Treatment Strategy for Rifampin-Susceptible Tuberculosis.

BACKGROUND: Tuberculosis is usually treated with a 6-month rifampin-based regimen. Whether a strategy involving shorter initial treatment may lead to similar outcomes is unclear. METHODS: In this adaptive, open-label, noninferiority trial, we randomly assigned participants with rifampin-susceptible pulmonary tuberculosis to undergo either standard treatment (rifampin and isoniazid for 24 weeks with pyrazinamide and ethambutol for the first 8 weeks) or a strategy involving initial treatment with an 8-week regimen, extended treatment for persistent clinical disease, monitoring after treatment, and retreatment for relapse. There were four strategy groups with different initial regimens; noninferiority was assessed in the two strategy groups with complete enrollment, which had initial regimens of high-dose rifampin-linezolid and bedaquiline-linezolid (each with isoniazid, pyrazinamide, and ethambutol). The primary outcome was a composite of death, ongoing treatment, or active disease at week 96. The noninferiority margin was 12 percentage points. RESULTS: Of the 674 participants in the intention-to-treat population, 4 (0.6%) withdrew consent or were lost to follow-up. A primary-outcome event occurred in 7 of the 181 participants (3.9%) in the standard-treatment group, as compared with 21 of the 184 participants (11.4%) in the strategy group with an initial rifampin-linezolid regimen (adjusted difference, 7.4 percentage points; 97.5% confidence interval [CI], 1.7 to 13.2; noninferiority not met) and 11 of the 189 participants (5.8%) in the strategy group with an initial bedaquiline-linezolid regimen (adjusted difference, 0.8 percentage points; 97.5% CI, -3.4 to 5.1; noninferiority met). The mean total duration of treatment was 180 days in the standard-treatment group, 106 days in the rifampin-linezolid strategy group, and 85 days in the bedaquiline-linezolid strategy group. The incidences of grade 3 or 4 adverse events and serious adverse events were similar in the three groups. CONCLUSIONS: A strategy involving initial treatment with an 8-week bedaquiline-linezolid regimen was noninferior to standard treatment for tuberculosis with respect to clinical outcomes. The strategy was associated with a shorter total duration of treatment and with no evident safety concerns. (Funded by the Singapore National Medical Research Council and others; TRUNCATE-TB ClinicalTrials.gov number, NCT03474198.).

A randomized cross-over study of cryopreserved platelets in prophylactic transfusions of thrombocytopenic patients.

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] ×109 /L at 1-4 h, p < .001; 5.3 [4.84] vs. 18.2 [9.52] ×109 /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.

Association between Baseline NIHSS Limb Motor Score and Functional Recovery after Stroke: Analysis Based on a Multicountry Dataset.

INTRODUCTION: Motor skills are the domains most often affected by stroke, but a comprehensive assessment of motor function is often impractical in the acute setting. It could be useful to have a brief simple tool allowing the stratification of patients at the time of inclusion in clinical studies. Hence, our primary objective was to evaluate whether the baseline NIH Stroke Scale limb motor score (b-NIHSS-LMS), obtained by summing the four motor items 5a to 6b of the NIHSS, is associated with functional recovery assessed by the modified Rankin Score (mRS). A secondary objective was to apply this new tool in the context of a clinical trial. METHODS: The analysed population considered for this research included subjects from a large published, double-blind, multicentre trial, randomised to receive either a combination of various herbal and non-herbal components (MLC601) or placebo, administered within 72 h after an acute ischaemic stroke of intermediate severity (defined by baseline NIH Stroke Scale [b-NIHSS] score of 8-14). Associations between b-NIHSS-LMS and favourable outcome, i.e., mRS 0-1 at month 3, were evaluated using logistic regression adjusted for baseline covariates and study treatment. RESULTS: The analysis included 533 subjects with an acute ischaemic stroke of intermediate severity assessed at month 3. Analyses showed that b-NIHSS-LMS was independently associated with a favourable outcome (OR 0.84; 95% confidence interval 0.76-0.92; p < 0.0003) at 3 months. Furthermore, in the clinical study considered, a selection of patients based upon a sufficient level of motor impairment at study entry (b-NIHSS-LMS ≥3) would result in the detection of a more pronounced and longer-lasting treatment effect. Indeed, ORs of treatment effect versus placebo in the selected subgroup (b-NIHSS-LMS ≥3) were statistically significant from months 3-24. DISCUSSION/CONCLUSIONS: As an independent association between b-NIHSS-LMS and functional recovery after an acute ischaemic stroke of intermediate severity was established in this study, we suggest that the b-NIHSS-LMS can be used as a stratification factor in large clinical trials to define a target population with poststroke motor impairments.

Comparative clinical evaluation of removable partial denture frameworks fabricated traditionally or with selective laser melting: A randomized controlled trial.

STATEMENT OF PROBLEM: The clinical efficacy of selective laser melting (SLM) for fabricating removable partial dentures (RPDs) is not well established. PURPOSE: The purpose of this clinical study was to compare the performance of SLM-fabricated frameworks with that of those fabricated via traditional lost wax casting. MATERIAL AND METHODS: A double-blind, randomized, crossover design was used to compare cobalt-chromium partial denture frameworks (n=29) fabricated by using SLM or traditional methods. The time taken for adjustments and the clinical fit and stability of the adjusted frameworks were appraised. The accuracy of the frameworks was assessed by measuring the space between the occlusal rest seat and the corresponding rest seat. Statistical comparisons between the 2 frameworks were carried out by using a linear mixed-effect model for repeated measurements (α=.05). RESULTS: Frameworks fabricated by using both SLM and traditional techniques had an acceptable fit based on subjective clinical evaluation. The overall mean ±standard deviation space between the occlusal rest and rest seat for SLM frameworks (273.7 ±44.5 µm) was comparable with that of traditional frameworks (242.2 ±44.5 µm). The clinical fit adjustment time, 7.76 ±6.43 minutes for SLM and 5.49 ±6.39 minutes for traditionally fabricated frameworks, was statistically similar (P=.067). CONCLUSIONS: Dentures fabricated via SLM and traditional techniques had comparable accuracy of fit and clinical fitting time.

Real-World Data on the Diagnosis, Treatment, and Management of Hepatocellular Carcinoma in the Asia-Pacific: The INSIGHT Study.

Introduction: Hepatocellular carcinoma (HCC) is the sixth most commonly diagnosed cancer and the third leading cause of cancer death worldwide. While there has been rapid evolution in the treatment paradigm of HCC across the past decade, the extent to which these newly approved therapies are utilized in clinical practice in the real world is, however, unknown. The INSIGHT study was an investigator-initiated, multi-site longitudinal cohort study conducted to reflect real-world epidemiology and clinical practice in Asia-Pacific in the immediate 7-year period after the conclusion of the BRIDGE study. Methods: Data were collected both retrospectively (planned 30% of the total cohort size) and prospectively (planned 70%) from January 2013 to December 2019 from eligible patients newly diagnosed with HCC from 33 participating sites across 9 Asia-Pacific countries. Results: A total of 2,533 newly diagnosed HCC patients (1,052 in retrospective cohort and 1,481 in prospective cohort) were enrolled. The most common risk factor was hepatitis B in all countries except Japan, Australia, and New Zealand, where the prevalence of hepatitis C and diabetes were more common. The top three comorbidities reported in the INSIGHT study include cirrhosis, hypertension, and diabetes. We observe high heterogeneity in the first-line treatment recorded across countries and across disease stages, which significantly affects survival outcomes. Stratification by factors such as etiologies, tumor characteristics, the presence of extrahepatic metastases or macrovascular invasion, and the use of subsequent lines of treatment were performed. Conclusion: The INSIGHT study describes a wide spectrum of clinical management practices in HCC, where patient demographics, differential costs, and patient access to therapies may lead to wide geographical variations through the patient's treatment cycle, from diagnosis to clinical outcome. The high heterogeneity in patient outcomes demonstrates the need for more robust and clinical management strategies to be designed and adopted to bring about better patient outcomes.

Ischemic Stroke and Savings in Time to Achieve Functional Recovery: Experience from NeuroAiD.

Despite recent progress with revascularisation interventions after acute ischemic stroke, many patients remain disabled after stroke. Using data from a multi-centre, randomised, double-blind, placebo-controlled trial of a neuro-repair treatment (NeuroAiD/MLC601) with a long-term follow-up, we analysed the savings in time to functional recovery, measured by a modified Rankin Scale (mRS) score of 0 or 1, in patients receiving a 3-month oral course of MLC601. Analysis of time to recovery was assessed by a log-rank test and hazard ratios (HRs) adjusted for prognosis factors. A total of 548 patients with baseline NIHSS scores 8-14, mRS scores ≥ 2 at day 10 post-stroke, and at least one mRS assessment on or after month 1 were included in the analysis (placebo = 261; MLC601 = 287). Time to functional recovery was significantly shortened for patients receiving MLC601 versus patients receiving placebo (log-rank test: p = 0.039). This result was confirmed by Cox regression adjusting for the main baseline prognostic factors (HR: 1.30 [0.99, 1.70]; p = 0.059) and was more pronounced in patients with additional poor prognosis factors. The Kaplan-Meier plot showed that approximately 40% cumulative incidence of functional recovery was achieved within 6 months after stroke onset in the MLC601 group versus 24 months in the placebo group. The main findings are that MLC601 reduced the time to achieve functional recovery, and a 40% functional recovery rate was achieved 18 months earlier compared to placebo.

Spinal cord injury - assessing tolerability and use of combined rehabilitation and NeuroAiD (SATURN) study - primary results of an exploratory study.

OBJECTIVE: MLC601/MLC901 has demonstrated neuroprotective and neuroregenerative properties that enhance neurological recovery in stroke and traumatic brain injury. We aimed to evaluate its safety and potential efficacy in patients with severe spinal cord injury. METHODS: Patients with American Spinal Injury Association (ASIA) Impairment Scale (AIS) A and B were included in an open-label cohort study. Each received a course of MLC601/MLC901 for 6 months in addition to standard care and rehabilitation. Key endpoints were safety, AIS grade and motor scores at month 6 (M6). RESULTS: Among 30 patients included (mean age 42.2 ± 17.6 years, 24 men), 20 patients had AIS A while 10 patients had AIS B at baseline. Ten patients experienced 14 adverse events including one serious adverse event and six deaths, none were considered treatment-related. AIS improved in 25% of AIS A and 50% of AIS B. Improvement in ASIA motor score was seen most with cervical injury (median change from baseline 26.5, IQR: 6-55). These findings appear to be better than reported rates of spontaneous recovery for SCI AIS A and B. CONCLUSION: MLC601/MLC901 is safe and may have a role in the treatment of patients with SCI. A controlled trial is justified.

Rosuvastatin adjunctive therapy for rifampicin-susceptible pulmonary tuberculosis: a phase 2b, randomised, open-label, multicentre trial.

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.