The perspective of current and retired world class, elite and national athletes on the inclusion and eligibility of transgender athletes in elite sport.

There has been limited empirical study allowing athletes to voice their opinions on transgender participation in elite sport. This study surveyed 175 national, elite and world class athletes eligible to compete in the female category regarding transgender inclusion and eligibility. The study compared current Olympic versus current Olympic Recognised sports, elite versus world class, and current versus retired Olympic sport athletes. Most athletes favoured biological sex categorisation (58%) and considered it unfair for trans women to compete in the female category, except for precision sports. This view was held most strongly by world class athletes regarding their own sport (77% unfair, 15% fair). For trans men inclusion in the male category, most athletes considered it fair, except for Olympic sport athletes regarding contact sports (49% unfair, 27% fair) and sports heavily reliant on physical capacity (53% unfair, 29% fair). Notwithstanding those views, athletes (81%) believed sporting bodies should improve inclusivity for transgender athletes. Opinion varied somewhat according to career stage, competitive level and sport type. Nevertheless, athletes in the present study favoured categorisation by biological sex and did not support trans women eligibility for the female category in sports reliant on performance-related biological factors that differ between sexes.

Thrombosis with thrombocytopenia syndrome (TTS) following adenovirus vector COVID-19 vaccination in Canada.

INTRODUCTION: Identifying and monitoring adverse events following vaccination contributed to the safety and effectiveness of COVID-19 mass vaccination campaigns. In March 2021, international reports emerged of an adverse event following vaccination with adenovirus vector COVID-19 vaccines (ChAdOx1-S [recombinant] and Ad26.COV2.S) of thrombosis with low platelet counts, referred to as thrombosis with thrombocytopenia syndrome (TTS). We described TTS reports in Canada following adenovirus vector COVID-19 vaccines and investigated whether the observed number of events were higher than expected. METHODS: Reports of TTS following receipt of ChAdOx1-S [recombinant] or Ad26.COV2.S meeting the Canadian case definition for TTS and diagnostic certainty levels 1-3 of the Brighton Collaboration case definition, submitted to the Canadian Adverse Events Following Immunization Surveillance System and Canada Vigilance Database between February 26, 2021 and October 31, 2022 were included. Demographics and characteristics of the TTS reports are described along with an analysis comparing the observed number of reports to the expected number. RESULTS: As of October 31, 2022, 56 reports of TTS following administration of ChAdOx1-S [recombinant] and no reports following Ad26.COV2.S vaccines were reported in Canada, of which 37 had functionally positive anti-PF4 antibodies. The median age was 56 years; males accounted for 54 % of reports. Five deaths were reported. The observed number of reports exceeded the expected for all ages and sexes combined, as well as for males aged 30-49 and 60-69 years, and females aged 40-59 years. CONCLUSION: Based on international surveillance data, Canada evaluated a statistical signal of TTS following adenovirus vector vaccines. The investigation of this signal demonstrated how post-market vaccine safety surveillance systems were successful in investigating rare adverse events during the rollout of COVID-19 vaccines in Canada. As adenovirus vector vaccines continue to be administered, characterization of the association between the vaccine and TTS informs immunization programs and policies.

Clonality, local population structure and gametophyte sex ratios in cryptic species of the Sphagnum magellanicum complex.

BACKGROUND AND AIMS: Sphagnum (peatmoss) comprises a moss (Bryophyta) clade with ~300-500 species. The genus has unparalleled ecological importance because Sphagnum-dominated peatlands store almost a third of the terrestrial carbon pool and peatmosses engineer the formation and microtopography of peatlands. Genomic resources for Sphagnum are being actively expanded, but many aspects of their biology are still poorly known. Among these are the degree to which Sphagnum species reproduce asexually, and the relative frequencies of male and female gametophytes in these haploid-dominant plants. We assess clonality and gametophyte sex ratios and test hypotheses about the local-scale distribution of clones and sexes in four North American species of the S. magellanicum complex. These four species are difficult to distinguish morphologically and are very closely related. We also assess microbial communities associated with Sphagnum host plant clones and sexes at two sites. METHODS: Four hundred and five samples of the four species, representing 57 populations, were subjected to restriction site-associated DNA sequencing (RADseq). Analyses of population structure and clonality based on the molecular data utilized both phylogenetic and phenetic approaches. Multi-locus genotypes (genets) were identified using the RADseq data. Sexes of sampled ramets were determined using a molecular approach that utilized coverage of loci on the sex chromosomes after the method was validated using a sample of plants that expressed sex phenotypically. Sex ratios were estimated for each species, and populations within species. Difference in fitness between genets was estimated as the numbers of ramets each genet comprised. Degrees of clonality [numbers of genets/numbers of ramets (samples)] within species, among sites, and between gametophyte sexes were estimated. Sex ratios were estimated for each species, and populations within species. Sphagnum-associated microbial communities were assessed at two sites in relation to Sphagnum clonality and sex. KEY RESULTS: All four species appear to engage in a mixture of sexual and asexual (clonal) reproduction. A single ramet represents most genets but two to eight ramets were dsumbers ansd text etected for some genets. Only one genet is represented by ramets in multiple populations; all other genets are restricted to a single population. Within populations ramets of individual genets are spatially clustered, suggesting limited dispersal even within peatlands. Sex ratios are male-biased in S. diabolicum but female-biased in the other three species, although significantly so only in S. divinum. Neither species nor males/females differ in levels of clonal propagation. At St Regis Lake (NY) and Franklin Bog (VT), microbial community composition is strongly differentiated between the sites, but differences between species, genets and sexes were not detected. Within S. divinum, however, female gametophytes harboured two to three times the number of microbial taxa as males. CONCLUSIONS: These four Sphagnum species all exhibit similar reproductive patterns that result from a mixture of sexual and asexual reproduction. The spatial patterns of clonally replicated ramets of genets suggest that these species fall between the so-called phalanx patterns, where genets abut one another but do not extensively mix because of limited ramet fragmentation, and the guerrilla patterns, where extensive genet fragmentation and dispersal result in greater mixing of different genets. Although sex ratios in bryophytes are most often female-biased, both male and female biases occur in this complex of closely related species. The association of far greater microbial diversity for female gametophytes in S. divinum, which has a female-biased sex ratio, suggests additional research to determine if levels of microbial diversity are consistently correlated with differing patterns of sex ratio biases.

Divergent selection and climate adaptation fuel genomic differentiation between sister species of Sphagnum (peat moss).

BACKGROUND AND AIMS: New plant species can evolve through the reinforcement of reproductive isolation via local adaptation along habitat gradients. Peat mosses (Sphagnaceae) are an emerging model system for the study of evolutionary genomics and have well-documented niche differentiation among species. Recent molecular studies have demonstrated that the globally distributed species Sphagnum magellanicum is a complex of morphologically cryptic lineages that are phylogenetically and ecologically distinct. Here, we describe the architecture of genomic differentiation between two sister species in this complex known from eastern North America: the northern S. diabolicum and the largely southern S. magniae. METHODS: We sampled plant populations from across a latitudinal gradient in eastern North America and performed whole genome and restriction-site associated DNA sequencing. These sequencing data were then analyzed computationally. KEY RESULTS: Using sliding-window population genetic analyses we find that differentiation is concentrated within 'islands' of the genome spanning up to 400 kb that are characterized by elevated genetic divergence, suppressed recombination, reduced nucleotide diversity and increased rates of non-synonymous substitution. Sequence variants that are significantly associated with genetic structure and bioclimatic variables occur within genes that have functional enrichment for biological processes including abiotic stress response, photoperiodism and hormone-mediated signalling. Demographic modelling demonstrates that these two species diverged no more than 225 000 generations ago with secondary contact occurring where their ranges overlap. CONCLUSIONS: We suggest that this heterogeneity of genomic differentiation is a result of linked selection and reflects the role of local adaptation to contrasting climatic zones in driving speciation. This research provides insight into the process of speciation in a group of ecologically important plants and strengthens our predictive understanding of how plant populations will respond as Earth's climate rapidly changes.

Newly identified sex chromosomes in the Sphagnum (peat moss) genome alter carbon sequestration and ecosystem dynamics.

Peatlands are crucial sinks for atmospheric carbon but are critically threatened due to warming climates. Sphagnum (peat moss) species are keystone members of peatland communities where they actively engineer hyperacidic conditions, which improves their competitive advantage and accelerates ecosystem-level carbon sequestration. To dissect the molecular and physiological sources of this unique biology, we generated chromosome-scale genomes of two Sphagnum species: S. divinum and S. angustifolium. Sphagnum genomes show no gene colinearity with any other reference genome to date, demonstrating that Sphagnum represents an unsampled lineage of land plant evolution. The genomes also revealed an average recombination rate an order of magnitude higher than vascular land plants and short putative U/V sex chromosomes. These newly described sex chromosomes interact with autosomal loci that significantly impact growth across diverse pH conditions. This discovery demonstrates that the ability of Sphagnum to sequester carbon in acidic peat bogs is mediated by interactions between sex, autosomes and environment.

Viral infections likely mediate microbial controls on ecosystem responses to global warming.

Climate change is affecting how energy and matter flow through ecosystems, thereby altering global carbon and nutrient cycles. Microorganisms play a fundamental role in carbon and nutrient cycling and are thus an integral link between ecosystems and climate. Here, we highlight a major black box hindering our ability to anticipate ecosystem climate responses: viral infections within complex microbial food webs. We show how understanding and predicting ecosystem responses to warming could be challenging-if not impossible-without accounting for the direct and indirect effects of viral infections on different microbes (bacteria, archaea, fungi, protists) that together perform diverse ecosystem functions. Importantly, understanding how rising temperatures associated with climate change influence viruses and virus-host dynamics is crucial to this task, yet is severely understudied. In this perspective, we (i) synthesize existing knowledge about virus-microbe-temperature interactions and (ii) identify important gaps to guide future investigations regarding how climate change might alter microbial food web effects on ecosystem functioning. To provide real-world context, we consider how these processes may operate in peatlands-globally significant carbon sinks that are threatened by climate change. We stress that understanding how warming affects biogeochemical cycles in any ecosystem hinges on disentangling complex interactions and temperature responses within microbial food webs.

Demographic history and gene flow in the peatmosses Sphagnum recurvum and Sphagnum flexuosum (Bryophyta: Sphagnaceae).

Population size changes and gene flow are processes that can have significant impacts on evolution. The aim of this study was to investigate the relationship of geography to patterns of gene flow and population size changes in a pair of closely related Sphagnum (peatmoss) species: S. recurvum and S. flexuosum. Both species occur in eastern North America, and S. flexuosum also occurs in Europe. Genetic data from restriction-site-associated DNA sequencing (RAD-seq) were used in this study. Analyses of gene flow were accomplished using coalescent simulations of site frequency spectra (SFSs). Signatures of gene flow were confirmed by f 4 statistics. For S. flexuosum, genetic diversity of plants in glaciated areas appeared to be lower than that in unglaciated areas, suggesting that glaciation can have an impact on effective population sizes. There is asymmetric gene flow from eastern North America to Europe, suggesting that Europe might have been colonized by plants from eastern North America after the last glacial maximum. The rate of gene flow between S. flexuosum and S. recurvum is lower than that between geographically disjunct S. flexuosum populations. The rate of gene flow between species is higher among sympatric plants of the two species than between currently allopatric S. flexuosum populations. There was also gene flow from S. recurvum to the ancestor S. flexuosum on both continents which occurred through secondary contact. These results illustrate a complex history of interspecific gene flow between S. flexuosum and S. recurvum, which occurred in at least two phases: between ancestral populations after secondary contact and between currently sympatric plants.

Recruitment of Older African Americans in Alzheimer's Disease Clinical Trials Using a Community Education Approach.

Alzheimer's disease and related dementias (ADRD) is two times more prevalent among compared to non-Hispanic Whites. Despite the higher prevalence of ADRD among older African Americans, recent estimates suggest research enrollment by those who identify as African American remains limited. The purpose of the study is to 1) explore how a culturally tailored community education program impacts clinical trial interest and enrollment in ADRD research studies and to 2) identify how applicable the African American community perceived the culturally tailored curriculum. Using a community-engaged research approach, we collaborated with predominately African American serving community-based organizations to support content development and delivery of Aging with Grace (AWG), a culturally tailored ADRD educational curriculum. A total of five AWG presentations were given to 66 attendees. Most attendees (67%) expressed interest in participating in clinical trials after attending AWG. Enrollment increased within an observational study (84%) and lifestyle prevention clinical trials (52%) from 2018 to 2019. Attendees (32%) also perceived an increase in ADRD knowledge from attending AWG and 89.1% believed more African Americans should participate in research. Our work demonstrates the effectiveness of a culturally tailored community education program to enhance knowledge, clinical trial interest, and recruitment into observational studies and lifestyle ADRD clinical trials among older African Americans. Education programs developed in partnership with the community can serve as bridge to research participation for underrepresented minorities in clinical research. Future studies should assess long-term retention of knowledge and research readiness.

Draft Metagenome Sequences of the Sphagnum (Peat Moss) Microbiome from Ambient and Warmed Environments across Europe.

We present 49 metagenome assemblies of the microbiome associated with Sphagnum (peat moss) collected from ambient, artificially warmed, and geothermally warmed conditions across Europe. These data will enable further research regarding the impact of climate change on plant-microbe symbiosis, ecology, and ecosystem functioning of northern peatland ecosystems.

Phylogenomic structure and speciation in an emerging model: the Sphagnum magellanicum complex (Bryophyta).

Sphagnum magellanicum is one of two Sphagnum species for which a reference-quality genome exists to facilitate research in ecological genomics. Phylogenetic and comparative genomic analyses were conducted based on resequencing data from 48 samples and RADseq analyses based on 187 samples. We report herein that there are four clades/species within the S. magellanicum complex in eastern North America and that the reference genome belongs to Sphagnum divinum. The species exhibit tens of thousands (RADseq) to millions (resequencing) of fixed nucleotide differences. Two species, however, referred to informally as S. diabolicum and S. magni because they have not been formally described, are differentiated by only 100 (RADseq) to 1000 (resequencing) of differences. Introgression among species in the complex is demonstrated using D-statistics and f4 ratios. One ecologically important functional trait, tissue decomposability, which underlies peat (carbon) accumulation, does not differ between segregates in the S. magellanicum complex, although previous research showed that many closely related Sphagnum species have evolved differences in decomposability/carbon sequestration. Phylogenetic resolution and more accurate species delimitation in the S. magellanicum complex substantially increase the value of this group for studying the early evolutionary stages of climate adaptation and ecological evolution more broadly.

Unraveling the effect of intra- and intercellular processes on acetaminophen-induced liver injury.

In high dosages, acetaminophen (APAP) can cause severe liver damage, but susceptibility to liver failure varies across individuals and is influenced by factors such as health status. Because APAP-induced liver injury and recovery is regulated by an intricate system of intra- and extracellular molecular signaling, we here aim to quantify the importance of specific modules in determining the outcome after an APAP insult and of potential targets for therapies that mitigate adversity. For this purpose, we integrated hepatocellular acetaminophen metabolism, DNA damage response induction and cell fate into a multiscale mechanistic liver lobule model which involves various cell types, such as hepatocytes, residential Kupffer cells and macrophages. Our model simulations show that zonal differences in metabolism and detoxification efficiency are essential determinants of necrotic damage. Moreover, the extent of senescence, which is regulated by intracellular processes and triggered by extracellular signaling, influences the potential to recover. In silico therapies at early and late time points after APAP insult indicated that prevention of necrotic damage is most beneficial for recovery, whereas interference with regulation of senescence promotes regeneration in a less pronounced way.

Experiences of Multidisciplinary Working: Perspectives from the Wessex Ghana Stroke Partnership.

INTRODUCTION: Substantial gaps remain in our understanding of stroke in Africa as well as in stroke care, practice and policy on the continent. The effective organization of preventative, therapeutic and rehabilitative stroke services continue to be challenging in many African countries. METHODOLOGY: In this article we define the nature, function and benefits of effective multidisciplinary team (MDT) working. The experiences and perspectives of members of the MDT were collated by focus group discussions as well as individual and country specific contributions. RESULTS: The experiences and perspectives of multidisciplinary team members from the United Kingdom and Ghana implementing these practices at the first stroke unit in Korle Bu Teaching Hospital, Accra, with a transparent discussion of successes and challenges faced throughout development of the service, is presented. MDT working has improved outcomes for patients and families who use the services, including encouraging better shared treatment planning and compliance. More stroke rehabilitation services are provided than previously, including greater self-management education and better secondary prevention care. CONCLUSION: It is hoped that this article will provide an inspirational model for others working to provide stroke care in low-resource settings in Africa and worldwide.

INTRODUCTION: Des lacunes substantielles subsistent dans notre compréhension de l'accident vasculaire cérébral en Afrique ainsi que dans les pratiques et politiques sur le continent. L'organisation efficace des services de prévention, de traitement et de réadaptation des AVC reste un défi dans de nombreux pays africains. MÉTHODOLOGIE: Dans cet article, nous définissons la nature, la fonction et les avantages d'une équipe multidisciplinaire efficace (PCT).Les expériences et les points de vue des membres de la PCT ont été recueillis par des discussions de groupes de réflexion ainsi que contributions individuelles et spécifiques à chaque pays. RÉSULTATS: Les expériences et les perspectives des membres d'équipes multidisciplinaires du Royaume-Uni et du Ghana, qui ont mis en œuvre ces pratiques dans la première unité d'AVC du de l'hôpital universitaire Korle Bu, à Accra, avec une discussion transparente des succès et des défis rencontrés tout au long du développement du service, sont présentées. Le travail de la PCT a amélioré les résultats pour les patients et les familles qui utilisent les services, notamment en encourageant un meilleur partage du traitement, l'organisation et la complaisance. Davantage de services de réadaptation après un AVC sont fournis plus qu'auparavant, y compris une meilleure éducation à l'autogestion et de meilleurs soins de prévention secondaire. CONCLUSION: Nous espérons que cet article constituera un modèle inspirant pour d'autres personnes travaillant à la prise en charge d'AVC dans des contextes à faibles ressources en Afrique et dans le monde. Mots clés: Unité de expériences, multidisciplinaire, Ghana, partenariat.

Habitat-adapted microbial communities mediate Sphagnum peatmoss resilience to warming.

Sphagnum peatmosses are fundamental members of peatland ecosystems, where they contribute to the uptake and long-term storage of atmospheric carbon. Warming threatens Sphagnum mosses and is known to alter the composition of their associated microbiome. Here, we use a microbiome transfer approach to test if microbiome thermal origin influences host plant thermotolerance. We leveraged an experimental whole-ecosystem warming study to collect field-grown Sphagnum, mechanically separate the associated microbiome and then transfer onto germ-free laboratory Sphagnum for temperature experiments. Host and microbiome dynamics were assessed with growth analysis, Chla fluorescence imaging, metagenomics, metatranscriptomics and 16S rDNA profiling. Microbiomes originating from warming field conditions imparted enhanced thermotolerance and growth recovery at elevated temperatures. Metagenome and metatranscriptome analyses revealed that warming altered microbial community structure in a manner that induced the plant heat shock response, especially the HSP70 family and jasmonic acid production. The heat shock response was induced even without warming treatment in the laboratory, suggesting that the warm-microbiome isolated from the field provided the host plant with thermal preconditioning. Our results demonstrate that microbes, which respond rapidly to temperature alterations, can play key roles in host plant growth response to rapidly changing environments.

Dickkopf-1 directs periosteal bone formation in two murine models of inflammatory arthritis.

OBJECTIVE: The Wnt signalling antagonist Dickkopf-1 (DKK1) inhibits osteoblast differentiation and function and has been described to play a central role in promoting bone loss, while blockade of DKK1 increases bone formation. We investigated the effects of DKK1 on periosteal new bone formation in two murine models of inflammatory arthritis, the antigen-induced arthritis (AIA) and K/BxN serum transfer arthritis (STA) models. METHOD: The flare variant of AIA was induced in wild-type mice and a blocking antibody to DKK1, control rat immunoglobulin G (IgG), or phosphate-buffered saline (PBS) was administered starting on day 14, a time at which inflammation and erosions are known to be established. Knees were assessed for histological inflammation and periosteal new bone formation was quantitated. In addition, STA was generated in transgenic (Tg) mice with osteoblast-specific overexpression of Dkk1 and littermate controls. New bone formation around the wrists of these mice was quantified by micro-computed tomography. RESULTS: Blockade of DKK1 in arthritic mice resulted in significantly more periosteal new bone formation compared to mice treated with control rat IgG or PBS. Conversely, in the setting of increased Dkk1 expression, arthritic Dkk1 Tg mice developed significantly less periosteal new bone than arthritic controls. CONCLUSION: DKK1 is a regulator of periosteal bone formation in inflammatory arthritis. Thus, regulation of DKK1 may be considered as a therapeutic approach in inflammatory diseases in which patients suffer from excessive periosteal bone formation, such as spondyloarthritis.

Crizotinib in patients with tumors harboring ALK or ROS1 rearrangements in the NCI-MATCH trial.

The NCI-MATCH was designed to characterize the efficacy of targeted therapies in histology-agnostic driver mutation-positive malignancies. Sub-protocols F and G were developed to evaluate the role of crizotinib in rare tumors that harbored either ALK or ROS1 rearrangements. Patients with malignancies that progressed following at least one prior systemic therapy were accrued to the NCI-MATCH for molecular profiling, and those with actionable ALK or ROS1 rearrangements were offered participation in sub-protocols F or G, respectively. There were five patients who enrolled on Arm F (ALK) and four patients on Arm G (ROS1). Few grade 3 or 4 toxicities were noted, including liver test abnormalities, and acute kidney injury. For sub-protocol F (ALK), the response rate was 50% (90% CI 9.8-90.2%) with one complete response among the 4 eligible patients. The median PFS was 3.8 months, and median OS was 4.3 months. For sub-protocol G (ROS1) the response rate was 25% (90% CI 1.3-75.1%). The median PFS was 4.3 months, and median OS 6.2 months. Data from 3 commercial vendors showed that the prevalence of ALK and ROS1 rearrangements in histologies other than non-small cell lung cancer and lymphoma was rare (0.1% and 0.4% respectively). We observed responses to crizotinib which met the primary endpoint for ALK fusions, albeit in a small number of patients. Despite the limited accrual, some of the patients with these oncogenic fusions can respond to crizotinib which may have a therapeutic role in this setting.

Implementation of initiatives designed to improve healthcare worker health and wellbeing during the COVID-19 pandemic: comparative case studies from 13 healthcare provider organisations globally.

BACKGROUND: Healthcare workers are at a disproportionate risk of contracting COVID-19. The physical and mental repercussions of such risk have an impact on the wellbeing of healthcare workers around the world. Healthcare workers are the foundation of all well-functioning health systems capable of responding to the ongoing pandemic; initiatives to address and reduce such risk are critical. Since the onset of the pandemic healthcare organizations have embarked on the implementation of a range of initiatives designed to improve healthcare worker health and wellbeing. METHODS: Through a qualitative collective case study approach where participants responded to a longform survey, the facilitators, and barriers to implementing such initiatives were explored, offering global insights into the challenges faced at the organizational level. 13 healthcare organizations were surveyed across 13 countries. Of these 13 participants, 5 subsequently provided missing information through longform interviews or written clarifications. RESULTS: 13 case studies were received from healthcare provider organizations. Mental health initiatives were the most commonly described health and wellbeing initiatives among respondents. Physical health and health and safety focused initiatives, such as the adaption of workspaces, were also described. Strong institutional level direction, including engaged leadership, and the input, feedback, and engagement of frontline staff were the two main facilitators in implementing initiatives. The most common barrier was HCWs' fear of contracting COVID-19 / fear of passing COVID-19 to family members. In organizations who discussed infection prevention and control initiatives, inadequate personal protective equipment and supply chain disruption were highlighted by respondents. CONCLUSIONS: Common themes emerge globally in exploring the enablers and barriers to implementing initiatives to improve healthcare workers health and wellbeing through the COVID-19 pandemic. Consideration of the themes outlined in the paper by healthcare organizations could help influence the design and deployment of future initiatives ahead of implementation.

Representation of Racial and Ethnic Minority Populations in Dementia Prevention Trials: A Systematic Review.

Despite older racial and ethnic minorities (REMs) being more likely to develop dementia they are underrepresented in clinical trials focused on neurological disorders. Inclusion of REMs in dementia prevention studies is vital to reducing the impact of disparities in dementia risk. We conducted a systematic review to characterize the number of REM enrolled in brain health and prevention randomized controlled trials (RCTs). RTCs published from January 1, 2004 to April 21, 2020 were included. Participants were normal cognitive adults aged 45 years and older who participated in a Phase II or Phase III U.S. based preventative trial. Analyses were performed to examine differences in trial characteristics between RCTs that did and those that did not report race/ethnicity and to calculate the pooled proportion of each racial/ethnic group in randomized brain healthy prevention trials. A total of 42 studies consisting of 100,748 participants were included in the final analyses. A total of 26 (62%) reported some racial/ethnic identity data. The pooled proportion of REM participants was 0.256 (95% CI, 0.191, 0.326). There is a lack of racial/ethnic reporting of participants and REMs remain underrepresented in brain health prevention RCTs.

Novel metabolic interactions and environmental conditions mediate the boreal peatmoss-cyanobacteria mutualism.

Interactions between Sphagnum (peat moss) and cyanobacteria play critical roles in terrestrial carbon and nitrogen cycling processes. Knowledge of the metabolites exchanged, the physiological processes involved, and the environmental conditions allowing the formation of symbiosis is important for a better understanding of the mechanisms underlying these interactions. In this study, we used a cross-feeding approach with spatially resolved metabolite profiling and metatranscriptomics to characterize the symbiosis between Sphagnum and Nostoc cyanobacteria. A pH gradient study revealed that the Sphagnum-Nostoc symbiosis was driven by pH, with mutualism occurring only at low pH. Metabolic cross-feeding studies along with spatially resolved matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) identified trehalose as the main carbohydrate source released by Sphagnum, which were depleted by Nostoc along with sulfur-containing choline-O-sulfate, taurine and sulfoacetate. In exchange, Nostoc increased exudation of purines and amino acids. Metatranscriptome analysis indicated that Sphagnum host defense was downregulated when in direct contact with the Nostoc symbiont, but not as a result of chemical contact alone. The observations in this study elucidated environmental, metabolic, and physiological underpinnings of the widespread plant-cyanobacterial symbioses with important implications for predicting carbon and nitrogen cycling in peatland ecosystems as well as the basis of general host-microbe interactions.

Genetic landscape of patients with ALK-rearranged non-small-cell lung cancer (NSCLC) and response to ceritinib in ASCEND-1 study.

OBJECTIVES: To better understand genetic determinants of response to ceritinib, an exploratory analysis was conducted using tumor biopsies from anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small-cell lung cancer (NSCLC) patients treated with ceritinib at doses of ≥ 300 mg in the ASCEND-1 study. METHODS: ASCEND-1 was an open-label, multicentre, phase 1, dose-escalation and expansion study of ceritinib (fasted) in ALK inhibitor (ALKi)-naïve or ALKi-pretreated patients with locally advanced or metastatic ALK + NSCLC. Biopsies were assayed by next-generation sequencing (NGS) using a Foundation Medicine panel targeting 295 genes. Somatic alterations were correlated with clinical outcome (cut-off 14-Apr-2014). A total of 285 ALK + NSCLC patients were treated with ceritinib at doses ≥ 300 mg. RESULTS: NGS data were generated for 85 pts (ALKi-pretreated [n = 54]; ALKi-naïve [n = 31]), 57 were collected from patients before exposure to any ALKi. NGS did not detect ALK rearrangement in 14 of 85 patients; several of these ALK NGS negative cases harbored alternative drivers, e.g. EGFR mutation. Of the 71 biopsies with NGS confirmed ALK rearrangement, the most frequently detected rearrangements were EML4-ALK variant 1 (V1) and EML4-ALK V3 (36.6% [26/71] and 32.4% [23/71] respectively). Eight (six crizotinib-pretreated and two pretreated with crizotinib followed by alectinib) of the 21 ALKi-pretreated patients carried a point mutation of the ALK TKD, and had the biopsy collected between 1 and 14 days before ceritinib; with the exception of one patient with a G1202R point mutation, all patients derived clinical benefit from ceritinib treatment. Of the 14 ALKi-naïve patients, ceritinib was effective in almost all patients, including a patient carrying a concomitant ERBB4 and HGF amplification. CONCLUSIONS: This exploratory analysis highlights the potential role of NGS in improving our understanding of response and resistance to ceritinib. It also illustrates that ceritinib is active against almost all ALK resistance mutations found in ALKi-pretreated patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01283516. Registered January 26, 2011, https://clinicaltrials.gov/ct2/show/NCT01283516.