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On the basis of a qualitative study of three different operational oil and gas and petrochemical sites, in the Middle East, Asia-Pacific and Europe, we examine how actors construe error prevention and error management and how they reconcile these approaches in their everyday practice. Our repertory grid data reveal that actors recognise the importance of error prevention, but also appreciate that emergent and unexpected issues require error management in order to trap, address or mitigate problems in the making. Errors are also regarded to play an important role in adaptation, innovation and learning. However, our interview data and analysis of incident investigation reports reflect a narrower range of factors and indicates a strongly institutionalised predisposition towards error prevention. There are practical implications for the management of process safety and for incident analysis, which may be overlooking the importance of error management, and also for individuals at the sharp end who may be coping with the gap between what they believe is important in terms of process safety and what they bring to the surface, share and document.

Prostate cancers are considered “cold” tumors characterized by minimal T cell infiltrates, absence of a type I interferon (IFN) signature, and the presence of immunosuppressive cells. This non-inflamed phenotype is likely responsible for the lack of sensitivity of prostate cancer patients to immune checkpoint blockade (ICB) therapy. Oncolytic virus therapy can potentially overcome this resistance to immunotherapy in prostate cancers by transforming cold tumors into “hot,” immune cell-infiltrated tumors. We investigated whether the combination of intratumoral oncolytic reovirus, followed by targeted blockade of Programmed cell death protein 1 (PD-1) checkpoint inhibition and/or the immunomodulatory CD73/Adenosine system can enhance anti-tumor immunity. Treatment of subcutaneous TRAMP-C2 prostate tumors with combined intratumoral reovirus and anti-PD-1 or anti-CD73 antibody significantly enhanced survival of mice compared with reovirus or either antibody therapy alone. Only combination therapy led to rejection of pre-established tumors and protection from tumor re-challenge. This therapeutic effect was dependent on CD4+ T cells and natural killer (NK) cells. NanoString immune profiling of tumors confirmed that reovirus increased tumor immune cell infiltration and revealed an upregulation of the immune-regulatory receptor, B- and T-lymphocyte attenuator (BTLA). This expression of BTLA on innate antigen-presenting cells (APCs) and its ligand, Herpesvirus entry mediator (HVEM), on T cells from reovirus-infected tumors was in keeping with a role for the HVEM-BTLA pathway in promoting the potent anti-tumor memory response observed., Graphical Abstract, Immunotherapy in prostate cancer is limited because of a lack of immune cells within the tumor. Annels et al. used oncolytic viruses to recruit immune cells into the tumor and showed that in combination with checkpoint inhibitors, which take the brake off of the immune system, established tumors were rejected.

Outsourcing generates risks for client firms but these vary according to the contracted task. This systematic literature review reports on 50 empirical studies that investigate the safety risk factors associated with outsourcing aligning them with the three categories of safety risk factors identified by Underhill and Quinlan in their PDR-Model. By using a 2x2 framework based on the strategic value of the task to the client firm (core or peripheral) and its level of complexity (complex or routine) we could combine studies of outsourced relationships between firms with those between firms and individuals. This demonstrated that there is little empirical evidence available for the safety risk factors associated with complex outsourced tasks. It also showed that routine tasks core to the client business contained risk factors associated with both economic and reward pressure and disorganization. Finally, safety risk factors associated with routine peripheral tasks were mainly due to economic and reward pressures in firm-to-individual contracting, but due to disorganization in firm-to-firm contracting.

Background and purpose Differences in the microstructure of fronto-parietal white matter tracts have been associated with mathematical achievement. However, much of the supporting evidence relies on nonspecific diffusion-weighted magnetic resonance imaging, making it difficult to isolate the role of myelin in math ability. Methods We used myelin water imaging to measure brain myelin. We related myelin water fraction (MWF) to Woodcock-Johnson III (WJ-III) basic math scores using region of interest (ROI) and tract-based spatial statistics (TBSS) analyses, in 14 typically developing and 36 learning challenged youth aged 9-17 years. Results The ROI analysis found a positive relationship between fronto-parietal MWF and math in typically developing youth, but not in learning challenged youth. The relationship between fronto-parietal MWF and math observed in typically developing youth was fully mediated by age. No group differences in fronto-parietal MWF were found between typically developing and learning challenged youth. TBSS also found no group differences in MWF values. TBSS indicated math-MWF relationships extend beyond fronto-parietal tracts to descending and ascending projection tracts in typically developing youth. TBSS identified math-MWF relationships in the cerebral peduncles of learning challenged youth. Conclusions Our results suggest that in typically developing youth, brain myelination contributes to individual differences in basic math achievement. In contrast, youth with learning challenges appear to have less capacity to leverage myelin to improve math achievement.

ObjectivesThis study aimed to explore the experiences of parents caring for children with intellectual and developmental disabilities (IDD) during the UK national lockdown in spring 2020, resulting from the COVID-19 pandemic.DesignParticipants were identified using opportunity sampling from the IMAGINE-ID national (UK) cohort and completed an online survey followed by a semistructured interview. Interviews were analysed using thematic analysis.SettingInterviews were conducted over the telephone in July 2020 as the first UK lockdown was ending.Participants23 mothers of children with intellectual and developmental disabilities aged 5–15 years were recruited.ResultsThemes reported by parents included: managing pre-existing challenges during a time of extreme change, having mixed emotions about the benefits and difficulties that arose during the lockdown and the need for appropriate, individualised support.ConclusionsOur findings confirm observations previously found in UK parents of children with IDD and provide new insights on the use of technology during the pandemic for schooling and healthcare, as well as the need for regular check-ins.

Objective Spinal arteriovenous malformations (SAVMs) are a very rare and complex spinal cord pathology that require high clinical acumen to diagnose and treat. Management includes both nonoperative and operative paradigms. A review of the literature yields a paucity of data regarding the surgical outcomes of SAVMs, with the majority of data limited to single-center outcomes and/or small sample sizes. The purpose of this study was to use a multi-institutional international database to study the natural history of SAVMs. Methods We used the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database to select patients that underwent laminectomy for surgical excision of a SAVM between 2008 and 2017. Results The data from 196 patients were studied (65.8% male, 34.2% female). A majority of cases were in the thoracic region (53.6%), followed by thoracolumbar (31.6%) and cervical (14.8%) regions. The mean age was 57.4 years and 52.5% patients were graded ASA class 3–5 before the operation. The mean operation time was 215 minutes, with a significantly lower operative time for thoracic arteriovenous malformations (195.6 minutes) when compared with cervical (266.6 minutes) and thoracolumbar (223.7 minutes). The mean length of hospital stay was 6.4 days. Patients had a 6.6% readmission rate and a 4.6% reoperation rate within 30 days. Conclusions This study presents the largest analysis of patients undergoing surgery for SAVMs and 30-day postoperative outcomes. Operative time differed based on SAVM location. The three most frequent complications (deep vein thrombosis, wound infection, and UTI) occurred at rates of 3.6% or less.

Background Primary melanocytic neoplasms of the central nervous system (CNS) are rare and account for 1% of all melanomas. This study used the Surveillance, Epidemiology, and End Results (SEER) database to evaluate the epidemiology of primary CNS melanoma and further characterize their treatment. Methods Data from the National Cancer Institute SEER program, collected from 1973–2015, were retrospectively analyzed. A total of 86 records of malignant melanoma cases with CNS as the primary site were identified, and 54 patients were studied based on the inclusion criteria. Demographic, tumor, and treatment regimen effectiveness were studied. Results A total of 54 patients were included in this study. Tumors were distributed evenly in size and localized primarily to the cerebral meninges and spinal cord. A total of 13% of patients underwent biopsy, 40.7% gross total resection (GTR), 7.4% subtotal resection (STR), 46.3% radiation therapy (RT), and 27.3% chemotherapy (CT) in a variety of treatment combinations. GTR alone and STR + RT resulted in increased disease-specific survival compared to biopsy alone, but no survival benefit was found with biopsy with RT and/or CT as well as STR alone. Conclusions To our knowledge, this is the largest single database study completed for primary malignant melanoma of the CNS. The study identified the need for tumor resection for the proper treatment of these lesions, particularly GTR. GTR could be paired with adjuvant RT or RT + CT providing survival benefit as well. In cases when GTR is unable to be completed, STR + RT provides significant improvement in survival compared to biopsy alone.

Background\ud The introduction of antimicrobial surfaces into healthcare environments is believed to impact positively on the rate of healthcare-associated infections by significantly decreasing pathogen presence on surfaces.\ud Aim\ud To report on a novel efficacy test that uses a dry bacterial inoculum to measure the microbicidal efficacy of antimicrobial surfaces.\ud Methods\ud An aerosolized dry inoculum of Staphylococcus aureus or Acinetobacter baumannii was deposited on copper alloy surfaces or a hospital-grade stainless-steel surface. Surviving bacteria were enumerated following incubation of the inoculated surfaces at an environmentally relevant temperature and relative humidity. Damage caused to bacteria by the aerosolization process and by the different surfaces was investigated.\ud Findings\ud Dry inoculum testing showed a

ObjectivesWe aimed to review the evidence for a living systematic benefit risk assessment for convalescent plasma use amongst patients with severe COVID-19 disease, based on currently available data.MethodsThe assessment used the Benefit-Risk Action Team (BRAT) framework. Convalescent plasma treatment in severe COVID-19 was compared to standard of care, placebo or other treatments. A literature search was conducted to identify published papers from January 1st, 2019 until July 8th, 2020. A value tree was constructed which included ranked key benefits and risks.ResultsWe screened 396 papers from PubMed and 127 papers from Embase. Four studies were eligible for inclusion as they contained comparative data. Results from a randomised controlled trial revealed a non-statistically significant shortening of time to clinical improvement of 2.15 days (95% CI, −5.28 to 0.99 days) in the intervention group compared with the control group, with a possible signal of increased efficacy amongst a small subset of patients with severe disease (but not life threatening disease), however this study may have been underpowered. Interpretation of findings amongst the three controlled non-randomised studies were limited by small patient numbers, lack of randomisation, and confounding by co-administration of other treatments. Limited data availability at the current time precluded construction of a data summary table and further quantitative analysis.ConclusionsThere was insufficient evidence from controlled studies to complete a data summary table for a systematic benefit-risk assessment of the use of CP for severe COVID-19 disease at the current time, and as such a benefit-risk conclusion could not be made. Whilst uncontrolled case series have suggested positive findings with CP, results from these studies are very difficult to interpret. We provide a framework which can be updated when further data that have an impact on the benefit-risk become available.Article SummaryStrengths and limitations of this studyprovides a living systematic benefit risk assessment based on currently available data for the use of convalescent plasma in patients with severe COVID-19 diseaseestablishes a framework inclusive of ranked key benefits and risks for convalescent plasma in severe COVID-19 disease, into which additional data can be added as this becomes available facilitating re-assessment of the benefit risk profileuses a transparent framework (BRAT framework) which can be applied to other potential treatment options in this disease contextinsufficient data available at the current time from comparative studies to form a benefit risk conclusion

Part 1 of this 2-part review outlined the importance of disease classification in diabetes genetic studies, as well as the ways in which genetic variants may contribute to risk of a complex disease within an individual, or within a particular group of individuals. Part 2, presented here, describes in more detail our current understanding of the genetics of canine diabetes mellitus compared to our knowledge of the human disease. Ongoing work to improve our knowledge, using new technologies, is also introduced.

Introduction and Objective: COVID-19 is an ongoing, global public health crisis for which safe and effective treatments need to be identified. The benefit-risk balance for the use of lopinavir-ritonavir in COVID-19 needs to be monitored on an ongoing basis, therefore a systematic benefit-risk assessment was designed and conducted. A key objective of this study was to provide a platform for a dynamic systematic benefit-risk evaluation; although initially this evaluation is likely to contain limited information, it is required because of the urgent unmet public need. Importantly, it allows additional data to be incorporated as they become available, and re-evaluation of the benefit-risk profile.Methods: A systematic benefit-risk assessment was conducted using the Benefit-Risk Action Team (BRAT) framework. The exposure of interest was lopinavir-ritonavir treatment in severe COVID-19 compared to standard of care, placebo or other treatments. A literature search was conducted in PubMed and Embase to identify peer-reviewed papers reporting clinical outcomes. Two clinicians constructed a value tree and ranked key benefits and risks in order of considered clinical importance.Results: We screened 143 papers from PubMed and 264 papers from Embase for lopinavir-ritonavir; seven papers were included in the final benefit-risk assessment. In comparison to standard of care, data for several key benefits and risks were identified for lopinavir-ritonavir. Time to clinical improvement was not significantly different for lopinavir-ritonavir in comparison to standard of care (hazard ratio 1.31, 95% confidence interval 0.95–1.80). From one study, there were fewer cases of acute respiratory distress syndrome with lopinavir-ritonavir compared with standard of care (13% vs 27%). There also appeared to be fewer serious adverse events with lopinavir-ritonavir (20%) vs standard of care (32%). Limited data were available for comparison of lopinavir-ritonavir to other treatments.Conclusions: Based on currently available data, there was no clear benefit for the use of lopinavir-ritonavir compared to standard of care in severe COVID-19. Risk data suggested a possible decrease in serious adverse events. There was a reduction in acute respiratory distress syndrome with lopinavir-ritonavir in one study. Overall, the benefit-risk profile for lopinavir-ritonavir in severe COVID-19 cannot be considered positive until further efficacy and effectiveness data become available.

BackgroundCOVID-19 is an ongoing, global public health crisis for which safe and effective treatments need to be identified. The benefit-risk balance for use of lopinavir-ritonavir in COVID-19 needs to be monitored on an ongoing basis, therefore a systematic benefit-risk assessment was designed and conducted. A key objective of this study was to provide a platform for a dynamic systematic benefit-risk evaluation; although initially this evaluation is likely to contain limited information, it is required due to the urgent unmet public need. Importantly it allows additional data to be incorporated as it becomes available, and re-evaluation of the benefit-risk profile.MethodsA systematic benefit-risk assessment was conducted using the Benefit-Risk Action team (BRAT) framework. The exposure of interest was lopinavir-ritonavir treatment in COVID-19 compared to standard of care, placebo or other treatments. A literature search was conducted in PubMed and EmBase to identify peer-reviewed papers reporting clinical outcomes. Two clinicians constructed a value tree and ranked key benefits and risks in order of considered clinical importance.ResultsIn comparison to standard of care, data for several key benefits and risks were identified for lopinavir-ritonavir. Time to clinical improvement was not significantly different for lopinavir-ritonavir in comparison to standard of care (HR=1.31, 95% CI:0.95, 1.80). There appeared to be fewer serious adverse events with lopinavir-ritonavir (20%) vs standard of care (32%). In particular, there were fewer cases of acute respiratory distress syndrome with lopinavir-ritonavir compared to standard of care (13% vs 27%). Limited data were available for comparison of lopinavir-ritonavir to other treatments.ConclusionsBased on currently available data, there was no clear benefit for use of lopinavir-ritonavir compared to standard of care in severe COVID-19. Risk data suggested a possible decrease in serious adverse events, including acute respiratory distress syndrome. Overall, the benefit-risk profile for lopinavir-ritonavir in severe COVID-19 cannot be considered positive until further efficacy and effectiveness data become available.

Background Use of antibiotics to treat humans and animals is increasing worldwide, but evidence from low- and middle-income countries (LMICs) is limited. We conducted cross-sectional surveys in households and farms in Uganda to assess patterns of antibiotic use among humans and animals. Methods Between May and December 2018, a convenience sample of 100 households in Nagongera (rural), 174 households in Namuwongo (urban) and 115 poultry and piggery farms in Wakiso (peri-urban) were selected and enrolled. Using the ‘drug bag’ method, participants identified antibiotics they used frequently and the sources of these medicines. Prevalence outcomes were compared between different sites using prevalence ratios (PRs) and chi-squared tests. Results Nearly all respondents in Nagongera and Namuwongo reported using antibiotics to treat household members, most within the past month (74.7% Nagongera versus 68.8% Namuwongo, P = 0.33). Use of metronidazole was significantly more common in Namuwongo than in Nagongera (73.6% versus 40.0%, PR 0.54, 95% CI: 0.42–0.70, P Conclusions Antibiotics are used differently across Uganda. Further research is needed to understand why antibiotics are relied upon in different ways in different contexts. Efforts to optimize antibiotic use should be tailored to specific settings.

Objective Type II odontoid fractures of the axis (C2) account for more than 20% of all cervical fractures. If an odontoid screw is contraindicated, the treatment approach for type II C2 fractures typically involves C1–C2 posterior fusion or occipito-cervical (O-C) fusion, each of which has distinct advantages and disadvantages. In this study, postoperative outcomes of C1–C2 fusion and O-C fusion for high cervical fractures were compared. Methods The American College of Surgeons National Surgical Quality Improvement Program database was queried to determine 30-day surgical outcomes of posterior C1–C2 fusion versus O-C fusion for adult patients with C2 fractures between 2005 and 2016. Demographics, operative factors, and postoperative events were analyzed, including returns to the operating room, readmission, and death. Results In total, 165 patients were identified. A majority of the patients (142, 86.1%) had independent functional status, although 133 (80.6%) had an American Society of Anesthesiologists classification ranging from 3 to 5, representing poor preoperative health. A significantly greater proportion of O-C (9.1%) versus C1–C2 fusion (1.7%) returned to the operating room (odds ratio 6.465, confidence interval 1.079–38.719, P = 0.041). The length of operation approached statistical significance (P = 0.053) between the 2 groups, with O-C fusion group having a longer average length of operation (196.4 minutes) versus the C1–C2 group (164.0 minutes). Conclusions This study provides a snapshot of the risk profiles of C1–C2 and O-C fusion for C2 fracture, demonstrating a statistically higher risk of reoperation in O-C fusion versus C1–C2 fusion. Future randomized trials are needed to identify the preferred technique to improve patient outcomes.

Most applications of nanotechnology in cancer have focused on systemic delivery of cytotoxic drugs. Systemic delivery relies on accumulation of nanoparticles in a target tissue through enhanced permeability of leaky vasculature and retention effect of poor lymphatic drainage to increase the therapeutic index. Systemic delivery is limited, however, by toxicity and difficulty crossing natural obstructions, like the blood spine barrier. Magnetic drug targeting (MDT) is a new technique to reach tumors of the central nervous system. Here, we describe a novel therapeutic approach for high-grade intramedullary spinal cord tumors using magnetic nanoparticles (MNP). Using biocompatible compounds to form a superparamagnetic carrier and magnetism as a physical stimulus, MNP-conjugated with doxorubicin were successfully localized to a xenografted tumor in a rat model. This study demonstrates proof-of-concept that MDT may provide a novel technique for effective, concentrated delivery of chemotherapeutic agents to intramedullary spinal cord tumors without the toxicity of systemic administration.

As a clinical setting in which local live biological therapy is already well established, non-muscle invasive bladder cancer (NMIBC) presents intriguing opportunities for oncolytic virotherapy. Coxsackievirus A21 (CVA21) is a novel intercellular adhesion molecule-1 (ICAM-1)-targeted immunotherapeutic virus. This study investigated CVA21-induced cytotoxicity in a panel of human bladder cancer cell lines, revealing a range of sensitivities largely correlating with expression of the viral receptor ICAM-1. CVA21 in combination with low doses of mitomycin-C enhanced CVA21 viral replication and oncolysis by increasing surface expression levels of ICAM-1. This was further confirmed using 300-μm precision slices of NMIBC where levels of virus protein expression and induction of apoptosis were enhanced with prior exposure to mitomycin-C. Given the importance of the immunogenicity of dying cancer cells for triggering tumor-specific responses and long-term therapeutic success, the ability of CVA21 to induce immunogenic cell death was investigated. CVA21 induced immunogenic apoptosis in bladder cancer cell lines, as evidenced by expression of the immunogenic cell death (ICD) determinant calreticulin, and HMGB-1 release and the ability to reject MB49 tumors in syngeneic mice after vaccination with MB49 cells undergoing CVA21 induced ICD. Such CVA21 immunotherapy could offer a potentially less toxic, more effective option for the treatment of bladder cancer. Keywords: bladder cancer, coxsackievirus A21, intercellular adhesion molecule-1

Background: Some country guidelines recommend that people with type 2 diabetes (T2D) limit their consumption of eggs and cholesterol. Our previously published 3-mo weight-maintenance study showed that a high-egg (≥12 eggs/wk) diet compared with a low-egg diet (

Background: Intramedullary spinal cord tumors (IMSCTs) account for 8–10% of all spinal cord tumors and affect patients of all ages. Although uncommon, IMSCTs carry risk of neurological morbidity and mortality, with 5-year survival rates ranging from 50% to 80%. In this study, we utilize the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database to determine the effect of steroid administration on 30-day outcomes following surgery for IMSCTs. Methods: ACS-NSQIP data for patients undergoing surgery for intramedullary tumors from 2005 to 2015 was reviewed. Patients were selected based on current procedural terminology (CPT) codes 63285 (Laminectomy, intradural, intramedullary, cervical), 63286 (Laminectomy, intradural, intramedullary, thoracic), and 63287 (Laminectomy, intradural, intramedullary, thoracolumbar). ICD-9 and ICD-10 codes were chosen based on the diagnosis of a tumor. The 30-day clinical outcome data, including reoperations and readmission rates, were collected and compared. Results: A total of 259 patients were reviewed. 181 patients had benign intramedullary tumors and 78 had malignant intramedullary tumors. The majority of IMSCTs were at the thoracic level (n=100), followed by the cervical (n=99), and thoracolumbar (n=39) levels. Thirty-one patients were on corticosteroid therapy prior to surgery. Patients with preoperative steroid administration had no significant difference in reoperation and readmission rates. No significant differences were noted between steroid vs. non-steroid therapy for discharge destination, length of hospital stay, or other postoperative complications. Conclusions: Contrary to previous reports, corticosteroid use prior to surgery for IMSCTs does not have a significant impact on 30-day risk of readmission, reoperation, and risk of postoperative complications.

BackgroundAs concerns about the prevalence of infections that are resistant to available antibiotics increase, attention has turned toward the use of these medicines both within and outside of formal healthcare settings. Much of what is known about use beyond formal settings is informed by survey-based research. Few studies to date have used comparative, mixed-methods approaches to render visible patterns of use within and between settings as well as wider points of context shaping these patterns.DesignThis article analyses findings from mixed-methods anthropological studies of antibiotic use in a range of rural and urban settings in Zimbabwe, Malawi and Uganda between 2018 and 2020. All used a ‘drug bag’ survey tool to capture the frequency and types of antibiotics used among 1811 households. We then undertook observations and interviews in residential settings, with health providers and key stakeholders to better understand the stories behind the most-used antibiotics.ResultsThe most self-reported ‘frequently used’ antibiotics across settings were amoxicillin, cotrimoxazole and metronidazole. The stories behind their use varied between settings, reflecting differences in the configuration of health systems and antibiotic supplies. At the same time, these stories reveal cross-cutting features and omissions of contemporary global health programming that shape the contours of antibiotic (over)use at national and local levels.ConclusionsOur findings challenge the predominant focus of stewardship frameworks on the practices of antibiotic end users. We suggest future interventions could consider systems—rather than individuals—as stewards of antibiotics, reducing the need to rely on these medicines to fix other issues of inequity, productivity and security.

Spinal epidural lipomatosis (SEL) is a rare pathologic growth of histologically normal unencapsulated adipose tissue in the epidural space. Although rare, SEL can compress the spinal cord or nerve roots causing myelopathy or radiculopathy. While SEL has been associated with long-term exposure to endogenous or exogenous steroids and obesity, idiopathic forms of SEL are much rarer. In this report, we present the first case of SEL isolated to the cervical region compressing the spinal cord in a healthy, non-obese, preadolescent patient. Idiopathic SEL in the pediatric population is a rare entity. This is the first case of epidural lipomatosis isolated to the cervical region in an adult or child patient. In refractory, symptomatic cases of idiopathic SEL, surgical decompression is often required.

Despite successful repair in early life, patients with coarctation of the aorta (CoA) are predisposed to several cardiovascular complications in later life related to systemic hypertension or left ventricular (LV) dysfunction, or both, the pathogenesis of which is unclear.Three-week-old Sprague-Dawley rats underwent transverse aortic constriction (TAC) or a sham operation, with release of the constriction 3 weeks later. Twenty-five weeks after the repair operation, animals underwent hemodynamic assessment, LV gene profiling, and histologic analysis.Animals with repaired aortic constriction exhibited a significantly elevated central systolic pressure (116 ± 5 mm Hg vs 103 ± 4 mm Hg; p0.05) despite the absence of any significant pressure gradient across the former constriction site compared with shams (5 ± 4 mm Hg vs 0 ± 2 mm Hg; p = 0.2). They also had more than a 2-fold increase in LV collagen deposition (4.86% ± 0.24% vs 2.40% ± 0.18%; p0.001). However, no significant differences were noted between the groups in maximum LV pressure (116 ± 3 mm Hg vs 107 ± 3 mm Hg; p = 0.1), LV mass indexed to tibial length (p = 0.07), or myocyte size. There was no significant differential expression of hypertrophy or fibrosis-related genes in the left ventricles of the repaired animals compared with shams.Despite successful early relief of simulated CoA in early life, relative hypertension and LV fibrosis were demonstrable late consequences in this animal model. This abnormal fibrosis persists in the absence of altered LV hemodynamics and gene expression.

The prevalence of depression in those with obesity is reported to be as high as double that in individuals of normal weight. There is potentially a bi-directional relationship between obesity and depression. Some research has suggested that depression results in weight gain and obesity, and other studies have suggested that those with obesity are more likely to develop depression at a later stage. The aim of this study was to investigate the association of depression symptoms with weight change over a 12-month study. Seventy participants undertook a 3-month lifestyle (diet and exercise) weight loss intervention, and were followed up as part of a 12-month study. Participants completed the Beck Depression Inventory-II (BDI-II) and had their body weight measured throughout the study. Baseline body mass index (BMI) of participants (mean ± standard deviation [SD]) was 31.1 ± 3.9 kg m-2 , body weight was 89.4 ± 16.1 kg, and age was 45.4 ± 11.1 years; 63% of the cohort were female. The mean weight change from baseline to 3 months was -5.2% (±SD 4.3%), and from baseline to 12 months was -4.2% (±SD 6.1%). There was a significant decrease in BDI-II scores over the 12-month study, and a 1-unit decrease in BDI-II score was associated with a further decrease in body weight of -0.4%. The current study indicated that weight loss was associated with improvements in mood for non-clinically depressed individuals with obesity, and these improvements persisted during a period of 3-12 months of follow-up.

Background A drug-drug interaction study between dolutegravir and doravirine in healthy volunteers found no evidence of untoward interaction. Whilst we hypothesize that the combination would be safe and effective, there is no supportive clinical data. We aimed to assess the rationale for use of dolutegravir and doravirine in combination and clinical outcomes among persons with HIV infection (PWH) receiving care at the Washington DC VAMC. Methods A quality improvement initiative utilized the clinical case registry to identify all PWH receiving both dolutegravir and doravirine. We conducted chart review to examine (a) the reasons for switch from other ART to dolutegravir and doravirine, and comorbidities, HIV resistance mutations or drug interactions precluding the use of standard ART, (b) adverse events or side effects and (c) achievement of virologic suppression. Results A case registry search revealed 21 individuals receiving combination dolutegravir doravirine from 2018–2020 (Table 1 and Figure 1). Side effects were not noted except one patient developed mild diarrhea that improved with continuation of therapy. Four patients were hospitalized during the follow-up period for reasons unrelated to the medications. One patient who was admitted to the ICU with shock and multi-organ failure was switched on admission but died four days later and therefore was not included in the analysis of viral outcome (Table 2). One patient had cardiac arrest following missed dialysis, hyperkalemia and rectal hemorrhage from metastatic rectal cancer. Table 1: Patient Demographics. Figure 1: Reasons for Switching to Dolutegravir with Doravirine. Table 2: Virologic Control Before and After Switching to Dolutegravir with Doravirine. Conclusion In an era of abundant ART options, we identified a subset of older PWH whose treatment options are defined by extensive comorbidities, viral resistance, and medication interactions or toxicities. Doravirine is attractive for this population as it can be used in renal impairment, moderate hepatic impairment, is unaffected by timing of meals, and (unlike rilpivirine) has no interaction with proton pump inhibitors. Dolutegravir is included in NRTI-sparing regimens that HHS guidelines suggest should be considered in older PWH, especially with CKD. We found that dolutegravir with doravirine is well tolerated, and achieves virologic suppression in the majority of PWH, indicating this combination is useful when other ART options cannot be used. Disclosures All Authors: No reported disclosures

Central nervous system (CNS) embryonal tumors are malignant neoplasms of undifferentiated embryonic cells that typically occur in the pediatric population. They are further divided into many subgroups by distinct histologic and genetic profiles. We present the largest study to date to identify differential survival outcomes within each subgroup by treatment regimen.The SEER (Surveillance Epidemiology and End Results) database was queried from 1973 to 2015 for embryonal tumors of primary CNS origin (n = 3900). The effects of patient demographics, tumor characteristics, and treatment regimen were analyzed using a multivariate Cox proportional hazard model in CNS embryonal tumor subtypes divided into medulloblastoma, atypical teratoid/rhabdoid tumor, and primitive neuroectodermal tumor.No significant patient demographic factors were found to be associated with increased mortality. In all 3 CNS embryonal tumor subtypes, most monotherapy and combinatorial treatment paradigms showed a higher hazard ratio compared with gross total resection with adjuvant chemoradiotherapy (hazard ratio, 1.72-22.94; P0.05 for all). In a subgroup analysis of patients with medulloblastoma ≤3 years of age, patients who did not receive radiation showed lower survival probabilities at 1, 5, and 10 years (odds ratio [OR], 0.37, P0.0001; OR, 0.39, P0.0001; OR, 0.34, P0.0001, respectively). Kaplan-Meier analysis of medulloblastoma histologic subtypes showed that use of radiation imparted a higher survival probability in the desmoplastic/nodular medulloblastoma and medulloblastoma not otherwise specified groups (P0.001 for both).CNS embryonal tumors are highly malignant in all populations and the best survival is seen with aggressive combination therapies. Radiation therapy may have a role in prolonging survival in patients with medulloblastoma ≤3 years of age.

Objectives: To assess sleep quality and timing in children with Angelman syndrome (AS) with sleep problems using questionnaires and actigraphy and contrast sleep parameters to those of typically developing (TD) children matched for age and sex.Methods: Week-long actigraphy assessments were undertaken with children with AS (n = 20) with parent-reported sleep difficulties and compared with age and sex matched TD controls. The presence of severe sleep problems was assessed using the modified Simonds and Parraga sleep questionnaire. Sleep hygiene was measured using the Family Inventory of Sleep Habits.Results: Actigraphy and parent-completed sleep diary data indicated that children with AS had significantly earlier bedtimes (p = .003, Cohen d = .47) and poorer sleep efficiency (78%, p = .04, d = .33) than TD children (84%). No significant differences in total sleep time, sleep onset latency or wake after sleep onset were found between the two groups. The expected relationship between later bedtimes and increasing age found for the TD group (p < .001, β.78) was not evidenced for the AS group (p = .09, β.39). Considerable inter-individual and night to night variation in actigraphy assessed total sleep time and wake after sleep onset was found for children with AS compared to TD children. Parent report indicated that a greater proportion of children with AS had severe night waking problems compared to TD children (81 versus 5%). No significant differences in sleep hygiene and excessive daytime sleepiness were found between the two groups (p > .05).Conclusions: This study reports the largest objective dataset of sleep quality parameters in children with AS. Sleep quality in this group was characterised by poor efficiency and significant intra- and inter-individual variability that warrants further investigation. This variability should inform assessment and intervention for sleep in children with AS, as averages of total sleep, even across a 7 day period may not capture the difficulties with night waking highlighted by parental questionnaire report.

Study Objectives The objectives of the study were (1) to compare both actigraphy and questionnaire-assessed sleep quality and timing in children with Smith–Magenis syndrome (SMS) to a chronologically age-matched typically developing (TD) group and (2) to explore associations between age, nocturnal and diurnal sleep quality, and daytime behavior. Methods Seven nights of actigraphy data were collected from 20 children with SMS (mean age 8.70; SD 2.70) and 20 TD children. Daily parent/teacher ratings of behavior and sleepiness were obtained. Mixed linear modeling was used to explore associations between total sleep time and daytime naps and behavior. Results Sleep in children with SMS was characterized by shorter total sleep time (TST), extended night waking, shorter sleep onset, more daytime naps, and earlier morning waking compared to the TD group. Considerable inter-daily and inter-individual variability in sleep quality was found in the SMS group, so caution in generalizing results is required. An expected inverse association between age and TST was found in the TD group, but no significant association was found for the SMS group. No between-group differences in sleep hygiene practices were identified. A bidirectional negative association between TST and nap duration was found for the SMS group. In the SMS group, increased afternoon sleepiness was associated with increased irritability (p = .007) and overactivity (p = .005). Conclusion These findings evidence poor sleep quality in SMS and the need to implement evidence-based interventions in this population.

Primary intracranial germ cell tumors are rare neoplasms derived from gonadal cells. They are categorized as germinoma, non-germinomatous germ cell tumor (NGCCT), or teratoma, with the latter two sparking controversy regarding the role of different treatment strategies. We provide the largest multicenter analysis of treatment outcomes for iGCTs to date. The Surveillance, Epidemiology, and End Result (SEER) database were used to record patient demographics, tumor, and treatment characteristics. Cox proportional hazards model and multiple comparisons for the Logrank test with Sidak correction was applied to compare the different treatment regimens and survival. 1043 iGCT cases were divided into three cohorts of Germinoma, Malignant Teratoma (MT), and NGGCT. The mean age was 17.7 years for germinoma, 9.5 years for MT, and 14.4 years for NGGCT groups. Males comprised 77% of overall patient population. For Germinomas, both biopsy (hazard ratio [HR] = 4.6) and resection (HR = 14.1) had significantly worse survival outcomes compared to solo radiation therapy, with no difference between radiation and chemotherapy. For MT, no treatment combination had significantly different survival outcomes compared to resection alone. For NGGCTs, resection + chemotherapy + radiotherapy (HR = 0.012) and resection + chemotherapy (HR = 0.0049) had significantly better survival compared to resection alone. In germinomas, radiotherapy alone had superior survival outcomes compared to biopsy and resection, but no change in survival when compared to chemotherapy alone. Addition of radiotherapy or chemotherapy did not improve survival in MTs when compared to resection alone. Adding chemotherapy in NGGCT patients undergoing resection improved survival compared to resection alone.

Understanding the prevalence and types of antibiotics used in a given human and/or animal population is important for informing stewardship strategies. Methods used to capture such data often rely on verbal elicitation of reported use that tend to assume shared medical terminology. Studies have shown the category ‘antibiotic’ does not translate well linguistically or conceptually, which limits the accuracy of these reports. This article presents a ‘Drug Bag’ method to study antibiotic use (ABU) in households and on farms, which involves using physical samples of all the antibiotics available within a given study site. We present the conceptual underpinnings of the method, and our experiences of using this method to produce data about antibiotic recognition, use and accessibility in the context of anthropological research in Africa and South-East Asia. We illustrate the kinds of qualitative and quantitative data the method can produce, comparing and contrasting our experiences in different settings. The Drug Bag method can produce accurate antibiotic use data as well as provide a talking point for participants to discuss antibiotic experiences. We propose it can help improve our understanding of antibiotic use in peoples’ everyday lives across different contexts, and our reflections add to a growing conversation around methods to study ABU beyond prescriber settings, where data gaps are currently substantial.

Objective To validate an electronic nutrition literacy assessment tool (e-NutLit). Design Cross-sectional. Setting An Australian teaching hospital obesity clinic (clinical cohort) and university (dietetic cohort). Participants A convenience sample of patients with obesity (body mass index > 35 kg m−2) (obese participants [OP]) and dietetic interns (DI). Interventions The e-NutLit was administered to OP and scores were compared with performance on the Newest Vital Sign and e-NutLit scores of the DI to establish construct validity. A subset of OP completed the e-NutLit again to examine instrument temporal stability. Internal consistency was assessed using Cronbach α. Main Outcome Measures Construct validity, temporal stability, and internal consistency. Analysis Parametric and nonparametric tests and general linear modeling were used as appropriate. Results A total of 103 participants completed the study (OP: n = 59; 64.4% female; DI: n = 44; 86.4% female). Newest Vital Sign and e-NutLit scores were significantly and positively associated (rs = 0.66; P 0.9 indicating a good level of internal consistency. The OP test and retest scores were not significantly different, supporting instrument temporal stability. Conclusion and Implications The results support the validity of the e-NutLit, for both clinicians and researchers.