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The density of wood is a key indicator of the carbon investment strategies of trees, impacting productivity and carbon storage. Despite its importance, the global variation in wood density and its environmental controls remain poorly understood, preventing accurate predictions of global forest carbon stocks. Here we analyse information from 1.1 million forest inventory plots alongside wood density data from 10,703 tree species to create a spatially explicit understanding of the global wood density distribution and its drivers. Our findings reveal a pronounced latitudinal gradient, with wood in tropical forests being up to 30% denser than that in boreal forests. In both angiosperms and gymnosperms, hydrothermal conditions represented by annual mean temperature and soil moisture emerged as the primary factors influencing the variation in wood density globally. This indicates similar environmental filters and evolutionary adaptations among distinct plant groups, underscoring the essential role of abiotic factors in determining wood density in forest ecosystems. Additionally, our study highlights the prominent role of disturbance, such as human modification and fire risk, in influencing wood density at more local scales. Factoring in the spatial variation of wood density notably changes the estimates of forest carbon stocks, leading to differences of up to 21% within biomes. Therefore, our research contributes to a deeper understanding of terrestrial biomass distribution and how environmental changes and disturbances impact forest ecosystems.

Abstract Background Sex differences in patient-reported outcomes (PROs) are not well investigated after anterior cruciate ligament (ACL) reconstruction in football players. The aim was to study sex differences in player-related factors, ACL injury characteristics and PROs after primary ACL reconstruction in football players. Methods In this cross-sectional cohort study a survey was sent to 390 male and 403 female football players who were injured when playing football and had undergone a primary ACL reconstruction in the previous 1–3 years. Player-related factors, ACL injury characteristics, and PROs covering knee function, satisfaction with activity level and knee function, and readiness to return to sport were compared between male and females. The questionnaires International Knee Documentation Committee Subjective Knee Evaluation Form (IKDC-SKF), Knee injury and Osteoarthritis Outcome Score (KOOS), ACL-Quality of Life (ACL-QoL) and ACL-Return to Sport after Injury (ACL-RSI) were used. Results Ninety males (23%) and 283 (70%) females answered the survey, 65 males and 198 females fulfilled the inclusion criteria. Males had returned to football to a higher degree (77% vs 59%, p = 0.008) at any time after ACL reconstruction, but at the time of the survey, an equal number of males and females played football (55% vs 47%, p = 0.239) and had similar activity level according to the Tegner Activity Score (median, 9; interquartile range [IQR], 7, vs median, 8; IQR, 7; p = 0.740). Males were more satisfied with their knee function and activity level and rated higher scores in the IKDC-SKF (mean ± standard deviation, 83 ± 16 vs 76 ± 16, p = 0.006), KOOS Sport/Recreation (79 ± 19 vs 72 ± 22, p = 0.034), KOOS Quality of Life (73 ± 22 vs 64 ± 20, p = 0.008), ACL-QoL (7.6 ± 2 vs 6.8 ± 1.8, p = 0.008), and ACL-RSI (6.7 ± 2.1 vs 5.5 ± 2.3, p

Abstract Breastfeeding provides many health benefits, but its impact on respiratory health remains unclear. This study addresses the complex and dynamic nature of the mother-milk-infant triad by investigating maternal genomic factors regulating human milk oligosaccharides (HMOs), and their associations with respiratory health among human milk-fed infants. Nineteen HMOs are quantified from 980 mothers of the CHILD Cohort Study. Genome-wide association studies identify HMO-associated loci on chromosome 19p13.3 and 19q13.33 (lowest P = 2.4e–118), spanning several fucosyltransferase (FUT) genes. We identify novel associations on chromosome 3q27.3 for 6′-sialyllactose (P = 2.2e–9) in the sialyltransferase (ST6GAL1) gene. These, plus additional associations on chromosomes 7q21.32, 7q31.32 and 13q33.3, are replicated in the independent INSPIRE Cohort. Moreover, gene-environment interaction analyses suggest that fucosylated HMOs may modulate overall risk of recurrent wheeze among preschoolers with variable genetic risk scores (P

Understanding what controls global leaf type variation in trees is crucial for comprehending their role in terrestrial ecosystems, including carbon, water and nutrient dynamics. Yet our understanding of the factors influencing forest leaf types remains incomplete, leaving us uncertain about the global proportions of needle-leaved, broadleaved, evergreen and deciduous trees. To address these gaps, we conducted a global, ground-sourced assessment of forest leaf-type variation by integrating forest inventory data with comprehensive leaf form (broadleaf vs needle-leaf) and habit (evergreen vs deciduous) records. We found that global variation in leaf habit is primarily driven by isothermality and soil characteristics, while leaf form is predominantly driven by temperature. Given these relationships, we estimate that 38% of global tree individuals are needle-leaved evergreen, 29% are broadleaved evergreen, 27% are broadleaved deciduous and 5% are needle-leaved deciduous. The aboveground biomass distribution among these tree types is approximately 21% (126.4 Gt), 54% (335.7 Gt), 22% (136.2 Gt) and 3% (18.7 Gt), respectively. We further project that, depending on future emissions pathways, 17-34% of forested areas will experience climate conditions by the end of the century that currently support a different forest type, highlighting the intensification of climatic stress on existing forests. By quantifying the distribution of tree leaf types and their corresponding biomass, and identifying regions where climate change will exert greatest pressure on current leaf types, our results can help improve predictions of future terrestrial ecosystem functioning and carbon cycling.

BACKGROUND: Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear. METHODS: We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points. RESULTS: We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values

Abstract Background Epidemiological research on fractures in children under the age of two is of great importance to help understand differences between accidental and abusive trauma. Objective This systematic review aimed to evaluate studies reporting on the incidence of fractures in children under two years of age, excluding birth injuries. Secondary outcome measures included fracture location, mechanisms of injury and fracture characteristics. Methods A systematic literature review (1946 to February 7th 2024), including prospective and retrospective cohort studies and cross-sectional cohort studies, was performed. Studies including children from other age groups were included if the actual measures for those aged 0–2 years could be extracted. We also included studies restricted to infants. Annual incidence rates of fractures were extracted and reported as the main result. Critical appraisal of was performed using the Appraisal tool for Cross-Sectional Studies. Results Twelve moderate to good quality studies met eligibility criteria, of which seven were based on data from medical records and five were registry studies. Studies investigated different aspects of fractures, making comprehensive synthesis challenging. There was an overall annual fracture incidence rate of 5.3 to 9.5 per 1,000 children from 0–2 years of age; with commonest sites being the radius/ulna (25.2–40.0%), followed by tibia/fibula (17.3–27.6%) and the clavicle (14.6–14.8%) (location based on 3 studies with a total of 407 patients). In infants, the reported incidence ranged between 0.7 to 4.6 per 1,000 (based on 3 studies), with involvement of the clavicle in 22.2% and the distal humerus in 22.2% of cases (based on 1 study). Only a single metaphyseal lesion was reported (proximal humerus of an 11-month-old infant). Fracture mechanisms were detailed in four studies, with fall from chair, bed, table, own height or fall following indoor activities causing 50–60% of fractures. Conclusions There is a paucity of good quality data on fracture incidence in children under the age of two. Larger, prospective and unbiased studies would be helpful in determining normal pattern of injuries, so that differences from abusive trauma may be better understood.

Determining the drivers of non-native plant invasions is critical for managing native ecosystems and limiting the spread of invasive species1,2. Tree invasions in particular have been relatively overlooked, even though they have the potential to transform ecosystems and economies3,4. Here, leveraging global tree databases5-7, we explore how the phylogenetic and functional diversity of native tree communities, human pressure and the environment influence the establishment of non-native tree species and the subsequent invasion severity. We find that anthropogenic factors are key to predicting whether a location is invaded, but that invasion severity is underpinned by native diversity, with higher diversity predicting lower invasion severity. Temperature and precipitation emerge as strong predictors of invasion strategy, with non-native species invading successfully when they are similar to the native community in cold or dry extremes. Yet, despite the influence of these ecological forces in determining invasion strategy, we find evidence that these patterns can be obscured by human activity, with lower ecological signal in areas with higher proximity to shipping ports. Our global perspective of non-native tree invasion highlights that human drivers influence non-native tree presence, and that native phylogenetic and functional diversity have a critical role in the establishment and spread of subsequent invasions.

The Hazard Ratio (HR) is a well-established treatment effect measure in randomized trials involving right-censored time-to-events, and the Cardiovascular Outcome Trials (CVOTs) conducted since the FDA’s 2008 guidance have indeed largely evaluated excess risk by estimating a Cox HR. On the other hand, the limitations of the Cox model and of the HR as a causal estimand are well known, and the FDA’s updated 2020 CVOT guidance invites us to reassess this default approach to survival analyses. We highlight the shortcomings of Cox HR-based analyses and present an alternative following the causal roadmap—moving in a principled way from a counterfactual causal question to identifying a statistical estimand, and finally to targeted estimation in a large statistical model. We show in simulations the robustness of Targeted Maximum Likelihood Estimation (TMLE) to informative censoring and model misspecification and demonstrate a targeted learning analogue of the original Cox HR-based analysis of the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial. We discuss the potential reliability, interpretability, and efficiency gains to be had by updating our survival methods to incorporate the recent decades of advancements in formal causal frameworks and efficient nonparametricestimation.

Objective: This study aimed to evaluate the impact of root canal treatment on Oral Health-Related Quality of Life (OHRQoL) in general dental practice and compare it with tooth extraction. Additionally, patient satisfaction following tooth-preserving treatment was assessed. Material and methods: In all, 65 patients were recruited from 6 general dental clinics in Västra Götaland over 8 weeks, with 37 starting root canal treatment and 28 having extractions. Questionnaires, including Oral Health Impact Profile-14 (OHIP-14) and 9 questions assessing patient satisfaction, were administered at treatment initiation, and at 1, 6, and 12 months. The responses from both modalities were analysed using descriptive and analytical statistical methods. Results: The response rate ranged from 73.8% to 92.3%. Regarding OHRQoL, differences between the groups were few compared to baseline. However, significant improvements were observed in the extraction group at the 6- and 12-month follow-ups, in the ‘total score’, and the dimensions ‘pain’, ‘discomfort’, and ‘handicap’. Patient satisfaction was generally high, with cost being the least satisfactory item. Pain intensity remained consistently low. Conclusions: In this prospective cohort study few differences were found between the two treatment modalities. However, significant improvements were observed in the extraction group in several dimensions. The patient satisfaction regarding root canal treatment was considered high.

Abstract Background Psychological readiness is an important consideration for athletes and clinicians when making return to sport decisions following anterior cruciate ligament reconstruction (ACLR). To improve our understanding of the extent of deficits in psychological readiness, a systematic review is necessary. Objective To investigate psychological readiness (measured via the Anterior Cruciate Ligament-Return to Sport after Injury scale (ACL-RSI)) over time after ACL tear and understand if time between injury and surgery, age, and sex are associated with ACL-RSI scores. Methods Seven databases were searched from the earliest date available to March 22, 2022. Articles reporting ACL-RSI scores after ACL tear were included. Risk of bias was assessed using the ROBINS-I, RoB-2, and RoBANS tools based on the study design. Evidence certainty was assessed for each analysis. Random-effects meta-analyses pooled ACL-RSI scores, stratified by time post-injury and based on treatment approach (i.e., early ACLR, delayed ACLR, and unclear approach). Results A total of 83 studies were included in this review (78% high risk of bias). Evidence certainty was ‘weak’ or ‘limited’ for all analyses. Overall, ACL-RSI scores were higher at 3 to 6 months post-ACLR (mean = 61.5 [95% confidence interval (CI) 58.6, 64.4], I2 = 94%) compared to pre-ACLR (mean = 44.4 [95% CI 38.2, 50.7], I2 = 98%), remained relatively stable, until they reached the highest point 2 to 5 years after ACLR (mean = 70.7 [95% CI 63.0, 78.5], I2 = 98%). Meta-regression suggests shorter time from injury to surgery, male sex, and older age were associated with higher ACL-RSI scores only 3 to 6 months post-ACLR (heterogeneity explained R2 = 47.6%), and this reduced 1–2 years after ACLR (heterogeneity explained R2 = 27.0%). Conclusion Psychological readiness to return to sport appears to improve early after ACL injury, with little subsequent improvement until ≥ 2-years after ACLR. Longer time from injury to surgery, female sex and older age might be negatively related to ACL-RSI scores 12–24 months after ACLR. Due to the weak evidence quality rating and the considerable importance of psychological readiness for long-term outcomes after ACL injury, there is an urgent need for well-designed studies that maximize internal validity and identify additional prognostic factors for psychological readiness at times critical for return to sport decisions. Registration: Open Science Framework (OSF), https://osf.io/2tezs/ .

The aim of this study was to validate the Neuropathic Pain for Post-Surgical Patients (NeuPPS) scale against clinically verified neuropathic pain (NP) by quantitative sensory testing (QST) as well as evaluation of other psychometric properties. The NeuPPS is a validated 5-item scale designed to evaluate NP in surgical populations.

Abstract Forest biomass is an essential resource in relation to the green transition and its assessment is key for the sustainable management of forest resources. Here, we present a forest biomass dataset for Europe based on the best available inventory and satellite data, with a higher level of harmonisation and spatial resolution than other existing data. This database provides statistics and maps of the forest area, biomass stock and their share available for wood supply in the year 2020, and statistics on gross and net volume increment in 2010–2020, for 38 European countries. The statistics of most countries are available at a sub-national scale and are derived from National Forest Inventory data, harmonised using common reference definitions and estimation methodology, and updated to a common year using a modelling approach. For those counties without harmonised statistics, data were derived from the State of Europe’s Forest 2020 Report at the national scale. The maps are coherent with the statistics and depict the spatial distribution of the forest variables at 100 m resolution.

INTRODUCTION: Increasing interest in real-world evidence has fueled the development of study designs incorporating real-world data (RWD). Using the Causal Roadmap, we specify three designs to evaluate the difference in risk of major adverse cardiovascular events (MACE) with oral semaglutide versus standard-of-care: (1) the actual sequence of non-inferiority and superiority randomized controlled trials (RCTs), (2) a single RCT, and (3) a hybrid randomized-external data study. METHODS: The hybrid design considers integration of the PIONEER 6 RCT with RWD controls using the experiment-selector cross-validated targeted maximum likelihood estimator. We evaluate 95% confidence interval coverage, power, and average patient time during which participants would be precluded from receiving a glucagon-like peptide-1 receptor agonist (GLP1-RA) for each design using simulations. Finally, we estimate the effect of oral semaglutide on MACE for the hybrid PIONEER 6-RWD analysis. RESULTS: In simulations, Designs 1 and 2 performed similarly. The tradeoff between decreased coverage and patient time without the possibility of a GLP1-RA for Designs 1 and 3 depended on the simulated bias. In real data analysis using Design 3, external controls were integrated in 84% of cross-validation folds, resulting in an estimated risk difference of -1.53%-points (95% CI -2.75%-points to -0.30%-points). CONCLUSIONS: The Causal Roadmap helps investigators to minimize potential bias in studies using RWD and to quantify tradeoffs between study designs. The simulation results help to interpret the level of evidence provided by the real data analysis in support of the superiority of oral semaglutide versus standard-of-care for cardiovascular risk reduction.

Increasing emphasis on the use of real-world evidence (RWE) to support clinical policy and regulatory decision-making has led to a proliferation of guidance, advice, and frameworks from regulatory agencies, academia, professional societies, and industry. A broad spectrum of studies use real-world data (RWD) to produce RWE, ranging from randomized trials with outcomes assessed using RWD to fully observational studies. Yet, many proposals for generating RWE lack sufficient detail, and many analyses of RWD suffer from implausible assumptions, other methodological flaws, or inappropriate interpretations. The Causal Roadmap is an explicit, itemized, iterative process that guides investigators to prespecify study design and analysis plans; it addresses a wide range of guidance within a single framework. By supporting the transparent evaluation of causal assumptions and facilitating objective comparisons of design and analysis choices based on prespecified criteria, the Roadmap can help investigators to evaluate the quality of evidence that a given study is likely to produce, specify a study to generate high-quality RWE, and communicate effectively with regulatory agencies and other stakeholders. This paper aims to disseminate and extend the Causal Roadmap framework for use by clinical and translational researchers; three companion papers demonstrate applications of the Causal Roadmap for specific use cases.

Universal screening for defective mismatch repair (dMMR) in colorectal cancer utilizes immunohistochemical staining for MLH1, MSH2, MSH6 and PSM2. Additionally, BRAF V600E mutations status and MLH1 hypermethylation should be performed to distinguish germline and somatic dMMR alterations. A decade of Danish population-based registries has been analysed regarding screening uptake, detection rate and referral to genetic counselling. MMR testing was performed in 71·8% (N = 34,664) of newly diagnosed colorectal cancers with an increasing trend to 88·8% coverage in the study's final year. The likelihood of undergoing MMR testing was reduced in males with 2% (95% CI 0·4–2·7, p = 0·008), with 4·1% in patients above age 70 years (95% CI 1·5–6·6, p = 0·003) compared in patients below age 51 years, with 16·3% in rectal cancers (95% CI 15·1–17·6, p < 0·001) and 1·4% left-sided colon cancers (95% CI 0·1–1·7, p = 0·03) compared to right-sided colon cancers. Tumour stage II and III increased the likelihood of being tested, with 3·7% for stage II (95% CI 2·2–5·6, p < 0·001) and 3·3% for stage III tumours (95% CI 1·8–4·8, p < 0·001) compared to stage I tumours, whereas the likelihood for stage IV tumours is reduced by 35·7% (95% CI 34·2–37·2, p < 0·001). Test rates significantly differed between the Danish health care regions. dMMR was identified in 15·1% (95% CI 14·8–15·6, p < 0·001) cases with somatic MMR inactivation in 6·7% of the cases. 8·3% tumours showed hereditary dMMR expression patterns, and 20·0% of those were referred to genetic counselling. Despite the high uptake rates, we found disparities between patient groups and missed opportunities for genetic diagnostics.

ABSTRACT Similarly to other strict blood feeders, leeches from the Haementeria genus (Hirudinida: Glossiphoniidae) have established a symbiotic association with bacteria harbored intracellularly in esophageal bacteriomes. Previous genome sequence analyses of these endosymbionts revealed co-divergence with their hosts, a strong genome reduction, and a simplified metabolism largely dedicated to the production of B vitamins, which are nutrients lacking from a blood diet. ‘Candidatus Providencia siddallii‘ has been identified as the obligate nutritional endosymbiont of a monophyletic clade of Mexican and South American Haementeria spp. However, the Haementeria genus includes a sister clade of congeners from Central and South America, where the presence or absence of the aforementioned symbiont taxon remains unknown. In this work, we report on a novel bacterial endosymbiont found in a representative from this Haementeria clade. We found that this symbiont lineage has evolved from within the Pluralibacter genus, known mainly from clinical but also environmental strains. Similarly to Ca. Providencia siddallii, the Haementeria-associated Pluralibacter symbiont displays clear signs of genome reduction, accompanied by an A+T-biased sequence composition. Genomic analysis of its metabolic potential revealed a retention of pathways related to B vitamin biosynthesis, supporting its role as a nutritional endosymbiont. Finally, comparative genomics of both Haementeria symbiont lineages suggests that an ancient Providencia symbiont was likely replaced by the novel Pluralibacter one, thus constituting the first reported case of nutritional symbiont replacement in a leech without morphological changes in the bacteriome.IMPORTANCEObligate symbiotic associations with a nutritional base have likely evolved more than once in strict blood-feeding leeches. Unlike those symbioses found in hematophagous arthropods, the nature, identity, and evolutionary history of these remains poorly studied. In this work, we further explored obligate nutritional associations between Haementeria leeches and their microbial symbionts, which led to the unexpected discovery of a novel symbiosis with a member of the Pluralibacter genus. When compared to Providencia siddallii, an obligate nutritional symbiont of other Haementeria leeches, this novel bacterial symbiont shows convergent retention of the metabolic pathways involved in B vitamin biosynthesis. Moreover, the genomic characteristics of this Pluralibacter symbiont suggest a more recent association than that of Pr. siddallii and Haementeria. We conclude that the once-thought stable associations between blood-feeding Glossiphoniidae and their symbionts (i.e., one bacteriome structure, one symbiont lineage) can break down, mirroring symbiont turnover observed in various arthropod lineages.

Background and purpose: Thumb carpometacarpal (CMC) joint osteoarthritis (OA) is increasingly treated with total joint arthroplasty (TJA). We aimed to perform a systematic review and meta-analysis of the benefits and harms of the TJA for thumb CMC OA compared with other treatment strategies. Patients and methods: We performed a systematic search on MEDLINE and CENTRAL databases on August 2, 2023. We included randomized controlled trials investigating the effect of TJA in people with thumb CMC joint OA regardless of the stage or etiology of the disease or comparator. The outcomes were pooled with a random effect meta-analysis. Results: We identified 4 studies randomizing 420 participants to TJA or trapeziectomy. At 3 months, TJA’s benefits for pain may exceed the clinically important difference. However, after 1-year follow-up TJA does not improve pain compared with trapeziectomy (mean difference 0.53 points on a 0 to 10 scale; 95% confidence interval [CI] 0.26–0.81). Furthermore, it provides a transient benefit in hand function at 3 months (measured with Disabilities of Arm, Shoulder, and Hand questionnaire, scale 0–100, lower is better) compared with trapeziectomy with or without ligament reconstruction tendon interposition. The benefit in function diminished to a clinically unimportant level at 1-year follow-up (4.4 points better; CI 0.42–8.4). Conclusion: Transient benefit in hand function for TJA implies that it could be a preferable option over trapeziectomy for people who consider fast postoperative recovery important. However, current evidence fails to inform us if TJA carries long-term higher risks of revisions compared with trapeziectomy.