The current standard of care of inflammatory bowel disease.

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Health-related quality of life across disease stages in patients with amyotrophic lateral sclerosis: results from a real-world survey.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by a rapid disease course, with disease severity being associated with declining health-related quality of life (HRQoL) in persons living with ALS (pALS). The main objective of this study was to assess the impact of disease progression on HRQoL across King's, Milano-Torino Staging (MiToS), and physician-judgement clinical staging. Additionally, we evaluated the impact of the disease on the HRQoL of care partners (cALS). METHODS: Data were sourced from the Adelphi ALS Disease Specific Programme (DSP)™, a cross-sectional survey of neurologists, pALS and cALS presenting in a real-world clinical setting between July 2020 and March 2021 in Europe and the United States. RESULTS: Neurologists (n = 142) provided data for 880 pALS. There were significant negative correlations between all three clinical staging systems and EuroQol (European Quality of Life) Five Dimension Five Level Scale (EQ-5D-5L) utility scores and visual analogue scale (VAS) ratings. Although not all differences were significant, 5-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-5) scores showed a stepwise increase in HRQoL impairment at each stage of the disease regardless of the staging system. At later stages, high levels of fatigue and substantial activity impairment were reported. As pALS disease states progressed, cALS also experienced a decline in HRQoL and increased burden. CONCLUSIONS: Across outcomes, pALS and cALS generally reported worse outcomes at later stages of the disease, highlighting an unmet need in this population for strategies to maximise QoL despite disease progression. Recognition and treatment of symptoms such as pain and fatigue may lead to improved outcomes for pALS and cALS.

Comparison of Trihalomethane exposure assessment metrics in epidemiologic analyses of reproductive and developmental outcomes.

BACKGROUND: Researchers have developed exposure assessment metrics for disinfection by-products (DBPs) utilizing drinking water monitoring data and accounting for spatial and temporal variability, water consumption, and showering and bathing time with an expectation of decreasing exposure misclassification compared to the use of measured concentrations at public water supply (PWS) monitoring locations alone. OBJECTIVE: We used exposure data collected for a previous study of DBPs to evaluate how different sources of information impact trihalomethane (THM) exposure estimates. METHODS: We compared gestational exposure estimates to THMs based on water utility monitoring data alone, statistical imputation of daily concentrations to incorporate temporal variability, and personal water consumption and use (bathing and showering). We used Spearman correlation coefficients and ranked kappa statistics to compare exposure classifications. RESULTS: Exposure estimates based on measured or imputed daily THM concentrations, self-reported consumption, or bathing and showering differed substantially from estimates based solely on concentrations from PWS quarterly monitoring reports. Ranked exposure classifications, high to low quartiles or deciles, were generally consistent across each exposure metric (i.e., a subject with "high" exposure based on measured or imputed THM concentrations generally remained in the "high" category across exposure metrics.) The measured concentrations and imputed daily (i.e., spline regression) concentrations were highly correlated (r = 0.98). The weighted kappa statistics comparing exposure estimates using different exposure metrics ranged from 0.27 to 0.89, with the highest values for the ingestion + bathing/showering metrics compared to metrics for bathing/showering only (0.76 and 0.89). Bathing and showering contributed the most to "total" THM exposure estimates. IMPACT STATEMENT: We compare exposure metrics capturing temporal variability and multiple estimates of personal THM exposure with THM concentrations from PWS monitoring data. Our results show exposure estimates based on imputed daily concentrations accounting for temporal variability were very similar to the measured THM concentrations. We observed low agreement between imputed daily concentrations and ingestion-based estimates. Considering additional routes of exposure (e.g., inhalation and dermal) slightly increased agreement with the measured PWS exposure estimate in this population. Overall, the comparison of exposure assessment metrics allows researchers to understand the added value of additional data collection for future epidemiologic analyses of DBPs.

Risks of obstructive genitourinary birth defects in relation to trihalomethane and haloacetic acid exposures: expanding disinfection byproduct mixtures analyses using relative potency factors.

BACKGROUND: Some disinfection byproducts (DBPs) are teratogens based on toxicological evidence. Conventional use of predominant DBPs as proxies for complex mixtures may result in decreased ability to detect associations in epidemiological studies. OBJECTIVE: We assessed risks of obstructive genitourinary birth defects (OGDs) in relation to 12 DBP mixtures and 13 individual component DBPs. METHODS: We designed a nested registry-based case-control study (210 OGD cases; 2100 controls) in Massachusetts towns with complete quarterly 1999-2004 data on four trihalomethanes (THMs) and five haloacetic acids (HAAs). We estimated temporally-weighted average DBP exposures for the first trimester of pregnancy. We estimated adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for OGD in relation to individual DBPs, unweighted mixtures, and weighted mixtures based on THM/HAA relative potency factors (RPF) from animal toxicology data for full-litter resorption, eye defects, and neural tube defects. RESULTS: We detected elevated aORs for OGDs for the highest of bromodichloromethane (aOR = 1.75; 95% CI: 1.15-2.65), dibromochloromethane (aOR = 1.71; 95% CI: 1.15-2.54), bromodichloroacetic acid (aOR = 1.56; 95%CI: 0.97-2.51), chlorodibromoacetic acid (aOR = 1.97, 95% CI: 1.23-3.15), and tribromoacetic acid (aOR = 1.90; 95%CI: 1.20-3.03). Across unweighted mixture sums, the highest aORs were for the sum of three brominated THMs (aOR = 1.74; 95% CI: 1.15-2.64), the sum of six brominated HAAs (aOR = 1.43; 95% CI: 0.89-2.31), and the sum of nine brominated DBPs (aOR = 1.80; 95% CI: 1.05-3.10). Comparing eight RPF-weighted to unweighted mixtures, the largest aOR differences were for two HAA metrics, which both were higher with RPF weighting; other metrics had reduced or minimally changed ORs in RPF-weighted models.

UK Haemoglobin Disorders Peer Review: A Quality Standards-based review programme for sickle cell disease and thalassaemia.

We evaluated the impact of peer reviews in driving improvement in healthcare quality for people with haemoglobinopathy in the United Kingdom. We analysed compliance to four Quality Standards (QS)-based peer reviews from 2010 to 2020 to evaluate its impact in driving healthcare quality. Seventeen paediatric and 29 adult haemoglobinopathy centres were reviewed in 2010/11 and 2012/13 respectively; 33 paediatric and 33 adult centres were reviewed in 2014/16, and 32 paediatric and 32 adult centres were reviewed in 2018/2020. Compliance with QS and participant feedback were analysed to assess the impact of peer review programmes to drive improvement in quality of care. We noted that haemoglobinopathy centres significantly improved their compliance to QS between the first two review programmes, but not in the final review programme. In comparison to other disease-group reviews, the haemoglobinopathy departments were less able to address critical peer review recommendations in their own institutions. The peer review programme was unable to drive sustained improvement in healthcare quality, underscoring the need for sustained development and support for haemoglobinopathy services in the National Health Service. Further work is needed to understand why disparities exist among peer review-driven improvement initiatives within different disease groups.

Erratum: AAV vector production: Troublesome host innate responses in another setting.

[This corrects the article DOI: 10.1016/j.omtm.2023.02.008.].

FAM20A mutations and transcriptome analyses of dental pulp tissues of enamel renal syndrome.

AIM: Biallelic loss-of-function FAM20A mutations cause amelogenesis imperfecta (AI) type IG, better known as enamel renal syndrome (ERS), characterized by severe enamel hypoplasia, delayed/failed tooth eruption, intrapulpal calcifications, gingival hyperplasia and nephrocalcinosis. FAM20A binds to FAM20C, the Golgi casein kinase (GCK) and potentiates its function to phosphorylate secreted proteins critical for biomineralization. While many FAM20A pathogenic mutations have been reported, the pathogeneses of orodental anomalies in ERS remain to be elucidated. This study aimed to identify disease-causing mutations for patients with ERS phenotypes and to discern the molecular mechanism underlying ERS intrapulpal calcifications. METHODOLOGY: Phenotypic characterization and whole exome analyses were conducted for 8 families and 2 sporadic cases with hypoplastic AI. A minigene assay was performed to investigate the molecular consequences of a FAM20A splice-site variant. RNA sequencing followed by transcription profiling and gene ontology (GO) analyses were carried out for dental pulp tissues of ERS and the control. RESULTS: Biallelic FAM20A mutations were demonstrated for each affected individual, including 7 novel pathogenic variants: c.590-5T>A, c.625T>A (p.Cys209Ser), c.771del (p.Gln258Argfs*28), c.832_835delinsTGTCCGACGGTGTCCGACGGTGTC CA (p.Val278Cysfs*29), c.1232G>A (p.Arg411Gln), c.1297A>G (p.Arg433Gly) and c.1351del (p.Gln451Serfs*4). The c.590-5T>A splice-site mutation caused Exon 3 skipping, which resulted in an in-frame deletion of a unique region of the FAM20A protein, p.(Asp197_Ile214delinsVal). Analyses of differentially expressed genes in ERS pulp tissues demonstrated that genes involved in biomineralization, particularly dentinogenesis, were significantly upregulated, such as DSPP, MMP9, MMP20 and WNT10A. Enrichment analyses indicated overrepresentation of gene sets associated with BMP and SMAD signalling pathways. In contrast, GO terms related to inflammation and axon development were underrepresented. Among BMP signalling genes, BMP agonists GDF7, GDF15, BMP3, BMP8A, BMP8B, BMP4 and BMP6 were upregulated, while BMP antagonists GREM1, BMPER and VWC2 showed decreased expression in ERS dental pulp tissues. CONCLUSIONS: Upregulation of BMP signalling underlies intrapulpal calcifications in ERS. FAM20A plays an essential role in pulp tissue homeostasis and prevention of ectopic mineralization in soft tissues. This critical function probably depends upon MGP (matrix Gla protein), a potent mineralization inhibitor that must be properly phosphorylated by FAM20A-FAM20C kinase complex.

Intensive Blood Pressure Management Preserves Functional Connectivity in Patients with Hypertension from the Systolic Blood Pressure Intervention Randomized Trial.

BACKGROUND AND PURPOSE: The Systolic Blood Pressure Intervention (SPRINT) randomized trial demonstrated that intensive blood pressure management resulted in slower progression of cerebral white matter hyperintensities, compared with standard therapy. We assessed longitudinal changes in brain functional connectivity to determine whether intensive treatment results in less decline in functional connectivity and how changes in brain functional connectivity relate to changes in brain structure. MATERIALS AND METHODS: Five hundred forty-eight participants completed longitudinal brain MR imaging, including resting-state fMRI, during a median follow-up of 3.84 years. Functional brain networks were identified using independent component analysis, and a mean connectivity score was calculated for each network. Longitudinal changes in mean connectivity score were compared between treatment groups using a 2-sample t test, followed by a voxelwise t test. In the full cohort, adjusted linear regression analysis was performed between changes in the mean connectivity score and changes in structural MR imaging metrics. RESULTS: Four hundred six participants had longitudinal imaging that passed quality control. The auditory-salience-language network demonstrated a significantly larger decline in the mean connectivity score in the standard treatment group relative to the intensive treatment group (P = .014), with regions of significant difference between treatment groups in the cingulate and right temporal/insular regions. There was no treatment group difference in other networks. Longitudinal changes in mean connectivity score of the default mode network but not the auditory-salience-language network demonstrated a significant correlation with longitudinal changes in white matter hyperintensities (P = .013). CONCLUSIONS: Intensive treatment was associated with preservation of functional connectivity of the auditory-salience-language network, while mean network connectivity in other networks was not significantly different between intensive and standard therapy. A longitudinal increase in the white matter hyperintensity burden is associated with a decline in mean connectivity of the default mode network.

Maternal exposure to nitrosamines in drinking water during pregnancy and birth outcomes in a Chinese cohort.

Maternal exposure to regulated disinfection by-products (DBPs) during pregnancy has been linked with adverse birth outcomes. However, no human studies have focused on drinking water nitrosamines, a group of emerging unregulated nitrogenous DBPs that exhibits genotoxicity and developmental toxicity in experimental studies. This cohort study included 2457 mother-infant pairs from a single drinking water supply system in central China, and maternal trimester-specific and entire pregnancy exposure of drinking water nitrosamines were evaluated. Multivariable linear and Poisson regression models were used to estimate the associations between maternal exposure to nitrosamines in drinking water and birth outcomes [birth weight (BW), low birth weight (LBW), small for gestational age (SGA) and preterm delivery (PTD)]. Elevated maternal N-nitrosodimethylamine (NDMA) exposure in the second trimester and N-nitrosopiperidine (NPIP) exposure during the entire pregnancy were associated with decreased BW (e.g., ß = -88.6 g; 95% CI: -151.0, -26.1 for the highest vs. lowest tertile of NDMA; p for trend = 0.01) and increased risks of PTD [e.g., risk ratio (RR) = 2.16; 95% CI: 1.23, 3.79 for the highest vs. lowest tertile of NDMA; p for trend = 0.002]. Elevated maternal exposure of N-nitrosodiethylamine (NDEA) in the second trimester was associated with increased risk of SGA (RR = 1.80; 95% CI: 1.09, 2.98 for the highest vs. lowest tertile; p for trend = 0.01). Our study detected associations of maternal exposure to drinking water nitrosamines during pregnancy with decreased BW and increased risks of SGA and PTD. These findings are novel but require replication in other study populations.

Digital restorative workflows for developmental dental defects in young patients: A case series.

BACKGROUND: Digital technology is rapidly changing the provision of oral health care, although its adoption for the oral health care of young patients has lagged. The authors describe digitally supported treatment approaches for managing treatment of developmental dental defects in the early permanent dentition. CASE DESCRIPTION: Four adolescent patients with amelogenesis imperfecta received transitional anterior restorations for esthetic and functional rehabilitation using a variety of digital workflows. Combinations of restoration type, materials, and fabrication methods were selected to meet the needs of each patient on the basis of their specific amelogenesis imperfecta phenotype and chief symptoms. These cases highlight the application of digital technology in pediatric and adolescent dentistry for managing the treatment of developmental dental defects. PRACTICAL IMPLICATIONS: Digitally supported restorative approaches, as described in this report, offer broad applicability of materials and techniques directed at treating the complex restorative needs of young patients in the transitional and early permanent dentition.

Systematic review and meta-analysis of birth weight and PFNA exposures.

We used a systematic review that included risk of bias and study sensitivity analysis to identify 34 studies examining changes in birth weight (BWT) in relation to PFNA biomarker measures (e.g., maternal serum/plasma or umbilical cord samples). We fit a random effects model of the overall pooled estimate and stratified estimates based on sample timing and overall study confidence. We conducted a meta-regression to further examine the impact of gestational age at biomarker sample timing. We detected a -32.9 g (95%CI: -47.0, -18.7) mean BWT deficit per each ln PFNA increase from 27 included studies. We did not detect evidence of publication bias (pE = 0.30) or between-study heterogeneity in the summary estimate (pQ = 0.05; I2 = 36%). The twelve high confidence studies yielded a smaller pooled effect estimate (ß = -28.0 g; 95%CI: -49.0, -6.9) than the ten medium (ß = -39.0 g; 95%CI: -61.8, -16.3) or four low (ß = -36.9 g; 95%CI: -82.9, 9.1) confidence studies. The stratum-specific results based on earlier pregnancy sampling periods in 11 studies showed smaller deficits (ß = -22.0 g; 95%CI: -40.1, -4.0) compared to 10 mid- and late-pregnancy (ß = -44.2 g; 95%CI: -64.8, -23.5) studies and six post-partum studies (ß = -42.9 g; 95%CI: -88.0, 2.2). Using estimates of the specific gestational week of sampling, the meta-regression showed results consistent with the categorical sample analysis, in that as gestational age at sampling time increases across these studies, the summary effect estimate of a mean BWT deficit got larger. Overall, we detected mean BWT deficits for PFNA that were larger and more consistent across studies than previous PFAS meta-analyses. Compared to studies with later sampling, BWT deficits were smaller but remained sizeable for even the earliest sampling periods. Contrary to earlier meta-analyses for PFOA and PFOS, BWT deficits that were detected across all strata did not appear to be fully explained by potential bias due to pregnancy hemodynamics from sampling timing differences.

Comparative susceptibility of children and adults to neurological effects of inhaled manganese: A review of the published literature.

BACKGROUND: Manganese (Mn) is neurotoxic in adults and children. Current assessments are based on the more extensive adult epidemiological data, but the potential for greater childhood susceptibility remains a concern. To better understand potential lifestage-based variations, we compared susceptibilities to neurotoxicity in children and adults using Mn biomarker data. METHODS: We developed a literature search strategy based on a Population, Exposures, Comparators, and Outcomes statement focusing on inhalation exposures and neurological outcomes in humans. Screening was performed using DistillerSR. Hair biomarker studies were selected for evaluation because studies with air measurements were unavailable or considered inadequate for children. Studies were paired based on concordant Mn source, biomarker, and outcome. Comparisons were made based on reported dose-response slopes (children vs. adults). Study evaluation was conducted to understand the confidence in our comparisons. RESULTS: We identified five studies evaluating seven pairings of hair Mn and neurological outcomes (cognition and motor effects) in children and adults matched on sources of environmental Mn inhalation exposure. Two Brazilian studies of children and one of adults reported intelligent quotient (IQ) effects; effects in both comparisons were stronger in children (1.21 to 2.03-fold difference). In paired analyses of children and adults from the United States, children exhibited both stronger and weaker effects compared to adults (0.37 to 1.75-fold differences) on postural sway metrics. CONCLUSION: There is limited information on the comparative susceptibility of children and adults to inhaled Mn. We report that children may be 0.37 to 2.03 times as susceptible as adults to neurotoxic effects of Mn, thereby providing a quantitative estimate for some aspects of lifestage variation. Due to the limited number of paired studies available in the literature, this quantitative estimate should be interpreted with caution. Our analyses do not account for other sources of inter-individual variation. Additional studies of Mn-exposed children with direct air concentration measurements would improve the evidence base.

Sex differences in response to exercise heat stress in the context of the military environment.

Women can now serve in ground close combat (GCC) roles, where they may be required to operate alongside men in hot environments. However, relative to the average male soldier, female soldiers are less aerobically fit, with a smaller surface area (A D), lower mass (m) with higher body fat and a larger A D/m ratio. This increases cardiovascular strain, reduces heat exchange with the environment and causes a greater body temperature increase for a given heat storage, although a large A D/m ratio can be advantageous. Physical employment standards for GCC roles might lessen the magnitude of fitness and anthropometric differences, yet even when studies control for these factors, women sweat less than men at high work rates. Therefore, the average female soldier in a GCC role is likely to be at a degree of disadvantage in many hot environments and particularly during intense physical activity in hot-arid conditions, although heat acclimation may mitigate some of this effect. Any thermoregulatory disadvantage may be exacerbated during the mid-luteal phase of the menstrual cycle, although the data are equivocal. Likewise, sex differences in behavioural thermoregulation and cognition in the heat are not well understood. Interestingly, there is often lower reported heat illness incidence in women, although the extent to which this is influenced by behavioural factors or historic differences in role allocation is unclear. Indeed, much of the extant literature lacks ecological validity and more work is required to fully understand sex differences to exercise heat stress in a GCC context.