Excess methane emissions from shallow water platforms elevate the carbon intensity of US Gulf of Mexico oil and gas production.

The Gulf of Mexico is the largest offshore fossil fuel production basin in the United States. Decisions on expanding production in the region legally depend on assessments of the climate impact of new growth. Here, we collect airborne observations and combine them with previous surveys and inventories to estimate the climate impact of current field operations. We evaluate all major on-site greenhouse gas emissions, carbon dioxide (CO2) from combustion, and methane from losses and venting. Using these findings, we estimate the climate impact per unit of energy of produced oil and gas (the carbon intensity). We find high methane emissions (0.60 Tg/y [0.41 to 0.81, 95% confidence interval]) exceeding inventories. This elevates the average CI of the basin to 5.3 g CO2e/MJ [4.1 to 6.7] (100-y horizon) over twice the inventories. The CI across the Gulf varies, with deep water production exhibiting a low CI dominated by combustion emissions (1.1 g CO2e/MJ), while shallow federal and state waters exhibit an extraordinarily high CI (16 and 43 g CO2e/MJ) primarily driven by methane emissions from central hub facilities (intermediaries for gathering and processing). This shows that production in shallow waters, as currently operated, has outsized climate impact. To mitigate these climate impacts, methane emissions in shallow waters must be addressed through efficient flaring instead of venting and repair, refurbishment, or abandonment of poorly maintained infrastructure. We demonstrate an approach to evaluate the CI of fossil fuel production using observations, considering all direct production emissions while allocating to all fossil products.

Deep analysis of CD4 T cells in the rhesus CNS during SIV infection.

Virologic suppression with antiretroviral therapy (ART) has significantly improved health outcomes for people living with HIV, yet challenges related to chronic inflammation in the central nervous system (CNS)-known as Neuro-HIV- persist. As primary targets for HIV-1 with the ability to survey and populate the CNS and interact with myeloid cells to co-ordinate neuroinflammation, CD4 T cells are pivotal in Neuro-HIV. Despite their importance, our understanding of CD4 T cell distribution in virus-targeted CNS tissues, their response to infection, and potential recovery following initiation of ART remain limited. To address these gaps, we studied ten SIVmac251-infected rhesus macaques using an ART regimen simulating suboptimal adherence. We evaluated four macaques during the acute phase pre-ART and six during the chronic phase. Our data revealed that HIV target CCR5+ CD4 T cells inhabit both the brain parenchyma and adjacent CNS tissues, encompassing choroid plexus stroma, dura mater, and the skull bone marrow. Aligning with the known susceptibility of CCR5+ CD4 T cells to viral infection and their presence within the CNS, high levels of viral RNA were detected in the brain parenchyma and its border tissues during acute SIV infection. Single-cell RNA sequencing of CD45+ cells from the brain revealed colocalization of viral transcripts within CD4 clusters and significant activation of antiviral molecules and specific effector programs within T cells, indicating CNS CD4 T cell engagement during infection. Acute infection led to marked imbalance in the CNS CD4/CD8 ratio which persisted into the chronic phase. These observations underscore the functional involvement of CD4 T cells within the CNS during SIV infection, enhancing our understanding of their role in establishing CNS viral presence. Our findings offer insights for potential T cell-focused interventions while underscoring the challenges in eradicating HIV from the CNS, particularly in the context of sub-optimal ART.

Diet-induced metabolic and immune impairments are sex-specifically modulated by soluble TNF signaling in the 5xFAD mouse model of Alzheimer's disease.

Emerging evidence indicates that high-fat, high carbohydrate diet (HFHC) impacts central pathological features of Alzheimer's disease (AD) across both human incidences and animal models. However, the mechanisms underlying this association are poorly understood. Here, we identify compartment-specific metabolic and inflammatory dysregulations that are induced by HFHC diet in the 5xFAD mouse model of AD pathology. We observe that both male and female 5xFAD mice display exacerbated adiposity, cholesterolemia, and dysregulated insulin signaling. Independent of biological sex, HFHC diet also resulted in altered inflammatory cytokine profiles across the gastrointestinal, circulating, and central nervous systems (CNS) compartments demonstrating region-specific impacts of metabolic inflammation. Interestingly, inhibiting the inflammatory cytokine, soluble tumor necrosis factor (TNF) with the brain-permeant soluble TNF inhibitor XPro1595 was able to restore aspects of HFHC-induced metabolic inflammation, but only in male mice. Targeted transcriptomics of CNS regions revealed that inhibition of soluble TNF was sufficient to alter expression of hippocampal and cortical genes associated with beneficial immune and metabolic responses. Collectively, these results suggest that HFHC diet impairs metabolic and inflammatory pathways in an AD-relevant genotype and that soluble TNF has sex-dependent roles in modulating these pathways across anatomical compartments. Modulation of energy homeostasis and inflammation may provide new therapeutic avenues for AD.

Rotavirus core shell protein sites that regulate intra-particle polymerase activity.

IMPORTANCE: Rotaviruses are important causes of severe gastroenteritis in young children. A characteristic feature of rotaviruses is that they copy ribonucleic acid (RNA) inside of the viral particle. In fact, the viral polymerase (VP1) only functions when it is connected to the viral inner core shell protein (VP2). Here, we employed a biochemical assay to identify which sites of VP2 are critical for regulating VP1 activity. Specifically, we engineered VP2 proteins to contain amino acid changes at structurally defined sites and assayed them for their capacity to support VP1 function in a test tube. Through this work, we were able to identify several VP2 residues that appeared to regulate the activity of the polymerase, positively and negatively. These results are important because they help explain how rotavirus synthesizes its RNA while inside of particles and they identify targets for the future rational design of drugs to prevent rotavirus disease.

Osteocyte Sptbn1 Deficiency Alters Cell Survival and Mechanotransduction Following Formation of Plasma Membrane Disruptions (PMD) from Mechanical Loading.

We and others have shown that application of high-level mechanical loading promotes the formation of transient plasma membrane disruptions (PMD) which initiate mechanotransduction. We hypothesized that increasing osteocyte cell membrane fragility, by disrupting the cytoskeleton-associated protein ß2-spectrin (Sptbn1), could alter osteocytic responses and bone adaptation to loading in a PMD-related fashion. In MLO-Y4 cells, treatment with the spectrin-disrupting agent diamide or knockdown of Sptbn1 via siRNA increased the number of PMD formed by fluid shear stress. Primary osteocytes from an osteocyte-targeted DMP1-Cre Sptbn1 conditional knockout (CKO) model mimicked trends seen with diamide and siRNA treatment and suggested the creation of larger PMD, which repaired more slowly, for a given level of stimulus. Post-wounding cell survival was impaired in all three models, and calcium signaling responses from the wounded osteocyte were mildly altered in Sptbn1 CKO cultures. Although Sptbn1 CKO mice did not demonstrate an altered skeletal phenotype as compared to WT littermates under baseline conditions, they showed a blunted increase in cortical thickness when subjected to an osteogenic tibial loading protocol as well as evidence of increased osteocyte death (increased lacunar vacancy) in the loaded limb after 2 weeks of loading. The impaired post-wounding cell viability and impaired bone adaptation seen with Sptbn1 disruption support the existence of an important role for Sptbn1, and PMD formation, in osteocyte mechanotransduction and bone adaptation to mechanical loading.

Temporal tau asymmetry spectrum influences divergent behavior and language patterns in Alzheimer's disease.

Understanding the psychiatric symptoms of Alzheimer s disease (AD) is crucial for advancing precision medicine and therapeutic strategies. The relationship between AD behavioral symptoms and asymmetry in spatial tau PET patterns is not well-known. Braak tau progression implicates the temporal lobes early. However, the clinical and pathological implications of temporal tau laterality remain unexplored. This cross-sectional study investigated the correlation between temporal tau PET asymmetry and behavior assessed using the neuropsychiatric inventory and composite scores for memory, executive function, and language, using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. In the entire cohort, continuous right and left temporal tau contributions to behavior and cognition were evaluated, controlling for age, sex, education, and tau burden on the contralateral side. Additionally, a temporal tau laterality index was calculated to define "asymmetry-extreme" groups (individuals with laterality indices greater than two standard deviations from the mean). 695 individuals (age = 73.9 ± 7.6 years, 372 (53.5 %) females) were included, comprising 281 (40%) cognitively unimpaired (CU) amyloid negative, 185 (27%) CU amyloid positive, and 229 (33%) impaired (CI) amyloid positive participants. In the full cohort analysis, right temporal tau was associated with worse behavior (B = 8.14, p-value = 0.007), and left temporal tau was associated with worse language (B = 1.4, p-value < 0.001). Categorization into asymmetry-extreme groups revealed 20 right- and 27 left-asymmetric participants. Within these extreme groups, there was additional heterogeneity along the anterior-posterior dimension. Asymmetrical tau burden is associated with distinct behavioral and cognitive profiles. Wide multi-cultural implementation of social cognition measures is needed to understand right-sided asymmetry in AD.

Repeated exposure to physiologically effective doses of contraceptive hormones ethinyl estradiol or levonorgestrel do not alter the reinforcing effects of a brief visual stimulus in ovary-intact rats.

Estradiol and progesterone potentiate and attenuate reward processes, respectively. Despite these well-characterized effects, there is minimal research on the effects of synthetic estrogens (e.g., ethinyl estradiol, or EE) and progestins (e.g., levonorgestrel, or LEVO) contained in clinically-utilized hormonal contraceptives. The present study characterized the separate effects of repeated exposure to EE or LEVO on responding maintained by a reinforcing visual stimulus. Forty ovary-intact female Sprague-Dawley rats received either sesame oil vehicle (n = 16), 0.18 µg/day EE (n = 16), or 0.6 µg/day LEVO (n = 8) subcutaneous injections 30-min before daily one-hour sessions. Rats' responding was maintained by a 30-sec visual stimulus on a Variable Ratio-3 schedule of reinforcement. The day after rats' last session, we determined rats estrous cycle phase via vaginal cytology before sacrifice and subsequently weighing each rat's uterus to further verify the contraceptive hormone manipulation. The visual stimulus functioned as a reinforcer, but neither EE nor LEVO enhanced visual stimulus maintained responding. Estrous cytology was consistent with normal cycling in vehicle rats and halting of normal cycling in EE and LEVO rats. EE increased uterine weights consistent with typical uterotrophic effects observed with estrogens, further confirming the physiological impacts of our EE and LEVO doses. In conclusion, a physiologically effective dose of neither EE nor LEVO did not alter the reinforcing efficacy of a visual stimulus reinforcer. Future research should characterize the effects of hormonal contraceptives on responding maintained by other reinforcer types to determine the generality of the present findings.

Effect of cognitive behavioural therapy and yoga for generalised anxiety disorder on sleep quality in a randomised controlled trial: the role of worry, mindfulness, and perceived stress as mediators.

Sleep disturbances are present in ~65% of individuals with generalised anxiety disorder (GAD). Although both Kundalini yoga (KY) and cognitive behavioural therapy (CBT) are effective treatment options for GAD, little is known about how these treatments compare in improving sleep for GAD and what drives these changes. Accordingly, we examined the effects of CBT, KY, and stress education (SEdu; an attention control condition) on subjective sleep quality (as measured by the Pittsburgh Sleep Quality Index [PSQI] and Insomnia Severity Index [ISI]) in a randomised controlled trial of 226 adults with GAD (mean age 33.37 years; 70% female; 79% White). We hypothesised that both CBT and KY would outperform SEdu in improving sleep disturbances. Three potential mediators of sleep improvement (worry, mindfulness, perceived stress) were also examined. In line with hypotheses, PSQI and ISI scores significantly improved from pre- to post-treatment for all three treatment groups (all p < 0.001, all d > 0.97). However, contrary to predictions, sleep changes were not significantly greater for CBT or KY compared to SEdu. In mediation analyses, within-person deviations in worry, mindfulness, and stress each significantly mediated the effect of time on sleep outcomes. Degree of change in sleep attributable to worry (CBT > KY > SEdu) and perceived stress (CBT, KY > SEdu) was moderated by treatment group. Personalised medicine as well as combined treatment approaches should be studied to help reduce sleep difficulties for patients with GAD who do not respond.

The Relationship Between Loneliness, Social Isolation, and Inflammatory Bowel Disease: A Narrative Review.

BACKGROUND: There is clear evidence that loneliness and social isolation have profound health consequences. Documenting the associations of loneliness and social isolation with inflammatory bowel disease (IBD) symptoms, disease severity, and treatment outcomes could meaningfully improve health and quality of life in patients with IBD. PURPOSE: The purpose of this narrative review was to synthesize the empirical evidence on the associations of loneliness and social isolation with IBD symptoms, disease severity, and treatment outcomes. METHODS: Articles were identified through systematic database searches. Quantitative studies that enrolled patients with IBD were included if they examined one of the following outcomes: (a) loneliness or social isolation or (b) IBD-related symptoms, disease severity, or treatment outcomes. RESULTS: We identified 1,816 articles after removing duplicates. Of the 18 studies that met the inclusion criteria, 15 were cross-sectional and 3 were longitudinal. Overall, studies found that loneliness was associated with greater disease activity, functional gastrointestinal symptoms, IBD illness stigma, depressive symptoms, daily IBD symptom burden, reduced resilience, and poorer quality of life. Social isolation was associated with higher prevalence of IBD hospitalizations, premature mortality, and depression. CONCLUSIONS: Findings suggest that loneliness and social isolation are associated with poorer health and quality of life in patients with IBD. Prospective cohort studies examining the biobehavioral mechanisms accounting for the associations of loneliness and social isolation with IBD-related outcomes are needed to guide the development of psychological interventions for individuals living with IBD.

This article explores the connection between loneliness, social isolation, and health outcomes in people with inflammatory bowel disease (IBD). While loneliness and social isolation are known to negatively impact health in other chronic diseases, their specific effects within IBD have been far less studied. This study conducted a narrative review and found that loneliness is linked to more severe IBD symptoms, including increased disease activity, greater gastrointestinal distress, and lower quality of life. Similarly, social isolation is associated with higher rates of IBD-related hospitalizations, depression, and reduced coping abilities. These findings highlight the importance of addressing loneliness and social isolation in patients with IBD. Doing so may be key to developing psychological interventions that improve the well-being and health of those living with IBD.

Choroid plexus mis-splicing and altered cerebrospinal fluid composition in myotonic dystrophy type 1.

Myotonic dystrophy type 1 is a dominantly inherited multisystemic disease caused by CTG tandem repeat expansions in the DMPK 3' untranslated region. These expanded repeats are transcribed and produce toxic CUG RNAs that sequester and inhibit activities of the MBNL family of developmental RNA processing factors. Although myotonic dystrophy is classified as a muscular dystrophy, the brain is also severely affected by an unusual cohort of symptoms, including hypersomnia, executive dysfunction, as well as early onsets of tau/MAPT pathology and cerebral atrophy. To address the molecular and cellular events that lead to these pathological outcomes, we recently generated a mouse Dmpk CTG expansion knock-in model and identified choroid plexus epithelial cells as particularly affected by the expression of toxic CUG expansion RNAs. To determine if toxic CUG RNAs perturb choroid plexus functions, alternative splicing analysis was performed on lateral and hindbrain choroid plexi from Dmpk CTG knock-in mice. Choroid plexus transcriptome-wide changes were evaluated in Mbnl2 knockout mice, a developmental-onset model of myotonic dystrophy brain dysfunction. To determine if transcriptome changes also occurred in the human disease, we obtained post-mortem choroid plexus for RNA-seq from neurologically unaffected (two females, three males; ages 50-70 years) and myotonic dystrophy type 1 (one female, three males; ages 50-70 years) donors. To test that choroid plexus transcriptome alterations resulted in altered CSF composition, we obtained CSF via lumbar puncture from patients with myotonic dystrophy type 1 (five females, five males; ages 35-55 years) and non-myotonic dystrophy patients (three females, four males; ages 26-51 years), and western blot and osmolarity analyses were used to test CSF alterations predicted by choroid plexus transcriptome analysis. We determined that CUG RNA induced toxicity was more robust in the lateral choroid plexus of Dmpk CTG knock-in mice due to comparatively higher Dmpk and lower Mbnl RNA levels. Impaired transitions to adult splicing patterns during choroid plexus development were identified in Mbnl2 knockout mice, including mis-splicing previously found in Dmpk CTG knock-in mice. Whole transcriptome analysis of myotonic dystrophy type 1 choroid plexus revealed disease-associated RNA expression and mis-splicing events. Based on these RNA changes, predicted alterations in ion homeostasis, secretory output and CSF composition were confirmed by analysis of myotonic dystrophy type 1 CSF. Our results implicate choroid plexus spliceopathy and concomitant alterations in CSF homeostasis as an unappreciated contributor to myotonic dystrophy type 1 CNS pathogenesis.

Florbetaben amyloid PET acquisition time: Influence on Centiloids and interpretation.

INTRODUCTION: Amyloid positron emission tomography (PET) acquisition timing impacts quantification. METHODS: In florbetaben (FBB) PET scans of 245 adults with and without cognitive impairment, we investigated the impact of post-injection acquisition time on Centiloids (CLs) across five reference regions. CL equations for FBB were derived using standard methods, using FBB data collected between 90 and 110 min with paired Pittsburgh compound B data. Linear mixed models and t-tests evaluated the impact of acquisition time on CL increases. RESULTS: CL values increased significantly over the scan using the whole cerebellum, cerebellar gray matter, and brainstem as reference regions, particularly in amyloid-positive individuals. In contrast, CLs based on white matter-containing reference regions decreased across the scan. DISCUSSION: The quantification of CLs in FBB PET imaging is influenced by both the overall scan acquisition time and the choice of reference region. Standardized acquisition protocols or the application of acquisition time-specific CL equations should be implemented in clinical protocols. HIGHLIGHTS: Acquisition timing affects florbetaben positron emission tomography (PET) scan quantification, especially in amyloid-positive participants. The impact of acquisition timing on quantification varies across common reference regions. Consistent acquisitions and/or appropriate post-injection adjustments are needed to ensure comparability of PET data.

Athletic prognosis following arthroscopic removal of osteochondral fragments of the proximal dorsal sagittal ridge of the fetlock in Thoroughbreds intended for flat racing.

OBJECTIVE: To establish racing prognosis in Thoroughbred yearlings with proximal sagittal ridge osteochondral lesions and compare them to dorsoproximal and palmar/plantar first phalanx osteochondral lesions. ANIMALS: A total of 47 horses had proximal sagittal ridge lesions, 34 had palmar/plantar first phalanx lesions, and 115 had dorsoproximal first phalanx lesions. STUDY DESIGN: Retrospective case series. METHODS: Medical records of Thoroughbred yearling racing prospects treated arthroscopically for fetlock osteochondral lesions were reviewed. Data were collected from a public database, including the ability to train and race, earnings, starts, wins, and placed races. Racing prognosis was analyzed and compared between three lesion locations. RESULTS: Of the proximal sagittal ridge group, 76.6% raced, 65.71% of the palmar/plantar first phalanx group, and 74.58% of the dorsoproximal first phalanx group. Career length was similar for all lesions. A lower number of "starts" in the group "five years old and older" was found for the dorsoproximal first phalanx group compared to the cohort with proximal sagittal ridge lesions. Mares had more "earnings" at two years old but fewer "starts" at "five years old" compared to colts and geldings. Forelimb lesions were predictive for fewer total career starts. CONCLUSION: Proximal sagittal ridge lesions had similar prognoses to dorsoproximal and palmar/plantar first phalanx lesions. In older horses, there was an increase in the number of starts for the proximal sagittal ridge group compared to the dorsoproximal first phalanx group. Mares and forelimb lesions were associated with decreased racing starts. CLINICAL SIGNIFICANCE: These findings aid in prognostication for Thoroughbreds with osteochondral lesions removed arthroscopically in the fetlock joint.

FOUR CASES OF SEVERED PEDUNCLES IN BOTTLENOSE DOLPHINS (TURSIOPS TRUNCATUS) ALONG THE ALABAMA COAST.

Alabama (AL) is a hotspot in the Gulf of Mexico (GoM) for human interaction-related cetacean strandings, including harassment, vessel strikes, and fisheries interactions. We examined four bottlenose dolphins (Tursiops truncatus) stranded dead along the AL coast during 2012-2017 with severed peduncles suspected to be related to human interaction (HI). Evidence from each case, including photographs, gross necropsy results, and histopathologic findings when available, was reviewed to determine the mode of severance and whether it contributed to death. In each case, the severance site had smooth, clean edges on at least one side, indicating the use of a sharp instrument to remove the caudal peduncle and flukes. Three cases also had evidence of fisheries interactions, including linear impressions around the rostrum, fins and/or flukes, indicating that these animals may have been entangled in fisheries gear prior to death. Histopathology in one of these cases revealed that the severance occurred perimortem; speculatively, the caudal peduncle and flukes may have been cut off to facilitate removing the dolphin from its entanglement. Although cases of amputation and mutilation are not uncommon globally among stranding reports, few cases have been described and analyzed in the literature. This paper is the first to document and compare multiple cases of severed peduncles with evidence of HI, including fisheries, in the GoM. This case series enhances our understanding of the types of HI occurring in bottlenose dolphins and highlights the need for continued public education, policy, and management to address cases like these.

Chediak-Higashi syndrome.

PURPOSE OF REVIEW: Chediak-Higashi syndrome is a rare autosomal recessive disorder characterized by congenital immunodeficiency, bleeding diathesis, pyogenic infection, partial oculocutaneous albinism, and progressive neurodegeneration. Treatment is hematopoietic stem cell transplantation or bone marrow transplantation; however, this does not treat the neurologic aspect of the disease. Mutations in the lysosomal trafficking regulator (LYST) gene were identified to be causative of Chediak-Higashi, but despite many analyses, there is little functional information about the LYST protein. This review serves to provide an update on the clinical manifestations and cellular defects of Chediak-Higashi syndrome. RECENT FINDINGS: More recent papers expand the neurological spectrum of disease in CHS, to include hereditary spastic paraplegia and parkinsonism. Granule size and distribution in NK cells have been investigated in relation to the location of mutations in LYST. Patients with mutations in the ARM/HEAT domain had markedly enlarged granules, but fewer in number. By contrast, patients with mutations in the BEACH domain had more numerous granules that were normal in size to slightly enlarged, but demonstrated markedly impaired polarization. The role of LYST in autophagosome formation has been highlighted in recent studies; LYST was defined to have a prominent role in autophagosome lysosome reformation for the maintenance of lysosomal homeostasis in neurons, while in retinal pigment epithelium cells, LYST deficiency was shown to lead to phagosome accumulation. SUMMARY: Despite CHS being a rare disease, investigation into LYST provides an understanding of basic vesicular fusion and fission. Understanding of these mechanisms may provide further insight into the function of LYST.

Altered Response Pattern following AZD5582 Treatment of SIV-Infected, ART-Suppressed Rhesus Macaque Infants.

The "shock and kill" strategy for HIV-1 cure incorporates latency-reversing agents (LRA) in combination with interventions that aid the host immune system in clearing virally reactivated cells. LRAs have not yet been investigated in pediatric clinical or preclinical studies. Here, we evaluated an inhibitor of apoptosis protein (IAP) inhibitor (IAPi), AZD5582, that activates the noncanonical NF-κB (ncNF-κB) signaling pathway to reverse latency. Ten weekly doses of AZD5582 were intravenously administered at 0.1 mg/kg to rhesus macaque (RM) infants orally infected with SIVmac251 at 4 weeks of age and treated with a triple ART regimen for over 1 year. During AZD5582 treatment, on-ART viremia above the limit of detection (LOD, 60 copies/mL) was observed in 5/8 infant RMs starting at 3 days post-dose 4 and peaking at 771 copies/mL. Of the 135 measurements during AZD5582 treatment in these 5 RM infants, only 8 were above the LOD (6%), lower than the 46% we have previously reported in adult RMs. Pharmacokinetic analysis of plasma AZD5582 levels revealed a lower Cmax in treated infants compared to adults (294 ng/mL versus 802 ng/mL). RNA-Sequencing of CD4+ T cells comparing pre- and post-AZD5582 dosing showed many genes that were similarly upregulated in infants and adults, but the expression of key ncNF-κB genes, including NFKB2 and RELB, was significantly higher in adult RMs. Our results suggest that dosing modifications for this latency reversal approach may be necessary to maximize virus reactivation in the pediatric setting for successful "shock and kill" strategies. IMPORTANCE While antiretroviral therapy (ART) has improved HIV-1 disease outcome and reduced transmission, interruption of ART results in rapid viral rebound due to the persistent latent reservoir. Interventions to reduce the viral reservoir are of critical importance, especially for children who must adhere to lifelong ART to prevent disease progression. Here, we used our previously established pediatric nonhuman primate model of oral SIV infection to evaluate AZD5582, identified as a potent latency-reversing agent in adult macaques, in the controlled setting of daily ART. We demonstrated the safety of the IAPi AZD5582 and evaluate the pharmacokinetics and pharmacodynamics of repeated dosing. The response to AZD5582 in macaque infants differed from what we previously showed in adult macaques with weaker latency reversal in infants, likely due to altered pharmacokinetics and less inducibility of infant CD4+ T cells. These data supported the contention that HIV-1 cure strategies for children are best evaluated using pediatric model systems.

Health Justice Standards in Graduate Medical Education: Moving from Performative to Concrete Change.

BACKGROUND: Inadequate support for underrepresented-in-medicine physicians, lack of physician knowledge about structural drivers of health, and biased patient care and research widen US health disparities. Despite stating the importance of health equity and diversity, national physician education organizations have not yet prioritized these goals. AIM: To develop a comprehensive set of Health Justice Standards within our residency program to address structural drivers of inequity. SETTING: The J. Willis Hurst Internal Medicine Residency Program of Emory University is an academic internal medicine residency program located in Atlanta, Georgia. PARTICIPANTS: This initiative was led by the resident-founded Churchwell Diversity and Inclusion Collective, modified by Emory IM leadership, and presented to Emory IM residents. PROGRAM DESCRIPTION: We used an iterative process to develop and implement these Standards and shared our progress with our coresidents to evaluate impact. PROGRAM EVALUATION: In the year since their development, we have made demonstrable progress in each domain. Presentation of our work significantly correlated with increased resident interest in advocacy (p<0.001). DISCUSSION: A visionary, actionable health justice framework can be used to generate changes in residency programs' policies and should be developed on a national level.

Keratinocytes and immune cells in the epidermis are key drivers of inflammation in hidradenitis suppurativa providing a rationale for novel topical therapies.

BACKGROUND: Hidradenitis suppurativa (HS) is a debilitating inflammatory skin disease characterized by painful nodules, drainage and scarring in skin folds. Injectable adalimumab is the only drug approved by the US Food and Drug Administration for the treatment of HS. Although systemic Janus kinase (JAK) inhibitors show promise, serious side-effects have been reported. There are no highly effective topical treatments for HS; furthermore, the contribution of epidermal keratinocytes to the intense inflammation has largely been unexplored. OBJECTIVES: We investigated the role of keratinocytes and epidermal immune cells in HS inflammation at all Hurley stages of disease severity. We aimed to determine whether ruxolitinib can mitigate inflammation from keratinocytes and to develop a better understanding of how topical therapeutics might benefit patients with HS. METHODS: We used skin samples from 87 patients with HS (Hurley stages I-III) and 39 healthy controls to compare keratinocyte- and immune cell-driven epidermal inflammation, in addition to the response of lesional HS keratinocytes to treatment with interferon (IFN)-γ and ruxolitinib. We used haematoxylin and eosin staining, immunohistochemistry, immunoblotting and quantitative reverse-transcription polymerase chain reaction assessments in whole skin, isolated epidermis, and cultured keratinocytes from healthy controls and both nonlesional and lesional HS skin to identify and define epidermal and keratinocyte-mediated inflammation in HS and how this may be targeted by therapeutics. RESULTS: HS lesional keratinocytes autonomously secreted high levels of chemokines, such as CCL2, CCL3 and CXCL3, which recruited neutrophils, CD8 T cells, and natural killer cells to the epidermis. Keratinocytes were the dominant source of tumour necrosis factor-α and interleukin (IL)-6 in HS lesions with little to no contribution from underlying dermal immune cells. In the presence of IFN-γ, which is dependent on immune cell infiltrate in vivo, keratinocytes expressed increased levels of additional cytokines including IL-1ß, IL-12, IL-23 and IL-36γ. The JAK inhibitor ruxolitinib mitigated the expression of inflammatory cytokines and chemokines in HS lesional keratinocytes, thus providing a rationale for future study as a topical treatment for HS. CONCLUSIONS: This study demonstrates that keratinocytes actively recruit immune cells to HS epidermis and interactions between these cells drive a broad inflammatory profile in HS epidermis. Targeting epidermal inflammation in HS with novel topical formulations may be highly efficacious with reduced systemic side-effects.

Adult-Onset Transcriptomic Effects of Developmental Exposure to Benzene in Zebrafish (Danio rerio): Evaluating a Volatile Organic Compound of Concern.

Urban environments are afflicted by mixtures of anthropogenic volatile organic compounds (VOCs). VOC sources that drive human exposure include vehicle exhaust, industrial emissions, and oil spillage. The highly volatile VOC benzene has been linked to adverse health outcomes. However, few studies have focused on the later-in-life effects of low-level benzene exposure during the susceptible window of early development. Transcriptomic responses during embryogenesis have potential long-term consequences at levels equal to or lower than 1 ppm, therefore justifying the analysis of adult zebrafish that were exposed during early development. Previously, we identified transcriptomic alteration following controlled VOC exposures to 0.1 or 1 ppm benzene during the first five days of embryogenesis using a zebrafish model. In this study, we evaluated the adult-onset transcriptomic responses to this low-level benzene embryogenesis exposure (n = 20/treatment). We identified key genes, including col1a2 and evi5b, that were differentially expressed in adult zebrafish in both concentrations. Some DEGs overlapped at the larval and adult stages, specifically nfkbiaa, mecr, and reep1. The observed transcriptomic results suggest dose- and sex-dependent changes, with the highest impact of benzene exposure to be on cancer outcomes, endocrine system disorders, reproductive success, neurodevelopment, neurological disease, and associated pathways. Due to molecular pathways being highly conserved between zebrafish and mammals, developmentally exposed adult zebrafish transcriptomics is an important endpoint for providing insight into the long term-effects of VOCs on human health and disease.

Nonsuicidal self-injury and rumination: A meta-analysis.

Trait rumination is the tendency to overthink and focus on negative emotions and events and is related to a number of psychological disorders and maladaptive behaviors including nonsuicidal self-injury (NSSI). The purpose of this study was to conduct a meta-analysis of the relationship between trait rumination and NSSI behaviors. Results from 60 samples showed small effect sizes between trait rumination and NSSI engagement, NSSI frequency, and the number of methods used to self-injure in cross-sectional samples. Results from 13 samples showed small effect sizes between trait rumination and NSSI engagement and NSSI frequency in longitudinal samples. Moderator analyses indicated that this relationship is similar whether the type of rumination is depressive or not and is generally consistent across different ages, genders, and ethnicities. These results help clarify the role of trait rumination as a risk factor for NSSI.

Injection Adipocytolysis for Body and Jawline Contouring: Real-World Experience and Treatment Considerations.

BACKGROUND: The role of ATX-101 in submental fat reduction has been well documented; however, its applicability across multiple anatomic areas is to be explored. OBJECTIVES: The authors sought to describe the experience with ATX-101 subcutaneous injections for body and jawline contouring and evaluate its safety. METHODS: This single-arm, single-center observational study included 201 patients who underwent injection adipocytolysis with ATX-101 (area-adjusted dose of 2 mg/cm2) in the jowl, abdomen (upper/lower), thigh (inner/outer/banana roll), arm, anterior periaxillary fat, back (lower/upper/nape/lipoma), knee (anterior/medial), chest, and/or neck. The number of treatment sessions, treatment volumes, doses, injections required for each anatomic area, and associated adverse events were recorded. RESULTS: The mean number of treatment sessions conducted was 1.8. Multiple sessions were common for the jowl (mean: 2.0 and mean volume administered varied significantly between persons receiving 1 or multiple sessions [P = 0.005]). The mean volume and mean number of injections per session were highest in the chest (84.7 mL and 423.5, respectively) and lowest in the jowl (0.8 mL and 4.6, respectively). The chest (0.2 mL) and nape (0.2 mL) received the highest mean ATX-101 dose per injection site per session, whereas the inner thigh (0.11 mL) and upper back (0.11 mL) received the least. Adverse events observed were localized to the injection site. All patients experienced edema after each session, whereas numbness, tenderness, bruising, and paresis were experienced by 99.6%, 94.2%, 33.1%, and 2.6% of patients, respectively. Alopecia was not observed. CONCLUSIONS: ATX-101 was well tolerated for body and jawline contouring.