Correction For Multiple Testing Research Articles

Clinical and molecular predictors of very late recurrence in oestrogen receptor-positive breast cancer patients.

Risk of recurrence from primary ER+ breast cancer continues for at least 20 years. We aimed to identify clinical and molecular features associated with risk of recurrence after 10 years. ER+ breast cancers from patients with and without recurrence were analysed with the BC360 NanoString Panel and an 87 gene targeted-exome panel. Frequency of clinical, pathologic and molecular characteristics was compared between cases (recurred between 10 and 20 years) and controls (no recurrence by 20 years) in the Very Late Recurrence (VLR) cohort. Analogous data from METABRIC were examined to confirm or refute findings. VLR cases had larger tumours and higher node positivity. Both VLR and METABRIC cases had higher clinical treatment score at 5 years (CTS5). There was a trend for fewer GATA3 mutations in cases in both VLR and METABRIC but no statistically significant differences in mutation frequency. Cell cycle and proliferation genes were strongly expressed in VLR cases. Immune-related genes and cell cycle inhibitors were highly expressed in controls. Neither of these changes were significant after correction for multiple testing. Clinicopathologic features are prognostic beyond 10 years. Conversely, molecular features, such as copy number alterations, TP53 mutations and intrinsic subtype which have early prognostic significance, have little prognostic value after 10 years.

Causal relationships between gut microbiota and dementia: A two-sample, bidirectional, Mendelian randomization study

BACKGROUND Existing evidence suggests that gut microbiota represent a significant environmental risk factor for various forms of dementia, including Alzheimer's dementia, vascular dementia, and dementia in other diseases classified elsewhere. However, the exact causal relationships between gut microbiota and the different forms of dementia or their subtypes remain unclear. AIM To investigate putative causal relationships between gut microbiota and dementia or its subtypes using Mendelian randomization (MR) analysis. METHODS A bidirectional, two-sample, MR analysis was conducted utilizing publicly available gut microbiota-related genome-wide association study (GWAS) summary data from the MiBioGen consortium alongside GWAS summary statistics for dementia and its subtypes from the FinnGen consortium. Instrumental variables were selected according to the fundamental tenets of MR and their strengths were evaluated using the F -statistic. Five MR methods were employed, and the robustness of our findings was validated. To account for multiple comparisons, we applied the Bonferroni method for P -value adjustment. RESULTS We identified several gut microbiota taxa exhibiting putative causal relationships with dementia or its subtypes, potentially serving as risk or protective factors for the disease. In addition, reverse MR analysis indicated that the relative abundance of several gut microbiota taxa might be influenced by dementia or its subtypes. An exhaustive sensitivity analysis confirmed the absence of heterogeneity and horizontal pleiotropy. After applying correction for multiple testing, we observed that the order Bacillales (odds ratio: 0.830, 95% confidence interval: 0.740-0.932, P = 0.00155, P adjust = 0.0311) exhibited a strong association with Alzheimer’s disease-related dementia. CONCLUSION The results suggest that gut microbiota is causally associated with dementia. Our findings provide novel insights into the pathophysiology of dementia and have important implications for its treatment and prevention.

Surging Liver Transplantation for Nonalcoholic Steatohepatitis from 2000-2022: A National Database Study.

Our aim was to provide an up-to-date, large-scale overview of the trends and clinicodemographics for NASH LTs performed in the United States compared with all other LT indications between 2000 and 2022. We also examined the demographic factors that will predict future demand for NASH LT. Our analysis of NASH LT from the Organ Procurement & Transplantation Network database spanning 2000-2022 consisted primarily of descriptive statistics and hypothesis testing with corrections for multiple testing when necessary. Trend lines and linear correlations were also explored. NASH LTs have experienced a remarkable surge, escalating from 0.12% of all LTs in 2000 to a substantial 14.7% in 2022, marking a 100-fold increase. Examining demographic trends, a significant proportion of NASH LTs recipients fall within the 50- to 64-year-old age group. Moreover, 52% of these recipients concurrently exhibit type 2 diabetes mellitus, a notably higher percentage than the 19% observed in all LT recipients. Type 2 diabetes mellitus emerges as a prominent risk factor for NASH progressing to end-stage liver disease. The phenomenon of repeat transplantation is noteworthy; although 6% of all LTs necessitate repeat procedures, this figure dramatically drops to 0.6% for NASH LTs. Ethnic disparities are apparent, with African Americans representing a mere 2% of NASH LT recipients, significantly lower than their representation in the overall population. Regionally, the East Coast has a higher proportion of NASH LT recipients compared with waitlist additions. This trend holds true across demographics. Our findings underscore the need for increased resources, particularly for minority, uninsured, or noncitizen individuals requiring LT for NASH. This analysis provides valuable insights into the dynamic landscape of LTs in the context of NASH, shaping the trajectory of medical interventions in the 21st century.

Dried fruit intake can lower the risk of ulcerative colitis: evidence from a Mendelian randomization study.

This study aims to examine the causal relationship between dietary factors and ulcerative colitis (UC). The analysis utilized data from genome-wide association studies (GWAS). Dried fruit, vegetables, processed meat, fresh fruit, and cereal intake were examined as exposure factors. UC was considered the outcome. Two-sample Mendelian randomization (TSMR) analysis was performed using methods. Heterogeneity and horizontal pleiotropy assessments were conducted to ensure the robustness of our findings. Additionally, we applied False Discovery Rate (FDR) corrections for multiple tests. The analysis revealed a significant inverse causal relationship between dried fruit intake and UC risk (odds ratio [OR]: 0.488, 95% confidence interval [CI]: 0.261 to 0.915, p = 0.025). No significant association was observed between vegetable intake (OR: 1.742, 95% CI: 0.561 to 5.415, p = 0.337), processed meat intake (OR: 1.136, 95% CI: 0.552 to 2.339, p = 0.729), fresh fruit intake (OR: 0.977, 95% CI: 0.465 to 2.054, p = 0.952), cereal intake (OR: 1.195, 95% CI: 0.669 to 2.134, p = 0.547). The low heterogeneity observed across analyses and the confirmation of stability through leave-one-out analysis reinforce the reliability of these results. Moreover, after adjusting for multiple tests, none of the dietary factors reached a p-value below the conventional significance threshold of 0.05. This study provides evidence of a potential association between dried fruit intake and a reduced risk of UC. Further MR studies incorporating larger GWAS datasets are needed to confirm these findings.

Urinary eicosanoid levels in early life and risk of atopic disease in childhood

IntroductionEicosanoids are lipid mediators including thromboxanes (TXs), prostaglandins (PGs) and leukotrienes (LTs) with a pathophysiological role in established atopic disease. However, their role in the inception of disease is unclear. We aimed to investigate the association between urinary eicosanoids in early life and development of atopic disease. MethodsWe quantified the levels of 21 eicosanoids in urine from children from the COPSAC2010 (age 1 year, n=450) and VDAART (age 3 years, n=575) mother-child cohorts and analyzed the associations with development of wheeze/asthma, atopic dermatitis, and biomarkers of Type-2 inflammation, applying FDR5% multiple testing correction. ResultsIn both cohorts, analyses adjusted for environmental determinants showed that higher TXA2 eicosanoids in early life were associated with increased risk of developing atopic dermatitis (P<FDR5%) and Type-2 inflammation (p<0.05). In VDAART, lower PGE2 and PGI2 eicosanoids and higher isoprostanes were also associated with increased risk of atopic dermatitis (P<FDR5%). For wheeze/asthma, analyses in COPSAC2010 showed that lower isoprostanes and PGF2 eicosanoids and higher PGD2 eicosanoids at age 1 year associated with an increased risk at age 1-10 years (p<0.05), whereas analyses in VDAART showed that lower PGE2 and higher TXA2 eicosanoids at age 3 years associated with an increased risk at 6 years (P<FDR5%). ConclusionsThis study suggests that early life perturbations in the eicosanoid metabolism are present before the onset of atopic disease in childhood, which provides pathophysiological insight in the inception of atopic diseases.

The influence of pre- and postnatal exposure to air pollution and green spaces on infant’s gut microbiota: Results from the MAMI birth cohort study

BackgroundAnimal and human studies indicate that exposure to air pollution and natural environments might modulate the gut microbiota, but epidemiological evidence is very scarce. ObjectivesTo assess the potential impact of pre- and postnatal exposure to air pollution and green spaces on infant gut microbiota assembly and trajectories during the first year of life. MethodsMAMI (“MAternal MIcrobes”) birth cohort (Valencia, Spain, N = 162) was used to study the impact of environmental exposure (acute and chronic) on infant gut microbiota during the first year of life (amplicon-based 16S rRNA sequencing). At 7 days and at 1, 6 and 12 months, residential pre- and postnatal exposure to air pollutants (NO2, black carbon -BC-, PM2.5 and O3) and green spaces indicators (NDVI and area of green spaces at 300, 500 and 1000 m buffers) were obtained. For the association between exposures and alpha diversity indicators linear regression models (cross-sectional analyses) and mixed models, including individual as a random effect (longitudinal analyses), were applied. For the differential taxon analysis, the ANCOM-BC package with a log count transformation and multiple-testing corrections were used. ResultsAcute exposure in the first week of life and chronic postnatal exposure to NO2 were associated with a reduction in microbial alpha diversity, while the effects of green space exposure were not evident. Acute and chronic (prenatal or postnatal) exposure to NO2 resulted in increased abundance of Haemophilus, Akkermansia, Alistipes, Eggerthella, and Tyzerella populations, while increasing green space exposure associated with increased Negativicoccus, Senegalimassilia and Anaerococcus and decreased Tyzzerella and Lachnoclostridium populations. DiscussionWe observed a decrease in the diversity of the gut microbiota and signs of alteration in its composition among infants exposed to higher levels of NO2. Increasing green space exposure was also associated with changes in gut microbial composition. Further research is needed to confirm these findings.

Unraveling the immunologic vulnerabilities of diffuse hemispheric glioma, H3 G34-mutant.

2082 Background: Recent insights into the molecular basis of diffuse hemispheric glioma, H3 G34-mutant (DHG-G34), an incurable high-grade glioma, have opened new therapeutic possibilities. The oncohistone mutation in DHG-G34 impairs the epigenetic regulator SETD2, which normally orchestrates DNA-mismatch-repair and negatively regulates the transcriptional silencing activity of the Polycomb Repressive Complex 2 (PRC2). In DHG-G34, a mismatch-repair-deficiency phenotype is predicted, but an anti-tumor immune response is notably absent in clinical observations, which we posit is linked to the aberrant transcriptional repression by PRC2. Here, we investigate DHG-G34 immunosuppression mechanisms in a large real-world multi-omics cohort and human cell lines. Methods: Clinical, molecular, and immunologic characteristics of a DHG-G34 cohort, sequenced (DNA and RNA) at Caris Life Sciences (Phoenix, AZ), are contrasted against diffuse midline glioma (DMG) and pediatric low-grade glioma (LGG). A significant difference between genomic subgroups was defined as fold-change &gt; 1.2. Statistical significance was determined using chi-square, Fishers-exact, and Mann Whitney U tests with corrections for multiple hypothesis testing (q &lt; 0.05).Hazard ratio (HR) was calculated using the Cox proportional hazards model. KNS-42 DHG-G34 cell line was exposed in triplicate to 1 µM valemetostat (an EZH1/2 inhibitor) or DMSO in vitro. Flow cytometry and RNA-sequencing were utilized to determine differential immunologic characteristics. Results: 29 DHG-G34, 51 DMG, and 52 LGG were identified in Caris database. Median OS among DHG-G34 was 15.4 mo., similar to DMG (HR = 1.1, 95% CI: 0.70-1.73, p = 0.686). Most frequent alterations in DHG-G34 were TP53 (93.1%), ATRX (69.0%), PDGFRA (31.0%). Tumor mutational burden (TMB) was high, &gt;=10mt/MB, in 10% of DHG-G34 and 0/51 in DMG and 0/52 LGG (p &lt; 0.01, q &gt; 0.05), but immune fractions including dendritic cells, T cells, macrophages, microglia, and antigen-presenting genes were decreased (fold-change: 0.19 – 0.83, q &lt; 0.05). In KNS-42, PRC2 inhibition upregulated MHC class 1 (p &lt; 0.001). Of 402 KNS-42 missense variants, transcription of 43 were upregulated following EHZ2 inhibition, and 4 were downregulated (q &lt; 0.05). Among immunostimulatory genes, P2RX7, which engages T-cells and stimulates an inflammatory response, was downregulated in patient samples (q &lt; 0.001) and upregulated in KNS-42 following EZH2 inhibition (q &lt; 0.001). Conclusions: DHG-G34 has an increased propensity for high TMB but remains immunologically cold. Our pilot experiment suggests inhibiting PRC2’s unique role in DHG-G34 may sensitize DHG-G34 to an immune response by inducing MHC class 1 expression and transcriptional readthrough of mutated transcripts. Understanding whether treatment induces TMB in DHG-G34 may affect timing of an immunotherapeutic intervention.

CCNE1 amplification as marker of poor prognosis and novel therapeutic target in advanced breast cancer.

1040 Background: Cyclin E1 (CCNE1) overexpression or gene amplification is linked to dismal outcomes in various tumors, including breast cancer (BC). Recent studies suggest that CCNE1 amplification is a potential target for new synthetic lethality-based treatments, including CDK2-selective and PKMYT1 inhibition. This study explores the clinical and genomic characteristics of CCNE1-amplified BCs. Methods: We analyzed genomic and clinical data from consecutive BCs that underwent clinical tumor-normal targeted panel sequencing (MSK-IMPACT) between April 2014 and December 2021. Allele-specific copy number, including CCNE1 amplification, and fraction genome altered (FGA) were calculated by FACETS. Mutual exclusivity and co-occurrence analyses were performed using CoMEt. Benjamini–Hochberg method for multiple testing correction (q) was applied. Real-world progression-free survival (rwPFS) was assessed by the Kaplan Meier method and Cox models, focusing on patients with available pre-treatment samples. Results: Out of 3,753 BCs, 125 (3.3%) had CCNE1 amplification. A higher occurrence of CCNE1 amplification was noted in post-treatment (n=2,368) compared to treatment-naïve tumors (n=1,385; 4% vs 2.4%, p=0.007). CCNE1 amplification was less common in hormone receptor (HR)+/HER2- BCs (2%) compared to HER2+ (7.6%) and triple-negative (7.2%) tumors (p&lt;0.001). BCs with CCNE1 amplification showed higher median FGA, indicating increased genomic instability. In primary BC, TP53 alterations were more frequent in CCNE1-amplified tumors (q&lt;0.001), while CDH1 alterations were mutually exclusive (q&lt;0.001) suggesting that lobular BCs rarely harbor CCNE1 amplification. Similar trends were seen in post-treatment samples. CCNE1 amplification detected at baseline was linked to shorter median rwPFS in HR+/HER2- metastatic BCs treated with CDK4/6 inhibitors plus endocrine therapy (8.8 vs 15.2 months in CCNE1-amplified [n=9] vs CCNE1-non amplified [n=402]; hazard ratio [HR] 2.82, 95% CI 1.38-5.75), and in HER2+ metastatic BCs treated with first-line THP regimen (7.3 vs 20.8 months in CCNE1-amplified [n=5] vs CCNE1-non amplified [n=106]; HR 3.1, 95% CI 1.24-7.87). In a CCNE1-amplified triple-negative cell model (HCC1569), treatment with the PKMYT1 inhibitor RP-6306 significantly reduced tumor growth. Conclusions: CCNE1 amplification in BCs is associated with greater genomic instability and characterizes a group of metastatic BCs with poor response to standard of care therapies. Novel therapies targeting CCNE1-amplified tumors are under evaluation in preclinical and clinical studies.

Statistical investigation of interdependence of trabecular microarchitectural parameters from micro-computed tomography

Standard microarchitectural analysis of bone using micro-computed tomography produces a large number of parameters that quantify the structure of the trabecular network. Analyses that perform statistical tests on many parameters are at elevated risk of making Type I errors. However, when multiple testing correction procedures are applied, the risk of Type II errors is elevated if the parameters being tested are strongly correlated. In this article, we argue that four commonly used trabecular microarchitectural parameters (thickness, separation, number, and bone volume fraction) are interdependent and describe only two independent properties of the trabecular network. We first derive theoretical relationships between the parameters based on their geometric definitions. Then, we analyze these relationships with an aggregated in vivo dataset with 2987 images from 1434 participants and a synthetically generated dataset with 144 images using principal component analysis (PCA) and linear regression analysis. With PCA, when trabecular thickness, separation, number, and bone volume fraction are combined, we find that 92 % to 97 % of the total variance in the data is explained by the first two principal components. With linear regressions, we find high coefficients of determination (0.827–0.994) and fitted coefficients within expected ranges. These findings suggest that to maximize statistical power in future studies, only two of trabecular thickness, separation, number and bone volume fraction should be used for statistical testing.

The UFMylation pathway is impaired in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by the presence of neurofibrillary tangles made of hyperphosphorylated tau and senile plaques composed of beta-amyloid. These pathognomonic deposits have been implicated in the pathogenesis, although the molecular mechanisms and consequences remain undetermined. UFM1 is an important, but understudied ubiquitin-like protein that is covalently attached to substrates. This UFMylation has recently been identified as major modifier of tau aggregation upon seeding in experimental models. However, potential alterations of the UFM1 pathway in human AD brain have not been investigated yet. Here we used frontal and temporal cortex samples from individuals with or without AD to measure the protein levels of the UFMylation pathway in human brain. We used multivariable regression analyses followed by Bonferroni correction for multiple testing to analyze associations of the UFMylation pathway with neuropathological characteristics, primary biochemical measurements of tau and additional biochemical markers from the same cases. We further studied associations of the UFMylation cascade with cellular stress pathways using Spearman correlations with bulk RNAseq expression data and functionally validated these interactions using gene-edited neurons that were generated by CRISPR-Cas9. Compared to controls, human AD brain had increased protein levels of UFM1. Our data further indicates that this increase mainly reflects conjugated UFM1 indicating hyperUFMylation in AD. UFMylation was strongly correlated with pathological tau in both AD-affected brain regions. In addition, we found that the levels of conjugated UFM1 were negatively correlated with soluble levels of the deUFMylation enzyme UFSP2. Functional analysis of UFM1 and/or UFSP2 knockout neurons revealed that the DNA damage response as well as the unfolded protein response are perturbed by changes in neuronal UFM1 signaling. There are marked changes in the UFMylation pathway in human AD brain. These changes are significantly associated with pathological tau, supporting the idea that the UFMylation cascade might indeed act as a modifier of tau pathology in human brain. Our study further nominates UFSP2 as an attractive target to reduce the hyperUFMylation observed in AD brain but also underscores the critical need to identify risks and benefits of manipulating the UFMylation pathway as potential therapeutic avenue for AD.

Impact of gene-by-trauma interaction in MDD-related multimorbidity clusters

BackgroundMajor depressive disorder (MDD) is considerably heterogeneous in terms of comorbidities, which may hamper the disentanglement of its biological mechanism. In a previous study, we classified the lifetime trajectories of MDD-related multimorbidities into seven distinct clusters, each characterized by unique genetic and environmental risk-factor profiles. The current objective was to investigate genome-wide gene-by-environment (G × E) interactions with childhood trauma burden, within the context of these clusters. MethodsWe analyzed 77,519 participants and 6,266,189 single-nucleotide polymorphisms (SNPs) of the UK Biobank database. Childhood trauma burden was assessed using the Childhood Trauma Screener (CTS). For each cluster, Plink 2.0 was used to calculate SNP × CTS interaction effects on the participants' cluster membership probabilities. We especially focused on the effects of 31 candidate genes and associated SNPs selected from previous G × E studies for childhood maltreatment's association with depression. ResultsAt SNP-level, only the high-multimorbidity Cluster 6 revealed a genome-wide significant SNP rs145772219. At gene-level, MPST and PRH2 were genome-wide significant for the low-multimorbidity Clusters 1 and 3, respectively. Regarding candidate SNPs for G × E interactions, individual SNP results could be replicated for specific clusters. The candidate genes CREB1, DBH, and MTHFR (Cluster 5) as well as TPH1 (Cluster 6) survived multiple testing correction. LimitationsCTS is a short retrospective self-reported measurement. Clusters could be influenced by genetics of individual disorders. ConclusionsThe first G × E GWAS for MDD-related multimorbidity trajectories successfully replicated findings from previous G × E studies related to depression, and revealed risk clusters for the contribution of childhood trauma.

Modifiable risk factors and inflammation-related proteins in polymyalgia rheumatica: genome-wide meta-analysis and Mendelian randomisation.

Polymyalgia rheumatica (PMR) is an age-related inflammatory disease of unknown cause. We aimed to identify potentially modifiable risk factors and therapeutic targets for preventing or treating PMR. We meta-analysed genetic association data from 8,156 cases of PMR (defined using diagnostic codes and self-report) and 416,495 controls of European ancestry from the UK Biobank and FinnGen. We then performed Mendelian randomization analyses to estimate the association between eight modifiable risk factors (using data from up to 1.2 million individuals) and 65 inflammation-related circulating proteins (up to 55,792 individuals), using the inverse variance weighted and pleiotropy robust methods. We identified three novel genome-wide significant loci in the IL1R1, NEK6 and CCDC88B genes and confirmation of previously described associations with HLA-DRB1 and ANKRD55. Genetically predicted smoking intensity (OR 1.32; 95%CI 1.08-1.60; p = 0.006) and visceral adiposity (OR 1.22; 95%CI 1.10-1.37; p = 3.10x10-4) were associated with PMR susceptibility. Multiple circulating proteins related to IL-1 family signaling were associated with PMR. IL-1 receptor-like 2, also known as IL-36 receptor (OR 1.25; p = 1.89x10-32), serum amyloid A2 (OR 1.06, 9.91x10-10) and CXCL6 (OR 1.09, p = 4.85x10-7) retained significance after correction for multiple testing. Reducing smoking and visceral adiposity at a population level might reduce incidence of PMR. We identified proteins that may play causal roles in PMR, potentially suggesting new therapeutic opportunities. Further research is needed before these findings are applied to clinical practice.

#1089 Urinary Protein Biomarkers for Assessing Disease Activity and Chronicity in IgA Nephropathy

Abstract Background and Objectives IgA nephropathy (IgAN) is a progressive kidney disease characterized by the mesangial deposition of galactose-deficient IgA1, leading to kidney damage and may eventually lead to end-stage kidney disease. Current treatment decisions for IgAN patients rely on the degree of proteinuria. However, this is a non-specific parameter that can be the result of inflammatory disease activity and/or chronic glomerular damage. In this study, we employed the Olink proximity extension assay to comprehensively analyze the urinary proteome of IgAN patients. Our goal was to identify biomarkers capable of distinguishing between IgAN disease activity and disease chronicity. Method Urine samples were collected from 41 IgAN patients and 41 age- and eGFR-matched controls. Patient characteristics are shown in Table 1. Using Olink Proteomics, we measured 276 proteins in urine, from the inflammation, organ damage, and cardiometabolic panels. Comparisons were made between IgAN patients and controls, as well as between those with mild (eGFR ≥ 60 ml/min/1.73 m2 and uPCR &amp;lt; 100 mg/mmol) and active IgAN (eGFR ≥ 60 ml/min/1.73 m2 and uPCR ≥ 100 mg/mmol) to identify biomarkers for disease activity. Additionally, we compared IgAN patients with eGFR ≥ 60 ml/min/1.73 m2 to those with eGFR ≤ 30 ml/min/1.73 m2 to identify biomarkers associated with disease chronicity. Mann-Whitney U tests were used for group comparisons. Correction for multiple testing was performed using the Benjamini-Hochberg procedure. Disease activity and chronicity scores were calculated by averaging the z-scores of the identified biomarkers. Results L-Selectin (SELL), leukocyte inhibitory factor (LIF), interleukin-6 (IL-6), and carbonic anhydrase 1 (CA1) were most prominently elevated in IgAN patients compared to controls (Fig. 1A). SELL and CA1 were also markedly elevated in the active versus mild IgAN patients, and were therefore selected as biomarkers of disease activity (Fig. 1B). Contactin 2 (CNTN2) and chemokine (C-C motif) ligand 25 (CCL25) were most prominently elevated in IgAN patients with eGFR ≤ 30 ml/min/1.73 m2, and were selected as biomarkers of disease chronicity (Fig. 1C). We plotted the disease activity and chronicity scores calculated from the identified biomarkers to distinguish the different IgAN disease stages (Fig. 1D). Conclusion This study identified urine biomarkers indicative of IgAN disease activity and chronicity. Calculating an activity and chronicity score using these biomarkers offers a new approach to distinguish between inflammatory disease activity and chronicity, providing an alternative to proteinuria for guiding treatment decisions in IgAN patients. Validation of these biomarkers, and the scores calculated from them, in a larger cohort of IgAN patients is currently underway.

#1600 The effect of integrated real-time hemodialysis surveillance on staff workload and time efficacy—a multicenter prospective study

Abstract Background and Aims For many years, dialysis data have been manually registered and transferred to the patients’ electronic health records by dialysis staff. However, manual documentation can be associated with poor data completeness, delayed recognition of inadequate dialysis prescriptions, and high staff workload. We studied the effect of introducing a new integrated, digitalized haemodialysis surveillance system, the Treatment Guidance System (TGS), on staff workload and time saving in clinics from a large multi-national dialysis provider. To measure the effect of introducing the new TGS system on staff workload and time saving. Method This was a prospective, observational multicenter study conducted between November 2021 and January 2023 in five countries: Saudi Arabia, Spain, Portugal, UK, and Kazakhstan. Inclusion criteria were clinics with adequate digital infrastructure, introducing the TGS. Only staff without prior experience with TGS were included in this study. Staff workload was determined using the NASA Task Load Index (TLS) at three timepoints: 1: two weeks prior to introduction of the TGS, 2: one month after introduction of the TGS, and 3: three months after introduction of the TGS. Time saving was determined by observation of the time used for dialysis data documentation by an independent person at timepoints 1 and 3. Differences in staff workload were determined by Friedman's two-way analysis of variance by ranks with Bonferroni correction for multiple tests, while time saving was determined by Wilcox signed rank test. Results In total, 223 participants from 20 clinics were included in the study, 56% were female, age distribution was 32.1% &amp;lt;30 years, 58.8% 30-49 years, and 9.1% ≥50 years, and dialysis experience was 17.5% ≤2 years, 27.9% 2-5 years, 33.3% 5-10 years, and 21.2% &amp;gt;10 years. The staff adaptability to the introduction of TGS at their workplace and the workload perception improved significantly over all domains of the NASA TLS (Table 1). While most domains improved by approximately 50%, median physical demand improved by more than 60% (Table 1). There was some variation of the observed time used for documentation between different countries, however, the observed time decreased in all countries from median (25-75%) 9:35 (5:36-14:41) minutes at timepoint 1 to 5:22 (2:05-9:22) minutes at timepoint 3 (p &amp;lt; 0.001). The largest saving was noted in the United Kingdom (14:06 (11:01-18:25) to 5:17 (4:56-5:45) minutes), while the smallest saving was noted in Kazakhstan, where only 3 individuals were observed (3:37 to 3:08). Conclusion Introduction of the novel, digitalized, integrated real-time dialysis documentation system TGS greatly reduced staff workload and time spent with documentation of dialysis treatments. Digitalization and automation of haemodialysis treatment has the potential to improve dialysis treatment, which will be further elucidated by the analysis of data quality and completeness in the current study.

Exploring the kynurenine pathway in mild traumatic brain injury: A longitudinal study.

A potential source of novel biomarkers for mTBI is the kynurenine pathway (KP), a metabolic pathway of tryptophan (Trp), that is up-regulated by neuroinflammation and stress. Considering that metabolites of the KP (kynurenines) are implicated in various neuropsychiatric diseases, exploration of this pathway could potentially bridge the gap between physiological and psychological factors in the recovery process after mTBI. This study, therefore, set out to characterize the KP after mTBI and to examine associations with long-term outcome. Patients were prospectively recruited at the emergency department (ED), and blood samples were obtained in the acute phase (<24 h; N = 256) and at 1-month follow-up (N = 146). A comparison group of healthy controls (HC; N = 32) was studied at both timepoints. Trp, kynurenines, and interleukin (IL)-6 and IL-10 were quantified in plasma. Clinical outcome was measured at six months post-injury. Trp, xanthurenic acid (XA), and picolinic acid (PA) were significantly reduced in patients with mTBI relative to HC, corrected for age and sex. For Trp (d = -0.57 vs. d = -0.29) and XA (d = -0.98 vs. d = -0.32), larger effects sizes were observed during the acute phase compared to one-month follow-up, while for PA (d = -0.49 vs. d = -0.52) effect sizes remained consistent. Findings for other kynurenines (e.g., kynurenine, kynurenic acid, and quinolinic acid) were non-significant after correction for multiple testing. Within the mTBI group, lower acute Trp levels were significantly related to incomplete functional recovery and higher depression scores at 6 months post-injury. No significant relationships were found for Trp, XA, and PA with IL-6 or IL-10 concentrations. In conclusion, our findings indicate that perturbations of the plasma KP in the hyperacute phase of mTBI and 1 month later are limited to the precursor Trp, and glutamate system modulating kynurenines XA and PA. Correlations between acute reductions of Trp and unfavorable outcomes may suggest a potential substrate for pharmacological intervention.

Elevated levels of IL-12/IL-23p40 in Nova Scotia Duck Tolling Retrievers with autoimmune disease and lymphoma

The Nova Scotia Duck Tolling Retriever (NSDTR) is predisposed to immune mediated rheumatic disease (IMRD), steroid-responsive meningitis-arteritis (SRMA) and certain forms of cancer. Cytokines are the main regulators of the immune system. Interleukin 2 is a cytokine involved in activation of T regulatory cells, playing a role in central tolerance and tumor immunity. Interleukin 12 and interleukin 23 share the same subunit, p40, and are both pro-inflammatory cytokines. The aim of this study was to compare levels of IL-2 in healthy NSDTRs to those with cancer or autoimmune disease and to compare levels of IL-12/IL-23p40 in healthy NSDTRs and beagles versus NSDTRs with cancer or autoimmune disease. 62 dogs were included in the analysis of IL-12/IL-23p40; healthy NSDTRs (n = 16), healthy beagles (n = 16), NSDTRs autoimmune (n = 18) and NDSTRs lymphoma/mastocytoma (n = 12) and 68 dogs for IL-2; healthy (n = 20), autoimmune (n = 36) and lymphoma/mastocytoma/adenocarcinoma (n = 12). NSDTRs with autoimmune disease had higher levels of IL-12/IL-23p40 compared to healthy dogs (p = 0.008). NSDTRs with lymphoma also had higher levels of IL-12/IL-23p40 compared to healthy NSDTRs (p = 0.002). There was no difference in levels of IL-2 between healthy and diseased NSDTR. Statistical analysis was performed using Bonferroni corrections for multiple testing. These findings can contribute to the knowledge of autoimmune disease and cancer in dogs.

The etiology and differential diagnosis of "autoimmune hepatitis-like liver disease" in children: a single-center retrospective study.

Children with autoimmune hepatitis (AIH) often present with symptoms similar to those of other liver diseases. This study consists of a comparison between the clinical and histological characteristics of AIH and those of other four AIH-like liver diseases [i.e., drug-induced liver injury (DILI), gene deficiency, infectious liver disease and other etiology of liver disease], as well as an evaluation of the AIH scoring system's diagnostic performance. All children with AIH-like liver disease at our center from January 2013 to December 2022 were included. The clinical and histological characteristics of the AIH group were retrospectively analyzed and compared with those of the other four groups. A total of 208 children were included and divided into AIH group (18 patients), DILI group (38 patients), gene deficiency group (44 patients), infectious liver disease group (74 patients), and other etiology group (34 patients). The antinuclear antibodies (ANA) ≥ 1:320 rate was significantly higher in the AIH compared to the other four groups after multiple testing correction (p < 0.0125), while patients with positive antibodies to liver-kidney microsomal-1 (anti-LKM1, n = 3) and smooth muscle antibodies (SMA, n = 2) were only observed in the AIH group. The positive rates of antibodies to liver cytosol type1 (anti-LC1) and Ro52 were higher than those in the other four groups. The serum immunoglobulin G (IgG) and globulin levels, as well as the proportions of portal lymphoplasmacytic infiltration, lobular hepatitis with more than moderate interface hepatitis, and lobular hepatitis with lymphoplasmacytic infiltration, were significantly higher in the AIH group than in the other four groups after multiple testing correction (p < 0.0125). The cirrhosis rate in the AIH group was higher than that in the DILI and infectious liver disease groups (p < 0.0125). Both the simplified (AUC > 0.73) and the revised systems (AUC > 0.93) for AIH have good diagnostic performance, with the latter being superior (p < 0.05). Positive autoantibodies (ANA ≥ 1:320 or anti-LKM1 positive, or accompanied by SMA, anti-LC1 or Ro-52 positive) and elevated serum IgG or globulin levels contribute to early recognition of AIH. The presence of lobular hepatitis with more than moderate interface hepatitis and lymphoplasmacytic infiltration contribute to the diagnosis of AIH.

Effect of Project Orbis participation by the Swiss regulator on submission gaps, review times, and drug approval decisions between 2020 and 2022: a comparative analysis

Expedited market access for novel and efficacious drugs is warranted for patients. Since 2020, Swissmedic (The Swiss Agency for Therapeutic Products) has been participating in Project Orbis, a collaborative parallel-review programme launched by the US Food and Drug Administration (FDA) in 2019 to expedite patient access to cancer drugs. This programme allows regulatory agencies to remain independent in their decisions. We aimed to evaluate the effect of the first 2 years of Project Orbis from the Swissmedic perspective. In this comparative analysis, we compared submission gap (time between submission at the FDA and Swissmedic), review time, approval and consensus decision rate, and the approved indications between Swissmedic and the FDA for marketing authorisation applications (MAAs) in oncology submitted to Swissmedic through Project Orbis (Orbis MAAs) or outside of Project Orbis (non-Orbis MAAs) from Jan 1, 2020, to Dec 31, 2021. Swissmedic review time was evaluated with a decision until June 30, 2022. For the decision comparison analysis, non-Orbis oncology MAAs submitted and evaluated from Jan 1, 2009, to Dec 31, 2018 (referred to as the pre-Orbis era) were also considered. Inferential statistics were done using Wilcoxon rank-sum test and the 95% CI for the median was based on binomial distribution. For each hypothesis testing, the significance level was set to 5%. No correction for multiple testing was performed. We analysed the submission gap, review time, and regulatory decision for 31 Orbis MAAs and 41 non-Orbis MAAs during the Orbis era. The median submission gap was 33·0 days (95% CI 19·0-57·0) for Orbis MAAs versus 168·0 days (56·0-351·0) for non-Orbis MAAs (p<0·0001). The median review time at Swissmedic was 235·5 days (198·0-264·0) for Orbis MAAs versus 314·0 days (279·0-354·0) for non-Orbis MAAs (p=0·0002). Approval rates at Swissmedic were consistent between Orbis MAAs (20 [77%] of 26) and non-Orbis MAAs (31 [76%] of 41). The rate of consensus decisions between Swissmedic and the FDA was 21 (81%) of 26 for Orbis MAAs and 31 (76%) of 41 for non-Orbis MAAs. Swissmedic approval rates were lower for indication extensions than for new active substances for Orbis MAAs (13 [72%] of 18 vs seven [88%] of eight) and non-Orbis MAAs (17 [71%] of 24 vs 14 [82%] of 17). Divergent decisions between agencies were predominantly observed for indication extensions (11 [73%] of 15 divergent decisions). During the pre-Orbis era, Swissmedic approved 61 (88%) of 69 MAAs for new active substances. Submission gap and review time for oncology applications at Swissmedic were significantly reduced by participation in Project Orbis, and approval consensus decisions were increased between agencies. These findings suggests that participating in Project Orbis could lead to faster patient access to drugs. None.

Examining longitudinal associations between prenatal exposure to infections and child brain morphology

BackgroundMaternal infection during pregnancy has been identified as a prenatal risk factor for the later development of psychopathology in exposed offspring. Neuroimaging data collected during childhood has suggested a link between prenatal exposure to maternal infection and child brain structure and function, potentially offering a neurobiological explanation for the emergence of psychopathology. Additionally, preclinical studies utilizing repeated measures of neuroimaging data suggest that effects of prenatal maternal infection on the offspring’s brain may normalize over time (i.e., catch-up growth). However, it remains unclear whether exposure to prenatal maternal infection in humans is related to long-term differential neurodevelopmental trajectories. Hence, this study aimed to investigate the association between prenatal exposure to infections on child brain development over time using repeated measures MRI data. MethodsWe leveraged data from a population-based cohort, Generation R, in which we examined prospectively assessed self-reported infections at each trimester of pregnancy (N = 2,155). We further used three neuroimaging assessments (at mean ages 8, 10 and 14) to obtain cortical and subcortical measures of the offspring’s brain morphology with MRI. Hereafter, we applied linear mixed-effects models, adjusting for several confounding factors, to estimate the association of prenatal maternal infection with child brain development over time. ResultsWe found that prenatal exposure to infection in the third trimester was associated with a slower decrease in volumes of the pars orbitalis, rostral anterior cingulate and superior frontal gyrus, and a faster increase in the middle temporal gyrus. In the temporal pole we observed a divergent pattern, specifically showing an increase in volume in offspring exposed to more infections compared to a decrease in volume in offspring exposed to fewer infections. We further observed associations in other frontal and temporal lobe structures after exposure to infections in any trimester, though these did not survive multiple testing correction. ConclusionsOur results suggest that prenatal exposure to infections in the third trimester may be associated with slower age-related growth in the regions: pars orbitalis, rostral anterior cingulate and superior frontal gyrus, and faster age-related growth in the middle temporal gyrus across childhood, suggesting a potential sensitive period. Our results might be interpreted as an extension of longitudinal findings from preclinical studies, indicating that children exposed to prenatal infections could exhibit catch-up growth. However, given the lack of differences in brain volume between various infection groups at baseline, there may instead be either a longitudinal deviation or a subtle temporal deviation. Subsequent well-powered studies that extend into the period of full brain development (∼25 years) are needed to confirm whether the observed phenomenon is indeed catch-up growth, a longitudinal deviation, or a subtle temporal deviation.

Sex and disease severity-based analysis of steroid hormones in ME/CFS.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by persistent fatigue and decreased daily activity following physical and/or cognitive exertion. While ME/CFS affects both sexes, there is a higher prevalence in women. However, studies evaluating this sex-related bias are limited. Circulating steroid hormones, including mineralocorticoids (aldosterone), glucocorticoids (cortisol, corticosterone, 11-deoxycortisol, cortisone), androgens (androstenedione, testosterone), and progestins (progesterone, 17α-hydroxyprogesterone), were measured in plasma samples using ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Samples were obtained from mild/moderate (ME/CFSmm; females, n=20; males, n=8), severely affected patients (ME/CFSsa; females, n=24; males, n=6), and healthy controls (HC, females, n=12; males, n=17). After correction for multiple testing, we observed that circulating levels of 11-deoxycortisol, 17α-hydroxyprogesterone in females, and progesterone in males were significantly different between HC, ME/CFSmm, and ME/CFSsa. Comparing two independent groups, we found that female ME/CFSsa had higher levels of 11-deoxycortisol (vs. HC and ME/CFSmm) and 17α-hydroxyprogesterone (vs. HC). In addition, female ME/CFSmm showed a significant increase in progesterone levels compared to HC. In contrast, our study found that male ME/CFSmm had lower circulating levels of cortisol and corticosterone, while progesterone levels were elevated compared to HC. In addition to these univariate analyses, our correlational and multivariate approaches identified differential associations between our study groups. Also, using two-component partial least squares discriminant analysis (PLS-DA), we were able to discriminate ME/CFS from HC with an accuracy of 0.712 and 0.846 for females and males, respectively. Our findings suggest the potential value of including steroid hormones in future studies aimed at improving stratification in ME/CFS. Additionally, our results provide new perspectives to explore the clinical relevance of these differences within specific patient subgroups.