Search Results (755)

Protein C (PC) and its activated form, activated protein C (APC), are well-established regulators of coagulation and cytoprotection. While their systemic functions are extensively characterized, their physiological roles in the retina have only recently begun to be explored. This gap persists despite the observation that congenital PC deficiency is consistently associated with severe ocular complications. Emerging evidence, including the development of a murine model of severe protein C deficiency (SPCD), indicates that APC contributes to retinal integrity and vascular homeostasis under physiological conditions. Beyond its physiological function, APC has shown therapeutic activity in several models of retinal disease. Recent findings from our group further demonstrated that intravenously administered APC and its cytoprotective analog, 3K3A-APC, can cross the blood–retina barrier via the endothelial protein C receptor (EPCR), despite their relatively large molecular weight (~62 kDa), and induce cytoprotective activities in the retina. These findings highlight the translational potential of 3K3A-APC and support its further development as a systemically delivered therapeutic approach for retinal pathologies. This review integrates current knowledge of the molecular biology of the PC/APC pathways with its emerging physiological functions in the retina, and the accumulating preclinical and early clinical evidence that supports its therapeutic relevance. Full article

Autoinflammatory diseases are characterized by inappropriate activation of innate immunity resulting in excessive or persistent inflammation in the absence of infection. γδ T cells possess innate-like properties, including rapid responsiveness to stress-induced self-molecules, phosphoantigens, and inflammasome-derived cytokines, while retaining adaptive effector functions. Neutrophils and macrophages are well-established drivers of autoinflammatory disease, but increasing evidence implicates γδ T cells as key intermediaries by linking innate immune activation to tissue-specific inflammatory pathology. Here, we review evidence that in both monogenic and multifactorial autoinflammatory diseases—including, for example, familial Mediterranean fever, hyper-immunoglobulin (Ig) D syndrome, gout, Behçet’s disease, Still’s disease, atherosclerosis, and neurodegenerative disorders—γδ T cells display altered frequencies, activation states, cytokine polarization, and tissue recruitment. In inflammasome-driven diseases, skewing of γδ T cells toward interleukin (IL)-17 production has been observed, often accompanied by reduced interferon (IFN)γ secretion, thereby amplifying neutrophilic inflammation and tissue damage. In other diseases, e.g., Behcet’s disease, IFNγ and tumor necrosis factor (TNF)α producton predominate. Transcriptomic and tissue-based analyses support the accumulation and functional specialization of γδ T cells at sites of sterile inflammation. Collectively, these findings position γδ T cells as central amplifiers and modulators of inappropriate innate immune activation in the context of autoinflammatory diseases. Improved understanding of γδ T cell subset-specific regulation may inform novel therapeutic strategies targeting autoinflammatory diseases. Full article

Background: Placenta accreta spectrum (PAS) is a serious obstetric condition characterized by abnormal placental adherence to the uterus that can lead to major maternal morbidity. While hysterectomy has traditionally been the standard management, uterus-preserving approaches are increasingly used to preserve fertility. The risk of recurrent PAS in subsequent pregnancies and the overall fertility outcomes following conservative management remain unclear. Objective: We aimed to estimate the recurrence risk of PAS in subsequent pregnancies after conservative management and to assess fertility outcomes, including pregnancy and live-birth rates. Methods: This systematic review and meta-analysis followed PRISMA guidelines. A comprehensive literature search was performed across multiple databases to identify studies reporting subsequent pregnancies after conservative PAS management. Data extraction and quality assessment were independently conducted. Pooled recurrence and pregnancy success rates were calculated using random-effects meta-analysis. Results: Eleven studies met the inclusion criteria, involving 2642 patients who underwent conservative PAS management. The pooled recurrence risk of PAS in subsequent pregnancies was 20.9% (95% CI: 12.2–29.6). Successful pregnancy rates following conservative treatment were 69.7% (95% CI: 49.9–89.5). Conclusions: While conservative PAS management poses a risk of recurrence, it remains a viable fertility-preserving option, with high subsequent pregnancy success rates. These findings support informed clinical decision-making, though further prospective studies are needed to optimize management strategies and patient outcomes. Full article

Background: Psoriasis is a chronic systemic inflammatory disease with established extra-cutaneous manifestations. While the association between uveitis and spondyloarthritis (SpA)-related disorders is well recognized, the incident risk of uveitis among broader psoriasis populations remains inadequately defined due to methodological limitations and inconsistent findings across previous studies. We aimed to estimate the incidence of uveitis in a large, nationwide population-based cohort and identify specific clinical and treatment-related predictors of ocular inflammation. Methods: This retrospective cohort study utilised electronic health records from Clalit Health Services, Israel’s largest health maintenance organization (2002–2024). We identified 157,360 patients with dermatologist-confirmed psoriasis and 156,927 age- and sex-matched controls. The primary outcome was incident uveitis, with risk estimated using Cox proportional hazards models. Within the psoriasis cohort, multivariable logistic regression was employed to identify predictors of uveitis, ensuring appropriate temporal sequencing between psoriasis treatment exposure and outcome. Results: Over a median follow-up of 12.6 years, psoriasis was associated with a significantly higher risk of incident uveitis (adjusted Hazard Ratio [aHR] 1.80; 95% CI, 1.50–2.15). Stratified analysis revealed a graded risk pattern: mild psoriasis showed no increased risk (aHR 1.01; 95% CI, 0.91–1.13), whereas severe disease (aHR 1.59; 95% CI, 1.25–2.03) and concomitant SpA (aHR 2.21; 95% CI, 1.87–2.61) demonstrated markedly elevated risks. Within the psoriasis cohort, independent predictors included SpA, diabetes mellitus, systemic lupus erythematosus, and sarcoidosis. Exposure to biologics, particularly etanercept (OR 3.37; 95% CI, 2.42–4.54), was associated with higher odds of uveitis, potentially reflecting higher disease severity. Conclusions: Incident uveitis risk in psoriasis is primarily driven by the magnitude of systemic inflammatory burden, with the highest risk observed in severe disease and those with concomitant SpA. Clinicians should maintain heightened vigilance for ocular symptoms in these high-risk subgroups to ensure timely intervention. Full article

Background: Percutaneous left atrial appendage closure (LAAC) provides an alternative to oral anticoagulation (OAC) in atrial fibrillation (AF) patients who are at high bleeding risk. Prior studies have suggested sex-related differences in procedural outcomes, with women demonstrating higher peri-procedural complication rates. Data on long-term outcomes, however, remain inconsistent. Methods: We analyzed 407 consecutive patients with AF who underwent LAAC between 2010 and 2023 in four Israeli medical centers participating in the LEADER registry. Baseline characteristics, procedural data, and clinical outcomes were compared between men and women. The primary efficacy endpoint was ischemic stroke or systemic embolism at 1 year. The primary safety endpoint was a composite of all-cause mortality, procedural complications, or major bleeding at 1 year. Results: Of 407 patients, 285 (70%) were men and 122 (30%) were women. The mean age was 77 ± 8.4 years with similar CHA₂DS₂-VASc and HAS-BLED scores across sexes. Device implantation exceeded 99% in both sexes. Major peri-procedural complications occurred in 6.4% overall, without significant sex-based differences (men 7.0%, women 4.9%, p = 0.51). At 1-year follow-up, Kaplan–Meier estimates for the primary efficacy endpoint of ischemic stroke/systemic embolism (2.6%), the primary safety endpoint (19.2%), major bleeding (8.9%), and all-cause mortality (9.3%) were comparable between men and women (all p > 0.1). Conclusions: In contrast to prior large registries reporting higher peri-procedural risk in women, this real-world multicenter experience demonstrated no significant sex differences in either peri-procedural or long-term outcomes following LAAC. These findings support LAAC as an effective and safe stroke-prevention strategy in AF, irrespective of sex. Full article

Advances in affordable genetic engineering have accelerated the creation and large-scale environmental release of genetically modified microorganisms (GMMs). While beneficial applications exist, GMMs may present unique, long-term risks to human and environmental health. Unlike static chemicals, GMMs are biologically active, self-replicating entities capable of rapid mutation and global dispersal. Current regulatory frameworks place responsibility on each country to regulate GMMs, without a clear, coordinated international policy. This review details critical risk scenarios, including horizontal gene transfer to native species and the possible disruption of vital human microbiomes (gut, oral, and infant), which could increase resistance to degradation, promote traits that expand a microbe’s range of hosts or ecological niches, and enhance the production of novel metabolites with unexpected biological activity. In soil, GMMs may support the emergence of “super bugs” or destabilize carbon sequestration cycles, potentially impacting climate resilience. Engineered microbial enzymes in the food supply may also act as environmental drivers of autoimmunity. Given the limited understanding of microbial ecology, we propose a decision-based biosafety workflow emphasizing pre-release risk assessment and continuous post-release monitoring. We urge national and international regulators to adopt the precautionary principle to better protect human health and the environment from the potential negative outcomes of GMMs. Full article

Objectives: To develop a prediction model able to accurately predict which patients will harbor higher risk prostate cancer in the systematic biopsy template compared to the targeted biopsy during MRI/US fusion biopsy. Methods: We included patients who underwent fusion biopsy. Clinical and radiographic variables were collected from patients’ records. The outcome of the model was higher risk prostate cancer in the systematic compared with targeted biopsies. An extreme gradient boosting model was trained and tested. We evaluated variable importance and clinical benefit. Results: Five hundred and twenty-nine patients were included. Eighty-two (15.5%) patients had higher risk prostate cancer in the systematic biopsies. The area under the ROC curve and negative predictive value were 0.82 and 0.92, respectively. The four most important features for outcome prediction were prostate volume, PSAD, patient’s age, and PSA. The decision curve showed increased clinical benefit of our model at threshold probabilities of 0–0.5. Limitations include the retrospective design of the study and the lack of external validation of the model. Conclusions: We developed a prediction model able to accurately predict which patients must undergo systematic and targeted biopsy. This prediction model has the potential to help in the decision whether to perform SB and thus may lower the adverse event rate while keeping a high detection rate. Full article

Background: Burning Mouth Syndrome (BMS) is a chronic orofacial pain condition characterized by a burning sensation in the oral cavity without identifiable lesions. It predominantly affects women (especially postmenopausal) but can occur in men. BMS is considered a multifactorial neuropathic pain disorder involving both peripheral small-fiber neuropathy and central dysregulation, often accompanied by taste alterations (dysgusia) and xerostomia despite normal oral exams. Treatment is challenging, with modest responses to agents like clonazepam, tricyclic antidepressants, or gabapentinoids. Observations: We present a 67-year-old male with recalcitrant primary BMS who showed complete remission temporally associated with occipital nerve blockade, likely affecting central trigeminocervical pathways. Initial therapy with amitriptyline (25 mg) and gabapentin (900 mg/day) yielded ~30% pain relief. Given suspected central sensitization, greater and lesser occipital nerve (GON) blocks were administered in series. After the first, second, and third ON blocks, pain was reduced by ~50%, 80%, and 100%, respectively. Remission persisted at one-year follow-up under continued medications. A mild recurrence (~20% of baseline pain) responded fully to a fourth GON block, maintaining another year of pain-free status. Lessons: This case underscores the complex central mechanisms in BMS and illustrates that modulating central pain circuits via occipital nerve blockade, through trigeminocervical convergence mechanisms, without direct trigeminal intervention. We discuss the diagnostic challenges of BMS, the rationale of occipital neuromodulation, and how this novel therapeutic strategy compares with current literature, supporting the hypothesis of central sensitization in BMS. Full article

Background: Eosinophilia, defined as peripheral blood eosinophil counts > 0.5 K/μL, is associated with various clinical conditions, including allergic, infectious, and malignant diseases. Emerging evidence suggests that eosinophils may contribute to thrombo-inflammatory processes, but their association with thromboembolic events and mortality remains insufficiently characterized. This study aimed to evaluate whether eosinophilia is independently associated with increased risk of thromboembolic events and mortality in hospitalized patients. Methods: We conducted a retrospective cohort study using electronic medical records from Sheba Medical Center (2011–2020). Eosinophilia was classified as mild (0.5–1.5 K/μL) or hypereosinophilia (HE, >1.5 K/μL). Patients with eosinophilia were matched 1:1 to controls with normal eosinophil counts based on age, sex, and follow-up duration. Results: Among 93,320 patients (46,660 with eosinophilia and 46,660 controls), thromboembolic events occurred in 20.9% of eosinophilic patients vs. 9.8% of controls. Eosinophilia was independently associated with thrombosis (OR = 1.33; 95% CI, 1.28–1.38; p < 0.0001), with increased risk from counts ≥ 0.7 K/μL. Mortality was also higher among eosinophilic patients (HR = 1.17; 95% CI, 1.13–1.20; p < 0.0001). Conclusions: Eosinophilia is associated with increased thromboembolic and mortality risk, highlighting the importance of eosinophil monitoring in clinical practice. Full article

Hemostasis and thrombosis reflect a delicate balance, regulated by the interplay between procoagulant and anticoagulant mechanisms. Hemophilia is traditionally viewed as a bleeding disorder, but emerging evidence highlights the paradoxical risks of thrombosis in hemophilia patients. We explore the landscape of hemophilia management, emphasizing challenges of balancing hemostasis in the context of aging, novel non-factor replacement therapies (NRTs), and comorbidity-driven thrombotic complications. Therapeutic approaches, including innovative NRTs, such as emicizumab, or rebalancing agents (e.g., concizumab, marstacimab, fitusiran), offer promising advancements in bleeding prophylaxis but may increase thrombotic risks. Conversely, novel anticoagulants, such as FXI inhibitors, offer potential thrombosis protection with minimal bleeding risk. Our review examines the impact of aging-related comorbidities, including cardiovascular disease, atrial fibrillation, HIV-associated complications, and acute coronary syndromes, on thrombotic risk in hemophilia patients. Evidence-based strategies for balancing hemostasis and thrombosis are outlined alongside experimental models, thrombin generation assays, and advancements in rebalancing coagulation through natural anticoagulant modulation. FXI inhibition emerges as a paradigm shift in thrombosis management, offering reduced bleeding risks while preserving vascular health. Finally, this review highlights the need for global laboratory assays to personalize treatments, emphasizing strategies to optimize safety and efficacy, particularly as hemophilia patients live longer with complex comorbidity profiles. Full article

Background/Objectives: AI models such as ChatGPT-4 have shown strong performance in dermatology; however, the diagnostic value of AI-generated clinical image descriptions remains underexplored. This study assesses whether ChatGPT-4’s image descriptions can support accurate dermatologic diagnosis and evaluates their potential integration into the Electronic Medical Record (EMR) system. Materials & Methods: In this Exploratory cross-sectional study, we analyzed images and descriptions from teledermatology consultations conducted between December 2023 and February 2024. ChatGPT-4 generated clinical descriptions for each image, which two senior dermatologists then used to formulate differential diagnoses. Diagnoses based on ChatGPT-4’s output were compared to those derived from the original clinical notes written by teledermatologists. Concordance was categorized as Top1 (exact match), Top3 (correct within top three), Partial, or No match. Results: The study included 154 image descriptions from 67 male and 87 female patients, aged 0 to 93 years. ChatGPT-4 descriptions averaged 74.3 ± 33.1 words, compared to 7.9 ± 3.0 words for teledermatologists. At least one of the two dermatologists achieved a Top 3 concordance rate of 82.5% using ChatGPT-4’s descriptions and 85.3% with teledermatologist descriptions. Conclusions: Preliminary findings highlight the potential integration of ChatGPT-4-generated descriptions into EMRs to enhance documentation. Although AI descriptions were longer, they did not enhance diagnostic accuracy, and expert validation remained essential. Full article

Background/Objective: Ketorolac is an effective alternative and addition to opioids for postoperative pain control; however, there is concern of perioperative bleeding risk with its use. Within gynecology, this risk has not yet been explored in the context of hysterectomy. This study aimed to evaluate the risk of postoperative bleeding complications with ketorolac administration in the context of hysterectomy. Methods: This was a retrospective cohort study that included all patients who underwent hysterectomy for benign indications between 2015 and 2024 at a quaternary care academic hospital. Inclusion criteria were any type of hysterectomy during the study period, while exclusion criteria were malignancy and peripartum status. Complication data for up to thirty days post operation were collected. Multivariable regression analysis, including age, American Society of Anesthesiology category, use of celecoxib before surgery, anticoagulant treatment, uterus size, surgical approach, increased surgical complexity, and lysis of adhesions, was performed to identify the adjusted odds of postoperative bleeding complications. The primary outcome was a composite of any postoperative bleeding complications by use of postoperative ketorolac, including postoperative transfusion, readmission, or reoperation for bleeding. Results: In total, 4236 patients underwent hysterectomy for benign indications during our study period, of which 76% (n = 3236) received ketorolac postoperatively. The composite postoperative bleeding rate was lower in the ketorolac group (2.1% vs. 4.1%, p = 0.001). There was no association between ketorolac use and risk of postoperative bleeding in multivariable regression analysis (aOR 1.02, 95% CI 0.36–2.88). There was no difference in overall intraoperative or perioperative complications (p = 0.070 for both). Major perioperative complications were less likely in the ketorolac group (p = 0.046). Additionally, there were no differences in postoperative complications except for ileus, which was less likely in the ketorolac group (p = 0.034). Conclusions: Ketorolac administration was not associated with a higher risk of bleeding complications after hysterectomy, including when celecoxib was used preoperatively as part of an enhanced recovery protocol. It may safely be administered as an opioid-sparing pain medication in this setting. Full article

Background: Veno-venous extra-corporeal membrane oxygenation (ECMO) cannulations are mostly performed while patients are heavily sedated and mechanically ventilated. For patients with acute respiratory distress syndrome (ARDS), cannulating for ECMO while awake and spontaneously breathing, as well as treating without sedation and mechanical ventilation, has potential advantages. This study aimed to compare clinical outcomes between patients cannulated for ECMO while awake and patients cannulated while sedated and mechanically ventilated. Methods: A retrospective multicenter study. Data were accessed from the Israeli ECMO registry of patients with COVID-19-induced ARDS treated at eight ECMO centers in Israel. The study group comprised 24 patients who were cannulated while awake and spontaneously breathing. A control group comprised 96 patients who were cannulated after sedation and mechanical ventilation, matched 1:4 by age, sex, and body mass index. The primary outcome was six-month survival. Secondary outcomes were: the duration of ECMO therapy, the duration of invasive mechanical ventilation-free ECMO therapy, and the duration of invasive mechanical ventilation. Results: The mean age was 52 + 11 years; 78% were males. Fifteen patients (63%) in the study group were eventually intubated. The mean durations on ECMO and in the intensive care unit did not differ between the groups. The study group had a higher six-month survival (75% vs. 49%, p = 0.02) and fewer infectious complications such as pneumonia or bacteremia (21% vs. 40%, p < 0.001) compared to the control group. After adjusting for PO₂/FiO₂ ratio and for the COVID-19 variant, the hazard ratio was 0.45 (C.I 0.19–1.06, p = 0.069). Conclusions: Awake VV-ECMO cannulation in COVID-19-induced ARDS is feasible in selected patients and was associated with higher survival in unadjusted analyses. However, after adjustment for key covariates, this association was attenuated and did not reach statistical significance. Full article

Objective: To evaluate the clinical success outcomes and risk factors associated with dental implants placed with simultaneous bone augmentation in a large-scale, real-world cohort. Methods: A retrospective analysis was conducted on 158,824 implants, including 45,715 Dental Bone Grafts, placed between 2014 and 2022 within a national healthcare network. Multivariate Generalized Estimating Equations were utilized to assess the impact of demographic, anatomical, and procedural variables on implant failure. Results: The augmented cohort demonstrated a high clinical success rate of 97.83% (2.17% failure), statistically comparable to the general implant population. Failures were predominantly early (<1 year), accounting for 70% of losses. Significant independent risk factors included immediate implant placement (3.08% failure vs. 2.07% for delayed), male gender, and maxillary location. Notably, low socioeconomic status (SES) emerged as a significant predictor, with a failure rate of 3.07% compared to 2.06% in high-SES groups. Conclusions: Simultaneous bone augmentation is a predictable modality that does not inherently increase implant failure risk, supporting the stabilization hypothesis. However, failure is modulated by specific variables. The identification of lower SES, male gender, and immediate placement as significant risk indicators highlights the necessity for personalized risk assessment and targeted protocols to optimize outcomes in augmented sites. Full article

Objective: Current data on the association between attention-deficit/hyperactivity disorder (ADHD) and essential hypertension (EH) in pediatric populations are very limited, as most research has focused on adults. This study investigated the long-term prevalence of EH in Israeli youth aged 5–18 years with ADHD, examining also trends in antihypertensive medication use. Methods: A retrospective cohort study was conducted using data from Leumit Health Services. The ADHD cohort (N = 18,558) was compared in a 1:2 ratio to controls (N = 37,116), who were strictly matched for age, gender, birth year and quarter, socioeconomic status (SES), sectors, region, and cumulative years of LHS membership up to the index date. Diagnoses of ADHD and EH were identified using ICD-9/10 codes, depending on the year of diagnosis. Logistic regression analyses were used to assess the associations between ADHD, EH and the use of antihypertensive medications over a 20-year follow-up. Results: ADHD-diagnosed children had a higher prevalence of EH, with odds ratios (ORs) of 3.17 (95% CI: 1.46–7.16, p = 0.0017) at 5 years, 2.94 (95% CI: 1.45–6.09, p = 0.0013) at 10 years, and 1.92 (95% CI: 1.26–2.93, p = 0.0015) at 20 years. ADHD patients showed a greater use of antihypertensive medications, including calcium channel blockers (OR 1.85, 95% CI: 1.02–3.35, p = 0.035), renin angiotensin system blockers (OR 2.20, 95% CI: 1.15–4.25, p = 0.013), and diuretics (OR 1.77, 95% CI: 1.21–2.60, p = 0.0028). Conclusions: These findings highlight an association between ADHD diagnosis and EH, suggesting regular cardiovascular monitoring of children with ADHD. Further studies are needed to uncover the role of stimulant medications and shared biological and behavioral factors involved in the pathogenesis. Full article