Descriptive Epidemiology of New York City Older Adult Patients With Multiple Chronic Conditions.

We characterized comorbidity profiles and cardiometabolic risk factors among older adults with multiple chronic conditions (MCCs) in New York City using an intersectionality approach. Electronic health record data were obtained from the INSIGHT Clinical Research Network on 367,901 New York City residents aged 50 years or older with MCCs. Comorbidity profiles were heterogeneous. The most common profile across sex and racial and ethnic groups was co-occurring hypertension and hyperlipidemia; prevalence of these 2 conditions differed across groups (4.7%-7.3% co-occurrence alone, 65.1%-88.0% with other conditions). Significant sex and racial and ethnic differences were observed, which may reflect accumulated disparities in risk factors and health care access across the life course.

Current Treatments for Generalized Pustular Psoriasis: A Narrative Summary of a Systematic Literature Search.

Generalized pustular psoriasis (GPP) is a rare, chronic and potentially life-threatening autoinflammatory skin disease characterized by widespread eruption of sterile pustules, with or without systemic inflammation. GPP can significantly reduce patients' quality of life (QoL). Several therapeutic approaches have been described in the literature, but there is no consensus on optimal treatment. In this review, we summarize published literature on efficacy, safety and QoL outcomes associated with current treatment of GPP with both approved and non-approved products. Embase and MEDLINE databases were searched (1980-September 2023). A search protocol was designed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered on the PROSPERO database (CRD42021215437). Details on publication, population, intervention, efficacy, safety and QoL were captured and checked by independent reviewers. In total, 118 publications were included, with only 19% of publications reporting on the results of clinical trials. Treatment modalities reported for GPP included non-biologic systemic therapies such as retinoids, cyclosporine and methotrexate, topical agents, biologics and small molecules, among others. Results were highly heterogeneous and methodological quality was very low, with only the interleukin-36R inhibitor spesolimab reporting results from placebo-controlled randomized trials; based on this, spesolimab is now approved for GPP treatment in regions including the USA, Japan, China, the EU and several other countries. Some other biologics are approved exclusively in Japan and Taiwan for the treatment of GPP based on open-label studies with small patient numbers in lieu of double-blind studies. Non-standardization of clinical outcomes across studies remains a major hurdle in reaching a consensus on optimal treatment. However, recently trials have been conducted using well-defined, disease-specific endpoints to evaluate GPP-targeted treatments, which will hopefully advance patient care. In conclusion, this review highlights the need for prospective randomized studies with GPP-specific endpoints to determine the optimal treatment strategy.

Generalized pustular psoriasis (GPP) is a rare, chronic skin condition characterized by painful, sterile pustules that can occur all over the body. These pustules may also be accompanied by systemic inflammation, which can lead to serious health complications. GPP significantly impacts patients' quality of life and can even be life-threatening. Because the disease is so rare, treatment guidelines have typically been based on those for plaque psoriasis. However, these guidelines do not specifically address the unique needs of GPP. In this review, we analysed the published literature on GPP management, focussing on treatment efficacy, safety and quality of life outcomes. We searched the literature databases Embase and MEDLINE for articles published between 1980 and September 2023. In total, we identified 118 publications on this topic, covering a wide range of therapies; only one of these therapies, spesolimab, reported results from placebo-controlled randomized trials. Based on these trials, spesolimab is now approved for GPP treatment in the USA, Japan, China, the EU and several other countries. Some other therapies are approved exclusively in Japan and Taiwan based on small, open-label studies in the absence of higher-quality data. To date, comparing treatments has been challenging because of different clinical outcomes used to measure effectiveness. However, well-defined endpoints specific to GPP have recently been developed and used in trials. In conclusion, our review highlights the need for prospective randomized studies with GPP-specific endpoints to determine the best treatment strategy.

Ecological roles and importance of sharks in the Anthropocene Ocean.

In ecosystems, sharks can be predators, competitors, facilitators, nutrient transporters, and food. However, overfishing and other threats have greatly reduced shark populations, altering their roles and effects on ecosystems. We review these changes and implications for ecosystem function and management. Macropredatory sharks are often disproportionately affected by humans but can influence prey and coastal ecosystems, including facilitating carbon sequestration. Like terrestrial predators, sharks may be crucial to ecosystem functioning under climate change. However, large ecosystem effects of sharks are not ubiquitous. Increasing human uses of oceans are changing shark roles, necessitating management consideration. Rebuilding key populations and incorporating shark ecological roles, including less obvious ones, into management efforts are critical for retaining sharks' functional value. Coupled social-ecological frameworks can facilitate these efforts.

Inflammation altered correlation between CYP2C19 genotype and CYP2C19 activity in patients receiving voriconazole.

Voriconazole is the cornerstone of the treatment and prevention of fungal infections. While there is a good correlation between CYP2C19 genotype and voriconazole exposure during prophylactic treatment, no correlation was found in patients with invasive aspergillosis. Proinflammatory cytokines result in inhibition of CYP2C19 enzyme activity (and may result in phenoconversion). Here we investigated the relationship between inflammation, CYP2C19 genotype-predicted-phenotype, and CYP2C19 activity in patients receiving voriconazole. Data were obtained from two prospective studies investigating voriconazole treatment (NCT02074462 and NCT00893555). Dose-corrected voriconazole plasma concentration and C-reactive protein (CRP) were used as proxies for CYP2C19 activity and inflammation, respectively. After data extraction and synthesis, data from 39 patients with paired voriconazole and CRP measurements were available. The distribution of CYP2C19 genotype-predicted metabolizer phenotypes was 31% intermediate (IM), 41% normal (NM), and 28% rapid metabolizer (RM). During inflammation, dose-corrected voriconazole levels were increased by 245%, 278%, and 486% for CYP2C19 NMs IMs and RMs, respectively. Patients with moderate or high CRP levels (>50 mg/L) were phenoconverted to a lower metabolizer phenotype irrespective of their CYP2C19 genotype. In a subgroup analysis of eight patients with longitudinal data available with and without inflammation, the pattern of the dose-corrected voriconazole and CRP measurements were similar, with CYP2C19 activity following decreasing or increasing CRP levels. In conclusion, voriconazole plasma concentrations increase during inflammation due to downregulation of CYP2C19 activity. While this effect appears largest for CYP2C19 RMs, no clinically relevant differences were observed between the CYP2C19 genotypes.

Switching from Dose-Intensified intravenous to SubCutaneoUS infliximab in Inflammatory Bowel Disease (DISCUS-IBD): protocol for a multicentre randomised controlled trial.

INTRODUCTION: A substantial proportion of patients with inflammatory bowel disease (IBD) on intravenous infliximab require dose intensification. Accessing additional intravenous infliximab is labour-intensive and expensive, depending on insurance and pharmaceutical reimbursement. Observational data suggest that subcutaneous infliximab may offer a convenient and safe alternative to maintain disease remission in patients requiring dose-intensified infliximab. A prospective, controlled trial is required to confirm that subcutaneous infliximab is as effective as dose-intensified intravenous infliximab, to identify predictors of disease flare and to establish the role of subcutaneous infliximab therapeutic drug monitoring. METHODS AND ANALYSIS: The DISCUS-IBD trial is an investigator-initiated, prospective, multicentre, randomised, open-label non-inferiority study comparing the rate of disease flares in participants randomised to continue dose-intensified intravenous infliximab to those switched to subcutaneous infliximab after 48 weeks. Participants are adult patients with IBD in sustained corticosteroid-free remission on any regimen of dose-intensified infliximab up to a maximum of 10 mg/kg 4-weekly intravenously. Participants allocated to intravenous infliximab will continue infliximab at the same dose-intensified regimen they were receiving at study enrolment. Subcutaneous infliximab dosing will be stratified by prior intravenous infliximab dosing. Clinical (Harvey-Bradshaw Index, partial Mayo score), biochemical (C reactive protein, faecal calprotectin), pharmacokinetic (drug-level±antidrug antibodies) and qualitative data are collected 12-weekly until study conclusion at week 48. 13 sites across Australia will participate in recruitment to reach a calculated sample size of 120 participants. ETHICS AND DISSEMINATION: Multisite ethics approval was obtained from the Health District Human Research Ethics Committee (HREC) at The Alfred Hospital under a National Mutual Acceptance (NMA) agreement (HREC/90559/Alfred-2022; Local Reference: Project 618/22, version 1.6, 2 March 2023). Findings will be reported at national and international gastroenterology meetings and published in peer-reviewed journals. DISCUS-IBD was prospectively registered with the Australian and New Zealand Clinical Trials Registry (ANZCTR) prior to commencing recruitment. TRIAL REGISTRATION NUMBER: ACTRN12622001458729.

Preventive Service Usage and New Chronic Disease Diagnoses: Using PCORnet Data to Identify Emerging Trends, United States, 2018-2022.

Background: Data modernization efforts to strengthen surveillance capacity could help assess trends in use of preventive services and diagnoses of new chronic disease during the COVID-19 pandemic, which broadly disrupted health care access. Methods: This cross-sectional study examined electronic health record data from US adults aged 21 to 79 years in a large national research network (PCORnet), to describe use of 8 preventive health services (N = 30,783,825 patients) and new diagnoses of 9 chronic diseases (N = 31,588,222 patients) during 2018 through 2022. Joinpoint regression assessed significant trends, and health debt was calculated comparing 2020 through 2022 volume to prepandemic (2018 and 2019) levels. Results: From 2018 to 2022, use of some preventive services increased (hemoglobin A1c and lung computed tomography, both P < .05), others remained consistent (lipid testing, wellness visits, mammograms, Papanicolaou tests or human papillomavirus tests, stool-based screening), and colonoscopies or sigmoidoscopies declined (P < .01). Annual new chronic disease diagnoses were mostly stable (6% hypertension; 4% to 5% cholesterol; 4% diabetes; 1% colonic adenoma; 0.1% colorectal cancer; among women, 0.5% breast cancer), although some declined (lung cancer, cervical intraepithelial neoplasia or carcinoma in situ, cervical cancer, all P < .05). The pandemic resulted in health debt, because use of most preventive services and new diagnoses of chronic disease were less than expected during 2020; these partially rebounded in subsequent years. Colorectal screening and colonic adenoma detection by age group aligned with screening recommendation age changes during this period. Conclusion: Among over 30 million patients receiving care during 2018 through 2022, use of preventive services and new diagnoses of chronic disease declined in 2020 and then rebounded, with some remaining health debt. These data highlight opportunities to augment traditional surveillance with EHR-based data.

Topical Cannabidiol Application May Not Attenuate Muscle Soreness or Improve Performance: A Randomized, Double-Blinded, Placebo-Controlled Pilot Study.

Purpose: The purpose of this pilot study was to investigate cannabidiol (CBD) cream's effects on muscle soreness and performance after exercise. Materials and Methods: This double-blinded, placebo-controlled experiment included 15 men and 13 women (n = 28; mean ± standard deviation age: 23.29 ± 2.54 years) untrained in lower-body resistance training. Participants were randomized into control (NG, n = 9), CBD (CG, n = 9), or placebo (PG, n = 10) groups. Participants completed a lower-body fatigue protocol (FP) consisting of unilateral maximal concentric and eccentric isokinetic muscle actions of the quadriceps and hamstrings (5 sets, 10 repetitions, both legs). CG and PG participants applied ∼100 mg CBD or placebo cream, respectively, matched for weight and appearance to the quadriceps on three separate days. NG participants engaged in a sitting rest period matched in duration to cream application processes. Questionnaires, pressure-pain threshold (PPT), peak torque test (PTT), and countermovement jump (CMJ) were assessed. Mixed-model analysis of variance was conducted to assess main effects and interactions (group × muscle × time; group × time). Results: There were no significant interactions or main effects for group for PPT, CMJ, or PTT. There were main effects for time (p < 0.05) for all soreness questions, PPT, CMJ, and PTT. There was one significant interaction (group × time; p = 0.045) for cream/rest effect questions, in which PG participants perceived the effect of cream to be greater than the effect of rest for NG participants. There were main effects for group (p ≤ 0.031) for all soreness questions, in which PG participants perceived enhanced recovery. Conclusions: The present pilot study did not discover any significant impacts of CBD cream use for muscle recovery. For individuals seeking to attenuate muscle soreness and improve performance, the current dose of this topical CBD product may not be an effective treatment.

Combining treat-to-target principles and shared decision-making: International expert consensus-based recommendations with a novel concept for minimal disease activity criteria in atopic dermatitis.

BACKGROUND: Current treat-to-target recommendations for atopic dermatitis (AD) may not include high enough treatment targets and do not fully consider patient needs. OBJECTIVE: To develop recommendations for optimized AD management, including disease severity assessments, treatment goals and targets, and guidance for treatment escalation/modification. METHODS: An international group of expert dermatologists drafted a series of recommendations for AD management using insights from a global patient study and 87 expert dermatologists from 44 countries. Experts voted on recommendations using a modified eDelphi voting process. RESULTS: The Aiming High in Eczema/Atopic Dermatitis (AHEAD) recommendations establish a novel approach to AD management, incorporating shared decision-making and a concept for minimal disease activity (MDA). Consensus (≥70% agreement) was reached for all recommendations in 1 round of voting; strong consensus (≥90% agreement) was reached for 30/34 recommendations. In the AHEAD approach, patients select their most troublesome AD feature(s); the clinician chooses a corresponding patient-reported severity measure and objective severity measure. Treatment targets are chosen from a list of 'moderate' and 'optimal' targets, with achievement of 'optimal' targets defined as MDA. CONCLUSIONS: Patient and expert insights led to the development of AHEAD recommendations, which establish a novel approach to AD management. Patients were not involved in the eDelphi voting process used to generate consensus on each recommendation. However, patient perspectives were captured in a global, qualitative patient research study that was considered by the experts in their initial drafting of the recommendations.

Spesolimab Reduces Inflammation in Generalized Pustular Psoriasis: Molecular Characterisation of Flare Treatment in EFFISAYIL® 1.

EFFISAYIL® 1 was a randomized, placebo-controlled study of spesolimab, an anti-IL-36 receptor antibody, in patients presenting with a generalized pustular psoriasis (GPP) flare. Treatment with spesolimab led to more rapid pustular and skin clearance versus placebo in approximately half of the patients. Here we present histologic, transcriptomic, and proteomic analyses of lesional and non-lesional skin, and whole-blood samples collected from EFFISAYIL® 1. Treatment with spesolimab led to a transition toward a non-lesional profile, with a downregulation of gene expression in the skin of IL-36 transcripts (IL-36α, IL-36ß, IL-36γ) and those associated with neutrophil recruitment (CXCL1, CXCL6, CXCL8), proinflammatory cytokines (IL-6, IL-19, IL-20), and skin inflammation (DEFB4A, S100A7, S100A8). Changes were manifest at Week 1 and sustained to Week 8. At the systemic level, reductions in serum biomarkers of inflammation (IL-17, IL-8, IL-6) were sustained until 12 weeks post-spesolimab treatment. Considerable overlap was observed in the spesolimab-induced changes in gene and protein expression from skin and blood samples, demonstrating the molecular basis of the effects of spesolimab on controlling local and systemic inflammation. Data are consistent with the mode of action of spesolimab, whereby inhibition of the IL-36 pathway leads to subsequent reductions in the key local and systemic pathologic events associated with acute GPP flares.

Seeking American Society of Clinical Oncology-Quality Oncology Practice Initiative (ASCO-QOPI) certification in a northern New England rural health system and cancer care network.

In 2006 following several years of preliminary study, the American Society of Clinical Oncology (ASCO) launched the Quality Oncology Practice Initiative (QOPI). This cancer-focused quality initiative evolved considerably over the next decade-and-a-half and is expanding globally. QOPI is undoubtedly the leading standard-bearer for quality cancer care and contemporary medical oncology practice. The program garners attention and respect among federal programs, private insurers, and medical oncology practices across the nation. The MaineHealth Cancer Care Network (MHCCN) has undergone expansive growth since 2017. The network provides cancer care to more than 70% of the cases in Maine in a largely rural health system in Northern New England. In fall 2020, the MHCCN QOPI project leadership, following collaborative discussions with the ASCO-QOPI team, elected to proceed with a health system-cancer network-wide QOPI certification. Key themes emerged over the course of our two-year journey including: (1) Developing a highly interprofessional team committed to the project; (2) Capitalizing on a single electronic medical record for data transmission to CancerLinQ; (3) Prior experience, especially policy development, in other cancer-focused accreditation programs across the network; and (4) Building consensus through quarterly stakeholder meetings and awarding Continuing Medical Education (CME) and American Board of Medical Specialists (ABMS) Maintenance of Certification (MOC) credits to oncologists. All participants demonstrated a genuine spirit to work together to achieve certification. We report our successful journey seeking ASCO-QOPI certification across our network, which to our knowledge is the first-of-its-kind endeavor.

PROGnostic RolE of strain measurements in stress cardiac MRI in predicting major adverse cardiac events.

OBJECTIVES: We aimed to investigate the role of feature-tracking (FT) strain in long-term risk stratification of patients with known or suspected coronary artery disease (CAD) who underwent stress cardiac MRI with dipyridamole; to determine if contrast-free stress cardiac MRI with strain measurements could provide comparable prognostic value to myocardial perfusion. MATERIALS AND METHODS: This retrospective study included consecutive patients with stable symptoms suggesting possible cardiac ischemia who underwent stress cardiac MRI with dipyridamole. The mean follow-up period was 5.8 years ±1.2 [SD]. FT cardiac MRI analysis was performed for each patient to obtain 2D global peak circumferential strain (GCS). The primary outcome measure was major adverse cardiac events (MACE), defined as nonfatal myocardial infarction and cardiac death. RESULTS: A total of 729 patients (mean age, 63 years ±10 [SD]; 616 males) were included. MACE occurred in 70 (9.6%) patients. The presence of late gadolinium enhancement (LGE) ([HR] 2.74, [95% CI: 1.53, 4.88]; P < .001) and stress GCS (HR, 1.06 [95% CI: 1.01, 1.12]; P = .016) were independently associated with MACE. A model based on contrast-free assessment of LVEF and stress GCS showed similar performance for predicting MACE than LVEF and perfusion (P = .056). CONCLUSIONS: In patients with known or suspected CAD undergoing stress cardiac MRI with dipyridamole, GCS and LGE presence were independent predictors of MACE. Contrast-free stress cardiac MRI with stress GCS measurement offered prognostic value akin to myocardial perfusion assessment. CLINICAL RELEVANCE STATEMENT: Stress global circumferential strain represented an additional method to predict major adverse cardiac events in patients undergoing stress cardiac MRI, even without the use of contrast agents. This would be of particular significance in patients with severe renal impairment.

Identification of ATP-Competitive Human CMG Helicase Inhibitors for Cancer Intervention that Disrupt CMG-Replisome Function.

The human CMG helicase (Cdc45-MCM-GINS) is a novel target for anti-cancer therapy. Tumor-specific weaknesses in the CMG are caused by oncogene-driven changes that adversely affect CMG function, and a requirement for CMG activity during recovery from replicative stresses such as chemotherapy. Here, we developed an orthogonal biochemical screening approach and identified CMG inhibitors (CMGi) that inhibit ATPase and helicase activities in an ATP-competitive manner at low micromolar concentrations. Structure-activity information, in silico docking, and testing with synthetic chemical compounds indicate that CMGi require specific chemical elements and occupy ATP binding sites and channels within MCM subunits leading to the ATP clefts, which are likely used for ATP/ADP ingress or egress. CMGi are therefore also MCM complex inhibitors (MCMi). Biological testing shows that CMGi/MCMi inhibit cell growth and DNA replication using multiple molecular mechanisms distinct from other chemotherapy agents. CMGi/MCMi block helicase assembly steps that require ATP binding/hydrolysis by the MCM complex, specifically MCM ring assembly on DNA and GINS recruitment to DNA-loaded MCM hexamers. During S-phase, inhibition of MCM ATP binding/hydrolysis by CMGi/MCMi causes a 'reverse allosteric' dissociation of Cdc45/GINS from the CMG that destabilizes replisome components Ctf4, Mcm10, and DNA polymerase-a, -d, -e, resulting in DNA damage. CMGi/MCMi display selective toxicity toward multiple solid tumor cell types with K-Ras mutations, targeting the CMG and inducing DNA damage, Parp cleavage, and loss of viability. This new class of CMGi/MCMi provides a basis for small chemical development of CMG helicase-targeted anti-cancer compounds with distinct mechanisms of action.

Identification of risk factors of Long COVID and predictive modeling in the RECOVER EHR cohorts.

BACKGROUND: SARS-CoV-2-infected patients may develop new conditions in the period after the acute infection. These conditions, the post-acute sequelae of SARS-CoV-2 infection (PASC, or Long COVID), involve a diverse set of organ systems. Limited studies have investigated the predictability of Long COVID development and its associated risk factors. METHODS: In this retrospective cohort study, we used electronic healthcare records from two large-scale PCORnet clinical research networks, INSIGHT (~1.4 million patients from New York) and OneFlorida+ (~0.7 million patients from Florida), to identify factors associated with having Long COVID, and to develop machine learning-based models for predicting Long COVID development. Both SARS-CoV-2-infected and non-infected adults were analysed during the period of March 2020 to November 2021. Factors associated with Long COVID risk were identified by removing background associations and correcting for multiple tests. RESULTS: We observed complex association patterns between baseline factors and a variety of Long COVID conditions, and we highlight that severe acute SARS-CoV-2 infection, being underweight, and having baseline comorbidities (e.g., cancer and cirrhosis) are likely associated with increased risk of developing Long COVID. Several Long COVID conditions, e.g., dementia, malnutrition, chronic obstructive pulmonary disease, heart failure, PASC diagnosis U099, and acute kidney failure are well predicted (C-index > 0.8). Moderately predictable conditions include atelectasis, pulmonary embolism, diabetes, pulmonary fibrosis, and thromboembolic disease (C-index 0.7-0.8). Less predictable conditions include fatigue, anxiety, sleep disorders, and depression (C-index around 0.6). CONCLUSIONS: This observational study suggests that association patterns between investigated factors and Long COVID are complex, and the predictability of different Long COVID conditions varies. However, machine learning-based predictive models can help in identifying patients who are at risk of developing a variety of Long COVID conditions.

Most people who develop COVID-19 make a full recovery, but some go on to develop post-acute sequelae of SARS-CoV-2 infection, commonly known as Long COVID. Up to now, we did not know why some people are affected by Long COVID whilst others are not. We conducted a study to identify risk factors for Long COVID and developed a mathematical modeling approach to predict those at risk. We find that Long COVID is associated with some factors such as experiencing severe acute COVID-19, being underweight, and having conditions including cancer or cirrhosis. Due to the wide variety of symptoms defined as Long COVID, it may be challenging to come up with a set of risk factors that can predict the whole spectrum of Long COVID. However, our approach could be used to predict a variety of Long COVID conditions.

Detection of human papillomavirus (HPV) in malignant melanoma.

The most common type of melanoma is cutaneous melanoma (CM). The predominant mutational signature is that of ultraviolet radiation (UVR) exposure. The Cancer Genome Atlas (TCGA) molecular classification includes four major subtypes of CM based on common genetic alterations involving the following genes: BRAF, NRAS, and NF1, with a small fraction being "triple" wild-type. The two main signaling pathway abnormalities in CM are the mitogen-activated protein kinase (MAPK) pathway and the phosphoinositol-3-kinase (PI3K) pathway. Other less common types include mucosal melanomas (MM) and uveal melanoma (UM), which have a significantly different genomic landscape. Although few studies reported rare cases with HPV-positive (HPV+) melanoma, the clinicopathological and molecular characteristic of this entity has not been well-described. Among the 2084 melanoma cases queried at our institution, we identified seven patients diagnosed with HPV+ melanoma (prevalence 0.03 %), including five instances of CM and two of MM. The majority of cases were positive for HPV16 (n = 6). Most of the patients were elderly and with advanced disease (n = 6), although this finding may be attributed to the relative frequency of our institution testing advanced-stage tumors. Histologically, most cases showed high degree of pleomorphism and high mitotic count (5 or more mitoses/mm2) (n = 6). UVR signature was present in the CM, but not in the MM cases. Alterations in either MAPK and/or PI3K pathways were detected in the majority of cases (n = 6). The most common genetic abnormalities detected in this study occurred in the TERT promoter (TERTp) (n = 5), a finding that has been reported to be associated with aggressive disease. Our data shows that while HPV+ melanoma is rare, identifying this disease entity could help guide therapy given the demonstrated genomic alterations.

High Prevalence and Broad Distribution of Trichomonas gypaetinii in Bald Eagles (Haliaceetus leucocephalus) in the USA.

Trichomonas gypaetinii was detected in 117 (88%) of 133 Bald Eagles (Haliaceetus leucocephalus) and in 0 of 7 Golden Eagles (Aquila chrysaetos) in the USA, with no sex or age prevalence difference. All eagles lacked associated lesions. This study indicated that T. gypaetinii is common and widespread in Bald Eagles, but rarely associated with disease.

The genome sequence of a false flower beetle, Anaspis maculata (Geoffroy in Fourcroy, 1785).

We present a genome assembly from an individual female Anaspis maculata (false flower beetle; Arthropoda; Insecta; Coleoptera; Scraptiidae). The genome sequence is 757.8 megabases in span. Most of the assembly is scaffolded into 8 chromosomal pseudomolecules, including the X sex chromosome. The mitochondrial genome has also been assembled and is 16.31 kilobases in length. Gene annotation of this assembly on Ensembl identified 21,965 protein coding genes.

Comparative pharmacokinetics of a single oral dose of meloxicam in the California sea lion (Zalophus californianus) and Pacific harbor seal (Phoca vitulina richardii).

Pharmacokinetics studies have investigated meloxicam, a non-steroidal anti-inflammatory drug, dosing strategies in a wide variety of non-domestic animals; however, there is no prior study examining well-founded dosing for pinnipeds. To develop dosing protocols, pharmacokinetic information is needed, with an examination of differences between pinniped species. Apparently, healthy California sea lions (Zalophus californianus: CSL; n = 13) and Pacific harbor seals (Phoca vitulina richardii: PHS; n = 17) that had completed rehabilitation were enrolled into a population-based pharmacokinetic study. Each animal was administered a single oral dose of meloxicam at 0.1 mg/kg, and two blood samples were collected from each animal at varying intervals during a 96-h study period. Plasma concentrations of meloxicam were determined by high-pressure liquid chromatography. Data were analyzed with nonlinear mixed effects modeling (Phoenix® NLME™, Certara, St. Louis, MO 63105, USA). The results indicated that in PHS, peak plasma concentration (Cmax) was 0.33 µg/mL with an elimination half-life (Ke t½) of 31.53 h. In CSL, Cmax was 0.17 µg/mL with Ke t½ of 32.71 h. All animals enrolled completed the study without outward adverse clinical signs. The elimination half-life was longer than previously recommended dosing intervals for pinnipeds; however, we cannot speculate in the optimum clinical dose from these results.

Sarcoidosis versus Granulomatous and Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency: A Comparative Review.

Sarcoidosis and Granulomatous and Lymphocytic Interstitial Lung Diseases (GLILD) are two rare entities primarily characterised by the development of Interstitial Lung Disease (ILD) in the context of systemic immune dysregulation. These two conditions partially share the immunological background and pathologic findings, with granuloma as the main common feature. In this narrative review, we performed a careful comparison between sarcoidosis and GLILD, with an overview of their main similarities and differences, starting from a clinical perspective and ending with a deeper look at the immunopathogenesis and possible target therapies. Sarcoidosis occurs in immunocompetent individuals, whereas GLILD occurs in patients affected by common variable immunodeficiency (CVID). Moreover, peculiar extrapulmonary manifestations and radiological and histological features may help distinguish the two diseases. Despite that, common pathogenetic pathways have been suggested and both these disorders can cause progressive impairment of lung function and variable systemic granulomatous and non-granulomatous complications, leading to significant morbidity, reduced quality of life, and survival. Due to the rarity of these conditions and the extreme clinical variability, there are still many open questions concerning their pathogenesis, natural history, and optimal management. However, if studied in parallel, these two entities might benefit from each other, leading to a better understanding of their pathogenesis and to more tailored treatment approaches.

Differential gene expression and chromatin accessibility in the medial prefrontal cortex associated with individual differences in rat behavioral models of opioid use disorder.

Opioid use disorder (OUD) is a neuropsychological disease that has a devastating impact on public health. Substantial individual differences in vulnerability exist, the neurobiological substrates of which remain unclear. To address this question, we investigated genome-wide gene transcription (RNA-seq) and chromatin accessibility (ATAC-seq) in the medial prefrontal cortex (mPFC) of male and female rats exhibiting differential vulnerability in behavioral paradigms modeling different phases of OUD: Withdrawal-Induced Anhedonia (WIA), Demand, and Reinstatement. Ingenuity Pathway Analysis (IPA) of RNA-seq revealed greater changes in canonical pathways in Resilient (vs. Saline) rats in comparison to Vulnerable (vs. Saline) rats across 3 paradigms, suggesting brain adaptations that might contribute to resilience to OUD across its trajectory. Analyses of gene networks and upstream regulators implicated processes involved in oligodendrocyte maturation and myelination in WIA, neuroinflammation in Demand, and metabolism in Reinstatement. Motif analysis of ATAC-seq showed changes in chromatin accessibility to a small set of transcription factor (TF) binding sites as a function either of opioid exposure (i.e., morphine versus saline) generally or of individual vulnerability specifically. Some of these were shared across the 3 paradigms and others were unique to each. In conclusion, we have identified changes in biological pathways, TFs, and their binding motifs that vary with paradigm and OUD vulnerability. These findings point to the involvement of distinct transcriptional and epigenetic mechanisms in response to opioid exposure, vulnerability to OUD, and different stages of the disorder.