Examining biopsychosocial predictors of risk for cognitive impairment among a racially diverse sample of men who have sex with men living with HIV.

Background: Cognitive decline among people living with HIV (PLWH) is growing concern as world populations become increasing older including higher proportions of PLWH. It is vitally important to understand psychosocial predictors of age-related cognitive decline men who have sex with men (MSM) living with HIV. Objectives: The current study seeks to examine psychosocial risk factors the contribute to the risk of age-related cognitive impairment as measured by Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) score in a racially diverse sample of MSM living with HIV. Design: The present analysis utilizes data from the baseline (n = 196) and 6-month follow-up (n = 135) time points of a longitudinal cohort study of PLWH. Methods: Using a self-report survey, we examine the associations between psychosocial predictors (e.g. trauma, mental health, chronic pain, sleep disturbance, etc.) and risk of dementia using the CAIDE risk score. Analyses include linear and logistic regression. Results: In adjusted model stress, chronic pain, Black racial identity, and having a sexual identity that is bisexual or another category are all positively associated with CAIDE scores. Childhood sexual abuse history was negatively associated with CAIDE scores indicating a protective effect. Sleep disorder has a positive association with CAIDE scores after adjusting for the baseline CAIDE scores. Conclusion: These results indicate modifiable correlates of cognitive risk (stress and chronic pain). Interventions should seek to address these comorbid factors including the consideration of minority stress and stigma. Interventions should seek to reach Black and bisexual men living with HIV, including possible cultural tailoring to interventions and messaging. Lastly, future research should examine the impact of variation within childhood sexual abuse histories to better understand their association with cognitive impairment later in life. This may include considering the nature, severity, and potential treatment of trauma symptoms.

What makes middle-aged or older people who have HIV more likely to have memory problems later in life? We asked a racially diverse group of gay and bisexual men who have HIV. Why was the study done? Older people are becoming a larger portion of our communities including older people living with HIV. It's important to understand what makes older people more likely to have memory problems as they age including older people living with HIV. What did the researchers do? We asked 196 middle-aged and older adults who have HIV to answer questions about their health including things that we know might make them more likely to have memory problems later in life. What did the researchers find? We found that having more stress or reoccurring pain was related to being more likely to have memory problems later in life. People who have trouble sleeping were more likely to have memory problems later in life. We also found that Black people were more likely to have memory problems later in life. People who had been abused sexually as children were less likely to have memory problems later in life. What do the findings mean? These findings help us understand things that may make someone more likely to have memory problems later in life. These include things that could be changed like reoccurring pain and troubles sleeping. It also highlighted that Black people may need more support to prevent memory problems later in life.

The impact of low-mode symmetry on inertial fusion energy output in the burning plasma state.

Indirect Drive Inertial Confinement Fusion Experiments on the National Ignition Facility (NIF) have achieved a burning plasma state with neutron yields exceeding 170 kJ, roughly 3 times the prior record and a necessary stage for igniting plasmas. The results are achieved despite multiple sources of degradations that lead to high variability in performance. Results shown here, for the first time, include an empirical correction factor for mode-2 asymmetry in the burning plasma regime in addition to previously determined corrections for radiative mix and mode-1. Analysis shows that including these three corrections alone accounts for the measured fusion performance variability in the two highest performing experimental campaigns on the NIF to within error. Here we quantify the performance sensitivity to mode-2 symmetry in the burning plasma regime and apply the results, in the form of an empirical correction to a 1D performance model. Furthermore, we find the sensitivity to mode-2 determined through a series of integrated 2D radiation hydrodynamic simulations to be consistent with the experimentally determined sensitivity only when including alpha-heating.

Site-Specific Photochemistry along a Protonated Peptide Scaffold.

We present a detailed study of the time-dependent photophysics and photochemistry of a known conformation of the two protonated pentapeptides Leu-enkephalin (Tyrosine-Glycine-Glycine-Phenylalanine-Leucine, YGGFL) and its chromophore-swapped analogue FGGYL, carried out under cryo-cooled conditions in the gas phase. Using ultraviolet-infrared (UV-IR) double resonance, we record excited state IR spectra as a function of time delay between UV and IR pulses. We identify unique Tyr OH stretch transitions due to the S1 state and the vibrationally excited triplet state(s) formed by intersystem crossing, Tn(v). Photofragment mass spectra are recorded out of the S1 origin and following UV-IR double resonance. Several competing site-specific fragmentation pathways are discovered involving peptide backbone cleavage, Tyr side chain loss, and N-terminal NH3 loss mediated by electron transfer. In YGGFL, IR excitation in the S1 state promotes electron transfer (ET) from the aromatic ring to the N-terminal R-NH3+ group leading to loss of neutral NH3. This product channel is missing in FGGYL due to the larger distance for ET from Y(4) to NH3+. Selective loss of the Tyr side chain occurs out of an excited state process following UV excitation and is further enhanced by IR excitation in S1 and Tn(v) states of both YGGFL and FGGYL. Finally, IR excitation in the S1 or Tn(v) states fragments the peptide backbone exclusively at amide(4), producing the b4 cation. We postulate that this selective fragmentation results from intersystem crossing to produce vibrationally excited triplets with enough energy to launch the proton along a proton conduit present in the known starting structure.

PML::RARA and GATA2 proteins interact via DNA templates to induce aberrant self-renewal in mouse and human hematopoietic cells.

The underlying mechanism(s) by which the PML::RARA fusion protein initiates acute promyelocytic leukemia is not yet clear. We defined the genomic binding sites of PML::RARA in primary mouse and human hematopoietic progenitor cells with V5-tagged PML::RARA, using anti-V5-PML::RARA chromatin immunoprecipitation sequencing and CUT&RUN approaches. Most genomic PML::RARA binding sites were found in regions that were already chromatin-accessible (defined by ATAC-seq) in unmanipulated, wild-type promyelocytes, suggesting that these regions are "open" prior to PML::RARA expression. We found that GATA binding motifs, and the direct binding of the chromatin "pioneering factor" GATA2, were significantly enriched near PML::RARA binding sites. Proximity labeling studies revealed that PML::RARA interacts with ~250 proteins in primary mouse hematopoietic cells; GATA2 and 33 others require PML::RARA binding to DNA for the interaction to occur, suggesting that binding to their cognate DNA target motifs may stabilize their interactions. In the absence of PML::RARA, Gata2 overexpression induces many of the same epigenetic and transcriptional changes as PML::RARA. These findings suggested that PML::RARA may indirectly initiate its transcriptional program by activating Gata2 expression: Indeed, we demonstrated that inactivation of Gata2 prior to PML::RARA expression prevented its ability to induce self-renewal. These data suggested that GATA2 binding creates accessible chromatin regions enriched for both GATA and Retinoic Acid Receptor Element motifs, where GATA2 and PML::RARA can potentially bind and interact with each other. In turn, PML::RARA binding to DNA promotes a feed-forward transcriptional program by positively regulating Gata2 expression. Gata2 may therefore be required for PML::RARA to establish its transcriptional program.

Design of the first fusion experiment to achieve target energy gain G>1.

In this work we present the design of the first controlled fusion laboratory experiment to reach target gain G>1 N221204 (5 December 2022) [Phys. Rev. Lett. 132, 065102 (2024)10.1103/PhysRevLett.132.065102], performed at the National Ignition Facility, where the fusion energy produced (3.15 MJ) exceeded the amount of laser energy required to drive the target (2.05 MJ). Following the demonstration of ignition according to the Lawson criterion N210808, experiments were impacted by nonideal experimental fielding conditions, such as increased (known) target defects that seeded hydrodynamic instabilities or unintentional low-mode asymmetries from nonuniformities in the target or laser delivery, which led to reduced fusion yields less than 1 MJ. This Letter details design changes, including using an extended higher-energy laser pulse to drive a thicker high-density carbon (also known as diamond) capsule, that led to increased fusion energy output compared to N210808 as well as improved robustness for achieving high fusion energies (greater than 1 MJ) in the presence of significant low-mode asymmetries. For this design, the burnup fraction of the deuterium and tritium (DT) fuel was increased (approximately 4% fuel burnup and a target gain of approximately 1.5 compared to approximately 2% fuel burnup and target gain approximately 0.7 for N210808) as a result of increased total (DT plus capsule) areal density at maximum compression compared to N210808. Radiation-hydrodynamic simulations of this design predicted achieving target gain greater than 1 and also the magnitude of increase in fusion energy produced compared to N210808. The plasma conditions and hotspot power balance (fusion power produced vs input power and power losses) using these simulations are presented. Since the drafting of this manuscript, the results of this paper have been replicated and exceeded (N230729) in this design, together with a higher-quality diamond capsule, setting a new record of approximately 3.88MJ of fusion energy and fusion energy target gain of approximately 1.9.

Observations and properties of the first laboratory fusion experiment to exceed a target gain of unity.

An indirect-drive inertial fusion experiment on the National Ignition Facility was driven using 2.05 MJ of laser light at a wavelength of 351 nm and produced 3.1±0.16 MJ of total fusion yield, producing a target gain G=1.5±0.1 exceeding unity for the first time in a laboratory experiment [Phys. Rev. E 109, 025204 (2024)10.1103/PhysRevE.109.025204]. Herein we describe the experimental evidence for the increased drive on the capsule using additional laser energy and control over known degradation mechanisms, which are critical to achieving high performance. Improved fuel compression relative to previous megajoule-yield experiments is observed. Novel signatures of the ignition and burn propagation to high yield can now be studied in the laboratory for the first time.

Partitioning of nutrient variation in alfalfa and corn silage by source on New York dairy farms.

Variation in feed components contributes to variation and uncertainty of diets delivered to dairy cows. Forages often have a high inclusion rate (50 to 70% of DM fed) and variable composition, thus are an important contributor to nutrient variability of delivered diets. Our objective was to quantify the variation and identify the main sources of variability in corn silage and alfalfa-grass haylage composition at harvest (fresh forage) and feed-out (fermented forage) on NY dairy farms. Corn silage and alfalfa-grass haylage were sampled on 8 NY commercial dairy farms during harvest in the summer and fall of 2020 and during their subsequent feed-out in the winter and spring of 2021. At harvest, a composite sample of fresh chopped forage of every 8-ha section of individual fields was collected from piles delivered for silo filling. During a 16-week feed-out period, 2 independent samples of each forage were collected 3 times per week. The fields-of-origin of each forage sample during feed-out were identified and recorded using silo maps created at filling. A mixed-model analysis quantified the variance of corn silage DM, NDF, and starch and haylage DM, NDF, and CP content. Fixed effects included soil type, weather conditions, and management practices during harvest and feed-out while random effects were farm, silo unit, field, and day. At harvest, between-farm variability was the largest source of variation for both corn silage and haylage, but within-farm sources of variation exceeded farm-to-farm variation for haylage at feed-out. At feed-out, haylage DM and NDF content had higher within-farm variability than corn silage. In contrast, corn silage starch showed higher within-farm variation at feed-out than haylage CP content. For DM content at feed-out, day-to-day variation was the most relevant source of within-farm variation for both forages. However, for the nutrient components at feed-out (NDF and CP for haylage; NDF and starch for corn silage) silo-to-silo variation was the largest source of variability. Weather conditions systematically explained a proportion of the farm-to-farm variability for both forages at harvest and feed-out. We concluded that because of the high farm-to-farm variation, corn silage and haylage must be sampled on individual farms. We also concluded that due to the high silo-to-silo variability, and the still significant day-to-day and field-to-field variability within-farm, corn silage and haylage should be sampled within individual silos to better capture changes in forage components at feed-out.

A case-control study of the association between the gut microbiota and colorectal cancer: exploring the roles of diet, stress, and race.

BACKGROUND: The gut microbiota is associated with risk for colorectal cancer (CRC), a chronic disease for which racial disparities persist with Black Americans having a higher risk of CRC incidence and mortality compared to other groups. Given documented racial differences, the gut microbiota may offer some insight into previously unexplained racial disparities in CRC incidence and mortality. A case-control analysis comparing 11 women newly diagnosed with CRC with 22 cancer-free women matched on age, BMI, and race in a 1:2 ratio was conducted. Information about participants' diet and perceived stress levels were obtained via 24-h Dietary Recall and Perceived Stress Scale-10 survey, respectively. Participants provided stool samples from which microbial genomic DNA was extracted to reveal the abundance of 26 genera chosen a priori based on their previously observed relevance to CRC, anxiety symptoms, and diet. RESULTS: Significantly lower alpha diversity was observed among cancer-free Black women compared to all other race-cancer status combinations. No group differences were observed when comparing beta diversity. Non-Hispanic White CRC cases tended to have higher relative abundance of Fusobacteria, Gemellaceae, and Peptostreptococcus compared to all other race-cancer combination groups. Perceived stress was inversely associated with alpha diversity and was associated with additional genera. CONCLUSIONS: Our findings suggest that microbiome-CRC associations may differ by racial group. Additional large, racially diverse population-based studies are needed to determine if previously identified associations between characteristics of the gut microbiome and CRC are generalizable to Black women and other racial, ethnic, and gender groups.

Adapting suicide safety plans for youth with intellectual and developmental disabilities.

INTRODUCTION: Although risk for suicide appears elevated in individuals with intellectual and developmental disorders (I/DD), few interventions or tools addressing suicide prevention have been adapted for this population. Among evidence-based interventions for preventing suicide, safety planning interventions are an effective and commonly employed intervention for reducing suicide-related risk. METHODS: By drawing on Special Education praxis for supporting the learning needs of individuals with I/DD, we provide recommendations for adapting suicide safety planning interventions for youth with I/DD. RESULTS: Specific visual, content, teaching, and communication components of the safety plan intervention can be adapted to better meet the needs of youth with I/DD. DISCUSSION: Although future research is needed to evaluate these recommendations, these modifications may support clinicians serving youth with I/DD and suicide-related risk.

A Bacterial-Sourced Protein Diet Induces Beneficial Shifts in the Gut Microbiome of the Zebrafish, Danio rerio.

Background: Bacterial-sourced single-cell proteins (SCPs) offer an alternative protein source for diet formulation for Zebrafish (Danio rerio) and other aquaculture models. In addition, the use of a single-cell bacterial protein source derived from multiple species provides a unique insight into the interplay among nutrients in the diet, microbial populations in the diet, and the gut microbiome in D. rerio. Objective: Our objective in this study was to evaluate the impact of dietary replacement of fish protein hydrolysate in a standard reference (SR) with a single-cell bacterial protein source on D. rerio gut microbiome. Methods: We investigated gut microbial compositions of D. rerio fed an open-formulation standard reference (SR) diet or a bacterial-sourced protein (BP) diet, utilizing microbial taxonomic co-occurrence networks, and predicted functional profiles. Results: Microbial communities in the SR diet were primarily composed of Firmicutes. In contrast, the BP diet was mainly composed of Proteobacteria. Alpha diversity revealed significant differences in microbial communities between the 2 diets, and between the guts of D. rerio fed either of the 2 diets. D. rerio fed with the SR diet resulted in abundance of Aeromonas and Vibrio. In contrast, D. rerio fed with a BP diet displayed a large abundance of members from the Rhodobacteraceae family. Taxonomic co-occurrence networks display unique microbial interactions, and key taxons in D. rerio gut samples were dependent on diet and gender. Predicted functional profiling of the microbiome across D. rerio fed SR or BP diets revealed distinct metabolic pathway differences. Female D. rerio fed the BP diet displayed significant upregulation of pathways related to primary and secondary bile acid synthesis. Male D. rerio fed the BP diet revealed similar pathway shifts and, additionally, a significant upregulation of the polyketide sugar unit biosynthesis pathway. Conclusions: The use of a BP dramatically affects the composition and activity of the gut microbiome. Future investigations should further address the interplay among biological systems and diet and may offer insights into potential health benefits in preclinical and translational animal models.

Energy Principles of Scientific Breakeven in an Inertial Fusion Experiment.

Fusion "scientific breakeven" (i.e., unity target gain G_{target}, total fusion energy out > laser energy input) has been achieved for the first time (here, G_{target}∼1.5). This Letter reports on the physics principles of the design changes that led to the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce target gain greater than unity and exceeded the previously obtained conditions needed for ignition by the Lawson criterion. Key elements of the success came from reducing "coast time" (the time duration between the end of the laser pulse and implosion peak compression) and maximizing the internal energy delivered to the "hot spot" (the yield producing part of the fusion fuel). The link between coast time and maximally efficient conversion of kinetic energy into internal energy is explained. The energetics consequences of asymmetry and hydrodynamic-induced mixing were part of high-yield big radius implosion design experimental and design strategy. Herein, it is shown how asymmetry and mixing consolidate into one key relationship. It is shown that mixing distills into a kinetic energy cost similar to the impact of implosion asymmetry, shifting the threshold for ignition to higher implosion kinetic energy-a factor not normally included in most statements of the generalized Lawson criterion, but the key needed modifications clearly emerge.

THE 3P MODEL AND ORAL HEALTH IMPACT: DEMONSTRATING THE IMPORTANCE OF BEHAVIORAL AND SOCIAL SCIENCES IN THE FUTURE OF EVIDENCE-BASED DENTISTRY.

Oral health impact or oral health related quality of life is an increasingly important and well-known metric in dental care and research. There have been recent calls for greater integration of the behavioral and social sciences into oral health research and practice, including the need for frameworks and theories to guide this work. One such framework for understanding the role of predisposing, precipitating, and perpetuating biopsychosocial mechanisms in health and disease is the "3P" model. Here, the 3P model is described and applied to case examples to help understand the development and maintenance of oral health impact. Additionally, this paper outlines how this conceptualization using the 3P model and oral health impact makes way for greater integration of behavioral interventions to prevent, mitigate, or treat the negative impact that oral, craniofacial, or dental disease may have on individuals. Doing this allows for a broadening of what evidence-based dentistry means for the future and provides a roadmap going forward.

Lessons learned and recommendations in conducting solutions-driven environmental and public health research.

Solutions-driven research is a transdisciplinary approach that incorporates diverse forms of expertise to identify solutions to stakeholder-identified environmental problems. This qualitative evaluation of early solutions-driven research projects provides transferable recommendations to improve researcher and stakeholder experiences and outcomes in transdisciplinary environmental research projects. Researchers with the U.S. Environmental Protection Agency (EPA) Office of Research and Development recently piloted a solutions-driven research approach in two parallel projects; one addressing nutrient management related to coastal waters and another studying wildland fire smoke impacts on indoor air quality. Studying the experiences of those involved with these pilots can enhance the integration of researcher and experiential expertise, improving solutions-driven research outcomes. Data collection included semi-structured interviews with 17 EPA researchers and 12 other stakeholders and reflective case narratives from the authors. We used conventional content analysis to qualitatively analyze perspectives on implementing innovative engagement and research approaches in a solutions-driven process. Findings that reflect common perspectives include the importance of continuous engagement, the challenges of differing timelines and priorities for researchers and stakeholders, and the need to define consistent markers of success across researchers and stakeholders. Key lessons to improve transdisciplinary research identified from the analysis are (1) improving clarity of roles and responsibilities; (2) planning to provide sufficient, continuous project funding over multiple years; (3) expecting research needs and plans to adapt to evolving circumstances; and (4) clearly defining the end of the project.

Long term methionine restriction: Influence on gut microbiome and metabolic characteristics.

The Methionine restriction (MR) diet has been shown to delay aging and extend lifespan in various model organisms. However, the long-term effects of MR diet on the gut microbiome composition remain unclear. To study this, male mice were started on MR and control diet regimens at 6 months and continued until 22 months of age. MR mice have reduced body weight, fat mass percentage, and bone mineral density while having increased lean mass percentage. MR mice also have increased insulin sensitivity along with increasing indirect calorimetry markers such as energy expenditure, oxygen consumption, carbon dioxide production, and glucose oxidation. Fecal samples were collected at 1 week, 18 weeks, and 57 weeks after the diet onset for 16S rRNA amplicon sequencing to study the gut microbiome composition. Alpha and beta diversity metrics detected changes occurring due to the timepoint variable, but no changes were detected due to the diet variable. The results from LEfSe analysis surprisingly showed that more bacterial taxa changes were linked to age rather than diet. Interestingly, we found that the long-term MR diet feeding induced smaller changes compared to short-term feeding. Specific taxa changes due to the diet were observed at the 1 or 18-week time points, including Ileibacterium, Odoribacter, Lachnoclostridium, Marinifilaceae, and Lactobacillaceae. Furthermore, there were consistent aging-associated changes across both groups, with an increase in Ileibacterium and Erysipelotrichaceae with age, while Eubacterium_coprostanoligenes_group, Ruminococcaceae, Peptococcaceae, and Peptococcus decreased with age.

Associations between dietary habits, socio-demographics and gut microbial composition in adolescents.

The relationship between dietary habits and microbiota composition during adolescence has not been well examined. This is a crucial knowledge gap to fill considering that diet-microbiota interactions influence neurodevelopment, immune system maturation and metabolic regulation. This study examined the associations between diet and the gut microbiota in a school-based sample of 136 adolescents (Mage = 12·1 years; age range 11-13 years; 48 % female; 47 % Black, 38 % non-Hispanic White, 15 % Hispanic or other minorities) from urban, suburban and rural areas in the Southeast USA. Adolescents completed the Rapid Eating Assessment for Participants and provided stool samples for 16S ribosomal RNA gene sequencing. Parents reported their child and family socio-demographic characteristics. The associations between diet and socio-demographics with gut microbiota diversity and abundance were analysed using multivariable regression models. Child race and ethnicity, sex, socio-economic status and geographic locale contributed to variation within microbiota composition (ß-diversity). Greater consumption of processed meat was associated with a lower microbial α-diversity after adjusting for socio-demographic variables. Multi-adjusted models showed that frequent consumption of nutrient-poor, energy-dense foods (e.g. sugar-sweetened beverages, fried foods, sweets) was negatively associated with abundances of genera in the family Lachnospiraceae (Anaerostipes, Fusicatenibacter and Roseburia), which are thought to play a beneficial role in host health through their production of short-chain fatty acids (SCFAs). These results provide new insights into the complex relationships among socio-demographic factors, diet and gut microbiota during adolescence. Adolescence may represent a critical window of opportunity to promote healthy eating practices that shape a homoeostatic gut microbiota with life-long benefits.

Syphilis Prevalence, Incidence, and Demographic Differences in a Longitudinal Study of Young Sexual and Gender Minority Adults Assigned Male at Birth.

BACKGROUND: Syphilis rates in the United States have increased. Few studies have examined syphilis incidence and prevalence prospectively among young sexual and gender minorities (YSGM). METHODS: This study of YSGM assigned male at birth comes from a Chicago-based prospective cohort at 2 visits 6 months apart (N = 882). Syphilis cases were identified through serologic test results and self-reported history. RESULTS: In this sample, 25.1% had a lifetime prevalence, and 3.3% were incident cases with a crude incidence rate of 6.76 per 100 person-years. CONCLUSIONS: Lifetime syphilis and incidence are high in this sample of YSGM relative to general population samples.

Mood disturbance, but not overall diet quality, is associated with fecal microbiome diversity in free-living adults.

OBJECTIVES: To investigate the gut-brain axis, we explored the relationships among mood disturbance (MD), diet quality (DQ), and fecal microbiota in free-living adults. METHODS: A cross-sectional analysis was conducted with data from 75 healthy adults enrolled in two studies. Anthropometrics, 16s rRNA gene sequencing of fecal microbes, DQ as assessed by Healthy Eating Index-2015 (HEI), and MD determined by Profile of Mood States (POMS) were included. Alpha-diversity and DQ differences were explored between low (n = 37) and high MD (n = 38) groups. Spearman correlations were used to investigate relationships between alpha-diversity, DQ, and POMS subscales. Moderation analysis explored the effect of HEI score on the relationship between MD and alpha-diversity. RESULTS: Participants were mostly white (67%), 54.5 years old (±11.8), and overweight (28.5 ± 6.5 kg/m2). Shannon and Simpson indices indicate higher alpha-diversity in participants with low MD compared to high MD (p = 0.004 and p = 0.008, respectively). Simpson and Shannon indices were correlated with subscale of anger (rho = -0.303, p = 0.011; rho = -0.265, p = 0.027, respectively)and total MD (rho = -0.404, p = 0.001; rho = -0.357, p = 0.002, respectively). Refined grains were associated with fatigue and tension subscales (rho = 0.428, p < 0.001; rho = 0.302, p = 0.014, respectively). DQ did not significantly moderate the relationship between alpha-diversity and mood disturbance (F(7, 53) = 2.00, p = 0.072, R2 = 0.209). Shannon index was a significant predictor of MD (b = -4.39, t(53) = -2.55, p = 0.014), but total HEI score and the interaction (Shannon index*HEI score) were not significant. DISCUSSION: Greater bacterial diversity was associated with lower MD, and DQ was associated with various mood state subscales in this sample of adults.

SOX10 Loss Sensitizes Melanoma Cells to Cytokine-Mediated Inflammatory Cell Death.

The transcription factor, SOX10, plays an important role in the differentiation of neural crest precursors to the melanocytic lineage. Malignant transformation of melanocytes leads to the development of melanoma, and SOX10 promotes melanoma cell proliferation and tumor formation. SOX10 expression in melanomas is heterogeneous, and loss of SOX10 causes a phenotypic switch toward an invasive, mesenchymal-like cell state and therapy resistance; hence, strategies to target SOX10-deficient cells are an active area of investigation. The impact of cell state and SOX10 expression on antitumor immunity is not well understood but will likely have important implications for immunotherapeutic interventions. To this end, we tested whether SOX10 status affects the response to CD8+ T cell-mediated killing and T cell-secreted cytokines, TNFα and IFNγ, which are critical effectors in the cytotoxic killing of cancer cells. We observed that genetic ablation of SOX10 rendered melanoma cells more sensitive to CD8+ T cell-mediated killing and cell death induction by either TNFα or IFNγ. Cytokine-mediated cell death in SOX10-deficient cells was associated with features of caspase-dependent pyroptosis, an inflammatory form of cell death that has the potential to increase immune responses. IMPLICATIONS: These data support a role for SOX10 expression altering the response to T cell-mediated cell death and contribute to a broader understanding of the interaction between immune cells and melanoma cells.

Radiographic analysis of the dorsal hoof wall thickness in clinically normal draft horses.

OBJECTIVE: To evaluate the radiographic thickness of the dorsal hoof wall in normal draft horse feet. ANIMALS: 33 adult draft horses with no history of laminitis, no clinically obvious lameness, and visibly unremarkable front feet were included. METHODS: This was a prospective, descriptive study of clinically normal draft horses' front feet. Lateromedial radiographs were acquired of the front feet. A ratio of the dorsal hoof wall thickness to the length of the distal phalanx (DHWP3 ratio) was calculated. RESULTS: The dorsal hoof wall thickness to length of the distal phalanx was calculated as 0.33 ± 0.03 (range of 0.28 to 0.39) in this population of draft horses. CLINICAL RELEVANCE: With very few exceptions, the heterogeneous population of draft horses evaluated in this study had a DHWP3 ratio greater than previously published values in lighter breeds (< 0.30).

Variation in the clinical management of self-harm by area-level socio-economic deprivation: findings from the multicenter study of self-harm in England.

BACKGROUND: We investigated disparities in the clinical management of self-harm following hospital presentation with self-harm according to level of socio-economic deprivation (SED) in England. METHODS: 108 092 presentations to hospitals (by 57 306 individuals) after self-harm in the Multicenter Study of Self-harm spanning 17 years. Area-level SED was based on the English Index of Multiple Deprivation. Information about indicators of clinical care was obtained from each hospital's self-harm monitoring systems. We assessed the associations of SED with indicators of care using mixed effect models. RESULTS: Controlling for confounders, psychosocial assessment and admission to a general medical ward were less likely for presentations by patients living in more deprived areas relative to presentations by patients from the least deprived areas. Referral for outpatient mental health care was less likely for presentations by patients from the two most deprived localities (most deprived: adjusted odd ratio [aOR] 0.77, 95% CI 0.71-0.83, p < 0.0001; 2nd most deprived: aOR 0.80, 95% CI 0.74-0.87, p < 0.0001). Referral to substance use services and 'other' services increased with increased SED. Overall, referral for aftercare was less likely following presentations by patients living in the two most deprived areas (most deprived: aOR 0.85, 95% CI 0.78-0.92, p < 0.0001; 2nd most deprived: aOR 0.86, 95% CI 0.79-0.94, p = 0.001). CONCLUSIONS: SED is associated with differential care for patients who self-harm in England. Inequalities in care may exacerbate the risk of adverse outcomes in this disadvantaged population. Further work is needed to understand the reasons for these differences and ways of providing more equitable care.