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•EDs play a crucial role in Hepatitis C screening and linkage to care.•Predictors of linkage to care failure may be used to enhance linkage efforts.•Predictors of linkage failure were identified for 1674 patients with Hepatitis C.•Young age, white race, homelessness, substance use, & mental illness increased risk.•Medical comorbidities and HIV co-infection protected against linkage failure. We implemented a nontargeted, opt-out HCV testing and linkage to care (LTC) program in an academic tertiary care emergency department (ED). Despite research showing the critical role of ED-based HCV testing programs, predictors of LTC have not been defined for patients identified through the nontargeted ED testing strategy. In order to optimize health outcomes for patients with HCV, we sought to identify predictors of LTC failure. This was a retrospective cohort study of adult patients who were tested for HCV in the ED between August 2015 and September 2018 and were confirmed to have chronic HCV infection through RNA testing. We used logistic regression to assess the relationship between candidate predictors and the primary outcome, LTC failure, which was defined as a patient not being seen by an HCV treating provider after discharge from the ED. Of 53,297 patients tested, 1,674 (3.1%) had HCV on confirmatory testing, and 355 (21%) linked to care. Predictors of LTC failure included younger age (OR 0.96, 95% CI 0.95–0.97), white race (OR 1.65, 95% CI 1.23–2.22), homelessness (OR 1.91, 95% CI 1.19–3.08), substance use (OR 1.77, 95% CI 1.34–2.34), and comorbid psychiatric illness (OR 2.16, 95% CI 1.59–2.94). Patients with significant medical comorbidities (OR 0.57, 95% CI 0.41–0.78) or HIV co-infection (OR 0.11, 95% CI 0.03–0.46) were less likely to experience LTC failure. One in five HCV-infected patients identified by ED-based nontargeted testing successfully linked to an HCV treating provider. Predictors of LTC failure may guide the development of targeted interventions to improve LTC success.

A challenge that conservation practitioners face is manipulating behavior of nuisance species. The turkey vulture ( Cathartes aura ) can cause substantial damage to aircraft if struck. The goal of this study was to assess vulture responses to unmanned aircraft systems (UAS) for use as a possible dispersal tool. Our treatments included three platforms (fixed-wing, multirotor, and a predator-like ornithopter [powered by flapping flight]) and two approach types (30 m overhead or targeted towards a vulture) in an operational context. We evaluated perceived risk as probability of reaction, reaction time, flight-initiation distance (FID), vulture remaining index, and latency to return. Vultures escaped sooner in response to the fixed-wing; however, fewer remained after multirotor treatments. Targeted approaches were perceived as riskier than overhead. Vulture perceived risk was enhanced by flying the multirotor in a targeted approach. We found no effect of our treatments on FID or latency to return. Latency was negatively correlated with UAS speed, perhaps because slower UAS spent more time over the area. Greatest visual saliency followed as: ornithopter, fixed-wing, and multirotor. Despite its appearance, the ornithopter was not effective at dispersing vultures. Because effectiveness varied, multirotor/fixed-wing UAS use should be informed by management goals (immediate dispersal versus latency).

Primary human hepatocytes (PHHs) are widely used as in vitro models for liver function and drug metabolism studies, yet their metabolic stability post-thawing remains an open question. To better characterize early metabolic changes, we conducted a time-course experiment using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to analyze metabolic shifts in PHHs cultured in suspension. Unexposed and exposed (acetaminophen-treated) samples were evaluated, and TITAN analysis was applied to determine the time point of maximal metabolic change at both individual metabolite and global metabolic profile levels. Our results indicate that the majority of metabolic shifts occur within the first five hours post-thawing. In the early culture time points, substantial metabolic overlap was observed between unexposed and exposed cells, suggesting a conserved biological response likely related to cellular recovery. However, at later time points, metabolite profiles diverged, with acetaminophen treatment-specific metabolic changes emerging, potentially reflecting differences in homeostatic restoration versus hepatotoxic responses. Our study highlights the importance of considering early post-thawing metabolic dynamics in experimental design and offers insights for optimizing hepatocyte culture protocols to better replicate in vivo physiological conditions.

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1 , not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response. Statins are effectively used to prevent and manage cardiovascular disease, but patient response to these drugs is highly variable. Here, the authors identify two new genes associated with the response of LDL cholesterol to statins and advance our understanding of the genetic basis of drug response.

The European Starling (Sturnus vulgaris) has expanded beyond its native Eurasian range, exploiting both natural cavities and human structures for nesting. We hypothesized that starling exposure to enhanced risk of nest predation at nest boxes (surrogates for nest sites in other structures), due to predator access, would negatively affect occupancy (establishment of a nest and ≥1 egg) and subsequent nest success. We also hypothesized that starlings would show no distinction in occupancy between nest boxes relative to the presence/absence of old nest material (i.e., material from the previous season), conditions that can contribute to nest predation risk. We conducted our study from April to June 2021 in Erie County, Ohio, USA, using 120 wooden nest boxes. Our treatments comprised protected/swept (nest boxes protected by a predator guard below the nest box and swept of old nest material), protected/unswept (containing old nest material), and unprotected/unswept nest boxes. To maximize sample size per treatment, we opted to forego use of unprotected/swept nest boxes, thereby preventing assessment of possible, enhanced nest predation (from below the nest box) at unprotected nest boxes due to the presence of old nest material. We used generalized linear models and nonparametric approaches in our comparisons. Starlings occupied and fledged young in unprotected nest boxes and nest boxes containing old nest material through the breeding season, despite possible, elevated perceived predation risk. There was no advantage of protection or disadvantage of presence of old nest material on reproductive metrics in protected/unswept nest boxes, because of predation from raptors (Accipitridae) and arboreal mammals (Sciuridae). The absolute amount of nest predation was, not surprisingly, highest in unprotected/unswept nest boxes across laying, incubation, and brood stages, but occurred primarily during brood rearing for protected boxes. El estornino Sturnus vulgaris se ha expandido más allá de su rango nativo Eurasiático, explotando tanto cavidades naturales como estructuras humanas para anidar. Hipotetizamos que la exposición del estornino a riesgos aumentados de depredación en cajas nido (sustitutos para sitios de anidación en otras estructuras) debido a acceso de depredadores afectaría la ocupación (establecimiento de nido y ≥1 huevo) y éxito de nido sucesivo. También hipotetizamos que los estorninos no mostrarían diferencia en ocupación entre cajas nido relativas a la presencia/ausencia de material viejo de nido (es decir, material de estaciones anteriores), condiciones que pueden contribuir al riesgo de depredación. Condujimos nuestro estudio de abril a junio del 2021 en el condado Erie, Ohio, Estados Unidos, usando 120 cajas nido de madera. Nuestros tratamientos consistieron en cajas nido protegidas/barridas (cajas nido protegidas por guardián de depredadores bajo la caja nido y barrida de material viejo de nido), protegida/sin barrer (que contenía material viejo de nido) y sin proteger/sin barrer. Para maximizar el tamaño de muestra por tratamiento, optamos por no usar cajas nido sin proteger/barridas, previniendo así la medición de un posible aumento de depredación de nido (desde abajo de la caja nido) a cajas nido sin proteger debido a la presencia de material viejo de nido. Usamos modelos lineales generalizados y un acercamiento no paramétrico para nuestras comparaciones. Los estorninos ocuparon y emanciparon crías en cajas nido sin protección y en cajas nido que contenían material viejo de nido durante la estación reproductiva, a pesar del posible elevado riesgo percibido de depredación. No hubo ventaja en protección o desventaja en presencia de material viejo de nido en métricas reproductivas en cajas nido protegidas/sin barrer, debido a la depredación por rapaces (Accipitridae) y mamíferos arbóreos (Sciuridae). La cantidad absoluta de depredación de nidos fue, sin ninguna sorpresa, mayor en cajas nido sin protección/ sin barrer en puesta, incubación y crianza, pero ocurrión mayormente durante la crianza de los polluelos en cajas protegidas. Palabras clave: depredación de nidos, selección de sitio de anidación, reproducción, especies que anidan en cavidades secundarias.

The European Starling (Sturnus vulgaris) has expanded beyond its native Eurasian range, exploiting both natural cavities and human structures for nesting. We hypothesized that starling exposure to enhanced risk of nest predation at nest boxes (surrogates for nest sites in other structures), due to predator access, would negatively affect occupancy (establishment of a nest and [greater than or equal to]1 egg) and subsequent nest success. We also hypothesized that starlings would show no distinction in occupancy between nest boxes relative to the presence/absence of old nest material (i.e., material from the previous season), conditions that can contribute to nest predation risk. We conducted our study from April to June 2021 in Erie County, Ohio, USA, using 120 wooden nest boxes. Our treatments comprised protected/swept (nest boxes protected by a predator guard below the nest box and swept of old nest material), protected/unswept (containing old nest material), and unprotected/unswept nest boxes. To maximize sample size per treatment, we opted to forego use of unprotected/swept nest boxes, thereby preventing assessment of possible, enhanced nest predation (from below the nest box) at unprotected nest boxes due to the presence of old nest material. We used generalized linear models and nonparametric approaches in our comparisons. Starlings occupied and fledged young in unprotected nest boxes and nest boxes containing old nest material through the breeding season, despite possible, elevated perceived predation risk. There was no advantage of protection or disadvantage of presence of old nest material on reproductive metrics in protected/unswept nest boxes, because of predation from raptors (Accipitridae) and arboreal mammals (Sciuridae). The absolute amount of nest predation was, not surprisingly, highest in unprotected/unswept nest boxes across laying, incubation, and brood stages, but occurred primarily during brood rearing for protected boxes. Received 6 January 2023. Accepted 30 December 2023.

Beneficial microbial associations enhance the fitness of most living organisms, and wood-feeding insects offer some of the most striking examples of this. Odontotaenius disjunctus is a wood-feeding beetle that possesses a digestive tract with four main compartments, each of which contains well-differentiated microbial populations, suggesting that anatomical properties and separation of these compartments may enhance energy extraction from woody biomass. Here, using integrated chemical analyses, we demonstrate that lignocellulose deconstruction and fermentation occur sequentially across compartments, and that selection for microbial groups and their metabolic pathways is facilitated by gut anatomical features. Metaproteogenomics showed that higher oxygen concentration in the midgut drives lignocellulose depolymerization, while a thicker gut wall in the anterior hindgut reduces oxygen diffusion and favours hydrogen accumulation, facilitating fermentation, homoacetogenesis and nitrogen fixation. We demonstrate that depolymerization continues in the posterior hindgut, and that the beetle excretes an energy- and nutrient-rich product on which its offspring subsist and develop. Our results show that the establishment of beneficial microbial partners within a host requires both the acquisition of the microorganisms and the formation of specific habitats within the host to promote key microbial metabolic functions. Together, gut anatomical properties and microbial functional assembly enable lignocellulose deconstruction and colony subsistence on an extremely nutrient-poor diet. Using integrated metagenomics, metaproteomics and metabolomics approaches, the authors characterize the microbial taxa and metabolic pathways facilitating lignocellulose degradation across gut compartments of a wood-feeding beetle.

Background/objectivesObesity, defined as excessive fat accumulation that represents a health risk, is increasing in adults and children, reaching global epidemic proportions. Body mass index (BMI) correlates with body fat and future health risk, yet differs in prediction by fat distribution, across populations and by age. Nonetheless, few genetic studies of BMI have been conducted in ancestrally diverse populations. Gene expression association with BMI was assessed in the Multi-Ethnic Study of Atherosclerosis (MESA) in four self-identified race and ethnicity (SIRE) groups to identify genes associated with obesity.Subjects/methodsRNA-sequencing was performed on 1096 MESA participants (37.8% white, 24.3% Hispanic, 28.4% African American, and 9.5% Chinese American) and linear models were used to assess the association of expression from each gene for its effect on BMI, adjusting for age, sex, sequencing center, study site, five expression and four genetic principal components in each self-identified race group. Sample-size-weighted meta-analysis was performed to identify genes with BMI-associated expression across ancestry groups.ResultsWithin individual SIRE groups, there were zero to three genes whose expression is significantly (p < 1.97 × 10–6) associated with BMI. Across all groups, 45 genes were identified by meta-analysis whose expression was significantly associated with BMI, explaining 29.7% of BMI variation. The 45 genes are expressed in a variety of tissues and cell types and are enriched for obesity-related processes including erythrocyte function, oxygen binding and transport, and JAK-STAT signaling.ConclusionsWe have identified genes whose expression is significantly associated with obesity in a multi-ethnic cohort. We have identified novel genes associated with BMI as well as confirmed previously identified genes from earlier genetic analyses. These novel genes and their biological pathways represent new targets for understanding the biology of obesity as well as new therapeutic intervention to reduce obesity and improve global public health.

Haemophilus influenzae is an opportunistic pathogen. The emergence of virulent, non-typeable strains (NTHi) emphasizes the importance of developing new interventional targets. We screened the NTHi supragenome for genes encoding surface-exposed proteins suggestive of immune evasion, identifying a large family containing Sel1-like repeats (SLRs). Clustering identified ten SLR-containing gene subfamilies, each with various numbers of SLRs per gene. Individual strains also had varying numbers of SLR-containing genes from one or more of the subfamilies. Statistical genetic analyses of gene possession among 210 NTHi strains typed as either disease or carriage found a significant association between possession of the SlrVA subfamily (which we have termed, macrophage survival factor, msf) and the disease isolates. The PittII strain contains four chromosomally contiguous msf genes. Deleting all four of these genes (msfA1-4) (KO) resulted in a highly significant decrease in phagocytosis and survival in macrophages; which was fully complemented by a single copy of the msfA1 gene. Using the chinchilla model of otitis media and invasive disease, the KO strain displayed a significant decrease in fitness compared to the WT in co-infections; and in single infections, the KO lost its ability to invade the brain. The singly complemented strain showed only a partial ability to compete with the WT suggesting gene dosage is important in vivo. The transcriptional profiles of the KO and WT in planktonic growth were compared using the NTHi supragenome array, which revealed highly significant changes in the expression of operons involved in virulence and anaerobiosis. These findings demonstrate that the msfA1-4 genes are virulence factors for phagocytosis, persistence, and trafficking to non-mucosal sites.

Clonal hematopoiesis of indeterminate potential (CHIP) is a common precursor state for blood cancers that most frequently occurs due to mutations in the DNA‐methylation modifying enzymes DNMT3A or TET2. We used DNA‐methylation array and whole‐genome sequencing data from four cohorts together comprising 5522 persons to study the association between CHIP, epigenetic clocks, and health outcomes. CHIP was strongly associated with epigenetic age acceleration, defined as the residual after regressing epigenetic clock age on chronological age, in several clocks, ranging from 1.31 years (GrimAge, p < 8.6 × 10−7) to 3.08 years (EEAA, p < 3.7 × 10−18). Mutations in most CHIP genes except DNA‐damage response genes were associated with increases in several measures of age acceleration. CHIP carriers with mutations in multiple genes had the largest increases in age acceleration and decrease in estimated telomere length. Finally, we found that ~40% of CHIP carriers had acceleration >0 in both Hannum and GrimAge (referred to as AgeAccelHG+). This group was at high risk of all‐cause mortality (hazard ratio 2.90, p < 4.1 × 10−8) and coronary heart disease (CHD) (hazard ratio 3.24, p < 9.3 × 10−6) compared to those who were CHIP−/AgeAccelHG−. In contrast, the other ~60% of CHIP carriers who were AgeAccelHG− were not at increased risk of these outcomes. In summary, CHIP is strongly linked to age acceleration in multiple clocks, and the combination of CHIP and epigenetic aging may be used to identify a population at high risk for adverse outcomes and who may be a target for clinical interventions. Clonal hematopoiesis of indeterminate potential (CHIP) and epigenetic age acceleration are the two important aging phenomenon associated with adverse clinical outcomes. We found that mutations in most CHIP genes were associated with increased age acceleration in multiple epigenetic clocks. Individuals with CHIP and age acceleration had a greatly increased risk of mortality and coronary heart disease compared to individuals with only CHIP or age acceleration.