Derivation of a Protein Risk Score for Cardiovascular Disease Among a Multiracial and Multiethnic HIV+ Cohort

Background Cardiovascular disease risk prediction models underestimate CVD risk in people living with HIV (PLWH). Our goal is to derive a risk score based on protein biomarkers that could be used to predict CVD in PLWH. Methods and Results In a matched case-control study, we analyzed normalized protein expression data for participants enrolled in 1 of 4 trials conducted by INSIGHT (International Network for Strategic Initiatives in Global HIV Trials). We used dimension reduction, variable selection and resampling methods, and multivariable conditional logistic regression models to determine candidate protein biomarkers and to generate a protein score for predicting CVD in PLWH. We internally validated our findings using bootstrap. A protein score that was derived from 8 proteins (including HGF [hepatocyte growth factor] and interleukin-6) was found to be associated with an increased risk of CVD after adjustment for CVD and HIV factors (odds ratio: 2.17 [95% CI: 1.58-2.99]). The protein score improved CVD prediction when compared with predicting CVD risk using the individual proteins that comprised the protein score. Individuals with a protein score above the median score were 3.10 (95% CI, 1.83-5.41) times more likely to develop CVD than those with a protein score below the median score. Conclusions A panel of blood biomarkers may help identify PLWH at a high risk for developing CVD. If validated, such a score could be used in conjunction with established factors to identify CVD at-risk individuals who might benefit from aggressive risk reduction, ultimately shedding light on CVD pathogenesis in PLWH

Anti-influenza hyperimmune intravenous immunoglobulin for adults with influenza A or B infection (FLU-IVIG): a double-blind, randomised, placebo-controlled trial

BACKGROUND: Since the 1918 influenza pandemic, non-randomised studies and small clinical trials have suggested that convalescent plasma or anti-influenza hyperimmune intravenous immunoglobulin (hIVIG) might have clinical benefit for patients with influenza infection, but definitive data do not exist. We aimed to evaluate the safety and efficacy of hIVIG in a randomised controlled trial. METHODS: This randomised, double-blind, placebo-controlled trial was planned for 45 hospitals in Argentina, Australia, Denmark, Greece, Mexico, Spain, Thailand, UK, and the USA over five influenza seasons from 2013-14 to 2017-18. Adults (≥18 years of age) were admitted for hospital treatment with laboratory-confirmed influenza A or B infection and were randomly assigned (1:1) to receive standard care plus either a single 500-mL infusion of high-titre hIVIG (0·25 g/kg bodyweight, 24·75 g maximum; hIVIG group) or saline placebo (placebo group). Eligible patients had a National Early Warning score of 2 points or greater at the time of screening and their symptoms began no more than 7 days before randomisation. Pregnant and breastfeeding women were excluded, as well as any patients for whom the treatment would present a health risk. Separate randomisation schedules were generated for each participating clinical site using permuted block randomisation. Treatment assignments were obtained using a web-based application by the site pharmacist who then masked the solution for infusion. Patients and investigators were masked to study treatment. The primary endpoint was a six-category ordinal outcome of clinical status at day 7, ranging in severity from death to resumption of normal activities after discharge. The choice of day 7 was based on haemagglutination inhibition titres from a pilot study. It was analysed with a proportional odds model, using all six categories to estimate a common odds ratio (OR). An OR greater than 1 indicated that, for a given category, patients in the hIVIG group were more likely to be in a better category than those in the placebo group. Prespecified primary analyses for safety and efficacy were based on patients who received an infusion and for whom eligibility could be confirmed. This trial is registered with ClinicalTrials.gov, NCT02287467. FINDINGS: 313 patients were enrolled in 34 sites between Dec 11, 2014, and May 28, 2018. We also used data from 16 patients enrolled at seven of the 34 sites during the pilot study between Jan 15, 2014, and April 10, 2014. 168 patients were randomly assigned to the hIVIG group and 161 to the placebo group. 21 patients were excluded (12 from the hIVIG group and 9 from the placebo group) because they did not receive an infusion or their eligibility could not be confirmed. Thus, 308 were included in the primary analysis. hIVIG treatment produced a robust rise in haemagglutination inhibition titres against influenza A and smaller rises in influenza B titres. Based on the proportional odds model, the OR on day 7 was 1·25 (95% CI 0·79-1·97; p=0·33). In subgroup analyses for the primary outcome, the OR in patients with influenza A was 0·94 (0·55-1·59) and was 3·19 (1·21-8·42) for those with influenza B (interaction p=0·023). Through 28 days of follow-up, 47 (30%) of 156 patients in the hIVIG group and in 45 (30%) of 152 patients in the placebo group had the composite safety outcome of death, a serious adverse event, or a grade 3 or 4 adverse event (hazard ratio [HR] 1·06, 95% CI 0·70-1·60; p=0·79). Six (4%) patients in the hIVIG group and five (3%) in the placebo group died, but these deaths were not necessarily related to treatment. INTERPRETATION: When administered alongside standard care (most commonly oseltamivir), hIVIG was not superior to placebo for adults hospitalised with influenza infection. By contrast with our prespecified subgroup hypothesis that hIVIG would result in more favourable responses in patients with influenza A than B, we found the opposite effect. The clinical benefit of hIVIG for patients with influenza B is supported by antibody affinity analyses, but confirmation is warranted. FUNDING: NIAID and NIH. Partial support was provided by the Medical Research Council (MRC_UU_12023/23) and the Danish National Research Foundation

Impact of local recharge on arsenic concentrations in shallow aquifers inferred from the electromagnetic conductivity of soils in Araihazar, Bangladesh

The high-degree of spatial variability of dissolved As levels in shallow aquifers of the Bengal Basin has been well documented but the underlying mechanisms remain poorly understood. We compare here As concentrations measured in groundwater pumped from 4700 wells <22 m (75 ft) deep across a 25 km2 area of Bangladesh with variations in the nature of surface soils inferred from 18,500 measurements of frequency domain electromagnetic induction. A set of 14 hand auger cores recovered from the same area indicate that a combination of grain size and the conductivity of soil water dominate the electromagnetic signal. The relationship between pairs of individual EM conductivity and dissolved As measurements within a distance of 50 m is significant but highly scattered (r2 = 0.12; n = 614). Concentrations of As tend to be lower in shallow aquifers underlying sandy soils and higher below finer-grained and high conductivity soils. Variations in EM conductivity account for nearly half the variance of the rate of increase of As concentration with depth, however, when the data are averaged over a distance of 50 m (r2 = 0.50; n = 145). The association is interpreted as an indication that groundwater recharge through permeable sandy soils prevents As concentrations from rising in shallow reducing groundwater

Field, Experimental, and Modeling Study of Arsenic Partitioning across a Redox Transition in a Bangladesh Aquifer

To understand redox-dependent arsenic partitioning, we performed batch sorption and desorption experiments using aquifer sands subjected to chemical and mineralogical characterization. Sands collected from the redox transition zone between reducing groundwater and oxic river water at the Meghna riverbank with HCl extractable Fe(III)/Fe ratio ranging from 0.32 to 0.74 are representative of the redox conditions of aquifers common in nature. One brown suboxic sediment displayed a partitioning coefficient (K_d) of 7-8 L kg^-1 at equilibrium with 100 μg L^-1 As(III), while two gray reducing sediments showed K_d of 1-2 L kg^-1. Lactate amendment to aquifer sands containing 91 mg kg^-1 P-extractable As resulted in the reduction of As and Fe with sediment Fe(III)/Fe decreasing from 0.54 to 0.44, and mobilized an equivalent of 64 mg kg^-1 As over a month. Desorption of As from nonlactate-amended sediment was negligible with little change in sediment Fe(III)/Fe. This release of As is consistent with microbial reduction of Fe(III) oxyhydroxides and the resulting decrease in the number of surface sites on Fe(III) oxyhydroxides. Arsenic partitioning (K_d) in iron-rich, sulfur-poor aquifers with circumneutral pH is redox-dependent and can be estimated by HCl leachable sediment Fe(III)/Fe ratio with typical Fe concentrations

Combining motivational and volitional approaches to reducing excessive alcohol consumption in pre-drinkers: A theory-based intervention protocol

Background: Pre-drinking refers to the consumption of alcohol at home or a private residence prior to attending a subsequent social event. We present the study protocol of an online theory-based intervention to reduce pre-drinking and related harm in pre-drinking undergraduates, using behavior change techniques targeting the motivational and volitional phases of behaviour. Design: A fully randomized 2 (autonomy support: present vs. absent) x 2 (implementation intention: present vs. absent) between-participants design will be used to ascertain the effectiveness of the intervention in reducing pre-drinking alcohol consumption and alcohol-related harm. Participants will complete a range of theory-based measures prior to being allocated to one of the four experimental conditions. Four weeks later, participants will complete a follow-up questionnaire comprised of theoretical and behavioral measures. Analyses: The main and interactive effects of the intervention components in reducing our primary dependent variables, namely, pre-drinking alcohol consumption and alcohol-related harm at four-week follow-up will be tested. Baseline alcohol consumption and demographic information will be included in the analysis as covariates. Discussion: This online intervention is the first to be developed to reduce pre-drinking alcohol consumption, a behaviour linked to increased risk of alcohol-related harm. The intervention targets motivational and volitional components of the behaviour change process and is therefore likely to lead to greater reductions in pre-drinking alcohol consumption and experience of alcohol-related harm compared to either approach in isolation. If successful, the intervention can be implemented across various contexts and in populations where pre-drinking is prevalent. © 2016 Caudwell et al

Chronic lymphocytic leukaemia Australasian consensus practice statement

Chronic lymphocytic leukaemia (CLL) is the most common haematological malignancy in Australia and New Zealand (ANZ). Considerable changes to diagnostic and management algorithms have occurred within the last decade. The availability of next-generation sequencing and measurable residual disease assessment by flow cytometry allow for advanced prognostication and response assessments. Novel therapies, including inhibitors of Bruton's tyrosine kinase (BTKi) and B-cell lymphoma 2 (BCL2) inhibitors, have transformed the treatment landscape for both treatment-naïve and relapsed/refractory disease, particularly for patients with high-risk genetic aberrations. Recommendations regarding appropriate supportive management continue to evolve, and special considerations are required for patients with CLL with respect to the global SARS-CoV-2 pandemic. The unique funding and treatment environments in Australasia highlight the need for specific local guidance with respect to the investigation and management of CLL. This consensus practice statement was developed by a broadly representative group of ANZ experts in CLL with endorsement by peak haematology bodies, with a view to providing this standardised guidance

Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial

BACKGROUND: We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19. METHODS: In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978. FINDINGS: Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50-72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74-1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67-1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74-1·58]; BRII-196 plus BRII-198 1·00 [0·68-1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91-1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88-1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90. INTERPRETATION: Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19. FUNDING: US National Institutes of Health and Operation Warp Speed

Hyperimmune immunoglobulin for hospitalised patients with COVID-19 (ITAC): a double-blind, placebo-controlled, phase 3, randomised trial

BACKGROUND: Passive immunotherapy using hyperimmune intravenous immunoglobulin (hIVIG) to SARS-CoV-2, derived from recovered donors, is a potential rapidly available, specific therapy for an outbreak infection such as SARS-CoV-2. Findings from randomised clinical trials of hIVIG for the treatment of COVID-19 are limited. METHODS: In this international randomised, double-blind, placebo-controlled trial, hospitalised patients with COVID-19 who had been symptomatic for up to 12 days and did not have acute end-organ failure were randomly assigned (1:1) to receive either hIVIG or an equivalent volume of saline as placebo, in addition to remdesivir, when not contraindicated, and other standard clinical care. Randomisation was stratified by site pharmacy; schedules were prepared using a mass-weighted urn design. Infusions were prepared and masked by trial pharmacists; all other investigators, research staff, and trial participants were masked to group allocation. Follow-up was for 28 days. The primary outcome was measured at day 7 by a seven-category ordinal endpoint that considered pulmonary status and extrapulmonary complications and ranged from no limiting symptoms to death. Deaths and adverse events, including organ failure and serious infections, were used to define composite safety outcomes at days 7 and 28. Prespecified subgroup analyses were carried out for efficacy and safety outcomes by duration of symptoms, the presence of anti-spike neutralising antibodies, and other baseline factors. Analyses were done on a modified intention-to-treat (mITT) population, which included all randomly assigned participants who met eligibility criteria and received all or part of the assigned study product infusion. This study is registered with ClinicalTrials.gov, NCT04546581. FINDINGS: From Oct 8, 2020, to Feb 10, 2021, 593 participants (n=301 hIVIG, n=292 placebo) were enrolled at 63 sites in 11 countries; 579 patients were included in the mITT analysis. Compared with placebo, the hIVIG group did not have significantly greater odds of a more favourable outcome at day 7; the adjusted OR was 1·06 (95% CI 0·77–1·45; p=0·72). Infusions were well tolerated, although infusion reactions were more common in the hIVIG group (18·6% vs 9·5% for placebo; p=0·002). The percentage with the composite safety outcome at day 7 was similar for the hIVIG (24%) and placebo groups (25%; OR 0·98, 95% CI 0·66–1·46; p=0·91). The ORs for the day 7 ordinal outcome did not vary for subgroups considered, but there was evidence of heterogeneity of the treatment effect for the day 7 composite safety outcome: risk was greater for hIVIG compared with placebo for patients who were antibody positive (OR 2·21, 95% CI 1·14–4·29); for patients who were antibody negative, the OR was 0·51 (0·29–0·90; pinteraction=0·001). INTERPRETATION: When administered with standard of care including remdesivir, SARS-CoV-2 hIVIG did not demonstrate efficacy among patients hospitalised with COVID-19 without end-organ failure. The safety of hIVIG might vary by the presence of endogenous neutralising antibodies at entry. FUNDING: US National Institutes of Health

Suppressor of cytokine signaling-2: A growth hormone-inducible inhibitor of intestinal epithelial cell proliferation

AbstractBackground & Aims: Growth hormone (GH) and insulin-like growth factor-I (IGF-I) increase intestinal growth. GH is thought to act indirectly via IGF-I. In several models, including rats given total parenteral nutrition (TPN), IGF-I more potently stimulates mucosal growth than GH, even when GH induces similar circulating IGF-I levels. These studies test the hypothesis that GH induces a suppressor of cytokine signaling (SOCS), which inhibits intestinal epithelial cell (IEC) proliferation. Methods: Rats on TPN received vehicle, GH, or IGF-I. Jejunal SOCS (SOCS-1, -2, -3, and cytokine-inducible SH2-domain-containing protein [CIS]) and IGF-I messenger RNA (mRNA) were quantified. Caco-2, IEC-6 cells, and SOCS-2 null and wild-type (WT) mice were used to examine the expression and functional role of SOCS-2. Results: As reported previously, IGF-I, but not GH, prevented mucosal atrophy during TPN, although GH elevated plasma IGF-I and increased body weight. GH, but not IGF-I, induced jejunal SOCS-2 mRNA. SOCS-2 mRNA levels in GH and IGF-I-treated rats inversely correlated with mucosal weight. SOCS-2 is expressed in Caco-2 cells, and elevated SOCS-2 expression in postconfluent cells is associated with reduced proliferative rates. SOCS-2 overexpression in Caco-2 cells inhibited cell proliferation and promoted differentiation. In IEC-6 cells, GH induced SOCS-2 and reduced basal or IGF-I-induced proliferation. GH also reduced proliferative activity in isolated crypts from WT but not SOCS-2 null mice, and SOCS-2 null crypts showed enhanced proliferative responses to GH and IGF-I. SOCS-2 null mice have increased intestinal weight and length. Conclusions: SOCS-2 is a GH-inducible, novel inhibitor of intestinal epithelial cell proliferation and intestinal growth

The Curing Coma Campaign: Framing Initial Scientific Challenges—Proceedings of the First Curing Coma Campaign Scientific Advisory Council Meeting

Abstract: Coma and disordered consciousness are common manifestations of acute neurological conditions and are among the most pervasive and challenging aspects of treatment in neurocritical care. Gaps exist in patient assessment, outcome prognostication, and treatment directed specifically at improving consciousness and cognitive recovery. In 2019, the Neurocritical Care Society (NCS) launched the Curing Coma Campaign in order to address the “grand challenge” of improving the management of patients with coma and decreased consciousness. One of the first steps was to bring together a Scientific Advisory Council including coma scientists, neurointensivists, neurorehabilitationists, and implementation experts in order to address the current scientific landscape and begin to develop a framework on how to move forward. This manuscript describes the proceedings of the first Curing Coma Campaign Scientific Advisory Council meeting which occurred in conjunction with the NCS Annual Meeting in October 2019 in Vancouver. Specifically, three major pillars were identified which should be considered: endotyping of coma and disorders of consciousness, biomarkers, and proof-of-concept clinical trials. Each is summarized with regard to current approach, benefits to the patient, family, and clinicians, and next steps. Integration of these three pillars will be essential to the success of the Curing Coma Campaign as will expanding the “curing coma community” to ensure broad participation of clinicians, scientists, and patient advocates with the goal of identifying and implementing treatments to fundamentally improve the outcome of patients