While gender and economic outcomes in negotiation have been studied for decades, much less is known about gender differences in subjective outcomes, such as trust, rapport, and willingness to negotiate again, despite their importance for long-term success. In a series of studies with over 2,000 participants, we find that people consistently report better subjective outcomes when negotiating with women. This preference persists even in anonymous negotiations where gender is unknown and cannot be inferred from behavior, as well as in conditions where negotiation partner gender is randomly assigned. Importantly, we find no gender difference in economic outcomes. To understand why, we analyzed transcripts of real negotiations for any behavioral differences. These findings reveal an overlooked gender dynamic: While men and women achieve similar economic results, women foster stronger interpersonal relationships, which in turn lead to greater satisfaction and greater desire for future negotiations with women.
In the US heart allocation system, when transplant centers submit applications for status exceptions to increase waitlist priority, patients obtain the requested status upgrades immediately while their applications are sent to the regional review boards (RRBs) and reviewed retrospectively. How often transplants occur during this period is unknown. Using the Scientific Registry of Transplant Recipients, we identified all adult heart transplant candidates listed between October 18, 2018, and May 31, 2025, with submitted applications for status exceptions. We assessed (1) the time elapsed between submission of exception applications and their receipt by the RRBs and (2) the rate of heart transplantation during this travel time, stratified by whether the applications were eventually approved or denied. Additionally, we estimated how many listed patients were skipped by candidates who received transplants with exceptions that were ultimately denied. 138 transplant centers submitted status exception requests on behalf of 11 508 adult candidates during the study period, of whom 913 (7.9%) received a denial at least once. The median time from obtaining status upgrades to application receipt by the RRBs was 3 days. Three thousand seven out of 11 508 (26.1%) patients received transplants before the RRBs even received their applications, with 174 (19.1%) among 913 with eventual denials and 2833 (26.7%) among 10 595 with approvals. The cumulative incidence of heart transplantation before application receipt for eventual denials was 19.1% (95% CI, 16.6%-21.7%), and that for approvals was 27.2% (95% CI, 26.4%-28.0%; P<0.001) at 2 weeks. Candidates who received transplants despite being denied exceptions bypassed more than 11 thousand potential transplant recipients. More than 25% of patients with status exception requests receive heart transplants before their applications are even received by their RRBs, raising significant concerns about the fairness of retrospective review of exception requests for the allocation of donor hearts.
Reliable identification of the thoracic duct (TD) is critical during esophagectomy to prevent clinically significant chylothorax. Although various fat-loading and imaging techniques exist, many require specialized equipment or large-volume administration. We standardized a protocol using a small dose of high-fat ice cream administered three hours before anesthesia induction to facilitate lymphatic opacification. In our experience, this protocol was well-tolerated, without anesthesia-related adverse events, and achieved successful TD visualization in all cases without specialized imaging systems such as indocyanine-green fluorescence. Several practical lessons emerged from this decade-long experience. First, combined with thoracoscopic magnification, this approach enables reliable visualization down to the TD branches. This not only prevents inadvertent injury but also allows for the immediate identification and secure repair of any leakage. Second, preserving a clearly visualized TD was associated with fewer clinically relevant chyle leaks, even within a perioperative pathway incorporating very early enteral feeding. Third, TD preservation under direct visualization did not appear to compromise oncologic adequacy, with comparable survival and recurrence patterns in appropriately selected cases. In conclusion, safe intraoperative TD management may depend less on routine en bloc resection than on strategic preservation enabled by reliable visualization. This simple, widely accessible fat-loading protocol facilitates consistent TD identification, and supports selective preservation guided by oncologic considerations without increasing technical complexity. This practical framework enhances surgical safety and optimizes perioperative outcomes in modern esophageal surgery.
Perceptions of chlamydia and gonorrhoea may influence sexually transmitted infection (STI) testing and prevention. Understanding these perceptions is essential, as many countries are considering more restrictive chlamydia testing. This study compared perceived susceptibility and severity of chlamydia and gonorrhoea among young heterosexuals in the Netherlands and explored underlying determinants and reasons. An online cross-sectional survey (April-June 2024) among young people (16-34 year-old) was distributed via social media and sexual health clinics. Multivariable logistic regression identified determinants of perceived susceptibility and severity. Thematic analysis explored underlying reasons. Among participants (n = 1605), perceived susceptibility was low for chlamydia (75%) and gonorrhoea (81%), but both were considered severe (chlamydia 76%; gonorrhoea 82%). Determinants of perceived susceptibility differed by partner type. For those with steady partners, low impulsivity was associated with low perceived susceptibility, while multiple partners and low health goals were associated with high susceptibility. Among those with casual partners, multiple partners, no condom use at last sex, and low health goals were associated with high susceptibility. Perceived severity was lower among those with university education, low health goals, and multiple partners. Reasons for susceptibility related to sexual behaviour; severity to relationship concerns and STI aversion. Most young heterosexuals perceive chlamydia and gonorrhoea as severe, but many underestimate their personal risk, even when engaging in behaviours associated with increased risk of acquiring an STI. Misconceptions and limited awareness contribute to gaps between risk perception and preventive action. Targeted interventions and clear, infection-specific communication are needed as STI testing policies evolve.
Military medicine has been organized for 2 decades around the time interval between injury and definitive surgical care. The Golden Hour mandate in Afghanistan, paired with Tactical Combat Casualty Care guidelines and damage-control resuscitation, produced some of the lowest battlefield mortality rates in the history of armed conflict. More recent conflicts complicate this framework. In northwest Syria, deliberate attacks on hospitals reduced outpatient and trauma care for weeks following each strike, with population-level reductions in service use rather than individual mortality the dominant signal. In Ukraine, drone-contested evacuation, degraded hospital function, and disrupted medical logistics have failed concurrently under large-scale combat operations, in a pattern that the Golden Hour model was not designed to address. This Commentary argues that across these 3 mature conflict settings, the dominant clinical risk has broadened from individual-casualty survival to compound treatment-system degradation. The argument describes one axis of change rather than a universal trajectory: the French experience in the Sahel illustrates that prolonged casualty care can become the dominant problem even without deliberate hospital targeting or system collapse, and other conflicts including Sudan and the occupied Palestinian territory require their own analyses. What is consistent across the contemporary record, however, is that hospital protection, logistics resilience, and continuity of evacuation now sit at the center of military-medical capability rather than at its margin. Three doctrinal implications follow. First, hospital protection and facility dispersal should be incorporated into clinical-readiness curricula. They produce measurable effects on patient outcomes and warrant treatment as clinical capabilities rather than as adjacent engineering problems. Second, prolonged field care must shift from contingency planning to baseline operational capability, as the Sahel, Syrian, and Ukrainian experiences converge on this point, even though their underlying mechanisms differ. Third, medical logistics deserves the same operational rigor as direct patient care, including blood distribution, cold-chain continuity, warehouse dispersion, and cyber resilience of supply-management systems. Preliminary signals from the ongoing 2026 U.S.-Israeli-Iranian conflict, including verified attacks on health care, regional supply-chain disruption, and a cyber-mediated interruption affecting medical-device manufacturing, are broadly concordant with this trajectory. They are presented as hypothesis-generating only, not as evidence of a validated new doctrinal phase. The main limitations are selective conceptual synthesis and the asymmetry between mature peer-reviewed evidence and ongoing-event reporting. The conclusion is operationally direct: military medicine is no longer adequately described by transport time alone. Trauma-care survivability under threat is now the central problem.
The bacterial 16S rRNA gene is widely used to characterize host-associated and environmental microbiomes, most commonly through sequencing short hypervariable regions. Recent improvements in PacBio sequencing chemistry and concatenation approaches can now enable high-throughput, full-length 16S rRNA gene sequencing with high accuracy and depth. However, errors introduced during library preparation remain a major limitation, particularly during PCR amplification of full-length amplicons, where error accumulation may be elevated due to longer sequence lengths. These challenges are amplified when samples vary widely in microbial biomass, making it difficult to select a single optimal number of PCR cycles. Here, we evaluated PCR cycle autonormalization for PacBio Kinnex full-length 16S rRNA gene sequencing across seven agriculturally relevant specimen types. We compared conventional fixed-cycle PCR protocols (20, 24, and 30 cycles) with an autonormalization approach in which individual reactions were terminated during exponential amplification based on real-time fluorescence thresholds. Under the workflow tested here, autonormalized libraries generally retained a high proportion of sequences following denoising and chimera removal, exhibited low residual error rates (<0.005%), and yielded relatively even read distributions across heterogeneous sample inputs. Overamplified reactions (30 cycles) showed elevated residual error rates and greater sequence loss, particularly in samples with higher microbial biodiversity, whereas low-cycle libraries produced more variable read output among specimens. Importantly, the PCR protocol had relatively minor effects on overall community composition compared with specimen type. These results support PCR cycle autonormalization as a useful workflow strategy for heterogeneous full-length 16S library preparation, while also highlighting the importance of library design, pooling strategy, and downstream processing in shaping technical outcomes.IMPORTANCEAmplicon-based sequencing of the 16S rRNA gene is a foundational tool in microbiome research, yet PCR amplification remains a major source of library-preparation error. This challenge is magnified for full-length 16S rRNA sequencing and for workflows that process specimen types with widely varying microbial biomass. Selecting a single PCR cycle number can underamplify low-biomass samples or overamplify high-titer samples, increasing artifacts and sequence loss during downstream processing. Here, we show that PCR cycle autonormalization can be integrated into a PacBio full-length 16S rRNA workflow and, under the conditions tested, provides low residual error rates and relatively even sample representation across heterogeneous inputs. Autonormalization also enables blind pooling of amplicons without post-PCR quantification or equimolar normalization, reducing hands-on time and sample loss. These benefits make cycle autonormalization particularly valuable for high-throughput and production-scale library preparation applications handling diverse specimen types.
Water used in healthcare facilities for human consumption can pose a health risk to patients, healthcare workers, and visitors. Directive (EU) 2020/2184, transposed in Italy by Legislative Decree 18/23 promotes a preventive, risk-based approach along the entire water supply chain through the Water Safety Plans (WSPs). Quantitative Microbial Risk Assessment (QMRA), combined with Cost Benefit Analysis (CBA), allows integrated evaluation of health impacts and economic sustainability of control strategies.This study aimed to develop a decision support method to define a hospital water network surveillance strategy in the Apulia region (Italy) by estimating the risk of Legionella infection and the related costs and benefits under different exposure scenarios. All wards were included, comparing two surveillance strategies: total surveillance (SA) of all water endpoints, and reduced surveillance (SRED), with a limited number of sampling points. Using a Bayesian framework and a dose-response model, the probability of infection and the expected number of Legionnaires' disease cases were estimated for wards with different risk levels. In parallel, CBA evaluated direct costs, including microbiological analyses, point of use filters, and hospitalization days, economic indicators such as Net Benefit (NB), Willingness to Pay (WP), Incremental Cost Effectiveness Ratio (ICER), and Expected Incremental Benefit (EIB). Results showed lower infection probabilities with SA (2.6×10-5-2.95 × 10-7) compared to SRED (3.2×10-5-3.1 × 10-6), with expected cases of 0.4 vs 1.7. However, SRED was more cost-effective (€276,700 vs €422,900), showing positive NB (€149,959) and EIB (€ 348,787) and negative ICER (-9621.7). Even assuming a WTP of €25,000 per prevented case, surveillance costs exceeded benefits.
Failed abdominal aortic aneurysm (AAA) repair due to disease progression, graft migration, or type Ia endoleak presents a complex management challenge. While open conversion remains the traditional treatment, fenestrated/branched endovascular aneurysm repair (F/B-EVAR) offers a less invasive alternative but is technically challenging due to added anatomic constraints and presence of previous graft material. We evaluate outcomes of F/B-EVAR for failed prior AAA repair at centers without access to custom-made devices (CMDs). We retrospectively reviewed prospectively maintained databases of patients with failed AAA repairs rescued with F/B-EVAR between 2013-2025 at two tertiary centers without access to CMDs, under senior author's investigational device exemption (IDE). Primary endpoints were technical success (completion of F/B-EVAR without open conversion, target vessel loss, or type Ia/b/III endoleak), device integrity, and vessel patency. Secondary endpoints were major adverse events (MAEs), mortality, and reintervention. Among 486 patients who underwent F/B-EVAR, 75 (15.4%) had a failed prior AAA repair. Median age was 77 years (IQR, 72-82), and 91.8% were male. Prior failed repairs included infrarenal EVAR (80.0%), prior open repair (14.7%), and prior FEVAR (5.3%); 48.0% had ≥ 1 prior reintervention. The primary indication was proximal seal failure, most commonly type Ia endoleak (78.7%). Technical success was 100%. Device modification was frequently required, including main graft shortening (26.7%), distal bifurcated graft use (61.3%), inverted distal limb configuration (34.8% of bifurcated repairs), and distal graft shortening (8.7%). A total of 277 target vessels were successfully incorporated. Perioperative morbidity occurred in 8 patients (10.7%), including renal failure without need for dialysis in 5.3%, paraplegia in 1.3%, and compartment syndrome in 2.7%. Two patients (2.7%) died during the index hospitalization. At a mean follow-up of 42 ± 37 months, 21.0% required reintervention. Primary and primary-assisted branch patency were 97.5% and 99.6%, respectively. Sac regression >5 mm occurred in 51 patients (68.0%). Kaplan-Meier estimated freedom from reintervention was 85.8% at 1 year and 76.2% at 5 years; with overall survival of 95.7% and 84.0%, respectively. F/B-EVAR for failed AAA repair is feasible and effective, even at centers without CMD, with excellent technical success and durable mid- to long-term outcomes. These findings support F/B-EVAR as a viable alternative to open conversion across a broad risk spectrum.
Off-label antipsychotic prescribing for non-psychotic disorders is increasing, often at low doses and over extended periods. While cardiometabolic adverse effects are documented among individuals treated with antipsychotics for psychotic disorders, the consequences of long-term off-label antipsychotic use are not well-known. This systematic review synthesises evidence for cardiometabolic adverse effects of long-term antipsychotic therapy in adults and the elderly with non-psychotic disorders. We searched electronic databases for randomised controlled trials or observational studies of ≥1 year duration. Adverse events included weight gain, hyperglycaemia, dyslipidaemia, hypertension, metabolic syndrome, ischaemic heart disease, thrombosis and cardiometabolic mortality. We found 13 observational studies with high heterogeneity. Among adults, antipsychotic-treated individuals displayed increased prevalence of weight gain (28.8-77.9%), hyperglycaemia (4.8-23.2%) and dyslipidaemia (15.8-47.5%) compared with untreated patients. Second-generation antipsychotics had a larger effect than first-generation agents. A weak association was observed for cardiometabolic mortality. Results were sparse for the elderly, with one study indicating increased prevalence of metabolic syndrome and its components, and an inverse correlation of treatment duration with the risk for myocardial infarction. Studies were judged to have moderate-high methodological quality using suitable standardised risk of bias assessment tools. Despite heterogeneity in included studies, this review highlights adverse cardiometabolic outcomes associated with long-term antipsychotic use in adults with non-psychotic disorders, which is concerning given the high proportion of off-label use. Clinicians should exercise caution when prescribing antipsychotics off-label, especially where alternative options are available, and support even low-dose use with regular metabolic monitoring.
Arsenic is a known carcinogen that may contaminate human drinking water. Since 2000, regulations in the United States (US) have limited arsenic in the water to 10 parts per billion (ppb). However, evidence suggests that even low levels of arsenic may still increase the risks of bladder, prostate and kidney cancer. We performed an ecological study in Washington State (WA) to examine the relationship between low levels of arsenic in drinking water and incident urologic cancers. Average county-level arsenic levels in drinking water were estimated from public water systems in WA (2000-2018). Incident bladder, prostate and kidney cancer cases in WA (2014-2018) were ascertained from the Department of Health. Multivariable Poisson regression was conducted to estimate adjusted incidence rate ratios (aIRRs) for the associations between arsenic exposure and cancer risk. We found that average arsenic levels at the county-level were 3.8 ppb (SD 1.1). When comparing the highest (4.16-7.50 ppb) versus lowest (1.65-3.14 ppb) quartiles for arsenic levels in drinking water, the highest quartile was associated with an increased risk of bladder cancer (aIRR: 1.21, 95%CI 1.09-1.35), prostate cancer (aIRR: 1.20, 95%CI 1.12-1.29), with a suggestive positive association with kidney cancer (aIRR: 1.10, 95%CI 0.97-1.26). These findings demonstrate that low levels (<10ppb) of arsenic were associated with an increased risk of incident bladder and prostate cancer. Additionally, these data suggest that US drinking water standards may not adequately reduce the risk of cancer associated with low levels of arsenic exposure.
para-Menthane-3,8-diol (PMD) is a widely used bio-based insect repellent. However, its conventional synthesis is limited by protracted reaction times. Herein, we report an ultrasound-assisted Prins cyclization of citronellal, a monoterpenoid aldehyde, to PMD under 20 kHz irradiation. Using pure citronellal, ultrasound irradiation at 40% amplitude (∼48 µm) afforded PMD with 98% GC-FID purity within 2 h, compared with 87% PMD obtained after 10 h under conventional heating. Even at 100% amplitude (∼120 µm), the reaction proceeded within 10 min while maintaining a high PMD content of approximately 93%. For lemon eucalyptus (Eucalyptus citriodora) oil, ultrasound irradiation at 40-60% amplitude (∼48-72 µm) reduced reaction times from 15 h to 0.5-2.0 h while providing PMD contents comparable to those obtained by conventional heating. Notably, crystallization from the natural oil feedstock increased the cis-isomer content to 90%, compared with 65% obtained from pure citronellal. The observed cis stereoselectivity is proposed to arise from steric effects associated with the 3-methyl substituent of citronellal during intramolecular cyclization. Density functional theory calculations qualitatively support the proposed stereoselective mechanism. These findings provide an efficient approach for the synthesis and purification of PMD while offering mechanistic insights into stereochemical control in Prins cyclization reactions.
Glioblastoma is a highly malignant brain tumor, and accurate lesion segmentation in MRI is essential for diagnosis, treatment planning, and prognosis assessment. This paper proposes a knowledge-guided 3D hybrid Transformer-CNN framework, GL-Net, which integrates prior knowledge through a Gaussian Gating Module (GGM) and a Layered Refinement Module (LRM), together with a novel Edge-Region Voxel Dynamic Weighted Loss Function. These modules collaboratively enhance feature activation, refine label-specific structures, and improve edge delineation, enabling robust segmentation even under limited-sample conditions. The proposed GL-Net was evaluated on the BraTS2019 and BraTS2021 datasets, achieving average Dice Similarity Coefficients (DSC) of 0.877 and 0.913, and Hausdorff Distances (HD) of 1.83 and 1.55, respectively-demonstrating highly competitive performance and a substantial reduction in boundary errors relative to the reported benchmarks of current data-driven approaches. Furthermore, to assess its clinical applicability, VASARI (Visually Accessible Rembrandt Images) feature extraction was performed using both the GL-Net-generated segmentation masks and the ground truth labels on the BraTS2019 dataset for glioblastoma (GBM) diagnosis. The diagnostic performances were nearly identical (GT AUC: 0.954 / GL-Net AUC: 0.949), and the DeLong test (p = 0.99) indicated no statistically significant difference between the two. These results suggest that GL-Net not only achieves highly competitive segmentation accuracy but also produces radiomic features comparable to expert manual annotations, providing complementary evidence of its potential clinical relevance. The proposed framework shows strong clinical potential for precise and consistent glioma delineation, providing valuable support for surgical planning, radiotherapy targeting, and diagnostic decision-making in clinical workflows.
Human toxocariasis is a parasitic infection caused by Toxocara species and is important in the differential diagnosis of patients presenting with unexplained eosinophilia. A case of toxocariasis with an eosinophilic pleural effusion is presented. A 67-year-old Japanese man presented with progressive dyspnea. Laboratory investigations showed marked peripheral eosinophilia and a markedly elevated serum immunoglobulin E level. Chest imaging demonstrated bilateral ground-glass opacities and a left-sided pleural effusion. Analysis of the pleural fluid showed eosinophil predominance without evidence of malignancy or bacterial infection. Extensive diagnostic evaluations, including autoimmune serology, bone marrow examination, and genetic analyses for myeloid neoplasms with eosinophilia, yielded negative results. Serological test using an enzyme-linked immunosorbent assay demonstrated elevated anti-Toxocara antibody level, which were subsequently confirmed by western blot analysis, leading to a diagnosis of human toxocariasis presenting with visceral larva migrans. The patient had no clear history of animal contact or ingestion of raw meat or liver. Treatment with oral albendazole for four weeks resulted in marked clinical improvement, with resolution of the pleural effusion and pulmonary infiltrates, normalization of peripheral eosinophil counts, and a significant decrease in anti-Toxocara antibody level. This case emphasizes the importance of considering toxocariasis in the differential diagnosis of an eosinophilic pleural effusion and pulmonary infiltrates, even in the absence of identifiable exposure risks. Early serological testing can facilitate prompt diagnosis and appropriate anthelmintic therapy, potentially preventing unnecessary invasive procedures and delayed treatment.
Indoor air pollution caused by particulate matter, VOCs, and pathogenic microorganisms has become more and more serious. The use of numerous petroleum-based polymer filters also causes environmental pollution. Therefore, it is urgent to develop green, degradable, and long-term-stable indoor air filters with synergistic purification of multiple pollutants. Polylactic acid nonwovens are considered candidates for the next generation of air filters because of their green and degradable properties. Herein, we developed a multistage S-scheme heterojunction (Ag3PO4/MXene/Bi2WO6, AMB)-modified PLA electrospun nanofiber membrane (AMB/PLA ENM) using continuous electrospinning equipment. The AMB/PLA ENMs not only exhibit high-efficiency air-filtration performance but also demonstrate robust photocatalytic activity for formaldehyde, bacteria, and viruses. The filtration performance of AMB/PLA ENMs for PM0.3 achieved 99.99%/77.21 Pa at 32 L/min. Moreover, AMB/PLA ENMs exhibit excellent visible-light-driven photocatalytic activities for gaseous formaldehyde, reaching 76.77% within 200 min, and for liquid ciprofloxacin at 82.25% within 240 min. The establishment of the built-in electric field and the increased oxygen vacancies by MXene in the AMB heterojunction significantly enhance the photocatalytic performance of AMB/PLA ENMs. It also shows a significant killing rate of 99.99% against Escherichia coli, Staphylococcus aureus, and the H1N1 virus. This synergistic purification of multiple pollutants is attributed to a dual-functional strategy that integrates multistage S-scheme heterojunction photocatalysts with a PLA electrospun nanofiber membrane to achieve highly efficient and low-pressure air filtration and long-term stable photocatalytic performance. In addition, the AMB/PLA ENMs maintain self-cleaning, good mechanical properties, and degradability, even after long-term utilization.
Classical liquid-liquid phase separation predicts that droplets grow continuously via Brownian coalescence or Ostwald ripening, yet many nanoscale biomolecular condensates remain stable for hours or days without active regulation. Such condensates often arise through complex coacervation between oppositely charged macromolecules, making this interaction motif broadly relevant in biology and soft matter. Here we combine experiments, theory, and simulations to identify a merging-limited coarsening (MLC) regime in which merging of condensates decreases sharply below a critical droplet size. Chain-length asymmetry between oppositely charged polymers drives entropic interfacial charge separation even at globally neutral stoichiometry, imparting net droplet charges and generating long-range electrostatic repulsion. These size-dependent barriers lead to exponential rather than classical power-law growth and trap droplets in long-lived metastable states. Our framework unifies suppressed MLC and classical Brownian coalescence within a single predictive model and provides a general mechanism for condensate stability in both synthetic systems and living cells.
Mfd, the canonical bacterial transcription-repair coupling factor, is a highly conserved ATP-dependent DNA translocase with a complex architecture undergoing major rearrangements during its functional cycle. These changes regulate its ATPase and motor activities and are tuned by Mfd interactions with DNA, RNA polymerase and the UvrA subunit of the nucleotide excision repair excinuclease, Uvr(A)BC. Due to its role in accelerating molecular evolution and the development of antibiotic resistance, Mfd is also rapidly emerging as a prime target for the development of anti-evolution drugs to be administered in combination with narrow-spectrum antibiotics to prevent the rise of resistance and combat infection over a wider time window. Here we present the crystal structure of Thermus thermophilus Mfd in its nucleotide-free state. We note the pronounced disorder of the N-terminal UvrB homology module, which was previously seen in Escherichia coli to be engaged in a "clamp" interaction with the C-terminal domain, resulting in autoinhibition of its ATP-dependent functions. Thus, we conclude that the autoinhibitory interdomain interactions, such as the clamp, are not a universal feature of transcription-repair coupling factors. Consistent with this, Thermus thermophilus Mfd, unlike E. coli Mfd, translocates robustly on DNA even in the absence of RNA polymerase and displays DNA binding that is largely nucleotide independent. Our work brings mechanistic insight into the species-specific differences in Mfd structure and function and provides a structural framework for the design of anti-evolution drugs to combat antimicrobial resistance.
Chronic venous disease (CVD) is a progressive disease that often begins with venous symptoms even without visible signs. This systematic review and meta-analysis aimed to evaluate the effectiveness of micronized purified flavonoid fraction (MPFF) in patients with early-stage CVD (CEAP C0s/C1). A systematic search was conducted following the PRISMA guidelines. Medline, Embase, and Cochrane databases were searched from inception until November 2023. Prospective studies (randomized controlled trials and comparative, single-arm, observational studies) assessing MPFF (1000 mg daily orally) in C0s/C1 patients were included. Outcomes included leg venous symptoms (pain, heaviness, cramps) and quality of life. The data were analyzed using a random-effects meta-analysis model. Five studies involving 411 patients were analyzed. The patients' mean age was 40.1 (8.0) years, and 96.6% of them were female. Patients were classified as CEAP C1 (80%) and C0s (20%). MPFF significantly reduced pain intensity (mean change, -2.3 cm; 95% CI, -3.1 to -1.6), reduced heaviness (mean change, -2.8 cm; 95% CI, -3.5 to -2.1), and improved quality of life (mean change, -16.0; 95% CI, -20.7 to -11.3). Two studies reported complete resolution of symptoms for pain (100.0%), heaviness (87.9%), and cramps (97.8%). Two studies had a high risk of bias and heterogeneity level was frequently high among studies. The present meta-analysis reinforces the evidence supporting MPFF effectiveness in alleviating venous leg symptoms and improving quality of life in C0s/C1 patients and support the use of MPFF treatment in early disease management.
In low- and middle-income settings, routine health information systems (RHIS) and digital health projects often coexist, but their epidemiological outputs are rarely compared-even though integrating digital tools could strengthen RHIS by reducing reporting challenges. We conducted a retrospective, facility-level analysis of quarterly data (2017-2021) from Adamawa State, Nigeria, comparing ALMANACH, a clinical decision support system used in primary health care, with the state RHIS for malaria, pneumonia, gastrointestinal disorders, and measles in children under five years of age. The primary outcome was the facility-aggregated quarterly absolute relative difference (ARD) between the two reporting systems; temporal trends and facility-level heterogeneity were also assessed. Paired non-parametric tests, effect sizes with 95% confidence intervals (95% CI), and linear mixed-effects models accounted for clustering and repeated measurements. Across the study period, ALMANACH reported fewer cases than RHIS for malaria (116,018 vs 233,548; ARD 80.6%, 95% CI: 64.4-89.6, p < 0.01), gastrointestinal disorders (43,003 vs 62,412; ARD 32.6%, 95% CI: 17.1-47.4, p < 0.01), and pneumonia (20,980 vs 29,416; ARD 34.0%, 95% CI: 32.3-48.0, p < 0.05), but more measles cases (4,355 vs 2,508; ARD 86.2%, 95% CI: 45.6-162.8, p < 0.01). Mixed-effects models showed that RHIS recorded, per facility-quarter, on average 40.2 (95% CI: 31.1-49.3) more malaria, 6.6 (95% CI: 4.3-8.0) more gastrointestinal disorders, and 2.9 (95% CI: 1.2-4.6) more pneumonia cases than ALMANACH (all p < 0.01), while ALMANACH reported 0.6 (95% CI: 0.07-1.2) more measles cases (p < 0.05). Divergence widened as ALMANACH scaled up. Without a gold standard, these results quantify discrepancies without implying superiority and highlight the need for data integration, harmonized case definitions, and stronger data-use practices. They underscore the importance of sustained stakeholder engagement and user involvement for effective digital health scale-up in resource-limited settings.
West Nile virus (WNV) is a mosquito-borne pathogen of global concern that can cause fatal neuroinvasive disease, and no specific prophylaxis or treatment exists for infections by WNV and most related orthoflaviviruses. Here, we isolated and characterized antibodies from WNV convalescent individuals and report that neutralizing autoantibodies against type I interferons did not impair antiviral antibody development. Among the monoclonal antibodies with potent neutralizing activity against WNV that were identified, W010 targeted a distinct epitope within the envelope protein domain III (EDIII) and conferred both pre- and post-exposure protection in a murine WNV model, even when interferon signaling was impaired. A second protective antibody, W014, exhibited broad cross-neutralization of other pathogenic orthoflavivirus members, including Japanese encephalitis virus, Murray Valley encephalitis virus, Saint Louis encephalitis virus, and Usutu virus. These findings identify key neutralizing epitopes on WNV EDIII and provide candidates for the development of antibody-based interventions against encephalitic orthoflavivirus infections.
This study investigates the application of fluid bed processing (FBP) to improve the tabletability of a poorly compactable drug substance through the aqueous suspension layering onto coprocessed excipient for direct compression to produce orodispersible minitablets (ODMTs). For for this purpose, the aqueous drug suspension was sprayed-layered onto two coprocessed excipients using the FBP technology. The produced batches were compressed into ODMTs and systematically compared to the direct compression (DC) batches with equivalent composition. The tableting of the DC batches progressively deteriorated with increasing drug loading and was halted at higher drug loads due to reaching the machine safety limits. Moreover, the produced tablets exhibited several tablet defects (capping and sticking) and poor content uniformity. On the other hand, the tableting performance was evaluated through the ejection forces recorded, tablet defects observed and content uniformity assessment. The FBP batches successfully enabled tableting, achieving drug loading of the investigated active pharmaceutical ingredient up to ∼ 66 % (w/w) per ODMT with no tableting defects and acceptance values compliant with the Level 1 of the European Pharmacopoeia. Confocal raman microscopy and micro computed tomography imaging demonstrated that FBP improved blend uniformity thereby facilitating uniform drug distribution throughout the tablet matrix which was not the case for the DC blend. These findings demonstrate the benefit of the FBP step to enable the tableting of this poorly compactable drug substance even at higher drug loads while maintaining content uniformity and tablet integrity.