The effect of Asparagopsis taxiformis, Ascophyllum nodosum, and Fucus vesiculosus on ruminal methanogenesis and metagenomic functional profiles in vitro.

The ruminant-microorganism symbiosis is unique by providing high-quality food from fibrous materials but also contributes to the production of one of the most potent greenhouse gases-methane. Mitigating methanogenesis in ruminants has been a focus of interest in the past decades. One of the promising strategies to combat methane production is the use of feed supplements, such as seaweeds, that might mitigate methanogenesis via microbiome modulation and direct chemical inhibition. We conducted in vitro investigations of the effect of three seaweeds (Ascophyllum nodosum, Asparagopsis taxiformis, and Fucus vesiculosus) harvested at different locations (Iceland, Scotland, and Portugal) on methane production. We applied metataxonomics (16S rRNA gene amplicons) and metagenomics (shotgun) methods to uncover the interplay between the microbiome's taxonomical and functional states, methanogenesis rates, and seaweed supplementations. Methane concentration was reduced by A. nodosum and F. vesiculosus, both harvested in Scotland and A. taxiformis, with the greatest effect of the latter. A. taxiformis acted through the reduction of archaea-to-bacteria ratios but not eukaryotes-to-bacteria. Moreover, A. taxiformis application was accompanied by shifts in both taxonomic and functional profiles of the microbial communities, decreasing not only archaeal ratios but also abundances of methanogenesis-associated functions. Methanobrevibacter "SGMT" (M. smithii, M. gottschalkii, M. millerae or M. thaueri; high methane yield) to "RO" (M. ruminantium and M. olleyae; low methane yield) clades ratios were also decreased, indicating that A. taxiformis application favored Methanobrevibacter species that produce less methane. Most of the functions directly involved in methanogenesis were less abundant, while the abundances of the small subset of functions that participate in methane assimilation were increased. IMPORTANCE: The application of A. taxiformis significantly reduced methane production in vitro. We showed that this reduction was linked to changes in microbial function profiles, the decline in the overall archaeal community counts, and shifts in ratios of Methanobrevibacter "SGMT" and "RO" clades. A. nodosum and F. vesiculosus, obtained from Scotland, also decreased methane concentration in the total gas, while the same seaweed species from Iceland did not.

Assessment of laparoscopic surgery practice, knowledge, and training goals in Liberia: A mixed-methods study among Liberian surgeons.

BACKGROUND: Laparoscopy training remains inaccessible in many low- and middle-income countries, including Liberia. We assessed the availability of laparoscopy and feasibility of implementing a laparoscopic program among Liberian surgeons and trainees. METHODS: This mixed-methods study utilized a 32-item survey and semi-structured interviews on laparoscopic experience, knowledge, desires, barriers, patient perceptions, and training opportunities among surgeons and trainees at Liberia's two main teaching hospitals in March 2023. Data analysis utilized summed knowledge and desirability scores, descriptive statistics, and qualitative content analysis. RESULTS: 31 interns, residents, and consultants participated, comprising 60% of Liberia's surgeons. Laparoscopic training (32%) and experience (16%) was low, with exposure limited to those training outside Liberia (p = 0.001). While laparoscopy knowledge varied (29% low, 55% medium, 16% high), participants expressed high interest in training (100%) and willingness to pay (52%). Interviews revealed four themes: desires for training, patient acceptability, feasibility of technology-based training, and barriers including limited equipment and expert trainers. At the time of survey, the only minimally invasive surgeries ever performed in Liberia were two diagnostic laparoscopies. CONCLUSIONS: This is the first mixed-methods study assessing laparoscopy in Liberia. Our sample, though small, comprised approximately 60% of Liberian surgeons in both rural and urban hospitals. Findings demonstrated limited experience, variable knowledge, and high desires for training, showing feasibility for laparoscopy implementation in Liberia.

Health effects and user perceptions of the US Customs and Border Patrol One™ mobile application: A qualitative analysis among asylum seekers at the Mexico-US border.

Background: The number of migrants at the Mexico-US border has increased to historic levels, and frequently changing immigration policy impacts this population as they await entry into the US. This study evaluated the usability and health effects of the Customs and Border Protection (CBP) One™ mobile application among asylum seekers near the US port of entry in Reynosa, Mexico. Methods: We conducted semi-structured qualitative interviews with 20 asylum seekers in Reynosa, Mexico, in February 2023. Our objective was to explore the subjective experiences of migrants, usability of CBP One™, and presence of perceived health effects from using the application. Interviews were conducted until saturation occurred, transcribed verbatim into Word, coded in NVivo using a validated, team-based coding methodology, and analyzed according to internal domains, external domains, and health effects regarding CBP One™. Results: Twenty participants originated from eight countries throughout Latin America and the Caribbean. In total, 18 subthemes were identified among internal, external, and effects domains. Internal themes included a confusing application interface (80%), technical malfunction (60%), and perceived racial bias from the photo-capture features (15%). External themes challenging CBP One™ use included unavailable appointment slots (80%), inequity and inaccessibility (35%), and inadequate internet (25%). Most perceived effects were negative (85%), including worsening mental health effects (40%), exacerbation of pre-existing physical conditions (35%), and forgoing health expenditures to pay for internet (25%). Conclusions: Our findings suggest that asylum seekers at the Reynosa port of entry perceive CBP One™ negatively, with detrimental effects towards their mental and physical health. This study highlights how immigration policy can influence health and suggests that more creative and humane approaches are needed for people seeking asylum at the Mexico-US border.

Web-CONEXS: an inroad to theoretical X-ray absorption spectroscopy.

Accurate analysis of the rich information contained within X-ray spectra usually calls for detailed electronic structure theory simulations. However, density functional theory (DFT), time-dependent DFT and many-body perturbation theory calculations increasingly require the use of advanced codes running on high-performance computing (HPC) facilities. Consequently, many researchers who would like to augment their experimental work with such simulations are hampered by the compounding of nontrivial knowledge requirements, specialist training and significant time investment. To this end, we present Web-CONEXS, an intuitive graphical web application for democratizing electronic structure theory simulations. Web-CONEXS generates and submits simulation workflows for theoretical X-ray absorption and X-ray emission spectroscopy to a remote computing cluster. In the present form, Web-CONEXS interfaces with three software packages: ORCA, FDMNES and Quantum ESPRESSO, and an extensive materials database courtesy of the Materials Project API. These software packages have been selected to model diverse materials and properties. Web-CONEXS has been conceived with the novice user in mind; job submission is limited to a subset of simulation parameters. This ensures that much of the simulation complexity is lifted and preliminary theoretical results are generated faster. Web-CONEXS can be leveraged to support beam time proposals and serve as a platform for preliminary analysis of experimental data.

Variation in surgical approach and postoperative complication among older adults undergoing ventral hernia repair.

BACKGROUND: Surgical decision-making for preference-sensitive operations among older adults is understudied. Ventral hernia repair (VHR) is one operation where granular data are limited to guide preoperative decision-making. We aimed to determine risk for VHR in older adults given clinically nuanced data including surgical and hernia characteristics. METHODS: We performed a retrospective analysis of the Michigan Surgical Quality Collaborative Core Optimization Hernia Registry from January 2020 to March 2023. The primary outcome was postoperative complication across age groups: 18-64, 65-74, and ≥ 75 years, with secondary outcome of surgical approach. Mixed-effects logistic regression evaluated association between minimally invasive surgery (MIS) and 30-day complications, controlling for patient and hernia characteristics. RESULTS: Among 8,659 patients, only 7% were 75 or older. MIS rates varied across hospitals [Median = 31.4%, IQR: (14.8-51.6%)]. The overall complication rate was 2.2%. Complication risk for undergoing open versus MIS approach did not vary between age groups; however, patients over age 75 undergoing laparoscopic repair had increased risk (aOR = 4.58, 95% CI 1.13-18.67). Other factors associated with risk included female sex (aOR = 2.10, 95% CI 1.51-2.93), higher BMI (aOR = 1.18, 95% CI 1.03-1.34), hernia width ≥ 6 cm (aOR = 3.15, 95% CI 1.96-5.04), previous repair (aOR = 1.44, 95% CI 1.02-2.05), and component separation (aOR = 1.98, 95% CI 1.28-3.05). Patients most likely to undergo MIS were female (aOR = 1.21, 95% CI 1.09-1.34), black (aOR = 1.30, 95% CI 1.12-1.52), with larger hernias: 2-5.9 cm (aOR = 1.76, 95% CI 1.57-1.97), or intraoperative mesh placement (aOR = 14.4, 95% CI 11.68-17.79). There was no difference in likelihood to receive MIS across ages when accounting for hospital (SD of baseline likelihood = 1.53, 95% CI 1.14-2.05) and surgeon (SD of baseline likelihood = 2.77, 95% CI 2.46-3.11) variation. CONCLUSIONS: Our findings demonstrate that hernia, intraoperative, and patient characteristics other than age increase probability for complication following VHR. These findings can empower surgeons and older patients considering preoperative risk for VHR.

Implementation science in humanitarian assistance: applying a novel approach for humanitarian care optimization.

Humanitarian assistance is hindered by a lack of strategies to optimize care delivery through research and organized networks. Distinct from global health, humanitarian assistance struggles to address its multifaceted challenges, including duplicative resources, uncoordinated communication, unregulated staff expertise and safety, financial waste, and poor-quality metrics and care delivery. Implementation science provides an exciting and underutilized approach that can be applied to address these challenges, by studying how to effectively design, implement, optimize, and scale evidence-based interventions. Though successful in well-resourced and global health systems, implementation science approaches are rare in humanitarian assistance. Adopting implementation science approaches including identifying determinants, creating accessible evidence-based intervention bundles, adapting study methodologies for the humanitarian context, and partnering with implementation experts could make these promising approaches more accessible for thousands of humanitarian actors delivering healthcare for millions of vulnerable patients worldwide.

The circularly permuted globin domain of androglobin exhibits atypical heme stabilization and nitric oxide interaction.

In the decade since the discovery of androglobin, a multi-domain hemoglobin of metazoans associated with ciliogenesis and spermatogenesis, there has been little advance in the knowledge of the biochemical and structural properties of this unusual member of the hemoglobin superfamily. Using a method for aligning remote homologues, coupled with molecular modelling and molecular dynamics, we have identified a novel structural alignment to other hemoglobins. This has led to the first stable recombinant expression and characterization of the circularly permuted globin domain. Exceptional for eukaryotic globins is that a tyrosine takes the place of the highly conserved phenylalanine in the CD1 position, a critical point in stabilizing the heme. A disulfide bond, similar to that found in neuroglobin, forms a closed loop around the heme pocket, taking the place of androglobin's missing CD loop and further supporting the heme pocket structure. Highly unusual in the globin superfamily is that the heme iron binds nitric oxide as a five-coordinate complex similar to other heme proteins that have nitric oxide storage functions. With rapid autoxidation and high nitrite reductase activity, the globin appears to be more tailored toward nitric oxide homeostasis or buffering. The use of our multi-template profile alignment method to yield the first biochemical characterisation of the circularly permuted globin domain of androglobin expands our knowledge of the fundamental functioning of this elusive protein and provides a pathway to better define the link between the biochemical traits of androglobin with proposed physiological functions.

Life Over Limb: Why Not Both? Revisiting Tourniquet Practices Based on Lessons Learned From the War in Ukraine.

The use of tourniquets for life-threatening limb hemorrhage is standard of care in military and civilian medicine. The United States (U.S.) Department of Defense (DoD) Committee on Tactical Combat Casualty Care (CoTCCC) guidelines, as part of the Joint Trauma System, support the application of tourniquets within a structured system reliant on highly trained medics and expeditious evacuation. Current practices by entities such as the DoD and North Atlantic Treaty Organization (NATO) are supported by evidence collected in counter-insurgency operations and other conflicts in which transport times to care rarely went beyond one hour, and casualty rates and tactical situations rarely exceeded capabilities. Tourniquets cause complications when misused or utilized for prolonged durations, and in near-peer or peer-peer conflicts, contested airspace and the impact of high-attrition warfare may increase time to definitive care and limit training resources. We present a series of cases from the war in Ukraine that suggest tourniquet practices are contributing to complications such as limb amputation, overall morbidity and mortality, and increased burden on the medical system. We discuss factors that contribute to this phenomenon and propose interventions for use in current and future similar contexts, with the ultimate goal of reducing morbidity and mortality.

Social Media Posts About Carpal Tunnel Release: A Cross-Sectional Analysis of Patient and Surgeon Perspectives.

BACKGROUND: Social media provides an increasingly popular, unfiltered source of perspectives on healthcare. The objective of this study is to characterize the landscape of social media posts regarding carpal tunnel release (CTR). METHODS: Content was queried from Instagram between February 2, 2019 to August 12, 2021 using the hashtags #carpaltunnelrelease and #carpaltunnelsurgery. The 1500 most-liked posts were analyzed. Poster demographics including age, gender, region, and symptom qualities and post characteristics including type, number, timing relative to surgery, tone, and satisfaction were collected. Categorical variables were compared utilizing chi-squared test. Univariate and multivariate regression were performed. RESULTS: The most popular post types included single photo (55.2%), multiple photos (18.8%), or single video (18.2%). Of all, 70.6% posts had fewer than 50 "likes." Patients accounted for 51.8% of posts, followed by surgeons (13.3%), other health care providers (11.7%), and physical therapists (8.8%). Women (66.7%) outnumbered men (33.3%). Fifty-five percent of posts were domestic. Posts mostly depicted postoperative care (85.6%). The most frequently mentioned symptoms were pain, burning, numbness, and tingling. Of all posts, 45.1% had a positive tone, 49.1% neutral, and 5.7% negative. Univariate analysis revealed that posters who were patients, underwent open CTR, and were female were more likely to post negative sentiments. CONCLUSIONS: Most posts regarding CTR are from patients, are postoperative, and are positive or neutral. Although rare, negative posts were more likely to originate from posters who are patients, female, or underwent open CTR. With this information, surgeons will be better prepared to address patient concerns, set patient expectations, and enter the social media themselves.

Epidemiology of asylum seekers and refugees at the Mexico-US border: a cross-sectional analysis from the migrant settlement camp in Matamoros, Mexico.

BACKGROUND: The number of migrants and asylum seekers at the Mexico-US border has increased to historic levels. Our objective was to determine the medical diagnoses and treatments of migrating people seeking care in humanitarian clinics in Matamoros, Mexico. METHODS: We conducted a cross-sectional study of patient encounters by migrating people through a humanitarian clinic in Matamoros, Mexico, from November 22, 2019, to March 18, 2021. The clinics were operated by Global Response Medicine in concert with local non-governmental organizations. Clinical encounters were each coded to the appropriate ICD-10/CPT code and categorized according to organ system. We categorized medications using the WHO List of Essential Medicines and used multivariable logistic regression to determine associations between demographic variables and condition frequency. RESULTS: We found a total of 8,156 clinical encounters, which included 9,744 diagnoses encompassing 132 conditions (median age 26.8 years, female sex 58.2%). People originated from 24 countries, with the majority from Central America (n = 5598, 68.6%). The most common conditions were respiratory (n = 1466, 15.0%), musculoskeletal (n = 1081, 11.1%), and skin diseases (n = 473, 4.8%). Children were at higher risk for respiratory disease (aOR = 1.84, 95% CI: 1.61-2.10), while older adults had greater risk for joint disorders (aOR = 3.35, 95% CI: 1.73-6.02). Women had decreased risk for injury (aOR = 0.50, 95% CI: 0.40-0.63) and higher risk for genitourinary diseases (aOR = 4.99, 95% CI: 3.72-6.85) compared with men. Among 10,405 medications administered, analgesics were the most common (n = 3190, 30.7%) followed by anti-infectives (n = 2175, 21.1%). CONCLUSIONS: In this large study of a migrating population at the Mexico-US border, we found a variety of clinical conditions, with respiratory, musculoskeletal, and skin illnesses the most common in this study period which encompassed a period of restrictive immigration policy and the first year of the COVID-19 pandemic.

Social Media Posts About Distal Radius Fracture: A Cross-Sectional Analysis of Patient and Provider Perspectives.

BACKGROUND: Social media offers a popular, unfiltered source of patient and provider perspectives on health care. This study investigated the characteristics of social media posts referencing distal radius fracture (DRF). METHODS: Content was queried from Instagram from February 06, 2019, to December 08, 2021, using the hashtags "#distalradiusfracture" and "#wristfracture." The 1500 most-liked posts were analyzed. Poster demographics including age, gender, region, laterality, and treatment type and post characteristics including post type, number, content, timing relative to treatment, tone, and satisfaction were examined. Variables were compared using χ2 tests. Univariate, multivariate, and stepwise regression were performed. RESULTS: The most popular post formats were single photo (44.5%), multiple photos (32.3%), and single video (13.9%). Patients (40.3%) were the most common poster followed by surgeons (33.4%). Men (48.7%) and women (51.3) were evenly represented. Of the total posts, 87.7% depicted the post-treatment phase of care; 54.8% of posts depicted operative management, while 26.6% depicted non-operative management; and 73.7% of posts were positive in tone, 18.7% neutral, and 7.6% negative. Univariate analysis demonstrated that posters who were patients, friends/family of patients, female, and posts with >100 "likes" were more likely to share negative tones. Multivariate and stepwise regression were consistent with the above. CONCLUSION: Most posts regarding DRF originate from patients, are post-treatment, and are positive. Negative tone is associated with posts from patients, family/friends of patients, female posters, and posts with >100 likes. With this information, surgeons will be better prepared to address patient concerns, manage expectations, and actively participate in social media themselves.

The use of a mobile obstetric emergency system to improve obstetric referrals in Bong County, Liberia: A pre-post study.

OBJECTIVE: Liberia experiences an unmet need for cesarean section with about 5% population coverage, lower than 9%-19% coverage associated with improved maternal and newborn outcomes. Delays in the referral process for comprehensive emergency obstetric and newborn care (CEmONC) services due to ineffective communication between a rural health facility (RHF) and a district hospital contribute to the low CS rate. This study examined the association between mobile obstetric emergency system (MORES) implementation and referral time for obstetric emergencies as well as maternal/newborn outcomes. METHODS: A pre-post descriptive analysis was conducted on data collected from 20 rural health facilities (RHFs) and two hospitals in Bong County. Women with referral data from both RHFs and hospitals were matched and information including transfer time, reasons for referral, and maternal and newborn outcomes were extracted. Descriptive analysis and logistic regression models examined the relationship between the intervention's implementation and mode of delivery, maternal outcome, newborn outcome, and transfer time from RHF to district hospital. Ethics approval was obtained from two study centers. RESULTS: Women had higher odds of undergoing a CS at endline (OR: 1.86 95% CI: 0.99-3.46) compared to baseline. Additionally, newborns had lower odds of showing non-vigorous symptoms (OR: 0.31; 95% CI: 0.14-0.68), defined as a newborn with poor respiratory effort, muscle tone, or heart rate. There was no significant association between the intervention's implementation and transfer time. CONCLUSION: The MORES intervention is a promising means to increase timely care seeking along the referral pathway which may enhance access to cesarean section as well as improved newborn outcome in low- and middle-income countries.

Patients Who Have a Prior History of Pulmonary Embolism Require Increased Postoperative Care Following Total Joint Arthroplasty.

BACKGROUND: This study examined the effect of prior pulmonary embolism (PE) on total joint arthroplasty (TJA) outcomes. METHODS: We reviewed patients who had a prior PE undergoing TJA at a single tertiary medical center between January 1, 2012 and January 1, 2021. There were 177 TJA patients who had a prior PE who underwent 1:3 propensity-matching to patients without a history of prior PE. Bivariable and multivariable analyses were performed. Changes over time were evaluated. RESULTS: Patients undergoing total knee arthroplasty who had a prior PE had more complications (25.3% versus 2.0%, P < .001), and postoperative PE (17.3% versus 0.0%, P < .001).and longer hospitalizations (3.15 versus 2.32 days, P = .006). Patients undergoing total hip arthroplasty who had a prior PE demonstrated more complications (14.7% versus 1.77%, P < .001) more postoperative PE (17.3% versus 0.0%, P < .001), and longer hospitalizations (3.30 versus 2.11 days, P < .001). Over the study, complication rates and hospitalizations lengths remained elevated in patients who had a prior PE. On multivariate analyses, prior PE was associated with longer hospitalizations (ß: 0.67, P = .015) and increased complications (odds ratio [OR]: 9.44, P < .001) among total hip arthroplasty patients. Total knee arthroplasty patients had increased readmission (OR: 4.89, P = .003) and complication rates (OR: 21.4, P < .001). CONCLUSIONS: Patients undergoing TJA who had a prior PE are at higher risk of requiring postoperative care. Therefore, thorough preoperative evaluation must be implemented, especially in clinical environments lacking resources for acute care escalation.

Patients Who Have Pre-Existing Atrial Fibrillation Require Increased Postoperative Care Following Total Joint Arthroplasty.

BACKGROUND: Approximately 9% of total joint arthroplasty (TJA) patients have pre-existing atrial fibrillation (AF). This study examined the effect of pre-existing AF on TJA outcomes. METHODS: We conducted a 1:3 propensity match of 545 TJA patients who have pre-existing AF to TJA patients who do not have AF at a tertiary care center between January 1st, 2012, and January 1st, 2021. Bivariate and multivariate regressions were performed. Changes over time were evaluated. RESULTS: Patients undergoing total knee arthroplasty (TKA) who have pre-existing AF, experienced more post-operative AFs (P < .001), acute kidney injuries (P = .026), post-operative complications (POC) (P < .001), and 30-day readmissions (P = .036). Patients undergoing total hip arthroplasty (THA) who have pre-existing AF experienced more post-operative AFs (P < .001), pulmonary embolisms (P < .001), increased estimated blood losses (P = .007), more blood transfusions (P = .002), more POCs (P < .001), and longer lengths of stay (LOS) (P < .002). Over time, POC and LOS decreased in both groups, but remained increased in TJA patients who have pre-existing AF. Multivariate analyses of TKA patients showed an increased odds ratio (OR) of any POCs (P < .001), while THA patients had an increased OR of any POCs (P = .01), and LOS (P = .002). CONCLUSION: Patients who have pre-existing AF undergoing TJA have more POCs. TKA patients have more readmissions. THA patients have longer LOS. These findings demonstrate the importance of enhanced peri-operative medical management in patients who have pre-existing AF undergoing TJA.

Nivolumab Plus Ipilimumab in Patients With Solid Tumors With ATM Mutations: Results From the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.

PURPOSE: The Targeted Agent and Profiling Utilization Registry Study is a phase II basket study evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancers with genomic alterations known to be drug targets. Results of a cohort of patients with solid tumors with ATM mutations treated with nivolumab plus ipilimumab are reported. METHODS: Eligible patients had measurable disease (RECIST v.1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. Primary end point was disease control (DC), defined as complete (CR) or partial (PR) response or stable disease (SD) of at least 16 weeks duration (SD16+). Low-accruing histology-specific cohorts with ATM mutations treated with nivolumab plus ipilimumab were collapsed into a single histology-pooled cohort for this analysis. The results were evaluated based on a one-sided exact binomial test with a null DC rate of 15% versus 35% (power = .84; α = .10). Secondary end points were objective response (OR), progression-free survival, overall survival, duration of response, duration of SD, and safety. RESULTS: Twenty-nine patients with 10 tumor types with ATM mutations were enrolled from January 2018 to May 2020. One patient was not evaluable for efficacy. One CR, three PR, and three SD16+ were observed for DC and OR rates of 24% (P = .13; one-sided 90% CI: 14 to 100) and 14% (95% CI: 4 to 32), respectively. The null hypothesis of 15% DC rate was not rejected. Eleven patients had one treatment-related grade 3 adverse event (AE) or serious AE. There were two treatment-related patient deaths including immune-related encephalitis and respiratory failure. CONCLUSION: Nivolumab plus ipilimumab did not meet prespecified criteria to declare a signal of activity in patients with solid tumors with ATM mutations.

Methane prediction equations including genera of rumen bacteria as predictor variables improve prediction accuracy.

Methane (CH4) emissions from ruminants are of a significant environmental concern, necessitating accurate prediction for emission inventories. Existing models rely solely on dietary and host animal-related data, ignoring the predicting power of rumen microbiota, the source of CH4. To address this limitation, we developed novel CH4 prediction models incorporating rumen microbes as predictors, alongside animal- and feed-related predictors using four statistical/machine learning (ML) methods. These include random forest combined with boosting (RF-B), least absolute shrinkage and selection operator (LASSO), generalized linear mixed model with LASSO (glmmLasso), and smoothly clipped absolute deviation (SCAD) implemented on linear mixed models. With a sheep dataset (218 observations) of both animal data and rumen microbiota data (relative sequence abundance of 330 genera of rumen bacteria, archaea, protozoa, and fungi), we developed linear mixed models to predict CH4 production (g CH4/animal·d, ANIM-B models) and CH4 yield (g CH4/kg of dry matter intake, DMI-B models). We also developed models solely based on animal-related data. Prediction performance was evaluated 200 times with random data splits, while fitting performance was assessed without data splitting. The inclusion of microbial predictors improved the models, as indicated by decreased root mean square prediction error (RMSPE) and mean absolute error (MAE), and increased Lin's concordance correlation coefficient (CCC). Both glmmLasso and SCAD reduced the Akaike information criterion (AIC) and Bayesian information criterion (BIC) for both the ANIM-B and the DMI-B models, while the other two ML methods had mixed outcomes. By balancing prediction performance and fitting performance, we obtained one ANIM-B model (containing 10 genera of bacteria and 3 animal data) fitted using glmmLasso and one DMI-B model (5 genera of bacteria and 1 animal datum) fitted using SCAD. This study highlights the importance of incorporating rumen microbiota data in CH4 prediction models to enhance accuracy and robustness. Additionally, ML methods facilitate the selection of microbial predictors from high-dimensional metataxonomic data of the rumen microbiota without overfitting. Moreover, the identified microbial predictors can serve as biomarkers of CH4 emissions from sheep, providing valuable insights for future research and mitigation strategies.

Cobimetinib Plus Vemurafenib in Patients With Solid Tumors With BRAF Mutations: Results From the Targeted Agent and Profiling Utilization Registry Study.

PURPOSE: The Targeted Agent and Profiling Utilization Registry Study is a phase II basket study evaluating antitumor activity of commercially available targeted agents in patients with advanced cancers with genomic alterations known to be drug targets. The results in a cohort of patients with solid tumors with BRAF mutations treated with cobimetinib plus vemurafenib are reported. METHODS: Eligible patients had measurable disease (RECIST v.1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. The primary end point was disease control (DC), defined as complete response (CR) or partial response (PR) or stable disease of at least 16-weeks duration (SD16+). Low-accruing histology-specific cohorts with BRAF mutations treated with cobimetinib plus vemurafenib were collapsed into a single histology-pooled cohort for this analysis. The results were evaluated on the basis of a one-sided exact binomial test with a null DC rate of 15% versus 35% (power, .82; α, .10). The secondary end points were objective response (OR), progression-free survival, overall survival, duration of response, duration of stable disease, and safety. RESULTS: Thirty-one patients with solid tumors with BRAF mutations were enrolled. Twenty-eight patients were evaluable for efficacy. Patients had tumors with BRAF V600E (n = 26), K601E (n = 2), or other (n = 3) mutations. Two patients with CR (breast and ovarian cancers; V600E), 14 with PR (13 V600E, one N581I), and three with SD16+ (two V600E, one T599_V600insT) were observed with a DC rate of 68% (P < .0001; one-sided 90% CI, 54 to 100) and an OR rate of 57% (95% CI, 37 to 76). Nineteen patients experienced ≥one drug-related grade 3-5 adverse event or serious adverse event including one death attributed to treatment-related kidney injury. CONCLUSION: Cobimetinib plus vemurafenib showed antitumor activity in patients with advanced solid tumors with BRAF V600E mutations; additional study is warranted to confirm the antitumor activity in tumors with non-V600E BRAF mutations.

Probing the Interactions of Thiazole Abietane Inhibitors with the Human Serine Hydrolases ABHD16A and ABHD12.

12-Thiazole abietanes are highly selective reversible inhibitors of hABHD16A that could potentially alleviate neuroinflammation. In this study, we used synthetic chemistry, competitive activity-based protein profiling, and computational methodologies to try to establish relevant structural determinants of activity and selectivity of this class of compounds for inhibiting ABHD16A over ABHD12. Five compounds significantly inhibited hABHD16A but also very efficiently discriminated between inhibition of hABHD16A and hABHD12, with compound 35 being the most effective, at 100 µM (55.1 ± 8.7%; p < 0.0001). However, an outstanding switch in the selectivity toward ABHD12 was observed in the presence of a ring A ester, if the C2' position of the thiazole ring possessed a 1-hydroxyethyl group, as in compound 28. Although our data were inconclusive as to whether the observed enzyme inhibition is allosteric or not, we anticipate that the structure-activity relationships presented herein will inspire future drug discovery efforts in this field.

LAP-MALDI MS Profiling and Identification of Potential Biomarkers for the Detection of Bovine Tuberculosis.

Detecting bovine tuberculosis (bTB) primarily relies on the tuberculin skin test, requiring two separate animal handling events with a period of incubation time (normally 3 days) between them. Here, we present the use of liquid atmospheric pressure (LAP)-MALDI for the identification of bTB infection, employing a three-class prediction model that was obtained by supervised linear discriminant analysis (LDA) and tested with bovine mastitis samples as disease-positive controls. Noninvasive collection of nasal swabs was used to collect samples, which were subsequently subjected to a short (<4 h) sample preparation method. Cross-validation of the three-class LDA model from the processed nasal swabs provided a sensitivity of 75.0% and specificity of 90.1%, with an overall classification accuracy of 85.7%. These values are comparable to those for the skin test, showing that LAP-MALDI MS has the potential to provide an alternative single-visit diagnostic platform that can detect bTB within the same day of sampling.