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Rapid advances in biological knowledge and technological innovation have greatly advanced the fields of stem cell and gene therapies to combat a broad spectrum of neurologic disorders. Researchers are currently exploring a variety of stem cell types (e.g., embryonic, progenitor, induced pluripotent) and various transplantation strategies, each with its own advantages and drawbacks. Similarly, various gene modification techniques (zinc finger, TALENs, CRISPR-Cas9) are employed with various delivery vectors to modify underlying genetic contributors to neurologic disorders. While these two individual fields continue to blaze new trails, it is the combination of these technologies which enables genetically engineered stem cells and vastly increases investigational and therapeutic opportunities. The capability to culture and expand stem cells outside the body, along with their potential to correct genetic abnormalities in patient-derived cells or enhance cells with extra gene products, unleashes the full biological potential for innovative, multifaceted approaches to treat complex neurological disorders. In this review, we provide an overview of stem cell and gene therapies in the context of neurologic disorders, highlighting recent advances and current shortcomings, and discuss prospects for future therapies in clinical settings.
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BACKGROUND: The pathogenesis of amyotrophic lateral sclerosis (ALS) involves both genetic and environmental factors. This study investigates associations between metal measures in plasma and urine, ALS risk and survival and exposure sources. METHODS: Participants with and without ALS from Michigan provided plasma and urine samples for metal measurement via inductively coupled plasma mass spectrometry. ORs and HRs for each metal were computed using risk and survival models. Environmental risk scores (ERS) were created to evaluate the association between exposure mixtures and ALS risk and survival and exposure source. ALS (ALS-PGS) and metal (metal-PGS) polygenic risk scores were constructed from an independent genome-wide association study and relevant literature-selected single-nucleotide polymorphisms. RESULTS: Plasma and urine samples from 454 ALS and 294 control participants were analysed. Elevated levels of individual metals, including copper, selenium and zinc, significantly associated with ALS risk and survival. ERS representing metal mixtures strongly associated with ALS risk (plasma, OR=2.95, CI=2.38-3.62, p<0.001; urine, OR=3.10, CI=2.43-3.97, p<0.001) and poorer ALS survival (plasma, HR=1.37, CI=1.20-1.58, p<0.001; urine, HR=1.44, CI=1.23-1.67, p<0.001). Addition of the ALS-PGS or metal-PGS did not alter the significance of metals with ALS risk and survival. Occupations with high potential of metal exposure associated with elevated ERS. Additionally, occupational and non-occupational metal exposures were associated with measured plasma and urine metals. CONCLUSION: Metals in plasma and urine associated with increased ALS risk and reduced survival, independent of genetic risk, and correlated with occupational and non-occupational metal exposures. These data underscore the significance of metal exposure in ALS risk and progression.
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OBJECTIVE: To determine bidirectional associations between the timing of chronic diabetes complications (CDCs) and mental health disorders (MHDs) in individuals with type 1 or type 2 diabetes. RESEARCH DESIGN AND METHODS: We used a nationally representative health care claims database to identify matched individuals with type 1 or 2 diabetes or without diabetes using a propensity score quasirandomization technique stratified by age (0-19, 20-39, 40-59, and 60+ years). CDCs and MHDs were identified using ICD-9/10 codes. We fit Cox proportional hazards models with time-varying diagnoses of CDCs or MHDs to investigate their association with the hazard of developing MHDs or CDCs, respectively. RESULTS: From 2001 to 2018, a total of 553,552 individuals were included (44,735 with type 1 diabetes, 152,187 with type 2 diabetes, and 356,630 without diabetes). We found that having a CDC increased the hazard of developing an MHD (hazard ratio [HR] 1.9-2.9; P < 0.05, with higher HRs in older age strata), and having an MHD increased the hazard of developing a CDC (HR 1.4-2.5; P < 0.05, with the highest HR in age stratum 0-19 years). In those age <60 years, individuals with type 1 diabetes were more likely to have CDCs, whereas individuals with type 2 diabetes were more likely to have MHDs. However, the relationship between CDCs and MHDs in either direction was not affected by diabetes type (P > 0.05 for interaction effects). CONCLUSIONS: We found a consistent bidirectional association between CDCs and MHDs across the life span, highlighting the important relationship between CDCs and MHDs. Prevention and treatment of either comorbidity may help reduce the risk of developing the other.
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PURPOSE: This study aimed to elucidate the experiences and perceptions of mid-career to senior clinician-scientists in academic medicine regarding pursuing, attaining, or rejecting leadership roles as well as their conceptualization of the influence of leadership in their broader career trajectories. METHOD: The authors conducted a qualitative analysis of in-depth, semistructured interviews conducted in 2022 with a diverse sample of clinician-scientists who received new National Institutes of Health K08 or K23 Career Development Awards between 2006 and 2009. A total of 859 of the 915 survey respondents (94%) were eligible to be recruited for the qualitative study. Qualitative analysis was informed by thematic analysis and used a social constructionist approach to understanding participants' conceptualizations of their experiences. Interview transcripts were coded using an iterative, inductive coding process. Themes were generated by reviewing coded data and identifying common patterns in participant narratives, affording particular attention to participants' discussion of the effect of race and/or gender on their leadership experiences. RESULTS: Sixty clinician-scientists participated in individual interviews. Five themes were generated surrounding participants' conceptualizations of their leadership experiences. Themes were (1) feeling unprepared for leadership roles, (2) reluctance and lack of intention in attaining leadership positions, (3) influence of networks on leadership access and decision-making, (4) impact-related benefits and downsides of leadership, and (5) confining ideas of who leaders are. CONCLUSIONS: The study highlighted the need for formal leadership training in academic medicine and the importance of mentorship and sponsorship in attaining and succeeding in leadership positions. Individuals from communities underrepresented in leadership positions faced additional challenges internalizing a leadership identity. Efforts to encourage current leaders to engage in intentional succession planning and development of faculty towards leadership roles, including expansion of institutional leadership development programs, are needed to promote equitable distribution of leadership opportunities.
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Importance: Studies reveal that most physicians report symptoms of burnout. Less is known about burnout in mid-career medical faculty specifically. Objective: To characterize burnout and its risk factors, particularly differences by gender, among mid-career medical faculty. Design, Setting, and Participants: Between August 2021 and August 2022, a survey was sent to 1430 individuals who received new National Institutes of Health K08 and K23 career development awards from 2006 to 2009. Data were analyzed between June and October 2023. Main Outcomes and Measures: Personal and work-related burnout as evaluated using the Copenhagen Burnout Inventory (CBI). The CBI score ranges from 0 to 100, with a score of 50 or higher indicating a high degree of burnout. Multivariable models were used to investigate associations between burnout and participant characteristics, including race and ethnicity, sexual orientation and gender identity, academic rank, work climate, experiences of workplace sexual harassment, sleep hours, work and domestic caregiving time, and time allocation changes in work and domestic work hours compared with before the COVID-19 pandemic. Work climate was evaluated by a general climate elements scale assessing elements such as friendliness, respect, and collegiality, and a diversity, equity, and inclusion climate elements scale assessing elements such as homogeneity, sexism, and homophobia; higher scores indicated a more favorable view of the climate. Results: In all, 1430 surveys were sent, 926 candidates responded (65% response rate), and the analytic cohort was limited to the 841 respondents who were still in academic medicine (50.7% men). Burnout was significantly more common for women than men (mean [SD] CBI personal scores, 46.6 [19.4] vs 37.5 [17.2]; P < .001; mean [SD] CBI work-related scores, 43.7 [20.4] vs 34.6 [19.7]; P < .001). In multivariable models, personal burnout was significantly more likely for women (adjusted odds ratio [AOR], 2.29 [95% CI, 1.54-3.41]; P < .001) and with more weekly hours of patient care (AOR, 1.07 [95% CI, 1.00-1.15] for each 5-hour increase; P = .04). Personal burnout was less likely with more nightly sleep hours (AOR, 0.68 [95% CI, 0.56-0.81] for each 1-hour increase; P < .001) and with an improved general work climate rating (AOR, 0.64 [95% CI, 0.48-0.85] for each 1-point increase in general work climate scale score; P = .002). Work-related burnout was also significantly more likely for women than men (AOR, 1.77 [95% CI, 1.17-2.69]; P = .007). Greater work-related burnout was associated with an increase of 8 or more work hours per week compared with before the COVID-19 pandemic (AOR, 1.87 [95% CI, 1.13-3.08]; P = .01), more weekly hours of patient care (AOR, 1.11 [95% CI, 1.03-1.19] for each 5-hour increase; P = .007), and a workplace sexual harassment experience in the past 2 years (AOR, 1.71 [95% CI, 1.11-2.62]; P = .01). Work-related burnout was significantly less likely with more nightly sleep hours (AOR, 0.80 [95% CI, 0.66-0.96] for each 1-hour increase; P = .02) and with an improved general work climate rating (AOR, 0.49; [95% CI, 0.36-0.65] for each 1-point increase in general work climate scale score; P < .001). Conclusions and Relevance: This survey study of K grant awardees revealed substantial rates of burnout among mid-career medical faculty, and burnout rates differed by gender. Evidence-based interventions are needed to realize the benefits of workforce diversity and vitality.
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Agotamiento Profesional , COVID-19 , Docentes Médicos , Humanos , Agotamiento Profesional/epidemiología , Agotamiento Profesional/psicología , Femenino , Masculino , Docentes Médicos/psicología , Docentes Médicos/estadística & datos numéricos , Adulto , COVID-19/epidemiología , COVID-19/psicología , Persona de Mediana Edad , SARS-CoV-2 , Encuestas y Cuestionarios , Estados Unidos/epidemiología , Factores de Riesgo , Factores Sexuales , Lugar de Trabajo/psicologíaRESUMEN
The COVID-19 pandemic has caused major disruptions in clinical services for people with chronic long-term conditions. In this narrative review, we assess the indirect impacts of the COVID-19 pandemic on diabetes services globally and the resulting adverse effects on rates of diagnosing, monitoring, and prescribing in people with type 2 diabetes. We summarise potential practical approaches that could address these issues and improve clinical services and outcomes for people living with diabetes during the recovery phase of the pandemic.
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COVID-19 , Diabetes Mellitus Tipo 2 , SARS-CoV-2 , Humanos , COVID-19/epidemiología , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Pandemias , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiología , Hipoglucemiantes/uso terapéuticoRESUMEN
BACKGROUND AND OBJECTIVES: Distal symmetric polyneuropathy (DSP) is a disabling, often painful condition associated with falls and reduced quality of life. Non-Hispanic Black people and people with low income are underrepresented in existing DSP studies; therefore, it is unknown whether data accurately reflect the prevalence, risk factors, and burden of disease in these populations. METHODS: Patients older than 40 years presenting to an outpatient internal medicine clinic predominantly serving Medicaid patients in Flint, Michigan, were enrolled in a cross-sectional study. Demographics, clinical characteristics, including medication use, anthropomorphic measurements, fasting lipids, and hemoglobin A1c were collected. DSP was defined using the modified Toronto Clinical Neuropathy Score (mTCNS). Multivariable logistic regression was performed to model DSP and undiagnosed DSP as a function of potential risk factors age, metabolic syndrome, and race. DSP burden was measured using Peripheral Neuropathy Quality of Life Instrument-97. RESULTS: Two hundred participants were enrolled, and 169 (85%) completed all data collection. The population was 55% female of mean age (SD) 58.2 years (10.4) and 69% non-Hispanic Black. Among the population, 50% had diabetes, 67% had metabolic syndrome, and 47% had a household income <$20,000. DSP was present in 73% of the population, of which 75% were previously undiagnosed. Neuropathic pain was documented in 57% of participants with DSP. DSP based on mTCNS criteria was associated with older age (odds ratio [OR] 1.1 [95% confidence interval (CI) 1.03-1.2]) and metabolic syndrome (OR 4.4 [1.1-18.1]). Non-Hispanic Black participants had lower odds of DSP (OR 0.1 [0.01-0.4]) than non-Hispanic White and Hispanic participants. DSP burden was high, including increased pain, health-related worry, and poorer quality of life (all p < 0.001). DISCUSSION: DSP is extremely common and often underrecognized in this predominantly non-Hispanic Black, low-income population and leads to substantial disease burden. Metabolic syndrome is a highly prevalent, modifiable risk factor in this population that should be managed to lower DSP prevalence.
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Negro o Afroamericano , Pobreza , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Transversales , Michigan/epidemiología , Polineuropatías/epidemiología , Polineuropatías/etnología , Prevalencia , Calidad de Vida , Factores de Riesgo , Hispánicos o Latinos , BlancoRESUMEN
BACKGROUND: Environmental exposures impact amyotrophic lateral sclerosis (ALS) risk and progression, a fatal and progressive neurodegenerative disease. Better characterization of these exposures is needed to decrease disease burden. OBJECTIVE: To identify exposures in the residential setting that associate with ALS risk, survival, and onset segment. METHODS: ALS and control participants recruited from University of Michigan completed a survey that ascertained exposure risks in the residential setting. ALS risk was assessed using logistic regression models followed by latent profile analysis to consider exposure profiles. A case-only analysis considered the contribution of the residential exposure variables via a Cox proportional hazards model for survival outcomes and multinomial logistic regression for onset segment, a polytomous outcome. RESULTS: This study included 367 ALS and 255 control participants. Twelve residential variables were associated with ALS risk after correcting for multiple comparison testing, with storage in an attached garage of chemical products including gasoline or kerosene (odds ratio (OR) = 1.14, padjusted < 0.001), gasoline-powered equipment (OR = 1.16, padjusted < 0.001), and lawn care products (OR = 1.15, padjusted < 0.001) representing the top three risk factors sorted by padjusted. Latent profile analysis indicated that storage of these chemical products in both attached and detached garages increased ALS risk. Although residential variables were not associated with poorer ALS survival following multiple testing corrections, storing pesticides, lawn care products, and woodworking supplies in the home were associated with shorter ALS survival using nominal p values. No exposures were associated with ALS onset segment. CONCLUSION: Residential exposures may be important modifiable components of the ALS susceptibility and prognosis exposome.
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Esclerosis Amiotrófica Lateral , Exposición a Riesgos Ambientales , Fenotipo , Humanos , Esclerosis Amiotrófica Lateral/epidemiología , Esclerosis Amiotrófica Lateral/mortalidad , Femenino , Masculino , Michigan/epidemiología , Estudios de Casos y Controles , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/estadística & datos numéricos , Persona de Mediana Edad , Anciano , Factores de Riesgo , AdultoRESUMEN
Importance: Despite increasing evidence and recognition of persistent gender disparities in academic medicine, qualitative data detailing the association of gender-based experiences with career progression remain sparse, particularly at the mid- to senior-career stage. Objective: To investigate the role gender has played in everyday professional experiences of mid- to senior-career women clinician-scientists and their perceptions of gender-related barriers experienced across their careers. Design, Setting, and Participants: In this qualitative study, a total of 60 of 159 invited clinician-scientists who received National Institutes of Health K08 or K23 awards between 2006 and 2009 and responded to a survey in 2021 agreed to participate. Invitees were selected using random, purposive sampling to support sample heterogeneity. Semistructured in-depth interviews were conducted January to May 2022. For this study, interviews from 31 women were analyzed using the framework approach to thematic analysis. Data analyses were performed between August and October 2023. Main Outcomes and Measures: Descriptive themes of participant experiences of gender and gender-based barriers in academic medicine. Results: A total of 31 women clinician-scientists (8 identifying as Asian [25.8%], 14 identifying as White [45.2%], and 9 identifying as members of a minority group underrepresented in medicine [29.0%]; 14 aged 40-49 years [45.2%] and 14 aged 50-59 years [45.2%]) were included. Among them, 17 participants (54.8%) had children who required adult supervision or care, 7 participants (22.6%) had children who did not require supervision or care, and 6 participants (19.4%) did not have children. There were 4 dominant themes identified within participant experiences in academic medicine: the mental burden of gendered expectations at work and home, inequitable treatment of women in bureaucratic processes, subtle and less subtle professional exclusion of women, and value of communities built on shared identities, experiences, and solidarity. Conclusions and Relevance: This study found that women perceived the institution of academic medicine as a male-centric system misaligned with the needs of women, with associated feelings of exclusion, disillusionment, and loss of trust in their institutions. Findings suggest that the confluence of domestic obligations and unaccommodating institutional environments may make it difficult for women clinician-scientists to achieve established timelines of career progression and productivity; these findings may have long-term implications for the well-being and retention of women in academic medicine.
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Medicina , Adulto , Femenino , Humanos , Asiático , Exactitud de los Datos , Análisis de Datos , Investigación Cualitativa , Estados Unidos , Persona de Mediana Edad , Blanco , Grupos MinoritariosRESUMEN
BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease whose pathobiology associates with peripheral blood immune cell levels and activation patterns in an age and sex-dependent manner. This study's objective was to identify immune profile associations with ALS progression, whether the associations are age and sex-specific, and whether immune profiles can predict a future disease course. METHODS: Flow cytometry immune profiles (a combination of 22 peripheral blood immune markers) were generated for 241 participants with ALS and linked to ALS progression, using progression-free survival, which is a composite combining the revised ALS Functional Rating Scale and survival. Participants were first grouped by immune profiles using unsupervised hierarchical clustering, and clusters were associated with subsequent progression-free survival. Next, individual immune markers were associated with progression-free survival using least absolute shrinkage and selection operator-Cox regression. Analyses were stratified by age and sex to identify demographic-specific immune mechanisms. Finally, random forest determined the predictive power of immune profiles on ALS progression in the whole population and again stratified by age and sex. RESULTS: Progression-free survival differed between clusters of participants with similar immune profiles, particularly reduced natural killer (NK)-cell activation associated with slower progression. Individual markers such as neutrophil levels and NK-cell NKp46 expression associated with faster ALS progression while overall NK-cell levels and NK-cell subpopulations associated with slower progression; the strength of these associations varied by age and sex. Adding these immune markers to prediction models dramatically increased short-term prediction compared with routine clinical prognostic variables alone, and the addition of NK-cell markers further improved the prediction accuracy in female participants. DISCUSSION: Specific immune profiles likely contribute to ALS progression in an age and sex-dependent manner, and peripheral immune markers enhance the prediction of short-term clinical outcomes. These findings suggest a complex milieu of immune profiles associated with ALS progression, and more detailed immunophenotyping in ALS will facilitate personalized immunotherapeutics in ALS.
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Esclerosis Amiotrófica Lateral , Enfermedades Neurodegenerativas , Masculino , Humanos , Femenino , Progresión de la Enfermedad , Pronóstico , BiomarcadoresRESUMEN
Background and Objectives: Amyotrophic lateral sclerosis (ALS) causes profound impairments in neurological function and a cure for this devastating disease remains elusive. Early detection and risk stratification are crucial for timely intervention and improving patient outcomes. This study aimed to identify predisposing genetic, phenotypic, and exposure-related factors for Amyotrophic lateral sclerosis using multi-modal data and assess their joint predictive potential. Methods: Utilizing data from the UK Biobank, we analyzed an unrelated set of 292 ALS cases and 408,831 controls of European descent. Two polygenic risk scores (PRS) are constructed: "GWAS Hits PRS" and "PRS-CS," reflecting oligogenic and polygenic ALS risk profiles, respectively. Time-restricted phenome-wide association studies (PheWAS) were performed to identify pre-existing conditions increasing ALS risk, integrated into phenotypic risk scores (PheRS). A poly-exposure score ("PXS") captures the influence of environmental exposures measured through survey questionnaires. We evaluate the performance of these scores for predicting ALS incidence and stratifying risk, adjusting for baseline demographic covariates. Results: Both PRSs modestly predicted ALS diagnosis, but with increased predictive power when combined (covariate-adjusted receiver operating characteristic [AAUC] = 0.584 [0.525, 0.639]). PheRS incorporated diagnoses 1 year before ALS onset (PheRS1) modestly discriminated cases from controls (AAUC = 0.515 [0.472, 0.564]). The "PXS" did not significantly predict ALS. However, a model incorporating PRSs and PheRS1 improved prediction of ALS (AAUC = 0.604 [0.547, 0.667]), outperforming a model combining all risk scores. This combined risk score identified the top 10% of risk score distribution with a 4-fold higher ALS risk (95% CI: [2.04, 7.73]) versus those in the 40%-60% range. Discussions: By leveraging UK Biobank data, our study uncovers predisposing ALS factors, highlighting the improved effectiveness of multi-factorial prediction models to identify individuals at highest risk for ALS.
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PURPOSE: To understand time allocation of a national medical faculty cohort 1.5-2 years after the COVID-19 pandemic began, compared to before. METHOD: From August 2021-April 2022, the authors conducted a retrospective survey of 1,430 clinician-researchers who received National Institutes of Health career-development awards between 2006-2009 asking about domestic and professional time allocation pre-pandemic and at the time of surveys (TOS). Of 915 respondents (64%), the 830 who remained in academic positions constituted the analytic sample. Multivariable regression models identified demographic factors associated with each time outcome and change in time between pre-pandemic and TOS, and having experienced ≥8-hour increase of total self-reported weekly professional work hours and domestic labor hours. RESULTS: Median self-reported weekly professional work hours were 55 hours/week pre- pandemic and 60 at TOS. On multivariable analysis, significant predictors of self-reported weekly professional work hours at TOS were having a non-child other dependent (+2.6 hours, P = .03), academic rank (associate -3.1 hours, assistant -9.0 hours; P < .001), and specialty (P < .001). Average self-reported TOS weekly domestic-labor hours were 23.1 among men and 30.2 among women (P < .001). Predictors of total self-reported TOS weekly domestic hours were being a woman (+5.6 hours; P < .001) and having children requiring supervision (+10.2 hours; P < .001). Overall, 9.3% of men (42/450) and 21.6% of women (88/407) experienced a ≥ 8 hour increase in domestic labor (P < .001). On multivariable analysis, women had higher odds of substantial domestic-labor increase (OR = 2.33, 95% CI: 1.47, 3.68), as did those with children requiring supervision (OR = 1.93, 95% CI: 1.25, 2.98) or other dependents (OR = 1.83, 95% CI: 1.13, 2.98). CONCLUSIONS: This study illuminates demands on women and faculty with dependents during the COVID-19 pandemic and suggests increased flexibility and resources are of heightened importance.
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Peripheral neuropathy (PN) is a severe and frequent complication of obesity, prediabetes, and type 2 diabetes characterized by progressive distal-to-proximal peripheral nerve degeneration. However, a comprehensive understanding of the mechanisms underlying PN, and whether these mechanisms change during PN progression, is currently lacking. Here, gene expression data were obtained from distal (sciatic nerve; SCN) and proximal (dorsal root ganglia; DRG) injury sites of a high-fat diet (HFD)-induced mouse model of obesity/prediabetes at early and late disease stages. Self-organizing map and differentially expressed gene analyses followed by pathway enrichment analysis identified genes and pathways altered across disease stage and injury site. Pathways related to immune response, inflammation, and glucose and lipid metabolism were consistently dysregulated with HFD-induced PN, irrespective of injury site. However, regulation of oxidative stress was unique to the SCN while dysregulated Hippo and Notch signaling were only observed in the DRG. The role of the immune system and inflammation in disease progression was supported by an increase in the percentage of immune cells in the SCN with PN progression. Finally, when comparing these data to transcriptomic signatures from human patients with PN, we observed conserved pathways related to metabolic dysregulation across species, highlighting the translational relevance of our mouse data. Our findings demonstrate that PN is associated with distinct site-specific molecular re-programming in the peripheral nervous system, identifying novel, clinically relevant therapeutic targets.
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Ganglios Espinales , Perfilación de la Expresión Génica , Ratones Endogámicos C57BL , Estado Prediabético , Nervio Ciático , Animales , Ganglios Espinales/metabolismo , Ganglios Espinales/patología , Estado Prediabético/metabolismo , Estado Prediabético/genética , Estado Prediabético/patología , Masculino , Nervio Ciático/metabolismo , Nervio Ciático/lesiones , Nervio Ciático/patología , Ratones , Dieta Alta en Grasa/efectos adversos , Transcriptoma , Humanos , Enfermedades del Sistema Nervioso Periférico/genética , Enfermedades del Sistema Nervioso Periférico/patología , Enfermedades del Sistema Nervioso Periférico/metabolismoRESUMEN
Background: The pathogenesis of amyotrophic lateral sclerosis (ALS) involves both genetic and environmental factors. This study investigates associations between metal measures in plasma and urine, ALS risk and survival, and exposure sources. Methods: Participants with and without ALS from Michigan provided plasma and urine samples for metal measurement via inductively coupled plasma mass spectrometry. Odds and hazard ratios for each metal were computed using risk and survival models. Environmental risk scores (ERS) were created to evaluate the association between exposure mixtures and ALS risk and survival and exposure source. ALS (ALS-PGS) and metal (metal-PGS) polygenic risk scores were constructed from an independent genome-wide association study and relevant literature-selected SNPs. Results: Plasma and urine samples from 454 ALS and 294 control participants were analyzed. Elevated levels of individual metals, including copper, selenium, and zinc, significantly associated with ALS risk and survival. ERS representing metal mixtures strongly associated with ALS risk (plasma, OR=2.95, CI=2.38-3.62, p<0.001; urine, OR=3.10, CI=2.43-3.97, p<0.001) and poorer ALS survival (plasma, HR=1.42, CI=1.24-1.63, p<0.001; urine, HR=1.52, CI=1.31-1.76, p<0.001). Addition of the ALS-PGS or metal-PGS did not alter the significance of metals with ALS risk and survival. Occupations with high potential of metal exposure associated with elevated ERS. Additionally, occupational and non-occupational metal exposures associated with measured plasma and urine metals. Conclusion: Metals in plasma and urine associated with increased ALS risk and reduced survival, independent of genetic risk, and correlated with occupational and non-occupational metal exposures. These data underscore the significance of metal exposure in ALS risk and progression.
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This survey study examines gender differences in mid- to senior-career faculty experiences of receiving and providing mentorship and sponsorship during early career development.
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Docentes Médicos , Mentores , Humanos , Factores SexualesRESUMEN
Neurodegenerative diseases are increasing in prevalence and place a significant burden on society. The causes are multifactorial and complex, and increasing evidence suggests a dynamic interplay between genes and the environment, emphasizing the importance of identifying and understanding the role of lifelong exposures, known as the exposome, on the nervous system. This review provides an overview of recent advances toward defining neurodegenerative disease exposomes, focusing on Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. We present the current state of the field based on emerging data, elaborate on key themes and potential mechanisms, and conclude with limitations and future directions. ANN NEUROL 2024;95:635-652.
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Enfermedad de Alzheimer , Exposoma , Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Humanos , Enfermedades Neurodegenerativas/genética , Enfermedad de Alzheimer/genética , Enfermedad de Parkinson/genéticaRESUMEN
OBJECTIVE: Diabetic peripheral neuropathy (DPN) is common; however, the features and burden of neuropathic pain (NP) in type 1 diabetes (T1D) are poorly understood. We evaluated the incidence of first occurrence, annual prevalence, remission, and risk factors for NP during long-term follow-up of participants with T1D. RESEARCH DESIGN AND METHODS: The Michigan Neuropathy Screening Instrument (MNSI) was administered annually (1994-2020) for 1,324 participants in the Epidemiology of Diabetes Interventions and Complications (EDIC) study. NP with clinical signs of DPN (NP DPN+) was defined according to self-reported NP plus an examination score >2, while NP without clinical signs of DPN (NP DPN-) was defined according to self-reported NP and an examination score ≤2. RESULTS: At EDIC year 1, median age for participants was 36 years (interquartile range 30, 41), diabetes duration 13 years (10, 18), and HbA1c 7.9% (7.2, 8.9). At year 26 (median diabetes duration 39 years), cumulative incidence of NP was 57%, regardless of concomitant clinical signs of DPN (36% NP DPN+ vs. 46% NP DPN-). NP prevalence was 20% at 26 years (11% NP DPN+ and 9% NP DPN-), suggesting frequent remission. Annualized remission rates were similar regardless of pain medication use. In addition to HbA1c, female sex was associated with NP DPN-. CONCLUSIONS: NP incidence in T1D was high and frequently occurred in the absence of clinical signs of neuropathy, as assessed with the MNSI. Pain remission was not explained by pain medication use. Effective clinical strategies for identification and management are needed.
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INTRODUCTION: Environmental exposures strongly influence ALS risk and identification is needed to reduce ALS burden. Participation in hobbies and exercise may alter ALS risk and phenotype, warranting an assessment to understand their contribution to the ALS exposome. METHODS: Participants with ALS and healthy controls were recruited from University of Michigan and self-completed a survey to ascertain hobbies, exercise, and avocational exposures. Exposure variables were associated with ALS risk, survival, onset segment, and onset age. RESULTS: ALS (n = 400) and control (n = 287) participants self-reported avocational activities. Cases were slightly older (median age 63.0 vs. 61.1 years, p = 0.019) and had a lower educational attainment (p < 0.001) compared to controls; otherwise, demographics were well balanced. Risks associating with ALS after multiple comparison correction included golfing (odds ratio (OR) 3.48, padjusted = 0.004), recreational dancing (OR 2.00, padjusted = 0.040), performing gardening or yard work (OR 1.71, padjusted = 0.040) five years prior to ALS and personal (OR 1.76, padjusted = 0.047) or family (OR 2.21, padjusted = 0.040) participation in woodworking, and personal participation in hunting and shooting (OR 1.89, padjusted = 0.040). No exposures associated with ALS survival and onset. Those reporting swimming (3.86 years, padjusted = 0.016) and weightlifting (3.83 years, padjusted = 0.020) exercise 5 years prior to ALS onset had an earlier onset age. DISCUSSION: The identified exposures in this study may represent important modifiable ALS factors that influence ALS phenotype. Thus, exposures related to hobbies and exercise should be captured in studies examining the ALS exposome.