Interspecies regulatory landscapes and elements revealed by novel joint systematic integration of human and mouse blood cell epigenomes.

Knowledge of locations and activities of cis-regulatory elements (CREs) is needed to decipher basic mechanisms of gene regulation and to understand the impact of genetic variants on complex traits. Previous studies identified candidate CREs (cCREs) using epigenetic features in one species, making comparisons difficult between species. In contrast, we conducted an interspecies study defining epigenetic states and identifying cCREs in blood cell types to generate regulatory maps that are comparable between species, using integrative modeling of eight epigenetic features jointly in human and mouse in our Validated Systematic Integration (VISION) Project. The resulting catalogs of cCREs are useful resources for further studies of gene regulation in blood cells, indicated by high overlap with known functional elements and strong enrichment for human genetic variants associated with blood cell phenotypes. The contribution of each epigenetic state in cCREs to gene regulation, inferred from a multivariate regression, was used to estimate epigenetic state Regulatory Potential (esRP) scores for each cCRE in each cell type, which were used to categorize dynamic changes in cCREs. Groups of cCREs displaying similar patterns of regulatory activity in human and mouse cell types, obtained by joint clustering on esRP scores, harbored distinctive transcription factor binding motifs that were similar between species. An interspecies comparison of cCREs revealed both conserved and species-specific patterns of epigenetic evolution. Finally, we showed that comparisons of the epigenetic landscape between species can reveal elements with similar roles in regulation, even in the absence of genomic sequence alignment.

Risk of anthracycline-induced cardiac dysfunction in adolescent and young adult (AYA) cancer survivors: role of genetic susceptibility loci.

There is a known genetic susceptibility to anthracycline-induced cardiac dysfunction in childhood cancer survivors, but this has not been adequately shown in adolescent and young adult (AYA) patients. Our aim was to determine if the previously identified variants associated with cardiac dysfunction in childhood cancer patients affect AYA cancer patients similarly. Forty-five variants were selected for analysis in 253 AYAs previously treated with anthracyclines. We identified four variants that were associated with cardiac dysfunction: SLC10A2:rs7319981 (p = 0.017), SLC22A17:rs4982753 (p = 0.019), HAS3:rs2232228 (p = 0.023), and RARG:rs2229774 (p = 0.050). HAS3:rs2232228 and SLC10A2:rs7319981 displayed significant effects in our AYA cancer survivor population that were in the opposite direction than that reported in childhood cancer survivors. Genetic variants in the host genes were further analyzed for additional associations with cardiotoxicity in AYA cancer survivors. The host genes were then evaluated in a panel of induced pluripotent stem cell-derived cardiomyocytes to assess changes in levels of expression when treated with doxorubicin. Significant upregulation of HAS3 and SLC22A17 expression was observed (p < 0.05), with non-significant anthracycline-responsivity observed for RARG. Our study demonstrates that there is a genetic influence on cardiac dysfunction in AYA cancer patients, but there may be a difference in the role of genetics between childhood and AYA cancer survivors.

Multi-ancestry Genome-Wide Association Meta-Analysis Identifies Novel Loci in Atopic Dermatitis.

Atopic dermatitis (AD) is a highly heritable and common inflammatory skin condition affecting children and adults worldwide. Multi-ancestry approaches to AD genetic association studies are poised to boost power to detect genetic signal and identify ancestry-specific loci contributing to AD risk. Here, we present a multi-ancestry GWAS meta-analysis of twelve AD cohorts from five ancestral populations totaling 56,146 cases and 602,280 controls. We report 101 genomic loci associated with AD, including 15 loci that have not been previously associated with AD or eczema. Fine-mapping, QTL colocalization, and cell-type enrichment analyses identified genes and cell types implicated in AD pathophysiology. Functional analyses in keratinocytes provide evidence for genes that could play a role in AD through epidermal barrier function. Our study provides new insights into the etiology of AD by harnessing multiple genetic and functional approaches to unveil the mechanisms by which AD-associated variants impact genes and cell types.

The feasibility of robot assisted laser interstitial thermal therapy (LITT) for brain tumors in octogenarians.

BACKGROUND: The use of robot assisted laser interstitial thermal therapy (LITT) is emerging as a viable treatment option for brain tumors patients aged between 80-90 years (octogenarians). Correspondingly the aim of this study was to describe the clinical feasibility of octogenarians undergoing LITT procedure for brain tumors at our institution. METHODS: A retrospective review was conducted of all robot assisted LITT procedures performed at our institution between 2013-2023 for octogenarians. Comparison of continuous variables was by student t-tests, and Kaplan-Meier estimates were used to estimate survival outcomes. RESULTS: A total of 20/311 (6%) LITT patients in the search cohort were octogenarians. Mean age was 82.6 years (range, 80.1-88.0) with 13 (65%) females. Brain tumor lesions most commonly were located on the left side (65%), and for ablation, all were single trajectories with mean number of 2.3 ablations. No operative complications were seen during hospitalization, with mean length of stay of 1.6 days and most common disposition destination being home (95%). There were no 30- or 90-day readmissions or emergency room presentations. Mean follow-up was 12.4 months without any complications in that time. The most common pathology in our cohort was glioblastoma (GBM, 55%). CONCLUSION: Robot assisted LITT is a safe and effective treatment option for brain tumors in octogenarians with a very low morbidity risk. Therefore, further investigations is required to understand how LITT can translate to therapeutic benefit in patients aged over 80 years old with brain tumors.

Programme science methodologies and practices that address "FURRIE" challenges: examples from the field.

INTRODUCTION: "Programme science" deploys scientific methods to address questions that are a priority to support the impact of public health programmes. As such, programme science responds to the challenges of making such studies: (1) feasible to undertake, (2) useful, (3) rigorous, (4) real-world-relevant, (5) informative, and undertaken by (6) equitable partnerships. The acronym "FURRIE" is proposed to describe this set of six challenges. This paper discusses selected HIV/STI (sexually transmitted infection) programme science case studies to illustrate how programme science rises to the FURRIE challenges. DISCUSSION: One way in which programme science is made more feasible is through the analysis and interpretation of data collected through service delivery. For some questions, these data can be augmented through methods that reach potential clients of services who have not accessed services or been lost to follow-up. Process evaluation can enhance the usefulness of programme science by studying implementation processes, programme-client interactions and contextual factors. Ensuring rigour by limiting bias and confounding in the real-world context of programme science studies requires methodological innovation. Striving for scientific rigour can also have the unintended consequence of creating a gap between what happens in a study, and what happens in the "real-world." Community-led monitoring is one approach to grounding data collection in the real-world experience of clients. Evaluating complex, context-specific strategies to strengthen health outcomes in a way that is informative for other settings requires clear specification of the intervention packages that are planned and delivered in practice. Programme science provides a model for equitable partnership through co-leadership between programmes, researchers and the communities they serve. CONCLUSIONS: Programme science addresses the FURRIE challenges, thereby improving programme impact and ultimately health outcomes and health equity. The adoption and adaptation of the types of novel programme science approaches showcased here should be promoted within and beyond the HIV/STI field.

A minimal RNA substrate with dual fluorescent probes enables rapid kinetics and provides insight into bacterial RNase P active site interactions.

Bacterial ribonuclease P (RNase P) is a tRNA processing endonuclease that occurs primarily as a ribonucleoprotein with a catalytic RNA subunit (P RNA). As one of the first ribozymes discovered, P RNA is a well-studied model system for understanding RNA catalysis and substrate recognition. Extensive structural and biochemical studies have revealed the structure of RNase P bound to precursor tRNA (ptRNA) and product tRNA. These studies also helped to define active site residues and propose the molecular interactions that are involved in substrate binding and catalysis. However, a detailed quantitative model of the reaction cycle that includes the structures of intermediates and the process of positioning active site metal ions for catalysis is lacking. To further this goal, we used a chemically modified minimal RNA duplex substrate (MD1) to establish a kinetic framework for measuring the functional effects of P RNA active site mutations. Substitution of U69, a critical nucleotide involved in active site Mg2+ binding, was found to reduce catalysis >500-fold as expected, but had no measurable effect on ptRNA binding kinetics. In contrast, the same U69 mutations had little effect on catalysis in Ca2+ compared to reactions containing native Mg2+ ions. CryoEM structures and SHAPE mapping suggested increased flexibility of U69 and adjacent nucleotides in Ca2+ compared to Mg2+. These results support a model in which slow catalysis in Ca2+ is due to inability to engage U69. These studies establish a set of experimental tools to analyze RNase P kinetics and mechanism and can be expanded to gain new insights into the assembly of the active RNase P-ptRNA complex.

Cementless Total Knee Arthroplasty: A State-of-the-Art Review.

¼ The demographic profile of candidates for total knee arthroplasty (TKA) is shifting toward younger and more active individuals.¼ While cemented fixation remains the gold standard in TKA, the interest is growing in exploring cementless fixation as a potentially more durable alternative.¼ Advances in manufacturing technologies are enhancing the prospects for superior long-term biological fixation.¼ Current research indicates that intermediate to long-term outcomes of modern cementless TKA designs are comparable with traditional cemented designs.¼ The selection of appropriate patients is critical to the success of cementless fixation techniques in TKA.¼ There is a need for high-quality research to better understand the potential differences and relative benefits of cemented vs. cementless TKA systems.

Optimizing pediatric periprocedural pain management part II-Adjunct therapies to support the use of infiltrative anesthetics.

Pediatric procedure-related pain management is often incompletely understood, inadequately addressed, and critical in influencing a child's lifelong relationship with the larger healthcare community. We present a comprehensive review of infiltrative anesthetics, including a comparison of their mechanisms of action and relative safety and efficacy data to help guide clinical selection. We also describe the multimodal utilization of adjunct therapies-in series and in parallel-to support the optimization of pediatric periprocedural pain management, enhance the patient experience, and provide alternatives to sedation medication and general anesthesia.

Low thiamine status in adults following low-carbohydrate / ketogenic diets: a cross-sectional comparative study of micronutrient intake and status.

BACKGROUND: Low-carbohydrate diets (LCD) are popular for weight loss but lack evidence about micronutrient sufficiency in real-life use. This study assessed the intake and biochemical status of selected micronutrients in people voluntarily following LCDs. METHODS: A cross-sectional study was conducted (2018-20) among 98 adults recruited as self-reporting either LCD (n = 49) or diets not restricting carbohydrates (controls; n = 49). Diets were assessed using the 130-item EPIC-Norfolk food-frequency questionnaire. Red-blood-cell thiamine diphosphate (TDP) was measured for thiamine status using HPLC. Plasma magnesium, zinc, copper, and selenium were measured using inductively coupled plasma mass spectrometry. Between-group biomarker comparisons were conducted using ANCOVA and adjusted for age, sex, body mass index (BMI), and diabetes status. RESULTS: LCD-followers (26% male, median age 36 years, median BMI 24.2 kg/m2) reported adhering to LCDs for a median duration of 9 months (IQR 4-36). The most followed LCD type was 'their own variations of LCD' (30%), followed by ketogenic (23%), 'palaeolithic' (15%), and Atkins diets (8%). Among controls, 41% were male (median age 27 years, median BMI 23 kg/m2). Median macronutrient intakes for LCD vs control groups were carbohydrate 16%Energy (E) vs. 50%E; protein 25%E vs. 19%E; and fat 55%E vs 34%E (saturated fat 18%E vs. 11%E). Two-thirds of LCD followers (32/49) and half of the controls (24/49) reported some use of dietary supplements (p = 0.19). Among LCD-followers, assessing from food data only, 21 (43%) failed to meet the reference nutrient intake (RNI) for thiamine (vs.14% controls, p = 0.002). When thiamine from supplementation (single- or multivitamin) was included, there appeared to be no difference in thiamine intake between groups. Still, red-blood-cell TDP was lower in LCD-followers than controls (407 ± 91 vs. 633 ± 234 ng/gHb, p < 0.001). Three LCD-followers were thiamine-deficient (RBC thiamine < 275 ng/gHb) vs. one control. There were no significant differences in dietary intakes or plasma concentrations of magnesium, zinc, copper, and selenium between groups. CONCLUSIONS: Following LCDs is associated with lower thiamine intake and TDP status than diets without carbohydrate restriction, incompletely corrected by supplement use. These data, coupled with a lack of RCT evidence on body weight control, do not support recommending LCDs for weight management without appropriate guidance and diet supplementation.

Association of physical function with connectivity in the sensorimotor and dorsal attention networks: why examining specific components of physical function matters.

Declining physical function with aging is associated with structural and functional brain network organization. Gaining a greater understanding of network associations may be useful for targeting interventions that are designed to slow or prevent such decline. Our previous work demonstrated that the Short Physical Performance Battery (eSPPB) score and body mass index (BMI) exhibited a statistical interaction in their associations with connectivity in the sensorimotor cortex (SMN) and the dorsal attention network (DAN). The current study examined if components of the eSPPB have unique associations with these brain networks. Functional magnetic resonance imaging was performed on 192 participants in the BNET study, a longitudinal and observational trial of community-dwelling adults aged 70 or older. Functional brain networks were generated for resting state and during a motor imagery task. Regression analyses were performed between eSPPB component scores (gait speed, complex gait speed, static balance, and lower extremity strength) and BMI with SMN and DAN connectivity. Gait speed, complex gait speed, and lower extremity strength significantly interacted with BMI in their association with SMN at rest. Gait speed and complex gait speed were interacted with BMI in the DAN at rest while complex gait speed, static balance, and lower extremity strength interacted with BMI in the DAN during motor imagery. Results demonstrate that different components of physical function, such as balance or gait speed and BMI, are associated with unique aspects of brain network organization. Gaining a greater mechanistic understanding of the associations between low physical function, body mass, and brain physiology may lead to the development of treatments that not only target specific physical function limitations but also specific brain networks.

Streamlining heterologous expression of top carbonic anhydrases in Escherichia coli: bioinformatic and experimental approaches.

BACKGROUND: Carbonic anhydrase (CA) enzymes facilitate the reversible hydration of CO2 to bicarbonate ions and protons. Identifying efficient and robust CAs and expressing them in model host cells, such as Escherichia coli, enables more efficient engineering of these enzymes for industrial CO2 capture. However, expression of CAs in E. coli is challenging due to the possible formation of insoluble protein aggregates, or inclusion bodies. This makes the production of soluble and active CA protein a prerequisite for downstream applications. RESULTS: In this study, we streamlined the process of CA expression by selecting seven top CA candidates and used two bioinformatic tools to predict their solubility for expression in E. coli. The prediction results place these enzymes in two categories: low and high solubility. Our expression of high solubility score CAs (namely CA5-SspCA, CA6-SazCAtrunc, CA7-PabCA and CA8-PhoCA) led to significantly higher protein yields (5 to 75 mg purified protein per liter) in flask cultures, indicating a strong correlation between the solubility prediction score and protein expression yields. Furthermore, phylogenetic tree analysis demonstrated CA class-specific clustering patterns for protein solubility and production yields. Unexpectedly, we also found that the unique N-terminal, 11-amino acid segment found after the signal sequence (not present in its homologs), was essential for CA6-SazCA activity. CONCLUSIONS: Overall, this work demonstrated that protein solubility prediction, phylogenetic tree analysis, and experimental validation are potent tools for identifying top CA candidates and then producing soluble, active forms of these enzymes in E. coli. The comprehensive approaches we report here should be extendable to the expression of other heterogeneous proteins in E. coli.

Comparison of test performance of a conventional PCR and two field-friendly tests to detect Coxiella burnetii DNA in ticks using Bayesian latent class analysis.

Introduction: Coxiella burnetii (C. burnetii)-infected livestock and wildlife have been epidemiologically linked to human Q fever outbreaks. Despite this growing zoonotic threat, knowledge of coxiellosis in wild animals remains limited, and studies to understand their epidemiologic role are needed. In C. burnetii-endemic areas, ticks have been reported to harbor and spread C. burnetii and may serve as indicators of risk of infection in wild animal habitats. Therefore, the aim of this study was to compare molecular techniques for detecting C. burnetii DNA in ticks. Methods: In total, 169 ticks from wild animals and cattle in wildlife conservancies in northern Kenya were screened for C. burnetii DNA using a conventional PCR (cPCR) and two field-friendly techniques: Biomeme's C. burnetii qPCR Go-strips (Biomeme) and a new C. burnetii PCR high-resolution melt (PCR-HRM) analysis assay. Results were evaluated, in the absence of a gold standard test, using Bayesian latent class analysis (BLCA) to characterize the proportion of C. burnetii positive ticks and estimate sensitivity (Se) and specificity (Sp) of the three tests. Results: The final BLCA model included main effects and estimated that PCR-HRM had the highest Se (86%; 95% credible interval: 56-99%), followed by the Biomeme (Se = 57%; 95% credible interval: 34-90%), with the estimated Se of the cPCR being the lowest (24%, 95% credible interval: 10-47%). Specificity estimates for all three assays ranged from 94 to 98%. Based on the model, an estimated 16% of ticks had C. burnetii DNA present. Discussion: These results reflect the endemicity of C. burnetii in northern Kenya and show the promise of the PCR-HRM assay for C. burnetii surveillance in ticks. Further studies using ticks and wild animal samples will enhance understanding of the epidemiological role of ticks in Q fever.

The Impact of Perilesional Heatsink Structures on Ablation Volumes in Laser Interstitial Thermal Therapy for Brain Metastases.

BACKGROUND AND OBJECTIVES: Laser interstitial thermal therapy (LITT) has demonstrated promise in surgical neuro-oncology because of its effectiveness in delivering precise thermal energy to lesions. The extent of ablation (EOA) is a prognostic factor in improving patient outcomes but is often affected by perilesional heatsink structures, which can lead to asymmetric ablations. The purpose of this study was to quantitatively evaluate the impact of various perilesional heatsink structures on the EOA in LITT for brain metastases. METHODS: Twenty-seven procedures for 22 unique patients with brain metastases fit the inclusion criteria. Intracranial heatsink structures were identified: sulci, meninges, cerebrospinal fluid (CSF) spaces, and vasculature. Asymmetric ablation was determined by measuring 3 pairs of orthogonal distances from the proximal, midpoint, and distal locations along the laser catheter to the farthest edge of the ablation zone bilaterally. Distances from the same points on the laser catheter to the nearest heatsink were also recorded. The Heatsink Effect Index was created to serve as a proxy for asymmetric ablation. Pearson correlations, t-tests, and analysis of variance were the statistical analyses performed. RESULTS: From the midpoint of the catheter, the 27 heatsinks were meninges (40.7%), sulci (22.2%), vasculature (22.2%), and CSF spaces (14.8%). Across all points along the catheter track, there was a significant generalized heatsink effect on asymmetric ablations (P < .0001). There was a negative correlation observed between asymmetric ablations and EOA from the midpoint of the laser catheter (r = -0.445, P = .020). Compared with sulci, CSF spaces trended toward a greater effect on asymmetric ablation volumes (P = .069). CONCLUSION: This novel quantitative analysis shows that perilesional heatsinks contribute to asymmetric ablations. CSF spaces trended toward higher degrees of asymmetric ablations. Importantly, neurosurgeons may anticipate asymmetric ablations preoperatively if heatsinks are located within 13.3 mm of the laser probe midpoint. These preliminary results may guide surgical decision-making in LITT for metastatic brain lesions.

Preclinical evidence for employing MEK inhibition in NRAS mutated pediatric gastroenteropancreatic neuroendocrine-like tumors.

BACKGROUND: Pediatric gastroenteropancreatic neuroendocrine tumors are exceedingly rare, resulting in most pediatric treatment recommendations being based on data derived from adults. Trametinib is a kinase inhibitor that targets MEK1/2 and has been employed in the treatment of cancers harboring mutations in the Ras pathway. METHODS: We utilized an established human pediatric gastroenteropancreatic neuroendocrine-like tumor patient-derived xenograft (PDX) with a known NRAS mutation to study the effects of MEK inhibition. We evaluated the effects of trametinib on proliferation, motility, and tumor growth in vivo. We created an intraperitoneal metastatic model of this PDX, characterized both the phenotype and the genotype of the metastatic PDX and again, investigated the effects of MEK inhibition. RESULTS: We found target engagement with decreased ERK1/2 phosphorylation with trametinib treatment. Trametinib led to decreased in vitro cell growth and motility, and decreased tumor growth and increased animal survival in a murine flank tumor model. Finally, we demonstrated that trametinib was able to significantly decrease gastroenteropancreatic neuroendocrine intraperitoneal tumor metastasis. CONCLUSIONS: The results of these studies support the further investigation of MEK inhibition in pediatric NRAS mutated solid tumors.

Episodes of acute methotrexate-related neurotoxicity linked to compromised long-term neurocognitive function.

Methotrexate is a critical component of curative chemotherapy for pediatric acute lymphoblastic leukemia (ALL), but is associated with neurotoxicity. Information on long-term outcomes following an acute neurotoxic event is limited. Therefore, this report compares neurocognitive performance more than 12 months post diagnosis (mean = 4 years) between ALL patients with (n = 25) and without (n = 146) a history of acute neurotoxicity. Compared to children with no documented on-treatment neurotoxic event, children who experienced a neurotoxic event during treatment exhibited poorer performance on measures of fine motor function (p = .02) and attention (p = .02). Children with ALL who experience acute neurotoxicity may be candidates for early neuropsychological screening and intervention.

The effects of intermittent fasting on body composition and cardiometabolic health in adults with prediabetes or type 2 diabetes: A systematic review and meta-analysis.

AIM: To perform a meta-analysis to investigate the effects of intermittent fasting (IF), as compared with either a control diet (CON) and/or calorie restriction (CR), on body composition and cardiometabolic health in individuals with prediabetes and type 2 diabetes (T2D). METHODS: PubMed, Web of Science, and Scopus were searched from their inception to March 2024 to identify original randomized trials with parallel or crossover designs that studied the effects of IF on body composition and cardiometabolic health. Weighted mean differences (WMDs) or standardized mean differences with 95% confidence intervals (CIs) were calculated using random-effects models. RESULTS: Overall, 14 studies involving 1101 adults with prediabetes or T2D were included in the meta-analysis. IF decreased body weight (WMD -4.56 kg [95% CI -6.23 to -2.83]; p = 0.001), body mass index (BMI; WMD -1.99 kg.m2 [95% CI -2.74 to -1.23]; p = 0.001), glycated haemoglobin (HbA1c; WMD -0.81% [95% CI -1.24 to -0.38]; p = 0.001), fasting glucose (WMD -0.36 mmol/L [95% CI -0.63 to -0.09]; p = 0.008), total cholesterol (WMD -0.31 mmol/L [95% CI -0.60 to -0.02]; p = 0.03) and triglycerides (WMD -0.14 mmol/L [95% CI -0.27 to -0.01]; p = 0.02), but did not significantly decrease fat mass, insulin, low-densitiy lipoprotein, high-density lipoprotein, or blood pressure as compared with CON. Furthermore, IF decreased body weight (WMD -1.14 kg [95% CI -1.69 to -0.60]; p = 0.001) and BMI (WMD -0.43 kg.m2 [95% CI -0.58 to -0.27]; p = 0.001), but did not significantly affect fat mass, lean body mass, visceral fat, insulin, HbA1c, lipid profiles or blood pressure. CONCLUSION: Intermittent fasting is effective for weight loss and specific cardiometabolic health markers in individuals with prediabetes or T2D. Additionally, IF is associated with a reduction in body weight and BMI compared to CR, without effects on glycaemic markers, lipid profiles or blood pressure.

Celecoxib-tramadol co-crystal in patients with moderate-to-severe pain following bunionectomy with osteotomy: Secondary analyses by baseline pain intensity and use of rescue medication of a phase 3, randomized, double-blind, factorial, active- and placebo-controlled trial.

BACKGROUND: In the randomized, phase 3, SUSA-301 trial, celecoxib-tramadol co-crystal (CTC) provided significantly greater analgesia compared with celecoxib, tramadol, or placebo in adults with acute, moderate-to-severe, postoperative pain. This post hoc, secondary analysis further evaluated the use of rescue medication and the incidence of treatment-emergent adverse events (TEAEs). METHODS: Patients (N = 637) were randomized 2:2:2:1 to receive oral CTC 200 mg twice daily (BID; n = 184), tramadol 50 mg four times daily (QID; n = 183), celecoxib 100 mg BID (n = 181), or placebo QID (n = 89). Post hoc analyses were conducted on the use of rescue medications up to 4 and 48 h post-study drug dose, stratified by baseline pain intensity (moderate/severe), and on the incidence of TEAEs, stratified by rescue medication use. RESULTS: A significantly lower proportion of patients received any rescue medication within 4 h post-study dose with CTC (49.5%) versus tramadol (61.7%, p = 0.0178), celecoxib (65.2%, p = 0.0024), and placebo (75.3%, p = 0.0001); this was also seen for oxycodone use. Fewer patients in the CTC group received ≥3 doses of rescue medication compared with the other groups, irrespective of baseline pain intensity. In patients who did not receive opioid rescue medication, CTC was associated with a lower incidence of nausea and vomiting TEAEs versus tramadol alone. In patients who received rescue oxycodone, the incidence of nausea was similar in the CTC and tramadol groups, and higher versus celecoxib and placebo. CONCLUSION: Celecoxib-tramadol co-crystal was associated with reduced rescue medication use and an acceptable tolerability profile compared with tramadol or celecoxib alone in adults with acute, moderate-to-severe, postoperative pain.

A large-scale assessment of eastern whip-poor-will (Antrostomus vociferus) occupancy across a gradient of forest management intensity using autonomous recording units.

Conservationists spend considerable resources to create and enhance wildlife habitat. Monitoring how species respond to these efforts helps managers allocate limited resources. However, monitoring efforts often encounter logistical challenges that are exacerbated as geographic extent increases. We used autonomous recording units (ARUs) and automated acoustic classification to mitigate the challenges of assessing Eastern Whip-poor-will (Antrostomus vociferus) response to forest management across the eastern USA. We deployed 1263 ARUs in forests with varying degrees of management intensity. Recordings were processed using an automated classifier and the resulting detection data were used to assess occupancy. Whip-poor-wills were detected at 401 survey locations. Across our study region, whip-poor-will occupancy decreased with latitude and elevation. At the landscape scale, occupancy decreased with the amount of impervious cover, increased with herbaceous cover and oak and evergreen forests, and exhibited a quadratic relationship with the amount of shrub-scrub cover. At the site-level, occupancy was negatively associated with basal area and brambles (Rubus spp.) and exhibited a quadratic relationship with woody stem density. Implementation of practices that create and sustain a mosaic of forest age classes and a diverse range of canopy closure within oak (Quercus spp.) dominated landscapes will have the highest probability of hosting whip-poor-wills. The use of ARUs and a machine learning classifier helped overcome challenges associated with monitoring a nocturnal species with a short survey window across a large spatial extent. Future monitoring efforts that combine ARU-based protocols and mappable fine-resolution structural vegetation data would likely further advance our understanding of whip-poor-will response to forest management.