To evaluate the safety and efficacy of artificial endothelial layer (EndoArt®) implantation in patients with chronic corneal edema with or without prior endothelial keratoplasty at a tertiary referral center. This retrospective, non-comparative study reviewed medical records of consecutive patients who underwent EndoArt® (EyeYon Medical, Israel) implantation between December 2024 and November 2025. Patients with chronic corneal oedema and a minimum 12-week follow-up were included; eyes with prior penetrating keratoplasty were excluded. Primary outcome was central corneal thickness (CCT) measured by anterior segment optical coherence tomography. Secondary outcomes included best-corrected distance visual acuity (BCDVA), intraocular pressure, resuturing/rebubbling rates, and complications. Nine eyes of nine patients were included (mean age: 72±17 years; 55% female). Four patients (44%) had previous failed endothelial keratoplasty. Mean follow-up was 27±14 weeks. Mean baseline CCT decreased significantly from 780±106μm [95% CI: 710.0, 861.3μm] to 574±107μm [95% CI 502.8, 643.1μm], postoperatively (adjusted for implant thickness), representing a 35% reduction (265±89 μm; 95% CI: -338.8 to -190.8μm; p<0.01). Mean BCDVA improved from 2.28±0.54 LogMAR [95% CI 1.87, 2.71 LogMAR] to 1.16±0.79 LogMAR [95% CI 0.55, 1.78 LogMAR]. Three patients (33%) achieved postoperative BCDVA of ≤0.5 LogMAR. Two patients (22%) required re-suturing; no rebubbling was performed. No endophthalmitis, inflammatory reactions, or chronic intraocular pressure elevation occurred. Artificial corneal endothelial implant was associated with significant reduction in corneal thickness (35%) and improvements in visual acuity in eyes with chronic endothelial dysfunction, with or without prior endothelial keratoplasty. The procedure was feasible in complex eyes with prior failed endothelial keratoplasty and glaucoma drainage devices. EndoArt® represents a viable donor-tissue-independent alternative for high-risk patients in whom traditional keratoplasty carries a guarded prognosis. What is already known on this topic: Endothelial keratoplasty (DSAEK/DMEK) is effective for endothelial failure but remains dependent on donor tissue availability.Repeat keratoplasty and complex eyes (e.g. prior graft failure, glaucoma drainage devices) have higher risks and more guarded prognosis.There is a global mismatch between corneal tissue supply and demand, driving interest in donor-independent alternatives.EndoArt is a synthetic posterior corneal “artificial endothelial layer” designed to restore corneal deturgescence via a passive barrier mechanism without donor tissue.Most published EndoArt data to date are in high-risk/complex cohorts, with limited evidence in patients with more regular anatomy and/or mixed histories of prior EK. What this study adds: EndoArt implantation produced a significant mean CCT reduction of ~35% (780 μm to 574 μm after adjusting for implant thickness) over a mean follow-up of ~27 weeks.Mean BCDVA improved from 2.28 to 1.16 logMAR, with 33% achieving 0.5 logMAR or better.The procedure was feasible in eyes with and without prior failed endothelial keratoplasty, including complex cases with glaucoma drainage devices and prior vitrectomy.Reintervention was limited to re-suturing in 22%, with no rebubbling required; two eyes were partially attached at last follow-up under observation.No endophthalmitis, inflammatory reactions, or chronic IOP elevation occurred during follow-up. How this study might affect research, practice or policy: Supports EndoArt as a practical donor-tissue-independent option for selected patients with chronic corneal oedema, particularly high-risk or repeat-graft scenarios.Suggests a higher-risk subgroup for attachment issues (vitrectomised eyes/limited tamponade), informing surgical planning and follow-up (e.g. use of multiple transfixing sutures and AS-OCT–guided adjustment).Provides real-world tertiary-centre data to inform patient counselling on expected anatomic improvement and realistic visual outcomes in comorbid eyes.Strengthens the rationale for larger prospective studies comparing EndoArt with standard EK, including longer-term outcomes and clearer selection criteria.Highlights the potential role of donor-independent implants in pathways where tissue access is delayed or prognosis for traditional keratoplasty is poor.
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Rabies is a fatal but vaccine-preventable disease. Health care workers (HCWs) in endemic areas may receive repeated rabies vaccination because of occupational exposure, yet data on long-term antibody persistence and booster response after multiple prior vaccine regimens remain limited. This study aimed to determine the rabies antibody profile of HCWs previously vaccinated with rabies vaccine. We analyzed 126 HCWs from the Research Institute for Tropical Medicine (RITM) and Muntinlupa Animal Bite Treatment Centers (ABTCs) in the Philippines. Vaccination records were reviewed, and booster doses consisting of 0.1 mL purified Vero cell rabies vaccine (PVRV) were administered intradermally on days 0 and 3. Pre- and post-booster rabies antibody levels were measured using the rapid fluorescent focus inhibition test (RFFIT). All HCWs vaccinated within the previous year retained pre-booster antibody titers ≥ 0.5 IU/mL. Participants who had received three or more prior rabies vaccine regimens also maintained protective pre-booster antibody levels within 3-5 years after the last vaccination. After booster administration, all participants achieved antibody titers above the protective threshold ≥ 0.5 IU/mL, regardless of prior vaccination history or time since last vaccination. Repeated rabies vaccination was linked to sustained antibody persistence, while previous vaccination history was associated with preserved booster responsiveness among HCWs. These findings suggest that, in addition to time since last vaccination, the number of prior rabies vaccine regimens may help inform about the persistence of protective antibody levels in previously immunized individuals.
To validate a treadmill talk test (TT) protocol based on the 6-minute walk test predicted average speed (6MWS) to evaluate exercise intensity in adults with cardiovascular disease (CVD). A cardiopulmonary exercise test was performed on the first day. Two TT were performed on different days. The initial workload (WL) of the proposed TT protocol (treadmill TT protocol based on 6MWS [TT-T6M]) was set at a 2% incline and 70% of the 6MWS. Speed or grade was increased at each subsequent 2-minute stage. Participants recited a paragraph during the final 30 seconds of each stage and were asked if they could speak comfortably. They could respond "yes" (TT+), "uncertain" (TT±), or "no" (TT-). To determine validity, heart rate and WL were collected at ventilatory thresholds (VT) and TT stages, and then correlated using the Pearson or Spearman correlation coefficient. Test-retest, intrarater, and interrater reliability were assessed using the intraclass correlation coefficient (ICC2,1), with TT stages and total time as variables. Twenty-five patients with CVD (15 men, 60 ± 8 years) were included. Test reliability was excellent (ICC2,1 = .86), with no difference in test-retest duration. The heart rate and WL values were similar between VT1 and the last TT+ stage and between VT2 and the TT- stage. Intrarater and interrater agreements for the speech comfort assessment were also excellent (ICC2,1 > .90). The treadmill TT protocol based on 6MWS is valid, reproducible, and reliable. It can be used to evaluate, prescribe, and monitor the exercise intensity zone, which occurs between the last TT+ and TT- stages, for individuals with CVD.
Acetabular bone defects remain a challenging problem in revision total hip arthroplasty (THA). Structural allografts can restore the native hip center of rotation and replenish bone stock for potential future revisions, offering a cost-effective alternative in settings with limited access to porous metal augments. This study aimed to evaluate the short- to mid-term clinical and radiographic outcomes of acetabular revisions using structural homologous bone block grafts combined with cemented acetabular components. We retrospectively reviewed 13 consecutive patients (13 hips) with Paprosky type 2B, 2C, 3A, or 3B acetabular defects who underwent revision THA between February 2016 and October 2021. All cases were reconstructed using a structural homologous bone block graft, fixed to the ilium with screws, and a cemented polyethylene acetabular cup. Harris Hip Score (HHS) and standardized radiographs were assessed at the last follow-up. Implant survival and graft origin were analyzed using Kaplan-Meier curves and the log-rank test. The mean patient age was 67.3 years (range, 44-85), and the mean follow-up was 54 months (range, 19-88). Two patients (15.4%) experienced reconstruction failure due to graft fragmentation and cup migration. The remaining 11 cases demonstrated satisfactory clinical and radiographic outcomes, with evidence of graft integration and no radiographic signs of loosening. Mean HHS improved from 34.5 ± 7.0 preoperatively to 70.1 ± 10.3 postoperatively. Structural allograft with a cemented acetabular component provided good short- to mid-term functional outcomes and radiographic stability in most patients. This technique remains a valuable, lower-cost option for managing major acetabular defects in resource-limited settings. Level of evidence: IV, retrospective case series.
Amphibians are among the most vulnerable vertebrates, with 41% of assessed species at risk of extinction. The genus Oophaga has most of its species currently listed as threatened by the IUCN. Oophaga vicentei, an endangered species endemic to central Panama, is facing strong pressures from habitat fragmentation and mining. Despite its threat status, little is known about its population structure and size. Reduced representation approaches are cost efficient alternative to obtain genome-wide estimates of genetic diversity in non-model species. We herein genotyped thousands of exonic SNPs using RNA-seq data to uncover the genetic structure and effective population size of O. vicentei. Population structure analyses revealed two main genetic clusters: a West group (formed by individuals of Calovébora, La Empalizada, and Loma Grande) and an East group with individuals from La Ceiba. A further subdivision of the West cluster was apparent on the PCA with two localities (Calobévora, La Empalizada) splitting from the other Loma Grande. The La Ceiba locality was genetically the most divergent from the rest, with Calovébora and La Empalizada being the most similar. Effective population size of O. vicentei peaked around the Last Interglacial period and declined after the Last Glacial Maximum, with the locality La Ceiba showing the most pronounced decline towards present time. The significant amount of data we obtained validates the applicability of mRNA sequences to elucidate the population structure and demography of a species. Our results reveal strong genetic structure in O. vicentei, with the two main population clusters showing significant differences in their most recent demographic history. These findings provide a genomic baseline for conservation strategies, emphasizing the need to protect all known populations of this endangered species.
Patrilocality (post-marital residence in the husband's natal household) is common across South Asia and shapes women's autonomy, caregiving roles, and exposure to conflict, violence, and economic control, yet it is rarely defined or measured consistently in perinatal mental health research. We conducted a scoping review (Arksey and O'Malley; Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews [PRISMA-ScR]) of studies from South Asia and South-Asian diaspora populations published since 2000, searching eight databases and Google Scholar (last search November 2025). Thirty-two studies met inclusion criteria, spanning cross-sectional surveys, longitudinal cohorts, qualitative work, medico-legal series, intervention evaluations, and policy analyses. Evidence linked patrilocal residence and in-law co-residence to poorer maternal mental health through household status practices (for example, eating last), reduced decision-making power and mobility, relationship conflict, caregiver identity, and frequent in-law and partner violence and economic abuse. Associations with mother-in-law involvement varied by timing and conflict: some studies reported lower depressive symptoms early postpartum but higher symptoms later in conflictual households. Across studies, patrilocality was often invoked but operationalized heterogeneously (family-type categories, co-residence rosters, status markers, relationship-quality scales, or violence and economic-abuse measures), limiting comparability and obscuring patrilocality as a primary perinatal exposure. Perinatal research and services should specify residence patterns, adopt standardized measures of patrilocality and household authority, assess in-law relationship quality and violence and economic abuse, and evaluate family-centered interventions that engage supportive in-laws while addressing harmful dynamics.
To investigate the effect of Angelica sinensis on thymic cortical regeneration in rapamycin-treated mice and its underlying mechanisms. The chemical components of Angelica sinensis were analyzed using high-resolution liquid chromatography-mass spectrometry (LC-MS) and ultra-performance liquid chromatography (UPLC). Seventy-two 6-8-week-old female BALB/c mice were randomly assigned by weight into six groups (n=12 per group): blank control, model control, normal regeneration, and Angelica sinensis small- (1 g/kg), medium- (2 g/kg), and large-dose (4 g/kg) groups. Except for the blank control group, acute thymic involution was induced in all other groups via intraperitoneal injection of rapamycin (1 mg·kg－1·d－1) for 3 consecutive days. After modeling, the Angelica sinensis-treated groups received oral gavage of corresponding doses for 7 days, while the normal regeneration and blank control groups received an equal volume of saline. Body weight and dorsal hair growth were recorded daily. Forelimb grip strength was measured 2 hours after the last administration. Thymic structure and the spatial distribution of thymic epithelial cells (TECs) and thymocytes were assessed by hematoxylin-eosin (HE) and immunofluorescence staining. Development and homeostasis of T-cell subsets in the thymus and peripheral blood were analyzed by flow cytometry and rapid Wright-Giemsa staining. T-cell receptor excision circles (TRECs) in genomic DNA from peripheral blood mononuclear cells were detected by quantitative PCR (qPCR). The mRNA expression levels of thymic function-related genes, inflammatory factors, and Wnt pathway-related genes were measured by quantitative reverse transcription PCR (qRT-PCR). Potential targets and pathways were screened by integrating network pharmacology prediction and molecular docking. Rapamycin successfully induced acute thymic atrophy. The model control group showed an approximately 50% decrease in thymic index (P<0.01), significantly weakened grip strength (P<0.05), and no obvious hair regeneration. Histologically, the thymic cortical area was reduced, with a blurred corticomedullary junction, disrupted continuity of the cortical TEC (cTEC) cytoplasmic process network, early-stage blockade of thymocyte development, disturbed spatial distribution, and inhibited thymic output. Compared with the normal regeneration group, medium and large doses of Angelica sinensis dose-dependently increased the cortical area, significantly enhanced the density of cortical CK8+ TECs and restored the continuity of their cytoplasmic process network (P<0.01), while upregulating the expression of Foxn1 (P<0.01) and its downstream target gene Dll4. Regarding thymocyte development, Angelica sinensis (large dose) significantly increased the proportion of CD3+ TCRβ+ thymocytes (P<0.05), promoted the balanced differentiation of CD4+CD8+ cells into mature single-positive (SP) thymocytes, and re-established normal spatial localization, manifested as increased density of CD8+ and CD4+CD8+ cells in the cortex and reaggregation of TCRβ+ cells in the medulla. Furthermore, Angelica sinensis (medium dose) significantly reduced the mRNA levels of thymic pro-inflammatory factors TNF-α, TGF-β, and IGFBP5 (P<0.05), thereby improving the local inflammatory microenvironment. For peripheral homeostasis, Angelica sinensis intervention maintained and increased the proportion of peripheral blood CD3+ T cells, elevated the percentage of CD34+ hematopoietic stem cells across all dosage groups (P<0.05), and upregulated the expression of the thymic homing factor Ccl25. Mechanistically, network pharmacology predicted the Wnt pathway as a potential target of Angelica sinensis active components. Experimental validation revealed that Angelica sinensis (medium dose) significantly upregulated Wnt4 mRNA expression, inhibited Gsk3β, and increased CTNNB1 (β-catenin) levels in the thymus (P<0.05), indicating activation of the Wnt/CTNNB1/Foxn1 signaling pathway to drive cTEC cytoskeletal repair and thymic regeneration. Angelica sinensis promotes cortical regeneration and functional recovery after rapamycin-induced acute thymic involution by activating the Wnt/CTNNB1/Foxn1 signaling pathway and improving the thymic inflammatory microenvironment, which collaboratively facilitate cortical thymic epithelial cell cytoskeletal repair and hematopoietic stem cell homing. This suggests its potential benefit for counteracting immune aging. 目的: 探讨当归促进雷帕霉素处理后的小鼠胸腺的皮质再生作用及其机制。方法: 采用高分辨液相色谱-质谱联用（LC-MS）、超高效液相色谱（UPLC）分析当归化学成分。6~8周龄雌性BALB/c小鼠72只，按体重随机分为空白对照组、模型对照组、正常再生组及当归小（1 g/kg）、中（2 g/kg）、大剂量组（4 g/kg），每组12只。除空白对照组外，其余各组通过腹腔注射雷帕霉素（1 mg·kg-1·d-1，连续3 d）建立急性胸腺退化模型。造模后，当归各剂量组连续灌胃给药7 d，正常再生组和空白对照组给予等量等渗氯化钠溶液。实验期间每日记录体重及背部毛发生长情况;于末次给药2 h后测定四肢抓力。采用苏木精-伊红（HE）染色和免疫荧光染色评估胸腺结构、胸腺上皮细胞（TEC）及胸腺细胞的空间分布;流式细胞术和快速瑞特-吉姆萨染色染色分析胸腺及外周血T细胞亚群发育及稳态;定量PCR检测小鼠外周血单个核细胞基因组DNA中T细胞受体切除环（TREC）水平;定量逆转录PCR检测小鼠胸腺功能、炎症因子和Wnt通路相关基因表达水平;结合网络药理学预测及分子对接筛选潜在靶点和通路。结果: 雷帕霉素成功诱导急性胸腺萎缩，模型对照组胸腺指数降低约50%（P<0.01），四肢抓力显著减弱（P<0.05）且未观察到明显毛发再生迹象。组织学显示胸腺皮质面积减少，皮髓质分界模糊，皮质TEC胞突网络连续性破坏，胸腺细胞发育早期受阻，空间分布紊乱，胸腺输出受抑制。与正常再生组比较，当归中、大剂量组能剂量依赖性增加胸腺皮质面积，显著提升皮质CK8+胸腺上皮细胞密度并修复其胞突网络连续性（P<0.01），同时上调Foxn1及其下游靶基因Dll4表达（均P<0.05）。在胸腺细胞发育层面，当归（大剂量）显著提升了CD3+TCRβ+胸腺细胞比例（P<0.05），促进CD4+CD8+细胞向功能成熟的单阳性胸腺细胞均衡分化，并重建了胸腺细胞正常空间定位，表现为皮质CD8+及CD4+CD8+细胞密度增加，TCRβ+细胞重新聚集于髓质区。此外，当归（中剂量）显著降低了胸腺促炎因子TNF-α、TGF-β及IGFBP5的mRNA水平（P<0.05），改善局部炎症微环境。在外周稳态方面，当归能维持并增加外周血CD3+T细胞比例，同时各剂量组均能增加CD34+造血干细胞的比例（P<0.05），并上调胸腺归巢因子Ccl25表达。网络药理学分析结果提示，当归活性成分可能靶向Wnt通路;实验验证发现，当归（中剂量）能显著上调胸腺内Wnt4 mRNA表达，抑制Gsk3β，并提高CTNNB1水平（P<0.05），表明其通过激活Wnt/CTNNB1/Foxn1信号通路驱动皮质TEC骨架修复与胸腺再生。结论: 当归通过激活Wnt/CTNNB1/Foxn1信号通路，并改善胸腺炎症微环境，协同促进皮质胸腺上皮细胞骨架修复与造血干细胞归巢，进而有效促进短期雷帕霉素诱导的急性胸腺退化后的皮质再生与功能恢复，可能具有抗免疫衰老的潜在益处。.
Immunoglobulin M nephropathy (IgMN) is a pathological term defining glomerulonephritis with IgM deposition. The clinical significance is still a matter of debate. The aim was to evaluate children with IgM nephropathy (IgMN) in terms of clinical and pathological features, along with treatment responses and outcomes. The children with idiopathic nephrotic syndrome (INS) who underwent kidney biopsy at our center (n=41) were evaluated retrospectively. Twenty-one children with IgMN were included. The female to male ratio was 0.9, the median age was 3.5 years in the study group. The mean disease duration and follow-up periods were 11.8 and 11.3years, respectively. At admission, 14% of the patients had hypertension, and 19% had microscopic hematuria. Steroid-dependent nephrotic syndrome (SDNS) was observed in 62% of the patients at admission and 81% at last visit. The patients with IgM (≥2+) depositions had more SDNS than those with IgM (1+). The most common light microscopic diagnosis was mesangial proliferative glomerulonephritis (MesPGN) (47.6%). Focal segmental glomerulosclerosis (FSGS) elevated significantly from 14% at initial biopsy to 57% at follow-up biopsies. Patients who progressed to FSGS mostly had C3 co-deposition, high IgM intensity (≥2+), diagnosis of MesPGN, and SDNS clinic. The most frequently used adjuvant agent was cyclosporine-A (n=19) with mean duration of 68 months. It provided lower relapse rates. Rituximab (n=4) showed 75% remission rate. None of the patients had needed renal replacement treatment. Two patients who were steroid-resistant at admission had FSGS in their first biopsies, acted as multi-drug resistance at follow-up, and ended up in Stage-2 chronic kidney disease (CKD). This study shows IgMN is mainly presented with SDNS clinic and MesPGN pathology. Evolution to FSGS may be related to steroid resistance, MesPGN, high IgM intensity, and C3 co-deposition.
In the last decade, numerous laboratory experiments have demonstrated that when marine phytoplankton are exposed to thermal stress, they can evolve high temperature tolerance in a short time (months). This evolutionary potential may ensure the persistence of marine phytoplankton species under current and future global warming. However, the effect of such adaptation on the phytoplankton's interaction with the environment and other organisms depends on how cellular metabolism shifts during the evolutionary process. In order to elucidate which cellular strategies allow the emergence of thermo-tolerant lines, we analysed the proteomic changes in a marine diatom (Chaetoceros simplex) following both thermal acclimation and evolutionary adaptation. We found that the high temperature-tolerant lines exhibit a conservative cellular strategy when acclimated to high, above-optimal temperature, where nitrogen recycling, reallocation of carbon and nitrogen, and protein repair or protection are favoured at the expense of new proteins and photosynthetic structures biosynthesis and rapid growth. While this strategy gives the lines that evolved high temperature tolerance an advantage under thermal stress, the shift to resource reallocation may explain the absence of high-temperature adaptation when cells are exposed to low nitrate availability.
Thousands of metric tonnes of diverse sludge wastes are generated annually in the pulp and paper industry. Due to a high moisture content and an abundance of inorganic material, many types of sludge are hard to recycle and instead accumulate in landfills, causing environmental damage. During storage, forestry sludge waste appears recalcitrant to natural attenuation, indicating limited degradation of wood- and process-derived fibers and polymers by environmental microbes. Intentional enzymatic or microbial hydrolysis of carbohydrates within the sludge may, however, be a feasible approach to reduce waste volume and prevent transfer to landfill. Here, we show that a previously validated biomass-degrading enzyme cocktail lacks efficacy on a metal-rich sludge obtained from a Swedish pulp and paper mill, possibly due to enzyme inhibition. Hypothesising that microbes dwelling within sludge may host enzymes better adapted to this complex contaminated substrate, we assessed whether a native sludge microbiome could be identified, and whether it degrades carbohydrates during incubation in microcosms. Marker gene profiling revealed diverse bacterial and fungal communities undergoing genus-level changes over time, and the most abundant species could be enriched via serial cultivation with pulp-derived carbon sources. Complementary chemical analyses showed that biopolymers were largely removed after a 10-week incubation, leading to sludge solubilization and volume reduction. This confirms the capacity for fiber degradation by native microbiomes and suggests the waste as a potential source of microbes and enzymes capable of sludge polymer degradation, the mechanism of which remains to be explored, but which could reduce the need for future landfilling.IMPORTANCEAccording to European and Swedish guidelines, the top priority in waste handling is prevention, followed by reuse, recycling, energy recovery, and, as a last resort, landfill. While effective in municipal contexts, these guidelines are difficult to apply to pulp and paper industries when managing heterogeneous sludge wastes. Process-derived sludges are hugely abundant but have low economic value as their high moisture content prevents combustion, and the complex mixture of organic fibers prevents metal recovery. According to industrial reports, less than 10% of sludge is used for energy, and under 50% is recycled. Our results demonstrate that biological treatment of sludge could be a method of waste reduction to reduce landfilling, specifically targeting hygroscopic carbohydrate-based polymers. Mapping the microorganisms in this under-explored industrial waste material, using combined "omic" technologies and chemical analysis, lays a foundation for discovering robust organisms and enzymes that withstand harsh conditions, such as low water activity and high metal content.
Meningococcal vaccination of adolescents/young adults is recommended in various countries, including the United States (US). This phase 3b, observer-blind study (NCT04318548) evaluated the safety, reactogenicity, and immunogenicity of serogroup B vaccine, 4CMenB, and quadrivalent conjugate vaccine, MenACWY-CRM, when co-administered to healthy individuals aged 16-18 y, as per US Advisory Committee on Immunization Practices recommendations. Adolescents, who had received MenACWY vaccination ≥4 y previously, were randomized (N = 940; 1:1:1) to one of three groups to assess co-administration versus 4CMenB and MenACWY-CRM administered alone. Co-primary objectives were to demonstrate the non-inferiority of antibody responses after concomitant administration to antibody responses after 4CMenB (two doses administered 2 months apart) and MenACWY-CRM (single dose), as measured by human serum bactericidal assay (hSBA). Vaccine safety and reactogenicity were assessed as another primary objective. The co-primary endpoints were met: the lower limit of 2-sided 95% confidence intervals for all between-group ratios of hSBA geometric mean titers was >0.5 for the concomitant administration group versus 4CMenB group and MenACWY-CRM group. hSBA data after two 4CMenB doses and one MenACWY-CRM dose showed comparable between-group geometric mean ratios versus baseline, and percentages of participants with 4-fold rises in titers and titers ≥lower limit of quantitation. The safety profile of 4CMenB co-administered with MenACWY-CRM was comparable with that of 4CMenB administered alone. In conclusion, 4CMenB and MenACWY-CRM co-administration was well tolerated in adolescents aged 16-18 y and immune responses were comparable versus administration of each vaccine alone, which is consistent with a previous study of co-administration in infants. Invasive meningococcal disease, caused by the bacterium Neisseria meningitidis, poses a life-threatening risk but can be prevented through vaccination. Effective vaccines are available against the most common disease-causing meningococcal serogroups, A, B, C, W, and Y. Evidence from clinical studies and immunization programs over the last decade with the 4-component meningococcal serogroup B vaccine, 4CMenB, and serogroups A, C, W, and Y vaccine, MenACWY-CRM, confirms the effectiveness of both vaccines in population age groups at higher risk of meningococcal disease, including infants and adolescents. It was previously shown that the administration of 4CMenB and MenACWY-CRM to healthy infants at the same visit induced good immune responses and was well tolerated by young children. Adolescent vaccination with 4CMenB and MenACWY-CRM is recommended in various countries, including in the United States. We conducted a study to test the safety of concomitant administration and its ability to induce immune responses in 945 healthy adolescents aged 16–18 y; 834 from the United States and 111 from Italy. We found that most reactions to the 4CMenB and MenACWY-CRM injections were mild or moderate, and were similar whether the vaccines were given together or separately, with no unexpected side effects. Co-administration to adolescents induced robust immune responses against serogroup B and serogroups A, C, W, and Y. These results support the use of concomitant meningococcal vaccinations in adolescent immunization programs.
Tyrosine kinase inhibitors (TKIs) have transformed chronic-phase chronic myeloid leukemia (CML) into a chronic condition with excellent long-term survival. As outcomes improve, attention has shifted toward treatment-related metabolic effects and survivorship issues. Body weight and body mass index (BMI) are important indicators of metabolic health; however, the long-term effects of TKIs on these parameters remain incompletely characterized, particularly in real-world settings. This study evaluated longitudinal changes in body weight and BMI in adults with chronic-phase CML treated with TKIs. We conducted a retrospective longitudinal observational study at a tertiary care center between January 2016 and December 2023. Adult patients with chronic-phase CML who initiated TKI therapy and had baseline and follow-up weight measurements were included. Patients with major preexisting metabolic conditions or factors likely to confound weight were excluded. Body weight and BMI were assessed at predefined time points up to 7 years. Paired analyses evaluated within-patient changes over time, and stratified analyses were performed according to initial TKI and cumulative exposure patterns. A total of 175 patients were included in the analytic cohort (82.9% male; mean age 39.2 ± 11.7 years). Mean baseline weight was 68.2 ± 14.4 kg, and baseline BMI was 24.6 ± 3.9 kg/m². Weight increased significantly from baseline at 6 months (+4.27 kg), 12 months (+6.00 kg), 18 months (+6.63 kg), and 24 months (+6.41 kg) (all p<0.001). At the last follow-up, the mean weight gain was 6.12 kg (p < 0.001), with 56.9% of patients achieving≥5% weight gain. The temporal pattern showed rapid weight gain during the first 6-12 months, followed by stabilization through 2-3 years with persistent elevation thereafter. Weight and BMI increases were observed across all first-line TKIs and cumulative exposure groups, without statistically significant differences between agents. In this real-world cohort of adults with chronic-phase CML, TKI therapy was associated with early and sustained increases in body weight and BMI, largely occurring within the first year of treatment. These changes likely reflect a combination of treatment-related metabolic effects and reversal of cancer-associated catabolism. Given the long life expectancy of patients with CML, routine metabolic surveillance and early lifestyle interventions should be incorporated into long-term management.
Intrusive thoughts are prevalent across the lifespan and can be particularly distressing during adolescence and young adulthood. Despite their high prevalence, many individuals lack access to effective strategies for managing these thoughts. Brief, accessible, and evidence-based interventions are needed to help individuals cope with intrusive thought-related distress. The present study aimed to pilot the effectiveness of a brief online Acceptance and Commitment Therapy (ACT)-based single-session intervention (SSI) that provided psychoeducation on intrusive thoughts and strategies for managing distress arising from negative appraisals in young adults. We recruited individuals aged 18-25 who reported that they experienced distressing thoughts in the last week. Distress associated with intrusive thoughts and hopelessness was measured at pre-intervention, post-intervention, and at two-week follow-up. Within-subject ANOVAs revealed significant reductions in intrusive thought-related distress and hopelessness from pre- to post-intervention across all time points for both groups. The active SSI group had a significant reduction in distress compared to the active control group. There were no other significant interaction effects observed, either when considering hopelessness or at the follow-up time point. These preliminary findings highlight the importance of single-session interventions in helping youth understand and cope with intrusive thoughts. Future research should explore the relative contributions of different intervention components and the long-term effects on mental health outcomes.
Decentralised clinical trials (DCTs) may help address underrepresentation in digital mental health research, but their effectiveness in reaching underserved populations is unclear. This review assessed the reporting of equity-relevant demographic data in DCTs to identify groups at risk of exclusion and barriers and facilitators to inclusive participation. A systematic search was conducted in MEDLINE, PsycINFO, Embase, CINAHL, Cochrane Central Register of Controlled Trials, and Web of Science. We included studies reporting on mental health interventions evaluated via remote, online, virtual, or hybrid DCTs, published in English from 2020-2026 (last search date: 01/07/2025), that reported participant demographics. Demographic data were extracted and summarised according to the PROGRESS-Plus framework. Demographic frequencies were compared to national population statistics. Thematic analysis identified barriers and enablers to inclusive participation in DCTs. Fifty-nine papers reporting 57 DCTs were included. Studies involved a range of mental health and neurodevelopmental conditions across the ages. Gender (100%) and age (100%) were universally reported. Reporting of other PROGRESS-Plus variables across the 57 DCTs was limited: social capital (43.9%); race/ethnicity (40.4%); occupation (36.8%); socioeconomic status (35.1%); place of residence (12.3%); religion (5.3%), and non-mental health disability (1.8%). Participants from ethnic minority backgrounds, males, unemployed individuals, and those with lower educational attainment were consistently underrepresented. While rural populations were better represented in Australian studies, data on poverty, religion, and social capital were limited and varied in representativeness. Most studies focused on adults aged 18-50 years. Thematic analysis identified key barriers including, digital exclusion, low digital literacy, cognitive and sensory challenges. Facilitators included therapist or navigator support and simplified onboarding. Equity variables are persistently underreported. DCTs do not effectively engage underserved populations in mental health research, meaning digital interventions are evaluated on unrepresentative samples. This risks perpetuating, and exacerbating, existing health inequalities, limiting the real-world impact of digital mental health solutions.
We conducted an open-label study to assess the pharmacokinetics, safety, and tolerability of nacubactam-a β-lactamase inhibitor-administered alone or in combination with β-lactam antibiotic. Japanese healthy male participants received a single dose of nacubactam 2 g on Day 1, a single dose of β-lactam antibiotic (cefepime 2 g, aztreonam 2 g, meropenem 2 g, and piperacillin 4 g in Cohorts 1, 2, 3, and 4, respectively) on Day 3, and the combination of nacubactam and β-lactam antibiotic on Day 5. The study drugs were intravenously administered over 60 min. A total of 32 participants (8 in each cohort) were enrolled in the study. All participants completed the study and were included in the analysis. Exposures to nacubactam or β-lactam antibiotic (maximum plasma concentration [Cmax], area under the plasma concentration-time curve from time zero to the last quantifiable time [AUC0-t], and AUC from time zero to infinity [AUC0-∞]) were similar between the treatment periods (monotherapy vs combination therapy) in all cohorts. Coadministration of nacubactam and β-lactam antibiotic did not affect the pharmacokinetic profile of nacubactam or β-lactam antibiotic with the 90% confidence intervals for the geometric least squares mean ratios (combination therapy/monotherapy) of Cmax, AUC0-t, and AUC0-∞ contained within the equivalence range of 0.80 to 1.25 for all study drugs. Nacubactam and β-lactam antibiotics were well tolerated. All treatment emergent adverse events were mild in severity and resolved without treatment. Our results support the further clinical development of nacubactam coadministered with these β-lactam antibiotics.
Children with cancer requiring PICU admission have a relatively high mortality. This study reports trends in management and outcomes for a large cohort of unplanned PICU admissions for children with underlying oncology diagnoses. A retrospective cohort study, analysing all unplanned oncology admissions for all English PICUs from 2008 to 2022, captured by PICANet, a quality-assured, prospectively collected national database. Unplanned oncology admissions to the PICU aged 1 month to 16 years were included. Patients with benign disease were excluded. A total of 4371 admissions from 3277 children underwent further analysis. Unplanned oncology admissions increased from 209 in 2008, peaking at 357 in 2020, representing 1.2 and 1.9%, respectively, of all PICU admissions in those years. Haematological malignancies had the largest rise. Presentations with infections also rose, making up over half of oncology admissions by 2022. The percentage invasively ventilated fell from 55.8 to 48.1%, but significant changes in the use of vasoactive agents, non-invasive ventilation and renal support were not seen. Mean PIM score (0.085 to 0.06) at admission fell, reflecting lower overall acuity. Mortality in unplanned oncology admissions fell from 16.7 to 12.2%. Survival, when banded for PIM risk group, showed no improvement except possibly in those with over 30% risk of death, where a downward trend in actual mortality was seen.  Unplanned admissions of children with cancer to PICU remain at a relatively high risk of death. The cause of the improved overall percentage mortality is likely related to increased low-acuity admissions. • Significant improvements have been seen in mortality for unplanned oncology admissions to the PICU over the last few decades. • Studies have attempted to define these trends; however, heterogeneity between patient populations and outcome measures included makes it difficult to draw meaningful conclusions from them. • Overall mortality in all PICU admissions for children with oncological diagnoses in England decreased. • The improvement in PICU percentage mortality is likely due to a reduced admission threshold rather than specific improvements in clinical or oncological care for these patients.
Rotator cuff-related shoulder pain is highly prevalent in middle-aged and older adults and is associated with pain, functional limitations, and reduced quality of life. This systematic review and meta-analysis aimed to evaluate the effectiveness of exercise-based interventions on pain, function, range of motion (ROM), and strength in middle-aged and older adults with rotator cuff-related shoulder pain. A systematic review and meta-analysis were conducted according to PRISMA 2020 guidelines and registered in PROSPERO (CRD420251236625). Searches were performed in PubMed, Scopus, Web of Science, PEDro, and Cochrane Library databases for studies published within the last 10 years. Randomized controlled trials including adults with rotator cuff-related shoulder pain were included. A total of 1,152 participants across 21 studies were analyzed. Exercise-based interventions primarily targeted the rotator cuff and scapular stabilizer muscles through strengthening, stretching, stabilization, and neuromuscular exercise programs, and were compared with usual care, other exercise approaches, or adjunct therapies. Functional outcomes were mainly assessed using validated instruments such as SPADI, DASH/QuickDASH, and the Constant-Murley Score. Effect sizes were calculated using standardized mean differences, and heterogeneity was assessed with the I² statistic. Twenty-one randomized controlled trials were included. Exercise-based interventions produced significant improvements in pain (g = -1.454, p < 0.001), function (g = 0.457, p < 0.001), and ROM (g = -2.477, p < 0.001). Improvements in strength were smaller and did not reach statistical significance (g = 0.229, p = 0.085). Although strengthening exercises showed positive trends across studies, the pooled effect on strength was not statistically significant. High heterogeneity was observed (I² = 95.96%), likely due to differences in intervention protocols, participant characteristics, and outcome assessment methods. Exercise-based interventions are effective in reducing pain and improving function and ROM in middle-aged and older adults with rotator cuff-related shoulder pain. However, effects on strength appear more limited. Further high-quality studies using standardized exercise protocols and longer follow-up periods are needed to optimize rehabilitation strategies.
Atypical antipsychotics (AAPs) are increasingly prescribed for bipolar spectrum disorders in children and adolescents. This study aimed to investigate the prevalence and trends of AAP prescriptions among Korean children and adolescents with bipolar spectrum disorders. We analyzed data from the Korean National Health Insurance Review and Assessment Service to assess AAP use among Koreans aged 0-18 years with bipolar spectrum disorders between 2010 and 2022. This population-based study used an annual cross-sectional assessment to evaluate trends in AAP prescription. The prevalence of AAP prescriptions for children and adolescents with bipolar spectrum disorders increased over the 13-year study period, rising from 0.14 in 2010 up to 1.23 per 1000 persons in 2022. During this time, the dominant AAP shifted from risperidone to aripiprazole. Data from 2022 revealed that the most prescribed AAP for children was aripiprazole, followed by risperidone, quetiapine, and olanzapine. Children and adolescents with bipolar spectrum disorders and psychiatric comorbidities, particularly ADHD, were prescribed AAPs more frequently (p < 0.001). The prescription of AAPs in Korean children and adolescents with bipolar spectrum disorders has increased over the last decade. This trend was particularly pronounced among individuals with psychiatric comorbidities, especially ADHD. Future research is needed to develop more evidence-based AAP treatments for bipolar spectrum disorders in this population.
Polyploidy, the result of whole genome duplication, is widespread in plants. Over long timescales, polyploids seem to go extinct more often than diploids. Clear genomic signs of long-term polyploid success exist across plants, but they are comparatively rare within individual lineages. To address the 'polyploid paradox' - early success followed by long-term decline - we propose a three-step framework. The first step is 'Supply', the rate at which new polyploids arise, which can spike in stressful conditions because of elevated formation of gametes with unreduced genomes and relatively weak ecological filtering of the generated polyploids. The second step is 'Bridging', which can occur in one or other of two ways: a short-term route, in which genome duplication increases phenotypic and genetic variation and rarely produces phenotypes that fit the new environment; or a longer-term route, when processes that normally exclude rare cytotypes are weakened and polyploids can persist despite the early costs. The third and last step, 'Consolidation' determines evolutionary outcomes, where some polyploids achieve niche divergence and persist alone or jointly with diploids, while many are removed by long-term costs. As a result, even though polyploids often succeed in the short term, relatively few persist over macroevolutionary timescales. We refer to this sequence as Supply-Bridging-Consolidation (SBC). In this view, polyploid success reflects demographic assembly and ecological opportunity; adaptation usually follows establishment, rather than causing it. The framework yields testable predictions and offers a unified understanding of when polyploids flourish and when they falter, and why only a small fraction is ultimately retained.