-
Medicine May 2024β-Thalassemia is the world's number 1 single-gene genetic disorder and is characterized by suppressed or impaired production of β-pearl protein chains. This results in... (Review)
Review
β-Thalassemia is the world's number 1 single-gene genetic disorder and is characterized by suppressed or impaired production of β-pearl protein chains. This results in intramedullary destruction and premature lysis of red blood cells in peripheral blood. Among them, patients with transfusion-dependent β-thalassemia face the problem of long-term transfusion and iron chelation therapy, which leads to clinical complications and great economic stress. As gene editing technology improves, we are seeing the dawn of a cure for the disease, with its reduction of ineffective erythropoiesis and effective prolongation of survival in critically ill patients. Here, we provide an overview of β-thalassemia distribution and pathophysiology. In addition, we focus on gene therapy and gene editing advances. Nucleic acid endonuclease tools currently available for gene editing fall into 3 categories: zinc finger nucleases, transcription activator-like effector nucleases, and regularly interspaced short palindromic repeats (CRISPR-Cas9) nucleases. This paper reviews the exploratory applications and exploration of emerging therapeutic tools based on 3 classes of nucleic acid endonucleases in the treatment of β-thalassemia diseases.
Topics: beta-Thalassemia; Humans; Gene Editing; Genetic Therapy; CRISPR-Cas Systems; Transcription Activator-Like Effector Nucleases; Zinc Finger Nucleases
PubMed: 38701251
DOI: 10.1097/MD.0000000000038036 -
Cureus Apr 2024Sickle cell disease is the most common genetic hemoglobinopathy worldwide, characterized by a single-nucleotide mutation that predisposes to hemoglobin polymerization...
Sickle cell disease is the most common genetic hemoglobinopathy worldwide, characterized by a single-nucleotide mutation that predisposes to hemoglobin polymerization and erythrocyte sickling in hypoxic states. This report describes a 62-year-old male obese patient with a history of sickle cell disease, who presented with worsening nocturnal pain crises without any apparent triggering factor. A thorough evaluation at the outpatient department revealed obstructive sleep apnea. Airway obstruction or decreased respiratory effort during sleep may induce hypoventilation and hypoxia in the context of sleep-disordered breathing, with severe cardiopulmonary complications. Sleep-disordered breathing is considered common in children with sickle cell disease, but the prevalence in adults has not been sufficiently documented. Our patient responded favorably to treatment with continuous positive airway pressure during sleep, showing complete resolution of his symptoms. Timely diagnosis and management are fundamental to improve outcomes and prevent severe complications.
PubMed: 38699085
DOI: 10.7759/cureus.57462 -
Scientific Reports May 2024β-Thalassaemia is one of the most common genetic diseases worldwide. During the past few decades, life expectancy of patients has increased significantly owing to...
β-Thalassaemia is one of the most common genetic diseases worldwide. During the past few decades, life expectancy of patients has increased significantly owing to advance in medical treatments. Cognitive impairment, once has been neglected, has gradually become more documented. Cognitive impairment in β-thalassaemia patients is associated with natural history of the disease and socioeconomic factors. Herein, to determined effect of β-thalassaemia intrinsic factors, 22-month-old β-thalassaemia mouse was used as a model to assess cognitive impairment and to investigate any aberrant brain pathology in β-thalassaemia. Open field test showed that β-thalassaemia mice had decreased motor function. However, no difference of neuronal degeneration in primary motor cortex, layer 2/3 area was found. Interestingly, impaired learning and memory function accessed by a Morris water maze test was observed and correlated with a reduced number of living pyramidal neurons in hippocampus at the CA3 region in β-thalassaemia mice. Cognitive impairment in β-thalassaemia mice was significantly correlated with several intrinsic β-thalassaemic factors including iron overload, anaemia, damaged red blood cells (RBCs), phosphatidylserine (PS)-exposed RBC large extracellular vesicles (EVs) and PS-exposed medium EVs. This highlights the importance of blood transfusion and iron chelation in β-thalassaemia patients. In addition, to improve patients' quality of life, assessment of cognitive functions should become part of routine follow-up.
Topics: Animals; beta-Thalassemia; Cognitive Dysfunction; Mice; Hippocampus; Disease Models, Animal; Male; Neurons; Iron Overload; Extracellular Vesicles; Erythrocytes; Pyramidal Cells; Maze Learning
PubMed: 38698053
DOI: 10.1038/s41598-024-60459-y -
Scientific Reports Apr 2024Hemoglobin (Hb) Lepore is a rare deletional δβ-thalassemia caused by the fusion between delta-beta genes, and cannot be identified by traditional thaltassemia gene...
Hemoglobin (Hb) Lepore is a rare deletional δβ-thalassemia caused by the fusion between delta-beta genes, and cannot be identified by traditional thaltassemia gene testing technology. The aim of this study was to conduct molecular diagnosis and clinical analysis of Hb Lepore in four unrelated Chinese families using third generation sequencing. Decreased levels of mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and an abnormal Hb band were observed in the probands of the four families. However, no common α and β-thalassemia variants were detected in the enrolled families using polymerase chain reaction-reverse dot blot hybridization based traditional thalassemia gene testing. Further third-generation sequencing revealed similar Hb Lepore-Boston-Washington variants in all the patients, which were resulted from partial coverage of the HBB and HBD globin genes, leading to the formation of a delta-beta fusion gene. Specific gap-PCR and Sanger sequencing confirmed that all the patients carried a similar Hb Lepore-Boston-Washington heterozygote. In addition, decreased levels of MCH and Hb A2 were observed in the proband's wife of family 2, an extremely rare variant of Hb Nanchang (GGT > AGT) (HBA2:c.46G > A) was identified by third-generation sequencing and further confirmed by Sanger sequencing. This present study was the first to report the similar Hb Lepore-Boston-Washington in Chinese population. By combining the utilization of Hb capillary electrophoresis and third-generation sequencing, the screening and diagnosis of Hb Lepore can be effectively enhanced.
Topics: Humans; Hemoglobins, Abnormal; Female; Male; Asian People; Adult; Pedigree; High-Throughput Nucleotide Sequencing; China; beta-Globins; beta-Thalassemia; East Asian People
PubMed: 38693200
DOI: 10.1038/s41598-024-60604-7 -
BMJ Open May 2024Non-communicable diseases (NCDs) constitute approximately 74% of global mortality, with 77% of these deaths occurring in low-income and middle-income countries. Tanzania...
Cost analysis for initiating an integrated package of essential non-communicable disease interventions (PEN-Plus) in Kondoa District Hospital, Tanzania: a time-driven activity-based costing (TDABC) study protocol.
INTRODUCTION
Non-communicable diseases (NCDs) constitute approximately 74% of global mortality, with 77% of these deaths occurring in low-income and middle-income countries. Tanzania exemplifies this situation, as the percentage of total disability-adjusted life years attributed to NCDs has doubled over the past 30 years, from 18% to 36%. To mitigate the escalating burden of severe NCDs, the Tanzanian government, in collaboration with local and international partners, seeks to extend the integrated package of essential interventions for severe NCDs (PEN-Plus) to district-level facilities, thereby improving accessibility. This study aims to estimate the cost of initiating PEN-Plus for rheumatic heart disease, sickle cell disease and type 1 diabetes at Kondoa district hospital in Tanzania.
METHODS AND ANALYSIS
We will employ time-driven activity-based costing (TDABC) to quantify the capacity cost rates (CCR), and capital and recurrent costs associated with the implementation of PEN-Plus. Data on resource consumption will be collected through direct observations and interviews with nurses, the medical officer in charge and the heads of laboratory and pharmacy units/departments. Data on contact times for targeted NCDs will be collected by observing a sample of patients as they move through the care delivery pathway. Data cleaning and analysis will be done using Microsoft Excel.
ETHICS AND DISSEMINATION
Ethical approval to conduct the study has been waived by the Norwegian Regional Ethics Committee and was granted by the Tanzanian National Health Research Ethics Committee NIMR/HQ/R.8a/Vol.IX/4475. A written informed consent will be provided to the study participants. This protocol has been disseminated in the Bergen Centre for Ethics and Priority Setting International Symposium, Norway and the 11th Muhimbili University of Health and Allied Sciences Scientific Conference, Tanzania in 2023. The findings will be published in peer-reviewed journals for use by the academic community, researchers and health practitioners.
Topics: Humans; Tanzania; Noncommunicable Diseases; Hospitals, District; Costs and Cost Analysis; Anemia, Sickle Cell; Research Design
PubMed: 38692717
DOI: 10.1136/bmjopen-2023-080510 -
In Vivo (Athens, Greece) 2024Cardiovascular pathologies are ubiquitous in sickle cell disease (SCD). A targeted literature review was conducted to compare the overall epidemiology of selected...
BACKGROUND/AIM
Cardiovascular pathologies are ubiquitous in sickle cell disease (SCD). A targeted literature review was conducted to compare the overall epidemiology of selected vasculopathies seen in SCD (SCDVs) compared to the general population. Since many SCDV may originate in childhood, the study also focused on the retrospective investigation of SCDVs in a pediatric cohort at the Harbor-UCLA Medical Center.
PATIENTS AND METHODS
SCDVs were studied along patient age, β-globin genotypes, and fetal hemoglobin (HbF). Urine microalbumin/creatinine ratios (UM/Cr), trans-cranial doppler (TCD) and tricuspid regurgitant jet velocities (TRJV) were analyzed as well. Retinographies and overt vasculopathies were presented descriptively.
RESULTS
Among 20 females and 20 males [average 8.3 years (2.3-19 years)], 70% had HbSS/Sβ0, 22.5% HbSC and 7.5%-HbSβ+. The mean(±SD) HbF% was 17.4±12.7% (30% higher in <10 vs. ≥10 y/o, and 3 times higher in SS/Sβ0). Twenty-six patients received hydroxyurea and 13/26, L-glutamine. Thirty-six patients had TCDs within 1.4±0.9 years and all laboratory values were obtained within the last 12 months. TCDs showed low-normal velocities, but 2 were higher for HbSS/Sβ0 vs. HbSC/Sβ+ (MCA-96 vs. 86 cm/s, p=0.03; and PCA-50 vs. 41, p<0.001). Nineteen of 28 patients with echocardiograms had measurable TRJV (2.46±0.19 m/s); 9 had TRJV ≥2.5-2.8 m/s, but BNP ≤80 pg/ml. SS/Sβ0 was associated with higher UM/Cr. There were 2 cases with silent infarcts, 1-Moyamoya, 2-persistent macroalbuminuria, and 1-hematuria/renal papillary necrosis. Most ≥9 y/o patients had retinographies without SCD-related changes. There was no correlation among TCD (MCA), TRJV, and UM/Cr (n=17); thus, in this subpopulation, pathologies of cerebral, cardiopulmonary, and renal vasculatures evolved independently. Patients with higher TRJV and/or overt vasculopathy (n=14) were older than ones without (12.5±4.7 vs. 6.1±3.1 y/o, p<0.001), and had lower HbF (11.4±7.6 vs. 20.6±13.8%, p=0.026).
CONCLUSION
While overt SCDVs are less frequent in children, age-dependent trends/surrogate markers suggest their early origination in youth, justifying intense screening to prevent their progression with disease-modifying measures.
Topics: Humans; Anemia, Sickle Cell; Female; Male; Child; Adolescent; Child, Preschool; Young Adult; Vascular Diseases; Retrospective Studies
PubMed: 38688623
DOI: 10.21873/invivo.13556 -
Malaria Journal Apr 2024Introduction: Malaria continues to be the leading cause of hospitalization and death in Angola, a country in sub- Saharan Africa. In 2023, in the first quarter,... (Observational Study)
Observational Study
INTRODUCTION
Introduction: Malaria continues to be the leading cause of hospitalization and death in Angola, a country in sub- Saharan Africa. In 2023, in the first quarter, 2,744,682 cases were registered, and of these 2,673 patients died due to malaria disease. Previous studies have shown that the ABO blood group can affect the progression of malaria to severe conditions after P. falciparum infection, while the sickle cell gene offers relative protection.
OBJECTIVE
We investigated changes in the blood count according to blood groups (ABO/Rh) and sickle cell trait in patients with malaria in Luanda, capital of Angola.
METHODOLOGY
This was a longitudinal, prospective and observational study with 198 patients hospitalized for malaria.
RESULTS
Of the 198 patients studied, 13(6.6%) were ABRh(+), 4(2.0%) were ARh(-), 49(24.7%) were ARh(+), 42(21, 2%) were BRh (+), 5(2.5%) were ORh(-) and 85(42.9%) were ORh(+). For sickle cell trait, 145(73.2%) were AA, 37(18.7%) were AS and 16(8.1%) were SS. No statistical relationship was observed between age group, sex, parasitemia, clinical picture, hematocrit, MCV, HCM, MCHC, leukocytes, NEUT, LINF and PTL values with blood groups (p<0.05), but there was a relationship between values of hemoglobin and ABO/Rh blood groups (p>0.05). There was no relationship between age, parasitemia, clinical condition, MCV, HCM and MCHC values, leukocytes, NEUT and LINF with sickle cell trait (p<0.05), but there was a relationship between sex, hemoglobin and PTL and sickle cell values. sickle cell trait (p>0.05).
CONCLUSION
It is imperative to differentiate patients with malaria based on blood groups and sickle cell trait, taking into account mainly the blood count parameters that demonstrate that there are patients who, depending on blood group or sickle cell trait, may react weakly to malaria infection regardless of the degree of parasitemia and medical prognosis.
Topics: Humans; Sickle Cell Trait; Male; Female; Prospective Studies; Adult; Child; Adolescent; Child, Preschool; Young Adult; Longitudinal Studies; Angola; Middle Aged; ABO Blood-Group System; Blood Cell Count; Malaria, Falciparum; Rh-Hr Blood-Group System; Infant; Aged
PubMed: 38685081
DOI: 10.1186/s12936-024-04886-2 -
PharmacoEconomics Jun 2024Gene therapies for sickle cell disease (SCD) may offer meaningful benefits for patients and society. This study evaluated the cost-effectiveness of lovotibeglogene...
BACKGROUND AND OBJECTIVE
Gene therapies for sickle cell disease (SCD) may offer meaningful benefits for patients and society. This study evaluated the cost-effectiveness of lovotibeglogene autotemcel (lovo-cel), a one-time gene therapy administered via autologous hematopoietic stem cell transplantation, compared with common care for patients in the United States (US) with SCD aged ≥ 12 years with ≥ 4 vaso-occlusive events (VOEs) in the past 24 months.
METHODS
We developed a patient-level simulation model accounting for lovo-cel and SCD-related events, complications, and mortality over a lifetime time horizon. The pivotal phase 1/2 HGB-206 clinical trial (NCT02140554) served as the basis for lovo-cel efficacy and safety. Cost, quality-of-life, and other clinical data were sourced from HGB-206 data and the literature. Analyses were conducted from US societal and third-party payer perspectives. Uncertainty was assessed through probabilistic sensitivity analysis and extensive scenario analyses.
RESULTS
Patients treated with lovo-cel were predicted to survive 23.84 years longer on average (standard deviation [SD], 12.80) versus common care (life expectancy, 62.24 versus 38.40 years), with associated discounted patient quality-adjusted life-year (QALY) gains of 10.20 (SD, 4.10) and direct costs avoided of $1,329,201 (SD, $1,346,446) per patient. Predicted societal benefits included discounted caregiver QALY losses avoided of 1.19 (SD, 1.38) and indirect costs avoided of $540,416 (SD, $262,353) per patient. Including lovo-cel costs ($3,282,009 [SD, $29,690] per patient) resulted in incremental cost-effectiveness ratios of $191,519 and $124,051 per QALY gained from third-party payer and societal perspectives, respectively. In scenario analyses, the predicted cost-effectiveness of lovo-cel also was sensitive to baseline age and VOE frequency and to the proportion of patients achieving and maintaining complete resolution of VOEs.
CONCLUSIONS
Our analysis of lovo-cel gene therapy compared with common care for patients in the US with SCD with recurrent VOEs estimated meaningful improvements in survival, quality of life, and other clinical outcomes accompanied by increased overall costs for the health care system and for broader society. The predicted economic value of lovo-cel gene therapy was influenced by uncertainty in long-term clinical effects and by positive spillover effects on patient productivity and caregiver burden.
Topics: Humans; Anemia, Sickle Cell; Cost-Benefit Analysis; Genetic Therapy; United States; Quality-Adjusted Life Years; Adult; Female; Male; Adolescent; Hematopoietic Stem Cell Transplantation; Child; Quality of Life; Young Adult; Models, Economic; Middle Aged; Recurrence
PubMed: 38684631
DOI: 10.1007/s40273-024-01385-9 -
Iranian Journal of Microbiology Feb 2024This study aimed to compare the production of antibodies in three different groups of patients with COVID-19. These groups included patients with pulmonary and cerebral...
BACKGROUND AND OBJECTIVES
This study aimed to compare the production of antibodies in three different groups of patients with COVID-19. These groups included patients with pulmonary and cerebral symptoms, as well as those with mild symptoms.
MATERIALS AND METHODS
Blood samples were collected from 80 patients admitted to COVID-19-specific hospitals. The patients had various forms of SARS-CoV-2 disease, including those with pulmonary symptoms, brain involvement, and those with positive PCR test results but mild symptoms. The enzyme-linked immunosorbent assay (ELISA) technique was used to determine the levels of IgM and IgG antibody titers.
RESULTS
The levels of IgM and IgG antibody production differed significantly between groups of patients experiencing pulmonary symptoms and cerebral symptoms, with mild symptom patients also showing differences (P=0.0068), (P=0.0487), (P<0.0001), and (P=0.0120), respectively. Furthermore, there was no significant relationship between IgM antibody secretion and age or pulmonary involvement (P=0.1959). However, there was a direct and significant relationship between age and brain involvement (P=0.0317).
CONCLUSION
The findings of this study revealed that the risk of central nervous system involvement increases with age and that older people have lower antibody levels than younger people. Consequently, strengthening the immune systems of people over the age of 78 during this pandemic through vaccination and nutrition is very effective in reducing mortality in this age group.
PubMed: 38682065
DOI: 10.18502/ijm.v16i1.14881 -
Cell Transplantation 2024While exagamglogene autotemcel (Casgevy) and lovotibeglogene autotemcel (Lyfgenia) have been approved by the US Food and Drug Administration (FDA) as the first... (Review)
Review
While exagamglogene autotemcel (Casgevy) and lovotibeglogene autotemcel (Lyfgenia) have been approved by the US Food and Drug Administration (FDA) as the first cell-based gene therapies for the treatment of patients 12 years of age and older with sickle cell disease (SCD), this treatment is not universally accessible. Allogeneic hematopoietic stem cell transplant (HSCT) has the potential to eradicate the symptoms of patients with SCD, but a significant obstacle in HSCT for SCD is the availability of suitable donors, particularly human leukocyte antigen (HLA)-matched related donors. Furthermore, individuals with SCD face an elevated risk of complications during stem cell transplantation due to SCD-related tissue damage, endothelial activation, and inflammation. Therefore, it is imperative to consider optimal conditioning regimens and investigate HSCT from alternative donors. This review encompasses information on the use of HSCT in patients with SCD, including the indications for HSCT, conditioning regimens, alternative donors, and posttransplant outcomes.
Topics: Humans; Anemia, Sickle Cell; Hematopoietic Stem Cell Transplantation; Transplantation Conditioning
PubMed: 38680015
DOI: 10.1177/09636897241246351