Applying Comfort Theory to Improve Outcomes for People in Sickle Cell Crisis.

When people with sickle cell disease in vaso-occlusive crisis need hospitalization, they often experience fragmented and disparate treatment. Racial, gender, and socioeconomic treatment bias by providers, including nurses, is complicated by the current reactionary United States (US) controlled substance policies. To provide high-quality and respectful care, nurses can use Kolcaba's Comfort Theory as the framework for a holistic plan to assess, deliver individualized interventions, and evaluate outcomes for people experiencing vaso-occlusive crisis. Once in the electronic medical record, it can guide care during future hospitalizations. By refocusing on the nursing value of providing comfort care to individuals in distress, nurses can change treatment outcomes for clients.

[Sickle cell disease in French Guiana: assessing 30 years of neonatal screening (1992-2021)]. / La drépanocytose en Guyane : bilan de 30 années de dépistage néonatal (1992-2021).

Background: Sickle cell disease is one of the most common genetic diseases in France. In French Guiana, neonatal screening was introduced in 1992, at the same time as other screening programs for childhood diseases. The aim of this study is to describe the organization of newborn screening for sickle cell disease in French Guiana. Materials and methods: We used several data sources: data collected from hospital records since 2005, activity reports from the national neonatal screening program and data from screening campaigns organized by the Drepaguyane association between 2010 and 2021 on 1,300 subjects. Blood samples from newborns are collected by capillary or venous sampling and absorbed on blotting paper (Guthrie) at the same time as those for other neonatal screenings. The dried papers are sent to the inter-regional laboratory in Lille, for further processing. In Saint-Laurent-du-Maroni, in order to reduce the proportion of people lost to follow-up, a double screening is carried out and the results are returned before discharge from the maternity hospital. All data were entered into an anonymous Excel file. The data were analyzed using STATA software. Results: Among the 175,593 screened neonates between 1992 and 2021, screening detected 823 infants with sickle cell disease and 17,950 heterozygotes. Sickle cell genotypes include 493 SS (60%), 302 SC (37%) and 28 S-Beta-thalassemia (3%). The incidence of sickle cell disease was 1/213, 95% CI [1/236-1/204], and that of heterozygotes 1/10, IC 95% [1/12-1/8]. The majority of these children (52%) were from the Maroni region. The delay between screening and test results was 7 days. Only pathological results (homozygous, heterozygous) were communicated to parents and/or the attending physician by post. These data confirm the upward trend in the number of children screened for sickle cell disease in French Guiana. Data from screening campaigns organized by the Drepaguyane association have enabled to describe the distribution of the various abnormal hemoglobin fractions, and to confirm that HbS is more frequent in Western French Guiana. In Cayenne, in 2021, the active file comprised 699 patients, including 266 children under 18 years old. Discussion and conclusion: This study provides valuable data on 30 years of neonatal screening for sickle cell disease in French Guiana, and on the evolution of sickle cell disease patients. It confirms that French Guiana is the French territory with the highest incidence of sickle cell disease. This incidence continues to rise over time. The study reveals the improvement in the organization of sickle cell disease management in French Guiana between 1992, when screening was introduced, and the present day. It highlights the role of patient associations in the fight against this disease, by organizing awareness and screening campaigns. These data will be used to guide public health policies in the pursuit of improved care and primary prevention.

[Blood count abnormalities in the association of sickle cell disease and malaria in clinical hematology at the CNHU-HKM in Cotonou (Bénin)]. / Anomalies de l'hémogramme dans l'association drépanocytose et paludisme chez l'adulte en hématologie clinique au CNHU-HKM de Cotonou (Bénin).

Introduction: Although a protective effect of hemoglobin S has been described, malaria has frequently been associated with increased morbidity and mortality in sickle cell disease patients in Africa. Various cytopenias are frequently found on the haemograms of these patients. In Benin, a malaria-endemic zone with a high prevalence of sickle cell disease, the aim of this study was to establish and compare the blood count profile according to hemoglobin type in the association of sickle cell disease and malaria. Material and method: This was a prospective descriptive study. It covered a 24-month period from October 2020 to October 2022. It included all patients with major sickle cell syndrome seen in clinical haematology and with a positive thick drop/parasite density, whatever the parasitaemia value. For each patient, a blood count was performed on the Sysmex XT 4000i machine, supplemented by a smear study after staining with May-Grunwald Giemsa. Data were analyzed using R 3.6.1 software. Results: Three hundred non-redundant cases with a positive thick smear were identified in sickle cell patients, including 208 SS homozygotes (69.3%) and 92 SC heterozygotes (30.7%). In contrast, there were 181 non-redundant cases with a negative thick smear, including 119 SS homozygotes (65.7%) and 62 SC heterozygotes (34.3%). Among subjects with a positive thick smear, the majority of patients (70%) exhibited clinical symptoms. Severe malaria was observed in 58% of the cases. The proportion of severe malaria was higher in SS homozygote patients than in double heterozygote SC patients (p < 0.0001). The mean parasite density was higher in SS individuals (4 320.7 ± 2 185 trophozoites/pL) compared to SC individuals (1 564.4 ± 1 221 trophozoites/pL; p < 0.0001). Plasmodium falciparum was the only species identified. The mean hemoglobin level in impaludated SS subjects was 6.1 g/dL, significantly lower than that in non-impaludated SS subjects (p < 0.0001). The average white blood cell count in impaludated SS subjects was 16.58 G/L, compared to 13.2 G/L in those with a negative thick smear (p < 0.0001). Twenty cases of thrombocytopenia were found in SS subjects with a positive thick smear, compared to 6 cases in those with a negative thick smear. As for SC subjects with a positive thick smear, the average hemoglobin levels and white blood cell counts were 9.8 g/dL and 10.63 G/L, respectively, compared to 11.27 g/dL and 7.3 G/L in SC subjects with a negative thick smear. Eighteen cases of thrombocytopenia were found in subjects with a positive thick smear, compared to 17 cases in those with a negative thick smear. Discussion: Sickle cell disease and malaria represent two major public health problems. However, contrary to popular belief, sickle cell disease is not immune to malaria infestation. Malaria is recognized as one of the main causes of morbidity and mortality in sickle cell patients, particularly children. In Benin, its association with sickle cell emergencies has already been reported.Our study found that malaria was predominantly associated with the homozygous SS form (p < 0.00001). Severe malaria was the most common clinical form. All malaria infestations in our series were due to Plasmodium falciparum, and parasitaemia was significantly higher in SS patients (p < 0.0001).The hematological profile of the association of sickle cell disease and malaria in homozygous SS individuals in our series showed characteristics of a normocytic normochromic anemia with neutrophil-predominant leukocytosis. Compared to non-malaria-infected SS individuals, there was a significant worsening of anemia, neutrophil-predominant leukocytosis, and a decrease in the average platelet count. In SC individuals, there was rather a microcytic normochromic regenerative anemia associated with neutrophil-predominant leukocytosis. Compared to non-malaria-infected SC individuals, there was a significant decrease in the rate of anemia and neutrophil-predominant leukocytosis. Anemia is a constant feature in homozygous sickle cell disease, and the low values recorded illustrate the hemolytic nature of malaria, especially in SS individuals, and the better tolerance of SC individuals. Furthermore, the low baseline hemoglobin levels make SS individuals more vulnerable to malaria-induced anemia compared to SC individuals. The observed leukocytosis is generally accompanied by reticulocytosis in the case of major sickle cell syndrome, which must be taken into account for result validation. It is the expression of compensatory bone marrow reaction to anemia and inflammatory mechanisms resulting from malaria infestation. Finally, thrombocytopenia was significantly more common in SC patients, even though they were adults living in malaria-endemic areas. Malaria can frequently induce thrombocytopenia through platelet consumption during the "rosetting" phenomenon. In SS patients, the effects of "rosetting" could be compensated for by the bone marrow stimulation induced by anemia. In our series with adult subjects living in an endemic area, thrombocytopenia is not a frequent biological disturbance. In a clinicalbiological context combining a systemic inflammatory response syndrome with anemia and neutrophil-predominant leukocytosis in a SS or SC sickle cell patient, the clinician should be able to consider malaria and confirm or rule out this diagnosis.

Predictors of health-related quality of life in a large cohort of adult patients living with sickle cell disease in France: the DREPAtient study.

Background: Sickle cell disease (SCD) is an inherited autosomal recessive disorder exhibiting a range of symptoms and acute and/or chronic complications that affect the quality of life. This study aimed to assess health-related quality of life (HRQoL) and to identify the associated factors in adult patients with SCD in France. Methods: DREPAtient is a cross-sectional, multicenter study conducted from June 2020 to April 2021 in France and in certain French overseas territories where SCD is highly prevalent. Sociodemographic and clinical data were collected online. HRQoL was assessed by the French version of the 36-Item Short Form Survey (SF-36) questionnaire. HRQoL determinants were identified using multivariable linear regression analysis. Results: In total, 570 participants were included, mostly women (68.9%), with a mean age of 33.3 (±10.7) years. The highest mean score HRQoL was found in the Physical functioning domain (67.5 ± 21.8) and the lowest mean score in the General Health perception domain (37.7 ± 20.3). The mean score of the physical composite (PCS) and mental composite (MCS) of SF-36 summary scores was 40.6 ± 8.9 and 45.3 ± 9.8, respectively. Participants receiving oxygen therapy (ß = -3.20 [95%CI: -5.56; -0.85]), those with a history of femoral osteonecrosis (-3.09 [-4.64; -1.53]), those hospitalized for vaso-occlusive crisis (VOC) or acute chest syndrome (ACS) (-2.58 [-3.93; -1.22]), those with chronic complications (-2.33 [-4.04; -0.62]), female participants (-2.17 [-3.65; -0.69]), those with psychological follow-up (-2.13 [-3.59; -0.67]), older participants (-1.69 [-3.28; -0.09]), and those receiving painkillers (-1.61 [-3.16; -0.06]) reported worse PCS score. By contrast, those who had completed secondary or high school (4.36 [2.41; 6.31]) and those with stable financial situation (2.85 [0.94, 4.76]) reported better PCS scores. Worse MCS scores were reported among participants with psychological follow-up (-2.54 [-4.28; -0.80]) and those hospitalized for VOC/ACS in the last 12 months (-2.38 [-3.99; -0.77]), while those who had relatives' support (5.27 [1.92; 8.62]) and those with stable financial situation (4.95 [2.65; 7.26]) reported better MCS scores. Conclusion: Adults with major SCD reported poor physical and mental HRQoL scores. Hospitalization for VOC/ACS, chronic complications, use of painkillers, perceived financial situation, and support from relatives are important predictors of HRQoL in SCD patients. Interventions to improve HRQoL outcomes SCD should be considered.

Nothing about us without us: Advocacy and engagement in genetic medicine.

The development of new genetic medicines to treat sickle cell disease highlights the need for greater collaboration between researchers and people with lived experiences. Drawing on the adage "Nothing about us, without us," we call for increased investments in community advocacy and engagement.

Understanding patient-related barriers to hydroxyurea use among adolescent and adult patients with sickle cell disease in Mulago and Kiruddu hospitals, Uganda, a qualitative study.

BACKGROUND: In 2016, Uganda added Hydroxyurea (HU) to the list of essential drugs to treat sickle cell disease SCD. However, Hydroxyurea utilization has been low for several countries in sub-Saharan Africa. This study examined patient-related barriers to hydroxyurea use among adolescent and adult patients with sickle cell disease in Mulago and Kiruddu hospitals, in Uganda. METHODS: To understand the patient-related barriers to hydroxyurea use among adolescent and adult patients with sickle cell disease, we conducted a parallel convergent mixed methods study at outpatient departments of two national referral hospitals in Uganda from October 2022 to January 2023. The cross-sectional mixed-methods study employed both quantitative and qualitative methods. We collected survey data from a systematic sample of 259 participants and conducted individual interviews with a purposive sample of 40 participants (20 adolescents or their caregivers and 20 adult patients with SCD) and interviewed them individually on their knowledge, perceptions, barriers, and facilitators of HU utilization. Descriptive data were analyzed using Stata 16, whereas qualitative data were analyzed thematically using an inductive approach supported by NVivo 12 software. We triangulated data to determine the concordance of qualitative and quantitative data. RESULTS: The study enrolled 40 participants for qualitative interviews and 259 patients for quantitative, with an average age of 16, over half being female, 46% having secondary education, and 96% unmarried. The prevalence of HU use was 78%. The study identified three themes as follows: Patient barriers at the individual including Inadequate knowledge about HU, Persistent pain, Poor adherence to HU, Poor communication with health care workers, and Psychosocial and emotional challenges. At the facility level, long queues and poor quality of care, drug-related side effects that affect HU, and drug stock-outs were reported. Myths, rumors, and misconceptions about HU, and gender-related barriers were reported to affect HU utilization at a community level. Facilitators for the use of HU and recommendations for improvement. Facilitators included perceived benefits, long duration on HU, information sharing by healthcare workers, availability of complementary drugs, confirmation of diagnosis, and availability of medication at public health facilities or private pharmacies. Patients suggested continuous adherence support, encouragement from healthcare workers, sensitization about benefits and risks, a peer-to-peer approach, and financial support for adolescents and women to start businesses to resolve financial problems. CONCLUSION: Implementing the use of HU has been challenging in Uganda and needs improvement. Facilitators to hydroxyurea use have been highlighted, though Patient-identified barriers at individual, facility, and community levels that need to be resolved. The experiences and insights shared by our participants provide invaluable guidance for increasing the uptake of HU. Further studies are needed to establish validated instruments to assess patients' pain communication and adherence to the HU regimen.

Laboratory predictors of sickle cell disease severity: a cross-sectional study.

Sickle cell disease (SCD) is the most common monogenic disorder, although the diversity and heterogenicity of clinical presentations render estimations of disease severity unpredictable. This cross-sectional study aimed to determine if laboratory markers could serve as indicators of SCD severity. We enrolled 90 adult patients with SCD with a mean age of 32.33 ± 11.84 years from the eastern province of Saudi Arabia, where SCD is more common than in other regions. Our study revealed a positive significant association between the number of hospitalizations and emergency visits with white blood cells (WBC) (R = 0.241, R = 0.207), respectively. Similarly, positive significant associations were found between the number of hospitalizations and emergency visits with platelets (R = 0.393, R = 0.276), respectively. Conversely, negative significant relationships were found between the number of hospitalizations and emergency visits (ER) with hemoglobin (Hb) F (R = -0.268, R = -0.263), respectively. Additionally, significant negative relationships were found between Hb F (R = -0.223) and the frequency of ICU admission. Only the number of hospitalizations and emergency visits annually were significantly predicted with P values of 0.021 and 0.038, respectively. Moreover, an increase in WBC was found to significantly increase the chance of undergoing splenectomy by 23.02%. SCD is a multisystemic disease with heterogeneous clinical presentations and disease severity. Inflammatory markers are valuable tools for better risk stratification and could be translated into developing new therapeutic strategies and modifying the treatment paradigm.

Mortality related to sickle cell disease and COVID-19 in Brazil, 2020.

OBJECTIVE: The ability to cause death is the definitive measure of an infectious disease severity, particularly one caused by a novel pathogen like severe acute respiratory syndrome-CoV-2 (COVID-19). This study describes sickle cell disease-related mortality issues during the COVID-19 pandemic in Brazil. METHODS: The provisional 2020 mortality data originated from the public databases of the Mortality Information System and were investigated using the multiple-cause-of-death methodology. RESULTS: In 2020, 688 sickle cell disease-related deaths occurred, of which 422 (61.3%) had an underlying cause of death and 266 (38.7%) had an associated cause of death. Furthermore, 98 COVID-19-related deaths occurred, of which 78 were underlying cause of death among sickle cell disease associated (non-underlying) cause of death. Sickle cell disease-related deaths occurred mostly among young adults aged 25-49 years. COVID-19 deaths occurred at ages older than among sickle cell disease-related deaths. Majority of deaths happened in the southeast (42.3%) and northeast regions (34.0%), while COVID-19 deaths prevailed in the northeast region (42.9%). Regarding overall deaths, the leading underlying cause of death was sickle cell disease itself, followed by infectious and parasitic diseases (14.8%), owing to COVID-19 deaths, and diseases of the circulatory system (8.9%). Next, in males, diseases of the digestive system (4.8%) occurred, while, in females, maternal deaths succeeded, included in the chapter on pregnancy, childbirth, and the puerperium, accounting for 5.9% of female deaths. The leading overall associated (non-underlying) cause of deaths were septicemias (29.4%), followed by respiratory failure (20.9%), pneumonias (18.3%), and renal failure (14.7%). CONCLUSION: In Brazil, COVID-19 deaths produced trend changes in sickle cell disease-related causes of death, age at death, and regional distribution of deaths in 2020.

Burden and outcome of respiratory morbidities among children and adolescents with sickle cell disease-A retrospective review of emergency presentations in some Nigerian tertiary institutions.

BACKGROUND: Despite the huge burden of sickle cell disease (SCD) among Nigerian children, the burden and outcome of respiratory illnesses remain undocumented. Thus, we aimed to describe the spectrum and outcome of respiratory illnesses among SCD childrenand adolescentadmissions in ten Nigerian tertiary hospitals. METHOD: A retrospective review of the SCD admission records of children and adolescents with a confirmed diagnosis of respiratory illnesses from 2012 to 2021 in ten tertiary health facilities across five geopolitical zones in Nigeria was conducted. The data, collectedbetween March and June 2023, included the age, sex, diagnosis, complications, duration and outcome of hospitalization. RESULTS: Of the 72,333 paediatric admissions, 7,256 (10.0%) had SCD; the proportion of SCD from the total admission ranged from 2.1 to 16.3% in the facilities. Of the 7,256 children and adolescents with SCD, 1,213 (16.7%) had respiratory morbidities. Lower respiratory disease was the most common (70.0%) respiratory entity and the majority were pneumonia (40.1.0%), followed by acute chest syndrome (26.7%). Seventeen (1.4%) patients died; all had lower respiratory diseases [(acute chest syndrome ACS (11, 64.7%), pneumonia; 5, 29.4%, and asthma (1, 5.9%). Based on the proportion of deaths among overall SCD, the 17 death cases contributed 9.4% (95% CI 5.9 to 14.5). Factors associated with deaths included duration of hospitalization less than 72 hours and lower respiratory tract diseases. CONCLUSION: Sickle cell disease is a major contributor to hospitalization among Nigerian children and adolescents, with high respiratory morbidity and mortality. Pneumonia and acute chest syndrome were associated with mortality, andthe highest risk of death within the first 72 hours.

A miniaturized wash-free microfluidic assay for electrical impedance-based assessment of red blood cell-mediated microvascular occlusion.

The production of HbS - an abnormal hemoglobin (Hb) - in sickle cell disease (SCD) results in poorly deformable red blood cells (RBCs) that are prone to microcapillary occlusion, causing tissue ischemia and organ damage. Novel treatments, including gene therapy, may reduce SCD morbidity, but methods to functionally evaluate RBCs remain limited. Previously, we presented the microfluidic impedance red cell assay (MIRCA) for rapid assessment of RBC deformability, employing electrical impedance-based readout to measure RBC occlusion of progressively narrowing micropillar openings. We describe herein the design, development, validation, and clinical utility of the next-generation MIRCA assay, featuring enhanced portability, rapidity, and usability. It incorporates a miniaturized impedance analyzer and features a simplified wash-free operation that yields an occlusion index (OI) within 15 min as a new metric for RBC occlusion. We show a correlation between OI and percent fetal hemoglobin (%HbF), other laboratory biomarkers of RBC hemolysis, and SCD severity. To demonstrate the assay's versatility, we tested RBC samples from treatment-naïve SCD patients in Uganda that yielded OI levels similar to those from hydroxyurea (HU)-treated patients in the U.S., highlighting the role of %HbF in protecting against microcapillary occlusion independent of other pharmacological effects. The MIRCA assay could also identify a subset of HU-treated patients with high occlusion risks, suggesting that they may require treatment adjustments including a second-line therapy to improve their outcomes. This work demonstrates the potential of the MIRCA assay for accelerated evaluation of RBC health, function, and therapeutic effect in an ex vivo model of the microcapillary networks.

Cardiac diastolic maladaptation is associated with the severity of exercise intolerance in sickle cell anemia patients.

This pilot study focusing on Sickle Cell Anemia (SCA) patients offers a comprehensive and integrative evaluation of respiratory, cardiovascular, hemodynamic, and metabolic variables during exercise. Knowing that diastolic dysfunction is frequent in this population, we hypothesize that a lack of cardiac adaptation through exercise might lead to premature increase in blood lactate concentrations in SCA patients, a potential trigger for acute disease complication. SCA patients were prospectively included in PHYSIO-EXDRE study and underwent a comprehensive stress test with a standardized incremental exercise protocol up to 4 mmol L-1 blood lactate concentration (BL4). Gas exchange, capillary lactate concentration and echocardiography were performed at baseline, during stress test (at ∼ 2 mmol L-1) and BL4. The population was divided into two groups and compared according to the median value of percentage of theoretical peak oxygen uptake (% V ˙ O 2 p e a k t h ) at BL4. Twenty-nine patients were included (42 ± 12 years old, 48% of women). Most patients reached BL4 at low-intensity exercise [median value of predicted power output (W) was 37%], which corresponds to daily life activities. The median value of % V ˙ O 2 p e a k t h at BL4 was 39%. Interestingly, diastolic maladaptation using echocardiography during stress test along with hemoglobin concentration were independently associated to early occurrence of BL4. As BL4 occurs for low-intensity exercises, SCA patients may be subject to acidosis-related complications even during their daily life activities. Beyond assessing physical capacities, our study underlines that diastolic maladaptation during exercise is associated with an early increase in blood lactate concentration.

Lipid and hemolysis parameters predicting acute chest syndrome in adulthood with sickle cell disease.

Sickle cell disease (SCD) is a lifelong blood disorder affecting approximately 100,000 people in the United States and is one of the most common monogenic diseases. A serious complication of SCD is acute chest syndrome (ACS). ACS is a condition with a high rate of morbidity and mortality. The aim of the study was to assess hemolysis and lipid parameters in a cohort of confirmed SCD patients to predict ACS development in the following year.Standard lipid were performed (triglycerides, total cholesterol, high-density cholesterol, low-density cholesterol) panel to calculate of non-HDL-C, large buoyant LDL cholesterol (lbLDL-C) and small dense LDL cholesterol (sdLDL-C) with Sampson equation. Hemolysis and hematologic parameters were also evaluated.Among 91 patients included between September 2018 and June 2021, thirty-seven patients had history of ACS and 6 patients developed ACS during following year. In unadjusted logistic regression, total bilirubin was associated with ACS occurrence (RR: 1.2 [1.05-1.51] p = 0.013). Concerning lipid profile, non-HDL-C (RR: 0.87 [0.0.67-0.99] p = 0.04) and sdLDL-C (RR: 0.78 [0.49-0.96] p = 0.03) were associated with ACS occurrence decrease. C-reactive protein was associated with ACS occurrence (RR: 1.27 [1.065-1.85] p = 0.011).Based on these findings, this study demonstrated that several biomarker easily available can be used at steady state to predict ACS in the following year. The validation of these results are required to ensure the reproducibility of the findings.

Barriers and facilitators to community acceptability of integrating point-of-care testing to screen for sickle cell disease in children in primary healthcare settings in rural Upper East Region of Northern Ghana.

INTRODUCTION: Sickle cell disease (SCD) remains a public health problem especially in sub-Saharan Africa including Ghana. While pilot initiatives in Africa have demonstrated that neonatal screening coupled with early intervention reduces SCD-related morbidity and mortality, only 50-70% of screen-positive babies have been successfully retrieved to benefit from these interventions. Point-of-care testing (POCT) with high specificity and sensitivity for SCD screening can be integrated into existing immunization programs in Africa to improve retrieval rates. This study explored community acceptability of integrating POCT to screen for SCD in children under 5 years of age in primary healthcare facilities in Northern Ghana. METHOD: This was an exploratory study using qualitative research approach where 10 focus group discussions and 20 in-depth interviews were conducted with community members and health workers between April and June 2022. The recorded interviews were transcribed verbatim after repeatedly listening to the recordings. Data was coded into themes using QSR Nvivo 12 software before thematic analysis. RESULTS: Most participants (70.9%) described SCD as serious and potentially life-threatening condition affecting children in the area. Of 148 community members and health workers, 141 (95.2%) said the screening exercise could facilitate diagnosis of SCD in children for early management. However, discrimination, fear of being tested positive, stigmatization, negative health worker attitude linked with issues of maintaining confidentiality were reported by participants as key factors that could affect uptake of the SCD screening exercise. Most participants suggested that intensive health education (78.3%), positive attitude of health workers (69.5%), and screening health workers not being biased (58.8%) could promote community acceptability. CONCLUSION: A large majority of participants viewed screening of SCD in children as very important. However, opinions expressed by most participants suggest that health education and professionalism of health workers in keeping patients' information confidential could improve the uptake of the exercise.

Current and Future Therapeutics for Treating Patients with Sickle Cell Disease.

Sickle cell disease (SCD) is the most common genetic blood disorder in the United States, with over 100,000 people suffering from this debilitating disease. SCD is caused by abnormal hemoglobin (Hb) variants that interfere with normal red blood cell (RBC) function. Research on SCD has led to the development and approval of several new SCD therapies in recent years. The recent FDA-approved novel gene therapies are potentially curative, giving patients an additional option besides a hematopoietic bone marrow transplant. Despite the promise of existing therapies, questions remain regarding their long-term pharmacological effects on adults and children. These questions, along with the exorbitant cost of the new gene therapies, justify additional research into more effective therapeutic options. Continual research in this field focuses on not only developing cheaper, more effective cures/treatments but also investigating the physiological effects of the current therapies on SCD patients, particularly on the brain and kidneys. In this article, we undertake a comprehensive review of ongoing clinical trials with completion dates in 2024 or later. Our exploration provides insights into the landscape of current therapeutics and emerging novel therapies designed to combat and potentially eradicate SCD, including the latest FDA-approved gene therapies.

Antioxidant supplementation for sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) refers to a group of genetic disorders characterized by the presence of an abnormal haemoglobin molecule called haemoglobin S (HbS). When subjected to oxidative stress from low oxygen concentrations, HbS molecules form rigid polymers, giving the red cell the typical sickle shape. Antioxidants have been shown to reduce oxidative stress and improve outcomes in other diseases associated with oxidative stress. Therefore, it is important to review and synthesize the available evidence on the effect of antioxidants on the clinical outcomes of people with SCD. OBJECTIVES: To assess the effectiveness and safety of antioxidant supplementation for improving health outcomes in people with SCD. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 15 August 2023. SELECTION CRITERIA: We included randomized and quasi-randomized controlled trials comparing antioxidant supplementation to placebo, other antioxidants, or different doses of antioxidants, in people with SCD. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed the risk of bias and certainty of the evidence, and reported according to Cochrane methodological procedures. MAIN RESULTS: The review included 1609 participants in 26 studies, with 17 comparisons. We rated 13 studies as having a high risk of bias overall, and 13 studies as having an unclear risk of bias overall due to study limitations. We used GRADE to rate the certainty of evidence. Only eight studies reported on our important outcomes at six months. Vitamin C (1400 mg) plus vitamin E (800 mg) versus placebo Based on evidence from one study in 83 participants, vitamin C (1400 mg) plus vitamin E (800 mg) may not be better than placebo at reducing the frequency of crisis (risk ratio (RR) 1.18, 95% confidence interval (CI) 0.64 to 2.18), the severity of pain (RR 1.33, 95% CI 0.40 to 4.37), or adverse effects (AE), of which the most common were headache, nausea, fatigue, diarrhoea, and epigastric pain (RR 0.56, 95% CI 0.31 to 1.00). Vitamin C plus vitamin E may increase the risk of SCD-related complications (acute chest syndrome: RR 2.66, 95% CI 0.77 to 9.13; 1 study, 83 participants), and increase haemoglobin level (median (interquartile range) 90 (81 to 96) g/L versus 93.5 (84 to 105) g/L) (1 study, 83 participants) compared to placebo. However, the evidence for all the above effects is very uncertain. The study did not report on quality of life (QoL) of participants and their caregivers, nor on frequency of hospitalization. Zinc versus placebo Zinc may not be better than placebo at reducing the frequency of crisis at six months (rate ratio 0.62, 95% CI 0.17 to 2.29; 1 study, 36 participants; low-certainty evidence). We are uncertain whether zinc is better than placebo at improving sickle cell-related complications (complete healing of leg ulcers at six months: RR 2.00, 95% CI 0.60 to 6.72; 1 study, 34 participants; very low-certainty evidence). Zinc may be better than placebo at increasing haemoglobin level (g/dL) (MD 1.26, 95% CI 0.44 to 1.26; 1 study, 36 participants; low-certainty evidence). The study did not report on severity of pain, QoL, AE, and frequency of hospitalization. N-acetylcysteine versus placebo N-acetylcysteine (NAC) 1200 mg may not be better than placebo at reducing the frequency of crisis in SCD, reported as pain days (rate ratio 0.99 days, 95% CI 0.53 to 1.84; 1 study, 96 participants; low-certainty evidence). Low-certainty evidence from one study (96 participants) suggests NAC (1200 mg) may not be better than placebo at reducing the severity of pain (MD 0.17, 95% CI -0.53 to 0.87). Compared to placebo, NAC (1200 mg) may not be better at improving physical QoL (MD -1.80, 95% CI -5.01 to 1.41) and mental QoL (MD 2.00, 95% CI -1.45 to 5.45; very low-certainty evidence), reducing the risk of adverse effects (gastrointestinal complaints, pruritus, or rash) (RR 0.92, 95% CI 0.75 to 1.14; low-certainty evidence), reducing the frequency of hospitalizations (rate ratio 0.98, 95% CI 0.41 to 2.38; low-certainty evidence), and sickle cell-related complications (RR 5.00, 95% CI 0.25 to 101.48; very low-certainty evidence), or increasing haemoglobin level (MD -0.18 g/dL, 95% CI -0.40 to 0.04; low-certainty evidence). L-arginine versus placebo L-arginine may not be better than placebo at reducing the frequency of crisis (monthly pain) (RR 0.71, 95% CI 0.26 to 1.95; 1 study, 50 participants; low-certainty evidence). However, L-arginine may be better than placebo at reducing the severity of pain (MD -1.41, 95% CI -1.65 to -1.18; 2 studies, 125 participants; low-certainty evidence). One participant allocated to L-arginine developed hives during infusion of L-arginine, another experienced acute clinical deterioration, and a participant in the placebo group had clinically relevant increases in liver function enzymes. The evidence is very uncertain whether L-arginine is better at reducing the mean number of days in hospital compared to placebo (MD -0.85 days, 95% CI -1.87 to 0.17; 2 studies, 125 participants; very low-certainty evidence). Also, L-arginine may not be better than placebo at increasing haemoglobin level (MD 0.4 g/dL, 95% CI -0.50 to 1.3; 2 studies, 106 participants; low-certainty evidence). No study in this comparison reported on QoL and sickle cell-related complications. Omega-3 versus placebo Very low-certainty evidence shows no evidence of a difference in the risk of adverse effects of omega-3 compared to placebo (RR 1.05, 95% CI 0.74 to 1.48; 1 study, 67 participants). Very low-certainty evidence suggests that omega-3 may not be better than placebo at increasing haemoglobin level (MD 0.36 g/L, 95% CI -0.21 to 0.93; 1 study, 67 participants). The study did not report on frequency of crisis, severity of pain, QoL, frequency of hospitalization, and sickle cell-related complications. AUTHORS' CONCLUSIONS: There was inconsistent evidence on all outcomes to draw conclusions on the beneficial and harmful effects of antioxidants. However, L-arginine may be better than placebo at reducing the severity of pain at six months, and zinc may be better than placebo at increasing haemoglobin level. We are uncertain whether other antioxidants are beneficial for SCD. Larger studies conducted on each comparison would reduce the current uncertainties.

Systematic Review of Genetic Modifiers Associated with the Development and/or Progression of Nephropathy in Patients with Sickle Cell Disease.

Sickle cell nephropathy (SCN) is a common complication of sickle cell disease (SCD) that significantly contributes to morbidity and mortality. In addition to clinical and life-style factors, genetic variants influence this risk. We performed a systematic review, searching five databases. Studies evaluating the effect of genetic modifiers on SCN were eligible. Twenty-eight studies (fair-to-good quality) were included: one genome-wide association study, twenty-six case-control studies, and one article combining both approaches. APOL1 was significantly associated with albuminuria and hyperfiltration in children and with worse glomerular filtration in adults. On the other hand, alpha-thalassemia protected patients against albuminuria and hyperfiltration, while BCL11A variants were protective against albuminuria alone. The HMOX1 long GT-tandem repeat polymorphism led to a lower glomerular filtration rate. No modifiers for the risk of hyposthenuria were identified. A genome-wide association approach identified three new loci for proteinuria (CRYL1, VWF, and ADAMTS7) and nine loci were linked with eGFR (PKD1L2, TOR2A, CUBN, AGGF1, CYP4B1, CD163, LRP1B, linc02288, and FPGT-TNNI3K/TNNI3K). In conclusion, this systematic review supports the role of genetic modifiers in influencing the risk and progression of SCN. Incorporating and expanding this knowledge is crucial to improving the management and clinical outcomes of patients at risk.

A Mixed-Methods Evaluation of a Project ECHO Program for the Evidence-Based Management of Sickle Cell Disease.

Sickle cell disease (SCD) is a group of chronic, genetic disorders of the red blood cells with significant gaps in access to evidence-based clinical care. Sickle Treatment and Outcomes Research in the Midwest (STORM), a provider network, utilized Project ECHO (Extension for Community Health Outcomes), a telementoring model, to deliver evidence-based education about SCD management. The purpose of this mixed-methods study is to evaluate the utility of Project ECHO as an educational strategy for healthcare providers treating children and adults with SCD. Annual evaluations were administered to STORM TeleECHO participants from 2016 to 2021. Survey data showed a statistically significant change in self-reported provider confidence in the ability to provide care for adult patients with SCD; identify suitable candidates for disease-modifying therapies; and confidence to prescribe disease-modifying therapies. Participants who attended at least 10 sessions were invited to participate in a semi-structured interview. Qualitative data were analyzed using thematic analysis and several themes emerged about the benefits, including (1) increased confidence, (2) integrated best-practice care, (3) connection to provider network and access to experts, (4) high-quality educational presentations and (5) opportunities for collaboration and a sense of community. This suggests that Project ECHO is accessible and leads to increased confidence in providers caring for individuals with SCD. Overall, participant knowledge gains successfully demonstrated the utility of Project ECHO as an educational resource for providers.

Mortality trends and sociodemographic factors associated with early death in sickle cell disease patients in the state of São Paulo.

OBJECTIVE: To estimate trends in mortality rate and average age of death, and identify sociodemographic factors associated with early death in patients with sickle cell disease (SCD). METHODS: An ecological and cross-sectional study was conducted using data from the Mortality Information System. All deaths of patients residing in the state of São Paulo from 1996 to 2015 with at least one International Disease Code for SCD in any field of the death certificate were included. Simple linear regression was used to estimate trends. The Log-rank test and multiple Cox regression were used to identify factors associated with early death. RESULTS: The age-standardized mortality rate per million inhabitants increased by 0.080 per year (R2=0.761; p<0.001). When the events were stratified by age at death, the increase was 0.108 per year for those occurring at age 20 years or older, (R2=0.789; p<0.001) and 0.023 per year for those occurring before age 20 years old (R2=0.188; p=0.056). The average age at death increased by 0.617 years (7.4 months) per year (R2=0.835; p<0.001). Sociodemographic factors associated with early death identified were male gender (hazard ratio - HR=1.30), white race (HR=1.16), death occurring in the hospital (HR=1.29), and living in the Greater São Paulo (HR=1.13). CONCLUSIONS: The mortality rate and the average age of death in patients with SCD have increased over the last two decades. Sociodemographic factors such as gender, race, place of occurrence, and residence were found to be associated with early death.

Thrombotic microangiopathy in patients with sickle cell disease.

OBJECTIVE: To describe two cases of patients who had thrombotic microangiopathy (TMA) associated with sickle cell disease (SCD). CASE DESCRIPTION: Both patients started with a painful crisis and had acute chest syndrome during hospitalization. They showed significant worsening of hemolytic anemia, with very high levels of lactate dehydrogenase, thrombocytopenia, lowered level of consciousness, organ damage and the presence of schistocytes in peripheral blood. Due to the possibility of TMA, despite the very rare association with SCD, they were treated with fresh frozen plasma replacement and plasmapheresis, with good response. COMMENTS: TMA is a serious, life-threatening disease, characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ damage. The association of SCD and TMA is difficult to diagnose, since they can share a similar clinical presentation. Recognizing this association and promptly instituting treatment may impact the survival of these patients.