During recombinant adeno-associated virus (rAAV) production, certain components of the manufacturing system can be encapsidated as unwanted nucleic acid contaminants. Prior work has established that the p5 promoter is critical for efficient vector production and is responsible for a significant portion of this aberrant cross-packaging. The Rep binding element (RBE) and terminal resolution site (TRS)-mimic loop on p5 putatively facilitate off-target packaging of DNA directly adjacent to p5 into rAAV particles. To prevent this, we replaced AAV2 p5 with homologues from several closely related AAV serotypes. All homologues tested that maintained vector production efficiency continued to package p5-adjacent sequences. However, specific mutations of the TRS-mimic site prevented contaminant incorporation but reduced expression of p5-derived Rep proteins and overall production efficiency. When Rep78/68 isoform expression was restored, these new TRS-modified p5 plasmids enabled rAAV production at comparable titers, with significantly reduced p5-associated contaminants, irrespective of scale and serotype. P5-associated contaminants were also observed in the context of rAAV production using covalently closed linear DNA, for which the TRS-mimic modification also significantly reduced DNA contamination while maintaining vector titers. Our findings have implications for efficiently producing rAAVs with increased purity for gene therapy.
Psychological outcome measures guide research and clinical decision-making, yet many widely used tools were developed with limited psychometric rigour. Although advanced methods (e.g., item response theory, structural equation modelling) are now widely available, their added value in applied research remains uncertain and applied researcher perspective regarding such are unexplored. We aimed to address this gap in knowledge by examining key stakeholder perspective. To explore how these methods are perceived, we conducted semi-structured interviews with 21 stakeholders spanning psychometrics, clinical practice, applied research, statistics and academia. Data were analysed using reflexive thematic analysis. Analysis identified three overarching themes: (1) growing recognition that heterogeneity in latent traits challenges assumptions underlying many measures, (2) the enduring use of entrenched but psychometrically weak tools and (3) nuanced views on when advanced methods meaningfully influence research findings. Participants acknowledged gaps in psychometric literacy and emphasised the need for more training and collaboration with psychometricians. These findings highlighted persistent limitations in measurement practice, clarify contexts where psychometric methods add genuine value, and point to opportunities for strengthening outcome measurement in psychology and psychiatry research.
Thirty-six Polypay crossbred wether lambs (33.49 ± 2.81 kg) were used to determine the relative bioavailability of supplemental potentiated zinc oxide (PZO) in comparison to zinc sulfate (ZnSO4) and resulting effects on zinc (Zn) retention, nutrient digestibility, and nitrogen (N) balance. Wethers were sorted by body weight (BW) into 3 blocks and stagger-started on trial. On day -25 (relative to collection period start), wethers were housed in group pens and began a low-Zn diet (25 mg Zn/kg DM) that was fed for the entirety of the study. Wethers were moved to individual crates on day -10, where they acclimated for 5 days before dietary treatments began on day -5. Zinc treatments were top-dressed using ground corn as a carrier: 1) Control (CON) - no additional Zn supplementation, 2) HiZox® (PZO) - 40 mg of supplemented Zn from a potentiated Zn oxide, and 3) Zinc sulfate (ZS) - 40 mg of supplemented Zn from ZnSO4. Day 1 began a 5-day total collection period of feces and urine that was utilized for determination of Zn and N retention, as well as dry matter (DM), organic matter (OM), and neutral detergent fiber (NDF) digestibility. Blood was collected on day -5, before starting treatment, and on day 1 and day 5 of the collection period to assess circulating plasma Zn concentrations. Mineral solubility was evaluated and filtrate Zn content was analyzed. Data were analyzed using the mixed procedure of SAS 9.4 (SAS Institute, Cary, NC). Contrasts compared CON vs. ZINC (PZO and ZS together) and the two Zn sources (PZO vs. ZS). Significance was declared at P ≤ 0.05 and tendencies at 0.05 < P ≤ 0.10. Dietary treatment did not affect DM, OM, or NDF intake, fecal output, or N intake, fecal and urinary output, and retention (mg/d and percent of intake; P ≥ 0.24). Nitrogen retention was greater in wethers supplemented with Zn (P = 0.02). Zinc intake, fecal output, retention (mg/d and percent of intake), and apparent absorption were greater for ZINC compared with CON (P ≤ 0.01) but did not differ between Zn sources (P ≥ 0.44). The inclusion of supplemental Zn improved N apparent absorption (P = 0.02), however, no differences were observed between Zn sources (P = 0.25). The PZO was less soluble in both solutions compared to the ZS (P ≤ 0.01). These data indicate the potentiated Zn oxide has a similar relative bioavailability compared to Zn sulfate and elicited similar effects on diet digestibility and N utilization. Zinc is an essential mineral added to livestock diets to support growth and efficient nutrient use. This study compared a novel zinc oxide product with zinc sulfate, a commonly used zinc supplement, to evaluate how effectively each source would be utilized by wethers. Researchers measured how much zinc the wethers absorbed and retained, as well as the effects of zinc supplementation on diet digestibility and nitrogen utilization. Results showed the wethers supplemented with either zinc source performed similarly to each other and better than the lambs that received no zinc, indicating both sources effectively provided zinc to the wethers. In addition, zinc supplementation improved nitrogen absorption. These findings suggest that the novel zinc oxide is an effective alternative to zinc sulfate and that the addition of dietary zinc can improve nitrogen utilization in lambs.
Inhibition of terminal complement activation is an effective therapeutic strategy for acetylcholine receptor antibody-positive generalized myasthenia gravis (gMG) and aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (NMOSD), but it increases the risk of invasive meningococcal infections. Consequently, vaccination against meningococcal serogroups A, C, W, Y, and B is mandatory for all patients receiving complement inhibitors. This article provides expert consensus recommendations for managing meningococcal vaccination in patients with NMOSD and gMG receiving complement-inhibiting therapies in Germany, Austria, and Switzerland. The timing and procedures of vaccination should be adapted to the underlying diagnosis and the individual risk of disease exacerbation in this population. In NMOSD, treatment often must begin promptly, particularly after an acute attack; in such cases, vaccination should be administered at treatment initiation together with antibiotic prophylaxis. By contrast, treatment urgency in gMG is typically lower, allowing vaccination to be completed in advance and thereby avoiding antibiotic exposure, which may worsen gMG symptoms. For both diseases, ceftriaxone is recommended as first-line therapy for suspected infection, rifampicin for prophylaxis, and either rifampicin or intramuscular ceftriaxone for post-exposure chemoprophylaxis. Patients should also carry a standby dose of ciprofloxacin for emergency self-administration at the first signs of meningitis, followed by immediate clinical evaluation. These recommendations should be reviewed regularly and updated as necessary to reflect emerging evidence and new vaccine options. How to prevent serious infections during treatment for NMOSD and myasthenia gravis Blocking terminal complement activation is an effective treatment for people with acetylcholine receptor antibody–positive generalized myasthenia gravis (gMG) and aquaporin-4 antibody–positive neuromyelitis optica spectrum disorder (NMOSD). However, this treatment increases the risk of serious meningococcal infections. For this reason, all patients receiving complement inhibitors must be vaccinated against meningococcal serogroups A, C, W, Y, and B. This article presents expert consensus recommendations on how to manage meningococcal vaccination in patients with NMOSD and gMG receiving complement-inhibiting therapies in Germany, Austria, and Switzerland. The timing and approach to vaccination should be adapted to the specific disease and to each patient’s risk of worsening symptoms. In NMOSD, treatment often needs to start quickly, especially after an acute attack. In these cases, vaccination should be given at the start of complement inhibitor therapy together with preventive antibiotic treatment. In contrast, treatment for gMG is usually less urgent. This often allows vaccination to be completed before therapy begins and helps avoid antibiotic use, which may worsen gMG symptoms. For both diseases, ceftriaxone is recommended as the first treatment if infection is suspected. Rifampicin is recommended for preventive antibiotic treatment, and either rifampicin or intramuscular ceftriaxone can be used after possible exposure to infection. Patients should also carry a standby dose of ciprofloxacin to take immediately if early signs of meningitis appear, followed by urgent medical evaluation. These recommendations should be reviewed regularly and updated as new evidence and vaccines become available.
There has been a growing trend of combining traditional Chinese medicine and Western medicine, but the safety of co-prescribing Salvia miltiorrhiza (Danshen) and anticoagulants remains uncertain. This study aimed to evaluate the bleeding risk following the concurrent prescribing of S. miltiorrhiza and anticoagulants in a real-world setting. A self-controlled case series study was conducted. This study used the Chang Gung Research Database to identify adult patients co-prescribed oral anticoagulants and S. miltiorrhiza, and having records of bleeding events. Bleeding events included any bleeding event (gastrointestinal, intracranial, or urogenital bleeding) and major bleeding events (hemorrhages requiring hospitalization or transfusion). Exposure periods were defined as days of concurrent prescribing of S. miltiorrhiza and anticoagulants, while control periods included days of anticoagulant use without S. miltiorrhiza. Conditional Poisson regression was applied to estimate bleeding risk during exposure periods relative to control periods, and results were presented as adjusted incidence rate ratio (aIRR) and 95% confidence interval (95%CI). Among 525 patients receiving both medications, 146 experienced bleeding events. The risk of any bleeding increased significantly during days 1-14 (aIRR: 3.98; 95% CI: 3.29-4.77) and days 15-28 (aIRR: 3.99; 95% CI: 3.23-4.79) after concurrent prescribing of S. miltiorrhiza and anticoagulants. Elevated risks of gastrointestinal bleeding (aIRR: 3.79; 95% CI: 2.95-4.53) and intracranial hemorrhage (aIRR: 3.59; 95% CI: 2.79-5.03) were observed within the first 14 days. Concurrent use of S. miltiorrhiza and anticoagulants significantly increased bleeding risk, particularly during the first 28 days of coadministration. These findings highlight the need for careful monitoring during the initial period of combined therapy. Concurrent use of Danshen (a Chinese herbal medicine) and anticoagulants may increase bleeding risk Danshen, also known as Salvia miltiorrhiza, is a traditional Chinese medicine that is commonly used for heart and circulation problems. In Taiwan, Danshen is frequently prescribed together with modern Western medications. One group of these medicines, called anticoagulants, are commonly used to prevent blood clots in people with conditions such as atrial fibrillation or heart disease. While anticoagulants are effective, they can increase the risk of bleeding. It has been uncertain whether using Danshen at the same time might make this risk even greater. In this study, we used a large medical records database to investigate the real-world safety of taking Danshen together with anticoagulants. We included 525 adults who were prescribed both treatments and 146 of them had records of bleeding events. To minimize differences between individuals, we applied a self-controlled case series (SCCS) study design, where each patient served as their own control. We found that the risk of bleeding was significantly higher during the first 28 days after patients started taking Danshen with an anticoagulant. The risk was especially high for gastrointestinal and intracranial bleeding. On average, the first bleeding event happened about 16 days after starting combined treatment. Importantly, most patients in our study already had a high baseline risk of bleeding, but even after adjusting for other factors, the increased risk remained clear. These findings suggest that patients who take Danshen alongside anticoagulants should be monitored carefully, particularly during the first few weeks of combined use. This study highlights the need for careful communication about herbal and conventional medicine use.
The Hawaiian phoneme inventory includes a consonant ('okina) typically described as glottal stop. Recent studies have found that 'okina is rarely produced with full glottal closure utterance-medially, and is instead produced as a period of creaky phonation. This study investigated the acoustic correlates of utterance-initial 'okina following a pause. Although visible creaky phonation did not occur for utterance-initial 'okina, several reliable acoustic correlates were found during the first vowels of utterances that started with 'okina. Vowels preceded by 'okina had higher fundamental frequency, more abrupt onsets of acoustic energy, greater acoustic energy both in the fundamental frequency and across all frequency ranges, lower harmonics-to-noise ratios, and higher jitter than vowels that started without a preceding 'okina. Linear discriminant analyses of the data showed that these acoustic correlates were able to correctly categorize ∼75% of productions. Although no concurrent articulatory data were collected, arguments are provided to suggest that 'okina is regularly produced as full glottal closure utterance-initially in Hawaiian, possibly because of effects of prosodic strengthening. We believe the present study is the first to establish a relationship between utterance-initial glottal stop and these acoustic effects on the following vowel.
Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory noninfectious disease of the bone that predominantly affects children and adolescents. Bisphosphonates (BPs) are used to treat of CNO with most clinical experience involving pamidronate. Neridronate (NER) is an amino BP with a chemical structure and potency close to pamidronate. This study aims to evaluate the effectiveness and safety of NER in patients with CNO. Monocentric retrospective cohort study. This is a retrospective cohort study conducted on patients included in the monocentric CAMELOT (Chronic non-bActerial osteoMyELitis: A mOnocentric regisTry) registry. Response to treatment was evaluated semiquantitatively based on clinical, laboratory, and radiological domains. The cohort consisted of 27 subjects. Thirteen (48%) received NER alone. At baseline, patients receiving NER alone tended to have a higher rate of vertebral fractures than those treated with combination therapy (46% vs 29%; p = 0.4). The median number of peripheral lesions at magnetic resonance imaging was clearly lower in patients treated with NER alone (0 (interquartile range (IQR) 0-2) vs 2 (IQR 1-5); p = 0.01). An overall response (complete or partial) to NER was documented in all but one patient (96%). Six patients (22%) achieved a complete response in all the three domains, 83% of whom (n = 5) received NER without any other concomitant treatments. Interestingly, using a Receiver Operating Characteristic-derived cutoff of 2 years from CNO diagnosis, all patients who achieved a complete response (100%) had received NER within the first 2 years from diagnosis, compared with 57% (n = 12) of those who did not (p = 0.07). No long-term NER complications were observed. Neridronate appears to be a safe and effective option for CNO, particularly in patients with recent-onset disease, spinal involvement, and fewer peripheral lesions. Early initiation may be associated with higher rates of complete response, though further studies are needed to confirm these findings. Neridronate treatment for chronic nonbacterial osteomyelitis: Real-world evidence on effectiveness, safety, and the importance of early treatment Chronic nonbacterial osteomyelitis (CNO) is a rare inflammatory bone disease that can cause bone pain, swelling, and fractures, particularly affecting children and young adults. Because the disease is uncommon, there is limited information on the best treatment options and on their long-term safety. Neridronate is a medication that reduces bone inflammation and is increasingly used in CNO, but real-life data on its effectiveness are still scarce. In this study, we analyzed patients with CNO included in the CAMELOT registry, a single-center database that collects clinical information from routine care. We evaluated how well patients responded to neridronate by looking at symptoms, blood tests for inflammation, and imaging findings. We also assessed possible side effects. A total of 27 patients were included. Almost half received neridronate alone, while others received it together with additional treatments. Overall, neridronate was effective in nearly all patients, with improvement seen in symptoms, laboratory markers, or imaging findings. About one in five patients achieved a complete response, meaning improvement in all evaluated areas. Most of these patients were treated with neridronate alone. Importantly, all patients who achieved a complete response had started neridronate within two years of being diagnosed with CNO. This suggests that earlier treatment may lead to better outcomes. Neridronate was well tolerated, and no long-term safety concerns were observed during follow-up. In summary, neridronate appears to be a safe and effective treatment for chronic nonbacterial osteomyelitis, especially when started early in the disease course and in patients with spinal involvement or fewer affected bones. Further studies are needed to confirm these findings in larger groups of patients.
Understanding which posts spark conversation, and how large those conversations grow, is vital for moderation, resource allocation, and anticipating information cascades on Reddit and other social platforms. We study discussion initiation and growth on Reddit by modelling whether a root post receives any comments and how large the resulting thread becomes. Using reconstructed threads from r/politics, r/CryptoCurrency, and r/Conspiracy, we extract compact textual, semantic, temporal, domain, and author features from each post. We train subreddit-specific classifiers with small, transparent feature sets and use SHAP for interpretation. Across communities, the external domain a post links to, and, in news ecosystems, the domain's centrality, consistently emerge as predictors of both the start and scale of discussion. Author activity is also predictive: posts from highly active users are more likely to receive comments. Simple textual cues help too: longer subjects and fewer question marks are associated with a higher likelihood of eliciting replies. Community context moderates these effects: in r/politics, linking familiar mid-tier but well-connected news sources is associated with larger threads, while the r/Conspiracy and r/CryptoCurrency communities prefer novel sources. Predicting whether a discussion will start is notably easier than forecasting its eventual size, as adjacent size classes are often confounded. Still, a concise, interpretable feature set captures a substantial proportion of the predictive signal. Our results suggest practical applications for triage: flagging posts likely to trigger substantial discussion could support targeted, pre-emptive moderation and fact-checking without relying on complex, opaque models.
A variety of etiologies can lead a patient to present with symptoms that appear manic. A wide differential should be considered, including delirium, which may in turn be caused by multiple etiologies. Substance ingestion, specifically of dietary supplements, is one potential trigger that is not always considered. A 40-year-old male patient with a history of long-standing attention-deficit/hyperactivity disorder (ADHD), anxiety, and depression presented with anxiety, restlessness, memory gaps, nausea, low appetite, and insomnia. Prior to admission, the patient started taking an herbal supplement for 15 days and stopped taking lisdexamfetamine for 1.5 weeks. Upon initial presentation, the patient was hypertensive and tachycardic. The physical exam was significant for bilateral conjunctival injection and hand tremors. He was disoriented to time and had tangential, pressured speech. A comprehensive medical work-up was largely unremarkable. The urine drug screen was positive for amphetamines and marijuana. The Psychiatry Consultation and Liaison Service evaluated this patient and diagnosed him with delirium, possibly secondary to the supplement side effects. The supplement was discontinued, and the patient's symptoms resolved within 24 hours. While many diagnoses were considered for this patient, delirium, possibly triggered by starting a new herbal supplement, was determined to be the most likely etiology. Many supplements have not been well-studied and are inadequately regulated. This case highlights the potential for clinically significant adverse effects associated with supplement use and emphasizes the need for further research into their safety profiles, pharmacokinetics, and neuropsychiatric consequences to improve patient care and education.
The disappearance of spontaneous student-generated drawings in examinations induced us to start developing anatomical drawing tasks that would be useful learning aids in veterinary medical education. Through a series of drawing workshops, we aimed to broaden the study skills repertoire of students by developing their haptic and observational skills. Data were collected via a questionnaire and analyses of student-generated drawings by comparing the details of the drawings with the purpose of the drawing tasks. Prior experience in drawing or visual arts strongly motivated participation in the workshops. Drawing was mainly used as a self-study aid in subsequent anatomy courses, and respondents reported improved deep learning, evident in the student-generated drawings as well. Bone drawings of wildlife species showed details and interspecific variation beyond the structures taught during the curriculum-based osteology course on domestic animal species. In one drawing task, the detailed observation by students led into a discussion on the functional meaning of the noted structures between the students and the anatomy teacher. The incorporation of proven drawing tasks and tips as part of an ongoing anatomy course instead of separate workshop holds promise as a time-effective way to introduce drawing as a learning aid in veterinary anatomy.
The growing use of phytotherapy and the increasing heterogeneity of available formulations require community pharmacists to critically assess marketed products based on criteria of quality, safety, and efficacy. To design an operational protocol to support community pharmacists in the evaluation and decision-making process regarding plant-based products. A consensus process was conducted by the SEFAC Fitoterapia Commission, involving the development and integration of structured checklists and the selection of open-access data sources. A decision tree was defined, starting from the legal classification, and an analytical framework for product evaluation was established. Finally, a rapid reporting template was designed for use in community pharmacy practice. The resulting protocol provides a structured approach to the evaluation of phytotherapeutic products, organized into five sections and a rapid report. It is based on a sequential assessment of legal classification, scientific evidence, quality, safety, and patient information. Its implementation is supported by official, reliable, and openly accessible databases available to community pharmacists. The proposed protocol facilitates consistent and traceable pharmaceutical decision-making by integrating regulatory and scientific information into a practical and applicable tool for community pharmacy. El aumento del consumo de fitoterapia y la oferta de formulaciones cada vez es más heterogénea. Esta variabilidad requiere que el farmacéutico comunitario conozca y analice la información disponible sobre los productos comercializados con criterios de calidad, seguridad y eficacia. Diseñar un protocolo operativo que oriente al farmacéutico comunitario en la evaluación y la toma de decisiones sobre productos a base de plantas. Proceso de consenso de la Comisión de Fitoterapia de SEFAC, elaboración e integración de listados de aspectos a considerar y selección de fuentes de datos de acceso abierto. Se definió un árbol de decisión que partió de la clasificación legal y se decidió en qué consistiría el análisis transversal del producto evaluado. Finalmente, se diseñó una plantilla de informe rápido para ser utilizada por el farmacéutico comunitario. Se obtuvo un protocolo operativo que guía la evaluación de productos fitoterápicos, estructurado en cinco secciones y un informe rápido. El protocolo se fundamenta en el análisis secuencial de criterios de clasificación legal, evidencia científica, calidad, seguridad e información al paciente. Su aplicación se apoya en bases de datos oficiales, rigurosas y accesibles en línea para todos los farmacéuticos comunitarios. El protocolo, concebido para garantizar decisiones coherentes y trazables, facilita la valoración de productos fitoterápicos, integrando información normativa y científica de acceso abierto en una herramienta práctica y aplicable en farmacia comunitaria.
Preoperative weight loss is often recommended before metabolic and bariatric surgery, although its impact on postoperative outcomes, particularly in high body mass index (BMI) patients (e.g., 50.0-59.9, ≥60), is not fully established. To test the hypothesis that preoperative body mass index reduction (PBR) is associated with improved postoperative outcomes. Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program, 2015-2023. A total of 1,795,127 records were examined, and primary cases were selected while excluding emergencies, revisions, conversions, cases with incomplete data, and preoperative BMI <30 kg/m2. PBR was expressed as a percentage of the highest preoperative BMI. No BMI loss, <10% loss, and ≥10% loss categories were arbitrarily analyzed. Regression analysis was used to analyze outcomes, including prolonged length of stay (>5 days), serious complications, and readmissions. Among 1,316,050 cases, close to 83% achieved PBR and 6.5% achieved ≥10% PBR. Across all starting BMI, PBR was associated with a lower risk of prolonged length of stay (>5 days). Additionally, for BMI ≥60, there was a significant reduction in serious complications with <10% PBR. Similar trends persisted for >10% PBR for serious complications and readmissions. PBR has selective benefits for high-BMI metabolic and bariatric surgery patients. Although complications overall are uncommon, PBR's effect on the risk of these outcomes varies. Focused studies examining well-controlled groups are needed to better understand the potential differences in PBR across the BMI spectrum.
Bone involvement in pediatric Langerhans cell histiocytosis (LCH) causes pain, functional impairment, and frequent relapse, creating a need for adjunctive therapies with rapid skeletal benefit. At National University Hospital, Singapore, a tertiary pediatric hematology-oncology referral centre, we retrospectively evaluated eight children with osseous LCH treated with intravenous zoledronate between January 2020 and December 2025. Three had multisystem disease (two risk-organ-positive), four had multifocal bone LCH, and one had unifocal bone LCH. Pain response (clinical improvement) and radiologic outcome (lesion stability or sclerosis) and adverse effects, and concurrent therapies were recorded. Prior treatment exposure was heterogeneous, ranging from no prior systemic therapy to multi-agent chemotherapy, oral maintenance therapy, targeted therapy, radiotherapy, pamidronate, and indomethacin. Zoledronate was given for painful active bone lesions, particularly in weight-bearing sites, and in selected patients for progressive relapsed osseous disease, poor tolerance of oral chemotherapy, or as a chemotherapy-sparing bone-directed approach. Zoledronate was started at a median age of 60 months. All 4 symptomatic patients experienced pain improvement (100%), with a median time to improvement of 18 days post-infusion. Among 8 patients with imaging follow-up, 2 exhibited complete radiographic resolution and 6 showed improvement. The treatment was well tolerated; transient fever occurred in 4 patients. Three patients received concomitant oral chemotherapy for active systemic disease, either in other systems or in new bone lesions. No cases of clinically significant hypocalcemia or osteonecrosis of the jaw were observed.
Adding ibrutinib to standard, first-line immunochemotherapy improves failure-free survival in adult patients aged 18-65 years with mantle cell lymphoma, according to the first results from the TRIANGLE trial. With prolonged follow-up, we investigated whether the addition of autologous stem-cell transplantation (ASCT) to an ibrutinib-containing regimen improves failure-free survival, and evaluated effects on overall survival. We conducted a three-arm, randomised, open-label, phase 3 superiority trial (TRIANGLE) in 165 secondary or tertiary clinical centres, with experience in mantle cell lymphoma treatment and the capability to perform ASCT or an association with such a centre, in 13 European countries and Israel. Patients aged 18-65 years with untreated, stage II-IV mantle cell lymphoma and suitable for ASCT were randomly assigned (1:1:1) to control group A or experimental groups A + I or I. Randomisation was done using computer-generated random numbers and stratified by study groups and Mantle Cell Lymphoma International Prognostic Index risk groups. Treatment in group A consisted of six alternating, 21-day cycles of R-CHOP (intravenous rituximab 375 mg/m2 on day 0 or 1, cyclophosphamide 750 mg/m2 on day 1, doxorubicin 50 mg/m2 on day 1, vincristine 1·4 mg/m2 on day 1 [up to a maximum of 2 mg], and oral prednisone 100 mg on days 1-5) and R-DHAP or R-DHAOx (intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous or oral dexamethasone 40 mg on days 1-4, high-dose intravenous cytarabine 2 × 2 g/m2 for 3 h every 12 h on day 2, plus either intravenous cisplatin 100 mg/m2 over 24 h on day 1 [R-DHAP] or intravenous oxaliplatin 130 mg/m2 on day 1 [R-DHAOx]), followed by ASCT. In group A + I, oral ibrutinib (560 mg daily) was added on days 1-19 of R-CHOP cycles and as 2-year maintenance after ASCT. In group I, ibrutinib was given the same way, but ASCT was omitted. Rituximab maintenance was allowed in all treatment groups according to national guidelines. Three pairwise, one-sided, log-rank tests for the primary outcome (failure-free survival) were statistically monitored. The primary analysis was by intention to treat and included all randomly assigned patients, ignoring protocol deviations. Safety was assessed in randomly assigned patients who started any trial treatment component of the respective treatment phase. The trial is registered with ClinicalTrials.gov (NCT02858258) and is complete. Between July 29, 2016, and Dec 28, 2020, 870 patients (662 [76%] were male, 208 [24%] were female) were randomly assigned to group A (n=288), group A + I (n=292), or group I (n=290). After median follow-up of 54·9 months (95% CI 54·4-56·0), group A + I did not show superiority over group I, with 4-year failure-free survival of 82% (95% CI 78-87) versus 81% (76-86; hazard ratio [HR] 0·86 [one-sided 98·33% CI 0·00-1·27]; one-sided p=0·21). Group A + I remained superior to group A (82% [78-87] vs 70% [65-76]; HR 0·63 [one-sided 98·33% CI 0·00-0·89]; one-sided p=0·0026) and, as before, group A did not show superiority over group I (70% [65-76] vs 81% [76-86]; HR 1·45 [one-sided 98·33% CI 0·00-2·02]; one-sided p=0·99). 4-year overall survival was 88% (95% CI 84-92) in group A + I versus 81% (76-85) in group A (HR 0·59 [95% CI 0·38-0·92], p=0·0036) and 90% (87-94) in group I versus 81% (76-85) in group A (0·57 [0·36-0·90], p=0·0019). During maintenance or follow-up, the most common grade 3-5 adverse events were haematological disorders, reported in 127 (54%) of 234 patients in group A + I versus 74 (28%) of 269 in group I and 56 (23%) of 240 patients in group A, and infections, reported in 80 (34%) of 234 patients in group A + I versus 71 (26%) of 269 in group I and 37 (15%) of 240 patients in group A. Infections and infestations were the most common fatal adverse events during maintenance or follow-up, occurring in four (2%) of 234 patients in group A + I and five (2%) of 269 patients in group I. After a prolonged follow-up of 55 months, both ibrutinib-containing groups showed relevant improvements not only in failure-free survival-a modified form of progression-free survival-but also in overall survival. In contrast, the addition of ASCT to an ibrutinib-containing regimen had no supplementary benefit but increased toxicity. Induction treatment with ibrutinib and R-CHOP plus R-DHAP (or R-DHAOx), followed by 2 years of maintenance treatment with ibrutinib, should be considered as a new standard of care for younger patients with mantle cell lymphoma. Janssen.
To describe characteristics of patients with hormone receptor positive, HER2 negative, metastatic breast cancer (HR + MBC) who have long-term disease control with single-agent, first-line endocrine therapy (ET). Patients with HR + MBC starting first-line ET between January 1, 2011 and October 13, 2021 were selected from a US-based electronic health record-derived de-identified database. The group was divided by duration of disease control: long-term, ≥3 years without progression, and short-term, < 3 years to progression. Characteristics were compared between groups. Demographic and clinical variables were included in the multivariable analysis. Of the 2374 included patients, 296 (12.5%) were progression-free at 3 years and 136 (5.7%) were progression-free at 5-years. In multivariable analysis, higher number of comorbidities (1 vs none [OR = 1.64, p < .001] or 2 + comorbidities vs none [OR = 1.71, p < .01]) and Medicare insurance coverage (Medicare alone versus commercial OR = 2.89, p < .001) and Medicare/other coverage versus commercial (OR = 2.67, p < .001)] were associated with long-term disease control. Factors inversely associated with disease control included older age (OR = 0.95, p < .001), being in the category of ``All other'' race (not Black or Hispanic) (OR = 0.66, p < .01), worse performance (PS 2 vs 0, p < .001), the presence of visceral metastases compared to with bone-only metastases (OR = 0.60, p < .001), and having ER+/PR- status compared to those with ER/PR + status (OR = 0.55, p < .001). One in 8 patients with HR + MBC has long-term disease control with first-line, single-agent ET. These are younger patients with good performance status, non-visceral metastases, and tumors that express PR. Further research is needed to identify tumor characteristics that predict long-term disease control with ET alone.
Screening and treatment for unhealthy alcohol use (UAU) and alcohol use disorder (AUD) are recommended but underutilized, particularly in hospital settings. To determine whether a comprehensive screening and treatment protocol for UAU in hospitalized patients can help reduce alcohol use. Quality improvement study at single-center safety-net hospital. 27,914 patients were admitted from 9/2022 to 9/2024, and 18,146 (65.0%) were screened with AUDIT-PC, with 1085 (6.0%) screening positive (≥ 5). Substance use navigators (SUNs) identified 257 additional patients with UAU through referral methods. SUNs approached eligible patients and conducted full AUDIT and brief behavioral counseling. Patients with AUDIT ≥ 12 were offered medications for AUD (MAUD) during hospitalization and at discharge. Intervention delivery, 30-day return hospital encounters (readmission or emergency department), and change in AUDIT score among high-risk patients. Of the 1342 intervention-eligible patients, 81% were men, and the mean age was 51 years. 54% were Caucasian, 30% Hispanic/Latinx, and 9% Black. 17% were unhoused, and 18% were uninsured. Of these 1342, 800 (59.6%) patients engaged in the intervention. The mean AUDIT score was 15 (median 14, IQR 8-21). For the 489 (61.1%) patients with AUDIT ≥ 12, 231 (47.2%) were started on medication before discharge. For the 126 patients with repeat AUDIT (25.8%), the mean reduction was 14.2 points (95% CI: -15.4, -12.2). For those with AUDIT ≥ 12, 128 (26.2%) patients had a return hospital encounter within 30 days of discharge. Patients without return encounters had significantly larger reductions in AUDIT score than those who had return encounters (mean reduction -16.2 vs -9.1 points (difference -7.1, 95% CI: -3.1, -11.0)). UAU screening and risk-stratified treatment (including pharmacotherapy) can be delivered in diverse hospitalized patients, and were accompanied by short-term changes in alcohol risk score among patients reached for follow-up.
The rising shift from paper-based to electronic health management information systems (EHMIS) among global health systems has shown promising strides over the past decade. Yet, most African health systems have continued to use paper records with attendant gaps and challenges. Most African governments have now started transitioning from paper to EHMIS but lack adequate guidance to support this shift. There is therefore a need for harmonised regional guidance to ensure that such transitions are carried out systematically and take into account country-specific contexts. The objective of this study protocol is to conduct a scoping review to generate evidence that will inform the development of a comprehensive guide to support countries in the WHO African Region in transitioning from paper-based to EHMIS. The review will follow established methodological guidance for scoping reviews as outlined by Arksey and O'Malley and further refined by Levac et al and the Joanna Briggs Institute, with reporting guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews checklist. A search strategy will be developed to systematically identify relevant studies from both published and grey literature sources including PubMed, Cochrane Library, Scopus and African Index Medicus. Other sources will include Google Scholar, Emerald Journal, the WHO Regional Office for Africa Library and websites of WHO, ITU and Ministries of Health. Reference lists of the retrieved published articles will be manually searched to identify additional relevant studies. Descriptive qualitative content analysis will be undertaken using the policy analysis framework and key findings will be summarised and presented using tables, charts and maps. This study does not involve the collection of primary data; therefore, ethical approval will not be required. On completion of the study, findings will be submitted for publication in a peer-reviewed scientific journal and will also be presented at national, regional and international conferences to support knowledge sharing and policy engagement.
This study reports the facile one‑pot hydrothermal synthesis of a magnetite‑embedded magnetic biochar (Bv‑MBC) derived from Bauhinia variegata leaves and its application as a heterogeneous Fenton‑like catalyst for malachite green (MG) dye degradation. FESEM revealed a highly porous structure with uniformly distributed spherical iron oxide nanoparticles (mean size: 32.65 nm) embedded within the biochar matrix. BET analysis showed a specific surface area of 10.64 m2/g. XRD confirmed the presence of crystalline magnetite with an average crystallite size of 19.91 nm, along with an amorphous carbon signal. VSM measurements gave a saturation magnetization of 30.11 emu/g, sufficient to permit rapid magnetic collection of the catalyst after use. In batch trials, Bv-MBC acted as an efficient Fenton-like catalyst for MG, removing 75.01 ± 1.78% of the dye within 180 min at an initial concentration of 5 mg/L. The kinetic data were described by a second-order model, with the apparent rate constant falling from 0.0034 to 0.0003 L mg-1 min-1 as the starting MG concentration increased from 5 to 25 mg/L. The synthesized Bv‑MBC exhibited good stability, retaining 85.11% of its initial catalytic activity after five successive reuse cycles. The catalyst showed effective MG removal in multiple real water matrices, indicating potential applicability in complex aqueous environments. Hence, this study highlights a promising and easily separable magnetic catalyst to treat dye-contaminated wastewater.
Fluorine exhibits unique atomic properties that profoundly influence the biological and chemical characteristics of compounds. Fluorinated compounds are widely applied in pharmaceuticals and agrochemicals, with the difluoromethyl (CF₂H) group being particularly valuable. The industrialization of photocatalytic reactions is complex, and non-photocatalytic difluoromethylation methods predominantly rely on transition metals. Therefore, the development of a metal-free protocol for difluoromethylation holds considerable significance. This study aims to develop a metal-free, direct C-H quinoxalin-2(1H)-ones/coumarins difluoromethylation method using inexpensive and readily available raw materials and to evaluate the antifungal activity of selected substrates against phytopathogenic fungi. In the difluoromethylation reaction, [Bis(trifluoroacetoxy)iodo]benzene served as the difluoromethylating source, with mCPBA as the oxidant, to carry out the difluoromethylation of quinoxalin-2(1H)-ones/coumarins in the solvent ethyl acetate. We evaluated the antifungal activity using the mycelial growth rate method. This approach is applicable to diverse quinoxalin-2(1H)-ones/coumarins, demonstrates excellent functional group tolerance, and is scalable to gram-scale reactions. Additionally, antifungal assays identified compound 7 as the most effective against R. solani, F. graminearum, and C. orbiculare. This metal-free protocol enables quinoxalin-2(1H)-ones/coumarins difluoromethylation and scales to gram quantities without significant yield loss, facilitating industrial applications. Selected compounds exhibit potent antifungal activity and merit further study. We developed a simple, metal-free protocol for the direct oxidative C-H difluoromethylation of quinoxalin-2(1H)-ones/coumarins using inexpensive, readily available starting materials. Upon evaluation of the antifungal activity of selected substrates against phytopathogenic fungi, compound 7 exhibited the strongest inhibitory effects and demonstrated potential for the synthesis of agrochemical intermediates.
Valproate, commonly used for epilepsy and bipolar disorder, carries known teratogenic risks when taken by women during pregnancy. In 2023, the Medicines and Healthcare products Regulatory Agency (MHRA) issued updated guidance suggesting a possible link between valproate use in males around conception and neurodevelopmental disorders in offspring. However, awareness among male patients and documentation of advice in general practice remains inconsistent. To ensure that 100% of male patients on valproate were informed of MHRA guidance regarding family planning risks and advised on effective contraception within a 2-month period. Using EMIS, 22 male patients on valproate were identified. An Accurx text message was sent outlining MHRA guidance, contraception advice, and encouraging contact if planning a family. The text auto-coded advice into the EMIS record. Follow-up phone calls were made over two attempts to confirm receipt and provide verbal guidance where needed. All 22 patients received the text; only one responded. Phone contact was successful with 18 patients: eight confirmed receiving the text, and 10 had not. Five were already aware of the MHRA alert, while 13 were informed during calls. Four patients could not be contacted. No patients requested further information or took additional action such as starting contraception or seeking pharmacist advice. This quality improvement project improved documentation and patient awareness of valproate-associated family planning risks. Text messaging alone was ineffective; personalised phone calls were more successful. Future strategies should include routine medication reviews, pharmacist-led discussions, and system alerts to ensure ongoing patient education.