Childhood Obesity, Hypothalamic Inflammation, and the Onset of Puberty: A Narrative Review.

The onset of puberty, which is under the control of the hypothalamic-pituitary-gonadal (HPG) axis, is influenced by various factors, including obesity, which has been associated with the earlier onset of puberty. Obesity-induced hypothalamic inflammation may cause premature activation of gonadotropin-releasing hormone (GnRH) neurons, resulting in the development of precocious or early puberty. Mechanisms involving phoenixin action and hypothalamic microglial cells are implicated. Furthermore, obesity induces structural and cellular brain alterations, disrupting metabolic regulation. Imaging studies reveal neuroinflammatory changes in obese individuals, impacting pubertal timing. Magnetic resonance spectroscopy enables the assessment of the brain's neurochemical composition by measuring key metabolites, highlighting potential pathways involved in neurological changes associated with obesity. In this article, we present evidence indicating a potential association among obesity, hypothalamic inflammation, and precocious puberty.

Comparison of Clinical Outcomes After Different Surgical Approaches for Lateral Epicondylitis: A Systematic Review and Meta-analysis.

Background: Lateral epicondylitis (LE) is one of the most common causes of lateral elbow pain. When nonoperative treatment fails, 1 of the 3 surgical approaches-open, percutaneous, or arthroscopic-is used. However, determining which approach has the superior clinical outcome remains controversial. Purpose: To review the outcomes of different operative modalities for LE qualitatively and quantitatively. Study Design: Systematic review; Level of evidence, 4. Methods: This review was performed and reported according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Studies published in PubMed, Medline (via EBSCO), and ScienceDirect databases that treated LE with open, percutaneous, or arthroscopic approaches with at least 12 months of follow-up were included. Study quality was assessed using the Cochrane Risk of Bias 2 tool and the Methodological Index for Non-Randomized Studies score. The primary outcome was the success rate of each operative treatment approach-open, percutaneous, and arthroscopic. Results: From an initial search result of 603 studies, 43 studies (n = 1941 elbows) were ultimately included. The arthroscopic approach had the highest success rate (91.9% [95% CI, 89.2%-94.7%]) compared with the percutaneous (91% [95% CI, 87.3%-94.6%]) and open (82.7% [95% CI, 75.6%-89.8%]) approaches for LE surgery with changes in the mean visual analog scale pain score of 5.54, 4.90, and 3.63, respectively. According to the Disabilities of the Arm, Shoulder and Hand score, the functional outcome improved in the arthroscopic group (from 54.11 to 15.47), the percutaneous group (from 44.90 to 10.47), and the open group (from 53.55 to 16.13). The overall improvement was also found in the Mayo Elbow Performance Score, the arthroscopic group (from 55.12 to 90.97), the percutaneous group (from 56.31 to 87.65), and the open group (from 64 to 93.37). Conclusion: Arthroscopic surgery had the highest rate of success and the best improvement in functional outcomes among the 3 approaches of LE surgery.

Molecular epidemiology of HIV among people who inject drugs after the HIV-outbreak in Athens, Greece: Evidence for a 'slow burn' outbreak.

BACKGROUND: New diagnoses of HIV-1 infection among people who inject drugs (PWID) in Athens, Greece, saw a significant increase in 2011 and a subsequent decline after 2013. Despite this, ongoing HIV-1 transmission persisted from 2014 to 2020 within this population. Our objective was to estimate the time of infection for PWID in Athens following the HIV-1 outbreak, explore the patterns of HIV-1 dispersal over time, and determine the duration from infection to diagnosis. METHODS: Time from HIV-1 infection to diagnosis was estimated for 844 individuals infected within 4 PWID-specific clusters and for 8 PWID infected with sub-subtype A6 diagnosed during 2010-2019. Phylogeny reconstruction was performed using the maximum-likelihood method. HIV-1 infection dates were based on molecular clock calculations. RESULTS: In total 86 of 92 (93.5%) sequences from PWID diagnosed during 2016-2019 were either related to the previously identified PWID-specific clusters (n = 81) or belonged to a new A6 cluster (n = 5). The median time between infection and diagnosis was 0.42 years during the outbreak period and 0.70 years during 2016-2019 (p < 0.001). The proportion of clustered sequences from PWID was very low at 5.3% during the pre-outbreak period (1998-2009), saw an increase to 41.7% one year before the outbreak in 2010, and consistently remained high during the whole period after 2011, spanning the post-outbreak period (2016-2019) with a range from 92.9% to 100%. CONCLUSIONS: The substantial proportion of clustered infections (93.5%) during 2016-2019 implies a persistent 'slow burn' HIV outbreak among PWID in Athens, suggesting that the outbreak was not successfully eliminated. The consistently high proportion of clustered sequences since the onset of the outbreak suggests the persistence of ongoing HIV-1 transmission attributed to injection practices. Our findings underscore the importance of targeted interventions among PWID, considering the ongoing transmission rate and prolonged time from infection to diagnosis.

Long-Term Efficacy and Safety of Direct Oral Anticoagulants at Reduced Doses in the Secondary Prevention of Venous Thromboembolism and Post-Thrombotic Syndrome.

Background: Anticoagulation for venous thromboembolism (VTE) is required for at least three to six months; however, it is advisable to extend the duration in certain cases, in which case a reduced dose of Direct Oral Anticoagulants (DOACs) may be an option. Our objective was to investigate the efficacy and safety of reduced-dose DOACs in extended anticoagulation treatment compared to full doses. Methods and Results: This retrospective single-centre study included 185 patients treated with DOACs for at least 6 months who were divided into two groups: (1) the Full Dose (FD) group (n = 113) and (2) the Reduced Dose (RD) group (n = 72), which included patients treated with Apixaban at 2.5 mg bis in die (BID) and Rivaroxaban at 10 mg once daily (OD). Post-thrombotic syndrome (PTS) and its progression were evaluated. During an overall follow-up of 48.32 ± 29.49 months, no VTE occurred, and no patients experienced major bleeding; clinically relevant non-major bleeding occurred in three patients in each group (2.7% vs. 4.2% in FD vs. RD, respectively, p = 0.57). From baseline to follow-up, the prevalence of PTS was not significantly decreased in either group (FD: 54.9% vs. 51.3%, p = 0.29; RD 51.4% vs. 44.4%, p = 0.12); conversely, the Villalta score values were significantly decreased at the last follow-up (FD: 5.51 ± 4.18 vs. 5.51 ± 4.18, p < 0.001; RD 5.49 ± 4.06 vs. 5.11 ± 3.73, p = 0.006). Conclusion: In this real-world retrospective registry, very long-term extended anticoagulant therapy with DOACs at full or reduced doses showed comparable efficacy, safety, and impact on PTS progression. Larger studies are needed.

Studies on Loading Salicylic Acid in Xerogel Films of Crosslinked Hyaluronic Acid.

During the last decades, salicylic acid (SA) and hyaluronic acid (HA) have been studied for a wide range of cosmetic and pharmaceutical applications. The current study investigated the drug loading potential of SA in HA-based crosslinked hydrogel films using a post-loading (osmosis) method of the unmedicated xerogels from saturated aqueous solutions of salicylic acid over a range of pH values. The films were characterized with Fourier-transform infra-red spectroscopy (FT-IR) and ultraviolet-visible (UV-Vis) spectrophotometry in order to elucidate the drug loading profile and the films' integrity during the loading process. Additional studies on their weight loss (%), gel fraction (%), thickness increase (%) and swelling (%) were performed. Overall, the studies showed significant film disintegration at highly acidic and basic solutions. No drug loading occurred at neutral and basic pH, possibly due to the anionic repulsion between SA and HA, whereas at, pH 2.1, the drug loading was promising and could be detected via UV-Vis analysis of the medicated solutions, with the SA concentration in the xerogel films at 28% w/w.

Allosteric PI3Kα Inhibition Overcomes On-target Resistance to Orthosteric Inhibitors Mediated by Secondary PIK3CA Mutations.

PIK3CA mutations occur in ∼8% of cancers, including ∼40% of HR-positive breast cancers, where the PI3K-alpha (PI3Kα)-selective inhibitor alpelisib is FDA approved in combination with fulvestrant. Although prior studies have identified resistance mechanisms, such as PTEN loss, clinically acquired resistance to PI3Kα inhibitors remains poorly understood. Through serial liquid biopsies and rapid autopsies in 39 patients with advanced breast cancer developing acquired resistance to PI3Kα inhibitors, we observe that 50% of patients acquire genomic alterations within the PI3K pathway, including PTEN loss and activating AKT1 mutations. Notably, although secondary PIK3CA mutations were previously reported to increase sensitivity to PI3Kα inhibitors, we identified emergent secondary resistance mutations in PIK3CA that alter the inhibitor binding pocket. Some mutations had differential effects on PI3Kα-selective versus pan-PI3K inhibitors, but resistance induced by all mutations could be overcome by the novel allosteric pan-mutant-selective PI3Kα-inhibitor RLY-2608. Together, these findings provide insights to guide strategies to overcome resistance in PIK3CA-mutated cancers. SIGNIFICANCE: In one of the largest patient cohorts analyzed to date, this study defines the clinical landscape of acquired resistance to PI3Kα inhibitors. Genomic alterations within the PI3K pathway represent a major mode of resistance and identify a novel class of secondary PIK3CA resistance mutations that can be overcome by an allosteric PI3Kα inhibitor. See related commentary by Gong and Vanhaesebroeck, p. 204 . See related article by Varkaris et al., p. 240 . This article is featured in Selected Articles from This Issue, p. 201.

Effects of newer-generation anti-diabetics on diabetic retinopathy: a critical review.

Diabetic retinopathy (DR) is the leading etiology of blindness in the working population of the USA. Its long-term management relies on effective glycemic control. Seven anti-diabetic classes have been introduced for patients with type 2 diabetes (T2D) in the past two decades, with different glucose-lowering and cardiovascular benefits. Yet, their effects specifically on DR have not been studied in detail. A systematic review of the literature was conducted to investigate this topic, focusing on the available clinical data for T2D. Published studies were evaluated based on their level of statistical evidence, as long as they incorporated at least one endpoint or adverse event pertaining to retinal health. Fifty nine articles met our inclusion criteria and were grouped per anti-diabetic class as follows: alpha-glucosidase inhibitors (1), peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists (8), amylin analogs (1), glucagon-like peptide-1 (GLP-1) receptor agonists (28), dipeptidyl peptidase 4 (DPP-4) inhibitors (9), and sodium glucose co-transporter-2 (SGLT-2) inhibitors (9), plus one retrospective study and two meta-analyses evaluating more than one of the aforementioned anti-diabetic categories. We also reviewed publicly-announced results of trials for the recently-introduced class of twincretins. The available data indicates that most drugs in the newer anti-diabetic classes are neutral to DR progression; however, there are subclasses differences in specific drugs and T2D populations. In particular, there is evidence suggesting there may be worse diabetic macular edema with PPAR-gamma agonists, potential slight DR worsening with semaglutide (GLP-1 receptor agonist), and potential slight increase in the incidence of retinal vein occlusion in elderly and patients with advanced kidney disease receiving SGLT-2 inhibitors. All these warrant further investigation. Longer follow-up and systematic assessment of at least one DR-related endpoint are highly recommended for all future trials in the T2D field, to ultimately address this topic.

Temporal Tracking of Plasma Cells in vivo Using J-chain CreERT2 Reporter System.

Plasma cells (PCs) are essential for humoral immunity, as they are responsible for the production of antibodies and contribute to immunological memory. Despite their importance, differentiating between long-lived and short-lived PCs in vivo remains a challenge due to a lack of specific markers to distinguish these populations. Addressing this gap, our study introduces a novel J-chain CreERT2 GFP allele (IgJCreERT2) for precise genetic studies of PCs. This model takes advantage of PC-restricted expression of the J-chain gene, enabling temporal and cell-specific tracking of PCs utilizing a tamoxifen-inducible Cre recombinase. Our in vitro and in vivo validation studies of the inducible Cre allele confirmed the fidelity and utility of this model and demonstrated the model's ability to trace the long-lived PC population in vivo following immunization. The IgJCreERT2 model allowed for detailed analysis of surface marker expression on PCs, revealing insights into PC heterogeneity and characteristics. Our findings not only validate the IgJCreERT2 mouse as a reliable tool for studying PCs but also facilitate the investigation of PC dynamics and longevity, particularly in the context of humoral immunity and vaccine responses. This model represents a significant advancement for the in-depth study of PCs in health and disease, offering a new avenue for the exploration of PC biology and immunological memory.

KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance.

Lung cancer treatment has benefited greatly through advancements in immunotherapies. However, immunotherapy often fails in patients with specific mutations like KEAP1, which are frequently found in lung adenocarcinoma. We established an antigenic lung cancer model and used it to explore how Keap1 mutations remodel the tumor immune microenvironment. Using single-cell technology and depletion studies, we demonstrate that Keap1-mutant tumors diminish dendritic cell and T cell responses driving immunotherapy resistance. This observation was corroborated in patient samples. CRISPR-Cas9-mediated gene targeting revealed that hyperactivation of the NRF2 antioxidant pathway is responsible for diminished immune responses in Keap1-mutant tumors. Importantly, we demonstrate that combining glutaminase inhibition with immune checkpoint blockade can reverse immunosuppression, making Keap1-mutant tumors susceptible to immunotherapy. Our study provides new insight into the role of KEAP1 mutations in immune evasion, paving the way for novel immune-based therapeutic strategies for KEAP1-mutant cancers.

Alterations in Appetite-Regulating Hormones in Girls with Central Early or Precocious Puberty.

The prevalence of central precocious puberty (CPP) in girls has increased worldwide and is often associated with obesity in childhood as well as high fat/high glycemic index diets. Evidence suggests that subjects with obesity present with alterations in appetite-regulating hormones. The arcuate and paraventricular nuclei of the hypothalamus are the centers of action of appetite hormones, as well as the location of gonadotropin-releasing hormone (GnRH) neurons, the activation of which results in the onset of puberty. This anatomical proximity raises the question of possible alterations in appetite-regulating hormones in patients with CPP. Furthermore, diet-induced hypothalamic inflammation constitutes a probable mechanism of the pathophysiology of CPP, as well as alterations in appetite-regulating hormones in young children. In this article, we summarize the evidence investigating whether girls with CPP present with alterations in appetite-regulating hormones. We present evidence that leptin concentrations are elevated in girls with CPP, ghrelin concentrations are lower in girls with CPP, nesfatin-1 and orexin-A concentrations are elevated among girls with premature thelarche, and insulin concentrations are increased in girls with early menarche.

Decreased Levels of Soluble Developmental Endothelial Locus-1 Are Associated with Thrombotic Microangiopathy in Pregnancy.

HELLP (Hemolysis, Elevated Liver enzymes and Low Platelets) syndrome is a life-threatening complication of pregnancy, which is often secondary to preeclampsia. To date, there is no biomarker in clinical use for the early stratification of women with preeclampsia who are under increased risk of HELLP syndrome. Herein, we show that the levels of circulating developmental endothelial locus-1 (DEL-1), which is an extracellular immunomodulatory protein, are decreased in patients with HELLP syndrome compared to preeclampsia. DEL-1 levels are also negatively correlated with the circulating levels of kidney injury molecule-1 (KIM-1), which is a biomarker for disorders associated with kidney damage. Receiver-operating characteristic curve analysis for DEL-1 levels and the DEL-1 to KIM-1 ratio demonstrates that these values could be used as a potential biomarker that distinguishes patients with HELLP syndrome and preeclampsia. Finally, we show that placental endothelial cells are a source for DEL-1, and that the expression of this protein in placenta from patients with HELLP syndrome is minimal. Taken together, this study shows that DEL-1 is downregulated in HELLP syndrome both in the circulation and at the affected placental tissue, suggesting a potential role for this protein as a biomarker, which must be further evaluated.

Tumor-intrinsic LKB1-LIF signaling axis establishes a myeloid niche to promote immune evasion and tumor growth.

Tumor mutations can influence the surrounding microenvironment leading to suppression of anti-tumor immune responses and thereby contributing to tumor progression and failure of cancer therapies. Here we use genetically engineered lung cancer mouse models and patient samples to dissect how LKB1 mutations accelerate tumor growth by reshaping the immune microenvironment. Comprehensive immune profiling of LKB1 -mutant vs wildtype tumors revealed dramatic changes in myeloid cells, specifically enrichment of Arg1 + interstitial macrophages and SiglecF Hi neutrophils. We discovered a novel mechanism whereby autocrine LIF signaling in Lkb1 -mutant tumors drives tumorigenesis by reprogramming myeloid cells in the immune microenvironment. Inhibiting LIF signaling in Lkb1 -mutant tumors, via gene targeting or with a neutralizing antibody, resulted in a striking reduction in Arg1 + interstitial macrophages and SiglecF Hi neutrophils, expansion of antigen specific T cells, and inhibition of tumor progression. Thus, targeting LIF signaling provides a new therapeutic approach to reverse the immunosuppressive microenvironment of LKB1 -mutant tumors.

Tibialis anterior tendon transfer using suture anchor provides excellent alternative treatment for relapse clubfoot: A case report.

INTRODUCTION: Relapsed clubfoot is defined as the recurrence of any component of deformity after a complete correction. While the Ponseti method has been known to have excellent outcomes, several relapse cases have been reported. Thus, further surgical intervention is needed to achieve a good and reliable long-term outcome. PRESENTATION OF THE CASE: We report a presentation of a 5-year-old boy who came to the clinic with a relapsed bilateral clubfoot after serial Ponseti casting. Plantar fascia release, Achilles tendon lengthening, and tibialis anterior tendon transfer (TATT) were performed respectively followed by an above-knee cast. The patient gained acceptable walking balance and ability to perform high impact sports at one year follow-up. CLINICAL DISCUSSION: There are several factors contributing to the relapse clubfoot including adherence to post op foot abduction brace (FAB) protocol, muscle imbalance or inadequate correction of initial deformities. The current case report described a relapse clubfoot following serial Ponseti casting caused by non-compliance of the use of foot abduction brace. Further surgical interventions must be performed in the presence of relapse case of clubfoot. CONCLUSION: Relapse clubfoot is the presence of any recurring deformity following correction. Surgical intervention, especially TATT procedure provides a favorable outcome in treating patients with relapse clubfoot.

Probabilistic machine learning for breast cancer classification.

A probabilistic neural network has been implemented to predict the malignancy of breast cancer cells, based on a data set, the features of which are used for the formulation and training of a model for a binary classification problem. The focus is placed on considerations when building the model, in order to achieve not only accuracy but also a safe quantification of the expected uncertainty of the calculated network parameters and the medical prognosis. The source code is included to make the results reproducible, also in accordance with the latest trending in machine learning research, named Papers with Code. The various steps taken for the code development are introduced in detail but also the results are visually displayed and critically analyzed also in the sense of explainable artificial intelligence. In statistical-classification problems, the decision boundary is the region of the problem space in which the classification label of the classifier is ambiguous. Problem aspects and model parameters which influence the decision boundary are a special aspect of practical investigation considered in this work. Classification results issued by technically transparent machine learning software can inspire more confidence, as regards their trustworthiness which is very important, especially in the case of medical prognosis. Furthermore, transparency allows the user to adapt models and learning processes to the specific needs of a problem and has a boosting influence on the development of new methods in relevant machine learning fields (transfer learning).

Down-regulation of KLF2 in lung fibroblasts is linked with COVID-19 immunofibrosis and restored by combined inhibition of NETs, JAK-1/2 and IL-6 signaling.

Kruppel-like factor 2 (KLF2) has been linked with fibrosis and neutrophil-associated thromboinflammation; however, its role in COVID-19 remains elusive. We investigated the effect of disease microenvironment on the fibrotic potential of human lung fibroblasts (LFs) and its association with KLF2 expression. LFs stimulated with plasma from severe COVID-19 patients down-regulated KLF2 expression at mRNA/protein and functional level acquiring a pre-fibrotic phenotype, as indicated by increased CCN2/collagen levels. Pre-incubation with the COMBI-treatment-agents (DNase I and JAKs/IL-6 inhibitors baricitinib/tocilizumab) restored KLF2 levels of LFs to normal abolishing their fibrotic activity. LFs stimulated with plasma from COMBI-treated patients at day-7 expressed lower CCN2 and higher KLF2 levels, compared to plasma prior-to-treatment, an effect not observed in standard-of-care treatment. In line with this, COMBI-treated patients had better outcome than standard-of-care group. These data link fibroblast KLF2 with NETosis and JAK/IL-6 signaling, suggesting the potential of combined therapeutic strategies in immunofibrotic diseases, such as COVID-19.

La violencia de género. Entre la intersubjetividad y las relaciones de poder a través del cuerpo femenino / Gender violence. Between intersubjectivity and power relations through the female body

Desde una perspectiva psicosocial, este artículo hace una reflexión sobre la importancia de dar una mirada intersubjetiva a la violencia de género, considerando que es una problemática que debe ser entendida como el producto del entrecruzamiento de relaciones establecidas socialmente desde el cuerpo, el poder y las relaciones psicológicas. La violencia en las relaciones de pareja ha sido concebida históricamente como un asunto cultural. Se desarrolla en primer lugar una síntesis conceptual de género, cuerpo, estructuras psíquicas de poder, para posibilitar la apertura hacia la intersubjetividad como punto convergente entre lo social, individual y cultural, como puntos de partida para la comprensión de la violencia de género desde una mirada contemporánea.

From a psychosocial perspective, this article reflects on the importance of giving an intersubjective look at gender violence, considering that it is a problem that must be understood as the product of the cross-linking of socially established relationships from the body, power and individual psychological relationships. Violence in relationships has historically been conceived as a cultural issue. First, a conceptual synthesis of gender, body, psychic structures of power is developed, in order to enable openness towards intersubjectivity as a convergent point between the social, individual and cultural, as starting points for the understanding of gender violence from a contemporary look.