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Maralixibat Treatment Response in Alagille Syndrome is Associated with Improved Health-Related Quality of Life.
Kamath, BM, Goldstein, A, Howard, R, Garner, W, Vig, P, Marden, JR, Billmyer, E, Anderson, A, Kirson, N, Jacquemin, E, et al
The Journal of pediatrics. 2023;:68-75.e5
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Abstract
OBJECTIVE The objective of this study was to assess the impact of treatment response to the ileal bile acid transporter inhibitor maralixibat on health-related quality of life (HRQoL) in children with Alagille syndrome. STUDY DESIGN This analysis used data from the ICONIC trial, a phase 2 study with a 4-week double-blind, placebo-controlled, randomized drug withdrawal period in children with Alagille syndrome with moderate-to-severe pruritus. Clinically meaningful treatment response to maralixibat was defined a priori as a ≥1-point reduction in the Itch-Reported Outcome (Observer) score, from baseline to week 48. HRQoL was assessed using the Pediatric Quality of Life Inventory Generic Core, Family Impact, and Multidimensional Fatigue scale scores, which were collected via the caregiver. The minimal clinically important difference for HRQoL ranged from 4 to 5 points, depending on the scale. RESULTS Twenty of the 27 patients (74%) included in this analysis achieved an Itch-Reported Outcome (Observer) treatment response at week 48. The mean (SD) change in Multidimensional Fatigue score was +25.8 (23.0) for responders vs -3.1 (19.8) for nonresponders (P = .03). Smaller and non-statistically significant mean changes were observed for the Pediatric Quality of Life Inventory Generic Core and Family Impact scores. Controlling for baseline Family Impact score, responders' Family Impact scores increased an average of 16.9 points over 48 weeks compared with non-responders (P = .05). Smaller and non-statistically significant point estimates were observed for the Pediatric Quality of Life Inventory Generic Core and Multidimensional Fatigue scores. CONCLUSION The significant improvements in pruritus seen with maralixibat at week 48 of the ICONIC study are clinically meaningful and are associated with improved HRQoL. TRIAL REGISTRATION ClinicalTrials.gov: NCT02160782.
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Unauthorized ingredients in "nootropic" dietary supplements: A review of the history, pharmacology, prevalence, international regulations, and potential as doping agents.
Jędrejko, K, Catlin, O, Stewart, T, Anderson, A, Muszyńska, B, Catlin, DH
Drug testing and analysis. 2023;(8):803-839
Abstract
The first nootropic prohibited in sport was fonturacetam (4-phenylpiracetam, carphedon) in 1998. Presented here 25 years later is a broad-scale consideration of the history, pharmacology, prevalence, regulations, and doping potential of nootropics viewed through a lens of 50 selected dietary supplements (DS) marketed as "cognitive enhancement," "brain health," "brain boosters," or "nootropics," with a focus on unauthorized ingredients. Nootropic DS have risen to prominence over the last decade often as multicomponent formulations of bioactive ingredients presenting compelling pharmacological questions and potential public health concerns. Many popular nootropics are unauthorized food or DS ingredients according to the European Commission including huperzine A, yohimbine, and dimethylaminoethanol; unapproved pharmaceuticals like phenibut or emoxypine (mexidol); previously registered drugs like meclofenoxate or reserpine; EU authorized pharmaceuticals like piracetam or vinpocetine; infamous doping agents like methylhexaneamine or dimethylbutylamine; and other investigational substances and peptides. Several are authorized DS ingredients in the United States resulting in significant global variability as to what qualifies as a legal nootropic. Prohibited stimulants or ß2-agonists commonly used in "pre-workout," "weight loss," or "thermogenic" DS such as octodrine, hordenine, or higenamine are often stacked with nootropic substances. While stimulants and ß2-agonists are defined as doping agents by the World Anti-Doping Agency (WADA), many nootropics are not, although some may qualify as non-approved substances or related substances under catch-all language in the WADA Prohibited List. Synergistic combinations, excessive dosing, or recently researched pharmacology may justify listing certain nootropics as doping agents or warrant additional attention in future regulations.
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Interferon-α promotes neo-antigen formation and preferential HLA-B-restricted antigen presentation in pancreatic β-cells.
Carré, A, Zhou, Z, Perez-Hernandez, J, Samassa, F, Lekka, C, Manganaro, A, Oshima, M, Liao, H, Parker, R, Nicastri, A, et al
bioRxiv : the preprint server for biology. 2023
Abstract
Interferon (IFN)-α is the earliest cytokine signature observed in individuals at risk for type 1 diabetes (T1D), but its effect on the repertoire of HLA Class I (HLA-I)-bound peptides presented by pancreatic β-cells is unknown. Using immunopeptidomics, we characterized the peptide/HLA-I presentation in in-vitro resting and IFN-α-exposed β-cells. IFN-α increased HLA-I expression and peptide presentation, including neo-sequences derived from alternative mRNA splicing, post-translational modifications - notably glutathionylation - and protein cis-splicing. This antigenic landscape relied on processing by both the constitutive and immune proteasome. The resting β-cell immunopeptidome was dominated by HLA-A-restricted ligands. However, IFN-α only marginally upregulated HLA-A and largely favored HLA-B, translating into a major increase in HLA-B-restricted peptides and into an increased activation of HLA-B-restricted vs. HLA-A-restricted CD8+ T-cells. A preferential HLA-B hyper-expression was also observed in the islets of T1D vs. non-diabetic donors, and we identified islet-infiltrating CD8+ T-cells from T1D donors reactive to HLA-B-restricted granule peptides. Thus, the inflammatory milieu of insulitis may skew the autoimmune response toward epitopes presented by HLA-B, hence recruiting a distinct T-cell repertoire that may be relevant to T1D pathogenesis.
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Estimated Glomerular Filtration Rate, Albuminuria, and Adverse Outcomes: An Individual-Participant Data Meta-Analysis.
, , Grams, ME, Coresh, J, Matsushita, K, Ballew, SH, Sang, Y, Surapaneni, A, Alencar de Pinho, N, Anderson, A, Appel, LJ, et al
JAMA. 2023;(13):1266-1277
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Abstract
IMPORTANCE Chronic kidney disease (low estimated glomerular filtration rate [eGFR] or albuminuria) affects approximately 14% of adults in the US. OBJECTIVE To evaluate associations of lower eGFR based on creatinine alone, lower eGFR based on creatinine combined with cystatin C, and more severe albuminuria with adverse kidney outcomes, cardiovascular outcomes, and other health outcomes. DESIGN, SETTING, AND PARTICIPANTS Individual-participant data meta-analysis of 27 503 140 individuals from 114 global cohorts (eGFR based on creatinine alone) and 720 736 individuals from 20 cohorts (eGFR based on creatinine and cystatin C) and 9 067 753 individuals from 114 cohorts (albuminuria) from 1980 to 2021. EXPOSURES The Chronic Kidney Disease Epidemiology Collaboration 2021 equations for eGFR based on creatinine alone and eGFR based on creatinine and cystatin C; and albuminuria estimated as urine albumin to creatinine ratio (UACR). MAIN OUTCOMES AND MEASURES The risk of kidney failure requiring replacement therapy, all-cause mortality, cardiovascular mortality, acute kidney injury, any hospitalization, coronary heart disease, stroke, heart failure, atrial fibrillation, and peripheral artery disease. The analyses were performed within each cohort and summarized with random-effects meta-analyses. RESULTS Within the population using eGFR based on creatinine alone (mean age, 54 years [SD, 17 years]; 51% were women; mean follow-up time, 4.8 years [SD, 3.3 years]), the mean eGFR was 90 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 11 mg/g (IQR, 8-16 mg/g). Within the population using eGFR based on creatinine and cystatin C (mean age, 59 years [SD, 12 years]; 53% were women; mean follow-up time, 10.8 years [SD, 4.1 years]), the mean eGFR was 88 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 9 mg/g (IQR, 6-18 mg/g). Lower eGFR (whether based on creatinine alone or based on creatinine and cystatin C) and higher UACR were each significantly associated with higher risk for each of the 10 adverse outcomes, including those in the mildest categories of chronic kidney disease. For example, among people with a UACR less than 10 mg/g, an eGFR of 45 to 59 mL/min/1.73 m2 based on creatinine alone was associated with significantly higher hospitalization rates compared with an eGFR of 90 to 104 mL/min/1.73 m2 (adjusted hazard ratio, 1.3 [95% CI, 1.2-1.3]; 161 vs 79 events per 1000 person-years; excess absolute risk, 22 events per 1000 person-years [95% CI, 19-25 events per 1000 person-years]). CONCLUSIONS AND RELEVANCE In this retrospective analysis of 114 cohorts, lower eGFR based on creatinine alone, lower eGFR based on creatinine and cystatin C, and more severe UACR were each associated with increased rates of 10 adverse outcomes, including adverse kidney outcomes, cardiovascular diseases, and hospitalizations.
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Enteric pathogen reduction targets for onsite non-potable water systems: A critical evaluation.
Jahne, MA, Schoen, ME, Kaufmann, A, Pecson, BM, Olivieri, A, Sharvelle, S, Anderson, A, Ashbolt, NJ, Garland, JL
Water research. 2023;:119742
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Abstract
Onsite non-potable water systems (ONWS) collect and treat local source waters for non-potable end uses such as toilet flushing and irrigation. Quantitative microbial risk assessment (QMRA) has been used to set pathogen log10-reduction targets (LRTs) for ONWS to achieve the risk benchmark of 10-4 infections per person per year (ppy) in a series of two efforts completed in 2017 and 2021. In this work, we compare and synthesize the ONWS LRT efforts to inform the selection of pathogen LRTs. For onsite wastewater, greywater, and stormwater, LRTs for human enteric viruses and parasitic protozoa were within 1.5-log10 units between 2017 and 2021 efforts, despite differences in approaches used to characterize pathogens in these waters. For onsite wastewater and greywater, the 2017 effort used an epidemiology-based model to simulate pathogen concentrations contributed exclusively from onsite waste and selected Norovirus as the viral reference pathogen; the 2021 effort used municipal wastewater pathogen data and cultivable adenoviruses as the reference viral pathogen. Across source waters, the greatest differences occurred for viruses in stormwater, given the newly available municipal wastewater characterizations used for modeling sewage contributions in 2021 and the different selection of reference pathogens (Norovirus vs. adenoviruses). The roof runoff LRTs support the need for protozoa treatment, but these remain difficult to characterize due to the pathogen variability in roof runoff across space and time. The comparison highlights adaptability of the risk-based approach, allowing for updated LRTs as site specific or improved information becomes available. Future research efforts should focus on data collection of onsite water sources.
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The long-term effect of intentional weight loss on changes in bone mineral density in persons with type 2 diabetes: results from the Look AHEAD randomized trial.
Johnson, KC, Anderson, A, Beavers, KM, Crandall, CJ, Hazuda, HP, Lewis, CE, Lipkin, E, Schwartz, AV, Pi-Sunyer, FX, Zhao, Q, et al
Archives of osteoporosis. 2023;(1):97
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Abstract
UNLABELLED Intentional weight loss has been shown to increase bone loss short term but the long-term effects are not known. Data from the Look AHEAD clinical trial shows that a long term intentional weight loss intervention was associated with greater bone loss at the hip in men. PURPOSE Intentional weight loss has been shown to increase bone loss short term and increase frailty fracture risk, but the long-term effects on bone mineral density (BMD) are not known. METHODS Data from a subgroup from the Look AHEAD (LA) multicenter, randomized clinical trial was used to evaluate whether a long term intentional weight loss intervention would increase bone loss. In a preplanned substudy, BMD was assessed at 5 of the 16 LA clinical centers using dual-energy X-ray absorptiometry at baseline, year 8, and the observational visit 12.6-16.3 years after randomization (year 12-16). RESULTS At year 8, bone density loss (%) was greater in the Intensive Lifestyle Intervention (ILI) group compared with the control group (DSE) for the femoral neck (p = 0.0122) but this finding was not observed at the year 12-16 visit. In analyses stratified by gender, bone density loss (%) was greater at the total hip for men in the ILI group than the DSE group at both the year 8 and year 12-16 visits (year 8 p = 0.0263 and year 12-16 p = 0.0062). This finding was not observed among women. CONCLUSION Long term intentional weight loss was associated with greater bone loss at the hip in men. These results taken with the previously published Look AHEAD data from the entire clinical trial showing increased frailty fracture risk with weight loss in the ILI group suggest that when intentional weight loss is planned, consideration of bone density preservation and fracture prevention strategies is warranted. TRIAL REGISTRATION Clinicaltrials.gov Identifier: NCT00017953. June 21, 2001.
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Examining the Composition of the Oral Microbiota as a Tool to Identify Responders to Dietary Changes.
Vach, K, Al-Ahmad, A, Anderson, A, Woelber, JP, Karygianni, L, Wittmer, A, Hellwig, E
Nutrients. 2022;(24)
Abstract
BACKGROUND The role of diet and nutrition in the prevention of oral diseases has recently gained increasing attention. Understanding the influence of diet on oral microbiota is essential for developing meaningful prevention approaches to oral diseases, and the identification of typical and atypical responders may contribute to this. METHODS We used data from an experimental clinical study in which 11 participants were exposed to different dietary regimens in five consecutive phases. To analyse the influence of additional nutritional components, we examined changes in bacterial concentrations measured by culture techniques compared to a run-in phase. A measure of correspondence between the mean and individual patterns of the bacterial composition is introduced. RESULTS The distance measures introduced showed clear differences between the subjects. In our data, two typical and three atypical responders appear to have been identified. CONCLUSIONS The proposed method is suitable to identify typical and atypical responders, even in small datasets. We recommend routinely performing such analyses.
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Applying Mendelian randomization to appraise causality in relationships between nutrition and cancer.
Wade, KH, Yarmolinsky, J, Giovannucci, E, Lewis, SJ, Millwood, IY, Munafò, MR, Meddens, F, Burrows, K, Bell, JA, Davies, NM, et al
Cancer causes & control : CCC. 2022;(5):631-652
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Abstract
Dietary factors are assumed to play an important role in cancer risk, apparent in consensus recommendations for cancer prevention that promote nutritional changes. However, the evidence in this field has been generated predominantly through observational studies, which may result in biased effect estimates because of confounding, exposure misclassification, and reverse causality. With major geographical differences and rapid changes in cancer incidence over time, it is crucial to establish which of the observational associations reflect causality and to identify novel risk factors as these may be modified to prevent the onset of cancer and reduce its progression. Mendelian randomization (MR) uses the special properties of germline genetic variation to strengthen causal inference regarding potentially modifiable exposures and disease risk. MR can be implemented through instrumental variable (IV) analysis and, when robustly performed, is generally less prone to confounding, reverse causation and measurement error than conventional observational methods and has different sources of bias (discussed in detail below). It is increasingly used to facilitate causal inference in epidemiology and provides an opportunity to explore the effects of nutritional exposures on cancer incidence and progression in a cost-effective and timely manner. Here, we introduce the concept of MR and discuss its current application in understanding the impact of nutritional factors (e.g., any measure of diet and nutritional intake, circulating biomarkers, patterns, preference or behaviour) on cancer aetiology and, thus, opportunities for MR to contribute to the development of nutritional recommendations and policies for cancer prevention. We provide applied examples of MR studies examining the role of nutritional factors in cancer to illustrate how this method can be used to help prioritise or deprioritise the evaluation of specific nutritional factors as intervention targets in randomised controlled trials. We describe possible biases when using MR, and methodological developments aimed at investigating and potentially overcoming these biases when present. Lastly, we consider the use of MR in identifying causally relevant nutritional risk factors for various cancers in different regions across the world, given notable geographical differences in some cancers. We also discuss how MR results could be translated into further research and policy. We conclude that findings from MR studies, which corroborate those from other well-conducted studies with different and orthogonal biases, are poised to substantially improve our understanding of nutritional influences on cancer. For such corroboration, there is a requirement for an interdisciplinary and collaborative approach to investigate risk factors for cancer incidence and progression.
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Sterol Biosynthesis Inhibition in Pregnant Women Taking Prescription Medications.
Genaro-Mattos, TC, Klingelsmith, KB, Allen, LB, Anderson, A, Tallman, KA, Porter, NA, Korade, Z, Mirnics, K
ACS pharmacology & translational science. 2021;(2):848-857
Abstract
Sterol biosynthesis is a critical homeostatic mechanism of the body. Sterol biosynthesis begins during early embryonic life and continues throughout life. Many commonly used medications, prescribed >200 million times in the United States annually, have a sterol biosynthesis inhibition side effect. Using our high-throughput LC-MS/MS method, we assessed the levels of post-lanosterol sterol intermediates (lanosterol, desmosterol, and 7-dehydrocholesterol (7-DHC)) and cholesterol in 1312 deidentified serum samples from pregnant women. 302 samples showing elevated 7-DHC were analyzed for the presence of 14 medications known to inhibit the 7-dehydrocholesterol reductase enzyme (DHCR7) and increase 7-DHC. Of the 302 samples showing 7-DHC elevation, 43 had detectable levels of prescription medications with a DHCR7-inhibiting side effect. Taking more than one 7-DHC-elevating medication in specific combinations (polypharmacy) might exacerbate the effect on 7-DHC levels in pregnant women, suggesting a potentially additive or synergistic effect. As 7-DHC and 7-DHC-derived oxysterols are toxic, and as DHCR7-inhibiting medications are considered teratogens, our findings raise potential concerns regarding the use of prescription medication with a DHCR7-inhibiting side effect during pregnancy. The use of prescription medications during pregnancy is sometimes unavoidable, but choosing a medication without a DHCR7-inhibiting side effect might lead to a heathier pregnancy and prevent putatively adverse outcomes for the developing offspring.
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A Log Ratio-Based Analysis of Individual Changes in the Composition of the Oral Microbiota in Different Dietary Phases.
Vach, K, Al-Ahmad, A, Anderson, A, Woelber, JP, Karygianni, L, Wittmer, A, Hellwig, E
Nutrients. 2021;(3)
Abstract
BACKGROUND Investigating the influence of nutrition on oral health has a long scientific history. Due to recent technical advances like sequencing techniques for the oral microbiota, this topic has gained scientific interest again. A basic challenge is to understand the influence of nutrition on the oral microbiota and on the interaction between the oral bacteria, which is also statistically challenging. METHODS Log-transformed ratios of two bacteria concentrations are introduced as the basic analytic tool. The framework is illustrated by application in an experimental study exposing eleven participants to different nutrition schemes in five consecutive phases. RESULTS The method could be sufficiently used to analyse the interrelation between the bacteria and to identify some bacterial groups with the same as well as different reactions to additional dietary components. It was found that the strongest changes in bacterial concentrations were achieved by the additional consumption of dairy products. CONCLUSION A log ratio-based analysis offers insights into the relation of different bacteria while taking specific features of compositional data into account. The presented methods allow becoming independent of the behaviour of other bacteria, which is a disadvantage of common analysis methods of compositions. The results indicate that modulations of the oral biofilm microbiota due to nutrition change can be attained.