Population-level Data Research Articles

Population based assessment of HER-2 and PD-L1 positivity in gastric and gastroesophageal junction adenocarcinomas in a Canadian population.

e16038 Background: Current standard of care for advanced gastric and gastroesophageal cancers combines systemic chemotherapy with either human epidermal growth factor receptor 2 (HER-2) or programmed death ligand 1 (PD-L1) targeting therapy. New data is emerging that for patients whose tumours are positive for both HER-2 overexpression and have a PD-L1 combined positive score (CPS) >1%, combining all three treatment modalities results in superior outcomes. There is limited international data, and no Canadian data, exploring the frequency of patients who have tumours that are both HER-2 and PD-L1 positive who will be eligible for this novel treatment approach. Objective: To determine the proportion of patients in Nova Scotia with HER-2 positive gastric and GEJ adenocarcinomas who have a PD-L1 CPS score above established clinical thresholds. Methods: A retrospective review of PD-L1 and HER-2 status for all patients diagnosed with gastric and GEJ adenocarcinomas in Nova Scotia between June 3, 2022 and August 13, 2023 was completed. PD-L1 CPS was evaluated using the 28-8 assay and was considered positive if >1%. HER-2 overexpression was evaluated by immunohistochemistry and in cases with equivocal expression, status was based on fluorescence in situ hybridization. Results: Over the study period, 56 cases of gastric and 42 cases of GEJ adenocarcinoma were identified for a total of 98 cases. The median age of the study population was 73 years (range 38 - 91). 73 patients (74%) were male and 25 patients (26%) were female. HER-2 expression was evaluated in 92 cases, and PD-L1 CPS was evaluated in 95 cases. 19 cases (21%) were HER-2 positive and 86 cases (91%) were PD-L1 positive. 17 HER-2 positive cases were also PD-L1 positive (89%). Conclusions: This study provides population level data in a Canadian context on patients with gastric and GEJ adenocarcinoma with respect to HER-2 overexpression and PD-L1 status. This data will be helpful in planning allocation of clinical and financial resources as a new standard of care for these patients is established.

Comparing the characteristics and outcomes of hospitalizations between cancer and non-cancer survivors.

12138 Background: Cancer prevalence is rising, with a corresponding increase in hospitalizations across the cancer continuum. However, little is known about how in-hospital patterns of care and outcomes of cancer survivors compare with non-cancer survivors as administrative data may not capture in-hospital details (e.g., investigations and medications) required for characterization. Understanding differences in how cancer and non-cancer inpatients are managed and their outcomes can help optimize their acute care delivery. Methods: In a multicenter registry of all patients (pts) admitted to medical wards across 26 hospitals (Ontario, Canada) from 2015-2022, we deterministically linked population-level administrative data, including ambulatory oncology data for cancer survivors, with each hospital’s electronic information (pharmacy, orders, notes, laboratory, imaging) at the patient level. Multivariable regression models compared resource use and outcomes between cancer and non-cancer pts for the top 5 discharge diagnoses among non-cancer pts. Results: Of 1,221,067 hospitalizations belonging to 666,569 pts, 30% of medical ward hospitalizations were for pts with a cancer history, with median admission date 4 years post-diagnosis; most common cancer sites were genitourinary (21%), gastrointestinal (20%), breast (12%), lung (10%). Most common discharge diagnoses among cancer pts were heart failure (HF) (5%), palliative care (5%), urinary tract infection (UTI) (2%), pneumonia (2%) renal failure (2%); while for non-cancer pts were HF (5%), myocardial infarction (3%), coronary artery disease (3%), COPD (2%) and UTI (2%). Compared to non-cancer pts, cancer pts were older (72 vs 66), had greater length of stay (LOS; 10 vs 8.7 days), in-hospital mortality (11% vs 6%) and 30 day re-admission rates (16% vs 11%) and were more likely to receive CTs (21% vs 15%), MRIs (9% vs 8%) and interventional procedures (6% vs 4%) (p < 0.001, all comparisons). When evaluating the top 5 discharge diagnoses among non-cancer patients, cancer survivors had higher LOS (aOR=1.06 95% [1.05-1.07] p<0.001), in-hospital mortality (aOR=1.20 [1.14-1.26] p<0.001), and 30 day re-admission rates (aOR=1.24 [1.14-1.35] p<0.001) and were more likely to receive CTs (aOR=1.25 [1.21-1.30] p<0.001), MRIs (aOR=1.36 [1.25-1.48] p<0.001) and interventional procedures (aOR=1.36 [1.25-1.47] p<0.001). Subgroup analyses focusing on cancer survivors admitted 3 and 5 years out from their diagnosis showed resource use and outcomes were closer to non-cancer patients. Conclusions: Cancer survivors represent a unique population on medical wards and have higher resource use, mortality and LOS compared to non-cancer patients, even for the same non-cancer diagnoses. Specialized models of care for hospitalized cancer survivors may be warranted, in particular for those admitted closer to their diagnosis date.

Substance use among individuals with cancer: A US population-based cohort study.

e23133 Background: The prevalence of concurrent substance use or comorbid substance use disorder (SUD) among individuals with a cancer diagnosis, and their participation in substance use treatment, has not yet been described in a large US population-based cohort. Methods: A population-based cohort study was conducted using cross-sectional survey data collected by the National Survey on Drug Use & Health (NSDUH) between 2015-2022. Descriptive statistics were calculated to describe two populations: those with any kind of cancer diagnosis within the preceding 12 months and either comorbid SUD as defined by the Diagnostic and Statistical Manual of Mental Illness (DSM)-5 or concurrent use of any of the following substances: alcohol, marijuana, cocaine, crack, heroin, methamphetamines, or misuse of prescription drugs. Chi-square tests were conducted to describe associations with the demographic and geographic characteristics of these individuals. Results: Between 2015-2022, 432,764 individuals (53% female) completed the survey. A total of 2,547 respondents had a cancer diagnosis in the preceding 12 months; the most common cancer types were breast cancer (17.0%), non-melanoma skin cancers (16.2%), and prostate or testicular cancer (11.0%). Among this cohort, 1,664 (65%) reported concurrent alcohol use, 354 (14%) reported marijuana use, and 82 (3%) reported illicit use of other substances. Among those with an active cancer diagnosis in the preceding 12 months, 103 (4%) met DSM-5 criteria for a comorbid SUD based on survey responses. Among individuals with a past-year cancer diagnosis, there was a statistically significant association between concurrent substance use and income bracket (X2 = 92.67, p < 0.001), concurrent substance use and race (X2=46.12, p< 0.001), and between concurrent substance use and population density (X2= 7.05, p = 0.029). Zero respondents with cancer and either concurrent substance use or comorbid SUD received outpatient treatment for substance use in the preceding year, three (0.002%) received inpatient treatment, and seven (0.004%) participated in a support group. Among respondents with comorbid SUD, many reported being recently asked by a healthcare professional about their alcohol (83%) or drug use (67%), while only 1.9% reported recently receiving information from a healthcare professional about substance use treatment. Conclusions: There is overlap between the population with a cancer diagnosis and that with concurrent substance use or comorbid SUD. Based on population-level survey data, these individuals have low rates of participation in outpatient or inpatient substance treatment, and report that they do not often receive information about substance use treatment from healthcare professionals. Describing this population may inform how providers approach their unique healthcare needs.

Improving rates of immunisation in refugee populations in Australia.

Despite an established humanitarian program running for many years, the health needs of refugees resettled in Australia, particularly immunisation, have not been met adequately. Under-immunisation is one of the top health issues for this population. While there is no population-level immunisation coverage data, seroprevalence studies based on small cohorts of refugees show suboptimal immunity to various vaccine-preventable diseases and lower vaccine coverage for this group than the general population. This is compounded by gaps in immunisation policy and service delivery that further perpetuate access issues and may contribute to under-immunisation. This is particularly pertinent against the backdrop of the coronavirus disease 2019 (COVID-19) pandemic, where there have been significant disruptions in the delivery of routine and catch-up immunisations. This paper briefly analyses the status quo and draws on the key policy considerations for enhancing the equitable provision of immunisation for refugees as recommended by the 2019 World Health Organisation technical guidance report to provide a clear, overarching direction for empirical work on immunisation service delivery for refugees in Australia.

KRAS mutations and their prognostic implications in appendiceal cancers.

4177 Background: Despite shared embryonic origin, appendiceal cancers (AC) have distinct clinical and molecular features compared to colorectal cancers (CRC). Detection of mutant KRAS has been associated with worse survival in CRC, whereas in AC the prognostic significance of mutant KRAS (55-65% prevalence) has yet to be characterized. Methods: AC tissues from 852 individual patients that underwent DNA (592, NextSeq, or whole exome sequencing) and whole transcriptome sequencing (NovaSeq) at Caris Life Sciences (Phoenix, AZ) were analyzed. Low-grade appendiceal mucinous neoplasms were excluded. Chi-square, Fishers-exact, and Mann Whitney U tests were used to determine statistical significance and were adjusted for multiple hypothesis testing (p< 0.05). Real-world overall survival (OS) was calculated using insurance claims of AC patients from time of sample collection to last contact. Hazard ratios (HRs) were calculated using the Cox proportional hazards model (log-rank test). Multivariate regression analysis was performed on age, sex, histology, site, comutations and KRASmut vs. KRASwt. Results: AC histological subtypes comprised mucinous adenocarcinoma (37.9%), goblet cell carcinoma (19.6%), signet ring cell carcinoma (12.1%), and adenocarcinoma- not otherwise specified (NOS, 30.4%). Among all AC specimens, KRAS was the most common mutation (49%). KRASmut vs. KRASwt tumors were more frequently associated with TP53mut (51.2% vs. 36.8%, respectively; p< 0.01) and GNASmut (41.1% vs. 5.7%, respectively; p < 0.00001). Most frequent co-mutant gene with KRAS was TP53 (61.2%) in adenocarcinoma-NOS, and GNAS (46.9%) in mucinous adenocarcinomas.Median OS among KRASmut vs. KRASwt was 33.3 vs. 25.1 months, respectively (HR 0.68, 95% CI: 0.58-0.80, p < 0.00001). KRASmut was associated with improved survival in mucinous adenocarcinomas (HR 0.71; 95% CI: 0.52-0.96, p = 0.028) and adenocarcinoma-NOS (HR 0.77; 95% CI: 0.62-0.97, p = 0.025), but not with signet ring cell (HR 1.92; 95% CI: 0.90-4.10, p = 0.087) or goblet cell carcinoma (HR 1.39; 95% CI: 0.50-3.91, p = 0.536). Multivariate analysis showed KRASmut was an independent prognostic factor for improved survival among all AC (HR 0.77, 95% CI: 0.64-0.93, p = 0.007) and mucinous adenocarcinoma (HR 0.60, 95% CI: 0.42-0.84, p<0.0001).Notably, GNASmut was associated with improved survival (HR 0.57, 95% CI: 0.47-0.70, p < 0.00001), while TP53mut was associated with poorer survival (HR 1.58, 95% CI: 1.35-1.86, p < 0.00001) among all AC. Conclusions: KRAS was one of most frequently mutated genes in ACs. In contrast to CRC, KRASmut was associated with significantly improved survival. This observed survival advantage remained consistent in the histologic subgroup of mucinous adenocarcinoma, but not in goblet and signet ring cell cancers. Further studies with population level data understanding the molecular profiles and their survival implications in histologically distinct AC are needed.

Identifying subtypes of type 2 diabetes mellitus with machine learning: development, internal validation, prognostic validation and medication burden in linked electronic health records in 420 448 individuals

IntroductionNone of the studies of type 2 diabetes (T2D) subtyping to date have used linked population-level data for incident and prevalent T2D, incorporating a diverse set of variables, explainable methods...

Identifying states for targeted alloHCT access initiatives using social vulnerability, physician density, and unmet need.

1528 Background: Access to allogeneic hematopoietic cell transplantation (alloHCT) is limited by many factors, with only 1 in 3 patients who may need a transplant receiving one. This study examined associations between social vulnerability index (SVI), physician density (PD), and alloHCT unmet need across the United States (U.S.) to identify geographic areas that may be most at-risk of access challenges. Methods: A retrospective analysis aggregated public data across 3,141 U.S. counties, including: SVI [Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry]; National Provider Identifier [Center for Medicare and Medicaid Services] data for all registered hematology-oncology and HCT physicians; and 2017 – 2021 alloHCT unmet need [Center for International Blood and Marrow Transplant Research (CIBMTR), NMDP]. PD was defined as providers per 10,000 population. All variables were collapsed into ordinal categories (very low, low, moderate, high) based on quartiles. Counties with moderate/high SVI and unmet need and low/very low PD were defined as at-risk. By state, linear regression and mediation analysis assessed exploratory relationships. Results: Among 396 counties defined as at-risk, top states are shown (Table). State (n=51) percent unmet need was correlated with SVI (r=0.494, p<0.001) and PD (r=-0.295, p=0.036). Univariate analysis revealed SVI (b=-0.223, p<0.001) and PD (b=-0.187, p=0.036) as predictors of unmet need. However, multivariate regression showed only SVI as significant when included with PD. Race/ethnicity as 1 of 4 SVI subthemes (socioeconomic status [SES], household characteristics [including age], race/ethnicity, and housing/transportation) was not correlated with PD, but all other themes were. SES and household characteristics were found to fully mediate the relationship between PD and unmet need. Conclusions: This study can help prioritize targeted initiatives through a better understanding of how SVI, PD, and unmet need relate to alloHCT access. This study cannot draw causal conclusions and uses multiple population-level data sources. However, data can examine trends on a regional level within at-risk states to allocate resources to overcome barriers to alloHCT, with special attention on SES and household factors like age. Relationships between variables should be further examined. [Table: see text]

Children and young people's body mass index measures derived from routine data sources: A national data linkage study in Wales.

Routine monitoring of Body Mass Index (BMI) in general practice, and via national surveillance programmes, is essential for the identification, prevention, and management of unhealthy childhood weight. We examined and compared the presence and representativeness of children and young people's (CYPs) BMI recorded in two routinely collected administrative datasets: general practice electronic health records (GP-BMI) and the Child Measurement Programme for Wales (CMP-BMI), which measures height and weight in 4-5-year-old school children. We also assessed the feasibility of combining GP-BMI and CMP-BMI data for longitudinal analyses. We accessed de-identified population-level GP-BMI data for calendar years 2011 to 2019 for 246,817 CYP, and CMP-BMI measures for 222,772 CYP, held within the Secure Anonymised Information Linkage Databank. We examined the proportion of CYP in Wales with at least one GP-BMI record, its distribution by child socio-demographic characteristics, and trends over time. We compared GP-BMI and CMP-BMI distributions. We quantified the proportion of children with a CMP-BMI measure and a follow-up GP-BMI recorded at an older age and explored the representativeness of these measures. We identified a GP-BMI record in 246,817 (41%) CYP, present in a higher proportion of females (54.2%), infants (20.7%) and adolescents. There was no difference in the deprivation profile of those with a GP-BMI measurement. 31,521 CYP with a CMP-BMI had at least one follow-up GP-BMI; those with a CMP-BMI considered underweight or very overweight were 87% and 70% more likely to have at least one follow-up GP-BMI record respectively compared to those with a healthy weight, as were males and CYP living in the most deprived areas of Wales. Records of childhood weight status extracted from general practice are not representative of the population and are biased with respect to weight status. Linkage of information from the national programme to GP records has the potential to enhance discussions around healthy weight at the point of care but does not provide a representative estimate of population level weight trajectories, essential to provide insights into factors determining a healthy weight gain across the early life course. A second CMP measurement is required in Wales.

Evaluating rural health outcomes: A methodological approach using population-level data.

The sustainability of rural surgical and obstetrical facilities depends on their efficacy and quality of care, which are difficult to measure in a rural context. In an evaluation of rural practice, it is often the case that the only comparators are larger referral facilities, for which facility-level comparisons are difficult due to differences in population demographics, acuity of patients, and services offered. This publication outlines these limitations and highlights a best-practice approach to making facility-level comparisons using population-level data, risk stratification, tests of noninferiority, and Firth logistic regression analysis. This includes an investigation of minimum sample-size requirements through Monte Carlo power analysis in the context of low-acuity rural surgical care. Monte Carlo power analysis was used to estimate the minimum sample size required to achieve a power of 0.8 for both logistic regression and Firth logistic regression models that compare the proportion of surgical adverse events against facility type, among other confounders. We provide guidelines for the implementation of a recommended methodology that uses risk stratification, Firth penalized logistic regression, and tests of noninferiority. We illustrate limitations in facility-level comparison of surgical quality among patients undergoing one of four index procedures including hernia repair, colonoscopy, appendectomy, and cesarean delivery. We identified minimum sample sizes for comparison of each index procedure that fluctuate depending on the level of risk stratification used. The availability of administrative data can provide an adequate sample size to allow for facility-level comparisons in surgical quality, at the rural level and elsewhere. When they are made appropriately, these comparisons can be used to evaluate the efficacy of general practitioners and nurse practitioners in performing low-acuity procedures.

SHORT-TERM COMPLICATIONS AND REOPERATION RATES AFTER HIP ARTHROSCOPY: A REVIEW OF 22,401 CASES IN ENGLAND FROM 2010 TO 2023

Hip arthroscopy (HA) is an effective treatment for various hip conditions but has a steep learning curve and its effect on long-term joint preservation is unclear. This study uses population-level data to assess (1) the 90-day complication rate, and (2) the frequency and timing of revision HA, total hip replacement (THR), and pelvic osteotomy (PO) following primary HA.We performed a retrospective analysis of the National Hospital Episode Statistics database, examining all patients who underwent primary HA in NHS hospitals in England from 2010 to 2023 using relevant OPCS-4 codes. We evaluated patient demographics, 90-day complications, and reoperation rates for revision HA, THR, and PO. Descriptive statistical analyses were performed to calculate frequencies and average time to reoperations.We included 22,401 HA procedures in the study. The mean LOS was 0.82±2.04 days. The 90-day readmission rate was 0.17% at a mean of 54.4±8.1 days. The most common reasons for readmission were reoperation (0.071%), followed by infection (0.031%), pulmonary embolism (0.027%), pain (0.022%), bleeding (0.018%), and deep vein thrombosis (0.004%). One patient died within 90 days.Overall, 4942 patients (22.1%) required further surgery at a mean of 2.71±2.27 years. The rates of revision HA, conversion to THR, and PO were 6.94%, 14.6%, and 0.50% at a mean of 2.39±1.79, 2.87±2.46, and 2.26±1.80 years respectively. Female patients had higher rates of reoperation than males for conversion to THR (9.99% vs 4.63%), revision HA (4.92% vs 2.02%), and subsequent PO (0.43% vs. 0.06%) (p<0.001).This study demonstrates a low short-term complication rate after primary HA, supporting existing literature. However, a large proportion of patients required further surgery, especially females. These findings highlight the need for careful patient selection and counselling before HA to optimise outcomes, as well as further research on factors influencing longer-term outcomes and cost-effectiveness.

A Real World Observational Study Characterizing Patients With Advanced Prostate Cancer Treated With or Without Androgen Receptor-Pathway-Inhibitor Therapies in Alberta, Canada

BackgroundData are needed to improve the current understanding of clinical management and characteristics of patients with advanced prostate cancer (PC) treated with androgen receptor pathway inhibition (ARPI) therapy. MethodsThis retrospective cohort study using real-world, population-level data from Alberta, Canada included all individuals diagnosed in 2017-2020 with de novo metastatic castration-sensitive PC (mCSPC) or nonmetastatic castration-resistant PC (nmCRPC) who initiated androgen deprivation therapy (ADT). For mCSPC, patients were classified as ARPI-exposed if they received an ARPI within 180 days of initiating ADT, while patients with nmCRPC were classified as ARPI-exposed if they received an ARPI within 2 years of diagnosis. ResultsThis study included 976 patients with mCSPC and 233 with nmCRPC of which 33.5% and 25.3% received an ARPI, respectively. The proportion of patients with mCSPC treated with an ARPI increased considerably for patients diagnosed in 2020 compared to 2017 (56.2% vs. 6.0%). In contrast, the use of ARPI to treat nmCRPC only increased marginally from 2017 to 2019/2020 (19.7% vs. 28.9%). Patients with mHSPC who were ARPI-exposed had longer median survival than patients who were ARPI-naive (38.47 (95% CI = 32.84-NA) vs. 34.19 (95% CI = 33.33-38.83; P = .03)), with a higher proportion of patients surviving to 2-years. For nmCRPC, survival was similar between ARPI-exposed and ARPI-naive. In multivariable analyses, receiving ARPI for mCSPC was associated with younger patient age, more recent diagnoses, fewer comorbidities, a higher number of metastatic sites, referral to a medical oncologist as well as receiving surgery and radiation before ADT. Receiving ARPI for nmCRPC was associated with referral to a medical oncologist, younger age, and more recent diagnoses. ConclusionsOutcome analyses in this population suggest a continued unmet clinical need and complex clinical management pathways. Given that treatment pathways have evolved considerably, continued follow-up to understand the impact of these advancements on patient outcomes are warranted.

Biological invasions are a population-level rather than a species-level phenomenon.

Biological invasions pose a rapidly expanding threat to the persistence, functioning and service provisioning of ecosystems globally, and to socio-economic interests. The stages of successful invasions are driven by the same mechanism that underlies adaptive changes across species in general-via natural selection on intraspecific variation in traits that influence survival and reproductive performance (i.e., fitness). Surprisingly, however, the rapid progress in the field of invasion science has resulted in a predominance of species-level approaches (such as deny lists), often irrespective of natural selection theory, local adaptation and other population-level processes that govern successful invasions. To address these issues, we analyse non-native species dynamics at the population level by employing a database of European freshwater macroinvertebrate time series, to investigate spreading speed, abundance dynamics and impact assessments among populations. Our findings reveal substantial variability in spreading speed and abundance trends within and between macroinvertebrate species across biogeographic regions, indicating that levels of invasiveness and impact differ markedly. Discrepancies and inconsistencies among species-level risk screenings and real population-level data were also identified, highlighting the inherent challenges in accurately assessing population-level effects through species-level assessments. In recognition of the importance of population-level assessments, we urge a shift in invasive species management frameworks, which should account for the dynamics of different populations and their environmental context. Adopting an adaptive, region-specific and population-focused approach is imperative, considering the diverse ecological contexts and varying degrees of susceptibility. Such an approach could improve and refine risk assessments while promoting mechanistic understandings of risks and impacts, thereby enabling the development of more effective conservation and management strategies.

Inequalities in emergency care use across transition from paediatric to adult care: a retrospective cohort study of young people with chronic kidney disease in England.

Sociodemographic inequalities in emergency secondary care usage were evident in this cohort across the transition period, independent of age, with some variation between admissions and A&E use, and evidence of effect modification by transfer. Such inequalities likely have multifactorial origin, but importantly, could represent differential meetings of care needs. • In chronic kidney disease (CKD), transfer from paediatric to adult healthcare is associated with declining health outcomes. • Known differences in CKD outcomes by sociodemographic factors have limited prior exploration in the context of transfer. • Population-level data was used to examine the impacts of transfer and sociodemographic factors on unplanned secondary care utilisation in CKD. • Healthcare utilisation trends may not reflect known CKD pathophysiology and there may be unexplored sociodemographic inequalities in the experiences of young people across transfer.

Treatment trends and clinical outcomes of endovascular embolization for unruptured intracranial aneurysms in the pediatric population

BackgroundOwing to the relative rarity of unruptured intracranial aneurysms (UIAs) in the pediatric population, evidence regarding treatment modalities and clinical outcomes remains limited.ObjectiveTo characterize the use and clinical outcomes of...

Traumatic brain injury and occupational risk of low-level blast exposure on adverse career outcomes: an examination of administrative and medical separations from Service (2005-2015).

Although traumatic brain injury (TBI) has been linked with adverse long-term health, less research has examined whether TBI is linked with non-clinical outcomes including involuntary job loss. Symptoms associated with TBI may influence one's ability to maintain gainful employment including employment in the U.S. military. That influence may impact military service members with exposure to repetitive low-level blast (LLB). Understanding the association between TBI and involuntary job loss outcomes among military populations is particularly important as it may be associated with differences in eligibility for post-service benefits. The purpose of the present research was to determine whether (1) TBI and related conditions are associated with involuntary job loss (i.e., medical and administrative separations from service) among military personnel, and (2) occupational risk of LLB is associated with involuntary job loss in both the presence and absence of clinical diagnoses of TBI and related conditions. This research leveraged population-level data from the Career History Archival Medical and Personnel System for enlisted personnel who served on active duty between 2005-2015. Risk of LLB exposure was categorized using military occupational specialty as a proxy. Medical diagnoses were identified using ICD-9 codes. Separations for medical and administrative reasons were identified. Risk for administrative separation differed across medical diagnoses of interest, but those who worked in high-risk occupations were more likely to be administratively separated than those working in low-risk occupations. Risk for medical separation was associated with occupational risk of LLB and each of the diagnoses of interest, though significant interactions suggested that the effects of certain diagnoses of interest (e.g., concussion, cognitive problems, postconcussive syndrome, migraines) on medical separations was greater among those working in high-risk occupations. Taken together, the present research suggests that TBI and associated medical conditions, as well as occupational risk of LLB, are associated with long-term involuntary job loss for medical reasons. This study is the first to demonstrate involuntary military job loss outcomes associated with TBI, mental health conditions, and conditions associated with blast exposure using both inpatient and outpatient population-level data and may have important implications for civilian employment and post-service benefits.

Estimating vaccine efficacy during open-label follow-up of COVID-19 vaccine trials based on population-level surveillance data

While rapid development and roll out of COVID-19 vaccines is necessary in a pandemic, the process limits the ability of clinical trials to assess longer-term vaccine efficacy. We leveraged COVID-19 surveillance data in the U.S. to evaluate vaccine efficacy in U.S. Government-funded COVID-19 vaccine efficacy trials with a three-step estimation process. First, we used a compartmental epidemiological model informed by county-level surveillance data, a “population model”, to estimate SARS-CoV-2 incidence among the unvaccinated. Second, a “cohort model” was used to adjust the population SARS-CoV-2 incidence to the vaccine trial cohort, taking into account individual participant characteristics and the difference between SARS-CoV-2 infection and COVID-19 disease. Third, we fit a regression model estimating the offset between the cohort-model-based COVID-19 incidence in the unvaccinated with the placebo-group COVID-19 incidence in the trial during blinded follow-up. Counterfactual placebo COVID-19 incidence was estimated during open-label follow-up by adjusting the cohort-model-based incidence rate by the estimated offset. Vaccine efficacy during open-label follow-up was estimated by contrasting the vaccine group COVID-19 incidence with the counterfactual placebo COVID-19 incidence. We documented good performance of the methodology in a simulation study. We also applied the methodology to estimate vaccine efficacy for the two-dose AZD1222 COVID-19 vaccine using data from the phase 3 U.S. trial (ClinicalTrials.gov # NCT04516746). We estimated AZD1222 vaccine efficacy of 59.1% (95% uncertainty interval (UI): 40.4%–74.3%) in April, 2021 (mean 106 days post-second dose), which reduced to 35.7% (95% UI: 15.0%–51.7%) in July, 2021 (mean 198 days post-second-dose). We developed and evaluated a methodology for estimating longer-term vaccine efficacy. This methodology could be applied to estimating counterfactual placebo incidence for future placebo-controlled vaccine efficacy trials of emerging pathogens with early termination of blinded follow-up, to active-controlled or uncontrolled COVID-19 vaccine efficacy trials, and to other clinical endpoints influenced by vaccination.

High-Quality, Chromosome-Level Reference Genomes of the Viviparous Caribbean Skinks Spondylurus nitidus and S. culebrae.

New World mabuyine skinks are a diverse radiation of morphologically cryptic lizards with unique reproductive biologies. Recent studies examining population-level data (morphological, ecological, and genomic) have uncovered novel biodiversity and phenotypes, including the description of dozens of new species and insights into the evolution of their highly complex placental structures. Beyond the potential for this diverse group to serve as a model for the evolution of viviparity in lizards, much of the taxonomic diversity is concentrated in regions experiencing increasing environmental instability from climate and anthropogenic change. Consequently, a better understanding of genome structure and diversity will be an important tool in the adaptive management and conservation of this group. Skinks endemic to Caribbean islands are particularly vulnerable to global change with several species already considered likely extinct and several remaining species either endangered or threatened. Combining PacBio long-read sequencing, Hi-C, and RNAseq data, here we present the first genomic resources for this group by describing new chromosome-level reference genomes for the Puerto Rican Skink Spondylurus nitidus and the Culebra Skink S. culebrae. Results indicate two high quality genomes, both ∼1.4 Gb, assembled nearly telomere to telomere with complete mitochondrion assembly and annotation.

Complex Polyploids: Origins, Genomic Composition, and Role of Introgressed Alleles.

Introgression allows polyploid species to acquire new genomic content from diploid progenitors or from other unrelated diploid or polyploid lineages, contributing to genetic diversity and facilitating adaptive allele discovery. In some cases, high levels of introgression elicit the replacement of large numbers of alleles inherited from the polyploid's ancestral species, profoundly reshaping the polyploid's genomic composition. In such complex polyploids, it is often difficult to determine which taxa were the progenitor species and which taxa provided additional introgressive blocks through subsequent hybridization. Here, we use population-level genomic data to reconstruct the phylogenetic history of Betula pubescens (downy birch), a tetraploid species often assumed to be of allopolyploid origin and which is known to hybridize with at least four other birch species. This was achieved by modeling polyploidization and introgression events under the multispecies coalescent and then using an approximate Bayesian computation rejection algorithm to evaluate and compare competing polyploidization models. We provide evidence that B. pubescens is the outcome of an autoploid genome doubling event in the common ancestor of B. pendula and its extant sister species, B. platyphylla, that took place approximately 178,000-188,000 generations ago. Extensive hybridization with B. pendula, B. nana, and B. humilis followed in the aftermath of autopolyploidization, with the relative contribution of each of these species to the B. pubescens genome varying markedly across the species' range. Functional analysis of B. pubescens loci containing alleles introgressed from B. nana identified multiple genes involved in climate adaptation, while loci containing alleles derived from B. humilis revealed several genes involved in the regulation of meiotic stability and pollen viability in plant species.

Voxelwise Multivariate Analysis of Brain-Psychosocial Associations in Adolescents Reveals 6 Latent Dimensions of Cognition and Psychopathology

BackgroundAdolescence heralds the onset of considerable psychopathology, which may be conceptualized as an emergence of altered covariation between symptoms and brain measures. Multivariate methods can detect such modes of covariation or latent dimensions, but none specifically relating to psychopathology have yet been found using population-level structural brain data. Using voxelwise (instead of parcellated) brain data may strengthen latent dimensions’ brain-psychosocial relationships, but this creates computational challenges. MethodsWe obtained voxelwise gray matter density and psychosocial variables from the baseline (ages 9–10 years) Adolescent Brain Cognitive Development (ABCD) Study cohort (N = 11,288) and employed a state-of-the-art segmentation method, sparse partial least squares, and a rigorous machine learning framework to prevent overfitting. ResultsWe found 6 latent dimensions, 4 of which pertain specifically to mental health. The mental health dimensions were related to overeating, anorexia/internalizing, oppositional symptoms (all ps < .002) and attention-deficit/hyperactivity disorder symptoms (p = .03). Attention-deficit/hyperactivity disorder was related to increased and internalizing symptoms related to decreased gray matter density in dopaminergic and serotonergic midbrain areas, whereas oppositional symptoms were related to increased gray matter in a noradrenergic nucleus. Internalizing symptoms were related to increased and oppositional symptoms to reduced gray matter density in the insular, cingulate, and auditory cortices. Striatal regions featured strongly, with reduced caudate nucleus gray matter in attention-deficit/hyperactivity disorder and reduced putamen gray matter in oppositional/conduct problems. Voxelwise gray matter density generated stronger brain-psychosocial correlations than brain parcellations. ConclusionsVoxelwise brain data strengthen latent dimensions of brain-psychosocial covariation, and sparse multivariate methods increase their psychopathological specificity. Internalizing and externalizing symptoms are associated with opposite gray matter changes in similar cortical and subcortical areas.

Iron Deficiency, Anemia, and Iron Supplementation in Patients With Heart Failure: A Population-Level Study.

Studies have shown an association between iron deficiency (ID) and clinical outcomes in patients with heart failure (HF), irrespective of the presence of ID anemia (IDA). The current study used population-level data from a large, single-payer health care system in Canada to investigate the epidemiology of ID and IDA in patients with acute HF and those with chronic HF, and the iron supplementation practices in these settings. All adult patients with HF in Alberta between 2012 and 2019 were identified and categorized as acute or chronic HF. HF subtypes were determined through echocardiography data, and ID (serum ferritin concentration <100 μg/L, or ferritin concentration between 100 and 300 μg/L along with transferrin saturation <20%), and IDA through laboratory data. Broad eligibility for 3 clinical trials (AFFIRM-AHF [Study to Compare Ferric Carboxymaltose With Placebo in Patients With Acute HF and ID], IRONMAN [Intravenous Iron Treatment in Patients With Heart Failure and Iron Deficiency], and HEART-FID [Randomized Placebocontrolled Trial of Ferric Carboxymaltose as Treatment for HF With ID]) was determined. Among the 17 463 patients with acute HF, 38.5% had iron studies tested within 30 days post-index-HF episode (and 34.2% of the 11 320 patients with chronic HF). Among tested patients, 72.6% of the acute HF and 73.9% of the chronic HF were iron-deficient, and 51.4% and 49.0% had IDA, respectively. Iron therapy was provided to 41.8% and 40.5% of patients with IDA and acute or chronic HF, respectively. Of ID patients without anemia, 19.9% and 21.7% were prescribed iron therapy. The most common type of iron therapy was oral (28.1% of patients). Approximately half of the cohort was eligible for each of the AFFIRM-AHF, intravenous iron treatment in patients with HF and ID, and HEART-FID trials. Current practices for investigating and treating ID in patients with HF do not align with existing guideline recommendations. Considering the gap in care, innovative strategies to optimize iron therapy in patients with HF are required.