Hydroxyurea in sickle cell disease and invasive bacterial infections: a case-control study.

Hydroxyurea decreases painful events among children with sickle cell disease but could increase the risk of infections in treated patients through leucopenia. We performed a case-control study, comparing hydroxyurea treatment for sickle cell disease in cases with an invasive bacterial infection and in controls without infection. No difference was found.

Red Cell Alloimmunisation Among Sickle Cell Disease and Thalassemia Patients Following Rh- and K-Matched Red Cell Transfusion in Southwestern Saudi Arabia: A Multicenter Study.

Background: Alloimmunisation remains a major consequence of blood transfusion among sickle cell disease (SCD) and thalassemia patients due to the exposure to non-self-red blood cell (RBC) antigen. The complication is associated with transfusion reactions and delayed transfusion procedure because of the difficulty of finding compatible blood. This study aims to determine the prevalence of alloimmunisation to RBC and alloantibody specificities among SCD and thalassemia patients in, an endemic area of SCD and thalassemia, Jazan province of Saudi Arabia, from three major hospitals. Methods: This is a retrospective, multicenter cross-sectional study conducted on 1027 patients with SCD and thalassemia, which received Rh/K matched transfusions in 2019 in the three centers. Demographic data and medical records of participants from three transfusion institutions were collected and analysed. Results: A total of 1027 were enrolled in the cohort; 906 (88.2%) and 121 (11.8%) patients with SCD and thalassemia, respectively. There were 483 (47%) males and 544 (53%) females with median age of 15 (range 1-48). Among the studied population, 78 were alloimmunised with an overall alloimmunisation rate of 7.6%. These patients developed a total of 108 alloantibodies, and anti-E was the most detected antibody (25.9%) followed by anti-K (24.1%). Conclusion: The overall rate of alloimmunisation to RBC antigen among the studied population in Jazan was low compared to other areas in the country. Most alloantibodies detected were against E and K antigens. The knowledge of most encountered alloantibodies in our population will aid in selecting the most appropriate antigen-negative red cells. Further research, however, is needed to explore factors associated with residual risk of alloimmunisation in these patients.

Other Wounds Encountered in Clinical Practice.

This chapter delves into uncommon wounds including pyoderma gangrenosum, sickle cell disease ulcers, vasculitic wounds, Martorell hypertensive ischemic leg ulcers, and malignant ulcers. Emphasizing a multidisciplinary approach, it covers diagnostics, treatments, and challenges, with case studies illustrating complexities in managing these conditions. The discussion extends to radiation-related wounds, underscoring the need for patient-centered care, interdisciplinary collaboration, and realistic goal setting. Overall, the chapter navigates the intricacies of uncommon wounds, emphasizing the importance of tailored approaches for improved outcomes in patients with diverse underlying conditions.

Can we use biomarkers to identify those at risk of acute pain from sickle cell disease?

INTRODUCTION: Acute pain episodes, also known as vaso-occlusive crises (VOC), are a major symptom of sickle cell disease (SCD) and lead to frequent hospitalizations. The diagnosis of VOC can be challenging, particularly in adults with SCD, 50% of whom have chronic pain. Several potential biomarkers have been proposed for identifying individuals with VOC, including elevation above the baseline of various vascular growth factors, cytokines, and other markers of inflammation. However, none have been validated to date. AREAS COVERED: We summarize prospective biomarkers for the diagnosis of acute pain in SCD, and how they may be involved in the pathophysiology of a VOC. Previous and current strategies for biomarker discovery, including the use of omics techniques, are discussed. EXPERT OPINION: Implementing a multi-omics-based approach will facilitate the discovery of objective and validated biomarkers for acute pain.

Trainees' perspectives on sickle cell education: a qualitative needs assessment.

BACKGROUND: Sickle cell disease (SCD) exemplifies many of the social, racial, and healthcare equity issues in the United States. Despite its high morbidity, mortality, and cost of care, SCD has not been prioritized in research and clinical teaching, resulting in under-trained clinicians and a poor evidence base for managing complications of the disease. This study aimed to perform a needs assessment, examining the perspectives of medical trainees pursuing hematology/oncology subspecialty training regarding SCD-focused education and clinical care. METHOD: Inductive, iterative thematic analysis was used to explore qualitative interviews of subspecialty hematology-oncology trainees' attitudes and preferences for education on the management of patients with SCD. Fifteen trainees from six programs in the United States participated in 4 focus groups between April and May 2023. RESULTS: Thematic analysis resulted in 3 themes: 1. Discomfort caring for patients with SCD. 2. Challenges managing complications of SCD, and 3. Desire for SCD specific education. Patient care challenges included the complexity of managing SCD complications, limited evidence to guide practice, and healthcare bias. Skill-building challenges included lack of longitudinal exposure, access to expert clinicians, and didactics. CONCLUSIONS: Variations in exposure, limited formal didactics, and a lack of national standardization for SCD education during training contributes to trainees' discomfort and challenges in managing SCD, which in turn, contribute to decreased interest in entering the SCD workforce. The findings underscore the need for ACGME competency amendments, dedicated SCD rotations, and standardized didactics to address the gaps in SCD education.

Secretory Phospholipase A2 Levels Are High in Women with Sickle Cell Disease and Menstruation-Induced Vaso-Occlusive Crises.

Menstruation-induced vaso-occlusive crisis (MIVOC) is a significant cause of morbidity in women with sickle cell disease (SCD). Secretory phospholipase A2 (sPLA2) is an inflammatory biomarker that is elevated in vaso-occlusive events such as acute chest syndrome (ACS), but its role in MIVOC is not previously studied. This study compared the serum level of sPLA2 among women with MIVOC and those without MIVOC. This is a comparative cross-sectional study. 354 women with SCD were screened for MIVOC using a structured questionnaire. sPLA2 levels were assayed using a standard ELISA while full blood counts were performed on an automated hematology analyzer. Data were analyzed using the SPSS software v26.0. Results were summarized as frequencies, percentages, and mean ± standard deviation. Variables were compared using the Student's t-test and Pearson's correlation. A p-value of <.05 was considered significant. The prevalence of MIVOC was 26.8%. Participants with MIVOC (n = 95) had significantly lower mean hemoglobin concentration (8.00 ± 2.03g/dL vs. 9.95 ± 4.15g/dL, p < .000), significantly higher mean platelets count (518.71 ± 84.58 × 109/L vs 322.21 ± 63.80 × 109/L, p < .000) and higher sPLA2 level (6.58 ± 1.94 IU vs 6.03 ± 0.42 IU, p = .008) compared to those without MIVOC (n = 95). Among participants with MIVOC, sPLA2 levels positively correlated with total white blood cell, absolute neutrophil, and lymphocyte counts. This study demonstrates that MIVOC is common among women with SCD and that the pathophysiology of MIVOC may have an inflammatory basis similar to that of ACS. The potential role of anti-inflammatory and antiplatelet agents in preventing and treating MIVOC may be explored.

A pharmacokinetic-pharmacodynamic analysis of l-glutamine for the treatment of sickle cell disease: Implications for understanding the mechanism of action and evaluating response to therapy.

The mechanisms of action of l-glutamine for the treatment of sickle cell disease (SCD) are not well understood and there are no validated clinical biomarkers to assess response. We conducted a three-week, dose-ascending trial of glutamine and measured the pharmacokinetic (PK) exposure parameters, peak concentration (Cmax) and area under the curve (AUC). We used a panel of biomarkers to investigate the pharmacodynamics (PD) of glutamine and studied PK-PD relationships. There was no plasma accumulation of glutamine, glutamate, arginine or other amino acids over time, but modestly improved arginine bioavailability was observed. In standard analysis by dose levels over time, there were no measurable effects on blood counts, viscosity, ektacytometry or reactive oxygen species (ROS). In PK-PD analysis, however, higher glutamine exposure (Cmax or AUC) was associated with increased whole blood viscosity and cellular dehydration, yet also with higher haemoglobin concentration, increased haematocrit-to-viscosity ratio, decreased reticulocyte ROS, improved RBC deformability and decreased point of sickling. This novel PK-PD analysis identified biomarkers reflecting the positive and negative effects of glutamine, helping to elucidate its mechanisms of action in SCD. PK-optimized dosing to achieve glutamine exposure (AUC or Cmax) that is associated with salutary biological effects should be studied to support its therapeutic use.

An Examination of John Henryism in Adults Living with Sickle Cell Disease.

BACKGROUND: John Henryism (JH) is a behavioral predisposition for high-effort coping with adversity. JH has been associated with hypertension in Black Americans with low socioeconomic status (SES) and is also found to be associated with psychological well-being. Sickle cell disease (SCD), a rare genetic disease largely affecting Black Americans in the United States, presents as a chronic condition that may benefit from a deeper understanding of the impact of JH on overall health. PURPOSE: This study examined the association between high and low JH and diastolic blood pressure, systolic blood pressure, hypertension prevalence, and sleep function. We relied on the biopsychosocial transaction model to adjust for relevant clinical and sociodemographic variables. METHODS: This was a cross-sectional secondary analysis of 274 adults with SCD living in the United States and recruited between 2014 and 2020. Study visits consisted of physical examinations, medical history, demographic, and psychosocial questionnaires. Adjusted linear regressions estimated associations between high and low JH and diastolic and systolic blood pressure as well as self-reported sleep function. Multivariable logistic regression was used to examine associations with hypertension prevalence. RESULTS: High JH was significantly associated with lower diastolic blood pressure (ß = - 2.98; 95% confidence interval = - 5.92, - 0.04) but higher sleep dysfunction (ß = 2.76; 95% confidence interval = 1.45, 4.07). CONCLUSIONS: Overall, we found positive psychological coping resources associated with high JH, with the exception of sleep. CLINICALTRIALS: gov Identifier: NCT02156102.

Diagnostic accuracy of mean corpuscular volume in detecting coexisting iron deficiency in patients of sickle cell disorders: A hospital-based study.

Background: Co-existing iron deficiency in patients of sickle cell disease (SCD) and trait may worsen anemia, and adversely affect neuro-cognitive development and growth. Determining a cut-off below which Mean corpuscular Volume (MCV) can predict iron deficiency in SCD patients can preclude use of more expensive test serum ferritin. Aims: This study was conducted to determine the diagnostic accuracy of low MCV in detecting iron deficiency compared to serum ferritin levels in patients with SCD. Methods: 60 consecutive patients with SS or AS pattern on hemoglobin electrophoresis were enrolled. The index test (MCV) and the reference standard test (serum ferritin) were performed in a blind and independent manner. The measures of diagnostic accuracy were calculated and the precision of the point estimates were expressed by 95% confidence intervals. As MCV is a continuous variable, we also used multi-level likelihood ratios to compute diagnostic accuracy of MCV at several cut-points. Results: The sensitivity of low MCV in detecting iron deficiency was 40.0% (95% CI-20.0-63.6), the specificity was 78.4% (95% CI-61.3-89.6) using serum ferritin as a reference standard. The sensitivity and specificity of predicting coexisting iron deficiency at this point was 60.9% (CI-38.6-80.3%) and 75.7% (CI-58.8-88.2%) respectively. Conclusions: The low sensitivity (40%) of microcytosis in detecting iron deficiency indicates that many cases will be missed if MCV alone is used to detect co-existing iron deficiency anemia in SCD patients. No single test is good enough to detect co-existing iron deficiency and a combination of tests might be useful.

A child with sickle cell disease admitted with coronavirus disease 2019 pneumonia and acute chest syndrome in pediatric intensive care unit: A case report.

Management of sickle cell disease complications in the setting of the coronavirus disease 2019 (COVID-19) pandemic is complicated with little published pediatric data. We report the first documented case of a 9-year-old boy with sickle cell disease, presenting with fever, cough, and shortness of breath, diagnosed to have acute chest syndrome and coronavirus disease 2019 (COVID-19) pneumonia with inflammatory storm requiring ventilation, exchange blood transfusion, immunomodulatory agents, and prophylactic anticoagulation. The patient responded satisfactorily to the management of the acute illness and was found to be well at the next visit to the pediatric hematology outpatient department following hospital discharge.

Emergency department utilization before and during the COVID-19 pandemic among individuals with sickle cell disease.

BACKGROUND: The emergency department (ED) is a vital source of healthcare for individuals living with sickle cell disease (SCD). Prior research indicates that during the COVID-19 pandemic some individuals with SCD avoided the ED for fear of acquiring COVID-19 or delayed visiting the ED by self-management of symptoms or pain crisis at home. The purpose of the current study was to understand ED utilization rates before and during the pandemic among individuals living with SCD. METHODS: We conducted a retrospective cohort study using population-based SCD surveillance systems in California, Georgia, Michigan, and Tennessee to assess the impact of the pandemic on ED utilization among people with SCD by (1) analyzing trends in monthly ED utilization from January 2019 - December 2020, with specific attention given to immediate changes at the onset of the pandemic; and (2) calculating changes in the volume of utilization by comparing the total ED visits made from March - December 2020 to the same period in 2019, both overall and by demographic characteristics. RESULTS: Across all states, a decline in ED utilization during the onset of the pandemic was seen, with the largest decline seen in those under age 10. By December 2020, utilization rates were higher than their lowest observed month of April 2020, but had not fully returned to pre-COVID levels. During the pandemic, ED visits in each state decreased by as much as 25%, and the number of people with any ED utilization decreased by as much as 26%. CONCLUSIONS: This study confirms and extends the existing literature related to the impact of the pandemic on healthcare utilization patterns in the US, in a unique population with increased healthcare needs.

The Ugandan sickle Pan-African research consortium registry: design, development, and lessons.

BACKGROUND: Sub-Saharan Africa bears the highest burden of sickle cell disease (SCD) globally with Nigeria, Democratic Republic of Congo, Tanzania, Uganda being the most affected countries. Uganda reports approximately 20,000 SCD births annually, constituting 6.67% of reported global SCD births. Despite this, there is a paucity of comprehensive data on SCD from the African continent. SCD registries offer a promising avenue for conducting prospective studies, elucidating disease severity patterns, and evaluating the intricate interplay of social, environmental, and genetic factors. This paper describes the establishment of the Sickle Pan Africa Research Consortium (SPARCo) Uganda registry, encompassing its design, development, data collection, and key insights learned, aligning with collaborative efforts in Nigeria, Tanzania, and Ghana SPARCo registries. METHODS: The registry was created using pre-existing case report forms harmonized from the SPARCo data dictionary and ontology to fit Uganda clinical needs. The case report forms were developed with SCD data elements of interest including demographics, consent, baseline, clinical, laboratory and others. That data was then parsed into a customized REDCap database, configured to suit the optimized ontologies and support retrieval aggregations and analyses. Patients were enrolled from one national referral and three regional referral hospitals in Uganda. RESULTS: A nationwide electronic patient-consented registry for SCD was established from four regional hospitals. A total of 5,655 patients were enrolled from Mulago National Referral Hospital (58%), Jinja Regional Referral (14.4%), Mbale Regional Referral (16.9%), and Lira Regional Referral (10.7%) hospitals between June 2022 and October 2023. CONCLUSION: Uganda has been able to develop a SCD registry consistent with data from Tanzania, Nigeria and Ghana. Our findings demonstrate that it's feasible to develop longitudinal SCD registries in sub-Saharan Africa. These registries will be crucial for facilitating a range of studies, including the analysis of SCD clinical phenotypes and patient outcomes, newborn screening, and evaluation of hydroxyurea use, among others. This initiative underscores the potential for developing comprehensive disease registries in resource-limited settings, fostering collaborative, data-driven research efforts aimed at addressing the multifaceted challenges of SCD in Africa.

Gene therapies on the horizon for sickle cell disease: a clinician's perspective.

INTRODUCTION: Sickle cell disease (SCD) is a monogenic disorder that exerts several detrimental health effects on those affected, ultimately resulting in significant morbidity and early mortality. There are millions of individuals globally impacted by this disease. Research in gene therapy has been growing significantly over the past decade, now with two FDA approved products, aiming to find another cure for this complex disease. AREAS COVERED: This perspective article aims to provide a clinician's insight into the current landscape of gene therapies, exploring the novel approaches, clinical advances, and potential impact on the management and prognosis of SCD. A comprehensive literature search encompassing databases such as PubMed, Web of Science and Google Scholar was employed. The search covered literature published from 1980 to 2024, focusing on SCD and curative therapy. EXPERT OPINION: After careful evaluation of the risks and benefits associated with the use of gene therapy for affected patients, the need for a cure outweighs the risks associated with treatment in most cases of SCD. With advances in current technologies, gene therapies can increase access to cures for patients with SCD.

The medication usage pattern and prevalence of polypharmacy among patients with sickle cell disease: a population-based study in southern Iran.

BACKGROUND: Due to the numerous complications associated with sickle cell disease (SCD), patients often receive a variety of medications alongside their SCD treatment. However, a notable gap exists in the current literature regarding medication use patterns among them. This study aimed to investigate medication usage patterns in patients with SCD. RESEARCH DESIGN AND METHODS: This cross-sectional study, conducted in Bushehr Province, employed a stratified random sampling method to select eligible participants with SCD. A thorough interview gathered various information, including details about the medications. The Anatomical Therapeutic Chemical classification system was utilized for drug classification. Polypharmacy was defined as the concurrent use of at least five medications. RESULTS: A total of 300 individuals with SCD were included in this study. Polypharmacy was observed in 26.3% (95% CI: 20.8%-32.8%) of the study population. The analyses revealed positive associations between the use of more concurrent medication use and higher age groups and having multimorbidity. Antianemic preparations (86.7%), antineoplastic agents (58.3%), and vitamins (41.0%) were the most frequent medication classes used by the study participants. CONCLUSIONS: Our study revealed notable underutilization of hydroxyurea and a high rate of polypharmacy, associated with age and multimorbidity, among patients with SCD in southern Iran.

Total Hip Arthroplasty Complications in Sickle Cell Disease: Systematic Review and Meta-Analysis.

Background: Microvascular occlusions caused by sickle-shaped erythrocytes in patients with sickle cell disease (SCD) can lead to increased intraoperative and postoperative complications during total hip arthroplasty (THA). This systematic review and meta-analysis aimed to estimate the overall rate of complications following THA in patients with SCD and to identify the predictors of these complications including the surgical approach. Methods: The search was conducted across the grey literature, Google Scholar, and seven databases: Scopus, MEDLINE Central/PubMed, ProQuest, SciELO, SAGE, and Web of Science. All observational studies reporting the proportional THA complications in SCD were included. The Newcastle-Ottawa Scale quality assessment tool was used to assess the quality of the studies. The random effect model was applied to estimate the pooled outcomes. A sub-group analysis for the different approaches was performed. A sensitivity analysis and meta-regression were used to explain heterogeneity and to identify the THA complication predictors. Results: Of 3230 citations, only 23 studies were eligible for the meta-analysis. The pooled proportion of total primary THA complications in patients with SCD was 42% (95% CI: 30-56%, I2 = 95%). The sub-group analysis highlighted the anterolateral approach as the approach accompanied with the least complications. The meta-regression revealed that the anterolateral approach decreases the complications significantly, -28.67 (95%CI, -56.45--0.88, p = 0.044), while the number of hips increased the complications by 0.43 (95%CI, 0.30-0.57, p < 0.001). Male gender, age, lateral approach, and HbSS non-significantly affect the THA complications in SCD 52.05, 0.18, 6.06, and 55.78, respectively. The pooled proportions for an SCD crisis 9% (95%CI, 5-14%, I2 = 61%), dislocation 4% (95%CI: 2-7%, I2 = 66%), aseptic loosening 12% (95%CI, 7-20%, I2 = 91%), revision 6% (3-11, I2 = 92%), heterotopic ossification 12% (95%CI, 3-35%, I2 = 95%), and prosthetic joint infection (PJI) 6% (95%CI, 3-11%, I2 = 92%). The most fitted model of meta-regression illustrated that HbSS significantly increases PJI, 0.05 (95%CI: 0.02-0.08, p = 0.009), and male gender and age non-significantly increase PJI, 2.28 (95%CI: -4.99-13.56, p = 0.311) and 0.001 (95%CI: -0.27-0.27, p = 0.990), respectively. Meanwhile, the anterolateral, lateral, and posterior approaches non-significantly decrease PJI, -3.55, -0.92, and -1.27, respectively. The pooled proportion for a sickle cell disease crisis after revision was 16% (95%CI: 6-36%, I2 = 0) and for aseptic loosening after revision, it was 24% (95%CI: 12-43%, I2 = 0). Conclusions: This study revealed the high rate of complications in patients with SCD and highlighted that the anterolateral approach was associated with the lowest rate of complications. Furthermore, this study illustrated that homozygous (HbSS) individuals are more susceptible to prosthetic joint infection.

A genome-wide association study of alloimmunization in the TOPMed OMG-SCD cohort identifies a locus on chromosome 12.

BACKGROUND: Red cell alloimmunization after exposure to donor red cells is a very common complication of transfusion for patients with sickle cell disease (SCD), resulting frequently in accelerated donor red blood cell destruction. Patients show substantial differences in their predisposition to alloimmunization, and genetic variability is one proposed component. Although several genetic association studies have been conducted for alloimmunization, the results have been inconsistent, and the genetic determinants of alloimmunization remain largely unknown. STUDY DESIGN AND METHODS: We performed a genome-wide association study (GWAS) in 236 African American (AA) SCD patients from the Outcome Modifying Genes in Sickle Cell Disease (OMG-SCD) cohort, which is part of Trans-Omics for Precision Medicine (TOPMed), with whole-genome sequencing data available. We also performed sensitivity analyses adjusting for different sets of covariates and applied different sample grouping strategies based on the number of alloantibodies patients developed. RESULTS: We identified one genome-wide significant locus on chr12 (p = 3.1e-9) with no evidence of genomic inflation (lambda = 1.003). Further leveraging QTL evidence from GTEx whole blood and/or Jackson Heart Study PBMC RNA-Seq data, we identified a number of potential genes, such as ARHGAP9, STAT6, and ATP23, that may be driving the association signal. We also discovered some suggestive loci using different analysis strategies. DISCUSSION: We call for the community to collect additional alloantibody information within SCD cohorts to further the understanding of the genetic basis of alloimmunization in order to improve transfusion outcomes.

Comorbid ADHD and Pediatric Sickle Cell Disease: Prevalence and Risk Factors.

Sickle cell disease (SCD) is a genetic blood condition that places youth at increased risk for deficits in complex attention suggestive of increased risk for Attention-Deficit/Hyperactivity Disorder (ADHD). We used systematic screening to assess the prevalence of ADHD in a clinic-based sample of youth with SCD and explored factors related to ADHD. Caregivers of 107 children with SCD (ages 7-11 years) completed routine psychosocial screening which included inattentive symptoms of ADHD. Follow-up diagnostic procedures were completed for patients with elevated inattentive symptoms to assess for ADHD diagnoses. Biomedical and social-environmental variables were examined from the screening and medical records. Twenty-six percent of patients showed elevated inattentive symptoms with 13% meeting diagnostic criteria for ADHD diagnoses. Most children (75%) who met criteria for ADHD had not been previously diagnosed. Disease severity did not predict inattentive symptoms or ADHD diagnoses, though a measure of chronic inflammation was associated with ADHD. Family functioning was related to elevated inattentive symptoms but not ADHD diagnoses. Children with SCD show relatively high rates of ADHD with many cases not detected through routine care. Screening for ADHD as part of hematology care may be a feasible strategy to improve identification and access to intervention.

Selectins in Biology and Human Disease: Opportunity in E-selectin Antagonism.

Selectins are cell adhesion proteins discovered in the 1980s. As C-type lectins, selectins contain an essential calcium ion in the ligand-binding pocket and recognize the isomeric tetrasaccharides sialyl Lewisx (sLex) and sialyl Lewisa (sLea). Three selectins, E-selectin, P-selectin, and L-selectin, play distinct, complementary roles in inflammation, hematopoiesis, and tumor biology. They have been implicated in the pathology of diverse inflammatory disorders, and several selectin antagonists have been tested clinically. E-selectin plays a unique role in leukocyte activation, making it an attractive target for intervention, for example, in sickle cell disease (SCD). This review summarizes selectin biology and pathology, structure and ligand binding, and selectin antagonists that have reached clinical testing with an emphasis on E-selectin.

Sickle Cell Screening in Adults: A Current Review of Point-of-Care Testing.

In adults, the sickle cell solubility test (SCST) is the most common screening test to determine the presence of hemoglobin S (HbS) within a blood sample. The assay is inexpensive, rapid, highly sensitive and specific. However, the SCST cannot accurately quantify the level of HbS in a test sample and requires confirmatory testing to distinguish between sickle trait and sickle cell disease. Despite these limitations, it remains the standard screening tool for HbS in a variety of settings such as screening in the US military or by the National Collegiate Athletic Association. With an increased awareness of the importance of screening for sickle cell in adults, we herein describe the current sensitivity, specificity, positive predictive value, and negative predictive value of this test. We also review overall clinical utility of this laboratory measure and briefly discuss new point-of-care techniques designed to overcome the SCST's shortcomings.