Hypoxia-inducible factors enhance the effector responses of CD8(+) T cells to persistent antigen.

Cytolytic activity by CD8(+) cytotoxic T lymphocytes (CTLs) is a powerful strategy for the elimination of intracellular pathogens and tumor cells. The destructive capacity of CTLs is progressively dampened during chronic infection, yet the environmental cues and molecular pathways that influence immunological 'exhaustion' remain unclear. Here we found that CTL immunity was regulated by the central transcriptional response to hypoxia, which is controlled in part by hypoxia-inducible factors (HIFs) and the von Hippel-Lindau tumor suppressor VHL. Loss of VHL, the main negative regulator of HIFs, led to lethal CTL-mediated immunopathology during chronic infection, and VHL-deficient CTLs displayed enhanced control of persistent viral infection and neoplastic growth. We found that HIFs and oxygen influenced the expression of pivotal transcription, effector and costimulatory-inhibitory molecules of CTLs, which was relevant to strategies that promote the clearance of viruses and tumors.

Validation of Population Pharmacokinetic Models for Clozapine Dosage Prediction.

BACKGROUND: Clozapine is unique in its capacity to ameliorate severe schizophrenia but at high risk of toxicity. A relationship between blood concentration and clinical response and evidence for concentration-response relationships to some adverse effects justify therapeutic drug monitoring of clozapine. However, the relationship between drug dose and blood concentration is quite variable. This variability is, in part, due to inductive and inhibitory interactions varying the activity of cytochrome P450 1A2 (CYP1A2), the principal pathway for clozapine elimination. Several population pharmacokinetic models have been presented to facilitate dose selection and to identify poor adherence in individual patients. These models have faced little testing for validity in independent populations or even for persisting validity in the source population. METHODS: Therefore, we collected a large population of clozapine-treated patients (127 patients, 1048 timed plasma concentrations) in whom dosing and covariate information could be obtained with high certainty. A population pharmacokinetic model was constructed with data collected in the first 6 weeks from study enrolment (448 plasma concentrations), to estimate covariate influences and to allow alignment with previously published models. The model was tested for its performance in predicting the concentrations observed at later time intervals up to 5 years. The predictive performances of 6 published clozapine population models were then assessed in the entire population. RESULTS: The population pharmacokinetic model based on the first 6 weeks identified significant influences of sex, smoking, and cotreatment with fluvoxamine on clozapine clearance. The model built from the first 6 weeks had acceptable predictive performance in the same patient population up to the first 26 weeks using individual parameters, with a median predictive error (PE) of -0.1% to -15.9% and median absolute PE of 22.9%-27.1%. Predictive performance fell progressively with time after 26 weeks. Bayesian addition of plasma concentration observations within each prediction period improved individual predictions. Three additional observations extended acceptable predictive performance into the second 6 months of therapy. When the published models were tested with the entire data set, median PE ranged from -8% to +35% with a median absolute PE of >39% in all models. Thus, none of the tested models was successful in external validation. Bayesian addition of single patient observations improved individual predictions from all models but still without achieving acceptable performances. CONCLUSIONS: We conclude that the relationship between covariates and blood clozapine concentrations differs between populations and that relationships are not stable over time within a population. Current population models for clozapine are not capturing influential covariates.

Host Cell Death and Modulation of Immune Response against Mycobacterium tuberculosis Infection.

Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), a prevalent infectious disease affecting populations worldwide. A classic trait of TB pathology is the formation of granulomas, which wall off the pathogen, via the innate and adaptive immune systems. Some key players involved include tumor necrosis factor-alpha (TNF-α), foamy macrophages, type I interferons (IFNs), and reactive oxygen species, which may also show overlap with cell death pathways. Additionally, host cell death is a primary method for combating and controlling Mtb within the body, a process which is influenced by both host and bacterial factors. These cell death modalities have distinct molecular mechanisms and pathways. Programmed cell death (PCD), encompassing apoptosis and autophagy, typically confers a protective response against Mtb by containing the bacteria within dead macrophages, facilitating their phagocytosis by uninfected or neighboring cells, whereas necrotic cell death benefits the pathogen, leading to the release of bacteria extracellularly. Apoptosis is triggered via intrinsic and extrinsic caspase-dependent pathways as well as caspase-independent pathways. Necrosis is induced via various pathways, including necroptosis, pyroptosis, and ferroptosis. Given the pivotal role of host cell death pathways in host defense against Mtb, therapeutic agents targeting cell death signaling have been investigated for TB treatment. This review provides an overview of the diverse mechanisms underlying Mtb-induced host cell death, examining their implications for host immunity. Furthermore, it discusses the potential of targeting host cell death pathways as therapeutic and preventive strategies against Mtb infection.

A Randomized Controlled Trial to Assess the Impact of Enhanced Recovery After Surgery on Patients Undergoing Elective Spine Surgery.

OBJECTIVE: To conduct a prospective, randomized controlled trial (RCT) of an enhanced recovery after surgery (ERAS) protocol in an elective spine surgery population. BACKGROUND: Surgical outcomes such as length of stay (LOS), discharge disposition, and opioid utilization greatly contribute to patient satisfaction and societal healthcare costs. ERAS protocols are multimodal, patient-centered care pathways shown to reduce postoperative opioid use, reduced LOS, and improved ambulation; however, prospective ERAS data are limited in spine surgery. METHODS: This single-center, institutional review board-approved, prospective RCT-enrolled adult patients undergoing elective spine surgery between March 2019 and October 2020. Primary outcomes were perioperative and 1-month postoperative opioid use. Patients were randomized to ERAS (n=142) or standard-of-care (SOC; n=142) based on power analyses to detect a difference in postoperative opioid use. RESULTS: Opioid use during hospitalization and the first postoperative month was not significantly different between groups (ERAS 112.2 vs SOC 117.6 morphine milligram equivalent, P =0.76; ERAS 38.7% vs SOC 39.4%, P =1.00, respectively). However, patients randomized to ERAS were less likely to use opioids at 6 months postoperatively (ERAS 11.4% vs SOC 20.6%, P =0.046) and more likely to be discharged to home after surgery (ERAS 91.5% vs SOC 81.0%, P =0.015). CONCLUSION: Here, we present a novel ERAS prospective RCT in the elective spine surgery population. Although we do not detect a difference in the primary outcome of short-term opioid use, we observe significantly reduced opioid use at 6-month follow-up as well as an increased likelihood of home disposition after surgery in the ERAS group.

Identification of Dietary Supplements Associated with Blood Metabolites in the Hispanic Community Health Study/Study of Latinos Cohort Study.

BACKGROUND: Metabolomics approaches have been widely used to define the consumption of foods but have less often been used to study exposure to dietary supplements. OBJECTIVES: This study aimed to identify dietary supplements associated with metabolite levels and to examine whether these metabolites predicted incident diabetes risk. METHODS: We studied 3972 participants from a prospective cohort study of 18-74-y-old Hispanic/Latino adults. At a baseline examination, we ascertained use of dietary supplements using recall methods and concurrently, a serum metabolomic panel. After adjustment for potential confounders, we identified dietary supplements associated with metabolites. We then examined the association of these metabolites with incident diabetes at the 6-y study examination. RESULTS: We observed a total of 110 dietary supplement-metabolite associations that met the criteria for statistical significance adjusted for age, sex, field center, Hispanic/Latino background, body mass index, diet, smoking, physical activity, and number of medications (adjusted P < 0.05). This included 13 metabolites uniquely associated with only one dietary supplement ingredient. Vitamin C had the most associated metabolites (n = 15), including positive associations with oxalate, tartronate, threonate, and isocitrate, which were each in turn protective for the risk of incident diabetes. Vitamin C was also associated with higher N-acetylvaline level, which was an unfavorable diabetes risk factor. Other findings related to branched chain amino acid related compounds including α-hydroxyisovalerate and 2-hydroxy-3-methylvalerate, which were inversely associated with thiamine or riboflavin intake and also predicted higher diabetes risk. Vitamin B12 had an inverse association with γ-glutamylvaline, levels of which were positively associated with the risk of diabetes. CONCLUSIONS: Our data point to potential metabolite changes associated with vitamin C and B vitamins, which may have favorable metabolic effects. Knowledge of blood metabolites that can be modified by dietary supplement intake may aid understanding the health effects of dietary supplements and identify potential biological mediators.

MRI features associated with HCC histologic subtypes: a western American and European bicenter study.

OBJECTIVES: To evaluate if preoperative MRI can predict the most frequent HCC subtypes in North American and European patients treated with surgical resection. METHODS: A total of 119 HCCs in 97 patients were included in the North American group and 191 HCCs in 176 patients were included in the European group. Lesion subtyping was based on morphologic features and immuno-histopathological analysis. Two radiologists reviewed preoperative MRI and evaluated the presence of imaging features including LI-RADS major and ancillary features to identify clinical, biologic, and imaging features associated with the main HCC subtypes. RESULTS: Sixty-four percent of HCCs were conventional. The most frequent subtypes were macrotrabecular-massive (MTM-15%) and steatohepatitic (13%). Necrosis (OR = 3.32; 95% CI: 1.39, 7.89; p = .0064) and observation size (OR = 1.011; 95% CI: 1.0022, 1.019; p = .014) were independent predictors of MTM-HCC. Fat in mass (OR = 15.07; 95% CI: 6.57, 34.57; p < .0001), tumor size (OR = 0.97; 95% CI: 0.96, 0.99; p = .0037), and absence of chronic HCV infection (OR = 0.24; 95% CI: 0.084, 0.67; p = .0068) were independent predictors of steatohepatitic HCC. Independent predictors of conventional HCCs were viral C hepatitis (OR = 3.20; 95% CI: 1.62, 6.34; p = .0008), absence of fat (OR = 0.25; 95% CI: 0.12, 0.52; p = .0002), absence of tumor in vein (OR = 0.34; 95% CI: 0.13, 0.84; p = .020), and higher tumor-to-liver ADC ratio (OR = 1.96; 95% CI: 1.14, 3.35; p = .014) CONCLUSION: MRI is useful in predicting the most frequent HCC subtypes even in cohorts with different distributions of liver disease etiologies and tumor subtypes which might have future treatment and management implications. KEY POINTS: • Representation of both liver disease etiologies and HCC subtypes differed between the North American and European cohorts of patients. • Retrospective two-center study showed that liver MRI is useful in predicting the most frequent HCC subtypes.

Are you vaccinated? COVID-19 vaccination rates and the effect of a vaccination program in a metropolitan mental health inpatient population in Australia.

OBJECTIVE: To assess the COVID-19 vaccination rates of a severe mental illness (SMI) population in Western Australia (WA) in January to March 2022, and to evaluate an inpatient COVID-19 vaccination program available to this group. METHOD: A retrospective audit of the COVID-19 vaccination status of inpatients at the Mental Health Unit (MHU) at a tertiary hospital in WA was conducted and compared with the state average. Additionally, the medical records were interrogated to determine whether eligible inpatients were offered and received COVID-19 vaccination via the inpatient vaccination program. RESULTS: Vaccination rates for the MHU population were substantially lower than those for the WA population, particularly earlier in 2022. During January, just 49.0% of admitted patients had received two doses of the vaccine, compared to 92.8% of WA. Over the three months, 67 (47.2%) of all admissions were eligible for vaccination during their admission and 19 of the eligible patients (28.4%) were successfully vaccinated. CONCLUSION: This audit has demonstrated a slow uptake of COVID-19 vaccinations in the SMI population, despite the wide availability for 12 months prior to this period. This indicates a significant potential for targeted, assertive programs to improve vaccination rates in this population group.

Tailored Feedback Based on Clinically Relevant Performance Metrics Expedites the Acquisition of Robotic Suturing Skills-An Unblinded Pilot Randomized Controlled Trial.

PURPOSE: Previously, we identified 8 objective suturing performance metrics highly predictive of urinary continence recovery after robotic-assisted radical prostatectomy. Here, we aimed to test the feasibility of providing tailored feedback based upon these clinically relevant metrics and explore the impact on the acquisition of robotic suturing skills. MATERIALS AND METHODS: Training surgeons were recruited and randomized to a feedback group or a control group. Both groups completed a baseline, midterm and final dry laboratory vesicourethral anastomosis (VUA) and underwent 4 intervening training sessions each, consisting of 3 suturing exercises. Eight performance metrics were recorded during each exercise: 4 automated performance metrics (derived from kinematic and system events data of the da Vinci® Robotic System) representing efficiency and console manipulation competency, and 4 suturing technical skill scores. The feedback group received tailored feedback (a visual diagram+verbal instructions+video examples) based on these metrics after each session. Generalized linear mixed model was used to compare metric improvement (Δ) from baseline to the midterm and final VUA. RESULTS: Twenty-three participants were randomized to the feedback group (11) or the control group (12). Demographic data and baseline VUA metrics were comparable between groups. The feedback group showed greater improvement than the control group in aggregate suturing scores at midterm (mean Δ feedback group 4.5 vs Δ control group 1.1) and final VUA (Δ feedback group 5.3 vs Δ control group 4.9). The feedback group also showed greater improvement in the majority of the included metrics at midterm and final VUA. CONCLUSIONS: Tailored feedback based on specific, clinically relevant performance metrics is feasible and may expedite the acquisition of robotic suturing skills.

Analysis of spin in vascular surgery randomized controlled trials with nonsignificant outcomes.

OBJECTIVE: Spin is the manipulation of language that distorts the interpretation of objective findings. The purpose of this study is to describe the characteristics of spin found in statistically nonsignificant randomized controlled trials (RCT) comparing carotid endarterectomy with carotid artery stenting for carotid artery stenosis (CS), and endovascular repair with open repair (OR) for abdominal aortic aneurysms (AAA). METHODS: A search of MEDLINE, EMBASE, and the Cochrane Controlled Register of Trials was performed in June 2020 for studies published describing AAA or CS. All phase III RCTs with nonsignificant primary outcomes comparing open repair with endovascular repair or carotid endarterectomy to carotid artery stenting were included. Studies were appraised for the characteristics and severity of spin using a validated tool. Binary logistic regression was performed to assess the association of spin grade to (1) funding source (commercial vs noncommercial) and (2) the publishing journal's impact factor. RESULTS: Thirty-one of 355 articles captured were included for analysis. Spin was identified in 9 abstracts (9/18) and 13 main texts (13/18) of AAA articles and 7 abstracts (7/13) and 10 main texts (10/13) of CS articles. For both AAA and CS articles, spin was most commonly found in the discussion section, with the most commonly used strategy being the interpretation of statistically nonsignificant primary results to show treatment equivalence or rule out adverse treatment effects. Increasing journal impact factor was associated with a statistically significant lower likelihood of spin in the study title or abstract conclusion (ß odds ratio, 0.96; 95% confidence interval, 0.94-0.98; P < .01); no significant association could be found with funding source (ß odds ratio, 1.33; 95% confidence interval, 0.30-5.92; P = .71). CONCLUSIONS: A large proportion of statistically nonsignificant RCTs contain interpretations that are inconsistent with their results. These findings should prompt authors and readers to appraise study findings independently and to limit the use of spin in study interpretations.

COVID-19 pandemic vaccination preparedness strategies for independent community pharmacies.

OBJECTIVE: This study aimed to determine independent community pharmacist preparedness for coronavirus disease 2019 (COVID-19) vaccination and to identify strategies for COVID-19 pandemic vaccination implementation in Pennsylvania. METHODS: This study used a complementary mixed-methods approach to recruit independent community pharmacists to participate in an electronic survey and 2 virtually conducted focus groups before the availability of the first COVID-19 vaccine. Information was gathered and compiled into 5 topic areas: (1) workflow, (2) resources, (3) staff and patient safety, (4) communication, and (5) documentation and training. Data collection occurred between October and December 2020. Survey data were analyzed using descriptive statistics. Focus group discussions were audiorecorded and transcribed. A directed, content analysis was conducted to identify strategies for each topic area, and supporting quotes were selected. RESULTS: A total of 88 and 11 independent community pharmacists participated in the survey and focus groups, respectively. Because of the small size of most independent pharmacies, participants recommended working with community partners to support off-site mass vaccination clinics. Leveraging partnerships with community organizations and universities could be used to support staffing for vaccination efforts. Using an appointment-based immunization model was identified as one tool to optimize patient and staff safety during the pandemic. Pharmacists suggested using existing scheduling tools and text messaging and automated phone calls for second-dose reminders. Finally, independent pharmacists recommended further training and process improvements to support vaccine documentation and transmission to the Pennsylvania Statewide Immunization Information System. CONCLUSION: Recommendations from this study were used to support planning and preparation for COVID-19 vaccinations across Pennsylvania. Incorporation of pharmacists' ideas and recommendations on pandemic vaccination implementation is an important strategy to efficiently expand vaccination administration during pandemics.

An Objective Assessment of Performance during Robotic Partial Nephrectomy: Validation and Correlation of Automated Performance Metrics with Intraoperative Outcomes.

PURPOSE: Automated performance metrics provide a novel approach to the assessment of surgical performance. Herein, we present a construct validation of automated performance metrics during robotic assisted partial nephrectomy. MATERIALS AND METHODS: Automated performance metrics (instrument motion tracking/system events) and synchronized surgical videos from da Vinci® Si systems during robotic assisted partial nephrectomy were recorded using a system data recorder. Each case was segmented into 7 steps: colon mobilization, ureteral identification/dissection, hilar dissection, exposure of tumor within Gerota's fascia, intraoperative ultrasound/tumor scoring, tumor excision, and renorrhaphy. Automated performance metrics from each step were compared between expert (≥150 cases) and trainee (<150 cases) surgeons by Mann-Whitney U test (continuous variables) and Pearson's chi-squared test (categorical variables). Clinical outcomes were collected prospectively and correlated to automated performance metrics and R.E.N.A.L. (radius, exophytic/endophytic, nearness of tumor to collecting system, anterior/posterior, location relative to polar line) nephrometry score by Spearman's correlation coefficients (r). RESULTS: A total of 50 robotic assisted partial nephrectomy cases were included for analysis, performed by 7 expert and 10 trainee surgeons. Automated performance metric profiles significantly differed between experts and novices in the initial 5 steps (p <0.05). Specifically, experts exhibited faster dominant instrument movement and greater dominant instrument usage (bimanual dexterity) than trainees in select steps (p ≤0.045). Automated performance metrics during tumor excision and renorrhaphy were significantly correlated with R.E.N.A.L. score (r ≥0.364; p ≤0.041). These included metrics related to instrument efficiency, task duration, and dominant instrument use. CONCLUSIONS: Experts are more efficient and directed in their movement during robotic assisted partial nephrectomy. Automated performance metrics during key steps correlate with objective measures of tumor complexity and may serve as predictors of clinical outcomes. These data help establish a standardized metric for surgeon assessment and training during robotic assisted partial nephrectomy.

A Novel Dissection Gesture Classification to Characterize Robotic Dissection Technique for Renal Hilar Dissection.

PURPOSE: Deconstruction of robotic surgical gestures into semantic vocabulary yields an effective tool for surgical education. In this study we disassembled tissue dissection into basic gestures, created a classification system, and showed its ability to distinguish between experts and novices. MATERIALS AND METHODS: Videos of renal hilum preparation during robotic assisted partial nephrectomies were manually reviewed to identify all discrete surgical movements. Identified dissection movements were classified into distinct gestures based on the consensus of 6 expert surgeons. This classification system was then employed to compare expert and novice dissection patterns during the renal hilum preparation. RESULTS: A total of 40 robotic renal hilum preparation videos were reviewed, representing 16 from 6 expert surgeons (100 or more robotic cases) and 24 from 13 novice surgeons (fewer than 100 robotic cases). Overall 9,819 surgical movements were identified, including 5,667 dissection movements and 4,152 supporting movements. Nine distinct dissection gestures were identified and classified into the 3 categories of single blunt dissection (spread, peel/push, hook), single sharp dissection (cold cut, hot cut and burn dissect) and combination gestures (pedicalize, 2-hand spread, and coagulate then cut). Experts completed 5 of 9 dissection gestures more efficiently than novices (p ≤0.033). In consideration of specific anatomical locations, experts used more peel/push and less hot cut while dissecting the renal vein (p <0.001), and used more pedicalize while dissecting the renal artery (p <0.001). CONCLUSIONS: Using this novel dissection gesture classification system, key differences in dissection patterns can be found between experts/novices. This comprehensive classification of dissection gestures may be broadly applied to streamline surgical education.

Association of liver enzymes with incident diabetes in US Hispanic/Latino adults.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) has been associated with increased risk of incident diabetes. But such evidence is lacking in the Hispanic/Latino population, which has high prevalence of obesity and NAFLD. METHODS: We conducted a prospective cohort study of 6,928 adults of Hispanic/Latino background who had no diabetes, did not report excessive alcohol use, and no hepatitis B and C infection at baseline (2008-2011). We estimated risk ratios (RR) for incident diabetes, identified from visit 2 examination by glucose measurements or antidiabetic medication use, with baseline liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT)). RESULTS: A total of 738 adults developed diabetes during 6 years of follow-up. After adjusting for participant characteristics at baseline, versus the lowest quartile, highest quartiles of ALT and GGT were associated with risks for incident diabetes (RR for ALT: 1.51 [95% CI 1.03-2.22], p-trend = 0.006; RR for GGT: 2.39 [1.60-3.55], p-trend = 0.001). Higher GGT levels predicted increased risk of incident diabetes even among those with ALT or AST below the median levels. The associations of ALT and GGT with incident diabetes were similar among most Hispanic background but were not seen among Dominicans (p for interaction <0.05). The association of AST with incident diabetes was found only among light-to-moderate alcohol drinkers (RR = 1.50 [1.20-1.86]) but not abstainers (RR = 0.91 [0.69-1.20], p for interaction = 0.006). CONCLUSION: Higher ALT and GGT levels are associated with increased risk of developing diabetes among Latinos. Liver enzyme tests might aid in diabetes prevention by identifying high-risk individuals.

Altered Gut Microbiota and Host Metabolite Profiles in Women With Human Immunodeficiency Virus.

BACKGROUND: Alterations in gut microbiota (GMB) and host metabolites have been noted in individuals with HIV. However, it remains unclear whether alterations in GMB and related functional groups contribute to disrupted host metabolite profiles in these individuals. METHODS: This study included 185 women (128 with longstanding HIV infection, 88% under antiretroviral therapy; and 57 women without HIV from the same geographic location with comparable characteristics). Stool samples were analyzed by 16S rRNA V4 region sequencing, and GMB function was inferred by PICRUSt. Plasma metabolomic profiling was performed using liquid chromatography-tandem mass spectrometry, and 133 metabolites (amino acids, biogenic amines, acylcarnitines, and lipids) were analyzed. RESULTS: Four predominant bacterial genera were identified as associated with HIV infection, with higher abundances of Ruminococcus and Oscillospira and lower abundances of Bifidobacterium and Collinsella in women with HIV than in those without. Women with HIV showed a distinct plasma metabolite profile, which featured elevated glycerophospholipid levels compared with those without HIV. Functional analyses also indicated that GMB lipid metabolism was enriched in women with HIV. Ruminococcus and Oscillospira were among the top bacterial genera contributing to the GMB glycerophospholipid metabolism pathway and showed positive correlations with host plasma glycerophospholipid levels. One bacterial functional capacity in the acetate and propionate biosynthesis pathway was identified to be mainly contributed by Bifidobacterium; this functional capacity was lower in women with HIV than in women without HIV. CONCLUSIONS: Our integrative analyses identified altered GMB with related functional capacities that might be associated with disrupted plasma metabolite profiles in women with HIV.

Association Between Chronic Hepatitis C Virus Infection and Myocardial Infarction Among People Living With HIV in the United States.

Hepatitis C virus (HCV) infection is common among people living with human immunodeficiency virus (PLWH). Extrahepatic manifestations of HCV, including myocardial infarction (MI), are a topic of active research. MI is classified into types, predominantly atheroembolic type 1 MI (T1MI) and supply-demand mismatch type 2 MI (T2MI). We examined the association between HCV and MI among patients in the Centers for AIDS Research (CFAR) Network of Integrated Clinical Systems, a US multicenter clinical cohort of PLWH. MIs were centrally adjudicated and categorized by type using the Third Universal Definition of Myocardial Infarction. We estimated the association between chronic HCV (RNA+) and time to MI while adjusting for demographic characteristics, cardiovascular risk factors, clinical characteristics, and history of injecting drug use. Among 23,407 PLWH aged ≥18 years, there were 336 T1MIs and 330 T2MIs during a median of 4.7 years of follow-up between 1998 and 2016. HCV was associated with a 46% greater risk of T2MI (adjusted hazard ratio (aHR) = 1.46, 95% confidence interval (CI): 1.09, 1.97) but not T1MI (aHR = 0.87, 95% CI: 0.58, 1.29). In an exploratory cause-specific analysis of T2MI, HCV was associated with a 2-fold greater risk of T2MI attributed to sepsis (aHR = 2.01, 95% CI: 1.25, 3.24). Extrahepatic manifestations of HCV in this high-risk population are an important area for continued research.

Genetic architecture of cardiometabolic risks in people living with HIV.

BACKGROUND: Advances in antiretroviral therapies have greatly improved the survival of people living with human immunodeficiency virus (HIV) infection (PLWH); yet, PLWH have a higher risk of cardiovascular disease than those without HIV. While numerous genetic loci have been linked to cardiometabolic risk in the general population, genetic predictors of the excessive risk in PLWH are largely unknown. METHODS: We screened for common and HIV-specific genetic variants associated with variation in lipid levels in 6284 PLWH (3095 European Americans [EA] and 3189 African Americans [AA]), from the Centers for AIDS Research Network of Integrated Clinical Systems cohort. Genetic hits found exclusively in the PLWH cohort were tested for association with other traits. We then assessed the predictive value of a series of polygenic risk scores (PRS) recapitulating the genetic burden for lipid levels, type 2 diabetes (T2D), and myocardial infarction (MI) in EA and AA PLWH. RESULTS: We confirmed the impact of previously reported lipid-related susceptibility loci in PLWH. Furthermore, we identified PLWH-specific variants in genes involved in immune cell regulation and previously linked to HIV control, body composition, smoking, and alcohol consumption. Moreover, PLWH at the top of European-based PRS for T2D distribution demonstrated a > 2-fold increased risk of T2D compared to the remaining 95% in EA PLWH but to a much lesser degree in AA. Importantly, while PRS for MI was not predictive of MI risk in AA PLWH, multiethnic PRS significantly improved risk stratification for T2D and MI. CONCLUSIONS: Our findings suggest that genetic loci involved in the regulation of the immune system and predisposition to risky behaviors contribute to dyslipidemia in the presence of HIV infection. Moreover, we demonstrate the utility of the European-based and multiethnic PRS for stratification of PLWH at a high risk of cardiometabolic diseases who may benefit from preventive therapies.

Using objective robotic automated performance metrics and task-evoked pupillary response to distinguish surgeon expertise.

PURPOSE: In this study, we investigate the ability of automated performance metrics (APMs) and task-evoked pupillary response (TEPR), as objective measures of surgeon performance, to distinguish varying levels of surgeon expertise during generic robotic surgical tasks. Additionally, we evaluate the association between APMs and TEPR. METHODS: Participants completed ten tasks on a da Vinci Xi Surgical System (Intuitive Surgical, Inc.), each representing a surgical skill type: EndoWrist® manipulation, needle targeting, suturing/knot tying, and excision/dissection. Automated performance metrics (instrument motion tracking, EndoWrist® articulation, and system events data) and TEPR were recorded by a systems data recorder (Intuitive Surgical, Inc.) and Tobii Pro Glasses 2 (Tobii Technologies, Inc.), respectively. The Kruskal-Wallis test determined significant differences between groups of varying expertise. Spearman's rank correlation coefficient measured associations between APMs and TEPR. RESULTS: Twenty-six participants were stratified by robotic surgical experience: novice (no prior experience; n = 9), intermediate (< 100 cases; n = 9), and experts (≥ 100 cases; n = 8). Several APMs differentiated surgeon experience including task duration (p < 0.01), time active of instruments (p < 0.03), linear velocity of instruments (p < 0.04), and angular velocity of dominant instrument (p < 0.04). Task-evoked pupillary response distinguished surgeon expertise for three out of four task types (p < 0.04). Correlation trends between APMs and TEPR revealed that expert surgeons move more slowly with high cognitive workload (ρ < - 0.60, p < 0.05), while novices move faster under the same cognitive experiences (ρ > 0.66, p < 0.05). CONCLUSIONS: Automated performance metrics and TEPR can distinguish surgeon expertise levels during robotic surgical tasks. Furthermore, under high cognitive workload, there can be a divergence in robotic movement profiles between expertise levels.

Comparison of clinical outcomes and automated performance metrics in robot-assisted radical prostatectomy with and without trainee involvement.

PURPOSE: In this study, we investigate the effect of trainee involvement on surgical performance, as measured by automated performance metrics (APMs), and outcomes after robot-assisted radical prostatectomy (RARP). METHODS: We compared APMs (instrument tracking, EndoWrist® articulation, and system events data) and clinical outcomes for cases with varying resident involvement. Four of 12 standardized RARP steps were designated critical ("cardinal") steps. Comparison 1: cases where the attending surgeon performed all four cardinal steps (Group A) and cases where a trainee was involved in at least one cardinal step (Group B). Comparison 2, where Group A is split into Groups C and D: cases where attending performs the whole case (Group C) vs. cases where a trainee performed at least one non-cardinal step (Group D). Mann-Whitney U and Chi-squared tests were used for comparisons. RESULTS: Comparison 1 showed significant differences in APM profiles including camera movement time, third instrument usage, dominant instrument moving time, velocity, articulation, as well as non-dominant instrument moving time and articulation (all favoring Group A p < 0.05). There was a significant difference in re-admission rates (10.9% in Group A vs 0% in Group B, p < 0.02), but not for post-operative outcomes. Comparison 2 demonstrated a significant difference in dominant instrument articulation (p < 0.05) but not in post-operative outcomes. CONCLUSIONS: Trainee involvement in RARP is safe. The degree of trainee involvement does not significantly affect major clinical outcomes. APM profiles are less efficient when trainees perform at least one cardinal step but not during non-cardinal steps.

Effectiveness of interventions on the appropriate use of opioids for noncancer pain among hospital inpatients: A systematic review.

AIMS: To summarise the effectiveness of interventions on appropriate opioid use for noncancer pain among hospital inpatients. METHODS: Two reviewers independently searched 6 databases up to March 2018 original research articles reporting on quantitative outcomes of interventions on appropriate opioid use among hospital inpatients. Appropriate opioid use was measured by changes in prescribing, such as the lowest effective opioid dose and duration, or clinical outcomes such as adequate pain control. Quality and intervention complexity assessments were performed by 2 independent reviewers. The full methodological approach was published on PROSPERO (ID: CRD42019145947). RESULTS: Of 398 full-text articles assessed for eligibility, 37 articles were included in the review. Most articles had a moderate or high risk of bias (27 of 37 studies). Thirty-one articles primarily addressed appropriate opioid use and 6 articles targeted opioid safety as a secondary outcome. A multifaceted approach was the most common primary intervention (16 studies) and adequate pain control was the main outcome measured (14 studies). Health provider education, reinforced by hard-copy material and feedback, was associated with a 13.0 to 29.5% increase in the proportion of opioid prescriptions written in concordance with local guidelines and reduced pain scores ranging from 7.0 to 34.5%. Interventions to improve opioid safety in patient-controlled analgesia reduced medication errors by up to 89.1%. CONCLUSION: Interventions involving academic detailing and education, especially when reinforced by feedback, show positive effects on appropriate opioid use among hospital inpatients. Future studies investigating the impact of administrative interventions on opioid use and related outcomes are warranted.

Methylphenidate improves weight control in childhood brain tumor survivors with hypothalamic obesity.

BACKGROUND: Hypothalamic obesity causes unrelenting weight gain for childhood brain tumor survivors. No single therapy has proven effective for treatment. We aimed to evaluate effectiveness of long-term methylphenidate therapy on body mass index (BMI) change in children with hypothalamic obesity. METHODS: A retrospective analysis included children with a history of brain tumor and hypothalamic obesity receiving methylphenidate (10-60 mg/day) for hypothalamic obesity. Subjects were evaluated for BMI trajectory before and after methylphenidate start. Given that z-scores can be skewed in severely obese children, we calculated BMI as a percent of the BMI at the 95th percentile for the child's age and gender (BMI% 95th). RESULTS: Twelve patients with hypothalamic obesity completed methylphenidate therapy for at least 6 months (median 3.1 years, range 1.0-5.8 years). All subjects had a suprasellar tumor (nine [75%] with craniopharyngioma) and pituitary dysfunction. Pretreatment median BMI percent of the 95th percentile was 125.6% (interquartile range [IQR] 25-75: 115.3-138.3%) with BMI z-score of 2.4 (IQR 25-75: 2.1-2.6). Following methylphenidate treatment, there was a 69.9% reduction in the median slope of BMI change. Eleven of 12 patients (92%) had a reduction in the slope of their BMI change on methylphenidate treatment. Postmethylphenidate median BMI percent of the 95th percentile decrease to 115.2% (IQR 25-75: 103.6-121.2%) with median BMI z-score of 2.1 (IQR 25-75: 1.8-2.2). Mild side effects were noted in six patients. CONCLUSIONS: Methylphenidate use reduced and sustained BMI change in children with hypothalamic obesity. Stimulant therapy is an effective first-line agent for treatment of hypothalamic obesity.