Machine Learning-Based Prediction of COVID-19 Prognosis Using Clinical and Hematologic Data.

The coronavirus disease 2019 (COVID-19) pandemic is challenging healthcare systems worldwide. The prediction of disease prognosis has a critical role in confronting the burden of COVID-19. We aimed to investigate the feasibility of predicting COVID-19 patient outcomes and disease severity based on clinical and hematological parameters using machine learning techniques. This multicenter retrospective study analyzed records of 485 patients with COVID-19, including demographic information, symptoms, hematological variables, treatment information, and clinical outcomes. Different machine learning approaches, including random forest, multilayer perceptron, and support vector machine, were examined in this study. All models showed a comparable performance, yielding the best area under the curve of 0.96, in predicting the severity of disease and clinical outcome. We also identified the most relevant features in predicting COVID-19 patient outcomes, and we concluded that hematological parameters (neutrophils, lymphocytes, D-dimer, and monocytes) are the most predictive features of severity and patient outcome.

Clinical and hematologic presentations of adults with COVID-19 patients in Jeddah: A case control study.

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), is associated with significant morbidity and mortality. The clinical features of COVID-19 were mentioned in previous studies. However, risk factors for COVID-19 are not fully recognized. The aim of this study is to characterize risk factors and clinical features of COVID-19 disease in Jeddah, Saudi Arabia. METHODS: A retrospective, chart-review, case-control study was conducted at King Abdulaziz University, Jeddah, Saudi Arabia. Demographic, clinical, radiological, and laboratory data on patients diagnosed between March 18 and May 18, 2020 were collected and analyzed. RESULTS: We reviewed medical records on 297 suspected cases of COVID-19. Of these, 175 (59%) tested positive for COVID-19 by polymerase chain reaction (PCR) and considered as cases, while 122 (41%) tested negative and considered as control. COVID-19 positive cases were more likely to be males, and non-health care providers. Hypertension (15%), diabetes (10%) and two or more concurrent comorbidities (54.4%) were more prevalent among COVID-19 patients. Patients presented with fever, cough, and loss of taste/smell were more likely to test positive for COVID-19 (P = 0.001, 0.008, 0.008; respectively). Radiological evidence of pneumonia was associated with confirmed COVID-19 disease (P = 0.001). Shortness of breath and gastrointestinal symptoms were not associated with the risk of COVID-19 at presentation. On admission, white blood cells, neutrophils, lymphocytes, eosinophils, basophils, and platelets were significantly lower among COVID-19 patients compared with controls. Surprisingly, D-Dimer levels were lower among COVID-19 positive patients when compared with controls. CONCLUSION: Male gender, hypertension, and diabetes are the most commonly observed risk factors associated with COVID-19 disease in Jeddah, Saudi Arabia. COVID-19 patient had significantly lower lymphocyte and neutrophil counts.

Thromboprophylaxis for orthopedic surgery; An updated meta-analysis.

BACKGROUND: Venous thromboembolism (VTE) is a serious complication of orthopedic surgery. Low molecular weight heparin (LMWH) has been the standard of care for thromboprophylaxis in this population. However, direct oral anticoagulants (DOACs) are increasingly being used as alternatives. OBJECTIVE: To assess the efficacy and safety of DOACs versus LMWH for thromboprophylaxis in orthopedic surgery. METHODS: We searched MEDLINE, Embase, and the Cochrane Collaboration Central Register of Controlled Trials from inception until April 2020, for randomized controlled trials (RCTs) comparing DOACs with LMWH for thromboprophylaxis in orthopedic surgery. RESULTS: Twenty-five RCTs met inclusion criteria, including 40,438 patients, with a mean age of 68 years and 50% were males. Compared to LMWH, DOACs were associated with a significant reduction of major VTE; defined as the composite events of proximal deep vein thrombosis (DVT), pulmonary embolism (PE), and VTE-related mortality (RR 0.33; 95% CI: 0.20-0.53; P<0.01), and total DVT (RR: 0.59; 95% CI: 0.48-0.73; P<0.01), but not PE (RR 0.81; 95% CI: 0.49-1.34; P=0.42). There was no statistically significant difference between both groups on the incidence of major bleeding (RR 0.99; 95% CI: 0.77-1.27; P=0.92), clinically relevant non-major bleeding (RR 1.04; 95% CI: 0.92-1.17; P=0.52), all-cause mortality (RR 1.06; 95% CI: 0.64-1.76; P=0.83), VTE-related mortality (RR 0.84; 95% CI: 0.40-1.74; P=0.64) and bleeding-related mortality (RR 1.24; 95% CI: 0.30-5.18; P=0.77). CONCLUSION: For patients undergoing orthopedic surgery, thromboprophylaxis with DOACs is associated with a significant reduction of major VTE and DVT, compared to LMWH. Safety outcomes were not significantly different between both treatment groups.

Implementing remote triage in large health systems: A qualitative evidence synthesis.

Remote triage (RT) allows interprofessional teams (e.g., nurses and physicians) to assess patients and make clinical decisions remotely. RT use has developed widespread interest due to the COVID-19 pandemic, and has future potential to address the needs of a rapidly aging population, improve access to care, facilitate interprofessional team care, and ensure appropriate use of resources. However, despite rapid and increasing interest in implementation of RT, there is little research concerning practices for successful implementation. We conducted a systematic review and qualitative evidence synthesis of practices that impact the implementation of RT for adults seeking clinical care advice. We searched MEDLINE®, EMBASE, and CINAHL from inception through July 2018. We included 32 studies in this review. Our review identified four themes impacting the implementation of RT: characteristics of staff who use RT, influence of RT on staff, considerations in selecting RT tools, and environmental and contextual factors impacting RT. The findings of our systemic review underscore the need for a careful consideration of (a) organizational and stakeholder buy-in before launch, (b) physical and psychological workplace environment, (c) staff training and ongoing support, and (d) optimal metrics to assess the effectiveness and efficiency of implementation. Our findings indicate that preimplementation planning, as well as evaluating RT by collecting data during and after implementation, is essential to ensuring successful implementation and continued adoption of RT in a health care system.

Direct oral anticoagulant versus low-molecular-weight heparin for treatment of venous thromboembolism in cancer patients: An updated meta-analysis of randomized controlled trials.

BACKGROUND: Cancer associated venous thromboembolism (VTE) results in significant morbidity and mortality. Low molecular weight heparin (LMWH) has been standard of care for treatment of cancer-associated VTE, however direct oral anticoagulants (DOACs) are emerging as alternative treatment options. OBJECTIVE: To compare the benefits and harms of DOACs versus LMWH for treatment of VTE in cancer. DATA SOURCES: MEDLINE, Embase, and the Cochrane Collaboration Central Register of Controlled Trials from inception to April 2020. STUDY SELECTION: Randomized controlled trials (RCT) comparing DOACs with LMWH for treatment of VTE in cancer patients. DATA SYNTHESIS: Four good-quality RCTs, met inclusion criteria. Compared with LMWH, DOACs were associated with lower rates of VTE recurrence (RR 0.62; 95% CI: 0.44-0.87; P = 0.006), and DVT recurrence (RR 0.61; 95% CI: 0.4-0.94; P = 0.02) but not PE recurrence (RR 0.73; 95% CI: 0.51-1.04; P = 0.08), in cancer patients. However, the risk of clinically relevant non-major bleeding (CRNMB) (RR 1.58; 95% CI: 1.11-2.24; P = 0.01), and major bleeding in gastrointestinal cancer (RR 2.55; 95% CI 1.24-5.27, P = 0.01), were higher with DOACs. The risk of overall major bleeding (RR 1.33; 95% CI: 0.84-2.1; P = 0.22), all-cause mortality (RR 0.99; 95% CI: 0.84-1.17; P = 0.92), VTE-related mortality (RR: 1; 95% CI: 0.29-3.44; P = 1) and bleeding-related mortality (RR: 0.71; 95% CI: 0.17-2.91; P = 0.63), were similar in both treatment groups. CONCLUSION: Among cancer patients with VTE, treatment with DOACs is associated with a significant reduction of VTE and DVT recurrence, compared to LMWH. These benefits were offset by an increased risk of CRNMB, and major bleeding in gastrointestinal cancer.

Synonymous Mutation in DKC1 Causes Telomerase RNA Insufficiency Manifesting as Familial Pulmonary Fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the most common of short telomere phenotypes. Familial clustering of IPF is common, but the genetic basis remains unknown in more than one-half of cases. We identified a 65-year-old man with familial IPF, short telomere length, and low telomerase RNA levels. He was diagnosed with a short telomere syndrome after developing hematologic complications post-lung transplantation, but no mutations were identified in a clinical testing pipeline. RESEARCH QUESTION: What is the molecular basis underlying the familial IPF and low telomerase RNA levels in this patient? STUDY DESIGN AND METHODS: We analyzed whole-genome sequence data and performed functional molecular studies on cells derived from the patient and his family. RESULTS: We identified a previously unreported synonymous variant c.942G>A p.K314K in DKC1, the gene encoding the dyskerin ribonucleoprotein, which is required for telomerase RNA biogenesis. The mutation created a competing de novo exonic splicing enhancer, and the misspliced product was degraded by nonsense-mediated decay causing an overall dyskerin deficiency in mutation carriers. In silico tools identified other rare silent DKC1 variants that warrant functional evaluation if found in patients with short telomere-mediated disease. INTERPRETATION: Our data point to silent mutation in telomere maintenance genes as a mechanism of familial pulmonary fibrosis. In contrast to DKC1 missense mutations, which primarily manifest in children as dyskeratosis congenita, hypomorphic mutations affecting dyskerin levels likely have a predilection to presenting in adults as pulmonary fibrosis.

Evaluation of a point-of-care method for screening blood donors for sickle cell status.

BACKGROUND: Turbidity tests are commonly used for screening blood units for the presence of sickle cell trait (SCT) before transfusion to specific patient populations, based on recommendations of the AABB. In this pilot study, we evaluate a new method for screening blood donors and blood units for the presence of sickle hemoglobin. STUDY DESIGN AND METHODS: This study was based at King Abdulaziz University Hospital in Jeddah, Saudi Arabia. Study participants were approached consecutively between July 24, 2016, and August 8, 2016. Blood donors, control individuals, and known patients with sickle cell disease (SCD) were tested using both a point-of-care testing technology (Sickle SCAN, Biomedomics, Inc.) and hemoglobin capillary electrophoresis (HEP). Corresponding blood units were also tested using Sickle SCAN. RESULTS: A total of 200 donors, 13 blood units, and 57 patients and controls were included. Sensitivity and specificity of Sickle SCAN for detection of SCT and SCD was 100%, when compared to HEP as the gold standard. CONCLUSION: Sickle SCAN is a rapid test that shows high sensitivity and specificity for identification of hemoglobin S among blood donors and when used for testing blood units.

Effectiveness of Acute Care Remote Triage Systems: a Systematic Review.

BACKGROUND: Technology-based systems can facilitate remote decision-making to triage patients to the appropriate level of care. Despite technologic advances, the effects of implementation of these systems on patient and utilization outcomes are unclear. We evaluated the effects of remote triage systems on healthcare utilization, case resolution, and patient safety outcomes. METHODS: English-language searches of MEDLINE (via PubMed), EMBASE, and CINAHL were performed from inception until July 2018. Randomized and nonrandomized comparative studies of remote triage services that reported healthcare utilization, case resolution, and patient safety outcomes were included. Two reviewers assessed study and intervention characteristics independently for study quality, strength of evidence, and risk of bias. RESULTS: The literature search identified 5026 articles, of which eight met eligibility criteria. Five randomized, two controlled before-and-after, and one interrupted time series study assessed 3 categories of remote triage services: mode of delivery, triage professional type, and system organizational level. No study evaluated any other delivery mode other than telephone and in-person. Meta-analyses were unable to be performed because of study design and outcome heterogeneity; therefore, we narratively synthesized data. Overall, most studies did not demonstrate a decrease in primary care (PC) or emergency department (ED) utilization, with some studies showing a significant increase. Evidence suggested local, practice-based triage systems have greater case resolution and refer fewer patients to PC or ED services than regional/national systems. No study identified statistically significant differences in safety outcomes. CONCLUSION: Our review found limited evidence that remote triage reduces the burden of PC or ED utilization. However, remote triage by telephone can produce a high rate of call resolution and appears to be safe. Further study of other remote triage modalities is needed to realize the promise of remote triage services in optimizing healthcare outcomes. PROTOCOL REGISTRATION: This study was registered and followed a published protocol (PROSPERO: CRD42019112262).

Quality of life outcomes in thalassaemia patients in Saudi Arabia: a cross-sectional study.

BACKGROUND: Research focusing on health-related quality of life (HRQoL) in thalassaemia patients remains limited in Saudi Arabia. AIMS: To report on HRQoL outcomes in thalassaemia patients, and study associations with psychosocial and clinical factors. METHODS: Thalassaemia patients attending King Abdulaziz University Hospital were sequentially approached for enrolment. HRQoL outcomes were assessed using a validated Arabic version of the Medical Outcomes Study Short form (SF-36). RESULTS: This study included 105 individuals with ß-thalassaemia major, with a mean age of 22.9 (± 11.7) (range 5-35) years, and 52.4% were male. Participants aged ≥ 14 years had a mean physical HRQoL score of 43.7 (± 10.1) and mental HRQoL score of 46.6 (± 10.5). Participants aged < 14 years, had corresponding scores of 48.4 (± 10.7) and 52.9 (± 8.0), respectively. Physical functioning scores were significantly worse for older patients, and those reporting chronic pain. Lower scores of vitality were associated with older age, chronic pain and history of splenectomy. Older age and history of splenectomy were associated with lower scores of mental health. Controlling for other variables, younger age and higher pretransfusion haemoglobin were associated with better mental HRQoL. Professional workers had better physical HRQoL scores compared to nonprofessional workers.. CONCLUSIONS: Controlling for other variables, higher pretransfusion haemoglobin and younger age were associated with better mental HRQoL outcomes in thalassaemia patients. Professionals reported better physical HRQoL outcomes, compared to non-professionals. Preventive and comprehensive care models are needed in Saudi Arabia to improve HRQoL outcomes in thalassaemia patients.

The prevalence of APOL1 gene variants in a cohort of renal disease patients in Western Saudi Arabia.

Two variants for APOL1; the gastrointestinal (G1) variant (S342G and 1384M substitutions) and the G2 variant (N388 and Y389 deletions) have been previously described to be associated with renal disease. The prevalence of APOL1 variants in Saudi Arabia is unknown. We aimed to determine the prevalence of APOL1 variants in a cohort of patients with renal disease in Saudi Arabia. Patients with renal disease followed up at King Abdulaziz University Hospital were approached consecutively at the out patient clinic, and unaffected controls were approached at the blood donation area. Clinical and laboratory data were collected from electronic medical records. Laboratory variables in controls were obtained on enrollment. This is a cross-sectional, cohort study. One hundred and one patients with a mean age of 54.5 (±19) years, and 119 unaffected controls with a mean age of 31.9 (±7.89) years, were enrolled. Seventy-four patients (68.5%) had hypertension and 62 (57.4%) had diabetes. The mean estimated glomerular filtration rate was 22.47 (± 27.6) mL/min. Two patients were heterozygous for G1 allele. Among the control group, two were heterozygous for G1 allele, and three were heterozygous for G2. All five controls had no evidence of renal disease and no family history of renal disease. The prevalence of APOL1 genetic risk variants in the study cohort was very low. Larger studies are needed to determine the prevalence among renal disease patients in Saudi Arabia.

iPSC modeling of severe aplastic anemia reveals impaired differentiation and telomere shortening in blood progenitors.

Aplastic Anemia (AA) is a bone marrow failure (BMF) disorder, resulting in bone marrow hypocellularity and peripheral pancytopenia. Severe aplastic anemia (SAA) is a subset of AA defined by a more severe phenotype. Although the immunological nature of SAA pathogenesis is widely accepted, there is an increasing recognition of the role of dysfunctional hematopoietic stem cells in the disease phenotype. While pediatric SAA can be attributable to genetic causes, evidence is evolving on previously unrecognized genetic etiologies in a proportion of adults with SAA. Thus, there is an urgent need to better understand the pathophysiology of SAA, which will help to inform the course of disease progression and treatment options. We have derived induced pluripotent stem cell (iPSC) from three unaffected controls and three SAA patients and have shown that this in vitro model mimics two key features of the disease: (1) the failure to maintain telomere length during the reprogramming process and hematopoietic differentiation resulting in SAA-iPSC and iPSC-derived-hematopoietic progenitors with shorter telomeres than controls; (2) the impaired ability of SAA-iPSC-derived hematopoietic progenitors to give rise to erythroid and myeloid cells. While apoptosis and DNA damage response to replicative stress is similar between the control and SAA-iPSC-derived-hematopoietic progenitors, the latter show impaired proliferation which was not restored by eltrombopag, a drug which has been shown to restore hematopoiesis in SAA patients. Together, our data highlight the utility of patient specific iPSC in providing a disease model for SAA and predicting patient responses to various treatment modalities.

Management of Menopause Symptoms with Acupuncture: An Umbrella Systematic Review and Meta-Analysis.

OBJECTIVES: Vasomotor symptoms (VMSs) are the most common symptoms reported during menopause. Although hormone therapy is effective for reducing VMSs, its use is restricted in some women. Many women with VMSs thus seek nonhormonal, nonpharmacologic treatment options such as acupuncture. DESIGN: An umbrella systematic review (SR) was conducted, supplemented by a search of published randomized controlled trials (RCTs), that assessed the effectiveness of acupuncture for VMSs, health-related quality of life (HRQOL), and adverse effects of treatment in perimenopausal or postmenopausal women. Meta-analyses were conducted using a random-effects model when data were sufficient. RESULTS: Three SRs and four new RCTs were identified that met eligibility criteria. Meta-analyses of this study revealed statistically significant standardized mean differences (SMDs) associated with acupuncture compared with no acupuncture at reducing VMS frequency (SMD -0.66, 95% confidence interval [CI] -1.06 to -0.26, I2 = 61.7%, 5 trials) and VMS severity (SMD -0.49, 95% CI -0.85 to -0.13, I2 = 18.1%, 4 trials) and improving HRQOL outcomes (SMD -0.93, 95% CI -1.20 to -0.67, I2 = 0.0%, 3 trials). SMDs were smaller or not statistically significant when acupuncture was compared with sham acupuncture. CONCLUSIONS: Evidence from RCTs supports the use of acupuncture as an adjunctive or stand-alone treatment for reducing VMSs and improving HRQOL outcomes, with the caveat that observed clinical benefit associated with acupuncture may be due, in part, or in whole to nonspecific effects. The safety of acupuncture in the treatment of VMSs has not been rigorously examined, but there is no clear signal for a significant potential for harm.

Quality of Life Outcomes in a Pediatric Thalassemia Population in Egypt.

Thalassemia is a disorder of hemoglobin (Hb) synthesis characterized by chronic hemolysis. In ß-thalassemias major (ß-TM), patients require regular transfusion at an early age due to severe anemia. Subsequently, intensive chelation therapy is initiated to mitigate the effects of the resultant iron overload. Clinical disease burden and the demanding treatment can affect health-related quality of life (HRQoL) outcomes in this population. The aim of this study was to assess HRQoL outcomes in Egyptian pediatric thalassemia patients. Patients were enrolled simultaneously from the hematology clinic at the National Research Institute in Cairo, Egypt. The Arabic version of SF36 tool was used to assess HRQoL outcomes. Socioeconomic data were collected by patient and parent interviews. Clinical data were collected by review of medical records. One hundred and thirty patients and 60 controls were enrolled, with a mean age of 5.4 ± 3.2 years and 6.3 ± 3.0, respectively. The HRQoL outcome scores were lower in all domains in the thalassemia group compared to the control group (p = 0.0001). Transfusion-dependent (TD) patients had lower HRQoL scores compared to nontransfusion-dependent (NTD) patients (p = 0.0001). Patient education and maternal education were independently associated with better HRQoL scores (p = 0.007, p = 0.028, respectively). Residents of rural areas reported lower scores compared to urban residents (p = 0.026). Thalassemia was associated with lower HRQoL scores, in all domains, compared to HRQoL in unaffected controls. Chronic transfusion independence, patient education, and maternal education were all associated with higher HRQoL scores. Psychological, social, and economic support for families with thalassemia are all essential tools to improve HRQoL outcomes.

Plasmapheresis in severe methemoglobinemia following occupational exposure.

Ferrous iron can be converted to ferric iron by oxidative stress which results in the formation of methemoglobin. Consequently, the oxygen dissociation curve is shifted to the left, which leads to tissue hypoxia and ultimately may cause death. Acquired methemoglobinemia can be due to a host of offending agents and chemicals including nitrites, local anesthetics, aniline and antimalarial drugs. There are several approaches to the management of methemoglobinemia. The first step is to stop the offending agent and initiate supportive measures. Methylene blue can be used successfully provided the patient has no evidence of glucose 6 phosphate deficiency. Hyperbaric oxygen and intravenous ascorbic acid are other treatment options. We present a case of unusually severe methemoglobinemia (82% methemoglobin) secondary to occupational exposure that failed to respond to several lines of management including methylene blue, red cell exchange, intravenous ascorbic acid, and hyperbaric oxygen. However, the patient responded swiftly to plasmapheresis started upon suspicion of concomitant thrombotic thrombocytopenic purpura, and he subsequently recovered completely. Thus, plasmapheresis may have a role in severe methemoglonbinemia unresponsive to standard treatment options.

Depression, quality of life, and medical resource utilization in sickle cell disease.

Sickle cell disease (SCD) is a chronic, debilitating disorder. Chronically ill patients are at risk for depression, which can affect health-related quality of life (HRQoL), health care utilization, and cost. We performed an analytic epidemiologic prospective study to determine the prevalence of depression in adult patients with SCD and its association with HRQoL and medical resource utilization. Depression was measured by the Beck Depression Inventory and clinical history in adult SCD outpatients at a comprehensive SCD center. HRQoL was assessed using the SF36 form, and data were collected on medical resource utilization and corresponding cost. Neurocognitive functions were assessed using the CNS Vital Signs tool. Pain diaries were used to record daily pain. Out of 142 enrolled patients, 42 (35.2%) had depression. Depression was associated with worse physical and mental HRQoL scores (P < .0001 and P < .0001, respectively). Mean total inpatient costs ($25 000 vs $7487, P = .02) and total health care costs ($30 665 vs $13 016, P = .01) were significantly higher in patients with depression during the 12 months preceding diagnosis. Similarly, during the 6 months following diagnosis, mean total health care costs were significantly higher in depressed patients than in nondepressed patients ($13 766 vs $8670, P = .04). Depression is prevalent in adult patients with SCD and is associated with worse HRQoL and higher total health care costs. Efforts should focus on prevention, early diagnosis, and therapy for depression in SCD.

Markers of endothelial dysfunction and leucocyte activation in Saudi and non-Saudi haplotypes of sickle cell disease.

Sickle cell disease (SCD) is an autosomal recessive inherited hemoglobinopathy, characterized by chronic hemolysis and recurrent vaso-occlusive crisis (VOC). This study investigates changes in leucocyte subsets and the relationship between cell adhesion molecule expression and disease manifestations in patients during steady state and acute VOC. We compared soluble E-selectin and P-selectin levels in 84 SCD patients, in steady state and during VOC to 84 healthy controls. Using immunophenotyping, we also compared lymphocyte subsets in these three groups. Further, we compared E-selectin and P-selectin levels in patients of Saudi ethnicity to non-Saudi patients, in all three groups. Lymphocyte subsets showed high percentages of total T lymphocytes, T helper and suppressor lymphocytes, B lymphocytes as well as NK cells in patients with SCD during steady state, while B lymphocytes and NK cells were significantly higher during acute VOC crisis. High levels of both soluble E-selectin (sE-selectin) and soluble P-selectin (sP-selectin) markers were demonstrated in the serum of patients with SCD during both steady state and acute VOC. Levels of selectins were significantly higher in acute VOC. The immunophenotypic expression of L-selectin, on leucocytes, was high in SCD both during steady state and during acute VOC in comparison to normal control subjects. There was no significant difference in all three study groups between Saudi and non-Saudi patients. These findings suggest that patients with SCD have increased expression of adhesion molecules: E-selectin and P-selectin, which play an important role in the pathogenesis of VOC. Despite the distinct phenotype of Saudi patients with SCD, there was no significant difference in levels of soluble E-selectin and soluble P-selectin between Saudi and non-Saudi patients in all three groups. While sickle cell disease is a well-recognized state of chronic inflammation, the role of specific adhesion molecules is steadily unraveling. Studies are underway to investigate the potential role of selectin antagonists, for prevention and reversal of acute vascular occlusions in SCD patients.

Concise Review: Getting to the Core of Inherited Bone Marrow Failures.

Bone marrow failure syndromes (BMFS) are a group of disorders with complex pathophysiology characterized by a common phenotype of peripheral cytopenia and/or hypoplastic bone marrow. Understanding genetic factors contributing to the pathophysiology of BMFS has enabled the identification of causative genes and development of diagnostic tests. To date more than 40 mutations in genes involved in maintenance of genomic stability, DNA repair, ribosome and telomere biology have been identified. In addition, pathophysiological studies have provided insights into several biological pathways leading to the characterization of genotype/phenotype correlations as well as the development of diagnostic approaches and management strategies. Recent developments in bone marrow transplant techniques and the choice of conditioning regimens have helped improve transplant outcomes. However, current morbidity and mortality remain unacceptable underlining the need for further research in this area. Studies in mice have largely been unable to mimic disease phenotype in humans due to difficulties in fully replicating the human mutations and the differences between mouse and human cells with regard to telomere length regulation, processing of reactive oxygen species and lifespan. Recent advances in induced pluripotency have provided novel insights into disease pathogenesis and have generated excellent platforms for identifying signaling pathways and functional mapping of haplo-insufficient genes involved in large-scale chromosomal deletions-associated disorders. In this review, we have summarized the current state of knowledge in the field of BMFS with specific focus on modeling the inherited forms and how to best utilize these models for the development of targeted therapies. Stem Cells 2017;35:284-298.

Concomitant multiple myeloma, gastric adenocarcinoma and Evan's syndrome in a patient presenting with anaemia.

An association between multiple myeloma (MM) and solid tumours has been previously described.1 Furthermore, autoimmune disorders can precede plasma cell dyscrasias, and the pathogenesis of MM maybe linked to chronic immune stimulation. 2 We describe a case of concomitant MM and gastric adenocarcinoma preceded by Evan's syndrome. A previously healthy woman presented to the emergency room with symptomatic anaemia. Her initial workup was compatible with autoimmune haemolytic anaemia and monoclonal gammopathy of undetermined significance. On progression of the anaemia and development of thrombocytopenia, she was diagnosed with Evan's syndrome. Two months later, she presented with severe back pain and her MRI revealed L4-5 vertebral collapse. The clinical picture was compatible with MM. Occult blood was repeatedly positive in stools, and she underwent oesophagogastroduodenoscopy and was found to have gastric adenocarcinoma. The patient refused surgical resection of the adenocarcinoma and refused active treatment for MM.