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OBJECTIVE: A higher proportion of circulating memory CD4(+) T cells is associated with prevalent diabetes mellitus in persons with HIV (PWH) and HIV-negative persons. We assessed whether circulating T cell subsets could also identify individuals who will subsequently develop diabetes. DESIGN: This is a longitudinal follow-up study of PWH and similar HIV-negative individuals from the Veterans Aging Cohort Study who provided peripheral mononuclear blood cells between 2005 and 2007. METHODS: We quantified T cell subsets using flow cytometry and functional assays to identify CD4(+) and CD8(+) naïve, activated, senescent, memory (central, effector, and effector RA(+)), and T(H)1, T(H)2, and T(H)17-phenotype cells. The occurrence of an incident diabetes diagnosis (i.e., after baseline blood draw) was adjudicated by a two-physician chart review. Cox proportional hazards models adjusted for traditional risk factors, cytomegalovirus serostatus, and plasma inflammatory biomarkers assessed the relationship between T cell subsets and incident diabetes. RESULTS: 1837 participants (1259 PWH) without diabetes at baseline were included; 69% were black, 95% were male, and median follow-up was 8.6 years. Higher baseline frequencies of CD4(+) T effector memory RA(+) (T(EMRA)) cells defined as CD45RA(+) CD27(−) (p=0.04) and senescent T cells defined as CD4(+) CD28(−) (p=0.04) were associated with incident diabetes in PWH only. CONCLUSIONS: Higher frequencies of CD4(+) T(EMRA) and CD4(+) CD28(−) T cells were associated with incident diabetes in PWH only after adjustment for other factors. Additional studies are necessary to assess whether these cells act in blood via inflammatory mediators or reflect T cell populations in metabolically active tissues.

Parole and parole boards play critical roles in criminal justice systems. With parolee numbers and imprisonment rates increasing in many countries, parole decision-making is a crucial contributor to prison population sizes and, more broadly, public confidence in the operation of correctional systems. This article examines the public understanding of and confidence in parole, from the perspectives of parole board members and other parole authority staff. It aims to determine whether and, if so, how, public opinion influences parole decision-making and how parole boards feel they can or should respond to this. It draws on interviews with 80 parole board members and other relevant staff in Australia, New Zealand, Canada and Scotland.

Wearing face masks in public is recommended under certain circumstances in order to prevent infectious diseases transmitted through droplets.The objective was to compile all German and English research results from peer-reviewed journal articles using a sensitive literature search on the effects of mask-wearing for preventing infectious diseases on the psychosocial development of children and adolescents.A systematic review was conducted considering different study designs (search period up until 12 July 2021). The risk of bias in the studies was determined using a risk of bias procedure. A descriptive-narrative synthesis of the results was performed.Thirteen studies were included, and the overall risk of bias was estimated to be high in all primary studies. There are some indications from the included surveys that children, adolescents, and their teachers in (pre)schools perceived facial expression processing as impaired due to mask wearing, which were confirmed by several experimental studies. Two studies reported psychological symptoms like anxiety and stress as well as concentration and learning problems due to wearing a mask during the COVID-19 pandemic. One survey study during the 2002/2003 SARS pandemic examined oral examination performance in English as a foreign language and showed no difference between the "mask" and "no mask" conditions.Only little evidence can be derived on the effects of wearing mouth-nose protection on different developmental areas of children and adolescents based on the small number of studies. There is a lack of research data regarding the following outcomes: psychological development, language development, emotional development, social behavior, school success, and participation. Further qualitative studies and epidemiological studies are required.HINTERGRUND: Zur Prävention tröpfchenübertragener Infektionskrankheiten wird das Tragen einer Maske im öffentlichen Raum unter bestimmten Bedingungen empfohlen.Ziel war, über eine sensitive Literatursuche möglichst alle deutsch- und englischsprachigen Forschungsergebnisse aus begutachteten Fachzeitschriftenartikeln zu den Auswirkungen des Masketragens zur Prävention von Infektionen auf die psychosoziale Entwicklung von Kindern und Jugendlichen zusammenzutragen.Es wurde ein systematischer Review unter Berücksichtigung verschiedener Studiendesigns durchgeführt (Suchzeitraum bis einschließlich 12.07.2021). Das Verzerrungsrisiko der Studien wurde mit einem Risk-of-Bias-Verfahren ermittelt. Es fand eine deskriptiv-narrative Ergebnissynthese statt.Es wurden 13 Studien eingeschlossen, wobei das Gesamtverzerrungsrisiko in allen Primärstudien als hoch eingeschätzt wurde. Es gibt Hinweise aus Befragungsstudien, dass die Fähigkeit zum Lesen der Mimik von Kindern/Jugendlichen und/oder ihren Betreuer:innen im (Vor‑)Schulsetting durch das Masketragen als beeinträchtigt erlebt wird, die durch mehrere Experimentalstudien bestätigt wurden. 2 Studien berichteten über psychische Symptome wie Ängste oder Stresserleben sowie Konzentrations- und Lernschwierigkeiten durch das Masketragen während der COVID-19-Pandemie. Eine Studie während der SARS-Pandemie 2002/2003 untersuchte mündliche Prüfungsleistungen in Englisch als Fremdsprache und zeigte keinen Unterschied zwischen den Bedingungen „Maske“ versus „keine Maske“.Zu den Auswirkungen des Masketragens auf verschiedene Entwicklungsbereiche von Kindern und Jugendlichen lassen sich basierend auf der unzureichenden Studienlage nur wenige Erkenntnisse ableiten. Es fehlen Forschungsdaten zu den Folgen für die Endpunkte psychische Entwicklung, Sprachentwicklung, sozioemotionale Entwicklung, soziales Verhalten, Schulerfolg und Teilhabe. Weitere qualitative Studien und epidemiologische Studien sind unbedingt nötig.

Immune thrombocytopenia (ITP) is an autoimmune disease causing platelet destruction, and is a common cause of symptomatic thrombocytopenia in children. Intravenous immune globulin (IVIG) is a treatment for ITP that increases the platelet counts of most patients within 24 to 48 hours. This study aimed to calculate the rate of rise in pediatric ITP after a dose of IVIG and to analyze if patient characteristics affected the rate. For 116 children treated for ITP with IVIG at Hershey Medical Center, the rate of rise of the platelet count for all patients was calculated. The rate of rise ranged from -0.1 to +4.2 K/µL/hour (average 1.3, median 1.2). 78% of patients had a rate of rise of over 0.5 K/µL/hour. There was a statistically significant correlation between the rate rise of the platelet count and the initial platelet count (P=0.0197), but rate was not affected by age or sex. This study was able to demonstrate that IVIG is effective in most patients and that demographic features do not affect the rate of rise. By providing a nomogram showing when to expect a meaningful rise in the platelet count after IVIG, we give guidance for timing of the postinfusion platelet count to avoid administering a second dose. Future studies are needed to test this nomogram prospectively.

Aims: This study aimed to analyze the association between any past-month cannabis use and advanced liver fibrosis. Background: Cannabinoid receptors play a role in acute and chronic liver injury, but human studies addressing the impact of cannabis use on liver fibrosis have shown mixed results. Objectives: The objective of this study was to explore and estimate the association between pastmonth cannabis use and advanced liver fibrosis (ALF) in a cohort of Russian HIV-positive individuals with heavy alcohol use and a high prevalence of hepatitis C virus (HCV) coinfection. Methods: Baseline data were analyzed from participants of the ZINC study, a trial that enrolled HIV-positive Russian patients without prior antiretroviral therapy. Cannabis use during the prior month was assessed at study entry. ALF was defined as FIB-4>3.25 and APRI>1.5. Transient elastography was used to detect advanced liver fibrosis among participants with FIB-4 values in the intermediate range (between 1.45 and 3.25). Results: Participants (n=248) were mostly male (72.6%), young (median age of 33.9 years), infected with HCV (87.9%), and did not have advanced immunosuppression (median CD4 count 465). Cannabis use was uncommon (12.4%), and the prevalence of advanced liver disease was 21.7%. The prevalence of ALF was similar among those who used cannabis compared to those who did not (25.8% vs. 21.7%). We were unable to detect an association between cannabis use and ALF (adjusted odds ratio: 1.28, 95% confidence interval: 0.53-3.12, p=0.59) in logistic regression models adjusting for age, sex, heavy drinking, BMI, and CD4 cell count. Conclusion: In this exploratory study among HIV-positive heavy drinking Russians, we did not detect an association between recent cannabis use and ALF. Larger scale studies, including more participants with cannabis use, are needed to examine this relationship further.

BACKGROUND Current guidelines recommend shared surgical decision-making, yet it is unclear whether shared decision-making improves health outcomes in patients who are considering knee and hip replacement. The purpose of the present study was to examine whether patients who made high-quality, informed, patient-centered (IPC) decisions had better health outcomes, higher satisfaction, and less decision regret compared with those who made lower-quality decisions. METHODS A multisite, randomized study of 2 decision aids for patients with hip and knee osteoarthritis was utilized to collect data on decision-making and health outcomes at 2 time points: shortly after the initial surgical evaluation and about 6 months after treatment. We calculated the percentage of patients who made an IPC decision and examined the a priori hypotheses that IPC decisions would be associated with better health outcomes, satisfaction, and less regret at 6 months. Linear and logistic regression models were utilized to examine the relationships. RESULTS The analytic sample included 854 patients with a mean age of 65 years (standard deviation, 9 years), of whom 58% were female, 93% were White non-Hispanic, 67% had knee (compared with hip) osteoarthritis, and 62% underwent operative treatment within 6 months of the initial evaluation. The majority of patients (68%) made IPC decisions. The IPC group had significantly larger gains in quality of life (mean difference in EuroQol-5 Dimension, 0.04; 95% confidence interval [CI], 0.02 to 0.07; p < 0.001) compared with the non-IPC group. For knee patients, the IPC group also had significantly better Knee injury and Osteoarthritis Outcome Scores (mean difference, 4.9; 95% CI, 1.5 to 8.3; p = 0.004), higher satisfaction (adjusted odds ratio [aOR], 1.7; 95% CI, 1.2 to 2.3; p = 0.003), much better pain relief (aOR, 2.1; 95% CI, 1.3 to 3.5; p = 0.002), and were more likely to have no decision regret (aOR, 2.3; 95% CI, 1.3 to 4.1; p = 0.003). For hip patients, IPC decisions were not associated with better Harris hip scores or satisfaction and were associated with more regret. CONCLUSIONS Higher-quality decisions predicted small improvements in health outcomes, as well as greater satisfaction and less regret for patients with knee osteoarthritis, but not for patients with hip osteoarthritis. LEVEL OF EVIDENCE Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Direct-acting antivirals (DAA) have replaced interferon (IFN)-based therapies for hepatitis C virus. In this retrospective clinical study, we examined differences in histopathologic features in paired liver biopsies collected from the same patient before and after DAA and correlated these findings with clinical outcome. Biopsies (n = 19) were evaluated by quantitative imaging analysis to measure steatosis and fibrosis. Most patients had decreased steatosis in their post-treatment, follow-up biopsies. However, one patient had a striking increase in steatosis (from 0.86 to 6.32%) and later developed decompensated cirrhosis and hepatocellular carcinoma (HCC). This patient had a marked increase in fibrosis between biopsies, with a CPA of 6.74 to 32.02. Another patient, who already had bridging fibrosis at the time of her pre-treatment biopsy, developed cholangiocarcinoma after DAA. Even though the overall inflammatory activity in the post-treatment biopsies significantly decreased after treatment, 60% of patients had persistent portal lymphocytic inflammation. In summary, DAAs decreased steatosis and hepatic inflammation in most patients, although some may have persistence of lymphocytic portal inflammation. Patients known to have advanced fibrosis at treatment initiation and who have other risk factors for ongoing liver injury, such as steatosis, should be followed closely for the development of adverse outcomes, such as portal hypertension and primary liver cancers.

Preservative-free topical medications have been introduced for glaucoma care to reduce ocular adverse events associated with preservatives. This is a systematic review and meta-analysis of randomized clinical trials (RCTs) comparing the efficacy and safety of beta-blockers, or combination using beta-blockers, with and without preservatives. PubMed, EMBASE and Web of Science were examined. Risk of bias was assessed using the Cochrane Handbook for Systematic Reviews. The primary outcome was change in intraocular pressure (IOP) from baseline to final follow-up. Secondary outcomes included ocular and systemic side effects, and other clinical and quality of life outcomes. Of 242 records identified, seven RCTs (1125 patients) were included. The follow-up period ranged from one to 12 months. Timolol was used in five studies, and two studies used a combination (timolol with bimatoprost or dorzolamide). The difference in mean change (MD) in IOP between the preservative-free and the preserved drugs was statistically significant but not clinically relevant: (MD 0.29 mmHg, 95% confidence interval 0.07-0.51 mmHg, p = 0.010; moderate-certainty evidence). Regarding adverse events: Level of evidence for all ocular surface outcome was low or very low and reported in few studies. No significant difference was observed on ocular surface symptoms. Tear break-up time (TBUT) was better with preservative-free drops (p < 0.001). Schirmer's test was better in the preservative-free group (p < 0.001). Level of evidence for all ocular surface outcomes was low or very low. There was no difference in other secondary outcomes. We found no clinically relevant difference in mean change in IOP between the preserved and the preservative-free treatments. Data on adverse events used different methods and were incompletely reported. Although some measures of ocular surface health favoured preservative-free medications, more evidence is needed. The increasing use of preservative-free drops may be associated with better ocular surface and tolerability, but strong evidence from RCTs would be welcome.

Unhealthy alcohol use, smoking, and depressive symptoms are risk factors for cardiovascular disease (CVD). Little is known about their co-occurrence – termed a syndemic, defined as the synergistic effect of two or more conditions—on CVD risk in people with HIV (PWH). We used data from 5621 CVD-free participants (51% PWH) in the Veteran’s Aging Cohort Study-8, a prospective, observational study of veterans followed from 2002 to 2014 to assess the association between this syndemic and incident CVD by HIV status. Diagnostic codes identified cases of CVD (acute myocardial infarction, stroke, heart failure, peripheral artery disease, and coronary revascularization). Validated measures of alcohol use, smoking, and depressive symptoms were used. Baseline number of syndemic conditions was categorized (0, 1, ≥ 2 conditions). Multivariable Cox Proportional Hazards regressions estimated risk of the syndemic (≥ 2 conditions) on incident CVD by HIV-status. There were 1149 cases of incident CVD (52% PWH) during the follow-up (median 10.1 years). Of the total sample, 64% met our syndemic definition. The syndemic was associated with greater risk for incident CVD among PWH (Hazard Ratio [HR] 1.87 [1.47–2.38], p < 0.001) and HIV-negative veterans (HR 1.70 [1.35–2.13], p < 0.001), compared to HIV-negative with zero conditions. Among those with the syndemic, CVD risk was not statistically significantly higher among PWH vs. HIV-negative (HR 1.10 [0.89, 1.37], p = .38). Given the high prevalence of this syndemic combined with excess risk of CVD, these findings support linked-screening and treatment efforts.

Over the course of medical school, students’ optimism and hopefulness often devolve into a cynical view of medicine that continues throughout clinical rotations and beyond (Neumann et al., Acad Med 86(8):996–1009, 2011). Here, we present a qualitative evaluation of a novel immersive elective in pediatric psycho-oncology coupled with narrative medicine and its impact on students. Participants were third- and fourth-year medical students who were relieved of traditional clinical duties. Alternatively, they shadowed pediatric cancer patients, keeping narrative journals of their observations and insights. A trained team of pre-clinical medical students and faculty conducted a retrospective analysis of 120 journals written between 2008 and 2019. They compared recurring concepts to assess how blending experiential learning and reflective writing influenced the attitudes and behaviors of students. Consistent themes emerged related to developing a rich understanding of patient experiences, a humanistic appreciation of the context of illness, the ability to meaningfully reflect on insights to critically ill children, and an appreciation for the unique learning opportunity. Additionally, families expressed gratitude for the students’ attentiveness to their emotional needs. By the conclusion of the elective, most students discovered that they had reignited their intrinsic empathic behaviors and were provided with beneficial insights that they believed would continue into future rotations. Experiential teaching methods paired with narrative reflection may be a valuable and therapeutic tool to learn the intricacies of the patient perspective, with the potential to enhance humanism in students during a critical time in their medical training when empathy tends to drift. Longitudinal and quantitative studies are warranted to better understand the degree and duration of specific benefits.

Objective We studied variation in perioperative opioid use after total joint arthroplasty with respect to patient and procedure characteristics in order to inform initiatives to optimize pain relief. Methods We recorded perioperative opioid consumption for a cohort of total joint arthroplasty patients to identify factors underlying variation in perioperative opioid use. Results Younger patient age, tobacco use, greater symptoms of depression, private insurance, and knee arthroplasty were associated with increased opioid consumption. Conclusions Awareness of the patient characteristics associated with increased perioperative opioid use can help inform implementation of targeted strategies for safe, optimal pain relief and satisfaction.

Australian governments fund many place‐based collective impact initiatives like Communities for Children (CfC); states fund family support services to keep at‐risk children out of the child protection system; and schools implement many extracurricular programmes. Do these services have a beneficial, cost‐effective collective impact on child well‐being? This paper describes a proof‐of‐concept attempt to address this question by linking for one CfC community individual‐level data on 5‐ to 12‐year‐old participation in programmes delivered through these three sectors with child outcomes. This exercise was unsuccessful despite the investigators’ prior experience; advice from a data linkage expert and our data custodian partners; five ARC reviews; partners’ good will; and ethical safeguards including written, informed parent/carer consent. Obstacles encountered included a lack of data of sufficient quality on children and families’ participation in services, lack of data on children’s outcomes, and prohibitive costs of linkages within government. We offer for others three key lessons: (1) make assumptions explicit; (2) talk to technical experts in data custodian organisations early in the planning process; and (3) undertake, if possible, an initial scoping exercise. We conclude that despite recent legislative and policy reforms many obstacles we encountered will persist in the absence of a national child well‐being strategy.

OBJECTIVE ABCC8 mutations cause neonatal diabetes mellitus that can be transient (TNDM) or, less commonly, permanent (PNDM); ∼90% of individuals can be treated with oral sulfonylureas instead of insulin. Previous studies suggested that people with ABCC8-PNDM require lower sulfonylurea doses and have milder neurological features than those with KCNJ11-PNDM. However, these studies were short-term and included combinations of ABCC8-PNDM and ABCC8-TNDM. We aimed to assess the long-term glycemic and neurological outcomes in sulfonylurea-treated ABCC8-PNDM. RESEARCH DESIGN AND METHODS We studied all 24 individuals with ABCC8-PNDM diagnosed in the U.K., Italy, France, and U.S. known to transfer from insulin to sulfonylureas before May 2010. Data on glycemic control, sulfonylurea dose, adverse effects including hypoglycemia, and neurological features were analyzed using nonparametric statistical methods. RESULTS Long-term data were obtained for 21 of 24 individuals (median follow-up 10.0 [range 4.1–13.2] years). Eighteen of 21 remained on sulfonylureas without insulin at the most recent follow-up. Glycemic control improved on sulfonylureas (presulfonylurea vs. 1-year posttransfer HbA1c 7.2% vs. 5.7%, P = 0.0004) and remained excellent long-term (1-year vs. 10-year HbA1c 5.7% vs. 6.5%, P = 0.04), n = 16. Relatively high doses were used (1-year vs. 10-year dose 0.37 vs. 0.25 mg/kg/day glyburide, P = 0.50) without any severe hypoglycemia. Neurological features were reported in 13 of 21 individuals; these improved following sulfonylurea transfer in 7 of 13. The most common features were learning difficulties (52%), developmental delay (48%), and attention deficit hyperactivity disorder (38%). CONCLUSIONS Sulfonylurea treatment of ABCC8-PNDM results in excellent long-term glycemic control. Overt neurological features frequently occur and may improve with sulfonylureas, supporting early, rapid genetic testing to guide appropriate treatment and neurodevelopmental assessment.

BACKGROUND: Electronic Medical Records (EMR) represent a rich source of data, but the value of EMR for health research relies on accurate ascertainment of clinical diagnoses. Identifying diabetes in EMR is complicated by the variety of accepted diagnostic criteria, some of which can be confounded by conditions such as HIV infection. We compared EMR-based criteria for estimating diabetes prevalence and incidence in the Veterans Administration (VHA), overall and by HIV status, against physician chart review and adjudication. RESEARCH DESIGN AND METHODS: We used laboratory values (serum glucose and hemoglobin A1c% [HbA1c]), ICD-9 codes, and medication records from the United States Veterans Aging Cohort Study Biomarker Cohort (VACS-BC) to identify veterans with any indication of diabetes in the EMR for subsequent physician adjudication. Sensitivity, specificity, PPV, NPV, and kappa statistics were used to evaluate agreement of EMR-based diabetes diagnoses with chart review adjudicated diagnoses. RESULTS: EMR entries were reviewed for 1546 persons with HIV (PWH) and 843 HIV-negative participants through 2015. Agreement was at least moderate overall (kappa ≥0.42) for all pre-specified measures and among PWH vs. HIV-negative, and African-American vs. white subgroups. Having at least one HbA1c ≥6.5% provided substantial agreement with chart adjudication for prevalent and incident diabetes (kappa = 0.89 and 0.73). CONCLUSIONS: Identification of those with diabetes nationally within the VHA can be used in future studies to evaluate treatments, health outcomes, and adjust for diabetes in epidemiologic studies. Our methodology may provide insights for other organizations seeking to use EMR data for accurate determination of diabetes.

Our aim was to validate a Finnish version of the Eating Assessment Tool (F-EAT-10) for clinical use and to test its reliability and validity in a multicenter nationwide study. Normative data were acquired from 180 non-dysphagic participants (median age 57.0 years, 62.2% female). Dysphagia patients (n = 117, median age 69.7 years, 53.0% female) referred to fiberoptic endoscopic evaluation of swallowing (FEES) completed F-EAT-10 before the examination and after 2 weeks. Patients underwent the 100-ml water swallow test (WST) and FEES was evaluated using the following three scales: the Yale Pharyngeal Residue Severity Rating Scale, Penetration-Aspiration Scale, and the Dysphagia Outcome Severity Scale. An operative cohort of 19 patients (median age 75.8 years, 57.9% female) underwent an endoscopic operation on Zenker’s diverticulum, tight cricopharyngeal muscle diagnosed in videofluorography, or both. Patients completed the F-EAT-10 preoperatively and 3 months postoperatively. The cut-off score for controls was p

Advances in process innovation within the chemical process industry are impeded by the cost of producing new innovative components. In this paper, various manufacturing process routes were evaluated for scaling up a micro-scale liquid-liquid extractor and multi-phase separator capable of separating immiscible phases that are used for the extraction of a chemical product into a lower boiling point solvent to make downstream distillation easier. A manufacturing process design methodology was used to evaluate both photochemical machining and binder jetting as a means for producing the micropost arrays within the separator. Cost curves show that for a 0.3 mm deep micropost array, photochemical machining was found to be much cheaper than binder jetting. However, because binder jetting processes enable microposts with over 13 times higher depth-to-width aspect ratios, binder jetting was found to decrease the overall costs of the extractor/separator by more than half for a 500 barrel per day plant, with breakeven as low as 15 barrels per day. These economics were confirmed by building extractor/separator plates and characterizing them dimensionally and functionally. The binder jet plates were found to perform better than photochemical plates leading to the complete separation of the organic phase from water. The use of slower sintering cycles combined with surface grinding provided acceptable dimensional tolerances for the binder jet plates. Using pressurized air during depowdering improved the economics for the binder jetting process.

PURPOSE OF REVIEW: We summarize recent literature on the contribution of substance use and depression to non-AIDS-related comorbidities. Discussion of recent randomized clinical trials and implementation research to curtail risk attributed to each behavioral health issue is provided. RECENT FINDINGS: Smoking, unhealthy alcohol use, opioid use, and depression are common among PWH and individually contribute to increased risk for non-AIDS-related comorbidities. The concurrence of these conditions is notable, yet understudied, and provides opportunity for linked-screening and potential treatment of more than one behavioral health factor. Current results from randomized clinical trials are inconsistent. Investigating interventions to reduce the impact of these behavioral health conditions with a focus on implementation into clinical care is important. SUMMARY: Non-AIDS-defining cancers, cardiovascular disease, liver disease and diabetes are leading causes of morbidity in people with HIV. Behavioral health factors including substance use and mental health issues, often co-occurring, likely contribute to the excess risk of non-AIDS-related comorbidities.

BACKGROUND: Liver fibrosis, is independently associated with incident heart failure (HF). Investigating the association between liver fibrosis and type of HF, specifically HF with reduced ejection fraction (EF; HFrEF) or HF with preserved ejection fraction (HFpEF), may provide mechanistic insight into this association. We sought to determine the association between liver fibrosis score (FIB-4) and type of HF, and to assess whether HIV or hepatitis C status modified this association. METHODS: We included patients alive on or after 4/1/2003 from the Veterans Aging Cohort Study. We followed patients without prevalent cardiovascular disease until their first HF event, death, last clinic visit, or 9/30/2015. We defined liver fibrosis as: likely advanced fibrosis (FIB-4 > 3.25), indeterminate (FIB-4 range 1.45–3.25), unlikely advanced fibrosis (FIB-4 < 1.45). Primary outcomes were HFrEF and HFpEF (defined using ICD-9 diagnoses for HF, and EF extracted from electronic medical records using natural language processing). Cox proportional hazards models were adjusted for potential confounders and used to estimate hazard ratios (HR). RESULTS: Among 108,708 predominantly male (96%) participants mean age was 49 years. Likely advanced fibrosis was present in 4% at baseline and was associated with an increased risk of HFpEF [HR (95% confidence interval)] [1.70 (1.3–2.3)]; and non-significantly with HFrEF [1.20 (0.9–1.7)]. These associations were not modified by HIV or hepatitis C status. CONCLUSION: Likely advanced fibrosis was independently associated with incident HFpEF but not HFrEF. This suggests that risk factors and/or mechanisms for liver fibrosis may have greater overlap with those for HFpEF than HFrEF.

Purpose: To assess the long-term anatomical and functional findings in patients with symptomatic vitreomacular traction (VMT), with or without full thickness macular hole (FTMH), after eye treatment with intravitreal ocriplasmin injection (IOI). Methods: This longitudinal case series includes 51 eyes from 51 symptomatic patients with VMT (

Argentina considers its first National HTA Agency (AGNET) amidst expectations that it would stop "the scourge of judicialization". We suspect this argument is counterintuitive: the creation of HTA Agencies, or Health Benefits Packages in the Region, whatever their breadth, have so far failed to contain judicialisation by themselves. We discuss that judicialization thrives not only because of the laws of the land, but also because the design and creation of these technical Agencies, informing benefits lists, has been largely divorced from the more difficult task of seeking system-wide priority-setting (PS) processes and institutions, capable of eliciting the social values on which difficult coverage decisions should rest. We propose that, in order for explicit PS to gain a foothold in Argentina, a social "agreement on scarcity" has to be built first, consciously and openly, by (a) seeking more transparency in the way healthcare is financed across sub-sectors, with public access to auditable data; and (b) debating optimal levels of satisfaction of individual right to health, as rights of access, within the inevitable distributive conflict of a collective right to health and access, and never in isolation.

Despite the high prevalence of diastolic dysfunction in adults living with HIV, the impact on cardiorespiratory fitness (CRF) is understudied. The objective of this cross-sectional study was to investigate the relationship between cardiac function and CRF in adults with HIV. Adults receiving antiretroviral therapy with no history of coronary artery disease (CAD) or heart failure were eligible to participate. Cardiac function was assessed by resting Doppler echocardiography. CRF was measured by oxygen utilization at peak exercise (VO(2)peak). The majority of participants were African American (86%) and male (97%) with a mean [standard deviation (SD)] age of 56.6 (7.1) years and median CD4 lymphocyte count of 492 cells/mL. The mean (SD) VO(2)peak was 26.1 (5.5) mL/(kg·min). Age, diabetes, hypertension, and hemoglobin were associated with VO(2)peak. Overall, diastolic dysfunction was present in 38% and was associated with lower VO(2)peak (p

While there is emerging literature describing the use of narcotics for post-operative pain control following TKA, little data is available regarding narcotic use in partial knee replacements. The aim of this study is to compare the early post-operative narcotic requirements after medial compartmental arthroplasty (UKA) and patellofemoral arthroplasty (PFA) with that of TKA.In this retrospective chart review, we identified 37 patients who underwent PFA and 71 patients who underwent UKA. We identified a cohort of TKA patients who were matched to the unicompartmental group based on sex and age (n = 108). The primary outcome measure was self-reported use of opioids for pain management at the first post-operative clinic visit. Opioid use between groups was compared using Chi-square analysis.The PFA group was younger (p 0.001) and consisted of more females (p 0.001) than the UKA group. The UKA cohort had more non-smoking patients (p = 0.044) compared to the PFA cohort. Self-reported opioid use at the first post-operative visit differed between the three groups of patients (p 0.001). A greater proportion of both PFA (38% vs. 11%; p 0.001) and TKA (41% vs. 11%; p = 0.01) patients reported opioid use when compared to UKA patients. No differences in opioid use existed between TKA and PFA groups (p = 0.61).The prevalence of PFA patients who report opioid use at the first post-operative visit is similar to that for patients following TKA, suggesting that pain management protocols for this specific subset of partial knee arthroplasty patients should be structured similar to TKA patients and separate from UKA patients.

Monogenic diabetes is a category of diabetes mellitus caused by a single gene mutation or chromosomal abnormality, usually sub-classified as either neonatal diabetes or maturity-onset diabetes of the young (MODY). Although monogenic diabetes affects up to 3.5% of all patients with diabetes diagnosed before age 30, misdiagnosis and/or improper treatment occurs frequently. The University of Chicago Monogenic Diabetes Registry, established in 2008, offers insight into the diagnosis, treatment, and natural history of individuals known or suspected to have monogenic diabetes. Those interested in participating in the Registry begin by completing a secure web-based registration form found on our website (http://monogenicdiabetes.uchicago.edu/registry/). Participants are then screened for eligibility and consented either by phone, video call, or in person. Relevant medical and family history is collected at baseline and then annually via surveys through our secure Research Electronic Data Capture (REDCap) database. The University of Chicago Monogenic Diabetes Registry has enrolled over 3800 participants from over 2000 families. Participants represent all 50 states and more than 20 different countries. To date, over 1100 participants have a known genetic cause of diabetes. While many Registry participants reported being referred through their diabetes care provider (54%), a large portion also learned about the Registry through web searching (24%), friends/family (18%), or other sources (13%). Around two-thirds of those with a known genetic cause had research-based genetic testing completed rather than clinical testing due to insurance coverage difficulties. Of those who were found to have monogenic diabetes, significant delays in diagnosis were identified, which highlights the need for increased access to clinical genetic testing covered by insurance companies specifically within the United States. Among genes that cause a MODY phenotype, GCK mutations were the most common (59%) followed by HNF1A mutations (28%), while mutations in KCNJ11 were the most common among genes that cause neonatal diabetes (35%) followed by INS (16%). Over the last decade, improvements in data collection for the University of Chicago Monogenic Diabetes Registry have resulted in increased knowledge of the natural history of monogenic diabetes, as well as a better understanding of the most effective treatments. The University of Chicago Monogenic Diabetes Registry serves as a valuable resource that will continue to provide evidence to support improved clinical care and patient outcomes in monogenic diabetes.

Over the past 20 years, Nipah virus (NiV) has emerged as a significant, highly pathogenic bat-borne paramyxovirus causing severe respiratory disease and encephalitis in humans, and human-to-human transmission has been demonstrated in multiple outbreaks. In addition to causing serious illness in humans, NiV is a zoonotic pathogen capable of infecting a wide range of other mammalian species, including pigs and horses. While NiV has caused less than 700 human cases since its discovery in 1998/1999, the involvement of intermediate agricultural hosts can result in significant economic consequences. Owing to the severity of disease, capacity for human-to-human transmission, zoonotic potential, and lack of available approved therapeutic treatment options, NiV has been listed by the World Health Organization in their Blueprint list of priority pathogens as one of the eight most dangerous pathogens to monitor and prepare countermeasures to prevent a pandemic. Here, we discuss progress towards the development of therapeutic measures for the treatment of NiV infection and disease.

RationaleA commonMUC5Bgene polymorphism, rs35705950-T, is associated with idiopathic pulmonary fibrosis, but its role in the SARS-CoV-2 infection and disease severity is unclear.ObjectivesTo assess whether rs35705950-T confers differential risk for clinical outcomes associated with COVID-19 infection among participants in the Million Veteran Program (MVP) and COVID-19 Host Genetics Initiative (HGI).MethodsMVP participants were examined for an association between the incidence or severity of COVID-19 and the presence of aMUC5Brs35705950-T allele. Comorbidities and clinical events were extracted from the electronic health records (EHR). The analysis was performed within each ancestry group in the MVP, adjusting for sex, age, age2,and first twenty principal components followed by a trans-ethnic meta-analysis. We then pursued replication and performed a meta-analysis with the trans-ethnic summary statistics from the HGI. A phenome-wide association study (PheWAS) of the rs35705950-T was conducted to explore associated pathophysiologic conditions.Measurements and Main ResultsA COVID-19 severity scale was modified from the World Health Organization criteria, and phenotypes derived from the International Classification of Disease-9/10 were extracted from EHR. Presence of rs35705950-T was associated with fewer hospitalizations (Ncases=25353, Ncontrols=631,024; OR=0.86 [0.80-0.93], p=7.4 × 10−5) in trans-ethnic meta-analysis within MVP and joint meta-analyses with the HGI (N=1641311; OR=0.89 [0.85-0.93], p =1.9 × 10−6). Moreover, individuals of European Ancestry with at least one copy of rs35705950-T had fewer post-COVID-19 pneumonia events (OR=0.85 [0.76-0.96], p =0.008). PheWAS exclusively revealed pulmonary involvement.ConclusionsTheMUC5Bvariant rs35705950-T is protective in COVID-19 infection.

Background People living with HIV have higher sudden cardiac death (SCD) rates compared with the general population. Whether HIV infection is an independent SCD risk factor is unclear. Methods and Results This study evaluated participants from the Veterans Aging Cohort Study, an observational, longitudinal cohort of veterans with and without HIV infection matched 1:2 on age, sex, race/ethnicity, and clinical site. Baseline for this study was a participant's first clinical visit on or after April 1, 2003. Participants were followed through December 31, 2014. Using Cox proportional hazards regression, we assessed whether HIV infection, CD4 cell counts, and/or HIV viral load were associated with World Health Organization (WHO)–defined SCD risk. Among 144 336 participants (30% people living with HIV), the mean (SD) baseline age was 50.0 years (10.6 years), 97% were men, and 47% were of Black race. During follow‐up (median, 9.0 years), 3035 SCDs occurred. HIV infection was associated with increased SCD risk (hazard ratio [HR], 1.14; 95% CI, 1.04–1.25), adjusting for possible confounders. In analyses with time‐varying CD4 and HIV viral load, people living with HIV with CD4 counts 3 (HR, 1.57; 95% CI, 1.28–1.92) or viral load >500 copies/mL (HR, 1.70; 95% CI, 1.46–1.98) had increased SCD risk versus veterans without HIV. In contrast, people living with HIV who had CD4 cell counts >500 cells/mm 3 (HR, 1.03; 95% CI, 0.90–1.18) or HIV viral load Conclusions HIV infection is associated with increased risk of WHO‐defined SCD among those with elevated HIV viral load or low CD4 cell counts.

Purpose: To investigate the trends and progresses in glaucoma research by searching two major clinical trial registries; clinicaltrials.gov, and Australianclinicaltrials.gov.au.Methods: All clinical trials with glaucoma covered by Clinicaltrials.gov, and Australianclinicaltrials.gov.au starting the study before 1 January 2021 were included. Trials evaluating glaucoma treatment were separated from non-treatment trials and divided into three major categories: “laser treatment,” “surgical treatment,” and “medical treatment.” In the category of “medical treatment,” new compounds and their individual targets were identified and subcategorized according to treatment strategy; intraocular pressure (IOP)-lowering, neuroprotective or vascular. The phase transition success rates were calculated.Results: One-thousand five hundred and thirty-seven trials were identified. Sixty-three percent (n = 971) evaluated glaucoma treatment, of which medical treatment accounted for the largest proportion (53%). The majority of medical trials evaluated IOP-lowering compounds, while trials with neuroprotective or vascular compounds accounted for only 5 and 3%, respectively. Eighty-eight new compounds were identified. Phase I, II, and III transition success rates were 63, 26, and 47%, respectively.Conclusion: The number of clinical trials in glaucoma research has increased significantly over the last 30 years. Among the most recently evaluated compounds, all three main treatment strategies were represented, but clinical trials in neuroprotection and vascular modalities are still sparse. In addition to traditional medicines, dietary supplements and growth factors are assessed for a potential anti-glaucomatous effect. Phase II and III success rates were below previously reported success rates for all diseases and ophthalmology in general. A stricter phenotyping of patients can improve the success rates in glaucoma and ophthalmological research and gain a better understanding of responders and non-responders.

Preceding coronavirus outbreaks resulted in social isolation, which in turn is associated with cardiovascular consequences. Whether the current COVID-19 pandemic negatively impacts cardiovascular health is unclear. The aim of the rapid review was to investigate, whether COVID-19 lockdown influences modifiable cardiovascular risk factors (i.e., physical inactivity, sedentary behaviour, smoking, alcohol use, unhealthy diet, obesity, bad blood lipids, and hypertension) in the general population. Medline and EMBASE were searched until March 2021. Title, abstracts, and full texts were screened by one reviewer and 20% by a second reviewer. Only studies using probability sampling were included in order to ensure the representativeness of the target population. Data extraction and critical appraisal were done by one reviewer and double-checked by another reviewer. We identified 32 studies that fulfilled our inclusion criteria. Findings show that physical activity decreased, and sedentary behaviour increased among all age groups during the COVID-19 lockdown. Among adults, alcohol consumption increased, dietary quality worsened, and the amount of food intake increased. Some adults reported weight gain. Studies on children and adolescents were sparse. This rapid review found a high number of epidemiological studies on the impact of COVID-19 lockdown measures on modifiable cardiovascular risk factors, but only a few used probability sampling methods.

Parametric texture models have been applied successfully to synthesize artificial images. Psychophysical studies show that under defined conditions observers are unable to differentiate between model-generated and original natural textures. In industrial applications the reverse case is of interest: a texture analysis system should decide if human observers are able to discriminate between a reference and a novel texture. Here, we implemented a human-vision-inspired novelty detection approach. Assuming that the features used for texture synthesis are important for human texture perception, we compare psychophysical as well as learnt texture representations based on activations of a pretrained CNN in a novelty detection scenario. Based on a digital print inspection scenario we show that psychophysical texture representations are able to outperform CNN-encoded features.

Background Pulmonary hypertension incidence based on echocardiographic estimates of pulmonary artery systolic pressure in people living with HIV remains unstudied. We aimed to determine whether people living with HIV have higher incidence and risk of pulmonary hypertension than uninfected individuals. Methods In this retrospective cohort study, we evaluated data from participants in the Veterans Aging Cohort Study (VACS) referred for echocardiography with baseline pulmonary artery systolic pressure measures of 35 mm Hg or less. Incident pulmonary hypertension was defined as pulmonary artery systolic pressure higher than 35 mm Hg on subsequent echocardiogram. We used Poisson regression to estimate incidence rates (IRs) of pulmonary hypertension by HIV status. We then estimated hazard ratios (HRs) by HIV status using Cox proportional hazards regression. We further categorised veterans with HIV by CD4 count or HIV viral load to assess the association between pulmonary hypertension risk and HIV severity. Models included age, sex, race or ethnicity, prevalent heart failure, chronic obstructive pulmonary disease, hypertension, smoking status, diabetes, body-mass index, estimated glomerular filtration rate, hepatitis C virus infection, liver cirrhosis, and drug use as covariates. Findings Of 21 314 VACS participants with at least one measured PASP on or after April 1, 2003, 13 028 VACS participants were included in the analytic sample (4174 [32%] with HIV and 8854 [68%] without HIV). Median age was 58 years and 12 657 (97%) were male. Median follow-up time was 3·1 years (IQR 0·9-6·8) spanning from April 1, 2003, to Sept 30, 2017. Unadjusted IRs per 1000 person-years were higher in veterans with HIV (IR 28·6 [95% CI 26·1-31·3]) than in veterans without HIV (IR 23·4 [21·9-24·9]; p=0·0004). The risk of incident pulmonary hypertension was higher among veterans with HIV than among veterans without HIV (unadjusted HR 1·25 [95% CI 1·12-1·40], p

Background Challenging emerging entities with distinctive molecular signatures may benefit from algorithms for diagnostic work-up. Methods Fusion sarcomas (2020–2021, during pandemic) were diagnosed by clinicoradiology, morphology, phenotype, and next-generation sequencing (NGS). Results Six fusion sarcomas in two males and four females involved the chest-wall, neck, or extremities; ages ranged 2-73, median 18 years. Sizes ranged 5.3-25.0, median 9.1 cm. These include high grade 1) TPR-NTRK1 of proximal femur with a larger rounded soft tissue mass, previously considered osteosarcoma yet without convincing tumor matrix. A pathologic fracture necessitated emergency hemipelvectomy (NED) and 2) novel KANK1-NTRK2 sarcoma of bone and soft tissue with spindled pleomorphic to epithelioid features (AWD metastases). 3) Novel ERC1-ALK unaligned fusion, a low grade infiltrative deep soft tissue hand sarcoma with prominent-vascularity, myopericytoid/lipofibromatosis-like ovoid cells, and collagenized stroma, was successfully treated with ALK-inhibitor (Crizotinib), avoiding amputation. These NTRK and ALK tumors variably express S100 and CD34 and were negative for SOX10. 4) and 5) CIC-DUX4 round cell tumors (rapid metastases/demise), one with COVID superinfection, were previously treated as Ewing sarcoma. These demonstrated mild pleomorphism and necrosis, variable myxoid change and CD99 reactivity, and a distinctive dot-like-Golgi WT1 immunostaining pattern. 6) A chest wall/thoracic round cell sarcoma, focal CD34/ keratins/CK7, revealed nuclear-STAT6, STAT6-NAB2 by NGS, confirming malignant solitary fibrous tumor, intermediate-risk-stratification (AWD metastases). Conclusions Recent fusion sarcomas include new KANK1-NTRK2 and ERC1-ALK, the latter successfully treated by targeted-therapy. ALK/NTRK fusion partners TPR and KANK1 suggest unusual high-grade morphology/behavior. Clinicoradiologic, morphologic, and phenotypic algorithms can prompt molecular-targeted immunostains or NGS for final classification and promising inhibitor therapy.

The use of molecular-based diagnostic testing, such as the Luminex Verigene system, to rapidly identify the most common bacterial isolates from blood cultures is an important tool that reduces the duration of inappropriate antibiotics and decreases mortality. However, 5 to 15% of microorganisms recovered from blood culture are unable to be identified by the Verigene Gram-negative (BC-GN) or Gram-positive (BC-GP) assays. In this retrospective, observational study, we evaluate the identities and antimicrobial susceptibility patterns of 229 isolates that were not identified by either the Verigene BC-GN or BC-GP assay. The results presented here suggest that important, clinically relevant information about antimicrobial susceptibility patterns can still be inferred even when isolates are not identified by Verigene. We also examined changes in antibiotic use for patients with “unidentified” Verigene results at our institution and found that this subgroup represents an opportunity to optimize empirical antibiotic therapy. IMPORTANCE Rapid diagnostic testing to identify bloodstream pathogens has arisen as an important tool both to ensure adequate antimicrobial therapy is given early and to aid in antimicrobial stewardship by allowing for more rapid deescalation of inappropriate antimicrobial therapy. However, there is a paucity of data regarding the significance of isolates that are not able to be identified by rapid diagnostic testing. In this study, we report the identification to the species level and antimicrobial susceptibilities among isolates that were not identified by one such rapid diagnostic platform, the Verigene system. This study provides important insight into how a strong understanding of the strengths and limitations of a given rapid diagnostic platform, coupled with insight into local antibiotic susceptibility patterns, can allow for more nuanced and thoughtful empirical antibiotic selection.

Background HIV infection and depression are each associated with increased ischemic stroke risk. Whether depression is a risk factor for stroke within the HIV population is unknown. Methods and Results We analyzed data on 106 333 (33 528 HIV‐positive; 72 805 HIV‐negative) people who were free of baseline cardiovascular disease from an observational cohort of HIV‐positive people and matched uninfected veterans in care from April 1, 2003 through December 31, 2014. International Classification of Diseases, Ninth Revision ( ICD‐9 ) codes from medical records were used to determine baseline depression and incident stroke. Depression occurred in 19.5% of HIV‐positive people. After a median of 9.2 years of follow‐up, stroke rates were highest among people with both HIV and depression and lowest among those with neither condition. In Cox proportional hazard models, depression was associated with an increased risk of stroke for HIV‐positive people after adjusting for sociodemographic characteristics and cerebrovascular risk factors (hazard ratio [HR], 1.18; 95% CI: 1.03–1.34; 0.014). The depression‐stroke relationship was attenuated by alcohol use disorders, cocaine use, and baseline antidepressant use, and unaffected by combined antiretroviral therapy use or individual antiretroviral agents. A numerically higher HR of depression on stroke was found among those younger than 60 years. Conclusions Depression is associated with an increased risk of stroke among HIV‐positive people after adjusting for sociodemographic characteristics, traditional cerebrovascular risk factors, and HIV‐specific factors. Alcohol use disorders, cocaine use, and baseline antidepressant use accounted for some of the observed stroke risk. Depression may be a novel, independent risk factor for ischemic stroke in HIV, particularly among younger people.

OBJECTIVE Multiple genome-wide association studies have identified a strong genetic linkage between the SKAP2 locus and type 1 diabetes (T1D), but how this leads to disease remains obscure. Here, we characterized the functional consequence of a novel SKAP2 coding mutation in a patient with T1D to gain further insight into how this impacts immune tolerance. RESEARCH DESIGN AND METHODS We identified a 24-year-old individual with T1D and other autoimmune and inflammatory conditions. The proband and first-degree relatives were recruited for whole-exome sequencing. Functional studies of the protein variant were performed using a cell line and primary myeloid immune cells collected from family members. RESULTS Sequencing identified a de novo SKAP2 variant (c.457G>A, p.Gly153Arg) in the proband. Assays using monocyte-derived macrophages from the individual revealed enhanced activity of integrin pathways and a migratory phenotype in the absence of chemokine stimulation, consistent with SKAP2 p.Gly153Arg being constitutively active. The p.Gly153Arg variant, located in the well-conserved lipid-binding loop, induced similar phenotypes when expressed in a human macrophage cell line. SKAP2 p.Gly153Arg is a gain-of-function, pathogenic mutation that disrupts myeloid immune cell function, likely resulting in a break in immune tolerance and T1D. CONCLUSIONS SKAP2 plays a key role in myeloid cell activation and migration. This particular mutation in a patient with T1D and multiple autoimmune conditions implicates a role for activating SKAP2 variants in autoimmune T1D.

Background Although HIV is associated with increased risk of heart failure (HF), it is not known if people living with HIV develop HF at a younger age compared with individuals without HIV. Crude comparisons of age at diagnosis of HF between individuals with and without HIV does not account for differences in underlying age structures between the populations. Methods and Results We used Veterans Health Administration data to compare the age at HF diagnosis between veterans with and without HIV, with adjustment for difference in population age structure. Statistical weights, calculated for each 1‐year strata of veterans with HIV in each calendar year from 2000 to 2018, were applied to the veterans without HIV to standardize the age structure. We identified 5093 veterans with HIV (98% men, 34% White) with first HF episode recorded after HIV diagnosis (median age at incidence of HF, 58 years), and 1 425 987 veterans without HIV (98% men, 78% White) with HF (corresponding age, 72 years), with an absolute difference of 14 years. After accounting for difference in age structure, the adjusted median age at HF diagnosis for veterans without HIV was 63 years, 5 years difference with veterans with HIV ( P Conclusions Veterans with HIV are diagnosed with HF at a significantly younger age compared with veterans without HIV. These findings may have implications for HF prevention in individuals with HIV. Future studies are needed to make the findings more generalizable.

Stigmatization from work-related COVID-19 exposure has not been investigated in detail yet. Therefore, we systematically searched three databases: Medline, Embase, and PsychInfo (until October 2020), and performed a grey literature search (until February 2021). We identified 46 suitable articles from 24 quantitative and 11 qualitative studies, 6 systematic reviews, 3 study protocols and 1 intervention. The assessment of stigmatization varied widely, ranging from a single-item question to a 22-item questionnaire. Studies mostly considered perceived self-stigma (27 of 35 original studies) in healthcare workers (HCWs) or hospital-related jobs (29 of 35). All articles reported on stigmatization as a result of work-related COVID-19 exposure. However, most quantitative studies were characterized by convenience sampling (17 of 24), and all studies—also those with an adequate sampling design—were considered of low methodological quality. Therefore, it is not possible to determine prevalence of stigmatization in defined occupational groups. Nevertheless, the work-related stigmatization of occupational groups with or without suspected contact to COVID-19 is a relevant problem and increases the risk for depression (odds ratio (OR) = 1.74; 95% confidence interval CI 1.29–2.36) and anxiety (OR = 1.75; 95% CI 1.29–2.37). For promoting workers’ health, anti-stigma strategies and support should be implemented in the workplace.

The University of Chicago National Monogenic Diabetes Registry houses a novel dataset of people presenting with possible or known monogenic diabetes and has over a decade of data points, despite the rarity of the disease relative to T1DM and especially T2DM. Currently, determination of genetic testing, including which specific panel or genes is most appropriate to sequence, is a manual process introducing variability and subjectivity. Aim: To test and compare performance of several models against the manual process and each other in identifying maturity-onset diabetes of the young (MODY) from available clinical information. Methods: Statistical models for prediction of monogenic diabetes were applied to clinical data for cases suspected of having MODY. The models tested in the study with this dataset ranged from the traditional methods of regression to more modern approaches of neural nets, classification trees, clustering, and other machine learning algorithms for classification of MODY against type 1 and type 2 and a possible subset of monogenic diabetes subtypes. Results: Using a sample size of N=330, with 70 testing positive for either GCK, HNF1A, or HNF4A, exploratory data models were able to achieve 75-80% validation accuracy (random validation data set at 10-20% of N) while internal human classification accuracy was roughly 42% over the same samples. The traditional logistic regression and neural net had equivalent performance. Conclusions: The 3750 participants within the Registry and more than a decade of follow-up presents a unique opportunity to assess which clinical features are most predictive in identifying those with monogenic diabetes. The results of this work will direct future testing efforts within the Registry to assist in efficient diagnosis of these uncommon yet clinically important forms of diabetes. Disclosure R. P. Mulligan: None. L. R. Letourneau-freiberg: None. T. L. Bowden: None. P. Tian: None. B. Kandasamy: None. L. H. Philipson: Advisory Panel; Self; Nevro Corp., Research Support; Self; Provention Bio, Inc. S. W. Greeley: None. R. N. Naylor: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK104942, P30DK020595)

Recent insights into human autoimmunity and immune tolerance have come from studies of rare monogenic disorders. For example, type 1 diabetes (T1D) and thyroid autoimmunity are frequent features in patients with mutations in AIRE and FOXP3. Dissecting the consequences of these mutations has improved our understanding of the role of central T cell tolerance and T regulatory cells in controlling these organ-specific autoimmune diseases. Over the last decade, rapid advances in genetic sequencing have now allowed for a deeper exploration and discovery of rare variants that are linked to disease with techniques like whole exome sequencing. Using this approach in both kindreds and outlier patients with de novo germline mutations, there has been expanding discovery of mutations in other pathways with a link to organ-specific autoimmunity that include STAT3, STAT1, CTLA4, and LRBA. Here, we utilized a similar approach on a single patient with T1D and other autoimmune and inflammatory conditions. We identified a de novo heterozygous c.457G>A/p.Gly153Arg mutation in the SKAP2 gene. SKAP2 encodes a critical mediator of integrin signaling pathways that regulate myeloid immune cell function. Monocyte-derived macrophages from the individual displayed enhanced activity of integrin pathways and a migratory phenotype in the absence of chemokine stimulation, consistent with SKAP2 p.Gly153Arg being constitutively active. The p.Gly153Arg variant, located in the well-conserved lipid-binding loop, induced similar phenotypes when expressed in a human macrophage cell line. We propose that SKAP2 p.Gly153Arg is a gain-of-function, pathogenic mutation that disrupts myeloid immune cell function, resulting in a break in immune tolerance and T1D. This particular mutation in a patient with T1D and multiple autoimmunity implicates a role for activating SKAP2 variants in autoimmune T1D. Disclosure C. Chamberlain: None. N. Rutsch: None. W. Dixon: None. L. R. Letourneau-freiberg: None. L. H. Philipson: Advisory Panel; Self; Nevro Corp., Research Support; Self; Provention Bio, Inc. M. German: Stock/Shareholder; Self; Viacyte, Inc. M. S. Anderson: Consultant; Self; Provention Bio, Inc., VielaBio, Stock/Shareholder; Self; Medtronic, Merck & Co., Inc. C. A. Lowell: None. Funding The Leona M. and Harry B. Helmsley Charitable Trust (G-2018PG-T1D018); Larry L. Hillblom Foundation (2014-D-004-NET); University of California San Francisco Parnassus Flow Core (RRID:SCR_018206); National Institutes of Health (P30 DK063720, S101S10OD021822-01); German Research Foundation (ZA428/11-1, ZA428/18-1, INST211/604-1)

The immensely complex realm of naval warfare presents challenges for which machine learning is uniquely suited. In this paper, we present a machine learning model to predict the location of unseen enemy ships in real time, based on the current known positions of other ships on the battlefield. More broadly, this research seeks to validate the ability of basic machine learning algorithms to make meaningful classifications and predictions of simulated adversarial naval behavior. Using gameplay data from World of Warships, we deployed an artificial neural network (ANN) model and a Random Forest model to serve as prediction engines that update as the battle progresses, overlaying probabilities over the battlefield map indicating the likelihood of the unseen ship being at each location. The models were trained and tested on gameplay data from a World of Warships tournament in which former naval officers served as commanders of competing fleets. This tournament structure ensured cohesive and coordinated naval fleet behavior, yielding data similar to that seen in real-world naval combat and increasing the applicability of our model. Both the Random Forest and ANN model were successful in their predictive capabilities, with the ANN proving to be the best method.

Use of continuous glucose monitoring (CGM) systems has become standard of care in type 1 diabetes (T1D) in many countries, particularly in children and adolescents (1,2). Results from clinical trials indicate that use of CGM leads to improved metabolic control and reduction in nonsevere hypoglycemia compared with self-monitoring of capillary blood glucose (3,4). Benefits are seen irrespective of insulin delivery method (pump or pen) (4,5) but are conditioned on near-daily sensor usage (4). Trial participants, however, are often biased toward higher education level, greater therapy adherence, and better self-management. Small sample size and short trial duration very often preclude appropriate assessment of CGM impact on rare events such as severe hypoglycemia (SH) or diabetic ketoacidosis (DKA). We therefore used real-world data from the German-Austrian-Swiss-Luxembourgian Diabetes Prospective Follow-up (DPV) registry to longitudinally assess HbA1c, SH, and DKA during the first year after initiation of CGM, including real-time CGM and intermittently scanned/viewed CGM. Anonymized patient registry records were analyzed. SH was defined as events requiring external assistance by another person and events resulting in coma/convulsion. DKA was defined by pH level

BACKGROUND As guidelines and payers increasingly recommend use of patient decision aids (DAs), evidence about the comparative effectiveness of available DAs is critical for organizations interested in implementing them. The primary purpose of this study was to compare 2 DAs with regard to their ability to help patients become informed and receive their preferred treatment (that is, make an informed patient-centered decision), shared decision-making, surgical rates, and surgeon satisfaction. METHODS We performed a multisite factorial randomized trial enrolling patients with hip or knee osteoarthritis. Patients were randomly assigned to use a long, detailed DA (long DA) or short, interactive DA (short DA). Eight surgeons were randomly assigned to receive a patient preference report detailing the patient's goals and treatment preferences or to administer usual care. RESULTS We distributed 1,636 pre-visit surveys, 1,220 of which were returned (75% response rate), and 1,124 post-visit surveys, 967 of which were returned (86% response rate). The patients in the sample had a mean age (and standard deviation) of 65 ± 10 years, 57% were female, 89% were white non-Hispanic, and 67% had knee osteoarthritis. The majority (67.2%) made informed patient-centered decisions, and the rate did not vary significantly between the DA groups (p = 0.97) or between the surgeon groups (p = 0.23). Knowledge scores were higher for the short-DA group (mean difference = 9%; p < 0.001). More than half of the sample (60.5%) had surgery within 6 months after the visit, and rates did not differ significantly by DA or surgeon group. Overall, the surgeons were highly satisfied and reported that the majority (88.7%) of the visits were of normal duration or shorter. CONCLUSIONS The DECIDE-OA study is, to our knowledge, the first randomized comparative effectiveness study of 2 orthopaedic DAs. The short DA outperformed the long DA with regard to knowledge scores and was comparable with respect to other outcomes. The surgeons reported high satisfaction and normal visit duration with both DAs. CLINICAL RELEVANCE Surgeons need to ensure that patients with osteoarthritis are well-informed and have a clear preference regarding whether to undergo hip or knee replacement surgery. The DAs used in this study may help surgeons involve patients in elective surgery decisions and meet the requirements of informed consent.

Background: Approximately 13% of black individuals carry 2 copies of the apolipoprotein L1 ( APOL1 ) risk alleles G1 or G2, which are associated with 1.5- to 2.5-fold increased risk of chronic kidney disease. There have been conflicting reports as to whether an association exists between APOL1 risk alleles and cardiovascular disease (CVD) that is independent of the effects of APOL1 on kidney disease. We sought to test the association of APOL1 G1/G2 alleles with coronary artery disease, peripheral artery disease, and stroke among black individuals in the Million Veteran Program. Methods: We performed a time-to-event analysis of retrospective electronic health record data using Cox proportional hazard and competing-risks Fine and Gray subdistribution hazard models. The primary exposure was APOL1 risk allele status. The primary outcome was incident coronary artery disease among individuals without chronic kidney disease during the 12.5-year follow-up period. We separately analyzed the cross-sectional association of APOL1 risk allele status with lipid traits and 115 cardiovascular diseases using phenome-wide association. Results: Among 30 903 black Million Veteran Program participants, 3941 (13%) carried the 2 APOL1 risk allele high-risk genotype. Individuals with normal kidney function at baseline with 2 risk alleles had slightly higher risk of developing coronary artery disease compared with those with no risk alleles (hazard ratio, 1.11 [95% CI, 1.01–1.21]; P =0.039). Similarly, modest associations were identified with incident stroke (hazard ratio, 1.20 [95% CI, 1.05–1.36; P =0.007) and peripheral artery disease (hazard ratio, 1.15 [95% CI, 1.01–1.29l; P =0.031). When both cardiovascular and renal outcomes were modeled, APOL1 was strongly associated with incident renal disease, whereas no significant association with the CVD end points could be detected. Cardiovascular phenome-wide association analyses did not identify additional significant associations with CVD subsets. Conclusions: APOL1 risk variants display a modest association with CVD, and this association is likely mediated by the known APOL1 association with chronic kidney disease.

Background: The mechanism of adverse limb events associated with peripheral artery disease remains incompletely understood. We investigated whether microvascular disease is associated with amputation in a large cohort of veterans to determine whether microvascular disease diagnosed in any location increases the risk of amputation alone and in concert with peripheral artery disease. Methods: Participants in the Veterans Aging Cohort Study were recruited from April 1, 2003 through December 31, 2014. We excluded participants with known prior lower limb amputation. Using time-updated Cox proportional hazards regression, we analyzed the effect of prevalent microvascular disease (retinopathy, neuropathy, and nephropathy) and peripheral artery disease status on the risk of incident amputation events after adjusting for demographics and cardiovascular risk factors. Results: Among 125 674 veterans without evidence of prior amputation at baseline, the rate of incident amputation over a median of 9.3 years of follow-up was 1.16 per 1000 person-years, yielding a total of 1185 amputations. In time-updated multivariable-adjusted analyses, compared with those without peripheral artery disease or microvascular disease, microvascular disease alone was associated with a 3.7-fold (95% CI, 3.0–4.6) increased risk of amputation; peripheral artery disease alone conferred a 13.9-fold (95% CI, 11.3–17.1) elevated risk of amputation; and the combination of peripheral artery disease and microvascular disease was associated with a 22.7-fold (95% CI, 18.3–28.1) increased risk of amputation. Conclusions: Independent of traditional risk factors, the presence of microvascular disease increases the risk of amputation alone and synergistically increases risk in patients with peripheral artery disease. Further research is needed to understand the mechanisms by which this occurs.

The primary aim of this review was to summarize the evidence on the relationship between being a daycare worker working with children and the possible increased risk of cytomegalovirus infection. We searched the Medline and Embase databases using search strings defined according to the population, exposure, comparison, and outcomes (PECO) applicable to our research questions in order to find studies published since 2000. Two independent reviewers evaluated the search hits using predefined inclusion and exclusion criteria. A manual search was performed to identify additional relevant literature. We extracted the resulting studies and assessed them in eight domains of bias. The pooled CMV seroprevalence for daycare workers compared to the general population was calculated. After evaluating the 6879 records, six methodologically adequate studies were identified: five cross-sectional studies and one cohort study. The pooled seroprevalence of daycare workers was 59.3% (95% CI 47.6–70.9). The four studies investigating risk of infection indicated an increased seroprevalence for daycare workers compared to a reference population (prevalence ratio, PR = 1.54, 95% CI 1.33–1.77). No study evaluated CMV seroconversions for daycare workers. Our findings suggest a higher CMV seroprevalence for daycare workers compared to the general population. Notwithstanding the need for longitudinal and intervention studies, preventative efforts are needed. A pooled PR of 1.54 is compatible with a doubled seroconversion risk corresponding to a vocational probability of 50% if the substantial underestimation of the actual occupational seroconversion risk by prevalence-based estimators is considered.

Peripheral artery disease (PAD) is a leading cause of cardiovascular morbidity and mortality; however, the extent to which genetic factors increase risk for PAD is largely unknown. Using electronic health record data, we performed a genome-wide association study in the Million Veteran Program testing ~32 million DNA sequence variants with PAD (31,307 cases and 211,753 controls) across veterans of European, African and Hispanic ancestry. The results were replicated in an independent sample of 5,117 PAD cases and 389,291 controls from the UK Biobank. We identified 19 PAD loci, 18 of which have not been previously reported. Eleven of the 19 loci were associated with disease in three vascular beds (coronary, cerebral, peripheral), including LDLR, LPL and LPA, suggesting that therapeutic modulation of low-density lipoprotein cholesterol, the lipoprotein lipase pathway or circulating lipoprotein(a) may be efficacious for multiple atherosclerotic disease phenotypes. Conversely, four of the variants appeared to be specific for PAD, including F5 p.R506Q, highlighting the pathogenic role of thrombosis in the peripheral vascular bed and providing genetic support for Factor Xa inhibition as a therapeutic strategy for PAD. Our results highlight mechanistic similarities and differences among coronary, cerebral and peripheral atherosclerosis and provide therapeutic insights.

La creatividad y las prácticas ligadas a fomentarla en el ámbito universitario constituyen en la actualidad un tema de interés. La creatividad en tanto fenómeno multidimensional requiere ser evaluada en sus distintas facetas, siendo la personalidad una de las que mayor relevancia reviste. Se propone así, adaptar localmente la Escala de Personalidad Creativa (EPC) de Gough para ser aplicada en el ámbito universitario. El instrumento se compone de 30 adjetivos a ser respondidos por los evaluados según se identifiquen o no con cada uno de ellos. Se realizó un análisis factorial exploratorio y de consistencia interna (n = 150) y otro confirmatorio y de validez convergente (n = 150) a partir de dos muestras independientes. El procedimiento exploratorio conservó ocho ítems y una estructura factorial unidimensional con una óptima consistencia interna (alfa ordinal = .853). Este modelo se verificó empíricamente mediante el análisis confirmatorio que arrojó óptimos índices de ajuste y un apropiado índice de consistencia interna. Adicionalmente se obtuvieron adecuadas evidencias de validez convergente del instrumento en relación a otros constructos teóricamente afines. Los resultados se discuten a la luz de la teoría y las limitaciones del diseño, destacando los alcances del estudio y las futuras líneas de investigación. Creativity and actions aimed at fostering it became a matter of interest in higher education. Since creativity is a multidimensional phenomenon, its diverse dimensions must be assessed. Among them, personality arises as the most relevant one. Therefore, the local adaptation of Gough’s Creative Personality Scale to be used in college students is proposed. This scale is composed of adjectives to be responded according to the examinees’ identification with each one of them. Two independent samples (n= 150 each) were employed to develop an exploratory factor analysis and an internal consistency analysis, on the one hand, and a confirmatory factor analysis and a convergent validity study. The exploratory procedure retained eight items and a 1-dimension structure with a good internal consistency (ordinal alpha= .853). This model was empirically verified by the confirmatory analysis which showed good fit indices, as well as an adequate internal consistency coefficient. Moreover, adequate convergent validity evidences were obtained. Findings are discussed taking into account the theoretical model and the study weaknesses along with practical and theoretical outcomes. Further research lines are proposed.

ObjectivesThe contribution of depression to mortality in adults with and without HIV infection is unclear. We hypothesized that depression increases mortality risk and that this association is stronger among those with HIV infection.MethodsVeterans Aging Cohort Study (VACS) data were analysed from the first clinic visit on or after 1 April 2003 (baseline) to 30 September 2015. Depression definitions were: (1) major depressive disorder defined using International Classification of Diseases, Ninth Revision (ICD-9) codes; (2) depressive symptoms defined as Patient Health Questionnaire (PHQ)-9 scores ≥10. The outcome was all-cause mortality. Covariates were demographics, comorbid conditions and health behaviours.ResultsAmong 129140 eligible participants, 30% had HIV infection, 16% had a major depressive disorder diagnosis, and 24% died over a median follow-up time of 11years. The death rate was 25.3 [95% confidence interval (CI) 25.0-25.6] deaths per 1000 person-years. Major depressive disorder was associated with mortality [hazard ratio (HR) 1.04; 95% CI1.01, 1.07]. This association was modified by HIV status (interaction P-value=0.02). In HIV-stratified analyses, depression was significantly associated with mortality among HIV-uninfected veterans but not among those with HIV infection. Among those with PHQ-9 data (n=7372), 50% had HIV infection, 22% had PHQ-9 scores ≥10, and 28% died over a median follow-up time of 12years. The death rate was 27.3 (95% CI 26.1-28.5) per 1000 person-years. Depressive symptoms were associated with mortality (HR 1.16; 95% CI 1.04, 1.28). This association was modified by HIV status (interaction P-value=0.05). In HIV-stratified analyses, depressive symptoms were significantly associated with mortality among veterans with HIV infection but not among those without HIV infection.ConclusionsDepression was associated with all-cause mortality. This association was modified by HIV status and method of depression ascertainment.