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Background: The short shelf-life of liquid-stored platelets (LP) at 20-24°C poses shortage and wastage challenges. Cryopreserved platelets have significantly extended shelf-life, and were safe and efficacious for therapeutic transfusions of bleeding patients in the Afghanistan conflict and phase 2 randomized studies. Although hematology patients account for half of platelets demand, there is no randomized study on prophylactic cryopreserved platelet transfusions in them., Methods: We performed a phase 1b/2a randomized cross-over study comparing the safety and efficacy of cryopreserved buffy coat-derived pooled platelets (CP) to LP in the prophylactic transfusions of thrombocytopenic hematology patients., Results: A total of 18 adults were randomly assigned 1:1 to CP and LP for their first thrombocytopenic period (TP) of up to 28-days. A total of 14 crossed over to the other platelet-arm for the second TP. Overall, 17 subjects received 51 CP and 15 received 52 LP. CP-arm had more treatment emergent adverse event (29.4% vs. 13.3% of subjects, 9.8% vs. 3.8% of transfusions) than LP-arm but all were mild. No thromboembolism was observed. Both arms had similar bleeding rates (23.5% vs. 26.7% of subjects) which were all mild. Subjects in CP-arm had lower average corrected count increments than LP-arm (mean [SD] 5.6 [4.20] vs. 22.6 [9.68] ×10 9 /L at 1-4 h, p < .001; 5.3 [4.84] vs. 18.2 [9.52] ×10 9 /L at 18-30 h, p < .001). All TEG parameters at 1-4 h and maximum amplitude (MA) at 18-30 h improved from baseline post-CP transfusion (p < .05) though improvements in K-time and MA were lower than LP (p < .05)., Discussion: During shortages, CP may supplement LP in prophylactic transfusions of thrombocytopenic patients., (© 2023 AABB.)

Background: Shorter treatments are needed for drug-susceptible tuberculosis. Adjunctive statins increase bactericidal activity in preclinical tuberculosis models. We investigated the safety and efficacy of adjunctive rosuvastatin in people with tuberculosis. We tested the hypothesis that adjunctive rosuvastatin accelerates sputum culture conversion within the first 8 weeks of treatment of rifampicin-susceptible tuberculosis., Methods: This phase 2b, randomised, open-label, multicentre trial conducted in five hospitals or clinics in three countries with high tuberculosis burden (ie, the Philippines, Viet Nam, and Uganda) enrolled adult participants aged 18-75 years with sputum smear or Xpert MTB/RIF positive, rifampicin-susceptible tuberculosis who had received less than 7 days of previous tuberculosis treatment. Participants were randomly assigned via a web-based system to receive either 10 mg rosuvastatin once per day for 8 weeks plus standard tuberculosis therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol; rosuvastatin group) or standard tuberculosis therapy alone (control group). Randomisation was stratified by trial site, history of diabetes, and HIV co-infection. Laboratory staff and central investigators involved in data cleaning and analysis were masked to treatment allocation, but study participants and site investigators were not. Both groups continued standard treatment to week 24. Sputum samples were collected once per week for the first 8 weeks after randomisation, and then at weeks 10, 12, and 24. The primary efficacy outcome was time to culture conversion (TTCC; days) in liquid culture by week 8, assessed in randomised participants who had microbiological confirmation of tuberculosis, took at least one dose of rosuvastatin, and who did not show resistance to rifampicin (modified intention-to-treat population), for which groups were compared with the Cox proportional hazards model. The main safety outcome was grade 3-5 adverse events by week 24, assessed in the intention-to-treat population, for which groups were compared with Fisher's exact test. All participants completed 24 weeks of follow-up. This trial is registered with ClinicalTrials.gov (NCT04504851)., Findings: Between Sept 2, 2020, and Jan 14, 2021, 174 participants were screened and 137 were randomly assigned to the rosuvastatin group (70 participants) or control group (67 participants). In the modified intention-to-treat population of 135 participants, 102 (76%) were men and 33 (24%) were women. Median TTCC in liquid media was 42 days (95% CI 35-49) in the rosuvastatin group (68 participants) and 42 days (36-53) in the control group (67 participants; hazard ratio 1·30 [0·88-1·91], p=0·19). Grade 3-5 adverse events occurred in six (9%) of 70 in the rosuvastatin group (none were considered related to rosuvastatin) and four (6%) of 67 in the control group (p=0·75). There were no serious adverse events that were considered to be related to rosuvastatin., Interpretation: Adjunctive rosuvastatin at 10 mg once per day was safe but did not produce substantive benefits on culture conversion in the overall study population. Future trials could explore the safety and efficacy of higher doses of adjunctive rosuvastatin., Funding: National Medical Research Council, Singapore., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Multinational studies have reported monogenic etiologies in 25%-30% of children with steroid-resistant nephrotic syndrome. Such large studies are lacking in Asia. We established Deciphering Diversities: Renal Asian Genetics Network (DRAGoN) and aimed to describe the genetic and clinical spectrums in Asians. We prospectively studied a cohort of 183 probands with suspected genetic glomerulopathies from South and Southeast Asia, of whom 17% had positive family history. Using multi-gene panel sequencing, we detected pathogenic variants in 26 (14%) probands, of whom one-third had COL4A4 or COL4A5 variants (n = 9, 5%). Of those with COL4A5 defects, only 25% had features suggestive of Alport syndrome. Besides traditional predictors for genetic disease (positive family history and extrarenal malformations), we identified novel predictors, namely older age (6.2 vs. 2.4 years; p = 0.001), hematuria (OR 5.6; 95% CI 2.1-14.8; p < 0.001), and proteinuria in the absence of nephrotic syndrome (OR 4.6; 95% CI 1.8-11.8; p = 0.001) at first manifestation. Among patients who first presented with proteinuria without nephrotic syndrome, the genetic diagnostic rates were >60% when a second risk factor (positive family history or extrarenal manifestation) co-existed. The genetic spectrum of glomerulopathies appears different in Asia. Collagen IV genes may be included in sequencing panels even when suggestive clinical features are absent., (© 2022 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

Objectives: Preclinical and clinical studies indicate a role for MLC901 (NeuroAiD II) in Alzheimer's disease (AD). The primary aim was to investigate its safety as add-on therapy to standard treatment and the secondary aims its effect on cognition and slowing disease progression., Design: Randomized double-blind placebo-controlled delayed-start study., Setting and Participant: Patients with mild to moderate probable AD by NINCDS-ADRDA criteria, stable on acetylcholinesterase inhibitors or memantine (n = 125), were randomized to receive MLC901 (early starters) or placebo (delayed starters) for 6 months, followed by a further 6 months when all patients received MLC901, in a delayed-start design (clinical trial registration: ClinicalTrials.gov, NCT03038035)., Methods: The primary outcome measure was occurrence of serious adverse events (SAEs) at 6 months. Secondary outcomes included the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and other assessment scales., Results: There was no significant difference in the risk of SAEs between early and delayed starters at month (M) 6 (22.6% vs 27.0%, risk difference -4.4%, 90% CI -16.9% to 8.3%). Similarly, there was no significant difference in the risk of adverse events and the occurrence of stroke or vascular events between early and delayed starters throughout the 12-month study period. Early starters did not differ significantly on ADAS-Cog from delayed starters at M6 [mean difference (MD) -1.0, 95% CI -3.3 to 1.3] and M12 (MD -2.35, 95% CI -5.45 to 0.74) on intention-to-treat analysis. Other cognitive assessment scales did not show significant differences., Conclusions and Implications: This study of 125 persons with dementia found no evidence of a significant increase in adverse events between MLC901 and placebo, thus providing support for further studies on both efficacy and safety. Analyses suggest the potential of MLC901 in slowing down AD progression, but this requires further confirmation in larger and longer studies using biomarkers for AD., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Parent-completed tools like the Ages and Stages Questionnaire Third Edition (ASQ-3) are important in developmental screening. As a screening tool, a high negative predictive value (NPV) is critical to avoid missing the diagnosis of developmental delay. This study evaluated the NPV and accuracy of the ASQ-3 in assessing the development of preterm infants., Methods: Infants born at <32 weeks and/or <1250 grams, presenting to the Neonatal Neurodevelopmental Clinic at the Singapore General Hospital for follow-up from January 2014 to June 2017, at 6, 12, and 18 months corrected age, were included. The ASQ-3 and standardized tests - Peabody Developmental Motor Scale-Second Edition (PDMS-2) and Preschool Language Scale, Fourth Edition UK (PLS-4 UK) - were administered. ASQ-3 gross motor and fine motor scores were compared to PDMS-2 at 6 and 12 months, and ASQ-3 communication scores to PLS-4 UK at 18 months., Results: At 6 months (n = 145), NPV for gross motor and fine motor were 96.4% (accuracy 80.0%) and 95.4% (accuracy 77.2%) respectively. At 12 months (n = 127), NPV for gross motor and fine motor were 88.9% (accuracy 79.8%) and 82.8% (accuracy 74.0%) respectively. At 18 months (n = 113), NPV for language was 56.9% (accuracy 63.7%)., Conclusions: The ASQ-3 showed high NPV and accuracy in screening gross motor and fine motor skills at 6 and 12 months, but not in screening language skills at 18 months. Judicious use of the ASQ-3 may allow for more effective utilization of resources.

Background: Most comparative clinical trials are designed to assess the treatment effect for efficacy endpoints, with less emphasis on the analysis of safety outcomes. However, an extensive analysis of safety data could demonstrate beneficial results in terms of effectiveness by reducing serious adverse events (SAEs), and their unfavourable clinical impact on the study population. We aimed to conduct an exploratory analysis of the CHInese Medicine Neuroaid Efficacy on Stroke recovery (CHIMES) study safety database comparing the frequency of SAEs and their clinical impacts among subjects having received MLC601 or placebo during the first 3 months post-stroke., Methods: Analyses were performed by using the safety database of the multicentre, randomised, double-blind, placebo-controlled CHIMES study of 3 months of NeuroAiD versus placebo in subjects with acute ischaemic stroke of intermediate severity in the preceding 72 h. SAEs as reported by investigators at any time-point during the 3-month study were analysed on their frequency and that of any of their outcomes (death, and life threatening, new and/or prolonged hospitalisation, disability, and medical importance, in surviving subjects), as well as their time to onset and resolution., Results: Of the 1,099 subjects in the CHIMES study, 1,087 were included in the safety analysis (MLC601 = 542) and (placebo = 545); the 12 who did not receive study treatment were excluded. There was a total of 135 subjects with SAEs (MLC601 = 60, placebo = 75). At baseline, overall, subjects with SAEs were older and had lower MMSE score. In the MLC601 group, they had higher NIHSS score, and more frequently a history of ischaemic heart disease and hyperlipidaemia. The number of SAEs per subjects was statistically significantly lower in the MLC601 group than placebo one, especially for subjects with ≥2 SAEs (6.7 vs. 29.3%; p < 0.001). This benefit was seen throughout the study period and during the initial hospitalisation. The main clinical impact of SAEs was an increase in hospitalisation time, reduced in the MLC601 arm with the rate of subjects hospitalised for a prolonged period being significantly threefold lower in surviving subjects (1.1 vs. 3.7%; p < 0.01)., Conclusions: This post hoc analysis of SAEs from the CHIMES study database shows that subjects receiving a 3-month course of MLC601 experienced fewer SAEs, with lower rates of harmful clinical impacts, especially in terms of hospitalisation duration. These findings could translate to a benefit in terms of reduction of both healthcare burden and additional medical costs., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Aims and Objectives: Malnutrition is common in children with congenital heart disease and may contribute to adverse outcomes. This study evaluates the impact of pre-operative nutritional status on outcomes after congenital heart surgery. Methods: We conducted a retrospective cohort study enrolling children under 10 years old who underwent congenital heart surgery at a tertiary children's hospital from 2012 to 2016. Patients who had patent ductus arteriosus ligation only, genetic syndromes, or global developmental delay were excluded. Outcome measures included 30-day mortality, intensive care unit (ICU) length of stay (LOS), hospital LOS, duration of mechanical ventilation, and number of inotropes used post-operatively. We performed univariate/multivariable logistic regression analysis, adjusting for age, cyanotic cardiac lesion, co-morbidity, and Risk Adjustment for Congenital Heart Surgery (RACHS-1) score. Results: Three hundred two children of median age 16.2 [interquartile range (IQR) 3.1, 51.4)] months were included. The most common cardiac lesions were ventricular septal defect (27.8%), atrial septal defect (17.9%), and Tetralogy of Fallot (16.6%). Median weight-for-age z-score (WAZ) was -1.46 (IQR -2.29, -0.61), height-for-age z-score (HAZ) was -0.94 (IQR -2.10, -0.10), and body mass index (BMI)-for-age z-score (BAZ) was -1.11 (IQR -2.19, -0.30). In multivariable analysis, there was an increased risk of 30-day mortality for WAZ ≤-2 vs. WAZ >-2 [adjusted odds ratio (aOR): 4.01, 95% CI: 1.22, 13.13; p = 0.022]. For HAZ ≤-2 vs. HAZ > -2, there was increased risk of hospital LOS ≥ 7 days (aOR: 2.08, 95% CI: 1.12, 3.89; p = 0.021), mechanical ventilation ≥48 h (aOR: 2.63, 95% CI: 1.32, 5.24; p = 0.006) and of requiring ≥3 inotropes post-operatively (aOR: 3.00, 95% CI: 1.37, 6.59; p = 0.006). Conclusion: In children undergoing congenital heart surgery, WAZ ≤ -2 is associated with higher 30-day mortality, while HAZ ≤ -2 is associated with longer durations of hospital LOS and mechanical ventilation, and increased risk of use of 3 or more inotropes post-operatively. Future studies are necessary to develop safe and efficacious peri-operative nutritional interventions, particularly in patients with WAZ and HAZ ≤ -2., (Copyright © 2019 Lim, Lim, Moorakonda, Ong, Mok, Allen, Wong, Tan and Lee.)

Aim: To compare ultrasound-detected inflammation with clinical manifestations at the wrist in rheumatoid arthritis (RA)., Method: Wrists assessed serially by assessors blinded to ultrasound findings were categorized into 4 groups: 1 = S0T0 (not swollen; not tender); 2 = S0T1 (not swollen; tender); 3 = S1T0 (swollen; not tender); 4 = S1T1 (swollen; tender). Ultrasound synovitis and tenosynovitis were graded semi-quantitatively (0-3) and dichotomously (0 or 1), respectively. The (a) power Doppler (PD), gray-scale (GS) and combined (PD + GS) ultrasound (CUS) scores and (b) their positivity (score > 0) were analyzed using a general linear repeated measures mixed model (a) assuming Gaussian errors and (b) with binary distribution and logit link, respectively. Pairwise comparisons among wrist groups were performed within context of the models., Results: In 122 wrist assessments (baseline = 64; 3 months = 58) from 32 treated RA patients (87.5% female; mean disease duration 42.8 months), significant differences among groups for (a) scores were: 4 vs 1 (PD, P = 0.0031; GS, P = 0.0159; CUS, P = 0.0045), 4 vs 2 (PD, P = 0.0176; GS, P = 0.0160; CUS, P = 0.0074), and 4 vs 3 (CUS, P = 0.0374); and (b) positivity were: 4 vs 1 (PD, P = 0.0007), 4 vs 2 (PD, P = 0.0234), and 3 vs 1 (PD, P = 0.0202). No significant differences in results were found for groups 2 vs 1. No significant effects were attributable to differences in wrist side or follow-up visit., Conclusion: Ultrasound detected substantial inflammation when wrist joint swelling and tenderness are both present. Joint swelling without tenderness is associated with significantly more frequent PD detection. Without swelling, joint tenderness is not associated with a significantly greater degree of ultrasound-detected inflammation., (© 2018 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Background: Mild cognitive impairment (MCI) is a phase in cognitive decline when it is still possible to intervene to reverse the decline. Cognitive stimulation delivered through psychosocial interventions provides both psychological intervention and social stimulation to improve cognition. A pilot open-label parallel-arms randomized controlled trial was undertaken to examine the effects of art therapy (AT) and music reminiscence activity (MRA) compared to the control, on the primary outcome of neurocognitive domain assessments in elderly people with MCI., Methods: Community-living elderly people with MCI (Petersen's criteria), assessed for study eligibility, were randomized using a web-based system with equal allocation to two intervention arms: AT (guided viewing of art pieces and production of visual arts) and MRA (listening, and recalling memories related to music) and a control arm (standard care without any intervention). Interventions were led by trained therapists weekly for 3 months, then fortnightly for 6 months. Neurocognitive domains (mean of memory, attention, and visuo-spatial abilities standardized scores), psychological wellbeing (subsyndromal depression and anxiety) and telomere length as a biological marker of cellular ageing, were assessed by intervention-blinded assessors at baseline, 3 months and 9 months., Results: In total, 250 people were screened and 68 were randomized and included in the analysis. In the AT arm, neurocognitive domains improved compared to the control arm at 3 months (mean difference (d) = 0.40; 90% CI 0.126, 0.679) and were sustained at 9 months (d = 0.31; 90% CI 0.068, 0.548). There was some improvement in depression and anxiety at 3 and 9 months and in telomere length at 9 months, but this was not significant. Similar improvements were observed in the MRA arm over the control arm, but they were not significant. There were no intervention-related adverse effects., Conclusions: Art therapy delivered by trained staff as "art as therapy" and "art psychotherapy" may have been the significant contributor to cognitive improvements. The findings support cognitive stimulation for elderly people with cognitive decline and signal the need for larger studies and further investigation of carefully designed psycho-social interventions for this group., Trial Registration: Clinical Trials.gov, NCT02854085 . Registered on 7 July 2016.

Background: Germline mutations in the BRCA 1 and BRCA 2 genes have significant clinical implications for both risk-reducing and early surveillance management. The third and most recent revision of the Manchester scoring system (MSS3) used to distinguish patients indicated for germline BRCA1/2 testing included further adjustments for triple negative breast cancer, high-grade serous ovarian cancer and human epidermal growth factor 2 (HER2) receptor status. This study aims to evaluate the relative effectiveness of MSS3 in a Southeast Asian population., Methods: All patients in our centre were tested using next-generation sequencing (NGS) panels that included full gene sequencing as well as coverage for large deletions/duplications in BRCA1/2 . We calculated MSS1-3 scores for index patients between 2014 and 2017 who had undergone BRCA1/2 genetic testing and recorded their genetic test results. MSS1-3 outcomes were compared using receiver operating characteristic analysis, while associations with predictors were investigated using Fisher's exact test and logistics regression. Calculations were performed using Medcalc17., Results: Of the 330 included patients, 47 (14.2%) were found to have a germline mutation in BRCA1 or BRCA2 . A positive HER2 receptor was associated with a lower likelihood of a BRCA1/2 mutation (OR=0.125, 95% CI 0.016 to 0.955; P=0.007), while high-grade serous ovarian cancer was conversely associated with an increased likelihood of a BRCA1/2 mutation (OR=5.128, 95% CI 1.431 to 18.370; P=0.012). At the 10% threshold, 43.0% (142/330) of patients were indicated for testing under MSS3, compared with 35.8% (118/330) for MSS1% and 36.4% (120/330) for MSS2. At the 10% threshold, MSS3 sensitivity was 91.5% and specificity 65.0%, significantly better than the previous MSS1 (P = 0.037) and MSS2 (P = 0.032) models., Conclusion: Our results indicate that the updated MSS3 outperforms previous iterations and relative to the Manchester population, is just as effective in identifying patients with BRCA1/2 mutations in a Southeast Asian population., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Since oxygen saturation from pulse oximetry (SpO 2 ) and partial pressure of arterial oxygen (PaO 2 ) are observed to improve immediately after surgical correction of cyanotic congenital heart disease (CHD), we postulate that cerebral (CrO 2 ) and somatic (SrO 2 ) oximetry also improves immediately post-correction. We aim to prospectively examine CrO 2 and SrO 2 , before, during, and after surgical correction as well as on hospital discharge in children with cyanotic CHD to determine if and when these variables increase., Methods: This is a prospective observational trial. Eligibility criteria included children below 18 years of age with cyanotic CHD who required any cardiac surgical procedure. CrO 2 and SrO 2 measurements were summarized at six time-points for comparison: (1) pre-cardiopulmonary bypass (CPB); (2) during CPB; (3) post-CPB; (4) Day 1 in the pediatric intensive care unit (PICU); (5) Day 2 PICU; and (6) discharge. Categorical and continuous variables are presented as counts (percentages) and median (interquartile range), respectively., Results: Twenty-one patients were analyzed. 15 (71.4%) and 6 (28.6%) patients underwent corrective and palliative surgeries, respectively. In the corrective surgery group, SpO 2 increased immediately post-CPB compared to pre-CPB [99 (98, 100) vs. 86% (79, 90); p  < 0.001] and remained in the normal range through to hospital discharge. Post-CPB CrO 2 did not change from pre-CPB [72.8 (58.8, 79.0) vs. 72.1% (63.0, 78.3); p  = 0.761] and even decreased on hospital discharge [60.5 (53.6, 62.9) vs. 72.1% (63.0, 78.3); p  = 0.005]. Post-CPB SrO 2 increased compared to pre-CPB [87.3 (77.2, 89.5) vs. 72.7% (65.6, 77.3); p  = 0.001] but progressively decreased during PICU stay to a value lower than baseline at hospital discharge [66.9 (57.3, 76.9) vs. 72.7% (65.6, 77.3); p  = 0.048]., Conclusion: CrO 2 and SrO 2 did not increase after corrective surgery of cyanotic CHD even up to hospital discharge. Future larger studies are required to validate these findings. (This study is registered with ClinicalTrials.gov ID: NCT02417259.).