The challenge of unprecedented floods and droughts in risk management.

Risk management has reduced vulnerability to floods and droughts globally1,2, yet their impacts are still increasing3. An improved understanding of the causes of changing impacts is therefore needed, but has been hampered by a lack of empirical data4,5. On the basis of a global dataset of 45 pairs of events that occurred within the same area, we show that risk management generally reduces the impacts of floods and droughts but faces difficulties in reducing the impacts of unprecedented events of a magnitude not previously experienced. If the second event was much more hazardous than the first, its impact was almost always higher. This is because management was not designed to deal with such extreme events: for example, they exceeded the design levels of levees and reservoirs. In two success stories, the impact of the second, more hazardous, event was lower, as a result of improved risk management governance and high investment in integrated management. The observed difficulty of managing unprecedented events is alarming, given that more extreme hydrological events are projected owing to climate change3.

Observed controls on resilience of groundwater to climate variability in sub-Saharan Africa.

Groundwater in sub-Saharan Africa supports livelihoods and poverty alleviation1,2, maintains vital ecosystems, and strongly influences terrestrial water and energy budgets3. Yet the hydrological processes that govern groundwater recharge and sustainability-and their sensitivity to climatic variability-are poorly constrained4,5. Given the absence of firm observational constraints, it remains to be seen whether model-based projections of decreased water resources in dry parts of the region4 are justified. Here we show, through analysis of multidecadal groundwater hydrographs across sub-Saharan Africa, that levels of aridity dictate the predominant recharge processes, whereas local hydrogeology influences the type and sensitivity of precipitation-recharge relationships. Recharge in some humid locations varies by as little as five per cent (by coefficient of variation) across a wide range of annual precipitation values. Other regions, by contrast, show roughly linear precipitation-recharge relationships, with precipitation thresholds (of roughly ten millimetres or less per day) governing the initiation of recharge. These thresholds tend to rise as aridity increases, and recharge in drylands is more episodic and increasingly dominated by focused recharge through losses from ephemeral overland flows. Extreme annual recharge is commonly associated with intense rainfall and flooding events, themselves often driven by large-scale climate controls. Intense precipitation, even during years of lower overall precipitation, produces some of the largest years of recharge in some dry subtropical locations. Our results therefore challenge the 'high certainty' consensus regarding decreasing water resources4 in such regions of sub-Saharan Africa. The potential resilience of groundwater to climate variability in many areas that is revealed by these precipitation-recharge relationships is essential for informing reliable predictions of climate-change impacts and adaptation strategies.

Counter-strategies to infanticide: The importance of cubs in determining lion habitat selection and social interactions.

Animal social and spatial behaviours are inextricably linked. Animal movements are driven by environmental factors and social interactions. Habitat structure and changing patterns of animal space use can also shape social interactions. Animals adjust their social and spatial behaviours to reduce the risk of offspring mortality. In territorial infanticidal species, two strategies are possible for males: they can stay close to offspring to protect them against rivals (infant-defence hypothesis) or patrol the territory more intensively to prevent rival intrusions (territorial-defence hypothesis). Here, we tested these hypotheses in African lions (Panthera leo) by investigating how males and females adjust their social and spatial behaviours in the presence of offspring. We combined datasets on the demography and movement of lions, collected between 2002 and 2016 in Hwange National Park (Zimbabwe), to document the presence of cubs (field observations) and the simultaneous movements of groupmates and competitors (GPS tracking). We showed a spatial response of lions to the presence of offspring, with females with cubs less likely to select areas close to waterholes or in the periphery of the territory than females without cubs. In contrast, these areas were more selected by males when there were cubs in the pride. We also found social responses. Males spent more time with females as habitat openness increased but the presence of cubs in the pride did not influence the average likelihood of observing males with females. Furthermore, rival males relocated further after an encounter with pride males when cubs were present in the prides, suggesting that the presence of cubs leads to a more vigorous repulsion of competitors. Males with cubs in their pride were more likely to interact with male competitors on the edge of the pride's home range and far from the waterholes, suggesting that they are particularly assiduous in detecting and repelling rival males during these periods. In general, the strategies to avoid infanticide exhibited by male lions supported the territorial-defence hypothesis. Our study contributes to answer the recent call for a behavioural ecology at the spatial-social interface.

Baseline Measures of Physical Activity and Function Do Not Predict Future Fall Incidence in Sedentary Older Adults: A Prospective Cohort Study.

Physical activity (PA) and physical function (PF) are modifiable risk factors for falls in older adults, but their ability to predict future fall incidence is unclear. The purpose of this study was to determine the predictive ability of baseline measures of PA, PF, and lower limb strength on future falls. A total of 104 participants underwent baseline assessments of PA, PF, and lower limb strength. Falls were monitored prospectively for 12 months. Eighteen participants fell at least once during the 12-month follow-up. Participants recorded almost exclusively sedentary levels of activity. PA, PF, and lower limb strength did not differ between fallers and nonfallers. Twelve participants, who reported a minor musculoskeletal injury in the past 6 months, experienced a fall. The results of this study suggest that in a cohort of highly functioning, sedentary older adults, PA does not distinguish fallers from nonfallers and that the presence of a recent musculoskeletal injury appears to be a possible risk factor for falling.

Bilirubin-associated single nucleotide polymorphism (SNP) and respiratory health outcomes: a mendelian randomization study.

BACKGROUND: Observational studies have shown an association between higher bilirubin levels and improved respiratory health outcomes. Targeting higher bilirubin levels has been proposed as a novel therapeutic strategy in COPD. However, bilirubin levels are influenced by multiple intrinsic and extrinsic factors, and these observational studies are prone to confounding. Genetic analyses are one approach to overcoming residual confounding in observational studies. OBJECTIVES: To test associations between a genetic determinant of bilirubin levels and respiratory health outcomes. METHODS: COPDGene participants underwent genotyping at the baseline visit. We confirmed established associations between homozygosity for rs6742078 and higher bilirubin, and between higher bilirubin and decreased risk of acute respiratory events within this cohort. For our primary analysis, we used negative binomial regression to test associations between homozygosity for rs6742078 and rate of acute respiratory events. RESULTS: 8,727 participants (n = 6,228 non-Hispanic white and 2,499 African American) were included. Higher bilirubin was associated with decreased rate of acute respiratory events [incidence rate ratio (IRR) 0.85, 95% CI 0.75 to 0.96 per SD increase in bilirubin intensity]. We did not find significant associations between homozygosity for rs6742078 and acute respiratory events (IRR 0.94, 95% CI 0.70 to 1.25 for non-Hispanic white and 1.09, 95% CI 0.91 to 1.31 for African American participants). CONCLUSIONS: A genetic determinant of higher bilirubin levels was not associated with better respiratory health outcomes. These results do not support targeting higher bilirubin levels as a therapeutic strategy in COPD.

Plain Language Summary of the iNNOVATE study: ibrutinib plus rituximab is well-tolerated and effective in people with Waldenström's macroglobulinemia.

WHAT IS THIS SUMMARY ABOUT?: This article provides a short summary of 5-year results from the iNNOVATE trial. The original paper was published in the Journal of Clinical Oncology in October 2021. People with Waldenström's macroglobulinemia (WM) were randomly divided into two groups of 75 people each. One group received a combination treatment composed of two drugs, ibrutinib plus rituximab, and the other group took placebo ("sugar pill") plus rituximab. Ibrutinib (also known by the brand name Imbruvica®) is a drug that reduces cancer cells' ability to multiply and survive. Ibrutinib is an FDA-approved drug for the treatment of WM. Rituximab is a drug that helps the immune system find and kill cancer cells. Participants in the trial were treated and their health monitored for up to 5 years (63 months). WHAT WERE THE RESULTS?: During the 5 years of monitoring, more people who took ibrutinib plus rituximab experienced an improvement in their disease and lived longer without their disease getting worse compared to those who took placebo plus rituximab. Side effects from ibrutinib and rituximab were manageable and generally decreased over time. Participants in both study groups reported improvements in quality of life, but those who took ibrutinib plus rituximab reported significantly greater improvement in their quality of life (as measured by FACT-An score) compared to those who took placebo plus rituximab. WHAT DO THE RESULTS MEAN?: These results show that ibrutinib plus rituximab is better than rituximab alone in people with WM and that ibrutinib plus rituximab is safe and effective in the long term. This information confirms the role of ibrutinib plus rituximab as a standard of care for WM. Clinical Trial Registration: NCT02165397 (ClinicalTrials.gov).

Association between P-pulmonale and respiratory morbidity in COPD: a secondary analysis of the BLOCK-COPD trial.

RATIONALE: Pulmonary hypertension (PH) in COPD confers increased risk of exacerbations (ECOPD). Electrocardiogram (ECG) indicators of PH are prognostic both in PH and COPD. In the Beta-Blockers for the Prevention of Acute Exacerbations of COPD (BLOCK-COPD) trial, metoprolol increased risk of severe ECOPD through unclear mechanisms. OBJECTIVE: We evaluated whether an ECG indicator of PH, P-pulmonale, would be associated with ECOPD and whether participants with P-pulmonale randomized to metoprolol were at higher risk of ECOPD and worsened respiratory symptoms given the potential detrimental effects of beta-blockers in PH. METHODS: ECGs of 501 participants were analyzed for P-pulmonale (P wave enlargement in lead II). Cox proportional hazards models evaluated for associations between P-pulmonale and time to ECOPD (all and severe) for all participants and by treatment assignment (metoprolol vs. placebo). Linear mixed-effects models evaluated the association between treatment assignment and P-pulmonale on change in symptom scores (measured by CAT and SOBQ). RESULTS: We identified no association between P-pulmonale and risk of any ECOPD or severe ECOPD. However, in individuals with P-pulmonale, metoprolol was associated with increased risk for ECOPD (aHR 2.92, 95% CI: 1.45-5.85). There was no association between metoprolol and ECOPD in individuals without P-pulmonale (aHR 1.01, 95% CI: 0.77-1.31). Individuals with P-pulmonale assigned to metoprolol experienced worsening symptoms (mean increase of 3.95, 95% CI: 1.32-6.58) whereas those assigned to placebo experienced a mean improvement in CAT score of -2.45 (95% CI: -0.30- -4.61). CONCLUSIONS: In individuals with P-pulmonale, metoprolol was associated with increased exacerbation risk and worsened symptoms. These findings may explain the findings observed in BLOCK-COPD.

Contrasting effects of human settlement on the interaction among sympatric apex carnivores.

In the face of a growing human footprint, understanding interactions among threatened large carnivores is fundamental to effectively mitigating anthropogenic threats and managing species. Using data from a large-scale camera trap survey, we investigated the effects of environmental and anthropogenic variables on the interspecific interaction of a carnivore guild comprising of tiger, leopard and dhole in Bhutan. We demonstrate the complex effects of human settlement density on large carnivore interactions. Specifically, we demonstrate that leopard-dhole co-occupancy probability was higher in areas with higher human settlement density. The opposite was true for tiger-leopard co-occupancy probability, but it was positively affected by large prey (gaur) abundance. These findings suggest that multi-carnivore communities across land-use gradients are spatially structured and mediated also by human presence and/or the availability of natural prey. Our findings show that space-use patterns are driven by a combination of the behavioural mechanism of each species and its interactions with competing species. The duality of the effect of settlement density on species interactions suggests that the benefits of exploiting anthropogenic environments are a trade-off between ecological opportunity (food subsidies or easy prey) and the risk of escalating conflict with humans.

Early-life seasonal, weather and social effects on telomere length in a wild mammal.

Early-life environmental conditions can provide a source of individual variation in life-history strategies and senescence patterns. Conditions experienced in early life can be quantified by measuring telomere length, which can act as a biomarker of survival probability in some species. Here, we investigate whether seasonal changes, weather conditions and group size are associated with early-life and/or early-adulthood telomere length in a wild population of European badgers (Meles meles). We found substantial intra-annual changes in telomere length during the first 3 years of life, where within-individual effects showed shorter telomere lengths in the winter following the first spring and a trend for longer telomere lengths in the second spring compared to the first winter. In terms of weather conditions, cubs born in warmer, wetter springs with low rainfall variability had longer early-life (3-12 months old) telomeres. Additionally, cubs born in groups with more cubs had marginally longer early-life telomeres, providing no evidence of resource constraint from cub competition. We also found that the positive association between early-life telomere length and cub survival probability remained when social and weather variables were included. Finally, after sexual maturity, in early adulthood (i.e., 12-36 months) we found no significant association between same-sex adult group size and telomere length (i.e., no effect of intrasexual competition). Overall, we show that controlling for seasonal effects, which are linked to food availability, is important in telomere length analyses, and that variation in telomere length in badgers reflects early-life conditions and also predicts first year cub survival.

Habitat use of and threats to African large carnivores in a mixed-use landscape.

Large carnivores increasingly inhabit human-affected landscapes, which exhibit heterogeneity in biotic resources, anthropogenic pressures, and management strategies. Understanding large carnivore habitat use in these systems is critical for their conservation, as is the evaluation of competing management approaches and the impacts of significant land-use changes. We used occupancy modeling to investigate habitat use of an intact eastern African large carnivore guild across the 45,000 km2 Ruaha-Rungwa landscape in south-central Tanzania. We determined the relative impact on five large carnivore species of biotic, anthropogenic, and management factors at the scales of home range selection and short-term use within home ranges. We also specifically tested the effect of abandonment of trophy hunting areas on large carnivore occurrence. Patterns of habitat use differed among species. Lions (Panthera leo) appeared affected by top-down limitation, as their occurrence was significantly negatively associated with illegal human activity (ß = -0.63 [SE 0.28]). African wild dogs (Lycaon pictus), instead, were limited by biotic features; the species was negatively associated with riverine areas of high sympatric predator density (ß = -1.00 [SE 0.43]) and used less-productive habitats. Spotted hyaena (Crocuta crocuta) and leopard (Panthera pardus) persisted in more disturbed areas and across habitat types. Large carnivore occurrence was not affected by whether an area was used for photographic or trophy hunting tourism; regular law enforcement was instead a better predictor of occurrence. All species fared better in actively managed hunting areas than those that had been abandoned by operators. Overall, our findings highlight the divergent habitat requirements within large carnivore guilds and the importance of adopting an integrated approach to large carnivore conservation planning in modern systems. We also identified a novel threat to African conservation areas in the form of decreased management investments associated with the abandonment of trophy hunting areas.

Uso de Hábitat y Amenazas para los Grandes Carnívoros de África en un Paisaje de Uso Mixto Resumen Cada vez más, los grandes carnívoros habitan paisajes afectados por los humanos, los cuales presentan heterogeneidad en los recursos bióticos, las presiones antropogénicas y las estrategias de manejo. El conocimiento sobre cómo usan el hábitat los grandes carnívoros en estos sistemas es crucial para su conservación, como lo es la evaluación de las estrategias competitivas de manejo y los impactos de los cambios significativos en el uso de suelo. Usamos modelos de ocupación para investigar el uso de hábitat por parte de un gremio intacto de grandes carnívoros en el este de África a lo largo de los 45,000 km2 del paisaje Ruaha-Rungwa en el centro-sur de Tanzania. Determinamos el impacto relativo que tienen los factores bióticos, antropogénicos y de manejo sobre cinco especies de grandes carnívoros a escala de selección de extensión doméstica y uso a corto plazo dentro de la extensión doméstica. También analizamos específicamente el efecto que tiene el abandono de las áreas de caza de trofeos sobre la presencia de los grandes carnívoros. Los patrones de uso de hábitat difirieron entre las especies. Los leones (Panthera leo) parecieron estar afectados por la limitación de arriba-abajo ya que su presencia estuvo asociada negativamente de manera importante con la actividad humana ilegal (ß = - 0.63 [SE 0.28]). El perro salvaje africano (Lycaon pictus) estuvo limitado por los elementos bióticos; la especie estuvo asociada negativamente con las áreas de alta densidad simpátrica de depredadores (ß = - 1.00 [SE 0.43]) y utilizó los hábitats menos productivos. La hiena moteada (Crocuta crocuta) y el leopardo (Panthera pardus) persistieron en áreas más perturbadas y en todos los tipos de hábitat. La presencia de los grandes carnívoros no se vio afectada si el área se usaba para caza de trofeos o turismo fotográfico; la aplicación regular de la ley fue un mejor pronóstico de la presencia. A todas las especies les fue mejor en las áreas de caza con gestión activa que en aquellas abandonadas por los operadores. En general, nuestros descubrimientos resaltan los distintos requerimientos de hábitat dentro de los gremios de grandes carnívoros y la importancia de adoptar un enfoque integrado para la planeación de la conservación de estas especies en los sistemas modernos. También identificamos una amenaza nueva para las áreas de conservación africana a manera de inversiones de manejo disminuidas asociadas con el abandono de las áreas de caza de trofeos.

Resources and predation: drivers of sociality in a cyclic mesopredator.

In socially flexible species, the tendency to live in groups is expected to vary through a trade-off between costs and benefits, determined by ecological conditions. The Resource Dispersion Hypothesis predicts that group size changes in response to patterns in resource availability. An additional dimension is described in Hersteinsson's model positing that sociality is further affected by a cost-benefit trade-off related to predation pressure. In the arctic fox (Vulpes lagopus), group-living follows a regional trade-off in resources' availability and intra-guild predation pressure. However, the effect of local fluctuations is poorly known, but offers an unusual opportunity to test predictions that differ between the two hypotheses in systems where prey availability is linked to intra-guild predation. Based on 17-year monitoring of arctic fox and cyclic rodent prey populations, we addressed the Resource Dispersion Hypothesis and discuss the results in relation to the impact of predation in Hersteinsson's model. Group-living increased with prey density, from 7.7% (low density) to 28% (high density). However, it remained high (44%) despite a rodent crash and this could be explained by increased benefits from cooperative defence against prey switching by top predators. We conclude that both resource abundance and predation pressure are factors underpinning the formation of social groups in fluctuating ecosystems.

Preferred Self-Administered Questionnaires to Assess Resilience, Optimism, Pain Acceptance, and Social Support in People with Pain: A Modified Delphi Study.

OBJECTIVES: The plethora of self-administered questionnaires to assess positive psychosocial factors complicates questionnaire selection. This study aimed to identify and reach consensus on the most suitable self-administered questionnaires to assess resilience, optimism, pain acceptance and social support in people with pain. DESIGN: A three-round modified Delphi study. PARTICIPANTS: Forty international experts. METHODS: In Round 1, the experts suggested questionnaires deemed appropriate to assess resilience, optimism, pain acceptance and/or social support. In Round 2, experts indicated whether they considered the suggested questionnaires to be suitable (Yes/No/Don't know) to assess these psychosocial factors, taking into consideration content, feasibility, personal experience and the measurement properties which we provided for each questionnaire. Questionnaires that were considered suitable by the majority of experts (≥60%) were retained for Round 3. In Round 3, the suitability of each questionnaire was rated on a 0-10 Likert scale. Consensus was reached if ≥75% of experts rated the questionnaire ≥7. RESULTS: From the 67 questionnaires suggested in Round 1, one questionnaire could be recommended per domain. For resilience: Pain Resilience Scale; for optimism: Revised Version of the Life Orientation Test; for pain acceptance: 8-item and Revised Versions of the Chronic Pain Acceptance Questionnaire; for social support: Emotional Support Item Bank of the PROMIS tool. Consensus for these questionnaires was also reached in a sensitivity analysis which excluded the ratings of experts involved in the development, translation and/or validation of relevant questionnaires. CONCLUSION: We advocate the use of these recommended questionnaires so data can be compared and pooled more easily.

Postoperative mortality risk prediction that incorporates intraoperative vital signs: development and internal validation in a historical cohort.

PURPOSE: Accurate risk reassessment after surgery is crucial for postoperative planning for monitoring and disposition. Existing postoperative mortality risk prediction models using preoperative features do not incorporate intraoperative hemodynamic derangements that may alter risk stratification. Intraoperative vital signs may provide an objective and readily available prognostic resource. Our primary objective was to derive and internally validate a logistic regression (LR) model by adding intraoperative features to established preoperative predictors to predict 30-day postoperative mortality. METHODS: Following Research Ethics Board approval, we analyzed a historical cohort that included patients aged ≥ 45 undergoing noncardiac surgery with an overnight stay at two tertiary hospitals (2013 to 2017). Features included intraoperative vital signs (blood pressure, heart rate, end-tidal carbon dioxide partial pressure, oxygen saturation, and temperature) by threshold and duration of exposure, as well as patient, surgical, and anesthetic factors. The cohort was divided temporally 75:25 into derivation and validation sets. We constructed a multivariable LR model with 30-day all-cause mortality as the outcome and evaluated performance metrics. RESULTS: There were 30,619 patients in the cohort (mean [standard deviation] age, 66 [11] yr; 50.2% female; 2.0% mortality). In the validation set, the primary LR model showed a c-statistic of 0.893 (99% confidence interval [CI], 0.853 to 0.927), a Nagelkerke R-squared of 0.269, a scaled Brier score of 0.082, and an area under precision-recall curve of 0.158 (baseline 0.017 for an uninformative model). The addition of intraoperative vital signs to preoperative factors minimally improved discrimination and calibration. CONCLUSION: We derived and internally validated a model that incorporated vital signs to improve risk stratification after surgery. Preoperative factors were strongly predictive of mortality risk, and intraoperative predictors only minimally improved discrimination. External and prospective validations are needed. STUDY REGISTRATION: www. CLINICALTRIALS: gov (NCT04014010); registered on 10 July 2019.

RéSUMé: OBJECTIF: Une réévaluation précise des risques après la chirurgie est cruciale pour la planification postopératoire du monitorage et du congé. Les modèles existants de prédiction du risque de mortalité postopératoire utilisant des caractéristiques préopératoires n'intègrent pas les perturbations hémodynamiques peropératoires, lesquelles pourraient modifier la stratification du risque. Les signes vitaux peropératoires peuvent fournir une ressource pronostique objective et facilement disponible. Notre objectif principal était de dériver et de valider en interne un modèle de régression logistique (RL) en ajoutant des caractéristiques peropératoires aux prédicteurs préopératoires établis pour prédire la mortalité postopératoire à 30 jours. MéTHODE: À la suite de l'approbation du Comité d'éthique de la recherche, nous avons analysé une cohorte historique qui comprenait des patients âgés de ≥ 45 ans bénéficiant d'une chirurgie non cardiaque avec un séjour d'une nuit dans deux hôpitaux tertiaires (2013 à 2017). Les caractéristiques comprenaient les signes vitaux peropératoires (tension artérielle, fréquence cardiaque, pression télé-expiratoire en CO2, saturation en oxygène et température) par seuil et durée d'exposition, ainsi que des facteurs propres au patient, chirurgicaux et anesthésiques. La cohorte a été divisée temporellement 75:25 en ensembles de dérivation et de validation. Nous avons élaboré un modèle de RL multivariée avec la mortalité toutes causes confondues à 30 jours comme critère, et évalué les mesures de performance. RéSULTATS: Il y avait 30 619 patients dans la cohorte (âge moyen [écart type], 66 [11] ans; 50,2 % de femmes; 2,0 % de mortalité). Dans l'ensemble de validation, le modèle de RL primaire a montré une statistique c de 0,893 (intervalle de confiance [IC] à 99 %, 0,853 à 0,927), un R carré de Nagelkerke de 0,269, un score de Brier mis à l'échelle de 0,082 et une aire sous la courbe de rappel et précision de 0,158 (ligne de base 0,017 pour un modèle non informatif). L'ajout de signes vitaux peropératoires aux facteurs préopératoires a amélioré de façon minimale la discrimination et l'étalonnage. CONCLUSION: Nous avons dérivé et validé en interne un modèle qui incorporait des signes vitaux pour améliorer la stratification des risques après la chirurgie. Les facteurs préopératoires étaient fortement prédictifs du risque de mortalité, et les prédicteurs peropératoires n'ont que que très peu amélioré la discrimination. Une validation externe et prospective est nécessaire. ENREGISTREMENT DE L'éTUDE: www.ClinicalTrials.gov (NCT04014010); enregistrée le 10 juillet 2019.

Evaluation of sound levels in elective orthopaedic theatres during primary hip and knee arthroplasty.

BACKGROUND: Orthopaedic surgery involves tools which could cause noise-induced hearing loss in theatre staff. Threshold levels for occupational noise exposure have been developed in the U.K., above which action is required to reduce exposure. The aims of our study were to determine whether equivalent continuous sound pressure levels during elective arthroplasty can be measured using readily available materials, and to assess whether noise exposure levels stand within acceptable occupational noise exposure levels. MATERIALS AND METHODS: Sound pressure levels of orthopaedic saws were recorded using the MicW i436 connected to an iPhone 4S and the iOS SoundMeter application, and using a professional sound meter. Equivalent sound pressure levels were recorded for total hip replacement (THR) and total knee replacement (TKR) using the MicW i436 SoundMeter application. Data obtained was then used to calculate a "worst case" daily exposure value to assess if sound levels were compliant with U.K. RESULTS: Sound pressure levels recorded using the MicW i436 and Soundmeter application were accurate compared to professional soundmeter readings. THR showed equivalent sound pressure levels (LAeq) of 77 dBA and TKR showed a LAeq of 80 db. Calculated "worst case" scenarios for daily noise exposure using these values did not meet the lower exposure action values set out by U.K. CONCLUSIONS: It is possible to accurately measure continuous sound pressure levels during elective orthopaedic surgery using readily available materials. Noise exposure values during TKR meet lower exposure action values, and when "worst case" daily exposure levels are calculated this level is still lower than the threshold.

Cycling injuries requiring orthopaedic intervention during the first COVID-19 lockdown period: A multi-centre SCottish Orthopaedic Research collaborativE (SCORE) study.

INTRODUCTION: The COVID-19 lockdown resulted in decreased vehicle use and an increased uptake in cycling. This study investigated the trends in cycling-related injuries requiring orthopaedic intervention during the COVID-19 lockdown period compared with similar time periods in 2018 and 2019. METHODS: Data were collected prospectively for patients in 2020 and collected retrospectively for 2019 and 2018, from hospitals within four NHS Scotland Health Boards encompassing three major trauma centres. All patients who sustained an injury as a result of cycling requiring orthopaedic intervention were included. Patient age, sex, mechanism of injury, diagnosis and treatment outcome from electronic patient records. RESULTS: Number of injuries requiring surgery 2020: 77 (mean age/years - 42.7); 2019: 47 (mean age/years - 42.7); 2018: 32 (mean age/years - 31.3). Overall incidence of cycling injuries 2020: 6.7%; 2019: 3.0%; 2018: 2.1%. Commonest mechanism of injury: fall from bike 2020 n = 54 (70.1%); 2019 n = 41 (65.1%); 2018 n = 25 (67.6%). Commonest injury type: fracture 2020 n = 68 (79.1%); 2019 n = 33 (70.2%); 2018 n = 20 (62.5%). Commonest areas affected: Upper extremity: 2020 n = 45 (58.5%); 2019 n = 25 (53.2%); 2018 n = 25 (78.1%). Lower extremity: 2020 n = 23 (29.9%); 2019 n = 14 (29.7%); 2018 n = 7 (21.8%). CONCLUSION: A significant increase in the number of cycling related injuries requiring orthopaedic intervention, a greater proportion of female cyclists and an older mean age of patients affected was observed during the COVID-19 lockdown period compared with previous years. The most common types of injury were fractures followed by lacerations and fracture-dislocations. The upper extremity was the commonest area affected.

Germline variation in the insulin-like growth factor pathway and risk of Barrett's esophagus and esophageal adenocarcinoma.

Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.

A phase 3, randomized study of ofatumumab combined with bendamustine in rituximab-refractory iNHL (COMPLEMENT A + B study).

The standard of care for indolent non-Hodgkin lymphoma (iNHL) is rituximab, an anti-CD20 antibody, with/without chemotherapy. However, multiple relapses are common in these patients. This phase 3, randomized study compared outcomes of a combination of ofatumumab (a second-generation anti-CD20 antibody) and bendamustine, with bendamustine alone in patients unresponsive to prior rituximab-based treatment. Overall, 346 patients were randomized to receive either the combination or bendamustine alone. Bendamustine was given for ≤8 cycles and ofatumumab for ≤12 cycles. The primary end-point was progression-free survival (PFS) after 215 protocol-defined events assessed by independent review committee (IRC). Median IRC-assessed PFS was 16·7 and 13·8 months in the combination and monotherapy arms respectively [hazard ratio (HR) = 0·82; P = 0·1390]. Median overall survival (OS) was 58·2 and 51·8 months in the combination and monotherapy arms respectively (HR = 0·89, P = 0·4968). The safety profile was consistent with previous reports. Overall, 73% and 80% of patients in the combination and monotherapy arms, respectively, experienced a ≥grade 3 adverse event. The study did not meet its primary end-point. No significant improvement in PFS and OS was seen with the combination of ofatumumab and bendamustine as compared with bendamustine alone in rituximab-refractory iNHL (NCT01077518).

Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström's Macroglobulinemia.

BACKGROUND: Single-agent ibrutinib has shown substantial activity in patients with relapsed Waldenström's macroglobulinemia, a rare form of B-cell lymphoma. We evaluated the effect of adding ibrutinib to rituximab in patients with this disease, both in those who had not received previous treatment and in those with disease recurrence. METHODS: We randomly assigned 150 symptomatic patients to receive ibrutinib plus rituximab or placebo plus rituximab. The primary end point was progression-free survival, as assessed by an independent review committee. Key secondary end points were response rates, sustained hematologic improvement from baseline, and safety. The mutational status of MYD88 and CXCR4 was assessed in bone marrow samples. RESULTS: At 30 months, the progression-free survival rate was 82% with ibrutinib-rituximab versus 28% with placebo-rituximab (hazard ratio for progression or death, 0.20; P<0.001). The benefit in the ibrutinib-rituximab group over that in the placebo-rituximab group was independent of the MYD88 or CXCR4 genotype. The rate of major response was higher with ibrutinib-rituximab than with placebo-rituximab (72% vs. 32%, P<0.001). More patients had sustained increases in hemoglobin level with ibrutinib-rituximab than with placebo-rituximab (73% vs. 41%, P<0.001). The most common adverse events of any grade with ibrutinib-rituximab included infusion-related reactions, diarrhea, arthralgia, and nausea. Events of grade 3 or higher that occurred more frequently with ibrutinib-rituximab than with placebo-rituximab included atrial fibrillation (12% vs. 1%) and hypertension (13% vs. 4%); those that occurred less frequently included infusion reactions (1% vs. 16%) and any grade of IgM flare (8% vs. 47%). The major hemorrhage rate was the same in the two trial groups (4%). CONCLUSIONS: Among patients with Waldenström's macroglobulinemia, the use of ibrutinib-rituximab resulted in significantly higher rates of progression-free survival than the use of placebo-rituximab, both among those who had received no previous treatment and among those with disease recurrence. Atrial fibrillation and hypertension were more common with ibrutinib-rituximab, whereas infusion reactions and IgM flare were more common with placebo-rituximab. (Funded by Pharmacyclics and Janssen Research and Development; ClinicalTrials.gov number, NCT02165397 .).

Anticipation of common buzzard population patterns in the changing UK landscape.

Harmonious coexistence between humans, other animals and ecosystem services they support is a complex issue, typically impacted by landscape change, which affects animal distribution and abundance. In the last 30 years, afforestation on grasslands across Great Britain has been increasing, motivated by socio-economic reasons and climate change mitigation. Beyond expected benefits, an obvious question is what are the consequences for wider biodiversity of this scale of landscape change. Here, we explore the impact of such change on the expanding population of common buzzards Buteo buteo, a raptor with a history of human-induced setbacks. Using Resource-Area-Dependence Analysis (RADA), with which we estimated individuals' resource needs using 10-day radio-tracking sessions and the 1990s Land Cover Map of GB, and agent-based modelling, we predict that buzzards in our study area in lowland UK had fully recovered (to 2.2 ind km-2) by 1995. We also anticipate that the conversion of 30%, 60% and 90% of economically viable meadow into woodland would reduce buzzard abundance nonlinearly by 15%, 38% and 74%, respectively. The same approach used here could allow for cost-effective anticipation of other animals' population patterns in changing landscapes, thus helping to harmonize economy, landscape change and biodiversity.

Seed dispersers shape the pulp nutrients of fleshy-fruited plants.

The dispersal-syndrome hypothesis posits that fruit traits are a product of selection by frugivores. Although criticized as adaptationist, recent studies have suggested that traits such as fruit or seed size, colour and odour exhibit signatures that imply selection by animal mutualists. These traits imply nutritional rewards (e.g. lipid, carbohydrate), attracting frugivores; however, this remains incompletely resolved. Here, we investigated whether fruit nutrients (lipid, sugar, protein, vitamin C, water content) moderate the co-adaptation of key disperser-group mutualisms. Multivariate techniques revealed that fruit nutrients assembled non-randomly and grouped according to key dispersal modes. Bird-dispersed fruits were richer in lipids than mammal-dispersed fruits. Mixed-dispersed fruits had significantly higher vitamin C than did mammal- or bird-dispersed fruits separately. Sugar and water content were consistently high irrespective of dispersal modes, suggesting that these traits appeal to both avian and mammalian frugivores to match high-energy requirements. Similarly, protein content was low irrespective of dispersal modes, corroborating that birds and mammals avoid protein-rich fruits, which are often associated with toxic levels of nitrogenous secondary compounds. Our results provide substantial over-arching evidence that seed disperser assemblages co-exert fundamental selection pressures on fruit nutrient trait adaptation, with broad implications for structuring fruit-frugivore mutualism and maintaining fruit trait diversity.