Category: Statistics

J Affect Disord. 2022 Apr 2:S0165-0327(22)00317-2. doi: 10.1016/j.jad.2022.03.070. Online ahead of print.

ABSTRACT

BACKGROUND: Altered metabolism of acylcarnitines – transporting fatty acids to mitochondria – may link cellular energy dysfunction to depression. We examined the potential causal role of acylcarnitine metabolism in depression by leveraging genomics and Mendelian randomization.

METHODS: Summary statistics were obtained from large GWAS: the Fenland Study (N = 9363), and the Psychiatric Genomics Consortium (246,363 depression cases and 561,190 controls). Two-sample Mendelian randomization analyses tested the potential causal link of 15 endogenous acylcarnitines with depression.

RESULTS: In univariable analyses, genetically-predicted lower levels of short-chain acylcarnitines C2 (odds ratio [OR] 0.97, 95% confidence intervals [CIs] 0.95-1.00) and C3 (OR 0.97, 95%CIs 0.96-0.99) and higher levels of medium-chain acylcarnitines C8 (OR 1.04, 95%CIs 1.01-1.06) and C10 (OR 1.04, 95%CIs 1.02-1.06) were associated with increased depression risk. No reverse potential causal role of depression genetic liability on acylcarnitines levels was found. Multivariable analyses showed that the association with depression was driven by the medium-chain acylcarnitines C8 (OR 1.04, 95%CIs 1.02-1.06) and C10 (OR 1.04, 95%CIs 1.02-1.06), suggesting a potential causal role in the risk of depression. Causal estimates for C8 (OR = 1.05, 95%CIs = 1.02-1.07) and C10 (OR = 1.05, 95%CIs = 1.02-1.08) were confirmed in follow-up analyses using genetic instruments derived from a GWAS meta-analysis including up to 16,841 samples.

DISCUSSION: Accumulation of medium-chain acylcarnitines is a signature of inborn errors of fatty acid metabolism and age-related metabolic conditions. Our findings point to a link between altered mitochondrial energy production and depression pathogenesis. Acylcarnitine metabolism represents a promising access point for the development of novel therapeutic approaches for depression.

PMID:35381295 | DOI:10.1016/j.jad.2022.03.070

J Allergy Clin Immunol. 2022 Apr 2:S0091-6749(22)00439-0. doi: 10.1016/j.jaci.2022.03.019. Online ahead of print.

ABSTRACT

BACKGROUND: Asthma with severe exacerbation is one of the most common causes of hospitalization among young children. Exacerbations are typically triggered by respiratory infections, but the host factors causing recurrent infections and exacerbations in some children are poorly understood. As a result, current treatment options and preventive measures are inadequate.

OBJECTIVE: To identify genetic interaction associated with the development of childhood asthma.

METHODS: We performed an exhaustive search for pairwise interaction between genetic variants, single nucleotide polymorphisms (SNPs), using 1204 cases with a specific phenotype of early childhood asthma with severe exacerbations (age 2-6 years) combined with 5328 non-asthmatic controls. Replication was attempted in 3 independent populations, and potential underlying immune mechanisms were investigated in the COPSAC2010 and COPSAC2000 birth cohorts.

RESULTS: We found evidence of interaction, including replication in independent populations, between the known childhood asthma loci, CDHR3 and GSDMB. The effect of CDHR3 was dependent on the GSDMB genotype and this interaction was more pronounced for severe and early onset of disease. Blood immune analyses suggested a mechanism related to increased IL-17A production after viral stimulation.

CONCLUSIONS: We found evidence of interaction between CDHR3 and GSDMB in development of early childhood asthma, possibly related to increased IL-17A response to viral infections. This study demonstrates the importance of focusing on specific disease subtypes for understanding the genetic mechanisms of asthma.

PMID:35381269 | DOI:10.1016/j.jaci.2022.03.019

Sci Total Environ. 2022 Apr 2:154992. doi: 10.1016/j.scitotenv.2022.154992. Online ahead of print.

ABSTRACT

Decision-making processes for clean-up of contaminated sites are often highly complex and inherently uncertain. It depends not only on hydrological and biogeochemical site variability, but also on the associated health, environmental, economic, and social impacts of taking, or not taking, action. These variabilities suggest that a dynamic framework is required for promoting sustainable remediation. For this, the decision support system DynSus is presented here for integrating a predeveloped contaminant fate and transport model with a sustainability assessment tool. Implemented within a system dynamics framework, the new tool uses model simulations to provide remediation scenario analysis and handling of uncertainty in various data. DynSus was applied to a site in south Sweden, contaminated with pentachlorophenol (PCP). Simulation scenarios were developed to enable a comparison between alternative remediation strategies and combinations of these. Such comparisons are provided for selected sustainability indicators and remediation performance (in terms of concentration at the recipient). This leads to identifying the most critical variables to ensure that sustainable solutions are chosen. Simulation results indicated that although passive practices, e.g., natural attenuation, were more sustainable at first (5-7 years after beginning remediation measures), they failed to compete with more active practices, e.g., bioremediation, over the entire life cycle of the project (from the beginning of remedial action to achieving the target concentration at the recipient). In addition, statistical tools (clustering and genetic algorithms) were used to further assess the available hydrogeochemical data. Taken together, the results reaffirmed the suitability of the simple analytical framework that was implemented in the contaminant transport model. DynSus outcomes could therefore enable site managers to evaluate different scenarios more quickly and effectively for life cycle sustainability in such a complex and multidimensional problem.

PMID:35381250 | DOI:10.1016/j.scitotenv.2022.154992

Obes Rev. 2022 Apr 5:e13454. doi: 10.1111/obr.13454. Online ahead of print.

NO ABSTRACT

PMID:35381113 | DOI:10.1111/obr.13454

N Engl J Med. 2022 Apr 5. doi: 10.1056/NEJMoa2201570. Online ahead of print.

ABSTRACT

BACKGROUND: On January 2, 2022, Israel began administering a fourth dose of BNT162b2 vaccine to persons 60 years of age or older. Data are needed regarding the effect of the fourth dose on rates of confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and of severe coronavirus disease 2019 (Covid-19).

METHODS: Using the Israeli Ministry of Health database, we extracted data on 1,252,331 persons who were 60 years of age or older and eligible for the fourth dose during a period in which the B.1.1.529 (omicron) variant of SARS-CoV-2 was predominant (January 10 through March 2, 2022). We estimated the rate of confirmed infection and severe Covid-19 as a function of time starting at 8 days after receipt of a fourth dose (four-dose groups) as compared with that among persons who had received only three doses (three-dose group) and among persons who had received a fourth dose 3 to 7 days earlier (internal control group). For the estimation of rates, we used quasi-Poisson regression with adjustment for age, sex, demographic group, and calendar day.

RESULTS: The number of cases of severe Covid-19 per 100,000 person-days (unadjusted rate) was 1.5 in the aggregated four-dose groups, 3.9 in the three-dose group, and 4.2 in the internal control group. In the quasi-Poisson analysis, the adjusted rate of severe Covid-19 in the fourth week after receipt of the fourth dose was lower than that in the three-dose group by a factor of 3.5 (95% confidence interval [CI], 2.7 to 4.6) and was lower than that in the internal control group by a factor of 2.3 (95% CI, 1.7 to 3.3). Protection against severe illness did not wane during the 6 weeks after receipt of the fourth dose. The number of cases of confirmed infection per 100,000 person-days (unadjusted rate) was 177 in the aggregated four-dose groups, 361 in the three-dose group, and 388 in the internal control group. In the quasi-Poisson analysis, the adjusted rate of confirmed infection in the fourth week after receipt of the fourth dose was lower than that in the three-dose group by a factor of 2.0 (95% CI, 1.9 to 2.1) and was lower than that in the internal control group by a factor of 1.8 (95% CI, 1.7 to 1.9). However, this protection waned in later weeks.

CONCLUSIONS: Rates of confirmed SARS-CoV-2 infection and severe Covid-19 were lower after a fourth dose of BNT162b2 vaccine than after only three doses. Protection against confirmed infection appeared short-lived, whereas protection against severe illness did not wane during the study period.

PMID:35381126 | DOI:10.1056/NEJMoa2201570

Endokrynol Pol. 2022;73(1):35-42. doi: 10.5603/EP.a2021.0110.

ABSTRACT

INTRODUCTION: The aim of this study was to test the effect of aripiprazole on leptin, insulin, acute phase proteins, and selected cytokines levels in patients with chronic schizophrenia. Additionally, levels of leptin, insulin, acute phase proteins, and cytokines were compared with body mass and body composition indexes.

MATERIAL AND METHODS: Levels of leptin, insulin, serum amyloid A (SAA), tumour necrosis factor alpha (TNF-α), and interleukins 17A (IL-17A) and 18 (IL-18) in blood serum were measured for 17 patients before and after 28 days of administering aripiprazole by means of enzyme-linked immunosorbent assay (ELISA). Before and after the study, body mass and waist circumference (WC) were also measured, and body mass index (BMI) and body fat percentage (BF%) were estimated. The sex of each patient was taken into account.

RESULTS: After administration of aripiprazole the reduction of levels of leptin, insulin, SAA, and TNF-a were statistically significant, similarly to body mass reduction and decrease in WC, BMI, and BF%, which were also statistically significant. A positive correlation between leptin and BF% and negative correlation between insulin and body mass and body composition indexes were observed before and after the study. High sensitivity C-reactive protein (hsCRP) and hsCRP/albumin positively correlated with BMI before the treatment. In the group of women a statistically significant positive correlation between TNF-α and IL-17A and body mass and body composition indexes was observed, and in the group of men a negative correlation between IL-18 and BMI, WC, and BF% was noted.

CONCLUSIONS: The effect of aripiprazole is connected to its anti-inflammatory activity. A 28-day treatment resulted in reduction of adipose tissue, and in the group of women it returned their leptin sensitivity to normal levels. A change of psychotropic treatment and administration of aripiprazole reduces cardiometabolic risks.

PMID:35381103 | DOI:10.5603/EP.a2021.0110

J Insect Sci. 2022 Mar 1;22(2):9. doi: 10.1093/jisesa/ieac015.

ABSTRACT

Termites are social insects living in colonies composed of worker, soldier, and reproductive castes. Termite hindguts are inhabited by all three domains of life- Eukarya (protists), Bacteria, and Archaea. These gut microorganisms are horizontally and vertically transferred by nestmates and reproductives, respectively. Prior evidence suggests that every colony potentially has a different gut microbiome that was transferred vertically and horizontally over time. However, we do not know if different colonies reared in the laboratory on the same diet will ultimately demonstrate similar microbial composition and structure. Therefore, we looked at gut bacteria in Eastern subterranean termite (Reticulitermes flavipes) colonies that were reared in the laboratory with identical diets and rearing conditions. Based on16S rRNA gene sequencing, the observed features, and Shannon’s diversity were significantly different between the colonies while differences in Pielou evenness and Faith phylogenetic diversity were not statistically significant. In addition, the microbial community structures were significantly different between colonies. Based on ANCOM (Analysis of Composition of Microbiomes), the taxa Elizabethkingia (Bacteroidetes: Flavobacteriales) and Chryseobacterium (Bacteroidetes: Flavobacteriales) were differentially abundant between the colonies. These results suggest that providing the exact same diet and rearing environment for >2 yr cannot result in identical gut microbiomes between termite colonies.

PMID:35381082 | DOI:10.1093/jisesa/ieac015

Blood Adv. 2022 Apr 5:bloodadvances.2021005648. doi: 10.1182/bloodadvances.2021005648. Online ahead of print.

ABSTRACT

Inflammatory stimuli have divergent effects on peripheral platelet counts, although the mechanisms of thrombocytopenic and thrombocytotic responses remain poorly understood. A candidate gene approach targeting 326 polymorphic genes enriched in thrombopoietic and cytokine signaling pathways was applied to identify single nucleotide variants (SNVs) implicated in enhanced platelet responses in cohorts with reactive (RT) or essential (myeloproliferative neoplasm [MPN]) thrombocytosis (ET). Cytokine profiles incorporating a 15-member subset, pathway topology, and functional interactive networks were distinct between ET and RT, consistent with distinct regulatory pathways of exaggerated thrombopoiesis. Genetic studies using aggregate (ET + RT) or ET-restricted cohorts identified associations with 2 IFNA16 (interferon-α16) SNVs, and the ET associations were validated in a second independent cohort (p-value 0.0002). Odds Ratio (OR) of the combined ET cohort (N = 105) was 4.92, restricted to the JAK2V617F-negative subset (OR 5.01). ET sub-stratification analysis by variant IFNA16 demonstrated statistically significant increase in interferon-α16 levels (p = 0.002) among 16 quantifiable cytokines. Recombinantly-expressed variant IFN-α16 encompassing 3 linked non-synonymous SNVs (E65 H95 P133) retained comparable antiviral (AV) and pSTAT signaling profiles as native IFN-α16 (V65 D95 A133) or IFN-α2, although both native and variant IFN-α16 demonstrated stage-restricted differences (compared to IFN-α2) of interferon-regulated genes in CD34+-stimulated megakaryocytes. These data implicate IFNA16 (IFN-α16 gene product) as a putative susceptibility locus (driver) within the broader disrupted cytokine network evident in MPNs, and provide a framework for dissecting functional interactive networks regulating stress or MPN thrombopoiesis.

PMID:35381074 | DOI:10.1182/bloodadvances.2021005648

Br J Surg. 2022 Apr 6:znac086. doi: 10.1093/bjs/znac086. Online ahead of print.

ABSTRACT

BACKGROUND: Non-operative management of uncomplicated acute appendicitis is an option, but omission of antibiotics from the regimen has not been tested.

METHODS: A double-blind, placebo-controlled, superiority RCT in adults with CT-confirmed uncomplicated acute appendicitis was designed to compare placebo with antibiotics (intravenous ertapenem followed by oral levofloxacin and metronidazole). The primary endpoint was treatment success (resolution resulting in discharge without appendicectomy within 10 days); secondary outcomes included pain scores, complications, hospital stay, and return to work.

RESULTS: From May 2017 to September 2020, 72 patients with a mean(s.d.) age of 37.5 (11.1) years were recruited at five hospitals. Six were excluded after randomization (5 early consent withdrawals, 1 randomization protocol violation), 35 were assigned to receive antibiotics, and 31 to receive placebo. Enrolment challenges (including hospital pharmacy resources in an acute-care surgery setting) meant that only the lowest sample size of three predefined scenarios was achieved. The 10-day treatment success rate was 87 (95 per cent c.i. 75 to 99) per cent for placebo and 97 (92 to 100) per cent for antibiotics. This clinical difference of 10 (90 per cent c.i. -0.9 to 21) per cent was not statistically different for the primary outcome (1-sided P = 0.142), and secondary outcomes were similar.

CONCLUSION: The lack of antibiotic superiority statistically suggests that a non-inferiority trial against placebo is warranted in adults with CT-confirmed mild appendicitis. Registration number: EudraCT 2015-003634-26 (https://eudract.ema.europa.eu/eudract-web/index.faces), NCT03234296 (http://www.clinicaltrials.gov).

PMID:35381080 | DOI:10.1093/bjs/znac086

JAMA. 2022 Apr 5. doi: 10.1001/jama.2022.4315. Online ahead of print.

ABSTRACT

IMPORTANCE: Corticosteroids improve strength and function in boys with Duchenne muscular dystrophy. However, there is uncertainty regarding the optimum regimen and dosage.

OBJECTIVE: To compare efficacy and adverse effects of the 3 most frequently prescribed corticosteroid regimens in boys with Duchenne muscular dystrophy.

DESIGN, SETTING, AND PARTICIPANTS: Double-blind, parallel-group randomized clinical trial including 196 boys aged 4 to 7 years with Duchenne muscular dystrophy who had not previously been treated with corticosteroids; enrollment occurred between January 30, 2013, and September 17, 2016, at 32 clinic sites in 5 countries. The boys were assessed for 3 years (last participant visit on October 16, 2019).

INTERVENTIONS: Participants were randomized to daily prednisone (0.75 mg/kg) (n = 65), daily deflazacort (0.90 mg/kg) (n = 65), or intermittent prednisone (0.75 mg/kg for 10 days on and then 10 days off) (n = 66).

MAIN OUTCOMES AND MEASURES: The global primary outcome comprised 3 end points: rise from the floor velocity (in rise/seconds), forced vital capacity (in liters), and participant or parent global satisfaction with treatment measured by the Treatment Satisfaction Questionnaire for Medication (TSQM; score range, 0 to 100), each averaged across all study visits after baseline. Pairwise group comparisons used a Bonferroni-adjusted significance level of .017.

RESULTS: Among the 196 boys randomized (mean age, 5.8 years [SD, 1.0 years]), 164 (84%) completed the trial. Both daily prednisone and daily deflazacort were more effective than intermittent prednisone for the primary outcome (P < .001 for daily prednisone vs intermittent prednisone using a global test; P = .017 for daily deflazacort vs intermittent prednisone using a global test) and the daily regimens did not differ significantly (P = .38 for daily prednisone vs daily deflazacort using a global test). The between-group differences were principally attributable to rise from the floor velocity (0.06 rise/s [98.3% CI, 0.03 to 0.08 rise/s] for daily prednisone vs intermittent prednisone [P = .003]; 0.06 rise/s [98.3% CI, 0.03 to 0.09 rise/s] for daily deflazacort vs intermittent prednisone [P = .017]; and -0.004 rise/s [98.3% CI, -0.03 to 0.02 rise/s] for daily prednisone vs daily deflazacort [P = .75]). The pairwise comparisons for forced vital capacity and TSQM global satisfaction subscale score were not statistically significant. The most common adverse events were abnormal behavior (22 [34%] in the daily prednisone group, 25 [38%] in the daily deflazacort group, and 24 [36%] in the intermittent prednisone group), upper respiratory tract infection (24 [37%], 19 [29%], and 24 [36%], respectively), and vomiting (19 [29%], 17 [26%], and 15 [23%]).

CONCLUSIONS AND RELEVANCE: Among patients with Duchenne muscular dystrophy, treatment with daily prednisone or daily deflazacort, compared with intermittent prednisone alternating 10 days on and 10 days off, resulted in significant improvement over 3 years in a composite outcome comprising measures of motor function, pulmonary function, and satisfaction with treatment; there was no significant difference between the 2 daily corticosteroid regimens. The findings support the use of a daily corticosteroid regimen over the intermittent prednisone regimen tested in this study as initial treatment for boys with Duchenne muscular dystrophy.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01603407.

PMID:35381069 | DOI:10.1001/jama.2022.4315