Substance Use Within Trials of Psychological Interventions for Psychosis: Sample Inclusion, Secondary Measures, and Intervention Effectiveness.

INTRODUCTION: Current clinical guidelines recommend that patients with co-occurring psychosis and alcohol or substance use disorders (A/SUD) receive evidenced-based treatment for both disorders, including psychological intervention for psychosis. However, the efficacy of such treatments for individuals with co-occurring psychosis and A/SUD is unclear. STUDY DESIGN: Randomized controlled trials (RCTs) of psychological interventions for psychosis were systematically reviewed, to investigate how alcohol and substance use has been accounted for across sample inclusion and secondary measures. Findings from trials including individuals with co-occurring alcohol or substance use issues were then narratively summarized using the Synthesis Without Meta-Analysis guidelines, to indicate the overall efficacy of psychological interventions for psychosis, for this comorbid population. STUDY RESULTS: Across the 131 trials identified, 60.3% of trials excluded individuals with alcohol or substance use issues. Additionally, only 6.1% measured alcohol or substance use at baseline, while only 2.3% measured alcohol or substance use as a secondary outcome. Across trials explicitly including individuals with alcohol or substance use issues, insufficient evidence was available to conclude the efficacy of any individual psychological intervention. However, preliminary findings suggest that psychoeducation (PE) and metacognitive therapy (MCT) may be proposed for further investigation. CONCLUSION: Overall, co-occurring alcohol and substance use issues have been largely neglected across the recent RCTs of psychological interventions for psychosis; highlighting the challenges of making treatment decisions for these individuals using the current evidence base.

Whole genome and transcriptome integrated analyses guide clinical care of pediatric poor prognosis cancers.

The role for routine whole genome and transcriptome analysis (WGTA) for poor prognosis pediatric cancers remains undetermined. Here, we characterize somatic mutations, structural rearrangements, copy number variants, gene expression, immuno-profiles and germline cancer predisposition variants in children and adolescents with relapsed, refractory or poor prognosis malignancies who underwent somatic WGTA and matched germline sequencing. Seventy-nine participants with a median age at enrollment of 8.8 y (range 6 months to 21.2 y) are included. Germline pathogenic/likely pathogenic variants are identified in 12% of participants, of which 60% were not known prior. Therapeutically actionable variants are identified by targeted gene report and whole genome in 32% and 62% of participants, respectively, and increase to 96% after integrating transcriptome analyses. Thirty-two molecularly informed therapies are pursued in 28 participants with 54% achieving a clinical benefit rate; objective response or stable disease ≥6 months. Integrated WGTA identifies therapeutically actionable variants in almost all tumors and are directly translatable to clinical care of children with poor prognosis cancers.

VOLTA: an enVironment-aware cOntrastive ceLl represenTation leArning for histopathology.

In clinical oncology, many diagnostic tasks rely on the identification of cells in histopathology images. While supervised machine learning techniques necessitate the need for labels, providing manual cell annotations is time-consuming. In this paper, we propose a self-supervised framework (enVironment-aware cOntrastive cell represenTation learning: VOLTA) for cell representation learning in histopathology images using a technique that accounts for the cell's mutual relationship with its environment. We subject our model to extensive experiments on data collected from multiple institutions comprising over 800,000 cells and six cancer types. To showcase the potential of our proposed framework, we apply VOLTA to ovarian and endometrial cancers and demonstrate that our cell representations can be utilized to identify the known histotypes of ovarian cancer and provide insights that link histopathology and molecular subtypes of endometrial cancer. Unlike supervised models, we provide a framework that can empower discoveries without any annotation data, even in situations where sample sizes are limited.

Understanding the Impacts of Online Mental Health Peer Support Forums: Realist Synthesis.

BACKGROUND: Online forums are widely used for mental health peer support. However, evidence of their safety and effectiveness is mixed. Further research focused on articulating the contexts in which positive and negative impacts emerge from forum use is required to inform innovations in implementation. OBJECTIVE: This study aimed to develop a realist program theory to explain the impacts of online mental health peer support forums on users. METHODS: We conducted a realist synthesis of literature published between 2019 and 2023 and 18 stakeholder interviews with forum staff. RESULTS: Synthesis of 102 evidence sources and 18 interviews produced an overarching program theory comprising 22 context-mechanism-outcome configurations. Findings indicate that users' perceptions of psychological safety and the personal relevance of forum content are foundational to ongoing engagement. Safe and active forums that provide convenient access to information and advice can lead to improvements in mental health self-efficacy. Within the context of welcoming and nonjudgmental communities, users may benefit from the opportunity to explore personal difficulties with peers, experience reduced isolation and normalization of mental health experiences, and engage in mutual encouragement. The program theory highlights the vital role of moderators in creating facilitative online spaces, stimulating community engagement, and limiting access to distressing content. A key challenge for organizations that host mental health forums lies in balancing forum openness and anonymity with the need to enforce rules, such as restrictions on what users can discuss, to promote community safety. CONCLUSIONS: This is the first realist synthesis of online mental health peer support forums. The novel program theory highlights how successful implementation depends on establishing protocols for enhancing safety and strategies for maintaining user engagement to promote forum sustainability. TRIAL REGISTRATION: PROSPERO CRD42022352528; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=352528.

The benefit of a complete reference genome for cancer structural variant analysis.

The complexities of cancer genomes are becoming more easily interpreted due to advancements in sequencing technologies and improved bioinformatic analysis. Structural variants (SVs) represent an important subset of somatic events in tumors. While detection of SVs has been markedly improved by the development of long-read sequencing, somatic variant identification and annotation remains challenging. We hypothesized that use of a completed human reference genome (CHM13-T2T) would improve somatic SV calling. Our findings in a tumour/normal matched benchmark sample and two patient samples show that the CHM13-T2T improves SV detection and prioritization accuracy compared to GRCh38, with a notable reduction in false positive calls. We also overcame the lack of annotation resources for CHM13-T2T by lifting over CHM13-T2T-aligned reads to the GRCh38 genome, therefore combining both improved alignment and advanced annotations. In this process, we assessed the current SV benchmark set for COLO829/COLO829BL across four replicates sequenced at different centers with different long-read technologies. We discovered instability of this cell line across these replicates; 346 SVs (1.13%) were only discoverable in a single replicate. We identify 49 somatic SVs, which appear to be stable as they are consistently present across the four replicates. As such, we propose this consensus set as an updated benchmark for somatic SV calling and include both GRCh38 and CHM13-T2T coordinates in our benchmark. The benchmark is available at: 10.5281/zenodo.10819636 Our work demonstrates new approaches to optimize somatic SV prioritization in cancer with potential improvements in other genetic diseases.

GlycA Levels Independently Predict Coronary Artery Calcium Incidence and Progression in the ELSA-Brasil Cohort (Brazilian Longitudinal Study of Adult Health).

Atherosclerosis is an inflammatory disease. Coronary artery calcium (CAC) is a marker of atherosclerotic disease events and mortality risk. Increased GlycA, an emerging marker of inflammation, is associated with a higher risk for coronary artery disease (CAD). However, there is conflicting evidence on whether GlycA predicts subclinical CAD progression. We hypothesized that GlycA can predict subclinical CAC incidence/progression in healthy participants. We included 2,690 ELSA-Brasil cohort participants without cardiovascular/chronic inflammatory disease not receiving statin therapy who had GlycA levels measured and 2 interval CAC assessments between 2010 and 2018. Multivariable logistic and linear regression models were computed to evaluate GlycA as a predictor of CAC incidence and progression. CAC incidence required a baseline CAC of 0. CAC progression required a baseline CAC >0. The mean age of participants was 48.6 ± 7.7 years, 56.7% were women, and 54.6% and 16.1% (429 of 2,690) were White and Black, respectively. The mean CAC interscan period was 5.1 ± 0.9 years, the mean GlycA level was 414.7 ± 65 µmol/L, and the incidence of CAC was 13.1% (280 of 2,129). The GlycA level odds ratio for CAC incidence was 1.002 (95% confidence interval 1.0005 to 1.005, p = 0.016), adjusted for demographics, lifestyle, a family history of early CAD (≤60 years), lipids, and co-morbidities. The GlycA (≤p25 vs ≥p75) odds ratio for CAC progression (Berry definition) was 1.77 (95% confidence interval 1.07 to 2.96, p = 0.03) in a similar multivariable-adjusted model. Higher GlycA levels were associated with CAC incidence and progression in a healthy Brazilian cohort.

Exploration of Germline Correlates and Risk of Immune-Related Adverse Events in Advanced Cancer Patients Treated with Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs) are increasingly used in the treatment of many tumor types, and durable responses can be observed in select populations. However, patients may exhibit significant immune-related adverse events (irAEs) that may lead to morbidity. There is limited information on whether the presence of specific germline mutations may highlight those at elevated risk of irAEs. We evaluated 117 patients with metastatic solid tumors or hematologic malignancies who underwent genomic analysis through the ongoing Personalized OncoGenomics (POG) program at BC Cancer and received an ICI during their treatment history. Charts were reviewed for irAEs. Whole genome sequencing of a fresh biopsy and matched normal specimens (blood) was performed at the time of POG enrollment. Notably, we found that MHC class I alleles in the HLA-B27 family, which have been previously associated with autoimmune conditions, were associated with grade 3 hepatitis and pneumonitis (q = 0.007) in patients treated with combination PD-1/PD-L1 and CTLA-4 inhibitors, and PD-1 inhibitors in combination with IDO-1 inhibitors. These data highlight that some patients may have a genetic predisposition to developing irAEs.

Canadian COVID-19 host genetics cohort replicates known severity associations.

The HostSeq initiative recruited 10,059 Canadians infected with SARS-CoV-2 between March 2020 and March 2023, obtained clinical information on their disease experience and whole genome sequenced (WGS) their DNA. We analyzed the WGS data for genetic contributors to severe COVID-19 (considering 3,499 hospitalized cases and 4,975 non-hospitalized after quality control). We investigated the evidence for replication of loci reported by the International Host Genetics Initiative (HGI); analyzed the X chromosome; conducted rare variant gene-based analysis and polygenic risk score testing. Population stratification was adjusted for using meta-analysis across ancestry groups. We replicated two loci identified by the HGI for COVID-19 severity: the LZTFL1/SLC6A20 locus on chromosome 3 and the FOXP4 locus on chromosome 6 (the latter with a variant significant at P < 5E-8). We found novel significant associations with MRAS and WDR89 in gene-based analyses, and constructed a polygenic risk score that explained 1.01% of the variance in severe COVID-19. This study provides independent evidence confirming the robustness of previously identified COVID-19 severity loci by the HGI and identifies novel genes for further investigation.

Injury-severity analysis of crashes involving defective vehicles and accounting for the underlying socioeconomic mediators.

Crashes occur from a combination of factors related to the driver, roadway, and vehicle factors. The impact of vehicles on road crashes is a critical consideration within road safety analysis, even though not much studies have been conducted in this area. This study assessed how various vehicle and other crash factors are significantly associated with crash outcomes. To do this, historical vehicle defect-related crashes were obtained for the state of Alabama from 2016 to 2020. After data cleaning, a crash injury severity model was developed using the random parameters multinomial logit with heterogeneity in means approach to account for possible unobserved heterogeneity in the data. A spatial analysis was further conducted to better understand vehicle defect crashes as a broader societal issue and potentially explore their connection with the socio-demographic characteristics of the drivers of these vehicles. The preliminary data analysis showed that brake and tire defects accounted for about 65% of the vehicle defects associated with the crashes. The model estimation results revealed that improper tread depth and headlight defects were associated with major injury outcomes, while brake defects were more associated with minor injuries. Also, crashes associated with speeding, drunk driving, failure to use seatbelts, and those that occurred on curved roads left with downgrades were likely to result in major injuries. Findings from the spatial analysis showed that postal codes with higher median incomes are more likely to record lower vehicle defect-related crashes, unlike those that have higher proportions of females and African Americans. The study's findings provide data-driven evidence for sustained safety campaigns, workshops, and training on basic vehicle maintenance practices in the low-income communities in the state.

Mitofusin 2 Variant Presenting With a Phenotype of Multiple System Atrophy of Cerebellar Subtype.

Objectives: To investigate the etiology of cerebellar ataxia in an adult male patient. Methods: We performed standard neurologic assessment and genome sequencing of a 62-year-old man with rapidly progressive balance and gait abnormalities. Results: The propositus exhibited cognitive dysfunction, mild appendicular bradykinesia, prominent appendicular ataxia, dysarthria, and hypomimia with minimal dysautonomic symptoms. Nerve conduction studies showed mild peripheral sensory neuropathy and normal motor nerve conduction velocities. Brain imaging showed progressive cerebellar atrophy and gliosis of the olivopontocerebellar fibers, characterized by T2 hyperintensity within the pons. Genetic testing revealed a likely pathogenic germline variant in MFN2 (NM_014874: c.[838C>T];[=], p.(R280C)) in the GTPase domain (G) interface; pathogenic variants of MFN2 typically cause hereditary sensory and motor neuropathy VI or Charcot-Marie-Tooth disease 2A. The presence of progressive ataxia, "hot cross bun" sign, and dysautonomia has been associated with multiple system atrophy, cerebellar type (MSA-C). Discussion: We describe progressive cerebellar ataxia in an individual with a deleterious variant in MFN2. Our findings suggest that pathogenic variants in MFN2 can result in a spectrum of phenotypes including cerebellar ataxia with cerebellar-pontine atrophy in the absence of significant neuropathy and in a manner closely resembling MSA-C.

Designing a Library of Lived Experience for Mental Health: integrated realist synthesis and experience-based co-design study in UK mental health services.

OBJECTIVE: Living Library events involve people being trained as living 'Books', who then discuss aspects of their personal experiences in direct conversation with attendees, referred to as 'Readers'. This study sought to generate a realist programme theory and a theory-informed implementation guide for a Library of Lived Experience for Mental Health (LoLEM). DESIGN: Integrated realist synthesis and experience-based co-design. SETTING: Ten online workshops with participants based in the North of England. PARTICIPANTS: Thirty-one participants with a combination of personal experience of using mental health services, caring for someone with mental health difficulties and/or working in mental health support roles. RESULTS: Database searches identified 30 published and grey literature evidence sources which were integrated with data from 10 online co-design workshops conducted over 12 months. The analysis generated a programme theory comprising five context-mechanism-outcome (CMO) configurations. Findings highlight how establishing psychological safety is foundational to productive Living Library events (CMO 1). For Readers, direct conversations humanise others' experiences (CMO 2) and provide the opportunity to flexibly explore new ways of living (CMO 3). Through participation in a Living Library, Books may experience personal empowerment (CMO 4), while the process of self-authoring and co-editing their story (CMO 5) can contribute to personal development. This programme theory informed the co-design of an implementation guide highlighting the importance of tailoring event design and participant support to the contexts in which LoLEM events are held. CONCLUSIONS: The LoLEM has appeal across stakeholder groups and can be applied flexibly in a range of mental health-related settings. Implementation and evaluation are required to better understand the positive and negative impacts on Books and Readers. TRIAL REGISTRATION NUMBER: PROSPERO CRD42022312789.

Current concepts: the hip, core and kinetic chain in the overhead athlete.

BACKGROUND: As overhead sports continue to grow in popularity, there has been increased interest in optimizing sports performance and injury prevention in these athletes. The hip, core, and kinetic chain have become a focus of research in recent decades, and their importance in upper extremity mechanics is now being recognized. METHODS: An extensive review was carried out to identify papers correlating the hip, core and/or kinetic chain in overhead athletic performance and injury. RESULTS: Recent literature has shown that efficiency and synchrony of the hips and core during an overhead movement (such as in baseball, golf, tennis, or volleyball) is essential for a powerful and precise execution of the task. Impairments of the hip and core, particularly abnormal joint mobility or weakness, can limit efficient energy transfer through the kinetic chain and may negatively impact performance. Recent epidemiologic studies have found hip pain to be common in adolescent, collegiate, and adult athletes. Moreover, hip pain in overhead athletes specifically has also been found to occur at a high rate. Abnormalities in hip range of motion, hip morphology, and core strength can lead to abnormal mechanics upstream in the kinetic chain, which may place athletes at risk of injuries. CONCLUSION: In this review, the complex and multifaceted relationship between the hip, core, and kinetic chain is highlighted with an emphasis on recent literature and relevant findings.

The impact of community teaching sessions on onward referral to specialist diabetic foot services.

INTRODUCTION: Prompt referral of patients with diabetic foot ulceration (DFU) to specialist services can lead to more timely assessment of these patients and subsequent improved rates of limb salvage and patient outcomes. In this study we wanted to determine the impact of education in the primary care setting on onward referrals to our specialist Diabetic Foot multi-disciplinary team (MDT) clinic. METHODS: As part of a Diabetic Foot Roadshow, four teaching sessions were delivered in primary care settings across Shropshire by our specialist team from 17th March to the 25th May 2022. Attendees included podiatrists, tissue viability nurses, district nurses and wound care practitioners. Hospital records were used to identify all onward referrals to our Diabetic Foot MDT clinic in the weeks before and after delivery of the roadshow education sessions. RESULTS: 184 referrals were made to the diabetic foot clinic from January to July 2022. There were 0.3 referrals per day in the months prior to the commencement of the education sessions, compared to 1.5 referrals per day following the commencement of the teaching sessions. This increase in referrals was statistically significant (p < 0.0001). CONCLUSION: Teaching sessions delivered to community specialist healthcare professionals significantly increase onward referral of patients to specialist services, facilitating more timely assessment and management of patients with DFUs.

How People With a Bipolar Disorder Diagnosis Talk About Personal Recovery in Peer Online Support Forums: Corpus Framework Analysis Using the POETIC Framework.

Background: Personal recovery is of particular value in bipolar disorder, where symptoms often persist despite treatment. We previously defined the POETIC (Purpose and Meaning, Optimism and Hope, Empowerment, Tensions, Identity, Connectedness) framework for personal recovery in bipolar disorder. So far, personal recovery has only been studied in researcher-constructed environments (eg, interviews and focus groups). Support forum posts can serve as a complementary naturalistic data resource to understand the lived experience of personal recovery. Objective: This study aimed to answer the question "What can online support forum posts reveal about the experience of personal recovery in bipolar disorder in relation to the POETIC framework?" Methods: By integrating natural language processing, corpus linguistics, and health research methods, this study analyzed public, bipolar disorder support forum posts relevant to the lived experience of personal recovery. By comparing 4462 personal recovery-relevant posts by 1982 users to 25,197 posts not relevant to personal recovery, we identified 130 significantly overused key lemmas. Key lemmas were coded according to the POETIC framework. Results: Personal recovery-related discussions primarily focused on 3 domains: "Purpose and meaning" (particularly reproductive decisions and work), "Connectedness" (romantic relationships and social support), and "Empowerment" (self-management and personal responsibility). This study confirmed the validity of the POETIC framework to capture personal recovery experiences shared on the web and highlighted new aspects beyond previous studies using interviews and focus groups. Conclusions: This study is the first to analyze naturalistic data on personal recovery in bipolar disorder. By indicating the key areas that people focus on in personal recovery when posting freely and the language they use, this study provides helpful starting points for formal and informal carers to understand the concerns of people diagnosed with a bipolar disorder and to consider how to best offer support.

Genomic structures and regulation patterns at HPV integration sites in cervical cancer.

Human papillomavirus (HPV) integration has been implicated in transforming HPV infection into cancer, but its genomic consequences have been difficult to study using short-read technologies. To resolve the dysregulation associated with HPV integration, we performed long-read sequencing on 63 cervical cancer genomes. We identified six categories of integration events based on HPV-human genomic structures. Of all HPV integrants, defined as two HPV-human breakpoints bridged by an HPV sequence, 24% contained variable copies of HPV between the breakpoints, a phenomenon we termed heterologous integration. Analysis of DNA methylation within and in proximity to the HPV genome at individual integration events revealed relationships between methylation status of the integrant and its orientation and structure. Dysregulation of the human epigenome and neighboring gene expression in cis with the HPV-integrated allele was observed over megabase-ranges of the genome. By elucidating the structural, epigenetic, and allele-specific impacts of HPV integration, we provide insight into the role of integrated HPV in cervical cancer.

A rational analysis and computational modeling perspective on IAM and déjà vu.

The proposed memory architecture by Barzykowski and Moulin is compelling, and could be improved by incorporating a rational analysis of the functional roles of involuntary autobiographical memory and déjà vu. Additionally, modeling these phenomena computationally would remove ambiguities from the proposal. We provide examples of past work that illustrate how the phenomena may be described more precisely.

The interplay between suicidal experiences, psychotic experiences and interpersonal relationships: a qualitative study.

BACKGROUND: Suicidal thoughts, acts, plans and deaths are considerably more prevalent in people with non-affective psychosis, including schizophrenia, compared to the general population. Social isolation and interpersonal difficulties have been implicated in pathways which underpin suicidal experiences in people with severe mental health problems. However, the interactions between psychotic experiences, such as hallucinations and paranoia, suicidal experiences, and the presence, and indeed, absence of interpersonal relationships is poorly understood and insufficiently explored. The current study sought to contribute to this understanding. METHODS: An inductive thematic analysis was conducted on transcripts of 22, individual, semi-structured interviews with adult participants who had both non-affective psychosis and recent suicidal experiences. A purposive sampling strategy was used. Trustworthiness of the analysis was assured with researcher triangulation. RESULTS: Participants relayed both positive and negative experiences of interpersonal relationships. A novel conceptual model is presented reflecting a highly complex interplay between a range of different suicidal experiences, psychosis, and aspects of interpersonal relationships. Three themes fed into this interplay, depicting dynamics between perceptions of i. not mattering and mattering, ii. becoming disconnected from other people, and iii. constraints versus freedom associated with sharing suicidal and psychotic experiences with others. CONCLUSION: This study revealed a detailed insight into ways in which interpersonal relationships are perceived to interact with psychotic and suicidal experiences in ways that can be both beneficial and challenging. This is important from scientific and clinical perspectives for understanding the complex pathways involved in suicidal experiences. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03114917), 14th April 2017. ISRCTN (reference ISRCTN17776666 .); 5th June 2017). Registration was recorded prior to participant recruitment commencing.

Impact of Ivermectin on the Gut Microbial Ecosystem.

Ivermectin is a an anti-helminthic that is critical globally for both human and veterinary care. To the best of our knowledge, information available regarding the influence of ivermectin (IVM) on the gut microbiota has only been collected from diseased donors, who were treated with IVM alone or in combination with other medicines. Results thus obtained were influenced by multiple elements beyond IVM, such as disease, and other medical treatments. The research presented here investigated the impact of IVM on the gut microbial structure established in a Triple-SHIME® (simulator of the human intestinal microbial ecosystem), using fecal material from three healthy adults. The microbial communities were grown using three different culture media: standard SHIME media and SHIME media with either soluble or insoluble fiber added (control, SF, ISF). IVM introduced minor and temporary changes to the gut microbial community in terms of composition and metabolite production, as revealed by 16S rRNA amplicon sequencing analysis, flow cytometry, and GC-MS. Thus, it was concluded that IVM is not expected to induce dysbiosis or yield adverse effects if administered to healthy adults. In addition, the donor's starting community influences the relationship between IVM and the gut microbiome, and the soluble fiber component in feed could protect the gut microbiota from IVM; an increase in short-chain fatty acid production was predicted by PICRUSt2 and detected with IVM treatment.

Assembly and annotation of the black spruce genome provide insights on spruce phylogeny and evolution of stress response.

Black spruce (Picea mariana [Mill.] B.S.P.) is a dominant conifer species in the North American boreal forest that plays important ecological and economic roles. Here, we present the first genome assembly of P. mariana with a reconstructed genome size of 18.3 Gbp and NG50 scaffold length of 36.0 kbp. A total of 66,332 protein-coding sequences were predicted in silico and annotated based on sequence homology. We analyzed the evolutionary relationships between P. mariana and 5 other spruces for which complete nuclear and organelle genome sequences were available. The phylogenetic tree estimated from mitochondrial genome sequences agrees with biogeography; specifically, P. mariana was strongly supported as a sister lineage to P. glauca and 3 other taxa found in western North America, followed by the European Picea abies. We obtained mixed topologies with weaker statistical support in phylogenetic trees estimated from nuclear and chloroplast genome sequences, indicative of ancient reticulate evolution affecting these 2 genomes. Clustering of protein-coding sequences from the 6 Picea taxa and 2 Pinus species resulted in 34,776 orthogroups, 560 of which appeared to be specific to P. mariana. Analysis of these specific orthogroups and dN/dS analysis of positive selection signatures for 497 single-copy orthogroups identified gene functions mostly related to plant development and stress response. The P. mariana genome assembly and annotation provides a valuable resource for forest genetics research and applications in this broadly distributed species, especially in relation to climate adaptation.