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Neurology. Genetics Jun 2024Omigapil is a small molecule which inhibits the GAPDH-Siah1-mediated apoptosis pathway. Apoptosis is a pathomechanism underlying the congenital muscular dystrophy...
BACKGROUND AND OBJECTIVES
Omigapil is a small molecule which inhibits the GAPDH-Siah1-mediated apoptosis pathway. Apoptosis is a pathomechanism underlying the congenital muscular dystrophy subtypes LAMA2-related dystrophy (LAMA2-RD) and COL6-related dystrophy (COL6-RD). Studies of omigapil in the (dy/dy) LAMA2-RD mouse model demonstrated improved survival, and studies in the (dy/dy) LAMA2-RD mouse model and the (Col6a1) COL6-RD mouse model demonstrated decreased apoptosis.
METHODS
A phase 1 open-label, sequential group, ascending oral dose, cohort study of omigapil in patients with LAMA2-RD or COL6-RD ages 5-16 years was performed (1) to establish the pharmacokinetic (PK) profile of omigapil at a range of doses, (2) to evaluate the safety and tolerability of omigapil at a range of doses, and (3) to establish the feasibility of conducting disease-relevant clinical assessments. Patients were enrolled in cohorts of size 4, with each patient receiving 4 weeks of vehicle run-in and 12 weeks of study drug (at daily doses ranging from 0.02 to 0.08 mg/kg). PK data from each cohort were analyzed before each subsequent dosing cohort was enrolled. A novel, adaptive dose-finding method (stochastic approximation with virtual observation recursion) was used to allow for dose escalation/reduction between cohorts based on PK data.
RESULTS
Twenty patients were enrolled at the NIH (LAMA2-RD: N = 10; COL6-RD: N = 10). Slightly greater than dose-proportional increases in systemic exposure to omigapil were seen at doses 0.02-0.08 mg/kg/d. The dose which achieved patient exposure within the pre-established target area under the plasma concentration-vs-time curve (AUC) range was 0.06 mg/kg/d. In general, omigapil was safe and well tolerated. No consistent changes were seen in the disease-relevant clinical assessments during the duration of the study.
DISCUSSION
This study represents the thus far only clinical trial of a therapeutic small molecule for LAMA2-RD and COL6-RD, completed with an adaptive trial design to arrive at dose adjustments. The trial met its primary end point and established that the PK profile of omigapil is suitable for further development in pediatric patients with LAMA2-RD or COL6-RD, the most common forms of congenital muscular dystrophy. While within the short duration of the study disease-relevant clinical assessments did not demonstrate significant changes, this study establishes the feasibility of performing interventional clinical trials in these rare disease patient populations.
CLASSIFICATION OF EVIDENCE
This study provides Class IV evidence of omigapil in a dose-finding phase 1 study.
TRIAL REGISTRATION INFORMATION
Clinical Trials NCT01805024.
PubMed: 38915423
DOI: 10.1212/NXG.0000000000200148 -
Scientific Reports Jun 2024Among the myriad of nanoparticles, silica nanoparticles (SiONPs) have gained significant attention since they are extensively produced and used across several kinds of...
Among the myriad of nanoparticles, silica nanoparticles (SiONPs) have gained significant attention since they are extensively produced and used across several kinds of industries. Because of its widespread usage, there has been increasing concern about the potential health effects. This study aims to evaluate the effects of SiONPs on Interleukin-6 (IL-6) gene expression in human lung epithelial cell lines (A549). In this study, A549 cells were exposed to SiONPs at concentrations of 0, 1, 10, 50, 100, and 200 µg/mL for 24 and 48 h. The IL-6 gene expression was assessed using Real-Time RT-PCR. Additionally, the impact of SiONPs on the viability of A549 cells was determined by MTT assay. Statistical analysis was performed using GraphPad Prism software 8.0. MTT assay results indicated a concentration-dependent impact on cell survival. After 24 h, survival decreased from 80 to 68% (1-100 µg/mL), rising to 77% at higher concentrations. After 48 h, survival dropped from 97 to 80%, decreasing to 90% at higher concentrations. RT-PCR showed a dose-response relationship in cellular toxicity up to 10 µg/mL. At higher concentrations, there was increased IL-6 gene expression, mitigating SiONP-induced cytotoxic effects. The study shows that the viability and proliferation of A549 cells are impacted by different SiONPs concentrations. There may be a potential correlation between IL-6 gene expression reduction and a mechanism linked to cellular toxicity. However, at higher concentrations, an unknown mechanism increases IL-6 gene expression, reducing SiONPs' cytotoxic effects. These effects are concentration-dependent and not influenced by exposure times. Further investigation is recommended to determine this mechanism's nature and implications, particularly in cancer research.
Topics: Humans; Silicon Dioxide; A549 Cells; Nanoparticles; Interleukin-6; Cell Survival; DNA Damage
PubMed: 38914713
DOI: 10.1038/s41598-024-65333-5 -
Communications Medicine Jun 2024While potential risk factors for multiple sclerosis (MS) have been extensively researched, it remains unclear how persons with MS theorize about their MS. Such theories...
BACKGROUND
While potential risk factors for multiple sclerosis (MS) have been extensively researched, it remains unclear how persons with MS theorize about their MS. Such theories may affect mental health and treatment adherence. Using natural language processing techniques, we investigated large-scale text data about theories that persons with MS have about the causes of their disease. We examined the topics into which their theories could be grouped and the prevalence of each theory topic.
METHODS
A total of 486 participants of the Swiss MS Registry longitudinal citizen science project provided text data on their theories about the etiology of MS. We used the transformer-based BERTopic Python library for topic modeling to identify underlying topics. We then conducted an in-depth characterization of the topics and assessed their prevalence.
RESULTS
The topic modeling analysis identifies 19 distinct topics that participants theorize as causal for their MS. The topics most frequently cited are Mental Distress (31.5%), Stress (Exhaustion, Work) (29.8%), Heredity/Familial Aggregation (27.4%), and Diet, Obesity (16.0%). The 19 theory topics can be grouped into four high-level categories: physical health (mentioned by 56.2% of all participants), mental health (mentioned by 53.7%), risk factors established in the scientific literature (genetics, Epstein-Barr virus, smoking, vitamin D deficiency/low sunlight exposure; mentioned by 47.7%), and fate/coincidence (mentioned by 3.1%). Our study highlights the importance of mental health issues for theories participants have about the causes of their MS.
CONCLUSIONS
Our findings emphasize the importance of communication between healthcare professionals and persons with MS about the pathogenesis of MS, the scientific evidence base and mental health.
PubMed: 38914643
DOI: 10.1038/s43856-024-00546-3 -
PloS One 2024Gaseous and semi-volatile organic compounds emitted by the transport sector contribute to air pollution and have adverse effects on human health. To reduce harmful...
Gaseous and semi-volatile organic compounds emitted by the transport sector contribute to air pollution and have adverse effects on human health. To reduce harmful effects to the environment as well as to humans, renewable and sustainable bio-hybrid fuels are explored and investigated in the cluster of excellence "The Fuel Science Center" at RWTH Aachen University. However, data on the effects of bio-hybrid fuels on human health is scarce, leaving a data gap regarding their hazard potential. To help close this data gap, this study investigates potential toxic effects of a Ketone-Ester-Alcohol-Alkane (KEAA) fuel blend on A549 human lung cells. Experiments were performed using a commercially available air-liquid interface exposure system which was optimized beforehand. Then, cells were exposed at the air-liquid interface to 50-2000 ppm C3.7 of gaseous KEAA for 1 h. After a 24 h recovery period in the incubator, cells treated with 500 ppm C3.7 KEAA showed significant lower metabolic activity and cells treated with 50, 250, 500 and 1000 ppm C3.7 KEAA showed significant higher cytotoxicity compared to controls. Our data support the international occupational exposure limits of the single KEAA constituents. This finding applies only to the exposure scenario tested in this study and is difficult to extrapolate to the complex in vivo situation.
Topics: Humans; A549 Cells; Lung; Biofuels; Cell Survival; Gases; Volatile Organic Compounds; Alkanes; Air Pollutants
PubMed: 38913629
DOI: 10.1371/journal.pone.0300772 -
Environmental Epidemiology... Dec 2023Manganese (Mn) is an essential nutrient and neurotoxicant, and the neurodevelopmental effects of Mn may depend on exposure timing. Less research has quantitatively...
BACKGROUND
Manganese (Mn) is an essential nutrient and neurotoxicant, and the neurodevelopmental effects of Mn may depend on exposure timing. Less research has quantitatively compared the impact of Mn exposure on neurodevelopment across exposure periods.
METHODS
We used data from 125 Italian adolescents (10-14 years) from the Public Health Impact of Metals Exposure Study to estimate prospective associations of Mn in three early life exposure periods with adolescent attention-related behaviors. Mn was quantified in deciduous teeth using laser ablation-inductively coupled plasma-mass spectrometry to represent prenatal (2nd trimester-birth), postnatal (birth ~1.5 years), and childhood (~1.5-6 years) exposure. Attention-related behavior was evaluated using the Conners Behavior Rating Scales in adolescence. We used multivariable linear regression models to quantify associations between Mn in each exposure period, and multiple informant models to compare associations across exposure periods.
RESULTS
Median tooth Mn levels (normalized to calcium) were 0.4 area under the curve (AUC) Mn:Ca × 10, 0.1 AUC Mn:Ca × 10, and 0.0006 Mn:Ca for the prenatal, postnatal, and childhood periods. A doubling in prenatal tooth Mn levels was associated with 5.3% (95% confidence intervals [CI] = -10.3%, 0.0%) lower (i.e., better) teacher-reported inattention scores, whereas a doubling in postnatal tooth Mn levels was associated with 4.5% (95% CI = -9.3%, 0.6%) and 4.6% (95% CI = -9.5%, 0.6%) lower parent-reported inattention and attention deficit/hyperactivity disorder index scores, respectively. Childhood Mn was not beneficially associated with reported attention-related behaviors.
CONCLUSION
Protective associations in the prenatal and postnatal periods suggest Mn is beneficial for attention-related behavior, but not in the childhood period.
PubMed: 38912396
DOI: 10.1097/EE9.0000000000000274 -
Environmental Epidemiology... Dec 2023Recent evidence suggests environmental health inequalities both within and between European countries and socially deprived groups may be more susceptible to pollution....
BACKGROUND
Recent evidence suggests environmental health inequalities both within and between European countries and socially deprived groups may be more susceptible to pollution. However, evidence is still inconclusive and additional studies are warranted. This study aims to investigate sociodemographic inequalities in long-term residential exposure to air pollution, road traffic noise, and greenness, taking lifestyle and degree of urbanization into account.
METHODS
In total 20,407 women, born 1914-48 residing in Uppsala County, Sweden, were followed between 1997 and 2017. Time-varying sociodemographic variables were obtained from registers, and questionnaires provided lifestyle information. Generalized estimating equations were used to compute beta-coefficients (β) and 95% confidence intervals (95% CI) for associations between sociodemographic and lifestyle variables and spatial-temporal modeled particulate matter (PM, PM), nitrogen dioxide (NO), road traffic noise and greenness. All models were additionally stratified by urbanization type.
RESULTS
Urban area residency was the most important predictor of high exposure to air pollution and noise, and to low greenness. For instance, β for NO was -2.92 (95% CI = -3.00, -2.83) and -3.10 (95% CI = -3.18, -3.01) µg/m in suburban and rural areas, respectively, compared with urban areas. For greenness, the opposite held true with corresponding β of 0.059 (95% CI = 0.056, 0.062) and 0.095 (95% CI = 0.092, 0.098). Within urban areas, elderly, unmarried and well-educated women had the highest environmental burden. However, less pronounced, and even reversed associations were found in suburban and rural areas.
CONCLUSION
This study provides evidence of a mixed pattern of environmental health inequalities across sociodemographic groups in urban areas.
PubMed: 38912394
DOI: 10.1097/EE9.0000000000000279 -
Environmental Epidemiology... Dec 2023We aimed to assess whether the influence of urban vegetation on asthma development in children (<13 years) varies by type (e.g., total vegetation, tree type, and grass)...
OBJECTIVE
We aimed to assess whether the influence of urban vegetation on asthma development in children (<13 years) varies by type (e.g., total vegetation, tree type, and grass) and season.
METHODS
We used a cohort of all children born in Montreal, Canada, between 2000 and 2015. Children and cases were identified from linked medico-administrative databases. Exposure to residential vegetation was estimated using the Normalized Difference Vegetation Index (NDVI) for total vegetation and using the total area covered by deciduous and evergreen crowns for trees in 250 m buffers centered on residential postal codes. Seasonal variations in vegetation were modeled by setting values to zero on days outside of pollen and leaf-on seasons. Cox models with vegetation exposures, age as a time axis, and adjusted for sex, material deprivation, and health region were used to estimate hazard ratios (HR) for asthma development.
RESULTS
We followed 352,946 children for a total of 1,732,064 person-years and identified 30,816 incident cases of asthma. While annual vegetation (total and trees) measures did not appear to be associated with asthma development, models for pollen and leaf-on seasons yielded significant nonlinear associations. The risk of developing asthma was lower in children exposed to high levels (>33,300 m) of deciduous crown area for the leaf-on season (HR = 0.69; 95% confidence interval [CI] = 0.67, 0.72) and increased for the pollen season (HR = 1.07; 95% CI =1.02, 1.12), compared with unexposed children. Similar results were found with the Normalized Difference Vegetation Index.
CONCLUSION
The relationship between urban vegetation and childhood asthma development is nonlinear and influenced by vegetation characteristics, from protective during the leaf-on season to harmful during the pollen season.
PubMed: 38912389
DOI: 10.1097/EE9.0000000000000280 -
Environmental Epidemiology... Dec 2023Adult males in Sweden exhibit an increased risk of cancer associated with an increased absorbed dose to the colon from the Chernobyl accident.
BACKGROUND
Adult males in Sweden exhibit an increased risk of cancer associated with an increased absorbed dose to the colon from the Chernobyl accident.
METHODS
A closed cohort, with information on hunter status, included all individuals living in northern Sweden in 1986. Complete annual information on exposure to Cs at the dwelling coordinate was available for a total of 2,104,101 individuals. A nested case-control method with four controls matched for year of cancer diagnosis and year of birth, was used. Individual absorbed organ doses were calculated between 1986 and 2020 including external and internal exposure. Hazard ratios (HR) per mGy with 95% confidence intervals (95% CI) were calculated using conditional logistic regression adjusted for rural/nonrural habitat, education level and pre-Chernobyl cancer incidence 1980 to 1985. A total of 161,325 cancer cases in males and 144,439 in females were included.
RESULTS
The adjusted HR per mGy for all cancer sites combined was 1.027 (95% CI = 1.022, 1.031) in males and 1.011 (95% CI = 1.006, 1.017) in females. In a post hoc analysis accounting for both remaining confounding from hunter lifestyle and the pre-Chernobyl cancer incidence by county, the adjusted HR per mGy for all cancer sites combined was 1.014 (95% CI = 1.009, 1.019) in males and 1.000 (95% CI = 0.994, 1.006) in females. The post hoc analysis suggested an increased risk of cancer in the colon, pancreas, and stomach, respectively, in males, and lymphoma in females.
CONCLUSIONS
Increased cancer risk estimates were found for some specific cancer sites but remaining uncontrolled confounding due to hunter lifestyle could not be ruled out.
PubMed: 38912388
DOI: 10.1097/EE9.0000000000000277 -
The Lancet. Microbe Jun 2024Microbiota alterations are common in patients hospitalised for severe infections, and preclinical models have shown that anaerobic butyrate-producing gut bacteria...
Association between butyrate-producing gut bacteria and the risk of infectious disease hospitalisation: results from two observational, population-based microbiome studies.
BACKGROUND
Microbiota alterations are common in patients hospitalised for severe infections, and preclinical models have shown that anaerobic butyrate-producing gut bacteria protect against systemic infections. However, the relationship between microbiota disruptions and increased susceptibility to severe infections in humans remains unclear. We investigated the relationship between gut microbiota and the risk of future infection-related hospitalisation in two large population-based cohorts.
METHODS
In this observational microbiome study, gut microbiota were characterised using 16S rRNA gene sequencing in independent population-based cohorts from the Netherlands (HELIUS study; derivation cohort) and Finland (FINRISK 2002 study; validation cohort). HELIUS was conducted in Amsterdam, Netherlands, and included adults (aged 18-70 years at inclusion) who were randomly sampled from the municipality register of Amsterdam. FINRISK 2002 was conducted in six regions in Finland and is a population survey that included a random sample of adults (aged 25-74 years). In both cohorts, participants completed questionnaires, underwent a physical examination, and provided a faecal sample at inclusion (Jan 3, 2013, to Nov 27, 2015, for HELIUS participants and Jan 21 to April 19, 2002, for FINRISK participants. For inclusion in our study, a faecal sample needed to be provided and successfully sequenced, and national registry data needed to be available. Primary predictor variables were microbiota composition, diversity, and relative abundance of butyrate-producing bacteria. Our primary outcome was hospitalisation or mortality due to any infectious disease during 5-7-year follow-up after faecal sample collection, based on national registry data. We examined associations between microbiota and infection risk using microbial ecology and Cox proportional hazards.
FINDINGS
We profiled gut microbiota from 10 699 participants (4248 [39·7%] from the derivation cohort and 6451 [60·3%] from the validation cohort). 602 (5·6%) participants (152 [3·6%] from the derivation cohort; 450 [7·0%] from the validation cohort) were hospitalised or died due to infections during follow-up. Gut microbiota composition of these participants differed from those without hospitalisation for infections (derivation p=0·041; validation p=0·0002). Specifically, higher relative abundance of butyrate-producing bacteria was associated with a reduced risk of hospitalisation for infections (derivation cohort cause-specific hazard ratio 0·75 [95% CI 0·60-0·94] per 10% increase in butyrate producers, p=0·013; validation cohort 0·86 [0·77-0·96] per 10% increase, p=0·0077). These associations remained unchanged following adjustment for demographics, lifestyle, antibiotic exposure, and comorbidities.
INTERPRETATION
Gut microbiota composition, specifically colonisation with butyrate-producing bacteria, was associated with protection against hospitalisation for infectious diseases in the general population across two independent European cohorts. Further studies should investigate whether modulation of the microbiome can reduce the risk of severe infections.
FUNDING
Amsterdam UMC, Porticus, National Institutes of Health, Netherlands Organisation for Health Research and Development (ZonMw), and Leducq Foundation.
PubMed: 38909617
DOI: 10.1016/S2666-5247(24)00079-X -
American Journal of Preventive Medicine Jun 2024Earth's temperature has risen by an average of 0.11°Fahrenheit per decade since 1850 and experts predict continued global warming. Studies have shown that exposure to...
INTRODUCTION
Earth's temperature has risen by an average of 0.11°Fahrenheit per decade since 1850 and experts predict continued global warming. Studies have shown that exposure to extreme temperatures is associated with adverse health outcomes. Missed primary care visits can lead to incomplete preventive health screenings and unmanaged chronic diseases. This study examines the associations between extreme temperature conditions and primary care utilization among adult Philadelphians.
METHODS
1,048,575 appointments from 91,580 patients age ≥ 18 years enrolled in the study at thirteen university-based outpatient clinics in Philadelphia from January 1, 2009, to December 31, 2019. Statistical analysis was performed from June to December 2023. Data on attended and missed appointments was linked with measures of daily maximum temperature and precipitation, stratified by warm and cold seasons. Sociodemographic variables and associations with chronic disease status were explored.
RESULTS
Rates of missed appointments increased by 0.72% for every 1°F decrease in daily maximum temperatures below 39°F and increased by 0.64% for every 1°F increase above 89°F. Individuals≥65 years and those with chronic conditions had stronger associations with an increased rate of missed appointments.
CONCLUSIONS
Temperature extremes were associated with higher rates of missed primary care appointments. Individuals with chronic diseases were more likely to have missed appointments associated with extreme temperatures. The findings suggest the need for primary care physicians to explore different modes of care delivery to support vulnerable populations, such as making telemedicine during extreme weather events a viable and affordable option.
PubMed: 38908724
DOI: 10.1016/j.amepre.2024.06.014