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JAMA Network Open Oct 2023Sickle cell disease (SCD) is a monogenic disorder, yet clinical outcomes are influenced by additional genetic factors. Despite decades of research, the genetics of SCD... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Sickle cell disease (SCD) is a monogenic disorder, yet clinical outcomes are influenced by additional genetic factors. Despite decades of research, the genetics of SCD remain poorly understood.
OBJECTIVE
To assess all reported genetic modifiers of SCD, evaluate the design of associated studies, and provide guidelines for future analyses according to modern genetic study recommendations.
DATA SOURCES
PubMed, Web of Science, and Scopus were searched through May 16, 2023, identifying 5290 publications.
STUDY SELECTION
At least 2 reviewers identified 571 original, peer-reviewed English-language publications reporting genetic modifiers of human SCD phenotypes, wherein the outcome was not treatment response, and the comparison was not between SCD subtypes or including healthy controls.
DATA EXTRACTION AND SYNTHESIS
Data relevant to all genetic modifiers of SCD were extracted, evaluated, and presented following STREGA and PRISMA guidelines. Weighted z score meta-analyses and pathway analyses were conducted.
MAIN OUTCOMES AND MEASURES
Outcomes were aggregated into 25 categories, grouped as acute complications, chronic conditions, hematologic parameters or biomarkers, and general or mixed measures of SCD severity.
RESULTS
The 571 included studies reported on 29 670 unique individuals (50% ≤ 18 years of age) from 43 countries. Of the 17 757 extracted results (4890 significant) in 1552 genes, 3675 results met the study criteria for meta-analysis: reported phenotype and genotype, association size and direction, variability measure, sample size, and statistical test. Only 173 results for 62 associations could be cross-study combined. The remaining associations could not be aggregated because they were only reported once or methods (eg, study design, reporting practice) and genotype or phenotype definitions were insufficiently harmonized. Gene variants regulating fetal hemoglobin and α-thalassemia (important markers for SCD severity) were frequently identified: 19 single-nucleotide variants in BCL11A, HBS1L-MYB, and HBG2 were significantly associated with fetal hemoglobin (absolute value of Z = 4.00 to 20.66; P = 8.63 × 10-95 to 6.19 × 10-5), and α-thalassemia deletions were significantly associated with increased hemoglobin level and reduced risk of albuminuria, abnormal transcranial Doppler velocity, and stroke (absolute value of Z = 3.43 to 5.16; P = 2.42 × 10-7 to 6.00 × 10-4). However, other associations remain unconfirmed. Pathway analyses of significant genes highlighted the importance of cellular adhesion, inflammation, oxidative and toxic stress, and blood vessel regulation in SCD (23 of the top 25 Gene Ontology pathways involve these processes) and suggested future research areas.
CONCLUSIONS AND RELEVANCE
The findings of this comprehensive systematic review and meta-analysis of all published genetic modifiers of SCD indicated that implementation of standardized phenotypes, statistical methods, and reporting practices should accelerate discovery and validation of genetic modifiers and development of clinically actionable genetic profiles.
Topics: Humans; Fetal Hemoglobin; alpha-Thalassemia; Anemia, Sickle Cell; Genotype; Genetic Variation
PubMed: 37851445
DOI: 10.1001/jamanetworkopen.2023.37484 -
American Journal of Obstetrics &... Sep 2023This study aimed to review the diagnostic criteria for mirror syndrome and describe its clinical presentation. (Review)
Review
OBJECTIVE
This study aimed to review the diagnostic criteria for mirror syndrome and describe its clinical presentation.
DATA SOURCES
Databases from PubMed, Scopus, Cochrane Library, ClinicalTrials.gov, and CINAHL were inquired for case series containing ≥2 cases of mirror syndrome from inception to February 2022.
STUDY ELIGIBILITY CRITERIA
Studies were included if they reported ≥2 cases of mirror syndrome and included case reports, case series, cohort studies, and case-control studies.
STUDY APPRAISAL AND SYNTHESIS METHODS
The studies' quality and risk of bias were independently assessed. Data were tabulated using Microsoft Excel and summarized using narrative review and descriptive statistics. This systematic review was conducted according to the Preferred Reporting Item for Systematic Reviews and Meta-Analyses statement. All eligible references were assessed. Screening of records and data extraction were independently performed, and a third author resolved disagreements.
RESULTS
Of 13 citations, 12 studies (n=82) reported diagnostic criteria for mirror syndrome: maternal edema (11/12), fetal hydrops (9/12), placental edema (6/12), placentomegaly (5/12), and preeclampsia (2/12); 12 studies (n=82) described the clinical presentation of mirror syndrome as maternal edema (62.2%), hypoalbuminemia (54.9%), anemia (39.0%), and new-onset hypertension (39.0%); 4 studies (n=36) reported that hemodilution was present in all patients; 8 studies (n=36) reported the etiology of fetal hydrops, with the most common being structural cardiac malformations (19.4%), alpha thalassemia (19.4%), Rh isoimmunization (13.9%), and nonimmune hydrops fetalis (13.9%); and 6 studies (n=47) reported maternal complications, 89.4% of which were major: postpartum hemorrhage (44.7%), hemorrhage requiring blood transfusion (19.1%), intensive care unit admission (12.8%), heart failure (10.6%), pulmonary edema (8.5%), and renal dysfunction (8.5%). In 39 cases, the reported fetal outcomes were stillbirth (66.6%) and neonatal or infant death (25.6%). The overall survival rate among continued pregnancies was 7.7%.
CONCLUSION
The diagnostic criteria of mirror syndrome differed considerably among studies. Mirror syndrome clinical presentation overlapped with preeclampsia. Only 4 studies discussed hemodilution. Significant maternal morbidity and fetal mortality were associated with mirror syndrome. Further research is warranted to elucidate the pathogenesis of mirror syndrome to better guide clinicians in identifying and managing the condition.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Edema; Hydrops Fetalis; Placenta; Pre-Eclampsia; Syndrome; Systematic Reviews as Topic
PubMed: 37385374
DOI: 10.1016/j.ajogmf.2023.101067 -
Cytotherapy Dec 2023Amidst the success of cell therapy for the treatment of onco-hematological diseases, the first recently Food and Drug Administration-approved gene therapy product for...
BACKGROUND AIMS
Amidst the success of cell therapy for the treatment of onco-hematological diseases, the first recently Food and Drug Administration-approved gene therapy product for patients with transfusion-dependent β-thalassemia (TDT) indicates the feasibility of gene therapy as curative for genetic hematologic disorders. This work analyzed the current-world scenario of clinical trials involving gene therapy for β-hemoglobinopathies.
METHODS
Eighteen trials for patients with sickle cell disease (SCD) and 24 for patients with TDT were analyzed.
RESULTS
Most are phase 1 and 2 trials, funded by the industry and are currently recruiting volunteers. Treatment strategies for both diseases are fetal hemoglobin induction (52.4%); addition of wild-type or therapeutic β-globin gene (38.1%) and correction of mutations (9,5%). Gene editing (52.4%) and gene addition (40.5%) are the two most used techniques. The United States and France are the countries with the greatest number of clinical trials centers for SCD, with 83.1% and 4.2%, respectively. The United States (41.1%), China (26%) and Italy (6.8%) lead TDT trials centers.
CONCLUSIONS
Geographic trial concentration indicates the high costs of this technology, logistical issues and social challenges that need to be overcome for gene therapy to reach low- and middle-income countries where SCD and TDT are prevalent and where they most impact the patient's health.
Topics: Humans; Hemoglobinopathies; Anemia, Sickle Cell; Cell- and Tissue-Based Therapy; China; Genetic Therapy
PubMed: 37318395
DOI: 10.1016/j.jcyt.2023.05.006 -
Critical Reviews in Oncology/hematology Oct 2023Existing treatment for chronic pain in sickle cell disease (SCD) is opioid-dependent, which is ineffective and carries risks. We conducted a scoping literature review to... (Review)
Review
Existing treatment for chronic pain in sickle cell disease (SCD) is opioid-dependent, which is ineffective and carries risks. We conducted a scoping literature review to assess the size and scope of available literature about controlled trials of therapies for SCD chronic pain and identify research gaps. The search strategy in PubMed and EMBASE utilized keywords for chronic pain and sickle cell and identified seven original articles that met inclusion criteria. Six of the studies recruited from clinics while one recruited from community sources. Cannabis and behavioral modification were associated with improvements in pain scores. However, existing evidence does not represent best practices for assessing chronic pain, and this along with small sample sizes prevents translation to clinical care. The limited evidence concerning treatment for SCD chronic pain highlights the need for larger trials of opioid alternatives and the utilization of chronic pain measures that capture nociplastic pain in SCD.
Topics: Humans; Chronic Pain; Analgesics, Opioid; Pain Management; Anemia, Sickle Cell; Randomized Controlled Trials as Topic
PubMed: 37541536
DOI: 10.1016/j.critrevonc.2023.104087 -
Reviews on Environmental Health Jun 2023Arsenic as a chemical is found in rock, soil, air and used in various industries and their products, such as colors, hairs, and fertilizers. Humans may be exposed to... (Review)
Review
OBJECT
Arsenic as a chemical is found in rock, soil, air and used in various industries and their products, such as colors, hairs, and fertilizers. Humans may be exposed to arsenic mainly through food and drinking water. Due to its adverse health effects, its presence in drinking water has become a public health concern.
METHODS
In this systematic review, we investigated the relationship between arsenic concentration in drinking water and the risk of kidney cancer in humans. For this reason, various electronic databases were searched from 1992 February to November 2021. In this review, three ecological studies, two case-control studies, and four cohort studies were investigated.
RESULTS
High levels of arsenic (100 μg/L) have been reported in many countries such as southwest Taiwan, Niigata, Argentine, and northern Chile. A significant relationship was observed between kidney cancer incidence and its mortality rate with high arsenic levels in drinking water.
CONCLUSIONS
Despite the limitations in some previous studies, reviewing and comparing the data of different regions indicates a scientific relationship between kidney cancer incidence and high concentrations of arsenic in drinking water.
Topics: Humans; Arsenic; Drinking Water; Water Pollutants, Chemical; Kidney Neoplasms; Incidence; Environmental Exposure
PubMed: 35286785
DOI: 10.1515/reveh-2021-0168 -
Blood Advances Feb 2024Advancements in orally bioavailable iron chelators and MRI methods have improved life expectancy and reproductive potential in thalassemia major (TM) and thalassemia... (Meta-Analysis)
Meta-Analysis
Advancements in orally bioavailable iron chelators and MRI methods have improved life expectancy and reproductive potential in thalassemia major (TM) and thalassemia intermedia (TI). Pregnancy is associated with adverse maternal and neonatal outcomes, frequency of which has not been well delineated. This systematic review aims to provide risk estimates of maternal and fetal outcomes in TM and TI and explore pregnancy's impact on iron homeostasis. Fifteen studies (429 participants, 684 pregnancies) were included. Meta-analysis revealed a higher thrombosis risk in TI (3.7%) compared to TM (0.92%), unchanged from prepregnancy. Heart failure risks in the earlier years appeared similar (TM 1.6% vs TI 1.1%), and maternal mortality in TM was 3.7%, but with current management, these risks are rare. Gestational diabetes and pre-eclampsia occurred in 3.9% and 11.3% of TM pregnancies, respectively. Caesarean section rates were 83.9% in TM and 67% in TI. No significant difference in stillbirth, small for gestational age neonates, or preterm birth incidence between TM and TI was observed. In TM pregnancies, red cell requirements significantly increased (from 102 to 139 ml/kg/year, P = 0.001), and 70% of TI pregnancies required blood transfusions. As expected, increased transfusion alongside chelation cessation led to a significant increase in serum ferritin during pregnancy (TM by 1005 ng/mL; TI by 332 ng/mL, P < 0.0001). Deterioration in iron status was further reflected by an increase in liver iron concentration (from 4.6 to 11.9 mg/g dry weight, P < 0.0001), and myocardial T2-star (T2∗) magnetic resonance imaging decreased (from 36.2 ± 2.5 ms to 31.1 ms) during pregnancy. These findings emphasize the elevated maternal risk of iron-related cardiomyopathy during pregnancy and labor, stressing the importance of cardiac monitoring and postpartum chelation therapy resumption.
Topics: Humans; Infant, Newborn; Pregnancy; Female; beta-Thalassemia; Iron; Pregnancy Outcome; Cesarean Section; Premature Birth
PubMed: 38181780
DOI: 10.1182/bloodadvances.2023011636 -
The Cochrane Database of Systematic... Aug 2023Sickle cell disease (SCD), one of the commonest severe monogenic disorders, is caused by the inheritance of two abnormal haemoglobin (beta-globin) genes. SCD can cause... (Review)
Review
BACKGROUND
Sickle cell disease (SCD), one of the commonest severe monogenic disorders, is caused by the inheritance of two abnormal haemoglobin (beta-globin) genes. SCD can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Kidney disease is a frequent and potentially severe complication in people with SCD. Chronic kidney disease (CKD) is defined as abnormalities of kidney structure or function present for more than three months. Sickle cell nephropathy refers to the spectrum of kidney complications in SCD. Glomerular damage is a cause of microalbuminuria and can develop at an early age in children with SCD, with increased prevalence in adulthood. In people with sickle cell nephropathy, outcomes are poor as a result of the progression to proteinuria and chronic kidney insufficiency. Up to 12% of people who develop sickle cell nephropathy will develop end-stage renal disease. This is an update of a review first published in 2017.
OBJECTIVES
To assess the effectiveness of any intervention for preventing or reducing kidney complications or chronic kidney disease in people with sickle cell disease. Possible interventions include red blood cell transfusions, hydroxyurea, and angiotensin-converting enzyme inhibitors (ACEIs), either alone or in combination.
SEARCH METHODS
We searched for relevant trials in the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, CENTRAL, MEDLINE, Embase, seven other databases, and two other trials registers.
SELECTION CRITERIA
Randomised controlled trials (RCTs) comparing interventions to prevent or reduce kidney complications or CKD in people with SCD. We applied no restrictions related to outcomes examined, language, or publication status.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed trial eligibility, extracted data, assessed the risk of bias, and assessed the certainty of the evidence (GRADE).
MAIN RESULTS
We included three RCTs with 385 participants. We rated the certainty of the evidence as low to very low across different outcomes according to GRADE methodology, downgrading for risk of bias concerns, indirectness, and imprecision. Hydroxyurea versus placebo One RCT published in 2011 compared hydroxyurea to placebo in 193 children aged nine to 18 months. We are unsure if hydroxyurea compared to placebo reduces or prevents progression of kidney disease assessed by change in glomerular filtration rate (mean difference (MD) 0.58 mL/min /1.73 m, 95% confidence interval (CI) -14.60 to 15.76; 142 participants; very low certainty). Hydroxyurea compared to placebo may improve the ability to concentrate urine (MD 42.23 mOsm/kg, 95% CI 12.14 to 72.32; 178 participants; low certainty), and may make little or no difference to SCD-related serious adverse events, including acute chest syndrome (risk ratio (RR) 0.39, 99% CI 0.13 to 1.16; 193 participants; low certainty), painful crisis (RR 0.68, 99% CI 0.45 to 1.02; 193 participants; low certainty); and hospitalisations (RR 0.83, 99% CI 0.68 to 1.01; 193 participants; low certainty). No deaths occurred in either trial arm and the RCT did not report quality of life. Angiotensin-converting enzyme inhibitors versus placebo One RCT published in 1998 compared an ACEI (captopril) to placebo in 22 adults with normal blood pressure and microalbuminuria. We are unsure if captopril compared to placebo reduces proteinuria (MD -49.00 mg/day, 95% CI -124.10 to 26.10; 22 participants; very low certainty). We are unsure if captopril reduces or prevents kidney disease as measured by creatinine clearance; the trial authors stated that creatinine clearance remained constant over six months in both groups, but provided no comparative data (very low certainty). The RCT did not report serious adverse events, all-cause mortality, or quality of life. Angiotensin-converting enzyme inhibitors versus vitamin C One RCT published in 2020 compared an ACEI (lisinopril) with vitamin C in 170 children aged one to 18 years with normal blood pressure and microalbuminuria. It reported no data we could analyse. We are unsure if lisinopril compared to vitamin C reduces proteinuria in this population: the large drop in microalbuminuria in both arms of the trial after only one month on treatment may have been due to an overestimation of microalbuminuria at baseline rather than a true effect. The RCT did not report serious adverse events, all-cause mortality, or quality of life.
AUTHORS' CONCLUSIONS
We are unsure if hydroxyurea improves glomerular filtration rate or reduces hyperfiltration in children aged nine to 18 months, but it may improve their ability to concentrate urine and may make little or no difference to the incidence of acute chest syndrome, painful crises, and hospitalisations. We are unsure if ACEI compared to placebo has any effect on preventing or reducing kidney complications in adults with normal blood pressure and microalbuminuria. We are unsure if ACEI compared to vitamin C has any effect on preventing or reducing kidney complications in children with normal blood pressure and microalbuminuria. No RCTs assessed red blood cell transfusions or any combined interventions to prevent or reduce kidney complications. Due to lack of evidence, we cannot comment on the management of children aged over 18 months or adults with any known genotype of SCD. We have identified a lack of adequately designed and powered studies, although we found four ongoing trials since the last version of this review. Only one ongoing trial addresses renal function as a primary outcome in the short term, but such interventions have long-term effects. Trials of hydroxyurea, ACEIs or red blood cell transfusion in older children and adults are urgently needed to determine any effect on prevention or reduction of kidney complications in people with SCD.
Topics: Child; Adult; Humans; Adolescent; Hydroxyurea; Antisickling Agents; Acute Chest Syndrome; Captopril; Lisinopril; Creatinine; Anemia, Sickle Cell; Kidney Failure, Chronic; Proteinuria; Angiotensin-Converting Enzyme Inhibitors; Ascorbic Acid
PubMed: 37539955
DOI: 10.1002/14651858.CD012380.pub3 -
Cureus Aug 2023Sickle cell anemia is a hemoglobinopathy that causes complications such as Vaso-Occlusive Crisis (VOC), stroke, priapism, Acute Chest Syndromes (ACS), and bone infarcts... (Review)
Review
Sickle cell anemia is a hemoglobinopathy that causes complications such as Vaso-Occlusive Crisis (VOC), stroke, priapism, Acute Chest Syndromes (ACS), and bone infarcts due to blood vessel occlusion, resulting in hypoxia, ischemia, and inflammation. Preventing these incidents improves the quality of life and lowers mortality rates in Sickle Cell Disease (SCD) patients. This systematic review aims to describe the drugs, their mechanisms of action, dosages, changes in hemoglobin parameters, decrease in VOCs, delay the time for the next VOC, decrease in the length of hospital stay, and side effects associated with these drugs. This review adheres to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020 guidelines. For this review, we searched the PubMed, Google Scholar, and Cochrane databases and screened them for full free texts published in English and studied in humans in the last five years beginning in 2018. Randomized clinical trials (RCT), observational studies, meta-analyses, systemic reviews, and traditional reviews were all included in the search. According to the type of study, quality assessment tools are used, and eight papers are chosen. Full-text articles from these papers are studied, analyzed, and tabulated. We discussed seven interventions that are used to treat sickle cell disease. Voxelotor, crizanlizumab, L-glutamate, long-term blood transfusions, Zinc (Zn), Niprisan®, and Ciklavit* were found to reduce the number and severity of VOC. We discovered that VOCs containing L -glutamate reduced the length of hospitalization. Magnesium (Mg) did not affect the number and severity of VOCs. This review includes a few articles for the study. Future papers on this subject should include a large sample size and many papers. More clinical trials are required to evaluate the dosages and outcomes of using these drugs in combination to prevent VOCs.
PubMed: 37664256
DOI: 10.7759/cureus.42785 -
Journal of Reproduction & Infertility 2023Cell-free fetal DNA (cffDNA) is a novel screening method for fetal aneuploidy that facilitated non-invasive prenatal testing (NIPT) through analysis of cffDNA in... (Review)
Review
BACKGROUND
Cell-free fetal DNA (cffDNA) is a novel screening method for fetal aneuploidy that facilitated non-invasive prenatal testing (NIPT) through analysis of cffDNA in maternal plasma. However, despite increased sensitivity, it has a number of limitations that may complicate of its results interpretation. Therefore, elucidating factors affecting fetal fraction, as a critical limitation, guides its clinical application.
METHODS
In this report, systematic search was carried out through PubMed, Web of Science, and Scopus databases until February 11, 2022 by using keywords consist of "noninvasive prenatal screening", "NIPT", "noninvasive prenatal", "cell free DNA" and "fetal fraction". The articles were screened for eligibility criteria before data extraction.
RESULTS
A total of 39 eligible studies, most published between 2010 and 2020, were included. Based on the results of studies, a negative correlation between maternal age and BMI/body weight with fetal fraction was found. Furthermore, LDL, cholesterol, triglyceride level, metformin, heparin and enoxaparin therapy, hemoglobin-related hemoglobinopathies, and physical activity showed to have negative associations. Interestingly, it seems the ethnicity of patients from South and East Asia has a correlation with fetal fraction compared to Caucasians. Positive correlation was observed between gestational age, free β-hCG, PAPP-A, living in high altitude, and twin pregnancy.
CONCLUSION
Considering each factor, there was significant inconsistency and controversy regarding their impact on outcomes. Indeed, multiple factors can influence the accuracy of NIPS results, and it is worth noting that the impact of these factors may vary depending on the individual's ethnic background. Therefore, it is important to recognize that NIPS remains a screening test, and comprehensive pre- and post-NIPS counseling should be conducted as part of standard clinical practice.
PubMed: 38164433
DOI: 10.18502/jri.v24i4.14149 -
Hematology (Amsterdam, Netherlands) Dec 2023Allogeneic hematopoietic stem cell transplant (HSCT) and gene therapy (GT) are two potentially curative approaches for sickle cell disease (SCD), but they have never...
INTRODUCTION
Allogeneic hematopoietic stem cell transplant (HSCT) and gene therapy (GT) are two potentially curative approaches for sickle cell disease (SCD), but they have never been compared in clinical trials.
OBJECTIVE
To compare the safety and efficacy of HSCT and GT to assist clinicians and patients in making informed treatment decisions.
METHODS
Phase I-III clinical trials and case reports/series were included. Regimens included HSCT from all stem cell sources, lentiviral gene therapy, and gene editing, with any conditioning regimen. We searched Medline and EMBASE databases as of 1st June 2020 for studies reporting HSCT and GT outcomes in SCD. The Newcastle-Ottawa scale was used to assess the risk of bias. Descriptive statistics and post-hoc imputation for standard deviations of mean change in FEV1 and FVC were performed.
RESULTS
In total, 56 studies (HSCT, = 53; GT, = 3) representing 1,198 patients met inclusion criteria (HSCT, = 1,158; GT, = 40). Length of follow-up was 3,881.5 and 58.7 patient-years for HSCT and GT, respectively. Overall quality of evidence was low, with no randomized controlled trials identified. Two-year overall survival for HSCT was 91%; mortality was 2.5% for GT. Acute chest syndrome and vaso-occlusive episodes were reduced post-HSCT and GT. Meta-analysis was not possible due to lack of comparator and heterogeneity in outcome measures reporting. Very few studies reported post-transplant end-organ function. Six secondary malignancies (5 post-HSCT, 1 post-GT) were reported.
DISCUSSION
Reporting of SCD-related complications and patient-important outcomes is lacking for both strategies. We advocate for standardized reporting to better compare outcomes within and between treatment groups.
Topics: Humans; Hematopoietic Stem Cell Transplantation; Anemia, Sickle Cell; Acute Chest Syndrome
PubMed: 36728286
DOI: 10.1080/16078454.2022.2163357