Prioritization of Psychopathological Symptoms and Clinical Characterization in Psychiatric Diagnoses: A Narrative Review.

Importance: Psychiatry mainly deals with conditions that are mediated by brain function but are not directly attributable to specific brain abnormalities. Given the lack of concrete biological markers, such as laboratory tests or imaging results, the development of diagnostic systems is difficult. Observations: This narrative review evaluated 9 diagnostic approaches. The validity of the DSM and the International Classification of Disorders (ICD) is limited. The Research Domain Criteria is a research framework, not a diagnostic system. The clinical utility of the quantitatively derived, dimensional Hierarchical Taxonomy of Psychopathology is questionable. The Psychodynamic Diagnostic Manual Version 2 follows psychoanalytic theory and focuses on personality. Unlike the personality assessments in ICD-11 or DSM-5's alternative model, based on pathological extremes of the big 5 traits (extraversion, agreeableness, openness, conscientiousness, and neuroticism), it lacks foundation in empirical evidence. Network analytic approaches are intriguing, but their complexity makes them difficult to implement. Staging would be easier if individually predictive biological markers were available. The problem with all these new approaches is that they abstract patient experiences into higher-order constructs, potentially obscuring individual symptoms so much that they no longer reflect patients' actual problems. Conclusions and Relevance: ICD and DSM diagnoses can be questioned, but the reality of psychopathological symptoms, such as hallucinations, depression, anxiety, compulsions, and the suffering stemming from them, cannot. Therefore, it may be advisable to primarily describe patients according to the psychopathological symptoms they present, and any resulting personal syndromes, embedded in a framework of contextual clinical characterization including personality assessment and staging. The DSM and ICD are necessary for reimbursement, but they should be simplified and merged. A primarily psychopathological symptoms-based, clinical characterization approach would be multidimensional and clinically useful, because it would lead to problem-oriented treatment and support transdiagnostic research. It should be based on a universally used instrument to assess psychopathology and structured clinical characterization.

HPV-YAP1 oncogenic alliance drives malignant transformation of fallopian tube epithelial cells.

High grade serous ovarian carcinoma (HGSOC) is the most common and aggressive ovarian malignancy. Accumulating evidence indicates that HGSOC may originate from human fallopian tube epithelial cells (FTECs), although the exact pathogen(s) and/or molecular mechanism underlying the malignant transformation of FTECs is unclear. Here we show that human papillomavirus (HPV), which could reach FTECs via retrograde menstruation or sperm-carrying, interacts with the yes-associated protein 1 (YAP1) to drive the malignant transformation of FTECs. HPV prevents FTECs from natural replicative and YAP1-induced senescence, thereby promoting YAP1-induced malignant transformation of FTECs. HPV also stimulates proliferation and drives metastasis of YAP1-transformed FTECs. YAP1, in turn, stimulates the expression of the putative HPV receptors and suppresses the innate immune system to facilitate HPV acquisition. These findings provide critical clues for developing new strategies to prevent and treat HGSOC.

Population Pharmacokinetics of Casirivimab and Imdevimab in Pediatric and Adult Non-Infected Individuals, Pediatric and Adult Ambulatory or Hospitalized Patients or Household Contacts of Patients Infected with SARS-COV-2.

INTRODUCTION: Casirivimab (CAS) and imdevimab (IMD) are two fully human monoclonal antibodies that bind different epitopes on the receptor binding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and block host receptor interactions. CAS + IMD and was developed for the treatment and prevention of SARS-CoV-2 infections. METHODS: A population pharmacokinetic (PopPK) analysis was conducted using pooled data from 7598 individuals from seven clinical studies to simultaneously fit concentration-time data of CAS and IMD and investigate selected covariates as sources of variability in PK parameters. The dataset comprised CAS + IMD-treated pediatric and adult non-infected individuals, ambulatory or hospitalized patients infected with SARS-CoV-2, or household contacts of patients infected with SARS-CoV-2. RESULTS: CAS and IMD concentration-time data were both appropriately described simultaneously by a two-compartment model with first-order absorption following subcutaneous dose administration and first-order elimination. Clearance estimates of CAS and IMD were 0.193 and 0.236 L/day, respectively. Central volume of distribution estimates were 3.92 and 3.82 L, respectively. Among the covariates identified as significant, body weight and serum albumin had the largest impact (20-34%, and ~ 7-31% change in exposures at extremes, respectively), while all other covariates resulted in small differences in exposures. Application of the PopPK model included simulations to support dose recommendations in pediatrics based on comparable exposures of CAS and IMD between different weight groups in pediatrics and adults following weight-based dosing regimens. CONCLUSIONS: This analysis provided important insights to characterize CAS and IMD PK simultaneously in a diverse patient population and informed pediatric dose selection.

Adolescent exposure to a mixture of per- and polyfluoroalkyl substances (PFAS) depletes the ovarian reserve, increases ovarian fibrosis, and alters the hippo pathway in adult female mice.

Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals known for their environmental persistence and resistance to biodegradation. This study investigated the impact of adolescent exposure to a PFAS mixture on adult ovarian function. Female CD-1 mice were orally exposed to vehicle control or a PFAS mixture (comprised of perfluorooctanoic acid [PFOA], perfluorooctanesulfonic acid [PFOS], undecafluoro-2-methyl-3-oxahexanoic acid [GenX/HFPO-DA], and perfluorobutanesulfonic acid [PFBS]) for 15 days. After a 42-day recovery period, reproductive hormones, ovarian fibrosis, and ovarian gene and protein expression were analyzed using ELISA, Picrosirius red (PSR) staining, qPCR, and immunoblotting, respectively. Results revealed that PFAS exposure did not affect adult body or organ weight, although ovarian weight slightly decreased. PFAS exposed mice exhibited a disturbed estrous cycle, with less time spent in proestrus than control mice. Follicle counting indicated a reduction in primordial and primary follicles. Serum analysis revealed no changes in steroid hormones, follicle-stimulating hormone, or anti-Müllerian hormone, but a significant increase in luteinizing hormone was observed in PFAS-treated mice. Ovaries collected from PFAS treated mice had increased mRNA transcripts for steroidogenic enzymes and fatty acid synthesis-related genes. PFAS exposure also increased collagen content in the ovary. Additionally, serum tumor necrosis factor-α levels were higher in PFAS treated mice. Finally, transcripts and protein abundance for Hippo pathway components were upregulated in the ovaries of the PFAS treated mice. Overall, these findings suggest that adolescent exposure to PFAS can disrupt ovarian function in adulthood.

Proton therapy toxicity outcomes for localized prostate cancer: Long-term results at a comprehensive cancer center.

Background: Proton therapy (PT) has unique biologic properties with excellent clinical outcomes for the management of localized prostate cancer. Here, we aim to characterize the toxicity of PT for patients with localized prostate cancer and propose mitigation strategies using a large institutional database. Methods: We reviewed medical records of 2772 patients with localized prostate cancer treated with definitive PT between May 2006 through January 2020. Disease risk was stratified according to National Comprehensive Cancer Network guidelines as low [LR, n = 640]; favorable-intermediate [F-IR, n = 849]; unfavorable-intermediate [U-IR, n = 851]; high [HR, n = 315]; or very high [VHR, n = 117]. Descriptive statistics and Kaplan-Meier estimates assessed toxicity and freedom from biochemical relapse (FFBR). Results: Median follow-up was 7.0 years. The median dose was 78 Gy(RBE)(range: 72-79.2 Gy) in 2.0 Gy(RBE) fractions; 63 % of patients received 78 Gy(RBE) in 39 fractions, and 29 % received 76 Gy(RBE) in 38 fractions. Overall rates of late grade ≥3 GU and GI toxicity were 0.87 % and 1.01 %, respectively. Two patients developed grade 4 late GU toxicity and seven patients with grade 4 late GI toxicity. All patients experiencing severe late grade 4 toxicities were treated to 78 Gy(RBE) in 39 fractions with 80 Gy(RBE) dose to the anterior rectal wall and/or bladder neck. The 10-year FFBR rates for patients with LR to U-IR disease were compared between those treated with 76 and 78 Gy(RBE); the rates were 94.5 % (95 % confidence interval [CI] 92.4-96.0 %) and 93.2 % (95 % CI 91.3-95.7 %), respectively (log-rank p = 0.22). Conclusions: Proton therapy is associated with low rates of late grade ≥3 GU and GI toxicity. While rare, late grade 4 toxicities occurred in nine (0.3 %) patients. De-escalation to a total dose of 76 Gy(RBE) yields excellent clinical outcomes for patients with LR to U-IR disease with the potential for significant reductions in grade ≥3 late toxicity.

Gut Microbiome Wellness Index 2 enhances health status prediction from gut microbiome taxonomic profiles.

Recent advancements in translational gut microbiome research have revealed its crucial role in shaping predictive healthcare applications. Herein, we introduce the Gut Microbiome Wellness Index 2 (GMWI2), an enhanced version of our original GMWI prototype, designed as a standardized disease-agnostic health status indicator based on gut microbiome taxonomic profiles. Our analysis involves pooling existing 8069 stool shotgun metagenomes from 54 published studies across a global demographic landscape (spanning 26 countries and six continents) to identify gut taxonomic signals linked to disease presence or absence. GMWI2 achieves a cross-validation balanced accuracy of 80% in distinguishing healthy (no disease) from non-healthy (diseased) individuals and surpasses 90% accuracy for samples with higher confidence (i.e., outside the "reject option"). This performance exceeds that of the original GMWI model and traditional species-level α-diversity indices, indicating a more robust gut microbiome signature for differentiating between healthy and non-healthy phenotypes across multiple diseases. When assessed through inter-study validation and external validation cohorts, GMWI2 maintains an average accuracy of nearly 75%. Furthermore, by reevaluating previously published datasets, GMWI2 offers new insights into the effects of diet, antibiotic exposure, and fecal microbiota transplantation on gut health. Available as an open-source command-line tool, GMWI2 represents a timely, pivotal resource for evaluating health using an individual's unique gut microbial composition.

Dupilumab: Mechanism of action, clinical, and translational science.

Allergic disease prevalence has increased globally with the subset of type 2 inflammatory diseases playing a substantial role. Type 2 inflammatory diseases may differ in clinical presentation, but they exhibit shared pathophysiology that is targeted by the unique pharmacology of dupilumab. Dupilumab binds to the interleukin (IL)-4 receptor alpha subunit (IL-4Rα) that blocks IL-4 and IL-13 signaling, two key drivers of type 2 inflammation. Herein, we review the mechanism of action and pharmacology of dupilumab, and the clinical evidence that led to the regulatory approvals of dupilumab for the treatment of numerous type 2 inflammatory diseases: atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis, eosinophilic esophagitis, and prurigo nodularis.

Leveraging technology to improve access to medical education in anatomy and physiology in resource-limited settings: A mixed methods study.

This study assesses the acceptability, appropriateness, feasibility, and efficacy of a novel asynchronous video-based intervention for teaching respiratory physiology and anatomy to medical students in resource-limited settings. A series of short video lectures on pleural anatomy, pulmonary physiology, and pathophysiology was created using Lightboard and screen capture technology. These were uploaded to YouTube and Google Drive and made available to 1st-3rd year medical students at two Latin American universities for 1 week. Employing a parallel-convergent mixed methods design, we conducted surveys, focus groups, interviews, and pre/post testing for qualitative and quantitative data. Thematic Analysis was used to analyze qualitative data and McNemar's test for quantitative analysis. Seventy-six students participated. The videos' short format, interactivity, and Lightboard style were highly valued for their flexibility, time efficiency, and educational impact. Students recognized their clinical relevance and trusted their content, suggesting potential applicability in similar settings. Despite infrastructure and connectivity challenges, the use of flexible streaming and downloadable options facilitated learning. Survey results indicated high levels of feasibility (99%), appropriateness (95%), and acceptability (95%), with significant knowledge gains observed (37% correct pre-test answers vs. 56% post-test, p < 0.0001). Our findings demonstrate high acceptability, appropriateness, feasibility, and efficacy of a targeted asynchronous education centered on short-format videos in resource-limited settings, enabling robust learning despite local barriers. Flexible access is key for overcoming localized barriers. Taking an adaptive, learner-centered approach to content creation and delivery to address constraints was pivotal to success. Our modular videos could serve as versatile models for flexible education in resource-constrained settings.

Validation of Different Dementia Code-Based Definitions in a Population-Based Study of Rheumatoid Arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) has been associated with an elevated dementia risk. This study aimed to examine how different diagnostic dementia definitions perform in patients with RA compared to individuals without RA. METHODS: The study population included 2050 individuals (1025 with RA) from a retrospective, population-based cohort in southern Minnesota and compared the performance of 3 code-based dementia diagnostic algorithms with medical record review diagnosis of dementia. For the overall comparison, each patient's complete medical history was used, with no time frames. Sensitivity analyses were performed using 1-, 2-, and 5-year windows around the date that dementia was identified in the medical record (reference standard). RESULTS: Algorithms performed very similarly in persons with and without RA. The algorithms generally had high specificity, negative predictive values, and accuracy, regardless of the time window studied (> 88%). Sensitivity and positive predictive values varied depending on the algorithm and the time window. Sensitivity values ranged 56.5-95.9%, and positive predictive values ranged 55.2-83.1%. Performance measures declined with more restrictive time windows. CONCLUSION: Routinely collected electronic health record (EHR) data were used to define code-based dementia diagnostic algorithms with good performance (vs diagnosis by medical record review). These results can inform future studies that use retrospective databases, especially in the same or a similar EHR infrastructure, to identify dementia in individuals with RA.

Bicarbonate and Serum Lab Markers as Predictors of Mortality in the Trauma Patient.

Introduction: Severe trauma-induced blood loss can lead to metabolic acidosis, shock, and death. Identification of abnormalities in the bicarbonate and serum markers may be seen before frank changes in vital signs in the hemorrhaging trauma patient, allowing for earlier lifesaving interventions. In this study the author aimed to evaluate the usefulness of serum bicarbonate and other lab markers as predictors of mortality in trauma patients within 30 days after injury. Methods: This retrospective, propensity-matched cohort study used the TriNetX database, covering approximately 92 million patients from 55 healthcare organizations in the United States, including 3.8 million trauma patients in the last two decades. Trauma patients were included if they had lab measurements available the day of the event. The analysis focused on mortality within 30 days post-trauma in comparison to measured lab markers. Cohorts were formed based on ranges of bicarbonate, lactate, and base excess levels. Results: Before propensity score matching, a total of 1,275,363 trauma patients with same-day bicarbonate, lactate, or base excess labs were identified. A significant difference in mortality was found across various serum bicarbonate lab ranges compared to the standard range of 21-27 milliequivalents per liter (mEq/L), post-propensity score matching. The relative risk of death was 6.806 for bicarbonate ≤5 mEq/L; 8.651 for 6-10; 6.746 for 11-15; 2.822 for 16-20; and 1.015 for bicarbonate ≥28. Serum lactate also displayed significant mortality outcomes when compared to a normal level of ≤2 millimoles per liter. Base excess showed similar significant correlation at different values compared to a normal base excess of -2 to 2 mEq/L. Conclusion: This study, approximately 100 times larger than prior studies, associated lower bicarbonate levels with increased mortality in the trauma patient. While lactate and base excess offer prognostic value, lower bicarbonate values have a higher relative risk of death. The greater predictive value of bicarbonate and accessibility during resuscitations suggests that it may be the superior prognostic marker in trauma.

Characterization of m6A Modifiers and RNA Modifications in Uterine Fibroids.

Uterine leiomyoma or fibroids are prevalent noncancerous tumors of the uterine muscle layer, yet their origin and development remain poorly understood. We analyzed RNA expression profiles of 15 epigenetic mediators in uterine fibroids compared to myometrium using publicly available RNA sequencing (RNA-seq) data. To validate our findings, we performed RT-qPCR on a separate cohort of uterine fibroids targeting these modifiers confirming our RNA-seq data. We then examined protein profiles of key N6-methyladenosine (m6A) modifiers in fibroids and their matched myometrium, showing no significant differences in concordance with our RNA expression profiles. To determine RNA modification abundance, mRNA and small RNA from fibroids and matched myometrium were analyzed by ultra-high performance liquid chromatography-mass spectrometry identifying prevalent m6A and 11 other known modifiers. However, no aberrant expression in fibroids was detected. We then mined a previously published dataset and identified differential expression of m6A modifiers that were specific to fibroid genetic subtype. Our analysis also identified m6A consensus motifs on genes previously identified to be dysregulated in uterine fibroids. Overall, using state-of-the-art mass spectrometry, RNA expression, and protein profiles, we characterized and identified differentially expressed m6A modifiers in relation to driver mutations. Despite the use of several different approaches, we identified limited differential expression of RNA modifiers and associated modifications in uterine fibroids. However, considering the highly heterogenous genomic and cellular nature of fibroids, and the possible contribution of single molecule m6A modifications to fibroid pathology, there is a need for greater in-depth characterization of m6A marks and modifiers in a larger and diverse patient cohort.

Relationship of cognitive measures to mRNA levels in lymphocytes from patients with schizophrenia and controls.

Patients with schizophrenia show substantial cognitive deficits and abnormalities in neurotransmitter-related levels of mRNA in brain or peripheral blood lymphocytes. However, the relationship of cognitive deficits as measured by the MATRICS battery and mRNA levels in brain or lymphocytes has not been sufficiently explored. We measured levels of methylation or neurotransmitter-related mRNAs in lymphocytes of 38 patients with chronic schizophrenia (CSZ) and 33 non-psychotic controls (controls) by qPCR using TaqMan probes. We assessed cognitive function in these patients and controls with the MATRICS battery. We used correlation analysis and scatter plots to assess the relationship of lymphocyte mRNA levels to MATRICS domain and composite scores. CSZ subjects had a consistently negative correlation between mRNA levels in lymphocytes and MATRICS cognitive variables of speed of processing, attention-vigilance, working memory, visual learning, and overall composite score. It is uncertain whether these negative correlations represent a causative relation between specific mRNA levels and cognitive deficits. Controls had either positive correlations or non-significant correlations between mRNA and most of the MATRICS variables. There were statistically significant differences in the correlations between mRNA and MATRICS variables between CSZ vs controls for several mRNAs (DNMT1, DNMT3A, BDNF, NR3C1, FPRF3, CNTNAP2). Our data show a different relationship between mRNA levels in peripheral blood lymphocytes and MATRICS cognitive variables in CSZ vs controls. The substantive significance of these differences needs further investigation.

Yao syndrome: a novel systemic autoinflammatory disease with cutaneous manifestations.

Yao syndrome (YAOS) is a novel systemic autoinflammatory disease linked to the nucleotide-binding oligomerization domain (NOD2) gene. It is characterized by periodic fevers, gastrointestinal (GI) symptoms, arthritis, and dermatitis, among other symptoms. A sparse literature exists on this disease, and little is known about its dermatological manifestations. A review of available literature was performed to characterize the cutaneous manifestations of Yao syndrome. Cutaneous manifestations were documented in 85.7% of patients, with common characteristic descriptions of erythematous patches and plaques involving the face, trunk, abdomen, and extremities. Based on our review of treatment modalities employed for Yao syndrome, prednisone is an appropriate initial approach, with oral sulfasalazine and other disease-modifying antirheumatic drugs serving as appropriate secondary options. YAOS should be considered in the differential diagnosis of patients presenting with a dermatitic rash, especially in the context of concurrent articular symptoms, periodic fever, and GI symptoms.

Pharmacokinetics and pharmacodynamics of itepekimab in adults with moderate-to-severe atopic dermatitis: Results from two terminated phase II trials.

Interleukin-33 (IL-33) is a proinflammatory alarmin cytokine released by damaged epithelial tissue cells that initiates and amplifies both type 1 and type 2 inflammatory cascades. A role for IL-33 in atopic dermatitis (AD; a chronic, relapsing type 2 inflammatory disease of the skin) has been proposed. Itepekimab is a novel human IgG4P monoclonal antibody against IL-33, currently in clinical development for chronic obstructive pulmonary disease (COPD). Two global phase II studies-a dose-ranging itepekimab monotherapy study (NCT03738423) and a proof-of-concept study of itepekimab alone and in combination with dupilumab (NCT03736967)-were conducted in patients with moderate-to-severe AD to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy; both studies were terminated following an interim analysis of the proof-of-concept study, which failed to demonstrate the efficacy of itepekimab. In these two studies, itepekimab exhibited linear and dose-proportional pharmacokinetics. Pharmacodynamics of total IL-33 indicated that itepekimab saturated binding to the target in serum at 300 mg q2w and q4w doses, and decreased blood eosinophil counts. Concentration-time profiles of itepekimab and total IL-33 were similar for itepekimab with or without dupilumab, and between East Asian and non-East Asian subgroups. Itepekimab was generally well tolerated, both alone and in combination with dupilumab. The lack of clinical efficacy for itepekimab observed in these studies suggests that IL-33 may not be a key pathogenic driver in moderate-to-severe AD.

Unraveling the role of lipid droplets and perilipin 2 in bovine luteal cells.

Steroidogenic tissues contain cytosolic lipid droplets that are important for steroidogenesis. Perilipin 2 (PLIN2), a structural coat protein located on the surface of lipid droplets in mammalian cells, plays a crucial role in regulating lipid droplet formation and contributing to various cellular processes such as lipid storage and energy homeostasis. Herein, we examine the role that PLIN2 plays in regulating progesterone synthesis in the bovine corpus luteum. Utilizing gene array databases and Western blotting, we have delineated the expression pattern of PLIN2 throughout the follicular to luteal transition. Our findings reveal the presence of PLIN2 in both ovarian follicular and steroidogenic luteal cells, demonstrating an increase in its levels as follicular cells transition into the luteal phase. Moreover, the depletion of PLIN2 via siRNA enhanced progesterone production in small luteal cells, whereas adenovirus-mediated overexpression of both PLIN2 and Perilipin 3 (PLIN3) induced an increase in cytosolic lipid droplet accumulation and decreased hormone-induced progesterone synthesis in these cells. Lastly, in vivo administration of the luteolytic hormone prostaglandin F2α resulted in an upregulation of PLIN2 mRNA and protein expression, accompanied by a decline in serum progesterone. Our findings highlight the pivotal role of PLIN2 in regulating progesterone synthesis in the bovine corpus luteum, as supported by its dynamic expression pattern during the follicular to luteal transition and its responsiveness to luteotropic and luteolytic hormones. We suggest PLIN2 as a potential therapeutic target for modulating luteal function.

A phase II trial of apalutamide for intermediate-risk prostate cancer and molecular correlates.

OBJECTIVES: To determine whether 6 months of preoperative apalutamide for intermediate-risk prostate cancer (IRPCa) reduces the aggregate postoperative radiotherapy risk and to evaluate associations of molecular perturbations with clinical outcomes in this study cohort. PATIENTS AND METHODS: Between May 2018 and February 2020, eligible patients with IRPCa (Gleason 3 + 4 or 4 + 3 and clinical T2b-c or prostate-specific antigen level of 10-20 ng/mL) were treated with apalutamide 240 mg/day for 6 months followed by radical prostatectomy (RP) in this single-arm, phase II trial. The primary endpoint was presence of any adverse pathological feature at risk of pelvic radiation (pathological T stage after neoadjuvant therapy [yp]T3 or ypN1 or positive surgical margins). Translational studies, including germline and somatic DNA alterations and RNA and protein expression, were performed on post-apalutamide RP specimens, and assessed for associations with clinical outcomes. RESULTS: A total of 40 patients underwent a RP, and only one patient discontinued apalutamide prior to 6 months. In all, 40% had adverse pathological features at time of RP, and the 3-year biochemical recurrence (BCR) rate was 15%, with 27.5% being not evaluable. Genomic alterations frequently seen in metastatic PCas, such as androgen receptor (AR), tumour protein p53 (TP53), phosphatase and tensin homologue (PTEN), or BReast CAncer associated gene (BRCA1/2) were underrepresented in this localised cohort. Adverse pathological features and BCR at 3-years were associated with increased expression of select cell cycle (e.g., E2F targets: adjusted P value [Padj] < 0.001, normalised enrichment score [NES] 2.47) and oxidative phosphorylation (Padj < 0.001, NES 1.62) pathways. CONCLUSIONS: Preoperative apalutamide did not reduce the aggregate postoperative radiation risk to the pre-specified threshold in unselected men with IRPCa. However, transcriptomic analysis identified key dysregulated pathways in tumours associated with adverse pathological outcomes and BCR, which warrant future study. Further investigation of preoperative therapy is underway for men with high-risk PCa.

Whole genome-based antimicrobial resistance and virulence profiling of Staphylococcus aureus isolates from chronic leg ulcer patients in Kilimanjaro, Tanzania.

BACKGROUND: Chronic leg ulcers are hard to treat and can be a burden, particularly in resource-limited settings where diagnosis is a challenge. Staphylococcus aureus is among the common bacteria isolated from chronic wounds with a great impact on wound healing, particularly in patients with co-morbidities. Antimicrobial resistance genes and virulence factors in Staphylococcus aureus isolates were assessed to support healthcare professionals to make better therapeutic choices, and importantly to curb the development and spread of antibiotic resistance. METHODS: A cross-sectional study involved both inpatients and outpatients with chronic leg ulcers was conducted from August 2022 to April 2023 in 2 health facilities in Kilimanjaro region in Tanzania. Antimicrobial susceptibility testing was done using the disk diffusion method. Further, whole genome sequencing was performed to study the genotypic characteristics of the isolates. RESULTS: A total of 92 participants were recruited in which 9 participants were only positive for 10 Staphylococcus aureus isolates upon culture. Five STs among 9 isolates were identified. Most of them belonged to ST8 (44%), with 1 isolate does not belong to any ST. Additionally, 50% of the isolates were methicillin-resistant Staphylococcus aureus (MRSA). All S. aureus isolates had almost similar virulence factors such as hemolysin, proteases and evasions that promote toxin production, protease production and host immune evasion respectively. Moreover, all mecA positive S. aureus isolates were phenotypically susceptible to cefoxitin. CONCLUSION: Presence of mecA positive S. aureus isolates which are also phenotypically susceptible to cefoxitin implies the possibility of classifying MRSA as MSSA. This may result in the possible emergence of highly cefoxitin - resistant strains in health care and community settings when subsequently exposed to beta-lactam agents. Therefore, combination of whole genome sequencing and conventional methods is important in assessing bacterial resistance and virulence to improve management of patients.

Interferon-tau infusion into the ovine corpus luteum delays luteolysis†.

Conceptus-derived interferon-tau (IFNT) initiates maternal recognition of pregnancy in ewes by paracrine actions on the endometrium and endocrine action on the corpus luteum (CL). To examine the effect of IFNT on the CL without inducing IFN-stimulated genes (ISGs) in the endometrium, recombinant ovine IFNT (roIFNT) or bovine serum albumin was delivered directly into CLs via osmotic pumps at a rate of 10, 50, or 100 ng/h from days 9 to 12 of the estrous cycle. Endometrial and CL samples were collected on day 12. 50 ng/h of roIFNT induced ISG15 in the CL on day 12 without affecting endometrial ISG15 concentrations. In a second experiment, roIFNT (50 ng/h) was infused into the CL from days 10 to 17 of the estrous cycle and serum samples were collected daily. Serum progesterone concentrations were significantly higher from days 15 to 17 in roIFNT-infused ewes compared to controls. Levels of LHCGR, STAR, CYP11A1, HSL, OPA1, and protein kinase A mRNA and proteins were higher in the roIFNT-infused CLs compared to the controls. Levels of ISG15 and MX1 mRNA increased in the CLs of roIFNT-infused ewes but not in the endometrium. Endometrial ESR1 mRNA and protein concentrations were higher in the controls compared to roIFNT-infused ewes. In conclusion, intra-luteal delivery of roIFNT induced ISGs, stabilized steroidogenesis in the CL, and delayed luteolysis without inducing endometrial IFN-stimulated genes. Inhibition of ESR1 in the endometrium of roIFNT-infused ewes was observed suggesting that direct delivery of IFNT to the CL has an additional anti-luteolytic effect on the endometrium.

Capturing relationships between suturing sub-skills to improve automatic suturing assessment.

Suturing skill scores have demonstrated strong predictive capabilities for patient functional recovery. The suturing can be broken down into several substep components, including needle repositioning, needle entry angle, etc. Artificial intelligence (AI) systems have been explored to automate suturing skill scoring. Traditional approaches to skill assessment typically focus on evaluating individual sub-skills required for particular substeps in isolation. However, surgical procedures require the integration and coordination of multiple sub-skills to achieve successful outcomes. Significant associations among the technical sub-skill have been established by existing studies. In this paper, we propose a framework for joint skill assessment that takes into account the interconnected nature of sub-skills required in surgery. The prior known relationships among sub-skills are firstly identified. Our proposed AI system is then empowered by the prior known relationships to perform the suturing skill scoring for each sub-skill domain simultaneously. Our approach can effectively improve skill assessment performance through the prior known relationships among sub-skills. Through the proposed approach to joint skill assessment, we aspire to enhance the evaluation of surgical proficiency and ultimately improve patient outcomes in surgery.