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The 2023 wildfire season in Canada was unprecedented in its scale and intensity, spanning from mid-April to late October and across much of the forested regions of Canada. Here, we summarize the main causes and impacts of this exceptional season. The record-breaking total area burned (~15 Mha) can be attributed to several environmental factors that converged early in the season: early snowmelt, multiannual drought conditions in western Canada, and the rapid transition to drought in eastern Canada. Anthropogenic climate change enabled sustained extreme fire weather conditions, as the mean May-October temperature over Canada in 2023 was 2.2 °C warmer than the 1991-2020 average. The impacts were profound with more than 200 communities evacuated, millions exposed to hazardous air quality from smoke, and unmatched demands on fire-fighting resources. The 2023 wildfire season in Canada not only set new records, but highlights the increasing challenges posed by wildfires in Canada.
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Wildfire is an important natural disturbance agent in Canadian forests, but it has also caused significant economic damage nationwide. Spatial fire growth models have emerged as important tools for representing wildfire dynamics across diverse landscapes, enabling the mapping of key wildfire hazard metrics such as location-specific burn probabilities or likelihoods of fire ignition. While these summary metrics have gained popularity, they often fall short in capturing the directional spread of wildfires and their potential spread distances. The metrics depicting the directional spread of wildfire can be derived from raw outputs generated with fire growth models, such as the perimeters and ignition locations of individual fires, but extracting this information requires complex data processing. To address this data gap, we present PostBP, an open-source Python package designed for post-processing the raw outputs of fire growth models - the ignition locations and perimeters of individual fires simulated over multiple stochastic iterations - into a matrix of fire spread likelihoods between all pairs of forest patches in a landscape. The PostBP also generates several other summary outputs, such as the source-sink ratio and the fire spread rose diagram. We provide an overview of PostBP's capabilities and demonstrate its practical application to a forested landscape.â¢Wildfire growth models generate large amounts of outputs, which are hard to summarize for practical decision-making.â¢The PostBP package calculates the summary metrics characterizing the directional spread of wildfires.â¢The fire risk summaries generated with PostBP can support the assessments of wildfire risk and mitigation measures.
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Satellite data are effective for mapping wildfires, particularly in remote locations where monitoring is rare. Geolocated fire detections can be used for enhanced fire management and fire modelling through daily fire progression mapping. Here we present the Canadian Fire Spread Dataset (CFSDS), encompassing interpolated progressions for fires >1,000 ha in Canada from 2002-2021, representing the day-of-burning and 50 environmental covariates for every pixel. Day-of-burning was calculated by ordinary kriging of active fire detections from the Moderate Resolution Imaging Spectroradiometer and the Visible Infrared Imaging Radiometer Suite, enabling a substantial improvement in coverage and resolution over existing datasets. Day of burning at each pixel was used to identify environmental conditions of burning such as daily weather, derived weather metrics, topography, and forest fuels characteristics. This dataset can be used in a broad range of research and management applications, such as retrospective analysis of fire spread, as a benchmark dataset for validating statistical or machine-learning models, and for forecasting the effects of climate change on fire activity.
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Sensitization of spinal nociceptive circuits plays a crucial role in neuropathic pain. This sensitization depends on new gene expression that is primarily regulated via transcriptional and translational control mechanisms. The relative roles of these mechanisms in regulating gene expression in the clinically relevant chronic phase of neuropathic pain are not well understood. Here, we show that changes in gene expression in the spinal cord during the chronic phase of neuropathic pain are substantially regulated at the translational level. Downregulating spinal translation at the chronic phase alleviated pain hypersensitivity. Cell-type-specific profiling revealed that spinal inhibitory neurons exhibited greater changes in translation after peripheral nerve injury compared to excitatory neurons. Notably, increasing translation selectively in all inhibitory neurons or parvalbumin-positive (PV+) interneurons, but not excitatory neurons, promoted mechanical pain hypersensitivity. Furthermore, increasing translation in PV+ neurons decreased their intrinsic excitability and spiking activity, whereas reducing translation in spinal PV+ neurons prevented the nerve injury-induced decrease in excitability. Thus, translational control mechanisms in the spinal cord, particularly in inhibitory neurons, play a role in mediating neuropathic pain hypersensitivity.
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The introduction of sex-as-a-biological-variable policies at funding agencies around the world has led to an explosion of very recent observations of sex differences in the biology underlying pain. This review considers evidence of sexually dimorphic mechanisms mediating pain hypersensitivity, derived from modern assays of persistent pain in rodent animal models. Three well-studied findings are described in detail: the male-specific role of spinal cord microglia, the female-specific role of calcitonin gene-related peptide (CGRP), and the female-specific role of prolactin and its receptor. Other findings of sex-specific molecular involvement in pain are subjected to pathway analyses and reveal at least one novel hypothesis: that females may preferentially use Th1 and males Th2 T cell activity to mediate chronic pain.
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Caracteres Sexuais , Animais , Humanos , Feminino , Masculino , Medula Espinal/fisiopatologia , Medula Espinal/metabolismo , Dor/fisiopatologia , Dor/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Hiperalgesia/fisiopatologia , Microglia/metabolismo , Microglia/fisiologia , Prolactina/metabolismoRESUMO
BACKGROUND: Chronic post-surgical pain (CPSP) significantly impacts patients' recovery and quality of life. Although environmental risk factors are well-established, genetic risk remains less understood. METHODS: A meta-analysis of genome-wide association studies followed by partitioned heritability was performed on 1350 individuals across five surgery types: hysterectomy, mastectomy, abdominal, hernia, and knee. In subsequent animal studies, withdrawal thresholds to evoked mechanical stimulation were measured in Rag1 null mutant and wild-type mice after plantar incision and laparotomy. Cell sorting by flow cytometry tracked recruitment of immune cell types. RESULTS: We discovered 77 genome-wide significant single-nucleotide polymorphism (SNP) hits, distributed among 24 loci and 244 genes. Meta-analysis of all cohorts estimated a SNP-based narrow-sense heritability for CPSP at â¼39%, indicating a substantial genetic contribution. Partitioned heritability analysis across a wide variety of tissues revealed enrichment of heritability in immune system-related genes, particularly those associated with B and T cells. Rag1 null mutant mice lacking both T and B cells exhibited exacerbated and prolonged allodynia up to 42 days after surgery, which was rescued by B-cell transfer. Recruitment patterns of B cells but not T cells differed significantly during the first 7 days after injury in the footpad, lymph nodes, and dorsal root ganglia. CONCLUSIONS: These findings suggest a key protective role for the adaptive immune system in the development of chronic post-surgical pain.
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Linfócitos B , Dor Crônica , Estudo de Associação Genômica Ampla , Dor Pós-Operatória , Animais , Feminino , Humanos , Masculino , Camundongos , Linfócitos B/imunologia , Dor Crônica/genética , Modelos Animais de Doenças , Hiperalgesia/genética , Camundongos Knockout , Dor Pós-Operatória/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Recently burned boreal forests have lower aboveground fuel loads, generating a negative feedback to subsequent wildfires. Despite this feedback, short-interval reburns (≤20 years between fires) are possible under extreme weather conditions. Reburns have consequences for ecosystem recovery, leading to enduring vegetation change. In this study, we characterize the strength of the fire-fuel feedback in recently burned Canadian boreal forests and the weather conditions that overwhelm resistance to fire spread in recently burned areas. We used a dataset of daily fire spread for thousands of large boreal fires, interpolated from remotely sensed thermal anomalies to which we associated local weather from ERA5-Land for each day of a fire's duration. We classified days with >3 ha of fire growth as spread days and defined burned pixels overlapping a fire perimeter ≤20 years old as short-interval reburns. Results of a logistic regression showed that the odds of fire spread in recently burned areas were ~50% lower than in long-interval fires; however, all Canadian boreal ecozones experienced short-interval reburning (1981-2021), with over 100,000 ha reburning annually. As fire weather conditions intensify, the resistance to fire spread declines, allowing fire to spread in recently burned areas. The weather associated with short-interval fire spread days was more extreme than the conditions during long-interval spread, but overall differences were modest (e.g. relative humidity 2.6% lower). The frequency of fire weather conducive to short-interval fire spread has significantly increased in the western boreal forest due to climate warming and drying (1981-2021). Our results suggest an ongoing degradation of fire-fuel feedbacks, which is likely to continue with climatic warming and drying.
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Florestas , Tempo (Meteorologia) , Incêndios Florestais , Incêndios Florestais/prevenção & controle , Incêndios Florestais/estatística & dados numéricos , Mudança Climática , Aquecimento GlobalRESUMO
G protein-coupled receptor 37-like 1 (GPR37L1) is an orphan GPCR with largely unknown functions. Here, we report that Gpr37l1/GRP37L1 ranks among the most highly expressed GPCR transcripts in mouse and human dorsal root ganglia (DRGs) and is selectively expressed in satellite glial cells (SGCs). Peripheral neuropathy induced by streptozotoxin (STZ) and paclitaxel (PTX) led to reduced GPR37L1 expression on the plasma membrane in mouse and human DRGs. Transgenic mice with Gpr37l1 deficiency exhibited impaired resolution of neuropathic pain symptoms following PTX- and STZ-induced pain, whereas overexpression of Gpr37l1 in mouse DRGs reversed pain. GPR37L1 is coexpressed with potassium channels, including KCNJ10 (Kir4.1) in mouse SGCs and both KCNJ3 (Kir3.1) and KCNJ10 in human SGCs. GPR37L1 regulates the surface expression and function of the potassium channels. Notably, the proresolving lipid mediator maresin 1 (MaR1) serves as a ligand of GPR37L1 and enhances KCNJ10- or KCNJ3-mediated potassium influx in SGCs through GPR37L1. Chemotherapy suppressed KCNJ10 expression and function in SGCs, which MaR1 rescued through GPR37L1. Finally, genetic analysis revealed that the GPR37L1-E296K variant increased chronic pain risk by destabilizing the protein and impairing the protein's function. Thus, GPR37L1 in SGCs offers a therapeutic target for the protection of neuropathy and chronic pain.
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Ácidos Docosa-Hexaenoicos , Gânglios Espinais , Neuroglia , Receptores Acoplados a Proteínas G , Transdução de Sinais , Animais , Humanos , Masculino , Camundongos , Gânglios Espinais/metabolismo , Homeostase , Camundongos Knockout , Camundongos Transgênicos , Neuralgia/metabolismo , Neuralgia/genética , Neuralgia/patologia , Neuroglia/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/genética , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismoRESUMO
Background: A clear understanding of the connectivity, structure, and composition of wildland fuels is essential for effective wildfire management. However, fuel typing and mapping are challenging owing to a broad diversity of fuel conditions and their spatial and temporal heterogeneity. In Canada, fuel types and potential fire behavior are characterized using the Fire Behavior Prediction (FBP) System, which uses an association approach to categorize vegetation into 16 fuel types based on stand structure and composition. In British Columbia (BC), provincial and national FBP System fuel type maps are derived from remotely sensed forest inventory data and are widely used for wildfire operations, fuel management, and scientific research. Despite their widespread usage, the accuracy and applicability of these fuel type maps have not been formally assessed. To address this knowledge gap, we quantified the agreement between on-site assessments and provincial and national fuel type maps in interior BC. Results: We consistently found poor correspondence between field assessment data and both provincial and national fuel types. Mismatches were particularly frequent for (i) dry interior ecosystems, (ii) mixedwood and deciduous fuel types, and (iii) post-harvesting conditions. For 58% of field plots, there was no suitable match to the extant fuel structure and composition. Mismatches were driven by the accuracy and availability of forest inventory data and low applicability of the Canadian FBP System to interior BC fuels. Conclusions: The fuel typing mismatches we identified can limit scientific research, but also challenge wildfire operations and fuel management decisions. Improving fuel typing accuracy will require a significant effort in fuel inventory data and system upgrades to adequately represent the diversity of extant fuels. To more effectively link conditions to expected fire behavior outcomes, we recommend a fuel classification approach and emphasis on observed fuels and measured fire behavior data for the systems we seek to represent. Supplementary Information: The online version contains supplementary material available at 10.1186/s42408-024-00249-z.
Antecedentes: Un entendimiento claro sobre la conectividad, estructura, y composición de los combustibles vegetales es esencial para un manejo efectivo de los incendios de vegetación. Sin embargo, la tipificación y mapeo de los combustibles son aspectos desafiantes debido a la amplia diversidad de las condiciones de los combustibles y su variabilidad espacial y temporal. En Canadá, los tipos de combustibles y el comportamiento potencial del fuego están caracterizados por el uso del Sistema de Predicción del Comportamiento del Fuego (Fire Behavior Prediction System, FBP), el cual usa una "aproximación asociada" para categorizar la vegetación en 16 tipos de combustibles basados en la estructura y composición de los rodales. En la Columbia Británica (BC) los mapas del sistema provincial y nacional de FBP son derivados de datos de inventarios tomados mediante sensores remotos, que son ampliamente usados para operaciones de incendios de vegetación, manejo de combustibles, e investigación científica. A pesar de su amplio uso, la exactitud y aplicabilidad de esos mapas de tipos de combustibles no han sido adecuadamente comprobadas. Para determinar este vacío en el conocimiento, cuantificamos la concordancia entre las determinaciones in situ y los mapas de combustibles provinciales y nacionales en el interior de BC. Resultados: Encontramos consistentemente una pobre correspondencia entre las determinaciones de los datos de campo y los tipos de combustibles provinciales y nacionales. Los desfasajes fueron particularmente frecuentes para: i) los ecosistemas secos del interior, ii) bosques mixtos y tipos de combustibles en bosques deciduos, y iii) condiciones de postcosecha. Para el 58% de las parcelas a campo, no hubo una concordancia adecuada entre la estructura y composición existentes. Estos desajustes fueron derivados de la exactitud y disponibilidad de datos del inventario forestal, y la baja aplicabilidad del Sistema FBP a los combustibles del interior de la Columba Británica. Conclusiones: Los desajustes en la determinación de los tipos de combustibles que nosotros identificamos pueden limitar la investigación científica, pero también es un desafío para las decisiones en las operaciones de incendios y en el manejo de los combustibles. El mejoramiento de la exactitud en la determinación de tipos de combustibles requerirá de un esfuerzo significativo en el inventario de datos y sistemas mejorados para representar adecuadamente la diversidad de los combustibles existentes. Para ligar más efectivamente las condiciones a los resultados del comportamiento, recomendamos una aproximación a la clasificación de los combustibles y énfasis en datos de los combustibles observados y del comportamiento medido para los sistemas que pretendemos representar.
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ABSTRACT: Temporomandibular disorders (TMDs), collectively representing one of the most common chronic pain conditions, have a substantial genetic component, but genetic variation alone has not fully explained the heritability of TMD risk. Reasoning that the unexplained heritability may be because of DNA methylation, an epigenetic phenomenon, we measured genome-wide DNA methylation using the Illumina MethylationEPIC platform with blood samples from participants in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. Associations with chronic TMD used methylation data from 496 chronic painful TMD cases and 452 TMD-free controls. Changes in methylation between enrollment and a 6-month follow-up visit were determined for a separate sample of 62 people with recent-onset painful TMD. More than 750,000 individual CpG sites were examined for association with chronic painful TMD. Six differentially methylated regions were significantly ( P < 5 × 10 -8 ) associated with chronic painful TMD, including loci near genes involved in the regulation of inflammatory and neuronal response. A majority of loci were similarly differentially methylated in acute TMD consistent with observed transience or persistence of symptoms at follow-up. Functional characterization of the identified regions found relationships between methylation at these loci and nearby genetic variation contributing to chronic painful TMD and with gene expression of proximal genes. These findings reveal epigenetic contributions to chronic painful TMD through methylation of the genes FMOD , PM20D1 , ZNF718 , ZFP57 , and RNF39 , following the development of acute painful TMD. Epigenetic regulation of these genes likely contributes to the trajectory of transcriptional events in affected tissues leading to resolution or chronicity of pain.
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Dor Crônica , Transtornos da Articulação Temporomandibular , Humanos , Epigênese Genética/genética , Dor Facial , Dor Crônica/genética , Dor Crônica/complicações , Doença Crônica , MetilaçãoRESUMO
G protein coupled receptor 37-like 1 (GPR37L1) is an orphan GPCR and its function remains largely unknown. Here we report that GPR37L1 transcript is highly expressed compared to all known GPCRs in mouse and human dorsal root ganglia (DRGs) and selectively expressed in satellite glial cells (SGCs). Peripheral neuropathy following diabetes and chemotherapy by streptozotocin and paclitaxel resulted in downregulations of surface GPR37L1 in mouse and human DRGs. Transgenic mice with Gpr37l1 deficiency exhibited impaired resolution of neuropathic pain symptom (mechanical allodynia), whereas overexpression of Gpr37l1 in mouse DRGs can reverse neuropathic pain. Notably, GPR37L1 is co-expressed and coupled with potassium channels in SGCs. We found striking species differences in potassium channel expression in SGCs, with predominant expression of KCNJ10 and KCNJ3 in mouse and human SGCs, respectively. GPR37L1 regulates the surface expression and function of KCNJ10 and KCNJ3. We identified the pro-resolving lipid mediator maresin 1 (MaR1) as a GPR37L1 ligand. MaR1 increases KCNJ10/KCNJ3-mediated potassium influx in SGCs via GPR37L1. MaR1 protected chemotherapy-induced suppression of KCNJ13/KCNJ10 expression and function in SGCs. Finally, genetic analysis revealed that the GPR37L1-E296K variant is associated with increased chronic pain risk by destabilizing the protein. Thus, GPR37L1 in SGCs offers a new target for neuropathy protection and pain control.
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Chronic pain is a complex condition influenced by a combination of biological, psychological and social factors. Using data from the UK Biobank (n = 493,211), we showed that pain spreads from proximal to distal sites and developed a biopsychosocial model that predicted the number of coexisting pain sites. This data-driven model was used to identify a risk score that classified various chronic pain conditions (area under the curve (AUC) 0.70-0.88) and pain-related medical conditions (AUC 0.67-0.86). In longitudinal analyses, the risk score predicted the development of widespread chronic pain, the spreading of chronic pain across body sites and high-impact pain about 9 years later (AUC 0.68-0.78). Key risk factors included sleeplessness, feeling 'fed-up', tiredness, stressful life events and a body mass index >30. A simplified version of this score, named the risk of pain spreading, obtained similar predictive performance based on six simple questions with binarized answers. The risk of pain spreading was then validated in the Northern Finland Birth Cohort (n = 5,525) and the PREVENT-AD cohort (n = 178), obtaining comparable predictive performance. Our findings show that chronic pain conditions can be predicted from a common set of biopsychosocial factors, which can aid in tailoring research protocols, optimizing patient randomization in clinical trials and improving pain management.
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Dor Crônica , Humanos , Dor Crônica/epidemiologia , Prognóstico , Doença Crônica , Fatores de Risco , Manejo da Dor/métodosRESUMO
Although broadleaf tree species of the boreal biome have a lower flammability compared to conifers, there is a period following snow melt and prior to leaf flush (i.e., greenup), termed the "spring window" by fire managers, when these forests are relatively conducive to wildfire ignition and spread. The goal of this study was to characterize the duration, timing, and fire proneness of the spring window across boreal Canada and assess the link between these phenological variables and the incidence of springtime wildfires. We used remotely sensed snow cover and greenup data to identify the annual spring window for five boreal ecozones from 2001 to 2021 and then compared seasonality of wildfire starts (by cause) and fire-conducive weather in relation to this window, averaged over the 21-year period. We conducted a path analysis to concomitantly evaluate the influence of the spring window's duration, the timing of greenup, and fire-conducive weather on the annual number and the seasonality of spring wildfires. Results show that the characteristics of spring windows vary substantially from year to year and among geographic zones, with the interior west of Canada having the longest and most fire-conducive spread window and, accordingly, the greatest springtime wildfire activity. We also provide support for the belief that springtime weather generally promotes wind-driven, rather than drought-driven wildfires. The path analyses show idiosyncratic behavior among ecozones, but, in general, the seasonality of the wildfire season is mainly driven by the timing of the greenup, whereas the number of spring wildfires mostly responds to the duration of the spring window and the frequency of fire-conducive weather. The results of this study allows us to better understand and anticipate the biome-wide changes projected for the northern forests of North America.
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Incêndios , Incêndios Florestais , Árvores , Canadá , FlorestasRESUMO
Traumatic brain injuries following motor vehicle collisions (MVCs) are ubiquitous. Surprisingly, there are no correlates between concussion impact force and long-term pain outcomes. To study the molecular underpinnings of chronic pain after MVC, we assembled a prospective cohort of 36 subjects that experienced MVC and suffered documented mild traumatic brain injuries. For each participant, a first blood sample was drawn within 72 hours of the collision, then a second one at the 6-month mark. Pain was also assessed at the second blood draw to determine if pain became chronic or resolved. Blood samples enabled transcriptomics analyses for immune cells. At the transcriptome-wide level, we found that Sterile Alpha Motif Domain Containing 15 (SAMD15) mRNA was significantly upregulated with time in subjects who resolved their pain whereas unregulated in those with persistent pain. Using several large publicly available datasets, such as the UK Biobank and the GTeX portal, we then linked elevated SAMD15 gene expression, elevated neutrophils cell counts, and decreased risk for chronic pain to increased dosage of the T allele at SNP rs4903580, situated within SAMD15's gene locus. The causality between the components of our model was established and supported by Mendelian randomization. Overall, our results support the role of SAMD15 as a potential gene effector for neutrophil-dependent chronic pain development. PERSPECTIVE: This article highlights the potential protective role of the SAMD15 gene against chronic pain following a mild traumatic brain injury. The expression of the gene is associated with a SNP rs4903580, which is itself associated with neutrophils counts as well as chronic pain in large genetic studies.
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Concussão Encefálica , Dor Crônica , Humanos , Dor Crônica/genética , Estudos Prospectivos , Transcriptoma , Motivo Estéril alfa , Veículos AutomotoresRESUMO
Chronic post-surgical pain affects a large proportion of people undergoing surgery, delaying recovery time and worsening quality of life. Although many environmental variables have been established as risk factors, less is known about genetic risk. To uncover genetic risk factors we performed genome-wide association studies in post-surgical cohorts of five surgery types- hysterectomy, mastectomy, abdominal, hernia, and knee- totaling 1350 individuals. Genetic associations between post-surgical chronic pain levels on a numeric rating scale (NRS) and additive genetic effects at common SNPs were evaluated. We observed genome-wide significant hits in almost all cohorts that displayed significance at the SNP, gene, and pathway levels. The cohorts were then combined via a GWAS meta-analysis framework for further analyses. Using partitioned heritability, we found that loci at genes specifically expressed in the immune system carried enriched heritability, especially genes related to B and T cells. The relevance of B cells in particular was then demonstrated in mouse postoperative pain assays. Taken altogether, our results suggest a role for the adaptive immune system in chronic post-surgical pain.
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ABSTRACT: Chronic pain is a prevalent disease with increasing clinical challenges. Genome-wide association studies in chronic pain patients have identified hundreds of common pathogenic variants, yet they only explained a portion of individual variance of chronic pain. With the advances in next-generation sequencing technologies, it is now feasible to conduct rarer variants studies in large-scale databases. Here, we performed gene-based rare variant analyses in 200,000 human subjects in the UK biobank whole-exome sequencing database for investigating 9 different chronic pain states and validated our findings in 3 other large-scale databases. Our analyses identified the SLC13A1 gene coding for sodium/sulfate symporter associated with chronic back pain and multisite pain at the genome-wide level and with chronic headache, knee, and neck and shoulder pain at the nominal level. Seven loss-of-function rare variants were identified within the gene locus potentially contributing to the development of chronic pain, with 2 of them individually associated with back pain and multisite pain. These 2 rare variants were then tested for replication in 3 other biobanks, and the strongest evidence was found for rs28364172 as an individual contributor. Transcriptional analyses of Slc13a1 in rodents showed substantial regulation of its expression in the dorsal root ganglia and the sciatic nerve in neuropathic pain assays. Our results stress the importance of the SLC13A1 gene in sulfate homeostasis in the nervous system and its critical role in preventing pain states, thus suggesting new therapeutic approaches for treating chronic pain in a personalized manner, especially in people with mutations in the SLC13A1 gene.
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Dor Crônica , Neuralgia , Simportadores , Humanos , Dor Crônica/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , SulfatosRESUMO
Introduction: Back pain is the leading cause of disability worldwide. Although most back pain cases are acute, 20% of acute pain patients experience chronic back pain symptoms. It is unclear whether acute pain and chronic pain have similar or distinct underlying genetic mechanisms. Objectives: To characterize the molecular and cellular pathways contributing to acute and chronic pain states. Methods: Cross-sectional observational genome-wide association study. Results: A total of 375,158 individuals from the UK Biobank cohort were included in the discovery of genome-wide association study. Of those, 70,633 (19%) and 32,209 (9%) individuals met the definition of chronic and acute back pain, respectively. A total of 355 single nucleotide polymorphism grouped into 13 loci reached the genome-wide significance threshold (5x10-8) for chronic back pain, but none for acute. Of these, 7 loci were replicated in the Nord-Trøndelag Health Study (HUNT) cohort (19,760 chronic low back pain cases and 28,674 pain-free controls). Single nucleotide polymorphism heritability was 4.6% (P=1.4x10-78) for chronic back pain and 0.81% (P=1.4x10-8) for acute back pain. Similar differences in heritability estimates between acute and chronic back pain were found in the HUNT cohort: 3.4% (P=0.0011) and 0.6% (P=0.851), respectively. Pathway analyses, tissue-specific heritability enrichment analyses, and epigenetic characterization suggest a substantial genetic contribution to chronic but not acute back pain from the loci predominantly expressed in the central nervous system. Conclusion: Chronic back pain is substantially more heritable than acute back pain. This heritability is mostly attributed to genes expressed in the brain.
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Enteric helminths form intimate physical connections with the intestinal epithelium, yet their ability to directly alter epithelial stem cell fate has not been resolved. Here we demonstrate that infection of mice with the parasite Heligmosomoides polygyrus bakeri (Hpb) reprograms the intestinal epithelium into a fetal-like state marked by the emergence of Clusterin-expressing revival stem cells (revSCs). Organoid-based studies using parasite-derived excretory-secretory products reveal that Hpb-mediated revSC generation occurs independently of host-derived immune signals and inhibits type 2 cytokine-driven differentiation of secretory epithelial lineages that promote their expulsion. Reciprocally, type 2 cytokine signals limit revSC differentiation and, consequently, Hpb fitness, indicating that helminths compete with their host for control of the intestinal stem cell compartment to promote continuation of their life cycle.