Adjustment For Multiple Comparisons Research Articles

Adverse Events Following One Dose of mRNA COVID-19 Vaccination Among US Nursing Home Residents With and Without a Previous SARS-CoV-2 Infection

ObjectivesTo compare rates of adverse events following Coronavirus Disease 2019 (COVID-19) vaccination among nursing home residents with and without previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. DesignProspective cohort. Setting and ParticipantsA total of 20,918 nursing home residents who received the first dose of messenger RNA COVID-19 vaccine from December 18, 2020, through February 14, 2021, in 284 facilities within Genesis Healthcare, a large nursing home provider spanning 24 US states. MethodsWe screened the electronic health record for adverse events, classified by the Brighton Collaboration, occurring within 15 days of a resident’s first COVID-19 vaccine dose. All events were confirmed by physician chart review. To obtain risk ratios, multilevel logistic regression model that accounted for clustering (variability) across nursing homes was implemented. To balance the probability of prior SARS-CoV-2 infection (previous positive test or diagnosis by the International Classification of Diseases, 10th Revision, Clinical Modification) more than 20 days before vaccination, we used inverse probability weighting. To adjust for multiplicity of adverse events tested, we used a false discovery rate procedure. ResultsStatistically significant differences existed between those without (n = 13,163) and with previous SARS-CoV-2 infection [symptomatic (n = 5617) and asymptomatic (n = 2138)] for all baseline characteristics assessed. Only 1 adverse event was reported among those with previous SARS-CoV-2 infection (asymptomatic), venous thromboembolism [46.8 per 100,000 residents 95% confidence interval (CI) 8.3–264.5], which was not significantly different from the rate reported for those without previous infection (30.4 per 100,000 95% CI 11.8–78.1). Several other adverse events were observed for those with no previous infection, but were not statistically significantly higher than those reported with previous infection after adjustments for multiple comparisons. Conclusions and ImplicationsAlthough reactogenicity increases with preexisting immunity, we did not find that vaccination among those with previous SARS-CoV-2 infection resulted in higher rates of adverse events than those without previous infection. This study stresses the importance of monitoring novel vaccines for adverse events in this vulnerable population.

The impact of COVID-19 on complementary and alternative medicine providers: A cross-sectional survey in Norway

BackgroundThe Norwegian authorities decided in March 2020 to implement a nationwide lockdown to prevent spread of the COVID-19 virus. The lockdown had vast socioeconomic consequences for the society. The aim of this study was to investigate how COVID-19 affected Complementary and Alternative Medicine (CAM) providers’ practice, financial situation, recommendations to patients, and how they perceived their future practice as CAM providers. MethodData were collected in this cross-sectional survey using a self-administrated electronic questionnaire. A total of 581 CAM providers completed the questionnaire, which was designed to describe consequences for CAM providers and their clinical practice caused by the nationwide lockdown. Descriptive statistics were carried out using frequency analyses to describe the demographics and consequences of the lockdown. Between group differences (gender and age) were analyzed using Pearson chi-square tests and Fisher’s exact tests for categorical variables, and ANOVA tests and t-tests for continuous variables. Significance level was defined as p < 0.05 without adjustment for multiple comparisons. ResultDuring the nationwide lockdown of Norway, 38.4% of the respondents were able to provide CAM treatment to their patients. Of those, the majority (96.4%) had reorganized their clinical practice in accordance with COVID-19 hygiene regulations, offered video consultations (57.4%) or telephone consultations (46.6%). To manage financially during the lockdown, half of the providers spent their savings (48.7%). More than one third (35.1%) was supported by their partner, and 26.7% received compensation from the Norwegian state. A total of 26.3% of the CAM providers had other paid work that provided them with income. Nearly a fifth (18.6%) borrowed money from friends and family, changed their loan terms, or took out new bank loans. More than half (62.7%) expressed uncertainty about the future of their practice. CAM providers who had reorganized their practice to online consultations were more optimistic. ConclusionThe impact of COVID-19 on CAM providers was considerable. It adversely affected their clinical practice, financial situation, and view on their future practice. To ensure that the health needs of the Norwegian population regarding CAM use are met during pandemic times like COVID-19, it is recommended to support and train CAM providers in the development of online CAM services, as well as efficient implementation of infection prevention and control measures.

Effects of Exercise and Weight Loss on Proximal Aortic Stiffness in Older Adults With Obesity.

Obesity may accelerate age-related increases in aortic stiffness. Although aerobic exercise training generally has favorable effects on aortic structure and function, exercise alone may not be sufficient to improve aortic stiffness in older adults with obesity. We determined the effects of aerobic exercise training with and without moderate- to high-caloric restriction (CR) on the structure and function of the proximal aorta in 160 older (65-79 years) men and women with obesity (body mass index=30-45 kg/m2). Participants were randomly assigned to 1 of 3 groups: aerobic exercise training only (treadmill 4 days/week for 30 minutes at 65% to 70% of heart rate reserve; n=56), aerobic exercise training plus moderate CR (n=55), or aerobic exercise training plus more intensive CR (n=49) for 20 weeks. Aortic pulse wave velocity, aortic distensibility, and other measures of aortic structure and function were assessed by cardiovascular magnetic resonance imaging. Pearson correlation coefficients were examined to assess associations between changes in proximal aortic stiffness and changes in fitness, fatness, and other potential confounders. Weight loss in the aerobic exercise training plus moderate CR (-8.0 kg [95% CI, -9.17 to -6.87]) and aerobic exercise training plus more intensive CR (-8.98 kg [95% CI, -10.23 to -7.73) groups was significantly greater compared with the aerobic exercise training-only group (-1.66 kg [95% CI, -2.94 to -0.38]; P<0.017 for both). There were significant treatment effects for descending aorta distensibility (P=0.008) and strain (P=0.004) and aortic arch pulse wave velocity (P=0.01) with the aerobic exercise training plus moderate CR group having a 21% increase in distensibility (P=0.016) and an 8% decrease in pulse wave velocity (P=0.058). None of the aortic stiffness measures changed significantly in the aerobic exercise training-only or aerobic exercise training plus more intensive CR groups, and there were no significant changes in any other measure of aortic structure or function in these groups. Overall, increases in aortic distensibility were correlated with improvements in body weight and body fat distribution, but these associations were not statistically significant after adjustment for multiple comparisons. In older adults with obesity, combining aerobic exercise with moderate CR leads to greater improvements in proximal aortic stiffness than exercise alone. Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT01048736.

Circulating blood metabolite trajectories and risk of rheumatoid arthritis among military personnel in the Department of Defense Biorepository

ObjectivesWe sought to identify metabolic changes potentially related to rheumatoid arthritis (RA) pathogenesis occurring in the blood prior to its diagnosis.MethodsIn a US military biorepository, serum samples collected at two...

The bacterial microbiota of Hunner lesion interstitial cystitis/bladder pain syndrome.

To undertake the first comprehensive evaluation of the urinary microbiota associated with Hunner lesion (HL) interstitial cystitis/bladder pain syndrome (IC/BPS). Despite no previous identification of a distinct IC/BPS microbial urotype, HL IC/BPS, an inflammatory subtype of IC/BPS, was hypothesized most likely to be associated with a specific bacterial species or microbial pattern. The bacterial microbiota of midstream urine specimens from HL IC/BPS and age- and gender-matched IC/BPS patients without HL (non-HL IC/BPS) were examined using the pan-bacterial domain clinical-level molecular diagnostic Pacific Biosciences full-length 16S gene sequencing protocol, informatics pipeline and database. We characterized the differential presence, abundances, and diversity of species, as well as gender-specific differences between and among HL and non-HL IC/BPS patients. A total of 59 patients with IC/BPS were enrolled (29 HL, 30 non-HL; 43 women, 16 men) from a single centre and the microbiota in midstream urine specimens was available for comparison. The species abundance differentiation between the HL and non-HL groups (12 species) was not significantly different after Bonferroni adjustments for multiple comparisons. Similarly, the nine differentiating species noted between female HL and non-HL patients were not significantly different after similar statistical correction. However, four species abundances (out of the 10 species differences identified prior to correction) remained significantly different between male HL and non-HL subjects: Negativicoccus succinivorans, Porphyromonas somerae, Mobiluncus curtisii and Corynebacterium renale. Shannon diversity metrics showed significantly higher diversity among HL male patients than HL female patients (P = 0.045), but no significant diversity differences between HL and non-HL patients overall. We were not able to identify a unique pathogenic urinary microbiota that differentiates all HL from all non-HL IC/BPS. It is likely that the male-specific differences resulted from colonization/contamination remote from the bladder. We were not able to show that bacteria play an important role in patients with HL IC/BPS.

Effect of Aerobic Exercise on White Matter Tract Microstructure in Young and Middle-Aged Healthy Adults

Recent evidence suggests that being physically active can mitigate age-related white matter (WM) changes. In a randomized clinical trial, the effect of 6-month aerobic exercise (AE) or stretching/toning interventions on measures of WM microstructure (WMM) was assessed in a sample of 74 adults aged 20–67 years. Major WM pathways were reconstructed. No significant group-level change in WM tract microstructure following an AE training was observed. Without adjustment for multiple comparisons, an increase in fractional anisotropy (FA) and a decrease in mean diffusivity (MD) of the uncinate fasciculus were observed post-intervention in the AE group in comparison with the stretching group. In the AE group, a significant increase in cardiorespiratory fitness was measured but did not correlate with FA and MD change. The present results of this study are in accordance with similar studies in healthy adults that did not show significant benefit on WMM after participating in an AE program.Clinical Trial Registration: Clinicaltrials.gov identifier, NCT01179958.

Abstract LB079: Circulating plasma phospholipid fatty acid levels &amp; breast cancer risk in the CPS-II Nutrition Cohort

Abstract Circulating plasma phospholipid fatty acid levels and breast cancer risk in the CPS-II Nutrition Cohort Background The association between dietary fat intake and breast cancer risk has been a source of controversy with conflicting results reported in past decades. Additional prospective studies that objectively measure circulating levels of fatty acids are now needed to better understand the associations between dietary fat and breast cancer development. MethodsWe assessed the relation between breast cancer risk and plasma levels of 60 phospholipid fatty acids in a nested case-control study of 2,718 postmenopausal women (905 breast cancer cases and 1,813 matched controls) enrolled in the Cancer Prevention Study II (CPS-II) Nutrition Cohort. Blood samples were collected at baseline (1997-1998). Multivariable-adjusted conditional logistic regression models that included established breast cancer risk factors (alcohol use, postmenopausal hormone use, smoking status, waist circumference, body mass index, and weight change from age 18 years to blood draw) were used to compute odds ratios (OR) and 95% confidence intervals (CI). The false discovery rate (FDR; q-value) was computed to control for multiple comparisons. ResultsAfter adjustment for multiple comparisons and in continuous log-transformed multivariable models, plasma levels of myristic acid (a saturated fatty acid) were positively associated with breast cancer risk (OR per log-value, 1.17, 95% CI: 1.07-1.28; q-value = 0.03), with similar magnitude associations found for estrogen receptor (ER) positive and ER negative breast cancer (p-interaction = 0.39). Positive associations were also found for plasma levels of monounsaturated fatty acid (OR per log-value, 1.09, 95% CI: 1.00-1.18; q-value = 0.24), palmitoleic acid (OR per log-value, 1.14, 95% CI: 1.04-1.24; q-value = 0.09), palmitic acid (OR per log-value, 1.12, 95% CI: 1.01-1.24; q-value = 0.17), dihomo-γ-linolenic acid (OR per log-value, 1.14, 95% CI: 1.04-1.25; q-value = 0.09), and adrenic acid (OR per log-value, 1.13, 95% CI: 1.03-1.24; q-value = 0.11) with breast cancer risk; however, after adjustment for multiple comparisons these associations did not reach the threshold of statistical significance. Similarly, inverse associations between plasma levels of trans α-linolenic acid (OR per log-value, 0.85, 95% CI: 0.76-0.96; q-value = 0.09), heptadecanoic acid (OR per log-value, 0.90, 95% CI: 0.82-0.99; q-value = 0.17), and vaccenic acid (OR per log-value, 0.88, 95% CI: 0.80-0.97; q-value = 0.11) with breast cancer risk were not statistically significant after adjustment for multiple comparisons. ConclusionThese findings suggest that higher circulating levels of myristic acid, that can be sourced from dietary intake of dairy foods or via de novo synthesis, may increase breast cancer risk. Additional studies are needed to replicate this finding and provide mechanistic insights. Citation Format: Michele Matta, Emily Deubler, Veronique Chajès, Marc Gunter, Neil Murphy, Mia M. Gaudet. Circulating plasma phospholipid fatty acid levels &amp; breast cancer risk in the CPS-II Nutrition Cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB079.

Mortality Before and After Border Wall Construction Along the US-Mexico Border, 1990-2017.

Objectives. To evaluate changes in mortality in US counties along the US-Mexico border in which there was substantial new border wall construction after the Secure Fence Act of 2006 relative to border counties in which there was no such border wall construction. Methods. Using complete 1990 to 2017 mortality microdata and a quasi-experimental difference-in-differences design, we evaluated changes in overall (all-cause) mortality, mortality from drug overdose, and mortality from homicide in the 10 counties with substantial new border wall construction and 11 counties with no such construction. We fit a linear model, adjusting for population characteristics and county and year fixed effects, with Bonferroni adjustments for multiple comparisons. Sensitivity analyses included the addition of adjacent inland counties and modifications to the statistical model. Results. Relative to counties without substantial new border wall construction, counties in which a substantial amount of new border wall was constructed exhibited a nonsignificant 0.02-percentage-point increase (95% confidence interval [CI] = -0.06, 0.10; P > .99) in overall mortality after construction. Border wall construction was not associated with changes in either deaths from overdose or deaths from homicide. Conclusions. Wall construction along the US-Mexico border after the Secure Fence Act of 2006 was not associated with discernible changes in mortality.

Comparison of Accuracy of Alginate Impression and Intraoral Scanner in Model with and without Orthodontic Brackets

Surgical splints are widely used in orthognathic surgery. The fitting of a surgical splint affects the success of the surgery. Stereolithography (STL), the method used to achieve accurate and reliable input files, is important for the manufacturing process of the surgical splint. Nowadays, data acquisition can be performed with the aid of an intraoral scanner (IOS) or impression materials. This in vitro study aimed to compare the trueness and precision of IOS (TRIOS3®, 3Shape, Copenhagen, Denmark) and alginate impression (Kromopan®, Lascod, Florence, Italy) in a full-arch dental model with/without orthodontic brackets. Custom complete arch models were fabricated with a refractive index similar to that of tooth structure. A TRIOS3® intraoral scanner (3Shape, Copenhagen, Denmark) and an alginate impression were used to duplicate the custom model without orthodontic brackets for complete arch scenarios (both upper and lower arches), n = 5. Subsequently, orthodontic brackets (Ormco®, Glendora, CA, USA) were attached to the custom model and the TRIOS® intraoral scanner and alginate impression were used again. Analysis was performed using 3-dimensional (3D) metrology software (GOM inspect®, GOM GmbH, Braunschweig, Germany) to measure surface deviations between the STL files from the custom model to evaluate and compare their trueness and precision. All data were entered into Microsoft Excel and then transferred to SPSS (Statistical Package for the Social Sciences). The average surface deviations were compared between the TRIOS3® intraoral scanner and the alginate impression using a repeated measures ANOVA (Analysis of Variance) with adjustment for multiple comparisons using Bonferroni’s correction. There were no significant differences in trueness and precision between TRIOS3® and alginate impression in full arch models with and without orthodontic brackets. Moreover, the accuracy of all groups was less than 100 microns, which was acceptable. Further in vivo studies are required to confirm these results.

Bosutinib Vs Imatinib for Newly Diagnosed Chronic Myeloid Leukemia in the BFORE Trial: Results By 3-Month BCR-ABL1 Transcript Level

Introduction: Bosutinib is a potent SRC/ABL tyrosine kinase inhibitor approved for treatment of Philadelphia chromosome-positive CML in adults resistant or intolerant to prior therapy. This analysis evaluated the efficacy of first-line bosutinib versus imatinib in the BFORE study (NCT02130557) by 3-month BCR-ABL1 transcripts ≤10% versus >10% and examined baseline and on-treatment characteristics as predictors of time to major molecular response (MMR).Methods: In this ongoing, multinational, phase 3, open-label study, 536 patients were randomized 1:1 to bosutinib 400 mg or imatinib 400 mg once daily. The present analysis is based on ≥12 months of follow-up. Baseline and on-treatment time-dependent covariates were analyzed using a proportional subdistribution hazards model predicting time to initial MMR. No adjustment for multiple comparisons was made.Results: The intent-to-treat (ITT) population included 268 patients in the bosutinib arm and 268 patients (including 3 untreated patients) in the imatinib arm. Among evaluable patients (≥3000 ABL1 analyzed) at 3 months in the ITT population, more patients in the bosutinib arm than in the imatinib arm had BCR-ABL1 transcripts ≤10% (80.6% of 248 patients vs 60.5% of 253 patients; P <0.0001). The MMR rate at 12 months was higher in evaluable patients who had transcripts ≤10% versus >10% at 3 months with bosutinib (117 [58.5%] vs 7 [14.6%], P <0.0001) and with imatinib (83 [54.2%] vs 14 [14.0%], P <0.0001). The cumulative MMR rates were also higher in evaluable patients with transcripts ≤10% with bosutinib (138 [69.0%] vs 12 [25%]; P <0.0001) and with imatinib (100 [65.4%] vs 30 [30.0%]; P <0.0001). In the ITT population, transcripts ≤10% (vs >10% or not evaluable) at 3 months was a predictor of time to MMR in both arms (Table; bosutinib: hazard ratio [HR]=6.44, P <0.0001; imatinib: HR=3.69, P <0.0001). The only other predictor of time to MMR among the covariates examined was not having a bosutinib dose reduction to 300 mg due to an adverse event.Conclusion: BOS treatment was associated with a higher number of patients presenting transcripts ≤10% at 3 months than those treated with IMA. Patients with transcripts ≤10% at 3 months had higher rates of 12-month MMR and achieved response faster than those with transcripts >10%. These findings suggest that the transcript level at 3 months may be a predictor of response to first-line bosutinib and imatinib. [Display omitted] DisclosuresHochhaus:Novartis: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Ariad: Research Funding; MSD: Research Funding; BMS: Research Funding. Gambacorti-Passerini:Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy. Deininger:BMS: Consultancy, Research Funding; ARIAD: Consultancy; Ariad Pharmaceuticals, Bristol Myers Squibb, CTI BioPharma Corp, Gilead, Incyte, Novartis, Pfizer, Celgene, Blue Print, Galena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Gilead: Research Funding; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Celgene: Research Funding. Mauro:Bristol-Myers Squibb: Consultancy. Chuah:Chiltern: Honoraria; BMS: Honoraria, Other: Travel; Novartis: Honoraria; Avillion: Honoraria. Kim:Il-Yang: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Milojkovic:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Honoraria, Speakers Bureau; ARIAD: Consultancy, Honoraria. le Coutre:BMS: Honoraria; Pfizer: Honoraria; Novartis: Honoraria, Research Funding; Incyte: Honoraria; ARIAD: Honoraria. García Gutiérrez:Incyte: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Reilly:Avillion LLP: Employment. Jeynes-Ellis:Avillion LLP: Employment, Equity Ownership. Crescenzo:Pfizer: Employment, Equity Ownership. Leip:Pfizer: Employment, Equity Ownership. Bardy-Bouxin:Pfizer: Employment, Equity Ownership. Brümmendorf:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Cortes:ARIAD: Consultancy, Research Funding; Teva: Research Funding; Sun Pharma: Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding.

A genetic polymorphism in P2RY1 impacts response to clopidogrel in cats with hypertrophic cardiomyopathy

Clopidogrel is converted to its active metabolite by cytochrome P450 isoenzymes and irreversibly inhibits platelet activation by antagonizing the adenosine-diphosphate (ADP) receptor. It is frequently used in cats with hypertrophic cardiomyopathy (HCM) to prevent thromboembolic complications. However, significant interpatient variability of the response to clopidogrel therapy has been suspected. In this study, we assessed the impact of single nucleotide polymorphisms (SNPs) within ADP receptor (P2RY1, P2RY12) and cytochrome P450 isoenzyme (CYP2C41) genes on platelet inhibition by clopidogrel administration in cats with HCM. Forty-nine cats completed the study, and blood samples were obtained before and after clopidogrel therapy to assess the degree of platelet inhibition based on flow cytometry and whole blood platelet aggregometry. Plasma concentrations of clopidogrel metabolites were measured after the last dose of clopidogrel. Whole blood platelet aggregometry revealed a significant reduction of platelet inhibition by clopidogrel in cats with the P2RY1:A236G and the P2RY12:V34I variants. The association with the P2RY1:A236G variant and clopidogrel resistance remained significant after adjustment for multiple comparisons. This study demonstrated that a genetic polymorphism in the P2RY1 gene altered response to clopidogrel therapy and suggests that clinicians may consider alternative or additional thromboprophylactic therapy in cats with the P2RY1:A236G variant.

The effects of vitamin D supplementation on types of falls.

To assess whether vitamin D supplementation prevents specific fall subtypes and sequelae (e.g., fracture). Secondary analyses of STURDY (Study to Understand Fall Reduction and Vitamin D in You)-a response-adaptive, randomized clinical trial. Two community-based research units. Six hundred and eighty-eight participants ≥70 years old with elevated fall risk and baseline serum 25-hydroxyvitamin D levels of 10-29 ng/ml. 200 IU/day (control), 1000 IU/day, 2000 IU/day, or 4000 IU/day of vitamin D3. Outcomes included repeat falls and falls that were consequential, were injurious, resulted in emergency care, resulted in fracture, and occurred either indoors or outdoors. After adjustment for multiple comparisons, the risk of fall-related fracture was greater in the pooled higher doses (≥1000 IU/day) group compared with the control (hazard ratio [HR]=2.66; 95% confidence interval [CI]:1.18-6.00). Although not statistically significant after multiple comparisons adjustment, time to first outdoor fall appeared to differ between the four dose groups (unadjusted p for overall difference=0.013; adjusted p= 0.222), with risk of a first-time outdoor fall 39% lower in the 1000 IU/day group (HR=0.61; 95% CI: 0.38-0.97; unadjusted p= 0.036; adjusted p= 0.222) and 40% lower in the 2000 IU/day group (HR=0.60; 95%CI 0.38-0.97; p= 0.037; adjusted p= 0.222), each versus control. Vitamin D supplementation doses ≥1000 IU/day might have differential effects on fall risk based on fall location and fracture risk, with the most robust finding that vitamin D doses between 1000 and 4000 IU/day might increase the risk of first time falls with fractures. Replication is warranted, given the possibility of type 1 error.

Using a consumer-based wearable activity tracker for physical activity goal setting and measuring steps in pregnant women with gestational diabetes mellitus: exploring acceptance and validity

BackgroundActivity monitoring devices may be used to facilitate goal-setting, self-monitoring, and feedback towards a step-based physical activity (PA) goal. This study examined the performance of the wrist-worn Fitbit Charge 3™ (FC3) and sought opinions on walking and stepping-in-place from women with gestational diabetes (GDM).MethodsParticipants completed six 2-min metronome-assisted over ground bouts that varied by cadence (67, 84, or 100 steps per minute) and mode (walking or stepping-in-place; N = 15), with the sequence randomized. Steps were estimated by FC3 and measured, in duplicate, by direct observation (hand-tally device, criterion). Equivalence testing by the two one-sided tests (TOST) method assessed agreement within ± 15%. Mean absolute percent error (MAPE) of steps were compared to 10%, the accuracy standard of the Consumer Technology Association (CTA)™. A subset (n = 10) completed a timed, 200-m self-paced walk to assess natural walking pace and cadence. All participants completed semi-structured interviews, which were transcribed and analyzed using descriptive and interpretive coding.ResultsMean age was 27.0 years (SD 4.2), prepregnancy BMI 29.4 kg/m2 (8.3), and gestational age 32.8 weeks (SD 2.6). The FC3 was equivalent to hand-tally for bouts of metronome-assisted walking and stepping-in-place at 84 and 100 steps per minute (i.e., P < .05), although walking at 100 steps per minute (P = .01) was no longer equivalent upon adjustment for multiple comparisons (i.e., at P < .007). The FC3 was equivalent to hand-tally during the 200-m walk (i.e., P < .001), in which mean pace was 68.2 m per minute (SD 10.7), or 2.5 miles per hour, and mean cadence 108.5 steps per minute (SD 6.5). For walking at 84 and 100 steps per minute, stepping-in-place at 100 steps per minute, and the 200-m walk, MAPE was within 10%, the accuracy standard of the CTA™. Interviews revealed motivation for PA, that stepping-in-place was an acceptable alternative to walking, and competing responsibilities made it difficult to find time for PA.ConclusionsThe FC3 appears to be a valid step counter during the third trimester, particularly when walking or stepping-in-place at or close to women’s preferred cadence.

Circulating Cytokines and Coronavirus Disease: A Bi-Directional Mendelian Randomization Study.

BackgroundImmune system functioning is relevant to vulnerability to coronavirus disease (COVID-19). Cytokines are important to immunity. To further elucidate the role of the immune system in COVID-19, we used Mendelian randomization (MR) to assess comprehensively and bi-directionally the role of cytokines in COVID-19.MethodsWe assessed primarily whether genetically different levels of 41 cytokines affected risk of any COVID-19 (laboratory confirmed, physician confirmed or self-reported, 36,590 cases, 1,668,938 controls), and conversely if genetic risk of liability to any COVID-19 affected these cytokines (n ≤ 8293) using the most recent genome-wide association studies. We obtained inverse variance weighting (IVW) estimates, conducted sensitivity analyses and used a Benjamini-Hochberg correction to account for multiple comparisons. We also assessed whether any findings were evident for hospitalized COVID-19 (hospitalized laboratory confirmed, 12,888 cases, 1,295,966 controls).ResultsMacrophage inflammatory protein-1β (MIP1b; more commonly known as Chemokine (C-C motif) ligands 4 (CCL4) was inversely associated with COVID-19 [odds ratio (OR) 0.97 per SD, 95% confidence interval (CI) 0.96–0.99] but not after adjustment for multiple comparisons. This finding replicated for hospitalized COVID-19 (OR 0.93, 95% CI 0.89–0.98). Liability to any COVID-19 was nominally associated with several cytokines, such as granulocyte colony-stimulating factor (GCSF) and hepatocyte growth factor (HGF) but not after correction.ConclusionA crucial element of immune response to infection (CCL4) was related to COVID-19, whether it is a target of intervention to prevent COVID-19 warrants further investigation.

Bilateral Bispectral Index Monitoring Performance in the Detection of Seizures in Nonanesthetized Epileptic Patients: An Observational Study.

The aim of this observational study was to determine whether bilateral bispectral index (BIS) monitoring can detect seizures in epileptic patients. Four-channel frontal BIS monitoring and standard 40-channel electroencephalography monitoring were conducted in epileptic patients undergoing evaluation for epilepsy surgery. The BIS numerical value, signal quality index, electromyography, suppression ratio, and color density spectral array were continuously recorded. In patients with electroencephalography-confirmed seizures, the mean value and trend (slope of linear regression) of bilateral BIS monitor parameters were analyzed from 1 minute before to 1 minute after seizure onset. Of 48 patients included in the study, 21 (43.8%) had at least 1 seizure. BIS numerical value was not able to detect focal or focal to bilateral tonic-clonic seizures. Considering all seizures, the only significant differences between recordings 1 minute before and 1 minute after seizure onset were a decrease in the signal quality index slope from 1 hemisphere (0.039±0.297 vs. -0.085±0.321, respectively; P =0.029) and in the mean signal quality index recorded from both hemispheres (left hemisphere: 65.775±30.599 vs. 61.032±26.285; P =0.016 and right hemisphere: 63.244±31.985 vs. 59.837±27.360; 0.029); these differences were not maintained after Hochberg adjustment for multiple comparisons. In seizures occurring during sleep, there was a change in the electromyography slope of 1 hemisphere before and after seizure onset (-0.141±0.176 vs. 0.162±0.140, respectively; P =0.038). There were variable responses in BIS parameters in the 3 patients who developed focal nonconvulsive seizure clusters. Bilateral BIS monitoring was not able to detect the occurrence of seizures in epileptic patients.

Maternal Biomarkers of Nutritional Status Prior to Pregnancy and Newborn Epigenetic Aging

ObjectivesMaternal diet prior to and during pregnancy has been related to child health across the lifespan; however, mechanisms remain unclear. Gestational age acceleration (GAA), a measure of epigenetic aging relative to clinically estimated gestational age (GA), has emerged as a potential biomarker predictive of childhood BMI and atopic diseases. Few studies have evaluated the associations of maternal nutrient biomarkers, including methyl donors and fatty acids (FA), with GAA. MethodsWe evaluated associations among 391 mother-child dyads in the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial. Women were randomized to low-dose aspirin (LDA) or placebo, both containing 400 μg folic acid, prior to and through 36 weeks pregnancy. Maternal folate, homocysteine, vitamin B-12, vitamin D, carotenoids, tocopherols, and plasma FAs were quantified from blood samples obtained ≤6 months prior to conception and at 8 weeks gestation. DNA methylation was measured with the Infinium MethylationEPIC BeadChip using cord blood DNA. Epigenetic GA was calculated using the Knight and Bohlin clocks. GAA was defined as the residual from a model regressing GA on epigenetic GA. We assessed associations between nutritional biomarkers and GAA using robust linear regression, controlling for maternal age, race, education, employment status, total cholesterol, and child sex. A false discovery rate (FDR) correction was applied to account for multiple comparisons using the Benjamini-Hochberg method. ResultsMean (SD, range) clinically estimated GA at delivery was 38.9 (1.5, 31.1–44.9) weeks and was positively correlated with epigenetic age (Knight clock r = 0.51, Bohlin clock r = 0.76). Being female was positively related to GAAKnight. Maternal age was positively associated with GAABohlin. In multivariable regression models, preconception folate was inversely related to GAABohlin (β = –0.004, 95% CI: –0.007–0.000, P = 0.04); however, this was not significant after adjustment for multiple comparisons (FDR P = 0.82). Other nutritional biomarkers and LDA were not related to GAA. ConclusionsMaternal nutritional biomarkers prior to conception and during early pregnancy were not related to newborn epigenetic age acceleration in predominantly term deliveries among women supplemented with folic acid. Funding SourcesSupported by the Intramural Research Program of the NICHD.

Comparison of Skin Carotenoid Content among Older Adults with Obesity, Hypertension, and Diabetes Mellitus

Abstract Objectives Carotenoids found in vegetables can be deposited in tissues following metabolism and used as antioxidants. The objective of this study was to compare skin carotenoid content (SCC) among older adults with varying conditions of metabolic-related disease (obesity, hypertension, and type 2 diabetes mellitus). Methods This was a cross-sectional analysis using baseline data from the Nutrition Interventions for Cognitive Enhancement study. Participants (n = 120) are cognitively normal (MMSE &amp;gt; 25) adults ≥65 years. SCC was determined by pressure-mediated reflection spectroscopy (VEGGIE METER®; Longevity Link Corporation). Three measurements were taken on the fingertip and averaged. Diagnosis of hypertension and/or diabetes mellitus type 2 (DM2) were self-reported and verified through vital signs/laboratory measures. Obesity was considered BMI ≥ 30.0 kg/m2. Mean differences between groups were assessed using ANOVA and Tukeys’ HSD adjustment for multiple comparisons in R (v. 3.6.2; R Foundation, Vienna, Austria). Significance was alpha = 0.05. Results The cohort (80% female) included n = 41 with diabetes, n = 62 with hypertension, and n = 8 with DM2. Further, n = 41 had no diagnosed conditions, n = 51 had any one of the diagnosed conditions, n = 24 had a combination of two conditions, and n = 4 had all three. The overall mean SCC was 277.4 ± 91.3. Obese individuals had a mean SCC score of 261.5 ± 96.9 versus 294.4 ± 82.3 for non-obese individuals (P = 0.047). Individuals with hypertension had a mean SCC score of 246.4 ± 85.2 versus 293.5 ± 90.7 for those who did not (P = 0.006). Mean SCC values for those diagnosed with zero conditions was 292.7 ± 87.4, one condition was 296.8 ± 89.8, two conditions was 218.3 ± 82.1, and three conditions was 227.5 ± 40.9. Individuals with 2 diagnoses had significantly lower SCC values versus those with zero conditions (P = 0.004) and one condition (P = 0.001). The number of individuals in this cohort with DM2 (n = 8) was too small for comparison. Conclusions Mean SCC measures differ between individuals with the inflammatory syndromes of obesity and hypertension. Future studies should consider how carotenoid deposition varies in inflammatory disease states where antioxidant requirements may be higher due to increased oxidative stress. Funding Sources NIH R01AG060157–01.

Linked color imaging, mucosal exposure device, their combination, and standard colonoscopy for adenoma detection: a randomized trial

By different mechanisms, image-enhancement techniques (linked color imaging [LCI]) and mucosal exposure devices (Endocuff-assisted colonoscopy [EAC]) can improve the adenoma detection rate (ADR) during screening colonoscopy. The impact of the combination of the 2 techniques has never been studied. This study aimed to compare the ADR between the combination of LCI and EAC (LCI+EAC), LCI alone, EAC alone, and standard high-definition (HD) colonoscopy. This prospective randomized controlled trial included participants who underwent screening colonoscopy. Participants were randomized to LCI+EAC, LCI, EAC, and standard HD colonoscopy. All colonoscopies were performed by endoscopists with a recorded ADR≥35%. The primary outcome was the ADR. Secondary outcomes were proximal ADR (pADR) and the mean number of adenomas per colonoscopy (APC). One thousand participants were included in the study. The LCI+EAC group provided the highest ADR and pADR. The ADRs in the LCI+EAC, LCI, EAC, and standard HD colonoscopy groups were 57.2%, 52.8%, 51.6%, and 47.6%, respectively, with pADRs of 38.4%, 34.8%, 33.6%, and 28.0%, respectively. The mean numbers of APC were 1.28, 1.20, 1.16, and .89, respectively. After a multiple comparison adjustment, a significant difference in pADR was only observed between the LCI+EAC and standard HD colonoscopy groups (difference, 10.3 percentage points; 95% confidence interval, .02%-17.4%; P= .05). The incidence rate ratios of the adenoma numbers were significantly higher in the LCI+EAC (1.43), LCI (1.34), and EAC (1.30) groups relative to the standard HD colonoscopy group (.89) (P< .009 for all comparisons). The combination of LCI and EAC can significantly improve the detection of pADR and APC but not ADR by high-ADR performers. (Clinical trial registration number: TCTR20190319001.).

Metabolomic profiling identifies complex lipid species and amino acid analogues associated with response to weight loss interventions.

Obesity is an epidemic internationally. While weight loss interventions are efficacious, they are compounded by heterogeneity with regards to clinically relevant metabolic responses. Thus, we sought to identify metabolic biomarkers that are associated with beneficial metabolic changes to weight loss and which distinguish individuals with obesity who would most benefit from a given type of intervention. Liquid chromatography mass spectrometry-based profiling was used to measure 765 metabolites in baseline plasma from three different weight loss studies: WLM (behavioral intervention, N = 443), STRRIDE-PD (exercise intervention, N = 163), and CBD (surgical cohort, N = 125). The primary outcome was percent change in insulin resistance (as measured by the Homeostatic Model Assessment of Insulin Resistance [%ΔHOMA-IR]) over the intervention. Overall, 92 individual metabolites were associated with %ΔHOMA-IR after adjustment for multiple comparisons. Concordantly, the most significant metabolites were triacylglycerols (TAGs; p = 2.3e-5) and diacylglycerols (DAGs; p = 1.6e-4), with higher baseline TAG and DAG levels associated with a greater improvement in insulin resistance with weight loss. In tests of heterogeneity, 50 metabolites changed differently between weight loss interventions; we found amino acids, peptides, and their analogues to be most significant (4.7e-3) in this category. Our results highlight novel metabolic pathways associated with heterogeneity in response to weight loss interventions, and related biomarkers which could be used in future studies of personalized approaches to weight loss interventions.

Regular Strength and Sprint Training Counteracts Bone Aging: A 10-Year Follow-Up in Male Masters Athletes.

ABSTRACTCross‐sectional and interventional studies suggest that high‐intensity strength and impact‐type training provide a powerful osteogenic stimulus even in old age. However, longitudinal evidence on the ability of high‐intensity training to attenuate age‐related bone deterioration is currently lacking. This follow‐up study assessed the role of continued strength and sprint training on bone aging in 40‐ to 85‐year‐old male sprinters (n = 69) with a long‐term training background. Peripheral quantitative computed tomography (pQCT)‐derived bone structural, strength, and densitometric parameters of the distal tibia and tibia midshaft were assessed at baseline and 10 years later. The groups of well‐trained (actively competing, sprint training including strength training ≥2 times/week; n = 36) and less‐trained (<2 times/week, no strength training, switched to endurance training; n = 33) athletes were formed according to self‐reports at follow‐up. Longitudinal changes in bone traits in the two groups were examined using linear mixed models. Over the 10‐year period, group‐by‐time interactions were found for distal tibia total bone mineral content (BMC), trabecular volumetric bone mineral density (vBMD), and compressive strength index, and for mid‐tibia cortical cross‐sectional area, medullary area, total BMC, and BMC at the anterior and posterior sites (polar mass distribution analysis) (p < 0.05). These interactions reflected maintained (distal tibia) or improved (mid‐tibia) bone properties in the well‐trained and decreased bone properties in the less‐trained athletes over the 10‐year period. Depending on the bone variable, the difference in change in favor of the well‐trained group ranged from 2% to 5%. The greatest differences were found in distal tibia trabecular vBMD and mid‐tibia posterior BMC, which remained significant (p < 0.05) after adjustment for multiple testing. In conclusion, our longitudinal findings indicate that continued strength and sprint training is associated with maintained or even improved tibial properties in middle‐aged and older male sprint athletes, suggesting that regular, intensive exercise counteracts bone aging. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.