The malaria hypothesis proposes that in areas with a high incidence of malaria transmission, there is likely to be a high prevalence of genetic variants that confer protection against the disease. These resistance variants, located at different loci, may be statistically associated, leading to a non-random alteration in allele frequencies and exhibiting fitness levels that are not independent across loci (epistatic interaction). The aim of this study was to investigate whether signatures of epistatic selection exist between the Duffy and G6PD loci and to estimate the adaptive values associated with their genotype combinations in the population of Buenaventura, a malaria-endemic region of the Colombian Pacific. To achieve this, the indices DST[2], DIS[2], D'IS[2], and D'ST[2] were calculated to partition the variance of linkage disequilibrium (LD) between pairs of loci, using the OhtaDstats package in R software. Additionally, fitness values and selection coefficients were estimated for the genotypic combinations of these variants. To our knowledge, this study provides the first evidence of epistatic selection between the Duffy and G6PD loci in a malaria-endemic population from the Colombian Pacific, an interaction not previously reported in the literature using a linkage disequilibrium-based approach. This finding is supported by the calculated indices, as well as by the higher fitness values observed in genotype combinations involving these resistance variants. The observed interaction may reflect complementary protection against different Plasmodium species and the absence of physiological antagonism between the two resistance mechanisms.

This article chronicles the life of James Earl Bostic, known affectionately to his family and friends as "King James." We provide a parental and family perspective on the incredibly challenging journey he faced with his family resulting from unnecessary suffering due to kernicterus, a completely preventable disease. As his mother, I struggled to understand the significant impact of hyperbilirubinemia triggered by glucose-6-phosphate dehydrogenase (G6PD) deficiency, while also raising his sibling and navigating broken systems of care. I became a tireless advocate, pushing his educational team to assume capability and ensure he had access to robust language and literacy skills. I also repeatedly advocated for deep brain stimulation (DBS) to manage his tone, which was only granted after going before an Independent Review Board while he experienced prolonged, life-threatening dystonic crisis. My advocacy proved highly effective. DBS gave him upward and downward eye movement that enabled him to successfully access an eye gaze activated communication device, finally gaining expressive communication. He leveraged that device to validate what those who loved him knew - he had language, emotions, and a very sarcastic sense of humor! King James later addressed medical professionals during the 2019 Kernicterus Symposium at the Pediatric Academic Societies (PAS), describing how hard it was for him without communication and urging everyone to provide a meaningful education to children with special health needs. His story shows the catastrophic impact of bilirubin neurotoxicity while also emphasizing the critical importance of nurturing the whole child, assuming capability, providing equitable access to a high-quality education, and honoring self-direction.

Background: G6PD deficiency is among the leading causes of neonatal hyperbilirubinemia and kernicterus. Following a 2022 New York State Department of Health recommendation to test high-risk neonates, we implemented universal G6PD deficiency screening in the well-baby nursery. Objectives: We aimed to increase the proportion of infants screened from 0% to more than 75% within 6 months and to describe the prevalence of G6PD deficiency and the early outcomes of affected neonates. Methods: This quality improvement (QI) initiative, guided by the Model for Improvement, included a cross-sectional analysis of screening yield and early neonatal outcomes. A statistical process control p-chart tracked monthly screening. Outcomes were compared between screen-positive and screen-negative infants using the Fisher exact test. Results: Screening rose from 0% to a sustained mean of 81.1%, exceeding the 75% aim. Of 580 screened neonates, 52 (9.0%) screened positive for G6PD deficiency. Screen-positive infants were more likely than screen-negative infants to undergo repeat serum bilirubin testing (38.5% vs. 19.3%; p = 0.002) and to reach a peak bilirubin above 10 mg/dL (30.8% vs. 10.2%; p < 0.001). A higher rate of readmission for phototherapy was also observed (5.8% vs. 0.9%; p = 0.028), though based on few events. Phototherapy during the birth hospitalization, IVIG, and exchange transfusion did not differ. Conclusions: Universal G6PD screening was feasibly implemented and sustained in a high-risk well-baby nursery through routine workflow changes, without additional phlebotomy. Nearly 1 in 11 screened neonates tested positive for G6PD deficiency.

Heinz bodies occur in patients experiencing specific drug-induced acute haemolytic crises, most often in those with an inherited deficiency in glucose-6-phosphate dehydrogenase activity. Laboratory methods for quantifying Heinz bodies in in vitro systems include direct microscopic counts from crystal violet-stained thin blood films or spectrophotometric measurement of free crystal violet in RBC suspensions treated for Heinz body induction. Each method is relatively laborious and prone to errors. In this study, we sought to evaluate and validate an improved flow cytometry-based method for detecting Heinz bodies in human red blood cells after in vitro exposure to phenylhydrazine using washed RBCs. We report good concordance between flow cytometric counts of Heinz bodies and microscopic and spectrophotometric analyses of the same suspensions. Flow cytometry offers a less laborious, more precise, and more accurate quantification of Heinz body formation, with strong potential to improve the ease of use in experimental applications.

Genomic sequencing has the potential to transform newborn screening (NBS) for rare diseases but raises significant pragmatic, clinical, psychosocial, ethical, and policy issues. Evidence is urgently needed to guide policy as healthcare systems around the world contemplate implementation. In 2025, four major genomic NBS (gNBS) studies, totaling over 10,800 newborns from the US, Belgium, and Australia, published initial results. The adoption of different approaches to key implementation issues in diverse healthcare systems by these studies allows us to draw comparisons and enable collective learning. All studies reported successful use of dried blood spots for DNA extraction, which supports integration with existing NBS infrastructure. Experience with automation of genomic data analysis and reporting was variable, with valuable insights gained about balancing sensitivity, specificity, scalability, and resource utilization going forward. The screen-positive rate ranged from 1.6% to 3.7%, with G6PD deficiency by far the most common condition identified. Further comparison of results was limited by wide variation in the number and type of conditions included and by inconsistencies in how outcomes were defined and reported, highlighting the need for greater harmonization of study designs and data collection. The ability to deliver gNBS at the scale and pace that would be required for a public screening program remains untested, and data on long-term outcomes and costs are still needed. Concerns also remain about inequitable access and outcomes, particularly for families at socioeconomic, linguistic, and geographical disadvantage, and these key questions need to be addressed next as the field continues to evolve.

Diabetes is a chronic condition characterised by hyperglycaemia due to impaired insulin secretion, insulin action, or both. Oxidative stress reduces insulin sensitivity and contributes to complications. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common enzymatic disorder of erythrocytes, impairs NADPH production and reduces the ability to counter oxidative stress. Given the involvement of redox imbalance in diabetes pathogenesis, the role of G6PD deficiency in diabetes development and progression remains unclear. Two reviewers independently searched PubMed, Cochrane Library, and Embase to August 10th, 2026, for primary studies on G6PD deficiency and diabetes, resolving discrepancies by discussion. Forty-two studies met inclusion criteria. G6PD deficiency was more prevalent in T2DM patients than in the general population. Diagnostic complications, including artificially reduced HbA1c, were identified. Specific G6PD variants were associated with increased risk and severity of diabetes-associated retinopathy. G6PD deficiency was also linked to increased risk of myocardial infarction, stroke, and arterial stiffness. Consistent evidence indicates a higher risk of complications associated with G6PD deficiency and diabetes, though associations with diabetes onset remain inconsistent. Future research should investigate genetic stratification, oxidative stress biomarkers, and strategies to reduce morbidity.

Single-nucleotide polymorphism (SNP) detection plays a critical role in early screening and genotyping of genetic diseases. In this study, hereditary glucose-6-phosphate dehydrogenase (G6PD) deficiency was used as a model to develop a CRISPR/Cas14a-based SNP genotyping platform (CRISPR/Cas14a-SNPT). The platform integrates recombinase polymerase amplification (RPA) signal amplification with optimized sgRNA design. By introducing a shortened optimized sgRNA (op-sgRNA) to enhance Cas14a activity, together with engineered sgRNA mismatch regulation, the system enables rapid, highly sensitive, and high-resolution SNP detection. The results demonstrated a limit of detection of 1 copy/μL for plasmid templates, and reliable discrimination of variant allele frequencies as low as 0.1%. In clinical validation, the method successfully identified three hotspot mutations (c.95A > G, c.1388G > A, and c.1376G > T) in 13 human blood samples, showing excellent agreement with pyrosequencing results. Furthermore, molecular dynamics simulations revealed the regulatory mechanism of Cas14a mismatch recognition at the molecular level, suggesting that additional mismatches induce duplex relaxation and structural compensation effects, thereby enhancing target discrimination specificity. This study provides an efficient and practical strategy for accurate genotyping and prenatal carrier screening of G6PD deficiency-associated SNPs, demonstrating strong potential for rapid detection of clinically relevant SNPs.

Malaria remains a leading cause of infectious morbidity worldwide, yet imported cases present a diagnostic challenge in non-endemic settings. We report a case of imported malaria in a previously healthy 35-year-old man, who presented with increasing fatigue, jaundice, and cyclical fevers following travel to an endemic area. Peripheral blood smear demonstrated Plasmodium falciparum trophozoites, prompting initiation of antimalarial therapy. Further testing detected previously undiagnosed glucose-6-phosphate dehydrogenase (G6PD) deficiency. The patient improved clinically and was discharged after five days of hospitalization. This case illustrates two important considerations in the management of imported malaria. First, Visiting Friends and Relatives (VFR) travelers, those who grew up in malaria-endemic areas and now reside in other countries, represent the highest-risk group for imported malaria. Nonetheless, this population is among the least likely to use chemoprophylaxis - a pattern driven by a misconception of residual immunity shared by both patients and clinicians. As a result, this misconception can delay diagnosis: the patient's presumed immunity contributed to an initial misattribution of symptoms to a viral illness, highlighting the need for a low threshold to test for malaria in febrile returning travelers. Second, this case underscores the importance of G6PD testing before initiating antimalarial regimens, as many first-line medications carry the risk of oxidative hemolysis in patients with G6PD deficiency. Recognition of these issues is imperative for safe and effective management of malaria in non-endemic settings.

Takayasu arteritis should be suspected in young females with limb claudication, absent pulses, recurrent arterial stenosis, and elevated inflammatory markers. Early diagnosis is crucial to prevent complications. In G6PD-deficient females, treatment must be modified, as specific immunosuppressants, like cyclophosphamide, can induce hemolysis. Accurate diagnosis ensures effective management.

Afghanistan faces a heavy and largely under‑recognized burden of hematological disorders, shaped by a uniquely complex interplay of high consanguinity, population‑specific genetic variants, widespread nutritional deficiencies, extreme environmental conditions, and decades of armed conflict. The national consanguinity rate (~ 46%) drives some of the world's highest prevalences of autosomal recessive hemoglobinopathies, particularly β‑thalassemia, with 1-1.5 million estimated carriers. β‑thalassemia carrier rates vary sharply by ethnicity, reaching 5-10% in Pashtun and Tajik groups, while the α‑globin novel mutation Hb Balkh has been identified in the central highlands of Aghaninstan. G6PD deficiency, predominantly the Mediterranean type, affects up to 8.9% of Pashtun males and make a barrier to cure malaria with primaquine. Nutritional anemias are equally pervasive: anemia affects 51% of pregnant women in some provinces, 44.2% of children under five have iron deficiency, and 25% of newly arrived Afghan refugees have vitamin B12 deficiency. Conflict aggravates every dimension of the hematologic disease burden trauma‑induced coagulopathy, a largely voluntary blood supply with transfusion‑transmissible infection markers in 4.36% of donations (HBV 2.95%, HCV 0.81%), and the near‑absence of newborn screening, HPLC, or molecular diagnostics. Management relies on splenectomy and irregular transfusions; premarital screening is not mandated. This review synthesizes peer‑reviewed evidence (2000-2026) to provide the first comprehensive narrative of hematological disorders in Afghanistan, critically appraises diagnostic and therapeutic gaps against regional standards, and proposes a pragmatic research and intervention agenda.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common inherited enzymatic disorder that predisposes blood cells to oxidative injury and haemolysis. It is typically diagnosed during childhood and affects males more frequently. We describe a patient presenting with profound acute haemolytic anaemia requiring transfusion following ingestion of fava bean-containing snacks. The patient presented with fatigue, dyspnoea on exertion, jaundice and dark urine. Laboratory evaluation revealed severe anaemia, elevated lactate dehydrogenase, indirect hyperbilirubinaemia and low haptoglobin levels, consistent with haemolysis. Autoimmune and infectious causes were considered unlikely after diagnostic evaluation. Initial and repeat testing confirmed G6PD deficiency. This case highlights the importance of considering G6PD deficiency in patients with unexplained haemolytic anaemia regardless of age, sex or ethnic background and underscores the need for dietary and medication counselling to prevent recurrent haemolytic episodes.

Pyruvate kinase deficiency (PKD) results from pathogenic variants in the PKLR gene and demonstrates marked clinical heterogeneity ranging from compensated hemolysis to severe transfusion-dependent anemia; however, novel variants continue to expand the genotypic spectrum of the disease. We report a case of a 10-month-old girl with transfusion-dependent chronic hemolytic anemia found to harbor a novel homozygous PKLR missense variant c.1376C>G (p.Ala459Gly). This variant has not previously been reported in the literature and was classified as a variant of uncertain significance (VUS) according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria. This report expands the mutational spectrum of PKD and highlights the importance of molecular testing in infants with unexplained chronic hemolytic anemia, especially in populations with high consanguinity rates. Although functional validation of the identified PKLR variant was not available, the patient's clinical and hematologic phenotype was highly consistent with severe PKD, supporting the variant as a candidate disease-associated alteration.