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Objective: To evaluate: (1) the effectiveness of wireless handheld computers for online information retrieval in clinical settings; (2) the role of MEDLINE in answering clinical questions raised at the point of care.Design: A prospective single-cohort study: accompanying medical teams on teaching rounds, five internal medicine residents used and evaluated MD on Tap, an application for handheld computers, to seek answers in real time to clinical questions arising at the point of care.Measurements: All transactions were stored by an intermediate server. Evaluators recorded clinical scenarios and questions, identified MEDLINE citations that answered the questions, and submitted daily and summative reports of their experience. A senior medical librarian corroborated the relevance of the selected citation to each scenario and question.Results: Evaluators answered 68% of 363 background and foreground clinical questions during rounding sessions using a variety of MD on Tap features in an average session length of less than four minutes. The evaluator, the number and quality of query terms, the total number of citations found for a query, and the use of auto-spellcheck significantly contributed to the probability of query success.Conclusion: Handheld computers with Internet access are useful tools for healthcare providers to access MEDLINE in real time. MEDLINE citations can answer specific clinical questions when several medical terms are used to form a query. The MD on Tap application is an effective interface to MEDLINE in clinical settings, allowing clinicians to quickly find relevant citations. [ABSTRACT FROM AUTHOR]

Aim. This paper reports a study designed to assess an automated non-invasive, patient vigilance system, the LG[1TM] system, for determining heart rate and respiration rate. The study uses collected data to optimize the L[G1TM],s alert management scheme for medical/surgical wards. Background. Thousands of patients die unnecessarily each year because of compromised patient safety in hospitals. Economic pressures to reduce hospitalization costs, exacerbated by increasing nursing shortages, have created a need for new approaches to patient vigilance. Advanced technologies may help nurses to provide high-quality care while controlling costs and improving patient safety. Methods. Heart and respiration waveforms from 287 patients were captured by sensor arrays embedded in the mattress coverlets of their beds. No real-time monitoring was performed. Raw data were processed by proprietary algorithms and compared with data captured by a standard reference device. Alert performance was verified by hand-scoring the signal data and matching it against clinical events observed through a systematic review of each patient's medical record. The data were collected between June 2004 and February 2005. Results. Experimental algorithms for heart rate had an accuracy of 1.47 (SD 1.90) and a precision of 4.60 (SD 2.46). Respiration rate algorithms showed an accuracy of 0.94 (SD 1.26) and a precision of 4.02 (SD 1.17). Algorithms identified 178 true-positive physiological alerts on 15 patients. None of the events was deemed clinically significant at chart review. The combined false-positive alert rate for the algorithms was 0.007 events per hour. Conclusion. This study demonstrates the accuracy and precision of the signal processing algorithms in the LG1TM system. Future work will focus on assessing the system's impact on patient outcomes and its integration into the nursing workflow. [ABSTRACT FROM AUTHOR]

BACKGROUND: Health care workers outside surgical suites in Asia use surgical-type face masks commonly. Prevention of upper respiratory infection is one reason given, although evidence of effectiveness is lacking. METHODS: Health care workers in a tertiary care hospital in Japan were randomized into 2 groups: 1 that wore face masks and 1 that did not. They provided information about demographics, health habits, and quality of life. Participants recorded symptoms daily for 77 consecutive days, starting in January 2008. Presence of a cold was determined based on a previously validated measure of self-reported symptoms. The number of colds between groups was compared, as were risk factors for experiencing cold symptoms. RESULTS: Thirty-two health care workers completed the study, resulting in 2464 subject days. There were 2 colds during this time period, 1 in each group. Of the 8 symptoms recorded daily, subjects in the mask group were significantly more likely to experience headache during the study period (P < .05). Subjects living with children were more likely to have high cold severity scores over the course of the study. CONCLUSION: Face mask use in health care workers has not been demonstrated to provide benefit in terms of cold symptoms or getting colds. A larger study is needed to definitively establish noninferiority of no mask use. [ABSTRACT FROM AUTHOR]

Gray leaf spot (GLS) is an important corn disease reportedly caused by Cercospora zeae-maydis and C. zeina. Recently, flutriafol, a demethylation inhibitor (azole) fungicide received EPA registration as Xyway® LFR®, a product that is applied at planting for management of fungal diseases in corn, including suppression of GLS. In this study, 448 Cercospora spp. isolates were collected in 2020 and 2021 from symptomatic corn leaf samples submitted from the United States and Ontario, Canada. The Cercospora spp. were identified using multi-locus genotyping of the internal transcribe spacer (ITS), elongation factor 1-α (EF1), calmodulin (CAL), histone H3 (HIS), and actin (ACT) gene. Based on the multi-locus phylogenetic analyses, six species were identified; C. cf. flagellaris (n = 77), C. kikuchii (n = 4), C. zeae-maydis (n = 361), Cercospora sp. M (n = 2), Cercospora sp. Q (n = 1), and Cercospora sp. T (n = 3). In subsequent pathogenicity tests using selected isolates from each of these species, only C. zeae-maydis resulted in symptoms on corn with no disease symptoms observed after inoculation with C. cf. flagellaris, C. kikuchii, Cercospora sp. M, Cercospora sp. Q, and Cercospora sp. T. While disease symptoms were observed on soybean following inoculation with C. cf. flagellaris, C. kikuchii, and Cercospora sp. Q, but not the other three species. Fungicide sensitivity of Cercospora spp. to flutriafol was assessed using a subset of 340 isolates. The minimum inhibitory concentration (MIC) to inhibit the growth of Cercospora spp. completely was determined based on growth of each species on flutriafol-amended clarified V8 agar at nine concentrations. The EC50 was also calculated from the same trial by measuring relative growth as compared to the non-amended control. Cercospora zeae-maydis was sensitive to flutriafol with mean MIC values of 2.5 µg/mL and EC50 values ranging from 0.016 to 1.020 µg/mL with a mean of 0.346 µg/mL. Cercospora cf. flagellaris, C. kikuchii, Cercospora sp. M, Cercospora sp. Q, and Cercospora sp. T had mean EC50 values of 1.25 µg/mL, 7.14 µg/mL, 2.48 µg/mL, 1.81 µg/mL, and 2.24 µg/mL respectively. These findings will assist in monitoring the sensitivity to the flutriafol fungicide in Cercospora spp. populations.

In the absence of antiretroviral therapy (ART), a subset of individuals, termed HIV controllers, have levels of plasma viremia that are orders of magnitude lower than non-controllers (NC) who are at higher risk for HIV disease progression. In addition to having fewer infected cells resulting in fewer cells with HIV RNA, it is possible that lower levels of plasma viremia in controllers are due to a lower fraction of the infected cells having HIV-1 unspliced RNA (HIV usRNA) compared with NC. To directly test this possibility, we used sensitive and quantitative single-cell sequencing methods to compare the fraction of infected cells that contain one or more copies of HIV usRNA in peripheral blood mononuclear cells (PBMC) obtained from controllers and NC. The fraction of infected cells containing HIV usRNA did not differ between the two groups. Rather, the levels of viremia were strongly associated with the total number of infected cells that had HIV usRNA, as reported by others, with controllers having 34-fold fewer infected cells per million PBMC. These results reveal that viremic control is not associated with a lower fraction of proviruses expressing HIV usRNA, unlike what is reported for elite controllers, but is only related to having fewer infected cells overall, maybe reflecting greater immune clearance of infected cells. Our findings show that proviral silencing is not a key mechanism for viremic control and will help to refine strategies toward achieving HIV remission without ART., Competing Interests: Competing interests statement:J.W.M. is a consultant to Gilead Sciences, has received research grants from Gilead Sciences to the University of Pittsburgh, and owns share options in Infectious Disease Connect (co-founder) and Galapagos, NV, unrelated to the current work on HIV. J.M.C. is a member of the Scientific Advisory Board and a Shareholder of ROME Therapeutics, Inc. and Generate Biomedicine, Inc., both unrelated to the current work on HIV.

Formally described in 2009, Phytophthora sansomeana is a pathogen of increasing interest in native, agricultural, and horticulturally important plant species. The objective of this study was to elucidate the symptomatic and asymptomatic host range of P. sansomeana on six agricultural crop species commonly used in field crop rotations in Michigan. In addition, sensitivity to oomicides commonly used in seed treatments, including oxathiapiprolin, mefenoxam, ethaboxam, and pyraclostrobin, was performed to aid in disease management recommendations. Plant biomass, quantity of P. sansomeana DNA in roots, and reisolations were used to assess pathogenicity and virulence of 18 isolates of P. sansomeana on each plant species using an inoculated seedling growth chamber assay. Isolates displayed varying levels of virulence to the hosts tested. Reisolations were completed for each plant species tested, and varying quantities of P. sansomeana DNA were found within all plant species root samples. Corn, wheat, soybean, dry bean, and winter cereal rye plants were symptomatic hosts with significant reduction observed in the total plant biomass. No significant reduction in total plant biomass was observed in oats, and oat roots harbored the least amount of P. sansomeana DNA. No P. sansomeana isolates were insensitive to the oomicide compounds tested with mean absolute inhibition (EC 50 ) values of fungicide required for 50% growth inhibition values of 7.8 × 10 -2 μg/ml for mefenoxam, 1.13 × 10 -1 μg/ml for ethaboxam, 2.6 × 10 -2 μg/ml for oxathiapiprolin, and 3.04 × 10 -1 μg/ml for pyraclostrobin. These results suggest that common crop rotations in Michigan may not be a viable option to reduce soilborne inoculum accumulation and oomicide seed treatments could be considered for early-season management of P. sansomeana ., Competing Interests: The author(s) declare no conflict of interest.

Sudden death syndrome (SDS), caused by Fusarium virguliforme , is an important yield-limiting disease of soybean ( Glycine max ). From 1996 to 2022, cumulative yield losses attributed to SDS in North America totaled over 25 million metric tons, which was valued at over US $7.8 billion. Seed treatments are widely used to manage SDS by reducing early season soybean root infection by F. virguliforme . Fluopyram (succinate dehydrogenase inhibitor [SDHI] - FRAC 7), a fungicide seed treatment for SDS management, has been registered for use on soybean in the United States since 2014. A baseline sensitivity study conducted in 2014 evaluated 130 F. virguliforme isolates collected from five states to fluopyram in a mycelial growth inhibition assay and reported a mean EC 50 of 3.35 mg/liter. This baseline study provided the foundation for the objectives of this research: to detect any statistically significant change in fluopyram sensitivity over time and geographical regions within the United States and to investigate sensitivity to the fungicide pydiflumetofen. We repeated fluopyram sensitivity testing on a panel of 80 historical F. virguliforme isolates collected from 2006 to 2013 (76 of which were used in the baseline study) and conducted testing on 123 contemporary isolates collected from 2016 to 2022 from 11 states. This study estimated a mean absolute EC 50 of 3.95 mg/liter in isolates collected from 2006 to 2013 and a mean absolute EC 50 of 4.19 mg/liter in those collected in 2016 to 2022. There was no significant change in fluopyram sensitivity ( P = 0.1) identified between the historical and contemporary isolates. A subset of 23 isolates, tested against pydiflumetofen under the same conditions, estimated an absolute mean EC 50 of 0.11 mg/liter. Moderate correlation was detected between fluopyram and pydiflumetofen sensitivity estimates ( R = 0.53; P < 0.001). These findings enable future fluopyram and pydiflumetofen resistance monitoring and inform current soybean SDS management strategies in a regional and national context., Competing Interests: The author(s) declare no conflict of interest.

Background: Improved coronavirus disease 2019 (COVID-19) prevention is needed for immunocompromised individuals., Methods: A prospective study was performed of health care workers (HCW) and immunocompromised participants with baseline serology following 2 mRNA vaccine doses and who were retested after dose 3 (D3); multivariable regression was used to identify predictors of serological responses. IFN-γ/TNF-α T-cell responses were assessed in a subset., Results: In total, 536 participants were included: 492 immunocompromised (206 solid organ transplant [SOT], 128 autoimmune, 80 hematologic malignancy [HM], 48 solid tumor, 25 HIV), and 44 HCW. D3 significantly increased spike IgG levels among all, but SOT and HM participants had the lowest median antibody levels post-D3 (increase from 0.09 to 0.83 and 0.27 to 1.92, respectively), versus HCW and persons with HIV, autoimmune conditions, and solid tumors (increases from 4.44 to 19.79, 2.9 to 15.75, 3.82 to 16.32, and 4.1 to 25.54, respectively). Seropositivity post-D3 was lowest for SOT (49.0%) and HM (57.8%), versus others (>90%). Neutralization post-D3 was lowest among SOT and HM. Predictors of lower antibody levels included low baseline levels and shorter intervals between vaccines. T-cell responses against spike increased significantly among HCW and nonsignificantly among immunocompromised individuals., Conclusions: D3 significantly improves serological but not T-cell responses among immunocompromised individuals. SOT and HM patients have suboptimal responses to D3., Competing Interests: Potential conflicts of interest. G. H. is a recipient of research grants from Allovir, Karius, and AstraZeneca; serves on the scientific advisory boards of Karius and AstraZeneca; and has received honoraria from the International AIDS Society, MDOutlook, and PeerView Medial Education. J. W. M. is a consultant to Gilead Sciences and Allovir; and owns share options in Infectious Disease Connection and Galapagos, NV, unrelated to the current work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The lack of interoperable data standards among reference genome data-sharing platforms inhibits cross-platform analysis while increasing the risk of data provenance loss. Here, we describe the FAIR bioHeaders Reference genome (FHR), a metadata standard guided by the principles of Findability, Accessibility, Interoperability and Reuse (FAIR) in addition to the principles of Transparency, Responsibility, User focus, Sustainability and Technology. The objective of FHR is to provide an extensive set of data serialisation methods and minimum data field requirements while still maintaining extensibility, flexibility and expressivity in an increasingly decentralised genomic data ecosystem. The effort needed to implement FHR is low; FHR's design philosophy ensures easy implementation while retaining the benefits gained from recording both machine and human-readable provenance., (Published by Oxford University Press 2024.)

Short-chain fatty acids (SCFA) and lactate in ruminal fluid are products resulting from the microbial fermentation of substrates and can be used to reflect the composition and activity of the ruminal microbiome. Determination of SCFA and D-/L-lactate in ruminal fluid currently requires two separate protocols, which is time-consuming and costly. In this study, we have optimised and validated a simple and unified 3-nitrophenylhydrazine (3-NPH) derivatisation protocol and a 20 min chiral-LC-MS method for the simultaneous quantification of all SCFA and D- and L-lactate in ruminal fluid. This method, which requires no sample pretreatment or purification shows adequate sensitivity (limit of detection (LOD): 0.01 µg/mL), satisfactory accuracy (recovery: 88-103%), and excellent reproducibility (relative standard deviation (RSD) for repeated analyses < 3% for most analytes). The application of this method to a cohort of 24 animals allowed us to reveal a large inter-cow variation in ruminal SCFA and lactate level, the concentration range for each species, the widespread correlation between different SCFA, and the strong correlation between D- and L-lactate.

The ATCC Genome Portal (AGP, https://genomes.atcc.org/) is a database of authenticated genomes for bacteria, fungi, protists, and viruses held in ATCC's biorepository. It now includes 3,938 assemblies (253% increase) produced under ISO 9000 by ATCC. Here, we present new features and content added to the AGP for the research community., Competing Interests: The authors declare no conflict of interest.

The classification of haematological neoplasms recently underwent revision, generating two separate schemes-the International Consensus Classification and the fifth edition of the WHO classification. The new division into separate classification systems presents challenges for haematopathologists, haematologists/oncologists and patients. While it is too early to assess the full clinical impact, we sought to identify diagnostic discordance which may arise from applying separate classification schemes in myeloid neoplasia, and particularly in the challenging category of myelodysplastic syndrome/myeloproliferative neoplasms. A review of 64 such cases found 1 case with a significant discrepancy between the WHO and International Consensus Classification systems, and 9 cases with nominal discrepancies. Confusion from the use of conflicting diagnostic terms represents a potential source of patient harm, increased pathologist workload and burnout and erosion of clinician and patient trust., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Functional human brown and white adipose tissue (BAT and WAT) are vital for thermoregulation and nutritional homeostasis, while obesity and other stressors lead, respectively, to cold intolerance and metabolic disease. Understanding BAT and WAT physiology and dysfunction necessitates clinical trials complemented by mechanistic experiments at the cellular level. These require standardized in vitro models, currently lacking, that establish references for gene expression and function. We generated and characterized a pair of immortalized, clonal human brown (hBA) and white (hWA) preadipocytes derived from the perirenal and subcutaneous depots, respectively, of a 40-year-old male individual. Cells were immortalized with hTERT and confirmed to be of a mesenchymal, nonhematopoietic lineage based on fluorescence-activated cell sorting and DNA barcoding. Functional assessments showed that the hWA and hBA phenocopied primary adipocytes in terms of adrenergic signaling, lipolysis, and thermogenesis. Compared to hWA, hBA were metabolically distinct, with higher rates of glucose uptake and lactate metabolism, and greater basal, maximal, and nonmitochondrial respiration, providing a mechanistic explanation for the association between obesity and BAT dysfunction. The hBA also responded to the stress of maximal respiration by using both endogenous and exogenous fatty acids. In contrast to certain mouse models, hBA adrenergic thermogenesis was mediated by several mechanisms, not principally via uncoupling protein 1 (UCP1). Transcriptomics via RNA-seq were consistent with the functional studies and established a molecular signature for each cell type before and after differentiation. These standardized cells are anticipated to become a common resource for future physiological, pharmacological, and genetic studies of human adipocytes., (Published by Oxford University Press on behalf of the Endocrine Society 2023.)

Secondary infection (SI) diagnosis in severe COVID-19 remains challenging. We correlated metagenomic sequencing of plasma microbial cell-free DNA (mcfDNA-Seq) with clinical SI assessment, immune response, and outcomes. We classified 42 COVID-19 inpatients as microbiologically confirmed-SI (Micro-SI, n = 8), clinically diagnosed-SI (Clinical-SI, n = 13, i.e., empiric antimicrobials), or no-clinical-suspicion-for-SI (No-Suspected-SI, n = 21). McfDNA-Seq was successful in 73% of samples. McfDNA detection was higher in Micro-SI (94%) compared to Clinical-SI (57%, p = 0.03), and unexpectedly high in No-Suspected-SI (83%), similar to Micro-SI. We detected culture-concordant mcfDNA species in 81% of Micro-SI samples. McfDNA correlated with LRT 16S rRNA bacterial burden (r = 0.74, p = 0.02), and biomarkers (white blood cell count, IL-6, IL-8, SPD, all p < 0.05). McfDNA levels were predictive of worse 90-day survival (hazard ratio 1.30 [1.02-1.64] for each log 10 mcfDNA, p = 0.03). High mcfDNA levels in COVID-19 patients without clinical SI suspicion may suggest SI under-diagnosis. McfDNA-Seq offers a non-invasive diagnostic tool for pathogen identification, with prognostic value on clinical outcomes., Competing Interests: Drs. Duttagupta and Ahmed were employed by Karius, Inc at the time of the study but are no longer employed by Karius, Inc. Drs. Kitsios and Haidar have received research funding from Karius, Inc. Drs. Kitsios and Morris have received research funding from Pfizer, Inc. Dr. Haidar serves on the Karius, Inc scientific advisory board. Dr. Mellors is a consultant to AlloVir, Infectious Disease Connect, Inc., and Gilead Sciences, Inc., has received research funding from Gilead Sciences, Inc. to the University of Pittsburgh, receives compensation from Abound Bio, Inc. (unrelated to the current work) and holds shares options in Galapogos, Infectious Disease Connect, Inc., and MingMed Biotechnology Co. Ltd. (unrelated to the current work). Dr. McVerry has received research funding from Bayer Pharmaceuticals, Inc. and consulting fees from Boehringer Ingelheim, both unrelated to this work., (© 2023 The Authors.)

TIM-3 expression is increased on peripheral regulatory T cells (Tregs) of virally suppressed persons with HIV-1 on antiretroviral therapy (PWH-ART). However, the relevance of TIM-3 expression in this setting is unclear. We used flow cytometry to evaluate the suppressive phenotype and signaling pathways in peripheral TIM-3- vs TIM-3+ Tregs in PWH-ART. TIM-3+ Tregs showed increased expression of IL-10 compared with persons without HIV-1. In addition, TIM-3+ Tregs displayed elevated signaling and activation, relative to TIM-3- Tregs from the same PWH-ART. Dramatically, TIM-3 blockade restrained the in vitro suppressive capacity of peripheral Tregs. Therefore, our data demonstrate not only that TIM-3 expression by Tregs is associated with an immunosuppressive response among PWH-ART, but also that TIM-3 contributes directly to the enhanced suppressive activity of Tregs in this setting., Competing Interests: Conflict of interest statement. J.W.M. has served as a consultant for AlloVir, Infectious Disease Connect, and Gilead Sciences, Inc.; has received grant funding from Gilead Sciences, Inc. to the University of Pittsburgh; has received compensation from Abound Bio, Inc. (unrelated to the current work); and holds share options in Infectious Disease Connect, Inc., and MingMed Biotechnology Co., Ltd. (unrelated to the current work). B.J.C.M has received research funding from AstraZeneca. No other authors have a commercial or any other relation that might represent a conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We administered severe acute respiratory syndrome coronavirus-2 viral-specific T cells (VSTs) under emergency investigational new drug applications to 6 immunocompromised patients with persistent coronavirus disease 2019 (COVID-19) and characterized clinical and virologic responses. Three patients had partial responses after failing other therapies but then died. Two patients completely recovered, but the role of VSTs in recovery was unclear due to concomitant use of other antivirals. One patient had not responded to 2 courses of remdesivir and experienced sustained recovery after VST administration. The use of VSTs in immunocompromised patients with persistent COVID-19 requires further study., Competing Interests: Potential conflicts of interest. G. H. reports research grants from AlloVir, Inc, Karius, the National Institutes of Health, and AstraZeneca; consulting fees for serving on the advisory boards of Karius and AstraZeneca; and honoraria from MDOutlook. Y. S. H. is supported by the Hillman Fellowship for Innovative Cancer Research. F. P. S. reports research grants from Ansun, Regeneron, and Merck and serves on the advisory boards for Takeda and Eurofins Viracor. A. M. L. is a cofounder and equity holder in AlloVir, Inc, and Marker Therapeutics and a consultant for AlloVir, Inc. W. L. M. and E. A. are former employees and current stockholders of AlloVir, Inc. M. M. and B. P. are current employees of AlloVir, Inc. J. W. M. is a consultant to Gilead Sciences, Inc; reports grant funding from Gilead Sciences, Inc, to the University of Pittsburgh and compensation from Abound Bio, Inc (unrelated to the current work); and has share options in Infectious Disease Connect, Inc, and Galapagos, NV (unrelated to the current work). All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Supplementation of beef cattle can be used to meet both nutrient requirements and production goals; however, supplementation costs influence farm profitability. Common supplementation delivery strategies are generally designed to provide nutrients to the mean of the group instead of an individual. Precision individual supplementation technologies, such as the Super SmartFeed (SSF, C-Lock Inc., Rapid City, SD, USA), are available but are generally cost prohibitive to producers. These systems require adaptation or training periods for cattle to utilize this technology. The objective of this research was to assess the training and adoption rates of three different groups of cattle (suckling calves, weaned steers, replacement heifers) to the SSF. Successful adaptation was determined if an individual's supplement intake was above the group average of total allotted feed consumed throughout the training period. Suckling calves (n = 31) underwent a 12 d training period on pasture; 45% of suckling calves adapted to the SSF and average daily intake differed ( p < 0.0001) by day of training. Weaned steers (n = 79) were trained in drylot for 13 d. Of the weaned steers, 62% were trained to the SSF, and average daily intake differed ( p < 0.0001) by day of training. Replacement heifers (n = 63) grazed tall fescue pastures and had access to SSF for 22 d of training. The success rate of replacement heifers was 73%. For replacement heifers, the daily intake did not differ ( p < 0.0001) by day of training. Results indicate production stage may influence cattle adaptation to precision technologies.

Accurate and rapid evaluation of SARS-CoV-2 half-maximal neutralizing antibody (nAb) titer (NT50) is an important research tool for measuring nAb responses after prophylaxis or therapeutics for COVID-19 prevention and management. Compared with ACE2-competitive enzyme immunoassays for nAb detection, pseudovirus assays remain low-throughput and labor intensive. A novel application of the Bio-Rad Bio-Plex Pro Human SARS-CoV-2 D614G S1 Variant nAb Assay was used to determine NT50 from COVID-19-vaccinated individuals and showed strong correlation to a laboratory-developed SARS-CoV-2 pseudovirus nAb assay. The Bio-Plex nAb assay could provide a rapid, high-throughput, culture-free method for NT50 determination in sera., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: G.H. is a recipient of research grants from Allovir, Karius, and AstraZeneca. G.H. also serves on the scientific advisory boards of Karius and AstraZeneca and has received honoraria from the International AIDS Society and MDOutlook. J.W.M. is a consultant for and receives grant support from Gilead Sciences, unrelated to the current work. J.W.M. owns share options in Infectious Disease Connect, unrelated to the current work. U.M.P. has a consulting agreement with Merck & Co., unrelated to the current work., (Copyright © 2023. Published by Elsevier B.V.)

Prolonged coronavirus disease 2019 may generate new viral variants. We report an immunocompromised patient treated with monoclonal antibodies who experienced rebound of viral RNA and emergence of an antibody-resistant (>1000-fold) variant containing 5 mutations in the spike gene. The mutant virus was isolated from respiratory secretions, suggesting the potential for secondary transmission., Competing Interests: Potential conflicts of interest. J. W. M. is a consultant to AlloVir, Infectious Disease Connect, and Gilead Sciences; has received grant funding from Gilead Sciences to the University of Pittsburgh; receives compensation from Abound Bio (unrelated to the current work); and holds share options in Infectious Disease Connect and MingMed Biotechnology Co (unrelated to the current work). G. H. is a recipient of research grants from AlloVir, Karius, NIH, and AstraZeneca; reports consulting fees for serving on the advisory boards of Karius and AstraZeneca; and has received honoraria from MDOutlook. E. M. has served on advisory boards for Shionogi and AbbVie related to COVID-19 therapeutics and has received speaker honorarium from Shionogi related to COVID-19 therapeutics. U. M. P. reports consulting fees from Merck & Co. B. J. C. M. has received research funds from AstraZeneca. J. R. B. holds shares/share options in CarePoint Holdings. All other authors report no potential conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Competing Interests: Conflicts of interest T.J. is an investigator for UCB and Eli Lilly. She reports consulting for Eli Lilly and Chemocentryx and receiving honoraria. She has received funds from Pfizer for research fellow support. The remaining authors declare that the research was conducted in the absence of any financial relationships that could be construed as a potential conflict of interest. She also has received funds from Dermatology Foundation, and Skin of Color Society, and NIH K12 (grant number: K12HD043446).

Introduction: Low- and middle-income countries (LMICs) are committed to achieving the Sustainable Development Goal 3.1 to reduce maternal mortality. The Ministry of Health and Family Welfare of India recommends prophylactic uterotonic administration to every woman following delivery to reduce the risk of postpartum hemorrhage (PPH), as PPH is the leading cause of maternal mortality in LMICs, including India. In 2018, the World Health Organization first recognized heat-stable carbetocin for PPH prevention. Governments are now considering its introduction into their public health systems., Methods: A decision-tree model was developed from the public healthcare system perspective to compare the value of heat-stable carbetocin versus oxytocin and misoprostol among women giving birth in public sector healthcare facilities in India. The model accounted for differences in PPH risk and costs based on mode of delivery and healthcare setting, as well as provider behavior to mitigate quality concerns of oxytocin. Model outcomes for each prophylactic uterotonic included the number of PPH events, DALYs due to PPH, deaths due to PPH, and direct medical care costs. The budget impact was estimated based on projected uterotonic uptake between 2022-2026., Results: Compared to oxytocin, heat-stable carbetocin avoided 5,468 additional PPH events, 5 deaths, and 244 DALYs per 100,000 births. Projected direct medical costs to the public healthcare system were lowered by US $171,700 (₹12.8 million; exchange rate of ₹74.65 = US$1 from 2 Feb 2022) per 100,000 births. Benefits were even greater when compared to misoprostol (7,032 fewer PPH events, 10 fewer deaths, 470 fewer DALYs, and $230,248 saved per 100,000 births). In the budget impact analysis, India's public health system is projected to save US$11.4 million (₹849 million) over the next five years if the market share for heat-stable carbetocin grows to 19% of prophylactic uterotonics administered., Conclusions: Heat-stable carbetocin is expected to reduce the number of PPH events and deaths, avoid more DALYs, and reduce costs to the public healthcare system of India. Greater adoption of heat-stable carbetocin for the prevention of PPH could advance India's efforts to achieve its maternal health goals and increase efficiency of its public health spending., (© 2023. The Author(s).)

Using direct-fed microbials to mitigate enteric methane emissions could be sustainable and acceptable to both consumers and producers. Forty lactating, multiparous, Holstein-Friesian cows were randomly allocated one of two treatments: (1) a base of ad libitum vetch (Vicia sativa) hay and 7.0 kg DM/d of a grain mix, or (2) the basal diet plus 10 mL of MYLO ® (Terragen Biotech Pty Ltd., Coolum Beach, Queensland, Australia) delivering 4.17 × 10 8 cfu of Lactobacillus per mL. Neither feed intake (25.4 kg/d vs. 24.8 kg/d) nor milk yield (29.9 vs. 30.3 kg/d) were affected by treatment. Feed conversion efficiency was not affected by treatment when expressed on an energy-corrected milk basis (1.15 vs. 1.18 kg/kg DMI). Neither methane yield (31.6 vs. 31.1 g/kg DMI) nor methane intensity (27.1 vs. 25.2 g/kg energy corrected milk) were affected by treatments. While these results are contrary to our expectations and not significant, all were numerically in a favorable direction. Given there are reports that diet and dose rate may impact the size of any effect, we recommend a dose-response study be undertaken using a basal diet that is commonly used in pasture-based dairy systems.

The COVID-19 pandemic has been accompanied by SARS-CoV-2 evolution and emergence of viral variants that have far exceeded initial expectations. Five major variants of concern (Alpha, Beta, Gamma, Delta, and Omicron) have emerged, each having both unique and overlapping amino acid substitutions that have affected transmissibility, disease severity, and susceptibility to natural or vaccine-induced immune responses and monoclonal antibodies. Several of the more recent variants appear to have evolved properties of immune evasion, particularly in cases of prolonged infection. Tracking of existing variants and surveillance for new variants are critical for an effective pandemic response.

Plasma SARS-CoV-2 viral RNA (vRNA) levels are predictive of COVID-19 outcomes in hospitalized patients, but whether plasma vRNA reflects lower respiratory tract (LRT) vRNA levels is unclear. We compared plasma and LRT vRNA levels in serially collected samples from mechanically ventilated patients with COVID-19. LRT and plasma vRNA levels were strongly correlated at first sampling (n = 33, r = 0.83, P < 10-9) and then declined in parallel in available serial samples except in nonsurvivors who exhibited delayed vRNA clearance in LRT samples. Plasma vRNA measurement may offer a practical surrogate of LRT vRNA burden in critically ill patients, especially early after ICU admission., Competing Interests: Potential conflicts of interest. J. S. L. reports a paid consultantship with Janssen R&D unrelated to this work; and clinical adjudication of severity outcomes in the ENSEMBLE study of COVID-19 vaccine. B. J. M. reports grants from NIH/NHLBI, the Translational Breast Cancer Research Consortium, and the UPMC Learning While Doing Program during the conduct of the study; grants from Bayer Pharmaceuticals, Inc; and personal consultation fees from Boehringer Ingelheim, Inc outside the submitted work. G. D. K. reports research funding from Karius, Inc. J. W. M. reports grants to University of Pittsburgh from NIH, USAID, and Gilead Sciences; serves as a consultant for Gilead Sciences, Inc as a Scientific Advisory Board Member; owns share options in Infectious Diseases Connect; is a part-time employee and shareholder of Abound Bio, Inc; and is employed by University of Pittsburgh. His holdings and roles in Infectious Diseases Connect and Abound Bio are unrelated to the current work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed, (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022.)

Background: Excessive complement activation has been implicated in the pathogenesis of coronavirus disease 2019 (COVID-19), but the mechanisms leading to this response remain unclear., Methods: We measured plasma levels of key complement markers, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and antibodies against SARS-CoV-2 and seasonal human common cold coronaviruses (CCCs) in hospitalized patients with COVID-19 of moderate (n = 18) and critical severity (n = 37) and in healthy controls (n = 10)., Results: We confirmed that complement activation is systemically increased in patients with COVID-19 and is associated with a worse disease outcome. We showed that plasma levels of C1q and circulating immune complexes were markedly increased in patients with severe COVID-19 and correlated with higher immunoglobulin (Ig) G titers, greater complement activation, and higher disease severity score. Additional analyses showed that the classical pathway was the main arm responsible for augmented complement activation in severe patients. In addition, we demonstrated that a rapid IgG response to SARS-CoV-2 and an anamnestic IgG response to the nucleoprotein of the CCCs were strongly correlated with circulating immune complex levels, complement activation, and disease severity., Conclusions: These findings indicate that early, nonneutralizing IgG responses may play a key role in complement overactivation in severe COVID-19. Our work underscores the urgent need to develop therapeutic strategies to modify complement overactivation in patients with COVID-19., Competing Interests: Potential conflicts of interest. U. B. N. reports grants from the National Science Foundation, and Texas A&M Institute of Data Science, and book royalties from Springer, un­related to the current work. J. M. reports grants from the National Institutes of Health (NIH), USAID, Gilead Sciences, and Janssen Pharmaceuticals; serves or has served as a consultant for Gilead Sciences, Accelevir Diagnostics, and Xi’an Yufan Biotechnologies; owns share options in Co-Crystal Pharmaceuticals and Infectious Diseases Connect; and is a shareholder of Abound Bio. His holdings in Co-Crystal Pharmaceuticals, Infectious Diseases Connect, and Abound Bio are unrelated to the current work. A. M. reports grants from the National Heart, Lung, and Blood Institute and the National Institute of Allergy and Infectious Diseases, NIH during the conduct of the study; B. J. M. reports grants from Bayer Pharmaceuticals, the Translational Breast Cancer Research Consortium, and the UPMC Learning While Doing Program, during the conduct of the study; consulting fees from Boehringer Ingelheim, the VeraMedica Institute; and the Patient-Centered Outcomes Research Institute for the ACCOMPLISH Trial, outside the submitted work. F. S. reports grants from the National Institute of General Medical Sciences, NIH, during the conduct of the study. B. J. C. M. reports grants from NIH and Gilead Sciences during the conduct of the study. D. B. reports leadership roles as president and board chair of Epistemix, director of the Magee Women’s Research Institute, and member of the Allegheny County Board of Health, unrelated to the current work, and is also a shareholder of Epistemix, unrelated to the current work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: We studied humoral responses after coronavirus disease 2019 (COVID-19) vaccination across varying causes of immunodeficiency., Methods: Prospective study of fully vaccinated immunocompromised adults (solid organ transplant [SOT], hematologic malignancy, solid cancers, autoimmune conditions, human immunodeficiency virus [HIV]) versus nonimmunocompromised healthcare workers (HCWs). The primary outcome was the proportion with a reactive test (seropositive) for immunoglobulin G to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain. Secondary outcomes were comparisons of antibody levels and their correlation with pseudovirus neutralization titers. Stepwise logistic regression was used to identify factors associated with seropositivity., Results: A total of 1271 participants enrolled: 1099 immunocompromised and 172 HCW. Compared with HCW (92.4% seropositive), seropositivity was lower among participants with SOT (30.7%), hematological malignancies (50.0%), autoimmune conditions (79.1%), solid tumors (78.7%), and HIV (79.8%) (P < .01). Factors associated with poor seropositivity included age, greater immunosuppression, time since vaccination, anti-CD20 monoclonal antibodies, and vaccination with BNT162b2 (Pfizer) or adenovirus vector vaccines versus messenger RNA (mRNA)-1273 (Moderna). mRNA-1273 was associated with higher antibody levels than BNT162b2 or adenovirus vector vaccines after adjusting for time since vaccination, age, and underlying condition. Antibody levels were strongly correlated with pseudovirus neutralization titers (Spearman r = 0.89, P < .0001), but in seropositive participants with intermediate antibody levels, neutralization titers were significantly lower in immunocompromised individuals versus HCW., Conclusions: Antibody responses to COVID-19 vaccines were lowest among SOT and anti-CD20 monoclonal recipients, and recipients of vaccines other than mRNA-1273. Among those with intermediate antibody levels, pseudovirus neutralization titers were lower in immunocompromised patients than HCWs. Additional SARS-CoV-2 preventive approaches are needed for immunocompromised persons, which may need to be tailored to the cause of immunodeficiency., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

The emergence of SARS-CoV-2 variants of concern (VOCs) requires the development of next-generation biologics with high neutralization breadth. Here, we characterized a human V H domain, F6, which we generated by sequentially panning large phage-displayed V H libraries against receptor binding domains (RBDs) containing VOC mutations. Cryo-EM analyses reveal that F6 has a unique binding mode that spans a broad surface of the RBD and involves the antibody framework region. Attachment of an Fc region to a fusion of F6 and ab8, a previously characterized V H domain, resulted in a construct (F6-ab8-Fc) that broadly and potently neutralized VOCs including Omicron. Additionally, prophylactic treatment using F6-ab8-Fc reduced live Beta (B.1.351) variant viral titers in the lungs of a mouse model. Our results provide a new potential therapeutic against SARS-CoV-2 variants including Omicron and highlight a vulnerable epitope within the spike that may be exploited to achieve broad protection against circulating variants., Competing Interests: W.L, C.C, J.W.M., and D.SD, are co-inventors of a patent, filed on January 06, 2022 by the University of Pittsburgh, related to VH F6 and F6-ab8-Fc described in this article. S.S. is a founder and CEO of Gandeeva Therapeutics Inc., (© 2022 The Author(s).)