Sickle-cell disease (SCD) is a severe autosomal recessive disorder. At-risk couples may prevent transmission either through prenatal diagnosis with possible termination of pregnancy or preimplantation genetic testing for monogenic disease (PGT-M). Data on PGT-M outcomes in this population remain scarce. We conducted a monocentric retrospective study (2006-2021). To assess ovarian response to stimulation, each PGT-M cycle for SCD was matched with two control cycles. Sixty couples underwent at least one ovarian stimulation for PGT procedure for SCD. Eight couples (13.3%) had one affected partner (S/S or S/C) and one carrier (A/S), while 52 couples (86.7%) were both carriers (A/S). Thirty-five couples (58.3%) already had an affected child, and 17 couples (28.3%) requested PGT-M with HLA typing. Median female age at first attempt was 33 years. Overall, 19 couples (31.7%) achieved at least one live birth following fresh or frozen embryo transfer. Among the 17 couples requesting HLA typing, three HLA-matched births (15.7%) and one unmatched healthy birth were achieved. None of the five women affected by SCD achieved a live birth. Ovarian response did not differ significantly between women with sickle cell trait and the controls. PGT-M is as a viable option for obtaining healthy offspring. These results bolster the argument that PGT-M serves as an alternative to prenatal diagnosis for eligible couples. Our study aims to assist geneticists, gynecologists, and hematologists in providing the necessary guidance before embarking couples on this long and often challenging journey.

Severe malaria is associated with impaired nitric oxide (NO) synthase (NOS)-dependent vasodilation, and reversal of this deficit improves survival in murine models. Malaria might have selected for genetic polymorphisms that increase endothelial NO signaling and now contribute to heterogeneity in vascular function among humans. One protein potentially selected for is alpha globin, which, in mouse models, interacts with endothelial NOS (eNOS) to negatively regulate NO signaling. We sought to evaluate the impact of alpha globin gene deletions on NO signaling and unexpectedly found human arteries use not only alpha but also beta globin to regulate eNOS. The eNOS-hemoglobin complex was characterized by multiphoton imaging, gene expression analysis, and coimmunoprecipitation studies of human resistance arteries. Novel contacts between eNOS and hemoglobin were mapped using molecular modeling and simulation. Pharmacological or genetic disruption of the eNOS-hemoglobin complex was evaluated using pressure myography. The association between alpha globin gene deletion and blood pressure was assessed in a population study. Alpha and beta globin transcripts were detected in the endothelial layer of the artery wall. Imaging colocalized alpha and beta globin proteins with eNOS at myoendothelial junctions. Immunoprecipitation demonstrated that alpha globin and beta globin form a complex with eNOS and cytochrome b5 reductase. Modeling predicted negatively charged glutamic acids at positions 6 and 7 of beta globin to interact with positively charged arginines at positions 97 and 98 of eNOS. Arteries from donors with a glutamic acid-to-valine substitution at beta globin position 6 (sickle trait) exhibited increased NOS-dependent vasodilation. Alpha globin gene deletions were associated with decreased arterial alpha globin expression, increased NOS-dependent vasodilation, and lower blood pressure. Mimetic peptides that targeted the interactions between hemoglobin and eNOS recapitulated the effects of these genetic variants on human arterial vasoreactivity. Alpha and beta globin subunits of hemoglobin interact with eNOS to restrict NO signaling in human resistance arteries. Malaria-protective genetic variants that alter the expression of alpha globin or the structure of beta globin are associated with increased NOS-dependent vasodilation. Targeting the hemoglobin-eNOS interface could potentially improve NO signaling in diseases of endothelial dysfunction such as severe malaria or chronic cardiovascular conditions.

The aspiration to improve health equity is fundamental to scholarly focus and action in public health, and highly relevant to addressing the global burden of pain-the leading contributor to disability worldwide. There is potential for advancement towards health equity to be facilitated by greater access to data that identifies the role of socio-demographic factors in pain and health outcomes. The 'Identifying Social factors that Stratify Health Opportunities and Outcomes (ISSHOOs) in Pain Research' project was a multi-stage process that aimed to reach consensus on the most important equity-relevant items to include in all human adult pain research. Conducted April 2022-May 2025, it incorporated two scoping reviews (published 2023), an international Delphi study (published 2025), consensus meetings and focus groups; prioritising global participation, patient perspectives, and interdisciplinary expertise throughout. Three hundred and four individuals from 45 countries, across six continents, contributed to developing two sets of items. Set A, the 'minimum dataset', is a globally relevant set of eight standardised socio-demographic items (age, sex, gender identity, place, race/ethnicity/cultural identity, education, financial position, work status), accompanied by concise guidance to assist implementation and setting-specific tailoring; Set B is an 'extended dataset' of optional items from which researchers can select items consistent with their study population and research questions. The ISSHOOs recommendations offer a culturally sensitive, cross-culturally relevant, practical and highly useful resource. Routine adoption and clear reporting of the ISSHOOs datasets across all human adult pain research will lead to improved and harmonious descriptions of research participants across health equity domains. Our goal is to promote equity-relevant awareness and understanding, and ultimately drive progress towards reducing avoidable disparities in health for people with pain, with potential for broader application to other fields of health. NHMRC (Australia); MAYDAY Fund; IASP; Canada Research Chair Program; European Horizon 2020 Research and Innovation Programme; ZonMw programs.

Plasma free hemoglobin (PFH) is a direct biomarker for hemolysis that has been associated with clinical complications such as pulmonary hypertension and death in patients with sickle cell disease (SCD). We sought to characterize the relationship between PFH and more clinically available hemolytic markers including lactate dehydrogenase (LDH), aspartate aminotransferase (AST), bilirubin, reticulocyte percentage and to derive a composite hemolysis score derived from principal component analysis (PCA) of these biomarkers. In 68 adult patients (median age 31 years old, IQR 25-39) with HbSS or HbSβ0-thalassemia enrolled in the IMPROVE II study, median PFH was elevated at 21.9 mg/dL (IQR 9.9-44.9 mg/dL) at steady state. Using Pearson correlation analysis, PFH had a stronger relationship to LDH (R = 0.699), AST (R = 0.587), and total bilirubin (R = 0.475), compared to reticulocyte count (R = 0.316). The hemolysis score was significantly associated with PFH (R = 0.677). When compared with other laboratory measures, PFH correlated with hemoglobin (R= -0.275) and HbS (R = 0.277), but did not correlate with white blood cell count (WBC) or HbF. The hemolysis score was significantly associated with WBC (R = 0.307), hemoglobin (R = -0.393), HbF (R=- 0.424), and HbS (R = 0.423). This study confirms that the conventional hemolytic biomarkers LDH, AST, bilirubin, and reticulocyte percentage correlate with PFH. Additionally, the hemolysis score is a valid tool to measure hemolysis and that it may be a marker of global hemolysis as opposed to PFH, which quantifies intravascular hemolysis. Further studies will be needed to elucidate the role of PFH and intravascular hemolysis in the development of clinical complications of sickle cell disease. Statements and Funding Declarations: The research leading to these results received funding from the National Heart, Lung, and Blood Institute (NHLBI) R01 HL142671 Grant under J.G. J.G. has also served as a consultant for CSL Behring, Novartis, and Novo Nordisk synteract DSMB and is supported by NHLBI RO1HL159116, R01 HL142671, R01 ES030717, UG1 HL138645, UH3 HL143192, U01HL167036, and the Doris Duke Charitable Foundation Advancing Cures grant. S.C. has served as a consultant for Pfizer and is supported by the NHLBI 5K23HL151884 grant. A.L. is supported by the NHLBI 5T32HL129974-05. C.J.M is supported by the NHLBI 5T32HL129974-05. P.S., and S.M. declare no conflicts and/or funding. Sickle cell disease (SCD) is characterized by intermittent vaso-occlusive events and chronic hemolytic anemia. Vaso-occlusive events result in tissue ischemia leading to acute and chronic pain as well as organ damage that can affect any organ system, including the bones, spleen, liver, brain, lungs, kidneys, and joints. Dactylitis (pain and/or swelling of the hands or feet) is often the earliest manifestation of SCD. In children, the spleen can become engorged with blood cells in a "splenic sequestration." The spleen is particularly vulnerable to infarction and the majority of individuals with SCD who are not on hydroxyurea or transfusion therapy become functionally asplenic in early childhood, increasing their risk for certain types of bacterial infections, primarily encapsulated organisms. Acute chest syndrome (ACS) is a major cause of mortality in SCD. Chronic hemolysis can result in varying degrees of anemia, jaundice, cholelithiasis, and delayed growth and sexual maturation as well as activating pathways that contribute to the pathophysiology directly. Individuals with the highest rates of hemolysis are at higher risk for pulmonary artery hypertension, priapism, and leg ulcers and may be relatively protected from vaso-occlusive pain. SCD encompasses a group of disorders characterized by the presence of at least one hemoglobin S allele (HbS; p.Glu6Val in HBB) and a second HBB pathogenic variant resulting in abnormal hemoglobin polymerization. Hb S/S (homozygous p.Glu6Val in HBB) accounts for the majority of SCD. Other forms of SCD result from compound heterozygosity for HbS with other specific pathogenic beta globin chain variants (e.g., sickle-hemoglobin C disease [Hb S/C], sickle beta-thalassemia [Hb S/β+-thalassemia and Hb S/β0-thalassemia], Hb S/D, Hb S/OArab, Hb S/E). The diagnosis of SCD is established by identification of significant quantities of HbS with or without an additional abnormal beta globin chain variant by hemoglobin assay or by identification of biallelic HBB pathogenic variants including at least one p.Glu6Val allele (e.g., homozygous p.Glu6Val; p.Glu6Val and a second HBB pathogenic variant) on molecular genetic testing. Newborn screening for SCD began in the United States in 1975 in New York and expanded to include all 50 states by 2006. Newborn screening programs perform isoelectric focusing and/or high-performance liquid chromatography (HPLC) of an eluate of dried blood spots. Some newborn screening programs confirm results with molecular testing. Targeted therapies: Disease-modulating pharmacotherapies (hydroxyurea, L-glutamine, and crizanlizumab); hematopoietic stem cell transplantation; gene therapy. Supportive care: Education of parents, caregivers, and affected individuals on avoidance of potential triggers of vaso-occlusion (dehydration, climate extremes, overexertion, and, when possible, trauma and infection), health maintenance, prophylactic medications, early interventions, warning signs of acute illness, pain management options, and urgent care plan; antibiotic prophylaxis for Streptococcus pneumoniæ; immunizations including those for asplenic individuals; folic acid supplementation; red blood cell (RBC) transfusion therapy and treatment for iron overload. Management of pain episodes includes reversal of inciting triggers, hydration, anti-inflammatory agents, and pain medication. Pain episodes are additionally managed with a multimodal approach (e.g., warmth, massage, distraction, acupuncture, biofeedback, self-hypnosis). RBC transfusion as needed for splenic sequestration; splenectomy may be necessary. Fever and suspected infection are treated with appropriate antibiotics. Life-threatening or severe complications (e.g., severe ACS, stroke, aplastic crisis, chronic kidney failure) are often treated with RBC transfusion or RBC exchange. Treatment of pulmonary hypertension generally includes treating inciting factors and optimizing SCD therapy to stop progression; severe priapism may require aspiration and irrigation. Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers for those with kidney disease with kidney transplant for end-stage kidney disease; mental health therapy and community resources. Surveillance: Periodic comprehensive medical and social evaluation, mental health and neurocognitive assessment, and routine dental care. Annual complete blood count with differential and reticulocyte count; annual transcranial Doppler to determine risk of stroke in all children with Hb S/S and Hb S/β0-thalassemia; annual developmental assessment throughout childhood; neurocognitive assessment prior to school entry and as needed; brain MRI in childhood when examination can be tolerated without anesthesia and repeated as needed; annual assessment of vitamin D level and kidney function (blood urea nitrogen, serum creatinine, urinalysis, and urine microalbumin or urine protein-to-creatinine ratio); ophthalmologic evaluation annually beginning at age ten years. Because of the high frequency and severity of cardiopulmonary complications there should be a particularly low threshold to obtain an echocardiogram, pulmonary function tests, six-minute walk test, N-terminal pro-brain natriuretic peptide (NT-proBNP), and sleep study in individuals of any age with cardiac or pulmonary concerns; EKG in those on medications that may alter corrected QT interval; growth assessments throughout childhood; annual assessment of iron status and liver function; MRI as needed to evaluate for iron overload; assessment of mental health and social needs at least annually. Agents/circumstances to avoid: Dehydration, extremes of temperature, physical exhaustion, extremely high altitude, trauma, infection, recreational drugs with vasoconstrictive or cardiac stimulation effects, and meperidine. Evaluation of relatives at risk: Early diagnosis of at-risk family members allows for genetic counseling as well as education and intervention before symptoms or end-organ damage are present. Pregnancy management: Women with SCD who become pregnant require close follow up and monitoring by a hematologist and obstetrician. Increased risk for preterm labor, thrombosis, preeclampsia, infectious complications, ACS, and acute painful episodes have been reported during pregnancy. Hydroxyurea should be discontinued during pregnancy. SCD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an HBB pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic beta globin chain variants and being affected, a 50% chance of inheriting one beta globin chain variant and being heterozygous, and a 25% chance of inheriting neither of the familial beta globin chain variants. If the SCD-related HBB pathogenic variants in a family are known, molecular genetic testing can be used to identify which at-risk family members are heterozygous; if only one (or neither) SCD-related HBB pathogenic variant in a family is known, HPLC can be used to detect common qualitative abnormalities (i.e., abnormal hemoglobins). Molecular genetic prenatal testing and preimplantation genetic testing for SCD are possible when both HBB pathogenic variants have been identified in an affected family member and the genetic status of the parents is known.

Sickle cell disease (SCD) is an inherited red blood cell disease caused by a mutation in the gene encoding the β-subunit of adult hemoglobin that leads to hemolysis, anemia, vaso-occlusive crises (VOCs), morbidity, and mortality. This study provides a real-world assessment of the clinical burden and health care resource utilization (HCRU) associated with SCD with recurrent VOCs in England. This retrospective study linked primary care records from the Clinical Practice Research Datalink database with secondary care records from the Hospital Episode Statistics database to identify patients with SCD with recurrent VOCs between July 1, 2008, and June 30, 2018. A VOC was defined as SCD with crisis, acute chest syndrome, or priapism. Eligible patients had SCD, ≥2 VOCs/year in any 2 consecutive years after a diagnosis of SCD, and ≥1 year of follow-up data from the index date. Patients were exact matched with 5 controls from the general population in the databases. Demographics were assessed at index. Mortality, clinical complications, and HCRU were summarized during follow-up. After applying eligibility criteria, 1117 patients with SCD with recurrent VOCs and 5585 controls were included in the study. Mean age at index was 25 years in both groups. The proportion of deaths (3.67% vs 0.68%; P < 0.001) and mortality rate (0.78 deaths per 100 person-years vs 0.16 deaths per 100 person-years) were substantially higher in patients with SCD with recurrent VOCs versus matched controls. Mean (standard deviation [SD]) age of death in patients with SCD with recurrent VOCs who died during the follow-up period was 40.17 (14.09) years. The mean (SD) rate of VOCs for patients with SCD with recurrent VOCs was 5.84 (12.50) per patient per year (PPPY) during follow-up. Compared with matched controls, patients with SCD with recurrent VOCs had substantially higher mean [SD] rates PPPY of inpatient hospitalizations (7.59 [14.50] vs 0.32 [2.71]), prescriptions (31.06 [60.62] vs 7.58 [27.77]), and outpatient visits (9.60 [10.69] vs 1.78 [4.18]). Older patients and those with increased numbers of VOCs had increased mortality, frequency of clinical complications, and HCRU. Despite currently available care, patients with SCD with recurrent VOCs in England have increased mortality, substantial clinical complications, and significant HCRU driven by VOCs and hospitalizations. Elevated mortality and clinical complications in patients with SCD with recurrent VOCs highlight the need for novel therapies in this space.