Drivers of Mercury Cycling in the Rapidly Changing Glacierized Watershed of the High Arctic's Largest Lake by Volume (Lake Hazen, Nunavut, Canada).

Across the Arctic, glaciers are melting and permafrost is thawing at unprecedented rates, releasing not only water to downstream aquatic systems, but also contaminants like mercury, archived in ice over centuries. Using concentrations from samples collected over 4 years and calibrated modeled hydrology, we calculated methylmercury (MeHg) and total mercury (THg) mass balances for Lake Hazen, the world's largest High Arctic lake by volume, for 2015 and 2016. Glacial rivers were the most important source of MeHg and THg to Lake Hazen, accounting for up to 53% and 94% of the inputs, respectively. However, due to the MeHg and THg being primarily particle-bound, Lake Hazen was an annual MeHg and THg sink. Exports of MeHg and THg out the Ruggles River outflow were consequently very low, but erosion and permafrost slumping downstream of the lake increased river MeHg and THg concentrations significantly before entering coastal waters in Chandler Fjord. Since 2001, glacial MeHg and THg inputs to Lake Hazen have increased by 0.01 and 0.400 kg yr-1, respectively, in step with dramatic increases in glacial melt. This study highlights the potential for increases in mercury inputs to arctic ecosystems downstream of glaciers despite recent reductions in global mercury emissions.

Tofacitinib in patients with moderate-to-severe chronic plaque psoriasis: long-term safety and efficacy in an open-label extension study.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor. Final safety and efficacy data from an open-label extension study of tofacitinib in psoriasis are reported. OBJECTIVES: To evaluate the long-term safety and durability of efficacy of tofacitinib in adults with moderate-to-severe chronic plaque psoriasis. METHODS: Eligible patients who completed qualifying phase II/III tofacitinib studies received tofacitinib 10 mg twice daily (q12h) until month 3; subsequently, the dose could be adjusted by investigators to either 5 or 10 mg q12h. Adverse events (AEs) are reported up to month 66 and laboratory data up to month 54. Efficacy end points up to month 54 included Physician's Global Assessment of 'clear' or 'almost clear' (PGA response) and 75% improvement in Psoriasis Area and Severity Index (PASI 75). RESULTS: Overall, 2867 patients received tofacitinib, with a median treatment duration of 35·6 months. Adverse events (AEs) and serious AEs were reported in 82·5% and 13·7% of patients, respectively; 13·9% of patients discontinued owing to AEs; and 29 patients died. Incidence rates (patients with event/100 patient-years) were 1·16 for serious infections, 0·67 for malignancies and 0·26 for major adverse cardiovascular events. After initial changes in qualifying studies, most laboratory parameters were generally stable over 54 months. PGA response was achieved by 52-62% of patients and PASI 75 by 56-74% of patients at each study visit through month 54. CONCLUSIONS: In patients with psoriasis, the safety profile of tofacitinib over 66 months was similar to previous reports in phase III studies and efficacy was sustained through 54 months (NCT01163253).

Inclusive fitness for in-laws.

Cooperation among kin is common across the natural world and can be explained in terms of inclusive fitness theory, which holds that individuals can derive indirect fitness benefits from aiding genetically related individuals. However, human kinship includes not only genetic kin but also kin by marriage: our affines (in-laws) and spouses. Can cooperation between these genetically unrelated kin be reconciled with inclusive fitness theory? Here, we argue that although affinal kin and spouses do not necessarily share genetic ancestry, they may have shared genetic interests in future reproduction and, as such, can derive indirect fitness benefits though cooperating. We use standard inclusive fitness theory to derive a coefficient of shared reproductive interest (s) that predicts altruistic investment both in genetic kin and in spouses and affines. Specifically, a behaviour that reduces the fitness of the actor by c and increases the fitness of the recipient by b will be favoured by natural selection when sb > c We suggest that the coefficient of shared reproductive interest may provide a valuable tool for understanding not only the evolution of human kinship but also cooperation and conflict across the natural world more generally.

Moving to human trials for argon neuroprotection in neurological injury: a narrative review.

Despite the global burden of brain injury, neuroprotective agents remain elusive. There are no clinically effective therapies which reduce mortality or improve long-term cognitive outcome. Ventilation could be an easily modifiable variable in resuscitation; gases are relatively simple to administer. Xenon is the prototypic agent of a new generation of experimental treatments which show promise. However, use is hindered by its prohibitive cost and anaesthetic properties. Argon is an attractive option, being cheaper, easy to transport, non-sedating, and mechanistically distinct from xenon. In vitro and in vivo models provide evidence of argon reducing brain injury, with improvements in neurocognitive, histological, and biomarker metrics, as well as improved survival. Current data suggest that the effect of argon is mediated via the toll-like receptors 2 and 4, the extracellular signal-regulated kinase 1/2, and phosphatidylinositol 3 kinase (PI-3K)-AKT pathways. Ventilation with argon appears to be safe in pigs and preliminary human trials. Given recent evidence that arterial hyperoxia may be harmful, the supplementation of high-concentration argon may not necessitate changes to clinical practice. Given the logistic benefits, and the evidence for argon neuroprotection summarized in this manuscript, we believe that the time has come to consider developing Phase II clinical trials to assess its benefit in acute neurological injury.

X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes.

X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4(-/-) mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.

Comparing hospital and telephone follow-up for patients treated for stage-I endometrial cancer (ENDCAT trial): a randomised, multicentre, non-inferiority trial.

OBJECTIVE: To evaluate the effectiveness of nurse-led telephone follow-up (TFU) for patients with stage-I endometrial cancer. DESIGN: Multicentre, randomised, non-inferiority trial. SETTING: Five centres in the North West of England. SAMPLE: A cohort of 259 women treated for stage-I endometrial cancer attending hospital outpatient clinics for routine follow-up. METHODS: Participants were randomly allocated to receive traditional hospital based follow-up (HFU) or nurse-led TFU. MAIN OUTCOME MEASURES: Primary outcomes were psychological morbidity (State Trait Anxiety Inventory, STAI-S) and patient satisfaction with the information provided. Secondary outcomes included patient satisfaction with service, quality of life, and time to detection of recurrence. RESULTS: The STAI-S scores post-randomisation were similar between groups [mean (SD): TFU 33.0 (11.0); HFU 35.5 (13.0)]. The estimated between-group difference in STAI-S was 0.7 (95% confidence interval, 95% CI -1.9 to 3.3); the confidence interval lies above the non-inferiority limit (-3.5), indicating the non-inferiority of TFU. There was no significant difference between groups in reported satisfaction with information (odds ratio, OR 0.9; 95% CI 0.4-2.1; P = 0.83). Women in the HFU group were more likely to report being kept waiting for their appointment (P = 0.001), that they did not need any information (P = 0.003), and were less likely to report that the nurse knew about their particular case and situation (P = 0.005). CONCLUSIONS: The TFU provides an effective alternative to HFU for patients with stage-I endometrial cancer, with no reported physical or psychological detriment. Patient satisfaction with information was high, with similar levels between groups. TWEETABLE ABSTRACT: ENDCAT trial shows effectiveness of nurse-led telephone follow-up for patients with stage-I endometrial cancer.

Usefulness of Video Review of Possible Concussions in National Youth Rugby League.

A new concussion interchange rule (CIR) was introduced in 2014 for the National Rugby League and National Youth Competition (NYC). The CIR allows a player suspected of having sustained a concussion to be removed from play and assessed without an interchange being tallied against the player's team. Participants included all NYC players who used the CIR during the 2014 season. 2 raters completed video analysis of 131 (of a total of 156 reported) uses of the CIR, describing injury characteristics, situational factors, and concussion signs. The incidence rate was 44.9 (95% CI: 38.5-52.3) uses of the CIR per 1 000 NYC player match hours, or approximately one CIR use every 1.3 games. Apparent loss of consciousness/unresponsiveness was observed in 13% of cases, clutching the head in 65%, unsteadiness of gait in 60%, and a vacant stare in 23%. Most incidences occurred from a hit-up (82%). There appeared to be some instances of video evidence of injury but the athlete was cleared to return to play in the same game. Video review appears to be a useful adjunct for identifying players suffering possible concussion. Further research is required on the usefulness of video review for identifying signs of concussive injury.

Comparison of ergometer- and track-based testing in junior track-sprint cyclists. Implications for talent identification and development.

Talent identification (TID) and talent development (TDE) programmes in track sprint cycling use ergometer- and track-based tests to select junior athletes and assess their development. The purpose of this study was to assess which tests are best at monitoring TID and TDE. Ten male participants (16.2 ± 1.1 year; 178.5 ± 6.0 cm and 73.6 ± 7.6 kg) were selected into the national TID squad based on initial testing. These tests consisted of two 6-s maximal sprints on a custom-built ergometer and 4 maximal track-based tests (2 rolling and 2 standing starts) using 2 gear ratios. Magnitude-based inferences and correlation coefficients assessed changes following a 3-month TDE programme. Training elicited meaningful improvements (80-100% likely) in all ergometer parameters. The standing and rolling small gear, track-based effort times were likely and very likely (3.2 ± 2.4% and 3.3 ± 1.9%, respectively) improved by training. Stronger correlations between ergometer- and track-based measures were very likely following training. Ergometer-based testing provides a more sensitive tool than track-based testing to monitor changes in neuromuscular function during the early stages of TDE. However, track-based testing can indicate skill-based improvements in performance when interpreted with ergometer testing. In combination, these tests provide information on overall talent development.

Pseudomonas aeruginosa Induced Airway Epithelial Injury Drives Fibroblast Activation: A Mechanism in Chronic Lung Allograft Dysfunction.

Bacterial infections after lung transplantation cause airway epithelial injury and are associated with an increased risk of developing bronchiolitis obliterans syndrome. The damaged epithelium is a source of alarmins that activate the innate immune system, yet their ability to activate fibroblasts in the development of bronchiolitis obliterans syndrome has not been evaluated. Two epithelial alarmins were measured longitudinally in bronchoalveolar lavages from lung transplant recipients who developed bronchiolitis obliterans syndrome and were compared to stable controls. In addition, conditioned media from human airway epithelial cells infected with Pseudomonas aeruginosa was applied to lung fibroblasts and inflammatory responses were determined. Interleukin-1 alpha (IL-1α) was increased in bronchoalveolar lavage of lung transplant recipients growing P. aeruginosa (11.5 [5.4-21.8] vs. 2.8 [0.9-9.4] pg/mL, p < 0.01) and was significantly elevated within 3 months of developing bronchiolitis obliterans syndrome (8.3 [1.4-25.1] vs. 3.6 [0.6-17.1] pg/mL, p < 0.01), whereas high mobility group protein B1 remained unchanged. IL-1α positively correlated with elevated bronchoalveolar lavage IL-8 levels (r(2)  = 0.6095, p < 0.0001) and neutrophil percentage (r(2)  = 0.25, p = 0.01). Conditioned media from P. aeruginosa infected epithelial cells induced a potent pro-inflammatory phenotype in fibroblasts via an IL-1α/IL-1R-dependent signaling pathway. In conclusion, we propose that IL-1α may be a novel therapeutic target to limit Pseudomonas associated allograft injury after lung transplantation.

Presence of a loner strain maintains cooperation and diversity in well-mixed bacterial communities.

Cooperation and diversity abound in nature despite cooperators risking exploitation from defectors and superior competitors displacing weaker ones. Understanding the persistence of cooperation and diversity is therefore a major problem for evolutionary ecology, especially in the context of well-mixed populations, where the potential for exploitation and displacement is greatest. Here, we demonstrate that a 'loner effect', described by economic game theorists, can maintain cooperation and diversity in real-world biological settings. We use mathematical models of public-good-producing bacteria to show that the presence of a loner strain, which produces an independent but relatively inefficient good, can lead to rock-paper-scissor dynamics, whereby cooperators outcompete loners, defectors outcompete cooperators and loners outcompete defectors. These model predictions are supported by our observations of evolutionary dynamics in well-mixed experimental communities of the bacterium Pseudomonas aeruginosa. We find that the coexistence of cooperators and defectors that produce and exploit, respectively, the iron-scavenging siderophore pyoverdine, is stabilized by the presence of loners with an independent iron-uptake mechanism. Our results establish the loner effect as a simple and general driver of cooperation and diversity in environments that would otherwise favour defection and the erosion of diversity.

The constant philopater hypothesis: a new life history invariant for dispersal evolution.

Surprising invariance relationships have emerged from the study of social interaction, whereby a cancelling-out of multiple partial effects of genetic, ecological or demographic parameters means that they have no net impact upon the evolution of a social behaviour. Such invariants play a pivotal role in the study of social adaptation: on the one hand, they provide theoretical hypotheses that can be empirically tested; and, on the other hand, they provide benchmark frameworks against which new theoretical developments can be understood. Here we derive a novel invariant for dispersal evolution: the 'constant philopater hypothesis' (CPH). Specifically, we find that, irrespective of variation in maternal fecundity, all mothers are favoured to produce exactly the same number of philopatric offspring, with high-fecundity mothers investing proportionally more, and low-fecundity mothers investing proportionally less, into dispersing offspring. This result holds for female and male dispersal, under haploid, diploid and haplodiploid modes of inheritance, irrespective of the sex ratio, local resource availability and whether mother or offspring controls the latter's dispersal propensity. We explore the implications of this result for evolutionary conflict of interests--and the exchange and withholding of contextual information--both within and between families, and we show that the CPH is the fundamental invariant that underpins and explains a wider family of invariance relationships that emerge from the study of social evolution.

Whole-exome sequencing points to considerable genetic heterogeneity of cerebral palsy.

Cerebral palsy (CP) is a common, clinically heterogeneous group of disorders affecting movement and posture. Its prevalence has changed little in 50 years and the causes remain largely unknown. The genetic contribution to CP causation has been predicted to be ~2%. We performed whole-exome sequencing of 183 cases with CP including both parents (98 cases) or one parent (67 cases) and 18 singleton cases (no parental DNA). We identified and validated 61 de novo protein-altering variants in 43 out of 98 (44%) case-parent trios. Initial prioritization of variants for causality was by mutation type, whether they were known or predicted to be deleterious and whether they occurred in known disease genes whose clinical spectrum overlaps CP. Further, prioritization used two multidimensional frameworks-the Residual Variation Intolerance Score and the Combined Annotation-dependent Depletion score. Ten de novo mutations in three previously identified disease genes (TUBA1A (n=2), SCN8A (n=1) and KDM5C (n=1)) and in six novel candidate CP genes (AGAP1, JHDM1D, MAST1, NAA35, RFX2 and WIPI2) were predicted to be potentially pathogenic for CP. In addition, we identified four predicted pathogenic, hemizygous variants on chromosome X in two known disease genes, L1CAM and PAK3, and in two novel candidate CP genes, CD99L2 and TENM1. In total, 14% of CP cases, by strict criteria, had a potentially disease-causing gene variant. Half were in novel genes. The genetic heterogeneity highlights the complexity of the genetic contribution to CP. Function and pathway studies are required to establish the causative role of these putative pathogenic CP genes.

Factors Associated with Sedentary Behavior in Patients with Intermittent Claudication.

OBJECTIVES: Time spent in sedentary behavior has been associated with cardio-metabolic risk factors in the general population and in patients with symptomatic peripheral artery disease (PAD). Given the association of sedentary behavior and poor health outcomes, it is important to identify factors associated with sedentary behavior in these patients. The aim of this study was to identify factors associated with the sedentary time in patients with symptomatic PAD. METHODS: The sample included 297 patients with symptomatic PAD. Sedentary behavior was assessed using a step activity monitor and the patients were divided into tertiles. Demographic data, body mass index, comorbid conditions, and measures of severity of PAD (ankle brachial index, ischemic window, claudication measurements, peak oxygen uptake and walking economy) were obtained. RESULTS: Patients in the highest tertile (i.e. more sedentary) had a higher body mass index and a higher prevalence of diabetes mellitus, metabolic syndrome, and obesity than patients in the lowest tertile, whereas their peak walking time, peak oxygen uptake, and walking economy were lower (p < .05 for all). Using multiple regression procedures, the factors associated with the sedentary time were male sex (b = .217, R2 = .180, p = .001), body mass index (b = .154, R2 = .059, p = .013), peak walking time (b = -.360, R2 = .066, p ≤ .001), and walking economy (b = -.187, R2 = .142, p = .004). CONCLUSION: In patients with symptomatic PAD, greater time spent in sedentary behavior was found in men, and in patients with higher body mass index, lower peak walking time, and lower walking economy.

A Video Analysis of Use of the New 'Concussion Interchange Rule' in the National Rugby League.

The National Rugby League (NRL) in Australia introduced a new 'concussion interchange rule' (CIR) in 2014, whereby a player suspected of having sustained a concussion can be removed from play, and assessed, without an interchange being tallied against the player's team. We conducted a video analysis, describing player and injury characteristics, situational factors, concussion signs, and return to play for each "CIR" event for the 2014 season. There were 167 reported uses of the CIR. Apparent loss of consciousness/unresponsiveness was observed in 32% of cases, loss of muscle tone in 54%, clutching the head in 70%, unsteadiness of gait in 66%, and a vacant stare in 66%. More than half of the players who were removed under the CIR returned to play later in the same match (57%). Most incidences occurred from a hit up (62%) and occurred during a tackle where the initial contact was with the upper body (80%). The new concussion interchange rule has been used frequently during the first season of its implementation. In many cases, there appeared to be video evidence of injury but the athlete was cleared to return to play. More research is needed on the usefulness of video review for identifying signs of concussive injury.

More on the genetical theory of multilevel selection.

In my article The genetical theory of multilevel selection, I provided a synthesis of the theory of multilevel selection (MLS) and the theory of natural selection in class-structured populations. I framed this synthesis within Fisher's genetical paradigm, taking a strictly genetical approach to traits and fitness. I showed that this resolves a number of long-standing conceptual problems that have plagued the MLS literature, including the issues of 'aggregate' vs. 'emergent' group traits, 'collective fitness1 ' vs. 'collective fitness2 ' and 'MLS1' vs. 'MLS2 '. In his commentary, Goodnight suggests this theoretical and conceptual synthesis is flawed in several respects. Here, I show this is incorrect, by: reiterating the theoretical and conceptual goals of my synthesis; clarifying that my genetical approach to traits is necessary for a proper analysis of the action of MLS independently of non-Darwinian factors; emphasizing that the Price-Hamilton approach to MLS provides a consistent, useful and conceptually superior theoretical framework; and explaining the role of reproductive value in the study of natural selection in class-structured populations. I also show that Goodnight's contextual analysis treatment of MLS in a class-structured population is mathematically, biologically and conceptually inadequate.

The genetical theory of multilevel selection.

The theory of multilevel selection (MLS) is beset with conceptual difficulties. Although it is widely agreed that covariance between group trait and group fitness may arise in the natural world and drive a response to 'group selection', ambiguity exists over the precise meaning of group trait and group fitness and as to whether group selection should be defined according to changes in frequencies of different types of individual or different types of group. Moreover, the theory of MLS has failed to properly engage with the problem of class structure, which greatly limits its empirical application to, for example, social insects whose colonies are structured into separate age, sex, caste and ploidy classes. Here, I develop a genetical theory of MLS, to address these problems. I show that taking a genetical approach facilitates a decomposition of group-level traits - including reproductive success - into the separate contributions made by each constituent individual, even in the context of so-called emergence. However, I uncover a novel problem with the group-oriented approach: in many scenarios, it may not be possible to express a meaningful covariance between trait and fitness at the level of the social group, because the group's constituents belong to separate, irreconcilable classes.

Effect of dietary methionine content on growth performance, carcass traits, and feather growth of Pekin duck from 15 to 35 days of age.

A study was conducted to establish the response of Pekin ducks to dietary Met from 15 to 35 d age. Experimental diets were formulated to contain 0.35, 0.45, 0.55, 0.65, and 0.75% Met (0.30, 0.39, 0.45, 0.56, and 0.68% on an analyzed basis, respectively) and 0.3% cysteine (0.25, 0.27, 0.26, 0.26, and 0.28% on an analyzed basis, respectively). Each diet was fed to 10 pens of 55 ducks/pen. Carcass yields and feather growth were determined at 28 and 35 d. Results showed that feeding 0.30% Met (0.55% Met+Cys) significantly impaired ADG, feed-to-gain (F:G) ratio, breast meat yield, and feather growth in comparison to the other dietary treatments (P < 0.05). BW, ADG, F: G, carcass and breast meat weight and yield, breast skin and subcutaneous fat weight and yield, the fourth primary wing feather length, and feather coverage showed significant quadratic broken-line or quadratic polynomial response to increasing dietary Met (P < 0.05). From 15 to 28 d age, the optimal Met requirement for the BW, breast meat yield, and the fourth primary wing feather length were 0.510, 0.445, and 0.404%, respectively, based on quadratic broken-line model, and correspondingly were 0.606, 0.576, and 0.559% by quadratic regression. For ducks from 15 to 35 d age, the optimal Met requirement for BW, breast meat yield, and feather coverage were 0.468, 0.408, and 0.484%, respectively, by quadratic broken-line model, and 0.605, 0.564, and 0.612%, by quadratic regression, respectively.

Evolution of paternal care in diploid and haplodiploid populations.

W. D. Hamilton famously suggested that the inflated relatedness of full sisters under haplodiploidy explains why all workers in the social hymenoptera are female. This suggestion has not stood up to further theoretical scrutiny and is not empirically supported. Rather, it appears that altruistic sib-rearing in the social hymenoptera is performed exclusively by females because this behaviour has its origins in parental care, which was performed exclusively by females in the ancestors of this insect group. However, haplodiploidy might still explain the sex of workers if this mode of inheritance has itself been responsible for the rarity of paternal care in this group. Here, we perform a theoretical kin selection analysis to investigate the evolution of paternal care in diploid and haplodiploid populations. We find that haplodiploidy may either inhibit or promote paternal care depending on model assumptions, but that under the most plausible scenarios it promotes - rather than inhibits - paternal care. Our analysis casts further doubt upon there being a causal link between haplodiploidy and eusociality.

Genomic imprinting and the units of adaptation.

Two guiding principles identify which biological entities are able to evolve adaptations. Williams' principle holds that, in order for an entity to evolve adaptations, there must be selection between such entities. Maynard Smith's principle holds that, in order for an entity to evolve adaptations, selection within such entities must be absent or negligible. However, although the kinship theory of genomic imprinting suggests that parent-of-origin-specific gene expression evolves as a consequence of natural selection acting between--rather than within--individuals, it evades adaptive interpretation at the individual level and is instead viewed as an outcome of an intragenomic conflict of interest between an individual's genes. Here, I formalize the idea that natural selection drives intragenomic conflicts of interest between genes originating from different parents. Specifically, I establish mathematical links between the dynamics of natural selection and the idea of the gene as an intentional, inclusive-fitness-maximizing agent, and I clarify the role that information about parent of origin plays in mediating conflicts of interest between genes residing in the same genome. These results highlight that the suppression of divisive information may be as important as the suppression of lower levels of selection in maintaining the integrity of units of adaptation.