Mixed-effects Negative Binomial Models Research Articles

Air pollution, mortality, and hospital admissions in Scotland: A 16 years register-based study

BackgroundAir pollution is associated with poor health and higher mortality. However, studies that link high spatial resolution air pollution data for several pollutants to individual-level data over prolonged period (>10 years) and assess multiple health outcomes are limited. In this study, we investigated the association between 16-years exposure to air pollution and all-cause and cause-specific (cardiovascular, respiratory, cancer, infectious, and mental/behavioural disorders) mortality and hospital admissions in Scotland.
 MethodsIndividual-level data from the “Scottish Longitudinal Study” for 202,237 individuals (2002-2017) were linked to yearly concentrations of NO2, SO2, PM10, and PM2.5 pollutants at 1-Km2 spatial resolution using the individual’s residential postcode. The association between air pollution and mortality and hospital admissions was examined using Cox Proportional-Hazards and multilevel mixed-effects negative binomial models, respectively.
 ResultsIncreasing concentrations of PM2.5, PM10, and NO2 pollutants were associated with higher rates of all-cause, cardiovascular, respiratory, cancer, and infectious mortality and hospital admissions. Mortality from respiratory diseases increased by 6.2% (95%CI=2.8%-9.6%), 2.5% (95%CI=0.5%-4.5%), and 1.2% (95%CI=0.5%-1.9%) per 1 µg/m3 increase in PM2.5, PM10 and NO2 pollutants, respectively. Exposure to SO2 was mainly linked to mental/behavioural disorders mortality (HR=1.05; 95%CI=1.02-1.07) and respiratory hospital admissions (IRR=1.02; 95%CI=1.01-1.03).
 ConclusionsThis study revealed a positive association between air pollution and mortality and hospital admissions in Scotland. Interventions on air pollution through stricter environmental regulations could help ease the mortality and hospital admission burden, for both physical and mental illness.

Nursing 12-Hour Shifts and Patient Incidents in Mental Health and Community Hospitals: A Longitudinal Study Using Routinely Collected Data

Shifts of 12 hours or longer are common in nursing services within general hospital wards. Concerns have been raised about their safety, but previous research has mostly used staff-reported measures of quality and safety and has occurred in general hospital settings only. This study aims to measure the association between the use of 12+ hour shifts in nursing staff (including registered nurses, healthcare support workers or nursing assistants, and nursing associates) and the rate of patient incidents in mental health and community hospitals. This is a longitudinal study using routinely collected data from two mental health and community NHS trusts in the South of England. We accessed rosters of nursing staff and patient incident data from April 2018 to March 2021. We extracted 1,018,971 shifts and excluded those not worked by nursing staff, with a final sample of 898,143 shifts. We extracted 53,078 incidents. We only included incidents that involved patients and that occurred in wards. Our final sample consisted of 38,373 patient incidents. We linked all patient incidents and nurses’ worked shifts at the ward-day level. Depending on the distribution of incident rates, we used either negative binomial mixed-effects models or Poisson mixed-effect models to investigate the association between the proportion of 12+ hour shifts and all patient incidents, violence against staff, falls, self-injury, disruptive behaviour, and medication management incidents at the ward-day level. We found a relationship between 12+ hour shifts and the incident rate. Compared to days in wards with no long shifts, increasing the proportion of long shifts was initially associated with a small increase in the overall rate of incidents, but the rate increased sharply as the proportion of long shifts was above 70%. Rates of self-injury increased more steadily as the proportion of long shifts increased. The mandatory implementation of long shifts should be discouraged.

Impact of COVID-19 epidemic on temporal pattern of new HIV diagnoses in Italy, 2021 database.

New HIV diagnoses in Italy decreased drastically in 2020 due to COVID-19 related effects: 50% fewer diagnoses were reported by the National HIV Surveillance System. COVID-19 pandemic impact on HIV surveillance is unclear. We estimated the expected number of new HIV diagnoses in 2020 in order to isolate the impact of the COVID-19 pandemic. We analyzed 29697 new HIV infections diagnosed from 2012 to 2020, reported to the National HIV Surveillance System. We assessed temporal trends of new HIV diagnoses applying negative binomial mixed effects models. We estimated the COVID-19 impact as the difference between the model-estimated slopes from 2012 to 2019 and the change reported in the diagnoses. The expected number of new HIV diagnoses in 2020 was also estimated and compared with the reported count. Based on the historical trend, we expected a 15% (95% CI: 5-25%) decline of new HIV diagnoses in 2020. We reported, however, a 49% decrease, yielding to a 34% net decrease in the number of new diagnoses. The strongest impact was estimated in northern regions (-40%) and MSM (-38%). We estimated 761 (95% prediction interval: 350-1277) missed diagnoses during 2020, the majority of them occurring in the North (465 cases), among MSM (416) and heterosexual males (217). In 2020, when excluding 15% decrease of new diagnoses attributable to the expected reduction, an additional 34% decrease was observed, representing a large decline in new HIV diagnoses associated with the COVID-19 pandemic.

Mixed-Effects Zero-Inflated Negative Binomial Crash Predictive Models for Unsignalized Intersections along Two-Lane Highways with Minor Roads Operating with Very Low Traffic Volumes

Current and past investigations into road accidents have mainly focused on high-volume roads which have experienced a significant number of collisions. However, low-volume roads also record crash data which merit analysis to understand the causes of accidents and find potential countermeasures. This study focuses on unsignalized intersections linking major highways and minor stop-controlled local roads that operate with very low traffic volumes. In this scenario, an over-abundance of zero observations has to be accounted for. To address this issue, zero-inflated Poisson and negative binomial regression models have been calibrated and analyzed to find the geometric and operational factors which contribute most to the crash rate. Random effects have also been considered to account for unobserved heterogeneity inherent in the grouping of intersections within the database. The results indicate that the mixed-effect negative binomial model had the best prediction performance. Developing models for subgroups of crashes, for example, failure-to-yield and other types of crash, resulted in better prediction performance. The major road’s average annual daily traffic and the surface type (i.e., paved or unpaved) of minor road approaches had a significant effect on the frequency of all crash types. The type of intersection (three- or four-legs), the skew angle of intersection, deviation angle of near curves, and operating speed differences also had statistically significant effects on the frequency of crashes that do not include the failure-to-yield.

Associations Between Sexual History Documentation in Electronic Health Records and Referral to Pre-Exposure Prophylaxis Navigator on Prescription of Pre-Exposure Prophylaxis at a Multi-Site Federally Qualified Health Center.

This cross-sectional study examined the relationships between sexual history screening (SHS) and referrals to a pre-exposure prophylaxis (PrEP) navigator (non-clinical staff member who assists patients in overcoming structural barriers to PrEP) on the proportion of days covered by PrEP for adult patients at a federally qualified health center. Patients' sociodemographics, PrEP prescriptions, referral to a PrEP navigator, and SHS data were extracted from the electronic health record (EHR). The analytic sample was 214 adult patients who were human immunodeficiency virus (HIV) negative and taking PrEP to prevent infection from January 2016 to December 2019. Mixed-effects negative binomial models were conducted accounting for clustering by patients' primary care providers. Documentation of SHS was associated with a higher proportion of days covered by PrEP (incidence rate ratio = 1.44, 95% confidence interval: 1.17-1.77). There was no significant effect of having a referral to the PrEP navigator on the proportion of days covered by PrEP, nor did having a referral to the PrEP navigator moderate the relationship between having SHS documented in the EHR and the proportion of days covered by PrEP. This study is the first to investigate the relationship between having sexual history documented in the EHR, referrals to a PrEP navigator, and their combined effect on the proportion of days covered by PrEP. Results of this study provide foundational evidence for future studies examining SHS as an opportunity to improve PrEP access and adherence and indicate the need for additional research exploring the value of PrEP navigators as an implementation strategy to overcome social and structural barriers to care.

Association of Hospital Procedural Volume With Outcomes of Left Ventricular Assist Device Placement

With the advancement in device technology, the use of durable left ventricular assist devices (LVADs) has increased significantly in recent years. However, there is a dearth of evidence to conclude whether patients who undergo LVAD implantation at high-volume centers have better clinical outcomes than those receiving care at low- or medium-volume centers. We analyzed the hospitalizations using the Nationwide Readmission Database for the year 2019 for new LVAD implantation. Baseline comorbidities and hospital characteristics were compared among low- (1-5 procedures/year), medium- (6-16 procedures/year) and high-volume (17-72 procedures/year) hospitals. The volume/outcome relationship was analyzed using the annualized hospital volume as a categorical variable (tertiles) as well as a continuous variable. Multilevel mixed-effect logistic regression and negative binomial regression models were used to determine the association of hospital volume and outcomes, with tertile 1 (low-volume hospitals) as the reference category. A total of 1533 new LVAD procedures were included in the analysis. The inpatient mortality rate was lower in the high-volume centers compared with the low-volume centers (9.04% vs 18.49%, aOR 0.41, CI0.21-0.80; P = 0.009). There was a trend toward lower mortality rates in medium-volume centers compared with low-volume centers; however, it did not reach statistical significance (13.27% vs 18.49%, aOR 0.57, CI0.27-1.23; P = 0.153). Similar results were seen for major adverse events (composite of stroke/transient ischemic attack and in-hospital mortality). There was no significant difference in bleeding/transfusion, acute kidney injury, vascular complications, pericardial effusion/hemopericardium/tamponade, length of stay, cost, or 30-day readmission rates between medium- and high-volume centers compared to low-volume centers. Our findings indicate lower inpatient mortality rates in high-volume LVAD implantation centers and a trend toward lower mortality rates in medium-volume LVAD implantation centers compared to lower-volume centers.

Determinants of worldwide antibiotic resistance dynamics across drug-bacterium pairs: a multivariable spatial-temporal analysis using ATLAS

Antibiotic resistance (ABR) is a major concern for global health. However, factors driving its emergence and dissemination are not fully understood. Identification of such factors is crucial to explain heterogeneity in ABR rates observed across space, time, and species and antibiotics. We analysed count data of clinical isolates from 51 countries over 2006-19 for thirteen drug-bacterium pairs taken from the ATLAS database. We characterised ABR spatial and temporal patterns and used a mixed-effect negative binomial model, accounting for country-year dependences with random effects, to investigate associations with potential drivers, including antibiotic sales, economic and health indicators, meteorological data, population density, and tourism. ABR patterns were strongly country and drug-bacterium pair dependent. In 2019, median ABR rates ranged from 6·3% (IQR 19·7% [0·5-20·2]) for carbapenem-resistant Klebsiella pneumoniae to 80·7% (41·8% [50·4-92·2]) for fluoroquinolone-resistant Acinetobacter baumannii, with heterogeneity across countries. From 2006 to 2019, carbapenem resistance increased in more than 60% of investigated countries; no global trend was observed for other resistances. Multivariable analyses identified significant associations of ABR with country-level selecting antibiotic sales, but only in fluoroquinolone-resistant-Escherichia coli, fluoroquinolone-resistant-Pseudomonas aeruginosa, and carbapenem-resistant-A baumannii. We also found a correlation between temperature and resistance in Enterobacteriaceae and with the health system quality for all drug-bacterium pairs except Enterococci and Streptococcus pneumoniae pairs. Despite wide consideration of possible explanatory variables, drug-bacterium pair ABR rates still showed unexplained spatial random effects variance. Our findings reflect the diversity of mechanisms driving global antibiotic resistance across pathogens and stress the need for tailored interventions to tackle bacterial resistance. Independent research Pfizer Global Medical Grant and ANR Labex IBEID.

The spatio-temporal distribution of acute encephalitis syndrome and its association with climate and landcover in Vietnam

BackgroundAcute encephalitis syndrome (AES) differs in its spatio-temporal distribution in Vietnam with the highest incidence seen during the summer months in the northern provinces. AES has multiple aetiologies, and the cause remains unknown in many cases. While vector-borne disease such as Japanese encephalitis and dengue virus and non-vector-borne diseases such as influenza and enterovirus show evidence of seasonality, associations with climate variables and the spatio-temporal distribution in Vietnam differs between these. The aim of this study was therefore to understand the spatio-temporal distribution of, and risk factors for AES in Vietnam to help hypothesise the aetiology.MethodsThe number of monthly cases per province for AES, meningitis and diseases including dengue fever; influenza-like-illness (ILI); hand, foot, and mouth disease (HFMD); and Streptococcus suis were obtained from the General Department for Preventive Medicine (GDPM) from 1998–2016. Covariates including climate, normalized difference vegetation index (NDVI), elevation, the number of pigs, socio-demographics, JEV vaccination coverage and the number of hospitals were also collected. Spatio-temporal multivariable mixed-effects negative binomial Bayesian models with an outcome of the number of cases of AES, a combination of the covariates and harmonic terms to determine the magnitude of seasonality were developed.ResultsThe national monthly incidence of AES declined by 63.3% over the study period. However, incidence increased in some provinces, particularly in the Northwest region. In northern Vietnam, the incidence peaked in the summer months in contrast to the southern provinces where incidence remained relatively constant throughout the year. The incidence of meningitis, ILI and S. suis infection; temperature, relative humidity with no lag, NDVI at a lag of one month, and the number of pigs per 100,000 population were positively associated with the number of cases of AES in all models in which these covariates were included.ConclusionsThe positive correlation of AES with temperature and humidity suggest that a number of cases may be due to vector-borne diseases, suggesting a need to focus on vaccination campaigns. However, further surveillance and research are recommended to investigate other possible aetiologies such as S. suis or Orientia tsutsugamushi.

Social participation and tooth loss, vision, and hearing impairments among older Brazilian adults.

Vision and hearing impairments can reduce participation in social activities. Given the prominent role of the mouth in face-to-face interactions, this study evaluated the associations of tooth loss, vision, and hearing impairments with social participation among older adults. This analysis included 1947 participants, aged 60+ years, who participated in three waves (2006, 2010, and 2015) of the Health, Wellbeing and Aging Study (SABE) in Brazil. Social participation was measured by the number of formal and informal social activities (requiring face-to-face interaction) participants were regularly involved in. Teeth were counted during clinical examinations and categorized as 0, 1-19, and 20+ teeth. Reports on vision and hearing impairments were classified into three categories (good, regular, and poor). The associations of each impairment with the 9-year change in the social participation score were tested in negative binomial mixed-effects models adjusting for time-variant and time-invariant covariates. Each impairment was associated with the baseline social participation score and the annual rate of change in the social participation score. Participants with 1-19 (incidence rate ratio: 0.96, 95% CI: 0.91-1.01) and no teeth (0.92, 95% CI: 0.87-0.97), those with regular (0.98, 95% CI: 0.95-1.01) and poor vision (0.86, 95% CI: 0.81-0.90), and those with regular (0.94, 95% CI: 0.91-0.98) and poor hearing (0.91, 95% CI: 0.87-0.95) had lower baseline social participation scores than those with 20+ teeth, good vision, and good hearing, respectively. Furthermore, participants with 1-19 (0.996, 95% CI: 0.990-1.002) and no teeth (0.994, 95% CI: 0.987-0.999), those with regular (0.996, 95% CI: 0.992-0.999) and poor vision (0.997, 95% CI: 0.991-1.003), and those with regular (0.997, 95% CI: 0.992-1.001) and poor hearing (0.995, 95% CI: 0.990-0.999) had greater annual declines in the social participation score than those with 20+ teeth, good vision and good hearing, respectively. This 9-year longitudinal study shows that tooth loss, vision, and hearing impairments are associated with reduced social participation among older adults.

130 Investigation of age, status, season, and sex on equine parasitic load in a university program

Strongyles are nematode parasites that can damage the horse's large intestine and cecum and cause symptoms of colic, anemia, and weight loss. Sixty-four horses from the University of Connecticut campus were used to study parasitic shedding patterns, to determine if there was a seasonal, age, sex or work status effect. Horses were assigned to different statuses based on living and exercise situations. The goal of analyses was to assess whether there was a change in parasite count over time, and whether horse age, status and sex had any effect on parasite count. Fecal samples of all horses were collected in March and October for 5 years. Fecal flotation testing was done to evaluate strongyle eggs per gram (EPG). Zero-inflated (ZI), negative binomial mixed effects models were used to evaluate changes in parasite counts over time. Both conditional (nonzero parasite counts) and ZI components were adjusted for status, age, sex, and the interaction of status and year. Horse ID was treated as a random effect, to account for repeated measurements. No sex effect on parasitic load was found with either the conditional or ZI models. Similarly, neither status norseason were significantly associated statistically with parasite counts. Initial age did have an effect on conditional parasite counts, with regression results suggesting that as age increased, parasite counts decreased. Although we have some evidence of declining parasite loads at UConn, this effect was only significant for spring sampling. Fall sampling occurred after the horses had been turned out over the summer, so perhaps they are then at greater risk for getting a heavier parasite load. The decline over the years in the March data could be due to the implementation of a parasitic control protocol by barn management 4 years into the study. This study appears to agree with other studies in that older horses are less affected by internal parasites than their younger counterparts. The parasitic control protocol implemented by barn management appears to have had a positive effect on horses in the spring. More research is needed to determine if this protocol will eventually have an effect on the fall as well.

Graphical abstracts are associated with greater Altmetric attention scores, but not citations, in sport science

This paper aimed to determine if papers published with a Graphical abstract (GA) in the sport science field were associated with higher Altmetric attention scores and more citations than papers published without. A multivariate negative binomial mixed effects model was used to determine whether Altmetric attention scores and citation counts were different between articles published with or without a GA longitudinally over five timepoints. Included articles were published between January 2019 and December 2020 from three journals ranked within the top quartile of the category of “Sport Science”. Of 562 articles, 96 were published with a GA. Articles with GA were associated with higher Altmetric attention score than those without (incidence rate ratio 1.89 [95% confidence interval [CI] 1.25–2.85]; p = 0.003; small effect), with no difference in citations (incidence rate ratio 0.97 [95% CI 0.72–1.30]; p = 0.829; trivial effect). This study suggests that publishing with a GA is associated with increased Altmetric attention scores, but not citations, in sport science. This may indicate that GAs improve research dissemination amongst the public, which is important in practical fields.

Impact of COVID-19 on Dental Care Utilization and Oral Health Conditions in the United States.

We aim to understand the impact of the COVID-19 on health care utilization and oral health conditions of patients at federally qualified health centers (FQHCs), where patients are disproportionately low income, publicly insured, or uninsured. Using deidentified electronic health records of patients at FQHCs in the United States from January 2019 through December 2020 (n = 431,509), variations in health care utilization since the COVID-19 outbreak were observed by procedure types and patient characteristics. Changes in dental utilization and oral health conditions were characterized using mixed-effect negative binomial and logistic regression models. Dental utilization decreased more drastically than medical utilization during shelter-in-place periods in 2020 and rebounded more slowly after the reopening. Greater demands for oral surgery and teledentistry and less demands for preventive services were observed in 2020. As compared to 2019, patients experienced more psychological stress-related dental conditions with odds ratios of 1.52 (95% confidence interval [CI], 1.31-1.76) for uninsured, 1.48 (95% CI, 1.07-2.02) for Medicaid enrollees, and 2.38 (95% CI, 1.68-3.40) for private insurance beneficiaries. As a result of COVID-19, patients received more invasive dental procedures due to delayed treatment and experienced a higher risk of psychological stress-related dental conditions. Continued support for statewide policies to expand access to oral health care and oral health promotion strategies for the vulnerable populations would be encouraged. Our study describes the impact of COVID-19 on dental care use and oral health conditions at Federally Qualified Health Centers, targeted to provide care for some of the most vulnerable populations in the United States. The results of this retrospective cohort study can be used by clinicians and policymakers on understanding the clinical needs of the vulnerable populations after the pandemic. It highlights the need for continued support to expand access to oral health care and oral health promotion to these populations.

Comparison of carcass condemnation causes in two broiler hybrids differing in growth rates

Experimental studies concluded that genetic factors enabling fast growth rate might negatively affect broiler health and welfare. Recently, the proportion of slower-growing broilers has been increasing. However, studies of health in broilers with different growth rates in commercial systems are still scarce. This repeated cross-sectional study aimed to describe causes of carcass condemnations in two broiler hybrids with different growth rates, Ross 308, and Hubbard JA787, and to estimate the effect of hybrid. The study sample consisted of 63,209,415 broilers slaughtered in 4295 batches from 139 farms. All broilers were slaughtered from January 1st, 2015, to June 22nd, 2021, by the same company (Norsk Kylling). All causes of condemnation, except fractures, were more prevalent in Ross 308. The five most common causes (ascites, discolouration, hepatitis, small and skin lesions) were investigated in greater detail, and the effect of hybrid was assessed using mixed effects negative binomial models with the condemnation codes as outcome variables. For the five selected causes, variation in prevalence between slaughter batches was considerable for Ross and minor for Hubbard. The notable differences between hybrids in prevalence and causes of condemnation have important implications for animal health, welfare, economy, and sustainability in broiler production.

Drug overdoses, geographic trajectories, and the influence of built environment and neighborhood characteristics

Much research has analyzed the spatial patterns of drug overdose events and identified features of the environment associated with heightened overdose levels. Generally absent from the literature are studies that analyze how unique trajectories of overdoses vary over time. We address this gap in the literature through an analysis of drug overdoses occurring in Passaic County, New Jersey from 2015 through 2019. A group-based trajectory analysis classifies block groups according to their overdose trends. A mixed-effects panel negative binomial regression model then examines the built environment and neighborhood characteristics associated with overall overdose levels. Results indicate that Passaic County block groups can be classified across three groups based upon their overdose levels over the study period: low and stable, low with moderate increase, and elevated and increasing. While the largest effects were observed for concentrated disadvantage in the regression analysis, most variables positively associated with overdose levels were built environment measures.

Influence of High School Socioeconomic Status on Athlete Injuries during the COVID-19 Pandemic: An Ecological Study.

It is presently unclear how the cessation of high school sport has affected injury incidence at different socioeconomic levels. The COVID-19 pandemic may have disproportionately affected athletes of lower socioeconomic status, potentially increasing injury risk in this population. To 1) Describe athlete injury incidence prior to and during the 2019-2020 and 2020-2021 school years in high school athletes by socioeconomic status; 2) Investigate the association between socioeconomic status and injury incidence in high school athletes. Ecological Study. High schools were matched between the 2019-2020 and 2020-2021 school years. All athletes from all sports were included. High school socioeconomic status was determined by the school district median household income. Socioeconomic strata were defined as <$30,000, $30,000-50,000, $50,001-100,000, and >$100,000. Injury incidence proportion with 95% confidence interval (95% CI) was calculated for each academic year. Mixed effects negative binomial models with robust errors were performed to assess the association between the incidence proportion ratio and high school median household income. Six states and 176 high schools were included (2019-2020: 98,487 athletes; 2020-2021: 72,521 athletes). Injury incidence increased in three of four socioeconomic strata during the 2020-2021 year (<$30,000: 2019-2020: 15.6 (13.1-18.1), 2020-2021: 26.3 (23.1-29.6); $30,000-50,000: 2019-2020: 7.8 (7.1-8.6), 2020-2021: 14.9 (13.8-15.9); $50,001-100,000: 2019-2020: 15.1 (14.7-15.4), 2020-2021: 21.3 (20.9-21.8); >$100,000: 2019-2020: 18.4 (18.1-18.8), 2020-2021: 17.3 (16.8-17.7)). An association was observed between injury incidence ratio and log median high school household income in 2019-2020 [1.6 (1.1-2.5)] but not 2020-2021 [1.1 (0.8-1.6)] school years. Athletes from lower socioeconomic high schools reported increased injury incidence compared to higher socioeconomic high schools during the 2020-2021 academic school year. These results highlight the increased COVID-19 pandemic vulnerability in athletes from lower socioeconomic high schools. High school sport stakeholders should consider how abrupt sport stoppage can affect lower socioeconomic athletes. 2.

Allometric Scaling of Anaerobic Capacity Estimated from a Unique Field-Based Data Set of Fish Swimming.

AbstractLocomotion is a defining characteristic that can dictate many aspects of an organism's life history in the pursuit of maximizing fitness, including escaping predators, capturing prey, and transitioning between habitats. Exhaustive exercise can have negative consequences for both short-term and long-term energetics and life history trade-offs, influencing fish survival and reproduction. Studies of swimming performance and exhaustive exercise in fish are often conducted on individual species, but few multispecies analyses exist and even fewer in field settings. In fish, swimming performance and exercise have historically been studied in the laboratory using swim tunnels, but an increasing body of work in recreational fisheries science provides a novel way to examine swimming capacity and exhaustion. Using fight time, the time it takes for a hooked fish to be landed on rod and reel fishing gear, as an opportunistic proxy for fish exhaustion, a multispecies meta-analysis of data from studies on recreational fisheries was conducted to elucidate the factors that most influence capacity for exhaustive exercise. Data from 39 species of freshwater and marine fish were aggregated, and negative binomial mixed effects models as well as phylogenetic least squares regression were used to identify the factors that most influenced exhaustive exercise in the field. Fish total length, aspect ratio of the caudal fin, and body form were significant factors in explaining the capacity for exhaustive exercise. Large migratory fish with high aspect ratios were able to fight, and therefore exercise, the longest. These results illustrate that body form and physiology are both deeply intertwined to inform function across fish species and point to angling fight time as a useful approximation of fish swimming capabilities that can be further developed for understanding the limits of fish exercise physiology.

No Evidence of BCMA Expression Loss or Systemic Immune Impairment after Treatment with the BCMA-Targeted Antibody-Drug Conjugate (ADC) Belantamab Mafodotin (Belamaf) in the DREAMM-1 and DREAMM-2 Trials of Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Introduction: Belamaf, a first-in-class humanized ADC, binds BCMA expressed on differentiated B cells and myeloma (MM) cells. Belamaf monotherapy demonstrated deep and durable responses in the DREAMM-2 trial of patients (pts) with RRMM. Belamaf eliminates MM cells by a multimodal mechanism of action (MoA): direct cell killing and anti-MM immune response. We explored whether complete target loss and/or immune impairment were observed in pts who received belamaf in the DREAMM-1 and -2 trials. Methods: DREAMM-1 was a phase 1 dose-escalation study to investigate the safety, PK/PD, immunogenicity, and clinical activity of belamaf. DREAMM-2 was an open-label, two-arm, phase 2 study of belamaf 2.5 mg/kg or 3.4 mg/kg IV Q3W. Both trials enrolled adult pts with RRMM with ≥3 prior lines of therapy including an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 monoclonal antibody (DREAMM-2 only). Free sBCMA, a shed form of BCMA that circulates in blood after cleavage from the membrane, was measured using an electrochemiluminescence assay on the MesoScale Discovery platform (Alliance Pharma, Malvern, PA; detection range 1.95-1000 ng/mL). Absolute concentrations of sBCMA were examined at baseline (BL), with absolute concentration and fold-change from BL assessed at best achieved response and latest progression. After the first post-infusion timepoint, samples were taken >4 days post-infusion to minimize belamaf interference. In this post hoc analysis, association of sBCMA with time-on-study was modeled using a linear mixed model to adjust for longitudinal categorical response, with time modeled as a quadratic function of square-root-time-on-study. A generalized additive mixed model was used to adjust the time-association for M-protein among pts with apparent secretory disease. Immune cell populations in peripheral blood were analyzed using flow cytometry and clinical hematology tests. Neutrophil-to-lymphocyte ratio and total lymphocyte counts were modeled by categorical pt visit adjusted for continuous or count-based biomarkers; T cell subpopulation counts were modeled using negative binomial mixed effects models. Results: At progression, sBCMA levels were detectable in 98% (50/51) of eligible pts in DREAMM-1 and 98.9% (181/183) of eligible pts in DREAMM-2, regardless of response status. Decreased sBCMA vs predose levels was observed immediately post-infusion in all response groups. In nonresponders, sBCMA returned to predose levels within 1 cycle. Responders (≥partial response) had a quantitatively lower but measurable sBCMA level, suggesting BCMA loss is not commonly observed in pts receiving belamaf. In 97% (64/66) of pts who responded but later progressed in DREAMM-2, sBCMA levels showed a pronounced drop during response but returned to near BL upon progression (Fig A). This suggests membrane BCMA expression is not lost following belamaf treatment and complete target loss is not the primary mechanism driving tumor escape in these pts. Previously, sBCMA levels have been shown to correlate with disease burden markers (e.g., M-protein) and ISS stage; we modeled sBCMA correcting for these associations to evaluate on-treatment dynamics, predicting a decrease in sBCMA with increasing time-on-treatment. After correcting for lower average BL and on-treatment sBCMA levels in responders, sBCMA levels tended to decrease over time. Longitudinal monitoring of pts' systemic immune cell populations showed no change in immune cell ratios (Fig B) or major cell populations regardless of response status. Immune cell profiles of responders and nonresponders were similar and consistent over time suggesting belamaf does not detrimentally affect total lymphocyte numbers while mediating anti-MM activity. Conclusions: Belamaf resistance and immune escape mechanisms are not well understood. We found no evidence that BCMA expression is completely lost after belamaf treatment. When sBCMA decreased after belamaf treatment, levels returned to BL upon progression. Regardless of response status, belamaf does not appear to negatively impact total lymphocyte numbers. These data may help inform clinical sequencing of belamaf with other BCMA-targeted therapies. Funding: GSK (205678/NCT03525678; 117159/NCT02064387). Drug linker technology licensed from Seagen, Inc; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Fluctuation in the sense of belongingness during college moderates within-person associations between perceived injunctive norms and subsequent drinking.

Explanations for associations between social norms and drinking often focus on wanting to fit in, gain social approval, and/or avoid social exclusion. From this perspective, students who believe that drinking is strongly linked to social approval should be more motivated to drink, especially if their sense of social approval or belongingness in college is low. To evaluate this hypothesis, we examined changes in drinking as a function of fluctuations in perceived injunctive norms (i.e., perceptions of others' approval of drinking) and belongingness (i.e., one's sense of social belonging in college). Participants included 383 (60% women) nonabstaining students who, beginning in their first or second year of college, completed assessments every 3 months over a 2-year period. Data were analyzed using multilevel mixed-effects negative binomial models followed by marginal tests to evaluate nonlinear interactions. Within-person results indicated that when individuals believed other students were more approving of alcohol, they subsequently increased their drinking, which is especially true when individuals' sense of belongingness was at or below average. Between-person effects revealed overall positive associations of injunctive norms and belongingness with drinking. In addition, greater alcohol consumption among individuals with higher injunctive norms was less evident among students with lower average levels of belongingness. Perceiving others as more approving of drinking corresponds to increased drinking only when personal levels of belongingness are at or below average. Elevated feelings of belongingness may buffer social influences on drinking. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Analysis of BRCA2 Copy Number Loss and Genomic Instability in Circulating Tumor Cells from Patients with Metastatic Castration-resistant Prostate Cancer

BackgroundBRCA2 alterations predict for a response to poly-ADP-ribose polymerase inhibition in metastatic castration-resistant prostate cancer (mCRPC). However, detection is hindered by insufficient tumor tissue and low sensitivity of cell-free DNA for detecting copy number loss. ObjectiveTo evaluate the BRCA2 loss detection using single-cell, shallow whole-genome sequencing (sWGS) of circulating tumor cells (CTCs) in patients with mCRPC. Design, setting, and participantsWe analyzed CTC samples collected concurrently with tumor biopsies intended for clinical sequencing in patients with progressing mCRPC. Outcome measurements and statistical analysisDifferences in proportions were evaluated using the chi-square test. Correlations between assays were analyzed in linear regression models. Associations between alterations and genomic instability were assessed on the single-cell level using mixed-effect negative binomial models. Results and limitationsWe identified 138 patients with concurrent CTC and biopsy samples. CTC sWGS generated copy number profiles in a similar proportion of patients to biopsy samples (83% vs 78%, p = 0.23), but was more effective than bone biopsies (79% vs 50%; p = 0.009). CTC sWGS detected BRCA2 loss in more patients than tissue at the ≥1 (42% vs 16%; p < 0.001) and ≥2 (27% vs 16%; p = 0.028) CTC thresholds. The overall prevalence of BRCA2 loss was not increased in CTCs using sample-level composite z scores (p = 0.4), but was significantly increased compared with a lower-than-expected prevalence in bone samples (21% vs 3%, p = 0.014). Positive/negative predictive values for CTC BRCA2 loss were 89%/96% using the ≥1 CTC threshold and 67%/92% using the composite z score. CTC BRCA2 loss was associated with higher genomic instability in univariate (1.4-fold large-scale transition difference, 95% confidence interval [CI]: 1.2–1.6; p < 0.001) and multivariable analysis (1.4-fold difference, 95% CI: 1.2–1.6; p < 0.001). ConclusionsCopy number profiles can reliably be generated using CTC sWGS, which detected a majority of tissue-confirmed BRCA2 loss and “CTC-only” losses. BRCA2 losses were supported by increases in genomic instability. Patient summaryCurrent testing strategies have limitations in their ability to detect BRCA2 loss, a relatively common alteration in prostate cancer that is used to identify patients who may benefit from targeted therapy. In this paper, we evaluated whether we could detect BRCA2 loss in individual tumor cells isolated from patient blood samples and found this method to be suitable for further analysis.

Patient-Reported Outcomes Correlate With Microbial Community Composition Independent of Mucosal Inflammation in Pediatric Inflammatory Bowel Disease.

Inflammatory bowel diseases (IBDs) involve an aberrant host response to intestinal microbiota causing mucosal inflammation and gastrointestinal symptoms. Patient-reported outcomes (PROs) are increasingly important in clinical care and research. Our aim was to examine associations between PROs and fecal microbiota in patients 0 to 22 years of age with IBD. A longitudinal, prospective, single-center study tested for associations between microbial community composition via shotgun metagenomics and PROs including stool frequency and rectal bleeding in ulcerative colitis (UC) and abdominal pain and stool frequency in Crohn's disease (CD). Mucosal inflammation was assessed with fecal calprotectin. A negative binomial mixed-effects model including clinical characteristics and fecal calprotectin tested for differentially abundant species and metabolic pathways by PROs. In 70 CD patients with 244 stool samples, abdominal pain correlated with increased relative abundance of Haemophilus and reduced Clostridium spp. There were no differences relative to calprotectin level. In 23 UC patients with 76 samples, both rectal bleeding and increased stool frequency correlated with increased Klebsiella and reduced Bacteroides spp. Conversely, UC patients with lower calprotectin had reduced Klebsiella. Both UC and CD patients with active symptoms exhibited less longitudinal microbial community stability. No differences in metabolic pathways were observed in CD. Increased sulfoglycolysis and ornithine biosynthesis correlated with symptomatic UC. Microbial community composition correlated with PROs in both CD and UC. Metabolic pathways differed relative to PROs in UC, but not CD. Data suggest that microbiota may contribute to patient symptoms in IBD, in addition to effects of mucosal inflammation.