Adjustment For Multiple Comparisons Research Articles

Search for clinical, genetic, morphological and immunohistochemical predictors of parathyroid cancer recurrence

Background. Currently, there is no consensus on postoperative risk stratification for parathyroid cancer (PC). The risk factors of disease progression are crucial for choosing the optimal treatment strategy, including adjuvant methods and patient,s follow-up. Aim. Identifying predictors of PC recurrence Materials and methods. We performed a retrospective observational study of 85 patients with verified PC divided into remission (n=61) and recurrence (n=19) groups after primary surgical treatment for the period 2004–2023. The analyzed parameters included demographic, laboratory and instrumental data of patients with PC, the presence of a mutation in the CDC73 gene, morphological and immunohistochemical characteristics of the primary tumor. Results. After adjustments for multiple comparisons, a statistically significant association of recurrence was found for preoperative calcium level (p0.001), pT4 stage (p0.001) according to TNM-classification (Tumor, Nodus, Metastasis) American Joint Committee on Cancer 2017. There was a statistical trend for calcium correction for hypoalbuminemia (p=0.002), presence of nephrolithiasis/nephrocalcinosis (p=0.021), parathyroid hormone level 6 months after primary surgery (p0.05), pT3 stage TNM (p=0.007), nuclear expression of parafibromin in tumor tissue (p0.05). We did not reveal any associations between disease recurrence and sex, age, volume of surgical treatment, germline mutation in the CDC73, parafibromin expression and Ki-67 in tumor tissue. Conclusion. Our study revealed several factors of poor prognosis, allowing to identify a risk group for recurrence, which can contribute to active dynamic monitoring and timely treatment.

Influence of angiotensin II type 1 receptors and angiotensin-converting enzyme I/D gene polymorphisms on the progression of Chagas' heart disease in a Brazilian cohort: Impact of therapy on clinical outcomes.

Chagas disease (CD), a neglected tropical disease, is caused by infection by the protozoan Trypanosoma cruzi. One-third of CD patients develop cardiac disease (CARD), an inflammatory and fibrotic process that may progress to heart failure associated with reduced left ventricular ejection fraction (LVEF). The determinants of CD progression are still uncertain. In non-infectious conditions, the angiotensin-converting enzyme (ACE) functional insertion (I)/deletion (D) and type 1 angiotensin II receptor (AT1R) +1166A>C gene polymorphisms have been linked to clinical outcomes. In a Brazilian cohort of 402 patients with positive serology for CD, in a case-control study we used PCR for genotyping the ACE rs4646994 I/D and AGTR1 rs5182C>T, rs275653 -119C>T, rs2131127A>G and rs5186 +1166A>C polymorphisms to evaluate association with CARD and progression to heart failure. Patients were classified as non-CARD (stage A; 109), and mild (stage B1; 161) or severe (stage C; 132) CARD. The groups were compared using unconditional logistic regression analysis and adjusted for non-genetic covariates (age, gender, and trypanocidal treatment). ACE II genotype appeared less frequent in C patients (15% in C vs 20% in B1 and 27% in A). After covariate adjustments, the ACE D allele showed a borderline association with susceptibility to severe CARD (C vs A: OR = 1.9; P = 0.08). AGTR1 +1166AC genotype showed a borderline association with protection against the progression and severity of CARD (C vs A: OR = 0.6; P = 0.09; C vs B1: OR = 0.6; P = 0.07; C vs A + B1: OR = 0.6; P = 0.05). However, adjustments for multiple comparisons showed no association of ACE I/D and AGTR1 polymorphisms with susceptibility and severity of CARD. The rs275653/rs2131127/rs5186/rs5182 T/A/C/T haplotype was protective against progression to the severe form of CARD (C vs B1: OR = 0.3; P = 0.03). Moreover, patients with ACE II and AGTR1 rs5186 +1166AC genotypes presented higher LVEF%. In C patients, TNF serum levels were higher in ACE D carriers than in II genotype. Although limited in number, a cross-sectional observation suggests that C-stage patients treated with benznidazole years prior to administration of ACE inhibitors/AT1R antagonists show reduced TNF serum levels and improved LVEF%. Therefore, variants of ACE and AGTR1 genes may influence the outcome of Chagas' heart disease and should be explored in precision medicine. Further, pharmacotherapies may improve immunological abnormality and clinical outcome in CD patients. Altogether, these data support prospective studies of this cohort and replication in other cohorts.

Genetic association of the kynurenine pathway to suicidal behavior

Suicidal behavior has been associated with dysfunctions in the kynurenine pathway, including alterations in the levels of neuroprotective and neurotoxic metabolites. Changes in the catalytic activity of enzymes within the pathway may contribute significantly. Variations in the genes encoding enzymes within the pathway can significantly affect their catalytic activity, playing a crucial role in the process. To explore this possibility, we hypothesized that these genetic variations would occur more frequently in patients with a history of suicidal behavior compared to non-suicidal individuals. Thus, we investigated the relationship between a history of suicide attempts and five single nucleotide polymorphisms (SNPs) within genes involved in the kynurenine pathway: IDO1 (rs7820268), IDO2 (rs10109853), KMO (rs1053230), KAT1 (rs10988134), and ACSMD (rs2121337). Our sample comprised 849 subjects: 325 individuals who had attempted suicide in their lifetime (SAs), 99 individuals with a history of major depression disorder but no previous suicide attempts (non-SAs), and 425 non-psychiatric controls (CTRL). We performed SNP association analyses using codominant, dominant, and recessive models. Adjustment for sex and multiple comparisons was applied. After adjustment, the analysis revealed that SAs showed a significantly higher frequency of T alleles and TT genotypes of the rs1053230 SNP compared to CTRL across nearly all models. Furthermore, in the recessive model, non-SAs displayed a higher prevalence of the TT genotype of the rs10109853 SNP compared to CTRL.The rs1053230 and rs10109853 SNPs could play a role in the previously observed metabolic dysregulation among SAs and non-SAs, respectively. To validate our findings, it is crucial to conduct functional analyses to investigate the impact of rs10109853 and rs1053230 SNPs on the expression and/or catalytic activity of the corresponding enzymes.

Residual post-infarct myocardial inflammation detected by 68Ga-DOTATATE PET/MRI predicts long-term adverse cardiac remodelling

Abstract Background Maladaptive inflammatory responses are associated with adverse cardiac remodelling after myocardial infarction (MI), but clinical methods for detecting residual myocardial inflammation post-MI are lacking. Purpose To investigate somatostatin receptor subtype 2 (SST2) positron emission tomography (PET)/magnetic resonance imaging (MRI) using 68Ga-DOTATATE after MI. Methods In a prospective observational cohort study, infarct-related myocardial inflammation detected by 68Ga-DOTATATE PET at 2wk and 3mo post-MI was compared with MRI characteristics including left ventricular (LV) volumetric changes at 1yr, as well circulating immune cell phenotyping and serum proteomic markers. Patients with a prior history of MI or heart failure were excluded. Histological SST2 expression was assessed in myocardial biopsies. Results 38 participants (mean age 60 [SD 9] years; 84% male) with recent MI were enrolled, of whom 58% had an ST-segment elevation MI. Mean peak Troponin I was 16,665 (range 408 to >25,000) ng/L and mean post-infarct LV ejection fraction was 51 (SD 9) %. 68Ga-DOTATATE maximum standardized uptake values (SUVmax) at 10 (SD 4) days accurately localised infarcted myocardial segments defined by late-gadolinium enhancement MRI (LGE; Fig. 1); were 14.2% higher in akinetic/hypokinetic vs. normo-kinetic segments (p<0.0001); and were correlated both with peak segmental strain (r=0.47, p=0.003) and segmental T1 values (r=0.51, p=0.02). Mean infarct SUVmax was 19.7% lower on repeat PET/MRI after a mean 102 (SD 22) days (p<0.0001), and this change was in keeping with parallel reductions in T2-weighted oedema signal on MRI and serum biomarkers of cardiac injury and systemic inflammation. Residual inflammation assessed by mean infarct SUVmax at 3mo was correlated with ΔLV indexed end-diastolic volume at 369 (SD 14) days, after adjustment for baseline infarct size and other clinical variables (p=0.038). The 3mo:2wk ratio of mean infarct SUVmax was an even stronger predictor of adverse myocardial remodelling (p=0.0025). Circulating SST2+ classical monocytes were correlated with infarct 68Ga-DOTATATE signal (r=0.47, p=0.02), and SST2 was co-expressed with CD68+ macrophages in inflamed myocardial specimens of patients with recent MI and ischaemic heart failure. After statistical feature selection and multiple comparisons adjustments, among the blood markers associated with 3mo:2wk infarct SUVmax was CCL25, a chemokine involved in macrophage recruitment which has been implicated in adverse cardiac remodelling. Conclusions Here, in the first prospective clinical study of serial SST2 PET/MRI after MI, we show that 68Ga-DOTATATE can identify and track resolving infarct-related myocardial inflammation. Moreover, residual inflammation detected by 68Ga-DOTATATE is associated with long-term adverse myocardial remodelling and could provide a potential future imaging biomarker to help stratify high-risk patients for emerging immunomodulatory therapies.Figure 1.68Ga-DOTATATE PET-MRI after MI

Heart rate and prognosis of heart failure with reduced ejection fraction in women and men in sinus rhythm

Abstract Background Resting heart rate (HR) is a well-established therapeutic target for treating heart failure (HF). Beta-blockers are the primary drugs to reduce HR. Elevated HR is associated with higher mortality in heart failure with reduced ejection fraction (HFrEF). However, the influence of HR on mortality and predictors of death in women with HFrEF in sinus rhythm is not well understood. Purpose to analyse mortality for HR ≤60>bpm and ≤70>bpm in women and men. Methods From February 2017 to January 2022, we analysed the influence of resting HR (≤60> and ≤70>bpm) on mortality and predictors of death in women and men with HFrEF in sinus rhythm. Baseline data included clinical characteristics and echocardiographic findings. The HR used in the analysis was obtained at the closest outpatient visit to the death event. We used the adjustment for multiple comparisons for the log-rank test of Kaplan-Meier (K-M) and Cox proportional hazards methods to analyse mortality rates and search for death predictors for women and men. Results We analysed 2,984 patients, with a mean age of 61 ± 13.8 years, 1,922 (64.4%) men. Age, body mass index, myocardial infarction, diabetes, chronic kidney disease, stroke, carvedilol dosage, hospitalization, and initial left ventricular ejection fraction (LVEF) were similar in both genders. Over the follow-up period of 3.7±1.6 years, we observed an increase in LVEF in men (29.5%±6.7% vs. 36.7%±12.9%; p<0.001) and women (29.9%±6.4 vs. 38.0%±13.4%; p<0.001), and HR reduced in men (73.1±13.0 to 72.1±11.8 bpm; p=0.007) and women (72.8±12.7 to 71.8±11.3 bpm; p=0.026). Death incidence was higher in men (43.7% vs. 36.7%; p<0.001). The cumulative incidence of death was higher in men with HR>60bpm (K-M: log-rank p<0.001) and >70bpm (K-M: log-rank p=0.011) compared to women. Cox regression for death, adjusted for covariates with p<0.25, showed age (HR=1.01;95%CL:1.008-1.017; p<0.001), men (HR=0.80;95%CL:0.71-0.90; p<0.001), LVEF (HR=0.986;95%CL:0.98-0.99; p=0.001), and HR (HR=1.005;95%CL:1.00-1.01; p=0.025) as independent death variables. For men, the independent variables were age (HR=1.01;95%CL:1.01-1.02; p=0.002), LVEF (HR=0.98;95%CL:0.97-0.99; p=0.001), and HR (HR=1.008;95%CL:1.00-1.01; p=0.008), and for women, only the age (HR=1.02;95%CL:1.01-1.02; p<0.001). Conclusion Increased HR was an independent variable of death in men but not in women. Future studies are needed to determine the best reference HR for a chronotropic drug intervention to reduce mortality in women with HFrEF in sinus rhythm.

Randomized Controlled Trial of Acceptance and Commitment Therapy for Fatigue Interference With Functioning in Metastatic Breast Cancer.

Fatigue is a highly prevalent and disabling symptom for patients with metastatic breast cancer (MBC). Evidence-based interventions for managing fatigue in advanced cancer populations are lacking. This phase II randomized controlled trial tested the effect of acceptance and commitment therapy (ACT) on fatigue interference with functioning in patients with MBC. Eligible patients were women with stage IV breast cancer who had moderate to severe fatigue interference. Patients completed a baseline assessment that included self-report measures of fatigue interference with activities, mood, and cognition (primary outcome) and sleep interference with functioning, engagement in daily activities, and quality of life (QOL; secondary outcomes). Then patients were randomly assigned to six weekly telephone-delivered sessions of either ACT (n = 116) or education/support (n = 120). Follow-up assessments occurred at 2 weeks, 3 months, and 6 months postintervention (means, 9.69, 20.51, and 33.59 weeks postbaseline, respectively). Linear mixed model analyses showed that compared with patients in the education/support condition, patients in the ACT condition reported significantly less fatigue interference (P = .018). These results were significant at 2 weeks and 6 months postintervention. ACT's effect on sleep interference was not statistically significant after the Sidak adjustment for multiple comparisons (P = .037). ACT patients showed a steady decline in sleep interference, a trend that was not found for education/support patients. Engagement in daily activities and QOL did not significantly differ between study groups, except for functional QOL (P = .006). Compared with education/support patients, ACT patients showed significantly better functional QOL at 2 weeks and 6 months postintervention. Results suggest that a brief, telephone-delivered ACT intervention can reduce fatigue interference with functioning in patients with MBC.

Gene expression of kynurenine pathway enzymes in depression and following electroconvulsive therapy.

This study aimed to investigate changes in mRNA expression of the kynurenine pathway (KP) enzymes tryptophan 2, 3-dioxygenase (TDO), indoleamine 2, 3-dioxygenase 1 and 2 (IDO1, IDO2), kynurenine aminotransferase 1 and 2 (KAT1, KAT2), kynurenine monooxygenase (KMO) and kynureninase (KYNU) in medicated patients with depression (n = 74) compared to age- and sex-matched healthy controls (n = 55) and in patients with depression after electroconvulsive therapy (ECT). Associations with mood score (24-item Hamilton Depression Rating Scale, HAM-D24), plasma KP metabolites and selected glucocorticoid and inflammatory immune markers known to regulate KP enzyme expression were also explored. HAM-D24 was used to evaluate depression severity. Whole blood mRNA expression was assessed using quantitative real-time polymerase chain reaction. KAT1, KYNU and IDO2 were significantly reduced in patient samples compared to control samples, though results did not survive statistical adjustment for covariates or multiple comparisons. ECT did not alter KP enzyme mRNA expression. Changes in IDO1 and KMO and change in HAM-D24 score post-ECT were negatively correlated in subgroups of patients with unipolar depression (IDO1 only), psychotic depression and ECT responders and remitters. Further exploratory correlative analyses revealed altered association patterns between KP enzyme expression, KP metabolites, NR3C1 and IL-6 in depressed patients pre- and post-ECT. Further studies are warranted to determine if KP measures have sufficient sensitivity, specificity and predictive value to be integrated into stress and immune associated biomarker panels to aid patient stratification at diagnosis and in predicting treatment response to antidepressant therapy.

Associations between pre-diagnostic plasma metabolites and biliary tract cancer risk in the prospective UK Biobank cohort.

Biliary tract cancer (BTC) is potentially influenced by metabolic dysregulation yet previous metabolomic evaluations are limited. To address this gap, we prospectively investigated associations of blood metabolites and BTC risk in the UK biobank cohort study. We used Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) between 249 plasma metabolites per standard deviation and BTC risk in 232,781 participants. We implemented exploratory factor analyses and evaluated associations between factors and BTC risk. Associations at p-value<0.001 were considered statistically significant after multiple comparison adjustments. In a median follow-up of 11.8 years, we identified 268 first primary incident BTC cases. Of 49 biomarkers significantly associated with BTC risk, 12% were fatty acids, and 49%, 31%, and 8% were cholesterol, triglyceride, and phospholipid to total lipids ratios, respectively. Multiple cholesterol ratios were inversely associated with BTC with HRs (95% CIs) of 0.74 (0.65-0.84), p<6.0x10-6. Conversely, a triglyceride ratio was positively associated with BTC with an HR (95% CI) of 1.40 (1.22-1.61), p=2.5x10-6. Congruently, a factor high in cholesterol measures and low in triglyceride measures was inversely associated with BTC. Multiple metabolite biomarkers were associated with BTC risk, suggesting metabolism has a substantial role in BTC etiology.

Intense simplified strategy for newly diagnosed type 2 diabetes in patients with severe hyperglycaemia: multicentre, open label, randomised trial

ObjectiveTo evaluate whether the intense simplified strategy, which comprises short term intensive insulin therapy (SIIT) followed by subsequent oral antihyperglycaemic regimens, could improve long term glycaemic outcomes in patients with...

The Progression of Epitope-specific Antibody Responses toPlasmodium falciparum Circumsporozoite Protein Following Consecutive Malaria Infections in Naïve Adults: A Repetitive Controlled Human Malaria Infection Study

Abstract Background With an estimated 249 million cases and 608,000 deaths in 2022 malaria continues to cause substantial morbidity and mortality worldwide, mostly in children in Sub-Saharan Africa due to Plasmodium falciparum. Circumsporozoite protein (CSP) coats the surface of the P. falciparum sporozoite and is the target of the two vaccines approved by the World Health Organization (WHO). CSP has three major regions: the N-terminus, the central repeat region, and the C-terminus, which contains highly variable T cell epitopes; only a fragment of the central repeat region and the C-terminus are represented by the two approved vaccines. The junction between the N-terminal Region 1 and the NANP repeat region (“junctional region”) is not represented in the approved vaccines and was recently found to be a target of protective antibody responses. Methods We used a repetitive controlled human malaria infection (rCHMI) model in which eight malaria-naïve participants were infected with P. falciparum up to three times over two years to identify immune responses associated with acquisition of natural immunity. We evaluated samples from the day of each CHMI and 18 days after each CHMI. We measured antibody responses using a peptide microarray inclusive of hundreds of P. falciparum proteins and focused our current study on the response to CSP. The amino acid sequences of CSP from the NF54 strain and 4 additional CSP variants were represented as 16-amino acid peptides with 13-amino acid overlap. Signal intensities at each amino acid position were estimated using a sliding window approach that averaged signals from adjacent overlapping peptides. Participants who comprised a “delayed parasitemia group” (n = 5) had onset of PCR-confirmed parasitemia 13 or more days after the last CHMI, a sign of developing humoral immunity. A “non-delayed parasitemia group” (n = 3) was comprised of those had onset of parasitemia within 12 or fewer days after the last CHMI. Along each amino acid position, the median signal intensities for all CSP variants are presented to describe the participants’ antibody responses at each time point. Wilcoxon signed rank test was used to compare medians between timepoints; p-values &amp;lt; 0.05 without adjustment for multiple comparisons were considered statistically significant. Results After three rCHMIs, participants developed antibody responses to amino acids corresponding to the junctional region and the central repeat region (P&amp;lt;0.05). When participants are grouped by time to parasitemia, those who showed delayed parasitemia development had strong immune responses to the junctional region while the non-delayed group did not. Antibody responses to the C-terminal region were more variable among the 5 CSP variant sequences compared to other regions. Conclusion Our results showed higher junctional region antibody response in participants with delayed time to parasitemia. We also demonstrate variable antibody response to the C-terminal region, a region with known greater genetic variability that has been previously associated with allele-specific vaccine escape and concern for decreased efficacy of current WHO-approved vaccines. Taken together, our results support future vaccine development that focuses on the conserved junctional region over the polymorphic C-terminal region.

Single simple question in axonal polyneuropathy.

The single simple question (SSQ), "What percentage of normal (0%-100%) do you feel regarding your disease?" has proven feasible and valid in assessing myasthenia gravis and a heterogeneous spectrum of neuropathies. This study explores the utility of the SSQ in axonal polyneuropathies (PNPs), encompassing diabetic neuropathy, and evaluates its responsiveness to scale changes. A retrospective chart review of 150 patients with axonal PNP responding to the SSQ was performed. Patients underwent clinical and electrophysiological evaluations, and were evaluated by clinical and disability scales, including the Medical Research Council sum score, modified Toronto Clinical Neuropathy score (mTCNS), Overall Neuropathy Limitation Scale, and Rasch-built Overall Disability Scale (RODS). The SSQ total scores correlated moderately with both the RODS score (r = .59, p < .001) and the mTCNS symptom score (r = -.43, p < .001), maintaining significance after adjustment for multiple comparisons. Longitudinally, after adjusting for multiple comparisons, the change in mTCNS symptom score retained statistical significance (adjusted p = .048). The SSQ did not show any association with electrophysiological parameters or sensory symptoms, other than a lower score in those with pain (100% with SSQ <40%, 85% with SSQ 40%-70%, and 34% with SSQ >70%). The SSQ is a feasible, valid scale that may be utilized to assess and follow patients with length-dependent axonal PNPs. Given that the SSQ is not strongly associated with clinical and disability scales or electrophysiological findings, additional investigations are required for a comprehensive assessment of PNP.

Longitudinal associations between microRNAs and weight in the diabetes prevention program.

Circulating microRNAs show cross-sectional associations with overweight and obesity. Few studies provided data to differentiate between a snapshot perspective on these associations versus how microRNAs characterize prodromal risk from disease pathology and complications. This study assessed longitudinal relationships between circulating microRNAs and weight at multiple time-points in the Diabetes Prevention Program trial. A subset of participants (n=150) from the Diabetes Prevention Program were included. MicroRNAs were measured from banked plasma using a Fireplex Assay. We used generalized linear mixed models to evaluate relationships between microRNAs and changes in weight at baseline, year-1, and year-2. Logistic regression was used to evaluate whether microRNAs at baseline were associated with weight change after 2 years. In fully adjusted models that included relevant covariates, seven miRs (i.e., miR-126, miR-15a, miR-192, miR-23a, and miR-27a) were statistically associated with weight over 2 years. MiR-197 and miR-320a remained significant after adjustment for multiple comparisons. Baseline levels of let-7f, miR-17, and miR-320c were significantly associated with 3% weight loss after 2 years in fully adjusted models. This study provided evidence for longitudinal relationships between circulating microRNAs and weight. Because microRNAs characterize the combined effects of genetic determinants and responses to behavioral determinants, they may provide insights about the etiology of overweight and obesity in the context or risk for common, complex diseases. Additional studies are needed to validate the potential genes and biological pathways that might be targeted by these microRNA biomarkers and have mechanistic implications for weight loss and disease prevention.

505 Utilizing porcine hepatocyte cultures to test the effect of short chain fatty acids on androstenone metabolism

Abstract Boar taint is an off-putting odor found in the meat of entire male pigs due to the accumulation of androstenone and skatole in the fat. Development of boar taint is dependent on the balance between the rate of synthesis and metabolism of these compounds. Prior studies have shown that feed ingredients high in fermentable carbohydrates, including chicory root, sugar beet pulp, and Jerusalem artichoke decreased the synthesis of skatole in the hindgut and altered the metabolism in the liver, resulting in a skatole concentrations comparable with castrated males. However, the mechanism of how these dietary fermentable carbohydrates affect liver metabolism is not well understood. Metabolism of boar taint compounds takes place in a two-phase process, regulated by various enzymes and cytochrome families. Short-chain fatty acids (SCFAs) are produced from the microbial fermentation of fiber and have been shown to have regulatory effects on histone deacetylases and gene expression in humans, providing a potential mechanism in which feed high in dietary fiber reduces boar taint. The purpose of this study was to assess if SCFA directly affect the metabolism of androstenone in liver hepatocytes. Primary hepatocytes were isolated from the liver of 6 [(Yorkshire x Landrace) x Duroc] boars weighing around 90 kg. Cells were treated in triplicate with acetate, butyrate, propionate, and various combinations for 24 h to alter gene expression. Two sets of wells acted as a control, not being treated with SCFAs. The cells were then incubated with androstenone for 3 h, and media was extracted, and metabolite production was analyzed using high-performance liquid chromatography. The effects of treatments were using a one-way ANOVA with a Dunnet’s adjustment for multiple comparisons to a control. Results showed the combined acetate, butyrate, and propionate treatment had the greatest effect on androstenone glucuronide production when compared with the control, resulting in significant increases (P &amp;lt; 0.05) ranging from 82 ± 1.6% to 1 ± 2.4% in individual boars. Other treatments had a similar effect, significantly increasing the production of androstenone glucuronide but to a lesser degree. Butyrate increased production ranging from 40 ± 2.2% to 5±1.5% (P &amp;lt; 0.05), propionate from 38 ± 3.6% to 3 ± 2.6% (P &amp;lt; 0.05), acetate and butyrate from 61±3.9% to 1 ± 2.8% (P &amp;lt; 0.05), acetate and propionate from 70±3.5% to 5±1.7% (P &amp;lt; 0.05), and butyrate and propionate from 82 ± 2.5% to 4 ± 1.1% (P &amp;lt; 0.05) when compared with the control. In conclusion, this trial provided evidence that SCFAs produced by the microbial fermentation of fiber can significantly increase hepatic androstenone metabolism in some animals, with a wide range in these effects among individual boars. Future research will involve assessing the effects of SCFAs on hepatic skatole metabolism.

Effect of 1800 MHz radiofrequency field exposure on cytokine and signal transduction protein expression in differentiated THP-1 cells

Purpose To evaluate the effects of 1800 MHz continuous wave (CW) and global system for mobile communications (GSM) modulated radiofrequency electromagnetic field (RFEMF) exposures on signal transduction (ST) protein and cytokine expression in differentiated human-derived monocytic THP-1 cells. Materials and methods THP-1 cells were differentiated into adherent macrophage-like cells using phorbol 12-myristate 13-acetate (PMA). Following differentiation, cells were exposed to 1800 MHz CW or GSM modulated RFEMF for 0.5, 4, or 24 h at a specific absorption rate (SAR) of 0 (sham) or 2.0 W/kg. Concurrent positive controls (lipopolysaccharide for cytokines; anisomycin for ST proteins) and negative controls were included in each experiment. The expression levels of cytokines (GM-CSF, IFN-γ, IL-1β, IL-6, IL-10, TNF-α) from culture media and phosphorylated and total ST proteins (CREB, JNK, NF-κB, p38, ERK1/2, Akt, p70S6k, STAT3, STAT5) from cell lysates were assessed using Milliplex magnetic bead array panels. Results No consistent effect of RFEMF exposure was observed in differentiated THP-1 cells. A statistically significant effect of overall exposure condition was observed for IL-6 with GSM modulation (P = 0.042), but no difference between RFEMF and sham for any exposure condition remained following adjustment for multiple comparisons (P ≥ 0.128). No statistically significant effect of exposure condition was detected for any other cytokine evaluated with either of the RFEMF modulations (P ≥ 0.078). There were no statistically significant changes in expression levels for any of the ST proteins under any studied exposure condition (P ≥ 0.320). Conclusions In this study, no evidence of changes were observed in differentiated human derived THP-1 cells following exposure of up to 24 h to 1800 MHz RFEMF at SARs of 0 and 2.0 W/kg on the expression of ST proteins or cytokines.

Validation and comparison of triage-based screening strategies for sepsis

ObjectiveThis study sought to externally validate and compare proposed methods for stratifying sepsis risk at emergency department (ED) triage. MethodsThis nested case/control study enrolled ED patients from four hospitals in Utah and evaluated the performance of previously-published sepsis risk scores amenable to use at ED triage based on their area under the precision-recall curve (AUPRC, which balances positive predictive value and sensitivity) and area under the receiver operator characteristic curve (AUROC, which balances sensitivity and specificity). Score performance for predicting whether patients met Sepsis-3 criteria in the ED was compared to patients' assigned ED triage score (Canadian Triage Acuity Score [CTAS]) with adjustment for multiple comparisons. ResultsAmong 2000 case/control patients, 981 met Sepsis-3 criteria on final adjudication. The best performing sepsis risk scores were the Predict Sepsis version #3 (AUPRC 0.183, 95 % CI 0.148–0.256; AUROC 0.859, 95 % CI 0.843–0.875) and Borelli scores (AUPRC 0.127, 95 % CI 0.107–0.160, AUROC 0.845, 95 % CI 0.829–0.862), which significantly outperformed CTAS (AUPRC 0.038, 95 % CI 0.035–0.042, AUROC 0.650, 95 % CI 0.628–0.671, p < 0.001 for all AUPRC and AUROC comparisons). The Predict Sepsis and Borelli scores exhibited sensitivity of 0.670 and 0.678 and specificity of 0.902 and 0.834, respectively, at their recommended cutoff values and outperformed Systemic Inflammatory Response Syndrome (SIRS) criteria (AUPRC 0.083, 95 % CI 0.070–0.102, p = 0.052 and p = 0.078, respectively; AUROC 0.775, 95 % CI 0.756–0.795, p < 0.001 for both scores). ConclusionsThe Predict Sepsis and Borelli scores exhibited improved performance including increased specificity and positive predictive values for sepsis identification at ED triage compared to CTAS and SIRS criteria.

Disease progression in Parkinson's disease patients with mild cognitive impairment: 5-year longitudinal study from the early Parkinson's disease longitudinal Singapore (PALS) cohort.

To investigate motor, non-motor and cognitive progression in early Parkinson's disease (PD) patients with Mild Cognitive Impairment (MCI). PD patients were recruited within 1 year of diagnosis and were classified into PD-MCI group and PD with normal cognition (PD-NC) group. H&Y staging scale, MDS-UPDRS part III were used to assess disease severity and motor progression. Non-motor symptom scale (NMSS) was used to evaluate the NMS progression. Cognitive progression was assessed from 5 cognitive domains. Annual progression changes in the longitudinal outcomes were examined via linear mixed model with random intercept effect. False discovery rate (FDR) method was performed to control for multiple testing comparison and q-value was calculated. We set the threshold of q-values as 0.1. A total of 205 PD patients, including 107 PD-MCI and 98 PD-NC patients were assessed prospectively over a 5-year period. PD-MCI patients, compared to PD-NC group, had a significantly higher progression rate in H&Y score (0.11 vs. 0.06, p=0.03, q=0.08), MDS-UPDRS motor score (3.11 vs. 1.90 p<0.001, q=0.06) and postural instability gait difficulty (PIGD) score (0.40 vs. 0.20, p=0.02, q=0.07). PD-MCI group also exhibited significantly faster deterioration in NMSS perceptual domain (PD-MCI vs. PD-NC: 0.38 vs. -0.04, p=0.01, q=0.06) and cognitive visuospatial domain (PD-MCI vs. PD-NC: 0.13 vs. -0.06, p=0.048, q=0.09) after adjustment for confounders and multiple comparisons. PD-MCI patients had faster decline in motor functions, visuo-perceptual and visuospatial performance. These findings provide a more comprehensive prognosis of PD-MCI, which could be helpful for clinician to manage PD-MCI patients.

Association between the third trimester maternal serum metabolome and child growth and development through the first year of life

Evidence suggests that maternal metabolome may be associated with child health outcomes. We analyzed the association between the maternal metabolome between 28–35 gestational weeks and child growth and development during the first year. A prospective cohort of 98 mother–child dyads was followed at birth, 1, 6, and 12 months. Maternal serum samples were collected for targeted LC–MS/MS analysis, which measured 132 metabolites. The child's growth and development were assessed at each time-point. Z-scores were calculated based on WHO growth standards, and the domains of development were assessed using the Ages and Stages Questionnaires (ASQ-3). Multiple linear mixed-effects models were performed and confounders were identified using a Diagram Acyclic Graph. The Benjamini–Hochberg correction was used for multiple comparison adjustments. We found a positive association between lysophosphatidylcholines (14:0; 16:0; 16:1; 17:0; 18:0; 18:1; 18:2; 20:4) with the z-score of weight-for-age, and lysophosphatidylcholines (14:0; 16:0; 16:1; 18:0) and taurine with the z-score of weight-for-length, and lysophosphatidylcholines (14:0; 16:0; 16:1; 17:0; 18:0; 18:1; 18:2; 20:4) and glycine with the z-score of BMI-for-age. The leucine, methionine, tryptophan, and valine were negatively associated with the fine motor skills domain. We observed an association between maternal metabolome and the growth and child's development throughout the first year.

Combined Physiotherapy and Cognitive Behavioral Therapy for Functional Movement Disorders

Functional movement disorders (FMDs) are frequent and disabling neurological disorders with a substantial socioeconomic impact. Few randomized studies have analyzed the effectiveness of combined physiotherapy and psychotherapy in patients' quality of life. To assess the efficacy of multidisciplinary treatment (physiotherapy plus cognitive behavioral therapy) in FMDs. This was a parallel, rater-blinded, single-center, randomized clinical trial. Recruitment took place from June 2022 to April 2023, and follow-up visits were performed at months 3 and 5, concluding in October 2023. Participants were recruited from a national referral center for movement disorders: the Movement Disorders Unit from the Hospital Universitario Virgen Rocio in Seville, Spain. Patients had to be 18 years or older with a confirmed FMD diagnosis and capable of giving consent to participate. Patients who did not meet eligibility criteria or refused to participate were excluded. Any uncontrolled psychiatric disorder was considered an exclusion criterion. Patients were randomly assigned, in a ratio of 1:1 to multidisciplinary treatment (physiotherapy plus cognitive behavioral therapy), or a control intervention (psychological support intervention). Primary outcomes: between-group differences in changes from baseline to month 3 and month 5 in patients' quality of life (EQ-5D-5L score: EQ Index and EQ visual analog scale [EQ VAS]; and 36-Item Short-Form Survey Physical Component Summary [SF-36 PCS] and SF-36 Mental Component Summary [MCS]). Linear mixed models were applied, controlling by baseline severity and applying Bonferroni correction. Of 70 patients screened with an FMD, 40 were enrolled (mean [SD] age, 43.5 [12.8] years; age range, 18-66 years; 32 female [80%]; mean [SD] age at FMD onset, 38.4 [12.1] years), and 38 completed all the follow-up visits and were included in the analysis for primary outcomes. Multidisciplinary treatment improved SF-36 PCS with a mean between-group difference at 3 months of 4.23 points (95% CI, -0.9 to 9.4 points; P = .11) and a significant mean between-group difference at 5 months of 5.62 points (95% CI, 2.3-8.9 points; P < .001), after multiple-comparisons adjustment. There were no significant differences in other quality-of-life outcomes such as SF-36 MCS (mean between-group difference at 3 and 5 months: 0.72 points; 95% CI, -5.5 to 7.0 points; P = .82 and 0.69 points; 95% CI, 2.3-8.9 points; P = .83, respectively), EQ VAS (9.34 points; 95% CI, -0.6 to 19.3 points; P = .07 and 13.7 points; 95% CI, -1.7 to 29.0 points; P = .09, respectively) and EQ Index (0.001 point; 95% CI, -0.1 to 0.1 point; P = .98 and 0.08 points; 95% CI, 0-0.2 points; P = .13, respectively). At months 3 and 5, 42% and 47% of patients, respectively, in the multidisciplinary group reported improved health using the EQ-5D system, compared with 26% and 16% of patients, respectively, in the control group. Results show that multidisciplinary treatment (physiotherapy plus cognitive behavioral therapy) effectively improves FMD symptoms and physical aspects of patients' quality of life. Further studies must be performed to evaluate the potential cost-effectiveness of this approach in FMD. ClinicalTrials.gov Identifier: NCT05634486.

Baker’s yeast beta glucan supplementation was associated with an improved innate immune mRNA expression response after exercise

Beta glucans are found in many natural sources, however, only Baker’s Yeast Beta Glucan (BYBG) has been well documented to have structure–function effects that are associated with improved innate immune response to stressors (e.g., exercise, infection, etc.). The purpose was to identify a BYBG-associated mRNA expression pattern following exercise. Participants gave IRB-approved consent and were randomized to BYBG (Wellmune®; N=9) or Placebo (maltodextrin; N=10) for 6-weeks prior to performing 90 min of whole-body exercise. Paxgene blood samples were collected prior to exercise (PRE), after exercise (POST), two hours after exercise (2H), and four hours after exercise (4H). Total RNA was isolated and analyzed for the expression of 770 innate immune response mRNA (730 mRNA targets; 40 housekeepers/controls; Nanostring nCounter). The raw data were normalized against housekeeping controls and expressed as Log2 fold change from PRE for a given condition. Significance was set at p < 0.05 with adjustments for multiple comparisons and false discovery rate. We identified 47 mRNA whose expression was changed after exercise with BYBG and classified them to four functional pathways: 1) Immune Cell Maturation (8 mRNA), 2) Immune Response and Function (5 mRNA), 3) Pattern Recognition Receptors and DAMP or PAMP Detection (25 mRNA), and 4) Detection and Resolution of Tissue Damage (9 mRNA). The identified mRNA whose expression was altered after exercise with BYBG may represent an innate immune response pattern and supports previous conclusions that BYBG improves immune response to a future sterile inflammation or infection.

Novel insights into causal effects of serum lipids, lipid metabolites, and lipid-modifying targets on the risk of intracerebral aneurysm.

Different serum lipid and lipid-lowering agents are reported to be related to the occurrence of intracerebral aneurysm (IA). However, the causal relationship between them requires further investigation. Mendelian randomization (MR) analysis was performed on IA and its subtypes by using instrumental variants associated with six serum lipids, 249 lipid metabolic traits, and 10 lipid-lowering agents that were extracted from the largest genome-wide association study. Phenome-wide MR analyses were conducted to identify potential phenotypes associated with significant lipid-lowering agents. After multiple comparison adjustments (p < 0.0083), genetically proxied triglyceride (TG) (odds ratio [OR] 1.25, 95% confidence interval [CI] 1.07-1.47, p = 0.005) and high-density lipoprotein cholesterol (HDL-C) levels (OR 0.93, 95% CI 0.89-0.98, p = 0.008) showed causal relationships with the risk of IA. Four lipid metabolic traits showed a causal relationship with the risk of IA (p < 0.0002). As confirmed by drug target MR, the causal relationship between the HMGCR target and IA, HMGCR target and subarachnoid hemorrhage (SAH), ANGPTL3 target and SAH, CETP target, and SAH remained statistically significant after multiple adjustments (p < 0.005). Additionally, phenome-wide MR did not identify other diseases linked to the significant lipid-lowering agent (p < 6.39 × 10-5). This study not only supports that serum lipids (TG and HDL-C) are associated with IA but also confirms the positive effect and absence of safety concerns of intervening HMGCR, ANGPTL3, and CETP targets in IA and its subtypes, opening new avenues for IA treatment.