Genomic Patterns of De Novo Mutation in Simplex Autism.

To further our understanding of the genetic etiology of autism, we generated and analyzed genome sequence data from 516 idiopathic autism families (2,064 individuals). This resource includes >59 million single-nucleotide variants (SNVs) and 9,212 private copy number variants (CNVs), of which 133,992 and 88 are de novo mutations (DNMs), respectively. We estimate a mutation rate of ∼1.5 × 10-8 SNVs per site per generation with a significantly higher mutation rate in repetitive DNA. Comparing probands and unaffected siblings, we observe several DNM trends. Probands carry more gene-disruptive CNVs and SNVs, resulting in severe missense mutations and mapping to predicted fetal brain promoters and embryonic stem cell enhancers. These differences become more pronounced for autism genes (p = 1.8 × 10-3, OR = 2.2). Patients are more likely to carry multiple coding and noncoding DNMs in different genes, which are enriched for expression in striatal neurons (p = 3 × 10-3), suggesting a path forward for genetically characterizing more complex cases of autism.

Proportion and number of cancer cases and deaths attributable to potentially modifiable risk factors in the United States, 2019.

In 2018, the authors reported estimates of the number and proportion of cancers attributable to potentially modifiable risk factors in 2014 in the United States. These data are useful for advocating for and informing cancer prevention and control. Herein, based on up-to-date relative risk and cancer occurrence data, the authors estimated the proportion and number of invasive cancer cases (excluding nonmelanoma skin cancers) and deaths, overall and for 30 cancer types among adults who were aged 30 years and older in 2019 in the United States, that were attributable to potentially modifiable risk factors. These included cigarette smoking; second-hand smoke; excess body weight; alcohol consumption; consumption of red and processed meat; low consumption of fruits and vegetables, dietary fiber, and dietary calcium; physical inactivity; ultraviolet radiation; and seven carcinogenic infections. Numbers of cancer cases and deaths were obtained from data sources with complete national coverage, risk factor prevalence estimates from nationally representative surveys, and associated relative risks of cancer from published large-scale pooled or meta-analyses. In 2019, an estimated 40.0% (713,340 of 1,781,649) of all incident cancers (excluding nonmelanoma skin cancers) and 44.0% (262,120 of 595,737) of all cancer deaths in adults aged 30 years and older in the United States were attributable to the evaluated risk factors. Cigarette smoking was the leading risk factor contributing to cancer cases and deaths overall (19.3% and 28.5%, respectively), followed by excess body weight (7.6% and 7.3%, respectively), and alcohol consumption (5.4% and 4.1%, respectively). For 19 of 30 evaluated cancer types, more than one half of the cancer cases and deaths were attributable to the potentially modifiable risk factors considered in this study. Lung cancer had the highest number of cancer cases (201,660) and deaths (122,740) attributable to evaluated risk factors, followed by female breast cancer (83,840 cases), skin melanoma (82,710), and colorectal cancer (78,440) for attributable cases and by colorectal (25,800 deaths), liver (14,720), and esophageal (13,600) cancer for attributable deaths. Large numbers of cancer cases and deaths in the United States are attributable to potentially modifiable risk factors, underscoring the potential to substantially reduce the cancer burden through broad and equitable implementation of preventive initiatives.

Global patterns in excess body weight and the associated cancer burden.

The prevalence of excess body weight and the associated cancer burden have been rising over the past several decades globally. Between 1975 and 2016, the prevalence of excess body weight in adults-defined as a body mass index (BMI) ≥ 25 kg/m2 -increased from nearly 21% in men and 24% in women to approximately 40% in both sexes. Notably, the prevalence of obesity (BMI ≥ 30 kg/m2 ) quadrupled in men, from 3% to 12%, and more than doubled in women, from 7% to 16%. This change, combined with population growth, resulted in a more than 6-fold increase in the number of obese adults, from 100 to 671 million. The largest absolute increase in obesity occurred among men and boys in high-income Western countries and among women and girls in Central Asia, the Middle East, and North Africa. The simultaneous rise in excess body weight in almost all countries is thought to be driven largely by changes in the global food system, which promotes energy-dense, nutrient-poor foods, alongside reduced opportunities for physical activity. In 2012, excess body weight accounted for approximately 3.9% of all cancers (544,300 cases) with proportion varying from less than 1% in low-income countries to 7% or 8% in some high-income Western countries and in Middle Eastern and Northern African countries. The attributable burden by sex was higher for women (368,500 cases) than for men (175,800 cases). Given the pandemic proportion of excess body weight in high-income countries and the increasing prevalence in low- and middle-income countries, the global cancer burden attributable to this condition is likely to increase in the future. There is emerging consensus on opportunities for obesity control through the multisectoral coordinated implementation of core policy actions to promote an environment conducive to a healthy diet and active living. The rapid increase in both the prevalence of excess body weight and the associated cancer burden highlights the need for a rejuvenated focus on identifying, implementing, and evaluating interventions to prevent and control excess body weight.

Cholesterol in the cargo membrane amplifies tau inhibition of kinesin-1-based transport.

Intracellular cargos are often membrane-enclosed and transported by microtubule-based motors in the presence of microtubule-associated proteins (MAPs). Whereas increasing evidence reveals how MAPs impact the interactions between motors and microtubules, critical questions remain about the impact of the cargo membrane on transport. Here we combined in vitro optical trapping with theoretical approaches to determine the effect of a lipid cargo membrane on kinesin-based transport in the presence of MAP tau. Our results demonstrate that attaching kinesin to a fluid lipid membrane reduces the inhibitory effect of tau on kinesin. Moreover, adding cholesterol, which reduces kinesin diffusion in the cargo membrane, amplifies the inhibitory effect of tau on kinesin binding in a dosage-dependent manner. We propose that reduction of kinesin diffusion in the cargo membrane underlies the effect of cholesterol on kinesin binding in the presence of tau, and we provide a simple model for this proposed mechanism. Our study establishes a direct link between cargo membrane cholesterol and MAP-based regulation of kinesin-1. The cholesterol effects uncovered here may more broadly extend to other lipid alterations that impact motor diffusion in the cargo membrane, including those associated with aging and neurological diseases.

MWF of the corpus callosum is a robust measure of remyelination: Results from the ReBUILD trial.

Myelin repair is an unrealized therapeutic goal in the treatment of multiple sclerosis (MS). Uncertainty remains about the optimal techniques for assessing therapeutic efficacy and imaging biomarkers are required to measure and corroborate myelin restoration. We analyzed myelin water fraction imaging from ReBUILD, a double-blind, randomized placebo-controlled (delayed treatment) remyelination trial, that showed a significant reduction in VEP latency in patients with MS. We focused on brain regions rich in myelin. Fifty MS subjects in two arms underwent 3T MRI at baseline and months 3 and 5. Half of the cohort was randomly assigned to receive treatment from baseline through 3 mo, whereas the other half received treatment from 3 mo to 5 mo post-baseline. We computed myelin water fraction changes occurring in normal-appearing white matter of corpus callosum, optic radiations, and corticospinal tracts. An increase in myelin water fraction was documented in the normal-appearing white matter of the corpus callosum, in correspondence with the administration of the remyelinating treatment clemastine. This study provides direct, biologically validated imaging-based evidence of medically induced myelin repair. Moreover, our work strongly suggests that significant myelin repair occurs outside of lesions. We therefore propose myelin water fraction within the normal-appearing white matter of the corpus callosum as a biomarker for clinical trials looking at remyelination.

Nanoelectrochemistry reveals how soluble Aß42 oligomers alter vesicular storage and release of glutamate.

Glutamate (Glu) is the major excitatory transmitter in the nervous system. Impairment of its vesicular release by ß-amyloid (Aß) oligomers is thought to participate in pathological processes leading to Alzheimer's disease. However, it remains unclear whether soluble Aß42 oligomers affect intravesicular amounts of Glu or their release in the brain, or both. Measurements made in this work on single Glu varicosities with an amperometric nanowire Glu biosensor revealed that soluble Aß42 oligomers first caused a dramatic increase in vesicular Glu storage and stimulation-induced release, accompanied by a high level of parallel spontaneous exocytosis, ultimately resulting in the depletion of intravesicular Glu content and greatly reduced release. Molecular biology tools and mouse models of Aß amyloidosis have further established that the transient hyperexcitation observed during the primary pathological stage is mediated by an altered behavior of VGLUT1 responsible for transporting Glu into synaptic vesicles. Thereafter, an overexpression of Vps10p-tail-interactor-1a, a protein that maintains spontaneous release of neurotransmitters by selective interaction with t-SNAREs, resulted in a depletion of intravesicular Glu content, triggering advanced-stage neuronal malfunction. These findings are expected to open perspectives for remediating Aß42-induced neuronal hyperactivity and neuronal degeneration.

Randomized Crossover Trial of 2-Week Ketone Ester Treatment in Patients With Type 2 Diabetes and Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a major cause of morbidity and mortality in patients with type 2 diabetes (T2DM). Acute increases in circulating levels of ketone body 3-hydroxybutyrate have beneficial acute hemodynamic effects in patients without T2DM with chronic heart failure with reduced ejection fraction. However, the cardiovascular effects of prolonged oral ketone ester (KE) treatment in patients with T2DM and HFpEF remain unknown. METHODS: A total of 24 patients with T2DM and HFpEF completed a 6-week randomized, double-blind crossover study. All patients received 2 weeks of KE treatment (25 g D-ß-hydroxybutyrate-(R)-1,3-butanediol × 4 daily) and isocaloric and isovolumic placebo, separated by a 2-week washout period. At the end of each treatment period, patients underwent right heart catheterization, echocardiography, and blood samples at trough levels of intervention, and then during a 4-hour resting period after a single dose. A subsequent second dose was administered, followed by an exercise test. The primary end point was cardiac output during the 4-hour rest period. RESULTS: During the 4-hour resting period, circulating 3-hydroxybutyrate levels were 10-fold higher after KE treatment (1010±56 µmol/L; P<0.001) compared with placebo (91±55 µmol/L). Compared with placebo, KE treatment increased cardiac output by 0.2 L/min (95% CI, 0.1 to 0.3) during the 4-hour period and decreased pulmonary capillary wedge pressure at rest by 1 mm Hg (95% CI, -2 to 0) and at peak exercise by 5 mm Hg (95% CI, -9 to -1). KE treatment decreased the pressure-flow relationship (∆ pulmonary capillary wedge pressure/∆ cardiac output) significantly during exercise (P<0.001) and increased stroke volume by 10 mL (95% CI, 0 to 20) at peak exercise. KE right-shifted the left ventricular end-diastolic pressure-volume relationship, suggestive of reduced left ventricular stiffness and improved compliance. Favorable hemodynamic responses of KE treatment were also observed in patients treated with sodium-glucose transporter-2 inhibitors and glucagon-like peptide-1 analogs. CONCLUSIONS: In patients with T2DM and HFpEF, a 2-week oral KE treatment increased cardiac output and reduced cardiac filling pressures and ventricular stiffness. At peak exercise, KE treatment markedly decreased pulmonary capillary wedge pressure and improved pressure-flow relationship. Modulation of circulating ketone levels is a potential new treatment modality for patients with T2DM and HFpEF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05236335.

The Global Incident Gastrointestinal Cancers Attributable to Suboptimal Diets From 1990 to 2018.

BACKGROUND & AIMS: The contribution of suboptimal diets to gastrointestinal (GI) cancer incidence globally remains unquantified, and we aimed to evaluate it. METHODS: Comprehensive meta-analyses and rigorous evidence-grading assessment identified the associations between suboptimal diets and 6 GI cancers and their subtypes. A comparative risk assessment model was used to estimate the proportional attributable burden and attributable rate of GI cancers to suboptimal diets by using the corroborative association estimates. In addition, correlation assessments with the Sociodemographic Index were carried out. RESULTS: In 2018, 21.5% (95% uncertainty interval, 19.1%-24.5%) of incident GI cancer cases globally were attributable to suboptimal diets, maintaining a relatively stable proportion since 1990 (22.4%; 19.7%-25.6%), whereas the absolute diet-attributable cases doubled from 580,862 (510,658-664,076) in 1990 to 1,039,877 (923,482-1,187,244) in 2018. Excessive processed meat consumption (5.9%; 4.2%-7.9%), insufficient fruit intake (4.8%; 3.8%-5.9%), and insufficient whole grain intake (3.6%; 2.8%-5.1%) were the most significant dietary risk factors in 2018, a shift from 1990 when the third major concern was insufficient nonstarchy vegetable intake. In addition, Central and Eastern Europe and Central Asia experienced the highest attributable burden across regions in both 1990 (31.6%; 27.0%-37.4%) and 2018 (31.6%; 27.3%-36.5%), and a positive correlation (P < .001) between the Sociodemographic Index and the attributable GI cancer incidence was observed. CONCLUSIONS: Although the proportional attributable GI incidence remains relatively stable, the doubling of absolute cases from 1990 to 2018, along with the discrepancies among urbanicity and countries/regions, informs dietary priorities and more targeted preventive measures.

Proportion and number of cancer cases and deaths attributable to potentially modifiable risk factors in the United States.

Contemporary information on the fraction of cancers that potentially could be prevented is useful for priority setting in cancer prevention and control. Herein, the authors estimate the proportion and number of invasive cancer cases and deaths, overall (excluding nonmelanoma skin cancers) and for 26 cancer types, in adults aged 30 years and older in the United States in 2014, that were attributable to major, potentially modifiable exposures (cigarette smoking; secondhand smoke; excess body weight; alcohol intake; consumption of red and processed meat; low consumption of fruits/vegetables, dietary fiber, and dietary calcium; physical inactivity; ultraviolet radiation; and 6 cancer-associated infections). The numbers of cancer cases were obtained from the Centers for Disease Control and Prevention (CDC) and the National Cancer Institute; the numbers of deaths were obtained from the CDC; risk factor prevalence estimates were obtained from nationally representative surveys; and associated relative risks of cancer were obtained from published, large-scale pooled analyses or meta-analyses. In the United States in 2014, an estimated 42.0% of all incident cancers (659,640 of 1570,975 cancers, excluding nonmelanoma skin cancers) and 45.1% of cancer deaths (265,150 of 587,521 deaths) were attributable to evaluated risk factors. Cigarette smoking accounted for the highest proportion of cancer cases (19.0%; 298,970 cases) and deaths (28.8%; 169,180 deaths), followed by excess body weight (7.8% and 6.5%, respectively) and alcohol intake (5.6% and 4.0%, respectively). Lung cancer had the highest number of cancers (184,970 cases) and deaths (132,960 deaths) attributable to evaluated risk factors, followed by colorectal cancer (76,910 cases and 28,290 deaths). These results, however, may underestimate the overall proportion of cancers attributable to modifiable factors, because the impact of all established risk factors could not be quantified, and many likely modifiable risk factors are not yet firmly established as causal. Nevertheless, these findings underscore the vast potential for reducing cancer morbidity and mortality through broad and equitable implementation of known preventive measures. CA Cancer J Clin 2018;68:31-54. © 2017 American Cancer Society.

Loop diuretic utilisation with or without heart failure: impact on prognosis.

BACKGROUND & AIMS: Many patients are prescribed loop diuretics without a diagnostic record of heart failure. Little is known about their characteristics and prognosis. METHODS: Glasgow regional health records (2009-2016) were obtained for adults with cardiovascular disease or taking loop diuretics. Outcomes were investigated using Cox models with hazard ratios adjusted for age, sex, socioeconomic deprivation, and co-morbid disease (adjHR). RESULTS: Of 198,898 patients (median age 65 years; 55% women), 161,935 (81%) neither took loop diuretics nor had a diagnostic record of heart failure (reference group), 23,963 (12%) were taking loop diuretics but had no heart failure recorded, 7,844 (4%) had heart failure recorded and took loop diuretics and 5,156 (3%) had heart failure recorded but were not receiving loop diuretics.Five-year mortality was only slightly higher for heart failure in absence of loop diuretics (22%; adjHR: 1.2 [95% CI 1.1-1.3]), substantially higher for those taking loop diuretics with no heart failure recorded (40%; adjHR: 1.8 [95% CI 1.7-1.8]) and highest for heart failure treated with loop diuretics (52%; adjHR: 2.2 [95% CI 2.0-2.2]). CONCLUSIONS: For patients with cardiovascular disease, many are prescribed loop diuretics without a diagnosis of heart failure being recorded. Mortality is more strongly associated with loop diuretic use than with a heart failure record. The diagnosis of heart failure may be often missed, or loop diuretic use is associated with other conditions with a prognosis similar to heart failure, or inappropriate loop diuretic use increases mortality; all might be true.

Ferric carboxymaltose and exercise capacity in heart failure with preserved ejection fraction and iron deficiency: the FAIR-HFpEF trial.

BACKGROUND AND AIMS: Evidence is lacking that correcting iron deficiency (ID) has clinically important benefits for patients with heart failure with preserved ejection fraction (HFpEF). METHODS: FAIR-HFpEF was a multicentre, randomized, double-blind trial designed to compare intravenous ferric carboxymaltose (FCM) with placebo (saline) in 200 patients with symptomatic HFpEF and ID (serum ferritin < 100 ng/mL or ferritin 100-299 ng/mL with transferrin saturation < 20%). The primary endpoint was change in 6-min walking test distance (6MWTD) from baseline to week 24. Secondary endpoints included changes in New York Heart Association class, patient global assessment, and health-related quality of life (QoL). RESULTS: The trial was stopped because of slow recruitment after 39 patients had been included (median age 80 years, 62% women). The change in 6MWTD from baseline to week 24 was greater for those assigned to FCM compared to placebo [least square mean difference 49 m, 95% confidence interval (CI) 5-93; P = .029]. Changes in secondary endpoints were not significantly different between groups. The total number of adverse events (76 vs. 114) and serious adverse events (5 vs. 19; rate ratio 0.27, 95% CI 0.07-0.96; P = .043) was lower with FCM than placebo. CONCLUSIONS: In patients with HFpEF and markers of ID, intravenous FCM improved 6MWTD and was associated with fewer serious adverse events. However, the trial lacked sufficient power to identify or refute effects on symptoms or QoL. The potential benefits of intravenous iron in HFpEF with ID should be investigated further in a larger cohort.

Strain surveillance during chemotherapy to improve cardiovascular outcomes: the SUCCOUR-MRI trial.

BACKGROUND AND AIMS: The detection of cancer therapy-related cardiac dysfunction (CTRCD) by reduction of left ventricular ejection fraction (LVEF) during chemotherapy usually triggers the initiation of cardioprotective therapy. This study addressed whether the same approach should be applied to patients with worsening of global longitudinal strain (GLS) without attaining thresholds of LVEF. METHODS: Strain sUrveillance during Chemotherapy for improving Cardiovascular Outcomes (SUCCOUR-MRI) was a prospective multicentre randomized controlled trial involving 14 sites. Of 355 patients receiving anthracyclines with normal baseline LVEF, 333 patients (age 59±13 years, 79% women) with at least one other CTRCD risk factor, able to undergo magnetic resonance imaging (MRI), GLS and 3D echocardiography were tracked over 12 months. A total of 105 patients (age 59±13 years, 75% women, 69% breast cancer) developing GLS-CTRCD (>12% relative reduction of GLS without a change in LVEF) between cardioprotection with neurohormonal antagonists versus usual care were randomized. The primary endpoint was 12-month change in MRI-LVEF; the secondary endpoint was MRI LVEF-defined CTRCD. RESULTS: During follow-up, 2 patients died and 2 developed heart failure. Most patients were randomized at 3 months (62%). Median doses of angiotensin inhibition/blockade and beta-blockade were 75% and 50% of respective targets; 21 (43%) had side-effects attributed to cardioprotection. Due to a smaller LVEF change from baseline with cardioprotection than usual care (-2.5±5.4% vs -5.6±5.9%, p=0.009), follow-up LVEF was higher after cardioprotection (59±5% vs 55±6%, p<0.0001). After adjustment for baseline LVEF, the mean (95% confidence interval) difference in the change in LVEF between the two groups was -3.6% (-1.8% to -5.5%, p<0.001). After cardioprotection, 1/49 patients developed 12-month LVEF-CTRCD, compared to 6/56 in usual care (p=0.075). GLS improved at 3 months post-randomization in the cardioprotection group, with little change with usual care. CONCLUSIONS: In patients with isolated GLS reduction after anthracyclines, cardioprotection is associated with better preservation of 12-month MRI-LVEF compared with usual care.

Semaglutide and diuretic use in obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF-DM trials.

BACKGROUND AND AIMS: In the STEP-HFpEF trial programme, treatment with semaglutide resulted in multiple beneficial effects in patients with obesity-related heart failure with preserved ejection fraction (HFpEF). Efficacy may vary according to baseline diuretic use, and semaglutide treatment could modify diuretic dose. METHODS: In this pre-specified analysis of pooled data from the STEP-HFpEF and STEP-HFpEF-DM trials (n = 1145), which randomized participants with HFpEF and body mass index ≥ 30 kg/m2 to once weekly semaglutide 2.4 mg or placebo for 52 weeks, we examined whether efficacy and safety endpoints differed by baseline diuretic use, as well as the effect of semaglutide on loop diuretic use and dose changes over the 52-week treatment period. RESULTS: At baseline, across no diuretic (n = 220), non-loop diuretic only (n = 223), and loop diuretic [<40 (n = 219), 40 (n = 309), and >40 (n = 174) mg/day furosemide equivalents] groups, there was progressively higher prevalence of hypertension and atrial fibrillation; and greater severity of obesity and heart failure. Over 52 weeks of treatment, semaglutide had a consistent beneficial effect on change in body weight across diuretic use categories (adjusted mean difference vs. placebo ranged from -8.8% [95% confidence interval (CI) -10.3, -6.3] to -6.9% [95% CI -9.1, -4.7] from no diuretics to the highest loop diuretic dose category; interaction P = .39). Kansas City Cardiomyopathy Questionnaire clinical summary score improvement was greater in patients on loop diuretics compared to those not on loop diuretics (adjusted mean difference vs. placebo: +9.3 [6.5; 12.1] vs. +4.7 points [1.3, 8.2]; P = .042). Semaglutide had consistent beneficial effects on all secondary efficacy endpoints (including 6 min walk distance) across diuretic subgroups (interaction P = .24-.92). Safety also favoured semaglutide vs. placebo across the diuretic subgroups. From baseline to 52 weeks, loop diuretic dose decreased by 17% in the semaglutide group vs. a 2.4% increase in the placebo group (P < .0001). Semaglutide (vs. placebo) was more likely to result in loop diuretic dose reduction (odds ratio [OR] 2.67 [95% CI 1.70, 4.18]) and less likely dose increase (OR 0.35 [95% CI 0.23, 0.53]; P < .001 for both) from baseline to 52 weeks. CONCLUSIONS: In patients with obesity-related HFpEF, semaglutide improved heart failure-related symptoms and physical limitations across diuretic use subgroups, with more pronounced benefits among patients receiving loop diuretics at baseline. Reductions in weight and improvements in exercise function with semaglutide vs. placebo were consistent in all diuretic use categories. Semaglutide also led to a reduction in loop diuretic use and dose between baseline and 52 weeks. CLINICAL TRIAL REGISTRATION: NCT04788511 and NCT04916470.

Renal Denervation to Treat Heart Failure.

Heart failure (HF) is a global pandemic with a poor prognosis after hospitalization. Despite HF syndrome complexities, evidence of significant sympathetic overactivity in the manifestation and progression of HF is universally accepted. Confirmation of this dogma is observed in guideline-directed use of neurohormonal pharmacotherapies as a standard of care in HF. Despite reductions in morbidity and mortality, a growing patient population is resistant to these medications, while off-target side effects lead to dismal patient adherence to lifelong drug regimens. Novel therapeutic strategies, devoid of these limitations, are necessary to attenuate the progression of HF pathophysiology while continuing to reduce morbidity and mortality. Renal denervation is an endovascular procedure, whereby the ablation of renal nerves results in reduced renal afferent and efferent sympathetic nerve activity in the kidney and globally. In this review, we discuss the current state of preclinical and clinical research related to renal sympathetic denervation to treat HF.

Leveraging data from a longitudinal birth cohort to improve attribution of diarrhea etiology among children in low-resource settings.

Attributing infectious causes of diarrhea is critical to inform treatment and burden estimates. The attributable fraction (AF) approach based on the association between pathogen quantity and diarrhea has been frequently used but may underestimate incidence. We leveraged data from the multisite birth-cohort Malnutrition and Enteric Disease (MAL-ED) Study, where diarrheal and non-diarrheal stools were collected from 1,715 children from 0-2 years. We compared attribution using a longitudinal AF (LAF) method that considers the temporal association between pathogen quantity and diarrhea symptoms to previously-published AF estimates. For rotavirus and Shigella, attribution did not meaningfully change. For others like adenovirus 40 & 41, astrovirus, norovirus GII, sapovirus, Campylobacter jejuni or C coli, ST ETEC, typical EPEC, and Cryptosporidium, attribution increased, demonstrating longitudinal data may be informative for pathogens with weak associations between quantity and diarrhea. We further derived accuracy-based, pathogen-specific quantity cut-offs that may improve attribution in the absence of longitudinal data.

Circulating Biomarkers, Fraction of Exhaled Nitric Oxide, and Lung Function in Patients With Human Immunodeficiency Virus and Tuberculosis.

BACKGROUND: Identification of proinflammatory factors responding to Mycobacterium tuberculosis is important to reduce long-term sequelae of pulmonary tuberculosis (TB). METHODS: We examined the association between plasma biomarkers, the fraction of exhaled nitric oxide (FeNO), and lung function among a prospective cohort of 105 adults newly diagnosed with TB/human immunodeficiency virus (HIV) in South Africa. Participants were followed for 48 weeks from antiretroviral therapy (ART) initiation with serial assessments of plasma biomarkers, FeNO, lung function, and respiratory symptoms. Linear regression and generalized estimating equations were used to examine the associations at baseline and over the course of TB treatment, respectively. RESULTS: At baseline, higher FeNO levels were associated with preserved lung function, whereas greater respiratory symptoms and higher interleukin (IL)-6 plasma levels were associated with worse lung function. After ART and TB treatment initiation, improvements in lung function were associated with increases in FeNO (rate ratio [RR] = 86 mL, 95% confidence interval [CI] = 34-139) and decreases in IL-6 (RR = -118 mL, 95% CI = -193 to -43) and vascular endothelial growth factor ([VEGF] RR = -178 mL, 95% CI = -314 to -43). CONCLUSIONS: Circulating IL-6, VEGF, and FeNO are associated with lung function in adults being treated for TB/HIV. These biomarkers may help identify individuals at higher risk for post-TB lung disease and elucidate targetable pathways to modify the risk of chronic lung impairment among TB survivors.

Epidemiology of Human Seasonal Coronaviruses Among People With Mild and Severe Acute Respiratory Illness in Blantyre, Malawi, 2011-2017.

BACKGROUND: The aim of this study was to characterize the epidemiology of human seasonal coronaviruses (HCoVs) in southern Malawi. METHODS: We tested for HCoVs 229E, OC43, NL63, and HKU1 using real-time polymerase chain reaction (PCR) on upper respiratory specimens from asymptomatic controls and individuals of all ages recruited through severe acute respiratory illness (SARI) surveillance at Queen Elizabeth Central Hospital, Blantyre, and a prospective influenza-like illness (ILI) observational study between 2011 and 2017. We modeled the probability of having a positive PCR for each HCoV using negative binomial models, and calculated pathogen-attributable fractions (PAFs). RESULTS: Overall, 8.8% (539/6107) of specimens were positive for ≥1 HCoV. OC43 was the most frequently detected HCoV (3.1% [191/6107]). NL63 was more frequently detected in ILI patients (adjusted incidence rate ratio [aIRR], 9.60 [95% confidence interval {CI}, 3.25-28.30]), while 229E (aIRR, 8.99 [95% CI, 1.81-44.70]) was more frequent in SARI patients than asymptomatic controls. In adults, 229E and OC43 were associated with SARI (PAF, 86.5% and 89.4%, respectively), while NL63 was associated with ILI (PAF, 85.1%). The prevalence of HCoVs was similar between children with SARI and controls. All HCoVs had bimodal peaks but distinct seasonality. CONCLUSIONS: OC43 was the most prevalent HCoV in acute respiratory illness of all ages. Individual HCoVs had distinct seasonality that differed from temperate settings.

Integrated approach to generate artificial samples with low tumor fraction for somatic variant calling benchmarking.

BACKGROUND: High-throughput sequencing (HTS) has become the gold standard approach for variant analysis in cancer research. However, somatic variants may occur at low fractions due to contamination from normal cells or tumor heterogeneity; this poses a significant challenge for standard HTS analysis pipelines. The problem is exacerbated in scenarios with minimal tumor DNA, such as circulating tumor DNA in plasma. Assessing sensitivity and detection of HTS approaches in such cases is paramount, but time-consuming and expensive: specialized experimental protocols and a sufficient quantity of samples are required for processing and analysis. To overcome these limitations, we propose a new computational approach specifically designed for the generation of artificial datasets suitable for this task, simulating ultra-deep targeted sequencing data with low-fraction variants and demonstrating their effectiveness in benchmarking low-fraction variant calling. RESULTS: Our approach enables the generation of artificial raw reads that mimic real data without relying on pre-existing data by using NEAT, a fine-grained read simulator that generates artificial datasets using models learned from multiple different datasets. Then, it incorporates low-fraction variants to simulate somatic mutations in samples with minimal tumor DNA content. To prove the suitability of the created artificial datasets for low-fraction variant calling benchmarking, we used them as ground truth to evaluate the performance of widely-used variant calling algorithms: they allowed us to define tuned parameter values of major variant callers, considerably improving their detection of very low-fraction variants. CONCLUSIONS: Our findings highlight both the pivotal role of our approach in creating adequate artificial datasets with low tumor fraction, facilitating rapid prototyping and benchmarking of algorithms for such dataset type, as well as the important need of advancing low-fraction variant calling techniques.

Elevated ITGA1 levels in type 2 diabetes: implications for cardiac function impairment.

AIMS/HYPOTHESIS: Type 2 diabetes mellitus is known to contribute to the development of heart failure with preserved ejection fraction (HFpEF). However, identifying HFpEF in individuals with type 2 diabetes early on is often challenging due to a limited array of biomarkers. This study aims to investigate specific biomarkers associated with the progression of HFpEF in individuals with type 2 diabetes, for the purpose of enabling early detection and more effective management strategies. METHODS: Blood samples were collected from individuals with type 2 diabetes, both with and without HFpEF, for proteomic analysis. Plasma integrin α1 (ITGA1) levels were measured and compared between the two groups. Participants were further categorised based on ITGA1 levels and underwent detailed transthoracic echocardiography at baseline and during a median follow-up period of 30 months. Multivariable linear and Cox regression analyses were conducted separately to assess the associations between plasma ITGA1 levels and changes in echocardiography indicators and re-hospitalisation risk. Additionally, proteomic data for the individuals' left ventricles, from ProteomeXchange database, were analysed to uncover mechanisms underlying the change in ITGA1 levels in HFpEF. RESULTS: Individuals with type 2 diabetes and HFpEF showed significantly higher plasma ITGA1 levels than the individuals with type 2 diabetes without HFpEF. These elevated ITGA1 levels were associated with left ventricular remodelling and impaired diastolic function. Furthermore, during a median follow-up of 30 months, multivariable analysis revealed that elevated ITGA1 levels independently correlated with deterioration of both diastolic and systolic cardiac functions. Additionally, higher baseline plasma ITGA1 levels independently predicted re-hospitalisation risk (HR 2.331 [95% CI 1.387, 3.917], p=0.001). Proteomic analysis of left ventricular myocardial tissue provided insights into the impact of increased ITGA1 levels on cardiac fibrosis-related pathways and the contribution made by these changes to the development and progression of HFpEF. CONCLUSIONS/INTERPRETATION: ITGA1 serves as a biomarker for monitoring cardiac structural and functional damage, can be used to accurately diagnose the presence of HFpEF, and can be used to predict potential deterioration in cardiac structure and function as well as re-hospitalisation for individuals with type 2 diabetes. Its measurement holds promise for facilitating risk stratification and early intervention to mitigate the adverse cardiovascular effects associated with diabetes. DATA AVAILABILITY: The proteomic data of left ventricular myocardial tissue from individuals with type 2 diabetes, encompassing both those with and without HFpEF, is available from the ProteomeXchange database at http://proteomecentral.proteomexchange.org .

HBI-8000 improves heart failure with preserved ejection fraction via the TGF-ß1/MAPK signalling pathway.

Heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of total heart failure patients and is characterized by peripheral circulation, cardiac remodelling and comorbidities (such as advanced age, obesity, hypertension and diabetes) with limited treatment options. Chidamide (HBI-8000) is a domestically produced benzamide-based histone deacetylase isoform-selective inhibitor used for the treatment of relapsed refractory peripheral T-cell lymphomas. Based on our in vivo studies, we propose that HBI-8000 exerts its therapeutic effects by inhibiting myocardial fibrosis and myocardial hypertrophy in HFpEF patients. At the cellular level, we found that HBI-8000 inhibits AngII-induced proliferation and activation of CFs and downregulates the expression of fibrosis-related factors. In addition, we observed that the HFpEF group and AngII stimulation significantly increased the expression of TGF-ß1 as well as phosphorylated p38MAPK, JNK and ERK, whereas the expression of the above factors was significantly reduced after HBI-8000 treatment. Activation of the TGF-ß1/MAPK pathway promotes the development of fibrotic remodelling, and pretreatment with SB203580 (p38MAPK inhibitor) reverses this pathological change. In conclusion, our data suggest that HBI-8000 inhibits fibrosis by modulating the TGF-ß1/MAPK pathway thereby improving HFpEF. Therefore, HBI-8000 may become a new hope for the treatment of HFpEF patients.