Lower objectively measured physical activity is linked with perceived risk of hypoglycemia in type 1 diabetes

Aims Compare physical activity (PA) levels in adults with and without type 1 diabetes and identify diabetes-specific barriers to PA. Methods Forty-four individuals with type 1 diabetes and 77 non-diabetic controls in the Coronary Artery Calcification in Type 1 Diabetes study wore an accelerometer for 2 weeks. Moderate-to-vigorous physical activity (MVPA) was compared by diabetes status using multiple linear regression. The Barriers to Physical Activity in Type 1 Diabetes questionnaire measured diabetes-specific barriers to PA, and the Clarke hypoglycemia awareness questionnaire measured hypoglycemia frequency. Results Individuals with type 1 diabetes engaged in less MVPA, fewer bouts of MVPA, and spent less time in MVPA bouts per week than individuals without diabetes (all p  0.05). The most common diabetes-specific barrier to PA was risk of hypoglycemia. Individuals with diabetes reporting barriers spent less time in MVPA bouts per week than those not reporting barriers (p = 0.047). Conclusions Individuals with type 1 diabetes engage in less MVPA than those without diabetes despite similar self-reported levels, with the main barrier being perceived risk of hypoglycemia. Adults with type 1 diabetes require guidance to meet current PA guidelines and reduce cardiovascular risk

A call to action: A need for initiatives that increase equitable access to COVID-19 therapeutics

Structural racism is endemic in the United States and causes inequitable health outcomes that have been amplified throughout the COVID-19 pandemic. Non-Hispanic Black, Hispanic/Latino, and Native American individuals have been disproportionately affected, and are twice as likely to be hospitalized or die from COVID-19 or related morbidities when compared to White Americans. Social determinants of health inequities contribute to these disparate outcomes, given that minoritized individuals are more likely to occupy essential worker roles and to live in high-density settings. Despite their higher risk of severe COVID-19 illness, racially and ethnically minoritized individuals are less likely to receive potentially lifesaving COVID-19 therapeutics.3 While several state health departments attempted to implement race-conscious interventions and narrow the disparities, these efforts have been met with fallacious claims of ‘reverse racism’ and the reversal of the proposed implementations

Liver transplant recipient survival benefit with living donation in the model for endstage liver disease allocation era

Receipt of a living donor liver transplant (LDLT) has been associated with improved survival compared with waiting for a deceased donor liver transplant (DDLT). However, the survival benefit of liver transplant has been questioned for candidates with Model for Endstage Liver Disease (MELD) scores <15, and the survival advantage of LDLT has not been demonstrated during the MELD allocation era, especially for low MELD patients. Transplant candidates enrolled in the Adult‐to‐Adult Living Donor Liver Transplantation Cohort Study after February 28, 2002 were followed for a median of 4.6 years. Starting at the time of presentation of the first potential living donor, mortality for LDLT recipients was compared to mortality for patients who remained on the waiting list or received DDLT (no LDLT group) according to categories of MELD score (<15 or ≥15) and diagnosis of hepatocellular carcinoma (HCC). Of 868 potential LDLT recipients (453 with MELD <15; 415 with MELD ≥15 at entry), 712 underwent transplantation (406 LDLT; 306 DDLT), 83 died without transplant, and 73 were alive without transplant at last follow‐up. Overall, LDLT recipients had 56% lower mortality (hazard ratio [HR] = 0.44, 95% confidence interval [CI] 0.32‐0.60; P < 0.0001). Among candidates without HCC, mortality benefit was seen both with MELD <15 (HR = 0.39; P = 0.0003) and MELD ≥15 (HR = 0.42; P = 0.0006). Among candidates with HCC, a benefit of LDLT was not seen for MELD <15 (HR = 0.82, P = 0.65) but was seen for MELD ≥15 (HR = 0.29, P = 0.043). Conclusion: Across the range of MELD scores, patients without HCC derived a significant survival benefit when undergoing LDLT rather than waiting for DDLT in the MELD liver allocation era. Low MELD candidates with HCC may not benefit from LDLT. (H EPATOLOGY 2011;54:1313–1321)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86878/1/24494_ftp.pd

Liver transplant recipient survival benefit with living donation in the MELD allocation era,,

Receipt of a living donor liver transplant (LDLT) has been associated with improved survival compared with waiting for a deceased donor liver transplant (DDLT). However, the survival benefit of liver transplant has been questioned for candidates with model for end-stage liver disease (MELD) scores< 15, and the survival advantage of LDLT has not been demonstrated during the MELD allocation era, especially for low MELD patients. Transplant candidates enrolled in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study after 02/28/02 were followed for a median of 4.6 years. Starting at the time of presentation of the first potential living donor, mortality for LDLT recipients was compared to mortality for patients who remained on the waiting list or received DDLT (no LDLT group) according to categories of MELD score

Adventures in the Enormous: A 1.8 Million Clone BAC Library for the 21.7 Gb Genome of Loblolly Pine

Loblolly pine (LP; Pinus taeda L.) is the most economically important tree in the U.S. and a cornerstone species in southeastern forests. However, genomics research on LP and other conifers has lagged behind studies on flowering plants due, in part, to the large size of conifer genomes. As a means to accelerate conifer genome research, we constructed a BAC library for the LP genotype 7-56. The LP BAC library consists of 1,824,768 individually-archived clones making it the largest single BAC library constructed to date, has a mean insert size of 96 kb, and affords 7.6X coverage of the 21.7 Gb LP genome. To demonstrate the efficacy of the library in gene isolation, we screened macroarrays with overgos designed from a pine EST anchored on LP chromosome 10. A positive BAC was sequenced and found to contain the expected full-length target gene, several gene-like regions, and both known and novel repeats. Macroarray analysis using the retrotransposon IFG-7 (the most abundant repeat in the sequenced BAC) as a probe indicates that IFG-7 is found in roughly 210,557 copies and constitutes about 5.8% or 1.26 Gb of LP nuclear DNA; this DNA quantity is eight times the Arabidopsis genome. In addition to its use in genome characterization and gene isolation as demonstrated herein, the BAC library should hasten whole genome sequencing of LP via next-generation sequencing strategies/technologies and facilitate improvement of trees through molecular breeding and genetic engineering. The library and associated products are distributed by the Clemson University Genomics Institute (www.genome.clemson.edu)

Cortical Representation of Lateralized Grasping in Chimpanzees (Pan troglodytes): A Combined MRI and PET Study

Functional imaging studies in humans have localized the motor-hand region to a neuroanatomical landmark call the KNOB within the precentral gyrus. It has also been reported that the KNOB is larger in the hemisphere contralateral to an individual's preferred hand, and therefore may represent the neural substrate for handedness. The KNOB has also been neuronatomically described in chimpanzees and other great apes and is similarly associated with handedness. However, whether the chimpanzee KNOB represents the hand region is unclear from the extant literature. Here, we used PET to quantify neural metabolic activity in chimpanzees when engaged in unilateral reach-and-grasping responses and found significantly lateralized activation of the KNOB region in the hemisphere contralateral to the hand used by the chimpanzees. We subsequently constructed a probabilistic map of the KNOB region in chimpanzees in order to assess the overlap in consistency in the anatomical landmarks of the KNOB with the functional maps generated from the PET analysis. We found significant overlap in the anatomical and functional voxels comprising the KNOB region, suggesting that the KNOB does correspond to the hand region in chimpanzees. Lastly, from the probabilistic maps, we compared right- and left-handed chimpanzees on lateralization in grey and white matter within the KNOB region and found that asymmetries in white matter of the KNOB region were larger in the hemisphere contralateral to the preferred hand. These results suggest that neuroanatomical asymmetries in the KNOB likely reflect changes in connectivity in primary motor cortex that are experience dependent in chimpanzees and possibly humans

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB

Resource discovery for distributed computing systems: A comprehensive survey

Large-scale distributed computing environments provide a vast amount of heterogeneous computing resources from different sources for resource sharing and distributed computing. Discovering appropriate resources in such environments is a challenge which involves several different subjects. In this paper, we provide an investigation on the current state of resource discovery protocols, mechanisms, and platforms for large-scale distributed environments, focusing on the design aspects. We classify all related aspects, general steps, and requirements to construct a novel resource discovery solution in three categories consisting of structures, methods, and issues. Accordingly, we review the literature, analyzing various aspects for each category

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124–159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie