Severe community-acquired pneumonia (CAP) remains a major cause of morbidity and mortality, requiring prompt empirical antibiotic therapy. The choice between amoxicillin/clavulanic acid (AMC) and third-generation cephalosporin (3GC) as first-line beta-lactam therapy in the ICU is still debated. To assess AMC and 3GC susceptibility in severe CAP or community-acquired aspiration pneumonia (CAAP) caused by Streptococcus pneumoniae (SP), Haemophilus influenzae (HI) and/or Staphylococcus aureus (SA), and to evaluate the appropriateness of empirical antibiotic therapy. We conducted a single-center retrospective study including patients admitted to the ICU between 01/01/2018 and 30/11/2022 for severe CAP/CAAP with microbiological documentation of at least one of the targeted pathogens. Clinical, microbiological, therapeutic, and outcome data were collected. The primary endpoint was AMC and 3GC susceptibility rates (expressed as percentage and [95% confidence intervals]). Among 104 included patients (median age 64 [48-71] years; 67% male), 60 (57.7%) had CAAP. AMC susceptibility rates were 81.5% [61.9-93.7], 78.0% [62.4-89.4], and 100% [92.6-100.0], while 3GC susceptibility rates were 96.3% [81.0-99.9], 95.1% [83.5-99.4], and 100% [92.6-100.0], for SP, HI, and SA, respectively. AMC was the empirical treatment in 59% of cases, and this choice was microbiologically appropriate in 86.9% of these prescriptions. Conversely, 3GC were prescribed empirically in 20% of cases, but this broad-spectrum choice was unjustified in 80% of those situations. Antibiotic de-escalation was performed in 28% of cases. In this single-center retrospective cohort, AMC appears to be a relevant empirical option for severe CAP/CAAP in the ICU, while 3GCs seem frequently overused. These findings required prospective multicenter validation before practice change can be recommended.
The tumor suppressor gene CDKN2/p16/MTS1, located on chromosome 9p21, is frequently inactivated in many human cancers through homozygous deletion. Recently, we have reported another pathway of inactivation that involves loss of transcription associated with de novo methylation of a 5' CpG island of CDKN2/p16 in lung cancers, gliomas, and head and neck squamous cell carcinomas. We now show that this aberrant CpG island methylation also occurs frequently in cell lines of breast cancer (33%), prostate cancer (60%), renal cancer (23%), and colon cancer (92%) and is associated with loss of transcription. Primary tumors of the breast (31%) and colon (40%) also displayed de novo methylation of this CpG island. This alteration of p16 in colon cancer was particularly striking, since inactivation does not occur through homozygous deletion in this tumor type. Our data show that in tumors, de novo methylation of the 5' CpG island is a frequent mode of inactivation of CDKN2/p16 and also firmly demonstrate that CDKN2/p16 is one of the most frequently altered genes in human neoplasia.
Incremental peritoneal dialysis (PD) is defined as prescribing a "less-than-standard" PD dose. High-certainty evidence to guide safe incremental PD prescription is lacking, resulting in substantial practice variability. We conducted a multi-national survey to evaluate current uptake, practice patterns and clinician perspectives on incremental PD. An online, unit-level survey, comprising 27 questions on incremental PD practice, was purposively disseminated to senior PD unit staff (physicians and/or nurses) from Australia, Canada and Thailand between June 2023 and September 2025. A total of 254 responses were received from 175 PD units (Australia: 55 (89%) of 62 units; Canada: 49 (60%) of 82 units; Thailand: 71 (34%) of 210 units). Incremental PD was reported as prescribed in fewer than 10% of patients in most units (56%, P=0.16). Incremental PD definitions varied substantially: CAPD with <4 daily exchanges (75%), APD or CAPD performed <7 days/week (65% and 61%), CAPD <8 L/day (50%), a single long overnight exchange (46%), or APD without a day dwell (44%), highlighting the absence of international consensus. Key reported advantages included increased patient satisfaction (81%), willingness to choose PD (75%) and preservation of residual kidney function (64%). Frequently cited disadvantages included patient or caregiver resistance to dose escalation (62%) and needing more frequent monitoring (31%). Quality of life was identified as the most important area for future research. Incremental PD is prescribed infrequently and variably. Concern about patient resistance to dose escalation is a barrier. High-quality data are needed to guide how incremental PD is defined, initiated and escalated.
Lumbosacral spinal solitary fibrous tumors (SFTs) are rare, and their clinicopathological profile, surgical management, and recurrence behavior have not been systematically characterized as a dedicated anatomical subgroup. We assembled a lumbosacral-specific cohort to describe these tumors and identify factors associated with recurrence, with particular attention to dural compartment, extent of resection, and compartment-specific surgical constraints. We systematically reviewed reported lumbosacral spinal SFTs-both STAT6-confirmed and historically classified-together with the present case, extracting clinical, imaging, surgical, histopathological, and follow-up data. Associations with recurrence were assessed for tumor size (Mann-Whitney U test), resection extent, and dural compartment (Fisher's exact test, Kaplan-Meier estimation, log-rank), with Cox regression for recurrence-free survival. Sixty patients were included (17 STAT6-positive, 43 historically classified). Tumors were predominantly extradural (20 of 33 with a documented compartment). Locoregional recurrence or distant metastasis occurred in 21.7% (crude); the Kaplan-Meier estimated cumulative probability of an RFS event was approximately 26% at 3 years and 37% at 5 years. Recurrent tumors were larger than non-recurrent tumors (median 6.7 vs. 3.0 cm; p = 0.021). Local recurrence was substantially less frequent after complete than after subtotal resection (16.1% vs. 55.6%; p = 0.029). In this pooled cohort, larger tumor size was associated with recurrence, and local recurrence was less frequent after complete than after subtotal resection. The dural compartment appears to influence the surgical technique and margin that can realistically be achieved rather than whether complete removal is possible: extradural tumors more often permit en bloc, margin-negative excision, whereas intradural lesions involving the cauda equina, though frequently removable in full, generally require piecemeal function-preserving removal. Given the potential for delayed recurrence, long-term postoperative surveillance is warranted.
The co-occurrence of species within the same area raises fundamental questions about how they can persist while sharing space and resources. One of the central aims of community ecology is to understand the processes that allow species to coexist over time. The sympatry between primates and ungulates has not received much specialized attention, despite long-term acknowledgment that the two groups frequently co-occur. In this contribution, we have reviewed and summarized empirical evidence from a set of published studies to determine the nature of primate and ungulate association in space and time, the ecological contexts within which such associations occur, and the types of interactions that have been reported. We particularly examined the trends in the study taxa, the geographic distribution of research, and the functional categories of interactions. Within the literature, interspecific interactions are frequently reported in Africa, between baboons (Papio sp.) and small to medium-sized ungulates. Foraging facilitation and antipredator benefits are among the most frequently documented interaction types, typically resulting in commensalistic or asymmetrical mutualistic outcomes favouring ungulate species. Nonetheless, mutualism and antagonistic interactions are also reported, which indicates the context-dependent nature of these relationships. The frequency and form of associations appear to further depend on seasonal variation and habitat structure, although these factors were not consistently taken into account in the studies considered in this review. This synthesis helps establish a set of research priorities to promote more systematic and focused studies of primate-ungulate sympatry.
Disseminated gonococcal infection (DGI) is an uncommon but serious complication of untreated Neisseria gonorrhoeae infection, which typically presents as either the classic dermatitis-tenosynovitis-migratory polyarthralgia syndrome or as septic arthritis. Diagnosis is often challenging because blood and synovial cultures are frequently negative. A 35-year-old male with past medical history of recurrent diverticulitis and syphilis, presented with arthritis involving the left knee and ankle, followed by a progressive rash starting on the palms and soles and spreading towards his trunk during a diverticulitis flare. History was notable for multiple sexual partners. Physical examination was significant for multiple skin lesions with variable morphology involving the palms and soles. Left knee joint exam revealed swelling and reduced range of motion. Labs showed elevated inflammatory markers, and reactive RPR of 1:32 with positive treponemal antibodies. Infective workup, including blood cultures, urine Chlamydia/gonorrhea NAAT were negative. Subsequent arthrocentesis of the left knee and left ankle revealed elevated nucleated cells (73,500/µl ankle, 76,250/µl knee) with positive monosodium urate crystals. Notably, broad range synovial PCR was positive for N. gonorrhea but joint cultures negative. He was diagnosed with DGI, and started on IV Ceftriaxone, and received IM Benzathine penicillin G weekly for 3 weeks for concurrent secondary syphilis. This case underscores the diagnostic value of targeted molecular testing in DGI, when urine NAAT and cultures are often negative. Since mucosal gonococcal infections are frequently asymptomatic or may have cleared before dissemination, urogenital testing alone may be misleading. Concurrent rash with stable RPR titers and history of prior syphilis raised concern for active secondary infection. This reinforces the need for comprehensive STI screening in all patients with DGI. Lastly, presence of monosodium urate crystals does not exclude septic arthritis. Clinicians should maintain suspicion for DGI in sexually active patients presenting with fever, rash, and arthritis despite initially negative screening tests.
Cushing's disease in pregnancy is rare and frequently underrecognized due to clinical overlap with physiologic gestational changes and hypertensive disorders of pregnancy, particularly preeclampsia. Delayed diagnosis may result in prolonged maternal morbidity and inappropriate management. A 30-year-old gravida 2, para 1 woman delivered at 37 weeks' gestation via induced vaginal delivery for preeclampsia without severe features. Her immediate postpartum course was unremarkable. At 12 weeks postpartum, she developed persistent proteinuria with associated hypercalciuria and hyperuricosuria despite preserved renal function. Over the following weeks, she developed hypokalemia, leukocytosis, and progressive cushingoid features including facial rounding, dorsocervical fat pad, central obesity, proximal muscle weakness, hypertension, easy bruising, hirsutism, and frequent falls. Endocrine evaluation revealed markedly elevated serum and urinary cortisol levels with concomitant hyperandrogenism. Magnetic resonance imaging demonstrated a 9-mm pituitary adenoma with evidence of hemorrhage. She was diagnosed with cyclic Cushing's disease with intermittent adrenal insufficiency and initiated on glucocorticoid replacement therapy. Transsphenoidal resection of the adenoma was performed at 26 weeks postpartum, resulting in improvement in blood pressure and clinical symptoms. At one year postpartum, she remained clinically stable on glucocorticoid replacement therapy. This case highlights the importance of maintaining a broad differential diagnosis in patients with hypertensive disorders of pregnancy. Persistent hypertension, proteinuria, and metabolic abnormalities should prompt evaluation for underlying endocrinopathies such as Cushing's disease. Early recognition and multidisciplinary management are critical to optimizing maternal outcomes and avoiding misattribution of symptoms to preeclampsia alone. Emerging biomarkers, including sFlt-1/PlGF ratios, may further aid in distinguishing preeclampsia from alternative pathologic processes.
BACKGROUND Coronary artery embolism (CAE) is an infrequent but clinically significant non-atherosclerotic cause of ST-elevation myocardial infarction (STEMI). It presents unique diagnostic and therapeutic challenges due to its varied etiologies and the frequent absence of significant coronary artery disease. While atrial fibrillation is the most recognized cardiac arrhythmia associated with coronary embolism, atrial flutter as an embolic source remains underreported. This report highlights the complexities of diagnosing and managing CAE manifesting as an atypical STEMI and sudden cardiac arrest in a patient with previously undiagnosed atrial flutter, emphasizing the critical importance of identifying underlying embolic sources, particularly atrial flutter, to guide appropriate therapy. CASE REPORT An 82-year-old woman with non-ischemic cardiomyopathy presented after an out-of-hospital ventricular fibrillation cardiac arrest. Her post-resuscitation electrocardiogram revealed an inferior STEMI. Emergency coronary angiography demonstrated abrupt embolic occlusions in the distal right coronary artery, without evidence of significant underlying atherosclerosis. Percutaneous coronary intervention was performed to restore blood flow. After the procedure, telemetry revealed new-onset atrial flutter, the presumed embolic source. Her hospital course was complicated by severe global hypokinesis out of proportion to the infarct territory and progressive respiratory failure, ultimately leading to a family decision to transition to comfort care. CONCLUSIONS This case underscores the critical need to consider coronary artery embolism in the differential diagnosis for STEMI, particularly in patients lacking significant atherosclerotic disease burden. The presence of arrhythmias, such as atrial flutter, should raise strong clinical suspicion for an embolic etiology. While a good outcome was not achieved in this specific case, early recognition of CAE remains crucial for guiding appropriate revascularization strategies and initiating prompt anticoagulation to prevent recurrent thromboembolic events in surviving patients.
Carbapenemase-producing Enterobacterales (CPE), particularly OXA-48-producing Enterobacterales, represent a major diagnostic and therapeutic challenge due to their frequent low-level carbapenem resistance and delayed microbiological detection. Rapid confirmation of carbapenemase production is essential to optimize antimicrobial therapy and infection control measures. This study evaluated the simplified carbapenem inactivation method (sCIM) for detection of OXA-48-producing Enterobacterales. Unlike the conventional mCIM, sCIM eliminates the preliminary carbapenem inactivation incubation step, simplifying the workflow and reducing turnaround time. A total of 150 OXA-48-producing Enterobacterales were analyzed, together with additional VIM-, KPC-producing, and non-carbapenemase-producing isolates collected from clinical specimens at the Hospital Central de la Defensa "Gómez-Ulla" in Spain. Carbapenemase production was confirmed using the Xpert® Carba-R molecular assay. The sCIM detected all OXA-48-producing Enterobacterales with 100% sensitivity (95% CI: 97.6-100%) and no indeterminate results, including isolates with low ertapenem MICs. Results were available after 16-18 h of incubation without previous 4-hour carbapenem inactivation step, simplifying laboratory workflow compared with the conventional mCIM. The rapid detection of OXA-48-producing Enterobacterales remains a major diagnostic challenge due to their frequently low carbapenem MICs and subtle phenotypic expression. This study demonstrates that sCIM provides a simple, reliable, and highly sensitive method for detecting these isolates, even in cases with borderline susceptibility profiles. Given its low cost and ease of implementation, sCIM represents a valuable tool for routine clinical laboratories, particularly in high-prevalence or resource-limited settings.
This study aims to comparatively examine the readability, accuracy, and quality of responses provided by artificial intelligence (AI)-based chatbots such as Perplexity, ChatGPT-5, and Gemini to questions about knee osteoarthritis (KOA), which accounts for approximately four-fifths of the global osteoarthritis (OA) burden. In this study, 8 keywords were determined by excluding repetitive, irrelevant or synonymous ones from the 25 most frequently used English keywords associated with KOA based on Google Trends data, and these terms were asked as questions to three different artificial intelligence-based chatbots. The study measured readability using formulas like Coleman-Liau Index (CLI), Automated Readability Index (ARI), and Linsear Write (LW). Reliability of the information was assessed using the Journal of the American Medical Association (JAMA) benchmarks along with the modified DISCERN instrument. To determine overall content quality, the Global Quality Score (GQS) and the Ensuring Quality Information for Patients (EQIP) scale were applied. Together, these tools provided a comprehensive assessment of how understandable, reliable, and high-quality each chatbot's responses were. The most frequently searched keywords related to OA were "osteoarthritis of knee," "knee pain," and "osteoarthritis knee pain." A readability analysis of responses from three different AI-based chat systems revealed that all platforms had text levels above the Grade 6 threshold, and this difference was statistically significant (p < 0.05). Comparisons demonstrated that ChatGPT-5 produced the most readable content (FRES:45, GFOG:11.9, FKGL:9.24, CLI:14.03, SMOG:8.37, ARI:11.37, LW:7.2). However, Perplexity achieved significantly higher scores than ChatGPT-5 across all quality and reliability assessments, yielding superior median scores (DISCERN: 4, JAMA: 2, GQS: 4, EQIP: 92.8). Perplexity also outperformed Gemini in the mDISCERN reliability assessment (p = 0.001), while no significant difference in quality or reliability was found between Gemini and ChatGPT-5. No statistically significant difference was found between Gemini and ChatGPT in reliability and quality surveys. This analysis of KOA highlights significant challenges regarding the potential of popular AI chatbots for patient information. When examining readability levels, responses from these tools consistently exceed the recommended comprehensibility threshold, making it difficult for patients to absorb critical information. Furthermore, the relatively low scores recorded in reliability and content quality assessments raise significant concerns about the scientific validity and integrity of the medical information presented. Given these findings, the sufficient quality, robustness, and appropriate levels of understandability of future AI-based tools can only be ensured by the establishment and operation of an effective oversight mechanism.
Introduction - Early neurological deterioration after ischemic stroke is associated with worse clinical outcome, yet little is known about the frequency and determinants of neurological worsening during the first 24 hours after admission. Dual antiplatelet therapy (DAPT) is recommended early after minor non-cardioembolic stroke to reduce recurrent ischemic events, but its relationship with very early deterioration (vEND) and potential differences across stroke etiologies remain unclear. Patients and methods - We conducted a retrospective single-center cohort study including consecutive adults with non-cardioembolic ischemic stroke admitted to a Swiss tertiary stroke center between 2014 and 2023. vEND was defined as neurological worsening within 24 hours using two thresholds (NIHSS increase ≥4 points [primary] and ≥2 points [secondary]). Patients were categorized according to antiplatelet strategy (newly initiated DAPT vs single antiplatelet therapy [SAPT]) and stroke etiology (large artery atherosclerosis [LAA] vs non-LAA). Associations between antiplatelet therapy and vEND were analyzed using propensity score-weighted logistic regression with stabilized inverse probability of treatment weights and doubly robust adjustment. Adjusted predicted probabilities and risk differences were estimated using marginal standardization. Results - Among 1,207 patients with non-cardioembolic stroke, vEND occurred in 22.2% using the primary definition (NIHSS increase ≥4 points) and in 25.8% using the secondary definition (NIHSS increase ≥2 points). vEND was more frequent in non-LAA than LAA stroke under both definitions (23.5% vs 17.6% and 26.4% vs 23.7%, respectively). Patients with LAA were more likely to receive DAPT than those without LAA (33.6% vs 14.4%, p<0.001). After weighting and adjustment, the association between antiplatelet therapy and vEND differed by stroke etiology (pinteraction<0.001 [primary] and pinteraction=0.007 [secondary]). In LAA stroke, DAPT was associated with a numerically lower risk of vEND compared with SAPT (adjusted risk difference [primary definition]: -7.3%, 95% CI -16.9% to 2.3%). In contrast, among non-LAA stroke patients, DAPT was associated with a higher vEND risk (adjusted risk difference [primary definition]: 16.6%, 95% CI 7.1% to 26.1%). Similar patterns were observed using the secondary vEND definition (NIHSS increase of ≥2 points). Discussion and conclusion - Very early neurological deterioration within the first 24 hours after non-cardioembolic stroke is common and occurs more frequently in non-LAA stroke. The association between DAPT and vEND appears to differ by stroke etiology. A lower risk was observed in LAA stroke, whereas the higher risk seen in non-LAA stroke likely reflects confounding by indication. Prospective studies are needed to determine whether intensified platelet inhibition may reduce very early deterioration in LAA-related stroke.
Treatment goal limitations, such as "do not resuscitate", "do not escalate" and "comfort terminal care" are frequent in acute hospital care for patients with advanced illness, multimorbidity or impending death. Their ethical defensibility depends on transparent documentation of medical indications, proportionality and, where relevant, patient will. To examine whether documentation made medical rationale, patient will, advance directives, relatives' involvement or ethics consultation visible. We retrospectively analyzed documentation in an Austrian internal medicine department with intensive care over 12 months. Documents were identified in the hospital information system and descriptively analyzed. Deceased patients with documented limitations underwent manual review. Data were anonymized and analyzed using Microsoft Excel for Microsoft 365 (Microsoft Corporation, Redmond, WA, USA) and IBM SPSS Statistics, version 29 (IBM Corp., Armonk, NY, USA). Across 3998 inpatient stays involving 1829 patients, 277 patients had a documented treatment goal limitation (15.1%). Among 174 deceased patients, 111 had a documented limitation at death (63.8%). The most frequent order was combined do not resuscitate/do not escalate (75/111; 67.6%), followed by isolated do not resuscitate (23/111; 20.7%). Complete records were available for 101 cases; in 10 the rationale was not clearly traceable. Among the 101 manually reviewed cases, an explicit or presumed patient will was documented in 7 cases (6.9%), involvement of relatives in 13 cases (12.9%) and ethics consultation in 1 case (1.0%); medical rationale or physician decision was documented in 90 of 91 cases with traceable rationale (98.9%). Treatment goal limitations were common and usually medically justified in the records. The findings do not imply inappropriate decisions or lack of communication but show limited reconstruction of patient-centered reasoning. Documentation should make clearer how benefit, care, respect for autonomy and justice informed treatment limitation.
Preterm (<37 weeks), early-term (37-38 weeks), or post-term (42 weeks) birth may elevate the risk of mental, neurodevelopmental, and cardiopulmonary disease in adulthood, potentially impacting work capacity. We examined the association between gestational age and early disability pension (DP) among 228 572 Finnish individuals born between 1 January 1987 and 30 September 1990. We identified the first DP decision from ages 16 to ∼32 years (2003-20) by using linked birth and DP records, including timing and diagnosis. Adjusted hazard ratios (HRs) with 95% confidence intervals were estimated by using Cox regression, with full-term birth (39-41 weeks) as the reference. A total of 9224 individuals (4.0%) received DPs. Adjusted for sex and birth year, the HRs for DP by gestational age groups of 23-31, 32-33, 34-36, 37-38, and 42 weeks were 5.20 (4.52-5.99), 2.47 (2.04-3.00), 1.55 (1.41-1.70), 1.22 (1.16-1.29), and 1.12 (1.01-1.25). Among preterm adults, the most common diagnoses included cerebral palsy, intellectual disability, depression, and schizophrenia. For early-term and post-term adults, depression and schizophrenia were the most frequent. Preterm, early-term, and post-term births were associated with early DPs, with slightly different diagnostic profiles. The risk was highest among those born very preterm (<32 weeks). High-quality perinatological care is crucial regarding future careers and societal costs.
Biosecurity measures (BSMs) are essential for preventing the introduction and spread of infectious diseases within pig production systems, thereby supporting animal health, welfare, productivity, and responsible antimicrobial use. Numerous BSMs applied on European pig farms are discussed in literature reviews. Hence, a meta-review was conducted to map these BSMs, to highlight knowledge gaps. Eleven reviews covering European pig production systems were identified. Forty biosecurity variables were defined a priori for data extraction and grouped into ten groups covering farm geography and environmental interface, contact control, transport of feed and animals, waste management, personnel and visitor management, feed and stock management, pig management, land and outdoor area management, animal health and care, and hygiene management. The extent to which each BSM was covered across reviews was assessed by experts. Overall, the existing review literature varied widely in scope and methodological approach. Core operational measures such as hygiene, transport, waste management, and animal health practices were frequently reported. However, approximately 50-70% of the reviews provided only limited detail on their implementation. In contrast, measures related to environmental interfaces, land and outdoor area management, and barriers for contact control were among the least represented, with approximately 50-67% assessed as "not mentioned" across the included reviews. A clear knowledge gap was identified regarding BSMs relevant to production systems in which pigs have access to outdoor environments. Findings from this meta-review point to the need for a standardized framework to guide documentation of biosecurity measures across literature reviews.
Once-daily, single-tablet regimens have transformed care for persons living with human immunodeficiency virus type 1 (HIV-1); however, challenges to adherence continue to limit effective treatment. Long-acting oral-drug combinations could offer new options with less frequent dose administration. We conducted a phase 3, double-blind, randomized, active-controlled, noninferiority trial in 12 countries to evaluate the efficacy and safety of a switch to once-weekly oral islatravir-lenacapavir (ISL/LEN) from once-daily oral bictegravir-emtricitabine-tenofovir alafenamide (B/F/TAF) in adults in whom HIV-1 had been virologically suppressed for at least 6 months while they were receiving B/F/TAF. Participants were assigned in a 1:1 ratio to receive once-weekly ISL/LEN (2 mg/300 mg) or to continue once-daily B/F/TAF for 96 weeks; all received matched placebo for the alternative regimen. The primary end point was the percentage of participants with an HIV-1 RNA level of 50 copies per milliliter or higher at week 48, as determined by the Food and Drug Administration-defined snapshot algorithm. Noninferiority was determined at a margin of 4 percentage points. A total of 607 participants underwent randomization; 304 were assigned to the ISL/LEN group and 303 to the B/F/TAF group. A total of 21% of the participants were women, 31% were Black, 26% were Hispanic or Latine, and 15% were 65 years of age or older. At week 48, an HIV-1 RNA level of 50 copies per milliliter or higher was reported in no participants in the ISL/LEN group and 1 (0.3%) in the B/F/TAF group (difference, -0.3 percentage points; 95.002% confidence interval [CI], -1.4 to 0.8); an HIV-1 RNA level of less than 50 copies per milliliter was reported in 284 (93.4%) and 280 (92.4%), respectively (difference, 1.0 percentage point, 95% CI, -3.2 to 5.2). The mean change in the CD4+ T-cell count at week 48 was -10 cells per microliter with ISL/LEN and -18 cells per microliter with B/F/TAF (least-squares mean difference, 12 cells per microliter; 95% CI, -16 to 39). The trial regimen was discontinued owing to adverse events in 6 participants (2.0%) in the ISL/LEN group and 5 (1.7%) in the B/F/TAF group; serious adverse events occurred in 16 (5.3%) and 14 (4.6%), respectively. Among persons with virologically suppressed HIV-1, once-weekly oral ISL/LEN was noninferior to once-daily B/F/TAF in maintaining HIV viral load suppression. (Funded by Gilead Sciences and Merck Sharp and Dohme; ISLEND-1 ClinicalTrials.gov number, NCT06630286.).
Fluorescein compounds are diprotic acids prone to tautomeric transformations. Due to their valuable spectral properties, they are among the most commonly used dyes. However, nitro- and aminofluoresceins have been studied much less frequently than other fluorescein derivatives. At the same time, these compounds exhibit behavior that is different from that of other fluoresceins. Studying complex equilibria in organic solvents allows to identify molecular structures and equilibrium constant relationships that are impossible to observe in aqueous solutions. This study examines the acid-base equilibria of amino, nitro, and mixed aminonitro derivatives of fluorescein in DMSO. Basing on our previous results, we selected eight dyes, to clarify further the scheme of protolytic equilibria in this series. Among them are newly synthesized by us 3'-nitro-, 3'-amino-, 4,5-dinitro-4'-amino-, and 4,5-dinitro-5'-aminofluorescein. The pKa values were determined using the spectrophotometric method. Tautomerism is considered using the absorption spectra of molecular and anionic forms of the dyes and their esters and ethers that are used as model (auxiliary) compounds. All fractions of the tautomers, α, and the microscopic dissociation constants, pk, of the dyes are determined. For the neutral form, H2R, the colorless lactone predominates. Depending on the nature and position of the substituents, colorless tautomers were observed for the HR- and R2- anions, along with ordinary intensively colored species, which is atypical for aqueous solutions. This feature leads to very different ratios of stepwise dissociation constants: from resolution of pKa1 and pKa2 in the range from 1.5 to 4.1 to inversion, pKa1 > pKa2, for 4'-aminofluorescein. The results were compared with those obtained in water and an aqueous ethanol solution. A summary of all α and pk values of these and previously studied dyes, a total of 25 compounds, provides a quantitative description of the detailed protolytic equilibrium scheme of all amino-, nitro-, and aminonitrofluoresceins in solution.
Fever can trigger seizures in several early-onset epilepsies. SCN1A-related epilepsies, including Dravet Syndrome, are the best characterised conditions in this spectrum, but a growing number of genes implicated in fever-sensitive epilepsies have emerged. We assessed the genetic heterogeneity of individuals who underwent testing because of seizures or epilepsy with fever sensitivity. In particular, we investigated the occurrence of ATP6V0C pathogenic variants and delineated its associated electro clinical features. We retrospectively reviewed individuals tested with epilepsy-targeted Next Generation Sequencing (NGS) panels and/or Whole Exome Sequencing (WES) between 2022 and 2025, selecting those with documented fever sensitivity (defined as seizure occurrence or exacerbation temporally linked to febrile episodes in subjects who suffer from both febrile and afebrile seizures). Variants were filtered for frequency, evaluated through segregation and prediction tools, and classified according to ACMG guidelines. Among 721 individuals tested with NGS or WES for neurological indications, 418 (58%) had a history of seizures, including 53 (7.3%) with fever-sensitive epilepsy. Pathogenic or likely pathogenic variants were identified in 30% of these cases. Notably, ATP6V0C variants accounted for 2/16 (12.5%) of all pathogenic/likely pathogenic findings and were identified in 3.8% of tested fever-sensitive epilepsy patients, ranking among the most frequently implicated genes in this cohort. Our findings support ATP6V0C as a relevant gene in the landscape of childhood epilepsies with fever sensitivity. The associated phenotype appears characterized by early febrile-triggered motor seizures, initially normal EEG followed by multifocal abnormalities, normal MRI and subsequent onset of neurodevelopmental impairment. These results highlight the importance of accurate molecular diagnosis in children presenting with fever-sensitive seizures, with potential implications for future precision therapies.
To evaluate the relationship between the histopathological diagnoses of maxillary periapical lesions obtained during periapical surgery and maxillary sinus changes of endodontic origin (MSEO). Clinical, CBCT, and histopathological records of 39 cases that underwent periapical surgery on maxillary premolar and molar teeth between 2015 and 2019 were retrospectively reviewed, all of which had a preoperative CBCT scan acquired within three months prior to surgery and histopathological evaluation of periapical tissues. Maxillary sinus changes were assessed according to the radiographic MSEO criteria defined in the 2018 position statement of the American Association of Endodontists. The shortest linear distances between the lesion and the maxillary sinus floor, and between the root apex and the maxillary sinus floor, were measured on multiplanar Distance measurements were compared according to the presence and patterns of MSEO using generalized estimating equations (α = 0.05). MSEO was detected on CBCT in 26 of 39 periapical lesions (64.9%), with equal distribution between periapical mucositis (PAM) and periapical osteitis (PAO) patterns. Periapical granuloma was the most frequent histopathological diagnosis (82.1%). Lesion-sinus floor and root apex-sinus floor distances were greater in cases without MSEO (mean differences: 2.03 mm and 2.55 mm, respectively; p < 0.05). In PAM cases, both distances were greater than those observed in PAO cases (p < 0.05). The findings indicate an association between MSEO and the proximity of the periapical lesion and root apex to the maxillary sinus floor, with shorter distances observed in osteoperiosteal response patterns. Evaluating the proximity of maxillary periapical lesions to the sinus floor on preoperative CBCT may help clinicians anticipate sinus tissue response patterns during surgical management of maxillary posterior teeth.
Support persons are essential in cancer care, particularly during surgical consultations that involve complex decision-making and emotional stress. However, the COVID-19 pandemic introduced visitor restrictions that limited in-person companion access, raising concerns about patient-centered care. This study examined patterns of companion presence during breast reconstruction consultations in 2020 and compared findings to a pre-COVID cohort to assess shifting predictors of support-seeking behavior. A retrospective review was conducted of all breast reconstruction consultations (N = 59) at a regional plastic surgery center during the first year of the COVID-19 pandemic. Demographics, cancer status, travel distance, and companion presence were extracted from electronic medical records. Companion types and behaviors were qualitatively assessed from provider notes. Results were compared to a previously published pre-COVID cohort (N = 421). Statistical analyses included chi-squared tests and independent samples t-tests (α = 0.05). Despite pandemic restrictions, 51% of patients brought a companion. Companion presence was significantly associated with having an active cancer diagnosis (71.9% vs. 25.9%, p = .004), while marital status and travel distance were not significant predictors. In contrast, pre-COVID data showed marital status and travel burden as significant predictors of accompaniment. Provider notes revealed companions frequently offered emotional support, clarified medical details, and assisted in decision-making. Support persons remained integral to breast cancer care during COVID-19, particularly for patients facing active disease. These findings underscore the importance of flexible institutional policies that preserve the patient-companion relationship during emotionally charged consultations.
Artificial grammar learning (AGL) has frequently been employed to investigate the procedural hypothesis of dyslexia. However, most studies did not distinguish whether performance depended upon the acquisition of grammatical rules (procedural memory), distributional knowledge (statistical learning) or reference to individual memory traces (instances). An AGL paradigm was administered to 32 young adults with dyslexia and 60 controls. During the learning phase, adults with dyslexia learned artificial grammar and then utilized procedural memory in the grammaticality judgment and recognition tasks to a similar extent as controls. An overall group difference was observed only on the grammaticality judgment task; however, the performance of both groups was similarly modulated by the grammaticality of the stimuli. Adults with dyslexia acquired and used individual memories (instances) in both grammaticality judgment and recognition tasks. However, they exhibited some difficulty in forming individual memories, as indicated by their greater tendency to mistakenly identify non-grammatical control items as previously seen during the training phase (recognition task). On untrained items, adults with dyslexia also showed an advantage with high compared to low-bigram frequency stimuli, indicating reliance on sublexical statistical cues to foster their performance. In conclusion, adults with dyslexia acquired procedural rules and showed sensitivity to the distributional properties of the stimuli, providing little support for the procedural hypothesis of dyslexia. This study highlighted both spared and compensatory mechanisms in adults with dyslexia. Previous conflicting results may depend on not having isolated which components (procedural vs declarative memory vs statistical learning) are involved in the AGL paradigm.