylactic acid-based biopolymer supplemented with a copper-based composite additive. Methods: An antimicrobial polylactic acid-based biopolymer was tested against several inoculants including Staphylococcus Aureus, MRSA, E. coli, Listeria, HCoV-229E (a SARS-CoV-2 surrogate), and HIV-1. Material safety was evaluated according to international testing standards for in vitro cytotoxicity. Results: The main findings of the present investigation showed a strong and long-lasting biocidal effect of a polylactic acid-based biopolymer embedded with a copper-based composite additive against Staphylococcus Aureus, MRSA, E. coli, Listeria, HCoV-229E (a SARS-CoV-2 surrogate), and HIV-1. Furthermore, the cytotoxicity and safety assessment of the antimicrobial biopolymer was found to be “non-toxic” and safe for human skin contact. Conclusions: The present investigation showed that the antimicrobial biopolymer exhibits strong and long-lasting biocidal properties against an array of viral and bacterial inoculants.

Purpose: Therapeutic targeting of RAF1 is promising, but it requires further investigation for the relation between clinical features and RAF1 aberrations regarding the MAPK signaling pathway in various solid tumors to realize the precision medicine. Methods: Between October 2019 and June 2023, Samsung Medical Center, 3,895 patients with metastatic cancer patients received a next-generation sequencing (NGS) using TruSight Oncology 500 (TSO500) assay as a routine clinical practice. We surveyed the incidence of RAF1 aberration including mutation (single-nucleotide variant [SNV]), amplification (copy-number variation), and fusion. Results: In 3,895 metastatic cancer patients, 77 (2.0%) had RAF1 aberrations in their tumor specimen. Of 77 patients, 44 (1.1%) had RAF1 mutations (SNV), 25 (0.6%) had RAF1 amplification and 10 (0.3%) had RAF1 fusions. Among 10 patients with RAF1 fusion, concurrent RAF1 amplification and RAF1 mutation were detected in one patient each. The most common tumor types were bladder cancer (11.5%), followed by ampulla of Vater (AoV) cancer (5.3%), melanoma (3.0%), gallbladder (GB) cancer (2.6%), and gastric cancer (2.3%). Microsatellite instability high (MSI-H) tumors were found in 5 out of 76 patients (6.6%) with RAF1 aberration, while MSI-H tumors were found only in 2.1% of patients with wild-type RAF1 cancer (p < 0.0001). Conclusion: We showed that when patients with metastatic solid cancer receive NGS test, approximately 2.0% have RAF1 aberrations in their tumor specimen.

The pharmacokinetic profile of fat-soluble vitamins A, E, K1, and D3 co-administered with liquid paraffin or water in an experimental rat model was investigated. Animals received a solution of the four vitamins orally through a probe, followed 10 minutes later by the administration of either the liquid paraffin product dissolved in water (Emuliquen Simple®) or water (control). Vitamin formulations were 20, 50, 0.30 and 0.10 mg/kg for vitamins A, E, K1, and D3, respectively. Blood samples were collected before dosing and at 0.17, 1, 2, 4, 8, and 24 hours post-dosing. Vitamin concentrations were quantified by liquid chromatography coupled with mass spectrometry. No relevant differences in the absorption of vitamins in terms of AUC0-last (area under the curve up to the last measurable concentration) or Cmax in the absence or presence of co-administration of the liquid paraffin product were observed. The difference of these parameters between the treatment groups for all vitamins was in the range of bioequivalence (≤ 20%). The liquid paraffin-based laxative product did not interfere with the absorption of vitamins A, E, K1, and D3 that are ingested in the diet, which is clinically relevant due to the high prevalence of functional constipation in children and adults.

Purpose: Glaucoma is the second leading cause of blindness, however, it remains incurable even with the appropriate treatment. Intraocular pressure (IOP) reduction is currently the only proven method to decline glaucoma progression. When medical therapy fails, surgical treatment usually arises as the solution to a better IOP control. Nevertheless, its success is compromised by frequent post-operative complications, most of them due to excessive fibrous tissue formation during wound healing process. Nanotechnology devices for glaucoma surgery can improve post-operative IOP control and reduce undesirable fibrosis. This systematic review aims to summarize some advances of nanotechnology application to ophthalmology, giving an overview about the state of the art of the nanotechnology based glaucoma drainage devices. Methods: A literature search in the PubMed/Medline database was performed using the keywords: “glaucoma surgery”, “glaucoma drainage device”, “nanotechnology”, “nanoparticles”, “nanomedicine” and “valve”. Were included articles published until March 1, 2023. A first identification of relevant articles was done through the title and abstract’s information, and a second selection was done by full-text articles assessment. Seven articles were included in this systematic review. Results: Nanotechnology-based glaucoma drainage devices included in this review promise to overcome the challenges of glaucoma surgical treatment by allowing a more effective control over post-operative scarring, a noninvasive and customized control of aqueous humour (AH) drainage while achieving optimal IOP reduction through all phases of the post-operative period. Conclusion: Despite the decreased post-operative complications and apparently enhanced biocompatibility of nano-based drainage devices, further in vivo tests and human studies are needed to evaluate cytotoxicity and corroborate the biocompatibility and efficacy showed in the initial testing results of these devices.

Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) is an acquired disease with significant morbidity that affects both children and adults. Effective tools to assess functional capacity (FC) are severely lacking which has significant consequences for timely diagnosis, assessments for patient disability benefits and assessing the impact and effectiveness of interventions. In interventional research the inability to assess FC can result in an incomplete assessment of the potential effect of the intervention. Specifically of concern is that if an intervention is effective in reducing symptom load, patients may increase their activity level to reach a pre-intervention symptom load. Thus, if FC is not accurately assessed, beneficial treatment outcomes may be missed. To address this issue, using extensive, repeated patient feedback we have developed a new questionnaire, FUNCAP, to achieve optimal FC assessment in ME/CFS patients. The questionnaire covers eight domains and activity types: A. Personal hygiene / basic functions, B. Walking / movement, C. Being upright, D. Activities in the home, E. Communication, F. Activities outside the home, G. Reactions to light and sound, and H. Concentration. Through five rounds of anonymous web-based surveys and a further test - retest validation round, two versions of the questionnaire were developed; a longer version comprising 55 questions (FUNCAP55) to improve diagnostic and disability benefit/ insurance FC assessments and a shorter version (FUNCAP27) for interventional research and less extensive FC assessments. FUNCAP may also be useful in other conditions where fatigue and PEM is present, such as Long Covid.

The scalp is a unique anatomical region with distinct challenges for reconstruction, especially in cases of melanoma excision. This study explores the utilization of the O-Z flap technique as an alternative approach for patients with melanoma, where traditional free flap reconstruction may not be feasible due to age or underlying health conditions. However, in this case, the patient had a history of angina and was unwilling to undergo a long operation due to his advanced age. This study highlights the importance of following NCCN guidelines for melanoma resection margins based on tumor thickness and underscores the value of staged resection planning to minimize deficits. This requires an individualized approach as each patient may have different circumstances (general health condition, age, compliance, etc.). So we planned a staged excision first. In the first surgery, we would resect the tumor minimally and then determine the exact size of the tumor. Then, in the second surgery, we resected it with a safety margin according to the guidelines. The O-Z flap, a local flap with an "O"-shaped defect and "Z"-shaped incision line, is introduced as a reconstructive option. The surgical procedure, advantages, and limitations of this approach are discussed. This study provides valuable insights into achieving successful scalp reconstruction while considering aesthetic outcomes and patient-specific factors.

Background: Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are the two most common subtypes within rare genetic photodermatoses, which can lead to incapacitating pain episodes. Methods: We reviewed previous and current treatment options for EPP/XLP, notably with a focus on metabolism, pharmacokinetics, mechanism of action, key clinical trial results, and limitations of Dersimelagon [MT-7117]. Results: In review of treatment modalities for EPP/XLP, Dersimelagon has demonstrated an acceptable safety profile with the ease of once-daily oral dosage. Conclusions: Dersimelagon should be a considered as a potential treatment for EPP/XLP. Ongoing studies will provide additional insights into expanding the treatment options for those suffering from EPP/XLP.

There is considerable interest in the use of doxycycline post exposure prophylaxis (PEP) to reduce the incidence of bacterial sexually transmitted infections (STIs). An important concern is that this could select for tetracycline resistance in these STIs and other species. We searched PubMed and Google Scholar, (1948–2023) for randomized controlled trials comparing tetracycline PEP with non-tetracycline controls. The primary outcome was antimicrobial resistance (AMR) to tetracyclines in all bacterial species with available data. Our search yielded 140 studies, of which three met the inclusion criteria. Tetracycline PEP had no effect on the prevalence of tetracycline resistance in Neisseria gonorrhoeae in any of the three trials or the pooled estimates. PEP did, however, have a marked effect on the tetracycline MIC distribution in the one study where this was assessed. Prophylactic efficacy was 100% at low MICs and 0% at high MICs. In the one study where this was assessed, PEP resulted in a significant increase in tetracycline resistance in commensal Neisseria species compared to the control group but no significant effect on the prevalence of tetracycline resistance in Staphylococcus aureus. The available evidence suggests that PEP with tetracyclines could be associated with selecting tetracycline resistance in N. gonorrhoeae and commensal Neisseria species.

Oxytocin (OXT), a pro-social peptide, is increasingly recognized as a potential protective substance against drug addiction. In the context of ethanol, previous researches have shown OXT properties to reduce self-administration, alleviate motor impairment in rodents, and reduce craving in humans. However, its role in behavioral sensitization, a neuroadaptive response resulting from repeated drug exposure linked to increased drug incentive, remains unexplored. OXT is also associated with modulating the Hypothalamic-Pituitary-Adrenal (HPA) axis, with corticosterone well-known as a significant factor in behavioral sensitization development. This study aimed to investigate the effects of Carbetocin (CBT), an analogue of OXT, on the expression of behavioral sensitization to ethanol and concurrent alterations in plasma corticosterone levels in male and female Swiss mice. We also aimed to confirm previous studies on OXT impact on ethanol consumption in male mice, but with a focus on CBT, using the two-bottle choice model and drinking in the dark (DID) methodology. For the sensitization study, mice received either ethanol (1.8 g/kg, ip) or saline treatments daily for 15 consecutive days, followed by treatment with carbetocin (0.64 mg/kg, ip) or a vehicle for 6 days. Subsequently, on day 22, all animals underwent an ethanol challenge to assess the expression of behavioral sensitization. Plasma corticosterone levels were measured on days 21 and 22. CBT effectively prevented the expression of ethanol-induced behavioral sensitization in both male and female subjects, with no alterations detected in corticosterone levels. In the ethanol consumption study, following an initial phase of ethanol acquisition, mice underwent a 6-day treatment with CBT i.p or saline before being reexposed to ethanol. We also found a reduction in ethanol consumption due to CBT treatment. In conclusion, carbetocin emerges as a promising and effective intervention in mitigating ethanol-induced behavioral sensitization and reducing ethanol intake, highlighting its potential significance in alcohol addiction treatment.

The Mediterranean diet (MED) is highly recommended. Medical nutrition therapy is the cornerstone of diabetes treatment. We assessed adherence to the MED, and resultant micronutrient intake and glycemic control in youth with type 1 diabetes. Twenty adolescents, median age 18 years (interquartile range: 15.5-21), median diabetes duration 9 years (7-14), using continuous glucose monitoring devices, received personalized diet regimes based on MED. At 6 months post-intervention, the caloric intake remained unchanged; however, the carbohydrate proportion was lower (p=0.058) and the intakes of some monounsaturated fats increased (p=0.049). Sodium intake exceeded the recommended daily allowance by 250% (p=0.653), before and after the intervention. For blood glucose, the percent time-in-range 70-180 mg/dL improved from 52% (38-60) to 63% (47-71) (p=0.047). The total insulin dose decreased marginally, from 0.76 u/kg (0.64-0.97) to 0.72u/kg (0.61-0.89) (p=0.067). BMI z-score and waist circumference did not change (p=0.316 and p=0.161, respectively). Diastolic blood pressure percentile decreased from 73% (68-88) to 69% (50-79) (p=0.028), and LDL cholesterol from 114mg/ dl (105-134) to 104mg/dl (96-124) (p=0.059). The Israeli Mediterranean diet screener score increased, from 8 (7-11) to 13 points (12-14) (p=<0.001). The MED-based intervention demonstrated feasibility and improvements in glycemic outcomes and in certain nutritional parameters.

Breast cancer and cardiovascular diseases (CVD) represent significant global health challenges, with CVD being the leading cause of mortality and breast cancer showing a complex pattern of incidence and mortality. We explore the intricate interplay between these two seemingly distinct medical conditions, shedding light on their shared risk factors and potential pathophysiological connections. A specific connection between hypertension (HTN), atrial fibrillation (AF), myocardial infarction (MI), and breast cancer was evaluated. HTN is explored in detail, emphasizing the role of aging, menopause, insulin resistance, and obesity as common factors linking HTN and breast cancer. Moreover, an attempt is made to identify the potential impact of antihypertensive medications and highlight the increased risk of breast cancer among those women, with a focus on potential mechanisms. A summary of key findings underscores the need for a multisystemic approach to understanding the relationship between CVD and breast cancer is also explored with a highlight for all the gaps in current research, such as the lack of clinical observational data on MI and breast cancer in humans and the need for studies specifically designed for breast cancer. This paper concludes that there should be a focus on potential clinical applications of further investigation in this field, including personalized prevention and screening strategies for women at risk. Overall, the authors attempt to provide a comprehensive overview of the intricate connections between breast cancer and cardiovascular diseases, emphasizing the importance of further research in this evolving field of cardio-oncology.

The epithelial-mesenchymal transition (EMT) is a major event in idiopathic pulmonary fibrosis pathogenesis. Here, we investigated whether growth arrest-specific protein 6 (Gas6) plays a protective role in lung fibrosis via suppression of the EMT and fibroblast activation. rGas6 ad-ministration inhibited the EMT in isolated mouse ATII cells 14 days post-BLM treatment based on morphologic cellular alterations, changes in mRNA and protein expression profiles of EMT markers, and induction of EMT-activating transcription factors. BLM-induced increases in gene expression of fibroblast activation-related markers and the invasive capacity of primary lung fi-broblasts in primary lung fibroblasts were reversed by rGas6 administration. Furthermore, the hydroxyproline content and collagen accumulation in interstitial areas with damaged alveolar structures in lung tissue were reduced by rGas6 administration. Targeting Gas6/Axl signaling events with specific inhibitors of Axl (BGB324), COX-2 (NS-398), EP1/EP2 receptor (AH-6809), or PGD2 DP2 receptor (BAY-u3405) reversed the inhibitory effects of rGas6 on EMT and fibroblast activation. Finally, we confirmed the antifibrotic effects of Gas6 using Gas6−/− mice. Therefore, Gas6/Axl signaling events play a potential role in inhibition of EMT process and fibroblast acti-vation via COX-2-derived PGE2 and PGD2 production, ultimately preventing the development of pulmonary fibrosis.

Systemic lupus erythematosus (SLE) is a chronic idiopathic autoimmune disease affecting various organs. Patients with SLE also present numerous neuropsychiatric manifestations. These neuro-psychiatric manifestations are referred to as neuropsychiatric systemic lupus erythematosus (NPSLE). Neuropsychiatric involvement in patients with SLE was first mentioned by Kaposi more than 100 years ago and is a generic term that refers to neurological and psychiatric symp-toms resulting directly from or as a complication of SLE. NPSLE affects both the CNS and PNS and can manifest as various symptoms, such as cognitive dysfunction, organic brain syndromes, delirium, seizures, headache, and psychosis. NPSLE was previously referred to as ‘lupus cerebri-tis’ or lupus sclerosis. However, these terms are no longer recommended because there is no de-finitive pathological cause for the neuropsychiatric manifestations of SLE.[2]

Tuberculosis (TB) continues to pose a global health challenge, exacerbated by the rise of drug-resistant strains. The development of new TB therapies is an arduous and time-consuming process. To expedite the discovery of effective treatments, computational structure-based drug re-purposing has emerged as a promising strategy. From this perspective, conditionally essential targets present a valuable opportunity, and the mycobactin biosynthesis pathway stands out as a prime example highlighting the intricate response of Mycobacterium tuberculosis (Mtb) to changes in iron availability. This study focuses on the re-purposing and revival of FDA-approved drugs (library) as potential inhibitors of MbtA, a crucial enzyme in mycobactin biosynthesis in Mtb conserved among all species of mycobacteria. Literature suggests this pathway to be associated with drug efflux pumps, which potentially contribute to drug resistance. This makes it a potential target for antitubercular drug discovery. Herein we utilized cheminformatics and structure-based drug repurposing approaches, viz., molecular docking, dynamics, and PCA analysis, to decode the intermolecular interactions and binding affinity of the FDA-reported molecules against MbtA. The virtual screening revealed ten molecules with significant binding affinities and interactions with MbtA. These drugs, originally designed for different therapeutic indications (4: antiviral, 3: anticancer, 1: CYP450 inhibitor, 1: ACE inhibitor, and 1: leukotriene antagonist), are repurposed as potential MbtA inhibitors. Furthermore, our study explores the binding modes and interactions between these drugs and MbtA, shedding light on the structural basis of their inhibitory potential. Principal component analysis highlighted significant motions in MbtA-bound ligands, emphasizing the stability of the top Protein-Ligand Complexes (PLCs). This computational approach provides a swift and cost-effective method for identifying new MbtA inhibitors, which can subsequently undergo validation through experimental assays. This streamlined process is facilitated by the fact that these compounds are already FDA-approved and have established safety and efficacy profiles. This study has the potential to lay the groundwork for addressing the urgent global health challenge at hand, specifically in the context of combating Antimicrobial Resistance (AMR) and Tuberculosis (TB).

Introduction: Silver nanoparticles have been extensively investigated in dental and orthopedic materials. However, the impregnation of bone graft with silver nanoparticles has been poorly investigated. Objectives: The aim of this study was to evaluate the in vitro antibiofilm activity of a bovine bone impregnated with silver nanoparticles. Methods: Bone scaffolds from cancellous bovine femur were used for the tests and impregnated with silver nanoparticles (50nm) by physical adsorption. Silver nitrate minimal inhibitory and bactericidal concentration were performed Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, Enterococcus faecalis, Acinetobacter baumannii, and Escherichia coli. Disc diffusion tests for silver nanoparticles susceptibility and quantification of biofilm production on plate and bone with sessile cell count were also performed. Results: All pathogens were susceptible to silver with low minimal inhibitory concentration (0.25 – 4 mg/L). The scaffold impregnated with silver nanoparticles presented a significant reduction in the biofilm cells for all microorganisms with a reduction of more than 3 logs in colony forming units count. Conclusion: Bone scaffolds impregnated with silver nanoparticles can significantly reduce biofilm, and it can be a strategical material to be used as an implant for different approaches.

We tested the bioactivity of a dalbavancin + heparin (DH) vs. dalbavancin (D) against biofilms of Staphylococcus aureus ATCC43300 (MRSA) and Staphylococcus epidermidis ATCC35984 (MRSE) comparing DH median value of cfu counts and metabolic activity with that obtained for D before and during storage under freezing up to 6 months. The addition of heparin to a dalbavancin lock solution did not affect its bioactivity against staphylococcal biofilms irrespective of its preservation time under freezing.

This study uses explainable artificial intelligence to analyze major predictors of poor self-rated health, dementia and their comorbidity, which include various aspects of social support. Data came from the Korean Longitudinal Study of Ageing (2016-2018), with 5527 participants aged 56 or more. The dependent variables were: (1) poor self-rated health (SRH) with 5 categories (very good, good, middle, poor, very poor); (2) dementia (no, yes); and (3) their comorbidity with 4 categories (SRH very good, good or middle, dementia no; SRH very good, good or middle, dementia yes; SRH poor or very poor, dementia no; SRH poor or very poor, dementia yes). The 49 demographic, socioeconomic and health-related predictors were included. The accuracy and area under the receiver operating characteristic curve (AUC) were compared for logistic regression and the random forest. Logistic regression and the random forest registered similar AUCs with the range of 0.80-0.87. Based on random forest variable importance, 18 out of top-20 predictors were identical for SRH, dementia and their comorbidity: previous SRH, life satisfaction - health, age, body mass index, income, chronic diseases, life satisfaction - economic, life satisfaction - overall, grandchildren alive, friendship meeting, brothers/sisters alive, class identity, children alive, social activity - friendship, education, children in weekly contact, religion and drinker. However, some variations were found among the three dependent variables, i.e., previous SRH for comorbidity (1st) and SRH (1st) compared to dementia (11th), grandchildren alive for SRH (6th) and dementia (4th) compared to comorbidity (9th), chronic diseases for comorbidity (6th) compared to SRH (10th) and dementia (10th). In terms of Shapley Additive Explanation (SHAP) values, the probability of dementia is expected to decrease by 5.57% in case a predictor grandchildren alive is included to the model. This study highlights the importance of social support for the prediction of poor self-rated health, dementia and their comorbidity. Specifically, the promotion of family support and friendship activity for elders would be vital for the prevention and management of their self-rated health and dementia.

This study presents a case report demonstrating an anomalous origin of the right subclavian artery from the aortic arch, accompanied by proximal dilation and a retro-esophageal course, characteristic of arteria lusoria and Kommerell's diverticulum. The research highlights the clinical significance of this anomaly and discusses its management strategies, emphasizing the importance of precise surgical intervention in addressing this condition.

Background: Implantation of an endovascular device disrupts the homeostatic CD31:CD31 interactions among quiescent endothelial cells, platelets, and circulating leukocytes. The aim of this study was to mask endovascu-lar stents with peptides imitating CD31, to mimic the device's surface to resemble that of a healthy vascular endothelium. Methods: Peptide design relied on established trans-homophilic sequences found within domains 1 and 2 of CD31. Subsequently, synthetic peptides were immobilized onto flat CoCr and nitinol discs and their impact on the primary human arterial endothelial cell phenotype was evaluated in vitro. Following this, clinical-grade CoCr and nitinol endovascular devices were coated with one of the peptides that demonstrated the capability to induce a pro-physiologic endothelial phenotype, implanted in the arteries of rabbits, and compared to un-coated controls. Results: Membrane-distal CD31 domains 1 and 2 peptides exhibited a distinct capability to foster a healthy endothelial phenotype in vitro. By day 7 post-aortic implantation, CoCr stents were evenly covered by whole-some endothelial cells, devoid of thrombo-inflammatory signs, in contrast to both bare metal and drug-eluting stents. At day 60, nitinol-coated flow diverters demonstrated enhanced performance in comparison to the control groups for excluding experimental carotid aneurysms, facilitating the formation of a seamless "neo-arterial" wall. Conclusion: Membrane-distal CD31 biomimetic peptides effectively camouflage the device surface, prevent-ing local reactions and promoting rapid and seamless endovascular integration.

(1) Background: The goal of the study was to evaluate psychological tolerance and health-related quality of life (QOL) in head and neck (HN) cancer patients treated with definitive accelerated radiotherapy (DART); (2) Methods: Seventy-six recurrence-free patients eligible for the study, who were treated with DART in the CAIR-2 phase III clinical study (median of follow-up=47 months), completed EORTC QLQ-C30 with H&amp;N35 module, Hospital Anxiety and Depression Scale (HADS) and Visual–Analog Scales (VAS) of pain in HN and the neck / arm area.; (3) Results: The most dominating symptoms measured with QLQ-C30 were: fatigue (44/100), sleeplessness (39/100), financial problems (38/100) and pain (32/100). Within H&amp;N35 the highest scores were reported on the subscales of sticky saliva (60/100), mouth dryness (65/100) and increased intake of painkillers (50/100). Pain (VAS) was reported by 87% (HN area) and 78% (shoulder) of the patients, with a mean score of 3/10. One-third reported depressive mood (HADS≥15 points) with an average score of 12.5/42 p. The depressed group, who smoked more as compared to non-depressed before DART (96% vs 78%) and required steroids treatment (85% vs 58%) during DART, also scored significantly worse on 23 of 35 subscales of QLQ-C30 and H&amp;N35 and experienced more intense pain (VAS). Women, and less advanced patients scored better in several aspects of the quality of life; (4) Conclusions: Patients treated with DART struggle with low quality of life and persisting treatment-related symptoms including constant pain. HNC survivors, especially those, who are depressed, may require additional psychosocial, rehabilitation and medical intervention programs..

Inflammatory bowel disease (IBD) comprises systemic inflammatory conditions primarily affecting the gastrointestinal tract, including Crohn's disease and ulcerative colitis. This research aims to analyze the clinical symptoms and pathogenesis of Dextran sodium sulfate (DSS)-induced canine IBD model, and evaluate the restorative effect of ginsenoside from a pathogenesis perspective. We established the DSS-induced canine IBD model and studied the pathological mechanisms. Additionally, we examined the therapeutic effect of ginsenosides by assessing the Canine Inflammatory Bowel Disease Activity Index (CIBDAI), C-reactive protein (CRP) levels, colonic tissue morphology, protein expression, and mucosal bacterial community analysis. Our findings revealed a total ginsenoside content of 22.7% in the ginsenoside extract. Animal experiments demonstrated that dogs with IBD exhibited decreased mental state, significantly increased CIBDAI and CRP levels, disrupted colonic epithelial tissue structure, decreased expression of mucin, tight junctions, and adherens junctions, as well as reduced diversity of the colonic mucosal bacterial community. Furthermore, correlation analysis highlighted a total of 38 bacterial strains correlated with physiological indices. Significantly, ginsenoside treatment could improve these symptoms and reverse the relative abundance of some bacterial communities. In conclusion, Alterations in the properties of the colonic mucus layer or the reduction of MUC2, its core component, in dogs with IBD can lead to bacterial penetration of the mucus layer and subsequent contact with intestinal epithelial cells, resulting in inflammation. Remarkably, ginsenoside intervention showcased the capacity to positively influence the relative abundance of bacteria and impact the colonic mucus layer properties, thereby offering promising prospects for IBD management and recovery.

Chronic Kidney Disease (CKD) is a major public health concern with an increasing proportion of sufferers progressing to renal replacement therapy (RRT). Early identification of those at risk of disease progression could be key in improving outcomes. We hypothesise that urinary liver-type fatty acid binding protein (uL-FABP) may be a suitable biomarker for CKD progression and can add value to currently established biomarkers such as urinary protein to creatinine ratio (uPCR) 583 participants with CKD 1-5 (not receiving renal replacement therapy) entered a 2-yr prospective longitudinal study. UPCR and uL-FABP were measured at baseline and CKD progression was defined as either i) a decline in eGFR of >5ml/min/1.73m2 or an increase in serum creatinine by 10% at 1-yr or ii) a decline in eGFR of >6 ml/min/1.73m2, or an increase in serum creatinine by 20% at 2-yrs or iii) the initiation of RRT. A combined outcome of initiating RRT or death was also included. Approximately 40% of participants showed CKD progression. UL-FABP predicted CKD progression at both years 1 and 2 (OR 1.01, p<0.01). Sensitivity and specificity were comparable to those of uPCR (AUC 0.623 v 0.706) and heat map analysis suggested that uL-FABP in the absence of significant proteinuria can predict an increase in serum creatinine of 10% at 1yr and 20% at 2yr. The risk of the combined outcome of initiating RRT or death was 23% higher in those with high uL-FABP (p<0.01) independent of uPCR. UL-FABP appears to be a highly sensitive and specific biomarker of CKD progression. The use of this biomarker could enhance the risk stratification of CKD and its progression and should be assessed further.

Background: Tacrolimus (TAC) effectively induces remission in refractory ulcerative colitis (UC). However, TAC therapy usually lasts for 3 months. Although azathioprine (AZA) is often used in maintenance therapy, the relapse rate remains high. Herein, we evaluated the efficacy of adalimumab (ADA) for remission maintenance in patients with UC after induction therapy with TAC. Methods: We prospectively enrolled patients with moderate-to-severe UC who achieved clinical remission after 3 months of TAC therapy with endoscopic non-mucosal healing (Cohort A). After TAC discontinuation, the remission maintenance rate for up to 1 year after starting ADA therapy was examined. We retrospectively enrolled patients with UC treated with TAC (Cohort B). Among patients in clinical remission after TAC treatment for 3 months, those who received AZA as remission maintenance therapy after TAC discontinuation constituted the AZA group. Patients in Cohort A who received ADA and AZA as remission maintenance therapy after TAC discontinuation constituted the ADA group. We compared the remission maintenance rates in AZA and ADA groups for up to 5 years after TAC discontinuation. Results: In Cohort A, of the 46 patients with UC treated with TAC, 17 were eligible for analysis after receiving ADA as remission maintenance therapy. A notable 88.2% (15/17) were still in remission 1 year after starting ADA. The ADA group (n=16) exhibited a significantly higher relapse-free rate than the AZA group (n=26) (p<0.05; log-rank test). Conclusion: Switching to ADA for remission maintenance in patients with refractory UC who achieved clinical remission with TAC is clinically useful.

The aim of the study was to analyze the oral etiology of patients with odontogenic sinusitis (ODS）and to compare the differences in demographic data, clinical symptoms, extent of sinus involvement, bone penetration of the maxillary sinus floor (MSF) between different etiologies. A retrospective investigation was conducted on 103 patients with ODS recruited from Beijing Tongren Hospital. All enrolled patients underwent sinus CT, nasal endoscopy, and oral examination. A comparison of the patients' clinical symptoms, extent of involvement of the sinuses, and bone resorption of the MSF according to odontogenic etiologies was conducted. Follow-up was based on symptoms, clinical examination. The most common odontogenic etiologies were endo-periodontal lesions (EPL. 49.5%), apical periodontitis (AP, 32.0%) and periodontitis (PE, 8.7%). There were statistically significant differences in age (P=0.002), sex (P=0.036), inflammation involving the ethmoid sinus (P=0.037), and bone penetration of the MSF (P<0.001) between the AP, EPL, and PE groups. There were no significant differences in sinusitis symptoms (P>0.005) among patients with different odontogenic etiologies. In conclusion, EPL is a neglected oral etiology with a destructive effect on the bone of the MSF, and Should receive more attention in diagnosis and treatment.

Intramedullary fixation with elastic stable intramedullary nailing and stabilization with an external fixator are standard methods for the treatment of diaphyseal femoral shaft fractures in children. A retrospective bi-centre cohort study was carried out, including all patients between the ages of 2 and 16 years with isolated traumatic diaphyseal femur fractures, treated either with intramedullary nailing or an external fixator. In total, 57 patients (17 female and 40 male) with a mean age of 6.5 ± 2.7 years (min. 2; max. 16 years) with a mean follow-up period of 6.1 ± 4.6 months (min. 2; max. 26 months), were included in this retrospective study. 33 patients were treated with elastic stable intramedullary nailing and 24 patients, and external fixation. In total, 18 patients (32%) experienced osteosynthesis-related complications: 8 patients (24%) in the elastic stable intramedullary nailing group and 10 (42%) in the external fixation group, leading to revision surgery in 10 patients (18%). At the latest follow-up, all fractures were radiologically healed with no evidence of malangulation or malrotation (defined as &gt;20°) and full weight-bearing. There was a lower rate of complications in the ESIN group than in the external fixation group. Overall, we were unable to show a significant difference between the two methods.

Dental polymers are often advertised and selected for use in restorations based upon the flexural strength of prefabricated discs, which may not accurately reflect their performance in dental applications. The objectives of this study were, therefore, to determine whether the three-point bending (3PB) test for flexural strength would be predictive of the “crunch-the-crown” CTC test for the failure load. Three brands of polymers (Trilor, Juvora, and Pekkton) were fabricated into rectangular bars and fully contoured crowns (10 specimens of each polymer brand, 30 specimens of each shape). Bars were tested in 3PB to determine flexural strength, and crowns were CTC tested to determine failure load after luting to resin abutments. Statistical significance was evaluated by one-way ANOVA ( = 0.05) and Pearson’s correlation coefficient. The fracture mechanisms were characterized by scanning electron microscopy (SEM). There were significant differences (p < 0.05) in the mean crown failure loads (Trilor [7,033 N] > Juvora [5,217 N] > Pekkton [3,023 N]) and mean flexural strengths of the bars (Trilor [468 MPa] > Juvora [197 MPa] = Pekkton [192 MPa]). There were no correlations between flexural strength and failure load. The mode of crown fracture was different between the polymers, and included deformation (Juvora), ductile-to-brittle fracture (Pekkton), and a combination of cracks and deformation (Trilor). The flexural strength was not correlated with the corresponding crown failure load. Dental practitioners should not rely on the value of flexural strength obtained from the three-point bending test, as advertised from the manufacturer, to predict the performance of polymeric crowns.

The emergence of M. tuberculosis strains resistant to Isoniazid (INH) and Rifampicin (RIF), the two most potent drugs of first-line anti-TB therapy is termed multidrug drug-resistant TB (MDR-TB). Multidrug-resistant tuberculosis has been a serious medical and epidemic problem all over the world. We present here a series of clinical cases consist of two patients diagnosed with isoniazid resistant tuberculosis. Histopathological examination supports the diagnosis of tuberculous granulomas. And the pathology molecular examination revealed the presence of Isoniazid-resistant Mycobacterium tuberculosis1,2 via the following mutation c.947G&gt;A; p.Gly316Asp. Isoniazid-resistance is associated with mutations in the furA-katG and fabG1-inhA operons, as well as mutations in the ahpC gene. 64% of the isoniazid-resistance phenotypes were associated with the katG315 mutation worldwide. The second most common mutation is inhA-15, and it has been reported in 19% of the Isoniazid-resistant isolates. The significant association between the two mutations, inhA c-15 and katG 315 respectively, and the high-level resistance is of interest in the interpretation of current and future molecular diagnostic testing, as an early prediction of the level of Isoniazid-resistance is essential to decide the benefit of high-dose Isoniazid use.

Leber’s hereditary optic neuropathy (LHON) is a common mitochondrial genetic disease, causing irreversible blindness in young individuals. Current treatments are inadequate, and there is no definitive cure. This study evaluates the effectiveness of delivering wildtype human NADH ubiquinone oxidoreductase subunit 4 (hND4) gene using mito-targeted AAV(MTSAAV) to rescue LHOH mice. We observed declining pattern electroretinograms amplitudes as mice aged across all groups (P&lt; 0.001), with significant differences among groups (P = 0.023, Control vs. LHON, P = 0.008; Control vs. Rescue, P = 0.228). Inner retinal thickness and intraocular pressure do not change significantly with age or groups. Compared to LHON mice, those rescued with wildtype hND4 exhibit improved retinal visual acuity (0.29± 0.1 cy/deg vs.0.15 ± 0.1 cy/deg) and increased functional hyperemia response (effect of flicker, P&lt;0.001, effect of Group, P=0.004; Interaction Flicker x Group, P&lt;0.001). Postmortem analysis shows a marked reduction in retinal ganglion cell density in the LHON group compared to the other groups (Effect of Group, P&lt;0.001, Control vs. LHON, P&lt;0.001, Control vs. Rescue, P=0.106). These results suggest that MTSAAV-delivered wildtype hND4 gene rescues, at least in part, visual impairment in an LHON mouse model and has the therapeutic potential to treat this disease.

Rhabdomyosarcoma is a cancer arising from arrested myogenic differentiation, seen mainly in children or adolescents. Metastatic rhabdomyosarcoma is often fatal even with aggressive cytotoxic chemotherapies, surgery, and irradiation. SALIQ is an acronym for a multidrug augmentation regimen designed as an adjunct to current rhabdomyosarcoma chemotherapies. SALIQ uses five common non-oncology drugs, repurposed from general medicine use, to promote malignant clone maturation and inhibit rhabdomyosarcoma growth. The five drugs are: the cholesterol lowering drug simvastatin, the acne medicine tretinoin (ATRA), the psychiatric drug lithium carbonate, the antifungal drug itraconazole, and the food supplement quercetin. All five drugs are in common use for non-cancer conditions, are cheap, have an eminently safe side effect profile, and all five have preclinical evidence and good rationale for inhibiting rhabdomyosarcoma growth.

Spinal cord injuries (SCI) can result in sensory and motor dysfunctions, which were long-considered permanent. Recent advancement in electrical neuromodulation has been proven to restore sensorimotor function in people with SCI. These stimulation protocols, however, were mostly invasive, expensive, and difficult to implement. In this study, transcutaneous electrical stimulation (tES) was used to restore over-ground walking of an individual with 21 years of chronic paralysis from a cervical SCI. After a total of 66 weeks of rehabilitation training with tES, which included standing, functional reaching, reclined sit-up, treadmill walking and active biking, significant improvement in lower-limb volitional movements and overall light touch sensation were shown by International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) score. By the end of the study, the participant could walk in a 4-meter walking test with the aid of a walking frame and ankle foot orthoses. The success in the sensorimotor recovery of our study participant sheds light on the future of non-invasive neuromodulation treatment for SCI paralysis.