Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma.

Immunosuppressive macrophages restrict anti-cancer immunity in glioblastoma (GBM). Here, we studied the contribution of microglia (MGs) and monocyte-derived macrophages (MDMs) to immunosuppression and mechanisms underlying their regulatory function. MDMs outnumbered MGs at late tumor stages and suppressed T cell activity. Molecular and functional analysis identified a population of glycolytic MDM expressing GLUT1 with potent immunosuppressive activity. GBM-derived factors promoted high glycolysis, lactate, and interleukin-10 (IL-10) production in MDMs. Inhibition of glycolysis or lactate production in MDMs impaired IL-10 expression and T cell suppression. Mechanistically, intracellular lactate-driven histone lactylation promoted IL-10 expression, which was required to suppress T cell activity. GLUT1 expression on MDMs was induced downstream of tumor-derived factors that activated the PERK-ATF4 axis. PERK deletion in MDM abrogated histone lactylation, led to the accumulation of intratumoral T cells and tumor growth delay, and, in combination with immunotherapy, blocked GBM progression. Thus, PERK-driven glucose metabolism promotes MDM immunosuppressive activity via histone lactylation.

Lower Range of Recurrent Instability Rates Following Bankart Repair and Remplissage Compared to Isolated Bankart Repair in Patients with "Non-Engaging/On-Track" Hill-Sachs Lesions and <20% Glenoid Bone Loss.

PURPOSE: To compare recurrent instability and return to sport rates along with external rotation differences between on-track (non-engaging) Hill-Sachs lesion patients undergoing either an isolated Bankart repair (IBR) or a Bankart repair augmented with a remplissage procedure (B+R). METHODS: A search was conducted using 3 databases (PubMed, EMBASE, CINAHL) in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. Only clinical comparative (level of evidence I-III) studies were considered for inclusion. Quality assessment was performed using the MINORS criteria. RESULTS: Six, level of evidence III studies, totaling 537 patients (202 B+R and 335 IBR) were included for analysis. All patients had <20% glenoid bone loss and a non-engaging, on-track Hill Sachs lesion. At a median final follow-up of 34.7 months, recurrent dislocation rates ranged from 0-7.7% and 3.5-30% in the B+R and IBR groups, respectively. Moreover, subjective instability and revision surgery rates presented lower ranges in the B+R upon comparison with the IBR cohort (0-32% versus 5-71.4% and 0-5% versus 0-35%, respectively). Furthermore, return to pre-injury level of sports ranged from 64-100% in the remplissage augmented group and 50-90% in the IBR cohort. Post-operative external rotation at side varied from 50-63º in the B+R and 55º-63º in the IBR arm. Additional subgroup analysis revealed recurrent dislocation rates in athletes and patients with near-track Hill-Sachs lesions undergoing remplissage augmentation to be 0-5% and 2-47% while ranging 8.8-30% and 9-66% for IBR patients, respectively. CONCLUSION: Upon qualitative analysis, ranges of recurrent instability measures including recurrent dislocation rates, are higher in patients undergoing IBR in comparison to B+R. Activity level influences outcomes as athletes were found to have a higher range of recurrent dislocation rates in the IBR group. The addition of remplissage showed a higher range of return to sport rates with comparable post-operative external rotation between groups. LEVEL OF EVIDENCE: Systematic Review of Level III studies.

Adults Have a Higher Incidence of Discoid Lateral Meniscus Tears Than Children-Adults Tend to Present With Complex Tears, While Horizontal Tear Patterns are Frequently Encountered in Children: A Systematic Review.

PURPOSE: To systematically review the available literature in patients with discoid lateral meniscus (DLM) with the goal of elucidating the rates and types of meniscal tears, clinical symptoms, treatment strategies, and postoperative clinical, and radiographic outcomes in adult patients compared with a pediatric population. METHODS: A literature search was performed using the PubMed, Embase, and Scopus databases from database inception to October 2023 according to the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Level of evidence I through IV human clinical studies evaluating rate and type of meniscal tears, clinical symptoms, patient-reported outcome measures, and postoperative radiographical assessments in patients with DLM were included. Comparisons were made by age below and above 16 years. Study quality was assessed using the Methodological Index for Non-Randomized Studies (MINORS) criteria. RESULTS: Thirteen studies comprising of 1772 adult patients (>16 years old) with DLM (n=1856 knees) and eight studies conducted in 304 pediatric patients (≤16 years old, n=353 knees) were include. The reported mean age ranged from 22.4 to 45 years (mean follow-up, 24 to 157.5 months) in the adult group and from 5 to 12.9 years (mean follow-up,37 to 234 months) in the pediatric DLM group. The majority of adult (n=553; 96.5%) and pediatric (n=163; 71.8%) patients had tears of the DLM. Complete DLM was the predominant type of DLM in both study groups (range in adults, 49.6 to 88%; range in pediatric, 19 to 100%) with complex (46.1%; range, 5.3-100%) and horizontal tears (18.2%; range, 20-37.5) being the most frequently described tear patterns in the adult and pediatric DLM groups, respectively. Pain was the predominant reported symptom in both study groups (range in adults, 12.1 to 99.3%; range in pediatrics, 32.4 to 100%). Partial meniscectomy was the most frequently reported treatment option conducted in 334 adult (39.5%; range, 24.2-100%) and 66 pediatric knees (63.5%; range, 15-100%).. Overall, improved postoperative clinical outcomes were reported in both study groups; however, radiographic progression of degenerative changes after subtotal meniscectomy was noted. CONCLUSIONS: More adult patients with DLM present with tears in the literature compared with the pediatric population. Complex and horizontal tear patterns are the most frequently reported tears in adult and pediatric patients, respectively. . Pain is the most relevant symptom in both study groups. There was generally significant improvement in postoperative clinical outcome scores; partial meniscectomy however remains the most frequently reported treatment option and is associated with fewer degenerative changes than in subtotal meniscectomy. . STUDY DESIGN: Level IV, Systematic review of Level I-IV studies.

Concomitant Treatment with Doxycycline and Rifampicin in Balb/c Mice Infected with Brucella abortus 2308 Fails to Reduce Inflammation and Motor Disability.

Brucellosis is an infection widely distributed around the world, and in some countries it is considered a public health problem. Brucellosis causes insidious symptoms that make it difficult to diagnose. Infection can also trigger chronic pain and neuropsychiatric complications. Antibiotics are not always effective to eradicate infection, contributing to chronicity. We aimed to investigate the effects of antibiotic treatment on proinflammatory cytokines, neurotransmitters, corticosterone, and behavior in a murine model of infecrion of B. abortus strain 2308. Four study groups were created: (a) control; (b) antibiotic control; (c) infected with B. abortus 2308; and (d) infected and treated with rifampicin and doxycycline. We determined B. abortus 2308 colony-forming units (CFUs), the count of dendritic cells, and macrophages in the spleen; serum levels of cytokines and corticosterone; levels of serotonin, dopamine, epinephrine, and norepinephrine in the brain; and equilibrium, physical strength, anxiety, and hopelessness tests. The infected and treated mice group was compared with the control and infected mice to assess whether treatment is sufficient to recover neuroimmunoendocrine parameters. Our results showed that despite the treatment of brucellosis with rifampicin and doxycycline, antibiotic-treated mice showed a persistence of B. abortus 2308 CFUs, an increased count in macrophage number, and higher circulating levels of corticosterone. Furthermore, the levels of IL-12, IL-6, and TNF-α remained higher. We found a decrease in muscular strength and equilibrium concomitant to changes in neurotransmitters in the hippocampus, cerebellum, and frontal cortex. Our data suggest that the remaining bacterial load after antibiotic administration favors inflammatory, neurochemical, and behavioral alterations, partly explaining the widespread and paradoxical symptomatology experienced by patients with chronic brucellosis.

Effect of Montelukast vs Placebo on Time to Sustained Recovery in Outpatients with COVID-19: The ACTIV-6 Randomized Clinical Trial.

Importance: The effect of montelukast in reducing symptom duration among outpatients with mild to moderate coronavirus disease 2019 (COVID-19) is uncertain. Objective: To assess the effectiveness of montelukast compared with placebo in treating outpatients with mild to moderate COVID-19. Design Setting and Participants: The ACTIV-6 platform randomized clinical trial aims to evaluate the effectiveness of repurposed medications in treating mild to moderate COVID-19. Between January 27, 2023, and June 23, 2023, 1250 participants ≥30 years of age with confirmed SARS-CoV-2 infection and ≥2 acute COVID-19 symptoms for ≤7 days, were included across 104 US sites to evaluate the use of montelukast. Interventions: Participants were randomized to receive montelukast 10 mg once daily or matched placebo for 14 days. Main Outcomes and Measures: The primary outcome was time to sustained recovery (defined as at least 3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of hospitalization, urgent care visit, emergency department visit, or death; COVID clinical progression scale; and difference in mean time unwell. Results: Among participants who were randomized and received study drug, the median age was 53 years (IQR 42-62), 60.2% were female, 64.6% identified as Hispanic/Latino, and 56.3% reported ≥2 doses of a SARS-CoV-2 vaccine. Among 628 participants who received montelukast and 622 who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio [HR] 1.02; 95% credible interval [CrI] 0.92-1.12; P(efficacy) = 0.63]). Unadjusted median time to sustained recovery was 10 days (95% confidence interval 10-11) in both groups. No deaths were reported and 2 hospitalizations were reported in each group; 36 participants reported healthcare utilization events (a priori defined as death, hospitalization, emergency department/urgent care visit); 18 in the montelukast group compared with 18 in the placebo group (HR 1.01; 95% CrI 0.45-1.84; P(efficacy)=0.48). Five participants experienced serious adverse events (3 with montelukast and 2 with placebo). Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with montelukast does not reduce duration of COVID-19 symptoms. Trial Registration: ClinicalTrials.gov ( NCT04885530 ).

Effects of a Nonlinear Program on Different Health Parameters in the Elderly.

BACKGROUND: The aim of this research was to evaluate the impact of a nonlinear training program on visceral adipose tissue (VAT) and systolic (SBP) and diastolic (DBP) blood pressure, as well as the response of biochemical parameters such as fasting plasma glucose (FPG), total cholesterol (TC), high-density cholesterol (HDL-C), low-density cholesterol (LDL-C), and triglycerides (TG). HYPOTHESIS: The nonlinear periodized program would produce greater improvements in outcomes than the linear periodized training program. STUDY DESIGN: Randomized cross-sectional design. LEVEL OF EVIDENCE: Level 3. METHODS: Older adults with no previous training experience (10 male and 8 female [age, 64 ± 2.1 years; height, 165.12 ± 7.5 cm; body mass, 72.5 ± 11.4 kg; body max index, 26.5 ± 3.2 kg/m2]) were randomized to linear (n = 9, TT) or undulating (n = 9, UT) periodization. After a 3-week familiarization period, all participants performed 3 sessions of resistance training per week; 8 weeks of training were conducted for each group. Dual x-ray absorptiometry was used to measure VAT, and SBP and DBP were measured using an OMRON M3 digital automatic blood pressure monitor. Blood samples were collected between 8:00 a.m. and 9:30 a.m. after 12-hour overnight fasting. RESULTS: Both interventions significantly (P < 0.05) decreased FPG, TC, LDL-C, and TG. A significant decrease in SBP and DBP was observed only in the UT group (P < 0.05). No significant between-group differences in outcomes were observed (P > 0.5). However, the effect size was marginally more pronounced for all outcomes in the UT group. CONCLUSION: An undulating periodization program was effective in improving VAT, TC, LDL-C, FPG, HDL-C, TG, and blood glucose levels in older adults. CLINICAL RELEVANCE: Resistance training can be programmed in an undulating or traditional way in older adults based on improvements in health parameters, considering adherence and individual preferences.

S100 proteins: a new frontier in fibromyalgia research.

Fibromyalgia (FM) is a chronic condition that causes widespread pain, fatigue, and other symptoms that significantly affect quality of life. The underlying mechanisms of fibromyalgia involve both the immune system and the central nervous system. It has been proposed that changes in multiple ascending and descending pathways in the central nervous system may contribute to increased pain sensitivity in individuals with this condition. Recent research has identified S100 proteins as a new area of interest in fibromyalgia studies. These proteins are a group of small molecular weight proteins involved in inflammation and various functions inside and outside of cells, and they may play a critical role in the development and progression of FM. Although S100B has been the most studied in FM patients, other studies have reported that S100A7, S100A8, S100A9, and S100A12 may also be useful as potential biomarkers or for a deeper understanding of FM pathophysiology. The potential role of S100 proteins in the pathophysiology of fibromyalgia could be mediated by RAGE and TLR4, which signal through JNK, ERK, and p38 to activate AP-1 and NF-κB and induce the release of proinflammatory cytokines, thereby producing the inflammation, fatigue, and chronic pain characteristic of fibromyalgia. To gain new perspectives on targeted therapeutic approaches, it is crucial to understand how S100 proteins could impact the pathophysiology of fibromyalgia. This review examines the potential role of S100 proteins in fibromyalgia and their impact on improving our comprehension of the condition, as well as facilitating further research on this interesting topic.

Predictive models and applicability of artificial intelligence-based approaches in drug allergy.

PURPOSE OF REVIEW: Drug allergy is responsible for a huge burden on public healthcare systems, representing in some instances a threat for patient's life. Diagnosis is complex due to the heterogeneity of clinical phenotypes and mechanisms involved, the limitations of in vitro tests, and the associated risk to in vivo tests. Predictive models, including those using recent advances in artificial intelligence, may circumvent these drawbacks, leading to an appropriate classification of patients and improving their management in clinical settings. RECENT FINDINGS: Scores and predictive models to assess drug allergy development, including patient risk stratification, are scarce and usually apply logistic regression analysis. Over recent years, different methods encompassed under the general umbrella of artificial intelligence, including machine and deep learning, and artificial neural networks, are emerging as powerful tools to provide reliable and optimal models for clinical diagnosis, prediction, and precision medicine in different types of drug allergy. SUMMARY: This review provides general concepts and current evidence supporting the potential utility of predictive models and artificial intelligence branches in drug allergy diagnosis.

CDH1 methylation analysis in invasive lobular breast carcinomas with and without gene mutation.

The proposed role of CDH1 (E-cadherin gene) methylation as a mechanism of gene inactivation in invasive lobular carcinoma (ILC) remains inconclusive. For many years, CDH1 promoter hypermethylation has been regarded as a mechanism for gene inactivation in ILC. However, this assumption has primarily relied on non-quantitative assays, which have reported CDH1 methylation frequencies ranging from 26 to 93% at CpG sites within the island region. Few studies employing quantitative methods and covering CpG island shores, regions of relatively low CpG density situated proximal to conventional promoter CpGs, have been conducted, revealing lower percentages of methylation ranging from 0 to 51%. Therefore, using the quantitative pyrosequencing method, we examined CDH1 methylation in the island region and shores in E-cadherin deficient ILC cases (15 with CDH1 mutation and 22 non-mutated), 19 cases of invasive breast carcinomas non-special type (IBC-NSTs), and five cases of usual ductal hyperplasia (UDH). Our analysis revealed CDH1 methylation frequencies ranging from 3 to 64%, with no significant increase in methylation levels in any group of ILCs (median = 12%) compared to IBC-NST (median = 15%). In addition, considering the poorly studied association between the number of tumor-infiltrating lymphocytes (TILs) and CDH1 methylation in breast cancer, we undertook a thorough analysis within our dataset. Our findings revealed a positive correlation between CDH1 methylation and the presence of TILs (r = 0.5; p-value < 0.05), shedding light on an aspect of breast cancer biology warranting further investigation. These findings challenge CDH1 methylation as a CDH1 inactivation mechanism in ILC and highlight TILs as a potential confounding factor in gene methylation.

Relationship between commonly defined metabolic health phenotypes and obesity with lung function in a working population: A cross-sectional study.

BACKGROUND: Four phenotypes relate metabolism and obesity: metabolically healthy (MHO) and unhealthy (MUO) people with obesity and metabolically healthy (MHNO) and unhealthy (MUNO) people without obesity. No studies have addressed the association between these categories and lung function in the working population. OBJECTIVES: The aim was to determine the relationship of phenotypes to lung ageing as measured by lung age and its relationship to lung dysfunction. METHODS: A descriptive cross-sectional study was conducted in a working population. The outcome variable was lung function assessed by lung age. The four phenotypes of obesity and metabolic health (MHNO, MHO, MUO and MUNO) were determined using NCEP-ATP III criteria. Lung dysfunctions were classified into restrictive, obstructive, and mixed patterns. RESULTS: The mean age of the participants was 43.7 years, ranging from 18 to 67 years. Of the 1860 workers, 51.3 % were women. The prevalences found were 71.4 %, 12 %, 10.6 % and 6 % for MHNO, MUO, MHO, and MUNO, respectively. MHO (ß = 0.66; p = 0.591) was not associated with increased lung ageing compared with MHNO, but MUO (ß = 7.1; p < 0.001) and MUNO (ß = 6.6; p < 0.001) were. Concerning pulmonary dysfunctions, MUNO (OR = 1.93; p < 0.001) and MUO (OR = 2.91; p < 0.001) were found to be related to the presence of a restrictive pattern, and MUNO (OR = 2.40; p = 0.028) to the mixed pattern. CONCLUSION: The results show that metabolic abnormalities, not obesity, are responsible for premature lung ageing and, therefore, lung function decline. In our study, having obesity without metabolic abnormality was not significantly associated with the presence of dysfunctional respiratory patterns.

Childhood-Onset Non-Infectious Uveitis in the "Biologic Era". Results From Spanish Multicenter Multidisciplinary Real-World Clinical Settings.

OBJECTIVE: To characterize and describe clinical experience with childhood-onset non-infectious uveitis. STUDY DESIGN: A multicenter retrospective multidisciplinary national web-based registry of 507 patients from 21 hospitals was analyzed. Cases were grouped as immune disease-associated (IMDu), idiopathic (IDIu) or ophthalmologically distinct. Characteristics of juvenile idiopathic arthritis-associated (non-HLA-B27-related) uveitis (JIAu), IDIu, and pars planitis (PP) were compared. RESULTS: IMDu (62.3%) and JIAu (51.9%) predominated in young females; and IDIu (22.7%) and PP (13.6%) in older children, without sex imbalance. Ocular complications occurred in 45.3% of cases (posterior synechiae [28%], cataracts [16%], band keratopathy [14%], ocular hypertension [11%] and cystoid macular edema [10%]) and were associated with synthetic (86%) and biologic (65%) disease-modifying antirheumatic drug (DMARD) use. Subgroups were significantly associated (p < 0.05) with different characteristics. JIAu was typically anterior (98%), insidious (75%), in ANA-positive (69%), young females (82%) with fewer complications (31%), better visual outcomes, and later use of uveitis-effective biologics. In contrast, IDIu was characteristically anterior (87%) or panuveitic (12.1%), with acute onset (60%) and more complications at onset (59%: synechiae [31%] and cataracts [9.6%]) and less DMARD use, while PP is intermediate, and was mostly bilateral (72.5%), persistent (86.5%) and chronic (86.8%), with more complications (70%; mainly posterior segment and cataracts at last visit), impaired visual acuity at onset, and greater systemic (81.2%), subtenon (29.1%) and intravitreal (10.1%) steroid use. CONCLUSION: Prognosis of childhood uveitis has improved in the "biologic era," particularly in JIAu. Early referral and DMARD therapy may reduce steroid use and improve outcomes, especially in PP and IDIu.

Single-Stage Posterior Vomerine Ostectomy, Premaxillary Setback, Bilateral Gingivoperiosteoplasties and Primary Bilateral Cheiloplasty in Patients with Protuberant Premaxilla.

Various patients with complete bilateral cleft lip and palate present with a protruded premaxilla. Several techniques have been described for correctional repair of the projection with a plethora of unsatisfactory outcomes. This poses a challenge not only for the cleft team providing care but also for the patients and their respective families. Multiple patients suffer from residual deformities after inadequate primary repair, which increase surgical, financial, and psychological burden. Premaxillary setback with posterior vomerine ostectomy and complete bilateral cleft lip repair can promote alignment of the premaxilla with the maxillary prominences. To effectively address this challenging deformity, we describe a single-stage surgical technique that includes vomerine ostectomy posterior to the vomero-premaxillary suture, bilateral gingivoperiosteoplasties with complete bilateral cleft lip repair, and primary cleft rhinoplasty. Careful surgical planning is essential for adequate matching between the length of the protruded premaxilla and the extent of ostectomy. The described technique offers several advantages for the management of complete bilateral cleft lip with a projected premaxilla. It can be applied anywhere around the world and is most beneficial in underprivileged areas where patients suffer from restricted access to healthcare, absence of presurgical orthodontics and lack of sufficient resources.

Neuromuscular electrical stimulation for physical function maintenance during hematopoietic stem cell transplantation: Study protocol.

Hematopoietic stem cell transplantation is a common life-saving treatment for hematologic malignancies, though can lead to long-term functional impairment, fatigue, muscle atrophy, with decreased quality of life. Although traditional exercise has helped reduce these effects, it is inconsistently recommended and infrequently maintained, and most patients remain sedentary during and after treatment. There is need for alternative rehabilitation strategies, like neuromuscular electrical stimulation, that may be more amenable to the capabilities of hematopoietic stem cell transplant recipients. Patients receiving autologous HCT are being enroled in a randomized controlled trial with 1:1 (neuromuscular electrical stimulation:sham) design stratified by diagnosis and sex. Physical function, body composition, quality of life, and fatigue are assessed prior to hematopoietic stem cell transplant (prior to initiating preparatory treatment) and 24±5 days post hematopoietic stem cell transplant (Follow-up 1); physical function and quality of life are also assessed 6-months post hematopoietic stem cell transplant (Follow-up 2). The primary outcome is between-group difference in the 6-minute walk test change scores (Follow-up 1-Pre-transplant; final enrolment goal N = 23/group). We hypothesize that 1) neuromuscular electrical stimulation will attenuate hematopoietic stem cell transplant-induced adverse effects on physical function, muscle mass, quality of life, and fatigue compared to sham at Follow-up 1, and 2) Pre-transplant physical function will significantly predict fatigue and quality of life at Follow-up 2. We will also describe feasibility and acceptability of neuromuscular electrical stimulation during hematopoietic stem cell transplant. This proposal will improve rehabilitative patient care and quality of life by determining efficacy and feasibility of a currently underutilized therapeutic strategy aimed at maintaining daily function and reducing the impact of a potent and widely used cancer treatment. This trial is registered with clinicaltrials.gov (NCT04364256).

Triglyceride to HDL Cholesterol Ratio for the Identification of MASLD in Obesity: A Liver Biopsy-Based Case-Control Study.

Associations between dyslipidemia and metabolic dysfunction-associated steatotic liver disease (MASLD) have been reported. Previous studies have shown that the triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio may be a surrogate marker of MASLD, assessed by liver ultrasound. However, no studies have evaluated the utility of this ratio according to biopsy-proven MASLD and its stages. Therefore, our aim was to evaluate if the TG/HDL-C ratio allows for the identification of biopsy-proven MASLD in patients with obesity. We conducted a case-control study in 153 patients with obesity who underwent metabolic surgery and had a concomitant liver biopsy. Fifty-three patients were classified as no MASLD, 45 patients as metabolic dysfunction-associated steatotic liver-MASL, and 55 patients as metabolic dysfunction-associated steatohepatitis-MASH. A receiver operating characteristic (ROC) analysis was performed to assess the accuracy of the TG/HDL-C ratio to detect MASLD. We also compared the area under the curve (AUC) of the TG/HDL-C ratio, serum TG, and HDL-C. A higher TG/HDL-C ratio was observed among patients with MASLD, compared with patients without MASLD. No differences in the TG/HDL-C ratio were found between participants with MASL and MASH. The greatest AUC was observed for the TG/HDL-C ratio (AUC 0.747, p < 0.001) with a cut-off point of 3.7 for detecting MASLD (sensitivity = 70%; specificity = 74.5%). However, no statistically significant differences between the AUC of the TG/HDL-C ratio and TG or HDL-C were observed to detect MASLD. In conclusion, although an elevated TG/HDL-C ratio can be found in patients with MASLD, this marker did not improve the detection of MASLD in our study population, compared with either serum TG or HDL-C.

The wildcat (Felis s. silvestris) in the Mediterranean forest: sighting through photo-trapping and non-invasive hair collection for genetic purposes.

The European wildcat (Felis silvestris silvestris) is a mesocarnivore species widely distributed in Europe, from Eastern Europe to Portugal and from Scotland to Italy. Recent biogeographical studies of wildcat populations have endeavoured to assess in detail the various issues that pose a threat to this species, including hybridization with domestic cats. The use of non-invasive sampling methods supported by photo-trapping and some attractants has made it possible to gather genetic material for the detection of native wildcats in locally threatened populations, some of which live in the Iberian Peninsula. Testimonies of naturalists, hunters and farm workers led our team to choose specific areas in two large territories of Mediterranean forests where the presence of wildcats has been historically attested: the Almonte River basin and the Sierra de San Pedro Mountains. Between 2014 and 2018, non-invasive hair sampling was performed using valerian (Valeriana officinalis) as an attractant and supported by photo-trapping to guarantee the collection of genuine biological material (hair samples). The hair samples were genetically assessed by sequencing the nuclear gene IRBP (interphotoreceptor retinoid-binding protein) and the mtDNA gene ND4 (NADH dehydrogenase subunit 4). Despite the low density of wildcats, this combined protocol proved to be an applicable tool for detecting the presence of elusive wildcats and other mesocarnivore species in this remote region of southern Europe. In addition, non-invasive hair trapping contributes to the collection of genetic material from current wildcat populations. This procedure could enhance future management actions focused on collecting quality individualized biological material.

Fully automatic mpMRI analysis using deep learning predicts peritumoral glioblastoma infiltration and subsequent recurrence.

Glioblastoma (GBM) is most aggressive and common adult brain tumor. The standard treatments typically include maximal surgical resection, followed adjuvant radiotherapy and chemotherapy. However, the efficacy of these treatment is often limited, as tumor often infiltrate into the surrounding brain tissue, often extending beyond the radiologically defined margins. This infiltration contributes to the high recurrence rate and poor prognosis associated with GBM patients, necessitating advanced methods for early and accurate detection of tumor infiltration. Despite the great promise traditional supervised machine learning shows in predicting tumor infiltration beyond resectable margins, these methods are heavily reliant on expert-drawn Regions of Interest (ROIs), which are used to construct multi-variate models of different Magnetic Resonance (MR) signal characteristics associated with tumor infiltration. This process is both time consuming and resource intensive. Addressing this limitation, our study proposes a novel integration of fully automatic methods for generating ROIs with deep learning algorithms to create predictive maps of tumor infiltration. This approach uses pre-operative multi-parametric MRI (mpMRI) scans, encompassing T1, T1Gd, T2, T2-FLAIR, and ADC sequences, to fully leverage the knowledge from previously drawn ROIs. Subsequently, a patch based Convolutional Neural Network (CNN) model is trained on these automatically generated ROIs to predict areas of potential tumor infiltration. The performance of this model was evaluated using a leave-one-out cross-validation approach. Generated predictive maps binarized for comparison against post-recurrence mpMRI scans. The model demonstrates robust predictive capability, evidenced by the average cross-validated accuracy of 0.87, specificity of 0.88, and sensitivity of 0.90. Notably, the odds ratio of 8.62 indicates that regions identified as high-risk on the predictive map were significantly more likely to exhibit tumor recurrence than low-risk regions. The proposed method demonstrates that a fully automatic mpMRI analysis using deep learning can successfully predict tumor infiltration in peritumoral region for GBM patients while bypassing the intensive requirement for expert-drawn ROIs.

Distinct gut microbiota signatures associated with progression of atherosclerosis in people living with HIV.

BACKGROUND: The relationship of microbiota composition dynamics and the progression of subclinical atherosclerosis in people with HIV (PWH) remains unknown. METHODS: 96-week, prospective, longitudinal study in virologically-suppressed PWH. Carotid intima-media thickness (cIMT) measurements and stool samples were obtained at baseline, 48-week and 96-week visits. cIMT progression was defined as an increase >10% and/or detection of new carotid plaque. To profile the gut microbiome, amplification and sequencing of 16S ribosomal-RNA (V3-V4 variable regions) were carried out following the Illumina protocol. Sequencing was performed with MiSeq platform. RESULTS: 191, 190 and 167 patients had available fecal samples for microbiome analysis at the baseline, 48- and 96-week visits, respectively. 87 (43%) participants showed atherosclerosis progression, and 54 (26.7%) presented new carotid plaque. No significant differences were observed in adjusted α-diversity indices between groups defined by cIMT progression. Beta-diversity determined through principal coordinate analysis distances showed that the groups exhibited distinct microbial profiles (PERMANOVA p-value = 0.03). Longitudinal analysis with ANCOM-BC2 adjusted for traditional cardiovascular risk factors, MSM and nadir CD4 count revealed that cIMT progression was consistently associated with Agathobacter and Ruminococcus_2, while non-progression was consistently associated with Prevotella_7. CONCLUSION: Progression of atherosclerosis in PWH might be associated with distinctive signatures in the gut microbiota.

Effectiveness of mRNA booster doses in preventing infections and hospitalizations due to SARS-CoV-2 and its dominant variant over time in Valencian healthcare workers, Spain.

OBJECTIVE: This study aimed to evaluate the effectiveness of SARS-CoV-2 mRNA vaccines in preventing infection and hospitalization among healthcare workers (HCWs) in the Valencian Community (Spain), considering vaccination timing, dose number, and predominant variant. METHODS: A test-negative case-control design estimated vaccine effectiveness against symptomatic disease and hospitalization due to SARS-CoV-2. HCWs who underwent PCR or antigen testing for SARS-CoV-2 from January 2021 to March 2022 were included. Cases had a positive diagnostic test, while controls had negative tests. Adjusted vaccine effectiveness (aVE) was calculated using the formula: aVE = (1 - Odds ratio) × 100. RESULTS: During the Delta variant's predominance, aVE against infection within 12-120 days post-second dose was 64.8 % (BNT162b2) and 59.4 % (mRNA-1273), declining to 21.2 % and 42.2 %, respectively, after 120 days. For the Omicron variant, aVE within 12-120 days post-second dose was 61.1 % (BNT162b2) and 85.1 % (mRNA-1273), decreasing to 36.7 % and 24.9 %, respectively, after 120 days. After a booster dose of mRNA-1273, aVE was 64.0 % (BNT162b2 recipients) and 65.9 % (initial mRNA-1273 recipients). Regardless of variant, aVE for hospitalization prevention after 2 doses was 87.0 % (BNT162b2) and 89.0 % (mRNA-1273). CONCLUSION: The administration of two doses of Moderna-mRNA-1273 against SARS-CoV-2 in HCWs proved to be highly effective in preventing infections and hospitalizations in the first 120 days after the second dose during the predominance of the Omicron variant. The decline in VE after 120 days since the administration of the second dose was significantly restored by the booster dose administration. This increase in VE was greater for the Pfizer vaccine. COVID-19 hospitalization prevention remained stable with both mRNA vaccines throughout the study period.

Features and Outcomes of Females and Males Requiring Postcardiotomy Extracorporeal Life Support.

BACKGROUND: Although cardiogenic shock requiring extracorporeal life support (ECLS) after cardiac surgery is associated with high mortality, the impact of sex on outcomes of post-cardiotomy ECLS remains unclear with conflicting results in literature. We compare patient characteristics, in-hospital outcomes, and overall survival between females and males requiring post-cardiotomy ECLS. METHODS: This retrospective, multicentre (34 centres), observational study included adults requiring post-cardiotomy ECLS between 2000 and 2020. Pre-operative, procedural, and ECLS characteristics, complications, and survival were compared between females and males. Association between sex and in-hospital survival was investigated through mixed-Cox proportional hazards models. RESULTS: This analysis included 1823 patients [females:40.8%; median age:66.0 (interquartile range:56.2-73.0 years)]. Females underwent more mitral (females:38.4%, males:33.1%, p=0.019) and tricuspid (females:18%, males:12.4%, p<0.001) valve surgery, while males had more coronary artery surgery (females:45.9%, males:52.4%, p=0.007). ECLS implantation was more common intra-operatively in females (females:64.1%, males:59.1%) and post-operatively in males (females:35.9%, males:40.9%, p=0.036). Ventricular unloading (females:25.1%, males:36.2%, p<0.001) and intra-aortic balloon pump (females: 25.8%, males:36.8%, p<0.001) were most frequently used in males. Females suffered more post-operative right ventricular failure (females:24.1%, males:19.1%, p=0.016) and limb ischemia (females:12.3%, males:8.8%, p=0.23). In-hospital mortality was 64.9% in females and 61.9% in males (p=0.199) with no differences in 5-year survival (females:20%, 95%CI:17-23; males:24%, 95%CI:21-28;p=0.069). Crude hazard ratio for in-hospital mortality in females was 1.12 (95%CI: 0.99-1.27,p=0.069) and did not change after adjustments. CONCLUSIONS: This study demonstrates that females and males requiring post-cardiotomy ECLS have different pre-operative and ECLS characteristics, as well as complications, without a statistical difference in in-hospital and 5-year survival.

The evolutionary conserved miR-137/325 tandem mediates obesity-induced hypogonadism and metabolic comorbidities by repressing hypothalamic kisspeptin.

BACKGROUND: Obesity-induced hypogonadism (OIH) is a prevalent, but often neglected condition in men, which aggravates the metabolic complications of overweight. While hypothalamic suppression of Kiss1-encoded kisspeptin has been suggested to contribute to OIH, the molecular mechanisms for such repression in obesity, and the therapeutic implications thereof, remain unknown. METHODS: A combination of bioinformatic, expression and functional analyses was implemented, assessing the role of the evolutionary-conserved miRNAs, miR-137 and miR-325, in mediating obesity-induced suppression of hypothalamic kisspeptin, as putative mechanism of central hypogonadism and metabolic comorbidities. The implications of such miR-137/325-kisspeptin interplay for therapeutic intervention in obesity were also explored using preclinical OIH models. RESULTS: MiR-137/325 repressed human KISS1 3'-UTR in-vitro and inhibited hypothalamic kisspeptin content in male rats, while miR-137/325 expression was up-regulated, and Kiss1/kisspeptin decreased, in the medio-basal hypothalamus of obese rats. Selective over-expression of miR-137 in Kiss1 neurons reduced Kiss1/ kisspeptin and partially replicated reproductive and metabolic alterations of OIH in lean mice. Conversely, interference of the repressive actions of miR-137/325 selectively on Kiss1 3'-UTR in vivo, using target-site blockers (TSB), enhanced kisspeptin content and reversed central hypogonadism in obese rats, together with improvement of glucose intolerance, insulin resistance and cardiovascular and inflammatory markers, despite persistent exposure to obesogenic diet. Reversal of OIH by TSB miR-137/325 was more effective than chronic kisspeptin or testosterone treatments in obese rats. CONCLUSIONS: Our data disclose that the miR-137/325-Kisspeptin repressive interaction is a major player in the pathogenesis of obesity-induced hypogonadism and a putative druggable target for improved management of this condition and its metabolic comorbidities in men suffering obesity. SIGNIFICANCE STATEMENT: Up to half of the men suffering obesity display also central hypogonadism, an often neglected complication of overweight that can aggravate the clinical course of obesity and its complications. The mechanisms for such obesity-induced hypogonadism remain poorly defined. We show here that the evolutionary conserved miR137/miR325 tandem centrally mediates obesity-induced hypogonadism via repression of the reproductive-stimulatory signal, kisspeptin; this may represent an amenable druggable target for improved management of hypogonadism and other metabolic complications of obesity.