Sustainable nutrient management is critical for maintaining soil fertility, improving agricultural productivity and mitigating environmental impacts. This study evaluated the impact of Ireland's Nitrates Action Programme (NAP) on soil pH, phosphorus (P) and potassium (K) dynamics over a 12‐year period across four meso‐scale agricultural catchments. Using a spatially defined field‐scale sampling approach, trends in studied chemical soil parameters were assessed in response to changing agricultural practices and policy interventions. Results indicate a notable increase in optimal soil pH levels (21%), likely as a result of recent targeted advisory efforts. While overall median soil test P (STP) levels decreased by 0.5 mg/L, variability among catchments was evident, with one catchment showing a significant increase due to intensive poultry manure applications. Additionally, the proportion of P Index 1 soils increased by 9%, suggesting uneven P distribution and highlighting challenges in on‐farm nutrient management. Median soil test K (STK) increased by 17.6 mg/L, with notable gains in tillage and dairy enterprises, indicating shifts in nutrient application strategies. The study also identifies critical source areas (CSAs) of P losses, which decreased by 2%, aligning with NAP objectives. However, nearly 80% of soils remain of suboptimal fertility, particularly for P and pH, underscoring the need for targeted advisory efforts, improved nutrient planning and region‐specific management strategies. Findings provide key insights into how regulatory measures influence soil nutrient trends, informing future policies for sustainable nutrient management and environmental protection in Irish agriculture.

Although autism has historically been conceptualized as a condition that emerges in early childhood1,2, many autistic people are diagnosed later in life3, 4–5. It is unknown whether earlier- and later-diagnosed autism have different developmental trajectories and genetic profiles. Using longitudinal data from four independent birth cohorts, we demonstrate that two different socioemotional and behavioural trajectories are associated with age at diagnosis. In independent cohorts of autistic individuals, common genetic variants account for approximately 11% of the variance in age at autism diagnosis, similar to the contribution of individual sociodemographic and clinical factors, which typically explain less than 15% of this variance. We further demonstrate that the polygenic architecture of autism can be broken down into two modestly genetically correlated (rg = 0.38, s.e. = 0.07) autism polygenic factors. One of these factors is associated with earlier autism diagnosis and lower social and communication abilities in early childhood, but is only moderately genetically correlated with attention deficit–hyperactivity disorder (ADHD) and mental-health conditions. Conversely, the second factor is associated with later autism diagnosis and increased socioemotional and behavioural difficulties in adolescence, and has moderate to high positive genetic correlations with ADHD and mental-health conditions. These findings indicate that earlier- and later-diagnosed autism have different developmental trajectories and genetic profiles. Our findings have important implications for how we conceptualize autism and provide a model to explain some of the diversity found in autism. A study of several longitudinal birth cohorts and cross-sectional cohorts finds only moderate overlap in genetic variants between autism that is diagnosed earlier and that diagnosed later, so they may represent aetiologically different conditions.

Alien species Trichopoda (Galactomyia) pictipennis Bigot, 1876 was found in southeasternBosnia and Herzegovina and Croatia in June and August 2024. This is the first recordof this species for Bosnia and Herzegovina and the southeastern part of Croatia.Additionally, this report includes the records from Montenegro and Bulgaria obtainedfrom the online data platform iNaturalist representing the first observations of T.pictipennis for Montenegro and the Black Sea coast in Bulgaria.

The genus Temnostoma comprises saproxylic hoverflies whose larvae develop by boring into wet, decaying wood, where they feed on microorganisms. Records of these species in the northwestern Balkans are sparse in the literature and nearly absent from openaccess databases. To enhance knowledge of their distribution in the region, we present new records of four Temnostoma species from Croatia, Bosnia and Herzegovina, and Serbia. Three species were recorded in all three countries, while T. apiforme was found exclusively in Croatia. This discovery marks not only the first record of this species in the country but also the first for the entire Balkan Peninsula. Furthermore, Temnostomameridionale was documented in Bosnia and Herzegovina for the first time. Given thatthese hoverflies are large and visually striking, we hope this study will inspire interestamong citizen scientists and encourage future contributions to the documentation ofthis genus in the region.

Pain remains one of the most burdensome symptoms in rheumatoid arthritis (RA), often persisting despite inflammatory remission and profoundly impairing quality of life. This review aimed to evaluate the clinical efficacy and mechanistic pathways by which Janus kinase (JAK) inhibitors alleviate RA-related pain. Evidence from randomized clinical trials demonstrates that JAK inhibitors have demonstrated rapid and significant pain relief, often exceeding that of methotrexate or biologic DMARDs. Improvements in patient-reported pain scores seem to typically emerge within 1–2 weeks and are sustained over time. Beyond anti-inflammatory effects, JAK inhibitors modulate central sensitization and nociceptive signaling by attenuating IL-6 and GM-CSF activity, reducing astrocyte and microglial activation, and downregulating nociceptor excitability in dorsal root ganglia and spinal pathways. Preclinical models further suggest that JAK inhibition interrupts neuroimmune feedback loops critical to chronic pain maintenance. Comparative and network meta-analyses consistently position JAK inhibitors among the most effective agents for pain control in RA. However, individual variability in response, partly due to differential JAK-STAT activation and cytokine receptor uncoupling, underscores the need for biomarker-guided treatment approaches. JAK inhibitors represent a mechanistically distinct and clinically impactful class of therapies that target both inflammatory and non-inflammatory pain in RA. Their integration into personalized pain management strategies offers a promising path to address one of RA’s most persistent unmet needs.

Summary Background For more than three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has provided a framework to quantify health loss due to diseases, injuries, and associated risk factors. This paper presents GBD 2023 findings on disease and injury burden and risk-attributable health loss, offering a global audit of the state of world health to inform public health priorities. This work captures the evolving landscape of health metrics across age groups, sexes, and locations, while reflecting on the remaining post-COVID-19 challenges to achieving our collective global health ambitions. Methods The GBD 2023 combined analysis estimated years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 375 diseases and injuries, and risk-attributable burden associated with 88 modifiable risk factors. Of the more than 310 000 total data sources used for all GBD 2023 (about 30% of which were new to this estimation round), more than 120 000 sources were used for estimation of disease and injury burden and 59 000 for risk factor estimation, and included vital registration systems, surveys, disease registries, and published scientific literature. Data were analysed using previously established modelling approaches, such as disease modelling meta-regression version 2.1 (DisMod-MR 2.1) and comparative risk assessment methods. Diseases and injuries were categorised into four levels on the basis of the established GBD cause hierarchy, as were risk factors using the GBD risk hierarchy. Estimates stratified by age, sex, location, and year from 1990 to 2023 were focused on disease-specific time trends over the 2010–23 period and presented as counts (to three significant figures) and age-standardised rates per 100 000 person-years (to one decimal place). For each measure, 95% uncertainty intervals [UIs] were calculated with the 2·5th and 97·5th percentile ordered values from a 250-draw distribution. Findings Total numbers of global DALYs grew 6·1% (95% UI 4·0–8·1), from 2·64 billion (2·46–2·86) in 2010 to 2·80 billion (2·57–3·08) in 2023, but age-standardised DALY rates, which account for population growth and ageing, decreased by 12·6% (11·0–14·1), revealing large long-term health improvements. Non-communicable diseases (NCDs) contributed 1·45 billion (1·31–1·61) global DALYs in 2010, increasing to 1·80 billion (1·63–2·03) in 2023, alongside a concurrent 4·1% (1·9–6·3) reduction in age-standardised rates. Based on DALY counts, the leading level 3 NCDs in 2023 were ischaemic heart disease (193 million [176–209] DALYs), stroke (157 million [141–172]), and diabetes (90·2 million [75·2–107]), with the largest increases in age-standardised rates since 2010 occurring for anxiety disorders (62·8% [34·0–107·5]), depressive disorders (26·3% [11·6–42·9]), and diabetes (14·9% [7·5–25·6]). Remarkable health gains were made for communicable, maternal, neonatal, and nutritional (CMNN) diseases, with DALYs falling from 874 million (837–917) in 2010 to 681 million (642–736) in 2023, and a 25·8% (22·6–28·7) reduction in age-standardised DALY rates. During the COVID-19 pandemic, DALYs due to CMNN diseases rose but returned to pre-pandemic levels by 2023. From 2010 to 2023, decreases in age-standardised rates for CMNN diseases were led by rate decreases of 49·1% (32·7–61·0) for diarrhoeal diseases, 42·9% (38·0–48·0) for HIV/AIDS, and 42·2% (23·6–56·6) for tuberculosis. Neonatal disorders and lower respiratory infections remained the leading level 3 CMNN causes globally in 2023, although both showed notable rate decreases from 2010, declining by 16·5% (10·6–22·0) and 24·8% (7·4–36·7), respectively. Injury-related age-standardised DALY rates decreased by 15·6% (10·7–19·8) over the same period. Differences in burden due to NCDs, CMNN diseases, and injuries persisted across age, sex, time, and location. Based on our risk analysis, nearly 50% (1·27 billion [1·18–1·38]) of the roughly 2·80 billion total global DALYs in 2023 were attributable to the 88 risk factors analysed in GBD. Globally, the five level 3 risk factors contributing the highest proportion of risk-attributable DALYs were high systolic blood pressure (SBP), particulate matter pollution, high fasting plasma glucose (FPG), smoking, and low birthweight and short gestation—with high SBP accounting for 8·4% (6·9–10·0) of total DALYs. Of the three overarching level 1 GBD risk factor categories—behavioural, metabolic, and environmental and occupational—risk-attributable DALYs rose between 2010 and 2023 only for metabolic risks, increasing by 30·7% (24·8–37·3); however, age-standardised DALY rates attributable to metabolic risks decreased by 6·7% (2·0–11·0) over the same period. For all but three of the 25 leading level 3 risk factors, age-standardised rates dropped between 2010 and 2023—eg, declining by 54·4% (38·7–65·3) for unsafe sanitation, 50·5% (33·3–63·1) for unsafe water source, and 45·2% (25·6–72·0) for no access to handwashing facility, and by 44·9% (37·3–53·5) for child growth failure. The three leading level 3 risk factors for which age-standardised attributable DALY rates rose were high BMI (10·5% [0·1 to 20·9]), drug use (8·4% [2·6 to 15·3]), and high FPG (6·2% [–2·7 to 15·6]; non-significant). Interpretation Our findings underscore the complex and dynamic nature of global health challenges. Since 2010, there have been large decreases in burden due to CMNN diseases and many environmental and behavioural risk factors, juxtaposed with sizeable increases in DALYs attributable to metabolic risk factors and NCDs in growing and ageing populations. This long-observed consequence of the global epidemiological transition was only temporarily interrupted by the COVID-19 pandemic. The substantially decreasing CMNN disease burden, despite the 2008 global financial crisis and pandemic-related disruptions, is one of the greatest collective public health successes known. However, these achievements are at risk of being reversed due to major cuts to development assistance for health globally, the effects of which will hit low-income countries with high burden the hardest. Without sustained investment in evidence-based interventions and policies, progress could stall or reverse, leading to widespread human costs and geopolitical instability. Moreover, the rising NCD burden necessitates intensified efforts to mitigate exposure to leading risk factors—eg, air pollution, smoking, and metabolic risks, such as high SBP, BMI, and FPG—including policies that promote food security, healthier diets, physical activity, and equitable and expanded access to potential treatments, such as GLP-1 receptor agonists. Decisive, coordinated action is needed to address long-standing yet growing health challenges, including depressive and anxiety disorders. Yet this can be only part of the solution. Our response to the NCD syndemic—the complex interaction of multiple health risks, social determinants, and systemic challenges—will define the future landscape of global health. To ensure human wellbeing, economic stability, and social equity, global action to sustain and advance health gains must prioritise reducing disparities by addressing socioeconomic and demographic determinants, ensuring equitable health-care access, tackling malnutrition, strengthening health systems, and improving vaccination coverage. We live in times of great opportunity. Funding Gates Foundation and Bloomberg Philanthropies.

Acinic cell carcinoma (ACC) of the breast is a very rare, primary salivary gland‐type breast malignancy, with ~100 reported cases in the literature. Limited information about the clinical features and outcomes of patients with ACC is available.

OBJECTIVES To compare the clinicopathologic features, treatment patterns, and survival outcomes of mucinous tubular and spindle cell carcinoma (MTSCC) with those of clear cell renal cell carcinoma (ccRCC) and papillary renal cell carcinoma (PRCC). SUBJECTS AND METHODS This retrospective cohort study used SEER data from 1983 to 2022, including 461 MTSCC, 133,229 ccRCC, and 29,442 PRCC cases. Demographic, clinical, and treatment variables were analyzed using chi-square, ANOVA/Kruskal-Wallis tests, and Kaplan-Meier methods. Cox proportional hazards regression models were applied to estimate hazard ratios (HRs) for overall (OS) and disease-specific survival (DSS), adjusting for age, sex, race, stage, grade, treatment, and metastasis status. RESULTS MTSCC patients were more often female (54.9%), Black (20.6%), and aged ≥70 years (50.5%) compared to ccRCC and PRCC (P < 0.001). MTSCC had a lower incidence of distant metastasis than ccRCC (8.7% vs. 9.5%), but higher than PRCC (4.2%). Although most MTSCC patients presented with early-stage disease and underwent surgery (87.9%), they had the shortest mean survival (47.9 months) and the highest proportion of deaths within 100 months (83.5%). Kaplan-Meier analysis showed higher early mortality for MTSCC, with survival curves converging after 75 to 100 months. In adjusted models, MTSCC was associated with a nonsignificant increase in mortality compared to ccRCC (OS HR: 1.36, P = 0.422; DSS HR: 1.13, P = 0.832), while PRCC had a significantly higher DSS risk (HR: 1.24, P = 0.001). Poor survival in MTSCC was associated with older age, high-grade tumors, distant metastases, and absence of surgery. CONCLUSION MTSCC shows distinct demographic and clinical features and a paradoxically shorter survival despite early-stage presentation. Early mortality may contribute to its poorer outcomes, indicating that MTSCC is not uniformly indolent. Closer surveillance and individualized risk assessment are warranted in selected patients.

Summary Background Comprehensive, comparable, and timely estimates of demographic metrics—including life expectancy and age-specific mortality—are essential for evaluating, understanding, and addressing trends in population health. The COVID-19 pandemic highlighted the importance of timely and all-cause mortality estimates for being able to respond to changing trends in health outcomes, showing a strong need for demographic analysis tools that can produce all-cause mortality estimates more rapidly with more readily available all-age vital registration (VR) data. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) is an ongoing research effort that quantifies human health by estimating a range of epidemiological quantities of interest across time, age, sex, location, cause, and risk. This study—part of the latest GBD release, GBD 2023—aims to provide new and updated estimates of all-cause mortality and life expectancy for 1950 to 2023 using a novel statistical model that accounts for complex correlation structures in demographic data across age and time. Methods We used 24 025 data sources from VR, sample registration, surveys, censuses, and other sources to estimate all-cause mortality for males, females, and all sexes combined across 25 age groups in 204 countries and territories as well as 660 subnational units in 20 countries and territories, for the years 1950–2023. For the first time, we used complete birth history data for ages 5–14 years, age-specific sibling history data for ages 15–49 years, and age-specific mortality data from Health and Demographic Surveillance Systems. We developed a single statistical model that incorporates both parametric and non-parametric methods, referred to as OneMod, to produce estimates of all-cause mortality for each age-sex-location group. OneMod includes two main steps: a detailed regression analysis with a generalised linear modelling tool that accounts for age-specific covariate effects such as the Socio-demographic Index (SDI) and a population attributable fraction (PAF) for all risk factors combined; and a non-parametric analysis of residuals using a multivariate kernel regression model that smooths across age and time to adaptably follow trends in the data without overfitting. We calibrated asymptotic uncertainty estimates using Pearson residuals to produce 95% uncertainty intervals (UIs) and corresponding 1000 draws. Life expectancy was calculated from age-specific mortality rates with standard demographic methods. For each measure, 95% UIs were calculated with the 25th and 975th ordered values from a 1000-draw posterior distribution. Findings In 2023, 60·1 million (95% UI 59·0–61·1) deaths occurred globally, of which 4·67 million (4·59–4·75) were in children younger than 5 years. Due to considerable population growth and ageing since 1950, the number of annual deaths globally increased by 35·2% (32·2–38·4) over the 1950–2023 study period, during which the global age-standardised all-cause mortality rate declined by 66·6% (65·8–67·3). Trends in age-specific mortality rates between 2011 and 2023 varied by age group and location, with the largest decline in under-5 mortality occurring in east Asia (67·7% decrease); the largest increases in mortality for those aged 5–14 years, 25–29 years, and 30–39 years occurring in high-income North America (11·5%, 31·7%, and 49·9%, respectively); and the largest increases in mortality for those aged 15–19 years and 20–24 years occurring in Eastern Europe (53·9% and 40·1%, respectively). We also identified higher than previously estimated mortality rates in sub-Saharan Africa for all sexes combined aged 5–14 years (87·3% higher in GBD 2023 than GBD 2021 on average across countries and territories over the 1950–2021 period) and for females aged 15–29 years (61·2% higher), as well as lower than previously estimated mortality rates in sub-Saharan Africa for all sexes combined aged 50 years and older (13·2% lower), reflecting advances in our modelling approach. Global life expectancy followed three distinct trends over the study period. First, between 1950 and 2019, there were considerable improvements, from 51·2 (50·6–51·7) years for females and 47·9 (47·4–48·4) years for males in 1950 to 76·3 (76·2–76·4) years for females and 71·4 (71·3–71·5) years for males in 2019. Second, this period was followed by a decrease in life expectancy during the COVID-19 pandemic, to 74·7 (74·6–74·8) years for females and 69·3 (69·2–69·4) years for males in 2021. Finally, the world experienced a period of post-pandemic recovery in 2022 and 2023, wherein life expectancy generally returned to pre-pandemic (2019) levels in 2023 (76·3 [76·0–76·6] years for females and 71·5 [71·2–71·8] years for males). 194 (95·1%) of 204 countries and territories experienced at least partial post-pandemic recovery in age-standardised mortality rates by 2023, with 61·8% (126 of 204) recovering to or falling below pre-pandemic levels. There were several mortality trajectories during and following the pandemic across countries and territories. Long-term mortality trends also varied considerably between age groups and locations, demonstrating the diverse landscape of health outcomes globally. Interpretation This analysis identified several key differences in mortality trends from previous estimates, including higher rates of adolescent mortality, higher rates of young adult mortality in females, and lower rates of mortality in older age groups in much of sub-Saharan Africa. The findings also highlight stark differences across countries and territories in the timing and scale of changes in all-cause mortality trends during and following the COVID-19 pandemic (2020–23). Our estimates of evolving trends in mortality and life expectancy across locations, ages, sexes, and SDI levels in recent years as well as over the entire 1950–2023 study period provide crucial information for governments, policy makers, and the public to ensure that health-care systems, economies, and societies are prepared to address the world's health needs, particularly in populations with higher rates of mortality than previously known. The estimates from this study provide a robust framework for GBD and a valuable foundation for policy development, implementation, and evaluation around the world. Funding Gates Foundation.

ABSTRACT Pulmonary arterial hypertension (PAH) is a life‐threatening condition with no cure, making research into its underlying mechanisms critical. The platelet‐derived growth factor (PDGF) signaling pathway plays a crucial role in vascular remodeling, a key factor in PAH progression. Anti‐PDGF receptor therapies, such as imatinib, show promise but are associated with significant side effects. Recent research identified PDGF‐D as a new risk gene in idiopathic PAH, highlighting the need for further investigation into the PDGF pathway in the disease. In this study, we investigated PDGF‐D, a specific PDGFRβ ligand, as a potential therapeutic target. RNA‐Seq data from healthy lungs indicated that PDGF‐D is predominantly expressed in inflammatory cells, whereas in vascular lesions of idiopathic PAH patients, PDGF‐D was produced by various cell types. In vitro, PDGF‐D induced mitogenic effects on pulmonary arterial smooth muscle cells. However, genetic deletion of PDGF‐D in the chronic hypoxia mouse model of pulmonary hypertension showed no significant impact on vascular muscularization, hemodynamic parameters, or right ventricular hypertrophy. But, the absence of hypoxia‐induced Pdgfrb upregulation and the lack of increased expression of PAH‐regulated genes, Fgf2 and Notch3, in PDGF‐D‐deficient mice, suggests activation of alternative mechanisms. MicroRNA analyses revealed PDGF‐d‐related alterations in the expression of miR‐21 and miR‐451, both important regulators in PAH, further supporting the notion that PDGF‐D plays a unique role in PAH development. Taken together, our data suggest that PDGF‐D may target a distinct population of PDGFRβ‐expressing cells, separate from those stimulated by PDGF‐B, positioning PDGF‐D as a potentially unique and compelling therapeutic target for PAH.

In this paper, the drainage of storm water from traffic roads is analysed by analysing the traditional method of drainage using a separate sewage system, and also by analysing the integral approach to the drainage of rainwater in the urban area. The research objectives for the treatment of the topic in this paper are set and processed for the needs of planning and development of the sewage system for the drainage of rainwater from roads in urban areas, as well as for the evaluation and ranking of conceptual solutions and the elaboration of plans for the general solution for the collection and drainage of surface water from roads. For relevant rain episodes, i.e. rainfall of appropriate duration and intensity, runoff coefficients and flows were considered and analysed according to the rational method, all for the purpose of obtaining data on the amount of rainwater entering the sewage system. According to the set research program, it was necessary to work on defining and establishing the amount of precipitation for the area that was the research polygon, and based on exact measurement data, the optimal transverse and longitudinal drops of the level of the road were determined in order to drain rainwater from the roads as efficiently and quickly as possible, within the framework of the rules that define this area.

Introduction: Vitamin D (VD) deficiency has become a global epidemic in the past 2 decades. Cardiac troponin is a specific biomarker for detecting myocardial injury, particularly in the context of myocardial infarction (MI), where elevated levels are indicative of myocardial necrosis. This study aimed to investigate the relationship between VD levels and troponin values in patients admitted to the Intensive Care Unit under suspicion of acute coronary syndrome, including comparisons with patients ultimately not diagnosed with ACS. Materials and Methods: This cross-sectional study included a group of 69 patients who were hospitalized in the Intensive Care Unit of the Hospital under suspicion of acute coronary syndrome. The control consisted of patients without ACS. The content of VD-(25[OH]D) in blood plasma was measured by enzyme-linked immunosorbent assay during June–August 2024. Blood samples were taken in tubes with ethylenediaminetetraacetic acid anticoagulant. The tubes without anticoagulant were used for collecting blood for VD, fibrinogen, D-dimer, and lipid parameter measurement. Results: A statistically significant difference in total cholesterol levels was observed between patients with angina pectoris and those with MI (P < 0.05). Pearson correlation analysis also demonstrated a moderate negative correlation between VD levels and troponin values in patients diagnosed with MI (P < 0.05), indicating that lower VD concentrations may be associated with greater myocardial injury. Conclusions: Based on the data obtained, the medical community is inclined to believe that correction of VD deficiency has great prognostic significance. Further clinical and experimental studies are needed to study in more detail the mechanisms of the negative effects of VD deficiency on the cardiovascular system.