Literature mining discerns latent disease-gene relationships.

MOTIVATION: Dysregulation of a gene's function, either due to mutations or impairments in regulatory networks, often triggers pathological states in the affected tissue. Comprehensive mapping of these apparent gene-pathology relationships is an ever-daunting task, primarily due to genetic pleiotropy and lack of suitable computational approaches. With the advent of high throughput genomics platforms and community scale initiatives such as the Human Cell Landscape project, researchers have been able to create gene expression portraits of healthy tissues resolved at the level of single cells. However, a similar wealth of knowledge is currently not at our finger-tip when it comes to diseases. This is because the genetic manifestation of a disease is often quite diverse and is confounded by several clinical and demographic covariates. RESULTS: To circumvent this, we mined ∼18 million PubMed abstracts published till May 2019 and automatically selected ∼4.5 million of them that describe roles of particular genes in disease pathogenesis. Further, we fine-tuned the pretrained bidirectional encoder representations from transformers (BERT) for language modeling from the domain of natural language processing to learn vector representation of entities such as genes, diseases, tissues, cell-types, etc., in a way such that their relationship is preserved in a vector space. The repurposed BERT predicted disease-gene associations that are not cited in the training data, thereby highlighting the feasibility of in silico synthesis of hypotheses linking different biological entities such as genes and conditions. AVAILABILITY AND IMPLEMENTATION: PathoBERT pretrained model: https://github.com/Priyadarshini-Rai/Pathomap-Model. BioSentVec-based abstract classification model: https://github.com/Priyadarshini-Rai/Pathomap-Model. Pathomap R package: https://github.com/Priyadarshini-Rai/Pathomap.

Transcriptome analysis of Huh7 cells upon Chikungunya virus infection and capsid transfection reveals regulation of distinct cellular and metabolic pathways.

Chikungunya virus (CHIKV) causes persistent arthritis and neurological problems imposing a huge burden globally. The present study aims to understand the interaction mechanism of Chikungunya virus and CHIKV-capsid in Huh7 cells. The RNA-sequencing and qRT-PCR method was used for the transcript and gene profiles of CHIKV virus and CHIKV capsid alone. Transcriptional analysis showed capsid induced 1114 and 956 differentially expressed genes (DEGs) to be upregulated and downregulated respectively, while in virus, 933 genes were upregulated and 956 were downregulated. Total 202 DEGs were common in both capsid and virus; and nine were validated using qRT-PCR. Identified DEGs were found to be associated with metabolic pathways such as Diabetes, cardiac disease, and visual impairment. Further, knock-down study on one of the DEGs (MafA) responsible for insulin regulation showed low viral proteins expression suggesting a reduction in virus-infection. Thus, the study provides insight into the interplay of the virus-host factors assisting virus replication.

Peripheral artery disease and extracorporeal membrane oxygenation: Examining a high-risk cohort over time.

OBJECTIVE: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is a resource-intensive approach for the management of refractory cardiogenic shock. Within this population exists a substantial cohort of patients with peripheral artery disease (PAD), which independently increases the risk of complications and all-cause mortality. We studied 10-year national trends of the impact of PAD among VA-ECMO recipients to better understand the prevalence of PAD and implications on outcomes in this vulnerable population. METHODS: This 10-year retrospective, propensity score-matched study identified all adult patients (≥18) who underwent VA-ECMO between 2009 and 2018, from a large US database (National Inpatient Sample). Patients with an ICD diagnosis of PAD were identified. The primary endpoints of in-hospital mortality, bleeding complications and major limb loss (above- or below-knee amputation) were compared between patients with PAD to those without. RESULTS: A total of 6768 patients were identified, of which 342 (5.3%) had PAD. The median age at admission was significantly higher in PAD patients [64 years vs. 55 years; p < .01], as was male gender [71% vs. 64%; p < .01]. Patients with PAD had higher rates of smoking (38.9% vs. 23.3%), hypertension (71.1% vs. 50%), diabetes (37.4% vs. 27.0%), chronic kidney disease (30.1% vs. 18.0%), coronary artery disease (76.0% vs. 35.0%) and dyslipidemia (76.0% vs. 35.0); all p < .01. After propensity-matching 2:1 for comorbidities, PAD patients were found to have significantly greater overall complications, including in-hospital mortality, bleeding, surgical wound infections, pseudoaneurysms, and major adverse limb events [71.9% vs. 63.9%; p < .01]. Subgroup analysis revealed greater in-hospital mortality [62.2% vs. 55.3%; p < .05], major amputations [4.1% vs. 0.3%; p < .01] and blood transfusions [32.2% vs. 26.2%; p < .05] in PAD patients. Over 2014-2018, the non-PAD group demonstrated statistically discernable trends in a 51.1% decrease in overall complications and a 28.1% increase in survival to discharge (all p < .01). Over the same time period the PAD cohort experienced a modest, nonsignificant, decrease in complications [7.0%, p = .40] and a decrease in those surviving to discharge [47.1% vs. 40.5%, p = .91]. CONCLUSION: Patients with PAD on VA-ECMO are sicker at baseline and experience significantly greater major amputations and higher in-hospital mortality. They have not benefitted from the considerable decrease in complication rates and increase in survival to discharge over time as compared to their non-PAD counterparts. These findings demonstrate the substantial frailty of the PAD population within an already high-risk cohort, and highlight the need for better procedural approaches and innovative technologies.

Magnetic resonance imaging organ at risk delineation for nasopharyngeal radiotherapy: Measuring the effectiveness of an educational intervention.

INTRODUCTION: Magnetic resonance imaging (MRI) demonstrates superior soft tissue contrast and is increasingly being used in radiotherapy planning. This study evaluated the impact of an education workshop in minimising inter-observer variation (IOV) for nasopharyngeal organs at risk (OAR) delineation on MRI. METHODS: Ten observers delineated 14 OARs on 4 retrospective nasopharyngeal MRI data sets. Standard contouring guidelines were provided pre-workshop. Following an education workshop on MRI OAR delineation, observers blinded to their original contours repeated the 14 OAR delineations. For comparison, reference volumes were delineated by two head and neck radiation oncologists. IOV was evaluated using dice similarity coefficient (DSC), Hausdorff distance (HD) and relative volume. Location of largest deviations was evaluated with centroid values. Observer confidence pre- and post-workshop was also recorded using a 6-point Likert scale. The workshop was deemed beneficial for an OAR if ≥50% of observers mean scores improved in any metric and ≥50% of observers' confidence improved. RESULTS: All OARs had ≥50% of observers improve in at least one metric. Base of tongue, larynx, spinal cord and right temporal lobe were the only OARs achieving a mean DSC score of ≥0.7. Base of tongue, left and right lacrimal glands, larynx, left optic nerve and right parotid gland all exhibited statistically significant HD improvements post-workshop (P < 0.05). Brainstem and left and right temporal lobes all had statistically significant relative volume improvements post-workshop (P < 0.05). Post-workshop observer confidence improvement was observed for all OARs (P < 0.001). CONCLUSIONS: The educational workshop reduced IOV and improved observers' confidence when delineating nasopharyngeal OARs on MRI.

Comparison of academic productivity and funding support between United States and international medical graduate vascular surgeons.

OBJECTIVE: The demand for vascular surgeons in the United States stands to far exceed the current supply. International medical graduates (IMGs) are not only vital to meeting the country's growing health care needs, but also help to advance clinical research and medical education in the field of vascular surgery. Nearly 17% of practicing vascular surgeons in the United States are IMGs, yet little is known about their relative contributions to academic vascular surgery. Our study aims to compare the academic profiles and funding support for IMG vascular surgeons to that of their US medical graduate (USMG) counterparts. METHODS: A cross-sectional study was performed on all IMG and USMG academic vascular surgeons practicing in US-based hospitals with vascular surgery residency and/or fellowship programs. In addition to the baseline surgeon characteristics, academic profiles and research output were also collected. Furthermore, the National Institutes of Health (NIH) research reporting tool and open payments database were queried for any funding/payments to surgeons in both groups. Matching for year of vascular surgery training program graduation was performed where appropriate. RESULTS: A total of 908 academic vascular surgeons were included; 759 (83.6%) were USMGs and 149 (16.4%) were IMGs. The median year of graduation was comparable between the two groups, but USMGs had a significantly higher proportion of female surgeons (23.6% vs 10.7%; P = .0003). There were no significant differences in the academic profiles and leadership positions between the two groups. Although research productivity is similar between the two groups, IMG surgeons were more likely to have first or senior-authorship papers (47.1% vs 37.5%; P < .001). Additionally, faculty departments chaired/cheifed by a USMG were less likely to be staffed with IMG vascular surgeons (1.6 surgeons vs 3.1 surgeons; P < .0001). Following grant analysis, USMG surgeons received more NIH R01 grants (5.7% vs 1.3%; P = .026). R01-funded surgeons had significantly greater research output by number of publications (121.0 vs 47.5), citations (3872 vs 938), H-index (32.0 vs 17.5), and average journal impact factor (>10: 86.7% vs 33.3%) (all P < .001). CONCLUSIONS: The efforts to further diversify vascular surgery are vital to better serving an increasingly diverse US population, amid growing disparities in health care. Although IMGs account for a minority of academic vascular surgeons, and contribute significantly to their published research, they had less NIH R01 funding, warranting further investigation.

Trends in gender of first and senior authors of articles published in JMIRO.

INTRODUCTION: Despite progress of women in science and medicine, women remain underrepresented in academic publication. The aim of this study was to evaluate potential gender differences in women authorship in the Journal of Medical Imaging and Radiation Oncology (JMIRO). METHODS: Gender of the first and senior author of all articles published in JMIRO between 2012 and 2021 were examined. Changes over time and differences among groups were compared using the chi-square test. RESULTS: In total, 1,138 articles were assessed. Women were first and senior authors on 34% and 25% of all articles respectively. The proportion of women as first author was 30%, 41% and 36% for medical imaging (MI), radiation oncology (RO) and combined MI/RO articles respectively. Similarly, the proportion of women as senior author was lower than men at 22%, 32% and 23% for MI, RO and MI/RO articles respectively. Women first authorship over the study period remained stable from 2014 (36%) to 2020 (38%); however, it decreased dramatically in 2021 to 28%. There was a trend of increasing women senior authorship from 2013 (15%) to 2017 (35%) but decreased to 23% in 2021. CONCLUSION: Over the past 10 years of publications, one in three first authors were women and only one in four senior authors were women. The acknowledgement of this imbalance is the first step to pave the way towards addressing underlying systemic issues related to academic publication and disparities in gender and other inequities.

Synchronous sinonasal and respiratory papilloma: could long-term positive pressure ventilation be the cause? A rare case report.

This case report describes a rare presentation of synchronous pathologies-sinonasal inverted papilloma (SIP) and recurrent respiratory papillomatosis (RRP)-in a 47-year-old man using continuous positive airway pressure (CPAP) ventilation for progressive obstructive sleep apnoea. As far as we know, this is the first case of concurrent SIP and RRP disease described in the literature. The patient initially presented for management of chronic rhinosinusitis symptoms. He was found to have an extensive nasal lesion on flexible nasendoscopy, for which surgical management was recommended. However, during anaesthetic induction, he obstructed unexpectedly and was found to have an occlusive supraglottic lesion that required expedient ENT airway management. Diagnosis was made clinically and was supported with histopathology of excised tissue. Management involved multiple staged procedures for excision of sinonasal and glottic lesions and regular follow-up and imaging.

Novel methodology to quantify dehydration in head and neck cancer radiotherapy using DIXON MRI.

INTRODUCTION: Head and neck cancer (HNC) patients are at risk of weight change, due to inadequate nutrition intake or dehydration, when receiving radiotherapy (RT). This study aimed to develop methodology to measure water content changes on magnetic resonance imaging (MRI) scans of the head and neck region over the course of RT. METHODS: Retrospective datasets of 54 patients were analysed. Eligible patients had been treated for HNC with cisplatin chemoradiation (CRT) or RT alone and underwent a minimum of 2 MRI scans from weeks 0, 3 and 6 of their treatment. Anatomical regions consisting of ≥90% water, on T2-weighted DIXON MRI sequences, were contoured. Water volume changes of all patients were evaluated, within an anatomically standardised external volume, by comparing the absolute water fraction volume (cc) (VEx90WF) and relative water fraction volume (%) (RelVEx90WF) at weeks 0 and 6 of RT. RESULTS: There was a statistically significant difference between the RelVEx90WF at weeks 0 and 6 (P = 0.005). However, no statistically significant difference was identified between weeks 0 and 6 VEx90WF (P = 0.064). There were no statistically significant differences identified between patients who received CRT versus RT alone. CONCLUSION: This study developed a novel method for measuring changes in water fraction volumes over time, using T2-weighted DIXON MRIs. The methodology created in this study requires further validation through phantom imaging, with known fat and water values.

Contrasting roles for G-quadruplexes in regulating human Bcl-2 and virus homologues KSHV KS-Bcl-2 and EBV BHRF1.

Herpesviruses are known to acquire several genes from their hosts during evolution. We found that a significant proportion of virus homologues encoded by HSV-1, HSV-2, EBV and KSHV and their human counterparts contain G-quadruplex motifs in their promoters. We sought to understand the role of G-quadruplexes in the regulatory regions of viral Bcl-2 homologues encoded by KSHV (KS-Bcl-2) and EBV (BHRF1). We demonstrate that the KSHV KS-Bcl-2 and the EBV BHRF1 promoter G-quadruplex motifs (KSHV-GQ and EBV-GQ) form stable intramolecular G-quadruplexes. Ligand-mediated stabilization of KS-Bcl-2 and BHRF1 promoter G-quadruplexes significantly increased the promoter activity resulting in enhanced transcription of these viral Bcl-2 homologues. Mutations disrupting KSHV-GQ and EBV-GQ inhibit promoter activity and render the KS-Bcl-2 and the BHRF1 promoters non-responsive to G-quadruplex ligand. In contrast, promoter G-quadruplexes of human bcl-2 gene inhibit promoter activity. Further, KS-Bcl-2 and BHRF1 promoter G-quadruplexes augment RTA (a virus-encoded transcription factor)-mediated increase in viral bcl-2 promoter activity. In sum, this work highlights how human herpesviruses have evolved to exploit promoter G-quadruplexes to regulate virus homologues to counter their cellular counterparts.

Outcomes of Thoracic Endovascular Aortic Repair in Octogenarians.

OBJECTIVE: The aim of this study is to compare outcomes between octogenarians and non-octogenarians undergoing thoracic endovascular aortic repair (TEVAR). METHODS: Using the National Inpatient Sample database, we identified octogenarians (≥80 years) and non-octogenarians (<80 years) who had undergone thoracic endovascular aortic repair between 2012 and 2017. We compared patients' demographic, socioeconomic, comorbidity data between the two groups as well as the procedure indications and perioperative outcomes. A multivariable logistic regression analysis was conducted to evaluate the impact of advanced age (≥80 years) on the in-hospital mortality rates in patients who underwent TEVAR. This analysis was also performed for a separate cohort which included only patients who underwent TEVAR for ruptured thoracic aortic aneurysm. RESULTS: A total of 4108 patients were included in our study; 3432 (83.5%) patients were <80 years (37.9% female; median age, 64 years; 34.3% non-white) and 676 (16.5%) patients were ≥80 years (50.7% female; median age, 83 years; 20.4% non-white). Non-ruptured thoracic aortic aneurysm was the most common indication for TEVAR in older patients (61.4%), whereas type B aortic dissection was the most common indication in younger patients (36.4%). In-hospital complications were comparable between the two groups except for respiratory complications that were higher in the younger patients (21.2% vs. 15.2%; P <.001). The multivariable analysis demonstrated that advanced age had no association with increased in-hospital mortality rates (adjusted odds ratio [aOR], 1.41; 95% confidence interval [CI], .97-2.05), However, in ruptured thoracic aortic aneurysm cohort, octogenarians had higher in-hospital mortality rates (aOR, 1.86; 95% CI, 1.04-3.32). CONCLUSIONS: Octogenarians have acceptable rates of perioperative morbidity and mortality compared to the younger group and should be considered for TEVAR. Octogenarians are at higher risk for in-hospital mortality in the setting of ruptured thoracic aortic aneurysm, supporting the appropriateness of elective TEVAR in selected Octogenarians.

Outcomes of Infrainguinal Bypass in Patients with Cannabis vs Opioid Use Disorder.

BACKGROUND: Marijuana and opioids are commonly used illicit drugs in the United States and their use continues to rise. Cannabis use disorder (CUD) and Opioid use disorder (OUD) are associated with adverse effects on public health and postoperative outcomes. However, their impact on vascular surgery, specifically infrainguinal bypass repair (IIB). is not well described in the literature. Therefore, our study aimed to assess perioperative outcomes in patients with CUD and OUD who underwent IIB. METHODS: A retrospective analysis of the National Inpatient Sample database for the years 2005 to 2018 was performed. Using the International Classification of Diseases Clinical Modification, Ninth and Tenth revisions, patients who were diagnosed with peripheral artery disease and underwent IIB repair.were identified. Our primary outcome was the comparison of rates of in-hospital complications between the groups, and the secondary outcomes included analysis of total hospital charges and length of stay. A 1:1 propensity score matching (PSM) CUD and OUD patients to their control groups without the disease was conducted using the nearest-neighbor method. The matching was based on select patient demographics and comorbidities included in our analyses. RESULTS: A total of 190,794 patients were identified: 972 patients with CUD and 682 patients with OUD. In the matched cohorts, patients with a diagnosis of CUD had a higher incidence of in-hospital cardiac complications (adjusted Odds Ratio [aOR], 1.76; 95% Confidence Interval [CI], 0.99-3.12) and acute kidney injury (AKI) (aOR, 1.51; CI, 1.09-2.08). Additionally, total hospital charges and mean length of stay were higher in the CUD group (P < 0.001). Those with OUD had a higher incidence of postoperative respiratory complications (aOR, 1.92; CI, 1.23-2.99), sepsis (aOR, 2.39; CI, 1.32-4.34), infection (aOR, 3.55; CI, 1.16-10.84), AKI (aOR, 2.11; CI,1.47-3.04), major amputations (aOR, 1.69; CI, 1.07-2.69), along with higher total charges and mean length of stay (P < 0.001). CONCLUSIONS: Both CUD and OUD have increased incidence of postoperative complications following IIB. The OUD group had generally worse outcomes compared to patients with CUD. Both were associated with a substantial increase in total hospital charges and length of hospital stay. A further prospective study is warranted to provide better insight on the effects of substance use disorders on the procedure's short- and long-term outcomes.

Variability of gross tumour volume delineation: MRI and CT based tumour and lymph node delineation for lung radiotherapy.

PURPOSE: To compare gross tumour volume (GTV) delineation of lung cancer on magnetic resonance imaging (MRI) and positron emission tomography (PET) versus computed tomography (CT) and PET. METHODS: Three experienced thoracic radiation oncologists delineated GTVs on twenty-six patients with lung cancer, based on CT registered to PET, T2-weighted MRI registered to PET and T1-weighted MRI registered with PET. All observers underwent education on reviewing T1 and T2 images along with guidance on window and level setup. Interobserver and intermodality variation was performed based on dice similarity coefficient (DSC), Hausdorff distance (HD), and average Hausdorff distance (AvgHD) metrics. To compute interobserver variability (IOV) a simultaneous truth and performance level estimation (STAPLE) volume for each image modality was used as reference volume. For intermodality analysis, each observers CT based primary and nodal GTV was used as reference volume. RESULTS: A mean DSC of 0.9 across all observers for primary GTV (GTVp) and a DSC of >0.7 for nodal GTV (GTVn) was demonstrated for IOV. Mean T2 and T1 GTVp and GTVn were smaller than CT GTVp and GTVn but the difference in volume between modalities was not statistically significant. Significant difference (p < 0.01) for GTVp and GTVn was found between T2 and T1 GTVp and GTVn compared to CT GTVp and GTVn based on DSC metrics. Large variation in volume similarity was noted based on HD of up-to 5.4 cm for observer volumes compared to STAPLE volume. CONCLUSION: Interobserver variability in GTV delineation was similar for MRI and PET versus CT and PET. The significant difference between MRI compared to CT delineated volumes needs to be further explored.

Resilience: a mediator of the negative effects of pandemic-related stress on women's mental health in the USA.

The role of resilience in mediating the negative effects of the COVID-19 pandemic on the mental health of US women is poorly understood. We examined socioeconomic factors associated with low resilience in women, the relationship of low resilience with psychiatric morbidity, and the mediating role of resilience in the relationship between pandemic-related stress and other coincident psychiatric morbidities. Using a quota-based sample from a national panel, we conducted a web-based survey of 3200 US women in April 2020. Weighted, multivariate logistic regression was used to model the odds of pandemic-related stress, and coincident depression and anxiety symptoms among those with and without low resilience. Structural equation modeling was used to evaluate resilience as a mediator of the relationship between pandemic-related stress and other coincident psychiatric morbidities. Risk factors for low resilience included younger age, lower household income, lower education, unemployment, East/Southeast Asian race, unmarried/unpartnered status, and higher number of medical comorbidities. Low resilience was significantly associated with greater odds of depression symptoms (OR = 3.78, 95% CI [3.10-4.60]), anxiety symptoms (OR = 4.17, 95% CI [3.40-5.11]), and pandemic-related stress (OR = 2.86, 95% CI [2.26-3.26]). Resilience acted as a partial mediator in the association between pandemic-related stress and anxiety symptoms (proportion mediated = 0.23) and depression symptoms (proportion mediated = 0.28). In the early days of the COVID-19 pandemic, low resilience mediated the association between pandemic-related stress and psychiatric morbidity. Strategies proven to enhance resilience, such as cognitive behavioral therapy, mindfulness-based stress reduction, and addressing socioeconomic factors, may help mitigate mental health outcomes.

Improvements in HOMA indices and pancreatic endocrinal tissues in type 2-diabetic rats by DPP-4 inhibition and antioxidant potential of an ethanol fruit extract of Withania coagulans.

CONTEXT: Withania coagulans (Stocks) Dunal fruits are used in the therapeutics of several ailments due to possessing of potent phytoconstituents which is also used traditionally for curing the diabetes. OBJECTIVE: The present study was assessing the amelioration potential of the phytochemicals of an ethanol fruit extract of W. coagulans (Stocks) Dunal in the HOMA (Homeostatic model assessment) indices and pancreatic endocrinal tissues by inhibition of DPP-4 and antioxidants activities. MATERIAL AND METHODS: The identification of phytoconstituents of the test extract was performed by LCMS. Further, assessments of in-vitro, in-vivo and in-silico were achieved by following standard methods. In-vivo studies were conducted on type-2 diabetic rats. RESULTS: The chosen extract inhibited DPP-4 activity by 63.2% in an in vitro assay as well as significantly inhibit serum DPP-4 levels. Accordingly, the administration of the ethanol fruit extract resulted in a significant (P ≤ 0.001) alterations in the lipid profile, antioxidant levels, and HOMA indices. Moreover, pancreatic endocrinal tissues (islet of Langerhans) appeared to have the restoration of normal histoarchitecture as evidenced by increased cellular mass. Molecular docking (Protein-ligands) of identified phytoconstituents with DPP-4 (target enzyme) shown incredibly low binding energy (Kcal/mol) as required for ideal interactions. ADMET analysis of the pharmacokinetics of the identified phytoconstituents indicated an ideal profile as per Lipinski laws. CONCLUSION: It can be concluded that the phytoconstituents of an ethanol fruit extract of W. coagulans have the potential to inhibit DPP-4 which result in improved glucose homeostasis and restoration of pancreatic endocrinal tissues in type-2 diabetic rats.

Change in Health-Related Socioeconomic Risk Factors and Mental Health During the Early Phase of the COVID-19 Pandemic: A National Survey of U.S. Women.

Background: During a pandemic, women may be especially vulnerable to secondary health problems driven by its social and economic effects. We examined the relationship between changes in health-related socioeconomic risks (HRSRs) and mental health. Materials and Methods: A cross-sectional survey of 3,200 women aged 18-90 years was conducted in April 2020 using a quota-based sample from a national panel (88% cooperation rate). Patterns of change in HRSRs (food insecurity, housing instability, interpersonal violence, and difficulties with utilities and transportation) were described. Weighted, multivariate logistic regression was used to model the odds of depression, anxiety, and traumatic stress symptoms among those with and without incident or worsening HRSRs. Results: More than 40% of women had one or more prepandemic HRSRs. In the early pandemic phase, 49% of all women, including 29% with no prepandemic HRSRs, had experienced incident or worsening HRSRs. By April 2020, the rates of depression and anxiety were twice that of prepandemic benchmarks (29%); 17% of women had symptoms of traumatic stress. The odds of depression, anxiety, and posttraumatic stress symptoms were two to three times higher among women who reported at least one incident or worsening HRSR; this finding was similar for women with and without prepandemic HRSRs. Conclusions: Increased health-related socioeconomic vulnerability among U.S. women early in the coronavirus disease 2019 (COVID-19) pandemic was prevalent and associated with alarmingly high rates of mental health problems. Pandemic-related mental health needs are likely to be much greater than currently available resources, especially for vulnerable women.

Discovery of new phenyl sulfonyl-pyrimidine carboxylate derivatives as the potential multi-target drugs with effective anti-Alzheimer's action: Design, synthesis, crystal structure and in-vitro biological evaluation.

Alzheimer's disease (AD) is multifactorial, progressive neurodegeneration with impaired behavioural and cognitive functions. The multitarget-directed ligand (MTDL) strategies are promising paradigm in drug development, potentially leading to new possible therapy options for complex AD. Herein, a series of novel MTDLs phenylsulfonyl-pyrimidine carboxylate (BS-1 to BS-24) derivatives were designed and synthesized for AD treatment. All the synthesized compounds were validated by 1HNMR, 13CNMR, HRMS, and BS-19 were structurally validated by X-Ray single diffraction analysis. To evaluate the plausible binding affinity of designed compounds, molecular docking study was performed, and the result revealed their significant interaction with active sites of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The synthesized compounds displayed moderate to excellent in vitro enzyme inhibitory activity against AChE and BuChE at nanomolar (nM) concentration. Among 24 compounds (BS-1 to BS-24), the optimal compounds (BS-10 and BS-22) displayed potential inhibition against AChE; IC50 = 47.33 ± 0.02 nM and 51.36 ± 0.04 nM and moderate inhibition against BuChE; IC50 = 159.43 ± 0.72 nM and 153.3 ± 0.74 nM respectively. In the enzyme kinetics study, the compound BS-10 displayed non-competitive inhibition of AChE with Ki = 8 nM. Respective compounds BS-10 and BS-22 inhibited AChE-induced Aß1-42 aggregation in thioflavin T-assay at 10 µM and 20 µM, but BS-10 at 10 µM and 20 µM concentrations are found more potent than BS-22. In addition, the aggregation properties were determined by the dynamic light scattering (DLS) and was found that BS-10 and BS-22 could significantly inhibit self-induced as well as AChE-induced Aß1-42 aggregation. The effect of compounds (BS-10 and BS-22) on the viability of MC65 neuroblastoma cells and their capability to cross the blood-brain barrier (BBB) in PAMPA-BBB were further studied. Further, in silico approach was applied to analyze physicochemical and pharmacokinetics properties of the designed compounds via the SwissADME and PreADMET server. Hence, the novel phenylsulfonyl-pyrimidine carboxylate derivatives can act as promising leads in the development of AChE inhibitors and Aß disaggregator for the treatment of AD.

Beware the respiratory epithelial adenomatoid hamartoma-a malignant masquerador.

Respiratory epithelial adenomatoid hamartoma (REAH) is a rare benign tumour, which can masquerade as a sinonasal malignancy. Commonly arising from the posterior nasal septum, we present the second described case of a lateral nasal cavity wall REAH in a 68-year-old male with a 2-year history of progressive left nasal obstruction. Clinical and radiological assessment predicted malignancy; however, histopathology identified a benign pathology. He was subsequently treated with narrow local excision under general anaesthetic with no evidence of recurrence at post-operative intervals.

Endotheliitis in Coronavirus Disease 2019-Positive Patients After Extremity Amputation for Acute Thrombotic Events.

BACKGROUND: Both arterial and venous thrombotic events of the extremities occur in coronavirus disease 2019 (COVID-19) infection, but the etiology of these events remains unclear. This study sought to evaluate pathology specimens of COVID-19-positive patients postamputation, who were found to have Rutherford 3 acute limb ischemia requiring amputation. METHODS: A retrospective review was performed of all vascular surgery emergency room and inpatient consultations in patients who presented to the Mount Sinai Health System from March 26, 2020, to May 10, 2020. Pathology specimens were examined using hematoxylin and eosin stain. The specimens were assessed for the following: inflammatory cells associated with endothelium/apoptotic bodies, mononuclear cells, small vessel congestion, and lymphocytic endotheliitis. Of the specimens evaluated, 2 patients with a known history of peripheral vascular disease were excluded. RESULTS: Inflammatory cells associated with endothelium/apoptotic bodies were seen in all 4 patients and in 4 of 5 specimens. Mononuclear cells were found in 2 of 4 patients. Small vessel congestion was seen in all patients. Lymphocytic endotheliitis was seen in 1 of 4 patients. CONCLUSIONS: This study shows endotheliitis in amputation specimens of four patients with COVID-19 disease and Rutherford Class 3 acute limb ischemia. The findings in these patients is more likely an infectious angiitis because of COVID-19.

Inhibition of Amyloid Fibrillation of HEWL by 4-Methylcoumarin and 4-Methylthiocoumarin Derivatives.

BACKGROUND: Several human diseases like Parkinson's, Alzheimer's disease, and systemic amyloidosis are associated with the misfolding and aggregation of protein molecules. OBJECTIVE: The present study demonstrated the comparison of 4-methyl coumarin and 4-methylthiocoumarin derivative for their anti-amyloidogenic and disaggregation activities. The hen egg-white lysozyme is used as a model system to study protein aggregation and disaggregation under in vitro conditions. METHODS: Techniques used in the study were Thioflavin T fluorescence assay, intrinsic fluorescence assay, circular dichroism, transmission electron microscopy, and molecular dynamics. RESULTS: Fifteen compounds were screened for their anti-amyloidogenic and disaggregation potential. Six compounds significantly inhibited the fibril formation, whereas ten compounds showed disaggregation property of pre-formed fibrils. Under in vitro conditions, the compound C3 and C7 showed significant inhibition of fibril formation in a concentration-dependent manner as compared to control. C3 and C7 demonstrated 93% and 76% inhibition of fibril formation, respectively. Furthermore, C3 and C7 exhibited 83% and 76% disaggregation activity, respectively, of pre-formed HEWL fibrils at their highest concentration. These anti-amyloidogenic and disaggregation potential of C3 and C7 were validated by intrinsic fluorescence, CD, molecular dynamics, and TEM study. DISCUSSION: 4-methylthiocoumarins derivatives have shown better anti-amyloidogenic activity as compared to 4-methylcoumarin derivatives for both amyloid formation as well as disaggregation of preformed amyloid fibrils. Structurally, the derivatives of 4-methylthiocoumarins (C3 and C7) contain thio group on 2nd position that might be responsible for anti-amyloidogenic activity as compared to 4- methylcoumarin derivatives (C2 and C4). CONCLUSION: C3 and C7 are novel 4-methylthiocoumarin derivatives that can be used as a lead for alleviation and symptoms associated with protein aggregation disorders.

Identification of phytochemicals as potential therapeutic agents that binds to Nsp15 protein target of coronavirus (SARS-CoV-2) that are capable of inhibiting virus replication.

BACKGROUND: Coronavirus disease 2019 (COVID-19) playing havoc across the globe caused 585,727 deaths and 13,616,593 confirmed cases so far as per World Health Organization data released till 17th July 2020. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2) is responsible for causing this pandemic across different continents. It is not only impacting the world economy but also quarantined millions of people in their homes or hospitals. PURPOSE: At present, there is no Food and Drug Administration-approved drug or vaccine available to treat this disease. Still, people are trying various pre-existing medicines that are known to have anti-viral or anti-parasitic effects. In view of this, the present study aimed to study the binding potential of various phytochemicals present in multiple natural plant extract as a secondary metabolite to non-structural protein 15 (Nsp15) protein, a drug target known to play a crucial role in virulence of coronavirus. METHOD: Nsp15 protein was selected because it shows 89% similarity to the other SARS-CoV, which caused the earlier outbreak. The assumption is that inhibition of Nsp15 slowdowns the viral replication. Phytochemicals are selected as these are present in various plant parts (seed, flower, roots, etc.), which are used in different food cuisines in different geographical regions across the globe. The molecular docking approach was performed using two different software, i.e., Autodock, and Swissdock, to study the interaction of various phytochemicals with Nsp15 protein. Hydroxychloroquine is used as a positive control as it is used by medical professionals showing some positive effects in dealing with coronavirus. RESULTS: The present study demonstrated the binding potential of approximately 50 phytochemicals with Nsp15 and capable of inhibiting the viral replication, although in vitro and in vivo tests are required to confirm these findings. CONCLUSIONS: In conclusion, the present study successfully demonstrated the binding of phytochemicals such as sarsasapogenin, ursonic acid, curcumin, ajmalicine, novobiocin, silymarin and aranotin, piperine, gingerol, rosmarinic acid, and alpha terpinyl acetate to Nsp15 viral protein and they might play a key role in inhibiting SARS-CoV-2 replication.