Occupational exposure to chromium trioxide (CAS number: 1333-82-0) remains a major concern in the electroplating sector. Risk assessment is regulated under both the REACH Regulation, which focuses on substance-related risks across the supply chain, and Occupational Safety and Health (OSH), which emphasizes workplace-specific exposure. The two regulatory frameworks adopt different approaches, particularly regarding the role of exposure models and monitoring for workplace risk assessment. This study investigated the outcomes of exposure assessment under REACH and OSH, comparing modeled exposure estimates with measured workplace data for occupational exposure to hexavalent chromium, in order to analyze differences in the exposure assessment process and the risk characterization under both approaches. The study focuses on four Italian companies involved in metal products manufacturing, which applied to ECHA for authorization to use chromium trioxide. Worker contributing scenarios were defined from Chemical Safety Reports. Exposure estimates were derived using the Advanced REACH Tool, while additionally measured data came from workplace monitoring campaigns, evaluated according to EN 689:2019. Comparisons between exposure estimates and measured data were made following the criteria of level of consistency and level of conservatism. Considerations on risk as risk characterization ratio (RCR) under OSH and excess risk under REACH were also made due to the different regulatory approach. Model estimates from ART frequently have allow level of consistency with measured workplace concentrations, in some cases by up to two orders of magnitude. RCR values calculated from each exposure measured and estimated data were always <1, although EN 689 testing revealed cases of noncompliance. Excess risk under REACH remained below the tolerable level defined but was closer to it than to the acceptable level. The analysis highlighted fundamental differences between REACH and OSH: REACH relies mostly on exposure models for registration. For Application for Authorizations, monitoring is more frequently applied. On the other hand, OSH prioritizes monitoring of carcinogenic agents by workplace measurements in any case. Models are useful tools, but their reliability depends amongst others on assessor expertise and contextualization with workplace data. Integrating REACH authorization conditions with OSH monitoring obligations can create a more consistent and effective strategy to protect workers from Cr(VI) exposure. As the concept of risk is framed differently in REACH and OSH, this study highlights how the exposure tools may be used at different levels, leading to mutual benefits for both approaches.
Upright reaching performed in different directions places distinct postural and coordination demands, as each direction requires specific adjustments of trunk and lower-limb segments to maintain stability while reaching. These direction-dependent changes make these tasks particularly informative for examining how whole-body coordination adapts to varying postural requirements. In this context, kinematic synergies provide a low-dimensional description of multi-joint coordination. We characterized how these direction-dependent demands shape whole-body coordination by extracting kinematic synergies underlying the movements and examining their variation across tasks. Healthy adults carried out unilateral and bilateral forward reaching, along with a lateral reaching task, while whole-body kinematics were recorded. Joint angle trajectories from twelve degrees of freedom were selected and decomposed using Principal Component Analysis to identify dominant coordination components. Across all reaching directions, two kinematic synergies reconstructed joint angle trajectories. The first synergy captured upper-limb elevation, while the second reflected adjustments of trunk, hip, and ankle joints. While this structure was maintained across tasks, synergy weights showed direction-dependent modulations. The lateral reach, in particular, had smaller inter-individual similarity of the second synergy, suggesting flexibility in managing mediolateral balance. These findings indicate that upright reaching relies on a compact yet adaptable coordination structure integrating arm movement with posture-related joint contributions. The consistency of the extracted synergies across individuals, along with the increased variability in lateral reaching, highlights both stereotyped and flexible features of whole-body coordination. These insights reinforce synergy-based models of motor organization and offer applications for rehabilitation and robotic systems that leverage natural coordination patterns.
Urinary incontinence (UI) is common among older women in Jordan and is often not discussed owing to embarrassment and social stigma. Home-based conservative programs may offer a practical and acceptable approach to symptom management. This study was aimed at reaching expert consensus on the essential components of a culturally appropriate, home-based multimodal pelvic health program for Jordanian women aged 55 years and older, using a modified e-Delphi method. A two-round modified e-Delphi study was conducted with Jordanian physiotherapists experienced in women's health. In Round 1, experts rated 34 evidence-based items covering pelvic floor muscle training, bladder training, behavioral and lifestyle adjustments, pelvic health education, breathing and postural exercise, adherence support, delivery format, and dosage. Items were rated on a six-point Likert scale, and consensus was defined as ≥ 75% agreement. Items that did not reach consensus were revised and re-rated in Round 2, along with one new subcomponent suggested by the experts. Nineteen experts completed both rounds. In Round 1, 32 of 34 items reached consensus. In Round 2, the newly proposed subcomponent, whole-body and core strengthening, achieved full consensus. Although weight management did not reach the predefined consensus threshold, it was retained in the final program owing to its clinical importance and evidence-based relevance. Printed educational materials did not achieve consensus and were excluded. The final program consisted of 33 expert-validated components. This study established expert consensus on the components of a culturally tailored home-based pelvic health program for older Jordanian women with UI. These components provide a practical foundation for program development.
We aimed to develop a data model and a natural language processing (NLP) pipeline for representing physical activity (PA) in Electronic Health Records (EHRs), and to evaluate transformer- and Large Language Model (LLM)-based classifiers for sentence-level PA attribute classification. We analyzed PA documentation across three patient cohorts (cancer, COVID, and Alzheimer's disease) using structured and unstructured EHR data. A conceptual schema was developed to represent PA and its linguistic attributes. Five BERT models and three modern LLMs (Llama3-8B, MedAlpaca-13B, and PMC-Llama-13B) were evaluated for classifying PA attributes (binary status, negation, exclusion, and an eleven-class Category) on pre-extracted PA-related sentences. Clinical notes were a richer source of PA information than structured ICD or SDoH data. On binary tasks, the best BERT model reached F1 0.619 (Exclusion); with Supervised Fine-Tuning (SFT), Llama3-8B reached F1 0.689 (Exclusion). On the 11-class Category task, performance was modest (best macro-F1 0.262, ROC-AUC 0.803, by Llama3-8B). In-Context Learning (ICL) was highly variable: while Llama3-8B-ICL achieved the best ROC-AUC on Category, the domain-specific MedAlpaca-13B and PMC-LLaMA-13B essentially failed. These results, together with sparsely represented PA elements (Amount, Frequency, Assessment) and the absence of a downstream evaluation, position this work as an initial proof of feasibility, with supervised domain adaptation still required for reliable clinical PA extraction. We contribute a PA data model, annotation schema, and a working NLP pipeline with a BERT/LLM benchmark for sentence-level PA attribute classification. The pipeline supports future end-to-end PA extraction and downstream applications such as phenotyping, risk prediction, and cohort identification.
Gold nanoparticles (AuNPs) underpin advances across numerous applications, yet most syntheses still rely on added chemical reductants and organic additives, constraining sustainability. Here, we report an aqueous, reductant-free route to AuNPs that leverages hydrophobic interfaces under mild conditions. When NaOH is added to aqueous HAuCl4 to reach basic conditions (pH 10-13), where [Au(OH)4]- predominates, AuNPs form spontaneously upon contact with hydrophobic fluoropolymer surfaces (e.g., PFA) without added reductants or surfactants. In contrast, almost no AuNP formation is observed on hydrophilic glass under otherwise identical conditions, indicating that interfacial rather than bulk properties govern nucleation and growth. Systematic pH tuning revealed that AuNP yield reaches a pronounced maximum at pH ≈ 12 and becomes negligible at very high alkalinity (pH 14), while particle size is tunable by varying HAuCl4 and NaOH concentrations. These results, together with the suppression of AuNP formation at high ionic strength, indicate that interfacial ion distributions, rather than bulk pH alone, play a decisive role in the reaction. A consistent interpretation is that hydrophobic interfaces promote preferential adsorption of OH-, giving rise to an electric double layer (EDL) with an ion distribution distinct from the bulk. Within this nanoscale-confined environment, ultrasmall Au(III) hydroxide-like species may form and, owing to strong size effects, undergo low-temperature transformation to yield AuNPs. These results establish interfacial EDL confinement as a basis for sustainable, reductant-free nanomaterial synthesis and suggest extension of this principle to other aqueous metal systems.
Genitourinary syndrome of menopause (GSM) is common, and non-hormonal treatment options are needed for women unsuitable for or reluctant to use estrogen therapy. To prospectively evaluate clinical outcomes and clinical improvement rates of photobiomodulation (PBM) for GSM. Twenty-seven postmenopausal women with GSM were enrolled in a prospective study conducted from January 2024 to July 2025. Participants received eight weekly 30-minute sessions of pulsed 660-nm PBM delivered through a stationary silicone vaginal light-guide probe. With the probe attached, target irradiance was 32.38mW/cm² at the probe tip and 13.38mW/cm² at the probe side, corresponding to per-session radiant exposures of 29.14J/cm² at the vaginal fornix and 12.04J/cm² at the vaginal wall. Assessments occurred at baseline (V1), pre-4th session (V2), pre-8th session (V3), and three months post-treatment (V4). The primary outcome was the Vaginal Health Index (VHI). Secondary outcomes included validated questionnaires for lower urinary tract symptoms (LUTS) and sexual function (FSFI). Clinical improvement was defined using established minimal clinically important differences (MCID), minimal detectable change (MDC), and cutoff scores as thresholds. The mean age of participants was 62.9 ± 9.7 years. Total VHI scores were significantly higher at all follow-up time points compared to baseline (p < 0.05), with all participants reaching the non-atrophic VHI threshold at V4. UDI-6, IIQ-7, OABSS, and several KHQ domains improved significantly (p < 0.05) and persisted through the 3-month follow-up. Total FSFI scores improved significantly (p < 0.05), but only 13.3% reached the clinical cutoff (≥26.5) at V4 for functional recovery. No adverse events were observed during the study period. Intravaginal 660-nm PBM is a well-tolerated, non-hormonal modality that may improve objective vaginal health and subjective symptoms in GSM. As an integrated therapeutic option, PBM may also improve GSM-related LUTS, suggesting potential relevance for geriatric patients with polypharmacy concerns. ClinicalTrials.gov NCT06074120.
Biological control tools such as Wolbachia incompatible-insect technique, are a promising class of interventions to modify and suppress Aedes aegypti mosquitoes to reduce risk of Aedes-borne diseases. Due to the spatial nature of the intervention, intervention effects can be spatio-temporally heterogeneous. Yet, most evaluations of field-based technologies rely on average treatment effects, which preclude characterization and understanding of treatment effect heterogeneities and the factors influencing it. Here, we developed a causal inference framework using distributional synthetic controls to explicitly account for spatio-temporal trap-level mosquito abundance data to ascertain the entomological efficacy of Wolbachia in suppressing Ae. aegypti abundance. This method is able to construct counterfactual distributions of intervened areas, provide detailed comparisons to actual distributions and quantify treatment effects of the intervention on mosquito abundance over different quantiles. By employing our framework to trap-level mosquito abundance data from 57,990 unique mosquito traps routinely maintained and measured twice a week, and a large-scale field trial of Wolbachia incompatible-insect technique coupled with sterile insect technique (IIT-SIT) in Singapore, we (1) quantified heterogeneous treatment effects for IIT-SIT across the time-since-intervention, over the traps' historical mosquito abundance, over calendar time, (2) quantified whether elimination of wild-type Aedes aegypti was possible in intervention locations and (3) addressed if suppressive effects in spillover locations adjacent to directly intervened locations were heterogeneous. IIT-SIT interventions led to a strong suppressive effect on adult Aedes aegypti abundance. From the onset of intervention in directly treated locations, sector-specific intervention effectiveness (IE) ranged from 24.04% in the earliest treatment period, and reached 86.08% in the latest treatment period. Raw reductions in aegypti abundance were also found to increase over time as sectors were intervened over longer time periods. In spillover sectors, IE was lower in magnitude and more variable, but average IE reached a maximum of 78.08% in 2-years post-treatment. Wolbachia interventions also led to an increase in the percentage of traps recording no mosquitoes from 6.8% at the start of intervention to 33.01% 124-weeks post-intervention. We found that IE was higher in sectors with lower historical mosquito abundance. However, IE converged across sectors with different historical mosquito abundance as intervention time increased. This study revealed spatial heterogeneities in suppressing wild-type female Ae. aegypti by IIT-SIT and provided strong evidence that IIT-SIT can drastically suppress wild-type Ae. aegypti populations despite heterogeneous treatment effects over time.
This study estimated FRAX®-based intervention thresholds for initiating osteoporosis treatment in Chinese postmenopausal women, using real-world data from the largest nationally representative osteoporosis survey in China and a validated Markov microsimulation model. Denosumab became cost-effective at a 10-year major osteoporotic fracture probability of 7%, and zoledronate at 12%, whereas alendronate and teriparatide did not reach cost-effectiveness at any FRAX probability evaluated. To determine drug-specific FRAX® thresholds for cost-effective initiation of osteoporosis treatment (alendronate, zoledronate, denosumab, teriparatide) in Chinese postmenopausal women using real-world data. A validated Markov microsimulation model was used to simulate lifetime costs and quality-adjusted life years (QALYs) of no treatment versus alendronate, zoledronate, denosumab, and teriparatide treatment. Baseline patient characteristics and risk factor distribution were sampled from the largest national osteoporosis survey in mainland China. The analysis was conducted from the societal perspective, applying a willingness-to-pay threshold of USD 13,000 per QALY gained (equivalent to one times China's GDP per capita). Denosumab was cost-effective at a 10-year major osteoporotic fracture probability of 7% and zoledronate at 12%; neither alendronate nor teriparatide became cost-effective. For denosumab, the cost-effective threshold of 10-year major osteoporotic fracture probability increased with age from 51 to 65 years and then declined in older women, ranging from 5 to 12%. For zoledronate treatment, the cost-effective thresholds of a 10-year major osteoporotic fracture probability were 8% at 51-55 years, 12% at 71-75 years, and 8.5% at 76-80 years. For Chinese postmenopausal women, denosumab was the most cost-effective treatment, while zoledronate also reached favorable thresholds in selected age groups. Implementing drug-specific FRAX®-guided thresholds may optimize treatment decisions for osteoporosis and support efficient healthcare resource use.
Understanding disease activity and therapy goals of patients with rheumatoid arthritis (RA) is important to provide patient-centered specialty pharmacy care and achieve positive therapy outcomes. The Routine Assessment of Patient Index Data 3 (RAPID3) is a validated metric to track patient-reported RA disease activity. Consistent and frequent monitoring of RAPID3 scores may provide clinically meaningful insights. To describe the trajectory of RAPID3 scores over time and factors related to changes in RAPID3 scores among patients new to specialty medications. Adult patients with RA who initiated specialty medications were included if they filled medications at least 3 times and had at least 2 RAPID3 scores documented in 6 months. Linear mixed effects regression models estimated trends in RAPID3 scores over time with respect to patient identifiers. Logistic regression models adjusted for baseline RAPID3 severity and estimated adjusted odds ratios (aOR) and associated 95% CIs of achieving a minimal clinically important improvement (≥3.8 points) or low severity/near remission (LS/NR) RAPID3 severity score at 6 months, by patient characteristics. Of 312 patients with RA, 195 (63%) had baseline high severity RAPID3 scores. Patients with baseline high severity achieved significant RAPID3 decreases over 6 months (5.9 points; P < 0.0001). Nearly half of patients (N = 147, 47%) had a clinically important improvement and 105 (34%) were LS/NR at follow-up; 67 patients (21%) met both criteria. After adjusting for baseline RAPID3 severity category, medication change (aOR, 0.39; 95% CI, 0.21-0.71) and opting out of full therapy management (aOR, 0.36; 95% CI, 0.19-0.65) were inversely associated with achieving a clinically important improvement. Being LS/NR at follow-up was also inversely associated with medication change (aOR, 0.19; 95% CI, 0.075-0.48) and opting out of full therapy management (aOR, 0.27; 95% CI, 0.12-0.63). Low medication adherence (aOR, 0.28; 95% CI, 0.11-0.72) and Medicaid insurance (aOR, 0.52; 95% CI, 0.29-0.93) were also inversely associated with being LS/NR at follow-up. RAPID3 is a valuable tool in the specialty pharmacy setting, helping assess patient outcomes beyond traditional metrics. Specialty pharmacies should support their patients in striving to reach clinically important improvement and/or achieving LS/NR as measures of quality pharmacy care during the crucial months after therapy initiation and throughout care. Active collaboration between patients and pharmacists is crucial in reaching positive RA disease activity outcomes. To support this, implementing programs that foster patient engagement with pharmacists may be important for optimizing care delivery.
In germinal centers, activated B cells modify their antigen receptors through somatic hypermutation (SHM), followed by antigenic selection that favors expansion of high affinity B cells. The affinity maturation process is critical for development of broadly neutralizing antibodies (bnAbs) against the human immunodeficiency virus-1 (HIV-1). BnAbs have been isolated from some people living with HIV-1. Because these antibodies target conserved epitopes of the HIV-1 Envelope (Env) protein, they inhibit a broad spectrum of viruses. Eliciting bnAbs by vaccination is a top priority for HIV-1 prevention, but reproducing the lengthy maturation of bnAbs is a major challenge. The problem is typified by VRC01 class antibodies, which recognize the CD4 binding site of HIV-1 Env protein. To reach the CD4 binding site, antibodies need to navigate through adjacent glycans. Accommodating the glycans requires multiple SHMs in germinal center (GC) B cells, including infrequent events. For this reason, VRC01 vaccine development often stalls at this point. We have generated a mouse model aimed at providing a potential solution for navigating this vaccine design impediment. To this end, we made a mouse model that expresses a stalled VRC01 intermediate conditionally in GC B cells. This system has three advantages: 1) direct expression of the intermediate obviates prior immunization steps, thereby shortening the immunization scheme; 2) the conditional expression system bypasses tolerance control checkpoints that sometimes delete B cells expressing bnAbs; 3) the intermediate responds to immunization in GCs, the physiological site of affinity maturation. With this model, we established an immunization method to mature the VRC01 intermediate into heterologous neutralizing antibodies against viruses with a native glycan shield. Since high mutation load is common among bnAbs, the germinal center conditional expression system could provide a general tool for boost immunogen design to overcome roadblocks in the maturation pathway.
The cold temperatures during winter contribute to significant discomfort, causing cold stress to the lives of people. In this study, we investigate the cold stress conditions and their trends over north India during November - February for the period 1982-2020, using Universal Thermal Climate Index (UTCI), a widely recognized biometeorological variable. The onset of cold stress typically initiates in the late evening (18 IST) and gradually spreads across the north India. It then intensifies over night into moderate cold stress, persisting from 20 IST until the early morning hours (7 IST). Cold stress is found to be most intense in January, with UTCI values ranging between 0 °C to -13 °C among winter months. During cold wave events, cold stress reaches its maximum spatial extent and intensity throughout the study region, with the most intense conditions observed in Jammu & Kashmir and Ladakh. Results show a significant increase in slight cold stress hours during the winter season over the period 1982-2020 in north India. This increase reflects a transition from stronger cold stress categories to the slight cold stress category. Such a shift indicates a reduction in the severity of cold stress rather than an intensification of cold conditions. Slight cold stress occurs when UTCI values range between 0 °C and -9 °C and the duration of such conditions has increased at a rate of 33.64 hours per decade. This increase is most prominent in the high-altitude regions of Jammu & Kashmir, Ladakh and Himachal Pradesh. In contrast, moderate cold stress which occurs when the UTCI values are in the range -9 °C to -13 °C shows a significant decreasing trend, particularly in Rajasthan, Punjab, Haryana and Uttar Pradesh. Despite this, cold stress remains a major contributor to cold wave-related mortality in north India. Uttar Pradesh recorded the highest number of deaths of 4449, followed by Punjab (2606) and Bihar (2479). Although these states generally experience only slight cold stress with UTCI values in the range of 0 °C to 9 °C, the impact is amplified by wind chill with a category of 'Tonic- very cold sub comfort' caused by cold, dry northwesterly winds blowing directly into the region. This compound effect of cold stress and wind chill considerably enhances the mortality risk during cold wave events across north India.
Tobacco use remains a leading cause of preventable morbidity and mortality and is commonly initiated in adolescence. We evaluated whether Smokerface-Poster, a low-intensity, appearance-based school campaign promoting a photoaging app, could attenuate smoking uptake among early adolescents. In this two-arm cluster-randomized controlled trial, 126 German secondary schools (9797 grade 6/7 students; 96.0% were 11-13 years old; 51.4% male; 48.6% female) were allocated to intervention or control. Intervention schools displayed two classroom posters for 24 months. Smoking behavior was assessed at baseline and 24 months. As primary outcome, we investigated the between‑group difference in the change in 30-day smoking prevalence, with a number needed to treat (NNT) of < 100 students predefined as clinically relevant per protocol. Baseline smoking prevalence was 7.4% in the control vs. 7.9% in the intervention group. At 24 months post-intervention, smoking prevalence increased by 19.2 %age points in control vs. 18.1 %age points in the intervention group (number needed to treat=93; adjusted ratio of odds ratios 0.87, 95% CI 0.69-1.09; p = 0.228). Favorable, non-significant patterns were also observed for anti-smoking intentions and attitudes. Although the between-group difference was not statistically significant, the intervention reached the predefined threshold for clinical relevance, with an NNT of 93. This suggests that, for every 93 students exposed to the Smokerface-Poster campaign, one fewer adolescent would be expected to smoke over the two-year follow-up. Given its low cost of < €50 per 100 students, the intervention appears to be a promising approach to supporting school-based smoking prevention.
Acute T cell-mediated rejection (TCMR) continues to be a major cause of graft dysfunction and loss despite advances in diagnostic methods and immunosuppression. Clinical practices regarding the treatment and follow-up of TCMR differ widely across transplant centers. The aim of our study was to describe current practices in Argentina concerning protocol biopsies, diagnosis, treatment, and follow-up of TCMR in kidney transplant patients. A national survey was conducted, promoted by the Sociedad Argentina de Trasplantes. All 58 certified kidney transplant centers in the country were invited to participate. The questionnaire, based on international surveys and adapted by local experts, explored the clinical strategies used to address TCMR. Forty-nine centers responded (84% response rate), showing high variability in the frequency of biopsies -including protocol biopsies- in the therapeutic regimens used, and in the definitions of borderline rejection and corticosteroid resistance. There is a notable heterogeneity in the management of TCMR among transplant centers in Argentina. Reaching consensus on definitions and therapeutic strategies will be essential to improve homogeneity of care and comparability across studies in our transplant centers. Introducción: El rechazo celular mediado por linfocitos T (TCMR) continúa siendo una causa relevante de disfunción y pérdida del injerto renal. A pesar de los avances en los métodos de diagnóstico y de inmunosupresión, las prácticas clínicas respecto al tratamiento y seguimiento del TCMR varían considerablemente entre distintos centros de trasplante. El objetivo de nuestro trabajo fue describir las prácticas actuales en Argentina en relación con las biopsias de protocolo (o vigilancia), el diagnóstico, el tratamiento y el seguimiento del TCMR en pacientes con trasplante renal. Materiales y métodos: Se realizó una encuesta nacional en formato digital, promovida por la Sociedad Argentina de Trasplante. Se invitó a participar a los 58 centros habilitados de trasplante renal del país. El cuestionario, basado en encuestas internacionales y adaptado por expertos locales, indagó sobre las estrategias clínicas empleadas frente al TCMR. Resultados: Respondieron 49 centros (84% de respuesta), y se evidenció gran variabilidad en la frecuencia de biopsias, incluyendo las biopsias de protocolo, en los esquemas terapéuticos utilizados y en las definiciones de rechazo borderline y de resistencia a los corticoesteroides. Conclusión: Existe una notable heterogeneidad en el manejo del TCMR entre los centros de trasplante de Argentina. Un consenso en las definiciones y las estrategias terapéuticas resultará esencial para mejorar la homogeneidad en la atención y la comparabilidad de los resultados clínicos entre los distintos centros de trasplante del país.
In 2019, the Latin American Observatory of National Immunization Programs (NIPs) was created to analyze their situation through an annual ranking. The objective of this study was to evaluate and compare the performance of NIPs in 19 countries in the region between 2021-2022, during the COVID-19 pandemic. A retrospective, observational, and descriptive study was conducted on different domains of the NIPs: vaccination schedules and coverage by age group, influenza and COVID-19 vaccination, immunization of special populations, and programatic aspects. Data were collected from official government sources, international health organizations, and interviews with experts from each country. A scoring system was applied to generate the ranking. More than 70% of the countries showed some recovery in vaccination coverage, although not reaching pre-pandemic levels. Chile, Uruguay, Costa Rica, and Panama maintained their leadership of previous years due to complete vaccination schedules and high programmatic standards. The lowest-scoring countries had limited schedules, low coverage rates, and gaps in data transparency and electronic immunization records. Following the decline in 2020-2021, 16 of the 18 evaluated countries (Venezuela was not compared) improved their scores in 2022. The NIPs ranking serves as a comparative tool to promote improvements in immunization policies across Latin America. The regional priority remains the recovery of vaccination coverage. Furthermore, strengthening electronic records, data transparency, and political commitment with sustained investment are essential to ensure robust programmatic structures and effective immunization strategies. Introducción: En 2019 se creó el Observatorio de Programas Nacionales de Inmunización (PNI) de América Latina para analizar su situación mediante un ranking anual. El objetivo de este estudio fue evaluar y comparar el desempeño de los PNI en 19 países de la región entre 2021‐2022, durante la pandemia de COVID-19. Materiales y métodos: Estudio retrospectivo, observacional y descriptivo sobre distintos dominios de los PNI: calendarios y coberturas de vacunación por grupos etarios, inmunización contra influenza, COVID-19, en poblaciones especiales y aspectos programáticos. Se recopilaron datos de fuentes oficiales gubernamentales, organismos internacionales y entrevistas con expertos de cada país. Se aplicó un sistema de puntuación para generar el ranking. Resultados: Más del 70% de los países mostraron recuperación en las coberturas vacunales, aunque sin alcanzar los niveles previos a la pandemia. Chile, Uruguay, Costa Rica y Panamá mantuvieron el liderazgo de años anteriores gracias a calendarios completos y altos estándares programáticos. Los países con menores puntajes presentaron calendarios acotados, coberturas bajas, brechas en transparencia de datos y registros electrónicos de inmunización. Tras la caída en 2020‐2021, 16 de 18 países (Venezuela no fue comparada) mejoraron su puntuación en 2022. Conclusión: El ranking de los PNI constituye una herramienta comparativa para promover mejoras en las políticas de inmunización en América Latina. La prioridad regional sigue siendo recuperar coberturas vacunales. Asimismo, el fortalecimiento de los registros electrónicos, la transparencia de datos y el compromiso político con inversión sostenida resultan esenciales para garantizar estructuras programáticas sólidas y estrategias efectivas de inmunización.
Do the genetic and clinical outcomes of monopronuclear blastocysts (MPBs) differ between standard insemination and intracytoplasmic sperm injection cycles, and what do these differences imply for risk stratification and individualized clinical decision-making? IVF-derived MPBs demonstrate significantly lower rates of uniparental inheritance than ICSI-derived MPBs (96.9% vs 65.9%) biparental inheritance (P < 0.001), with comparable clinical and neonatal outcomes to 2PN blastocysts following transfer of euploid biparental embryos. A proportion of monopronuclear (1PN) zygotes can develop into euploid blastocysts and, following transfer, result in healthy live births, yet these embryos are widely discarded following fertilization check due to atypical pronucleation. The mechanisms underlying 1PN formation are varied and include asynchronous pronuclear formation, early pronuclear fusion, and premature pronuclear breakdown, meaning a subset may represent normally fertilized diploid zygotes missed at static assessment. Retrospective cohort study of 1PN embryos (N = 13 203) derived from IVF (n = 5266) or ICSI (n = 5464) inseminations across 10 730 cycles performed at multiple Australian clinics between January 2010 and December 2023. Embryos were defined as 1PN by the appearance of a single pronucleus at fertilization check 16-18 h post-insemination. Time-lapse footage was reviewed on Day 3 to identify late appearing 1PNs and exclude late second pronucleus appearance. Suitable blastocysts underwent trophectoderm biopsy for pre-implantation genetic testing for aneuploidy (PGT-A) and short tandem repeat (STR)-based biparental inheritance testing; only euploid embryos with confirmed biparental inheritance were available for frozen embryo transfer. Outcomes assessed included ploidy, biparental inheritance, blastocyst development, utilization, morphokinetics, pregnancy, live birth, and maternal and neonatal outcomes. IVF-derived MPBs had similar aneuploidy rates to two pronuclei (2PN) embryos (37.3% vs 33.9%) and 440/454 (96.9%) demonstrated biparental inheritance. ICSI-derived MPBs had higher aneuploidy rates (45.5% vs 31.5%, P < 0.05) and only 108/164 (65.9%) had biparental inheritance. Uniparental inheritance was predominantly maternal (IVF 92.8%; ICSI 94.6%). Both IVF and ICSI MPBs were less likely to reach blastocyst stage by Day 5 than 2PN embryos (IVF 19.3% vs 63.3%; ICSI 9.7% vs 60.6%, P < 0.05), and biparental IVF-1PN zygotes were more likely to have more nucleoli compared with uniparental IVF-1PN zygotes (P = 0.008). For embryos with confirmed biparental inheritance, there was no significant difference in clinical pregnancy, ongoing pregnancy, live birth rates, or neonatal outcomes compared with 2PN blastocysts. In approximately one in six cycles containing a 1PN embryo, no utilizable 2PN embryo were available (IVF 15.6%; ICSI 16.7%), with the 1PN embryo representing the sole option for embryo utilization. Retrospective single-entity design introduces potential selection bias and limits generalizability. Uniform protocols across sites preclude the level of evidence required for formal guideline revision. Differential use of time-lapse imaging for ICSI versus static assessment for IVF embryos may contribute to differences in 1PN identification rates between fertilization methods. The STR-based biparental classification platform has not been validated against an orthogonal technology for parental origin calling in 1PN embryos, and the possibility of triploid misclassification or absorption into unreported inconclusive outcomes cannot be excluded. These findings support a risk-stratified approach to MPB management based on fertilization method. IVF-derived MPBs meeting specific morphological and developmental criteria demonstrate a low-risk profile that warrants reconsideration of genetic testing requirements and may inform individualized consent discussions, particularly where 2PN embryos are unavailable. ICSI-derived MPBs carry a substantially higher risk of uniparental inheritance and comprehensive genetic testing remains indicated. No funding was attached to this study. The authors declare no conflict of interest. N/A.
This pragmatic pilot study explored the potential effectiveness of a hybrid intervention combining transcutaneous auricular vagus nerve stimulation (taVNS) with slow breathing and assessed its feasibility, adherence, and acceptability among individuals with post-traumatic stress disorder (PTSD) symptoms related to the war in Ukraine. A delayed treatment within-subject design was used with five monthly assessments: one month before the intervention, pre- and postintervention (including physiologicdata), and two follow-ups with self-reported outcomes only. A total of 20 Ukrainian women (aged 18-49 years) with PTSD symptoms (PTSD checklist for DSM-5 [PCL-5] ≥31) practiced slow breathing paced by taVNS at 0.1 Hz (4-s inspiration and 6-s expiration with stimulation), twice daily for four weeks. Self-reported outcomes included PTSD symptoms (PCL-5), psychologic distress (Hopkins Symptom Checklist-25), well-being (World Health Organization-Five Well-Being Index), insomnia (Insomnia Severity Index), and somatic symptoms (Patient Health Questionnaire-15). Physiologic measures: heart rate, respiratory heart rate variability (respHRV), end-tidal CO2, and respiratory rate were collected at rest and during paced breathing to standardize respHRV measurement. Compared with the preintervention waiting period, improvements were observed during the intervention in most self-reported outcomes. The strongest effects were observed for insomnia (dz = 1.01) and somatic symptoms (dz = 0.84). PTSD improvement did not reach significance (p = 0.08, dz = 0.44). Follow-up data suggested partial persistence of benefits. No significant changes were found in physiologic outcomes. The intervention was well tolerated and positively evaluated, with mostly mild side effects. This study suggests that taVNS combined with slow breathing is feasible and potentially effective, with the most promising effects on insomnia and somatic symptoms. Further investigation in randomized controlled trials is warranted.
Anthelmintic resistance has prompted the search for alternative control strategies, such as the use of plant-derived compounds and biological control with nematophagous fungi. The aim of the present study was to evaluate the in vitro anthelmintic effect of linalool and its association with the fungus Arthrobotrys cladodes on gastrointestinal nematodes of sheep. The larvicidal activity of linalool, alone and in combination with A. cladodes conidia, was assessed using the Larval Motility Inhibition Test (LMIT) on infective larvae (L3). Ten (10) experimental groups were designed, each with eight replicates, comprising treatments with linalool and A. cladodes conidia, alone and in combination, as well as ivermectin (positive control) and distilled water (negative control). Larval motility was evaluated under optical microscopy after 1, 7, and 14 days of exposure. A significant reduction (p ≤ 0.05) in the number of L3 larvae was observed in the groups treated with linalool combined with A. cladodes (G7-G10) compared to the negative control group (G1), starting at 24 h and reaching 100% reduction after 14 days. The groups treated only with A. cladodes conidia (G3 and G4) showed less effective reductions compared to the combined treatments. The larvicidal activity of the groups treated solely with linalool (G5 and G6) did not differ statistically (p > 0.05) from those treated with the fungus and linalool. It is concluded that the combination of linalool and A. cladodes conidia exhibits anthelmintic activity against gastrointestinal nematodes of sheep, demonstrating a synergistic interaction between the nematophagous fungus and the monoterpene.
Very high energy electron (VHEE) radiotherapy has gained growing interest owing to its potential to reach deep-seated targets and induce FLASH effect. Dose calculations can be performed using analytical or Monte Carlo (MC) methods. Analytical approaches enable rapid dose computation but suffer from limited accuracy in heterogeneous media, whereas MC methods provide high accuracy at the expense of substantial computational cost. Macro Monte Carlo (MMC) is a local-to-global method designed to improve dose calculation efficiency compared to general-purpose MC methods. In MMC, particle transport is based on precalculated transport data generated with general-purpose MC simulations on specific geometries, which is subsequently used to model particle transport over macroscopic steps within the absorber, avoiding computationally expensive microscopic tracking. MMC made it to a standard electron dose calculation engine in a commercial treatment planning system. However, to date, MMC has not been investigated for electron energies above 25 MeV. To develop and validate an MMC framework for VHEE radiotherapy that improves dose calculation efficiency while preserving accuracy compared to general-purpose MC methods for electron energies up to 250 MeV. Local simulations were performed using EGSnrc with monoenergetic electron pencil beams incident perpendicularly on spherical geometries (0.2-25 MeV) with radii of 0.5-3 mm, and slab geometries (25-250 MeV) of 2 mm thickness, composed of various materials. Physical quantities including energy loss, lateral displacement, and angular distributions of primary and secondary particles were scored and stored in a database. This database was subsequently used to transport electrons step-by-step in the global simulations, employing slab-based transport at energies ≥25 MeV and switching to spherical geometries for electron energies <25 MeV to account for increased scattering. Energy deposition was scored in a 3D dose grid. MMC dose calculations were validated against EGSnrc for monoenergetic VHEE beams (50-250 MeV) incident on homogeneous and heterogeneous slab phantoms, using pencil beams, parallel spot beams with 1 mm radius, and parallel beams with a field size of 5 × 5 cm2. MMC and EGSnrc dose calculations were also performed for two patient CT datasets. Comparisons between MMC and EGSnrc were conducted using integrated depth dose curves, lateral dose profiles, and 3D gamma analysis with 2%/1 mm and 2%/2 mm (global) criteria and a 10% dose threshold. All simulations were performed with statistical uncertainties below 1%, and computation times were recorded. Integrated depth dose curves and lateral dose profiles agreed within 2% of the maximum dose for all cases considered. For homogeneous and heterogeneous phantoms, MMC dose distributions yielded gamma passing rates above 97% (2%/1 mm) and 99% (2%/2 mm), respectively, compared to EGSnrc. For patient CT datasets, gamma passing rates exceeded 94% (2%/1 mm) and 97% (2%/2 mm). Overall, MMC achieved up to a 27-fold improvement in dose calculation efficiency compared to EGSnrc. An MMC framework for VHEE dose calculation was successfully developed and validated for electron energies up to 250 MeV. The method demonstrated good agreement with EGSnrc while providing up to an order-of-magnitude improvement in dose calculation efficiency for the studied cases.
In expert centers, surgical resection rates of locally advanced pancreatic cancer (LAPC) following induction chemotherapy have increased beyond 20% with subsequent 25% five-year overall survival (OS). In the Netherlands, however, the historical low 8% LAPC resection rate compared with 23% in international expert centers reflects relative reluctance. Thereby, opportunities to achieve long-term survival in appropriately selected patients may be missed. This study evaluated whether nationwide implementation of international multidisciplinary best-practice for LAPC management is feasible while maintaining surgical safety benchmarks (in-hospital/30-day major morbidity <50% and mortality ≤5%). A multidisciplinary protocol was designed in collaboration with four international experts and prospectively implemented nationwide within the Dutch Pancreatic Cancer Group (DPCG) (2022-2024). This observational cohort included consecutive patients diagnosed with LAPC, defined by DPCG criteria. Eligible patients had radiologically non-progressive disease after at least four months of multi-agent chemotherapy. All patients who underwent resection were included in this safety analysis. A predefined sub-group analysis included patients with National Comprehensive Cancer Network (NCCN) LAPC. Primary outcomes included in-hospital/30-day major morbidity (i.e., Clavien-Dindo grade ≥IIIa) and mortality. The expected number of resections was 53. Overall, 180 patients with LAPC underwent surgical exploration, of whom 155 (86%) underwent resection in 11 centers. Most (74%) resections were performed in the three LAPC surgical centers. Extended resections were performed in 77% of patients, including portomesenteric venous (60%), multivisceral (23%), and arterial (21%) resections. In-hospital/30-day major morbidity rate was 44% and mortality rate was 0.6%, both within pre-established safety benchmarks. Benchmarks were also reached for patients with NCCN LAPC (49% major morbidity, 2% mortality). Nationwide implementation of the international best-practice for LAPC was feasible with nearly three times more resections performed than expected, while morbidity and mortality remained well within predefined safety benchmarks.
The goal of the following study was to rank EU countries on their progress in achieving SDG 4 "Ensure inclusive and equitable quality education and promote lifelong learning opportunities for all" in 2023 and to determine their distance from the target values set for 2030. Eurostat monitors and evaluates progress towards SDG 4 using six indicators. Based on these indicators, an aggregate measure was constructed according to the assumptions of a hybrid approach combining multidimensional scaling with linear ordering. The proposed method involves a non-compensatory approach and target-based data adjustment, which prevents high values of some indicators from offsetting shortfalls in others, thereby providing a more reliable assessment of progress towards policy targets. The results show that Nordic countries, along with the Netherlands and Estonia, rank highest, while Romania, Bulgaria, Cyprus and Greece remain the furthest from the 2030 targets. It is worth noting that no EU country has yet reached the aggregate SDG 4 target level, which highlights a substantial implementation gap at the EU level. The hybrid approach additionally makes it possible to visualise the multidimensional phenomenon in a two-dimensional space, enhancing interpretability of cross-country differences.