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Nonpharmaceutical interventions (NPI) and ring vaccination (i.e., vaccination that primarily targets contacts and contacts of contacts of Ebola cases) are currently used to reduce the spread of Ebola during outbreaks. Because these measures are typically initiated after an outbreak is declared, they are limited by real-time implementation challenges. Preventive vaccination may provide a complementary option to help protect communities against unpredictable outbreaks. This study aimed to assess the impact of preventive vaccination strategies when implemented in conjunction with NPI and ring vaccination.A spatial-explicit, individual-based model (IBM) that accounts for heterogeneity of human contact, human movement, and timing of interventions was built to represent Ebola transmission in the Democratic Republic of the Congo. Simulated preventive vaccination strategies targeted healthcare workers (HCW), frontline workers (FW), and the general population (GP) with varying levels of coverage (lower coverage: 30% of HCW/FW, 5% of GP; higher coverage: 60% of HCW/FW, 10% of GP) and efficacy (lower efficacy: 60%; higher efficacy: 90%).The IBM estimated that the addition of preventive vaccination for HCW reduced cases, hospitalizations, and deaths by ∼11 % to ∼25 % compared with NPI + ring vaccination alone. Including HCW and FW in the preventive vaccination campaign yielded ∼14 % to ∼38 % improvements in epidemic outcomes. Further including the GP yielded the greatest improvements, with ∼21 % to ∼52 % reductions in epidemic outcomes compared with NPI + ring vaccination alone. In a scenario without ring vaccination, preventive vaccination reduced cases, hospitalizations, and deaths by ∼28 % to ∼59 % compared with NPI alone. In all scenarios, preventive vaccination reduced Ebola transmission particularly during the initial phases of the epidemic, resulting in flatter epidemic curves.The IBM showed that preventive vaccination may reduce Ebola cases, hospitalizations, and deaths, thus safeguarding the healthcare system and providing more time to implement additional interventions during an outbreak.

The study aimed to identify novel genes for idiopathic hypogonadotropic hypogonadism (IHH).A cohort of 1387 probands with IHH underwent exome sequencing and de novo, familial, and cohort-wide investigations. Functional studies were performed on 2 p190 Rho GTPase-activating proteins (p190 RhoGAP), ARHGAP35 and ARHGAP5, which involved in vivo modeling in larval zebrafish and an in vitro p190A-GAP activity assay.Rare protein-truncating variants (PTVs; n = 5) and missense variants in the RhoGAP domain (n = 7) in ARHGAP35 were identified in IHH cases (rare variant enrichment: PTV [unadjusted P = 3.1E-06] and missense [adjusted P = 4.9E-03] vs controls). Zebrafish modeling using gnrh3:egfp phenotype assessment showed that mutant larvae with deficient arhgap35a, the predominant ARHGAP35 paralog in the zebrafish brain, display decreased GnRH3-GFP+ neuronal area, a readout for IHH. In vitro GAP activity studies showed that 1 rare missense variant [ARHGAP35 p.(Arg1284Trp)] had decreased GAP activity. Rare PTVs (n = 2) also were discovered in ARHGAP5, a paralog of ARHGAP35; however, arhgap5 zebrafish mutants did not display significant GnRH3-GFP+ abnormalities.This study identified ARHGAP35 as a new autosomal dominant genetic driver for IHH and ARHGAP5 as a candidate gene for IHH. These observations suggest a novel role for the p190 RhoGAP proteins in GnRH neuronal development and integrity.

Congenital heart defects are the leading cause of right heart failure in pediatric patients. Implantation of c-kitsup+/supcardiac-derived progenitor cells (CPCs) is being clinically evaluated to treat the failing right ventricle (RV), but faces limitations due to reduced transplant cell survival, low engraftment rates, and low retention. These limitations have been exacerbated due to the nature of cell delivery (narrow needles) and the non-optimal recipient microenvironment (reactive oxygen species (ROS)). Extracellular matrix (ECM) hydrogels derived from porcine left ventricular (LV) myocardium have emerged as a potential therapy to treat the ischemic LV and have shown promise as a vehicle to deliver cells to injured myocardium. However, no studies have evaluated the combination of an injectable biomaterial, such as an ECM hydrogel, in combination with cell therapy for treating RV failure. In this study we characterized LV and RV myocardial matrix (MM) hydrogels and performed in vitro evaluations of their potential to enhance CPC delivery, including resistance to forces experienced during injection and exposure to ROS, as well as their potential to enhance angiogenic paracrine signaling. While physical properties of the two hydrogels are similar, the decellularized LV and RV have distinct protein signatures. Both materials were equally effective in protecting CPCs against needle forces and ROS. CPCs encapsulated in either the LV MM or RV MM exhibited similar enhanced potential for angiogenic paracrine signaling when compared to CPCs in collagen. The RV MM without cells, however, likewise improved tube formation, suggesting it should also be evaluated as a potential standalone treatment.

ERI-type molecular sieves (SSZ-98, UZM-12, ERI-type zeolite, SAPO-17) are synthesized with varying Si/Al = 5–9 and Si/T-atoms = 0.034–0.12 using several organic structure-directing agents (OSDAs), and evaluated as catalysts for the methanol-to-olefins (MTO) reaction. SAPO-34 (Si/T-atoms = 0.089) and SSZ-13 (Si/Al = 15) are also prepared and tested for comparison. The ERI-type zeolites gave improved ethylene-to-propylene ratios (E/P = 1.1–1.9) over SSZ-13 (E/P = 0.82) and SAPO-34 (E/P = 0.85). The SAPO-17 samples produced an E/P of 0.7–1.1 and a generally high C₄+ fraction. The differences observed in the olefins product distributions between the zeolites with low framework Si/Al (E/P > 1.5) and SAPO-17 with low Si/T-atom < 0.1 (E/P ≤ 1 and high C₄+) are the result of slower maturation of aromatic hydrocarbon-pool (HP) species and the presence of aromatics with bulky alkyl-groups (C₃-C₄) in the SAPO-17 samples. The rapid formation of cyclic intermediates and the shift in their composition towards less-methylated ((CH₃)_(n≤4)) methylbenzenes and methylnaphthalenes are found to be key to enhancing the ethylene selectivity in ERI-type molecular sieves.

Whether alterations in the microtubule cytoskeleton affect the ability of endothelial cells (ECs) to sprout and form branching networks of tubes was investigated in this study. Bioassays of human EC tubulogenesis, where both sprouting behavior and lumen formation can be rigorously evaluated, were used to demonstrate that addition of the microtubule-stabilizing drugs, paclitaxel, docetaxel, ixabepilone, and epothilone B, completely interferes with EC tip cells and sprouting behavior, while allowing for EC lumen formation. In bioassays mimicking vasculogenesis using single or aggregated ECs, these drugs induce ring-like lumens from single cells or cyst-like spherical lumens from multicellular aggregates with no evidence of EC sprouting behavior. Remarkably, treatment of these cultures with a low dose of the microtubule-destabilizing drug, vinblastine, led to an identical result, with complete blockade of EC sprouting, but allowing for EC lumen formation. Administration of paclitaxel in vivo markedly interfered with angiogenic sprouting behavior in developing mouse retina, providing corroboration. These findings reveal novel biological activities for pharmacologic agents that are widely utilized in multidrug chemotherapeutic regimens for the treatment of human malignant cancers. Overall, this work demonstrates that manipulation of microtubule stability selectively interferes with the ability of ECs to sprout, a necessary step to initiate and form branched capillary tube networks.

This article is a reprint of a previously published article. For citation purposes, please use the original publication details: Coker AL, Davis KE, Arias I, et al. Physical and mental health effects of intimate partner violence for men and women. Am J Prev Med. 1985;1(6):1-8.Few population-based studies have assessed the physical and mental health consequences of both psychological and physical intimate partner violence (IPV) among women or men victims. This study estimated IPV prevalence by type (physical, sexual, and psychological) and associated physical and mental health consequences among women and men.The study analyzed data from the National Violence Against Women Survey (NVAWS) of women and men aged 18 to 65. This random-digit-dial telephone survey included questions about violent victimization and health status indicators.A total of 28.9% of 6790 women and 22.9% of 7122 men had experienced physical, sexual, or psychological IPV during their lifetime. Women were significantly more likely than men to experience physical or sexual IPV (relative risk [RR]=2.2, 95% confidence interval [CI]=2.1, 2.4) and abuse of power and control (RR=1.1, 95% CI=1.0, 1.2), but less likely than men to report verbal abuse alone (RR=0.8, 95% CI=0.7, 0.9). For both men and women, physical IPV victimization was associated with increased risk of current poor health; depressive symptoms; substance use; and developing a chronic disease, chronic mental illness, and injury. In general, abuse of power and control was more strongly associated with these health outcomes than was verbal abuse. When physical and psychological IPV scores were both included in logistic regression models, higher psychological IPV scores were more strongly associated with these health outcomes than were physical IPV scores.Both physical and psychological IPV are associated with significant physical and mental health consequences for both male and female victims.

Background and purpose Providing feedback is an important skill for all healthcare professionals both within and outside of their discipline. Although student pharmacists frequently receive feedback during both didactic and experiential education, training on how to provide feedback to others is less common. Educational activity and setting An elective was designed to expose second-year pharmacy students to “grand rounds” with practicing pharmacists as the presenters. Students provided feedback to presenters on presentation style and assessment questions. The primary objective of this research project was to determine if the elective improved students' motivations, comfort, and confidence in providing constructive written feedback. Findings Over two course offerings, 54% (19 of 35) of enrolled students completed both the pre- and post-surveys. At baseline, the majority of students self-identified as being motivated, comfortable, and confident with providing quality written feedback with the exception of two specific areas: motivation to provide quality written feedback and comfort with providing difficult or sensitive written feedback. At the end of the course, the majority of students self-identified as being motivated, comfortable, and confident across all areas queried. All students agreed or strongly agreed that the efficiency and quality of their written feedback improved during the course. Summary The course offered several benefits to students, including learning clinical topics from a variety of presenters and developing feedback skills. The implementation of the grand rounds elective provided students an opportunity to develop their motivation, comfort, and confidence with providing quality constructive written feedback.

Consistent individual differences in behaviour, or personality, likely influence patterns of space use and resource use in wild animals. However, studies on personality-dependent space use in natural ecosystems remain rare due to the difficulty of obtaining paired data sets on spatial dynamics and repeated personality measures from marked animals. We used repeated standardized assays (open field, mirror image stimulation, flight initiation distance and behaviour in trap) to perform the first characterization of personality in a free-ranging population of golden-mantled ground squirrels, Callospermophilus lateralis. We then used multilevel modelling to determine whether personality influenced 95% home range size, 50% core area size, movement speed or use of a preferred resource (‘perches’, vision-enhancing prominences such as rocks, which enhance survival) in nature. Data collected over 3 years showed that individual squirrels consistently differed in activity, sociability, boldness and aggressiveness (adjusted repeatability 0.16–0.44) and that activity was correlated with sociability (posterior mean correlation [95% credible interval] = 0.65 [0.39, 0.87]). We did not find an effect of personality on home range size, but bolder individuals maintained larger core areas than shyer individuals. More active and bolder individuals moved faster under natural conditions compared to their less active and shyer conspecifics. Individuals that scored higher for all four personality traits had more perches in both their home ranges and core areas compared to individuals with lower personality scores. Our results are indicative of personality-dependent space use and resource use in this study system. We hope our study will inspire future research that links animal personality with spatial ecology to inform wildlife management in natural ecosystems.

Objective To identify surgical resident and clinical rotation attributes which predict on-shift napping through objectively measured sleep patterns and work schedules over a 2-month period. Design In a cross-sectional study, participants provided schedules, completed the Epworth Sleepiness Scale (ESS), and wore sleep-tracking devices (Zulu watch) continuously for 8 weeks. Multiple linear regression predicted percent days with on-shift napping from resident and rotation characteristics. Setting Greater Washington, DC area hospitals. Participants Twenty-two (n = 22) surgical residents rotating in at least 1 of 5 different clinical rotation categories. Results Residents slept 6 hours within a 24-hour period (370 ± 129 minutes) with normal sleep efficiency (sleep efficiency (SE): 87.13% ± 7.55%). Resident ESS scores indicated excessive daytime sleepiness (11.64 ± 4.03). Ninety-five percent (n = 21) of residents napped on-shift. Residents napped on-shift approximately 32% of their working days and were most likely to nap when working between 23:00 and 05:00 hours. Earlier shift start times predicted less on-shift napping (B = −0.08, SE = 0.04, β = −2.40, t = −2.09, p = 0.05) while working more night shifts (B = 1.55, SE = 0.44, β = 4.12, t = 3.52, p = 0.003) and shifts over 24 hours (B = 1.45, SE = 0.55, β = 1.96, t = 2.63, p = 0.01) predicted more frequent on-shift napping. Conclusions Residents are taking advantage of opportunities to nap on-shift. Working at night seems to drive on-shift napping. However, residents still exhibit insufficient sleep and daytime sleepiness which could reduce competency and represent a safety risk to themselves and/or patients. These findings will help inform intervention strategies which are tailored to surgical residents using a biomathematical model of fatigue.

Aims To assess knowledge of diabetes-related eye disease in Australians with type 2 diabetes and its associations with diabetic retinopathy (DR), other ocular complications and vision-related quality of life. Methods A random sample from the Fremantle Diabetes Study Phase II cohort (n = 360) was invited to participate. Knowledge was assessed using 10 multiple-choice questions covering how diabetes affects the eyes, frequency of ophthalmic screening, risk factors, prevention, available treatments, and prognosis. DR was assessed from fundus photographs. Multiple linear regression was used to identify independent associates of the knowledge score (KS). Results We included 264 participants (mean ± SD age 72.1 ± 9.2 years, 56.8% male, median [IQR] diabetes duration 15.4 [11.1–22.3] years). The mean ± SD KS out of 10 was 5.3 ± 1.8. Most (67%) participants knew diabetes can affect the eye and lead to blindness. Only 13.6% knew that DR screening intervals depend on risk factors. Those with moderate non-proliferative DR (NPDR) or worse had a better knowledge score (B = 1.37,P = 0.008) after adjusting for age (B = −0.03, P = 0.004) and education beyond primary school (B = 1.75, P Conclusions Overall knowledge of diabetes-related ocular complications was suboptimal. Education targeting eye disease may benefit people with type 2 diabetes who are older, less well educated and/or who have no DR/mild NPDR.

Silica-supported phosphoric acid and metal phosphate catalyzed 1,3-butadiene (BDE) production from 2,3-butanediol (2,3-BDO) was studied using experimental and computational techniques. The catalyst was initially tested in a continuous flow reactor using commercially available 2,3-BDO, leading to maximum BDE yields of 63 C%. Quantum chemical mechanistic studies revealed 1,2-epoxybutane is a kinetically viable and thermodynamically stable intermediate, supported by experimental demonstration that this epoxide can be converted to BDE under standard reaction conditions. Newly proposed E2 and SN2’ elementary steps were studied to rationalize the formation of BDE and all detected side-products. Additionally, using QM/MM (ONIOM) calculations, we modeled silica-supported phosphate catalysts to study the effect of the alkali metal center. Natural population analysis showed that phosphate oxygen atoms are more negatively charged in CsH2PO4/SiO2 than in H3PO4/SiO2. In combination with temperature-programmed desorption experiments using CO2, the results of this study suggest that the improved selectivity achieved when adding the metal center is related to an increase in the basicity of the catalyst.

Substantial waning of antibody responses to the Pfizer-BioNTech mRNA vaccine 6 months after the second vaccination.

Purpose Sleep loss and fatigue, common in resident physicians, are related to increased medical errors and decreased physician wellbeing. Biomathematical modeling of fatigue can illuminate the relationship between surgical resident fatigue and work scheduling. Methods General surgery resident schedules were analyzed using the Sleep, Activity, Fatigue and Task Effectiveness model to predict resident performance during work hours. Hypothetical naps were built into the model to assess their effect on predicted performance and fatigue risk. Results 12 months of duty-hours logged by 89 residents, ranging from post-graduate year (PGY) 1–5, were analyzed. Residents had moderate levels of fatigue risk over 12 month schedules, with at least an 8-h sleep debt during 24.36% of shifts. Performance scores decreased as shift lengths increased. The addition of hypothetical naps increased predicted performance and reduced shift time with fatigue risk. Conclusions Biomathematical modeling of resident schedules and predicts a concerning level of fatigue and decreased effectiveness. Naps may improve performance without decreasing scheduled hours.

Introduction Frailty is an important prognostic factor, and the association with postoperative dependence is important outcome to older adults. We examined the association of frailty with long-term homecare utilization for older adults following cancer surgery. Methods In this population-based cohort study, we determined frailty status in all older adults (≥70 years old) undergoing cancer resection (2007–2017). Outcomes were receipt of homecare and intensity of homecare (days per month) over 5 years. We estimated the adjusted association of frailty with outcomes, and assessed interaction with age. Results Of 82,037 patients, 6443 (7.8%) had frailty. Receipt and intensity of homecare was greater with frailty, but followed similar trajectories over 5 years between groups. Homecare receipt peaked in the first postoperative month (51.4% frailty, 43.1% no frailty), and plateaued by 1 year until 5 years (28.5% frailty, 12.8% no frailty). After 1 year, those with frailty required 4 more homecare days per month than without frailty (14 vs 10 days/month). After adjustment, frailty was associated with increased homecare receipt (hazard ratio 1.40; 95%CI 1.35–1.45), and increasing intensity each year (year 1 incidence rate ratio [IRR] 1.22, 95%CI 1.18–1.27 to year 5 IRR 1.47, 95%CI 1.35–1.59). The magnitude of the association of frailty with homecare receipt decreased with age (pinteraction Conclusion While the trajectory of homecare receipt and intensity is similar between those with and without frailty, frailty is associated with increased receipt of homecare and increased intensity of homecare after cancer surgery across all age groups.

Background Rectal cancer patients undergoing preoperative radiotherapy experience a significant symptom burden. However, it is unknown whether symptoms during radiotherapy may portend adverse postoperative outcomes and healthcare utilization. Methods A retrospective cohort study was performed of rectal cancer patients undergoing neoadjuvant radiotherapy and proctectomy in Ontario from 2007 to 2014. The primary outcome was a complicated postoperative course–a dichotomous variable created as a composite of postoperative mortality, major morbidity, or hospital readmission. Patient-reported Edmonton Symptom Assessment System (ESAS) scores, collected routinely at outpatient provincial cancer center visits, were linked to administrative healthcare databases. The receiver-operating characteristic analysis was used to compare ESAS scoring approaches and to stratify patients into low versus high symptom score groups. Multivariable regression models were constructed to evaluate associations between preoperative symptom scores and postoperative outcomes. Results 1455 rectal cancer patients underwent sequential radiotherapy and proctectomy during the study period and recorded symptom assessments. Patients with high preoperative symptom scores were significantly more likely to experience a complicated postoperative course (OR 1.55, 95% CI 1.23-1.95). High preoperative ESAS scores were also associated with the secondary outcomes of emergency department visits (OR 1.34, 95% CI 1.08-1.66) and longer length of stay (IRR 1.23, 95% CI 1.04-1.45). Conclusions Rectal cancer patients reporting elevated symptom scores during neoadjuvant radiotherapy have increased odds of experiencing a complicated postoperative course. Preoperative patient-reported outcome screening may be a useful tool to identify at-risk patients and to efficiently direct perioperative supportive care.

Red blood cell transfusions (RBCT) remain a concern for patients undergoing hepatectomy. The effect of tranexamic acid (TXA), an anti-fibrinolytic, on receipt of RBCT in colorectal liver metastases (CRLM) resection was examined.Hepatectomies for CRLM over 2009-2014 were included. Primary outcome was 30-day receipt of RBCT. Secondary outcomes were 30-day major morbidity (Clavien-Dindo III-V) and 90-day mortality. Multivariable modelling examined the adjusted association between TXA and outcomes.Of 433 included patients, 146 (34%) received TXA. TXA patients were more likely to have inflow occlusion (41.8% vs. 23.1%; p 0.01) and major hepatectomies (56.1% vs. 45.6%; p = 0.0193). TXA was independently associated with lower risk of RBCT (Relative risk (RR) 0.59; 95% confidence interval (95%CI): 0.42-0.85), but not with 30-day major morbidity (adjusted RR 1.02; 95%CI: 0.64-1.60) and 90-day mortality (univariable RR 0.99; 95%CI: 0.95-1.03).Intraoperative TXA was associated with a 41% reduction in risk of 30 -day receipt of RBCT after hepatectomy for CRLM. This finding is important to potentially improve healthcare resource allocation and patient outcomes. Pending further evidence, intraoperative TXA may be an effective method of reducing RBCT in hepatectomy for CRLM.

Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10(−11)). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10(−15)). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.

Over the past century, governmental involvement in the delivery of health care has grown steadily through health policy initiatives and increased regulations. Traditionally, the involvement in this process for the orthopedic surgeon was minimal because they were focused primarily on direct patient care. These two pathways have met a crossroads, however, where it has now become necessary for the orthopedic surgeon to advocate on behalf of themselves and their patients to guide and influence the legislative and regulatory processes. This article reviews the background of orthopedic advocacy and discusses ways in which the interested surgeon can become involved.

Alzheimer’s disease (AD) is associated with disturbances in blood glucose regulation, and type-2 diabetes elevates the risk for dementia. A role for amyloid-β peptide (Aβ) in linking these age-related conditions has been proposed, tested primarily in transgenic mouse lines that overexpress mutated amyloid precursor protein (APP). Because APP has its own impacts on glucose regulation, we examined the BRI-Aβ42 line (“Aβ42-tg”), which produces extracellular Aβ1–42 in the CNS without elevation of APP. We also looked for interactions with diet-induced obesity (DIO) resulting from a high-fat, high-sucrose (“western”) diet. Aβ42-tg mice were impaired in both spatial memory and glucose tolerance. Although DIO induced insulin resistance, Aβ1–42 accumulation did not, and the impacts of DIO and Aβ on glucose tolerance were merely additive. Aβ42-tg mice exhibited no significant differences from wild-type in insulin production, body weight, lipidemia, appetite, physical activity, respiratory quotient, an-/orexigenic factors, or inflammatory factors. These negative findings suggested that the phenotype in these mice arose from perturbation of glucose excursion in an insulin-independent tissue. To wit, cerebral cortex of Aβ42-tg mice had reduced glucose utilization, similar to human patients with AD. This was associated with insufficient trafficking of glucose transporter 1 to the plasma membrane in parenchymal brain cells, a finding also documented in human AD tissue. Together, the lower cerebral metabolic rate of glucose and diminished function of parenchymal glucose transporter 1 indicate that aberrant regulation of blood glucose in AD likely reflects a central phenomenon, resulting from the effects of Aβ on cerebral parenchyma, rather than a generalized disruption of hypothalamic or peripheral endocrinology. The involvement of a specific glucose transporter in this deficit provides a new target for the design of AD therapies.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in late 2019 has triggered an ongoing global pandemic whereby infection may result in a lethal severe pneumonia-like disease designated as coronavirus disease 2019 (COVID-19). To date, millions of confirmed cases and hundreds of thousands of deaths have been reported worldwide, and there are currently no medical countermeasures available to prevent or treat the disease. The purported development of a vaccine could require at least 1-4 years, while the typical timeline from hit finding to drug registration of an antiviral is >10 years. Thus, repositioning of known drugs can significantly accelerate the development and deployment of therapies for COVID-19. To identify therapeutics that can be repurposed as SARS-CoV-2 antivirals, we developed and initiated a high-throughput cell-based screen that incorporates the essential viral papain-like protease (PLpro) and its peptide cleavage site into a luciferase complementation assay to evaluate the efficacy of known drugs encompassing approximately 15,000 clinical-stage or US Food and Drug Administration (FDA)-approved small molecules. Confirmed inhibitors were also tested to determine their cytotoxic properties. Here, we report the identification of four clinically relevant drugs that exhibit selective inhibition of the SARS-CoV-2 viral PLpro.

Summary Background Epithelioid sarcoma is a rare and aggressive soft-tissue sarcoma subtype. Over 90% of tumours have lost INI1 expression, leading to oncogenic dependence on the transcriptional repressor EZH2. In this study, we report the clinical activity and safety of tazemetostat, an oral selective EZH2 inhibitor, in patients with epithelioid sarcoma. Methods In this open-label, phase 2 basket study, patients were enrolled from 32 hospitals and clinics in Australia, Belgium, Canada, France, Germany, Italy, Taiwan, the USA, and the UK into seven cohorts of patients with different INI1-negative solid tumours or synovial sarcoma. Patients eligible for the epithelioid sarcoma cohort (cohort 5) were aged 16 years or older with histologically confirmed, locally advanced or metastatic epithelioid sarcoma; documented loss of INI1 expression by immunohistochemical analysis or biallelic SMARCB1 (the gene that encodes INI1) alterations, or both; and an Eastern Cooperative Oncology Group performance status score of 0–2. Patients received 800 mg tazemetostat orally twice per day in continuous 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed objective response rate measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints were duration of response, disease control rate at 32 weeks, progression-free survival, overall survival, and pharmacokinetic and pharmacodynamic analyses (primary results reported elsewhere). Time to response was also assessed as an exploratory endpoint. Activity and safety were assessed in the modified intention-to-treat population (ie, patients who received one or more doses of tazemetostat). This trial is registered with ClinicalTrials.gov , NCT02601950 , and is ongoing. Findings Between Dec 22, 2015, and July 7, 2017, 62 patients with epithelioid sarcoma were enrolled in the study and deemed eligible for inclusion in this cohort. All 62 patients were included in the modified intention-to-treat analysis. Nine (15% [95% CI 7–26]) of 62 patients had an objective response at data cutoff (Sept 17, 2018). At a median follow-up of 13·8 months (IQR 7·8–19·0), median duration of response was not reached (95% CI 9·2–not estimable). 16 (26% [95% CI 16–39]) patients had disease control at 32 weeks. Median time to response was 3·9 months (IQR 1·9–7·4). Median progression-free survival was 5·5 months (95% CI 3·4–5·9), and median overall survival was 19·0 months (11·0–not estimable). Grade 3 or worse treatment-related adverse events included anaemia (four [6%]) and weight loss (two [3%]). Treatment-related serious adverse events occurred in two patients (one seizure and one haemoptysis). There were no treatment-related deaths. Interpretation Tazemetostat was well tolerated and showed clinical activity in this cohort of patients with advanced epithelioid sarcoma characterised by loss of INI1/SMARCB1. Tazemetostat has the potential to improve outcomes in patients with advanced epithelioid sarcoma. A phase 1b/3 trial of tazemetostat plus doxorubicin in the front-line setting is currently underway ( NCT04204941 ). Funding Epizyme.

As the largest component of the United States health care workforce, nurses will play a critical role in radiological or nuclear disaster medical response. Despite this, the United States' schools of nursing are not currently providing radiation content (75% teach zero or1 hour), and much of the current nursing workforce may not have received adequate response education and training. Nurses working in emergency departments and those who work at hospitals within the Radiation Injury Treatment Network will be relied on heavily, but little is known about whether these nurses possess the knowledge and skills needed to care for and protect patients after a radiation emergency. Current federal and state radiological/nuclear preparedness plans may be built on false assumptions of readiness, which would have serious implications for national preparedness and the National Health Security Strategy. The purpose of this study was to assess nurses' knowledge and skill in emergency radiological or nuclear response and determine their willingness to use mobile technology for education and training in response to a large-scale radiation event.Descriptive cross-sectional survey of registered nurse members of the Emergency Nurses Association and/or those employed at Radiation Injury Treatment Network centers.Knowledge scores were low for all respondents. Prior attendance at a Radiation Emergency Medical Management course, use of online resources, and having a preparedness plan were associated with higher scores. Experience with a radiation emergency was associated with the highest score. Nurses are willing to use mobile technology during a radiological or nuclear disaster response.Key nurses may not possess adequate knowledge or clinical competence to participate in radiation response activities. The results of this assessment identified educational gaps and areas to strengthen nursing education and clinical skills.

Background This study evaluated the presence of the rotator cable intraoperatively and compared its prevalence according to both patient age and rotator cuff integrity. The study hypothesis was that the cable would be more prevalent in older patients and patients with partial-thickness tears. Methods Patients who were undergoing shoulder arthroscopy and were aged at least 16 years were included in this study, whereas those who had a cuff tear of more than 1 tendon or who had a video with poor visualization of the rotator cuff insertion were excluded. Intraoperative videos were collected, deidentified, and distributed to 7 orthopedic surgeons to define rotator cable and cuff tear characteristics. Results A total of 58 arthroscopic videos (average patient age, 46 years; range, 16-75 years) were evaluated. The observers were in the most agreement on identifying the presence of a cable, with a κ coefficient of 0.276. Patients with the rotator cable were significantly older than those without it (mean age, 52.1 years vs. 42.5 years; P = .008), and a positive and significant correlation was found between rotator cable presence and increasing patient age (r = 0.27, P = .04). A significant association was noted between tear degree and cable presence (P = .002). There was no significant association with cable presence in patients with a full-thickness tear. Conclusions In this study, an intraoperative analysis was performed to define the presence of the rotator cable and correlate this with both patient age and rotator cuff integrity. The hypothesis was confirmed in that patients older than 40 years had a significantly higher rotator cable prevalence.

The goal of this study was to investigate the impact of potassium deficiency on cotton seedling growth and development at the individual, physiological, biochemical, and molecular levels. Potassium is an important plant nutrient; our results show that potassium deficiency significantly affected cotton seedling growth and development, evidenced by reduced plant height, and total areas of the leaves and roots as well as further reduced both fresh and dry biomass of the entire plants. Potassium deficiency also significantly inhibited root and leaf respiration and leaf photosynthesis. Compared with the controls, potassium deficiency significantly inhibited root elongation and total root surface areas that further inhibited cotton seedlings to uptake nutrients from the medium. Potassium deficiency induced aberrant expression of both microRNAs (miRNAs) and their protein-coding targets. These miRNAs regulate plant root development as well as response to abiotic stresses. Potassium deficiency altered the expression of miRNAs that regulate the expression of protein-coding genes controlling root development and response to potassium deficiency. miRNAs regulate root development and further control plant development in cotton seedlings under potassium deficiency. In summary, potassium deficiency significantly affected the cotton seedling photosynthesis and respiration that resulted in inhibition of cotton seedling growth and development potentially due to the miRNA-mediated mechanism.

PIK3CA mutations may have prognostic value for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer, representing an important potential target for systemic therapy. Prognostic and predictive values associated with PIK3CA mutations are not well understood. A comprehensive search of PubMed/MEDLINE, EMBASE, Cochrane Central, and conference abstracts was performed for English-language articles published January 1993 through April 2019. Articles were categorized by treatment arms based on experimental and treatment drug classes. Information on progression-free survival (PFS), hazard ratios, overall survival, response rate, and clinical benefit rate was obtained. A total of 17 studies were included. Among those evaluating non-PI3Ki based therapies, 91% showed numerically shorter median PFS, ranging from 1.5 to 19.2 months and 1.8 to 29.6 months for the mutant versus non-mutant subgroups, respectively. Where reported (n = 13 studies), PFS was shorter between those arms offering endocrine monotherapy (range, 1.6-14.7 months) compared with a corresponding targeted therapy + endocrine monotherapy (range, 3.9-29.6 months). Of 5 PI3Ki-based arms comparing PFS, higher median PFS in PIK3CA mutant versus non-mutant cases was demonstrated. PFS was shorter for patients with PIK3CA mutant (range, 1.6-19.2 months) compared with PIK3CA wild-type (range, 1.8-29.6 months) in 10 (71%) of 14 treatment arms reporting PFS. Studies (n = 4) not reporting PFS reported response rate, but there were no clear directional trends. The presence of PIK3CA mutations may be associated with worse clinical outcomes in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. Clinical outcomes such as PFS may be improved using a combination of PI3Ki-based therapies and endocrine therapies among this population. However, more research is warranted to fully elucidate this association.

Objectives Lung cancer is associated with significant disease- and treatment-related morbidity. The Edmonton Symptom Assessment System (ESAS) is a tool developed to elicit patients' own assessment of the severity of common cancer-associated symptoms. The objective of this study was to examine symptom severity in the 12 months following diagnosis of lung cancer, and to identify predictors of high symptom burden. Materials and Methods : This was a retrospective population-based cohort study, including patients with stage I-III lung cancer diagnosed between 2007–2016, and who had symptom screening in the 12 months following diagnosis. The proportion of patients reporting severe symptoms (ESAS ≥ 7) in the year following diagnosis was plotted over time. Multivariable regression models were constructed to identify factors associated with severe symptoms. Results 69,440 unique symptom assessments were reported by 11,075 lung cancer patients. Tiredness was the most prevalent severe symptom (47.3 %), followed by shortness of breath (39.4 %) and poor wellbeing (36.5 %) among all disease stages. Patients diagnosed with higher stage disease reported more severe symptoms, but symptom trajectories were similar for all stages in the year following diagnosis. Disease stage (RR 1.10–2.01), comorbidity burden (RR 1.17–1.51), degree of socioeconomic marginalization (RR1.15-1.45), and female sex (RR 1.15–1.50) were associated with reporting severe symptoms in the year following diagnosis. Conclusion Severe physical and psychological symptoms persist throughout the first year following lung cancer diagnosis, regardless of disease stage. Those at risk of experiencing high symptom burden may benefit from targeted supportive care interventions, including psychosocial support aimed at improving health-related quality of life.

Tolerance to innocuous antigens from the diet and the commensal microbiota is a fundamental process essential to health. Why tolerance is efficiently induced to substances arising from the hostile environment of the gut lumen is incompletely understood but may be related to how these antigens are encountered by the immune system. We observed that goblet cell associated antigen passages (GAPs), but not other pathways of luminal antigen capture, correlated with the acquisition of luminal substances by lamina propria (LP) antigen presenting cells (APCs) and with the sites of tolerance induction to luminal antigens. Strikingly this role extended beyond antigen delivery. The GAP function of goblet cells facilitated maintenance of pre-existing LP T regulatory cells (Tregs), imprinting LP-dendritic cells with tolerogenic properties, and facilitating LP macrophages to produce the immunomodulatory cytokine IL-10. Moreover, tolerance to dietary antigen was impaired in the absence of GAPs. Thus, by delivering luminal antigens, maintaining pre-existing LP Tregs, and imprinting tolerogenic properties on LP-APCs GAPs support tolerance to substances encountered in the hostile environment of the gut lumen.

The Environmental Affordances Model theorizes that systemic racism disproportionately exposes African Americans in the United States to chronic everyday stressors (e.g., individual racism) while simultaneously shaping the availability of coping resources (e.g., fast food outlets) and engagement in self-regulatory strategies (e.g., emotional eating). Greater engagement in self-regulatory strategies is theorized to preserve mental health while contributing to medical morbidities and mortality.However, few studies have tested the Environmental Affordances Model, limiting our understanding of how the proposed pathways operate in the lives of African Americans.In the present study, the associations between systemic racism (institutional racism, cultural racism, neighborhood disadvantage), chronic everyday stressors (exposure to individual racism), emotional eating, and mental (anxiety symptomatology) and physical (self-rated overall physical health) health are assessed in a sample of 751 African Americans aged 18 to 88.The path analysis reveals that institutional and cultural racism are both positively associated with individual racism. Neighborhood disadvantage is inversely associated with individual racism. Individual racism is significantly associated with greater anxiety symptomatology but is unrelated to self-rated overall physical health. Institutional and cultural racism are associated with emotional eating although individual racism and neighborhood disadvantage are not. Moreover, engagement in emotional eating exacerbates, rather than mitigates, the impacts of individual racism on anxiety symptomatology.We conclude that institutional and cultural racism contribute to individual racism experiences and emotional eating whereas emotional eating exacerbates associations among individual racism and anxiety symptomatology.