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BACKGROUND: Hyperbaric oxygen (HBO2) treatment is used across a range of medical specialties for a variety of applications, particularly where hypoxia and inflammation are important contributors. Because of its hypoxia-relieving and anti-inflammatory effects HBO2 may be useful for new indications not currently approved by the Undersea and Hyperbaric Medical Society. Identifying these new applications for HBO2 is difficult because individual centers may only treat a few cases and not track the outcomes consistently. The web-based International Multicenter Registry for Hyperbaric Oxygen Therapy captures prospective outcome data for patients treated with HBO2 therapy. These data can then be used to identify new potential applications for HBO2, which has relevance for a range of medical specialties. OBJECTIVE: Although hyperbaric medicine has established indications, new ones continue to emerge. One objective of this registry study was to identify cases where HBO2 has been used for conditions falling outside of current Undersea and Hyperbaric Medical Society-approved indications and present outcome data for them. METHODS: This descriptive study used data from a web-based, multicenter, international registry of patients treated with HBO2. Participating centers agree to collect data on all patients treated using standard outcome measures, and individual centers send deidentified data to the central registry. HBO2 treatment programs in the United States, the United Kingdom, and Australia participate. Demographic, outcome, complication, and treatment data, including pre- and posttreatment quality of life questionnaires (EQ-5D-5L) were collected for individuals referred for HBO2 treatment. RESULTS: Out of 9726 patient entries, 378 (3.89%) individuals were treated for 45 emerging indications. Post-COVID-19 condition (PCC; also known as postacute sequelae of COVID-19; 149/378, 39.4%), ulcerative colitis (47/378, 12.4%), and Crohn disease (40/378, 10.6%) accounted for 62.4% (n=236) of the total cases. Calciphylaxis (20/378, 5.3%), frostbite (18/378, 4.8%), and peripheral vascular disease-related wounds (12/378, 3.2%) accounted for a further 13.2% (n=50). Patients with PCC reported significant improvement on the Neurobehavioral Symptom Inventory (NSI score: pretreatment=30.6; posttreatment=14.4; P<.001). Patients with Crohn disease reported significantly improved quality of life (EQ-5D score: pretreatment=53.8; posttreatment=68.8), and 5 (13%) reported closing a fistula. Patients with ulcerative colitis and complete pre- and post-HBO2 data reported improved quality of life and lower scores on a bowel questionnaire examining frequency, blood, pain, and urgency. A subset of patients with calciphylaxis and arterial ulcers also reported improvement. CONCLUSIONS: HBO2 is being used for a wide range of possible applications across various medical specialties for its hypoxia-relieving and anti-inflammatory effects. Results show statistically significant improvements in patient-reported outcomes for inflammatory bowel disease and PCC. HBO2 is also being used for frostbite, pyoderma gangrenosum, pterygium, hypospadias repair, and facial filler procedures. Other indications show evidence for improvement, and the case series for all indications is growing in the registry. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/18857.

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BACKGROUND: Sparse research exists on predictors of element concentrations measured in deciduous teeth. OBJECTIVE: To estimate associations between maternal/child characteristics, elements measured in home tap water during pregnancy and element concentrations in the dentin of shed deciduous teeth. METHODS: Our analysis included 152 pregnant person-infant dyads followed from the second trimester through the end of the first postnatal year from the New Hampshire Birth Cohort Study. During pregnancy and early infancy, we collected dietary and sociodemographic information via surveys, measured elements in home tap water, and later collected naturally exfoliated teeth from child participants. We measured longitudinal deposition of elements in dentin using LA-ICP-MS. Multivariable linear mixed models were used to estimate associations between predictors and dentin element concentrations. RESULTS: We measured 12 elements in dentin including those previously reported (Ba, Mn, Pb, Sr, Zn) and less frequently reported (Al, As, Cd, Cu, Hg, Li, and W). A doubling of Pb or Sr concentrations in water was associated with higher dentin Pb or Sr respectively in prenatally formed [9% (95%CI: 3%, 15%); 3% (1%, 6%)] and postnatally formed [10% (2%, 19%); 6% (2%, 10%)] dentin. Formula feeding from birth to 6 weeks or 6 weeks to 4 months was associated with higher element concentrations in postnatal dentin within the given time period as compared to exclusive human milk feeding: Sr: 6 weeks: 61% (36%, 90%) and 4 months: 85% (54%, 121%); Ba: 6 weeks: 35% (3.3%, 77%) and 4 months: 42% (10%, 83%); and Li: 6 weeks: 61% (33%, 95%) and 4 months: 58% (31%, 90%). SIGNIFICANCE: These findings offer insights into predictors of dentin elements and potential confounders in exposure-health outcome relationships during critical developmental periods.

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PURPOSE: Our purpose was to determine changes in patient-reported hematuria and urinary symptoms after hyperbaric oxygen (HBO2) treatment for radiation cystitis (RC). MATERIALS AND METHODS: We analyzed prospectively collected data from the Multicenter Registry for Hyperbaric Oxygen Therapy Consortium accumulated within a week of beginning and ending HBO2. Measures included the modified Radiation Therapy Oncology Group (RTOG) Hematuria Scale, Urinary Distress Inventory Short Form, and EuroQol Five Dimension Five Level instrument. RTOG hematuria and Urinary Distress Inventory Short Form scores were compared using the sign test. Logistic regression was used to evaluate characteristics associated with hematuria improvement. RESULTS: A total of 470 registry patients had RC. The median age, number of HBO2 sessions, and years after radiation were 73 (IQR 12) years, 39 (IQR 10) sessions, and 5 (IQR 8) years, respectively. Eighty-four percent of patients (393/470) had prostate cancer‒related radiation. EuroQol Five Dimension Five Level scores improved from 0.83 (IQR 0.14) to 0.85 (IQR 0.22; P < .001. Three hundred seventy patients had complete RTOG hematuria scores that improved from 2 (IQR 2) to 0 (IQR 2; P < .001. Two hundred forty-six patients had complete Urinary Distress Inventory Short Form ratings that decreased from 33.3 (IQR 44) to 22.2 (IQR 33; P < .001). Regression analysis of those with visible hematuria before HBO2 showed lower improvement odds associated with higher HBO2 hematuria scores (odds ratio [OR] 0.44, 95% CI 0.26-0.73; P < .01), a smoking history (OR 0.44, 95% CI 0.21-0.92; P = .03), or a nonprostate cancer history (OR 0.32, 95% CI 0.10-0.99; P = .05). CONCLUSIONS: HBO2 for RC improved reported hematuria, urinary function, and quality of life. Higher baseline hematuria scores, smoking, and nonprostate cancer history were associated with lower odds of hematuria improvement.

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We tested the hypotheses that adult cancer incidence and mortality in the Northeast region and in Northern New England (NNE) were different than the rest of the United States, and described other related cancer metrics and risk factor prevalence. Using national, publicly available cancer registry data, we compared cancer incidence and mortality in the Northeast region with the United States and NNE with the United States overall and by race/ethnicity, using age-standardized cancer incidence and rate ratios (RR). Compared with the United States, age-adjusted cancer incidence in adults of all races combined was higher in the Northeast (RR, 1.07; 95% confidence interval [CI] 1.07-1.08) and in NNE (RR 1.06; CI 1.05-1.07). However compared with the United States, mortality was lower in the Northeast (RR, 0.98; CI 0.98-0.98) but higher in NNE (RR, 1.05; CI 1.03-1.06). Mortality in NNE was higher than the United States for cancers of the brain (RR, 1.16; CI 1.07-1.26), uterus (RR, 1.32; CI 1.14-1.52), esophagus (RR, 1.36; CI 1.26-1.47), lung (RR, 1.12; CI 1.09-1.15), bladder (RR, 1.23; CI 1.14-1.33), and melanoma (RR, 1.13; CI 1.01-1.27). Significantly higher overall cancer incidence was seen in the Northeast than the United States in all race/ethnicity subgroups except Native American/Alaska Natives (RR, 0.68; CI 0.64-0.72). In conclusion, NNE has higher cancer incidence and mortality than the United States, a pattern that contrasts with the Northeast region, which has lower cancer mortality overall than the United States despite higher incidence. Significance: These findings highlight the need to identify the causes of higher cancer incidence in the Northeast and the excess cancer mortality in NNE.

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Compared with urban areas, rural areas have higher cancer mortality and have experienced substantially smaller declines in cancer incidence in recent years. In a New Hampshire (NH) and Vermont (VT) survey, we explored the roles of rurality and educational attainment on cancer risk behaviors, beliefs, and other social drivers of health. In February-March 2022, two survey panels in NH and VT were sent an online questionnaire. Responses were analyzed by rurality and educational attainment. Respondents (N = 1,717, 22%) mostly lived in rural areas (55%); 45% of rural and 25% of urban residents had high school education or less and this difference was statistically significant. After adjustment for rurality, lower educational attainment was associated with smoking, difficulty paying for basic necessities, greater financial difficulty during the COVID-19 pandemic, struggling to pay for gas (P < 0.01), fatalistic attitudes toward cancer prevention, and susceptibility to information overload about cancer prevention. Among the 33% of respondents who delayed getting medical care in the past year, this was more often due to lack of transportation in those with lower educational attainment (21% vs. 3%, P = 0.02 adjusted for rurality) and more often due to concerns about catching COVID-19 among urban than rural residents (52% vs. 21%; P < 0.001 adjusted for education). In conclusion, in NH/VT, smoking, financial hardship, and beliefs about cancer prevention are independently associated with lower educational attainment but not rural residence. These findings have implications for the design of interventions to address cancer risk in rural areas. Significance: In NH and VT, the finding that some associations between cancer risk factors and rural residence are more closely tied to educational attainment than rurality suggest that the design of interventions to address cancer risk should take educational attainment into account.

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The early COVID-19 pandemic was associated with cessation of screening services, but the prevalence of ongoing delays in cancer screening into the third year of the pandemic are not well-characterized. In February/March 2022, a population-based survey assessed cancer needs in New Hampshire and Vermont. The associations between cancer screening delays (breast, cervical, colorectal or lung cancer) and social determinants of health, health care access, and cancer attitudes and beliefs were tested. Distributions and Rao-Scott chi-square tests were used for hypothesis testing and weighted to represent state populations. Of 1717 participants, 55% resided in rural areas, 96% identified as White race, 50% were women, 36% had high school or less education. Screening delays were reported for breast cancer (28%), cervical cancer (30%), colorectal cancer (24%), and lung cancer (30%). Delays were associated with having higher educational attainment (lung), urban living (colorectal), and having Medicaid insurance (breast, cervical). Low confidence in ability to obtain information about cancer was associated with screening delays across screening types. The most common reason for delay was the perception that the screening test was not urgent (31% breast, 30% cervical, 28% colorectal). Cost was the most common reason for delayed lung cancer screening (36%). COVID-19 was indicated as a delay reason in 15-29% of respondents; 12-20% reported health system capacity during the pandemic as a reason for delay, depending on screening type. Interventions that address sub-populations and reasons for screening delays are needed to mitigate the impact of the COVID-19 pandemic on cancer burden and mortality.

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Background: Restrictive measures were widely introduced at the start of the COVID-19 pandemic to reduce the spread of the virus. These restrictions have been linked to reductions in laboratory-diagnosed infections and hospitalisations. It is unclear if the observed decreases reflect a reduction in health-seeking behaviour or results from fewer infections per se. Methods: We have explored trends in caregiver reports of respiratory infections and symptoms needing a doctor visit in children aged 0-11 years using data from the New Hampshire Birth Cohort Study in 2011-2021, comparing the prepandemic and pandemic periods. Generalized Estimating Equations were used to model pandemic/prepandemic risk ratios (RRs) with adjustment for maternal and child characteristics. Results: The overall probability of a report of an upper respiratory tract infection (RTI) needing a doctor visit in children aged 0-11 years was 16.7%. There was strong evidence of a decline during the pandemic: 17.9% pre pandemic versus 8.19% in the pandemic period, adjusted RR 0.51 (95% CI: 0.42 to 0.64). Similar trends were seen for any lower RTI, any respiratory symptom and any other acute symptom with overall probabilities of 4.33%, 24.8% and 13.8%, respectively, and adjusted rate ratios 0.61 (0.41 to 0.91), 0.59 (0.51 to 0.68) and 0.72 (0.59 to 0.87), respectively. In contrast, respiratory syncytial virus and bronchiolitis remained steady. Conclusions: The steep decline in caregiver-reported infections and symptoms mirrored trends reported in laboratory-diagnosed infections and hospitalisations and suggests a real decrease in prevalence. Longer follow-up is needed to determine later consequences of the reduction in childhood infections.

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BACKGROUND: In a 2018 descriptive study, cancer incidence in children (age 0-19) in diagnosis years 2003 to 2014 was reported as being highest in New Hampshire and in the Northeast region. METHODS: Using the Cancer in North America (CiNA) analytic file, we tested the hypotheses that incidence rates in the Northeast were higher than those in other regions of the United States either overall or by race/ethnicity group, and that rates in New Hampshire were higher than the Northeast region as a whole. RESULTS: In 2003 to 2014, pediatric cancer incidence was significantly higher in the Northeast than other regions of the United States overall and among non-Hispanic Whites and Blacks, but not among Hispanics and other racial minorities. However, there was no significant variability in incidence in the states within the Northeast overall or by race/ethnicity subgroup. Overall, statistically significantly higher incidence was seen in the Northeast for lymphomas [RR, 1.15; 99% confidence interval (CI), 1.10-1.19], central nervous system neoplasms (RR, 1.12; 99% CI, 1.07-1.16), and neuroblastoma (RR, 1.13; 99% CI, 1.05-1.21). CONCLUSIONS: Pediatric cancer incidence is statistically significantly higher in the Northeast than in the rest of the United States, but within the Northeast, states have comparable incidence. Differences in cancer subtypes by ethnicity merit further investigation. IMPACT: Our analyses clarify and extend previous reports by statistically confirming the hypothesis that the Northeast has the highest pediatric cancer rates in the country, by providing similar comparisons stratified by race/ethnicity, and by assessing variability within the Northeast.

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Despite substantial observational and experimental evidence that aspirin use can provide protection against the development of colorectal neoplasia, our understanding of the molecular mechanisms involved is inadequate and limits our ability to use this drug effectively and safely for chemoprevention. We employed an untargeted plasma metabolomics approach using liquid chromatography with high-resolution mass spectroscopy to explore novel metabolites that may contribute to the chemopreventive effects of aspirin. Associations between levels of metabolic features in plasma and aspirin treatment were investigated among 523 participants in a randomized placebo-controlled clinical trial of two doses of aspirin (81 or 325 mg/day) and were linked to risk of colorectal adenoma occurrence over 3 years of follow-up. Metabolic pathways that were altered with aspirin treatment included linoleate and glycerophospholipid metabolism for the 81-mg dose and carnitine shuttle for both doses. Metabolites whose levels increased with 81 mg/day aspirin treatment and were also associated with decreased risk of adenomas during follow-up included certain forms of lysophosphatidylcholine and lysophosphatidylethanolamine as well as trihydroxyoctadecenoic acid, which is a derivative of linoleic acid and is upstream of cyclooxygenase inhibition by aspirin in the linoleate and arachidonic acid metabolism pathways. In conclusion, our findings regarding lysophospholipids and metabolites in the linoleate metabolism pathway may provide novel insights into the chemopreventive effects of aspirin in the colorectum, although they should be considered hypothesis-generating at this time. PREVENTION RELEVANCE: This research used metabolomics, an innovative discovery-based approach, to identify molecular changes in human blood that may help to explain how aspirin use reduces the risk of colorectal neoplasia in some individuals. Ultimately, this work could have important implications for optimizing aspirin use in the prevention of colorectal cancer.

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OBJECTIVE: To examine changes in lung function over time in extremely prematurely born adolescents. WORKING HYPOTHESIS: Changes in lung function during adolescence would vary by ventilation mode immediately after birth. STUDY DESIGN: Longitudinal follow-up study. PATIENT SUBJECT SELECTION: Participants from the United Kingdom Oscillation Study who were randomized at birth to high-frequency oscillation (HFO) or conventional ventilation (CV) were assessed at 11-14 years (n = 319) and at 16-19 years (n = 159). METHODOLOGY: Forced expiratory flow (FEF), forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and lung volumes including functional residual capacity (FRC) were reported as z-scores. The diffusion capacity of the lungs for carbon monoxide (DLCO) was measured. Lung function trajectories were compared by mode of ventilation using mixed models. Changes in z-scores were scaled to 5-year average follow-up. RESULTS: There were significant changes in the mean FEF75, FEF50, FEF25, FEV1, FVC, and DLCO z-scores within the CV and HFO cohorts, but no significant differences in the changes between the two groups. The mean FRC z-score increased in both groups, with an average change of greater than one z-score. The mean FEV1/FVC z-score increased significantly in the CV group, but not in the HFO group (difference in slopes: p = 0.02). Across the population, deterioration in lung function was associated with male sex, white ethnicity, lower gestational age at birth, postnatal corticosteroids, oxygen dependency at 36 weeks postmenstrual age, and lower birth weight, but not ventilation mode. CONCLUSIONS: There was little evidence that the mode of ventilation affected changes in lung function over time.

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OBJECTIVES: Accurate assessment of tobacco smoke exposure is key to evaluate its effects. We sought to validate and establish cut-offs for self-reported smoking and secondhand smoke (SHS) exposure during pregnancy using urinary cotinine and 4-(methylnitrosamino)-1-(-3-pyridyl)-1-butanol (NNAL) in a large contemporary prospective study from the USA, with lower smoking prevalence than has previously been evaluated. DESIGN: Prospective birth cohort. SETTING: Pregnancy clinics in New Hampshire and Vermont, USA. PARTICIPANTS: 1396 women enrolled in the New Hampshire Birth Cohort Study with self-reported smoking, urinary cotinine, NNAL and pregnancy outcomes. PRIMARY AND SECONDARY OUTCOME MEASURES: Cut-offs for urinary cotinine and NNAL concentrations were estimated from logistic regression models using Youden's method to predict SHS and active smoking. Cotinine and NNAL were each used as the exposure in separate multifactorial models for pregnancy outcomes. RESULTS: Self-reported maternal smoking was: 72% non-smokers, 5.7% ex-smokers, 6.4% SHS exposure, 6.2% currently smoked, 10% unreported. Cotinine and NNAL levels were low and highly intercorrelated (r=0.91). Geometric mean cotinine, NNAL were 0.99 ng/mL, 0.05 pmol/mL, respectively. Cotinine cut-offs for SHS, current smoking were 1.2 ng/mL and 1.8 ng/mL (area under curve (AUC) 95% CI: 0.52 (0.47 to 0.57), 0.90 (0.85 to 0.94)). NNAL cut-off for current smoking was 0.09 pmol/mL (AUC=0.82 (95% CI 0.77 to 0.87)). Using cotinine and NNAL cut-offs combined gave similar AUC to cotinine alone, 0.87 (95% CI 0.82 to 0.91). Cotinine and NNAL gave almost identical effect estimates when modelling pregnancy outcomes. CONCLUSIONS: In this population, we observed high concordance between self-complete questionnaire smoking data and urinary cotinine and NNAL. With respect to biomarkers, either cotinine or NNAL can be used as a measure of tobacco smoke exposure overall but only cotinine can be used to detect SHS.

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INTRODUCTION AND MOTIVATION: Many health studies measure a continuous outcome and compare means between groups. Since means for biological data are often difficult to interpret clinically, it is common to dichotomise using a cut-point and present the 'percentage abnormal' alongside or in place of means. Examples include birthweight where 'abnormal' is defined as <2500 g (low birthweight), systolic blood pressure with abnormal defined as >140 mm Hg (high blood pressure) and lung function with varying definitions of the 'limit of normal'. In vulnerable populations with low means, for example, birthweight in a population of preterm babies, a given difference in means between two groups will represent a larger difference in the percentage with low birthweight than in a general population of babies where most will be full term. Thus, in general, the difference in percentage of patients with abnormal values for a given difference in means varies according to the reference population's mean value. This phenomenon leads to challenges in interpreting differences in means in vulnerable populations and in defining an outcome-specific minimal clinically important difference (MCID) in means since the proportion abnormal, which is useful in interpreting means, is not constant-it varies with the population mean. This has relevance for study power calculations and data analyses in vulnerable populations where a small observed difference in means may be difficult to interpret clinically and may be disregarded, even if associated with a relatively large difference in percentage abnormal which is clinically relevant. METHODS: To address these issues, we suggest both difference in means and difference in percentage (proportion) abnormal are considered when choosing the MCID, and that both means and percentages abnormal are reported when analysing the data. CONCLUSIONS: We describe a distributional approach to analyse proportions classified as abnormal that avoids the usual loss of precision and power associated with dichotomisation.

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OBJECTIVE: To evaluate the associations of depressive symptoms and antidepressant use during pregnancy with the risks of preterm birth, low birth weight, small for gestational age (SGA), and low Apgar scores. DATA SOURCES: MEDLINE, EMBASE, ClinicalTrials.gov, and PsycINFO up to June 2016. METHODS OF STUDY SELECTION: Data were sought from studies examining associations of depression, depressive symptoms, or use of antidepressants during pregnancy with gestational age, birth weight, SGA, or Apgar scores. Authors shared the raw data of their studies for incorporation into this individual participant data meta-analysis. TABULATION, INTEGRATION, AND RESULTS: We performed one-stage random-effects meta-analyses to estimate odds ratios (ORs) with 95% CIs. The 215 eligible articles resulted in 402,375 women derived from 27 study databases. Increased risks were observed for preterm birth among women with a clinical diagnosis of depression during pregnancy irrespective of antidepressant use (OR 1.6, 95% CI 1.2-2.1) and among women with depression who did not use antidepressants (OR 2.2, 95% CI 1.7-3.0), as well as for low Apgar scores in the former (OR 1.5, 95% CI 1.3-1.7), but not the latter group. Selective serotonin reuptake inhibitor (SSRI) use was associated with preterm birth among women who used antidepressants with or without restriction to women with depressive symptoms or a diagnosis of depression (OR 1.6, 95% CI 1.0-2.5 and OR 1.9, 95% CI 1.2-2.8, respectively), as well as with low Apgar scores among women in the latter group (OR 1.7, 95% CI 1.1-2.8). CONCLUSION: Depressive symptoms or a clinical diagnosis of depression during pregnancy are associated with preterm birth and low Apgar scores, even without exposure to antidepressants. However, SSRIs may be independently associated with preterm birth and low Apgar scores. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42016035711.

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The role of paclitaxel-coated balloons has been established in the coronary and peripheral arterial circulations with recent interest in the use of paclitaxel-coated balloons to improve patency rates following angioplasty of arteriovenous fistulas. To assess the efficacy of paclitaxel-coated angioplasty balloons to prolong the survival time of target lesion primary patency in arteriovenous fistulas, we designed an investigator-led multi-center randomized controlled trial with follow up time variable for a minimum of one year. Patients with an arteriovenous fistula who were undergoing an angioplasty for a clinical indication were included but patients with one or more lesions outside the treatment segment were excluded. Following successful treatment with a high-pressure balloon, 212 patients were randomized. In the intervention arm, the second component was insertion of a paclitaxel-coated balloon. In the control arm, an identical procedure was followed, but using a standard balloon. The primary endpoint was time to loss of clinically driven target lesion primary patency. Primary analysis showed no significant evidence for a difference in time to end of target lesion primary patency between groups: hazard ratio 1.18 with a 95% confidence interval of 0.78 to 1.79. There were no significant differences for any secondary outcomes, including patency outcomes and adverse events. Thus, our study demonstrated no evidence that paclitaxel-coated balloons provide benefit, following standard care high-pressure balloon angioplasty, in the treatment of arteriovenous fistulas. Hence, in view of the benefit suggested by other trials, the role of paclitaxel-coated angioplasty balloons remains uncertain.

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AIMS: We aimed to assess ethnic differences in inflammatory markers and their relationships with insulin sensitivity and regional adiposity between white European and black African men. METHODS: A total of 53 white European and 53 black African men underwent assessment of inflammatory markers alongside Dixon-magnetic resonance imaging to quantify subcutaneous and visceral adipose tissue and intrahepatic lipid. A hyperinsulinaemic-euglycaemic clamp was used to measure whole-body and adipose tissue insulin sensitivity. To assess ethnic differences in relationships, the statistical significance of an interaction term between adipokines and ethnic group was tested in multivariable regression models. RESULTS: The black African men exhibited significantly lower adiponectin and tumour necrosis factor-α (TNF-α) and greater interleukin-10 (IL-10) compared to white European men (all p < 0.05). There were no statistically significant ethnic differences in leptin, resistin, IL-6, interferon-γ, IL-13, IL-1ß, IL-8 and vascular endothelial growth factor. Several relationships differed significantly by ethnicity such that they were stronger in white European than black African men including IL-6 with visceral adipose tissue; adiponectin with subcutaneous adipose tissue; leptin with intrahepatic lipid; adiponectin, IL-6 and TNF-α with whole-body insulin sensitivity and TNF-α with adipose tissue insulin sensitivity (all pinteraction <0.05). Leptin significantly predicted whole-body insulin sensitivity in white European (R2  = 0.51) and black African (R2  = 0.29) men; however, adiponectin was a statistically significant predictor in only white European men (R2  = 0.22). CONCLUSIONS: While adiponectin is lower in black African men, its insulin sensitising effects may be greater in white men suggesting that the role of adipokines in the development of type 2 diabetes may differ by ethnicity.

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BACKGROUND: Hard domestic water has been reported to worsen atopic eczema (AE) and may contribute to its development in early life. OBJECTIVE: To review the literature on the relationship between the effect of water hardness (high calcium carbonate; CaCO3 ) on (a) the risk of developing AE, (b) the treatment of existing AE and (c) skin barrier function in human and animal studies. DESIGN , DATA SOURCES AND ELIGIBILITY CRITERIA: We systematically searched databases (MEDLINE, Embase, Cochrane CENTRAL, GREAT and Web of Science) from inception until 30/6/2020. Human and animal observational and experimental studies were included. The primary outcomes were risk of AE and skin barrier function. Studies were meta-analysed using a random effects model. Evidence certainty was evaluated using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. RESULTS: Sixteen studies were included. Pooled observational data from seven studies on 385,901 participants identified increased odds of AE in children exposed to harder versus softer water (odds ratio 1.28, 95% CI 1.09, 1.50; GRADE certainty: very low). Two mechanistic studies in humans reported higher deposition of the detergent sodium lauryl sulphate in those exposed to harder versus softer water. Two randomized controlled trials comparing water softeners with standard care did not show a significant difference in objective AE severity with softened water (standardized mean difference 0.06 standard deviations higher, 95% CI 0.16 lower to 0.27 higher; GRADE certainty: moderate). CONCLUSIONS & CLINICAL RELEVANCE: There was a positive association between living in a hard water (range: 76 to > 350 mg/L CaCO3 ) area and AE in children. There is no evidence that domestic water softeners improve objective disease severity in established AE. There may be a role of water hardness in the initiation of skin inflammation in early life, but there is a need for further longitudinal and interventional studies.

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