Low thiamine status in adults following low-carbohydrate / ketogenic diets: a cross-sectional comparative study of micronutrient intake and status.

BACKGROUND: Low-carbohydrate diets (LCD) are popular for weight loss but lack evidence about micronutrient sufficiency in real-life use. This study assessed the intake and biochemical status of selected micronutrients in people voluntarily following LCDs. METHODS: A cross-sectional study was conducted (2018-20) among 98 adults recruited as self-reporting either LCD (n = 49) or diets not restricting carbohydrates (controls; n = 49). Diets were assessed using the 130-item EPIC-Norfolk food-frequency questionnaire. Red-blood-cell thiamine diphosphate (TDP) was measured for thiamine status using HPLC. Plasma magnesium, zinc, copper, and selenium were measured using inductively coupled plasma mass spectrometry. Between-group biomarker comparisons were conducted using ANCOVA and adjusted for age, sex, body mass index (BMI), and diabetes status. RESULTS: LCD-followers (26% male, median age 36 years, median BMI 24.2 kg/m2) reported adhering to LCDs for a median duration of 9 months (IQR 4-36). The most followed LCD type was 'their own variations of LCD' (30%), followed by ketogenic (23%), 'palaeolithic' (15%), and Atkins diets (8%). Among controls, 41% were male (median age 27 years, median BMI 23 kg/m2). Median macronutrient intakes for LCD vs control groups were carbohydrate 16%Energy (E) vs. 50%E; protein 25%E vs. 19%E; and fat 55%E vs 34%E (saturated fat 18%E vs. 11%E). Two-thirds of LCD followers (32/49) and half of the controls (24/49) reported some use of dietary supplements (p = 0.19). Among LCD-followers, assessing from food data only, 21 (43%) failed to meet the reference nutrient intake (RNI) for thiamine (vs.14% controls, p = 0.002). When thiamine from supplementation (single- or multivitamin) was included, there appeared to be no difference in thiamine intake between groups. Still, red-blood-cell TDP was lower in LCD-followers than controls (407 ± 91 vs. 633 ± 234 ng/gHb, p < 0.001). Three LCD-followers were thiamine-deficient (RBC thiamine < 275 ng/gHb) vs. one control. There were no significant differences in dietary intakes or plasma concentrations of magnesium, zinc, copper, and selenium between groups. CONCLUSIONS: Following LCDs is associated with lower thiamine intake and TDP status than diets without carbohydrate restriction, incompletely corrected by supplement use. These data, coupled with a lack of RCT evidence on body weight control, do not support recommending LCDs for weight management without appropriate guidance and diet supplementation.

THE ROLE OF INTRAVITREAL METHOTREXATE AS AN ADJUNCT TO LOCAL OR SYSTEMIC CORTICOSTEROIDS IN VITRECTOMY FOR RHEGMATOGENOUS RETINAL DETACHMENT AND CHOROIDAL DETACHMENT: A Pilot Study.

PURPOSE: To evaluate the role of repeated intravitreal methotrexate as an adjunct to pars plana vitrectomy in the management of rhegmatogenous retinal detachment with choroidal detachment. METHOD: The authors compared anatomical and visual outcomes of rhegmatogenous retinal detachment with choroidal detachment eyes that underwent pars plana vitrectomy with (Group B) or without repeated intravitreal methotrexate (Group A). RESULTS: The study included 25 eyes of 25 patients, 16 eyes in Group A and nine in Group B. Both groups had similar baseline characteristics. In Group A, successful retinal attachment was achieved in 50% as compared with 89% in Group B; however, the difference was not statistically significant ( P = 0.08). Also, Group B had a significantly greater change in visual acuity from baseline to the last follow-up visit (1.6 + 1.5 logMAR units) compared with Group A (1.18 + 1 logMAR units) ( P = 0.05). There were no significant safety concerns with the use of intravitreal methotrexate. CONCLUSION: Repeated intravitreal methotrexate after vitrectomy for rhegmatogenous retinal detachment with choroidal detachment improves outcomes without posing major safety concerns. Nonetheless, further investigation is necessary to establish the optimal intravitreal methotrexate dosage and duration to prevent recurrence effectively.

The relationship between micronutrient status, frailty, systemic inflammation, and clinical outcomes in patients admitted to hospital with COVID-19.

BACKGROUND: Micronutrients have been associated with disease severity and poorer clinical outcomes in patients with COVID-19. However, there is a paucity of studies examining if the relationship with micronutrient status and clinical outcomes is independent of recognised prognostic factors, specifically frailty and the systemic inflammatory response (SIR). The aim of the present study was to examine the relationship between micronutrient status, frailty, systemic inflammation, and clinical outcomes in patients admitted with COVID-19. METHODS: Retrospective analysis of prospectively collected data was performed on patients with confirmed COVID-19, admitted to hospital between the 1st April 2020-6th July 2020. Clinicopathological characteristics, frailty assessment, biochemical and micronutrient laboratory results were recorded. Frailty status was determined using the Clinical Frailty scale. SIR was determined using serum CRP. Clinical outcomes of interest were oxygen requirement, ITU admission and 30-day mortality. Categorical variables were analysed using chi-square test and binary logistics regression analysis. Continuous variables were analysed using the Mann-Whitney U or Kruskal Wallis tests. RESULTS: 281 patients were included. 55% (n = 155) were aged ≥ 70 years and 39% (n = 109) were male. 49% (n = 138) of patients were frail (CFS > 3). 86% (n = 242) of patients had a serum CRP > 10 mg/L. On univariate analysis, frailty was significantly associated with thirty-day mortality (p < 0.001). On univariate analysis, serum CRP was found to be significantly associated with an oxygen requirement on admission in non-frail patients (p = 0.004). Over a third (36%) of non-frail patients had a low vitamin B1, despite having normal reference range values of red cell B2, B6 and selenium. Furthermore, serum CRP was found to be significantly associated with a lower median red cell vitamin B1 (p = 0.029). CONCLUSION: Vitamin B1 stores may be depleted in COVID-19 patients experiencing a significant SIR and providing rationale for thiamine supplementation. Further longitudinal studies are warranted to delineate the trend in thiamine status following COVID-19.

Fenfluramine in the treatment of Dravet syndrome: Results of a third randomized, placebo-controlled clinical trial.

OBJECTIVE: This study was undertaken to assess the safety and efficacy of fenfluramine in the treatment of convulsive seizures in patients with Dravet syndrome. METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial enrolled patients with Dravet syndrome, aged 2-18 years with poorly controlled convulsive seizures, provided they were not also receiving stiripentol. Eligible patients who had ≥6 convulsive seizures during the 6-week baseline period were randomized to placebo, fenfluramine .2 mg/kg/day, or fenfluramine .7 mg/kg/day (1:1:1 ratio) administered orally (maximum dose = 26 mg/day). Doses were titrated over 2 weeks and maintained for an additional 12 weeks. The primary endpoint was a comparison of the monthly convulsive seizure frequency (MCSF) during baseline and during the combined titration-maintenance period in patients given fenfluramine .7 mg/kg/day versus patients given placebo. RESULTS: A total of 169 patients were screened, and 143 were randomized to treatment. Mean age was 9.3 ± 4.7 years (±SD), 51% were male, and median baseline MCSF in the three groups ranged 12.7-18.0 per 28 days. Patients treated with fenfluramine .7 mg/kg/day demonstrated a 64.8% (95% confidence interval = 51.8%-74.2%) greater reduction in MCSF compared with placebo (p < .0001). Following fenfluramine .7 mg/kg/day, 72.9% of patients had a ≥50% reduction in MCSF compared with 6.3% in the placebo group (p < .0001). The median longest seizure-free interval was 30 days in the fenfluramine .7 mg/kg/day group compared with 10 days in the placebo group (p < .0001). The most common adverse events (>15% in any group) were decreased appetite, somnolence, pyrexia, and decreased blood glucose. All occurred in higher frequency in fenfluramine groups than placebo. No evidence of valvular heart disease or pulmonary artery hypertension was detected. SIGNIFICANCE: The results of this third phase 3 clinical trial provide further evidence of the magnitude and durability of the antiseizure response of fenfluramine in children with Dravet syndrome.

IMMEDIATE VITRECTOMY vs TAP AND INJECT IN EYES WITH ACUTE POSTCATARACT ENDOPHTHALMITIS AND VISUAL ACUITY ≥HM: A Randomized Clinical Trial.

PURPOSE: To compare the outcomes of immediate pars plana vitrectomy (PPV) and tap and inject in eyes with postcataract surgery endophthalmitis. METHODS: Patients presenting with acute postcataract surgery endophthalmitis and visual acuity between ≥ hand movement and <6/18 were randomized to receive either PPV (Group A) or tap and inject (Group B). RESULTS: There were 26 and 31 eyes in Group A and Group B, respectively. The final mean visual acuity at 6 weeks [0.14 (Snellen equivalent 6/7.5) versus 0.22 (Snellen equivalent 6/9.5) LogMAR in Groups A and B, respectively; P = 0.2] was similar. However, eyes in Group A had significantly greater mean letter gain in vision compared with Group B (66.36 vs. 43.36, P = 0.02), and more eyes in Group A (88%) than in Group B (65%) attained a visual acuity of ≥ 6/18 ( P = 0.06). Eyes in Group B needed more reinterventions including delayed vitrectomy after tap and inject than those in Group A (39% vs. 8%; P = 0.09). On subgroup analysis, the mean visual acuity at the final follow-up was significantly better in the immediate PPV group compared with the delayed PPV group ( P = 0.04). CONCLUSION: PPV resulted in earlier recovery, lesser interventions, and greater change in visual acuity than tap and inject in eyes with postcataract surgery endophthalmitis presenting with visual acuity of ≥HM.

Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Dravet syndrome is a rare, treatment-resistant developmental epileptic encephalopathy characterised by multiple types of frequent, disabling seizures. Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet syndrome. The aim of the present study was to assess the efficacy and safety of fenfluramine in patients with Dravet syndrome. METHODS: In this randomised, double-blind, placebo-controlled clinical trial, we enrolled children and young adults with Dravet syndrome. After a 6-week observation period to establish baseline monthly convulsive seizure frequency (MCSF; convulsive seizures were defined as hemiclonic, tonic, clonic, tonic-atonic, generalised tonic-clonic, and focal with clearly observable motor signs), patients were randomly assigned through an interactive web response system in a 1:1:1 ratio to placebo, fenfluramine 0·2 mg/kg per day, or fenfluramine 0·7 mg/kg per day, added to existing antiepileptic agents for 14 weeks. The primary outcome was the change in mean monthly frequency of convulsive seizures during the treatment period compared with baseline in the 0·7 mg/kg per day group versus placebo; 0·2 mg/kg per day versus placebo was assessed as a key secondary outcome. Analysis was by modified intention to treat. Safety analyses included all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov with two identical protocols NCT02682927 and NCT02826863. FINDINGS: Between Jan 15, 2016, and Aug 14, 2017, we assessed 173 patients, of whom 119 patients (mean age 9·0 years, 64 [54%] male) were randomly assigned to receive either fenfluramine 0·2 mg/kg per day (39), fenfluramine 0·7 mg/kg per day (40) or placebo (40). During treatment, the median reduction in seizure frequency was 74·9% in the fenfluramine 0·7 mg/kg group (from median 20·7 seizures per 28 days to 4·7 seizures per 28 days), 42·3% in the fenfluramine 0·2 mg/kg group (from median 17·5 seizures per 28 days to 12·6 per 28 days), and 19·2% in the placebo group (from median 27·3 per 28 days to 22·0 per 28 days). The study met its primary efficacy endpoint, with fenfluramine 0·7 mg/kg per day showing a 62·3% greater reduction in mean MCSF compared with placebo (95% CI 47·7-72·8, p<0·0001); fenfluramine 0·2 mg/kg per day showed a 32·4% reduction in mean MCSF compared with placebo (95% CI 6·2-52·3, p=0·0209). The most common adverse events (occurring in at least 10% of patients and more frequently in the fenfluramine groups) were decreased appetite, diarrhoea, fatigue, lethargy, somnolence, and decreased weight. Echocardiographic examinations revealed valve function within the normal physiological range in all patients during the trial and no signs of pulmonary arterial hypertension. INTERPRETATION: In Dravet syndrome, fenfluramine provided significantly greater reduction in convulsive seizure frequency compared with placebo and was generally well tolerated, with no observed valvular heart disease or pulmonary arterial hypertension. Fenfluramine could be an important new treatment option for patients with Dravet syndrome. FUNDING: Zogenix.

Prognostic factors in patients admitted to an urban teaching hospital with COVID-19 infection.

BACKGROUND: Severe COVID-19 infection results in a systemic inflammatory response (SIRS). This SIRS response shares similarities to the changes observed during the peri-operative period that are recognised to be associated with the development of multiple organ failure. METHODS: Electronic patient records for patients who were admitted to an urban teaching hospital during the initial 7-week period of the COVID-19 pandemic in Glasgow, U.K. (17th March 2020-1st May 2020) were examined for routine clinical, laboratory and clinical outcome data. Age, sex, BMI and documented evidence of COVID-19 infection at time of discharge or death certification were considered minimal criteria for inclusion. RESULTS: Of the 224 patients who fulfilled the criteria for inclusion, 52 (23%) had died at 30-days following admission. COVID-19 related respiratory failure (75%) and multiorgan failure (12%) were the commonest causes of death recorded. Age ≥ 70 years (p < 0.001), past medical history of cognitive impairment (p ≤ 0.001), previous delirium (p < 0.001), clinical frailty score > 3 (p < 0.001), hypertension (p < 0.05), heart failure (p < 0.01), national early warning score (NEWS) > 4 (p < 0.01), positive CXR (p < 0.01), and subsequent positive COVID-19 swab (p ≤ 0.001) were associated with 30-day mortality. CRP > 80 mg/L (p < 0.05), albumin < 35 g/L (p < 0.05), peri-operative Glasgow Prognostic Score (poGPS) (p < 0.05), lymphocytes < 1.5 109/l (p < 0.05), neutrophil lymphocyte ratio (p ≤ 0.001), haematocrit (< 0.40 L/L (male)/ < 0.37 L/L (female)) (p ≤ 0.01), urea > 7.5 mmol/L (p < 0.001), creatinine > 130 mmol/L (p < 0.05) and elevated urea: albumin ratio (< 0.001) were also associated with 30-day mortality. On multivariate analysis, age ≥ 70 years (O.R. 3.9, 95% C.I. 1.4-8.2, p < 0.001), past medical history of heart failure (O.R. 3.3, 95% C.I. 1.2-19.3, p < 0.05), NEWS > 4 (O.R. 2.4, 95% C.I. 1.1-4.4, p < 0.05), positive initial CXR (O.R. 0.4, 95% C.I. 0.2-0.9, p < 0.05) and poGPS (O.R. 2.3, 95% C.I. 1.1-4.4, p < 0.05) remained independently associated with 30-day mortality. Among those patients who tested PCR COVID-19 positive (n = 122), age ≥ 70 years (O.R. 4.7, 95% C.I. 2.0-11.3, p < 0.001), past medical history of heart failure (O.R. 4.4, 95% C.I. 1.2-20.5, p < 0.05) and poGPS (O.R. 2.4, 95% C.I. 1.1-5.1, p < 0.05) remained independently associated with 30-days mortality. CONCLUSION: Age ≥ 70 years and severe systemic inflammation as measured by the peri-operative Glasgow Prognostic Score are independently associated with 30-day mortality among patients admitted to hospital with COVID-19 infection.

Fenfluramine HCl (Fintepla® ) provides long-term clinically meaningful reduction in seizure frequency: Analysis of an ongoing open-label extension study.

OBJECTIVE: Fenfluramine has been shown to provide clinically meaningful and statistically significant reductions in convulsive seizure frequency in children and adolescents (aged 2-18 years) with Dravet syndrome in two randomized, placebo-controlled clinical trials. The objective of this analysis was to assess longer-term safety and efficacy of fenfluramine in patients who completed one of the double-blind studies and entered an open-label extension (OLE) study. METHODS: Patients enrolling in the OLE study initiated fenfluramine at 0.2 mg/kg/d regardless of their treatment assignment in the double-blind study. After 4 weeks, the fenfluramine dose could be titrated based on efficacy and tolerability to maximum of 0.7 mg/kg/d (absolute maximum 27 mg/d) or maximum of 0.4 mg/kg/d (absolute maximum 17 mg/d) in patients receiving concomitant stiripentol. The number and type of seizures were recorded daily in an electronic diary, and safety, including echocardiography, was assessed at Months 1, 2, and 3, and at 3-month intervals thereafter. RESULTS: A total of 232 patients were enrolled as of March 13, 2018. During this analysis period, patients were treated for a median 256 days (range = 46-634 days). Over the entire OLE analysis period, the median decrease in convulsive seizure frequency compared to baseline in the double-blind studies was -66.8% (range = -100% to 234.9%; P < .001). The median reduction in seizure frequency was similar in patients <6 (-75.7%) and ≥6 years old (-64.7%). The most commonly reported adverse events included pyrexia (21.6%), nasopharyngitis (19.4%), and decreased appetite (-15.9%). No valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) was observed. SIGNIFICANCE: Study results demonstrate that fenfluramine provides clinically meaningful (≥50%) seizure frequency reduction over an extended period in patients with Dravet syndrome. No patient developed VHD or PAH, and fenfluramine was generally well tolerated.

A prospective evaluation of thiamine and magnesium status in relation to clinicopathological characteristics and 1-year mortality in patients with alcohol withdrawal syndrome.

BACKGROUND: Alcohol withdrawal syndrome (AWS) is routinely treated with B-vitamins. However, the relationship between thiamine status and outcome is rarely examined. The aim of the present study was to examine the relationship between thiamine and magnesium status in patients with AWS. METHODS: Patients (n = 127) presenting to the Emergency Department with AWS were recruited to a prospective observational study. Blood samples were drawn to measure whole blood thiamine diphosphate (TDP) and serum magnesium concentrations. Routine biochemistry and haematology assays were also conducted. The Glasgow Modified Alcohol Withdrawal Score (GMAWS) measured severity of AWS. Seizure history and current medications were also recorded. RESULTS: The majority of patients (99%) had whole blood TDP concentration within/above the reference interval (275-675 ng/gHb) and had been prescribed thiamine (70%). In contrast, the majority of patients (60%) had low serum magnesium concentrations (< 0.75 mmol/L) and had not been prescribed magnesium (93%). The majority of patients (66%) had plasma lactate concentrations above 2.0 mmol/L. At 1 year, 13 patients with AWS had died giving a mortality rate of 11%. Male gender (p < 0.05), BMI < 20 kg/m2 (p < 0.01), GMAWS max ≥ 4 (p < 0.05), elevated plasma lactate (p < 0.01), low albumin (p < 0.05) and elevated serum CRP (p < 0.05) were associated with greater 1-year mortality. Also, low serum magnesium at time of recruitment to study and low serum magnesium at next admission were associated with higher 1-year mortality rates, (84% and 100% respectively; both p < 0.05). CONCLUSION: The prevalence of low circulating thiamine concentrations were rare and it was regularly prescribed in patients with AWS. In contrast, low serum magnesium concentrations were common and not prescribed. Low serum magnesium was associated more severe AWS and increased 1-year mortality.

Low serum magnesium and 1-year mortality in alcohol withdrawal syndrome.

BACKGROUND: In 2014, the WHO reported that 6% of all deaths were attributable to excess alcohol consumption. The aim of the present study was to examine the relationship between serum magnesium concentrations and mortality in patients with alcohol withdrawal syndrome (AWS). MATERIALS AND METHODS: A retrospective review of 700 patients with documented evidence of previous AWS indicating a requirement for benzodiazepine prophylaxis or evidence of alcohol withdrawal syndrome between November 2014 and March 2015. RESULTS: Of 380 patients included in the sample analysis, 64 (17%) were dead at 1 year following the time of treatment for AWS. The majority of patients had been prescribed thiamine (77%) and a proton pump inhibitor (66%). In contrast, the majority of patients had low circulating magnesium concentrations (<0.75 mmol/L) (64%) and had not been prescribed magnesium (90%). The median age of death at one year was 55 years (P = 0.002). On univariate analysis, age (P < 0.05), GMAWS (P < 0.05), BDZ (P < 0.05), bilirubin (P < 0.001), alkaline phosphatase (P < 0.001), albumin (P < 0.001), CRP (P < 0.05), AST:ALT ratio >2 (P < 0.001), sodium (P < 0.05), magnesium (P < 0.001), platelets (P < 0.05) and the use of proton pump inhibitor medication (P < 0.001) were associated with death at 1 year. On multivariate binary logistic regression analysis, age > 50 years (OR 3.37, 95% CI 1.52-7.48, P < 0.01), AST:ALT ratio >2 (OR 3.10, 95% CI 1.38-6.94, P < 0.01) and magnesium < 0.75 mmol/L (OR 4.11, 95% CI 1.3-12.8, P < 0.05) remained independently associated with death at 1 year. CONCLUSION: Overall, 1-year mortality was significantly higher among those patients who were magnesium deficient (<0.75 mmol/L) when compared to those who were replete (≥0.75 mmol/L; P < 0.001).

Regression Correction Equation to Adjust Serum Iron and Ferritin Concentrations Based on C-Reactive Protein and Albumin in Patients Receiving Primary and Secondary Care.

BACKGROUND: Systemic inflammation, even at low levels, can greatly interfere with measures of iron status, making diagnosis of iron deficiency difficult. The objective of the present study was to create linear regression correction equations to adjust serum ferritin and iron concentrations based on measurements of the acute-phase proteins C-reactive protein (CRP) and albumin. METHODS: Data from a cohort (1) of patients (n = 7226) in primary and secondary care who had serum ferritin, iron, CRP, and albumin measured at the same time point were examined. Linear regression coefficients were calculated for CRP and albumin with serum iron and ferritin as the outcome variables. Patients with ferritin <15 µg/L or serum iron <10 µmol/L were categorized as iron deficient. The equation was then applied to a cohort (2) of patients with colorectal cancer who had ferritin and iron measured preoperatively ( n = 356). RESULTS: In cohort 1 there was a significant difference in the proportions of patients with serum ferritin <15 µg/L and serum iron <10 µmol/L, respectively, when the unadjusted (7% and 55%), adjusted based on CRP alone (13% and 26%), adjusted based on albumin alone (11% and 37%), and adjusted based on both CRP and albumin (24% and 15%) values were compared (both P < 0.001). In cohort 2 there was a significant difference in the proportions of patients with serum ferritin <15 µg/L and serum iron <10 µmol/L, respectively, when the unadjusted (28% and 66%), adjusted based on CRP alone (39% and 57%), adjusted based on albumin alone (39% and 59%), and adjusted based on both CRP and albumin (46% and 44%) values were compared (P < 0.001 and P < 0.004). CONCLUSIONS: In both cohorts the greatest increase in the proportion of patients meeting definitions of iron deficiency was found when adjustment was made for both CRP and albumin together. Even low levels of inflammation had a significant effect on serum iron and ferritin values.

Telomere Homeostasis: Interplay with Magnesium.

Telomere biology, a key component of the hallmarks of ageing, offers insight into dysregulation of normative ageing processes that accompany age-related diseases such as cancer. Telomere homeostasis is tightly linked to cellular metabolism, and in particular with mitochondrial physiology, which is also diminished during cellular senescence and normative physiological ageing. Inherent in the biochemistry of these processes is the role of magnesium, one of the main cellular ions and an essential cofactor in all reactions that use ATP. Magnesium plays an important role in many of the processes involved in regulating telomere structure, integrity and function. This review explores the mechanisms that maintain telomere structure and function, their influence on circadian rhythms and their impact on health and age-related disease. The pervasive role of magnesium in telomere homeostasis is also highlighted.

Assessment of asymmetrical dimethylarginine metabolism in patients with critical illness.

BACKGROUND: Critically ill patients experience metabolic disorders including hypercatabolic state and hyperglycaemia, and these are associated with poor outcome. Hyperglycaemia and asymmetrical dimethylarginine (ADMA) are reported to have significant influences on endothelial dysfunction. The aim of this study was to examine the relationship between plasma ADMA and related arginine metabolism in patients with critical illness. MATERIALS AND METHOSDS: Two venous blood samples (EDTA) (104 patients), on admission and follow-up sample in the last day in intensive care unit (ICU) (died or discharge sample median 7, interquartile range (IQR) 6-8, range 5-15). Plasma ADMA, arginine, homoarginine and SDMA were measured by high-performance liquid chromatography (HPLC). RESULT: ADMA (P < 0·01) and SDMA (P < 0·05) were elevated, and homoarginine was decreased (P < 0·05) in nonsurvivors and was directly associated with predicted mortality rate (P < 0·05 and P < 0·001), Sequential Organ Failure Assessment (SOFA) (P < 0·05, P < 0·001), ICU stay (P < 0·05, P < 0·001) and mortality (P < 0·01, P < 0·05). ADMA was directly associated with SDMA (P < 0·001), albumin (P < 0·05), ICU stay and mortality (P < 0·01). SDMA was directly associated with creatinine (P < 0·001) and Acute physiology and Chronic Health Evaluation II score (P < 0·001). In the follow-up measurements, there was a significant decrease in SOFA score (P < 0·01), homoarginine (P < 0·01), aminotransferase (P < 0·01), Laboratory Glucose (P < 0·01) and albumin (P < 0·01). In contrast, there was an increase in arginine (P < 0·01), ADMA (P < 0·01), ADMA:SDMA ratio (P < 0·01) and the norepinephrine administration (P < 0·01). CONCLUSION: In the present longitudinal study, ADMA metabolism was altered in patients with critical illness and was associated with disease severity and mortality.

De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP.

Individuals with severe, sporadic disorders of infantile onset represent an important class of disease for which discovery of the underlying genetic architecture is not amenable to traditional genetic analysis. Full-genome sequencing of affected individuals and their parents provides a powerful alternative strategy for gene discovery. We performed whole-genome sequencing (WGS) on a family quartet containing an affected proband and her unaffected parents and sibling. The 15-year-old female proband had a severe epileptic encephalopathy consisting of early-onset seizures, features of autism, intellectual disability, ataxia, and sudden unexplained death in epilepsy. We discovered a de novo heterozygous missense mutation (c.5302A>G [p.Asn1768Asp]) in the voltage-gated sodium-channel gene SCN8A in the proband. This mutation alters an evolutionarily conserved residue in Nav1.6, one of the most abundant sodium channels in the brain. Analysis of the biophysical properties of the mutant channel demonstrated a dramatic increase in persistent sodium current, incomplete channel inactivation, and a depolarizing shift in the voltage dependence of steady-state fast inactivation. Current-clamp analysis in hippocampal neurons transfected with p.Asn1768Asp channels revealed increased spontaneous firing, paroxysmal-depolarizing-shift-like complexes, and an increased firing frequency, consistent with a dominant gain-of-function phenotype in the heterozygous proband. This work identifies SCN8A as the fifth sodium-channel gene to be mutated in epilepsy and demonstrates the value of WGS for the identification of pathogenic mutations causing severe, sporadic neurological disorders.

A simple iridicycle catalyst for efficient transfer hydrogenation of N-heterocycles in water.

A cyclometalated iridium complex is shown to catalyse the transfer hydrogenation of various nitrogen heterocycles, including but not limited to quinolines, isoquinolines, indoles and pyridinium salts, in an aqueous solution of HCO2H/HCO2Na under mild conditions. The catalyst shows excellent functional-group compatibility and high turnover number (up to 7500), with catalyst loadings as low as 0.01 mol % being feasible. Mechanistic investigation of the quinoline reduction suggests that the transfer hydrogenation proceeds via both 1,2- and 1,4-addition pathways, with the catalytic turnover being limited by the step of hydride transfer.

Regioselective acceptorless dehydrogenative coupling of N-heterocycles toward functionalized quinolines, phenanthrolines, and indoles.

A new strategy has been developed for the oxidant- and base-free dehydrogenative coupling of N-heterocycles at mild conditions. Under the action of an iridium catalyst, N-heterocycles undergo multiple sp(3) CH activation steps, generating a nucleophilic enamine that reacts in situ with various electrophiles to give highly functionalized products. The dehydrogenative coupling can be cascaded with Friedel-Crafts addition, resulting in a double functionalization of the N-heterocycles.

Primary amines by transfer hydrogenative reductive amination of ketones by using cyclometalated Ir(III) catalysts.

Cyclometalated iridium complexes are found to be versatile catalysts for the direct reductive amination (DRA) of carbonyls to give primary amines under transfer-hydrogenation conditions with ammonium formate as both the nitrogen and hydrogen source. These complexes are easy to synthesise and their ligands can be easily tuned. The activity and chemoselectivity of the catalyst towards primary amines is excellent, with a substrate to catalyst ratio (S/C) of 1000 being feasible. Both aromatic and aliphatic primary amines were obtained in high yields. Moreover, a first example of homogeneously catalysed transfer-hydrogenative DRA has been realised for ß-keto ethers, leading to the corresponding ß-amino ethers. In addition, non-natural α-amino acids could also be obtained in excellent yields with this method.