Search

Tafenoquine, co-administered with chloroquine, is approved for the radical cure (prevention of relapse) of Plasmodium vivax malaria. In areas of chloroquine resistance, artemisinin-based combination therapies are used to treat malaria. This study aimed to evaluate tafenoquine plus the artemisinin-based combination therapy dihydroartemisinin–piperaquine for the radical cure of P vivax malaria. In this double-blind, double-dummy, parallel group study, glucose-6-phosphate dehydrogenase-normal Indonesian soldiers with microscopically confirmed P vivax malaria were randomly assigned by means of a computer-generated randomisation schedule (1:1:1) to dihydroartemisinin–piperaquine alone, dihydroartemisinin–piperaquine plus a masked single 300-mg dose of tafenoquine, or dihydroartemisinin–piperaquine plus 14 days of primaquine (15 mg). The primary endpoint was 6-month relapse-free efficacy following tafenoquine plus dihydroartemisinin–piperaquine versus dihydroartemisinin-piperaquine alone in all randomly assigned patients who received at least one dose of masked treatment and had microscopically confirmed P vivax at baseline (microbiological intention-to-treat population). Safety was a secondary outcome and the safety population comprised all patients who received at least one dose of masked medication. This study is registered with ClinicalTrials.gov , NCT02802501 and is completed. Between April 8, 2018, and Feb 4, 2019, of 164 patients screened for eligibility, 150 were randomly assigned (50 per treatment group). 6-month Kaplan-Meier relapse-free efficacy (microbiological intention to treat) was 11% (95% CI 4–22) in patients treated with dihydroartemisinin–piperaquine alone versus 21% (11–34) in patients treated with tafenoquine plus dihydroartemisinin–piperaquine (hazard ratio 0·44; 95% CI [0·29–0·69]) and 52% (37–65) in the primaquine plus dihydroartemisinin-piperaquine group. Adverse events over the first 28 days were reported in 27 (54%) of 50 patients treated with dihydroartemisinin–piperaquine alone, 29 (58%) of 50 patients treated with tafenoquine plus dihydroartemisinin–piperaquine, and 22 (44%) of 50 patients treated with primaquine plus dihydroartemisinin–piperaquine. Serious adverse events were reported in one (2%) of 50, two (4%) of 50, and two (4%) of 50 of patients, respectively. Although tafenoquine plus dihydroartemisinin–piperaquine was statistically superior to dihydroartemisinin–piperaquine alone for the radical cure of P vivax malaria, the benefit was not clinically meaningful. This contrasts with previous studies in which tafenoquine plus chloroquine was clinically superior to chloroquine alone for radical cure of P vivax malaria. ExxonMobil, Bill & Melinda Gates Foundation, Newcrest Mining, UK Government all through Medicines for Malaria Venture; and GSK. For the Indonesian translation of the abstract see Supplementary Materials section. [ABSTRACT FROM AUTHOR]

Background: The World Health Organization recommends that primaquine should be given once weekly for 8-weeks to patients with Plasmodium vivax malaria and glucose-6-phosphate dehydrogenase (G6PD) deficiency, but data on its antirelapse efficacy and safety are limited. Methods: Within the context of a multicentre, randomised clinical trial of two primaquine regimens in P. vivax malaria, patients with G6PD deficiency were excluded and enrolled into a separate 12-month observational study. They were treated with a weekly dose of 0.75 mg/kg primaquine for 8 weeks (PQ8W) plus dihydroartemisinin piperaquine (Indonesia) or chloroquine (Afghanistan, Ethiopia, Vietnam). G6PD status was diagnosed using the fluorescent spot test and confirmed by genotyping for locally prevalent G6PD variants. The risk of P. vivax recurrence following PQ8W and the consequent haematological recovery were characterized in all patients and in patients with genotypically confirmed G6PD variants, and compared with the patients enrolled in the main randomised control trial. Results: Between July 2014 and November 2017, 42 male and 8 female patients were enrolled in Afghanistan (6), Ethiopia (5), Indonesia (19), and Vietnam (20). G6PD deficiency was confirmed by genotyping in 31 patients: Viangchan (14), Mediterranean (4), 357A-G (3), Canton (2), Kaiping (2), and one each for A-, Chatham, Gaohe, Ludhiana, Orissa, and Vanua Lava. Two patients had recurrent P. vivax parasitaemia (days 68 and 207). The overall 12-month cumulative risk of recurrent P. vivax malaria was 5.1% (95% CI: 1.3–18.9) and the incidence rate of recurrence was 46.8 per 1000 person-years (95% CI: 11.7–187.1). The risk of P. vivax recurrence was lower in G6PD deficient patients treated with PQ8W compared to G6PD normal patients in all treatment arms of the randomised controlled trial. Two of the 26 confirmed hemizygous males had a significant fall in haemoglobin (>5g/dl) after the first dose but were able to complete their 8 week regimen. Conclusions: PQ8W was highly effective in preventing P. vivax recurrences. Whilst PQ8W was well tolerated in most patients across a range of different G6PD variants, significant falls in haemoglobin may occur after the first dose and require clinical monitoring. Trial registration: This trial is registered at ClinicalTrials.gov (NCT01814683). Author summary: Fifty patients with P. vivax malaria and glucose-6-phosphate dehydrogenase (G6PD) deficiency were given the WHO-recommended, primaquine regimen of 0.75 mg/kg body weight once per week for 8 weeks. Treatment was highly effective and well tolerated in most patients. Two patients had a significant (>5g/dl) fall in haemoglobin and one was hospitalised for intravenous fluids; both were able to complete the primaquine regimen. [ABSTRACT FROM AUTHOR]

Introduction: Urethral reconstruction due to failure of the previous surgical procedure poses a challenge. Pelvic fracture urethral distraction defect (PFUDD) may be associated with disabling complication such as recurrent stricture, erectile dysfunction, and incontinence. In this article we report our experience using Redo Posterior End to End Anastomose Urethroplasty for a case with recurrent stricture after failures in previous surgical procedures which included a memokath urethral stent insertion. Case report: A 28 year-old man with suprapubic cystostomy, suffered from urinary retention since 4 years after his last surgery. He had a history of an accident 8 years ago with stable pelvic fracture, mild head injury and urinary retention. This patient has already underwent cystostomy and Primary Endoscopic Realignment, End to End anastomose, Buccal Mucosal Graft Urethroplasty, and memokath urethral stent insertion. All of procedures were failed. Th en we perform a Micturition Cystourethrography-Retrograde Urethrography (MCU-RGU) and showed total membranoprostatic stricture with memokath urethral stent. In the antegrade panendoscopic evaluation we found multiple stones inside his memokath urethral stent and Retrograde panendoscopic evaluation showed total posterior urethral obstruction. Lithotripsy and memokath urethral stent removal was done at first stage. He underwent a Redo Posterior End to End Anastomose Urethroplasty and 14 Fr silicon catheter a week later. This patient had spontaneous micturition with uroflowmetry examination showed Qmax 21.4 mL/s after urethral catheter removal with MCU-RGU result was patent urethral caliber. Discussion: A proper anastomotic urethroplasty remains essential in the management of PFUDD, even on previously failed urethral repairs. Buccal Muccosal Graft Urethroplasty and urethral stent has no place for definitive procedure in posterior urethral stricture due to its complication. [ABSTRACT FROM AUTHOR]

Introduction: The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a massive impact on the health sector, especially in patients with pre-existing comorbidities. This study aims to define the predictor factors for worse outcomes in kidney transplant patients infected with SARS-CoV-2 and affected by coronavirus disease 2019 (COVID-19). We have analyzed in these patients their prior medical history, their clinical symptoms, and their laboratory results. Method: We assessed outcomes of kidney transplant patients with confirmed COVID-19 until July 2021 from PubMed, Medline, Science Direct, Cochrane databases, EMBASE, Scopus, and EBSCO. We performed meta-analyses of nine published studies to estimate predictor factors. The analysis was analyzed by the Newcastle-Ottawa Scale (NOS) and then using the Review Manager 5.4 software. Result: Our analysis demonstrated that the most significant risk factors for the worse COVID-19 outcomes for kidney transplant patients included: age of 60 and older [MD 9.31(95% CI, 6.31–12.30), p < 0.0001, I2 = 76%], diabetic nephropathy [OR 2.13 (95% CI, 1.49–3.04), p < 0.0001, I2 = 76%], dyspnea [OR 4.53, (95% CI, 2.22–9.22), p < 0.0001, I2 = 76%], acute kidney injury (AKI) [OR 4.53 (95% CI, 1.10–5.21), p = 0.03, I2 = 58%], and some laboratory markers. Many patients had two or multiple risk factors in combination. Conclusion: Age and several comorbidities were the most significant factors for COVID-19 outcomes for kidney transplant recipients. [ABSTRACT FROM AUTHOR]

Abstract: Glucose-6-phosphate dehydrogenase (G6PD) is a potentially pathogenic inherited enzyme abnormality and, similar to other human red blood cell polymorphisms, is particularly prevalent in historically malaria endemic countries. The spatial extent of Plasmodium vivax malaria overlaps widely with that of G6PD deficiency; unfortunately the only drug licensed for the radical cure and relapse prevention of P. vivax, primaquine, can trigger severe haemolytic anaemia in G6PD deficient individuals. This chapter reviews the past and current data on this unique pharmacogenetic association, which is becoming increasingly important as several nations now consider strategies to eliminate malaria transmission rather than control its clinical burden. G6PD deficiency is a highly variable disorder, in terms of spatial heterogeneity in prevalence and molecular variants, as well as its interactions with P. vivax and primaquine. Consideration of factors including aspects of basic physiology, diagnosis, and clinical triggers of primaquine-induced haemolysis is required to assess the risks and benefits of applying primaquine in various geographic and demographic settings. Given that haemolytically toxic antirelapse drugs will likely be the only therapeutic options for the coming decade, it is clear that we need to understand in depth G6PD deficiency and primaquine-induced haemolysis to determine safe and effective therapeutic strategies to overcome this hurdle and achieve malaria elimination. [Copyright &y& Elsevier]

Anemia affects people worldwide and results in increased morbidity and mortality, particularly in children and reproductive-age women. Anemia is caused by an imbalance between red blood cell (RBC) loss and production (erythropoiesis), which can be caused by not only nutritional factors but also non-nutritional factors, such as inflammation and genetics. Understanding the complex and varied etiology of anemia is crucial for developing effective interventions and monitoring anemia control programs. This review focusses on two interrelated nonnutritional causes of anemia: malaria infection and RBC disorders (thalassemia and G6PD deficiency), as well as tuberculosis. According to the Haldane hypothesis, thalassemia occurs as a protective trait toward malaria infection, whereas G6PDd arises in malaria-endemic regions because of positive selection. Indonesia is a malariaendemic region; thus, the frequency of thalassemia and G6PD deficiency is high, which contributes to a greater risk for non-nutritional anemia. As Indonesia is the second global contributor to the newly diagnosed tuberculosis, and active pulmonary tuberculosis patients are more anemic, tuberculosis is also contributes to the increasing risk of anemia. Therefore, to reduce anemia rates in Indonesia, authorities must consider non-nutritional causes that might influence the local incidence of anemia, and apply co-management of endemic infectious disease such as malaria and tuberculosis, and of genetic disease i.e. thalassemia and G6PDd. [ABSTRACT FROM AUTHOR]

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme disorder in the world. Its main function is to generate NADPH that is required for anti-oxidative pathway in the cells especially in red blood cells (RBC). G6PD deficiency is X-linked and thus subject to random X-chromosome inactivation in women giving them mosaic expression of G6PD activities in their individual cells. This phenomenon makes it difficult for diagnosis with the currently available G6PD qualitative diagnostic tests. With the rolling out of newly marketed anti-malarial drug tafenoquine, which has a long half-life, screening for G6PD deficiency becomes a necessity where those with < 70% G6PD activity cannot receive this drug. Thus, evidence for a quantitative cut-off for G6PD activity is needed to ensure safe drug administration. Methods: RBC models were developed to analyse the effect of oxidant on RBC oxidative markers namely total glutathione (GSH)and malondialdehyde (MDA). G6PD activity was measured using quantitative assay from Trinity Biotech and was correlated with cytofluorometric assay. RBC from two G6PD heterozygous women with different G6PD activities were also analysed for comparison. Results: There was a negative correlation between G6PD activity and CuCl concentration and a strong association between G6PD activities and proportion of G6PD normal RBC in CuCl-treated models and in ex vivo RBC. However, in terms of oxidative stress markers analyses, unlike the hypothesis where the lower G6PD activity, the higher MDA and the lower GSH level, the CuCl RBC model showed that in low G6PD activities (10–30%) cells, the MDA level is lower compared to the rest of the models (p < 0.05). The ex vivo models however were in line with the hypothesis, although the result was not significant (p = 0.5). There was a significant difference between RBC with < 60% and those with > 80% G6PD activities in CuCl RBC model, but not in ex vivo RBC (p = 0.5). Genotyping heterozygous subjects showed G6PDViangchan variant with 2.97 U/gHb (33% activity) and 6.58 U/gHb (74% activity). Conclusions: The GSH analysis has pointed to the 60% G6PD activity cut-off and this data is supportive of the old World Health Organization threshold for intermediate upper limit of 60% G6PD activity. However, there are significant limitations in using MDA assay with CuCl RBC model because the RBC was already stressed due to the copper treatment and thus present a different result when compared to the ex vivo model. [ABSTRACT FROM AUTHOR]

Background: The introduction of novel short course treatment regimens for the radical cure of Plasmodium vivax requires reliable point-of-care diagnosis that can identify glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. While deficient males can be identified using a qualitative diagnostic test, the genetic make-up of females requires a quantitative measurement. SD Biosensor (Republic of Korea) has developed a handheld quantitative G6PD diagnostic (STANDARD G6PD test), that has approximately 90% accuracy in field studies for identifying individuals with intermediate or severe deficiency. The device can only be considered for routine care if precision of the assay is high., Methods and Findings: Commercial lyophilised controls (ACS Analytics, USA) with high, intermediate, and low G6PD activities were assessed 20 times on 10 Biosensor devices and compared to spectrophotometry (Pointe Scientific, USA). Each device was then dispatched to one of 10 different laboratories with a standard set of the controls. Each control was tested 40 times at each laboratory by a single user and compared to spectrophotometry results. When tested at one site, the mean coefficient of variation (CV) was 0.111, 0.172 and 0.260 for high, intermediate, and low controls across all devices respectively; combined G6PD Biosensor readings correlated well with spectrophotometry (rs = 0.859, p<0.001). When tested in different laboratories, correlation was lower (rs = 0.604, p<0.001) and G6PD activity determined by Biosensor for the low and intermediate controls overlapped. The use of lyophilised human blood samples rather than fresh blood may have affected these findings. Biosensor G6PD readings between sites did not differ significantly (p = 0.436), whereas spectrophotometry readings differed markedly between sites (p<0.001)., Conclusions: Repeatability and inter-laboratory reproducibility of the Biosensor were good; though the device did not reliably discriminate between intermediate and low G6PD activities of the lyophilized specimens. Clinical studies are now required to assess the devices performance in practice., Competing Interests: The authors have declared that no competing interests exist.

Background: To reduce the risk of drug-induced haemolysis, all patients should be tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDd) prior to prescribing primaquine (PQ)-based radical cure for the treatment of vivax malaria. This systematic review and individual patient meta-analysis assessed the utility of a qualitative lateral flow assay from Access Bio/CareStart (Somerset, NJ) (CareStart Screening test for G6PD deficiency) for the diagnosis of G6PDd compared to the gold standard spectrophotometry (International Prospective Register of Systematic Reviews [PROSPERO]: CRD42019110994)., Methods and Findings: Articles published on PubMed between 1 January 2011 and 27 September 2019 were screened. Articles reporting performance of the standard CSG from venous or capillary blood samples collected prospectively and considering spectrophotometry as gold standard (using kits from Trinity Biotech PLC, Wicklow, Ireland) were included. Authors of articles fulfilling the inclusion criteria were contacted to contribute anonymized individual data. Minimal data requested were sex of the participant, CSG result, spectrophotometry result in U/gHb, and haemoglobin (Hb) reading. The adjusted male median (AMM) was calculated per site and defined as 100% G6PD activity. G6PDd was defined as an enzyme activity of less than 30%. Pooled estimates for sensitivity and specificity, unconditional negative predictive value (NPV), positive likelihood ratio (LR+), and negative likelihood ratio (LR-) were calculated comparing CSG results to spectrophotometry using a random-effects bivariate model. Of 11 eligible published articles, individual data were available from 8 studies, 6 from Southeast Asia, 1 from Africa, and 1 from the Americas. A total of 5,815 individual participant data (IPD) were available, of which 5,777 results (99.3%) were considered for analysis, including data from 3,095 (53.6%) females. Overall, the CSG had a pooled sensitivity of 0.96 (95% CI 0.90-0.99) and a specificity of 0.95 (95% CI 0.92-0.96). When the prevalence of G6PDd was varied from 5% to 30%, the unconditional NPV was 0.99 (95% CI 0.94-1.00), with an LR+ and an LR- of 18.23 (95% CI 13.04-25.48) and 0.05 (95% CI 0.02-0.12), respectively. Performance was significantly better in males compared to females (p = 0.027) but did not differ significantly between samples collected from capillary or venous blood (p = 0.547). Limitations of the study include the lack of wide geographical representation of the included data and that the CSG results were generated under research conditions, and therefore may not reflect performance in routine settings., Conclusions: The CSG performed well at the 30% threshold. Its high NPV suggests that the test is suitable to guide PQ treatment, and the high LR+ and low LR- render the test suitable to confirm and exclude G6PDd. Further operational studies are needed to confirm the utility of the test in remote endemic settings., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: LvS receives a stipend as a Specialty Consulting Editor for PLOS Medicine and serves on the journal's editorial board. All other authors declare no competing interests.