Genetic influence on within-person longitudinal change in anthropometric traits in the UK Biobank.

The causes of temporal fluctuations in adult traits are poorly understood. Here, we investigate the genetic determinants of within-person trait variability of 8 repeatedly measured anthropometric traits in 50,117 individuals from the UK Biobank. We found that within-person (non-directional) variability had a SNP-based heritability of 2-5% for height, sitting height, body mass index (BMI) and weight (P ≤ 2.4 × 10-3). We also analysed longitudinal trait change and show a loss of both average height and weight beyond about 70 years of age. A variant tracking the Alzheimer's risk APOE- E 4 allele (rs429358) was significantly associated with weight loss ( ß = -0.047 kg per yr, s.e. 0.007, P = 2.2 × 10-11), and using 2-sample Mendelian Randomisation we detected a relationship consistent with causality between decreased lumbar spine bone mineral density and height loss (bxy = 0.011, s.e. 0.003, P = 3.5 × 10-4). Finally, population-level variance quantitative trait loci (vQTL) were consistent with within-person variability for several traits, indicating an overlap between trait variability assessed at the population or individual level. Our findings help elucidate the genetic influence on trait-change within an individual and highlight disease risks associated with these changes.

Loci on chromosome 20 interact with rs16969968 to influence cigarettes per day in European ancestry individuals.

BACKGROUND: The understanding of the molecular genetic contributions to smoking is largely limited to the additive effects of individual single nucleotide polymorphisms (SNPs), but the underlying genetic risk is likely to also include dominance, epistatic, and gene-environment interactions. METHODS: To begin to address this complexity, we attempted to identify genetic interactions between rs16969968, the most replicated SNP associated with smoking quantity, and all SNPs and genes across the genome. RESULTS: Using the UK Biobank European subsample, we found one SNP, rs1892967, and two genes, PCNA and TMEM230, that showed a significant genome-wide interaction with rs16969968 for log10 CPD and raw CPD, respectively, in a sample of 116 442 individuals who self-reported currently or previously smoking. We extended these analyses to individuals of South Asian descent and meta-analyzed the combined sample of 117 212 individuals of European and South Asian ancestry. We replicated the gene findings in a meta-analysis of five Finnish samples (N=40 140): FinHealth, FINRISK, Finnish Twin Cohort, GeneRISK, and Health-2000-2011. CONCLUSIONS: To our knowledge, this represents the first reliable epistatic association between single nucleotide polymorphisms for smoking behaviors and provides a novel direction for possible future functional studies related to this interaction. Furthermore, this work demonstrates the feasibility of these analyses by pooling multiple datasets across various ancestries, which may be applied to other top SNPs for smoking and/or other phenotypes.

Clostridioides difficile infection across the lifespan: Estimation using life tables.

Using a life tables approach with 2011-2017 claims data, we calculated lifetime risks of Clostridioides difficile infection (CDI) beginning at age 18 years. The lifetime CDI risk rates were 32% in female patients insured by Medicaid, 10% in commercially insured male patients, and almost 40% in females with end-stage renal disease.

In-field detection and characterization of B/Victoria lineage deletion variant viruses causing early influenza activity and an outbreak in Louisiana, 2019.

Background: In 2019, the Louisiana Department of Health reported an early influenza B/Victoria (B/VIC) virus outbreak. Method: As it was an atypically large outbreak, we deployed to Louisiana to investigate it using genomics and a triplex real-time RT-PCR assay to detect three antigenically distinct B/VIC lineage variant viruses. Results: The investigation indicated that B/VIC V1A.3 subclade, containing a three amino acid deletion in the hemagglutinin and known to be antigenically distinct to the B/Colorado/06/2017 vaccine virus, was the most prevalent circulating virus within the specimens evaluated (86/88 in real-time RT-PCR). Conclusion: This work underscores the value of portable platforms for rapid, onsite pathogen characterization.

Targeted amplification and genetic sequencing of the severe acute respiratory syndrome coronavirus 2 surface glycoprotein.

IMPORTANCE: The COVID-19 pandemic was accompanied by an unprecedented surveillance effort. The resulting data were and will continue to be critical for surveillance and control of SARS-CoV-2. However, some genomic surveillance methods experienced challenges as the virus evolved, resulting in incomplete and poor quality data. Complete and quality coverage, especially of the S-gene, is important for supporting the selection of vaccine candidates. As such, we developed a robust method to target the S-gene for amplification and sequencing. By focusing on the S-gene and imposing strict coverage and quality metrics, we hope to increase the quality of surveillance data for this continually evolving gene. Our technique is currently being deployed globally to partner laboratories, and public health representatives from 79 countries have received hands-on training and support. Expanding access to quality surveillance methods will undoubtedly lead to earlier detection of novel variants and better inform vaccine strain selection.

Characterization of the In Vivo Deuteration of Native Phospholipids by Mass Spectrometry Yields Guidelines for Their Regiospecific Customization.

Customization of deuterated biomolecules is vital for many advanced biological experiments including neutron scattering. However, because it is challenging to control the proportion and regiospecificity of deuterium incorporation in live systems, often only two or three synthetic lipids are mixed together to form simplistic model membranes. This limits the applicability and biological accuracy of the results generated with these synthetic membranes. Despite some limited prior examination of deuterating Escherichia coli lipids in vivo, this approach has not been widely implemented. Here, an extensive mass spectrometry-based profiling of E. coli phospholipid deuteration states with several different growth media was performed, and a computational method to describe deuterium distributions with a one-number summary is introduced. The deuteration states of 36 lipid species were quantitatively profiled in 15 different growth conditions, and tandem mass spectrometry was used to reveal deuterium localization. Regressions were employed to enable the prediction of lipid deuteration for untested conditions. Small-angle neutron scattering was performed on select deuterated lipid samples, which validated the deuteration states calculated from the mass spectral data. Based on these experiments, guidelines for the design of specifically deuterated phospholipids are described. This unlocks even greater capabilities from neutron-based techniques, enabling experiments that were formerly impossible.

Non-random Mating Patterns in Education, Mental, and Somatic Health: A Population Study on Within- and Cross-Trait Associations.

Partners resemble each other on many traits, such as health and education. The traits are usually studied one by one in data from established couples and with potential participation bias. We studied all Norwegian parents who had their first child between 2016 and 2020 (N=187,926) and the siblings of these parents. We analysed grade point averages (GPA), educational attainment (EA), and medical records with prospective diagnostic data on 10 mental and 10 somatic health conditions measured 10 to 5 years before childbirth. We found stronger partner similarity in mental (median r=0.14) than in somatic health conditions (median r=0.04), with ubiquitous cross-trait correlations for mental health conditions (median r=0.13). GPA correlated 0.43 and EA 0.47 between partners. High GPA or EA was associated with better mental (median r=-0.16) and somatic (median r=-0.08) health in partners. Elevated correlations for mental health (median r=0.25) in established couples indicated convergence. Analyses of data on siblings and in-laws revealed deviations from direct assortment, suggesting instead indirect assortment based on related traits. GPA and EA accounted for 30-40% of the partner correlations in health. This has implications for the distribution of risk factors among children and for studies of intergenerational transmission.

Recurrence of Metastatic Crohn's Disease after Surgical Resection.

A 36-year-old woman presented to the emergency department with a 1-day history of purulent perianal and vulvar discharge. She had a 25-year history of Crohn's disease (CD), and 13 years prior had received a total colectomy with end ileostomy. She had vulvar biopsies 5 years prior to presentation, demonstrating noncaseating granulomas consistent with metastatic Crohn's disease (MCD). Throughout the course of her disease, she had a failed treatment with adalimumab, certolizumab, methotrexate, and 6-mercaptopurine. She had received a radical vulvectomy 1 year prior to presenting to control recurrent vulvar abscesses and MCD while receiving monthly subcutaneous infliximab 10 mg/kg body weight. Dermatology was consulted at presentation, and the physical examination revealed tender, linear ulcerations with a granulated appearance and depigmentation on the natal cleft and vulva (Figures 1 and 2). Computerized tomography (CT) scan of the abdomen and pelvis indicated thickening of soft tissue without evidence of abscesses, fluid collection, or fistulae. Given the distribution and morphology of lesions with a history of biopsy-proven MCD, the patient was diagnosed with a flare of MCD.

The challenges of sociogenomics make it more, not less, worthy of careful and innovative investigation.

Influences on social traits involve a tangled interplay of genetic, social, and environmental factors. Moreover, there is increasing awareness that gene-environment correlations are real and potentially measurable. Such gene-environment correlations can mislead if they are uncontrolled and genetic associations are interpreted as being purely because of direct genetic effects. This complexity is cause for more and better investigation, not a reason to refrain from researching one of the potentially important factors (genetics) influencing trait variation.

Increased Incidence and Risk of Septicemia and Urinary Tract Infection After Clostridioides difficile Infection.

Background: Although increased occurrence of septicemia in persons with Clostridioides difficile infection (CDI) has been reported, incidence rates and risk of septicemia and urinary tract infection (UTI) after CDI are unclear. Methods: The first episode of CDI was identified using 2011-2017 MarketScan and CMS Medicare data and CDI cases categorized by standard surveillance definitions. Uninfected persons were frequency matched 4:1 to cases by the CDI case surveillance definition. Multivariable Cox proportional hazards models were used to identify risk factors for septicemia and UTI within 90 days of CDI onset, accounting for the competing risk of death in the Medicare population. Results: The incidence of septicemia was highest after hospital-onset CDI in the Medicare, younger commercial, and younger Medicaid populations (25.5%, 15.7%, and 19.5%, respectively) and lowest in those with community-associated CDI (3.8%, 4.3%, and 8.3%, respectively). In contrast, the incidence of UTI was highest in those with other healthcare facility onset CDI in all 3 populations (32.1%, 24.2%, and 18.1%, respectively). Hospital-onset CDI was associated with highest risk of septicemia compared with uninfected controls in all 3 populations. In the younger populations, risk of septicemia was more uniform across the CDI surveillance definitions. The risk of UTI was significantly higher in all CDI surveillance categories compared to uninfected controls, and among CDI cases it was lowest in those with community-associated CDI. Conclusions: The incidence of septicemia is high after CDI, particularly after hospital-onset infection. Additional preventive measures are needed to reduce infectious complications of CDI.

Evidence of correlations between human partners based on systematic reviews and meta-analyses of 22 traits and UK Biobank analysis of 133 traits.

Positive correlations between mates can increase trait variation and prevalence, as well as bias estimates from genetically informed study designs. While past studies of similarity between human mating partners have largely found evidence of positive correlations, to our knowledge, no formal meta-analysis has examined human partner correlations across multiple categories of traits. Thus, we conducted systematic reviews and random-effects meta-analyses of human male-female partner correlations across 22 traits commonly studied by psychologists, economists, sociologists, anthropologists, epidemiologists and geneticists. Using ScienceDirect, PubMed and Google Scholar, we incorporated 480 partner correlations from 199 peer-reviewed studies of co-parents, engaged pairs, married pairs and/or cohabitating pairs that were published on or before 16 August 2022. We also calculated 133 trait correlations using up to 79,074 male-female couples in the UK Biobank (UKB). Estimates of the 22 mean meta-analysed correlations ranged from rmeta = 0.08 (adjusted 95% CI = 0.03, 0.13) for extraversion to rmeta = 0.58 (adjusted 95% CI = 0.50, 0.64) for political values, with funnel plots showing little evidence of publication bias across traits. The 133 UKB correlations ranged from rUKB = -0.18 (adjusted 95% CI = -0.20, -0.16) for chronotype (being a 'morning' or 'evening' person) to rUKB = 0.87 (adjusted 95% CI = 0.86, 0.87) for birth year. Across analyses, political and religious attitudes, educational attainment and some substance use traits showed the highest correlations, while psychological (that is, psychiatric/personality) and anthropometric traits generally yielded lower but positive correlations. We observed high levels of between-sample heterogeneity for most meta-analysed traits, probably because of both systematic differences between samples and true differences in partner correlations across populations.

Healthcare Costs of Clostridioides difficile Infection in Commercially Insured Younger Adults.

In a US adult population aged <65 years, attributable costs due to Clostridioides difficile infection (CDI) were highest in persons with hospital onset and lowest in those with community-associated CDI treated outside a hospital. The economic burden of CDI in younger adults underscores the need for additional CDI-preventive strategies.

Manipulating Fermentation Pathways in the Hyperthermophilic Archaeon Pyrococcus furiosus for Ethanol Production up to 95°C Driven by Carbon Monoxide Oxidation.

Genetic engineering of hyperthermophilic organisms for the production of fuels and other useful chemicals is an emerging biotechnological opportunity. In particular, for volatile organic compounds such as ethanol, fermentation at high temperatures could allow for straightforward separation by direct distillation. Currently, the upper growth temperature limit for native ethanol producers is 72°C in the bacterium Thermoanaerobacter ethanolicus JW200, and the highest temperature for heterologously-engineered bioethanol production was recently demonstrated at 85°C in the archaeon Pyrococcus furiosus. Here, we describe an engineered strain of P. furiosus that synthesizes ethanol at 95°C, utilizing a homologously-expressed native alcohol dehydrogenase, termed AdhF. Ethanol biosynthesis was compared at 75°C and 95°C with various engineered strains. At lower temperatures, the acetaldehyde substrate for AdhF is most likely produced from acetate by aldehyde ferredoxin oxidoreductase (AOR). At higher temperatures, the effect of AOR on ethanol production is negligible, suggesting that acetaldehyde is produced by pyruvate ferredoxin oxidoreductase (POR) via oxidative decarboxylation of pyruvate, a reaction known to occur only at higher temperatures. Heterologous expression of a carbon monoxide dehydrogenase complex in the AdhF overexpression strain enabled it to use CO as a source of energy, leading to increased ethanol production. A genome reconstruction model for P. furiosus was developed to guide metabolic engineering strategies and understand outcomes. This work opens the door to the potential for 'bioreactive distillation' since fermentation can be performed well above the normal boiling point of ethanol. IMPORTANCE Previously, the highest temperature for biological ethanol production was 85°C. Here, we have engineered ethanol production at 95°C by the hyperthermophilic archaeon Pyrococcus furiosus. Using mutant strains, we showed that ethanol production occurs by different pathways at 75°C and 95°C. In addition, by heterologous expression of a carbon monoxide dehydrogenase complex, ethanol production by this organism was driven by the oxidation of carbon monoxide. A genome reconstruction model for P. furiosus was developed to guide metabolic engineering strategies and understand outcomes.

Declining autozygosity over time: An exploration in over 1 million individuals from three diverse cohorts.

Previous studies have hypothesized that autozygosity is decreasing over generational time. However, these studies were limited to relatively small samples (n < 11,000) lacking in diversity, which may limit the generalizability of their findings. We present data that partially support this hypothesis from three large cohorts of diverse ancestries, two from the US (All of Us, n = 82,474; the Million Veteran Program, n = 622,497) and one from the UK (UK Biobank, n = 380,899). Our results from a mixed-effect meta-analysis demonstrate an overall trend of decreasing autozygosity over generational time (meta-analyzed slope = -0.029, SE = 0.009, p = 6.03e-4). On the basis of our estimates, we would predict FROH to decline 0.29% for every 20-year increase in birth year. We determined that a model including an ancestry-by-country interaction term fit the data best, indicating that ancestry differences in this trend differ by country. We found further evidence to suggest a difference between the US and UK cohorts by meta-analyzing within country, observing a significant negative estimate in the US cohorts (meta-analyzed slope = -0.058, SE = 0.015, p = 1.50e-4) but a non-significant estimate in the UK (meta-analyzed slope = -0.001, SE = 0.008, p = 0.945). The association between autozygosity and birth year was substantially attenuated when accounting for educational attainment and income (meta-analyzed slope = -0.011, SE = 0.008, p = 0.167), suggesting they may partially account for decreasing autozygosity over time. Overall, we demonstrate decreasing autozygosity over time in a large, modern sample and speculate that this trend can be attributed to increases in urbanization and panmixia and differences in sociodemographic processes lead to country-specific differences in the rate of decline.

Genetic risk shared across 24 chronic pain conditions: identification and characterization with genomic structural equation modeling.

ABSTRACT: Chronic pain conditions frequently co-occur, suggesting common risks and paths to prevention and treatment. Previous studies have reported genetic correlations among specific groups of pain conditions and reported genetic risk for within-individual multisite pain counts (≤7). Here, we identified genetic risk for multiple distinct pain disorders across individuals using 24 chronic pain conditions and genomic structural equation modeling (Genomic SEM). First, we ran individual genome-wide association studies (GWASs) on all 24 conditions in the UK Biobank ( N ≤ 436,000) and estimated their pairwise genetic correlations. Then we used these correlations to model their genetic factor structure in Genomic SEM, using both hypothesis- and data-driven exploratory approaches. A complementary network analysis enabled us to visualize these genetic relationships in an unstructured manner. Genomic SEM analysis revealed a general factor explaining most of the shared genetic variance across all pain conditions and a second, more specific factor explaining genetic covariance across musculoskeletal pain conditions. Network analysis revealed a large cluster of conditions and identified arthropathic, back, and neck pain as potential hubs for cross-condition chronic pain. Additionally, we ran GWASs on both factors extracted in Genomic SEM and annotated them functionally. Annotation identified pathways associated with organogenesis, metabolism, transcription, and DNA repair, with overrepresentation of strongly associated genes exclusively in brain tissues. Cross-reference with previous GWASs showed genetic overlap with cognition, mood, and brain structure. These results identify common genetic risks and suggest neurobiological and psychosocial mechanisms that should be targeted to prevent and treat cross-condition chronic pain.

Epidemiology of Intensive Care Admissions for Children in the US From 2001 to 2019.

Importance: Estimates of the number of US children receiving intensive care unit (ICU) care and ICU admission patterns over time are lacking. Objective: To determine how ICU admission patterns, use of critical care services, and the characteristics and outcomes of critically ill children have changed from 2001 to 2019. Design, Setting, and Participants: This population-based retrospective cohort study used data from the Healthcare Cost and Utilization Project's state inpatient databases from a total of 21 US states in 2001, 2004, 2010, 2016, and 2019. Hospitalized children aged 0 to 17 years, excluding newborns (during birth hospitalization), were included. Patients admitted to rehabilitation institutions or psychiatric hospitals were also excluded. Data were analyzed from July 2021 to December 2022. Exposures: Care in a nonneonatal ICU. Main Outcomes and Measures: From extracted patient data, International Classification of Diseases, Ninth Revision, Clinical Modification, and Tenth Revision, Clinical Modification, codes were used to identify diagnoses, comorbid conditions, organ failures, and mechanical ventilation. Generalized linear Poisson regression and the Cuzick test were used to evaluate trends. US Census data were used to generate age- and sex-adjusted national estimates of ICU admissions and costs. Results: Of 2 157 991 pediatric admissions, 275 656 (12.8%) included ICU care. The mean (SD) age was 6.43 (6.10) years; 121 894 individuals were female (44.2%), and 153 731 were male (55.8%). From 2001 to 2019, the prevalence of ICU care among hospitalized children increased from 10.6% to 15.5%. The percentage of ICU admissions in children's hospitals rose from 51.2% to 85.1% (relative risk [RR], 1.66; 95% CI, 1.64-1.68). The percentage of children admitted to an ICU with an underlying comorbidity increased from 46.2% to 57.0% (RR, 1.23; 95% CI, 1.22-1.25), and the percentage with preadmission technology dependence increased from 16.4% to 23.5% (RR, 1.44; 95% CI, 1.40-1.48). The prevalence of multiple organ dysfunction syndrome increased from 6.8% to 21.0% (RR, 3.12; 95% CI, 2.98-3.26), while mortality decreased from 2.5% to 1.8% (RR, 0.72; 95% CI, 0.66-0.79). Hospital length of stay increased by 0.96 days (95% CI, 0.73-1.18) for ICU admissions from 2001 to 2019. After inflation adjustment, total costs for a pediatric admission involving ICU care nearly doubled between 2001 and 2019. Nationally, an estimated 239 000 children were admitted to a US ICU in 2019, corresponding to $11.6 billion in hospital costs. Conclusions and Relevance: In this study, the prevalence of children receiving ICU care in the US increased, as did length of stay, technology use, and associated costs. The US health care system must be equipped to care for these children in the future.

Catastrophic Health Care Expenditure Following Brachial Plexus Injury.

PURPOSE: Brachial plexus injuries (BPIs) are devastating to patients not only functionally but also financially. Like patients experiencing other traumatic injuries and unexpected medical events, patients with BPIs are at risk of catastrophic health expenditure (CHE) in which out-of-pocket health spending exceeds 40% of postsubsistence income (income remaining after food and housing expenses). The individual financial strain after BPIs has not been previously quantified. The purpose of this study was to assess the proportion of patients with BPIs who experience risk of CHE after reconstructive surgery. METHODS: Administrative databases were used from 8 states to identify patients who underwent surgery for BPIs. Demographics including age, sex, race, and insurance payer type were obtained. Inpatient billing records were used to determine the total surgical and inpatient facility costs within 90 days after the initial surgery. Due to data constraints, further analysis was only conducted for privately-insured patients. The proportion of patients with BPIs at risk of CHE was recorded. Predictors of CHE risk were determined from a multivariable regression analysis. RESULTS: Among 681 privately-insured patients undergoing surgery for BPIs, nearly one-third (216 [32%]) were at risk of CHE. Black race and patients aged between 25 and 39 years were significant risk factors associated with CHE. Sex and the number of comorbidities were not associated with risk of CHE. CONCLUSIONS: Nearly one-third of privately-insured patients met the threshold for being at risk of CHE after BPI surgery. CLINICAL RELEVANCE: Identifying those patients at risk of CHE can inform strategies to minimize long-term financial distress after BPIs, including detailed counseling regarding anticipated health care expenditures and efforts to optimize access to appropriate insurance policies for patients with BPIs.