Prevalence of HTLV-1 and Hepatitis B Surface Antigen (HBsAg) Positivity among MSM Attending a Large HIV Treatment Centre in Trinidad.

HIV-1, Hepatitis B and HTLV-1 have similar risk factors and shared routes of transmission and MSM are disproportionately affected by HIV. The aim of the study was to determine the prevalence of HTLV-1 and HBsAg positivity at initial enrolment among MSM attending a large HIV Clinic in Trinidad. Chart reviews were conducted between 2 and 15 January 2024, among self-identified MSM and a comparative group of randomly selected self-identified heterosexual males where sociodemographic, clinical and laboratory data were collected and analysed using SPSS Version 25. During the period April 2002-31 October 2023, in total there were 10,424 patients registered at the clinic, of whom 1255 (12.0%) were self-identified MSM, with an age range of 19-85 years and a median age of 40 years. There were 1822 randomly selected heterosexual males, with an age range of 18-94 years old and a median age of 52 years. Among the MSM, there were 21 (1.67%) patients who were HIV-1/HTLV-1-coinfected, 64 (5.10%) who were HIV-1/HBsAg-coinfected and two (0.16%) who were coinfected with all three viruses (HIV-1/HTLV-1/HBsAg) as compared to 47 ((2.58%) HIV-1/HTLV-1-coinfected (p = 0.12), 69 (3.79%) HIV-1/HBsAg-coinfected (p = 0.10) and three (0.16%) patients coinfected with all three viruses among the heterosexual males. There were no patients with HTLV-1-related diseases among the HIV-1/HTLV-1-coinfected patients and there were no deaths from chronic liver disease in patients coinfected with HIV-1/HBsAg. Despite the availability of an efficacious vaccine, there is a prevalence of hepatitis B of 5.1% among MSM attending the HIV Clinic in Trinidad; therefore, programmes to increase health literacy, screening and immunization are urgently needed.

Accounting for repeat intervention costs in the economic comparison of laser interstitial thermal therapy and anterior temporal lobectomy for treatment of refractory temporal lobe epilepsy.

OBJECTIVE: Laser interstitial thermal therapy (LITT) is an alternative to anterior temporal lobectomy (ATL) for the treatment of temporal lobe epilepsy that has been found by some to have a lower procedure cost but is generally regarded as less effective and sometimes results in a subsequent procedure. The goal of this study is to incorporate subsequent procedures into the cost and outcome comparison between ATL and LITT. METHODS: This single-center, retrospective cohort study includes 85 patients undergoing ATL or LITT for temporal lobe epilepsy during the period September 2015 to December 2022. Of the 40 patients undergoing LITT, 35 % (N = 14) underwent a subsequent ATL. An economic cost model is derived, and difference in means tests are used to compare the costs, outcomes, and other hospitalization measures. RESULTS: Our model predicts that whenever the percentage of LITT patients undergoing subsequent ATL (35% in our sample) exceeds the percentage by which the LITT procedure alone is less costly than ATL (7.2% using total patient charges), LITT will have higher average patient cost than ATL, and this is indeed the case in our sample. After accounting for subsequent surgeries, the average patient charge in the LITT sample ($103,700) was significantly higher than for the ATL sample ($88,548). A second statistical comparison derived from our model adjusts for the difference in effectiveness by calculating the cost per seizure-free patient outcome, which is $108,226 for ATL, $304,052 for LITT only, and $196,484 for LITT after accounting for the subsequent ATL surgeries. SIGNIFICANCE: After accounting for the costs of subsequent procedures, we found in our cohort that LITT is not only less effective but also results in higher average costs per patient than ATL as a first course of treatment. While cost and effectiveness rates will vary across centers, we also provide a model for calculating cost effectiveness based on individual center data.

MAVMET trial: maraviroc and/or metformin for metabolic dysfunction associated fatty liver disease in adults with suppressed HIV.

OBJECTIVE: Metabolic dysfunction associated fatty liver disease (MAFLD) is over-represented in people with HIV (PWH). Maraviroc (MVC) and/or metformin (MET) may reduce MAFLD by influencing inflammatory pathways and fatty acid metabolism. DESIGN: Open-label, 48-week randomized trial with a 2 x 2 factorial design. SETTING: Multicenter HIV clinics. PARTICIPANTS: Nondiabetic, virologically suppressed PLWH, aged at least 35 years, with confirmed/suspected MAFLD (≥1 biochemical/anthropometric/radiological/histological features). INTERVENTION: Adjunctive MVC; MET; MVC+MET vs. antiretroviral therapy (ART) alone. PRIMARY OUTCOME: Change in liver fat fraction (LFF) between baseline and week-48 using magnetic resonance proton density fat fraction (MR PDFF). RESULTS: Six sites enrolled 90 participants (93% male; 81% white; median age 52 [interquartile range, IQR 47-57] years) between March 19, 2018, and November 11, 2019. Seventy percent had imaging/biopsy and at least one 1 MAFLD criteria. The analysis included 82/90 with week-0 and week-48 scans. Median baseline MR PDFF was 8.9 (4.6-17.1); 40, 38, 8, and 14% had grade zero, one, two, and three steatosis, respectively. Mean LFF increased slightly between baseline and follow-up scans: 2.22% MVC, 1.26% MET, 0.81% MVC+MET, and 1.39% ART alone. Prolonged intervention exposure (delayed week-48 scans) exhibited greater increases in MR PDFF (estimated difference 4.23% [95% confidence interval, 95% CI 2.97-5.48], P  < 0.001). There were no differences in predicted change for any intervention compared to ART alone: MVC (-0.42% [95% CI -1.53 to 0.68, P  = 0.45]), MET (-0.62 [-1.81 to 0.56, P  = 0.30]), and MVC+MET (-1.04 [-2.74 to 0.65, P  = 0.23]). Steatosis grade remained unchanged in 55% and increased in 24%. CONCLUSION: Baseline levels of liver fat were lower than predicted. Contrary to our hypothesis, neither MVC, MET, or the combination significantly reduced liver fat as measured by MRPDFF compared to ART alone.

The incidence of histoplasmosis and cryptococcal antigenemia among patients attending a large HIV clinic in Trinidad.

Our aim was to determine the incidence disseminated histoplasmosis and cryptococcal antigenemia among 280 patients with a CD4<350 cells/mm3 attending a large HIV clinic in Trinidad over the period November 2021-June 2022. Sera were screened for cryptococcal antigen (CrAg) using the Immy CrAg Immunoassay (EIA) and the Immy CrAg lateral flow assay (LFA). Urine was screened for Histoplasma antigen using the Immy EIA and the Optimum Imaging Diagnostics (OIDx) LFA. For the purposes of analysis, it was assumed, that all patients with positive urine Histoplasma antigen tests by both EIA and LFA and those with a single positive urine Histoplasma antigen test and clinical features of disseminated histoplasmosis were true positives. The incidence of probable disseminated histoplasmosis and cryptococcal antigenemia were 6.4% (18/280) and 2.5% (7/280) respectively. The sensitivity and specificity of the Immy Histoplasma EIA were 100% (95% CI, 81.5%-100%) and 98.5% (95% CI, 96.1% - 99.6%) respectively as compared to the OIDx Histoplasma LFA of 88.9% (95% CI, 65.3% - 98.6%) and 93.9% (95% CI, 90.3% - 96.5%) respectively, with substantial agreement between the 2 test kits (Kappa value = 0.763; 95% CI 0.685, 0.841). Testing for disseminated histoplasmosis in HIV patients is important in endemic areas.

Clinical presentation of herpes simplex virus infection mimicking neoplasia on the face of persons living with HIV.

The clinical presentations of herpes simplex virus (HSV) infections are varied and range from asymptomatic to a prodrome of tingling and burning followed by painful vesicles, erosions and ulcers. Resolution leads to latent infection of the sensory ganglia. HSV-1 is associated with most of the nongenital HSV-induced infections and HSV-2 is generally associated with anogenital lesions; however, lesions at either site may be caused by both viruses. In persons living with HIV (PLHIV), the lesions have been described as verrucous/hypertrophic, exophytic or vegetative and may suggest a neoplastic rather than an infective process and this can be a diagnostic dilemma in resource-limited countries with no access to confirmatory diagnostic testing for HSV. We report on two PLHIV who developed rapidly growing lesions on the face that clinically mimicked neoplasia but were found to be HSV-associated squamous proliferative lesions which responded to high dose acyclovir.

Laboratory-identified vancomycin-resistant enterococci bacteremia incidence: A standardized infection ratio prediction model.

BACKGROUND: We analyzed 2017 healthcare facility-onset (HO) vancomycin-resistant Enterococcus (VRE) bacteremia data to identify hospital-level factors that were significant predictors of HO-VRE using the Centers for Disease Control and Prevention (CDC) National Healthcare Safety Network (NHSN) multidrug-resistant organism and Clostridioides difficile reporting module. A risk-adjusted model that can be used to calculate the number of predicted HO-VRE bacteremia events in a facility was developed, thus enabling the calculation of VRE standardized infection ratios (SIRs). METHODS: Acute-care hospitals reporting at least 1 month of 2017 VRE bacteremia data were included in the analysis. Various hospital-level characteristics were assessed to develop a best-fit model and subsequently derive the 2018 national and state SIRs. RESULTS: In 2017, 470 facilities in 35 states participated in VRE bacteremia surveillance. Inpatient VRE community-onset prevalence rate, average length of patient stay, outpatient VRE community-onset prevalence rate, and presence of an oncology unit were all significantly associated (all 95% likelihood ratio confidence limits excluded the nominal value of zero) with HO-VRE bacteremia. The 2018 national SIR was 1.01 (95% CI, 0.93-1.09) with 577 HO bacteremia events reported. CONCLUSION: The creation of an SIR enables national-, state-, and facility-level monitoring of VRE bacteremia while controlling for individual hospital-level factors. Hospitals can compare their VRE burden to a national benchmark to help them determine the effectiveness of infection prevention efforts over time.

Long-term cerebrovascular outcomes after bariatric surgery: A nationwide cohort study.

BACKGROUND: The proinflammatory state and metabolic changes associated with obesity contribute to cerebrovascular disease. Bariatric surgery can achieve a reliable reduction in body weight and improved metabolic profile in obese patients. However, its impact on cerebrovascular morbidity remains unexplored. This study investigates the effect of bariatric surgery on long-term risk of major cerebrovascular events. METHODS: A retrospective cohort study was designed. Data was extracted from the Clinical Practice Research Datalink. 4212 bariatric surgery patients were compared to 4212 age, sex, and BMI-matched controls. The primary composite endpoint was occurrence of any major adverse cerebrovascular event. Secondary endpoints included composite endpoints of ischaemic events, haemorrhagic events, individual components of the primary endpoint alone and all-cause mortality. An adjusted Cox proportional hazards model was implemented to analyse time to event data. RESULTS: Mean follow-up length was 11.4 years. The primary endpoint occurred in 73 patients. The bariatric surgery group had significantly lower adjusted major cerebrovascular event rates (HR 0.352, 95 %CI 0.195-0.637). Bariatric surgery was associated with lower rates of ischaemic events (HR 0.315, 95 %CI 0.156-0.635), particularly from transient ischaemic attacks (HR 0.364, 95 %CI 0.171-0.775). There was no difference in the rate of haemorrhagic events (HR 0.442, 95 %CI 0.147-1.330) or acute ischaemic stroke (HR 0.221, 95 %CI 0.046-1.054). In total 229 patients died during follow-up. Overall, all-cause mortality was significantly lower in the bariatric surgery group (HR 0.352, 95 %CI 0.195-0.637). CONCLUSIONS: This study identifies an association between bariatric surgery and lower long-term risk of major adverse cerebrovascular events in patients with obesity.

Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks.

National Healthcare Safety Network Standardized Antimicrobial Administration Ratios (SAARs): A Progress Report and Risk Modeling Update Using 2017 Data.

BACKGROUND: The Standardized Antimicrobial Administration Ratio (SAAR) is a risk-adjusted metric of antimicrobial use (AU) developed by the Centers for Disease Control and Prevention (CDC) in 2015 as a tool for hospital antimicrobial stewardship programs (ASPs) to track and compare AU with a national benchmark. In 2018, CDC updated the SAAR by expanding the locations and antimicrobial categories for which SAARs can be calculated and by modeling adult and pediatric locations separately. METHODS: We identified eligible patient-care locations and defined SAAR antimicrobial categories. Predictive models were developed for eligible adult and pediatric patient-care locations using negative binomial regression applied to nationally aggregated AU data from locations reporting ≥9 months of 2017 data to the National Healthcare Safety Network (NHSN). RESULTS: 2017 Baseline SAAR models were developed for 7 adult and 8 pediatric SAAR antimicrobial categories using data reported from 2156 adult and 170 pediatric locations across 457 hospitals. The inclusion of step-down units and general hematology-oncology units in adult 2017 baseline SAAR models and the addition of SAARs for narrow-spectrum B-lactam agents, antifungals predominantly used for invasive candidiasis, antibacterial agents posing the highest risk for Clostridioides difficile infection, and azithromycin (pediatrics only) expand the role SAARs can play in ASP efforts. Final risk-adjusted models are used to calculate predicted antimicrobial days, the denominator of the SAAR, for 40 SAAR types displayed in NHSN. CONCLUSIONS: SAARs can be used as a metric to prompt investigation into potential overuse or underuse of antimicrobials and to evaluate the effectiveness of ASP interventions.

Mesial temporal resection following long-term ambulatory intracranial EEG monitoring with a direct brain-responsive neurostimulation system.

OBJECTIVE: To describe seizure outcomes in patients with medically refractory epilepsy who had evidence of bilateral mesial temporal lobe (MTL) seizure onsets and underwent MTL resection based on chronic ambulatory intracranial EEG (ICEEG) data from a direct brain-responsive neurostimulator (RNS) system. METHODS: We retrospectively identified all patients at 17 epilepsy centers with MTL epilepsy who were treated with the RNS System using bilateral MTL leads, and in whom an MTL resection was subsequently performed. Presumed lateralization based on routine presurgical approaches was compared to lateralization determined by RNS System chronic ambulatory ICEEG recordings. The primary outcome was frequency of disabling seizures at last 3-month follow-up after MTL resection compared to seizure frequency 3 months before MTL resection. RESULTS: We identified 157 patients treated with the RNS System with bilateral MTL leads due to presumed bitemporal epilepsy. Twenty-five patients (16%) subsequently had an MTL resection informed by chronic ambulatory ICEEG (mean = 42 months ICEEG); follow-up was available for 24 patients. After MTL resection, the median reduction in disabling seizures at last follow-up was 100% (mean: 94%; range: 50%-100%). Nine patients (38%) had exclusively unilateral electrographic seizures recorded by chronic ambulatory ICEEG and all were seizure-free at last follow-up after MTL resection; eight of nine continued RNS System treatment. Fifteen patients (62%) had bilateral MTL electrographic seizures, had an MTL resection on the more active side, continued RNS System treatment, and achieved a median clinical seizure reduction of 100% (mean: 90%; range: 50%-100%) at last follow-up, with eight of fifteen seizure-free. For those with more than 1 year of follow-up (N = 21), 15 patients (71%) were seizure-free during the most recent year, including all eight patients with unilateral onsets and 7 of 13 patients (54%) with bilateral onsets. SIGNIFICANCE: Chronic ambulatory ICEEG data provide information about lateralization of MTL seizures and can identify additional patients who may benefit from MTL resection.

Publisher Correction: Copper adparticle enabled selective electrosynthesis of n-propanol.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Pathogens causing central-line-associated bloodstream infections in acute-care hospitals-United States, 2011-2017.

OBJECTIVE: To describe pathogen distribution and rates for central-line-associated bloodstream infections (CLABSIs) from different acute-care locations during 2011-2017 to inform prevention efforts. METHODS: CLABSI data from the Centers for Disease Control and Prevention (CDC) National Healthcare Safety Network (NHSN) were analyzed. Percentages and pooled mean incidence density rates were calculated for a variety of pathogens and stratified by acute-care location groups (adult intensive care units [ICUs], pediatric ICUs [PICUs], adult wards, pediatric wards, and oncology wards). RESULTS: From 2011 to 2017, 136,264 CLABSIs were reported to the NHSN by adult and pediatric acute-care locations; adult ICUs and wards reported the most CLABSIs: 59,461 (44%) and 40,763 (30%), respectively. In 2017, the most common pathogens were Candida spp/yeast in adult ICUs (27%) and Enterobacteriaceae in adult wards, pediatric wards, oncology wards, and PICUs (23%-31%). Most pathogen-specific CLABSI rates decreased over time, excepting Candida spp/yeast in adult ICUs and Enterobacteriaceae in oncology wards, which increased, and Staphylococcus aureus rates in pediatric locations, which did not change. CONCLUSIONS: The pathogens associated with CLABSIs differ across acute-care location groups. Learning how pathogen-targeted prevention efforts could augment current prevention strategies, such as strategies aimed at preventing Candida spp/yeast and Enterobacteriaceae CLABSIs, might further reduce national rates.

Molecular tuning of CO2-to-ethylene conversion.

The electrocatalytic reduction of carbon dioxide, powered by renewable electricity, to produce valuable fuels and feedstocks provides a sustainable and carbon-neutral approach to the storage of energy produced by intermittent renewable sources1. However, the highly selective generation of economically desirable products such as ethylene from the carbon dioxide reduction reaction (CO2RR) remains a challenge2. Tuning the stabilities of intermediates to favour a desired reaction pathway can improve selectivity3-5, and this has recently been explored for the reaction on copper by controlling morphology6, grain boundaries7, facets8, oxidation state9 and dopants10. Unfortunately, the Faradaic efficiency for ethylene is still low in neutral media (60 per cent at a partial current density of 7 milliamperes per square centimetre in the best catalyst reported so far9), resulting in a low energy efficiency. Here we present a molecular tuning strategy-the functionalization of the surface of electrocatalysts with organic molecules-that stabilizes intermediates for more selective CO2RR to ethylene. Using electrochemical, operando/in situ spectroscopic and computational studies, we investigate the influence of a library of molecules, derived by electro-dimerization of arylpyridiniums11, adsorbed on copper. We find that the adhered molecules improve the stabilization of an 'atop-bound' CO intermediate (that is, an intermediate bound to a single copper atom), thereby favouring further reduction to ethylene. As a result of this strategy, we report the CO2RR to ethylene with a Faradaic efficiency of 72 per cent at a partial current density of 230 milliamperes per square centimetre in a liquid-electrolyte flow cell in a neutral medium. We report stable ethylene electrosynthesis for 190 hours in a system based on a membrane-electrode assembly that provides a full-cell energy efficiency of 20 per cent. We anticipate that this may be generalized to enable molecular strategies to complement heterogeneous catalysts by stabilizing intermediates through local molecular tuning.

Antimicrobial-resistant pathogens associated with pediatric healthcare-associated infections: Summary of data reported to the National Healthcare Safety Network, 2015-2017.

OBJECTIVE: To describe common pathogens and antimicrobial resistance patterns for healthcare-associated infections (HAIs) among pediatric patients that occurred in 2015-2017 and were reported to the Centers for Disease Control and Prevention's National Healthcare Safety Network (NHSN). METHODS: Antimicrobial resistance data were analyzed for pathogens implicated in central line-associated bloodstream infections (CLABSIs), catheter-associated urinary tract infections (CAUTIs), ventilator-associated pneumonias (VAPs), and surgical site infections (SSIs). This analysis was restricted to device-associated HAIs reported from pediatric patient care locations and SSIs among patients <18 years old. Percentages of pathogens with nonsusceptibility (%NS) to selected antimicrobials were calculated by HAI type, location type, and surgical category. RESULTS: Overall, 2,545 facilities performed surveillance of pediatric HAIs in the NHSN during this period. Staphylococcus aureus (15%), Escherichia coli (12%), and coagulase-negative staphylococci (12%) were the 3 most commonly reported pathogens associated with pediatric HAIs. Pathogens and the %NS varied by HAI type, location type, and/or surgical category. Among CLABSIs, the %NS was generally lowest in neonatal intensive care units and highest in pediatric oncology units. Staphylococcus spp were particularly common among orthopedic, neurosurgical, and cardiac SSIs; however, E. coli was more common in abdominal SSIs. Overall, antimicrobial nonsusceptibility was less prevalent in pediatric HAIs than in adult HAIs. CONCLUSION: This report provides an updated national summary of pathogen distributions and antimicrobial resistance patterns among pediatric HAIs. These data highlight the need for continued antimicrobial resistance tracking among pediatric patients and should encourage the pediatric healthcare community to use such data when establishing policies for infection prevention and antimicrobial stewardship.

Antimicrobial-resistant pathogens associated with adult healthcare-associated infections: Summary of data reported to the National Healthcare Safety Network, 2015-2017.

OBJECTIVE: Describe common pathogens and antimicrobial resistance patterns for healthcare-associated infections (HAIs) that occurred during 2015-2017 and were reported to the Centers for Disease Control and Prevention's (CDC's) National Healthcare Safety Network (NHSN). METHODS: Data from central line-associated bloodstream infections (CLABSIs), catheter-associated urinary tract infections (CAUTIs), ventilator-associated events (VAEs), and surgical site infections (SSIs) were reported from acute-care hospitals, long-term acute-care hospitals, and inpatient rehabilitation facilities. This analysis included device-associated HAIs reported from adult location types, and SSIs among patients ≥18 years old. Percentages of pathogens with nonsusceptibility (%NS) to selected antimicrobials were calculated for each HAI type, location type, surgical category, and surgical wound closure technique. RESULTS: Overall, 5,626 facilities performed adult HAI surveillance during this period, most of which were general acute-care hospitals with <200 beds. Escherichia coli (18%), Staphylococcus aureus (12%), and Klebsiella spp (9%) were the 3 most frequently reported pathogens. Pathogens varied by HAI and location type, with oncology units having a distinct pathogen distribution compared to other settings. The %NS for most pathogens was significantly higher among device-associated HAIs than SSIs. In addition, pathogens from long-term acute-care hospitals had a significantly higher %NS than those from general hospital wards. CONCLUSIONS: This report provides an updated national summary of pathogen distributions and antimicrobial resistance among select HAIs and pathogens, stratified by several factors. These data underscore the importance of tracking antimicrobial resistance, particularly in vulnerable populations such as long-term acute-care hospitals and intensive care units.

Histopathologic and Genetic Features of Alveolar Capillary Dysplasia with Atypical Late Presentation and Prolonged Survival.

Alveolar capillary dysplasia typically presents with neonatal pulmonary hypertension and early mortality. However, there is growing evidence for a subset of disease with atypical late onset and/or prolonged survival. Here, we present the variable clinical, genetic, and pathology findings of 4 such patients.

Anti-PD1 'SHR-1210' aberrantly targets pro-angiogenic receptors and this polyspecificity can be ablated by paratope refinement.

Monoclonal anti-programmed cell death 1 (PD1) antibodies are successful cancer therapeutics, but it is not well understood why individual antibodies should have idiosyncratic side-effects. As the humanized antibody SHR-1210 causes capillary hemangioma in patients, a unique toxicity amongst anti-PD1 antibodies, we performed human receptor proteome screening to identify nonspecific interactions that might drive angiogenesis. This screen identified that SHR-1210 mediated aberrant, but highly selective, low affinity binding to human receptors such as vascular endothelial growth factor receptor 2 (VEGFR2), frizzled class receptor 5 and UL16 binding protein 2 (ULBP2). SHR-1210 was found to be a potent agonist of human VEGFR2, which may thereby drive hemangioma development via vascular endothelial cell activation. The v-domains of SHR-1210's progenitor murine monoclonal antibody 'Mab005' also exhibited off-target binding and agonism of VEGFR2, proving that the polyspecificity was mediated by the original mouse complementarity-determining regions (CDRs), and had survived the humanization process. Molecular remodelling of SHR-1210 by combinatorial CDR mutagenesis led to deimmunization, normalization of binding affinity to human and cynomolgus PD1, and increased potency in PD1/PD-L1 blockade. Importantly, CDR optimization also ablated all off-target binding, rendering the resulting antibodies fully PD1-specific. As the majority of changes to the paratope were found in the light chain CDRs, the germlining of this domain drove the ablation of off-target binding. The combination of receptor proteome screening and optimization of the antibody binding interface therefore succeeded in generating novel, higher-potency, specificity-enhanced therapeutic IgGs from a single, clinically sub-optimal progenitor. This study showed that highly-specific off-target binding events might be an under-appreciated phenomenon in therapeutic antibody development, but that these unwanted properties can be fully ameliorated by paratope refinement.

Copper adparticle enabled selective electrosynthesis of n-propanol.

The electrochemical reduction of carbon monoxide is a promising approach for the renewable production of carbon-based fuels and chemicals. Copper shows activity toward multi-carbon products from CO reduction, with reaction selectivity favoring two-carbon products; however, efficient conversion of CO to higher carbon products such as n-propanol, a liquid fuel, has yet to be achieved. We hypothesize that copper adparticles, possessing a high density of under-coordinated atoms, could serve as preferential sites for n-propanol formation. Density functional theory calculations suggest that copper adparticles increase CO binding energy and stabilize two-carbon intermediates, facilitating coupling between adsorbed *CO and two-carbon intermediates to form three-carbon products. We form adparticle-covered catalysts in-situ by mediating catalyst growth with strong CO chemisorption. The new catalysts exhibit an n-propanol Faradaic efficiency of 23% from CO reduction at an n-propanol partial current density of 11 mA cm-2.

Deep learning applied to whole-brain connectome to determine seizure control after epilepsy surgery.

OBJECTIVE: We evaluated whether deep learning applied to whole-brain presurgical structural connectomes could be used to predict postoperative seizure outcome more accurately than inference from clinical variables in patients with mesial temporal lobe epilepsy (TLE). METHODS: Fifty patients with unilateral TLE were classified either as having persistent disabling seizures (SZ) or becoming seizure-free (SZF) at least 1 year after epilepsy surgery. Their presurgical structural connectomes were reconstructed from whole-brain diffusion tensor imaging. A deep network was trained based on connectome data to classify seizure outcome using 5-fold cross-validation. RESULTS: Classification accuracy of our trained neural network showed positive predictive value (PPV; seizure freedom) of 88 ± 7% and mean negative predictive value (NPV; seizure refractoriness) of 79 ± 8%. Conversely, a classification model based on clinical variables alone yielded <50% accuracy. The specific features that contributed to high accuracy classification of the neural network were located not only in the ipsilateral temporal and extratemporal regions, but also in the contralateral hemisphere. SIGNIFICANCE: Deep learning demonstrated to be a powerful statistical approach capable of isolating abnormal individualized patterns from complex datasets to provide a highly accurate prediction of seizure outcomes after surgery. Features involved in this predictive model were both ipsilateral and contralateral to the clinical foci and spanned across limbic and extralimbic networks.

CO2 electroreduction to ethylene via hydroxide-mediated copper catalysis at an abrupt interface.

Carbon dioxide (CO2) electroreduction could provide a useful source of ethylene, but low conversion efficiency, low production rates, and low catalyst stability limit current systems. Here we report that a copper electrocatalyst at an abrupt reaction interface in an alkaline electrolyte reduces CO2 to ethylene with 70% faradaic efficiency at a potential of -0.55 volts versus a reversible hydrogen electrode (RHE). Hydroxide ions on or near the copper surface lower the CO2 reduction and carbon monoxide (CO)-CO coupling activation energy barriers; as a result, onset of ethylene evolution at -0.165 volts versus an RHE in 10 molar potassium hydroxide occurs almost simultaneously with CO production. Operational stability was enhanced via the introduction of a polymer-based gas diffusion layer that sandwiches the reaction interface between separate hydrophobic and conductive supports, providing constant ethylene selectivity for an initial 150 operating hours.