Range Of Clinical Outcomes Research Articles

The impact of fibre and prebiotic interventions on outcomes in cancer and haematopoietic stem cell transplantation: a systematic review

Background & aimsCancer therapy is associated with a range of toxicities that severely impact patient well-being and a range of clinical outcomes. Dietary fibre/prebiotics characteristically improve the gastrointestinal microenvironment, which consequently elicits beneficial downstream effects that could be relevant to the prevention and management of treatment-related toxicities. Despite the compelling theoretical scientific rationale there has been limited effort to synthesise the available evidence to conclude such scientific underpinning to the clinical use of fibre/prebiotics in cancer patients. Therefore, this systematic review aimed to evaluate the clinical impact of fibre/prebiotic-based interventions on gastrointestinal-side effects; gastrointestinal-microbiome; clinical outcomes; nutrition status and body composition; and quality-of-life in children and adults being treated for cancer or undergoing a haematopoietic stem cell transplant (HSCT). MethodsThis study was conducted in adherence to PRISMA guidelines, and the protocol was published prospectively with PROSPERO (CRD42022299428). Three databases (MEDLINE (Ovid), CINHAL, EMBASE) were searched from inception to December 2023. All articles were assessed for bias using the Cochrane risk-of-bias tool RoB 2.0 (for RCTs) and ROBINS-I (for non-RCTs). ResultsA total of 9989 de-duplicated records were identified, of these, 14 (paediatrics [n= 1], adults [n=13]) met the inclusion criteria (randomised controlled trials (RCT) [n = 11], observational or non-RCTs [n = 3]). The risk-of-bias was graded to be serious/high (n=6); moderate/some concerns (n=7); low (n=1). Interventions included prebiotic supplement (n=8), nutrition supplement/formula with added fibre/prebiotic (n=3) and dietary modification (n=3). The dose of fibre intervention ranged from 2.4g-30g per day. Substantial heterogeneity of target parameters was identified across a range all outcome categories, precluding definitive conclusions. ConclusionThe scientific rationale for fibre/prebiotics-based interventions for the prevention or management of cancer treatment-related toxicities is compelling. However, it is clear that the scientific and clinical field remains disconnected in how to effectively translate this approach to improve cancer outcomes. High-quality intervention studies translatable to clinical practice are now evidently crucial to determine if and how fibre/prebiotics should be used to support people undergoing cancer or HSCT therapy.

Dynamics of Trypanosoma cruzi infection in hamsters and novel association with progressive motor dysfunction.

Chagas disease is a zoonosis caused by the protozoan parasite Trypanosoma cruzi. Clinical outcomes range from long-term asymptomatic carriage to cardiac, digestive, neurological and composite presentations that can be fatal in both acute and chronic stages of the disease. Studies of T. cruzi in animal models, principally mice, have informed our understanding of the biological basis of this variability and its relationship to infection and host response dynamics. Hamsters have higher translational value for many human infectious diseases, but they have not been well developed as models of Chagas disease. We transposed a real-time bioluminescence imaging system for T. cruzi infection from mice into female Syrian hamsters (Mesocricetus auratus). This enabled us to study chronic tissue pathology in the context of spatiotemporal infection dynamics. Acute infections were widely disseminated, whereas chronic infections were almost entirely restricted to the skin and subcutaneous adipose tissue. Neither cardiac nor digestive tract disease were reproducible features of the model. Skeletal muscle had only sporadic parasitism in the chronic phase, but nevertheless displayed significant inflammation and fibrosis, features also seen in mouse models. Whereas mice had normal locomotion, all chronically infected hamsters developed hindlimb muscle hypertonia and a gait dysfunction resembling spastic diplegia. With further development, this model may therefore prove valuable in studies of peripheral nervous system involvement in Chagas disease.

Transperineal Laser Ablation of the Prostate for Symptomatic Benign Prostatic Hyperplasia: Long-Term Follow-Up in 40 Patients

PurposeTo evaluate the durability, effectiveness, and safety of transperineal laser ablation (TPLA) of the prostate. Materials and MethodsPatients with symptomatic benign prostatic hyperplasia (BPH) underwent TPLA with a 1,064-nm continuous-wave diode laser. International Prostate Symptom Score (IPSS), quality of life (QoL), postvoid residual (PVR), and prostate volume were evaluated at baseline and successive timepoints. ResultsForty prospectively enrolled patients had follow-up of ≥36 months; median duration of follow-up was 57 months (range, 36–76 months). Compared with baseline, the median reduction in IPSS at 12-month follow-up was 74% (interquartile range [IQR], 60%–81%) (P < .001). Median QoL score at 12 months was improved from 5 (IQR, 4–5) at baseline to 1 (IQR, 0–1) (P < .001). Median PVR at 12 months decreased from 108 mL (IQR, 38–178 mL) to 13.5 mL (IQR, 0–40.5 mL) (P < .001), a median reduction of 88% (IQR, 61%–100%). At 12 months, median prostate volume was significantly reduced from 66 mL (IQR, 48.5–86.5 mL) to 46 mL (IQR, 36–65 mL) (P < .001), a median reduction of 32% (IQR, 21%–45%). For all of these parameters, the benefit of TPLA persisted at last follow-up, and all changes were statistically significant compared with baseline. There were no intraprocedural adverse events; periprocedural adverse events consisted of 1 case of prostatitis and 1 case of urinary tract infection (both Society of Interventional Radiology [SIR] Grade I). ConclusionsTPLA for symptomatic BPH produced durable benefits across a range of clinical outcomes and was well tolerated in follow-up at median duration of 57 months.

Myelodysplastic neoplasms dissected into indolent, leukaemic and unfavourable subtypes by computational clustering of haematopoietic stem and progenitor cells

Myelodysplastic neoplasms (MDS) encompass haematological malignancies, which are characterised by dysplasia, ineffective haematopoiesis and the risk of progression towards acute myeloid leukaemia (AML). Myelodysplastic neoplasms are notorious for their heterogeneity: clinical outcomes range from a near-normal life expectancy to leukaemic transformation or premature death due to cytopenia. The Molecular International Prognostic Scoring System made progress in the dissection of MDS by clinical outcomes. To contribute to the risk stratification of MDS by immunophenotypic profiles, this study performed computational clustering of flow cytometry data of CD34+ cells in 67 MDS, 67 AML patients and 49 controls. Our data revealed heterogeneity also within the MDS-derived CD34+ compartment. In MDS, maintenance of lymphoid progenitors and megakaryocytic-erythroid progenitors predicted favourable outcomes, whereas expansion of granulocyte-monocyte progenitors increased the risk of leukaemic transformation. The proliferation of haematopoietic stem cells and common myeloid progenitors with downregulated CD44 expression, suggestive of impaired haematopoietic differentiation, characterised a distinct MDS subtype with a poor overall survival. This exploratory study demonstrates the prognostic value of known and previously unexplored CD34+ populations and suggests the feasibility of dissecting MDS into a more indolent, a leukaemic and another unfavourable subtype.

Neurophysiological Models in Individuals at Clinical High Risk for Psychosis: Using Translational EEG Paradigms to Forecast Psychosis Risk and Resilience.

Over the last several decades, there have been major research efforts to improve the identification of youth and young adults at clinical high-risk for psychosis (CHR-P). Among individuals identified as CHR-P based on clinical criteria, approximately 20% progress to full-blown psychosis over 2-3 years and 30% achieve remission. In more recent years, neurophysiological measures with established sensitivity to schizophrenia have gained traction in the study of CHR-P and its range of clinical outcomes, with the goal of identifying specific biomarkers that precede psychosis onset that 7 chapter, we review studies examining several translational electroencephalography (EEG) and event-related potential (ERP) measures, which have known sensitivity to schizophrenia and reflect abnormal sensory, perceptual, and cognitive processing of task stimuli, as predictors of future clinical outcomes in CHR-P individuals. We discuss the promise of these EEG/ERP biomarkers of psychosis risk, including their potential to provide (a) translational bridges between human studies and animal models focused on drug development for early psychosis, (b) target engagement measures for clinical trials, and (c) prognostic indicators that could enhance personalized treatment planning.

Acute epigastric pain unveiling biventricular myocardial infarction: A case report

Acute coronary syndromes are a clinical entity frequently encountered in practice and are responsible for significant morbidity and mortality, despite therapeutic advances. The initiation of early reperfusion therapy reduces mortality and morbidity and improves patients’ prognosis, but this depends on how quickly patients receive their treatment. Although it is often easy to diagnose in the presence of typical symptoms, certain patients, such as diabetics, sometimes have atypical symptoms, resulting in a delay in management. In nearly 50% of cases, inferior wall ischaemia is accompanied by right ventricular myocardial infarction; the clinical outcomes range from no hemodynamic compromise to severe hypotension and cardiogenic shock. In this article, we present the case of a 54-year-old male patient with active smoking and poorly controlled type 2 diabetes as cardiovascular risk factors who initially consulted at the first hour for epigastric pain, for which he received symptomatic treatment. As the symptoms persisted, he was admitted to our department at the eighth hour, where he was diagnosed with a biventricular infarction.

Measuring flexibility in autistic adults: Exploring the factor structure of the flexibility scale self report.

Cognitive flexibility differences are common for autistic individuals and have an impact on a range of clinical outcomes. However, there is currently a lack of well validated measurement tools to assess flexibility in adulthood. The Flexibility Scale was originally designed as a parent-report measure of real-world flexibility challenges in youth. The original Flexibility Scale provides a total score and five subscales: Routines and Rituals, Transitions and Change, Special Interests, Social Flexibility, and Generativity. In this study, we evaluate the factorial validity of the Flexibility Scale as a self-report (Flexibility Scale Self Report) measure of cognitive flexibility, adapted from the original Flexibility Scale, for use by autistic adults. This study includes both a primary sample (n = 813; mean age = 40.3; 59% female) and an independently recruited replication sample (n = 120; mean age = 32.8; 74% female) of individuals who completed the Flexibility Scale Self Report. The analysis consisted of an initial confirmatory factor analysis (CFA) of the original Flexibility Scale structure, followed by exploratory factor analysis (EFA) and factor optimization within a structural equation modeling framework to identify the optimal structure for the questionnaire in adults. The identified structure was then replicated through CFA in the replication sample. Our results indicate an alternative optimal scale structure from the original Flexibility Scale, which includes fewer items, and only three (Routines/Rituals, Transitions and Change, Special Interests) of the five subscales contributing to the flexibility total score. Comparisons revealed no structural differences within the scale based on sex assigned at birth. Here the Generativity and Social Flexibility scales are treated as independent but related scales. The implications for measurement of cognitive flexibility in clinical and research settings, as well as theoretical underpinnings are discussed.

SST2 Levels Show No Association with Helicobacter pylori Infection in Asymptomatic Patients: Implications for Biomarker Research

IntroductionHelicobacter pylori (H. pylori) is a prevalent stomach bacterium that can cause a range of clinical outcomes, including gastric cancer. In recent years, soluble suppression of tumorigenicity-2 (sST2) has gained attention as a biomarker associated with various diseases, such as gastric cancer. The purpose of this study was to explore the possible connection between H. pylori infection and sST2 levels in patients who do not exhibit symptoms.MethodsA total of 694 patients from the Salzburg Colon Cancer Prevention Initiative (Sakkopi) were included in the study. The prevalence of H. pylori infection was determined by histology, and sST2 levels were measured in serum samples. Clinical and laboratory parameters, such as age, sex, BMI, smoking status, hypertension, and metabolic syndrome, were also collected.ResultsThe median sST2 concentration was similar between patients with (9.62; 7.18–13.44 ng/mL; p = 0.66) and without (9.67; 7.08–13.06 ng/mL) H. pylori. Logistic regression analysis did not show any association (OR 1.00; 95%CI 0.97–1.04; p = 0.93) between sST2 levels and H. pylori infection, which remained so (aOR 0.99; 95%CI 0.95–1.03; p = 0.60) after adjustment for age, sex, educational status, and metabolic syndrome. In addition, sensitivity analyses stratified by age, sex, BMI, smoking status, educational status, and the concomitant diagnosis of metabolic syndrome could not show any association between sST2 levels and H. pylori infection.ConclusionThe results indicate that sST2 may not serve as a valuable biomarker in the diagnosis and treatment of H. pylori infection. Our findings are of relevance for further research investigating sST2, as we could not find an influence of asymptomatic H. pylori infection on sST2 concentration.What Is Already Known?Soluble suppression of tumorigenicity-2 (sST2) has gained attention as a biomarker associated with various diseases, such as gastric cancer.What Is New in This Study?The median sST2 concentration was similar between patients with (9.62; 7.18–13.44 ng/mL; p = 0.66) and without (9.67; 7.08–13.06 ng/mL) H. pylori.What Are the Future Clinical and Research Implications of the Study Findings?The results indicate that sST2 may not serve as a valuable biomarker in the diagnosis and treatment of H. pylori infection.

Automatic Stop Orders for Opioids

&#x0D; Automatic stop orders may reduce or have no significant effect on opioid-based prescriptions at the institutional level.&#x0D; We did not find any evidence regarding a range of clinical outcomes (e.g., rates of opioid dependence, misuse, and diversion; reduction in opioid dependence, health-related quality of life, and adverse events) associated with automatic stop orders.&#x0D; We did not find any evidence-based guidelines regarding the use of automatic stop orders for opioid prescriptions.&#x0D; Given the limited number and observational, nonrandomized design of the included studies, as well as the absence of any evidence-based guidelines regarding the use of automatic stop orders for opioid prescriptions, it was difficult to draw any firm conclusions about the clinical effectiveness of automatic stop orders for opioid prescriptions in the Canadian context.&#x0D;

BREADTH OF ADVERSE OUTCOMES ASSOCIATED WITH ANOREXIA/APPETITE LOSS IN OLDER POPULATIONS

Abstract The scope of the clinical problem of anorexia or appetite loss (AL) in older populations is potentially under-appreciated. A systematic literature review (SLR) was conducted following PRISMA guidelines to summarize associations of anorexia/AL in older adults with a range of clinical outcomes. Searches were run January/1/2011–July/31/2021 in PubMed, Embase®, and Cochrane databases to identify English-language studies of adults (aged ≥65 years) with anorexia/AL. Two independent reviewers screened titles/abstracts and full text against pre-defined inclusion/exclusion criteria. In all, 146 studies underwent full-text review; 58 met eligibility criteria. Most were from Europe (34/58 [58.6%]) or Asia (16/58 [27.6%]); only 3 (5.2%) were from the United States (US). Although mortality (n=18) and malnutrition (n=15) were the most reported outcomes, no US study reported on these outcomes. Other commonly reported outcomes included sarcopenia (n=7), functional status (n=6), need for increased care (n=6), and hospitalization (n=4). Significant associations of anorexia/AL were most consistently observed with mortality (17/18 studies), malnutrition (15/15 studies), and functional status (5/6 studies). Although the overall number of studies is small, associations have emerged with falls (2/3 studies), health related quality of life (2/3 studies), depression (2/2 studies), and cognition (2/2 studies). However, associations with hospitalization (1/4 studies), sarcopenia as assessed by muscle strength (2/4 studies) or by muscle mass (1/3 studies), and need for increased care (3/6 studies) were less consistent. Together, these studies highlight the breadth of adverse outcomes associated with anorexia/AL in older populations and a need for more US-based research into this common clinical problem.

Changes in avoidance and distress related to trauma reminders in PTSD psychotherapy

Background and objectivesResearch has examined reductions in patient distress recounting trauma narratives in Prolonged Exposure (PE) for posttraumatic stress disorder (PTSD). It remains unclear whether changes in distress and avoidance related to environmental trauma reminders matter in PE and other PTSD treatments, including non-exposure Interpersonal Psychotherapy (IPT). MethodsData came from adults with chronic PTSD (N = 92) who completed a treatment trial comparing PE, IPT, and Relaxation Therapy (RT). We employed the Self-Initiated In-Vivo Exposure Scale (SIIVES), which measures patient distress from and avoidance of situational trauma reminders, to calculate reliable change in distress and avoidance. PTSD symptoms, depression, quality of life, and functioning assessments were collected before and after 14 weeks of treatment. ResultsOverall, 48.1% of patients experienced reliable change in avoidance, while 51.9% showed reliable change in distress. Rates of reliable change did not differ by treatment group, although PE appeared to achieve reliable change earlier. Only one baseline characteristic predicted reliable change: patients with comorbid depression were less likely to reliably change in avoidance. At post-treatment, patients achieving reliable change had lower PTSD severity and depression and increased quality of life and social functioning. Statistical modeling revealed that changes in distress and avoidance related to subsequent reduction in PTSD symptoms in all three treatment groups, though this relationship appeared strongest in PE. LimitationsThe sample was relatively small. ConclusionsChange in avoidance and distress associated with situational trauma reminders was associated with a range of clinical outcomes and may represent important factors in multiple PTSD psychotherapies.

Systematic review and meta-analysis of intravenous iron-carbohydrate complexes in HFrEF patients with iron deficiency.

Iron deficiency (ID) is a common co-morbidity in patients with heart failure (HF). The present meta-analysis evaluates the effect of intravenous (IV) iron-carbohydrate complex supplementation in patients with HF with reduced ejection fraction (HFrEF) and ID/iron deficiency anaemia (IDA). Randomized controlled trials (RCTs) comparing IV iron-carbohydrate complexes with placebo/standard of care in patients with HFrEF with ID/IDA were identified using Embase (from 1957) and PubMed (from 1989) databases through 25 May 2021. Twelve RCTs including 2381 patients were included in this analysis. The majority (90.8%) of patients receiving IV iron-carbohydrate therapy were administered ferric carboxymaltose (FCM); 7.5% received iron sucrose and 1.6% received iron isomaltoside. IV iron-carbohydrate therapy significantly reduced hospitalization for worsening HF [0.53 (0.42-0.65); P<0.0001] and first hospitalization for worsening HF or death [0.75 (0.59-0.95); P=0.016], but did not significantly impact all-cause mortality, compared with control. IV iron-carbohydrate therapy significantly improved functional and exercise capacity compared with the control. There was no significant difference in outcome between IV iron-carbohydrate formulations when similar endpoints were measured. No significant difference in adverse events (AE) was observed between the treatment groups. IV iron-carbohydrate therapy resulted in improvements in a range of clinical outcomes and increased functional and exercise capacity, whereas AEs were not significantly different between IV iron-carbohydrate and placebo/standard of care arms. These findings align with the European Society of Cardiology's 2021 HF guidelines, which recommend the consideration of FCM in symptomatic patients with a left ventricular ejection fraction < 45% and ID.

Infection with different human influenza A subtypes affects the period of susceptibility to secondary bacterial infections in ferrets.

It is well-established that influenza virus infections predispose individuals to secondary bacterial infections (SBIs), which may result in a range of clinical outcomes from relatively mild (e.g. sinusitis and otitis media) to severe (e.g. pneumonia and septicaemia). The most common bacterial pathogen associated with SBI following influenza virus infections is Streptococcus pneumoniae(SPN). Of circulating human seasonal influenza viruses, influenza A viruses (IAV) of both the A(H1N1)pdm09 and A(H3N2) subtypes are associated with severe disease but have differing hospitalisation and complication rates. To study the interplay of these two IAV subtypes with SBI, we used a ferret model of influenza infection followed by secondary challenge with a clinical strain of SPN to determine the severity and the period of susceptibility for SBI. Ferrets challenged with SPN 5 days after infection with A(H3N2) or A(H1N1)pdm09 viruses developed severe disease that required euthanasia. When the time between viral infection and bacterial challenge was extended, A/H1N1pdm09-infected animals remained susceptible to SBI- for up to 10 days after the viral infection. For A(H3N2)- but not A(H1N1)pdm09-infected ferrets, susceptibility to SBI-associated disease could be extended out to 16 days postviral infection. While caution should be taken when extrapolating animal models to human infections, the differences between A(H3N2) and A(H1N1)pdm09 strains in duration of susceptibility to SBI observed in the ferret model, may provide some insight regarding the higher rates of SBI-associated disease associated with some strains of A(H3N2) viruses in humans.

CLINICO RADIOLOGICAL CORRELATION IN COVID-19 PATIENTS.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) is a pandemic infectious disease caused by a novel coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 genome is similar to that of SARS and Middle East respiratory syndrome. Infection by COVID-19 can result in a range of clinical outcomes, from asymptomatic to severe life-threatening course or death. Most of the 1 affected patients present with high temperature and dry cough Chest radiograph (CXR) played a role in determining the course and the severity of disease during the 2002 severe acute respiratory syndrome 2 (SARS) and the 2012 Middle East respiratory syndrome (MERS) outbreaks The diagnostic armamentarium of COVID-19 is inclusive of travel history, history of exposure, clinical features, and reverse transcriptase–polymerase chain reaction (RT-PCR) assay from specimens obtained by oropharyngeal or nasopharyngeal swab, assisted with 3 digital Chest radiograph (CXR) AIMS &amp; OBJECTIVES: 1.To Study clinical correlation to chest x ray in covid 19 patients. 2.To Study clinical correlation to outcome in covid 19 patients. METHODS &amp; MATERIALS: This is a prospective study which included 507 patients with laboratory-conrmed COVID-19 admitted in tertiary care hospital from May 2020 to Nov 2020. The patients were examined clinically , were assessed for signs&amp; symptoms and severity of pneumonia. All patients underwent a digital CXR examination. RESULTS: Out of 507 patients studied, 58.6% were males, 41.4%were females.Most of the affected patients are between 41-60 yrs of age group .Death percentage is more in critical group compared to noncritical group.Our observational study shows signicant correlation between clinical features , CXR and outcome in covid 19 patients.

A positive mental imagery intervention for targeting suicidal ideation in university students: A pilot study.

ObjectivesSuicide is a major public health concern and is now considered to be the leading cause of death in young people. Suicidal ideation within student populations has recently increased. The Broad‐Minded Affective Coping (BMAC) offers a brief psychological intervention targeting suicidal ideation by enabling access to competing positive emotions and thoughts using guided imagery. Its acceptability and feasibility in student populations are unclear.DesignA single arm pilot study investigated the feasibility and acceptability of a six‐session BMAC intervention for university students experiencing suicidal ideation.MethodRecruitment took place from university counselling services. Suicidal ideation and emotional states were assessed at baseline and after 6 and 12 weeks. Participants also completed corresponding sessional measures.ResultsTwelve eligible participants consented to take part with 11 receiving the intervention. Ten participants completed post treatment and follow up assessments. Retention to treatment was high with participants attending an average of 5.2 (87%; SD = 1.54) out of six intervention sessions. There were also good completion rates of the BMAC technique between sessions. Participants reported high levels of satisfaction with the intervention. There was an associated reduction across a range of clinical outcomes, including suicidal ideation, with large effect sizes.DiscussionThis pilot study showed promising results on the feasibility and acceptability of the BMAC intervention in students experiencing suicidal ideation. However, the study had a small sample size and no comparator control group. Further exploration of the BMAC intervention is warranted.

Genetic Diagnostic Strategies and Counseling for Families Affected by Congenital Diaphragmatic Hernia

Congenital diaphragmatic hernia (CDH) is a relatively common and severe birth defect with variable clinical outcome and associated malformations in up to 60% of patients. Mortality and morbidity remain high despite advances in pre-, intra-, and postnatal management. We review the current literature and give an overview about the genetics of CDH to provide guidelines for clinicians with respect to genetic diagnostics and counseling for families. Until recently, the common practice was (molecular) karyotyping or chromosome microarray if the CDH diagnosis is made prenatally with a 10% diagnostic yield. Undiagnosed patients can be reflexed to trio exome/genome sequencing with an additional diagnostic yield of 10 to 20%. Even with a genetic diagnosis, there can be a range of clinical outcomes. All families with a child with CDH with or without additional malformations should be offered genetic counseling and testing in a family-based trio approach.

Clinico-radiological profile of COVID-19 in a tertiary care hospital of western Rajasthan

Coronavirus disease 2019 (COVID-19) is a pandemic infectious disease caused by a novel coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Infection by COVID-19 can result in a range of clinical outcomes, from asymptomatic to severe life-threatening course or death. The purpose of our research was to evaluate the presentation of COVID19 disease based on the clinical and radiological characteristics of our population. 100 COVID19 patients recorded by RTPCR. Clinical, biochemical and radiological data from April-May, 2021. Of the 100 patients, in our study 66% were males and 26% patients had history of recent travel. Majority of patients were asymptomatic and don’t have comorbid illness. Thrombocytopenia and lymphopenia, increased levels of lactate dehydrogenase (LDH) and serum ferritin and C-reactive protein were common in these patients. CT finding were 63% had normal CT chest. Among the 37% patients who had CT chest findings, 25% had bilateral diseases, 8% patients had right lung involvement while 4% patients have left lung involvement. COVID-19 disease has a relatively mild course in this part of the subcontinent. Clinical and laboratory findings are similar to those found in viral diseases. Studies involving larger sample size and interventional trials are need of the hour.

Constitutional SAMD9L Mutations Cause Familial Myelodisplastic Syndrome with Monosomy 7 and Stable Revertant Mosaicism

Familial myelodysplastic syndromes (MDS) arise from haploinsufficiency of genes involved in hematopoiesis, show variable penetrance and are primarily associated with MDS in younger patients. The same genes involved in familial MDS might also cause sporadic manifestation, e.g. in GATA2 deficiency where ~2/3 of identified germline mutations arise de novo . In this study we aimed to discover the genetic cause in 7 patients of 4 unrelated pedigrees (Fig. A). The phenotypic denominator was MDS with progressive or transient loss of chromosome 7 and remarkably, spontaneous long-lasting remission was observed in 2 cases. Dysmorphic features or neurological symptoms were absent. Median age at diagnosis was 2 (1-42) years, all patients presented with thrombocytopenia with or without additional cytopenias and a hypocellular marrow without increase of blasts. There was no spontaneous growth in an in vitro GM-CSF hypersensitivity assay performed in 2 patients.Genomic studies identified constitutional mutations p.H880Q, p.R986H, p.R986C and p.V1512M in SAMD9L gene on 7q21 cytoband, with decreased allele frequency in hematopoiesis. Interestingly, similar (p.I981T, p.C1196S) or identical (p.H880Q, p.R986C) SAMD9L mutations had been recently reported in 4 families with Ataxia-Pancytopenia syndrome. Family testing in 3 pedigrees (Fig A), revealed an incomplete penetrance in 33% (3/9) of mutation carriers. In comparison with other germline variants, SAMD9L missense mutations showed significantly lower median allelic frequencies in blood across all patients (53% vs. 16%, p<.05). The nonrandom loss of mutated SAMD9L allele was attained through monosomy 7, deletion 7q, uniparental isodisomy 7q, or acquired truncating SAMD9L variants p.R1188X and p.S1317RfsX21 (Fig. B). TA-cloning confirmed cis orientation of both SAMD9L mutations in P1. Additionally, acquired mutations were found in oncogenes in P1 at CMML disease stage (SETBP1 p .D868N, EZH2 p.V582M, KRAS p.Q61P) and in P5 (RUNX1 c.413_427+5dup20bp). Functional studies in cell lines confirmed growth-restrictive effect of SAMD9L mutations p.R986C and p.V1512M. Double-mutated SAMD9L p.V1512M-p.R1188X vector resulted in stable expression of a truncated protein lacking p.V1512M (suggesting a compensatory effect).Leukemic progression from MDS to CMML was observed after 3.6 years in P1. In contrast, spontaneous remission occurred in P2 and P7, who showed transient monosomy 7 that had been replaced by large UPD7q clones with wildtype SAMD9L allelic duplication. Both patients maintained normal marrow morphology, cytogenetics, and blood counts until over 10 and 20 years from initial diagnosis.In conclusion, our study establishes constitutional SAMD9L mutations as a novel cause of hereditary MDS without accessory phenotypes and point to the notion that MDS with chromosome 7 loss can be the sole and common manifestation of SAMD9L-related disease. The clinical outcomes range from leukemic progress to spontanous remission. This is the first observation of sustained revertant mosaicism due to UPD7q and etiologic explanation for transient monosomy 7. Further studies will be essential to define the role of SAMD9L in hematopoiesis and explore the observed variable penetrance. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Abstract 14308: Integrative Epigenomic Analysis Identifies Enhancer Modifying Variants Linked to Cardiomyopathy Genes

Introduction: Inherited cardiomyopathy is caused by mutations in more than 100 genes. A well-recognized clinical feature of genetic cardiomyopathy is varying phenotypic expression. Even with identical primary mutations, there is a range of clinical outcomes. Genetic variants in protein coding regions have been shown to alter the phenotypic expression of primary cardiomyopathy-causing mutations. However, the contribution of noncoding variation has been less well studied. Methods and Results: We used an integrative analysis of &gt;20 publicly-available heart enhancer function and enhancer target datasets to identify genomic regions predicted to regulate the cardiomyopathy genes, MYH7 and LMNA . We identified two candidate enhancer clusters around the MYH7 gene and three clusters around the LMNA gene. We tested enhancers in these clusters using reporter assays and CRISPr-mediated deletion in human cardiomyocytes derived from induced pluripotent stem cells (iCMs). We identified a super enhancer upstream of MYH7 that is necessary for high MYH7 expression in iCMs. These regulatory regions contained sequence variants within transcription factor binding sites that altered enhancer function. We created an informatic pipeline that extended this strategy genomewide to identify an additional enhancer modifying variant upstream of MYH7 . This variant disrupts a transcription factor binding site upstream of MYH7 and limits MYH7 upregulation. We extended these analyses by examining clinical correlates, finding that this variant correlated with a more dilated left ventricle over time in patients with cardiomyopathy. Conclusions: We identified two enhancer regions important for MYH7 expression in iCMs. These enhancer regions may be utilized to induce MYH7 during human development and heart failure. MYH7 changes in heart failure have been linked to cardiomyopathy phenotypes. The variant upstream of MYH7 likely alters these changes and results in a more severe phenotype. These findings demonstrate that noncoding variants have clinical utility and targeted assessment of noncoding modifiers may become integrated into clinical care.

Microplegia in cardiac surgery: Systematic review and meta-analysis.

Consensus on the optimum choice of cardioplegia remains elusive. One possibility that has been suggested to have beneficial properties is microplegia, a cardioplegia of reduced crystalloid volume. The aim of this meta-analysis is to comprehensively investigate microplegia against a range of clinical outcomes. To identify potential studies, systematic searches were carried out in four databases (eg, Pubmed, EMBASE). The search strategy included the key concepts of "microplegia" OR "mini-cardioplegia" OR "miniplegia" AND "cardiac surgery." This was followed by a meta-analysis investigating: mortality, crystalloid volume; cardiopulmonary bypass time; cross-clamp time; intra-aortic balloon pump use; spontaneous heartbeat recovery; inotropic support; low cardiac output syndrome; myocardial infarction; acute renal failure; atrial fibrillation, reoperation for bleeding; creatine kinase myocardial band (CK-MB); intensive care unit (ICU) time and hospital stay. Eleven studies comprising 5798 participants were analyzed. Microplegia used a lower volume of crystalloids and led to a higher spontaneous return of heartbeat, odds ratio (OR) 4.271 (95% confidence intervals [CIs]: 1.935, 9.423; I2 = 76.57%; P < .001) and a lower requirement for inotropic support, OR: 0.665 (95% CI: 0.47, 0.941; I2 = 3.53%; P = .021). Microplegia was also associated with a lower CK-MB release, mean difference (MD) -6.448 ng/mL (95% CI: -9.386, -3.511; I2 = 0%; P < .001) and a shorter ICU stay, MD: -0.411 days (95% CI: -0.812, -0.009; I2 = 17.65%; P = .045). All other comparisons were nonsignificant. Microplegia has similar effects to other types of cardioplegia and is beneficial with regard to spontaneous return of heartbeat, inotropic support, ICU stay, and CK-MB release.