Identification of strontium in the merger of two neutron stars.

Half of all of the elements in the Universe that are heavier than iron were created by rapid neutron capture. The theory underlying this astrophysical r-process was worked out six decades ago, and requires an enormous neutron flux to make the bulk of the elements1. Where this happens is still debated2. A key piece of evidence would be the discovery of freshly synthesized r-process elements in an astrophysical site. Existing models3-5 and circumstantial evidence6 point to neutron-star mergers as a probable r-process site; the optical/infrared transient known as a 'kilonova' that emerges in the days after a merger is a likely place to detect the spectral signatures of newly created neutron-capture elements7-9. The kilonova AT2017gfo-which was found following the discovery of the neutron-star merger GW170817 by gravitational-wave detectors10-was the first kilonova for which detailed spectra were recorded. When these spectra were first reported11,12, it was argued that they were broadly consistent with an outflow of radioactive heavy elements; however, there was no robust identification of any one element. Here we report the identification of the neutron-capture element strontium in a reanalysis of these spectra. The detection of a neutron-capture element associated with the collision of two extreme-density stars establishes the origin of r-process elements in neutron-star mergers, and shows that neutron stars are made of neutron-rich matter13.

Using liver stiffness to predict and monitor the risk of decompensation and mortality in patients with alcohol-related liver disease.

BACKGROUND & AIMS: Liver stiffness measurement (LSM) is recommended for disease prognostication and monitoring. We evaluated if LSM, using transient elastography, and LSM changes predict decompensation and mortality in patients with alcohol-related liver disease (ALD). METHODS: We performed an observational cohort study of compensated patients at risk of ALD from Denmark and Austria. We evaluated the risk of decompensation and all-cause mortality, stratified for compensated advanced chronic liver disease (cACLD: baseline LSM ≥10 kPa) and LSM changes after a median of 2 years. In patients with cACLD, we defined LSM changes as (A) LSM increase ≥20% ("cACLD increasers") and (B) follow-up LSM <10 kPa or <20 kPa with LSM decrease ≥20% ("cACLD decreasers"). In patients without cACLD, we defined follow-up LSM ≥10 kPa as an LSM increase ("No cACLD increasers"). The remaining patients were considered LSM stable. RESULTS: We followed 536 patients for 3,008 patient-years-median age 57 years (IQR 49-63), baseline LSM 8.1 kPa (IQR 4.9-21.7)-371 patients (69%) had follow-up LSM after a median of 25 months (IQR 17-38), 41 subsequently decompensated and 55 died. Of 125 with cACLD at baseline, 14% were "cACLD increasers" and 43% "cACLD decreasers", while 13% of patients without cACLD were "No cACLD increasers" (n = 33/246). Baseline LSM, follow-up LSM and LSM changes accurately predicted decompensation (C-index: baseline LSM 0.85; follow-up LSM 0.89; LSM changes 0.85) and mortality (C-index: baseline LSM 0.74; follow-up LSM 0.74; LSM changes 0.70). When compared to "cACLD decreasers", "cACLD increasers" had significantly lower decompensation-free survival and higher risks of decompensation (subdistribution hazard ratio 4.39, p = 0.004) and mortality (hazard ratio 3.22, p = 0.01). CONCLUSION: LSM by transient elastography predicts decompensation and all-cause mortality in patients with compensated ALD both at diagnosis and when used for monitoring. IMPACT AND IMPLICATIONS: Patients at risk of alcohol-related liver disease (ALD) are at significant risk of progressive disease and adverse outcomes. Monitoring is essential for optimal disease surveillance and patient guidance, but non-invasive monitoring tools are lacking. In this study we demonstrate that liver stiffness measurement (LSM), using transient elastography, and LSM changes after a median of 2 years, can predict decompensation and all-cause mortality in patients at risk of ALD with and without compensated advanced chronic liver disease. These findings are in line with results from non-alcoholic fatty liver disease, hepatitis C and primary sclerosing cholangitis, and support the clinical utility of LSM, using transient elastography, for disease prognostication and monitoring in chronic liver diseases including ALD, as recommended by the Baveno VII.

Screening for Fibrosis Promotes Lifestyle Changes: A Prospective Cohort Study in 4796 Individuals.

BACKGROUND AND AIMS: Early detection of liver fibrosis is believed to promote lifestyle changes. We evaluated self-reported changes in alcohol intake, diet, exercise, and weight after participating in a screening study for liver fibrosis. METHODS: We conducted a prospective screening study of individuals at risk of alcohol-related liver disease (ALD) or metabolic dysfunction-associated steatotic liver disease (MASLD). We provided lifestyle advice to all participants and evaluated lifestyle changes by questionnaires after 1 week and 6 months, with re-examination of a subgroup after 2 years. RESULTS: A total of 1850 at risk of ALD and 2946 at risk of MASLD were included, of whom 383 (8%) were screening positive (transient elastography ≥8 kPa). A total of 84% replied to the 6-month questionnaire. In ALD participants, excessive drinking decreased from 46% to 32% after 6 months. Only 15% reported increased drinking, without differences between screening positive and negative individuals (P = .698). In high-risk drinkers, a positive screening test predicted abstinence or decreased alcohol use after 6 months (odds ratio, 2.45; 95% confidence interval, 1.32-4.57; P = .005). After 2 years, excessive drinking decreased from 52% to 41% in a subgroup of 752 individuals and a positive screening test predicted abstinence or decreased alcohol use after 2 years (odds ratio, 1.84; 95% confidence interval, 1.09-3.11, P = .023). MASLD participants showed similar improvements: 35% improved their diet, 22% exercised more, and 13% reported a weight loss ≥5% after 6 months. CONCLUSIONS: Screening for liver fibrosis is associated with sustained improvements in alcohol consumption, diet, weight, and exercise in at-risk ALD and MASLD. The changes are most pronounced in screening positive participants but not limited to this group.

Circulating TREM2 as a noninvasive diagnostic biomarker for NASH in patients with elevated liver stiffness.

BACKGROUND AND AIMS: Reliable noninvasive biomarkers are an unmet clinical need for the diagnosis of NASH. This study investigates the diagnostic accuracy of the circulating triggering receptor expressed on myeloid cells 2 (plasma TREM2) as a biomarker for NASH in patients with NAFLD and elevated liver stiffness. APPROACH AND RESULTS: We collected cross-sectional, clinical data including liver biopsies from a derivation ( n = 48) and a validation cohort ( n = 170) of patients with elevated liver stiffness measurement (LSM ≥ 8.0 kPa). Patients with NAFLD activity scores (NAS) ≥4 were defined as having NASH. Plasma TREM2 levels were significantly elevated in patients with NASH of the derivation cohort, with an area under the receiver operating characteristics curve (AUROC) of 0.92 (95% confidence interval [CI], 0.84-0.99). In the validation cohort, plasma TREM2 level increased approximately two-fold in patients with NASH, and a strong diagnostic accuracy was confirmed (AUROC, 0.83; 95% CI, 0.77-0.89; p < 0.0001). Plasma TREM2 levels were associated with the individual histologic features of NAS: steatosis, lobular inflammation, and ballooning ( p < 0.0001), but only weakly with fibrosis stages. Dual cutoffs for rule-in and rule-out were explored: a plasma TREM2 level of ≤38 ng/ml was found to be an optimal NASH rule-out cutoff (sensitivity 90%; specificity 52%), whereas a plasma TREM2 level of ≥65 ng/ml was an optimal NASH rule-in cutoff (specificity 89%; sensitivity 54%). CONCLUSIONS: Plasma TREM2 is a plausible individual biomarker that can rule-in or rule-out the presence of NASH with high accuracy and thus has the potential to reduce the need for liver biopsies and to identify patients who are eligible for clinical trials in NASH.

Effect of Calorie-Unrestricted Low-Carbohydrate, High-Fat Diet Versus High-Carbohydrate, Low-Fat Diet on Type 2 Diabetes and Nonalcoholic Fatty Liver Disease : A Randomized Controlled Trial.

BACKGROUND: It remains unclear if a low-carbohydrate, high-fat (LCHF) diet is a possible treatment strategy for type 2 diabetes mellitus (T2DM), and the effect on nonalcoholic fatty liver disease (NAFLD) has not been investigated. OBJECTIVE: To investigate the effect of a calorie-unrestricted LCHF diet, with no intention of weight loss, on T2DM and NAFLD compared with a high-carbohydrate, low-fat (HCLF) diet. DESIGN: 6-month randomized controlled trial with a 3-month follow-up. (ClinicalTrials.gov: NCT03068078). SETTING: Odense University Hospital in Denmark from November 2016 until June 2020. PARTICIPANTS: 165 participants with T2DM. INTERVENTION: Two calorie-unrestricted diets: LCHF diet with 50 to 60 energy percent (E%) fat, less than 20E% carbohydrates, and 25E% to 30E% proteins and HCLF diet with 50E% to 60E% carbohydrates, 20E% to 30E% fats, and 20E% to 25E% proteins. MEASUREMENTS: Glycemic control, serum lipid levels, metabolic markers, and liver biopsies to assess NAFLD. RESULTS: The mean age was 56 years (SD, 10), and 58% were women. Compared with the HCLF diet, participants on the LCHF diet had greater improvements in hemoglobin A1c (mean difference in change, -6.1 mmol/mol [95% CI, -9.2 to -3.0 mmol/mol] or -0.59% [CI, -0.87% to -0.30%]) and lost more weight (mean difference in change, -3.8 kg [CI, -6.2 to -1.4 kg]). Both groups had higher high-density lipoprotein cholesterol and lower triglycerides at 6 months. Changes in low-density lipoprotein cholesterol were less favorable in the LCHF diet group than in the HCLF diet group (mean difference in change, 0.37 mmol/L [CI, 0.17 to 0.58 mmol/L] or 14.3 mg/dL [CI, 6.6 to 22.4 mg/dL]). No statistically significant between-group changes were detected in the assessment of NAFLD. Changes were not sustained at the 9-month follow-up. LIMITATION: Open-label trial, self-reported adherence, unintended weight loss, and lack of adjustment for multiple comparisons. CONCLUSION: Persons with T2DM on a 6-month, calorie-unrestricted, LCHF diet had greater clinically meaningful improvements in glycemic control and weight compared with those on an HCLF diet, but the changes were not sustained 3 months after intervention. PRIMARY FUNDING SOURCE: Novo Nordisk Foundation.

Oro-facial function and quality of life in children and adolescents with large horizontal maxillary overjet-A case-control study.

BACKGROUND: Large horizontal maxillary overjet (overjet) is associated with reduced bite force (BF) and number of contacts, which influence the chewing effectivity (CE). Oral health, oro-facial function (OF) and malocclusion have great impact on psychological well-being and quality of life (QoL). OBJECTIVES: The aims of the study were to examine OF, temporomandibular disorders (TMD), BF, CE, QoL and well-being in children and adolescents with large overjet. METHODS: The study was a case-control study including healthy children with large overjet in the study group compared to a control group of healthy children with neutral occlusion, all 9-14 years old. OF was examined by use of Nordic Orofacial Test-Screening (NOT-S), Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) and registration of morphological and functional occlusion. QoL and well-being were examined using KIDSCREEN-10 and Strengths and Difficulties Questionnaire. RESULTS: The study and control groups included 37 and 32 participants, respectively. Significantly increased NOT-S score (p < .001) and reduced BF (p = .011), numbers of contacts (p < .001) and CE (p = .005) were found in the study group. BF, numbers of contacts and CE were negatively associated with erupting canines and premolars. No significant difference was found in age, gender, dental eruption, TMD diagnosis or QoL between the groups. Significantly increased emotional symptoms (p = .007), hyperactivity (p = .043) and total difficulties score (p = .009) were found in the study group. CONCLUSION: The study group showed higher NOT-S score and reduced BF, number of contacts and CE. No difference in QoL were found between the groups, although reduced well-being and increased emotional symptoms, hyperactivity and total difficulties were found in the study group.

Pressure ulcer point prevalence, classification, locations, and preventive measures: Insights from a Norwegian nursing home survey.

OBJECTIVE: To report data from a point pressure ulcer (PU) prevalence survey on prevalence, PU categories, locations and preventive interventions at one Norwegian nursing home. METHODS: A cross-sectional research design was used. One nursing home in Norway participated in the prevalence survey in 2020. The data were collected on one selected day. A total of 74 out of 88 residents (84.1%) participated. Descriptive statistical analyses were run. RESULTS: The overall prevalence of PUs was 27% amongst all participants in the nursing home, who together had a total of 57 PUs categorised as category I-III. One major finding was that the most common site of the PUs was on the residents' toes. Interestingly, the prevalence of PUs in the residents' sacrum was considerably low. The most frequently used PU preventive interventions were foam chair cushions, nutritional supplements and pressure-reducing heel protection. CONCLUSION: This study identified a high prevalence of PUs, predominantly on residents' toes. Although preventive strategies were implemented, their application appeared limited. Implementing obligatory care packages and annual nationwide PU surveys might be worth considering in municipalities.

Sleepiness in children with severe malocclusion compared with in children with neutral occlusion.

INTRODUCTION: The study aimed to compare daytime sleepiness in children with severe malocclusion with healthy children with neutral occlusion (controls) and to analyze associations between daytime sleepiness and craniofacial morphology in children with severe malocclusion. METHODS: In 120 children with severe malocclusion (73 girls, 47 boys; mean age, 11.96 years; mean body mass index [BMI] score, 18.97 kg/m2) and 35 controls (18 girls, 17 boys; mean age, 11.97 years; mean BMI score, 20.28 kg/m2), sleep and daytime sleepiness were recorded using Epworth Sleepiness Scale and Berlin Questionnaire. Occlusion was registered clinically, and craniofacial morphology was assessed on lateral cephalograms. Differences in daytime sleepiness and sleep between the groups and associations between daytime sleepiness and sleep and craniofacial morphology were analyzed by a general linear model adjusted for age, gender, and BMI score. RESULTS: Daytime sleepiness occurred significantly more often in children with malocclusion than in control subjects (P = 0.015). There was a tendency for children with malocclusion to feel extremely tired during the day more often than controls (P = 0.054). There was no significant difference between the groups in sleeping hours during night-time, but the amount of sleep was negatively associated with age (P <0.001) and BMI score (P = 0.004). Only maxillary inclination was significantly associated with daytime sleepiness (P = 0.043). CONCLUSIONS: Daytime sleepiness occurred significantly more often in children with severe malocclusion than in those with neutral occlusion, and the association between daytime sleepiness and craniofacial morphology may exist. The results might prove valuable in interdisciplinary collaboration between medical doctors and orthodontists in diagnostics, prevention, and treatment of children at risk for sleep-disordered breathing.

Using the ELF test, FIB-4 and NAFLD fibrosis score to screen the population for liver disease.

BACKGROUND & AIMS: There is a need for accurate biomarkers of fibrosis for population screening of alcohol-related and non-alcoholic fatty liver disease (ALD, NAFLD). We compared the performance of the enhanced liver fibrosis (ELF) test to the fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS), using transient elastography as the reference standard. METHODS: We prospectively included participants from the general population, and people at risk of ALD or NAFLD. Screening positive participants (TE ≥8 kPa) were offered a liver biopsy. We measured concomitant ELF, FIB-4, and NFS using validated cut-offs: ≥9.8, ≥1.3, ≥-1.45, respectively. RESULTS: We included 3,378 participants (1,973 general population, 953 at risk of ALD, 452 at risk of NAFLD), with a median age of 57 years (IQR: 51-63). Two hundred-and-forty-two were screening positive (3.4% in the general population, 12%/14% who were at-risk of ALD/NAFLD, respectively). Most participants with TE <8 kPa also had ELF <9.8 (88%) despite a poor overall correlation between ELF and TE (Spearman´s rho = 0.207). ELF was associated with significantly fewer false positives (11%) than FIB-4 and NFS (35% and 45%), while retaining a low rate of false negatives (<8%). A screening strategy of FIB-4 followed by ELF in indeterminate cases resulted in false positives in 8%, false negatives in 4% and the correct classification in 88% of cases. We performed a liver biopsy in 155/242 (64%) patients who screened positive, of whom 54 (35%) had advanced fibrosis (≥F3). ELF diagnosed advanced fibrosis with significantly better diagnostic accuracy than FIB-4 and NFS: AUROC 0.85 (95% CI 0.79-0.92) vs. 0.73 (0.64-0.81) and 0.66 (0.57-0.76), respectively. CONCLUSION: The ELF test alone or combined with FIB-4 for liver fibrosis screening in the general population and at-risk groups reduces the number of futile referrals compared to FIB-4 and NFS, without overlooking true cases. IMPACT AND IMPLICATIONS: We need referral pathways that are efficient at detecting advanced fibrosis from alcohol-related and non-alcoholic fatty liver disease in the population, but without causing futile referrals or excessive use of resources. This study indicates that a sequential test strategy of FIB-4 followed by the ELF test in indeterminate cases leads to few patients referred for confirmatory liver stiffness measurement, while retaining a high rate of detected cases, and at low direct costs. This two-step referral pathway could be used by primary care for mass, targeted, or opportunistic screening for liver fibrosis in the population. CLINICAL TRIAL NUMBER: Clinicaltrials.gov number NCT03308916.

A six-month low-carbohydrate diet high in fat does not adversely affect endothelial function or markers of low-grade inflammation in patients with type 2 diabetes: an open-label randomized controlled trial.

BACKGROUND: While a low-carbohydrate diet (LCD) reduces HbA1c in patients with type 2 diabetes (T2D), the associated high intake of fat may adversely affect cardiovascular risk factors. To address this, we examined the effect of a non-calorie-restricted LCD high in fat on endothelial function and markers of low-grade inflammation in T2D over 6 months. METHODS: In an open-label randomized controlled trial, 71 patients with T2D were randomized 2:1 to either a LCD (< 20 E% carbohydrates, 50-60 E% fat) or a control diet (50-60 E% carbohydrates, 20-30 E% fat) for six months. Flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID) were assessed by ultrasound in the brachial artery together with plasma interleukin-6 (IL-6) and serum high-sensitivity C-reactive protein (hsCRP) in the participants at baseline (n = 70) and after six months (n = 64). RESULTS: The FMD and NID were unaltered in both groups after six months, and there were no between-group differences in change of either FMD (p = 0.34) or NID (p = 0.53) in response to the interventions. The circulating hsCRP and IL-6 levels decreased only in response to LCD (both p < 0.05). However, comparing changes over time with the control diet, the LCD did not reduce either IL-6 (p = 0.25) or hsCRP (p = 0.07) levels. The lack of changes in FMD and NID in response to LCD persisted after adjustment for cardiovascular risk factors. CONCLUSION: A LCD high in fat for six months does not adversely affect endothelial function or selected markers of low-grade inflammation, which suggests that this nutritional approach does not increase the risk of cardiovascular disease. Trial registration ClinicalTrials.gov (NCT03068078).

Binge drinking episode causes acute, specific alterations in systemic and hepatic inflammation-related markers.

BACKGROUND: Frequent binge drinking is a known contributor to alcohol-related harm, but its impact on systemic and hepatic inflammation is not fully understood. We hypothesize that changes in immune markers play a central role in adverse effects of acute alcohol intake, especially in patients with early liver disease. AIM: To investigate the effects of acute alcohol intoxication on inflammation-related markers in hepatic and systemic venous plasma in people with alcohol-related liver disease (ArLD), non-alcoholic fatty liver disease (NAFLD) and healthy controls. METHODS: Thirty-eight participants (13 with ArLD, 15 with NAFLD and 10 healthy controls) received 2.5 mL of 40% ethanol per kg body weight via a nasogastric tube. Seventy-two inflammation-related markers were quantified in plasma from hepatic and systemic venous blood, at baseline, 60 and 180 min after intervention. RESULTS: Alcohol intervention altered the levels of 31 of 72 and 14 of 72 markers in the systemic and hepatic circulation. All changes observed in the hepatic circulation were also identified in the systemic circulation after 180 min. Only FGF21 and IL6 were increased after alcohol intervention, while the remaining 29 markers decreased. Differences in response to acute alcohol between the groups were observed for 8 markers, and FGF21 response was blunted in individuals with steatosis. CONCLUSION: Acute alcohol intoxication induced changes in multiple inflammation-related markers, implicated in alcohol metabolism and hepatocellular damage. Differences identified between marker response to binge drinking in ArLD, NAFLD and healthy controls may provide important clues to disease mechanisms and potential targets for treatment. CLINICAL TRIAL NUMBER: NCT03018990.

Validation of scores of PRO-C3 to predict liver-related events in alcohol-related liver disease.

BACKGROUND AND AIMS: Risk prediction in alcohol-related liver disease (ArLD) is an unmet need. We aimed to assess PRO-C3 models to predict liver-related events (LRE) in patients with a history of excessive alcohol use without an established diagnosis of chronic liver disease. METHODS: A prospective cohort study of 462 patients with ArLD, split into a derivation cohort of 221 secondary care patients and a validation cohort of 241 primary care patients. Baseline variables, including fibrogenesis marker PRO-C3, were used to develop a prediction model. Prognostic accuracy was compared to enhanced liver fibrosis (ELF), fibrosis-4-index (FIB-4), transient elastography (TE) and ADAPT. RESULTS: In the derivation and validation cohorts, 67 (30%) and 19 (8%) experienced an LRE during a median follow-up of 5.2 years (IQR: 3.2-6.8) and 4.0 years (IQR: 2.7-5.6). On top of PRO-C3 and ADAPT score, we generated a model (ALPACA) of independent predictors of LREs (PRO-C3, AST/ALT, platelets). ALPACA had high prognostic accuracy with a C-statistic of 0.85 in the derivation cohort, comparable to ELF (0.83) and TE (0.84) and significantly higher than FIB-4 (0.78), PRO-C3 (0.80) and ADAPT (0.81). In the validation cohort, all tests had comparable C-statistics. Compared to low-risk patients (ALPACA ≤11), high-risk patients (>11) had a subhazard ratio for LREs of 12.6 (95% CI 5.9-26.8, p < .001) and higher cumulative incidence (57% vs. 7%, p < .001; derivation cohort). We observed similar subhazard ratio in the validation cohort. CONCLUSIONS: PRO-C3-based scores are reliable tools to predict LREs in ArLD patients and are suitable for risk stratification in primary and secondary care.

Sympathetic activity is not a main cause of blood pressure reduction with exercise training in un-medicated middle-aged/older men.

BACKGROUND: This study tested the hypothesis that training reduces resting sympathetic activity and improves baroreflex control in both hypertensive and normotensive men but reduces blood pressure only in hypertensive men. METHODS: Middle-aged/older un-medicated stage-1 hypertensive males (mean age 55 ± 3 years; n = 13) and normotensive controls (mean age 60 ± 5 years; n = 12) participated in 8 weeks of supervised high-intensity interval spinning training. Before and after training, muscle sympathetic nerve activity (MSNA) and blood pressure were measured at rest and during a sympatho-excitatory cold pressor test (CPT). Based on the measurements, baroreceptor sensitivity and baroreceptor threshold were calculated. RESULTS: Resting MSNA and baroreceptor sensitivity were similar for the hypertensive and the normotensive groups. Training lowered MSNA (p < 0.05), expressed as burst frequency (burst/min), overall, and to a similar extent, in both groups (17% and 27%, respectively, in hypertensive and normotensive group), whereas blood pressure was only significantly (p < 0.05) lowered (by 4 mmHg in both systolic and diastolic pressure) in the hypertensive group. Training did not (p > 0.05) alter the MSNA or blood pressure response to CPT or increase baroreceptor sensitivity but reduced (p < 0.05) the baroreceptor threshold with a main effect for both groups. Training adherence and intensity were similar in both groups yet absolute maximal oxygen uptake increased by 15% in the normotensive group only. CONCLUSION: The dissociation between the training induced changes in resting MSNA, lack of change in baroreflex sensitivity and the change in blood pressure, suggests that MSNA is not a main cause of the blood pressure reduction with exercise training in un-medicated middle-aged/older men.

Signal quality of home polygraphy in children and adolescents.

AIM: The aims of the study were to examine the signal quality (SQ) of home polygraphy (PG) in children and adolescents and to compare automatic and manual scoring of the PGs. METHODS: Clinical Trials Registration: NCT04964830. Participants and caregivers were instructed to set up the equipment and perform home PGs themselves. The PGs were analysed according to SQ and their interpretability and differences in automatic vs. manual scoring regarding apnoea-hypopnoea index (AHI), apnoea index (AI), hypopnoea index (HI) and oxygen desaturation index (ODI) were examined. RESULTS: 54 healthy children aged 9-14 years participated in the study. 86% of the PGs were interpretable with mean SQ of 79.1% (CI 95%: 73.5%; 84.8%). Significant differences between the automatic and manual scoring were found for AHI, AI, HI and ODI (p < 0.0001). CONCLUSION: Home PGs of children and adolescents are feasible to be performed with good SQ. Significantly higher markers of sleep-disordered breathing were achieved in the automatic scoring in comparison with the manual scoring.

Hepatorenal Index by B-Mode Ratio Versus Imaging and Fatty Liver Index to Diagnose Steatosis in Alcohol-Related and Nonalcoholic Fatty Liver Disease.

OBJECTIVES: We aimed to evaluate the accuracy of the hepatorenal index by B-mode ratio to diagnose hepatic steatosis, compared to ultrasound steatosis score, controlled attenuation parameter, and the fatty liver index using histology as the gold standard. METHODS: We prospectively included participants with alcohol-related or nonalcoholic fatty liver disease for same-day noninvasive investigations and liver biopsy. RESULTS: We included 137 participants, 72% male, median age 60 years (53-65) and body mass index 32 kg/m2 (28-38). Eighty percent had steatosis (S0/S1/S2/S3 = 20/37/24/19%). B-mode ratio had moderate diagnostic accuracy for any steatosis (≥S1, area under the receiver operating characteristics curve [AUROC] = 0.79; 95% confidence interval 0.70-0.88), significant steatosis (≥S2, AUROC = 0.76; 0.66-0.85), and severe steatosis (=S3, AUROC = 0.74; 0.62-0.86), independent of disease etiology. The cutoff values to rule-out and rule-in any steatosis were 1.09 and 1.45. While B-mode ratio and controlled attenuation parameter correlated poorly, their diagnostic accuracies were comparable to each other and to ultrasound steatosis scoring. Fatty liver index did not differ from B-mode ratio in detecting any steatosis but had poor accuracy to detect higher steatosis grades. B-mode ratio measurements failed in 12% of patients, compared to 1% for ultrasound steatosis scoring and 2% for controlled attenuation parameter. CONCLUSION: The hepatorenal index by B-mode ratio diagnose steatosis with moderate accuracy in patients with alcohol-related or nonalcoholic fatty liver disease, comparable to B-mode ultrasound steatosis scoring and controlled attenuation parameter. However, its clinical use is limited by a high failure rate.

Gluten-free diet reduces autoimmune diabetes mellitus in mice across multiple generations in a microbiota-independent manner.

Experimental and clinical data suggest that a gluten-free diet attenuates the development of type 1 diabetes. A gluten-free diet changes the gut microbiota composition, and such microbial changes are expected to reduce the autoimmune responses. However, in experiments with laboratory mice, a gluten-free diet changes the gut microbiota differently under varying experimental settings, questioning the specific role of the gut microbes. Here we show that a maternal gluten-free diet until weaning of their pups, delayed type 1 diabetes in both dams (parent generation) and offspring (F1 generation) of untreated non-obese diabetic (NOD) mice and in mice treated with a full cocktail of antibiotics that eradicates most of the existing microbiota. Breeding a second (F2) generation of NOD mice, never exposed to the gluten-free diet or the associated microbial changes, also demonstrated a preventative effect on type 1 diabetes even though their parents (the F1 generation) had only been on a gluten-free diet very early in life. Collectively, the experimental data, thus, points towards microbiota-independent dietary protection. Furthermore, both the perinatal gluten-free diet and antibiotic treatment reduced inflammation in the salivary glands and improved glucose challenged beta cell function in the F1 offspring. However, in contrast to the autoimmune response in the pancreas, those changes appeared to be microbiota dependent, as they were missing in the antibiotic treated mice, and do, therefore, not seem to be related to the preventative effect on type 1 diabetes. Interestingly, adoptive transfer of splenocytes from gluten-free fed mice protected NOD.SCID mice from developing diabetes, demonstrating that the anti-diabetic effect of a gluten-free diet was based on early life changes in the evolving immune system. In particular, genes involved in regulation of lymphocyte activation, proliferation, and cell adhesion were highly expressed in the spleen in gluten-free fed mice at weaning compared to control fed mice of the F1 generation, which suggested that gluten promotes autoimmunity by inhibiting immune regulation, though the involvement of the specific genes needs further investigation. In conclusion, gluten-free diet reduces autoimmune inflammation in salivary glands and pancreas in NOD mice in a microbiota-dependent and -independent manner respectively, and has preventative effect on type 1 diabetes by modulating the systemic immune system.

Binge drinking induces an acute burst of markers of hepatic fibrogenesis (PRO-C3).

BACKGROUND & AIMS: Binge drinking is associated with an increased risk of liver disease. Morbidity and mortality of alcohol-related liver disease (ALD) is associated with collagen deposition in the hepatic extracellular matrix (ECM). However, the acute effects of binge drinking on ECM turnover are unknown. We aimed to investigate the effects on hepatic ECM turnover following a binge drinking episode. METHODS: We performed a pathophysiological intervention study with 15 non-alcoholic fatty liver disease (NAFLD) patients, 15 ALD patients and 10 healthy controls. We used 40% ethanol in 9 mg/mL NaCl administered through a nasogastric tube to simulate binge drinking. Hepatic vein catheterisation allowed simultaneous hepatic- and systemic vein sampling. Markers of ECM formation and degradation were measured with competitive ELISA. RESULTS: The interstitial matrix formation marker PRO-C3 increased by 1.2 ng/mL (10%, P < .001) 24 hours after binge drinking. In participants with existing liver fibrosis determined by elevated baseline PRO-C3, hepatic levels increased by 0.09 ng/mL (95% CI: 0.03-0.15, P = .005) while systemic PRO-C3 decreased 0.11 ng/mL (95% CI: -0.15 to -0.06, P < .001) in 3 hours. PRO-C8 increased by 30% (+0.9 ng/mL, P = .014) in liver-diseased patients with F0-F1 but not in any other group. Twenty-four-hour changes in systemic C3M and PRO-C3 were not associated (P = .911). CONCLUSIONS: Binge drinking induced an acute burst of PRO-C3 in healthy individuals and patients with liver disease. Markers of ECM degradation were not correlated to markers of ECM formation, suggesting that even a single episode of binge drinking promotes excessive hepatic fibrogenesis.

Effects of a 6-month, low-carbohydrate diet on glycaemic control, body composition, and cardiovascular risk factors in patients with type 2 diabetes: An open-label randomized controlled trial.

AIM: To investigate the efficacy and safety of a non-calorie-restricted low-carbohydrate diet (LCD) on glycaemic control, body composition, and cardiovascular risk factors in patients with type 2 diabetes (T2D) instructed to maintain their non-insulin antidiabetic medication and physical activity. MATERIALS AND METHODS: In an open-label randomized controlled trial, patients with T2D were randomized 2:1 to either a LCD with a maximum of 20 E% (percentage of total energy intake) from carbohydrates (n = 49) or a control diet with 50-60 E% from carbohydrates (n = 22) for 6 months. Examinations at enrolment and after 3 and 6 months included blood sample analyses, anthropometrics, blood pressure, accelerometer-based assessment of physical activity, and food diaries. Total fat mass and lean mass were determined by dual-energy x-ray absorptiometry scan. The mean difference in change between groups from baseline are reported. RESULTS: The LCD group decreased carbohydrate intake to 13.4 E% and increased fat intake to 63.2 E%, which was -30.5 ± 2.2 E% lower for carbohydrates and 30.6 ± 2.2 E% higher for fat, respectively, compared with the control group (all P < .001). The LCD reduced HbA1c after 3 months (-8.9 ± 1.7 mmol/mol; P < .0001), and this was maintained after 6 months (-7.5 ± 1.8 mmol/mol; P < .0001) compared with the control diet. The LCD also reduced weight (-3.9 ± 1.0 kg), body mass index (-1.4 ± 0.4 kg/m2 ), and waist circumference (-4.9 ± 1.3 cm) compared with the control diet (all P < .01), accompanied by reductions in total fat mass (-2.2 ± 1.0 kg; P = .027) and lean mass (-1.3 ± 0.6 kg; P = .017). No changes in blood lipids or blood pressure were seen after 6 months. The level of physical activity was maintained, and there were no episodes of severe hypoglycaemia. CONCLUSION: A non-calorie-restricted LCD high in fat has significant beneficial effects on glycaemic control and body composition, and does not adversely affect cardiovascular risk factors in patients with T2D. Reducing carbohydrate intake to 10-25 E% appears to be an effective and safe nutritional approach with respect to classical cardiovascular risk factors and hypoglycaemia.

Specific dento-craniofacial characteristics in non-syndromic children can predispose to sleep-disordered breathing.

AIM: To ascertain and illustrate specific clinical dento-craniofacial characteristics associated with sleep-disordered breathing (SDB) in non-syndromic children. METHODS: Narrative review of literature on SDB, dental occlusion and craniofacial morphology retrieved through online literature database search for these terms. The review focused on clinical examples and graphical illustrations in order to ascertain the association between dento-craniofacial characteristics and SDB. Only publications concerning healthy non-syndromic children without any somatic or psychological diagnosis were included. RESULTS: Dento-craniofacial characteristics such as anterior open bite, large overjet, cross bite and facial appearance such as convex profile due to mandibular retrognathia and inclination, narrow and high palate can predispose to SDB in non-syndromic children. Furthermore, extended head posture, mouth breathing and general adenoidal face may be symptoms or predisposing factors to SDB in non-syndromic children. CONCLUSION: Dento-craniofacial characteristics as anterior open bite, large overjet due to mandibular retrognathia, cross bite, and narrow and high palate can predispose to SDB in non-syndromic children. Facial characteristics predisposing to SDB can be a convex facial profile, extended head posture, mouth breathing and general adenoidal face. Interdisciplinary collaboration between medical doctors and dentists can prove valuable in diagnostics, prevention and treatment of SDB in non-syndromic children.

Early sarcomere and metabolic defects in a zebrafish pitx2c cardiac arrhythmia model.

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia. The major AF susceptibility locus 4q25 establishes long-range interactions with the promoter of PITX2, a transcription factor gene with critical functions during cardiac development. While many AF-linked loci have been identified in genome-wide association studies, mechanistic understanding into how genetic variants, including those at the 4q25 locus, increase vulnerability to AF is mostly lacking. Here, we show that loss of pitx2c in zebrafish leads to adult cardiac phenotypes with substantial similarities to pathologies observed in AF patients, including arrhythmia, atrial conduction defects, sarcomere disassembly, and altered cardiac metabolism. These phenotypes are also observed in a subset of pitx2c+/- fish, mimicking the situation in humans. Most notably, the onset of these phenotypes occurs at an early developmental stage. Detailed analyses of pitx2c loss- and gain-of-function embryonic hearts reveal changes in sarcomeric and metabolic gene expression and function that precede the onset of cardiac arrhythmia first observed at larval stages. We further find that antioxidant treatment of pitx2c-/- larvae significantly reduces the incidence and severity of cardiac arrhythmia, suggesting that metabolic dysfunction is an important driver of conduction defects. We propose that these early sarcomere and metabolic defects alter cardiac function and contribute to the electrical instability and structural remodeling observed in adult fish. Overall, these data provide insight into the mechanisms underlying the development and pathophysiology of some cardiac arrhythmias and importantly, increase our understanding of how developmental perturbations can predispose to functional defects in the adult heart.