Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY disease (CLARITY): statistical analysis plan for a randomised controlled Bayesian adaptive sample size trial.

The CLARITY trial (Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY disease) is a two-arm, multi-centre, randomised controlled trial being run in India and Australia that investigates the effectiveness of angiotensin receptor blockers in addition to standard care compared to placebo (in Indian sites) with standard care in reducing the duration and severity of lung failure in patients with COVID-19. The trial was designed as a Bayesian adaptive sample size trial with regular planned analyses where pre-specified decision rules will be assessed to determine whether the trial should be stopped due to sufficient evidence of treatment effectiveness or futility. Here, we describe the statistical analysis plan for the trial and define the pre-specified decision rules, including those that could lead to the trial being halted. The primary outcome is clinical status on a 7-point ordinal scale adapted from the WHO Clinical Progression scale assessed at day 14. The primary analysis will follow the intention-to-treat principle. A Bayesian adaptive trial design was selected because there is considerable uncertainty about the extent of potential benefit of this treatment.Trial registrationClinicalTrials.gov NCT04394117 . Registered on 19 May 2020Clinical Trial Registry of India CTRI/2020/07/026831Version and revisionsVersion 1.0. No revisions.

Kidney and cardiovascular protection with SGLT2 inhibitors: lessons from cardiovascular outcome trials and CREDENCE.

The burden of diabetic kidney disease is rising rapidly worldwide, and new therapies are of vital importance to reduce the risk of kidney failure and major cardiovascular events. Of the newer glucose-lowering agents, sodium-glucose co-transporter 2 (SGLT2) inhibitors have shown exciting potential in preventing these adverse events. The results of several large cardiovascular outcome trials, a single dedicated kidney outcome trial and a dedicated heart failure trial, demonstrate substantial clinical benefits for several different SGLT2 inhibitors. Emerging evidence raises the possibility that these benefits may extend to those with non-diabetic chronic kidney disease. This review summarises the current evidence for SGLT2 inhibitor benefits and harms, and examines which patients are most likely to gain from these therapies.

Design and methods of the REMOVAL-HD study: a tRial Evaluating Mid cut-Off Value membrane clearance of Albumin and Light chains in HaemoDialysis patients.

BACKGROUND: Removal of uraemic toxins is inadequate using current dialysis strategies. A new class of dialysis membranes have been developed that allow clearance of larger middle molecules. The REMOVAL-HD study (a tRial Evaluating Mid cut-Off Value membrane clearance of Albumin and Light chains in HaemoDialysis patients) will address safety, efficacy and the impact on patient-centred outcomes with the use of a mid cut-off (MCO) dialyser in a chronic haemodialysis (HD) population. METHODS: REMOVAL-HD is an open label, prospective, non-randomised, single-arm, multi-centre device study in 85 chronic HD participants. All visits will be conducted during regular HD sessions and participants will undergo a 1 month wash-in period using a standardised high flux dialyser, 6 months of intervention with a MCO dialyser and 1 month of wash-out using a high flux dialyser. The primary endpoint is change in pre-dialysis concentrations of serum albumin, with secondary endpoints including the efficacy of clearance of free light chains and ß-2 microglobulin, and patient-centred outcomes including quality of life, symptom burden, functional status, nutritional status, hospitalisation and death. DISCUSSION: MCO dialysers are a novel form of HD membrane. The REMOVAL-HD study is a pivotal study designed to monitor the immediate and medium-term effects following exposure to this dialyser. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry Number (ANZCTRN) 12616000804482 . Date of registration - 21/06/2016.

Prediction of 10-year vascular risk in patients with diabetes: the AD-ON risk score.

AIMS: To formulate a combined cardiovascular risk score in diabetes that could be useful both to physicians and healthcare funders. METHODS: Data were derived from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation Observational (ADVANCE-ON) study, a randomized controlled trial (mean duration 5 years) with a post-randomization follow-up (mean 4.9 years), that included 11 140 high-risk patients with diabetes. The outcome analysed was the occurrence of either fatal or non-fatal macrovascular or renal disease. A Cox regression model was used to determine weightings in the risk score. The resultant score was recalibrated to each of three major global regions, as covered by the ADVANCE-ON study. RESULTS: Over a median of 9.9 years, 1145 patients experienced at least one component of the combined outcome event. The resultant score, the AD-ON risk score, incorporated 13 demographic or clinical variables. Its discrimination was modest [c-statistic = 0.668 (95% confidence interval 0.651, 0.685)] but its calibration was excellent (predicted and observed risks coincided well, within disparate global regions). In terms of the integrated discrimination improvement index, its performance was marginally superior, over a 10-year risk horizon, to existing risk scores in clinical use, from a restricted version of the same data, for macrovascular and renal disease separately. CONCLUSIONS: The AD-ON risk score has advantages over the existing vascular risk scores in diabetes that used data from the original ADVANCE trial, which treat macrovascular and renal diseases separately. These advantages include its simplicity of use and global application.

Demographic profile and clinical outcome of patients diagnosed with parathyroid adenoma after one year of parathyroidectomy - A Makati Medical Center experience

Background: The paper aims to present the clinical profile and treatment outcomes of both asymptomatic and symptomatic hyperparathyroid patients in our institution. Methodology: This is a retrospective, descriptive study, which involved reviewing histopathology records from 2004 to 2008. Collected data were tabulated. Statistical means and percentages were used to present the results. A paired t test was used to compare continous variables. Results: A total of 12 patients were diagnosed with parathyroid adenoma on final histopathological diagnosis. Ten out of 12 patients underwent unilateral cervical parathyroidectomy, while two patients had incidental findings of parathyroid adenoma after total thyroidectomy. The difference between pre-operative ionized calcium levels of asymptomatic hyperparathyroid patients compared with symptomatic patients were not statistically significant, 1.88 mmol/L ± 0.43 mmol/L vs. 1.80 mmol/L ± 0.29 mmol/L, respectively. All asymptomatic patients satisfied one or more of the updated National Institute of Health guidelines for parathyroidectomy of asymptomatic hyperparathyroidism. Levels of intact PTH postoperatively showed decrease by more than 50% from the pre-operative values from 693.337 pg/mL (± 744.532 pg/mL) to 124.016 pg/mL (± 73.921 pg/ mL) after parathyroidectomy, showing 100% cure rate. Almost 50% of the patients suffered from hypocalcemic symptoms (mean calcium level 1.08 mmol/L) by the second to third post-operative day. Normocalcemia was achieved within one year post-parathyroidectomy. Conclusion: Our study showed that it is prudent to request for repeat serum ionized calcium during the first four days post-operatively, where most of the serum ionized calcium levels of our patients were noted to decrease. Furthermore, we should start our patients with calcium supplementation post-parathyroidectomy, even if initial serum ionized calcium are normal.

Lower blood pressure and risk of recurrent stroke in patients with chronic kidney disease: PROGRESS trial.

Recent epidemiological studies have shown a J-shaped association between the risk of stroke and systolic blood pressure (SBP) levels in people with chronic kidney disease (CKD). The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) was a randomized, placebo-controlled trial demonstrating that perindopril-based blood pressure (BP) lowering reduced the risk of stroke in 6105 participants with prior cerebrovascular disease. We estimated the effects of therapy on the risk of recurrent stroke in 1757 of these participants with stage 3 or greater CKD according to baseline BP and the relationship between achieved follow-up BP and the risk of stroke. Active therapy produced comparable and significant reductions in the risk of stroke across all baseline SBP levels. The age- and gender-adjusted incidence of stroke increased significantly in a log-linear relationship for achieved SBP levels and strokes per 1000 person-years. This association persisted after adjusting for potential confounding factors. We found that perindopril-based BP lowering effectively prevented recurrent stroke in people with CKD, across a wide range of BP levels, without evidence of an increased risk of stroke in people with low BP levels.

Synthesis of mycothiol, 1D-1-O-(2-[N-acetyl-L-cysteinyl]amino-2-deoxy-alpha-D-glucopyranosyl)-myo-inositol, principal low molecular mass thiol in the actinomycetes.

Members of the actinomycetes produce 1D-1-O-(2-[N-acetyl-L-cysteinyl]amino-2-deoxy-alpha-D-glucopyranosyl)-myo-inositol or mycothiol 1 as principal low molecular mass thiol. Chemical synthesis of a biosynthetic precursor of mycothiol, the pseudodisaccharide 1D-1-O-(2-amino-2-deoxy-alpha-D-glucopyranosyl)-myo-inositol 13 was achieved by the following steps: (1) Enantioselective synthesis gave the glycosyl acceptors (-)-2,3,4,5,6-penta-O-acetyl-D-myo-inositol D-7 and the corresponding L-isomer L-7. (2) Condensation of D-7 and L-7 with the glycosyl donor 3,4,6-tri-O-acetyl-2-deoxy-2-(2,4-dinitrophenylamino)-alpha-D-glucopyranosylbromide afforded the corresponding alpha and beta anomeric products, which could be resolved by silica gel chromatography. (3) Deprotection of these by hydrolysis using an anion exchange resin gave 1D- and 1L-1-O-(2-amino-2-deoxy-alpha-D-glucopyranosyl)-myo-inositol 13 and 15 and the corresponding beta-coupled anomers 14 and 16. Only 13, and to a much lesser extent 15, were used by enzymes present in an ammonium sulphate fraction of a cellfree extract of Mycobacterium smegmatis for the enzymatic synthesis of mycothiol. In the absence of acetyl-SCoA, the immediate biosynthetic precursor of 1, desacetylmycothiol, was the major product.

Omeprazole-induced interstitial nephritis.

Acute renal impairment secondary to interstitial nephritis is a rare complication of omeprazole. We describe a 50-year-old woman who took 20 mg omeprazole twice daily for endoscopically proved ulcerative esophagitis. At the same time, Duke's C colonic cancer was diagnosed and completely resected. Five fluorouracil/folinic acid adjuvant chemotherapy was tolerated without diarrhea or mouth ulceration. Renal function was normal before her first monthly cycle but markedly deteriorated immediately before the second cycle was due. The patient was symptomatic with lethargy, nausea, and mild vomiting, but she was clinically normotensive and only mildly dehydrated. Her serum creatinine concentration increased despite prolonged intravenous hydration, peaking at 4.4 mg/dl 1 week later. Results of a renal ultrasound were normal, and urinary microscopic findings were unremarkable. Renal biopsy showed interstitial nephritis, and renal function improved on cessation of omeprazole, eventually returning to normal. We describe the 12 cases of omeprazole-induced interstitial nephritis reported previously.

Biosynthesis of mycothiol: elucidation of the sequence of steps in Mycobacterium smegmatis.

Several members of the Actinomycetales, including the medically important mycobacteria, produce 1-D-myo-inosityl-2-(N-acetyl-L-cysteinyl)amino-2-deoxy-alpha-D- glucop yranoside (trivial name mycothiol) as their principal low-molecular-mass thiol. The pseudo-disaccharide component of mycothiol, 1-D-myo-inosityl-2-amino-2-deoxy-alpha-D-glucopyranoside (alpha-D-GI), was synthesized by ligation of 1-D,L-2,3,4,5, 6-penta-O-acetyl-myo-inositol to 3,4,6-tri-O-acetyl-2-deoxy- 2-(2,4-dinitrophenylamino)-alpha-D-glu- copyranosyl bromide to give, in the first instance, an isomeric mixture of alpha- and beta-linked pseudo-disaccharides. The alpha-coupled D,D and D,L isomers, alpha-D-GI and alpha-L-GI respectively, were purified from the mixture by TLC, followed by removal of the protecting groups. A cell-free extract of Mycobacterium smegmatis catalysed the ligation of cysteine, acetate and alpha-D-GI in the presence of ATP and Mg2+ to form mycothiol, as judged by HPLC. When no acetate was added to the incubation mixture, an additional thiol accumulated. In the presence of [14C]acetate no radiolabel was recovered in this species, but only in mycothiol. The additional thiol was isolated as the bimane derivative, and 1H and 1H-1H COSY NMR spectra confirmed its identity as desacetylmycothiol. A more complete conversion of desacetylmycothiol into mycothiol was achieved in the presence of acetyl-S-CoA. These results indicate that the biosynthesis of mycothiol proceeds by the sequential addition of cysteine and acetate to alpha-D-GI. The inositol moiety appears to be an important determinant of specificity, since alpha-L-GI was poorly utilized.

Physiological characteristics of rugby players including muscle glycogen content and muscle fibre composition.

There are few studies of the anthropomorphic and physiological characteristics of South African rugby players. Twenty-nine club rugby players were evaluated for body composition, maximal treadmill performance, muscle fibre composition and the muscle glycogen content, including the effects of carbohydrate-loading and playing a rugby match. The body composition and physiological characteristics of the players were similar to that previously reported for international players. Very high absolute values for maximum oxygen consumption (VO2 max) were measured in the forwards. Both backs and forwards had a preponderance of fast-twitch muscle fibres (57% and 53% respectively). Carbohydrate-loading increased pre-match muscle glycogen content but was unnecessary since severe muscle glycogen depletion did not occur during a match even in players on a normal mixed diet before competition. It is concluded that for forwards, a high absolute VO2 max, and for both backs and forwards a predominance of fast-twitch muscle fibres are pre-requisites for success in this sport. Pre-match carbohydrate-loading would appear to be necessary only when more than one match is to be played within 48 hours.

A clinical scale for the self-assessment of irritability.

To date there has been no suitable scale for the self-assessment of irritability in the clinical situation. Existing scales have either included aspects of personality trait together with present state or they have been constructed on non-clinical populations. A self-assessment scale has been constructed which seeks to overcome such faults. Measures of depression and of anxiety are included, together with measures of outwardly directed irritability and inwardly directed irritability. This scale should be known as the Irritability, Depression, Anxiety--or IDA--Scale.