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Amiloidosis , Artritis Reumatoide , Edema , Nefritis Lúpica , Proteinuria , Anciano , Femenino , Humanos , Diagnóstico Diferencial , Edema/diagnóstico , Edema/tratamiento farmacológico , Edema/etiología , Riñón/patología , Riñón/diagnóstico por imagen , Proteinuria/diagnóstico , Proteinuria/tratamiento farmacológico , Proteinuria/etiología , Dolor Abdominal/diagnóstico , Dolor Abdominal/etiología , Fiebre/diagnóstico , Fiebre/etiología , Mano/diagnóstico por imagen , Biopsia con Aguja Gruesa , Nefritis Lúpica/complicaciones , Nefritis Lúpica/diagnóstico , Nefritis Lúpica/patología , Amiloidosis/sangre , Amiloidosis/diagnóstico , Amiloidosis/tratamiento farmacológico , Artritis Reumatoide/sangre , Artritis Reumatoide/complicaciones , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/tratamiento farmacológico , Proteína Amiloide A Sérica/análisis

RESUMEN

BACKGROUNDMetastatic hormone-sensitive prostate cancer (mHSPC) is androgen dependent, and its treatment includes androgen deprivation therapy (ADT) with gonadal testosterone suppression. Since 2014, overall survival (OS) has been prolonged with addition of other systemic therapies, such as adrenal androgen synthesis blockers, potent androgen receptor blockers, or docetaxel, to ADT. HSD3B1 encodes the rate-limiting enzyme for nongonadal androgen synthesis, 3ß-hydroxysteroid dehydrogenase-1, and has a common adrenal-permissive missense-encoding variant that confers increased synthesis of potent androgens from nongonadal precursor steroids and poorer prostate cancer outcomes.METHODSOur prespecified hypothesis was that poor outcome associated with inheritance of the adrenal-permissive HSD3B1 allele with ADT alone is reversed in patients with low-volume (LV) mHSPC with up-front ADT plus addition of androgen receptor (AR) antagonists to inhibit the effect of adrenal androgens. HSD3B1 genotype was obtained in 287 patients with LV disease treated with ADT + AR antagonist only in the phase III Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer (ENZAMET) trial and was associated with clinical outcomes.RESULTSPatients who inherited the adrenal-permissive HSD3B1 allele had more favorable 5-year clinical progression-free survival and OS when treated with ADT plus enzalutamide or ADT plus nonsteroidal antiandrogen compared with their counterparts who did not have adrenal-permissive HSD3B1 inheritance. HSD3B1 was also associated with OS after accounting for known clinical variables. Patients with both genotypes benefited from early enzalutamide.CONCLUSIONThese data demonstrated an inherited physiologic driver of prostate cancer mortality is associated with clinical outcomes and is potentially pharmacologically reversible.FUNDINGNational Cancer Institute, NIH; Department of Defense; Prostate Cancer Foundation, Australian National Health and Medical Research Council.

Asunto(s)

Complejos Multienzimáticos , Progesterona Reductasa , Neoplasias de la Próstata , Esteroide Isomerasas , Masculino , Humanos , Progesterona Reductasa/genética , Progesterona Reductasa/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Esteroide Isomerasas/genética , Anciano , Complejos Multienzimáticos/genética , Persona de Mediana Edad , Antagonistas de Andrógenos/uso terapéutico , Benzamidas , Metástasis de la Neoplasia , Nitrilos , Feniltiohidantoína/uso terapéutico , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/antagonistas & inhibidores , Tasa de Supervivencia , Glándulas Suprarrenales/patología , Glándulas Suprarrenales/metabolismo

RESUMEN

The American Indian Enculturation Scale (AIES) was developed for American Indian populations to measure connection to traditional culture, but it has not been evaluated in Alaska Native people. While American Indian and Alaska Native individuals are grouped together, significant differences exist between groups. As a part of a randomized controlled trial for contingency management to reduce alcohol use, 160 Alaska Native adults completed the AIES. The confirmatory factor analysis indicated that a one-factor, 15-item version of the AIES, removing items 1 and 2 and correlating items 8 and 10, was a reliable (15 items; α = 0.896) and valid measure in this sample (χ2 [89] = 155.788, p<.001; CFI = 0.903; TLI = 0.886; RMSEA = 0.068 [90% confidence interval {CI} 0.050-0.086]; p<.001; SRMR = 0.060). The study provides limited evidence of enculturation's structural validity, as measured by the AIES, for Alaska Native adults. Future confirmatory work and potential adaptation is needed to evaluate the empirical utility of the AIES for Alaska Native individuals seeking help to reduce alcohol use.

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BACKGROUND: Higher cruciferous vegetable intake is associated with lower cardiovascular disease risk in observational studies. The pathways involved remain uncertain. We aimed to determine whether cruciferous vegetable intake (active) lowers 24-h brachial systolic blood pressure (SBP; primary outcome) compared to root and squash vegetables (control) in Australian adults with mildly elevated BP (SBP 120-160 mmHg inclusive). METHODS: In this randomized, controlled, crossover trial, participants completed two 2-week dietary interventions separated by a 2-week washout. Cruciferous vegetables were compared to root and squash vegetables (~ 300 g/day) consumed with lunch and dinner meals. Participants were blinded to which interventions were the active and control. Adherence was assessed using food diaries and biomarkers (S-methyl cysteine sulfoxide (SMCSO, active) and carotenoids (control)). Twenty-four-hour brachial ambulatory SBP and secondary outcomes were assessed pre- and post each intervention. Differences were tested using linear mixed effects regression. RESULTS: Eighteen participants were recruited (median (IQR) age: 68 (66-70); female: n = 16/18; mean ± SD clinic SBP: 135.9 ± 10.0 mmHg). For both interventions, 72% participants had 100% adherence (IQR: 96.4-100%). SMCSO and carotenoids were significantly different between interventions (mean difference active vs. control SMCSO: 22.93 mg/mL, 95%CI 15.62, 30.23, P < 0.0001; carotenoids: - 0.974 mg/mL, 95%CI - 1.525, - 0.423, P = 0.001). Twenty-four-hour brachial SBP was significantly reduced following the active vs. control (mean difference - 2.5 mmHg, 95%CI - 4.2, - 0.9, P = 0.002; active pre: 126.8 ± 12.6 mmHg, post: 124.4 ± 11.8 mmHg; control pre: 125.5 ± 12.1 mmHg, post: 124.8 ± 13.1 mmHg, n = 17), driven by daytime SBP (mean difference - 3.6 mmHg, 95%CI - 5.4, - 1.7, P < 0.001). Serum triglycerides were significantly lower following the active vs. control (mean difference - 0.2 mmol/L, 95%CI - 0.4, - 0.0, P = 0.047). CONCLUSIONS: Increased intake of cruciferous vegetables resulted in reduced SBP compared to root and squash vegetables. Future research is needed to determine whether targeted recommendations for increasing cruciferous vegetable intake benefits population health. TRIAL REGISTRATION: Clinical trial registry ACTRN12619001294145.  https://www.anzctr.org.au.

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Presión Sanguínea , Estudios Cruzados , Verduras , Humanos , Femenino , Masculino , Presión Sanguínea/fisiología , Presión Sanguínea/efectos de los fármacos , Anciano , Australia , Persona de Mediana Edad , Hipertensión/dietoterapia , Hipertensión/fisiopatología

RESUMEN

OBJECTIVES: Technology has the potential to increase access to evidence-based insomnia treatment. Patient preferences/perceptions of automated digital cognitive behavior therapy for insomnia (CBTI) and telehealth-delivered CBTI remain largely unexplored among middle-aged and older adults. Using a qualitative approach, the current study describes patients' reasons for participating in the clinical trial, preferences for digital CBTI (dCBTI) versus therapist-led CBTI, patient attitudes toward dCBTI, and patient attitudes toward telehealth-delivered therapist-led CBTI. METHOD: Middle-aged and older adults (N = 80) completed a semi-structured interview before CBTI exposure. Qualitative responses were coded, and themes were inductively extracted. RESULTS: Most (62.5%) of the participants expressed a preference for therapist-led CBTI to dCBTI. Convenience was the most commonly reported advantage of dCBTI (n = 55) and telehealth-delivered CBTI (n = 65). Decreasing transit time and pandemic-related health concerns were identified as advantages to dCBTI and telehealth-delivered CBTI. Lack of human connection and limited personalization were perceived as disadvantages of dCBTI. Only three participants reported technological barriers to dCBTI and telehealth-delivered CBTI. CONCLUSION: Findings suggest that, despite an overall preference for therapist-led treatment, most middle-aged and older adults are open to dCBTI. As both dCBTI and telehealth-delivered CBTI are perceived as convenient, these modalities offer the potential to increase access to insomnia care.

RESUMEN

STUDY OBJECTIVES: Evaluate a triaged stepped-care strategy among adults 50 and older with insomnia disorder. METHODS: Participants (N=245) were classified at baseline by a Triage-Checklist. Those projected to do better if they start treatment with therapist versus digitally delivered CBT-I (tCBT-I versus dCBT-I) constituted the YES stratum (n=137); the rest constituted the NO stratum (n=108). Participants were randomized within stratum to a strategy that utilized only dCBT-I (ONLN) or to a strategy that prospectively allocated the first step of care to dCBT-I or tCBT-I based on the Triage-Checklist and switched dCBT-I non-responders at 2-months to tCBT-I (STEP). Co-primary outcomes were the insomnia severity index (ISI) and the average nightly amount of prescription hypnotic medications used (MEDS), assessed at 2,4,6,9, and 12 months post-randomization. RESULTS: Mixed effects models revealed that, compared to ONLN, participants in STEP had greater reductions in ISI (p=0.001; η2=0.01) and MEDS (p=0.019, η2=0.01). Within the YES stratum, compared to ONLN, those in STEP had greater reductions in ISI (p=0.0001, η2=0.023) and MEDS (p=0.018, η2=0.01). Within the ONLN arm, compared to the YES stratum, those in the NO stratum had greater reductions in ISI (p=0.015, η2=0.01) but not in MEDS. Results did not change with treatment-dose covariate adjustment. CONCLUSIONS: Triaged-stepped care can help guide allocation of limited CBT-I treatment resources to promote effective and safe treatment of chronic insomnia among middle age and older adults. Further refinement of the Triage-Checklist and optimization of the timing and switching criteria may improve the balance between effectiveness and use of resources.

RESUMEN

INTRODUCTION: Tranexamic acid (TXA) administered early after traumatic brain injury (TBI) can decrease morbidity and mortality. The purpose of this study is to determine if the timing of TXA administration after TBI affects postinjury inflammatory markers or phosphorylated tau (p-tau) levels within the hippocampus. METHODS: Male mice (9-11 wk) were split into six groups based on injury and timing of TXA administration (n = 5 per group): Sham, TBI-only, 100 mg/kg TXA-only, TBI + TXA 10 min, TBI + TXA 1 h, and TBI + TXA 6 h. Moderate concussive TBI was induced via weight drop. Serum and brain homogenates were collected at 6 and 24 h postinjury and analyzed for 14 inflammatory cytokines via multiplex enzyme-linked immunosorbent assay. Serum was analyzed for glial fibrillary acidic protein levels. Additional cohorts were survived to 30 d for hippocampal p-tau quantification using immunohistochemistry. RESULTS: Serum levels of interleukin (IL) 1ß (IL-1ß), IL-3, IL-12, IL-17, monocyte chemoattractant protein-1, granulocyte-macrophage colony-stimulating factor, and regulated on activation, normal T-cell expressed and secreted were elevated in TBI mice compared to sham mice at 24 h. Levels of IL-1ß and monocyte chemoattractant protein-1 were lower in 6-h TXA-treated mice than 1-h TXA-treated mice following TBI. IL-12 and macrophage inflammatory protein-1α levels were decreased in 6-h TXA-treated mice compared to 10-min TXA-treated mice. Administration of TXA at 10 min and 6 h but not 1 h postTBI reduced serum glial fibrillary acidic protein levels compared to TBI-only mice. Hippocampal p-tau accumulation was increased after TBI but not reduced by TXA administration. CONCLUSIONS: Our results demonstrate that neither early nor delayed administration of TXA conveyed significant systemic or cerebral benefit in cytokine levels following TBI. Further research should be conducted to assess blood brain barrier integrity and neurobehavioral recovery following TXA administration postTBI.

RESUMEN

PURPOSE: Accelerated 3-year programs (A3YPs) at medical schools were developed to address student debt and mitigate workforce shortage issues. This study investigated whether medical school length (3 vs 4 years) was associated with early residency performance. The primary research question was as follows: Are the Accreditation Council for Graduate Medical Education Milestones (MS) attained by A3YP graduates comparable to graduates of traditional 4-year programs (T4YPs) at 6 and 12 months into internship? METHOD: The MS data from students entering U.S. medical schools in 2021 and 2022 from the 6 largest specialties were used: emergency medicine, family medicine, internal medicine, general surgery, psychiatry, and pediatrics. Three-year and 4-year graduates were matched for analysis (2,899 matched learners: 182 in A3YPs and 2,717 in T4YPs). The study used a noninferiority study design to examine data trends between the study cohort (A3YP) and control cohort (T4YP). To account for medical school and residency program effects, the authors used cross-classified random-effects regression to account for clustering and estimate group differences. RESULTS: The mean Harmonized MS ratings for the midyear and end-year reporting periods showed no significant differences between the A3YP and T4YP groups (mean [SE] cross-classified coefficient = 0.01 [0.02], P = .77). Mean MS ratings across internal medicine MS for the midyear and end-year reporting periods showed no significant differences between the A3YP and T4YP groups (mean [SE] cross-classified coefficient = -0.03 [0.03], P = .31). Similarly, for family medicine, there were no statistically significant differences between the A3YP and T4YP groups (mean [SE] cross-classified coefficient = 0.01 [0.02], P = .96). CONCLUSIONS: For the specialties studied, there were no significant differences in MS performance between 3-year and 4-year graduates at 6 and 12 months into internship. These results support comparable efficacy of A3YPs in preparing medical students for residency.

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This cohort study examines rates of vaccination for COVID-19 and for influenza among children receiving long-term home ventilation.

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Vacunas contra la COVID-19 , COVID-19 , Vacunas contra la Influenza , Gripe Humana , SARS-CoV-2 , Humanos , Niño , Gripe Humana/prevención & control , COVID-19/prevención & control , COVID-19/epidemiología , Vacunas contra la Influenza/administración & dosificación , Masculino , Femenino , Preescolar , Vacunas contra la COVID-19/administración & dosificación , Vacunación/estadística & datos numéricos , Adolescente , Respiración Artificial/estadística & datos numéricos , Lactante

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Internado y Residencia , Humanos , Niño , Relaciones Médico-Paciente , Ortopedia/educación , Empatía , Actitud del Personal de Salud , Educación de Postgrado en Medicina

RESUMEN

BACKGROUNDThe use of high-throughput technologies has enabled rapid advancement in the knowledge of host immune responses to pathogens. Our objective was to compare the repertoire, protection, and maternal factors associated with human milk antibodies to infectious pathogens in different economic and geographic locations.METHODSUsing multipathogen protein microarrays, 878 milk and 94 paired serum samples collected from 695 women in 5 high and low-to-middle income countries (Bangladesh, Finland, Peru, Pakistan, and the United States) were assessed for specific IgA and IgG antibodies to 1,607 proteins from 30 enteric, respiratory, and bloodborne pathogens.RESULTSThe antibody coverage across enteric and respiratory pathogens was highest in Bangladeshi and Pakistani cohorts and lowest in the U.S. and Finland. While some pathogens induced a dominant IgA response (Campylobacter, Klebsiella, Acinetobacter, Cryptosporidium, and pertussis), others elicited both IgA and IgG antibodies in milk and serum, possibly related to the invasiveness of the infection (Shigella, enteropathogenic E. coli "EPEC", Streptococcus pneumoniae, Staphylococcus aureus, and Group B Streptococcus). Besides the differences between economic regions and decreases in concentrations over time, human milk IgA and IgG antibody concentrations were lower in mothers with high BMI and higher parity, respectively. In Bangladeshi infants, a higher specific IgA concentration in human milk was associated with delayed time to rotavirus infection, implying protective properties of antirotavirus antibodies, whereas a higher IgA antibody concentration was associated with greater incidence of Campylobacter infection.CONCLUSIONThis comprehensive assessment of human milk antibody profiles may be used to guide the development of passive protection strategies against infant morbidity and mortality.FUNDINGBill and Melinda Gates Foundation grant OPP1172222 (to KMJ); Bill and Melinda Gates Foundation grant OPP1066764 funded the MDIG trial (to DER); University of Rochester CTSI and Environmental Health Sciences Center funded the Rochester Lifestyle study (to RJL); and R01 AI043596 funded PROVIDE (to WAP).

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Inmunoglobulina A , Inmunoglobulina G , Leche Humana , Humanos , Leche Humana/inmunología , Femenino , Inmunoglobulina A/sangre , Inmunoglobulina A/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Adulto , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunología , Bangladesh/epidemiología

RESUMEN

Importance: Chemotherapy-induced peripheral neuropathy (CIPN) is a substantial adverse effect of anticancer treatments. As such, the assessment of CIPN remains critically important in both research and clinic settings. Objective: To compare the validity of various patient-reported outcome measures (PROMs) with neurophysiological and sensory functional measures as the optimal method of CIPN assessment. Design, Setting, and Participants: This cohort study evaluated participants treated with neurotoxic chemotherapy across 2 cohorts using a dual-study design. Participants commencing treatment were assessed prospectively at beginning of neurotoxic treatment, midtreatment, and at the end of treatment. Participants who completed treatment up to 5 years prior were assessed cross-sectionally and completed a single assessment time point. Participants were recruited from oncology centers in Australia from August 2015 to November 2022. Data analysis occurred from February to November 2023. Exposures: Neurotoxic cancer treatment including taxanes, platinums, vinca-alkaloids, proteasome inhibitors, and thalidomide. Main Outcomes and Measures: CIPN was assessed via PROMs (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC-CIPN20], Functional Assessment of Cancer Therapy/Gynecological Cancer Group Neurotoxicity Questionnaire (FACT/GOG-Ntx), and the patient-reported outcomes version of the Common Terminology Criteria for Adverse Events [PRO-CTCAE]), neurological and neurophysiological assessment (Total Neuropathy Score and sural and tibial compound nerve amplitudes), and sensory measures (Grating orientation, Von Frey monofilament, and 2-point discrimination tasks). Core measurement properties of CIPN outcome measures were evaluated. Convergent and known-groups validity was assessed cross-sectionally following treatment completion, and responsiveness was evaluated prospectively during treatment. Neurological, neurophysiological, and sensory outcome measure scores were compared between those who reported high and low levels of CIPN symptoms using linear regressions. Results: A total of 1033 participants (median [IQR] age, 61 [50-59] years; 676 female [65.4%]) were recruited to this study, incorporating 1623 assessments. PROMs demonstrated best ability to accurately assess CIPN (convergent validity), especially the PRO-CTCAE composite score (r = 0.85; P < .001) and EORTC-CIPN20 (r = 0.79; P < .001). PROMS also demonstrated the best ability to discriminate between CIPN severity (known-groups validity) and to detect changes at onset of CIPN development (responsiveness), especially for EORTC-CIPN20 (d = 0.67; 95% CI, 0.52-0.83), FACT/GOG-Ntx (d = 0.65; 95% CI, 0.49-0.81) and the PRO-CTCAE (d = 0.83; 95% CI, 0.64-1.02). Other measures did not achieve threshold for convergent validity (α < 0.7). Neurophysiological and sensory measures did not demonstrate acceptable responsiveness. In regression models, neurological, neurophysiological, and sensory outcome measures were significantly impaired in participants who reported high levels of CIPN symptoms compared with those who reported low levels of CIPN symptoms. Conclusions and Relevance: In this cohort study of 1033 cancer patients, PROMs were the only measures to satisfy all 3 core measurement property criteria (convergent validity, known-groups validity, and responsiveness). These findings suggest that adoption of PROMs in clinical practice can equip clinicians with valuable information in assessing CIPN morbidity.

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Antineoplásicos , Medición de Resultados Informados por el Paciente , Enfermedades del Sistema Nervioso Periférico , Humanos , Femenino , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Antineoplásicos/efectos adversos , Estudios Transversales , Anciano , Australia , Neoplasias/tratamiento farmacológico , Reproducibilidad de los Resultados , Calidad de Vida , Estudios de Cohortes , Adulto , Estudios Prospectivos

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Currently, standardized magnetic resonance imaging (MRI) scoring systems and protocols for assessment of idiopathic inflammatory myopathies (IIMs) in children and adults are lacking. Therefore, we will perform a scoping review of the literature to collate and evaluate the existing semi-quantitative and quantitative MRI scoring systems and protocols for the assessment and monitoring of skeletal muscle involvement in patients with IIMs. The aim is to compile evidence-based information that will facilitate the future development of a universal standardized MRI scoring system for both research and clinical applications in IIM. A systematic search of electronic databases (PubMed, EMBASE, and Cochrane) will be undertaken to identify relevant articles published between January 2000 and October 2023. Data will be synthesized narratively. This scoping review seeks to comprehensively summarize and evaluate the evidence on the scanning protocols and scoring systems used in the assessment of diagnosis, disease activity, and damage using skeletal muscle MRI in IIMs. The results will allow the development of consensus recommendations for clinical practice and enable the standardization of research methods for the MRI assessment of skeletal muscle changes in patients with IIMs.

RESUMEN

Background and aims: Bone mineral density (BMD) and body composition play an important role in maintaining metabolic health and physical functioning. Plant-based diets (PBDs) are known to be lower in protein and calcium, which can impact BMD and body composition. This study aimed to investigate the relationship between various PBDs compared to regular meat diet and whole-body BMD, body composition, and weight status. Methods: A cross-sectional study was conducted with adults (n = 240) aged 30-75 years, who habitually followed dietary patterns: vegan, lacto-vegetarian, pesco-vegetarian, semi-vegetarian, or regular meat eater (48 per group). Parameters were measured using dual-energy x-ray absorptiometry (DXA), and multivariable regression analyses were used to adjust for lifestyle confounders, socioeconomic factors, and BMI. Results: After adjustments, whole-body BMD and body composition were not significantly different between those following PBDs and regular meat diets, except for lacto-ovo vegetarians, who had significantly lower lean mass by -1.46 kg (CI: -2.78, -0.13). Moreover, lacto-ovo vegetarians had a significantly lower T-score by -0.41 SD (CI: -0.81, -0.01) compared to regular meat eaters. Waist circumference was significantly lower in individuals adhering to a PBD compared to a regular meat diet: vegans by -4.67 cm (CI: -8.10, -1.24), lacto-ovo vegetarians by -3.92 cm (CI: -6.60, -1.23), pesco-vegetarians by -3.24 cm (CI: -6.09, -0.39), and semi-vegetarians by -5.18 cm (CI: -7.79, -2.57). There were no significant differences in lean mass (%), fat mass (% and total), android/gynoid measures, body weight, or BMI across dietary patterns. All dietary patterns met the recommended dietary intake for calcium and protein, and 25-hydroxy-vitamin D status was comparable across groups. Conclusions: This cross-sectional study found that adhering to a PBD characterized by varying degrees of dairy and meat restriction is not associated with meaningful changes in BMD or body composition, provided that the dietary patterns are planned appropriately with adequate levels of calcium and protein.

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Juvenile dermatomyositis (JDM) is a rare immune-mediated disease of childhood with putative links to microbial exposures. In this multi-center, prospective, observational cohort study, we evaluated whether JDM is associated with discrete oral and gut microbiome signatures. We generated 16S rRNA sequencing data from fecal, saliva, supragingival, and subgingival plaque samples from JDM probands (n = 28). To control for genetic and environmental determinants of microbiome community structure, we also profiled microbiomes of unaffected family members (n = 27 siblings, n = 26 mothers, and n = 17 fathers). Sample type (oral-vs-fecal) and nuclear family unit were the predominant variables explaining variance in microbiome diversity, more so than having a diagnosis of JDM. The oral and gut microbiomes of JDM probands were more similar to their own unaffected siblings than they were to the microbiomes of other JDM probands. In a sibling-paired within-family analysis, several potentially immunomodulatory bacterial taxa were differentially abundant in the microbiomes of JDM probands compared to their unaffected siblings, including Faecalibacterium (gut) and Streptococcus (oral cavity). While microbiome features of JDM are often shared by unaffected family members, the loss or gain of specific fecal and oral bacteria may play a role in disease pathogenesis or be secondary to immune dysfunction in susceptible individuals.

Asunto(s)

Dermatomiositis , Heces , Microbioma Gastrointestinal , Boca , ARN Ribosómico 16S , Humanos , Heces/microbiología , Dermatomiositis/microbiología , Dermatomiositis/genética , Femenino , Masculino , Niño , Boca/microbiología , ARN Ribosómico 16S/genética , Microbioma Gastrointestinal/genética , Estudios Prospectivos , Disbiosis/microbiología , Microbiota/genética , Preescolar , Adolescente , Saliva/microbiología , Adulto

RESUMEN

Genome-wide association studies (GWASs) have been successful at finding associations between genetic variants and human traits, including the immune-mediated diseases (IMDs). However, the requirement of large sample sizes for discovery poses a challenge for learning about less common diseases, where increasing volunteer numbers might not be feasible. An example of this is myositis (or idiopathic inflammatory myopathies [IIM]s), a group of rare, heterogeneous autoimmune diseases affecting skeletal muscle and other organs, severely impairing life quality. Here, we applied a feature engineering method to borrow information from larger IMD GWASs to find new genetic associations with IIM and its subgroups. Combining this approach with two clustering methods, we found 17 IMDs genetically close to IIM, including some common comorbid conditions, such as systemic sclerosis and Sjögren's syndrome, as well as hypo- and hyperthyroidism. All IIM subtypes were genetically similar within this framework. Next, we colocalized IIM signals that overlapped IMD signals, and found seven potentially novel myositis associations mapped to immune-related genes, including BLK, IRF5/TNPO3, and ITK/HAVCR2, implicating a role for both B and T cells in IIM. This work proposes a new paradigm of genetic discovery in rarer diseases by leveraging information from more common IMD, and can be expanded to other conditions and traits beyond IMD.