Serum microRNAs as new biomarkers for detecting subclinical hemolysis in the nonacute phase of G6PD deficiency.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is one of the most common enzymopathies worldwide. Patients with G6PD deficiency are usually asymptomatic throughout their life but can develop acute hemolysis after exposure to free radicals or certain medications. Several studies have shown that serum miRNAs can be used as prognostic biomarkers in various types of hemolytic anemias. However, the impact of G6PD deficiency on circulating miRNA profiles is largely unknown. The present study aimed to assess the use of serum miRNAs as biomarkers for detecting hemolysis in the nonacute phase of G6PD deficiency. Patients with severe or moderate G6PD Viangchan (871G > A) deficiency and normal G6PD patients were enrolled in the present study. The biochemical hemolysis indices were normal in the three groups, while the levels of serum miR-451a, miR-16, and miR-155 were significantly increased in patients with severe G6PD deficiency. In addition, 3D analysis of a set of three miRNAs (miR-451a, miR-16, and miR-155) was able to differentiate G6PD-deficient individuals from healthy individuals, suggesting that these three miRNAs may serve as potential biomarkers for patients in the nonhemolytic phase of G6PD deficiency. In conclusion, miRNAs can be utilized as additional biomarkers to detect hemolysis in the nonacute phase of G6PD deficiency.

Delineation of the role of G6PD in Alzheimer's disease and potential enhancement through microfluidic and nanoparticle approaches.

Alzheimer's disease (AD) is a neurodegenerative pathologic entity characterized by the abnormal presence of tau and macromolecular Aß deposition that leads to the degeneration or death of neurons. In addition to that, glucose-6-phosphate dehydrogenase (G6PD) has a multifaceted role in the process of AD development, where it can be used as both a marker and a target. G6PD activity is dysregulated due to its contribution to oxidative stress, neuroinflammation, and neuronal death. In this context, the current review presents a vivid depiction of recent findings on the relationship between AD progression and changes in the expression or activity of G6PD. The efficacy of the proposed G6PD-based therapeutics has been demonstrated in multiple studies using AD mouse models as representative animal model systems for cognitive decline and neurodegeneration associated with this disease. Innovative therapeutic insights are made for the boosting of G6PD activity via novel innovative nanotechnology and microfluidics tools in drug administration technology. Such approaches provide innovative methods of surpassing the blood-brain barrier, targeting step-by-step specific neural pathways, and overcoming biochemical disturbances that accompany AD. Using different nanoparticles loaded with G6DP to target specific organs, e.g., G6DP-loaded liposomes, enhances BBB penetration and brain distribution of G6DP. Many nanoparticles, which are used for different purposes, are briefly discussed in the paper. Such methods to mimic BBB on organs on-chip offer precise disease modeling and drug testing using microfluidic chips, requiring lower sample amounts and producing faster findings compared to conventional techniques. There are other contributions to microfluid in AD that are discussed briefly. However, there are some limitations accompanying microfluidics that need to be worked on to be used for AD. This study aims to bridge the gap in understanding AD with the synergistic use of promising technologies; microfluid and nanotechnology for future advancements.

Screening, genotyping and haematological analysis of glucose-6-phosphate dehydrogenase deficiency in the blood donors of Wuxi City, China.

BACKGROUND AND OBJECTIVES: To investigate the prevalence, genotype and haematological characteristics of glucose-6-phosphate dehydrogenase (G6PD) deficiency in the blood donor population of Wuxi area (Jiangsu Province, China) and to assess the impact of their red blood cell (RBC) units on clinical transfusion. MATERIALS AND METHODS: We conducted genotyping and large-scale screening for G6PD enzyme activity in the blood donors of Wuxi City. In addition, we assessed the haematological parameters of G6PD-deficient and non-deficient blood donors, and investigated the adverse transfusion reactions in patients transfused with G6PD-deficient blood. RESULTS: We investigated 17,113 blood donors, among whom 44 (0.26%) were tested positive for G6PD deficiency. We identified 40 G6PD gene variants, among which c.1388G>A, c.1376G>T, c.1024C>T and c.95A>G were common. In addition, we identified two novel G6PD gene variants, c.1312G>A and c.1316G>A. The G6PD-deficient and non-deficient blood samples showed a significant difference in the RBC, mean corpuscular volume (MCV), mean corpuscular Hb (MCH), RBC distribution width, total bilirubin (TBIL), direct bilirubin (DBIL) and indirect bilirubin (IBIL) values. However, the two samples showed no significant difference in the haemolysis rate at the end of the storage period. Finally, transfusion with G6PD-deficient RBC units did not lead to any adverse transfusion reactions. CONCLUSION: The positive rate of G6PD deficiency in the blood donor population of Wuxi City is 0.26%, and the genetic variants identified in this population are consistent with the common genetic variants observed in the Chinese population. Blood centres can establish a database on G6PD-deficient blood donors and mark their RBC units to avoid their use for special clinical patients.

Exploring the Possible Link Between Diabetic Ketoacidosis, Glucose-6-Phosphate Dehydrogenase Deficiency, and Methemoglobinemia.

One of the most widespread enzymopathies affecting human beings is glucose-6-phosphate dehydrogenase (G6PD) deficiency, which is brought on by inherited mutations in the X-linked gene. Red blood cells (RBCs) with a G6PD deficiency are more sensitive to oxidative assault and consequently to hemolysis. There are more than 200 known G6PD mutations, of which around half are polymorphic and thus prevalent in a variety of populations. We present a case of diabetic ketoacidosis (DKA), with severe hemolytic anemia and methemoglobinemia. The patient was admitted to the intensive care unit, treated for DKA, and received a blood transfusion. In addition, the patient presented with high methemoglobin levels and features of severe hemolytic anemia from the onset, which made the diagnostic consideration of G6PD highly likely. Accordingly, the patient was treated with several doses of ascorbic acid instead of methylene blue. In a nutshell, a patient with DKA who has hemolytic anemia has to have it properly evaluated and controlled. The link between methemoglobinemia, G6PD deficiency, and DKA should be recognized by medical professionals, particularly when oxygen saturation gaps are found.

Competitive oxidation of key pentose phosphate pathway enzymes modulates the fate of intermediates and NAPDH production.

The oxidative phase of the pentose phosphate pathway (PPP) involving the enzymes glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconolactonase (6PGL), and 6-phosphogluconate dehydrogenase (6PGDH), is critical to NADPH generation within cells, with these enzymes catalyzing the conversion of glucose-6-phosphate (G6P) into ribulose-5-phosphate (Ribu5-P). We have previously studied peroxyl radical (ROO•) mediated oxidative inactivation of E. coli G6PDH, 6PGL, and 6PGDH. However, these data were obtained from experiments where each enzyme was independently exposed to ROO•, a condition not reflecting biological reality. In this work we investigated how NADPH production is modulated when these enzymes are jointly exposed to ROO•. Enzyme mixtures (1:1:1 ratio) were exposed to ROO• produced from thermolysis of 100 mM 2,2'-azobis(2-methylpropionamidine) dihydrochloride (AAPH). NADPH was quantified at 340 nm, and protein oxidation analyzed by liquid chromatography with mass spectrometric detection (LC-MS). The data obtained were rationalized using a mathematical model. The mixture of non-oxidized enzymes, G6P and NADP+ generated ∼175 µM NADPH. Computational simulations showed a constant decrease of G6P associated with NADPH formation, consistent with experimental data. When the enzyme mixture was exposed to AAPH (3 h, 37 °C), lower levels of NADPH were detected (∼100 µM) which also fitted with computational simulations. LC-MS analyses indicated modifications at Tyr, Trp, and Met residues but at lower concentrations than detected for the isolated enzymes. Quantification of NADPH generation showed that the pathway activity was not altered during the initial stages of the oxidations, consistent with a buffering role of G6PDH towards inactivation of the oxidative phase of the pathway.

The global role of G6PD in infection and immunity.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathy in humans. G6PD is an essential enzyme in the pentose phosphate pathway (PPP), generating NADPH needed for cellular biosynthesis and reactive oxygen species (ROS) homeostasis, the latter especially key in red blood cells (RBCs). Beyond the RBC, there is emerging evidence that G6PD exerts an immunologic role by virtue of its functions in leukocyte oxidative metabolism and anabolic synthesis necessary for immune effector function. We review these here, and consider the global immunometabolic role of G6PD activity and G6PD deficiency in modulating inflammation and immunopathology.

Exploring Appropriate Reference Intervals and Clinical Decision Limits for Glucose-6-Phosphate Dehydrogenase Activity in Individuals From Guangzhou, China.

Background: Quantitative detection of glucose-6-phosphate dehydrogenase (G6PD) is commonly done to screen for G6PD deficiency. However, current reference intervals (RIs) of G6PD are unsuitable for evaluating G6PD-activity levels with local populations or associating G6PD variants with hemolysis risk to aid clinical decision-making. We explored appropriate RIs and clinical decision limits (CDLs) for G6PD activity in individuals from Guangzhou, China. Methods: We enrolled 5,852 unrelated individuals between 2020 and 2022 and screened their samples in quantitative assays for G6PD activity. We conducted further investigations, including G6PD genotyping, thalassemia genotyping, follow-up analysis, and statistical analysis, for different groups. Results: In Guangzhou, the RIs for the G6PD activities were 11.20-20.04 U/g Hb in male and 12.29-23.16 U/g Hb in female. The adjusted male median and normal male median (NMM) values were 15.47 U/g Hb and 15.51 U/g Hb, respectively. A threshold of 45% of the NMM could be used as a CDL to estimate the probability of G6PD variants. Our results revealed high hemolysis-risk CDLs (male: <10% of the NMM, female: <30% of the NMM), medium hemolysis-risk CDLs (male: 10%-45% of the NMM, female: 30%-79% of the NMM), and low hemolysis-risk CDLs (male: ≥ 45% of the NMM, female: ≥ 79% of the NMM). Conclusions: Collectively, our findings contribute to a more accurate evaluation of G6PD-activity levels within the local population and provide valuable insights for clinical decision-making. Specifically, identifying threshold values for G6PD variants and hemolysis risk enables improved prediction and management of G6PD deficiency, ultimately enhancing patient care and treatment outcomes.

Glucose-6-phosphate dehydrogenase enzyme deficiency as a diagnostic factor of diabetes mellitus: An original study.

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is one of the most common genetic disorders affecting approximately 400 million people worldwide. Several recent studies have reported a relationship between G6PD deficiency and the incidence of diabetes. Objectives: The aim of the present study was to evaluate and compare levels of G6PD deficiency in diabetes mellitus patients. Materials and Methods: G6PD activity and fasting glucose levels were measured in blood samples of 49 diabetic patients and 21 healthy controls. Results: G6PD activity was decreased in patients with diabetes mellitus as compared to healthy controls and showed that overall G6PD deficiency was significantly associated with diabetes mellitus as compared to nondiabetics. Conclusion: The study concluded that G6PD deficiency is noted in diabetics than in nondiabetics and can be a biomarker of oxidative stress and poor glycemic control in diabetes mellitus.

Functional Analysis of G6PD Variants Associated With Low G6PD Activity in the All of Us Research Program.

Glucose-6-phosphate dehydrogenase (G6PD) protects red blood cells against oxidative damage through regeneration of NADPH. Individuals with G6PD polymorphisms (variants) that produce an impaired G6PD enzyme are usually asymptomatic, but at risk of hemolytic anemia from oxidative stressors, including certain drugs and foods. Prevention of G6PD deficiency-related hemolytic anemia is achievable through G6PD genetic testing or whole-genome sequencing (WGS) to identify affected individuals who should avoid hemolytic triggers. However, accurately predicting the clinical consequence of G6PD variants is limited by over 800 G6PD variants which remain of uncertain significance. There also remains significant variability in which deficiency-causing variants are included in pharmacogenomic testing arrays across institutions: many panels only include c.202G>A, even though dozens of other variants can also cause G6PD deficiency. Here, we seek to improve G6PD genotype interpretation using data available in the All of Us Research Program and using a yeast functional assay. We confirm that G6PD coding variants are the main contributor to decreased G6PD activity, and that 13% of individuals in the All of Us data with deficiency-causing variants would be missed if only the c.202G>A variant were tested for. We expand clinical interpretation for G6PD variants of uncertain significance; reporting that c.595A>G, known as G6PD Dagua or G6PD Açores, and the newly identified variant c.430C>G, reduce activity sufficiently to lead to G6PD deficiency. We also provide evidence that five missense variants of uncertain significance are unlikely to lead to G6PD deficiency, since they were seen in hemi- or homozygous individuals without a reduction in G6PD activity. We also applied the new WHO guidelines and were able to classify two synonymous variants as WHO class C. We anticipate these results will improve the accuracy, and prompt increased use, of G6PD genetic tests through a more complete clinical interpretation of G6PD variants. As the All of Us data increases from 245,000 to 1 million participants, and additional functional assays are carried out, we expect this research to serve as a template to enable complete characterization of G6PD deficiency genotypes. With an increased number of interpreted variants, genetic testing of G6PD will be more informative for preemptively identifying individuals at risk for drug- or food-induced hemolytic anemia.

To Explore Potential Inhibitors Against Various Enzymatic Targets of Human African Trypanosomiasis.

Synthetic drugs currently prescribed for the treatment of Human African Trypanosomiasis (HAT) are non-specific, toxic, demand extended therapeutic regimes and are of varying efficacy. Along with the challenging demographic and socio-economic hurdles, the everincreasing risk of drug resistance is another major problem to be addressed. Cysteine protease, Heat shock proteins (HSP-90), Trypanothione reductase (TR), Farnesyl diphosphate synthase, Glucose-6-phosphate dehydrogenase, UP-4-galactose epimerase, and Cytidine triphosphate synthetase are potential enzymatic targets for the development of novel inhibitors against HAT which are the main focus of this review. The potential enzymatic targets of Trypanosoma brucei, especially small molecules like cysteine proteases and heat shock proteins are identified as major candidates for the sustenance of the parasite, their proliferation, infection, and spread of the disease. The development of new compounds to combat the disease by thorough ligand modification has been explored in the current review. Extracting these compounds and studying their efficacy, toxicity, and target mechanism extensively, this review has proposed a list of different compounds, including some synthetic and natural compounds along with multi-target inhibitors such as acoziborole, fexinidazole, etc. Potential inhibitors against these enzymatic targets of the T. brucei are important candidates for designing novel therapeutics against HAT. Multi-target inhibitors have also been identified as crucial molecules because of their potential advantage against the development of drug resistance.

Determinants, profile and outcomes of hepatitis A virus-associated severe acute liver injury in adults.

BACKGROUND AND OBJECTIVES: Hepatitis A virus (HAV)-related hepatitis is witnessing an epidemiological transition with increasing trends in adults. While uncomplicated hepatitis remains common, evidence suggests it to be a growing cause for acute liver failure (ALF). In between the two extremes exists severe acute liver injury (s-ALI) which has a propensity to transition to ALF. We aimed at describing the clinical profile of patients with HAV-related s-ALI and identifying potential predictors of progression to ALF. METHODS: This was a single-center retrospective analysis of adult patients admitted with HAV-related s-ALI between April 2022 and December 2023. Demographic and laboratory parameters were compared between patients with only s-ALI and those with ALF. Predictors of progression from s-ALI to ALF were identified using logistic regression. RESULTS: Forty-three patients satisfied criteria of s-ALI, of which 33 (76.7%) had only s-ALI, while 10 (23.3%) had ALF. Patients with s-ALI had lesser leukocytosis (6.3 ± 3 vs. 13.2 ± 4.8), less incidence of acute kidney injury (9.1% vs. 40%) and lower model for end-stage liver disease (MELD) (20 [18-24.5] vs. 31.5 [26-42]), arterial lactate (2.1 [1.3-3.1] vs. 6.3 [5.2-8.0]), arterial ammonia (94 [72-118] vs. 299 [188-573]), procalcitonin (0.5 [0.28-1.25] vs. 3.2 [1.2-6.1]) and ferritin (482 [213-1633] vs. 5186 [1341-11,053]) compared to HAV-ALF (p < 0.05 for all). Three patients (9.09%) with s-ALI progressed to ALF of whom one (3%) died. Baseline ammonia levels (unadjusted odds ratio [OR] 1.03 [1.01-1.06]) and leukocyte count (OR 1.00 [1.00-1.01]) tended to be associated with ALF progression, although none was significant after multi-variable adjustment. Ammonia levels had an area under receiver operating curve of 0.816 (0.64-0.93) (p = 0.009) (cut-off of 144 µmol/L). Additional comorbidities did not impact overall outcomes. CONCLUSION: HAV presents as s-ALI in young adults, with almost one in 10 progressing to ALF. Baseline ammonia may be an important predictor of progression even in s-ALI, but mandates larger well-designed studies.

Some pyrroles as inhibitors of the pentose phosphate pathways enzymes: An in vitro and molecular docking study.

Glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) are pentose phosphate pathway enzymes. Compounds with a heterocyclic pyrrole ring system containing this atom can be derivatized with various functional groups into highly effective bioactive agents. In this study, pyrrole derivatives on these enzyme's activity were investigated. The IC50 values of different concentrations of pyrrole derivatives for G6PD were found in the range of 0.022-0.221 mM Ki values 0.021 ± 0.003-0.177 ± 0.021 and for 6PGD IC50 values 0.020-0.147, mM Ki values 0.013 ± 0.002-0.113 ± 0.030 mM. The 2-acetyl-1-methylpyrrole (1g) showed the best inhibition value for G6PD and 6PGD enzymes. In addition, in silico molecular docking experiments were performed to elucidate how these pyrrole derivatives (1a-g) interact with the binding sites of the target enzymes. The study's findings on pyrrole derivatives could be used to create innovative therapeutics that could be a treatment for many diseases, especially cancer manifestations.

Talaromycosis from Wuhan: two-case report and literature review.

Background: Talaromycosis is a serious opportunistic infectious disease caused by Talaromyces marneffei, which mostly occurs in immunocompromised patients. The disease is mainly prevalent in tropical countries and regions of Southeast Asia and South Asia, but non-endemic areas also have patients with Talaromycosis. The disease has no characteristic clinical manifestations and is difficult to diagnose. Delayed diagnosis often leads to death. Case presentation: Both patients had cellular immunodeficiency. Case 1 had a history of acquired immune deficiency syndrome, and case 2 had a history of renal transplantation and glucose-6-phosphate dehydrogenase deficiency. They all had fever, anemia, fatigue, and skin lesions. Case 1 had gastrointestinal bleeding, enlarged lymph nodes, and hepatosplenomegaly. Case 2 had cough and dyspnea. Both patients had thrombocytopenia and hypoalbuminemia; an increased neutrophil ratio, procalcitonin, and C-reactive protein; and abnormal liver function and coagulation dysfunction. Case 1 sputum culture, blood culture, and bronchoalveolar lavage fluid were positive for T. marneffei. T. marneffei was detected in the blood culture of case 2, with infection of Candida parapsilosis and Pneumocystis jirovecii. Chest computed tomography scan mainly showed pulmonary exudative lesions. Although these two patients were actively treated, they died of poor efficacy. Conclusion: Talaromycosis has an insidious onset, long course, atypical clinical symptoms, imaging performance and laboratory results, difficult diagnosis, and high mortality. Therefore, it is important to promptly consider and treat Talaromycosis in immunocompromised patients upon infection in order to reduce mortality.

Human papillomavirus-16 E6 activates the pentose phosphate pathway to promote cervical cancer cell proliferation by inhibiting G6PD lactylation.

High-risk human papillomaviruses (HPVs) are the causative agents of cervical cancer. Here, we report that HPV16 E6E7 promotes cervical cancer cell proliferation by activating the pentose phosphate pathway (PPP). We found that HPV16 E6 activates the PPP primarily by increasing glucose-6-phosphate dehydrogenase (G6PD) enzyme activity. Mechanistically, HPV16 E6 promoted G6PD dimer formation by inhibiting its lactylation. Importantly, we suggest that G6PD K45 was lactylated during G6PD-mediated antioxidant stress. In primary human keratinocytes and an HPV-negative cervical cancer C33A cells line ectopically expressing HPV16 E6, the transduction of G6PD K45A (unable to be lactylated) increased GSH and NADPH levels and, correspondingly, decreasing ROS levels. Conversely, the re-expression of G6PD K45T (mimicking constitutive lactylation) in HPV16-positive SiHa cells line inhibited cell proliferation. In vivo, the inhibition of G6PD enzyme activity with 6-aminonicotinamide (6-An) or the re-expression of G6PD K45T inhibited tumor proliferation. In conclusion, we have revealed a novel mechanism of HPV oncoprotein-mediated malignant transformation. These findings might provide effective strategies for treating cervical and HPV-associated cancers.

Molecular biology of glucose-6-phosphate dehydrogenase and UDP-glucuronosyltransferase 1A1 in the development of neonatal unconjugated hyperbilirubinemia.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency and variants of the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene are the most common genetic causes of neonatal unconjugated hyperbilirubinemia (NUH). In this review, we searched PubMed for articles on the genetic causes of NUH published before December 31, 2022, and analyzed the data. On the basis of the results, we reached eight conclusions: (1) 37 mutations of the G6PD gene are associated with NUH; (2) the clinical manifestation of G6PD deficiency depends not only on ethnicity but also on the molecular mechanisms underlying the deficiency (and thus its severity); (3) of mutations in the UGT1A1 gene, homozygous c.-53A(TA)6TAA > A(TA)7TAA is the main cause of NUH in Caucasians and Africans, whereas homozygous c.211G > A is the main genetic cause of NUH in East Asians; (4) in Indonesian neonates, homozygous c.-3279T > G is the most common cause of NUH development, and neither c.-53 A(TA)6TAA > A(TA)7TAA nor c.211G > A causes it; (5) in breast-fed East Asian neonates, the TA7 repeat variant of the UGT1A1 gene protects against the development of NUH; (6) G6PD deficiency combined with homozygous c.211G > A variation of the UGT1A1 gene increases the risk of severe NUH; (7) in Pakistani and Caucasian patients with Crigler-Najjar syndrome type 2 (CN-2), point mutations of the UGT1A1 gene are widely distributed and frequently occur with variation at nucleotide -53, whereas in Asian patients with CN-2, compound homozygous variations in the coding region are frequently observed; and (8) records of G6PD deficiency and UGT1A1 variation status for a neonate offer useful pharmacogenomic information that can aid long-term care. These results indicate that timely diagnosis of NUH through molecular tests is crucial and that early initiation of treatment for the neonates and educational programs for their parents improves outcomes.

Kinetic properties of glucose 6-phosphate dehydrogenase and inhibition effects of several metal ions on enzymatic activity in vitro and cells.

Due to the non-degradable and persistent nature of metal ions in the environment, they are released into water bodies, where they accumulate in fish. In order to assess pollution in fish, the enzyme, glucose 6-phosphate dehydrogenase (G6PD), has been employed as a biomarker due to sensitivity to various ions. This study investigates the kinetic properties of the G6PD enzyme in yellow catfish (Pelteobagrus fulvidraco), and analyzes the effects of these metal ions on the G6PD enzyme activity in the ovarian cell line (CCO) of channel catfish (Ictalurus punctatus). IC50 values and inhibition types of G6PD were determined in the metal ions Cu2+, Al3+, Zn2+, and Cd2+. While, the inhibition types of Cu2+ and Al3+ were the competitive inhibition, Zn2+ and Cd2+ were the linear mixed noncompetitive and linear mixed competitive, respectively. In vitro experiments revealed an inverse correlation between G6PD activity and metal ion concentration, mRNA levels and enzyme activity of G6PD increased at the lower metal ion concentration and decreased at the higher concentration. Our findings suggest that metal ions pose a significant threat to G6PD activity even at low concentrations, potentially playing a crucial role in the toxicity mechanism of metal ion pollution. This information contributes to the development of a biomonitoring tool for assessing metal ion contamination in aquatic species.

Primaquine in glucose-6-phosphate dehydrogenase deficiency: an adaptive pharmacometric assessment of ascending dose regimens in healthy volunteers.

Background: Primaquine is an 8-aminoquinoline antimalarial. It is the only widely available treatment to prevent relapses of Plasmodium vivax malaria. The 8-aminoquinolines cause dose-dependent haemolysis in glucose-6-phosphate dehydrogenase deficiency (G6PDd). G6PDd is common in malaria endemic areas but testing is often not available. As a consequence primaquine is underused. Methods: We conducted an adaptive pharmacometric study to characterise the relationship between primaquine dose and haemolysis in G6PDd. The aim was to explore shorter and safer primaquine radical cure regimens compared to the currently recommended 8-weekly regimen (0.75 mg/kg once weekly), potentially obviating the need for G6PD testing. Hemizygous G6PDd healthy adult Thai and Burmese male volunteers were admitted to the Hospital for Tropical Diseases in Bangkok. In Part 1, volunteers were given ascending dose primaquine regimens whereby daily doses were increased from 7.5 mg up to 45 mg over 15-20 days. In Part 2 conducted at least 6 months later, a single primaquine 45 mg dose was given. Results: 24 volunteers were enrolled in Part 1, and 16 in Part 2 (13 participated in both studies). In three volunteers, the ascending dose regimen was stopped because of haemolysis (n=1) and asymptomatic increases in transaminases (n=2; one was hepatitis E positive). Otherwise the ascending regimens were well tolerated with no drug-related serious adverse events. In Part 1, the median haemoglobin concentration decline was 3.7 g/dL (range: 2.1-5.9; relative decline of 26% [range: 15-40%]). Primaquine doses up to 0.87 mg/kg/day were tolerated subsequently without clinically significant further falls in haemoglobin. In Part 2, the median haemoglobin concentration decline was 1.7 g/dL (range 0.9-4.1; relative fall of 12% [range: 7-30% decrease]). The ascending dose primaquine regimens gave seven times more drug but resulted in only double the haemoglobin decline. Conclusions: In patients with Southeast Asian G6PDd variants, full radical cure treatment can be given in under 3 weeks compared with the current 8-week regimen. Funding: Medical Research Council of the United Kingdom (MR/R015252/1) and Wellcome (093956/Z/10/C, 223253/Z/21/Z). Clinical trial number: Thai Clinical Trial Registry: TCTR20170830002 and TCTR20220317004.

Prevalence of glucose-6-phosphate dehydrogenase (G6PD) deficiency in Gia Lai Province, Vietnam.

Glucose-6-phosphate dehydrogenase (G6PD; EC 1.1.1.49) deficiency is one of the most common X-linked hereditary disorders worldwide. G6PD deficiency provides resistance against severe malaria, but paradoxically, G6PD deficiency is also a stumbling block in fighting against malaria. Primaquine (PQ), a drug for the radical cure of Plasmodium vivax, can cause lethal acute hemolytic anemia in malaria patients with inherited G6PD deficiency. In this study, we analyzed the phenotypic and genotypic G6PD deficiency status in 1721 individuals (963 males and 758 females) residing in three malaria-endemic areas within the Gia Lai province, Vietnam. The G6PD activity in individuals ranged from 3.04 to 47.82 U/g Hb, with the adjusted male median (AMM) of 7.89 U/g Hb. Based on the G6PD activity assay results, no phenotypic G6PD deficiency was detected. However, the multiplex polymerase chain reaction to detect G6PD variations in the gene level revealed that 26 individuals (7 males, 19 females) had Viangchan mutations (871 G > A). Sequencing analyses suggested that all the males were hemizygous Viangchan, whereas one was homozygous, and 18 were heterozygous Viangchan in females. These results suggested a relatively low prevalence of G6PD deficiency mutation rate (1.51%) in the minor ethnic populations residing in the Gia Lai province, Vietnam. However, considering these areas are high-risk malaria endemic, concern for proper and safe use of PQ as a radical cure of malaria is needed by combining a G6PD deficiency test before PQ prescription.

Anaesthetic Management of Distal Penile Hypospadias in a G6PD-Deficient Adolescent: Subarachnoid Block as a Safe Alternative.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common X-linked recessive red blood cell disease in humans. The highest prevalence of G6PD deficiency is reported to be in Africa, Southern Europe, the Middle East, Southeast Asia, and the islands of the Central and South Pacific. G6PD deficiency causes acute hemolysis upon exposure to oxidative stress. Various stress factors that can cause hemolysis include infections, fever, sepsis, various foods such as fava beans, and various medications. In this report, we describe the case of a 13-year-old child who was diagnosed with G6PD deficiency in childhood but did not experience typical complications, such as hemolysis or jaundice. This child underwent Mathieu's flip-flap surgery for the treatment of distal penile hypospadias under spinal anesthesia and underwent the procedure uneventfully, with no hemolytic complications, malignant hyperthermia, or methemoglobinemia. Therefore, the main goals of our anesthesia management are to avoid various agents that cause hemolysis, use agents with antioxidant properties, reduce the stress of surgery through appropriate pain management, and monitor for signs of hemolysis. Therefore, in our case, subarachnoid blockade was found to be a safe and effective anesthetic technique compared with general anesthesia in the treatment of children with G6PD deficiency. Dexmedetomidine has antioxidant properties, maintains upper respiratory tract patency, and has sedative effect. Therefore, in our case, it was administered intravenously for perioperative management.