Antimicrobial resistance (AMR) due to community carriage of antibiotic-resistant bacteria is highly prevalent in the WHO South-East Asia region. One of the major reasons is the misuse of antibiotics in animal farming practices and at community level, which threatens both human and animal health. However, this multifaceted One Health (OH) problem of antibiotic use (ABU) in poultry farms and respective farmers is not well studied in countries like Pakistan. Therefore, we conducted n OH cross-sectional study in rural Punjab to explore the current practices of ABU in poultry and poultry farmers, associated factors, their healthcare-seeking behaviour and biosecurity practices. We found all the participating farmers using antibiotics for poultry, 60% of which were Colistin sulphate and Amoxicillin trihydrate. The significant consumption of antibiotics in poultry farms (60%) and poultry farmers (50%) was without prescription. Most of the farms (85%) had no wastewater drainage system, causing direct shedding of poultry waste and antibiotic residue in the surrounding environment. Lack of farmers’ education, professional farm training and duration of farming experience were the significantly associated factors with ABU and knowledge of AMR. Our study implies the necessity of an integrated OH-AMR policy with the inclusion of farmers’ education, mass awareness, and strict antibiotic usage guidelines.

The objective of this study was to compare the mental well-being of French women who were and were not pregnant during the first COVID-19 pandemic lockdown. We performed a nationwide online quantitative survey including all women between 18 and 45 years of age during the second and third weeks of global lockdown (March 25–April 07, 2020). The main outcome measures was the mental well-being measured by the Warwick-Edinburgh Mental Well-Being Scale (WEMWBS). This study analysed 275 responses from pregnant women and compared them with those from a propensity score–matched sample of 825 non-pregnant women. The median WEMWBS score was 49.0 and did not differ by pregnancy status. Women living in urban areas reported better well-being, while those with sleep disorders or who spent more than an hour a day watching the news reported poorer well-being. During the first lockdown in France, women had relatively low mental well-being scores, with no significant difference between pregnant and non-pregnant women. More than ever, health-care workers need to find a way to maintain their support for women’s well-being. Minor daily annoyances of pregnancy, such as insomnia, should not be trivialised because they are a potential sign of poor well-being.

Asbestos-related risks have been estimated on the basis of data from the past, when professional exposures were higher. Fibers are present in the environment due to erosion of surface deposits and human activities unrelated to asbestos industry. If searched for, asbestos fibers are frequently found at autopsies. Bias can be encountered in asbestos research e.g. attributing of mesothelioma and lung cancer to asbestos when fibers are present, although cause-effect relationships remain unproven. Some studies rely on work or residence histories of questionable reliability. Asbestos is banned in some countries while others are increasing production and exports. Asbestos is a low-cost material and an excellent reinforcing fiber. Different asbestos types have their technical advantages and preferred application areas. The traffic is safer with asbestos-containing brake linings. Asbestos cement constructions are sturdy and inexpensive. The fireproofing properties of asbestos are well known. It can be reasonably assumed that the non-use of asbestos-containing brakes, fireproofing and insulation lagging has increased the damage and numbers of victims of traffic accidents, fires and armed conflicts. Nowadays, when a probability of conflicts seems to be enhanced, the attitude to asbestos should be changed. Most importantly, asbestos-related science must be separated from economical and political interests. Reliable information can be obtained in lifelong bioassays.

Introduction Hydroxychloroquine (HCQ) is an antimalarial agent that has been tried out in the treatment of COVID-19, however, evidence of efficacy remains limited. Although Hydroxychloroquine overdose is not common, growing cases of poisoning with HCQ have been reported during recent years. HCQ toxicity is characterized by life-threatening symptoms which require immediate medical intervention. This report presents a suicide attempt in a hyperglycemic patient, massive ingestion of HCQ manifested by hypokalemia and acidosis.Case summaryA 47-year-old man presented at the hospital hours after massive ingestion of HCQ (100 tablets), with generalized weakness and dizziness which had led to a fall. He was drowsy and had experienced episodes of nausea/vomiting. His past medical history was remarkable for uncontrolled diabetes mellitus, confirmed by the blood glucose of 345 mg/dL, and a previous history of hospitalization a few months ago, due to a suicide attempt. He developed marked hypokalemia accompanied by acidosis, plasma potassium of 2.8 mmol/L and pH 7.34, and hypotension, blood pressure of 80/51 mm Hg, but survived with close cardiac monitoring and immediate intervention including aggressive potassium replacement, bicarbonate infusion, and charcoal administration. ConclusionConsidering the significantly increased off-label use of HCQ during the COVID-19 pandemic, this report alerts the potential for HCQ to be associated with severe electrolyte disorders, especially in predisposing conditions like diabetes. Clinicians should keep in mind the possibility of hypoglycemia in diabetic patients under hypoglycemic medications and concurrent use of chloroquine/HCQ. This therapeutic approach also suggests the benefit of even a delayed activated charcoal administration in the treatment of HCQ poisoning.

Due to slow progression and susceptibility to radical forms of treatment low-grade PC is associ-ated with high overall survival (OS). With the clinical progression of PC the therapy is getting more complex. The immunosuppressive tumor microenvironment (TME) makes PC a difficult target for most immunotherapeutics. Its general immune resistance is established by i.e. immune evasion through Treg cells, synthesis of immunosuppressive mediators, and defective expression of surface neoantigens. The success of sipuleucel-T in clinical trials initiated several other clinical studies that specifically target the immune escape of the tumor and eliminate the immunosuppres-sive properties of TME. In the settings of PC treatment, this can be commonly achieved with radi-ation therapy (RT). Also, focal therapies usually applied for localized PC, such as high-intensity focused ultrasound (HIFU) therapy, cryotherapy, photodynamic therapy (PDT), or irreversible electroporation (IRE) were shown to boost anti-cancer response. Nevertheless, the present guide-lines restrict their application to localized and low-grade PC. This review explains how RT and focal therapies enhance the immune response. We also provide data supporting the combination of RT and focal treatments with immune therapies.

Background: Monitoring of antibiotic prescription practices in hospitals is essential to assess and facilitate appropriate use. This is relevant to halt the progression of antimicrobial resistance. Methods: Assessment of antibiotic prescribing patterns and completeness of antibiotic prescriptions among out-patients in 2021 was conducted at the University Hospital of Kwame Nkrumah University of Science and Technology in the Ashanti region of Ghana. We reviewed electronic medical records (EMR) of 49,660 patients who had 110,280 encounters in the year. Results: The patient encounters yielded 350,149 prescriptions. Every month, 33-36% of patient encounters resulted in antibiotic prescription, higher than the World Health Organization’s (WHO) recommended optimum of 27%. Almost half of the antibiotics prescribed belonged to WHO’s Watch group. Amoxicillin-clavulanic acid (50%), azithromycin (29%), ciprofloxacin (28%), metronidazole (21%), and cefuroxime (20%) were the most prescribed antibiotics. Antibiotic prescribing parameters (indication, name of drug, duration, dose, route and frequency) were documented in almost all prescriptions. Conclusions: Extending antimicrobial stewardship to the out-patient settings by developing standard treatment guidelines, an out-patient specific drug formulary and antibiograms can promote rational antibiotic use at the hospital. The EMR system of the hospital is a valuable tool for monitoring prescriptions that can be leveraged for future audits.

Background: Given the potential for additional development to clarify a better knowledge of the overall impact of COVID-19 on the pediatric population, the clinical symptoms of SARS-CoV-2 infection in children and adolescents are still being explored. Morbidity in children is characterized by a variable clinical course. Our study's goal was to compare clinical aspects of 230 pediatric patients who tested positive for SARS-CoV-2 and were hospitalized between April 2020 and March 2022. Methods: In a retrospective analysis, we compared two groups hospitalized in the infectious diseases clinical ward IX at the National Institute for Infectious Diseases "Prof. Dr. Matei Bals," Bucharest, Romania. The first group of 88 patients was admitted between (April–December 2020) and their clinical manifestations were compared with the second group of 142 children followed between July 2021 and March 2022. Results: Of 230 children, the median age was 4.5 (interquartile range 0.6-17) years, 53.9% were male. 88 (36.21%) patients (first group) were admitted during the second wave in Romania, mostly aged < 5 years old, and experienced digestive manifestations like fever (p=0.001), and diarrhoea (p=0.004). The second group experienced different clinical signs when compared with the first group, with higher temperature and increased respiratory symptoms analogous to those of acute respiratory viral infections. The proportion in the second group increased, and 64.5% had symptoms for a median interval of 5 days; age (0-4 -years old) and length of stay were both proportionally inversely (p<0.01) and with correlation with hospital admission (p = 0.04). We report two Paediatric Inflammatory Multisystem Syndrome (PIMS) in the second group, with favourable evolution under treatment. Comorbidities were risk factors for complications appear (p < 0.001) in both groups. All paediatric cases admitted to our clinic evolved favourably and no death was recorded. Conclusions: In the first group children experienced digestive symptoms, whereas the second group experienced mild and moderate respiratory symptoms. We confirmed risk factors for severe cases as manifestations across the age spectrum, 0-4 (digestive symptoms) and 5-12 years old (for respiratory symptoms), associated comorbidities, fever, and male gender. The potential effects of COVID-19 infection in children older than 5 years should encourage caregivers to vaccinate and improve the prognosis among pediatric patients at risk.

Echinocandins selectively inhibit fungal cell wall synthesis and, therefore, have few side effects. However, there are reports of hemodynamic and cardiac complications. We conducted this study to investigate the effects of caspofungin both on the noninvasive echocardiographic indices of myocardial function and on myocardial injury based on serum high-sensitivity cardiac troponin I (hs-cTnI) levels. This study was conducted on patients treated for candidemia. The hs-cTnI level and echocardiographic parameters were measured before and 1 hour after the infusion of the induction dose of caspofungin. Data were compared between central and peripheral venous drug administration routes. Fifteen patients were enrolled in the study. There were no significant differences in the echocardiographic parameters between the baseline and post-treatment period. The mean hs-cTnI level exhibited a significant rise following drug administration (0.24 ± 0.2 vs 0.32 ± 0.3; P = 0.006). There was also a significant difference concerning the hs-cTnI level between central and peripheral venous drug administration routes (P = 0.034). Due to differences in the hs-cTnI level, it appears that the administration of caspofungin may be associated with myocardial injury. Our findings also showed a higher possibility of cardiotoxicity via the central venous administration route.

Molecular mimicry between human and microbial/viral/parasite peptides is common and for a long time is associated with the etiology of autoimmune disorders provoked by exogenous pathogens. Increasing evidence accumulated from the past years suggests a strong correlation between the SARS-CoV-2 infection and autoimmunity. The article analyzes the immunogenic potential of the peptides shared between SARS-CoV-2 spike glycoprotein (S-protein and antigens of human endocrinocytes involved in most common autoimmune endocrinopathies. Totally the study revealed 14 pentapeptides shared by S-protein of SARS-CoV-2 and autoantigens of thyroid, pituitary, adrenal cortex and Langerhans’ islets beta-cells, 12 of them belong to immunoreactive epitopes of SARS-CoV-2. The discussion of the data links the results with clinical correlates of COVID-associated autoimmune endocrinopathies. Most common of them is an autoimmune thyroid disease, so the majority of shared pentapeptides belong to marker autoantigens of this disease. Most important in pathogenesis of severe COVID-19, according authors’ opinion, can be autoimmunity against adrenals, because their adequate response prevents from excessive systemic action of inflammatory mediators which cause cytokine storm and hemodynamic shock. The criticism of antigen mimicry concept is given with a statement that peptide sharing is not a guarantee, but just a prerequisite of autoimmunity excess provocation. The last event occurs in carriers of certain HLA haplotypes and in case when shared peptide is used in antigen processing only [1 figure, 5 tables, bibliography 38 references].

Background: Pharmacologic and non-pharmacologic treatments for stroke are essential but could be costly or harmful whereas probiotic has been a promising alternative. This scoping review aimed to synthesize the in vitro and in vivo evidence of probiotics on stroke-related neurological, biochemical, and histochemical outcomes. Method: We searched in PubMed, Embase, and Cochrane Central Register of Clinical up to May 7, 2021, and screened by two independent reviewers. We included the use of probiotics, prebiotics, and symbiotics both in vitro and in vivo for the prevention or treatment of the stroke-related model. Result: Of 6,293 articles, 4,990 passed the initial screen, of which 36 theme-related full-texts were assessed and 13 were included in this review. Probiotics could ameliorate the neurological deficit and show their property as an anti-inflammation and anti-oxidative stress. Histopathologically decreased loss of cerebral volume and inhibition of neuronal apoptosis were found. Conclusion: There are potential cognitive benefits of probiotic supplementation, especially among animal models, on decreasing cerebral volume, increasing neurological score, and decreasing the inflammatory response. However, further investigation is needed to validate these conclusions in various populations.

Background: Human epidermal growth factor receptor 2 (HER-2) overexpression can be found in 15-20% of breast cancers, and it strongly correlates with aggressive clinical behavior and adverse prognosis. The first-line treatment for HER-2 positive metastatic breast cancers is the combination of trastuzumab, pertuzumab, and taxane (PTH). ABP 980 is a biosimilar of the innovator trastuzumab and is characterized by highly comparable effectiveness. Methods: The group of 61 patients with HER-2 positive MBC received biosimilar ABP 980 plus pertuzumab and docetaxel from November, 18, 2018 to December, 24, 2019. The response to therapy, overall survival (OS), progression-free survival (PFS), metastases, and adverse effects among patients were determined and analyzed. Results: Initially, 42 women responded partially to the treatment and their median PFS was 27 months. Median PFS for the whole group was 18 months. Cardiotoxicity of treatment was noticed in all patients in the form of the reduction in left ventricular ejection fraction but only in 2 cases, it was the reason for withdrawing from therapy. Conclusion: Biosimilar ABP 980 is registered in the same indications as the innovator trastuzumab and their effectiveness, as well as side effects, are comparable. The costs of biosimilar make the therapy more accessible and thus more patients with MBC around the world can receive relevant treatment.

Abstract Background and Objective: Medical Microwave Radiometry (MWR) is used to capture the thermal properties of internal tissues and has usages in breast cancer detection. Our goal in this paper is to improve classification performance and investigate automated neural architecture search methods. Methods: We investigate optimizing the weights of a weight agnostic neural network using bi-population covariance matrix adaptation evolution strategy (BIPOP-CMA-ES) once the topology is found. We compare it against a weight agnostic and cascade correlation neural network. Results: The experiments are conducted on a breast cancer dataset of 4912 patients. Our proposed weight agnostic BIPOP-CMA-ES model achieved the best performance. It obtained an F1-score of 0.9225, accuracy of 0.9219, precision of 0.9228, recall of 0.9217 and topology of 153 connections. Conclusions: The results are an indication of the potential of MWR utilizing a neural network-based diagnostic tool for cancer detection. By separating the tasks of topology search and weight training, we are able to improve the overall performance.

Despite of over 20 years of community directed treatment with ivermectin (CDTI), a high prevalence of onchocerciasis and onchocerciasis-associated epilepsy were observed in rural villages in Mahenge, Tanzania. Therefore, we assessed the knowledge, attitude and practice about onchocerciasis in four rural villages in the Mahenge area. This was a qualitative study conducted between June and July 2019. Eleven focus group discussions were organized with persons with epilepsy and their caretakers, community resource persons, and community drug distributors (CDDs), and two in-depth interviews with district programme coordinators of neglected tropical diseases (NTD). Most participants were aware about symptoms of onchocerciasis using local terminologies such as “ukurutu/rough dry skin” and “kuwashwa/itching”. A small proportion of people did not take ivermectin during CDTI for fear of adverse reactions such as itching and swelling. Some men believed that ivermectin may decrease libido. Challenges for high CDTI coverage included, long walking distance by CDDs to deliver drugs to households, persons being away for farming, low awareness of the disease and limited supervision by the NTD coordinators. In conclusion, ivermectin uptake in Mahenge should be optimised by continuous advocacy about the importance of taking ivermectin to prevent onchocerciasis-associated morbidity and by improving supervision during CDTI.

Spinal Cord Stimulation (SCS) is an effective and validated treatment to address chronic refractory neuropathic pain in Persistent Spinal Pain Syndrome-Type 2 (PSPS-T2) patients. Surgical SCS lead placement is traditionally performed under general anesthesia due to its invasiveness. In parallel, recent works have suggested that Awake Anesthesia (AA), consisting in Target Controlled Intra-Veinous Anesthesia (TCIVA), could be an interesting tool to optimize lead anatomical placement using patient intra-operative feedback. We hypothesized that combining AA with Minimal Invasive Surgery (MIS) could improve SCS outcomes. The goal of this study was to evaluate SCS lead performance (defined by the area of pain adequately covered by paraesthesia generated via SCS), using an intraoperative objective quantitative mapping tool, and secondarily to assess pain relief, functional improvement and change in quality of life with a composite score. We analyzed data from a prospective multicenter study (ESTIMET) to compare the outcomes of 115 patients implanted with MIS under AA (MISAA group) or General Anesthesia (MISGA group), or by Laminectomy under General Anesthesia (LGA group). All in all, MISAA appears to show significantly better performance in terms of patient pain coverage, as well as improved secondary outcomes. One step further, our results suggest that MISAA combined with intra-operative hypnosis could potentialize patient intraoperative cooperation and could be proposed as a personalized package offered to PSPS-T2 patients eligible for SCS implantation in highly dedicated neuromodulation centers.

The COVID-19 pandemic has had a significant impact on all facets of life and has exacerbated many challenges faced by people living with tuberculosis (TB). This study aimed to assess the health-related quality of life (HRQoL) of TB patients in Guinea during the COVID-19 pandemic. A mixed-methods study was conducted using two validated psychometric tools to assess HRQoL and qualitative interviews among TB patients enrolled in treatment at three centers in Conakry, Guinea. Multinomial logistic regression was used to identify factors associated with the deterioration of HRQoL. We included 439 participants in the study, among whom 44% and 31% experienced pain and anxiety, respectively. We found that an increase in the number of household members and the distance from participants’ residence to the health centre were significantly associated with lower HRQoL. Qualitative interviews highlighted nutritional and financial concerns which were exacerbated during COVID-19 pandemic and beliefs that the Guinean Government’s assistance plan was insufficient. This study supports the implementation of specific relief plans for TB patients which includes nutritional and psychological support, especially those whose movements are limited by travel restrictions, impeding access to TB care, reducing work opportunities and exacerbating financial needs and stress.

Celiac disease (CD) is an autoimmune disorder triggered by gluten ingestion in genetically predisposed individuals. In addition to the typical gastrointestinal symptoms such as diarrhea, bloating, or chronic abdominal pain, CD may also present a wide spectrum of manifestations, including low bone mineral density (BMD) and osteoporosis. This review aims to describe the role of CD in the development of skeletal alterations, underlying important clinical aspects and therapeutic implications. The etiopathology of bone lesions in CD is multifactorial and their management is challenging. Here, we provide gastroenterologists and orthopedics with an up-to-date overview on the link between CD and osteoporosis to improve the management of the CD condition.

Salmonellosis is a bacterial zoonosis with array of health conditions. Non-typhoidal salmonellosis (NTS) have a discrete adaptation to certain animals; in poultry, pullorum and fowl typhoid are its primary disease manifestations. The diseases are prevalent in the Nigerian poultry and have been well studied in Nigeria, but less so in the north central Nigeria (NCN). Using field sampling, laboratory methods and semi structured questionnaire in 1000 poultry farms from NCN, we explore the incidence and risk factors for the persistence of NTS infection in poultry. Approximately 41.6% of the farms have experienced NTS but only 6.3% have current infection with NTS. Farm experience of NTS moderately predicted awareness of salmonellosis. Increasing stock in smallholder farms, self-mixing of concentrate on the farm, usage of stream water, pen odour, non-adherence and partial adherence of farms to recommended poultry vaccination against pullorum and fowl typhoid, and lack of and non-adherence to biosecurity were identified risk factors that increased the odds of NTS infection in poultry. Antibiotic use practice may have reduced the isolation rate of NTS, yet NTS continues to challenge poultry farms in Nigeria. Identified risk practices must be mitigated intentionally and biosecurity and hygiene must improve to reduce the burden of NTS.

Residual dizziness after a liberating maneuver is often referred to by patients as a more disabling set of symptoms than the positional vertigo itself. This situation seems to involve more than half of subjects with labyrintholithiasis. The authors examine the hypothesis according to which residual dizziness involves subjects with labyrintholithiasis on the basis of otoconia.

Objective: Several authors have analyzed the impact of the pandemic on the incidence rates of different conditions. Our aim was to analyze the impact of the COVID-19 pandemic on primary care new diagnoses of respiratory diseases. Methods: This was an observational retrospective study performed to describe the impact of COVID-19 pandemic on primary care new diagnosis of respiratory diseases other than lung cancer. Incidence rate ratio between pre-pandemic and pandemic period was calculated. Results: We found an decrease in the incidence of respiratory conditions (IRR 0.65) during the pandemic period. When we compared the different groups of diseases according to ICD-10, we found a significant decrease in the number of new cases during the pandemic period, except in the case of pulmonary tuberculosis, abscesses or necrosis of the lungs and other respiratory complications. Instead, we found increases in new diagnoses of flu and pneumonia (IRR 2.17) and respiratory interstitial diseases (IRR 1.41). Conclusion: There has been a decrease in new diagnosis of most respiratory diseases during the COVID-19 pandemic. The real clinical impact of this situation is still unknown. Large-scale real-life studies will make it possible to evaluate the long-term true impact of COVID-19 pandemic on the respiratory diseases management.

To describe the metabolic effect of cholecystokinin and its relationship with post-bariatric sugery patients. Methodology: This is a qualitative analysis in the form of integrative literature review, the theme chosen clearly and explicitly: "What is the metabolic profile of cholecystokinin and its effect on post-bariatric sugery patients?". After formulating the guiding question, the following keywords in Portuguese, English and Spanish were chosen: "bariatric surgery", "bariatric surgery", "cirugía bariátrica"; "cholecystokinin", "cholecystokinin", "cholecystokinin"; "fome", "hunger", "hambre"; "satiety response", "satiety response", "respuesta de saciedad", "Roux-en-Y anastomosis", "anastomosis Roux-en-Y", and "anastomosis en-Y de Roux", through the combination of the controlled descriptors, Medical Subjetc Heading (MeSH) and the Health Science Descriptors (DeCS) resources, as well as the Boolean operators "AND" and "OR". In the databases Latin American and Caribbean Literature on Health Sciences (LILACS), Virtual Health Library (VHL), PubMed, Scientific Electronic Library Online (SciELO) and Google Scholar, a search for clinical trials conducted in humans from 2012 to 2022 was performed. Results: 2,038 articles were identified. The final sample of this review consisted of eleven scientific articles; of these, four were found in the VHL database, two in PubMed, and five in Google Scholar. Thus, concepts about the digestion process and the hormones involved, bariatric surgery techniques and their hormonal effects, were observed in each of the selected articles. Conclusions: Cholecystokinin, a gastrointestinal hormone, is one of the major endocrine satiety signals. It is observed that with gastroplasty, the levels of the hormone CCK are elevated; thus, besides increasing satiety, cholecystokinin aids in weight loss. Therefore, bariatric surgery is highly effective in improving the patient's quality of life

Background: When we talk about zoonoses, it is undeniable that we have a human and animal population that has been isolated in studies over time. Besides human and animal health, zoonoses also impact the economy and society. Therefore, the integration of the analysis in this area is essential to optimize resources in public health decisions. We have new challenges in public health that we need to overcome in a more comprehensive method such as One Health. For better measures in public health, the dual burden of zoonoses seems a logical way to determine the integral impact of such diseases in society and thus take better measures to prevent and reduce the impact of these diseases. Methods: We follow the guidelines for “Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). We search human and animal zoonoses on Embase, Ovid Medline, Scopus, Web of Science, and Google Scholar, from an unrestricted period until November 2021. For the search, we consider the Disability Adjusted Life Years (DALYs) for the human zoonotic burden and the animal zoonotic burden in monetary terms. A librarian collaborates to optimize the search string for the databases, and two reviewers screen eligible articles (first by title, then by abstracts, and finally, by full-text assessment.) For the analysis, we aim to convert the burden of zoonoses of all selected studies into the zoonotic Disability Adjusted Life Years (zDALYs) – including the human and animal components. Discussion: The study results will provide information on published studies that have accounted for the dual burden of zoonoses (both human and animal health aspects.) In addition, the synthesis of the available literature will address the knowledge gap in this area in order to know to what extent it is possible to convert the burden of human zoonoses to the animal burden of zoonoses and integrate them into a more comprehensive approach (dual burden of zoonoses.)

Gestational diabetes mellitus (GDM) is a common complication of pregnancy that adversely affects maternal and offspring health. A variety of risk factors, such as BMI and age, have been associated with increased risks of gestational diabetes. However, in many cases gestational diabetes occurs in healthy nulliparous women with no obvious risk factors. Emerging data suggest that the tendency to develop gestational diabetes has genetic and environmental components. Here we develop a polygenic risk score for gestational diabetes. We further investigate relationships between the genetic architecture of GDM and genetically constructed risk factors and biomarkers. Our results show that genetics can be used as an early screening tool that identifies at-risk at higher risk of GDM before its onset to propose comprehensive monitoring and preventative programs to mitigate the risks.

Background: Primary central nervous system lymphomas (PCNSLs) are sensitive to chemotherapy. Standard treatment is high-dose methotrexate (MTX)-based chemotherapy. There are no reports of successful treatment of acute uric acid nephropathy with rasburicase after MTX administration in PCNSL. Case presentation: A 54-year-old man with a history of gout presented with character change and memory loss. MRI showed a large, enhancing mass spanning the bilateral frontal lobes and right temporal lobe. After endoscopic biopsy, MTX, procarbazine and vincristine (MPV) regimen was initiated for treatment of PCNSL. After initiation of chemotherapy, the patient suffered from a gout attack and blood examination revealed acute renal failure (ARF) and hyperuricemia. The considered causes of ARF included MTX toxicity and acute urid acid nephropathy. Since a good response to chemotherapy was observed, the latter was assumed. After improvement of renal function, MTX was resumed, initiating rasburicase for control of hyperuricemia. A complete response was obtained after induction chemotherapy. Hyperuricemia was controlled with rasburicase and renal function was preserved. Conclusions: Acute uric acid nephropathy should be considered when ARF occurs after initiation of MTX in PCNSL. For newly diagnosed PCNSL patients with large tumors or hyperuricemia, upfront usage of rasburicase should be considered to prevent it.

Depression continues to be a glaring global challenge. The most worrisome trend is eating up the youthful generation more than anyone could predict years back. As Addis & Martell (2004) note, these adolescents end up succumbing to conditions that can be traced wholly from depression. Behavioral activation can be a rewarding intervention that will go a long way in cutting down on these cases and ensure the youthful global population's lives are safeguarded if applied and monitored to ensure correct and collective implementation processes and systems. The insights and arguments presented in the research paper will focus on the utility of behavioral activation in reducing depression cases among adolescents.

Poxviridae have been successful pathogens throughout recorded history, infecting humans among a variety of other hosts. Although eradication of the notorious smallpox has been a globally successful healthcare phenomenon, the recent emergence of Monkeypox virus, also belonging to the Orthopoxvirus genus and causing human disease, albeit milder than smallpox, is a cause of significant public health concern. The ongoing outbreak of monkeypox, demonstrating human-human transmission, in previously non-endemic countries, calls for critical need into further research in the areas of viral biology, ecology and epidemiology to better understand, prevent and treat human infections. In the wake of these recent events, it becomes important to revisit poxviral infections, their pathogenesis and ability to cause infection across multiple non-human hosts and leap to a human host. The poxviruses that cause human diseases include Monkeypox virus, Molluscum contagiosum virus and Orf virus. In this review we summarize the current understanding of various poxviruses causing human diseases, provide insights into their replication and pathogenicity, disease progression and symptoms, preventive and treatment options and their importance in shaping modern medicine through application in gene therapy, oncolytic viral therapies for human cancers or as poxvirus vectors for vaccines.

Penile squamous cell carcinoma (SCC) is a rare disease. Treatment options for advanced penile cancer are often limited and prognosis remains poor. We reported a 52-year-old male recurrent and metastatic penile SCC patient with high PD-L1 expression(90%) and TMB(14.4 muts/Mb). He had undergone penectomy, bilateral inguinal lymph node dissection and excision of the abdominal wall mass during two surgeries. Despite cisplatin-based concurrent chemoradiotherapy and sequential chemotherapy with docetaxel plus cisplatin were then carried out, the carcinoma still had progressed. The patient then obtained progression free survival exceeding 32 months with continuous sintilimab, although new onset of ICI-induced diabetes after 24 cycles of sintilimab and required sustained insulin treatment. He didn’t have positive type 1 diabetes associated autoantibodies, but had susceptible HLA genotype DR3-DQ2 haplotype. This is the first patient with radiation and multichemorefractory penile SCC obtained remarkable anti-tumor effect of partial regression exceeding 32 months during continuous sintilimab.

Background: Coronavirus disease 2019 (COVID-19) remains a mystery in many respects. The importance of less common life-threatening diseases is still unclear. Therefore, in this study, it was attempted to determine the frequency of nontraumatic hemothorax, chylothorax, pleural, and pericardial effusion (PCE) in patients who underwent thoracic computed tomography during the pre-pandemic and pandemic period. Materials and Methods: This retrospective study included 147 patients over the age of 18 who were admitted to the emergency department between January 1st, 2019, and December 31st, 2020. The year 2019 was taken as the pre-pandemic period and the year 2020 was the pandemic period. Comorbidity, survival, and laboratory parameters of the patients were evaluated. Results: The mean age of the 147 patients included in the study was 66.41 ± 12.81 years, 54 (36.7%) were female, and the age range was 22–88 years. The mean plasma lactate dehydrogenase (LDH) level of the patients was 373.97 ± 115.77 U/L, plasma protein was 5.45 ± 1.00 gr/dL, fluid LDH was 229.37 ± 125.73 U/L, fluid/plasma LDH was 0.60 ± 0.23, fluid/plasma protein was 0.55 ± 0.29, and the amount of fluid discharged was 562.11 ± 243.01 mL. Bilateral lung involvement was present in 72 (49%) patients, and coagulation use was present in 59 (40.1%) patients. Pleural effusion (PE) was found in 43 (76.8%) of the hospitalized patients, hemothorax in 11 (19.6%) patients, and chylothorax in 4 (7.1%) patients. However, PCE was more common in the 16 (42.1%) patients admitted to the intensive care unit (ICU) (P < 0.001). While 38 (25.9%) of the patients were admitted to the ICU, mortality was observed in 30 (20.4%) patients. Conclusion: Although PE, nontraumatic hemothorax, chylothorax, and PCE are rare in COVID-19 patients, they can cause severe inflammation and poor prognosis.

Purpose: To meet the challenges of the precision medicine era, quality assessment of shared sarcoma care becomes pivotal. The MDT approach is the most important parameter for succesfull outcome. Because of all MDTs disciplines surgery is the key step to render sarcoma patients disease free, defining the spectrum of a sarcoma surgeon is critical. To the best of the authors knowledge, a comprehensive interoperable digital platform to assess the scope of sarcoma surgery and the experience of a sarcoma surgeon in its full complexity is lacking. Methods: A web-based real-world data (RWD) registry on sarcoma surgery has been created to assess the clinical exposure, tumor characteristics, and surgical settings and techniques applied for both resections and reconstructions of sarcomas and thereby the surgical exposure of an individual surgeon over time. Results: During 10 years, there were 723 sarcoma board/MDT meetings discussing 3130 patients. A total of 1094 patients underwent 1250 surgical interventions on mesenchymal tumors by one single sarcoma surgeon. These included 615 deep soft tissue tumors (197 benign, 102 intermediate, 281 malignant, 27 simulator, 7 metastasis, 1 blood), 116 superficial soft tissue tumors (45 benign, 12 intermediate, 40 malignant, 18 simulator, 1 blood) and 519 bone tumors (129 benign, 112 intermediate, 182 malignant, 18 simulator, 46 metastasis, 14 blood and 18 sequelae of 1st treatment). Detailed types of resections and reconstructions were analyzed. Conclusion: A web-based RWD sarcoma surgeon registry with transparent real-time descriptive analytics is feasible and enables large scale definition of the surgical complexity and ultimately quality of sarcoma care.

Modern oncological therapy utilizes various types of immunotherapy. Immune checkpoint inhib-itors (ICIs), chimeric antigen receptor T cells (CAR-T) therapy, cancer vaccines and bispecific an-tibodies are improving patients’ outcomes. However, stimulation of the immune system, benefi-cial in terms of fighting against cancer, generates the risk of harm to other cells in a patient's body. Kidney damage belongs to the relatively rare adverse events (AEs). Best described, but still, su-perficially, are renal AEs in patients treated with ICIs. International guidelines issued by Euro-pean Society for Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) cover the management of immune-related adverse events (irAEs) during ICI therapy. There are scarce data concerning renal adverse drug reactions of other immunotherapeutic methods. This implicates the need for the collection of safety data during ongoing clinical trials and in the re-al-life world to characterize the hazard related to the use of new immunotherapies and manage-ment of irAEs.

Laminopathies are a spectrum of diseases caused by LMNA mutations. In familial partial lipodystrophy of Dunnigan (FPLD), LMNA plays role in the differentiation and development of adipocytes and lipid metabolism. Changes in LMNA predict not only the differentiation of adipose-derived mesenchymal stem cells (AD-MSCs) but also the transformation of cancer cells. Hence, our in-depth study aimed to identify the molecular connection between disordered lipid metabolism and hepatic carcinogenesis. We first discovered significant positive correlations between pLMNA and two key rate-limiting enzymes in de novo fatty acid synthesis, acetyl-CoA-carboxylase 1 (ACC1) and fatty acid synthase (FASN), in the liver tissue but not in adipose tissue of obese model rats. Moreover, LMNA knockdown (KD) in rat AD-MSCs prevented the differentiation and maturation of adipocytes. To clarify the mechanistic relationship with lipogenesis, gain- and loss-of-function experiments in which functional changes and the related molecular pathways were investigated in a normal hepatocyte line (7701 cells). Adenosine 5'-monophosphate activated protein kinase α (AMPKα) was found to be activated by abnormalities in the LMNA structure under conditions of LMNA deletion, farnesyltransferase inhibitor (FTI) treatment and LMNA mutations associated with clinical FPLD pathogenic phenotype. Active AMPKα could directly phosphorylate ACC1 and thus inhibit lipid synthesis but induced glycolysis in both HCC cells and normal cells. The HCC cells could not survive with LMNA knockout (KO) or even KD. Lonafarnib (an FTI) combined with low-glucose conditions significantly decreased the proliferation of HepG2 and MHCC cells by inhibiting glycolysis and the maturation of prelamin A.

Human Adenovirus (HAdV) infection occurs in 14-16% of patients in the early months after pediatric hematopoietic cell transplantation (HCT) and this correlates with a higher risk to develop HAdV disease and overall 6-month mortality. The main risk factors for HAdV infection are T-cell depletion of the graft by ex vivo CD34+ selection or in vivo use of alemtuzumab or anti-thymocyte serum, the development of grade III-IV graft versus host disease (GVHD), the type of donor (unrelated donor, cord blood, haploidentical or HLA mismatched parent) and severe lymphopenia (< 0.2 x 109/L). The prevention of HAdV disease is based on early intervention with antivirals in the asymptomatic patient when the permitted viral load threshold on blood (> 102-3 copies/ml) and/or on the stool (109 copies/g stool) is exceeded. Cidofovir, a monophosphate nucleotide analog of cytosine, is the primary drug for preemptive therapy, used at 5 mg/kg/week for 2 weeks followed by 3-5 mg/kg every 2 weeks. The alternative schedule is 1 mg/kg every other day (three times/week). Enhancing virus-specific T-cell immunity in the first months post-HCT by donor-derived or third-party-derived virus-specific T cells represents an innovative and promising way of intervention applicable both in prevention and therapeutic setting.

Multiple sclerosis (MS) and necrotizing periodontitis (NP) are two diseases whose aetiology and pathophysiology do not seem to have a common link; however, the treatment of MS with monoclonal antibodies and the decrease in humoral immunity that this entails can be a trigger or an aggravation in patients who present NP. We present a clinical case of NP in which its clinical manifestations, treatment and evolution during therapy with ocrelizumab are reflected. During the evolution of the case, a rapid progression of NP was evidenced. During her evolution, the patient suffered bilateral pneumonia due to COVID requiring treatment with corticosteroids and antibiotics, which led to clinical relief of her NP. Given this important clinical finding, we consider of great interest the regulated dental monitoring of those patients with MS before, during and after the administration of monoclonal antibodies to prevent periodontal deterioration.

Hepatitis is the eighth highest cause of mortality globally and second-highest in Pakistan. The purpose of this study was to determine frequency of Hepatitis B and C and related lifestyle and socio-demographic risk factors among adults. The data were collected though questionnaire from Hepatitis B and C patients from Mayo and Jinnah hospital Lahore. The data was analyzed using SPSS version 18. There were 5095 patients with Hepatitis B and C out of which 146 patients (67 males and 79 females) filled questionnaire. The frequency of hepatitis C was higher than hepatitis B. The significant risk factors associated with hepatitis B and C were education, marital status, family history, household income, and type of food consumed. Therefore, socio-demographic and lifestyle risk factors related interventions are needed to reduce frequency of Hepatitis B and C.

The aim of this study is to test the effectiveness and safety of AE-AE surgery combining otoendoscopy and surgical microscopy in the treatment of acquired pars flaccida cholesteatoma in stages Ib and II of the Japan Otological Society classification occupying the tympanic cavity and attic. A historical cohort study on 65 patients. Of the total, 44 patients were treated by AE-AE surgery using an otoendoscope and 21 with canal wall-up tympanomastoidectomy (CWUT). Patients in whom the AE-AE technique was performed had a lower recurrence rate (9%) compared to those treated with CWUT (38%); p=0.013. In addition, the median time to recurrence was lower in the AE-AE group (4 years [P25-75= 1.25-2-75]) than in CWUT group (2 years [P25-75= 3.25-4.75]); p=0.048. Thresholds were higher in the CWUT group compared to the AE-AE group in pre-surgery (53±16 vs 44±15; p=0.039) and post-surgery (52±18 vs 42±16 dB dB; p=0.042), but not in pre-post-surgery comparisons neither in the AE-AE technique (p= 0.89) nor in the CWUT technique (p= 0.96). We concluded that AE with otoendoscopic support is an effective and safe technique for acquired cholesteatomas occupying box and attic in stages IB and II.

(1) Background: The monkeypox virus (MPV) is a double-stranded DNA virus belonging to the Poxviridae family, Chordopoxvirinae subfamily, and Or-thopoxvirus genu. It was called monkeypox because it was first discovered in monkeys, in a Danish laboratory, in 1958. However, the actual reservoir for MPV is still unknown. (2) Methods & Results: We have reviewed the existing literature on the options for Monkeypox virus. There are three available vaccines for orthopoxviruses: ACAM2000, JYNNEOS, and LC16, with the first being a replicating vaccine and the latter being non or minimally replicating. (3) Conclusions: Smallpox vaccinations previously provided coincidental im-munity to MPV. ACAM2000(a live‐attenuated replicating vaccine) and JYNNEOS (a live‐attenuated, non-replicating vaccine) are two US FDA‐approved vaccines that can prevent monkeypox. However, ACAM2000 may cause serious side effects, including cardiac problems, whereas JYNNEOS is associated with fewer com-plications. The recent outbreaks across the globe have once again highlighted the need for constant monitoring and the development of novel prophylactic and therapeutic modalities. Based on available data, there is still a need to develop an effective and safe new generation of vaccines specific for monkeypox that are killed or mRNA before monkeypox is declared a pandemic.

Laboratory medicine is a digital science. Every large hospital produces a wealth of data each day - from simple numerical results from e.g. sodium measurements to highly complex output of “-omics” analyses, as well as quality control results and meta-data. Processing, connecting, storing, and ordering extensive parts of these individual data requires Big Data techniques. Whereas novel technologies such as artificial intelligence and machine learning have exciting application for the augmentation of laboratory medicine, the Big Data concept remains fundamental for any sophisticated data analysis in large databases. To make laboratory medicine data optimally usable for clinical and research purposes, they need to be FAIR: findable, accessible, interoperable, and reusable. This can be achieved for example by automated recording, connection of devices, efficient ETL (Extract, Transform, Load) processes, careful data governance, and modern data security solutions. Enriched with clinical data, laboratory medicine data allow a gain in pathophysiological insights, can improve patient care, or they can be used to develop reference intervals for diagnostic purposes. Nevertheless, Big Data in laboratory medicine do not come without challenges: The growing number of analyses and data derived from them is a demanding task to be taken care of. Laboratory medicine experts are and will be needed to drive this development, take an active role in the ongoing digitalization, and provide guidance for their clinical colleagues engaging with the laboratory data in research.

The blood brain barrier (BBB) is an essential component in regulating and maintaining the homeostatic microenvironment of the central nervous system (CNS). During the occurrence and development of glioblastoma (GBM), BBB is pathologically disrupted with markedly increased permeability. Due to the obstruction imposed by the BBB, strategies currently employed for GBM therapeutics still obtain a very low success rate and lead to systemic toxicity. Moreover, chemotherapy could promote pathological BBB functional restoration, accompanied with a prominent decrease of intracerebral therapeutics transportion during GBM multiple administration, resulting in chemotherapy failure for GBM treatment. The effective delivery of therapeutics into the brain still faces with severe challenges. Regulation of pathological BBB for enhanced transporting of therapeutics across the barrier may provide new opportunities for effective and safe treatment of GBM. This article reviews the structure and function of BBB in physiological state, the mechanisms underlying BBB pathological fenestration during the development of GBM, and the therapeutic strategies of GBM based on BBB intervention and therapeutic drugs transporting across the BBB.

The polygenic and multifactorial nature of many psychiatric disorders has hampered the personalized medicine approach implementation in clinical practice. However, induced pluripotent stem cell (iPSC) technology has emerged as an innovative tool for patient-specific disease modeling to expand the pathophysiology knowledge and treatment perspectives in the last decade. Current technologies enable adult human somatic cell reprogramming into induced pluripotent stem cells (iPSCs) to generate neural cells and direct neural cell conversion to model organisms that exhibit phenotypes close to human diseases, thereby effectively representing relevant aspects of neuropsychiatric disorders. iPSCs reflect patient pathophysiology and pharmacological responsiveness, particularly when cultured under conditions that recapitulate spatial tissue organization in brain organoids. Recently, the application of iPSCs has been frequently associated with gene editing that targets the disease-causing gene to deepen the illness pathophysiology and conduct drug screening. Moreover, gene editing has provided a unique opportunity to repair the putative causative genetic lesions in patient-derived cells. Here, we review the use of iPSC technology to model and potentially treat neuropsychiatric disorders by illustrating the key studies on a series of mental disorders, including schizophrenia, major depression disorder, bipolar disorder, and autism spectrum disorder. The future perspective will involve the development of organ-on-a-chip platforms that control the microenvironmental conditions to reflect individual pathophysiological by adjusting physiochemical parameters according to personal health data. This strategy could open new ways to build a disease model that considers individual variability and tailors personalized treatments.

Background: Dengue is the most common arthropod-borne sickness worldwide, impacting at least 50 million people each year. The dengue virus has four primary serotypes. Infection with one serotype confers homotypic immunity but not heterologous immunity, and secondary infections may be more severe. Although blood transfusions and organ donations have also been observed, the Aedes aegypti mosquito is the primary vector for the transmission of dengue. Infection causes a continuum of clinical illness, from asymptomatic infection to dengue fever, DHF, and dengue shock syndrome (DSS).Aim: To assess the presence of anti DENV IgG and anti DENV IgM antibodies specific to the four dengue serotypes in blood donor service donors and the importance of pre-donation screening in routine blood collection procedures.Method: 3 mL of peripheral venous blood from 507 blood donors was collected in tubes with BD vacutainer gel tube for serum separation after epidemiological records were reviewed. After that, serum was separated and tests were performed by SD Bioline Dengue Duo. Participants in the study completed a social and epidemiological questionnaire that contained information such as age, gender, and dengue diagnosis.Result: Out of the 507 blood samples that were taken, 473 (93.3%) came from male blood donors, while the remaining 34 (6.7%) belonged to female blood donors. The ratio of males to females is 13.91 to 1. The age range is 18–60 years, and the mean and standard deviation are both 27.7 and 6.5. 183 of the 507 samples produced anti DENV IgG positivity, while 324 did not. The ratio of positive to negative was 1.25:2.Conclusion: According to the findings of this study, quantitative methods for determining the presence of anti-dengue antibodies or detecting the dengue virus in blood donors in endemic areas should be devised in order to ensure the quality of blood transfusions.

Background: The use of medicinal plants and their effective compounds as natural sources that have antioxidant properties, has been considered by researchers. Antioxidants are compounds that effectively inhibit the reaction of oxygen and nitrogen-free radicals with biomolecules in a variety of ways, reducing damage or preventing cell death, cardiovascular diseases, and cancers. Objective: In this study, chemical compounds of Adiantum capillus-veneris essential oil were used to evaluate its antioxidant and antimicrobial activity using water distillation and gas chromatography. Methods: The whole plant was dried at room temperature at 25 ° C and the distillation method with water with modifications was used using a Clevenger device for essential oil extraction. Gas chromatography-mass spectrometry (GC/MS) was used to identify the resulting essential oil compounds and the antioxidant and antibacterial activity of the essential oil was evaluated. Results: The most important chemical constituents of Adiantum capillus-veneris essential oil were carvone (33.00%), carvacrol (15.05%), hexadecanoic acid (7.02%), hexahydrofarnesyl acetone (4.25%) and n-nonanal (4.2%). The antibacterial activity of Adiantum capillus-veneris essential oils (mg/ml) was calculated and the highest antibacterial activity was determined by Staphylococcus aureus (8.23±1.07), Streptococcus pyogenes (12.46±1.62), and Diphtheroid (11.37±1.36) at a concentration of 100 mg/ml of essential oils. Conclusion: The results of the present study showed that the essential oil of Adiantum capillus-veneris prevented the growth of three pathogenic bacteria. This antibacterial property is due to the presence of flavonoid compounds in Adiantum capillus-veneris has the capacity for therapeutic and medical uses.

Segmentation of brain tumor images is a major research topic in medical imaging to have a refined detection and understanding of abnormal masses in the brain. This paper proposes a new segmentation method, consisting of three main steps, to detect brain lesions using magnetic resonance imaging (MRI). In the first step, the parts of the image delineating the skull bone are removed to exclude insignificant data. In the second step, which is the main contribution of this study, the particle swarm optimization (PSO) technique is applied to detect the block that contains the brain lesions. The fitness function, used to determine the best block among all candidate blocks, is based on a two-way fixed-effects analysis of variance (ANOVA). In the last step of the algorithm, the K-means segmentation method is used in the lesion block to classify it as tumor or not. A thorough evaluation of the proposed algorithm is performed using the MRI database provided by the Kouba imaging center in Algiers, Algeria. Estimates of the selected fitness function are first compared to those based on the sum-of-absolute-differences (SAD) dissimilarity criterion and demonstrate the efficiency and robustness of the ANOVA. The performance of the optimized brain tumor segmentation algorithm is then compared to the results of several state-of-the-art techniques, including fuzzy C-means, K-means, Otsu thresholding, local thresholding, and watershed segmentation. The results obtained using Dice coefficient, Jaccard distance, correlation coefficient, and root mean square error (RMSE) measurements demonstrate the superiority of the proposed optimized segmentation algorithm over equivalent techniques.

Diabetes mellitus (DM) and obesity account for the highest burden of non-communicable diseases. There is increasing evidence showing therapeutic patient education (TPE) as a clinically and cost-effective solution to improve biomedical and psychosocial outcomes among people with DM and obesity. The present systematic review and meta-analysis presents a critical synthesis of development of TPE interventions for DM and obesity and the efficacy of these interventions across a range of biomedical, psychosocial and psychological outcomes. A total of 54 of these RCTs were identified among patients with obesity and diabetes and were thus, qualitatively synthesized. Out of these, 47 were included into quantitative synthesis. There was substantial heterogeneity in reporting of these outcomes (I²= 88.35%, Q= 317.64), with significant improvement (SMD=0.36, 95% CI: 0.23 to 0.49) noted in biomedical outcomes in the intervention group. The effect sizes were comparable across interventions delivered by different modes and delivery agents. These interventions can be delivered by allied health staff, doctors or electronically as self-help programs, with similar effectiveness (P < 0.001). These interventions should be implemented in healthcare and community settings to improve health of patients suffering from DM and obesity.

The likelihood of pre-hypertensive young adults developing hypertension has been steadily increasing over the past few years. Despite the fact that aerobic exercise training (AET) has demonstrated positive results in lowering high blood pressure, the efficacy of different types of AET among pre-hypertensive young adults has not been well-established. The objective of this study was to evaluate the effectiveness of high-intensity interval training (HIIT) and continuous moderate-intensity training (CMT) on blood pressure (BP) of physically inactive pre-hypertensive young adults. 32 adults (age 20.0±1.1 years and BMI 21.5±1.8) were randomly assigned into 3 groups: HIIT, CMT and control (CON). HIIT and CMT groups participated in 5 weeks of AET; while the CON group followed a DASH diet plan only. The HIIT protocol consisted of 1:4 minute work to rest ratio of participants 80%-85% heart rate reserve (HR-reserve) and 40%-60% HR-reserve respectively for 20-minutes, CMT group exercised at 40%-60% of HR-reserve continuously for 20-minutes. In both HIIT and CMT groups, systolic blood pressure (SBP) (3.8±2.8 mmHg, P=0.002 VS 1.6±1.5 mmHg, P=0.011) was significantly reduced. While, significant reductions in the diastolic blood pressure (DBP) (2.9±2.2 mmHg, P=0.002) and mean arterial pressure (MAP) (3.1±1.6mmHg, P<0.0005) were noted only in the HIIT group. No significant differences in SBP (-0.4±3.7 mmHg, P=0.718), DBP (0.4±3.4 mmHg, P=0.714), or MAP (0.1±2.5mmHg, P= 0.892) were observed in the CON group. Both HIIT and CMT decreased the BP in physically inactive pre-hypertensive young adults; however, HIIT yielded more beneficial results in terms of reducing the SPB, DBP and MAP.

Malaria rapid diagnosis test (RDT) is crucial for managing the disease, and the effectiveness of detection depends on parameters such as sensitivity and specificity of the RDT. Several factors can affect the performance of RDT. In this study, we focus on pfhrp2 sequence variation and its impact on RDTs targeted by antigens encoded by pfhrp2. Field samples collected during cross-sectional surveys in Tanzania were sequenced to investigate pfhrp2 sequence diversity and evaluate the impact on HRP2-based RDT performance. We observed significant mean differences in amino acid repeats between current and previous studies. Several new amino acid repeats were found to occur at different frequencies, including types AAY, AHHAHHAAN and AHHAA. Based on the abundance of types 2 and 7 amino acid repeats, the binary predictive model was able to predict RDT insensitivity by about 69 % in the study area. About 85% of the major epitopes targeted by Monoclonal antibodies (MAbs) in RDT were identified. Our study suggests that the extensive sequence variation in the pfhrp2 could contribute to reduced RDT sensitivity. The correlation between the different combinations of amino acid repeats and the performance of RDT in different malaria transmission settings should be investigated further.

Fifty years on from the classical fluid-mosaic model of Singer and Nicolson, current views of the plasma membrane portray a much more complex view of this interface region. Compartmentalization, together with transbilayer and lateral asymmetries, provide the structural foundation for functional specializations at the cell surface, including the active role of the lipid microenvironment in the modulation of membrane-bound proteins. The chemical synapse, the site where neurotransmitter-coded signals are decoded by neurotransmitter receptors, adds another layer of complexity to the plasma membrane architectural intricacy, mainly due to the need to accommodate a sizeable number of molecules in a minute subcellular compartment with dimensions barely reaching the micrometer. In this review, we discuss how Nature has developed suitable adjustments to accommodate different types of membrane-bound receptors and scaffolding proteins via membrane microdomains, and how this “efford-sharing” mechanism has evolved to optimize crosstalk or separation or coupling where/when appropriate. To this end, we use a fast ligand-gated neurotransmitter receptor, the nicotinic acetylcholine receptor, and a second-messenger G-protein coupled receptor, the cannabinoid receptor, as paradigmatic example.

Good eyesight belongs to the most-valued attributes of health, and diseases of the eye are a significant health care burden. Case numbers are expected to further increase in the next decades due to an aging society. The development of drugs in ophthalmology, however, is difficult due to limited accessibility of the eye, in terms of drug administration and in terms of sampling of tissues for drug pharmacokinetics (PK) and pharmacodynamics (PD). Ocular quantitative systems pharmacology (QSP) models provide the opportunity to describe the distribution of drugs in the eye as well as the resulting drug-response in specific segments of the eye. In particular, ocular physiologically-based pharmacokinetic (PBPK) models are necessary to describe drug concentration levels in different regions of the eye. Further, ocular effect models employing molecular data from specific cellular systems are needed to develop dose-response correlations. We here describe the current status of PK/PBPK as well as PD models for the eye and describe cellular systems, data repositories as well as animal models in ophthalmology. The application of the various concepts is highlighted for the development of new treatments for post-operative fibrosis after glaucoma surgery.

Background: Current strategies in circulating tumor cell (CTC) isolation in pancreatic cancer heavily rely on the EpCAM and cytokeratin cell status. EpCAM is generally not considered as a good marker given its transitory change during Epithelial to Mesenchymal Transition (EMT) or reverse EMT. There is a need to identify other surface markers to capture the complete repertoire of PDAC CTCs. The primary objective of the study is to characterize alternate surface bi-omarkers to EpCAM on CTCs that express low or negligible levels of surface EpCAM in pancre-atic cancer patients. Methods: Flow cytometry and surface mass spectrometry were used to iden-tify proteins expressed on the surface of PDAC CTCs in culture. CTCs were grown under condi-tions of attachment and in co-culture with naïve neutrophils. Putative biomarkers were then validated in GEMMs and patient samples. Results: Surface proteomic profiling of CTCs identi-fied several novel protein biomarkers. ALCAM was identified as a novel robust marker in GEMM models and in patient samples. Conclusions: We identified several novel surface bi-omarkers on CTCs expressed under differing conditions of culture. ALCAM was validated and identified as a novel alternate surface marker on EpCAMlow CTCs.

Stress plays a central role in functioning for all life forms. As humans, we experience stress in a multitude of ways through various types of stimuli. Due to the constancy of stressors in our lives, the nervous system has learned to allosterically adapt to the stimuli, but when the body cannot adapt, chronic stress can have morphological and degenerative impacts on neuroanatomy and cognitive function that may or may not be reversible. This literature review aimed to identify the specific neuroanatomical structures impacted most by the long-term effects of chronic stress and the subsequent relationship the morphological changes had on cognitive function in rodent models. We examined articles published from PubMed, Google Scholar, and Science Direct, while focusing the search on anatomical and neurodegenerative effects associated with chronic stress stimuli. The degenerative effects of various types simulated physiological chronic stress showed the most impact on neurogenesis and neuronal development, brain plasticity, and spatial learning and memory with association to the hippocampus. The hippocampus, amygdala, prefrontal cortex, and hypothalamic-pituitary-adrenal axis (HPA) all had reversible and non-reversible morphological alterations, which also had a direct impact on the brain’s cognitive abilities. While studies regarding chronic stress are still being conducted, future research may be able to further highlight why stressful stimuli can particularly impact these structures and the tangential impacts that it may have on related or adjacent structures.

Covid-19 pandemic affected outcome in ST-elevation myocardial infarction (STEMI) patients in majority of countries. We aimed to assess retrospectively admissions, treatments, complications and mortality of STEMI patients in the northeast of Slovenia in the first (March-May 2020) and the second wave (October-December 2020) of Covid-19 pandemic and compare them with the data from 2019 (March-October). Comparing 2019 and both waves of Covid-19 pandemic we observed nonsignificant differences in the number of STEMI admissions, in baseline characteristics, in the use of primary percutaneous coronary intervention (PCI), either within the first 3 (40.5%* vs 30.2% vs 25%*, *p = 0.074) and 6 hours, nonsignificant differences in TIMI III flow after primary PCI and in hospital complications, except for significant increase in hospital heart failure (23.3% vs 42%, p = 0.015) and mitral regurgitation in the second wave (10% vs 26.9%, p = 0.008) of the pandemic with nonsignificant increase in hospital mortality (8.9% vs 9.4% vs 13.6%) in both waves of the pandemic. We conclude, that with increased severity of Covid-19 pandemic in the second wave there was a longer delay to primary PCI in STEMI patients, resulting in significantly increased hospital heart failure and nonsignificantly increased hospital mortality

While the global COVID-19 pandemic has been widely acknowledged to affect the mental health of health care workers (HCWs), attention to measures that protect those on the front lines of health outbreak response has been limited. In this cross-sectional study, we examine workplace contextual factors associated with how psychological distress was experienced in a South African setting where a severe first wave was being experienced with an objective of identifying factors that can protect against HCWs experiencing negative impacts. Consistent with mounting literature on mental health effects, we found a high degree of psychological distress (57.4% above General Health Questionnaire cut-off value) and a strong association between perceived risks associated with the presence of COVID-19 in the healthcare workplace and psychological distress (adjusted OR = 2.35, p <.01). Our research indicates that both training (adjusted OR 0.41, 95% CI 0.21 – 0.81) and the reported presence of supportive workplace relationships (adjusted OR 0.52, 95% CI 0.27 – 0.97) were associated with positive outcomes. This evidence that workplace resilience can be reinforced to better prepare for the onset of similar outbreaks in the future suggests that pursuit of further research into specific interventions to improve resilience is well merited.

Background: Studies have demonstrated the link between vitamin D-related genetic variations and non-skeletal outcomes. We aimed to identify all available data on the association of vitamin D-related genetic variations with non-alcoholic fatty liver disease (NAFLD). Methods: Potentially eligible studies were identified from Embase and Medline databases from inception to June 2022 using search strategy that comprised terms for “Vitamin D” and “NAFLD”. Eligible study must report the association between vitamin D-related genetic variations and presence, severity or response to treatment of NAFLD. Data were extracted from each eligible study. Results: A total of 3,495 articles were identified. After systematic review, twelve studies were in-cluded. A total of 26 genetic variations were identified. Presence of NAFLD was associated with variations of GC (rs222054, rs222020, rs10011000, rs7041), VDR (rs2228570, rs11168287, rs10783219, rs4752), CYP24A1 (rs3787557, rs6068816, rs2296241, rs2248359) and CYP27B1 (rs4646536). Severity of NAFLD was associated with variations of GC (rs4588), VDR (rs2228570, rs4334089), CYP2R1 (rs10741657), DHCR7 (rs1544410, rs3829251, rs12785878) and CYP24A1 (rs3787557, rs6068816, rs6097809, rs6127119, rs2248359, rs3787554, rs4809960, rs6022999). Response to calcitriol treatment was associated with variation of VDR (rs10735810). Conclusions: Multiple vitamin D-related genetic variations were associated with NAFLD, indi-cating the role of vitamin D in the pathogenesis of NAFLD.

The changing epidemiology of Staphylococcus aureus has created several gaps in its population structure and emergence of strains. Two global shifts in the aftermath of the past methicil-lin-resistant S. aureus (MRSA) pandemic are: a rise in healthcare-associated infections and evolu-tion of cutaneous and soft tissue infections with high morbidities and mortalities. Furthermore, bitter lessons from COVID-19 showed S. aureus necrotizing-pneumonia and skin conditions ag-gravating Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and Monkeypox manifestations. Limited data and paucity of high-quality evidence exist for many key clinical questions. Using clinical microbiology, molecular characterization, hospital data on age and in-fection sites, and antibiograms, we have investigated S. aureus infection patterns. We showed that age-specific distribution in both intensive care unit (ICU) and non-ICU revealed highest infection rates (94.7%) in senior-patients >50 years; most were MRSA (81.99%). However, specific distribu-tions of geriatric MRSA and MSSA rates were 46.5% and 4.6% in ICU and 35.48% and 8.065% in non-ICU, respectively. Intriguingly, age groups 0-20 years showed uniquely similar MRSA pat-terns in ICU and non-ICU patients (13.9%, 9.7%, respectively) and MSSA in ICU (11.6%). In age groups 20-50 years, MRSA were 2-fold in non-ICU (35%) than ICU (18.6%). Interestingly, highly significant association was found between infection-site and age-groups (P-value .000). Skin in-fections remained higher in all ages; pediatrics 32.14%, adults 56%, and seniors 25% while res-piratory infections were lower in pediatrics (14.3%) and adult 17%), and highest in seniors (38%). Blood and “other” sites in pediatrics recorded (28.6%; 25%, respectively), slightly lower in adults (18.6%; 8.6%) and seniors (14%); 22.8%), respectively. Further, significant association existed between infection-site and MRSA (Chi-Square Test, P-value .002). The common cutaneous infec-tions across all age-groups and the significant association of MRSA to geriatric-respiratory infec-tions have a high potential for skin-carriage as reservoir for endogenous infection. The similar frequencies of both lineages in youth in all settings imply MSSA-carriage as potential evolutionary origins for MRSA. These findings have important clinical implications for strategic planning in patient management and S. aureus control particularly in age-specific infections and vigilance for potential viral coinfections.

As the problem of traction injuries to brachial plexus is a common one and of high socio-economic significance, the analysis of the surgical outcomes in patients with this pathology is significant for neurosurgery, neurology, traumatology-orthopedics, and rehabilitation. The aim of the research is to compare the short-term outcomes of using various surgical methods for managing patients with closed traction injuries of brachial plexus. Material and methods. The research involved 61 patients with closed traction injury of brachial plexus divided into two groups homogeneous in sex, age and severity of their neurological deficit: Group I – 33 patients who underwent microsurgical neurolysis, Group II – 28 patients who underwent microsurgical neurolysis combined with one-level electrostimulation. The dynamic assessment of clinical and functional status of upper limbs was performed using scale methods and electrophysiological monitoring. Results. The research revealed a more evident recovery of the upper limb function in Group II patients suggesting the method of microsurgical neurolysis combined with electrostimulation to be preferable in case of closed traction injuries to brachial plexus. Conclusion. The combination of microsurgical neurolysis with one-level electrostimulation improves the short-term outcomes of surgical treatment in patients with closed traction injuries of brachial plexus due to a sooner decrease in pain in postoperative period, and positive dynamics of clinical and electrophysiological parameters.

Real-world evidence (RWE) is increasingly involved in the early benefit assessment of medicinal drugs. It is expected that RWE will help to speed up approval processes comparable to RWE developments in vaccine research during the COVID-19 pandemic. Definitions of RWE are diverse marking the highly fluid status in this field. So far, RWE comprises information produced from data routinely collected on patient’s health status and/or delivery of health care from various sources other than traditional clinical trials. These sources can include electronic health records, claims, patient-generated data including in home-use settings, data from mobile devices as well as patient, product and disease registries. The aim of the present update was to review the current RWE developments and guidelines mainly in the U.S., the UK, Europe and Germany field during the last decade. RWE has already been included in various approval procedures of regulatory authorities reflecting its actual acceptance and growing importance in evaluating and accelerating new therapies. However, since the RWE research is still in a transition process and since a number of gaps in this field have been explored, more guidance and a consented definition are necessary to increase the implementation of real-world data.

We have previously reported that a single test measuring oVEMP n10 to 4000Hz stimuli (either bone-conducted vibration (BCV) or air-conducted sound (ACS)) provides a definitive diagnosis of semicircular canal dehiscence (SCD) in 22 CT-verified patients with a sensitivity of 1.0 and specificity of 1.0. Such a single short screening test has great advantages of speed, minimizing testing time and the exposure of patients to stimulation. However some studies of the 4000Hz test for SCD have reported sensitivity and sensitivity values somewhat less that what we reported.

Nearly half a century has passed since the discovery of cytoplasmic inheritance of human chloramphenicol resistance. The inheritance was then revealed to take place maternally by mitochondrial DNA (mtDNA). Later, a number of mutations in mtDNA were identified as a cause of severe inheritable metabolic diseases with neurological manifestation, and the impairment of mitochondrial functions has been probed in the pathogenesis of a wide range of illnesses including neurodegenerative diseases. Recently growing number of preclinical studies has revealed that animal behaviors are influenced by the impairment of mitochondrial functions and possibly by the loss of mitochondrial stress resilience. Indeed, as high as 54% of patients with one of the most common primary mitochondrial diseases, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome, present psychiatric symptoms including cognitive impairment, mood disorder, anxiety, and psychosis. Mitochondria are multifunctional organelles which produce cellular energy and play a major role in other cellular functions including homeostasis, cellular signaling, and gene expression, among other. Mitochondrial functions are observed to be compromised and to become less resilient under continuous stress. Meanwhile, stress and inflammation have been linked to the activation of the tryptophan (Trp)-kynurenine (KYN) metabolic system, which observably contributes to development of pathological conditions including neurological and psychiatric disorders. This narrative review discusses the functions of mitochondria and the Trp-KYN system, the interaction of the Trp-KYN system with mitochondria, and the current understanding of the involvement of mitochondria and the Trp-KYN system in preclinical and clinical studies of major neurological and psychiatric diseases.

Infective endocarditis remains an illness that carries a significant burden to healthcare resources. In recent times, there has been a shift from Streptococcus sp to Staphylococcus sp as the primary organism of interest. This has significant consequences given the virulence of Staphylococcus and its propensity to form a biofilm, rendering non-surgical therapy ineffective. In addition, antibiotic resistance has affected treatment of this organism. The cohorts at most risk for Staphylococcal endocarditis are the elderly patients with multiple comorbidities. The innovation of transcatheter technologies alongside other cardiac interventions such as implantable devices have contributed to the increased risk attributable to this cohort. We examine the role of the heart team for diagnosis and treatment of this condition. In addition, we examine the determinants of virulence of Staphylococcus aureus, the interaction with hosts immunity and the discovery and emergence of a potential vaccine. We also examine the potential role of prophylactic antibiotics during dental procedures. With increasing rates of transcatheter device implantations, there is a projected increment of endocarditis especially in this high-risk group. A high index of suspicion is needed alongside early initiation of therapy and referral to the heart time to improve outcomes.

Ovarian cancer is the third most common female genital cancer. Therefore, the timely diagnosis and comprehensive treatment of postmenopausal patients with benign ovarian tumors remains crucial in the field of gynecology. The significance of ovarian tumors depends on their frequency and their effects on the quality of life of a woman, as well as the possible development of ovarian cancer. Most ovarian cancers are diagnosed late and as a result are difficult to treat and often carry a poor prognosis. Currently there is no clear algorithm available for examining and accurately diagnosing patients with postmenopausal ovarian tumors; moreover, reliable criteria allowing dynamic observation and determining surgical access and optimal surgical intervention measures in postmenopausal patients is lacking.

The COVID-19 pandemic has highlighted the vitalness of telehealth in our medical world, where considering a restructuring of healthcare services has become paramount. In fact, telemedicine has recently earned a valuable place in many specialties; and its implications in cardiology and cardiovascular medicine were among the leading interests. In this letter, we gathered previous evidence supporting the merit of telemedicine in the fields of cardiology and cardiovascular medicine—medical branches in which patients require meticulous care and continuous monitoring—as well as protrusions of concerns about the uncertainty regarding the efficacy of telemedicine’s future implications and technologies. In sum, in the context of this still on-going pandemic, medical institutions must strive to improve telehealth technologies and implement solid future research directions in this growing field—to be able to persevere in meeting the needs of the patients. As long as no conclusive evidence exists regarding the fields where telemedicine is most worthwhile, healthcare systems will always keep the dread of wasting resources on developing ineffective programs. We conclude that telemedicine has been attributed a considerable attention in managing cardiac and cardiovascular conditions; nevertheless, further studies with solid designs are still needed to confirm its validity and utility in those specialties.

There is a need to further characterize the antibody response to vimentin in relation to it possible involvement in pathogenicity of sarcoidosis, and other lung disorders. Objectives: We investigated serum samples from patients with sarcoidosis, healthy and diseased control subjects to evaluate levels and frequency of these antibodies. Materials and methods. A retrospective-prospective comparative study was performed in the years 2014-2017. 188 serum samples were examined for presence of autoantibodies to mutated citrullinated vimentin (anti-MCV). Patients with elevated anti-MCV levels were tested for antibodies to a cyclic citrullinated peptide (anti-CCP) and citrullinated vimentin (anti-Sa). Additionally, sera from 93 patients with sarcoidosis and 40 healthy subjects were evaluated for the presence of autoantibodies to non-modified vimentin. In all cases ELISA assays was used. The results were considered statistically significant at p-value less than 0.05. Results of the study. The high concentrations of anti-MCV. antibodies were more frequent in patients with sarcoidosis (40.9% of the cases, 38/93), compared to the control groups (23.6% and 25.0% of cases, respectively). In sarcoidosis, clinical symptoms similar to the autoimmune pathology were described. A moderate positive correlation between the anti-MCV and anti-Sa antibodies (r = 0.66) was found in 13 patients with sarcoidosis. There was no significant difference between the levels of the anti-MCV and the anti-CCP in patients with non-infectious lung diseases and the healthy control group. Conclusion. A high level of anti-MCV antibodies in patients with sarcoidosis characterizes the presence of an autoimmune process that is not related to citrullination. The absence of a significant difference in the level of antibodies to modifications of vimentin in patients with sarcoidosis may indicate the autoimmune process.

Staphylococcus aureus frequently causes subclinical mastitis around the world with high impact in milk industry and public health. Essential oils (EO) are recognized antimicrobials that can be synergistic with antibiotics. The main objective of this study was evaluating the essential oil (EO) of Melaleuca armillaris as an adjuvant of erythromycin (ERY) for the alternative treatment of bovine mastitis caused by S. aureus. The Minimum Inhibitory and Bactericidal Concentrations (MIC and MBC) of EO, ERY, and its combinations were established against S. aureus at different pHs (7.4, 6.5 and 5.0), emulating extra and intracellular conditions. Sensible (N=3) and resistant (N=3) strains to ERY and S. aureus ATCC 29213 as control were used. Math models were applied to described the antibacterial activity of EO and combinations EO-ERY. The EO was bactericidal against all the strains independently of the pH with a slightly improvement in acid conditions. The synergism between EO and ERY was estimated by the Fractional Inhibitory Concentration Index (FIC) and by mathematical modeling of the bacterial killing data. Synergism was observed with ERY, where combinations had bactericidal activity also even with pH modification. M. armillaris EO is an interesting adjuvant for ERY, being a promissory option for further analysis of intracellular efficacy against S. aureus.

In patients with unilateral tinnitus with normal hearing, several studies have compared the ipsilateral and contralateral ears; however, few studies have investigated its relationship with the duration of tinnitus. We compared the auditory brainstem response and otoacoustic emission parameters between ipsilateral and contralateral ears in adults with unilateral tinnitus and normal hearing. This retrospective review included 84 patients with unilateral tinnitus and normal hearing who underwent auditory brainstem response and otoacoustic emission; they were categorized according to the duration of tinnitus. The latencies and amplitudes of waves I, III, and V, and V/I ratio of both ears in auditory brainstem response, and the results of distortion-product otoacoustic emission and transient evoked otoacoustic emission were examined. The auditory brainstem response parameters, distortion-product otoacoustic emission parameters, and transient evoked otoacoustic emission parameters between the ipsilateral and contralateral ears along the duration of tinnitus were analyzed. Moreover, the failure rates of both distortion-product otoacoustic emission and transient evoked otoacoustic emission between the ears along with the duration and the effects of the variables on the amplitude and latency of each wave were examined. Although there was little significant difference between the ipsilateral and contralateral ears, laterality seemed to have an effect on wave I latency in the multiple linear regression analysis. The distortion-product otoacoustic emission failure rate of the ipsilateral ear was higher than that of the contralateral ear in all patients. However, there was no remarkable difference between the ears in the distortion-product otoacoustic emission and transient evoked otoacoustic emission parameters throughout the duration. We found that outer hair cells and the distal portion of the cochlear nerve are possible pathologic lesions in tinnitus with normal hearing and cochlear synaptopathy could be suspected. Further studies, including those on inner hair cells and higher central cortex, are needed.

Background: Immersive therapy through virtual reality represents a novel strategy used in psychological interventions, but there is still a need to strengthen the evidence on its effects on health professionals’ mental health. Objective: To analyze the results of immersive therapy through virtual reality in the levels of anxiety and secondly, well-being of the health professionals working in a regional hospital in Olot (Spain). Methods: Pilot quasi-experimental study including a group of 35 women (mean age=45.7, SD=8.43) health professionals who undertook immersive therapy for 8 weeks. The intervention was implemented through virtual reality, and its effect on anxiety levels and well-being was evaluated through the Hamilton and Eudemon scales, respectively. Data on age, gender, active pharmacological or psychological treatment, mental health disorders and number of sessions were also collected. Results: Statistically significant (p<0.001) improvement in anxiety and well-being was found, with large and moderate effect sizes (0.90 and 0.63 respectively). In addition, these changes were clinically significant. No significant associations were found between the improvements and the different variables, but a greater trend was identified among the group of professionals with untreated or unidentified levels of anxiety. Conclusion: This group of health professionals showed statistically and clinically significant improvement in anxiety and well-being after the application of immersive therapy using virtual reality. Further studies with a control group are necessary to further analyze this novel intervention.

Resistance to Immune Checkpoint Blockade (ICB) constitutes the current limiting factor for the optimal implementation of this novel therapy that otherwise demonstrates durable responses with acceptable toxicity scores. This limitation is exacerbated by a lack of robust biomarkers. In this study, we have dissected the basal TME composition at the gene expression and cellular levels that predict response to Nivolumab and prognosis. BCR, TCR and HLA profiling were employed for further characterization of the molecular variables associated with response. The findings were validated using a single-cell RNA-seq data of metastatic melanoma patients treated with ICB and by multispectral immunofluorescence. Finally, machine learning was employed to construct a prediction algorithm that was validated across eight metastatic melanoma cohorts treated with ICB. Using this strategy, we have unmasked a major role played by basal intratumoral plasma cells expressing high levels of IGKC in efficacy. IGKC, differentially expressed in good responders, was also identified within the Top response-related BCR clonotypes, together with IGK variants. These results were validated at gene, cellular and protein levels; CD138+ Plasma-like and Plasma cells were more abundant in good responders and correlated with the same RNA-seq defined fraction. Finally, we generated a 15-genes prediction model that outperformed the current reference score in eight ICB-treated metastatic melanoma cohorts. The evidenced major contribution of basal intratumoral IGKC and plasma cells in good response and outcome in ICB in metastatic melanoma is a groundbreaking finding in the field beyond the role of T lymphocytes.

Objective: To describe technique of platelet rich plasma injection into the olfactory cleft in patients with long-term COVID-19 olfactory dysfunction. Methods: The technique starts with the blood extraction and the isolation of PRP through a 10-min centrifugation (4,200 rpm). The supernatant was injected in nasal regions with a 27-G needle after a local anesthesia with Xylocain 10% spray. The injection was performed through a 0° rigid optic. Precisely, several points of 0.2–0.5 mL were performed in the nasal septum in regard of the head of the middle turbine, and in the head of the middle turbine in both sides. Clinical, psychophysical and pain outcomes were evaluated pre- to post-injection. Results: A 22-year-old female with 24-month post-COVID-19 anosmia was recruited for the injection of PRP. The olfactory cleft endoscopic scale score was 0 and the threshold, discrimination and identification scores were 1, 8 and 0, respectively. The Olfactory Disorder Questionnaire score was 51. The patient benefited from the injection of 2.2 mL of PRP in nasal regions, which was done without complication. The procedure pain level was 2/10, while the local anesthesia with xylocaine 10% was judged as the most annoyance step with a score of 3/10. At 2-month post-injection, the TDI scores reached 16, 16, and 16 (48), while the Olfactory Disorder Questionnaire was 73. The patient described its recovery as very rapid, lasting 3-4 days, and occurring 3-week post-injection. Conclusion: The injection of PRP into the olfactory cleft is a safe and easiness new approach that may improve the recovery of smell sense.

The accumulation of foam cells in arterial intima and the accompanied chronic inflammation are considered major causes of neoatherosclerosis and restenosis. However, both the underlying mechanism and effective treatment for the disease are yet to be uncovered. In this study, we combined transcriptome profiling of restenosis artery tissue and bioinformatic analysis to reveal that NLRP3 inflammasome is markedly upregulated in restenosis and that several restenosis re-lated DEGs are also targets of mulberry extract, a natural dietary supplement used in traditional Chinese medicine to improve liver vitality. Further pathway enrichment analysis identified MAPK signaling pathway to be involved in the inflammatory response of foam cells. Consistently, immunofluorescence microscopy shows co-localization of NLRP3 with CD68+ macrophages. We then evaluated the efficacy of mulberry extract in inhibiting both the formation of foam cells and their inflammatory response. We demonstrated that mulberry extract suppresses the formation of ox-LDL induced foam cells, possibly by upregulating the cholesterol efflux genes ABCA1 and ABCG1 to inhibit intracellular lipid accumulation. In addition, mulberry extract dampens NLRP3 inflammasome activation by stressing the MAPK signaling pathway. Collectively, our mecha-nistic and functional studies unveil the therapeutic value of mulberry extract in neoatherosclerosis and restenosis treatment by regulating lipid metabolism and inflammatory response of foam cells.

Suicidal behaviour is a public health problem whose magnitude is both substantial and increasing. Since many individuals seek medical treatment following a suicide attempt, strategies aimed at reducing further attempts in this population are a valid and feasible secondary prevention approach. An evaluation of the available evidence suggests that existing treatment approaches have limited efficacy in this setting, highlighting the need for innovative approaches to suicide prevention. Existing research on the neurobiology of social pain has highlighted the importance of this phenomenon as a risk factor for suicide, and has also yielded several attractive targets for pharmacological preventive strategies. In this paper, the available evidence related to these targets is synthesized and critically evaluated. The way in which social pain is related to the “anti-suicidal” properties of recently approved treatments, such as ketamine and psilocybin, is also examined. Such strategies may be effective for the short-term reduction of suicidal ideation and behaviour in individuals who have made a suicide attempt suicide prevention, particularly in cases where social pain is identified as a contributory factor. These pharmacological approaches may be effective regardless of the presence or absence of a specific psychiatric diagnosis.

Background: In the present study, we assessed the feasibility and success outcomes of voice prosthesis (VP) changes when performed by speech-language pathologist (SLP). Methods: Patients treated with total laryngectomy (TL) from January 2020 to December 2020 were prospectively recruited from our medical center. Patients benefited from tracheoesophageal puncture. The VP changes were performed by the senior SLP and the following data were collected for each VP change: date of placement; change or removal; VP type and size; reason for change or removal; and use of a washer for periprosthetic leakage. A patient-reported outcome questionnaire including 6 items was proposed to patients at each VP change (Appendix 1). Items were assessed with a 10-point Likert-scale. Results: Fifty-two VP changes were performed by the senior SLP during the study period. The mean duration of the SLP consultation, including patient history, examination and VP change procedure was 20 min (range: 15-30). The median prosthesis lifetime was 88 days. The main reasons for VP changes were transprosthetic (N=34; 79%) and periprosthetic (N=7; 21%) leakages, respectively. SLP successfully performed all VP changes. He did not change one VP but used a periprosthetic silastic to stop the periprosthetic leakages. In two cases, SLP needed the surgeon examination to discuss about the following indication: implant mucosa inclusion and autologous fat injection. The patient satisfaction was high according to the speed and the quality of care by the SLP. Conclusion: The delegation of VP change from the otolaryngologist-head and neck sur-geon to the speech-language pathologist (SLP) may be done without significant complications. The delegation of VP change procedure to SLP may be interesting in some rural regions with otolaryngologist shortage.

For the first time in history, we have witnessed the origin and development of a pandemic. To handle the accelerated accumulation of viral mutations and to comprehend the virus' evolutionary adaptation in humans, an unparalleled program of genetic sequencing and monitoring of SARS-CoV-2 variants has been undertaken. Several scientists have theorized that, with the Omicron surge producing a more contagious but less severe disease, the end of COVID-19 is near. However, by analyzing the behavior shown by this virus for 2 years, we have noted that pandemic viruses do not always show a decreased virulence. Instead, it appears there is an evolutionary equilibrium between transmissibility and virulence. We have termed this concept “intermittent virulence”. The present work analyzes the temporal and epidemiological behavior of SARS-CoV-2 and suggests that there is a high possibility that new virulent variants will arise in the near future, although it is improbable that SARS-CoV-2´s virulence will be the same as was seen during the pandemic phase.

Infectious keratitis (IK) represents a major cause of corneal blindness. This study aims to investigate the demographics, risk factors, microbiological characteristics and antibiotic susceptibility patterns of IK in Taiwan over the past 15 years. A retrospective population-based study was conducted using the Chang Gung Research Database. Patients with IK were identified by diagnostic codes for corneal ulcer from 2004 to 2019. Of 7807 included subjects, 45.2% of patients had positive corneal cultures. The proportion of contact lens-related IK declined, while that of IK related to systemic diseases grew. The percentage of isolated gram-positive bacteria surpassed that of gram-negative bacteria in the 15-year period. The prevalence of Pseudomonas aeruginosa showed a decreasing trend (p = 0.004), whereas coagulase-negative Staphylococcus (CNS) and Propionibacterium species were increasingly detected (p &lt; 0.001). Overall, the trend of antibiotic susceptibility of both gram-positive and gram-negative bacteria did not change throughout the study period. The susceptibility to the test antibiotics maintained over 90% in gram-negative isolates during 15 years. Vancomycin preserved 100% susceptibility to all gram-positive isolates. Since most tested antibiotics exhibited stable susceptibility over decades, this study reinforced that fluoroquinolones and fortified vancomycin continue to be good empiric therapies for treating bacterial keratitis in Taiwan.

Management of diabetic foot ulcers (DFUs) presents challenges to even the most experienced wound care providers. Because of the chronic, non-healing nature of many DFUs, advances in the treatment and care of this disease process are particularly relevant. This case study aims to report the efficacy of the application of dehydrated amniotic membrane allograft (DAMA) to a diabetic foot ulcer. The patient in this study is a 44-year-old male who presented with an aggressive infection on his right foot, which resulted in an open wound of 18 months duration. This patient received weekly applications of dual-layer DAMA over seven weeks. Upon examination at the initial application, the wound was classified as a Wagner grade 3 with necrosis of the underlying muscle. Upon inspection at the final visit, the wound was closed entirely. The results that were shown include improvements in the size, depth, edges, necrotic tissue amount, and epithelization of the wound. This case study demonstrates that the ap-plication of DAMA has the potential to augment the body’s natural DFU healing response; however, future nonrandomized and randomized controlled trials are needed to establish its efficacy further.

The Kalanchoe genus is composed of more than 100 species that usually thrive in tropical environments, which have been used in folkloric medicine to treat various illnesses, including dermatological conditions. With this, the present study assesses the pharmacognostical and pharmacological properties of different species of the Kalanchoe genus as elements for a potential treatment for dermatological-related conditions, from findings of existing literature and studies. It was analyzed that the Kalanchoe pinnata plant, or one of the most common species of Kalanchoe, have been observed to have distinct morphological and microscopic characteristics. Further, it was discovered that different species of Kalanchoe have anti-inflammatory, antioxidant, antibacterial, and wound healing properties, which enable the plant to be used for dermatological products that are available to the market. With this, it is recommended that further studies be conducted in other understudied species of Kalanchoe regarding their pharmacological properties, as well as the use of other structures of the Kalanchoe plant for treatment of various dermatological conditions.

Providing patient-centered care to manage chronic pain and opioid use disorder (OUD) is associated with improved health outcomes. However, adopting a holistic approach to providing care is often challenging in rural communities. This study aims to identify and contrast challenges to providing patient-centered care from the perspective of patients and providers. A participatory design approach was adopted to elicit the perceptions of providers and patients with lived experiences of chronic pain and OUD in Jefferson County, Wisconsin. Two focus groups were conducted with each stakeholder group to identify problems that participants face with respect to chronic pain management and OUD and possible solutions. Four interviews were conducted with providers experienced in chronic pain management. Analysis of focus group sessions and interviews show consensus among patients and providers that lack of behavioral health and recovery resources create barriers to effectively manage OUD and chronic pain. However, there was discordance among the two groups about other barriers such as patient and provider attitudes, tapering approach, and access to medications for OUD. This tension among patients and providers can influence patients’ retention in therapy. More efforts are needed to mitigate stigma among providers in rural communities and support psychosocial needs of patients.

Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of plasma cells in the bone marrow (BM) microenvironment. Despite the progress made in treatment, some MM patients still die within the first year of diagnosis. Numerous studies investigating microRNA (miRNA) expression patterns suggest they may be good prognostic markers. The primary aim of this study was to analyze the expression of selected miRNAs in the serum of MM patients subsequently treated with bortezomib-based regimens and determine their potential to predict early mortality. The study was conducted in 69 prospectively-recruited patients with newly-diagnosed MM admitted to the Department of Hematology of the Copernicus Memorial Hospital, Lodz (Poland) between 2017 and 2021. Among them, 17 patients experienced death within 12 months of diagnosis. The expression of 31 selected miRNAs was determined using miRCURY LNA miRNA Custom PCR Panel. The obtained clinical data included patient characteristics on diagnosis, treatment regimen, response to treatment, and follow-up. Differential expression analysis found two miRNAs to be significantly downregulated in the early mortality group: hsa-miR-328-3p (fold change- FC: 0.72, p=0.0342) and hsa-miR-409-3p (FC: 0.49, p=0.0357). Univariate and multivariate logistic regression analyses were performed to assess the early mortality rate. The final model consisted of hsa-miR-409-3p, hsa-miR-328-3p, age and R-ISS 3. It yielded an area under the curve (AUC) of 0.863 (95%CI: 0.761-0.965) with 88.2% sensitivity and 77.5% specificity. Further external validation of our model is necessary to confirm its clinical value.

Orbital fractures are a common finding in facial trauma and serious complications may arise when orbital reconstruction is not done properly. The virtual planning can be used to manufacture patient-specific titanium orbital implants (PSI) through the process of selective laser melting. This method is currently considered the most accurate technique for orbital reconstruction. Even with the most accurate tehniques of bone reconstruction, there are still situations where enophthalmos is present after reconstruction which may be produced by intraorbital soft tissue atrophy. The aim of this paper was to evaluate the orbital soft tissue after postraumatic reconstruction of the orbital walls fractures. 10 patients diagnosed with unilateral orbital fractures were included in this study. A CT scan of the head region with thin slices (0.6mm) and soft and bone tissue windows was done. After data processing, the STL files were exported and the intraorbital fat tissue volume and the muscular tissue volume were masured. The volumes of affected orbit tissues were compared with the volumes of the healthy orbit tissues for each patient. Our findings conclude that a higher or a lower grade of fat and muscular tissue loss is present in all cases of reconstructed orbital fractures.

Therapeutic efficacy of retroviral replicating vector (RRV)-mediated prodrug activator gene therapy has been demonstrated in a variety of tumor models, but clinical investigation of this approach has so far been restricted to glioma and gastrointestinal malignancies. In the present study, we evaluated replication kinetics, transduction efficiency, and therapeutic efficacy of RRV in experimental models of lung cancer. RRV delivering GFP as a reporter gene showed rapid viral replication in a panel of lung cancer cells in vitro, as well as robust intratumoral replication and high levels of tumor transduction in subcutaneous and orthotopic pleural dissemination models of lung cancer in vivo. Toca 511 (vocimagene amiretrorepvec), a clinical-stage RRV encoding optimized yeast cytosine deaminase (yCD) which converts the prodrug 5-fluorocytosine (5-FC) to the active drug 5-fluorouracil (5-FU), showed potent cytotoxicity in lung cancer cells upon exposure to 5-FC prodrug. In vivo, Toca 511 achieved significant tumor growth inhibition following 5-FC treatment in subcutaneous and orthotopic pleural dissemination models of lung cancer in both immunodeficient and immunocompetent hosts, resulting in significantly increased overall survival. This study demonstrates that RRV can serve as highly efficient vehicles for gene delivery to lung cancer, and indicates the translational potential of RRV-mediated prodrug activator gene therapy with Toca 511/5-FC as a novel therapeutic strategy for pulmonary malignancies.

Background: Upper extremities’ function impairments (UEFI) and gait impairment are frequently reported even in the early stages of Multiple Sclerosis (MS) disease. These motor deficits can negatively affect the quality of life (QOL) in MS patient. Exercise has been repeatedly introduced as a beneficial adjuvant therapy for MS, attenuating a wide range of physical and psychological symptoms without any side effects or increased risks of relapse or exacerbation in disease symptoms.Aim: This paper investigates the effect of multi-function swing suspension training (MFSST) program on upper and lower extremities’ function (ULEF), and QOL in MS women according to expanded disability status scale (EDSS) score.Design: Experimental method with a pre-test and post-test design with control group. Setting: The department of Sports Injuries and Corrective Exercise at the Shahid Bahonar University of Kerman.Population: Forty-seven MS women.Methods: Eligible subjects who matched the selection criteria were randomly assigned into three groups as follow: i. Intervention group A (EDSS of 2 – 4), ii. Intervention group B (EDSS of 4.5 – 6.5), and iii. Control group (EDSS of 2 – 6.5). The intervention groups have been trained by the SET program for a duration of 8 weeks. At baseline and after the intervention, the upper extremities’ function (UEF) and the lower extremities’ function (LEF) were assessed by 9-hole peg test (9HPT) and the timed 25-foot walk (T25FW) test, respectively. Moreover, participants’ QOL was measured using the Short Form questionnaire (SF-36).Results: A significant difference was found between the pre-test and post-test variables of walking speed and upper extremity endurance in intervention groups, and between the intervention groups and control group (P < 0.05). Compared to control group, both intervention groups showed improvements in all subscales of QOL, except emotional role limitation score.Conclusions: In summary, these results show that the present protocol of MFSST could be effective in improving ULEF and QOL in MS patients, showing the improvements after 4^th week. Moreover, this protocol was more useful for patients with an EDSS score of more than 4.5. Therefore, it seems that exercise therapy should be considered as a beneficial clinical intervention approach to improve ULEF and QOL in MS patients.

The COVID-19 was described as a respiratory illness, however further studies recognize it as a complex heterogeneous multisystemic disorder. Global efforts have been proposed to combat COVID-19, emerging diverse therapeutic options, in which discovering new drug therapies, development of vaccines and drug repurposing have been considered the most promising approaches to fight the virus. This study aimed to repurpose known drugs for use against the COVID-19, finding better therapeutic options. Seventeen biological databases were used in this study. The genetic algorithm (GA) was performed for a set of drug target classes and COVID-19 proteins as input, whose drug candidates are obtained according to the target similarities found in the target-target similarity predictive network, resulting in a drug-target interaction network. Thus, recommended drugs correspond to the union of the drug subsets found during each GA execution. Twenty-eight drugs were indicated to be the best therapeutic targets for the virus, in special, the Cyclosporine drug was administered as adjuvant to steroid treatment for COVID-19 patients which showed positive outcomes, reducing mortality in moderate and severe cases. The drugs found have used to treat other diseases, evidencing that the COVID-19 is a multisystemic disorder and suggests that the viruses’ mechanism of action presents some comorbidity with other human diseases. Evidence shows that the drugs found in this research might act together to fight the virus in a broader fashion, however further studies including in vitro and in vivo experiments are needed to find the best combination of these drugs.

Introduction: VULTO-VAN SILFHOUT-DE VRIES SYNDROME (VSVS;OMIM#615828) is an extremely rare hereditary disease associated with impaired intellectual development and speech, delayed psychomotor development and behavioral anomalies, including autistic behavioral traits and poor eye contact. To date, 27 patients with VSVS have been reported in the world literature. Materials and Methods: We describe a 23y.o. male patient with autism spectrum disorder (ASD) who was admitted to the gastroenterological hospital with signs of pseudomembranous colitis. ASD was first noted in the patient at the age of 2.5y.o. Later he developed epileptic seizers and prominent growth retardation. Prior to the hospitalization he was excluded chromosomal aberrations, Martin-Bell syndrome, aminoacidopathies/aminoacidurias associated with ASD. Whole genome sequencing was prescribed to the patient at 23y.o. Results: The patient appeared to be a heterozygous carrier of “de novo” variant c.662C>T (p.S221L) in ex 4 of the DEAF1 gene. c.662C> T had not been previously described in genomic databases. According to the ACMG criteria this missense variant was considered to be pathogenic. VSVS was diagnosed in the patient. Conclusions: The phenotype of the patient is very similar to the data presented in the world literature. However, growth retardation and cachexia, not previously described in the articles, are of interest.

Introduction: The proliferation of literature regarding COVID-19 pandemic has served to highlight a wide spectrum of disease manifestations and complications like thrombotic microangiopathies. Our review with a brief case presentation highlights the increasing recognition of TTP in COVID-19 and describes its salient characteristics. Methods: We screened the available literature in Pubmed, EMBASE and Cochrane database from inception till April 2022 of articles mentioning COVID-19 associated TTP in English Language. Results: From 404 records, we included 8 articles mentioning data of 11 patients in our review. TTP was predominantly reported in females (72%) with a mean age of 48.2 years (SD 15.1). Dyspnea was the most common symptom in 1/3rd of patients (36.6%). Neurological symptoms were reported in 27.3% of cases. The time to diagnosis of TTP was 10 days (SD: 5.8) from onset of Covid-19. All 11 cases underwent plasma exchange (PLEX), with a mean of 12 sessions per patient, whereas six cases received Rituximab (54.5%), and three received Caplacizumab (27.3%). One patient died from the illness. Conclusion: This review of available literature highlights the atypical and refractory nature of COVID-19 associated TTP. It required longer sessions of PLEX with half of the patients receiving at least one immunosuppressant.

Background. To describe the characteristics of anterior mediastinal masses on conventional magnetic resonance imaging (MRI) and to assess the role of the Apparent Diffusion Coefficient (ADC) value in distinguishing benign from malignant mediastinal lesions. Methods. We conducted a retrospective cross-sectional study on 55 patients with anterior mediastinal mass who performed MRI before treatment. Biopsy and histopathological assessments were done after that. A radiologist evaluates the changes of signal intensity on these sequences: T1- weighted VIBE DIXON pre and post-contrast with Gadolinium, T2 HASTE, T2 TIRM, DWI/ADC, to determine the size, margin of the lesion, the presence of fat, cystic in it. ADCs values were calculated from the ADC maps which were constructed from b = 0 and b = 2000 Results. The study was composed of 55 patients, with 5 benign lesions and 50 malignant lesions. The ADCmean, ADCmedian, ADC10, and ADC90 in the histogram-based approach and hot-spot-ROI-based mean ADC for the malignant lesions was significantly lower than those found in benign lesions (P-value <0.05). The hot-spot-ROI-based mean ADC had the highest value in differentiation between benign and malignant mediastinal lesions, between group A (benign lesions, thymoma A, AB, B1) and group B (thymoma B2, B3 and other malignant lesions). The cut-off point of the ADC value differentiating malignant from benign mediastinal lesions was 1,17x10-3mm2/s with sensitivity of 80%, and specificity of 80%. The cut off point of the ADC value differentiating group A from group B was 0.99 x10-3mm2/s with sensitivity of 78,4%, and specificity of 88.9%. The cut-off point of the ADC value differentiating lymphoma from other malignant lesions was 0,91 x10-3mm2/s with sensitivity of 100%, and specificity of 60.5%. Conclusion. Diffusion-weighted MRI and measurement of ADC value in histogram-based approach and hot-spot-ROI-based mean ADC are very helpful in the differentiation between benign and malignant anterior mediastinal lesions.

Systematic reviews of 591 primary studies of the modes of transmission for SARS-CoV-2 show significant methodological shortcomings and heterogeneity in the design, conduct, testing and reporting of SARS-CoV-2 transmission. While this is partly understandable at the outset of a pandemic, evidence rules of proof for assessing the transmission of this virus are needed for pre-sent and future pandemics of viral respiratory pathogens. We review the history of causality as-sessment related to microbial etiologies with a focus on respiratory viruses and suggest a hierar-chy of evidence to integrate clinical, epidemiologic, molecular and laboratory perspectives on transmission. The hierarchy, if applied to future studies, should narrow the uncertainty over the twin concepts of causality and transmission of human respiratory viruses. We attempt to address the translational gap between the current research evidence and the assessment of causality in the transmission of respiratory viruses with a focus on SARS-CoV-2. Experimentation, consistency and independent replication of research alongside our proposed framework provide a chain of evidence that can reduce the uncertainty over the transmission of respiratory viruses and increase the level of confidence in specific modes of transmission, informing the measures that should be undertaken to prevent transmission.

Management of inflammatory bowel disease (IBD) often relies on biological and immunomodulatory agents for remission through immunosuppression, raising concerns regarding the SARS-CoV-2 vaccine's effectiveness. The emergent variants have hindered the vaccine neutralization capacity, and whether the third vaccine dose has the capacity to neutralize SARS-CoV-2 variants in this population remains unknown. This study aims to evaluate the humoral response of SARS-CoV-2 variants in patients with IBD 60 days after the third vaccine dose [BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna)].56 su bjects with IBD and 12 healthy subjects were recruited. 90% of patients with IBD (49/56) were receiving biologics and/or immunomodulatory therapy. 24 subjects with IBD did not develop effective neutralizing capability against the Omicron variant. 70% (17/24) of those subjects were receiving anti-Tumor Necrosis Factor therapy [10= adalimumab, 7= infliximab], two of them had a history of COVID-19 infection, and one subject did not develop immune neutralization against three other variants: Gamma, Epsilon, and Kappa. All subjects in the control group developed detectable antibodies and effective neutralization against all seven SARS-CoV-2 variants. Our study shows that patients with IBD might not be protected against SARS-CoV-2 variants, and larger studies are needed to evaluate optimal immunity.

Sacrococcygeal pilonidal disease is a chronic inflammatory condition with an incidence of 26:100,000 in the United States. However, its etiology and optimal treatment remain controversial. We included 129 and 74 patients with simple and complex sacrococcygeal pilonidal disease, respectively. The primary outcome was pilonidal sinus recurrence after unroofing curettage. Secondary outcomes were pain scores, time to return to work/school, and time to complete recovery. At a median follow-up of 53 months, the recurrence rate was 4.9% in all patients, not significantly higher in subjects with the complex disease. Duration of surgery (15.4 vs. 12.2 min), time to return to school/work (9.8 vs. 7.7 days), and complete healing time (44 vs. 36 days) were longer in patients with the complex disease. Postoperative complication rates, pain scores, and quality of life scores between the two groups did not differ. Unroofing curettage may be a good first-choice treatment for both simple and complex sacrococcygeal pilonidal disease.

The supply of mental health processes in primary care has gaps. This study aims to analyze the association of agreement criteria and flows between primary care teams and the Family Health Support Center (NASF) for mental health collaborative care, considering the difference between capital and non-capital cities in Brazil. This cross-sectional study was conducted based on secondary data from the Primary Care Access and Quality Improvement Program. Agreement criteria and flows were obtained from 3883 NASF teams of the matrix support or collaborative care. The Chi-square test and multiple Poisson regression were used; p &lt; 0.05 was considered statistically significant. Prevalence ratios of negative associations demonstrated protective factors for support actions: follow-up at Psychosocial Care Center, management of psychopharmacotherapy, offer of other therapeutic actions, care process for users of psychoactive substances, and offer of activities to prevent the use of psychoactive substances. Collaborative care in primary care was effective, and capital cities were a protective factor compared with non-capital cities.

ABSTRACT Background It is important to be able to predict, for each individual patient, the likelihood of later metastatic occurrence, because the prediction can guide treatment plans tailored to a specific patient to prevent metastasis and to help avoid under- or over-treatment. Deep Neural Network (DNN) learning, commonly referred to as deep learning, has become popular due to its success in image detection and prediction, but questions such as whether deep learning outperforms other machine learning methods when using non-image clinical data remain unanswered. Grid search has been introduced to deep learning hyperparameter tunning for the purpose of improving its prediction performance, but the effect of grid search on other machine learning methods are under-studied. In this research, we take the empirical approach to study the performance of deep learning and other machine learning methods when using non-image clinical data to predict the occurrence of breast cancer metastasis (BCM) 5, 10, or 15-years after the initial treatment. We developed DNN models as well as models using 9 other machine learning methods including Naive Bayes (NB), Logistic Regression (LR), Support Vector Machine (SVM), LASSO, Decision Tree (DT), k-Nearest Neighbors (KNN), Random Forrest (RF), AdaBoost (ADB), and XGBoost (XGB). We used grid search to tune hyperparameters for all methods. We then compared the deep learning models to the models trained using the 9 other machine learning methods. Results Based on the mean test AUC results, DNN ranks 6th, 4th, and 3rd when predicting 5-year, 10-year, and 15-year BCM respectively, out of 10 machine learning methods. The top performing methods in predicting 5-year BCM are XGB(1^st), RF(2^nd), and KNN(3^rd). For predicting 10-year BCM the top performers are XGB (1^st), RF(2^nd), and NB(3^rd) . Finally, for 15-year BCM the top performers are SVM (1^st), LR and LASSO (tied for 2^nd), and DNN (3^rd). The ensemble methods RF and XGB outperform other methods when data are less balanced, while SVM, LR, LASSO, and DNN outperform other methods when data are more balanced. Our statistical testing results show that at a significance level of 0.05 DNN overall performs no worse than other machine learning methods when predicting 5-year, 10-year, and 15-year BCM. Conclusions Our results show that deep learning with grid search overall performs at least as well as other machine learning methods when using non-image clinical data. It is interesting to note that some of the other machine learning methods such as XGB, RF, and SVM are very strong competitors of DNN when incorporating grid search. It is also worth noting that the computation time required to do grid search with DNN is way more than that required to do grid search with the other 9 machine learning methods.

The skin acts as a protective barrier, guarding the body against microorganisms, chemicals, and several environmental factors. Accordingly, this all-important organ must be kept healthy to maintain its optimal functionality. One approach to maintain skin health is the application of multifunction bioactive sunscreens containing antioxidant molecule(s). Rosmarinic acid (RA), a phenolic compound, is known for its antioxidant activity. Herein, the safety and efficacy of a multifunction prototype sunscreen were investigated, aiming to probe putative synergies of this polyphenol with two known and widely used UV filters (bemotrizinol and octyl p-methoxycinnamate). Samples protected the DNA fragmentation compared to UV control, by the comet assay, and showed good skin compatibility in subjects. Formulations F1 and F3 were able to increase skin hydration, and, possibly, the RA interfered with this attribute. An increase in transepidermal water loss was observed for formulations F1, F2 and F4, which may be related to vehicle containing or not the RA. No decreases were observed in the inflammatory reaction caused by the ethyl nicotinate with any of the evaluated formulations. As a perspective, we suggest trials with a greater number of subjects or protocol modifications. Altering the vehicle qualitative and quantitative composition is also a pertinent perspective.

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi’s sarcoma, primary effusion lymphoma (PEL) and multicentric Castleman’s disease. During KSHV lytic infection, lytic-related genes, categorized as immediate-early, early, and late genes, are expressed in a temporal manner. The transcription of late genes requires the virus-specific pre-initiation complex (vPIC), which consists of viral transcription factors. However, the characterization of the protein-protein interactions of the vPIC factors has not been completely elucidated. KSHV ORF18 is one of the vPIC factors, and its interaction with other viral factors has not been sufficiently revealed. Here, we analyzed the interaction between ORF18 and another vPIC factor, ORF30, in living cells using the bimolecular fluorescence complementation (BiFC) assay. We identified four amino-acid residues (Leu29, Gln36, His41 and Trp170) on ORF18 that were responsible for its interaction with ORF30. The artificial intelligence (AI) system AlphaFold2 predicted that identified four residues are exposed to the surface of ORF18 and located in proximity to each other in the surface of ORF18. Thus, AI-predicted model supports the importance of four residues for binding of ORF18 to ORF30. Our results indicated that wet experiments in combination with AI may enhance the structural characterization of vPIC protein-protein interactions.

Like living organisms, cancer cells require energy to survive and interact with their environment. Mitochondria are the main organelles for energy production and cellular metabolism. Recently, investigators demonstrated that cancer cells can hijack mitochondria from immune cells. This behavior sheds light on a pivotal piece in the cancer puzzle, the ‘dependence’ on the normal cells. This article illustrates the benefits of new, functional mitochondria for cancer cells that urge them to hijack mitochondria. It describes how functional mitochondria help cancer cells’ survival in the harsh tumor microenvironment, immune evasion, progression, and treatment resistance. Recent evidence has put forward the pivotal role of mitochondria in cancer stem cells’ metabolism. This theory highlights the mitochondria in cancer biology and explains how targeted anti-mitochondrial treatments can improve oncological outcomes.

Chronic obstructive pulmonary disease (COPD) is strongly associated with tobacco smoking and it is the increasing cause of morbidity and mortality worldwide. The prevalence of COPD among never smokers varies widely across regions, areas, and nations. COPD in smokers has been extensively explored worldwide, however, COPD in non-smokers is under-explored and there is limited data available on non-smoking COPD. We determined the role of environmental pollution and biomass fuel exposure in COPD patients who were non-smokers. We evaluated the clinical profile of non-smokers with COPD in a retrospective observational study. 180 non-smoker COPD patients were selected from the year 2016-to 2018. We found that many patients with COPD are non-smokers and the incidence is higher among the rural population, suggesting that non-smoking COPD is evolving rapidly due to biomass smoke and other environmental pollutant exposures.

Human pluripotent stem cells (hPSCs) have become a powerful tool to generate various kinds of cell types comprising the human body. Recently, organoid technology emerged as a platform to build a physiologically relevant tissue-like structure from the PSCs, which provides a more relevant three-dimensional microenvironment to the actual human body than the conventional monolayer culture system for transplantation, disease modeling, and drug development. Although it holds so many advantages, the organoid culture system still has various problems related to culture methods, which became a challenge to get similar physiological properties to their original tissue counterparts. Here, we discuss the current development of organoid culture methods, including the problem that may arise from the currently available culture systems as well as the possible approach to overcoming the current limitation and improving their optimum utilization for translational application purposes.

The serious impact of Adolescent’s Free Sex Behavior will affect their developmental task. Having proper education and having optimal sex counseling are related to sexual behavior in adolescents. The alternative for this phenomenon recently has involved adolescents participating as peer counselors because they are more susceptible to peer influence. Online peer counselor programs may promote progression into depth understanding of sexual behavior among adolescents. This paper provides an overview of the effect of peer counselors on reproductive health among adolescents. It describes many conceptual frameworks about free sex behaviors, risk factors among adolescents, and the role of peer counselors in improving health reproductive behavior among adolescents.

Running at odds with the timing imposed by the circadian clock plays an important role in the process that leads to communicable and non communicable diseases. The primary objective of this study was to analyse whether early dinner eater children were at lower risks of acute respiratory infections than late dinner eater children, during the COVID-19 pandemic. Methods: This cross sectional study was conducted from July to December 2020 on children attending Majorcan emergency services. Clinical data collected included timing, symptoms, laboratory tests and imaging studies of current illness. Each diagnosis was validated by general paediatricians. Our survey on dinner time habits was carried out by using self-administered questionnaires. Results: A total of 669 children under age 18 were included in the study. The median of dinner time was 8:30 pm. Late dinner eaters accounted for a higher proportion of acute otitis media than early dinner eaters (7% vs 3%; P=0.028). Other infectious diseases were not associated with dinner time habits. Conclusions: We make a preliminary estimate of the link between late dinner habits and acute otitis media in children. However, no conclusions about causality can be established due to the observational design of the study.

Matrix metalloproteinases (MMPs) are critical enzymes involved in a variety of cellular processes. MMPs are well known for their ability to degrade the extracellular matrix (ECM) and their extracellular role in cell migration. Recently, more research has been conducted on investigating novel subcellular localizations of MMPs and their intracellular roles at the respective locations. In this review article, we focus on the subcellular localization and novel intracellular roles of two MMPs closely related: membrane-type-1 matrix metalloproteinase (MT1-MMP) and matrix metalloproteinase-2 (MMP-2). Although MT1-MMP is commonly known to localize on the cell surface, the protease also localizes to the cytoplasm, caveolae, Golgi, cytoskeleton, centrosome, and nucleus. At these subcellular locations, MT1-MMP functions in cell migration, macrophage metabolism, invadopodia development, spindle formation and genes expression, respectively. Similar to MT1-MMP, MMP-2 localizes to the caveolae, mitochondria, cytoskeleton, nucleus and nucleolus, and functions in calcium regulation, contractile dysfunction, genes expression and ribosomal RNA transcription. Our particular interest lies in the role MMP-2 and MT1-MMP serve within the nucleus, as it may provide critical insights into cancer epigenetics and tumor migration and invasion. We suggest that targeting nuclear MT1-MMP or MMP-2 to reduce or halt cell proliferation and migration may lead to the development of new therapies in cancer and other diseases.

Alzheimer’s disease (AD) is an irreversible neurodegenerative disease characterized by progressive cognitive decline. The two cardinal neuropathological hallmarks of AD include buildup of cerebral β amyloid (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau. The current disease-modifying treatments are still not effective enough to lower the rate of cognitive decline. The paucity of early detection and disease progression biomarkers also seems to present a major obstacle to AD drug development. The current established readouts based on expression levels of amyloid beta, tau and phospho tau have shown many discrepancies in patient samples when linked to disease progression. There is an urgent need to identify diagnostic and disease progression biomarkers from blood, CSF or other biofluids that can facilitate early detection of the disease and provide pharmacodynamic readouts for new drugs being tested in clinical trials. Advances in proteomic approaches using state-of-the-art mass spectrometry, are now being increasingly applied to study AD disease mechanisms, identify drug targets and novel disease biomarkers. In this report, we describe applications of the quantitative proteomic approaches for understanding AD pathophysiology, summarize the current knowledge gained from proteomic investigations of AD and discuss development and validation of new predictive and diagnostic disease biomarkers.

Lipoproteins are important cardiovascular (CV) risk biomarkers. This study aimed to investigate the associations of lipoprotein subclasses with micro- and macrovascular biomarkers to better understand how these subclasses relate to atherosclerotic CV diseases. One hundred fifty-eight serum samples from the EXAMIN AGE study, consisting of healthy individuals and CV risk patients, were analyzed by nuclear magnetic resonance (NMR) spectroscopy to quantify lipoprotein subclasses. Microvascular health was quantified by measuring retinal arteriolar and venular diameters. Macrovascular health was quantified by measuring carotid-to-femoral pulse wave velocity (PWV). Nineteen lipoprotein subclasses showed statistically significant associations with retinal vessel diameters and nine with PWV. These lipoprotein subclasses together explained up to 26% of variation (R²=0.26, F(29,121)=2.80, p<0.001) in micro- and 12% (R²=0.12, F(29,124)=1.70, p=0.025) of variation in macrovascular health. High-density (HDL-C) and low-density lipoprotein cholesterol (LDL-C) as well as triglycerides together explained up to 13% (R²=0.13, F(3,143)=8.42, p<0.001) of micro and 8% (R²=0.08, F(3,145)=5.46, p=0.001) of macrovascular variation. Lipoprotein subclasses seem to reflect micro- and macrovascular end organ damage more precisely as compared to only measuring HDL-C, LDL-C and triglycerides. Further studies are needed to analyse how the additional quantification of lipoprotein subclasses can improve CV risk stratification and CV disease prediction.

Young people living with perinatal infections of Human Immunodeficiency Virus (YLPHIV) face a chronic disease, with treatment including adherence to life-long antiretroviral treatment (ART). The aim of this QES was to explore adherence to ART for YLPHIV as an assemblage within the framework of the BPS model with a new materialist perspective. We searched up to November 2021 and followed the ENTREQ and Cochrane guidelines for QES. All screening, data extraction and critical appraisal was done in duplicate. We analysed and interpreted the findings innovatively, by creating images of meaning, a storyboard, and storylines. We then reported the findings in a narrative first person story. We included 47 studies and identified 9 storylines. We found that treatment adherence has less to do with humans’ preferences, motivations, needs and dispositions, and more to do with how bodies, viruses, things, ideas, institutions, environments, social processes, and social structures assemble. This QES highlights that adherence to ART for YLPHIV is a multisensorial experience in a multi agentic world. Future research into rethinking the linear and casual inferences we are accustomed too in evidence-based health care is needed if we are to adopt multidisciplinary approaches to address pressing issues such as adherence to ART.

Nowadays molecular and immunological research is essential for the better understanding of tumor cells pathophysiology. The increasing number of neoplasms is taken under ‘the molecular magnifying glass’ therefore it is possible to discover complex relationships between cytophysiology and immune system action. An example could be renal cell carcinoma (RCC) which has deep interactions with immune mediators such as Interleukin 17 (IL-17) - an inflammatory cytokine reacting to tissue damage and external pathogens. RCC is one of the most fatal urological cancer because of its often late diagnosis and poor susceptibility to therapies. IL-17 and its relation with tumors is extremely complex and constitute a recent topic for numerous research. What is worth highlighting is IL-17 dual character in cancer development - it could be pro- as well as antitumorigenic. The aim of this review is to summarize the newest data considering multiple connections between IL-17 and RCC.

The primary goal of this research is to examine the α-amylase inhibitory effect of phytoconstituents found in the roots of the Cyclea peltata plant. The extract will also be used to investigate the effect of root extract on α-amylase inhibition assay. The roots were gathered, processed, and extracted in petroleum ether before being kept at 4ºC. The extract was exposed to a preliminary phytochemical examination. The extract was employed in the α-amylase inhibition experiment at concentrations of 50, 100, 200, 400, 600, 800, and 1000 µg/ml with acarbose as a control. Molecular docking analysis was performed on the phytoconstituents cycleapeltine, cycleadrine, cycleacurine, cycleanorine, cycleahomine chloride, and acarbose on human pancreatic alpha-amylase 1B2Y. A preliminary phytochemical study revealed the presence of alkaloids, saponins, and terpenoids. The tests came back negative for flavonoids, steroids, and tannin. The root extract inhibited α-amylase at 69.42 ± 0.74 % at 1000 µg/ml and acarbose at 94.63 ± 0.57 %. The IC50 value was calculated and found to be 484.08 µg/ml for the extract and 42.47 µg/ml. The docking studies, revealed that cycleacurine (-4.751 Kcal/mol) has a comparable anti-diabetic effect to Acarbose (-6.713 Kcal/mol). Furthermore, the function groups –OH and –NH found in phytoconstituents interacted with the active site of 1B2Y similarly to acarbose. This provides evidence that the function groups –OH and –NH present in the phytoconstituents might inhibit alpha amylase.

Introduction: The development of effective vaccines has partially mitigated the trend of the SARS-CoV-2 pandemic, however, the need for orally available antiviral drugs persists. This study aims to investigate the activity of molnupiravir in combination with nirmatrelvir or GC376 on SARS-CoV-2 to verify the synergistic effect. Methods: The SARS-CoV-2 strains 20A.EU, BA.1 and BA.2 were used to infect Vero E6 in presence of antiviral compounds alone or in combinations using 5 two-fold serial dilution of compound concentrations ≤EC90. After 48 and 72 h post-infection, viability was performed using MTT reduction assay. Supernatants were collected for plaque-assay titration. All experiments were conducted three times and in triplicate. The synergistic score was calculated using Synergy Finder version 2. Results: All compounds reached micromolar EC90. Molnupiravir and GC376 showed a synergistic activity at 48 h with an HSA score of 19.33 (p<0.0001) and an additive activity at 72 h with an HSA score of 8.61 (p<0.0001). Molnupiravir and nirmatrelvir showed a synergistic activity both at 48 h and 72 h with an HSA score of 14.2 (p=0.01) and 13.08 (p<0.0001), respectively. Conclusion: Molnupiravir associated with one of the two protease-inhibitors nirmatrelvir and GC376 showed good additive-synergic activity in vitro.