Abstract
Building on previous multicountry surveillance studies of typhoid and others salmonelloses such as the Diseases of the Most Impoverished program and the Typhoid Surveillance in Africa ...Project, several ongoing blood culture surveillance studies are generating important data about incidence, severity, transmission, and clinical features of invasive Salmonella infections in sub-Saharan Africa and South Asia. These studies are also characterizing drug resistance patterns in their respective study sites. Each study answers a different set of research questions and employs slightly different methodologies, and the geographies under surveillance differ in size, population density, physician practices, access to healthcare facilities, and access to microbiologically safe water and improved sanitation. These differences in part reflect the heterogeneity of the epidemiology of invasive salmonellosis globally, and thus enable generation of data that are useful to policymakers in decision-making for the introduction of typhoid conjugate vaccines (TCVs). Moreover, each study is evaluating the large-scale deployment of TCVs, and may ultimately be used to assess post-introduction vaccine impact. The data generated by these studies will also be used to refine global disease burden estimates. It is important to ensure that lessons learned from these studies not only inform vaccination policy, but also are incorporated into sustainable, low-cost, integrated vaccine-preventable disease surveillance systems.
Look AHEAD, a randomized trial comparing intensive lifestyle intervention (ILI) and diabetes support and education (DSE) (control) in 5,145 individuals with overweight/obesity and type 2 diabetes, ...found no significant differences in all-cause or cardiovascular mortality or morbidity during 9.6 (median) years of intervention. Participants in ILI who lost ≥10% at 1 year had lower risk of composite cardiovascular outcomes relative to DSE. Since effects of ILI may take many years to emerge, we conducted intent-to-treat analyses comparing mortality in ILI over 16.7 years (9.6 years of intervention and then observation) to DSE. In a secondary exploratory analysis, we compared mortality by magnitude of weight loss in ILI relative to DSE.
Primary outcome was all-cause mortality from randomization to 16.7 years. Other outcomes included cause-specific mortality, interactions by subgroups (age, sex, race/ethnicity, and cardiovascular disease history), and an exploratory analysis by magnitude of weight loss in ILI versus DSE as reference. Analyses used proportional hazards regression and likelihood ratio.
The incidence of all-cause mortality did not differ significantly in ILI and DSE (549 and 589 participants, respectively) (hazard ratio HR 0.91 95% CI 0.81, 1.02; P = 0.11). There were no significant differences between treatments in cause-specific mortality or within prespecified subgroups. ILI participants who lost ≥10% at 1 year had a 21% reduced risk of mortality (HR 0.79 95% CI 0.67, 0.94; P = 0.007) relative to DSE.
ILI focused on weight loss did not significantly affect mortality risk. However, ILI participants who lost ≥10% had reduced mortality relative to DSE.
Lung cancer screening via annual low-dose computed tomography (LDCT) has poor adoption. We conducted a prospective case-control study among 958 individuals eligible for lung cancer screening to ...develop a blood-based lung cancer detection test that when positive is followed by an LDCT. Changes in genome-wide cell-free DNA (cfDNA) fragmentation profiles (fragmentomes) in peripheral blood reflected genomic and chromatin characteristics of lung cancer. We applied machine learning to fragmentome features to identify individuals who were more or less likely to have lung cancer. We trained the classifier using 576 cases and controls from study samples, and then validated it in a held-out group of 382 cases and controls. The validation demonstrated high sensitivity for lung cancer, and consistency across demographic groups and comorbid conditions. Applying test performance to the screening eligible population in a five-year model with modest utilization assumptions suggested the potential to prevent thousands of lung cancer deaths.
IMPORTANCE: Intravenous magnesium sulfate administered to pregnant individuals before birth at less than 30 weeks’ gestation reduces the risk of death and cerebral palsy in their children. The ...effects at later gestational ages are unclear. OBJECTIVE: To determine whether administration of magnesium sulfate at 30 to 34 weeks’ gestation reduces death or cerebral palsy at 2 years. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial enrolled pregnant individuals expected to deliver at 30 to 34 weeks’ gestation and was conducted at 24 Australian and New Zealand hospitals between January 2012 and April 2018. INTERVENTION: Intravenous magnesium sulfate (4 g) was compared with placebo. MAIN OUTCOMES AND MEASURES: The primary outcome was death (stillbirth, death of a live-born infant before hospital discharge, or death after hospital discharge before 2 years’ corrected age) or cerebral palsy (loss of motor function and abnormalities of muscle tone and power assessed by a pediatrician) at 2 years’ corrected age. There were 36 secondary outcomes that assessed the health of the pregnant individual, infant, and child. RESULTS: Of the 1433 pregnant individuals enrolled (mean age, 30.6 SD, 6.6 years; 46 3.2% self-identified as Aboriginal or Torres Strait Islander, 237 16.5% as Asian, 82 5.7% as Māori, 61 4.3% as Pacific, and 966 67.4% as White) and their 1679 infants, 1365 (81%) offspring (691 in the magnesium group and 674 in the placebo group) were included in the primary outcome analysis. Death or cerebral palsy at 2 years’ corrected age was not significantly different between the magnesium and placebo groups (3.3% 23 of 691 children vs 2.7% 18 of 674 children, respectively; risk difference, 0.61% 95% CI, −1.27% to 2.50%; adjusted relative risk RR, 1.19 95% CI, 0.65 to 2.18). Components of the primary outcome did not differ between groups. Neonates in the magnesium group were less likely to have respiratory distress syndrome vs the placebo group (34% 294 of 858 vs 41% 334 of 821, respectively; adjusted RR, 0.85 95% CI, 0.76 to 0.95) and chronic lung disease (5.6% 48 of 858 vs 8.2% 67 of 821; adjusted RR, 0.69 95% CI, 0.48 to 0.99) during the birth hospitalization. No serious adverse events occurred; however, adverse events were more likely in pregnant individuals who received magnesium vs placebo (77% 531 of 690 vs 20% 136 of 667, respectively; adjusted RR, 3.76 95% CI, 3.22 to 4.39). Fewer pregnant individuals in the magnesium group had a cesarean delivery vs the placebo group (56% 406 of 729 vs 61% 427 of 704, respectively; adjusted RR, 0.91 95% CI, 0.84 to 0.99), although more in the magnesium group had a major postpartum hemorrhage (3.4% 25 of 729 vs 1.7% 12 of 704 in the placebo group; adjusted RR, 1.98 95% CI, 1.01 to 3.91). CONCLUSIONS AND RELEVANCE: Administration of intravenous magnesium sulfate prior to preterm birth at 30 to 34 weeks’ gestation did not improve child survival free of cerebral palsy at 2 years, although the study had limited power to detect small between-group differences. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12611000491965
The canonical paradigm for converting genetic association to mechanism involves iteratively mapping individual associations to the proximal genes through which they act. In contrast, in the present ...study we demonstrate the feasibility of extracting biological insights from a very large region of the genome and leverage this strategy to study the genetic influences on autism. Using a new statistical approach, we identified the 33-Mb p-arm of chromosome 16 (16p) as harboring the greatest excess of autism's common polygenic influences. The region also includes the mechanistically cryptic and autism-associated 16p11.2 copy number variant. Analysis of RNA-sequencing data revealed that both the common polygenic influences within 16p and the 16p11.2 deletion were associated with decreased average gene expression across 16p. The transcriptional effects of the rare deletion and diffuse common variation were correlated at the level of individual genes and analysis of Hi-C data revealed patterns of chromatin contact that may explain this transcriptional convergence. These results reflect a new approach for extracting biological insight from genetic association data and suggest convergence of common and rare genetic influences on autism at 16p.
Frailty is common in older adults with obesity and diabetes. We compared prevalence of the frailty phenotype between intervention groups in long-term follow-up of Look AHEAD, a randomized trial ...comparing a multidomain intensive lifestyle intervention (ILI) that promoted weight loss and physical activity with a diabetes support and education (DSE) control group in adults with type 2 diabetes and overweight or obesity.
Participants included 2,979 individuals randomized to ILI or DSE in 2001-04 who completed frailty assessment in Look AHEAD - Extension Wave 1 (2016-2018) at average age of 72.1 ± 6.2 years. Frailty was assessed using a modified frailty phenotype (excluding weight loss) defined as the presence of 3 or more of: weakness, slow gait speed, low physical activity, and exhaustion. Frailty odds by intervention assignment (DSE vs. ILI) were estimated using multivariable logistic regression, adjusting for sex, clinic site, and time since randomization.
At median follow-up of 14.0 years IQR: 13.8-14.1, frailty prevalence was 10.9% in ILI compared with 11.6% in DSE (odds ratio for frailty in ILI vs. DSE =0.94, 95% confidence interval = 0.75-1.18, P =0.60). Frailty was more prevalent in participants who were older, female, non-white, of lower socioeconomic status, and at baseline had a higher BMI and waist circumference, longer duration of diabetes, history of CVD, and metabolic syndrome.
Prior randomization to ILI compared with DSE was not associated with a lower prevalence of frailty after a median follow-up of 14.0 years in adults with diabetes and overweight or obesity.
Background
There are important sex differences in Alzheimer’s disease (AD) including two‐fold higher prevalence and stronger association of the apolipoprotien‐ε e4 allele (APOE4) with AD risk in ...women versus men. Given the central role of sex hormones in brain structure/function, examining factors influencing lifetime exposure to sex hormones is critical to understanding sex differences in AD. Menopause is characterized by a marked reduction in ovarian hormones, leading to loss of sex hormone‐related neuroprotective effects and AD‐like changes in brain bioenergetics. Earlier age at menopause is associated with higher AD risk; however, the brain mechanisms by which menopausal age contributes to AD etiology and the role of APOE4 in this association are unclear. Among non‐demented, older female participants of the Wisconsin Registry for Alzheimer’s Prevention (WRAP) cohort, we examined the associations of age at menopause with later‐life hippocampal and whole brain volumes and the moderating role of APOE4 in these associations.
Method
177 postmenopausal women ≥ 60 years of age (age range:60–76, age mean=65.8, 96% White) with MRI volumetric data and APOE4 genotype data were examined. Multivariable linear regressions were used to examine associations of self‐reported age at menopause and its interaction with APOE4 carrier status with hippocampal and whole‐brain volumes. Models were adjusted for intracranial volume, MRI scanner, age, education, BMI at MRI, smoking, age at menarche, number of pregnancies, natural versus surgical menopause and ever‐use of hormone therapy or hormonal contraception.
Result
A significant age at menopause × APOE4 interaction on hippocampal volume (p=.05) revealed that earlier age at menopause related to smaller hippocampal volume (p=.016) among APOE4 carriers but not non‐carriers (p=.86; Figure 1). Age at menopause did not relate to whole brain volume regardless of APOE4 status. In the multivariable model, older age, less education and smaller intracranial volume also related to smaller hippocampal volume.
Conclusion
Results suggest that early menopause may be a risk factor for neurodegeneration among APOE4 carriers particularly in the AD‐sensitive hippocampus. The specificity of this relationship to APOE4 carriers indicates mechanistic interactions between APOE4 and sex hormones and offers a potential contributing factor to the more adverse effect of APOE4 in women.
Thank You to Our 2021 Peer Reviewers Rajaram, Harihar; Camargo, Suzana; Cappa, Christopher D. ...
Geophysical research letters,
16 May 2022, Letnik:
49, Številka:
9
Journal Article
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