High-quality evidence guiding opioid prescribing decisions for acute pain across common diagnoses is lacking. To describe pain trajectories and patterns of opioid and nonopioid treatment use among individuals who were offered opioids for the treatment of acute pain. This was a prospective cohort study of patients recruited from 5 US health systems between September 2020 and March 2023 in emergency departments (EDs), primary care clinics, dental practices, or after cesarean delivery or knee replacement. Eligible patients were opioid-naive adults aged 18 years or older at all study sites, as well as adolescents aged 15 to17 years undergoing impacted molar extraction at 1 site, who were offered an opioid prescription for acute pain. Analysis was conducted April 2023 through February 2026. Offer of a prescription for an opioid analgesic. Time to pain resolution (3 consecutive reports of no pain), patterns of opioid and nonopioid treatment use, and opioid-related adverse effects, ascertained from digital questionnaires. Among 1708 enrolled patients (median age, 38 years [IQR, 28-52 years]; 615 [36.0%] reporting race or ethnicity underrepresented in studies of acute pain management) followed up for 180 days, 915 (53.6%) were recruited in EDs, 307 (18.0%) in primary or urgent care, 263 (15.4%) in dental settings, and 223 (13.1%) in inpatient settings. Pain sources included dental (302 patients [17.7%]), trauma or injury (302 [17.7%]), obstetric (176 [10.3%]), musculoskeletal (131 [7.7%]), and low back (100 [5.9%]). Among 1502 patients reporting pain level at least once, median time to pain resolution irrespective of the treatment approach was 20 days (IQR, 8-88 days), with longer durations for surgical pain (74 days [IQR, 30 days to not reached]) and low back pain (69 days [IQR, 18 days to not reached]). The median time to opioid discontinuation among 1189 patients (69.6%) who reported any opioid use was 7 days (IQR, 2-31 days); an estimated 10.0% (95% CI, 7.7%-12.7%) of patients used opioids for at least 90 days, with higher rates in people reporting frequent pain before enrollment. Of 1482 patients (86.8%) completing at least 1 survey during the first 2 weeks of follow-up, 1153 (77.8%) reported using any opioids and 1287 (86.8%) reported using acetaminophen or ibuprofen. Among 619 (52.1%) patients with any opioid use who reported the dose of opioids taken in the first 15 days, daily doses were low (median, 10 [IQR, 5-15] morphine milligram equivalents). Most respondents reported leftover opioids (657 of 982 responding [66.9%]). In this cohort study of opioid-naive patients with acute pain, opioid use was generally low dose and of short duration, although some patients reported prolonged opioid use; most reported achieving pain resolution within 3 weeks, with longer times for surgical and low back pain. The findings suggest current guidelines for multimodal treatment and for short-duration opioid prescriptions if needed will serve many but not all patients, and treatment should be tailored to address individual patients' needs.
We hypothesized that an electronic health record (EHR) alert grounded in behavioral science could reduce new antipsychotic medication prescriptions for older adults with dementia. We conducted a pragmatic clinical trial at a large academic health system, randomizing providers to receive the alert (intervention) or not (control) when prescribing new antipsychotic medications to outpatients with dementia. Eligible providers were those who previously signed a new antipsychotic prescription (n = 150). The EHR alert contained: (1) text stating that antipsychotic medications increase mortality risk; (2) a link to an after-visit summary handout describing non-pharmaceutical approaches; (3) a default to a lower dose and pill-days. The primary outcome was mean total pill-days over 19 months. We used provider-level linear regression, controlling for provider characteristics including prior prescribing behavior. Secondary outcomes included order cancellations and exploratory analyses of treatment effects among providers with above-average baseline prescribing patterns. Between 9/15/2021 and 4/11/2023, 28 providers in the intervention and 21 in the control arm initiated prescriptions to eligible patients, resulting in 139 enrolled patients; mean patient age was 83 (SD 9.7); 67% female. After 19 months, raw mean (SD) pill-days were 126 (228) for the intervention and 225 (601) for the control group. Intervention assignment was not significantly associated with total pill-days among enrolled patients (primary outcome, mean difference -113 [95% CI: -256, +30], p = 0.12). Orders were canceled in 12/58 (21%) of intervention encounters. The intervention was estimated to reduce pill-days for providers with average baseline prescribing behavior (-126, 95% CI: -3, -248; p = 0.04); for each additional 10 baseline pill-days, this reduction effect increased by -8.8 pill-days (95% CI: -3.9, -13.6; p < 0.001). This EHR alert did not reduce the primary outcome of antipsychotic pill-days. However, the nonsignificant effect size was substantial, and exploratory analyses revealed that the intervention significantly reduced pill-days for providers with average baseline prescribing. Future alerts should test targeting high prescribers.
Accurate estimation of lesion-specific effective half-life (Teff) is essential for patient-specific dosimetry in radioiodine (I-131) therapy for differentiated thyroid cancer (DTC). Although conventional multi-timepoint imaging provides detailed kinetic information, it is often impractical for routine clinical implementation. This study prospectively evaluated a simplified dual-timepoint planar imaging protocol aimed at balancing quantitative reliability with clinical feasibility. Fifty patients with DTC undergoing I-131 therapy were prospectively analyzed. Whole-body planar images were acquired twice after administration: an early scan at 1.98-3.25 days (mean, 2.71 days) and a delayed scan at 8.97-17.16 days (interval between the two scans ranged from 6.18 to 14.28 days [mean, 12.35 days]). Lesion-specific Teff values were calculated assuming mono-exponential clearance between the two scans using a log-linear approximation of measured activity counts. Quantitative reproducibility was assessed by comparing activity-count calibration slopes derived from an internal reference I-131 capsule between independent imaging sessions. The mean Teff was 2.16 ± 0.56 days and 3.11 ± 0.74 days for thyroid bed (n = 35) and metastatic (n = 19; p < 0.001) lesions, respectively. Among metastatic sites, bone and lung metastases showed numerically similar Teff values (3.22 ± 0.76 and 3.36 ± 0.80 days, respectively); however, this subgroup comparison was limited by the small sample size. Calibration slopes derived from the internal reference capsule demonstrated only 5.0% inter-session variability, indicating high quantitative reproducibility. Dual-timepoint planar imaging incorporating internal capsule calibration enables reproducible estimation of lesion-specific Teff in patients undergoing I-131 therapy for DTC. This approach achieves a practical balance between quantitative accuracy and clinical feasibility, enabling reliable characterization of iodine kinetics with minimal imaging burden and supporting individualized dosimetry in routine clinical practice.
The purpose of this study is to determine the prevalence of arthrogenic muscle inhibition (AMI) after total knee arthroplasty (TKA) and to identify independent risk factors associated with its persistence during the early post-operative period. This retrospective monocentric study included 229 consecutive patients undergoing primary TKA between January 2024 and May 2025. AMI was assessed pre-operatively and post-operatively at 30 and 60 days using the Sonnery-Cottet (SANTI) clinical classification by trained rehabilitation physicians. Although not specifically validated in TKA patients, this classification was used due to the absence of a validated alternative. Multivariate logistic regression analyses were performed to identify factors associated with AMI. 51.1% were male with a mean age at surgery of 70.7 ± 9.6. Pre-operatively, 9.2% of patients showed signs of AMI. The post-operative prevalence was 44.5% at 30 days and decreased to 19.2% at 60 days. Independent risk factors for AMI at 30 days were body mass index ≥ 30 kg/m2 (odds ratio [OR] 1.97; p = 0.04), symptom duration ≥ 4 years (OR 2.60; p = 0.003), pre-operative AMI (OR 6.08; p = 0.003), post-operative morphine use (OR 2.15; p = 0.01) and pre-operative neutral limb alignment (hip-knee-ankle 175°-185°) (OR 0.38; p = 0.006). At 60 days, AMI persistence was associated with age ≥ 70 years (OR 3.67; p = 0.004), pre-operative AMI (OR 4.41; p = 0.022), Visual Analogue Scale ≥ 7 at Day 7 (OR 3.37; p = 0.044) and AMI at 30 days (OR 15.6; p < 0.001). AMI is a frequent issue after TKA, affecting 45% of patients at 1 month and 20% at 2 months. Its occurrence is associated with pre-operative inhibition, obesity, chronic symptoms, post-operative pain and age. Level III, retrospective cohort study.
COVID-19 remains a leading infectious cause of death and hospitalisation globally. Coinfections with SARS-CoV-2 and other respiratory pathogens may result in more severe illness, however the prevalence of coinfection in Australia is unknown. This Australian study aimed to determine the prevalence and microbiology of respiratory and bloodstream coinfections, antimicrobial use, and outcomes in hospitalised patients with moderate to severe COVID-19. This was a retrospective cohort study of adult patients with moderate to severe COVID-19, admitted at the Sunshine Coast University Hospital from February to July 2022. Data regarding patient characteristics, comorbidities, microbiological results, hospital length of stay, intensive care unit admission, and mortality were compared between the coinfection and no-coinfection groups. Logistic regression analysis was performed to identify factors associated with coinfection. Coinfection was documented in 23 (12%) of the 190 patients admitted with moderate-severe COVID-19. Bacterial infections were the most common (54% of coinfection episodes), followed by fungal (32%), and viral (14%). Antibiotics were prescribed for 74% of patients, for a median duration of 6 days (IQR 4-8 days). Patients with coinfection had a median length of stay of 9 days (IQR: 4-19.5) compared to 6 days in the no-coinfection group (IQR: 3-9; p = 0.047). There was no mortality difference between the two groups. Patients admitted to intensive care had higher odds of coinfection compared to patients not admitted to intensive care (OR 3.39, 95% CI 1.19-9.66, p = 0.02). Severe COVID-19 and Aboriginal and Torres Strait Islander descent were also associated with coinfection. The causal nature of these relationships requires further interrogation. The prevalence of respiratory and bloodstream coinfection was low in our cohort of hospitalised COVID-19 patients. Despite non-standardised microbiological testing, antibiotic use was disproportionately high. Further work is required to define risk factors and improve diagnosis of COVID-19-associated coinfection, to better inform antimicrobial stewardship.
Calcified coronary lesions present challenges during percutaneous coronary intervention, often impeding successful stent delivery and expansion. Rotational atherectomy (RA) facilitates plaque modification in such cases. However, clinical performance of a novel RA system remains unclear. This noninferiority study evaluated the safety and efficacy of the novel system. This trial included 2 prospective phases, a first-in-human (FIH) study and a pivotal randomized controlled trial. In the FIH study, 15 patients underwent percutaneous coronary intervention with the novel RA system, and clinical success was assessed. In pivotal trial, 224 patients with calcified lesions were randomized to receive RA using either the novel (n = 111) or established (n = 113) system, followed by stenting. The primary endpoint was freedom from major adverse cardiovascular events (MACEs), a composite of cardiac death, myocardial infarction, and target vessel revascularization, at 30 days. Secondary endpoints included MACEs at 12 months and quantitative imaging analyses. All FIH patients achieved clinical success. In pivotal study, the median follow-up time was 349.5 (IQR: 343, 359) days. Freedom from MACEs at 30 days was 97.3% (108 of 111 vs 110 of 113; 95% CI: 92.3%-99.4% vs 92.4%-99.5%) in both groups (P for noninferiority <0.0001). At 12 months, MACEs remained low in both groups (2.7%; 95% CI: 0.9%-8.1% vs 2.7%; 95% CI: 0.9%-8.0%; P = 1.0000). Postprocedural minimal stent area was similar on intravascular ultrasound between the 2 groups (5.29 ± 1.20 vs 5.29 ± 1.47 mm2, P = 0.9921). The novel RA system demonstrated noninferior safety and efficacy to established system, offering an effective alternative for the treatment of complex calcified coronary lesions. (CorOnary atheRectomy system in patiEnts with Coronary arTery calcification (CORECT); NCT05447585).
Digital remote monitoring technologies, including smartphones and wearables, offer promising avenues for early detection of psychosis relapse. However, selecting devices that are acceptable to participants and produce high-quality data remains challenging. The aim of this nested pilot study was to assess the acceptability and data quality of 3 commercially available wearable devices in people with psychosis recruited to the CONNECT cohort study. Participants recruited to the CONNECT study before July 31, 2024, were included in the pilot study and selected 1 of 3 wearable devices: a Fitbit Charge 5, Samsung Galaxy Watch 5, or Apple Watch SE. Baseline demographics were compared between device groups. Acceptability of devices to participants was assessed through a Wearable Device Satisfaction Questionnaire after 3 months of use, with the proportion of positive responses to each question calculated and compared. Data completeness was also assessed by calculating the number (and percentage) of valid days of step count, heart rate, and sleep data, and comparing between groups. Data quality was assessed through summarizing the amount of troubleshooting required, additional metrics available from the wearables, and continuity of data completeness by calculating the proportion of participants with at least 3 days of heart rate data per week for the first 20 weeks of follow-up. Predefined criteria were used to determine the next steps for the wider CONNECT study: if one device was superior, this would be selected; if none were found to be superior and the Fitbit was found to be noninferior, then Fitbit would be retained. Of the first 107 participants recruited to CONNECT, 105 were included in the pilot study evaluation. The Samsung Galaxy Watch was selected most frequently by participants (46/105, 43.8%), followed by the Apple Watch (27/105, 25.7%), and Fitbit Charge (23/105, 21.9%). Differences in participant demographics were observed across device groups. Self-reported acceptability after use did not differ substantially between devices. However, in terms of data completeness, the median proportion of valid heart rate data days was significantly lower for Samsung Galaxy (median 31.2%, IQR 8.5%-46.0%) compared to Fitbit (median 80.1%, IQR 26.7%-95.0%; P=.003) and Apple Watch (median 49.3%, IQR 21.5%-86.0%; P=.02). There was no significant difference between Fitbit and Apple Watch. Similar patterns were observed for step count and sleep data. The Samsung Galaxy Watch required more frequent troubleshooting for data flow issues and lacked additional physiological metrics, available from the other devices. Due to comparatively lower data quality and technical performance, the Samsung Galaxy Watch was discontinued for use in the subsequent phase of the CONNECT study. The study highlights the importance of incorporating nested evaluations of devices in long-term research.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an orphan, aggressive hematologic malignancy characterized by high CD123 expression. Tagraxofusp (TAG), a CD123-directed toxin, is the only approved therapy. Prior studies demonstrated BPDCN dependence on BCL2, sensitivity to venetoclax (VEN), and reversal of TAG resistance with azacitidine (AZA). We conducted a phase 2 study evaluating combination therapy with TAG, AZA, and VEN in patients with BPDCN (NCT03113643). Patients with previously untreated (1L) or relapsed/refractory (R/R) BPDCN received 28-day cycles of AZA (75 mg/m² days 1-7), VEN (400 mg days 1-21), and TAG (12 µg/kg days 4-6). Eligibility followed TAG guidelines to mitigate risk of capillary leak syndrome (CLS). Twenty-seven patients were enrolled (16 1L, 11 R/R), with median age of 70 years (range 21-81). Composite complete remission (CR/CRi/CRc) rates were 88% in 1L and 64% in R/R cohorts. Median duration of response was not reached in 1L and was 7.2 months in R/R patients. CLS occurred in 15% of patients; most were grade 2. In the 1L cohort, median overall and progression-free survival were not reached; the 2-year overall survival was 65% and 2-year progression-free survival was 53%. Median overall survival in R/R patients was 8.4 months. A high proportion of patients proceeded to allogeneic stem cell transplantation in remission (63% 1L, including 10 of 11 patients age 75 or younger; and 55% R/R). TAG-AZA-VEN is highly active in both untreated and relapsed BPDCN with a predictable and manageable safety profile, supporting its use as a new therapeutic option.
In this study, we investigated the association between time spent in Type 1 emergency departments (EDs) (consultant led 24-hour service with full resuscitation facilities) and all-cause mortality 30 days after leaving the department alive (either discharged home or admitted to inpatient care). This was a cross-sectional, retrospective, observational study using national linked data. We included individuals who visited a Type 1 ED between 21st March 2021 and 31st March 2022, under a nonimmediate acuity who survived to discharge or admission to inpatient care. Fitting a logistic regression model, we assessed the association between time spent in the ED and the risk of all-cause, 30-day death following departure. Of 6,721,179 individuals (mean age 41.3 years; 52.6% women, 81.4% White), 1.3% died within 30 days of visit. After controlling for confounders, compared with patients who spent 2 hours in the ED, the adjusted odds of postdischarge death were: 1.1 times higher (1.07 to 1.14) for 3 hours; 1.6 times (1.48 to 1.68) for 6 hours; 1.9 times (1.80 to 2.03) for 9 hours; and 2.1 times (2.02 to 2.28) for 12 hours. Longer time spent in the ED for nonimmediate care is associated with increased risk of all-cause mortality within 30 days of discharge or admission. However, the reasons for this association are uncertain and may reflect residual confounding, rather than a direct causal effect of time spent in the ED. Therefore, further research is needed to understand causal drivers of postdischarge mortality.
Nirmatrelvir/ritonavir (Paxlovid) is an oral antiviral for COVID-19. Although effective, its use is complicated by clinically important potential drug-drug interactions (DDIs). Long-term care facility (LTCF) residents are especially vulnerable to both COVID-19 and the adverse effects of potential DDIs because of advanced age, multimorbidity, and polypharmacy. The objective of this study was to quantify the prevalence and duration of potential DDIs among US LTCF residents administered nirmatrelvir/ritonavir. We conducted a cohort study of LTCF residents using electronic medication administration record data from the Long-Term Care Data Cooperative linked to Medicare claims (January 2022-January 2025). Days of nirmatrelvir/ritonavir administration were identified, and concurrent exposure to 236 potentially interacting medications was assessed. A potential DDI was defined as same-day coadministration, reflecting concurrent exposure rather than clinical adverse effects. We estimated the prevalence of potential DDIs and the median duration of overlapping exposure. Among 48,260 LTCF residents treated with nirmatrelvir/ritonavir, the mean age was 78.8 years (SD, 10.9), 58% were female, and 76% were non-Hispanic White. Overall, 86% were exposed to at least 1 potential DDI. The most common potentially interacting medications were atorvastatin (28.1%; 95% confidence limits [CLs], 27.7-28.50), amlodipine (21.6%; 95% CLs, 21.2-21.9), and apixaban (15.9%; 95% CLs, 15.6-16.3). Median days of overlapping exposure ranged from 5 to 6 days. Potential DDIs most frequently involve medications requiring temporary withholding or dose adjustment rather than contraindication. The high prevalence of potential DDIs likely reflects the complexity of medication management in LTCFs, where antiviral use must be weighed against comorbidities and polypharmacy. Potential DDIs with nirmatrelvir/ritonavir were common among LTCF residents, though contraindicated ones were uncommon. These findings underscore the need for ongoing medication reviews and clinician and pharmacist oversight to ensure safe antiviral use in LTCFs.
Introduction Apixaban reduces thromboembolic events, bleeding, and mortality compared with warfarin in patients with nonvalvular atrial fibrillation (NVAF). However, evidence in patients with kidney failure (KF) receiving peritoneal dialysis (PD) is limited. We evaluated the safety and effectiveness of apixaban versus warfarin in this population. Methods Using the US Renal Data System, we identified Medicare beneficiaries on PD with newly diagnosed NVAF (2014-2019) who had no prior oral anticoagulation (OAC) use. We included patients initiating apixaban or warfarin within 30 days after NVAF diagnosis. After propensity matching we estimated the hazard ratios for thromboembolic events, bleeding events, and mortality using Cox models accounting for competing risks, where applicable, and using both intent-to-treat and as-treated approaches. Results Among 6,571 OAC-naive PD patients with newly-diagnosed NVAF, 334 initiated apixaban and 717 initiated warfarin within 30 days. After 1:1 propensity matching, all observed characteristics of 330 apixaban and 330 warfarin users were balanced. The median CHA₂DS₂-VASc score was 4 (IQR 3-5). In intent-to-treat analyses, hazards of ischemic stroke (HR=0.92; 95%CI, 0.42-2.01) and the composite of other thromboembolic outcomes with cardiovascular death (HR=0.90; 95%CI, 0.66-1.22) did not differ between groups. The hazards of clinically important bleeding (HR=0.81; 95%CI, 0.62-1.07), major bleeding, intracranial hemorrhage, and all-cause mortality also did not differ between groups. Findings were consistent in as-treated analyses. Discussion Among PD patients with newly-diagnosed NVAF, we observed no statistically significant differences between apixaban and warfarin for effectiveness or bleeding outcomes. Given the challenges of warfarin management in KF, apixaban may represent a more practical option when anticoagulation is pursued.
Heat stress (HS) poses a significant challenge to broiler welfare and growth. While the effects of constant (24 hr/day) HS are well documented, the consequences of HS duration at specific ages and the capacity for subsequent recovery, remain less understood. Therefore, 630 one-day-old Cobb500 broilers were assigned to 7 treatments and reared during a 6 week period to investigate the effects of varying HS duration on broiler growth, and recovery at different ages of exposure. Broilers were housed either in a climate-controlled (CC) barn or a natural cyclic HS open-sided (OS) barn. Treatments included broilers continuously housed for 6 weeks in CC (6CC) or OS (6OS). In addition, three other treatments were transferred from CC to OS for the final 3 weeks (3OS), 2 weeks (2OS), or 1 week (1OS) of the experiment. The last two recovery treatments (REC1, REC2) were placed in the CC house followed by 1 or 2 weeks in the OS house, from day 21 or 28 until 35, before returning to CC for the final week of the experiment. Each treatment included six replicates, with 15 broilers per replicate pen at the start of the experiment. Cloacal temperature, growth performance, mortality, plasma corticosterone, protein carbonyls, and histological morphology of the heart and lung were evaluated. Exposure to HS increased the cloacal temperature by at least 1.5°C at all ages (P < 0.001). Sudden exposure to HS at 36 days of age (1OS) resulted in severe mortality (67%) compared to control (6CC) and broilers exposed to HS at younger age (3OS and 2OS). HS consistently reduced body weight (BW) and average daily feed intake (ADFI); 6OS broilers finished 40.1% lighter than 6CC broilers (P < 0.001). Upon returning to thermoneutral conditions, REC1 and REC2 broilers immediately resumed growth rates comparable to controls but did not exhibit compensatory growth to recover the accumulated BW deficit. Very short-term HS exposure (1OS) triggered a spike in plasma corticosterone (25.42 nmol/L) and protein carbonyls (1.92 nmol/mg) compared to 6CC controls (P < 0.001). Descriptive histological examination revealed that subendocardial erythrocyte accumulations were increased in 6OS hearts and were absent in CC-housed broilers. Taken together, sudden HS exposure at 36 days of age poses an unmanageable threat to survival. While broilers recover from HS quickly, lost performance is not regained through compensatory growth within the 6 week period.
Osteoporotic vertebral compression fractures (OVCF) are common and disabling. Augmentation techniques differ by access (uni vs. bi), trajectory (curved vs. straight), and implant platform, but direct head-to-head evidence is limited. We conducted a frequentist random-effects network meta-analysis (NMA) of randomized controlled trials (RCTs) with method-specific nodes (unipedicular percutaneous vertebroplasty (UPVP), bipedicular percutaneous vertebroplasty (BPVP), unipedicular percutaneous kyphoplasty (UPKP), bipedicular percutaneous kyphoplasty (BPKP), percutaneous curved vertebroplasty (PCVP), percutaneous curved kyphoplasty (PCKP), deflectable percutaneous kyphoplasty (DPKP), dual-plane UPVP, KIVA, TIVAD, and conservative care). Risk of bias was assessed using the Cochrane risk-of-bias tool. Outcomes were Visual Analog Scale score (VAS) (≤ 14 days, 1-3 months, > 6 months), the Oswestry Disability Index (ODI) (post-operative, long-term) (measured at the earliest post-procedural assessment and at long-term follow-up > 6 months), vertebral height restoration (%), local kyphotic angle (LKA) at last follow-up, bone-cement leakage, secondary vertebral fractures, and operative time. Twenty-eight RCTs (n = 3,049) were included. By P-scores, DPKP and dual-plane UPVP ranked highest for VAS ≤ 14 days (conservative ranked last), PCVP and UPKP ranked highest at 1-3 months, and dual-plane UPVP and PCVP ranked highest at > 6 months. For disability, PCKP and UPKP ranked best post-operatively, and dual-plane UPVP and PCKP ranked best at long-term follow-up. Radiographically, BPKP and KIVA ranked highest for vertebral height restoration, while PCKP and UPKP yielded the lowest LKA at last follow-up. Leakage was lowest with the Shield kyphoplasty system (Soteira), PCVP and PCKP, secondary fractures were lowest with TIVAD and KIVA, and operative time was shortest with UPKP and PCVP. In an RCT-based NMA of OVCF treatments, augmentation generally ranked above conservative care for pain, but no single technique dominated all endpoints. Procedure selection should be tailored to the clinical goal - pain control, height/alignment, safety, or efficiency - while considering patient factors.
The standard one-injection start (OIS) regimen of aripiprazole once-monthly (AOM) requires a 14-day oral overlap, which may present practical challenges in routine care. This study evaluated whether the accelerated two-injection start (TIS) strategy, which eliminates oral overlap, affects 1-year real-world outcomes in patients with bipolar disorder (BD). This retrospective observational study included 132 inpatients with Bipolar I disorder hospitalized for an acute manic episode (OIS: n = 88; TIS: n = 44) initiated on AOM between January and December 2024. Primary outcomes were 1-year rehospitalization and emergency room (ER) visits. Exploratory analyses examined relapse-related outcomes, timing of initiation, and baseline illness severity. Baseline and acute-phase characteristics were comparable between groups. Multivariable models confirmed the TIS regimen did not significantly increase the hazard of 1-year rehospitalization (aHR: 0.71, p = 0.435) or ER visits (aHR: 0.76, p = 0.378) compared to OIS. Among patients who relapsed, TIS was associated with fewer recurrent ER visits (p = 0.031) and a longer time to first ER visit (93.5 vs. 40.0 days). Exploratory analyses showed numerically lower ER utilization rates for the TIS regimen when initiated early (≤7 days) and among patients with higher baseline illness severity. The TIS regimen appears to be a feasible and safe alternative to OIS in BD, without compromising 1-year clinical outcomes or increasing adjunctive medication use. Exploratory findings suggested a potential trend toward a less intensive relapse course and delayed acute psychiatric service utilization among patients receiving TIS. Given the exploratory nature of these analyses, these observations require confirmation in larger prospective studies.
Myocardial fibrosis following myocardial infarction (MI) drives the progression of heart failure, yet effective therapeutic drugs remain unavailable. This study aimed to evaluate the anti-fibrotic effect of the natural small-molecule compound sennoside A (SA) on pathological fibrosis specifically at 28 days post-MI, and to explore its underlying molecular mechanism. Mouse MI models were established and treated with SA for 28 days. To evaluate therapeutic efficacy, cardiac function was assessed by echocardiography, and myocardial fibrosis was quantified using histopathological staining. For mechanistic investigation, molecular docking and enzymatic activity assays were performed to determine whether SA targets the histone demethylase KDM4B. In vitro experiments were conducted to characterize the effects of SA on fibroblast activation and extracellular matrix production. SA significantly improved cardiac function, as reflected by increased left ventricular ejection fraction (LVEF) and fractional shortening (FS). Histological analysis showed that SA significantly reduced fibrotic area and collagen deposition compared with untreated MI mice. Mechanistically, molecular docking predicted a stable interaction between SA and KDM4B, and enzymatic assays confirmed that SA inhibited KDM4B activity and increased the modification of H3K9me3. Meanwhile, IRX2 expression was significantly downregulated, which was accompanied by reduced expression of fibrotic markers, extracellular matrix deposition and fibroblast phenotypic transformation. This study identifies sennoside A binds to KDM4B and reduces the demethylase activity, thereby reducing IRX2 expression in a KDM4B-associated manner and ameliorating cardiac fibrosis after myocardial infarction and improving cardiac function.
Days with high diurnal temperature range (DTR) are commonly linked to morbidity and mortality, yet these health impacts are rarely connected with the underlying meteorological factors. To provide health researchers with much-needed context, we examine the climatology of DTR in the continental United States from 1950 to 2022 using the gridded ERA5 Land reanalysis archive. DTR has declined significantly over the period of record over much of the United States, with stronger signals in the east and north in summer and autumn. Extreme positive DTR values (95th percentile), which are commonly linked to morbidity, are also declining significantly. DTR declines can be ascribed to maximum temperatures increasing at a slower rate than minima, with minimum temperatures rising in response to increasing atmospheric humidity, cloud cover, and precipitation. Given that DTR trends are clearly linked to anthropogenic warming, this would imply reduced health risks, if DTR is a direct causal exposure. Because the most extreme DTR days occur under calm, low-humidity and cloud-free conditions, clinical evidence is needed to demonstrate how and why these weather conditions produce intra-day changes in exposure that are physiologically harmful.
CAR-T cell therapy is a cellular cancer immunotherapy that has impressively improved outcomes in hematological malignancies compared to conventional treatments. Yet, many patients do not respond permanently. Nonlinear mixed-effects modeling can support a better understanding of the unique and not fully understood dose-exposure and exposure-response relationships for CAR-T cell therapy by integrating available knowledge into a quantitative, physiology-motivated framework. However, to unfold its full potential, it requires informative and efficient study designs for clinical data collection. We aimed to develop an optimal experimental design framework informing a robust and feasible clinical CAR-T cell study design based on a published mechanistic model of CAR-T cell kinetics and tumor dynamics. By considering variability between study populations and parameter uncertainty, we (1) identified the minimal population size required to inform model parameters, (2) assessed different sampling strategies, and (3) informed flexible sampling windows instead of fixed sampling timepoints. The optimized study design consisted of 60 patients, three fixed assessments of tumor burden (days 0, 30 and 90), and three feasible CAR-T cell sampling windows (days 2-4, 12-18 and 32-47 after infusion). In stochastic simulation and estimation, the optimized design with sampling windows showed better performance in informing model parameters, including those characterizing heterogeneous outcomes, than designs with fixed sampling timepoints, confirming its efficiency and robustness. This framework shall facilitate future feasible and resource-efficient CAR-T cell clinical data collection, thus showcasing the potential of optimal experimental design to advance the development and optimization of complex cancer immunotherapies in clinical trials and clinical practice.
Paronychia is a painful periungual inflammation that can significantly impair quality of life and even necessitate modifications to cancer treatment. With the expanding use of epidermal growth factor receptor (EGFR) inhibitors and other targeted therapies, the reporting frequency of drug-induced paronychia in pharmacovigilance databases has increased. However, comprehensive assessment of the relative reporting patterns and temporal characteristics of drug-induced paronychia remains limited. We performed a disproportionality analysis of adverse event reports retrieved from the US FDA Adverse Event Reporting System (FAERS) and the Japanese Adverse Drug Event Report database (JADER). After case-level deduplication, paronychia was identified using MedDRA preferred term. Four signal detection algorithms were employed (Reporting Odds Ratio, Proportional Reporting Ratio, Bayesian Confidence Propagation Neural Network, and Multi-item Gamma Poisson Shrinker). A drug-paronychia pair was classified as a positive signal only when all four algorithms simultaneously satisfied thresholds (ROR lower 95% CI > 1; PRR ≥ 2 with χ2 ≥ 4; BCPNN IC025 > 0; MGPS EBGM05 > 2; each requiring N ≥ 3). Time-to-onset characteristics were analyzed using Weibull distribution parameters to distinguish early failure from random failure patterns. A total of 3,693 paronychia reports in FAERS and 338 in JADER were analyzed. In FAERS, females comprised 53.1% of reports; patients aged 18-64 years represented 36.6%. The ten drugs with the strongest disproportionality signals (ranked by ROR) were Dacomitinib [ROR 374.77; 95% CI 276.31-508.31], Selumetinib [304.66; 228.55-406.10], Afatinib [296.98; 264.27-333.74], Panitumumab [204.37; 183.10-228.11], Amivantamab [167.61; 124.71-225.26], Necitumumab [151.38; 67.14-341.35], Mobocertinib [117.03; 71.21-192.34], Erdafitinib [59.36; 33.57-104.99], Lapatinib [48.09; 39.71-58.24], and Gefitinib [47.28; 37.09-60.27]. Thirty-two drugs exhibited statistically significant associations with paronychia that were not listed in their FDA-approved labeling, highlighting a critical safety gap. Time-to-onset analysis of 30 drugs with valid TTO data revealed that median onset times ranged from 4 days (Necitumumab) to 575.5 days (Alendronate), with several of the most frequently reported EGFR and MEK inhibitors exhibiting an early-failure pattern (Weibull β < 1), supporting concentrated monitoring during the first weeks of therapy. This pharmacovigilance assessment identified drugs with notable disproportionality signals for drug-induced paronychia, underscoring the utility of real-world data for early detection of safety signals. The identification of unlabeled paronychia risks in 32 medications highlights critical gaps in current safety information. These findings, derived from spontaneous reporting data, indicate associations rather than causal risk and require further clinical and epidemiologic evaluation. The signals identified may help prioritize pharmacovigilance monitoring and future validation studies.
To compare short-term corneal epithelial thickness changes measured by optical coherence tomography (OCT) in eyes fitted with two different silicone hydrogel bandage contact lenses (BCL) following trans-epithelial photorefractive keratectomy (t-PRK). In this prospective contralateral-eye study, 60 eyes of 30 patients with myopia without astigmatism underwent t-PRK using WaveLight EX500 excimer laser. Balafilcon A was applied to one eye and senofilcon A to the fellow eye in a randomized manner. All BCLs were removed on postoperative day 5. Corneal epithelial thickness was assessed preoperatively and on postoperative days 5, 15, and 30 using spectral-domain optical coherence tomography (REVO FC). Measurements were obtained centrally and across eight mid-peripheral quadrants. Epithelial thickness and spherical equivalent (SE) were compared. The mean age of the participants was 27.11 ± 6.80 years. Preoperatively, no significant differences were observed between the groups in SE (- 2.93 ± 1.11 D vs. - 2.71 ± 1.44 D; p = 0.353), ablation depth, central corneal thickness, or epithelial thickness. On postoperative day 5, slightly higher epithelial thickness values were observed in the nasal, temporal, and superotemporal quadrants in the balafilcon A group in unadjusted analyses; however, these differences did not remain statistically significant after false discovery rate correction. No significant differences were observed between the other regions. By postoperative days 15 and 30, epithelial thickness was comparable across all quadrants. At 1 month, the SE values were similar (p = 0.302), although balafilcon A showed a trend toward values closer to emmetropia. Both bandage contact lens materials demonstrated broadly comparable short-term postoperative epithelial remodeling patterns and refractive outcomes after t-PRK. Minor early regional differences observed on OCT should be interpreted cautiously.
Swimming pool-related cryptosporidiosis outbreaks are a global issue disproportionately affecting young children. This study aimed to (1) quantify swimming pool outbreak detection timelines; (2) identify pathogen prevention and detection strategies from Australia, United Kingdom, United States, and World Health Organization guidelines for public swimming pools; and (3) review oocyst detection methods used in pool-related cryptosporidiosis investigations. Literature searches of peer-reviewed databases, public health publications, and relevant government guideline repositories were conducted. The interval between pool contamination, outbreak detection, and disinfection was estimated using an average response scenario. A comparative analysis of pool guidelines was performed based on Cryptosporidium prevention and testing strategies. Efficacy of proactive and reactive testing was estimated using oocyst detection yields from global studies. There was an average delay of 27 days between pool contamination and disinfection, contributing to the persistence of outbreaks in swimming pools. Cryptosporidium prevention strategies varied and were inconsistent across jurisdictions. Proactive surveillance was discouraged in many jurisdictions based on financial cost, methodological gaps, and sampling biases. Oocyst detection data showed a proactive approach provides surveillance and prevalence metrics in aquatic facilities. Reliance on notification-based outbreak identification and existing contamination prevention guidelines appear insufficient to prevent and reduce outbreaks in public swimming pools. Barriers to proactive surveillance can be addressed by monitoring high-risk settings using existing methods alongside current mandatory microbiological surveillance already occurring in swimming pools. Earlier detection of contamination events would significantly reduce pool-associated cryptosporidiosis outbreaks locally and globally, and reduce the burden of gastroenteric disease in young children.