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Abstract Current understanding of soil carbon dynamics suggests that plant litter quality and soil mineralogy control the formation of mineral-associated soil organic carbon (SOC). Due to more efficient microbial anabolism, high-quality litter may produce more microbial residues for stabilisation on mineral surfaces. To test these fundamental concepts, we manipulate soil mineralogy using pristine minerals, characterise microbial communities and use stable isotopes to measure decomposition of low- and high-quality litter and mineral stabilisation of litter-C. We find that high-quality litter leads to less (not more) efficient formation of mineral-associated SOC due to soil microbial community shifts which lower carbon use efficiency. Low-quality litter enhances loss of pre-existing SOC resulting in no effect of litter quality on total mineral-associated SOC. However, mineral-associated SOC formation is primarily controlled by soil mineralogy. These findings refute the hypothesis that high-quality plant litters form mineral-associated SOC most efficiently and advance our understanding of how mineralogy and litter-microbial interactions regulate SOC formation.

In this work, we study the relationship between slip localizations and local orientation gradients in a polycrystalline material. We employ a 3D spatially resolved crystal plasticity-based micromechanics technique that includes explicit intragranular slip band modeling, called SB-FFT (slip band fast Fourier transform). EBSD analysis reveals the development of slip localizations, with a rare few generating relatively large local orientation gradients in the neighboring grain. Our results find that several conditions need to be met simultaneously for large zone of intense orientation gradients to form within a grain and with this, offer an explanation for their scarcity. These conditions entail the localization of slip to a sufficient high intensity in the grain neighbor, the grain experiencing higher stress levels than the average stress of its nearest grain neighborhood, and a crystallographic orientation suitable for activating secondary slip under the stress field produced by the slip localization. Analysis of the 3D orientation distributions as they evolve in strain indicates that orientation gradient zones cause the distribution to become highly skewed, with the extreme tails extending further as strain increases. The numerical simulations with various grain neighborhoods show that this feature is, however, not a sufficient signature for such orientation gradients associated with slip localizations since triple junctions or quadruple points can also produce intragranular orientation gradients that have a similar impact on the grain orientation distribution. Last, comparison with several previously proposed slip transmission criteria indicates that this phenomenon is not relevant, contrary to current belief.

Abstract The Phase 3 randomized controlled trial, TBTC Study 31/ACTG A5349 (NCT02410772) demonstrated that a 4-month rifapentine-moxifloxacin regimen for drug-susceptible pulmonary tuberculosis was safe and effective. The primary efficacy outcome was 12-month tuberculosis disease free survival, while the primary safety outcome was the proportion of grade 3 or higher adverse events during the treatment period. We conducted an analysis of demographic, clinical, microbiologic, radiographic, and pharmacokinetic data and identified risk factors for unfavorable outcomes and adverse events. Among participants receiving the rifapentine-moxifloxacin regimen, low rifapentine exposure is the strongest driver of tuberculosis-related unfavorable outcomes (HR 0.65 for every 100 µg∙h/mL increase, 95%CI 0.54–0.77). The only other risk factors identified are markers of higher baseline disease severity, namely Xpert MTB/RIF cycle threshold and extent of disease on baseline chest radiography (Xpert: HR 1.43 for every 3-cycle-threshold decrease, 95%CI 1.07–1.91; extensive disease: HR 2.02, 95%CI 1.07–3.82). From these risk factors, we developed a simple risk stratification to classify disease phenotypes as easier-, moderately-harder, or harder-to-treat TB. Notably, high rifapentine exposures are not associated with any predefined adverse safety outcomes. Our results suggest that the easier-to-treat subgroup may be eligible for further treatment shortening while the harder-to-treat subgroup may need higher doses or longer treatment.

Abstract Individuals with chronic liver or kidney disease are at increased risk of severe COVID‐19. Molnupiravir is an orally administered antiviral authorized for the treatment of mild‐to‐moderate COVID‐19 in adults at risk of progression to severe disease. Two nonrandomized, open‐label, single‐dose, multicenter, phase 1 trials were conducted to investigate the effects of hepatic and renal impairment on the tolerability and pharmacokinetics of molnupiravir (800 mg) and its metabolite β‐D‐N4‐hydroxycytidine (NHC; NCT05386589/NCT05386758). The impact of renal impairment on urinary excretion of NHC was also assessed. The 90% CI for the geometric mean ratio of the plasma NHC area under the concentration–time curve (AUC) from zero to infinity was

Objective: To investigate the effects of sensory reweighting on postural control and cortical activity in individuals with Parkinson's disease (PD) compared to age-matched controls using a virtual reality sensory organization test (VR-SOT). Design: Cross-sectional pilot study. Setting: University research laboratory. Participants: Ten participants with idiopathic Parkinson's disease and 11 age- and sex-matched control participants without neurologic disorders. Interventions: Not applicable. Main Outcome Measures: Changes in center of pressure (COP) and electroencephalography (EEG) activity (ie, power) in the alpha band and the theta/beta ratio recorded during the VR-SOT were the main outcome variables. Results: PD participants exhibited greater COP displacement, particularly in the mediolateral direction across sensory conditions. They also showed increased alpha power when relying on visual inputs and increased theta/beta ratio power when depending on somatosensory inputs. Conclusion: PD affects sensory reweighting mechanisms involved in postural control, as evidenced by greater COP displacement and altered cortical activity. These findings emphasize the potential of EEG and VR-SOT in understanding and monitoring postural control impairments in PD.

Background: Cannabis may be an alternative or adjunct to opioid therapy for chronic pain. However, there are limited data on patterns of opioid medication and medical cannabis use. The current study investigated the feasibility of using Ecological Momentary Assessment (EMA) to assess patterns of prescription opioids and medical cannabis among individuals experiencing chronic pain. Method: The study included 133 participants recruited online. Participants were 42.6 (SD = 13.9) years old on average and the majority were men (57.9 %) and Non-Hispanic White (63.2 %). Participants completed a baseline assessment, followed by 30 days of EMA data collection with four randomly prompted past-hour surveys and one daily diary per day, and a follow-up survey that assessed perceived EMA burden. Simple and multivariable linear regression models were estimated to investigate participant predictors of the proportion of EMA surveys completed (past-hour surveys and daily diaries in separate models). Results: Compliance rates for EMA prompts were 89.7 % for daily diaries and 63.3 % for past-hour surveys. In multivariable regression, participants holding a graduate degree completed a lower proportion of daily diaries (b = −0.109, SE = 0.052, p

Abstract The telomere sequence, TTAGGG, is conserved across all vertebrates and plays an essential role in suppressing the DNA damage response by binding a set of proteins termed shelterin. Changes in the telomere sequence impair shelterin binding, initiate a DNA damage response, and are toxic to cells. Here we identify a family with a variant in the telomere template sequence of telomerase, the enzyme responsible for telomere elongation, that led to a non-canonical telomere sequence. The variant is inherited across at least one generation and one family member reports no significant medical concerns despite ~9% of their telomeres converting to the novel sequence. The variant template disrupts telomerase repeat addition processivity and decreased the binding of the telomere-binding protein POT1. Despite these disruptions, the sequence is readily incorporated into cellular chromosomes. Incorporation of a variant sequence prevents POT1-mediated inhibition of telomerase suggesting that incorporation of a variant sequence may influence telomere addition. These findings demonstrate that telomeres can tolerate substantial degeneracy while remaining functional and provide insights as to how incorporation of a non-canonical telomere sequence might alter telomere length dynamics.

Abstract Soil organic carbon (SOC) is a soil health indicator and understanding dynamics changing SOC stocks will help achieving net zero goals. Here we present four datasets featuring 11,750 data points covering co-located aboveground and below-ground metrics for exploring ecosystem SOC dynamics. Five sites across England with an established land use contrast, grassland and woodland next to each other, were rigorously sampled for aboveground (n = 109), surface (n = 33 soil water release curves), topsoil, and subsoil metrics. Commonly measured soil metrics were analysed in five soil increments for 0–1 metre (n = 4550). Less commonly measured soil metrics which were assumed to change across the soil profile were measured on a subset of samples only (n = 3762). Additionally, we developed a simple method for soil organic matter fractionation using density fractionation which is part of the less common metrics. Finally, soil metrics which may impact SOC dynamics, but with less confidence as to their importance across the soil profile were only measured on topsoil (~5–15 cm = mineral soil) and subsoil (below 50 cm) samples (n = 2567).

The composition Al-16Ce-1Mg has been developed as a dedicated alloy for processing by laser powder bed fusion (LPBF). Guided by thermodynamic considerations and exploiting the unique conditions during LPBF, the strongly hypereutectic alloy features nm-scale aluminum dendrites reinforced by a continuous intermetallic network. The unique temperature stability of Al-Ce alloys as well as the microstructure topology and scale grant the alloy high strength in as-printed state with excellent thermal stability. The superior mechanical properties of the continuously reinforced nanocomposite were established by comparison with the spheroidized, microstructure of similar scale.

Summary: Background: The HVTN 705 Imbokodo trial of 2636 people without HIV and assigned female sex at birth, conducted in southern Africa, evaluated a heterologous HIV-1 vaccine regimen: mosaic adenovirus 26-based vaccine (Ad26.Mos4.HIV) at Months 0, 3, 6, 12 and alum-adjuvanted clade C gp140 at Months 6, 12. Per-protocol vaccine efficacy (VE) against HIV-1 diagnosis from seven to 24 months was 14.1% (95% CI: −22.0% to 39.5%). Immune correlates analysis was performed for markers selected based on prior evidence in efficacy trials and/or nonhuman primate models. Methods: Humoral and cellular immune response markers at Month 7 were evaluated as immune correlates of risk and of protection in a breakthrough case–control cohort (n = 52 cases, 246 non-cases). Primary markers were IgG binding to vaccine-strain gp140, IgG3 binding to diverse Env antigens (IgG3 Env breadth), IgG3 binding to diverse V1V2 antigens (IgG3 V1V2 breadth), antibody-dependent phagocytosis against the vaccine-strain gp140, Env-specific CD4+ and CD8+ T-cell responses, and multi-epitope functions. Findings: No immune markers were statistically significant correlates of risk. IgG3 V1V2 breadth trended toward an inverse association: hazard ratio 0.70 (95% CI: 0.36 to 1.35; p = 0.29) per 10-fold increase and 0.51 (95% CI: 0.21 to 1.24; p = 0.14) in a Cox model with all primary markers. The VE estimate was 11.8% (95% CI: −17.9% to 34.0%) at all IgG3 V1V2 breadth values below 667 weighted geometric mean net MFI; just above this value, the VE estimate sharply increased to 62.6% (95% CI: −17.9% to 89.6%), and further increased to 80.9% (95% CI: −17.9% to 99.5%) at 1471 MFI, the 95th percentile of the marker distribution. Mediation analysis yielded a VE of 35.7% (95% CI: 15.0% to 51.3%) attributable to the vaccine's impact on this marker. Interpretation: The trend in association of greater IgG3 V1V2 antibody breadth with lower likelihood of HIV acquisition is consistent with the identification of antibodies against V1V2 as immune correlates in three other HIV vaccine efficacy trials and suggests that a greater emphasis should be placed on studying this region in the HIV-1 envelope as a vaccine immunogen. Funding: National Institute of Allergy and Infectious Diseases and Janssen Vaccines & Prevention BV.

Microbe-produced molecules (xenometabolites) found in foods or produced by gut microbiota are increasingly implicated in microbe-microbe and microbe-host communication. Xenolipids, in particular, are a class of metabolites for which the full catalog remains to be elaborated in mammalian systems. We and others have observed that cis-3,4-methylene-heptanoylcarnitine is a lipid derivative that is one of the most abundant medium-chain acylcarnitines in human blood, hypothesized to be a product of incomplete β-oxidation of one or more “odd-chain” long-chain cyclopropane fatty acids (CpFAs). We deduced two possible candidates, cis-11,12-methylene-pentadecanoic acid (cis-11,12-MPD) and cis-13,14-methylene-heptadecanoic acid (cis-13,14-MHD). Authentic standards were synthesized: cis-11-pentadecenoic acid and cis-13-heptadecenoic acid were generated (using Jones reagent) from cis-11-pentadecene-1-ol and cis-13-heptadecene-1-ol, respectively, and these were converted to CpFAs via a reaction involving diiodomethane. Using these standards in mass spectrometry analyses, we determined the presence/absence of cis-11,12-MPD and cis-13,14-MHD in archived piglet biospecimens. Both CpFAs were detected in rectal contents of sow and soy-fed piglets. Archived mass spectra were analyzed post hoc from a second independent study that used tissue-specific catheterization to monitor net metabolite flux in growing pigs. This confirmed the presence of both CpFAs in plasma and revealed a significant net uptake of the odd-chain CpFAs across the splanchnic tissue bed and liver. The results confirm that the novel xenolipids cis-11,12-MPD and cis-13,14-MHD can be components of the mammalian lipidome and are viable candidate precursors of cis-3,4-methylene-heptanoylcarnitine produced from partial β-oxidation in liver or other tissues.

The bacterial cell-division protein FtsZ has been a promising antibiotic target for over a decade now, but there is still a need for more work in this area. So far there are no FtsZ targeting drugs commercially available. We have analyzed a wide variety of prospective drugs and their interactions with multiple FtsZ species using both free and directed docking simulations. Our goal is to present a standardized computational screening method for potential drug compounds targeting FtsZ. Our work is an example of a way to compare many proposed drugs and FtsZ species combinations relatively quickly. A common method for comparison can yield new results that individual studies and varying methods might not show, as we demonstrate here. To our knowledge this is one of the first, if not the first, computational docking study on the new E. coli FtsZ structures obtained in 2020.

Background: Children with tuberculous meningitis (TBM) present with diagnostic challenges as they often have atypical clinical features. Objective: To describe the baseline characteristic features of children diagnosed with central nervous system (CNS) TB (TBM and tuberculoma). Design: Retrospective descriptive study. Methods: Children less than 12 years presenting with neurological signs and symptoms were assessed for a therapeutic TBM trial eligibility. The results of their clinical, laboratory, neuroimaging, cerebrospinal fluid evaluations were analysed for TBM diagnosis. Results: Of 600 children evaluated, 61(10%) had CNS tuberculosis; TBM 47, tuberculoma 14. 20(33%) had definite TBM. Mean age of children with TBM was 5 ± 3.4 years. Of 47, 13(28%), 21(45%) and 13(28%) had grade I, II, and III disease respectively. Abnormalities suggestive of TBM in MRI and computed tomography brain were observed in 76% (26/34) and 77% (24/31) respectively. Abnormal cerebrospinal fluid white blood cell count, protein and glucose were observed in 56% (24/43), 49% (22/45), 47% (21/45) respectively. Among 41 patients with TBM followed up until discharge, five died. Conclusion: Younger children with TBM have severe forms. Confirmatory results may not be available in all. A holistic approach to care including addressing complications of hydrocephalus and strokes is needed.

Estimating mortality of sea turtles incidentally captured in fishing gear is essential to understanding fishery impacts on sea turtle populations. Loggerhead turtles (Caretta caretta) are a component of bycatch in pelagic longline fisheries, including those operating in Atlantic Canada. In this study, we used pop-up satellite archival tags (PSATs) attached to 62 loggerhead turtles incidentally hooked in Atlantic Canadian shallow-set pelagic longline gear (2012–2018) to estimate associated post-release survival. Consistent with conventional fishing practices, hooks were not removed from turtles prior to release. Analysis of diving behaviour, ocean temperature, and ambient light level was used to assign fates to turtles. Post-release survival was calculated using the Kaplan-Meier estimator with right censoring. Based on this method, the annual survival probability of an individual loggerhead post-release is 0.877 ± SE 0.052. While it is commonly assumed that hook location is an important variable in predicting fates of turtles after release, there was no difference in survival of deep-hooked (swallowed hook) versus shallow-hooked turtles. These results indicate higher survivorship among hooked loggerheads captured in shallow-set pelagic longline gear than prevailing wisdom and suggest that at least some of the population impacts on loggerhead turtles conventionally attributed to pelagic longline interactions may be linked to other threats.

Abstract The influence of alcohol use on later neurocognitive functioning is well researched, yet few studies have investigated whether neurocognition post‐drinking initiation in adolescence predicts changes in later alcohol use. The objective of this study was to investigate neurocognitive task performance during maximum alcohol use in late adolescence as predictors of drinking behaviors 3–7 years later. Analyses (n = 105) were conducted on a longitudinal data set involving adolescents (12–13 years old) who were followed for 16 years. Time 1 (T1) was defined as the individuals' maximum drinking year within the first 10 study years and Time 2 (T2) was the first available data entry 3–7 years after T1. Four hierarchical linear regression models predicting follow‐up alcohol use were estimated: drinking days, average drinks per drinking day, peak drinks, and binge episodes. All models included inhibition/cognitive flexibility, visuospatial ability, verbal memory, working memory, and their interactions with sex, while covarying for age at T1, follow‐up duration, and controlling for T1 drinking. Better visuospatial ability at T1 predicted decreases in later binge episodes at T2 (β = −0.19, p = 0.048, partial r2 = 0.039). While better inhibition/cognitive flexibility at T1 predicted increases in follow‐up drinks per drinking day at T2 (β = 0.18, p = 0.016, partial r2 = 0.057). Findings suggest specific neurocognitive abilities during maximum drinking in late adolescence are useful as predictors of change in later drinking quantity per occasion and could potentially inform intervention research targeting this age group.

Women are disproportionately affected by symptoms of angina with nonobstructive coronary arteries (ANOCA) which is associated with significant mortality and economic impact. Although distinct endotypes of ANOCA have been defined, it is underdiagnosed and is often incompletely characterized when identified. Patients are often unresponsive to traditional therapeutic options, which are typically antianginal, and the current ability to guide treatment modification by specific pathways is limited. Studies have associated specific genetic loci, transcriptomic features, and biomarkers with ANOCA. Such panomic data, in combination with known imaging and invasive diagnostic techniques, should be utilized to define more precise pathophysiologic subtypes of ANOCA in women, which will in turn help to identify targeted, effective therapies. A precision medicine-based approach to managing ANOCA incorporating these techniques in women has the potential to significantly improve their clinical care.

Abstract Introduction Breast cancer treatment patterns and quality of care among patients experiencing incarceration are underexplored. This study examined associations between incarceration and breast cancer disease and treatment characteristics. Methods This retrospective analysis was conducted at a tertiary center in the Southeastern United States that serves as the state's safety‐net hospital and primary referral site for the state's prisons. All patients ≥18 years diagnosed with breast cancer between 4/14/2014–12/30/2020 were included. Incarceration status was determined through electronic health record review. Linear regression was used to estimate the association of incarceration with time to treatment. Unadjusted overall survival (OS) was estimated using the Kaplan–Meier method with log‐rank tests to compare groups. Results Of the 4329 patients included, 30 (0.7%) were incarcerated at the time of diagnosis or treatment (DI) and 4299 (99.3%) had no incarceration history (NI). Compared to patients who were NI, patients who were DI were younger (p

BackgroundWith the advent of electronic nicotine delivery systems, the use of nicotine and tobacco products (NTPs) among adolescents and young adults remains high in the US. Use of e-cigarettes additionally elevates the risk of problematic use of other substances like cannabis, which is often co-used with NTPs. However, their effects on brain health, particularly the hippocampus, and cognition during this neurodevelopmental period are poorly understood.MethodsHealthy late adolescents/young adults (N = 223) ages 16–22 completed a structural MRI to examine right and left hippocampal volumes. Memory was assessed with the NIH Toolbox Picture Sequence Memory Test (PSMT) and Rey Auditory Verbal Learning Test (RAVLT). Cumulative 6-month NTP and cannabis episodes were assessed and modeled continuously on hippocampal volumes. Participants were then grouped based on 6-month NTP use to examine relationships with the hippocampus and memory: current users (CU) endorsed weekly or greater use; light/abstinent users (LU) endorsed less than weekly; and never users (NU).ResultsNTP use predicted larger hippocampal volumes bilaterally while cannabis use had no impact nor interacted with NTP use. For memory, larger left hippocampal volumes were positively associated with PSMT performance, RAVLT total learning, short delay and long delay recall for the NU group. In contrast, there was a negative relationship between hippocampal volumes and performances for LU and CU groups. No differences were detected between NTP-using groups.ConclusionThese results suggest that the hippocampus is sensitive to NTP exposure during late adolescence/young adulthood and may alter typical hippocampal morphometry in addition to brain-behavior relationships underlying learning and memory processes.

Atmospheric entry of asteroids or comets can cause significant damage to Earth. Two international bodies, the International Asteroid Warning Network (IAWN), and the Space Mission Planning Advisory Group (SMPAG) are working on dealing with potential threats.

Abstract Marine heatwaves are increasing in frequency and duration, threatening tropical reef ecosystems through intensified coral bleaching events. We examined a strikingly variable spatial pattern of bleaching in Moorea, French Polynesia following a heatwave that lasted from November 2018 to July 2019. In July 2019, four months after the onset of bleaching, we surveyed > 5000 individual colonies of the two dominant coral genera, Pocillopora and Acropora, at 10 m and 17 m water depths, at six forereef sites around the island where temperature was measured. We found severe bleaching increased with colony size for both coral genera, but Acropora bleached more severely than Pocillopora overall. Acropora bleached more at 10 m than 17 m, likely due to higher light availability at 10 m compared to 17 m, or greater daily temperature fluctuation at depth. Bleaching in Pocillopora corals did not differ with depth but instead varied with the interaction of colony size and Accumulated Heat Stress (AHS), in that larger colonies (> 30 cm) were more sensitive to AHS than mid-size (10–29 cm) or small colonies (5–9 cm). Our findings provide insight into complex interactions among coral taxa, colony size, and water depth that produce high spatial variation in bleaching and related coral mortality.

Abstract Background Young adults have historically high levels of cannabis use at a time which coincides with emotional and cognitive development. Age of regular onset of cannabis use and sex at birth are hypothesized to influence the relationship between cannabis use and cognition. Here we investigated past 6-month cannabis use in relation to emotional and executive functioning. We further considered age of onset and sex in subgroup analyses. Method Young adults (N = 225; ages 16–22) completed a substance use interview and cognitive battery, including the Emotional Word-Emotional Face Stroop and NIH toolbox executive functioning tasks. Linear regressions examined relationships between past 6-month cannabis use episodes and performance. Subgroup analyses investigated whether age of onset or sex impacted relationships. Results After correcting for multiple comparisons, greater past 6-month cannabis use episodes were related to poorer Emotional Stroop Congruent Accuracy (p = .0004, FDR-p = .002) and List Sorting Working Memory (p = .02, FDR-p = .10) performance. Younger age of regular use onset marginally related to lower Emotional Stroop Congruent Accuracy performance (p = .03, FDR-p = .13). There were no cannabis use by sex interactions on cognition. Conclusions Consistent with prior findings, results suggest small reductions in cannabis-related performance in processing speed during emotional Stroop and working memory tasks. Age of onset was modestly related to Stroop performance, but not sex. Longitudinal studies which detail patterns of cannabis and other substance use are needed to better assess brain-behavior relationships and other factors (e.g., age of onset of regular use, sex) which could influence cannabis-related impairments in cognitive functioning.

Abstract Background The diagnosis of supernumerary X & Y chromosome variations has increased following the implementation of genetic testing in pediatric practice. Empirical evidence suggests that the delivery of the diagnosis has a lasting impact on how affected individuals and their parents perceive and adapt to the diagnosis. The purpose of this review is to synthesize the literature to obtain useful recommendations for delivering a pediatric diagnosis of a sex chromosome multisomy (SCM) based upon a growing body of quantitative and qualitative literature on patient experiences. Methods We conducted an integrative literature review using PubMed, Web of Science and CINAHL employing keywords “genetic diagnosis delivery,” “genetic diagnosis disclosure,” “sex chromosome aneuploidy,” “Klinefelter syndrome” or “”47, XXY,” “Jacob syndrome” or “47, XYY,” “Trisomy X,” “Triple X” or “47, XXX,” and “48 XXYY from January 1, 2000, to October 31, 2023. Results Literature supports that patients and parents value the provision of up-to-date information and connection with supportive resources. Discussion of next steps of care, including relevant referrals, prevents perceptions of provider abandonment and commitment to ongoing support. Proactively addressing special concerns such as disclosing the diagnosis to their child, family, and community is also beneficial. Tables are provided for useful information resources, medical specialties that may be required to support patients, and common misconceptions that interfere with accurate information about the diagnosis. Conclusion Patient experiences suggest there should be heightened attention to diagnosis delivery, in reference to the broader ethical and social impacts of a SCM diagnosis. We present recommendations for optimal disclosure of a SCM diagnosis in early and late childhood, adolescence, and young adulthood.

Abstract Background Specifying early developmental differences among neurodevelopmental disorders with distinct etiologies is critical to improving early identification and tailored intervention during the first years of life. Recent studies have uncovered important differences between infants with fragile X syndrome (FXS) and infants with familial history of autism spectrum disorder who go on to develop autism themselves (FH-ASD), including differences in brain development and behavior. Thus far, there have been no studies longitudinally investigating differential developmental skill profiles in FXS and FH-ASD infants. Methods The current study contrasted longitudinal trajectories of verbal (expressive and receptive language) and nonverbal (gross and fine motor, visual reception) skills in FXS and FH-ASD infants, compared to FH infants who did not develop ASD (FH-nonASD) and typically developing controls. Results Infants with FXS showed delays on a nonverbal composite compared to FH-ASD (as well as FH-nonASD and control) infants as early as 6 months of age. By 12 months an ordinal pattern of scores was established between groups on all domains tested, such that controls > FH-nonASD > FH-ASD > FXS. This pattern persisted through 24 months. Cognitive level differentially influenced developmental trajectories for FXS and FH-ASD. Conclusions Our results demonstrate detectable group differences by 6 months between FXS and FH-ASD as well as differential trajectories on each domain throughout infancy. This work further highlights an earlier onset of global cognitive delays in FXS and, conversely, a protracted period of more slowly emerging delays in FH-ASD. Divergent neural and cognitive development in infancy between FXS and FH-ASD contributes to our understanding of important distinctions in the development and behavioral phenotype of these two groups.

For oil and gas reservoir characterization, permeability prediction is indispensable because it helps identify potential flow pathways and lowers risk. Estimating permeability in heterogeneous media is challenging due to the limited number of measurement tools, low-resolution sampling methods, and sampling bias. To combat these issues, we employed a probe permeameter to produce a high-resolution (4 in [10 cm] spacing) permeability dataset for cores from the Strawn Formation, Katz Field, Permian Basin, Texas, USA. We structured our sampling to record permeability changes related to facies variability and fluctuating bioturbation intensity. We compared probe permeameter data to wireline logs and core-plug porosity and permeability data recorded at larger spacings. The results show that permeability is affected by facies type, bioturbation intensity, and cementation. The effects of bioturbation are non-linear; in our study, moderate bioturbation enhances permeability by improving connections between sands while intense bioturbation decreases permeability by redistributing fines. Core-plug and probe measurements gave similar permeability values, but the number of core plugs taken in the finer-grained intervals was insufficient. The probe, however, provided better resolution and gave larger net-to-gross sand ratios than core-plug-based evaluations. Using only the core-plug porosity–permeability relationship with wireline density log porosities led to permeability predictions too large by a factor of three or more compared to averaged probe permeameter values.

SUMMARY: The ongoing industry trend towards less intensive management systems is of interest to table egg producers, with antibiotic usage and stocking density being of primary concern. The present trial evaluated the effect of a Saccharomyces cerevisiae fermentation product and stocking density on hen production performance and egg quality. Eleven white egg layer strains were equally represented in cages at either high (471 cm2 per bird, HD) or low (497 cm2 per bird, LD) stocking densities. Hens were fed either a control diet (CN) or one supplemented with S. cerevisiae (Original XPC included at 0.68 kg/T, SC) from 17 to 41 wk on a commercially relevant scale (70 replicates for each of the 4 treatments and a total of 5,740 hens). Data were collected every 4 wk and analyzed in a 2 × 2 factorial design, with stocking density and diet being the main effects. Feed intake and egg production were increased in both the LD and SC groups. Improvements in egg size were also noted for SC hens, concurrent with a reduction in cracks, leaks, and vitelline elasticity. The combination of SC-LD resulted in improved hen day production, shorter time to 50% production, and increased percentage of large eggs. Overall, the main effects of SC and LD were associated with improved production performance, with larger egg size also being noted for the SC hens. The combination of SC and LD may benefit producers in achieving both production and egg size performance targets, providing an economic incentive to transition to alternative management systems.

Summary: Background: International distribution of contaminated foods can be a source of Salmonella infections in people and can contribute to the spread of antimicrobial-resistant bacteria across countries. We report an investigation led by the United States Centers for Disease Control and Prevention, the Food and Drug Administration (FDA), and state governmental officials into a multistate outbreak of salmonellosis linked to pig ear pet treats. Methods: Pig ear treats and companion dogs were tested for Salmonella by state officials and the FDA. Products were traced back to the country of origin when possible. Cases were defined as outbreak illnesses in people associated with one of seven Salmonella serotypes genetically related to samples from pig ear pet treats, with isolation dates from June 2015 to September 2019. Whole genome sequencing (WGS) of isolates was used to predict antimicrobial resistance. Findings: The outbreak included 154 human cases in 34 states. Of these, 107 of 122 (88%) patients reported dog contact, and 65 of 97 (67%) reported contact with pig ear pet treats. Salmonella was isolated from 137 pig ear treats, including some imported from Argentina, Brazil, and Colombia, and from four dogs. WGS predicted 77% (105/137) of human and 43% (58/135) of pig ear treat isolates were resistant to ≥3 antimicrobial classes. Interpretation: This was the first documented United States multistate outbreak of Salmonella infections linked to pig ear pet treats. This multidrug-resistant outbreak highlights the interconnectedness of human health and companion animal ownership and the need for zoonotic pathogen surveillance to prevent human illness resulting from internationally transported pet food products. Funding: Animal Feed Regulatory Program Standards award. Animal and product testing conducted by FDA Vet-LIRN was funded by Vet-LIRN infrastructure grants (PAR-22-063).

Background: Pain is often a significant symptom in patients with head and neck cancer (HNC). The objective of this study was to determine the prevalence of pain, factors limiting effective pain management, and whether differences in pain management exist between the public and private health sectors in South Africa in HNC patients after they have completed treatment. Methods: A cross-sectional survey using the Brief Pain Inventory was performed on adults over the age of 18 years treated for HNC of any subsite in both a public and private hospital in Cape Town, South Africa. Results: Overall pain scores indicated mild levels of pain and impact on daily activities. The domains of life most affected by pain were general activity, sleep and mood. There was no difference in pain scores between public hospital patients versus those with private insurance. Less than half of the patients reported receiving all their necessary medications. Most of the postoperative pain was managed with paracetamol, tramadol and ibuprofen, with only 12.8% of patients using morphine. Conclusion: This study provides a survey of pain experiences in HNC patients in a middle-income country. Insurance status did not significantly impact pain experiences, indicating equitable access to pain management resources. However, the overall utilisation of morphine and medications used to treat neuropathic pain is low. Further research is needed into the complex factors associated with pain in HNC patients. Contribution: This article is an example of a standard clinical study on patient-reported outcome measures.

Background Access to sample-level metadata is important when selecting public metagenomic sequencing datasets for reuse in new biological analyses. The Standards, Precautions, and Advances in Ancient Metagenomics community (SPAAM, https://spaam-community.org) has previously published AncientMetagenomeDir, a collection of curated and standardised sample metadata tables for metagenomic and microbial genome datasets generated from ancient samples. However, while sample-level information is useful for identifying relevant samples for inclusion in new projects, Next Generation Sequencing (NGS) library construction and sequencing metadata are also essential for appropriately reprocessing ancient metagenomic data. Currently, recovering information for downloading and preparing such data is difficult when laboratory and bioinformatic metadata is heterogeneously recorded in prose-based publications. Methods Through a series of community-based hackathon events, AncientMetagenomeDir was updated to provide standardised library-level metadata of existing and new ancient metagenomic samples. In tandem, the companion tool 'AMDirT' was developed to facilitate rapid data filtering and downloading of ancient metagenomic data, as well as improving automated metadata curation and validation for AncientMetagenomeDir. Results AncientMetagenomeDir was extended to include standardised metadata of over 6000 ancient metagenomic libraries. The companion tool 'AMDirT' provides both graphical- and command-line interface based access to such metadata for users from a wide range of computational backgrounds. We also report on errors with metadata reporting that appear to commonly occur during data upload and provide suggestions on how to improve the quality of data sharing by the community. Conclusions Together, both standardised metadata reporting and tooling will help towards easier incorporation and reuse of public ancient metagenomic datasets into future analyses.

Background & Aims: Altered plasma acylcarnitine levels are well-known biomarkers for a variety of mitochondrial fatty acid oxidation disorders and can be used as an alternative energy source for the intestinal epithelium when short-chain fatty acids are low. These membrane-permeable fatty acid intermediates are excreted into the gut lumen via bile and are increased in the feces of patients with inflammatory bowel disease (IBD). Methods: Herein, based on studies in human subjects, animal models, and bacterial cultures, we show a strong positive correlation between fecal carnitine and acylcarnitines and the abundance of Enterobacteriaceae in IBD where they can be consumed by bacteria both in vitro and in vivo. Results: Carnitine metabolism promotes the growth of Escherichia coli via anaerobic respiration dependent on the cai operon, and acetylcarnitine dietary supplementation increases fecal carnitine levels with enhanced intestinal colonization of the enteric pathogen Citrobacter rodentium. Conclusions: In total, these results indicate that the increased luminal concentrations of carnitine and acylcarnitines in patients with IBD may promote the expansion of pathobionts belonging to the Enterobacteriaceae family, thereby contributing to disease pathogenesis.

Abstract Frogs are an ecologically diverse and phylogenetically ancient group of anuran amphibians that include important vertebrate cell and developmental model systems, notably the genus Xenopus. Here we report a high-quality reference genome sequence for the western clawed frog, Xenopus tropicalis, along with draft chromosome-scale sequences of three distantly related emerging model frog species, Eleutherodactylus coqui, Engystomops pustulosus, and Hymenochirus boettgeri. Frog chromosomes have remained remarkably stable since the Mesozoic Era, with limited Robertsonian (i.e., arm-preserving) translocations and end-to-end fusions found among the smaller chromosomes. Conservation of synteny includes conservation of centromere locations, marked by centromeric tandem repeats associated with Cenp-a binding surrounded by pericentromeric LINE/L1 elements. This work explores the structure of chromosomes across frogs, using a dense meiotic linkage map for X. tropicalis and chromatin conformation capture (Hi-C) data for all species. Abundant satellite repeats occupy the unusually long (~20 megabase) terminal regions of each chromosome that coincide with high rates of recombination. Both embryonic and differentiated cells show reproducible associations of centromeric chromatin and of telomeres, reflecting a Rabl-like configuration. Our comparative analyses reveal 13 conserved ancestral anuran chromosomes from which contemporary frog genomes were constructed.

Abstract Use of gonadotropin-releasing hormone (GnRH) agonists has been widely adopted to provide reversible ovarian function suppression for pre-menopausal breast cancer patients who are also receiving aromatase inhibitor or tamoxifen therapy based on results of 25 randomized trials representing almost 15,000 women demonstrating a survival benefit with this approach. Past clinical trials designed to establish the efficacy of GnRH agonists have monitored testosterone in the prostate cancer setting and estradiol in the breast cancer setting. We explore the merits of various biomarkers including estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) and their utility for informing GnRH agonist treatment decisions in breast cancer. Estradiol remains our biomarker of choice in ensuring adequate ovarian function suppression with GnRH agonist therapy among pre-menopausal women with breast cancer. We recommend future trials to continue to focus on estradiol levels as the primary endpoint, as they have in the past.

Abstract Huntington's disease (HD) is a progressive neurodegenerative disorder caused by CAG trinucleotide repeat expansions in exon 1 of the HTT gene. In addition to germline CAG expansions, somatic repeat expansions in neurons also contribute to HD pathogenesis. The DNA mismatch repair gene, MSH3, identified as a genetic modifier of HD onset and progression, promotes somatic CAG expansions, and thus presents a potential therapeutic target. However, what extent of MSH3 protein reduction is needed to attenuate somatic CAG expansions and elicit therapeutic benefits in HD disease models is less clear. In our study, we employed potent di-siRNAs to silence mouse Msh3 mRNA expression in a dose-dependent manner in HdhQ111/+ mice and correlated somatic Htt CAG instability with MSH3 protein levels from simultaneously isolated DNA and protein after siRNA treatment. Our results reveal a linear correlation with a proportionality constant of ~ 1 between the prevention of somatic Htt CAG expansions and MSH3 protein expression in vivo, supporting MSH3 as a rate-limiting step in somatic expansions. Intriguingly, despite a 75% reduction in MSH3 protein levels, striatal nuclear HTT aggregates remained unchanged. We also note that evidence for nuclear Msh3 mRNA that is inaccessible to RNA interference was found, and that MSH6 protein in the striatum was upregulated following MSH3 knockdown in HdhQ111/+ mice. These results provide important clues to address critical questions for the development of therapeutic molecules targeting MSH3 as a potential therapeutic target for HD.

Abstract The Antibody Mediated Prevention (AMP) trials (NCT02716675 and NCT02568215) demonstrated that passive administration of the broadly neutralizing monoclonal antibody VRC01 could prevent some HIV-1 acquisition events. Here, we use mathematical modeling in a post hoc analysis to demonstrate that VRC01 influenced viral loads in AMP participants who acquired HIV. Instantaneous inhibitory potential (IIP), which integrates VRC01 serum concentration and VRC01 sensitivity of acquired viruses in terms of both IC50 and IC80, follows a dose-response relationship with first positive viral load (p = 0.03), which is particularly strong above a threshold of IIP = 1.6 (r = -0.6, p = 2e-4). Mathematical modeling reveals that VRC01 activity predicted from in vitro IC80s and serum VRC01 concentrations overestimates in vivo neutralization by 600-fold (95% CI: 300–1200). The trained model projects that even if future therapeutic HIV trials of combination monoclonal antibodies do not always prevent acquisition, reductions in viremia and reservoir size could be expected.

Abstract Buprenorphine has become an important medication in the context of the ongoing opioid epidemic. However, complex pharmacologic properties and varying government regulations create barriers to its use. This narrative review is intended to facilitate buprenorphine use—including non-traditional initiation methods—by providers ranging from primary care providers to addiction specialists. This article briefly discusses the opioid epidemic and the diagnosis and treatment of opioid use disorder (OUD). We then describe the basic and complex pharmacologic properties of buprenorphine, linking these properties to their clinical implications. We guide readers through the process of initiating buprenorphine in patients using full agonist opioids. As there is no single recommended approach for buprenorphine initiation, we discuss the details, advantages, and disadvantages of the standard, low-dose, bridging-strategy, and naloxone-facilitated initiation techniques. We consider the pharmacology of, and evidence base for, buprenorphine in the treatment of pain, in both OUD and non-OUD patients. Throughout, we address the use of buprenorphine in children and adolescent patients, and we finish with considerations related to the settings of pregnancy and breastfeeding.

Abstract Molnupiravir is an orally administered, small‐molecule ribonucleoside prodrug of β‐D‐N4‐hydroxycytidine (NHC) that has demonstrated potent, broad‐spectrum preclinical activity against RNA viruses and has a high barrier to the development of resistance. A double‐blind, placebo‐controlled, phase I trial was conducted to evaluate the pharmacokinetics (PKs), safety, and tolerability of 10.5‐day administration of multiple doses of molnupiravir and its metabolites in healthy, adult participants. Participants were randomly assigned (3:1) to receive molnupiravir (400 mg [n = 6], 600 mg [n = 6], and 800 mg [n = 12]) or matching placebo (n = 8) every 12 h (q12h) for 10.5 days. Blood was collected to evaluate the PKs of NHC in plasma and of its active metabolite, NHC‐triphosphate (NHC‐TP), in peripheral blood mononuclear cells (PBMCs). Molnupiravir was generally well‐tolerated. All adverse events were mild or moderate in severity and none led to treatment discontinuation. No clinically meaningful dose‐related safety findings were observed. Mean time to maximal concentration was ~1.50 to 1.98 h for plasma NHC and ~4.00 to 8.06 h for PBMC NHC‐TP. Accumulation was minimal (

Abstract The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 has modified our understanding of carcinogenesis. Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with different penetrance and expressivities: the four Lynch syndromes. No person has an “average sex “or a pathogenic variant in an “average Lynch syndrome gene” and results that are not stratified by gene and sex will be valid for no one. Carcinogenesis may be a linear process from increased cellular division to localized cancer to metastasis. In addition, in the Lynch syndromes (LS) we now recognize a dynamic balance between two stochastic processes: MSI producing abnormal cells, and the host’s adaptive immune system’s ability to remove them. The latter may explain why colonoscopy surveillance does not reduce the incidence of colorectal cancer in LS, while it may improve the prognosis. Most early onset colon, endometrial and ovarian cancers in LS are now cured and most cancer related deaths are after subsequent cancers in other organs. Aspirin reduces the incidence of colorectal and other cancers in LS. Immunotherapy increases the host immune system’s capability to destroy MSI cancers. Colonoscopy surveillance, aspirin prevention and immunotherapy represent major steps forward in personalized precision medicine to prevent and cure inherited MSI cancer.

Abstract Individuals with Parkinson’s disease (PD) typically receive a diagnosis once they have developed motor symptoms, at which point there is already significant loss of substantia nigra dopamine neurons, α-synuclein accumulation in surviving neurons, and neuroinflammation. Consequently, the point of clinical presentation may be too late to initiate disease-modifying therapy. In contrast to this clinical reality, animal models often involve acute neurodegeneration and potential therapies are tested concurrently or shortly after the pathogenic insult has begun rather than later when diagnostic clinical symptoms emerge. Therefore, we sought to develop a model that reflects the clinical situation more accurately. Middle-aged rats (7–9 months-old) received a single daily intraperitoneal injection of rotenone for 5 consecutive days and were observed over the next 8–9 months. Rotenone-treated rats showed transient motor slowing and postural instability during exposure but recovered within 9 days of rotenone cessation. Rats remained without behavioral deficits for 3–4 months, then developed progressive motor abnormalities over the ensuing months. As motor abnormalities began to emerge 3 months after rotenone exposure, there was significant loss of nigral dopaminergic neurons and significant microglial activation. There was delayed accumulation of α-synuclein in neurons of the substantia nigra and frontal cortex, which was maximal at 9 months post-rotenone. In summary, a brief temporally-remote exposure to rotenone causes delayed and progressive behavioral and neuropathological changes similar to Parkinson’s disease. This model mimics the human clinical situation, in which pathogenesis is well-established by the time diagnostic motor deficits appear. As such, this model may provide a more relevant experimental system in which to test disease-modifying therapeutics.

Abstract The COVID-19 pandemic has highlighted the importance of understanding what contributes to individual variability in experiences of stress. Increases in stress related to the pandemic have been especially pronounced in parents, indicating a need for research examining what factors contribute to parents’ perceptions of stress. Here, we assessed the relationship between parents’ perceptions of stress, control, loneliness, and experiences of childhood trauma in two populations of caregivers. In Study 1, we examined the relationship between perceptions of stress, control, loneliness, and history of early stress, along with indices of socioeconomic risk and resting parasympathetic nervous systema activity, which has been linked to variability in perceptions of stress, in caregivers of young children. Perceived control, loneliness, childhood stress, and resting parasympathetic nervous system activity predicted caregivers’ stress. In Study 2, we replicated these initial findings in a second sample of caregivers. Additionally, we examined how these processes change over time. Caregivers demonstrated significant changes in perceptions of control, loneliness, and stress, and changes in control and childhood trauma history were associated with changes in perceptions of stress. Together these results indicate the importance of assessing how caregivers perceive their environment when examining what contributes to increased risk for stress. Additionally, they suggest that caregivers’ stress-related processes are malleable and provide insight into potential targets for interventions aimed at reducing parents’ stress.

Adolescent traumatic brain injury (TBI) has long-term effects on brain functioning and behavior, impacting neural activity under cognitive load, especially in the reward network. Adolescent TBI is also linked to risk-taking behaviors including alcohol misuse. It remains unclear how TBI and neural functioning interact to predict alcohol experimentation during adolescence. Using Adolescent Brain Cognitive Development (ABCD) study data, this project examined if TBI at ages 9–10 predicts increased odds of alcohol sipping at ages 11–13 and if this association is moderated by neural activity during the Emotional EN-Back working memory task at ages 11–13. Logistic regression analyses showed that neural activity in regions of the fronto-basal ganglia network predicted increased odds of sipping alcohol by ages 11–13 (p

SARS-CoV-2 nsp13 helicase is an essential enzyme for viral replication and a promising target for antiviral drug development. This study compares the double-stranded RNA (dsRNA) unwinding activity of nsp13 and the Omicron nsp13R392C variant, which is predominant in currently circulating lineages. Using in vitro gel- and fluorescence-based assays, we found that both nsp13 and nsp13R392C have dsRNA unwinding activity with equivalent kinetics. Furthermore, the R392C mutation had no effect on the efficiency of the nsp13-specific helicase inhibitor SSYA10-001. We additionally confirmed the activity of several other helicase inhibitors against nsp13, including punicalagin that inhibited dsRNA unwinding at nanomolar concentrations. Overall, this study reveals the utility of using dsRNA unwinding assays to screen small molecules for antiviral activity against nsp13 and the Omicron nsp13R392C variant. Continual monitoring of newly emergent variants will be essential for considering resistance profiles of lead compounds as they are advanced towards next-generation therapeutic development.

ObjectiveThere are substantial barriers to conducting research among individuals with stigmatized and complicated health conditions like substance use disorders. These barriers slow progress when developing, refining, and assessing interventions to better treat underserved populations. Virtual focus groups are an innovative method for collecting data from individuals via a discreet and accessible platform which can inform novel as well as existing treatment approaches. This article reports on the feasibility and acceptability of virtual focus groups as a mechanism to recruit and engage geographically and demographically diverse samples of participants with substance use disorders that are otherwise logistically difficult to assess.MethodParticipants were assessed for eligibility for a virtual focus group study based on demographic features, drug use history, and psychiatric history via a remote, interview-based screening. Focus groups were completed anonymously without video or name-sharing. Discussion contributions, quantified with number of times speaking and total number of words spoken, were compared across gender, and treatment status. Participants provided quantitative and qualitative feedback on the focus group experience in a follow-up survey.ResultsFocus groups (N=26) based in geographical areas throughout the United States were conducted with 88 individuals with opioid use disorder or stimulant use disorder. Discussion contributions were comparable between genders and among individuals in treatment versus those seeking treatment. A follow-up survey (n=50, 57% of focus group participants) reflected high levels of enjoyment, comfort, and honesty during focus group discussions.DiscussionFindings suggest virtual focus groups can be an effective and efficient tool for substance use research.

Abstract Background Stigma associated with substance use and criminal involvement is pervasive and creates a barrier to evidence-based addiction care within the criminal legal system. Research has yet to examine a multi-level stigma intervention which targets the intersection of these stigmas among both criminal legal staff and legally-involved clients. Methods This paper presents the protocol for a non-randomized trial of a multi-level stigma intervention called Combatting Stigma to Aid Reentry and Recovery (CSTARR) that involves two interventions: (1) training for criminal legal staff to address public stigma and (2) group-based acceptance and commitment therapy to address self-stigma among legally-involved adults enrolled in substance use treatment. Staff and client participants are engaged with a program called the Tennessee Recovery Oriented Compliance Strategy in 6 East Tennessee counties. This study examines the feasibility, acceptability, and preliminary effectiveness of CSTARR using a type 1 hybrid implementation/effectiveness trial with pre to post follow-up. Discussion Stigma must be addressed in the criminal legal system to facilitate the uptake of evidence-based addiction care. This study is the first to evaluate a stigma intervention designed for the criminal legal setting and results will be used to inform a larger, randomized controlled trial. The rationale for this study, research design and measures, as well as potential implications for the field are described. Trial registration This clinical trial is registered at clinicaltrials.gov with the identifier NCT05152342. Registered 11/5/2021 at https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S000BIN8&selectaction=Edit&uid=U0005X4C&ts=2&cx=-u3wsbx .

Abstract Background People with substance use disorders (SUD) who have been involved in the legal system often experience stigma upon reentry into the community after incarceration. Although substance use treatment can sometimes be a source of stigma, it may also reduce stigma by facilitating connections with providers, reducing distress, or helping people feel more integrated in their community. However, research has rarely examined the potential for treatment to reduce stigma. Methods This study examined stigma experiences and the degree to which substance use treatment reduced stigma among 24 people with SUDs who were receiving care in an outpatient treatment facility after release from incarceration. Qualitative interviews were conducted and analyzed using a content analysis approach. Results Participants reported negative self-judgements as well as perceiving negative judgments from the community upon reentry. With regard to stigma reduction, themes emerged around substance use treatment repairing strained family relationships and reducing participants’ self-stigma. Aspects of treatment that reportedly reduced stigma included the treatment facility having a nonjudgmental atmosphere, patients trusting the staff, and working with peer navigators who had lived experience of SUD and incarceration. Conclusions Results from this study suggest that substance use treatment has the potential to decrease the negative impacts of stigma upon release from incarceration, which continues to be a major barrier. Though more research on stigma reduction is needed, we suggest some preliminary considerations for treatment programs and providers.

Abstract Background Nonhemorrhagic ascites (NHA) can be caused by cardiac diseases (cNHA) and noncardiac diseases (ncNHA). N‐terminal brain natriuretic peptide (NT‐proBNP), cardiac troponin‐I (cTnI), and point‐of‐care ultrasound (POCUS) may differentiate between cNHA and ncNHA. Hypothesis/Objectives We compared NT‐proBNP and cTnI concentrations as well as POCUS findings in dogs presented with cNHA and ncNHA. Animals Dogs (n = 60) were enrolled based on identification of NHA with an effusion packed cell volume

Purpose: The profession of genetic counselors has existed for over 50 years. This article provides an update on the global state of the genetic counseling (GC) profession in 2022 and 2023. Methods: We used a survey approach to collect data from individuals who were identified as being leaders in GC practice and/or education around the world. Results: Based on responses provided between October 2023 and January 2024, we estimate that there are over 10,250 genetic counselors in over 45 countries around the world. These numbers have increased significantly in the past 5 years, when there were ∼7000 genetic counselors. Key factors identified as driving the increase in genetic counselors are the number of training programs that have developed (>130 globally, mostly at a master’s degree level) and a growing number of national biobanks and/or population screening programs that require GC as part of the process. There is tremendous variability in how genetic counselors are regulated, with only a few countries holding national statutory regulation processes. There are many commonalities, but the GC profession appears nuanced to their specific country and its wider socio-political context and history. Conclusion: We hope that genetic counselors internationally will come together to assist each other in all aspects: training, statutory regulation, developing the workforce, and establishing GC as an academic discipline. We envision that establishing an international organization for the profession of genetic counselors might maintain such international connections and provide relevant data in future years.

Summary: Functional interactions between cytotoxic T cells and tumor cells are central to anti-cancer immunity. However, our understanding of the proteins involved is limited. Here, we present HySic (hybrid quantification of stable isotope labeling by amino acids in cell culture [SILAC]-labeled interacting cells) as a method to quantify protein and phosphorylation dynamics between and within physically interacting cells. Using co-cultured T cells and tumor cells, we directly measure the proteome and phosphoproteome of engaged cells without the need for physical separation. We identify proteins whose abundance or activation status changes upon T cell:tumor cell interaction and validate our method with established signal transduction pathways including interferon γ (IFNγ) and tumor necrosis factor (TNF). Furthermore, we identify the RHO/RAC/PAK1 signaling pathway to be activated upon cell engagement and show that pharmacologic inhibition of PAK1 sensitizes tumor cells to T cell killing. Thus, HySic is a simple method to study rapid protein signaling dynamics in physically interacting cells that is easily extended to other biological systems.

Abstract Phase I trials inform on the initial safety profile of a new molecule and impact whether further development is pursued or not. Understanding the effect of non‐pharmacological factors on the variability of routine safety parameters could improve decision making in these early clinical trials, helping to separate signals related to the new molecule from background “noise.” To understand the impact of non‐pharmacological factors on routine safety parameters, we evaluated pooled safety data from over 1000 healthy participants treated with placebo in phase I trials between 2009 and 2018. The phase I participants were predominantly men, less than or equal to 50 years, White, and non‐Hispanic; and approximately an equal proportion had body mass index in the normal and overweight/obese range. Following administration of placebo, vital signs, electrocardiogram, and laboratory parameters remained near predose baseline values. Large changes from baseline were observed for many safety parameters, but these occurred in a relatively small number of participants. At least one adverse event (AE) occurred in 49.7% of participants receiving placebo in single ascending dose (SAD) studies and in 72.4% of participants receiving placebo in multiple ascending dose (MAD) studies, with headache being the most commonly reported AE (18.7% in SAD and 28.3% in MAD studies). Overall, these analyses are consistent with non‐pharmacological factors having a small impact on routine safety parameters in a phase I trial. The provided supplemental data may be used to contextualize the magnitude and frequency of abnormal safety values and AEs observed in phase I trials.