Foot-and-Mouth Disease.

Foot-and-mouth disease (FMD) is a viral infection of livestock that is an important determinant of global trade in animal products. The disease causes a highly contagious vesicular syndrome of cloven-hoofed animals. Successful control of FMD is dependent upon early detection and recognition of the clinical signs, followed by appropriate notification and response of responsible government entities. Awareness of the clinical signs of FMD amongst producers and veterinary practitioners is therefore the key in protecting US agriculture from the catastrophic impacts of an FMD outbreak. This review summarizes key clinical and epidemiologic features of FMD from a US perspective.

Selective trace elements significantly enhanced methane production in coal bed methane systems by stimulating microbial activity.

Trace elements are associated with the microbial degradation of organic matter and methanogenesis, as enzymes in metabolic pathways often employ trace elements as essential cofactors. However, only a few studies investigated the effects of trace elements on the metabolic activity of microbial communities associated with biogenic coalbed methane production. We aimed to determine the effects of strategically selected trace elements on structure and function of active bacterial and methanogenic communities to stimulate methane production in subsurface coalbeds. Microcosms were established with produced water and coal from coalbed methane wells located in the Powder River Basin, Wyoming, USA. In initial pilot experiments with eight different trace elements, individual amendments of Co, Cu, and Mo lead to significantly higher methane production. Transcript levels of mcrA, the key marker gene for methanogenesis, positively correlated with increased methane production. Phylogenetic analysis of the mcrA cDNA library demonstrated compositional shifts of the active methanogenic community and increase of their diversity, particularly of hydrogenotrophic methanogens. High-throughput sequencing of cDNA obtained from 16S rRNA demonstrated active and abundant bacterial groups in response to trace element amendments. Active Acetobacterium members increased in response to Co, Cu, and Mo additions. The findings of this study yield new insights into the importance of essential trace elements on the metabolic activity of microbial communities involved in subsurface coalbed methane and provide a better understanding of how microbial community composition is shaped by trace elements.IMPORTANCEMicrobial life in the deep subsurface of coal beds is limited by nutrient replenishment. While coal bed microbial communities are surrounded by carbon sources, we hypothesized that other nutrients such as trace elements needed as cofactors for enzymes are missing. Amendment of selected trace elements resulted in compositional shifts of the active methanogenic and bacterial communities and correlated with higher transcript levels of mcrA. The findings of this study yield new insights to not only identify possible limitations of microbes by replenishment of trace elements within their specific hydrological placement but also into the importance of essential trace elements for the metabolic activity of microbial communities involved in subsurface coalbed methane production and provides a better understanding of how microbial community composition is shaped by trace elements. Furthermore, this finding might help to revive already spent coal bed methane well systems with the ultimate goal to stimulate methane production.

Inherent differences of small airway contraction and Ca2+ oscillations in airway smooth muscle cells between BALB/c and C57BL/6 mouse strains.

BALB/c and C57BL/6 mouse strains are widely used as animal model in studies of respiratory diseases, such as asthma. Asthma is characterized by airway hyperresponsiveness, which is eventually resulted from the excessive airway smooth muscle (ASM) contraction mediated by Ca2+ oscillations in ASM cells. It is reported that BALB/c mice have inherently higher airway responsiveness, but show no different contractive response of tracheal ring as compared to C57BL/6 mice. However, whether the different airway responsiveness is due to the different extents of small airway contraction, and what's underlying mechanism remains unknown. Here, we assess agonist-induced small airway contraction and Ca2+ oscillations in ASM cells between BALB/c and C57BL/6 mice by using precision-cut lung slices (PCLS). We found that BALB/c mice showed an intrinsically stronger extent of small airway narrowing and faster Ca2+ oscillations in ASM cells in response to agonists. These differences were associated with a higher magnitude of Ca2+ influx via store-operated Ca2+ entry (SOCE), as a result of increased expression of SOCE components (STIM1, Orai1) in the ASM cells of small airway of BALB/c mice. An established mathematical model and experimental results suggested that the increased SOC current could result in increased agonist-induced Ca2+ oscillations. Therefore, the inherently higher SOC underlies the increased Ca2+ oscillation frequency in ASM cells and stronger small airway contraction in BALB/c mice, thus higher airway responsiveness in BALB/c than C57BL/6 mouse strain.

Inferential implications of normalizing binomial proportions in a structural equation model: A simulation study motivated by feedlot data.

Most commercial software for implementation of structural equation models (SEM) cannot explicitly accommodate outcome variables of binomial nature. As a result, SEM modeling strategies of binomial outcomes are often based on normal approximations of empirical proportions. Inferential implications of these approximations are particularly relevant to health-related outcomes. The objective of this study was to assess the inferential implications of specifying a binomial variable as an empirical proportion (%) in predictor and outcome roles in a SEM. We addressed this objective first by a simulation study, and second by a proof-of-concept data application on beef feedlot morbidity to bovine respiratory disease (BRD). We simulated data on body weight at feedlot arrival (AW), morbidity count for BRD (Mb), and average daily gain (ADG). Alternative SEMs were fitted to the simulated data. Model 1 specified a directed acyclic causal diagram with morbidity fitted as a binomial outcome (Mb) and as a proportion (Mb_p) predictor. Model 2 specified a similar causal diagram with morbidity fitted as a proportion for both outcome and predictor roles within the network. Structural parameters for Model 1 were accurately estimated based on the nominal coverage probability of 95 % confidence intervals. In turn, there was poor coverage for most morbidity-related parameters under Model 2. Both SEM models showed adequate empirical power (>80 %) to detect parameters not equal to zero. Model 1 and Model 2 produced predictions that were reasonable from a management standpoint, as determined by calculating the root mean squared error (RMSE) through cross-validation. However, interpretability of parameter estimates in Model 2 was impaired due to the model misspecification relative to the data generation. The data application fitted SEM extensions, Model 1 * and Model 2 * , to a dataset from a group of feedlots in the Midwestern US. Models 1 * and 2 * included explanatory covariates, specifically percent shrink (PS), backgrounding type (BG), and season (SEA). Lastly, we tested if AW exerted both direct and BRD-mediated indirect effects on ADG using Model 2 * . In Model 1 * , mediation was not testable due to the incomplete path from morbidity as a binomial outcome through Mb_p as a predictor to ADG. Model 2 * supported a minor morbidity-mediated mechanism between AW and ADG, though parameter estimates were not directly interpretable. Our results indicate normal approximation to a binomial disease outcome in a SEM may be a viable option for inference on mediation hypotheses and for predictive purposes, despite limitations in interpretability due to inherent model misspecification.

Can changing neighborhoods influence mental health? An ecological analysis of gentrification and neighborhood-level serious psychological distress-New York City, 2002-2015.

Neighborhood conditions influence people's health; sustaining healthy neighborhoods is a New York City (NYC) Health Department priority. Gentrification is characterized by rapid development in historically disinvested neighborhoods. The gentrification burden, including increased living expenses, and disrupted social networks, disproportionally impacts certain residents. To ultimately target health promotion interventions, we examined serious psychological distress time trends in gentrifying NYC neighborhoods to describe the association of gentrification and mental health overall and stratified by race and ethnicity. We categorized NYC neighborhoods as hypergentrifying, gentrifying, and not-gentrifying using a modified New York University Furman Center index. Neighborhoods with ≥100% rent growth were hypergentrifying; neighborhoods with greater than median and <100% rent growth were gentrifying; and neighborhoods with less than median rent growth were not-gentrifying. To temporally align neighborhood categorization closely with neighborhood-level measurement of serious psychological distress, data during 2000-2017 were used to classify neighborhood type. We calculated serious psychological distress prevalence among adult populations using data from 10 NYC Community Health Surveys during 2002-2015. Using joinpoint and survey-weighted logistic regression, we analyzed serious psychological distress prevalence time trends during 2002-2015 by gentrification level, stratified by race/ethnicity. Among 42 neighborhoods, 7 were hypergentrifying, 7 were gentrifying, and 28 were not gentrifying. In hypergentrifying neighborhoods, serious psychological distress prevalence decreased among White populations (8.1% to 2.3%, ß = -0.77, P = 0.02) and was stable among Black (4.6% to 6.9%, ß = -0.01, P = 0.95) and Latino populations (11.9% to 10.4%, ß = -0.16, P = 0.31). As neighborhoods gentrified, different populations were affected differently. Serious psychological distress decreased among White populations in hypergentrifying neighborhoods, no similar reductions were observed among Black and Latino populations. This analysis highlights potential unequal mental health impacts that can be associated with gentrification-related neighborhood changes. Our findings will be used to target health promotion activities to strengthen community resilience and to ultimately guide urban development policies.

Modeled impacts of rapid and accurate cattle tracing in a Foot-and-Mouth Disease outbreak in the US.

The purpose of this study was to estimate the impacts of rapid and accurate tracing of cattle movements during a Foot-and-Mouth Disease (FMD) outbreak in the United States (US). To simulate introduction and spread of FMD we utilized InterSpread Plus, a spatially explicit disease transmission model, and a national livestock population file. The simulations began in one of four regions of the US via beef or dairy cattle as the index infected premises (IP). The first IP was detected 8, 14, or 21 days after introduction. The tracing levels were defined by the probability of a successful trace and the time to trace completion. We evaluated three tracing performance levels, a baseline that represents a mix of paper and electronic interstate shipment records, an estimated partial implementation of electronic identification (EID) tracing, and an estimated full implementation of EID tracing. To evaluate the potential to decrease the size of control areas and surveillance zones with full EID use, we compared the standard size for each to a reduced geographical area for each. The total number of IPs in an outbreak varied with the location of the index farms. Within index farm locations and across tracing performance levels, early detection (day 8) resulted in fewer IPs and a shorter duration of the outbreak. The impact of improving tracing was most evident within introduction region when detection was delayed (day 14 or 21). Full EID use decreased the 95th percentile but had a smaller impact on the median number of IPs. Improved tracing also decreased the number of farms impacted by control efforts in control areas (0-10 km) and surveillance zones (10-20 km) by decreasing outbreak size (total IPs). Decreasing the control area (0-7 km) and surveillance zone (7-14 km) sizes while using full EID tracing further decreased the number of farms under surveillance but increased the number of IPs slightly. Consistent with previous results, this supports the potential value of early detection and improved traceability to control FMD outbreaks. Further development of the EID system in the US is necessary to achieve the modeled results. Further research into the economic impacts of enhanced tracing and decreased zone sizes are needed to determine the full impact of these results.

Translational PK/PD Modeling of Tumor Growth Inhibition and Target Inhibition to Support Dose Range Selection of the LMP7 Inhibitor M3258 in Relapsed/Refractory Multiple Myeloma.

M3258 is an orally bioavailable, potent, selective, reversible inhibitor of the large multifunctional peptidase 7 (LMP7, ß5i, PSMB8) proteolytic subunit of the immunoproteasome, a component of the cellular protein degradation machinery, highly expressed in malignant hematopoietic cells including multiple myeloma. Here we describe the fit-for-purpose pharmacokinetic (PK)/pharmacodynamic (PD)/efficacy modeling of M3258 based on preclinical data from several species. The inhibition of LMP7 activity (PD) and tumor growth (efficacy) were tested in human multiple myeloma xenografts in mice. PK and efficacy data were correlated yielding a free M3258 concentration of 45 nM for half-maximal tumor growth inhibition (KC50). As M3258 only weakly inhibits LMP7 in mouse cells, both in vitro and in vivo bridging studies were performed in rats, monkeys, and dogs for translational modeling. These data indicated that the PD response in human xenograft models was closely reflected in dog PBMCs. A PK/PD model was established, predicting a free IC50 value of 9 nM for M3258 in dogs in vivo, in close agreement with in vitro measurements. In parallel, the human PK parameters of M3258 were predicted by various approaches including in vitro extrapolation and allometric scaling. Using PK/PD/efficacy simulations, the efficacious dose range and corresponding PD response in human were predicted. Taken together, these efforts supported the design of a phase Ia study of M3258 in multiple myeloma patients (NCT04075721). At the lowest tested dose level, the predicted exposure matched well with the observed exposure while the duration of LMP7 inhibition was underpredicted by the model. SIGNIFICANCE STATEMENT: M3258 is a novel inhibitor of the immunoproteasome subunit LMP7. The human PK and human efficacious dose range of M3258 were predicted using in vitro-in vivo extrapolation and allometric scaling methods together with a fit-for-purpose PK/PD and efficacy model based on data from several species. A comparison with data from the Phase Ia clinical study showed that the human PK was accurately predicted, while the extent and duration of PD response were more pronounced than estimated.

Psychological and Physical Intimate Partner Violence, Measured by the New York City Community Health Survey - New York City, 2018.

Purpose: Intimate partner violence (IPV) can damage long-term physical and mental health, yet IPV prevalence in New York City (NYC) is unknown. We described prevalence and health correlates of psychological and physical IPV in NYC. Method: The 2018 NYC Community Health Survey, a representative telephone survey among adult residents, asked about lifetime psychological or physical IPV experiences. We estimated age-adjusted physical and psychological prevalence, stratified by demographic variables, and created log-linear multivariable models with 95% CIs to measure the association of each IPV type with health conditions and behaviors. Results: Overall, 10,076 surveys were completed. We excluded responses with missing IPV values. Of 9,945 adults, 16.7% reported ever having experienced psychological IPV; higher prevalence among females (18.6%; CI:17.0-20.2) than males (14.5%; CI:13.1-16.2). Prevalence of not getting needed mental health treatment (PR: 4.5; CI:3.3-6.1) and current depression (PR:2.6 CI:2.1-3.1) was higher among adults who had ever experienced psychological IPV, compared with those who had not. Of 9,964 adults, 9.8% reported ever having experienced physical IPV; higher prevalence among females (12.4%; CI:11.1-13.8) than males (6.8%; CI:5.8-8.0). Prevalence of not getting needed mental health treatment (PR:3.9, CI:2.8-5.4) and current depression (PR:2.6, CI:2.1-3.2) was higher among adults who had ever experienced physical IPV, compared with those who had not. Conclusions: One in six (16.7%) and one in 10 (9.8%) NYC adults reported ever experiencing psychological IPV and ever experiencing physical IPV, respectively. Key implications suggest that IPV potentially underlies public health priority health conditions and behaviors. Supplementary Information: The online version contains supplementary material available at 10.1007/s10896-022-00442-1.

A systematic review and meta-analysis of published literature on prevalence of non-O157 Shiga toxin-producing Escherichia coli serogroups (O26, O45, O103, O111, O121, and O145) and virulence genes in feces, hides, and carcasses of pre- and peri-harvest cattle worldwide.

OBJECTIVE: The objective of this study was to summarize peer-reviewed literature on the prevalence and concentration of non-O157 STEC (O26, O45, O103, O111, O121, and O145) serogroups and virulence genes (stx and eae) in fecal, hide, and carcass samples in pre- and peri-harvest cattle worldwide, using a systematic review of the literature and meta-analyses. DATA SYNTHESIS: Seventy articles were eligible for meta-analysis inclusion; data from 65 articles were subjected to random-effects meta-analysis models to yield fecal prevalence estimates. Meta-regression models were built to explore variables contributing to the between-study heterogeneity. RESULTS: Worldwide pooled non-O157 serogroup, STEC, and EHEC fecal prevalence estimates (95% confidence interval) were 4.7% (3.4-6.3%), 0.7% (0.5-0.8%), and 1.0% (0.8-1.1%), respectively. Fecal prevalence estimates significantly differed by geographic region (P < 0.01) for each outcome classification. Meta-regression analyses identified region, cattle type, and specimen type as factors that contribute to heterogeneity for worldwide fecal prevalence estimates. CONCLUSIONS: The prevalence of these global foodborne pathogens in the cattle reservoir is widespread and highly variable by region. The scarcity of prevalence and concentration data for hide and carcass matrices identifies a large data gap in the literature as these are the closest proxies for potential beef contamination at harvest.

Association between Tulathromycin Treatment for Bovine Respiratory Disease and Antimicrobial Resistance Profiles among Gut Commensals and Foodborne Bacterial Pathogens Isolated from Feces of Beef Steers.

ABSTRACT: This study was conducted to evaluate the association between a therapeutic dose of tulathromycin for bovine respiratory disease in beef steers and the antimicrobial and multidrug resistance profiles of the gastrointestinal tract commensals Escherichia coli and Enterococcus spp. and the foodborne pathogens Salmonella enterica and Campylobacter spp. isolated from fecal samples. Individual fecal samples were collected on days 0, 14, and 28 from 70 beef steers that were housed in a single pen and had been treated or not treated with tulathromycin. Samples were cultured for bacterial isolation, and isolates were tested for antimicrobial susceptibility with the broth microdilution method to determine the MICs of clinically relevant antimicrobials used in both human and veterinary medicine. Generalized linear mixed effects models were fitted to estimate the prevalence of the bacterial species and the prevalence of resistant isolates over time and between treated and nontreated cattle and of multidrug-resistant isolates. Model-adjusted mean prevalences of E. coli, Enterococcus spp., S. enterica, and Campylobacter spp. were 99.5, 85.9, 1.5, and 17.7%, respectively. The prevalence of erythromycin-resistant Enterococcus spp. was significantly higher on day 14 (59.7%) than on day 28 (22.2%). A higher prevalence of erythromycin-resistant Enterococcus spp. was found in samples from treated (59.3%) than in samples from nontreated (27.6%) animals. Multidrug resistance (three or more antimicrobial classes) was observed in 8.4% of E. coli isolates and 62.7% of Enterococcus isolates. The administration of tulathromycin was significantly associated with an increased prevalence of erythromycin-resistant Enterococcus spp. isolates.

Origin and Diversification of the Saguaro Cactus (Carnegiea gigantea): A Within-Species Phylogenomic Analysis.

Reconstructing accurate historical relationships within a species poses numerous challenges, not least in many plant groups in which gene flow is high enough to extend well beyond species boundaries. Nonetheless, the extent of tree-like history within a species is an empirical question on which it is now possible to bring large amounts of genome sequence to bear. We assess phylogenetic structure across the geographic range of the saguaro cactus, an emblematic member of Cactaceae, a clade known for extensive hybridization and porous species boundaries. Using 200 Gb of whole genome resequencing data from 20 individuals sampled from 10 localities, we assembled two data sets comprising 150,000 biallelic single nucleotide polymorphisms (SNPs) from protein coding sequences. From these, we inferred within-species trees and evaluated their significance and robustness using five qualitatively different inference methods. Despite the low sequence diversity, large census population sizes, and presence of wide-ranging pollen and seed dispersal agents, phylogenetic trees were well resolved and highly consistent across both data sets and all methods. We inferred that the most likely root, based on marginal likelihood comparisons, is to the east and south of the region of highest genetic diversity, which lies along the coast of the Gulf of California in Sonora, Mexico. Together with striking decreases in marginal likelihood found to the north, this supports hypotheses that saguaro's current range reflects postglacial expansion from the refugia in the south of its range. We conclude with observations about practical and theoretical issues raised by phylogenomic data sets within species, in which SNP-based methods must be used rather than gene tree methods that are widely used when sequence divergence is higher. These include computational scalability, inference of gene flow, and proper assessment of statistical support in the presence of linkage effects. [Phylogenomics; phylogeography; rooting; Sonoran Desert.].

Accuracy in Near-Perfect Virus Phylogenies.

Phylogenetic trees from real-world data often include short edges with very few substitutions per site, which can lead to partially resolved trees and poor accuracy. Theory indicates that the number of sites needed to accurately reconstruct a fully resolved tree grows at a rate proportional to the inverse square of the length of the shortest edge. However, when inferred trees are partially resolved due to short edges, "accuracy" should be defined as the rate of discovering false splits (clades on a rooted tree) relative to the actual number found. Thus, accuracy can be high even if short edges are common. Specifically, in a "near-perfect" parameter space in which trees are large, the tree length $\xi$ (the sum of all edge lengths) is small, and rate variation is minimal, the expected false positive rate is less than $\xi/3$; the exact value depends on tree shape and sequence length. This expected false positive rate is far below the false negative rate for small $\xi$ and often well below 5% even when some assumptions are relaxed. We show this result analytically for maximum parsimony and explore its extension to maximum likelihood using theory and simulations. For hypothesis testing, we show that measures of split "support" that rely on bootstrap resampling consistently imply weaker support than that implied by the false positive rates in near-perfect trees. The near-perfect parameter space closely fits several empirical studies of human virus diversification during outbreaks and epidemics, including Ebolavirus, Zika virus, and SARS-CoV-2, reflecting low substitution rates relative to high transmission/sampling rates in these viruses.[Ebolavirus; epidemic; HIV; homoplasy; mumps virus; perfect phylogeny; SARS-CoV-2; virus; West Nile virus; Yule-Harding model; Zika virus.].

Adapting Survey Data Collection to Respond to the COVID-19 Pandemic: Experiences From a Local Health Department.

The New York City (NYC) Department of Health and Mental Hygiene ("Health Department") conducts routine surveys to describe the health of NYC residents. During the COVID-19 pandemic, the Health Department adjusted existing surveys and developed new ones to improve our understanding of the impact of the pandemic on physical health, mental health, and social determinants of health and to incorporate more explicit measures of racial inequities. The longstanding Community Health Survey was adapted in 2020 to ask questions about COVID-19 and recruit respondents for a population-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serosurvey. A new survey panel, Healthy NYC, was launched in June 2020 and is being used to collect data on COVID-19, mental health, and social determinants of health. In addition, 7 Health Opinion Polls were conducted from March 2020 through March 2021 to learn about COVID-19-related knowledge, attitudes, and opinions, including vaccine intentions. We describe the contributions that survey data have made to the emergency response in NYC in ways that address COVID-19 and the profound inequities of the pandemic. (Am J Public Health. 2021;111(12):2176-2185. https://doi.org/10.2105/AJPH.2021.306515).

Survey of emergency response plans for managing the movement of cattle during a foot-and-mouth disease outbreak in North America.

OBJECTIVE: To collect information from US state animal health officials (SAHOs) and beef feedlot managers and veterinarians regarding emergency response plans for movement of cattle in the event of a foot-and-mouth disease (FMD) outbreak in North America. SAMPLE: 36 SAHOs, 26 feedlot veterinarians, and 7 feedlot managers. PROCEDURES: 3 versions of an electronic questionnaire were created and distributed to SAHOs and US feedlot veterinarians and managers to gather information about planned or expected responses to an FMD outbreak that originated at 1 of 3 geographic locations (Mexico or Canada, a bordering state, or a nonbordering state). Descriptive data were reported. RESULTS: All respondents recognized that the risk of FMD transmission to livestock in their area or care increased as the outbreak got closer in proximity to their location. Most SAHOs indicated that they would immediately close their state's borders to livestock movement at the beginning of an FMD outbreak, particularly if the disease was identified in a bordering state. During an extended FMD outbreak, 29 of 36 (80.6%) SAHOs reported they would resume interstate movement of cattle under some conditions, including enhanced permitting, whereas feedlot veterinarians and managers commonly reported they would be willing to receive cattle from states where no FMD-infected animals were identified, regardless of permit requirements. CONCLUSIONS AND CLINICAL RELEVANCE: Information gained from this survey can be used to inform disease modeling and preparedness efforts to facilitate business continuity of US beef feedlots in the event of an FMD outbreak in North America.

Plastome Structural Evolution and Homoplastic Inversions in Neo-Astragalus (Fabaceae).

The plastid genomes of photosynthetic green plants have largely maintained conserved gene content and order as well as structure over hundreds of millions of years of evolution. Several plant lineages, however, have departed from this conservation and contain many plastome structural rearrangements, which have been associated with an abundance of repeated sequences both overall and near rearrangement endpoints. We sequenced the plastomes of 25 taxa of Astragalus L. (Fabaceae), a large genus in the inverted repeat-lacking clade of legumes, to gain a greater understanding of the connection between repeats and plastome inversions. We found plastome repeat structure has a strong phylogenetic signal among these closely related taxa mostly in the New World clade of Astragalus called Neo-Astragalus. Taxa without inversions also do not differ substantially in their overall repeat structure from four taxa each with one large-scale inversion. For two taxa with inversion endpoints between the same pairs of genes, differences in their exact endpoints indicate the inversions occurred independently. Our proposed mechanism for inversion formation suggests the short inverted repeats now found near the endpoints of the four inversions may be there as a result of these inversions rather than their cause. The longer inverted repeats now near endpoints may have allowed the inversions first mediated by shorter microhomologous sequences to propagate, something that should be considered in explaining how any plastome rearrangement becomes fixed regardless of the mechanism of initial formation.

Structure-Based Optimization and Discovery of M3258, a Specific Inhibitor of the Immunoproteasome Subunit LMP7 (ß5i).

Proteasomes are broadly expressed key components of the ubiquitin-dependent protein degradation pathway containing catalytically active subunits (ß1, ß2, and ß5). LMP7 (ß5i) is a subunit of the immunoproteasome, an inducible isoform that is predominantly expressed in hematopoietic cells. Clinically effective pan-proteasome inhibitors for the treatment of multiple myeloma (MM) nonselectively target LMP7 and other subunits of the constitutive proteasome and immunoproteasome with comparable potency, which can limit the therapeutic applicability of these drugs. Here, we describe the discovery and structure-based hit optimization of novel amido boronic acids, which selectively inhibit LMP7 while sparing all other subunits. The exploitation of structural differences between the proteasome subunits culminated in the identification of the highly potent, exquisitely selective, and orally available LMP7 inhibitor 50 (M3258). Based on the strong antitumor activity observed with M3258 in MM models and a favorable preclinical data package, a phase I clinical trial was initiated in relapsed/refractory MM patients.

Weather conditions associated with death attributed to bovine respiratory disease complex in high-risk auction market-sourced male beef calves.

OBJECTIVE: To evaluate associations between weather conditions and management factors with the incidence of death attributable to bovine respiratory disease complex (BRDC) in high-risk auction-sourced beef calves. ANIMALS: Cohorts (n = 3,339) of male beef calves (545,866) purchased by 1 large cattle feeding operation from 216 locations and transported to 1 of 89 feeding locations (backgrounding location or feedlot) with similar management protocols. PROCEDURES: Associations between weather conditions and management factors on the day of purchase (day P) and during the first week at the feeding location and cumulative BRDC mortality incidence within the first 60 days on feed were estimated in a mixed-effects negative binomial regression model. RESULTS: Significant factors in the final model were weaning status; degree of commingling; body weight; transport distance; season; precipitation, mean wind speed, and maximum environmental temperature on day P; environmental temperature range in the first week after arrival at the feeding location; and interactions between distance and wind speed and between body weight and maximum environmental temperature. Precipitation and wind speed on day P were associated with lower cumulative BRDC mortality incidence, but wind speed was associated only among calves transported long distances (≥ 1,082.4 km). Higher mean maximum temperature on day P increased the incidence of cumulative mortality among calves with low body weights (< 275.5 kg). CONCLUSIONS AND CLINICAL RELEVANCE: Several weather conditions on day P and during the first week after arrival were associated with incidence of BRDC mortality. The results may have implications for health- and economic-risk management, especially for high-risk calves and calves that are transported long distances.

Prevalence of SARS-CoV-2 Antibodies in New York City Adults, June-October 2020: A Population-Based Survey.

BACKGROUND: Serosurveys help to ascertain burden of infection. Prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serosurveys in New York City (NYC) used nonrandom samples. During June-October 2020, the NYC Health Department conducted a population-based survey estimating SARS-CoV-2 antibody prevalence in NYC adults. METHODS: Participants were recruited from the NYC 2020 Community Health Survey. We estimated citywide and stratified antibody prevalence using a hybrid design: serum tested with the DiaSorin LIAISON SARS-CoV-2 S1/S2 IgG assay and self-reported antibody test results were used together. We estimated univariate frequencies and 95% confidence intervals (CI), accounting for complex survey design. Two-sided P values ≤ .05 were statistically significant. RESULTS: There were 1074 respondents; 497 provided blood and 577 provided only a self-reported antibody test result. Weighted prevalence was 24.3% overall (95% CI, 20.7%-28.3%). Latino (30.7%; 95% CI, 24.1%-38.2%; P < .01) and black (30.7%; 95% CI, 21.9%-41.2%; P = .02) respondents had a higher weighted prevalence compared with white respondents (17.4%; 95% CI, 12.5%-23.7%). CONCLUSIONS: By October 2020, nearly 1 in 3 black and 1 in 3 Latino NYC adults had SARS-CoV-2 antibodies, highlighting unequal impacts of the coronavirus disease 2019 (COVID-19) pandemic on black and Latino NYC adults.

M3258 Is a Selective Inhibitor of the Immunoproteasome Subunit LMP7 (ß5i) Delivering Efficacy in Multiple Myeloma Models.

Large multifunctional peptidase 7 (LMP7/ß5i/PSMB8) is a proteolytic subunit of the immunoproteasome, which is predominantly expressed in normal and malignant hematolymphoid cells, including multiple myeloma, and contributes to the degradation of ubiquitinated proteins. Described herein for the first time is the preclinical profile of M3258; an orally bioavailable, potent, reversible and highly selective LMP7 inhibitor. M3258 demonstrated strong antitumor efficacy in multiple myeloma xenograft models, including a novel model of the human bone niche of multiple myeloma. M3258 treatment led to a significant and prolonged suppression of tumor LMP7 activity and ubiquitinated protein turnover and the induction of apoptosis in multiple myeloma cells both in vitro and in vivo Furthermore, M3258 showed superior antitumor efficacy in selected multiple myeloma and mantle cell lymphoma xenograft models compared with the approved nonselective proteasome inhibitors bortezomib and ixazomib. The differentiated preclinical profile of M3258 supported the initiation of a phase I study in patients with multiple myeloma (NCT04075721).

FGFR1 overexpression in non-small cell lung cancer is mediated by genetic and epigenetic mechanisms and is a determinant of FGFR1 inhibitor response.

Amplification of fibroblast growth factor receptor 1 (FGFR1) in non-small cell lung cancer (NSCLC) has been considered as an actionable drug target. However, pan-FGFR tyrosine kinase inhibitors did not demonstrate convincing clinical efficacy in FGFR1-amplified NSCLC patients. This study aimed to characterise the molecular context of FGFR1 expression and to define biomarkers predictive of FGFR1 inhibitor response. In this study, 635 NSCLC samples were characterised for FGFR1 protein expression by immunohistochemistry and copy number gain (CNG) by in situ hybridisation (n = 298) or DNA microarray (n = 189). FGFR1 gene expression (n = 369) and immune cell profiles (n = 309) were also examined. Furthermore, gene expression, methylation and microRNA data from The Cancer Genome Atlas (TCGA) were compared. A panel of FGFR1-amplified NSCLC patient-derived xenograft (PDX) models were tested for response to the selective FGFR1 antagonist M6123. A minority of patients demonstrated FGFR1 CNG (10.5%) or increased FGFR1 mRNA (8.7%) and protein expression (4.4%). FGFR1 CNG correlated weakly with FGFR1 gene and protein expression. Tumours overexpressing FGFR1 protein were typically devoid of driver alterations (e.g. EGFR, KRAS) and showed reduced infiltration of T-lymphocytes and lower PD-L1 expression. Promoter methylation and microRNA were identified as regulators of FGFR1 expression in NSCLC and other cancers. Finally, NSCLC PDX models demonstrating FGFR1 amplification and FGFR1 protein overexpression were sensitive to M6123. The unique molecular and immune features of tumours with high FGFR1 expression provide a rationale to stratify patients in future clinical trials of FGFR1 pathway-targeting agents.