Degree Relatives Research Articles

Rates of risk-reducing salpingo-oophorectomy in patients with CHEK2 mutations in a large healthcare system

Objectives: CHEK2 mutations are associated with increased risk of breast, colon, and prostate cancer but not ovarian cancer. Our study investigated if women with CHEK2 mutations underwent risk reducing salpingo-oophorectomies (RRSO), despite no known risk of ovarian cancer associated with CHEK2, and if personal or family history of ovarian cancer was related to uptake of salpingo-oophorectomy. Methods: Retrospective cohort study was conducted from 2015-2018 in a large integrated healthcare system. Eligible patients were female, at least 18 years old and identified as CHEK2 mutation carriers. Those with concurrent non-CHEK2 pathogenic gene mutations were excluded. Surgical indications, personal history, family history up to third degree relatives, and mutation type were collected retrospectively. Primary outcome was RRSO rates among women with pathogenic CHEK2 mutation. Secondary outcomes included association of personal and family cancer history in patients with salpingo-oophorectomy. Results: Of 11,640 men and women who had genetic testing, 150 (1.3%) were identified with pathogenic CHEK2 mutation. 37 patients were excluded because they had more than one gene mutation, and 11 men in the remaining cohort were excluded, resulting in 102 women with a pathogenic CHEK2 mutation in the final cohort. A total of eighteen (18%) patients underwent uni- or bilateral salpingo-oophorectomy (BSO) for any reason, and six (6%) were for risk-reduction. Mean age at time of surgery was 53.0 years for all patients who underwent salpingo-oophorectomy and 54.4 years for those who underwent RRSO. Four (4%) patients total had personal history of ovarian cancer. 24 (24%) patients had family history of ovarian cancer. Four (67%) of the six patients who underwent RRSO had family history of ovarian cancer (p=0.03). Of the two patients without family history: one chose to have BSO for risk-reducing purposes as opposed to follow up for a unilateral benign ovarian cyst after being counseled that there was no increased risk of ovarian cancer and the other chose BSO for hormonal management of breast cancer but also cited risk reduction of ovarian cancer as an indication. Conclusions: Although, personal history of ovarian cancer is uncommon, family history of ovarian cancer is present in almost one quarter of CHEK2 mutation carriers. Most women with CHEK2 mutations did not have RRSO and the majority of those who chose RRSO had family history of ovarian cancer. This suggests that women and providers correctly assessed risk of ovarian cancer related to CHEK2, with few electing for RRSO because of increased perceived risk.

Up- and Down-Operators on Young's Lattice

The up-operators $u_i$ and down-operators $d_i$ (introduced as Schur operators by Fomin) act on partitions by adding/removing a box to/from the $i$th column if possible. It is well known that the $u_i$ alone satisfy the relations of the (local) plactic monoid, and the present authors recently showed that relations of degree at most 4 suffice to describe all relations between the up-operators. Here we characterize the algebra generated by the up- and down-operators together, showing that it can be presented using only quadratic relations.

Artificial Intelligence-Enabled Electrocardiography to Screen Patients with Dilated Cardiomyopathy

Undiagnosed dilated cardiomyopathy (DC) can be asymptomatic or present as sudden cardiac death, therefore pre-emptively identifying and treating patients may be beneficial. Screening for DC with echocardiography is expensive and labor intensive and standard electrocardiography (ECG) is insensitive and non-specific. The performance and applicability of artificial intelligence-enabled electrocardiography (AI-ECG) for detection of DC is unknown. Diagnostic performance of an AI algorithm in determining reduced left ventricular ejection fraction (LVEF) was evaluated in a cohort that comprised of DC and normal LVEF control patients. DC patients and controls with 12-lead ECGs and a reference LVEF measured by echocardiography performed within 30 and 180 days of the ECG respectively were enrolled. The model was tested for its sensitivity, specificity, negative predictive (NPV) and positive predictive values (PPV) based on the prevalence of DC at 1% and 5%. The cohort consisted of 421 DC cases (60% males, 57±15 years, LVEF 28±11%) and 16,025 controls (49% males, age 69 ±16 years, LVEF 62±5%). For detection of LVEF≤45%, the area under the curve (AUC) was 0.955 with a sensitivity of 98.8% and specificity 44.8%. The NPV and PPV were 100% and 1.8% at a DC prevalence of 1% and 99.9% and 8.6% at a prevalence of 5%, respectively. In conclusion AI-ECG demonstrated high sensitivity and negative predictive value for detection of DC and could be used as a simple and cost-effective screening tool with implications for screening first degree relatives of DC patients.

Ten years follow up of first degree relatives of type 1 diabetes patients: presence of autoimmune biomarkers and the progression to diabetes in a retrospective cohort.

The aim of the study was to assess the autoimmunity in first degrees relatives (FDR) of patients with type 1 diabetes (T1DM) and the progression to T1DM after 10 years of follow up in the Brazilian population. Non-diabetic FDR of T1DM patients were interviewed and blood was drawn for autoantibodies measurement (GADA, IA-2A, IAA, ZnT8A). Serum samples were analyzed by standard radioligand binding assays performed at the Federal University of Rio de Janeiro (GADA, IAA and IA2A), and at the Skäne University Hospital, Sweden (ZnT8A). The FDR were interviewed by phone after 10 years to determine if they had developed T1DM. Descriptive statistical analysis was performed and results were described as means and standard deviation (SD). 81 individuals were analyzed. Thirteen subjects had positive autoantibodies associated with T1DM.10 were positive for 1 autoantibody and 3 subjects were positive for multiple autoantibodies (1 of them showed positivity for 2 autoantibodies - GADA, ZnT8A - and the other two were positive for 3 autoantibodies - GADA, IA2A, ZnT8A). The 3 subjects with multiple positive autoantibodies developed T1DM within 10 years. In Brazilian FDR of T1DM patients, the positivity for multiple autoantibodies indicate a greater chance of progression to T1DM, similar to observed in Caucasians. ZnT8A was helpful in the risk assessment for T1DM development.

Family history of cancer in first degree relatives and risk of cancer of unknown primary.

ObjectiveCancer of Unknown Primary (CUP) refers to the presence of metastatic lesions, with no identifiable primary site during the patient's lifetime. Poor survival and lack of available treatment highlight the need to identify potential CUP risk factors. We investigated whether a family history of cancer is associated with increased CUP risk.MethodsWe performed a case cohort analysis using data from the Netherlands Cohort Study, which included a total of 963 CUP cases and 4,288 subcohort members. A Cox Proportional Hazards Regression was used to compare CUP risk in participants who reported to have a family member with cancer to those who did not, whilst adjusting for confounders.ResultsIn general, we observed no increased CUP risk in those who reported a family history of cancer. CUP risk appeared slightly increased in those who reported cancer in a sibling (HR: 1.16, 95% CI: 0.97–1.38), especially in those with a sister with cancer compared with those without (HR: 1.23, 95% CI: 0.99–1.53), although these findings are not statistically significant.ConclusionHaving a family history of cancer is not an independent risk factor of CUP.

Darier's disease and Schizophrenia- A case report

Darier's disease is a rare autosomal dominant genodermatosis. There is a specific mutation in the ATP2A2 gene on chromosome 12q. Several neuropsychiatric manifestations have been described in association with Darier's disease. Most reports have come from western populations, with limited reports of Darier's disease and its neuropsychiatric associations among Asian people, although the demographic and clinical profiles are comparable. We present a case of 38 year old female from Kerala with Darier's disease presenting with schizophrenia spectrum disorder. Her first degree relatives have schizophrenia-like psychosis and dermatological manifestations suggestive of Darier's disease.

Screening for Premature Coronary Artery Disease (CAD) using Coronary Artery Calcium (CAC) Score: A Primary Prevention Pilot Study

Acute Coronary Syndrome (ACS) events can be accelerated by positive family history of young coronary artery disease (CAD). Risk factors assessment sometimes fail to predict ACS occurrence. Additional investigations with coronary artery calcium (CAC) score can be used independently in screening for primary prevention in some population. This was a cross-sectional study in asymptomatic population with first degree relatives (FDR) having premature CAD compared with a matched population with no family history of CAD from September 2017 to March 2018 at the Cardiology Clinic of Univeristi Kebangsaan Malaysia Medical Centre. A total of 36 subjects were recruited with equal number in each group. Female were the majority in each group (66.7%). The FDR group were slightly younger compared to the control group [mean (SD) age 36.9 (4.9) against 38 (3.8), respectively). Both groups represent high risk factors including overweight and obesity, abdominal obesity as well as dyslipidemia. Newly diagnosed dyslipidemia was significant in the group with family history (83.3% versus 44.4%, P<0.01). Both groups were screened either into the low or moderate risk Framingham Risk Score group. CAC score was higher in family history group (11.1% vs 0%, P>0.05). In conclusion, CAC may be irrelevant for screening in younger population. However, the yield of other risk factor is still alarming.

Glaucoma Screening in Family Members of Glaucoma Patients at a Tertiary Eye Hospital in Eastern Region of Nepal.

The second most common cause of blindness in the world is glaucoma. Family history plays an important role in early detection and management of patients with glaucoma. The main objective of this study was to determine the prevalence of glaucoma in first degree relatives of Primary open angle glaucoma (POAG) and Primary angle closure glaucoma (PACG) patients. Glaucoma awareness among the first degree relatives was also assessed. A cross sectional hospital based study was designed to examine and diagnose glaucoma among first degree relatives of patients with POAG and PACG, attending the outpatient department at Ramlal Golchha Eye Hospital in the Eastern region of Nepal from June 2016 to May 2017. A comprehensive eye examination was conducted by a glaucoma specialist at the hospital. All subjects underwent vision screening, refraction, slit lamp biomicroscopy, intraocular pressure (IOP) measurement, gonioscopy and a dilated fundus examination. All glaucoma suspects and those diagnosed with glaucoma were enrolled for visual field examination. Two hundred and twenty-seven first degree relatives of 72 patients were invited for the examination. Out of 227 individuals, 131 (males 67.94%, females 32.06%) agreed to participate in the study. A total of 23 (17.56%) individuals were diagnosed with glaucoma, 10 (43.47%) as POAG and 13 (56.52%) as PACG. Fourteen percent of parents, 22% of siblings and 9% of off-springs had open angle glaucoma. Among 13 PACG participants, 26.08% of parents, 26.08% of siblings and 4.34% of off-springs had angle closure glaucoma. Awareness among first degree relatives diagnosed with glaucoma was 21.74%. The prevalence of glaucoma among first degree relatives of glaucoma patients was higher than individuals without family history of glaucoma. Promoting awareness on glaucoma and the timely screening of family members can lead to early detection and prevention of blindness from the disease. .

Germline ERBB2 Variants Associate with Myeloproliferative Neoplasms

Background: The myeloproliferative neoplasms (MPN) and myelodysplastic syndrome (MDS) are usually sporadic diseases, however, familial cases are well-described. Approximately 10% of MPN cases display familial clustering, and there is a 5-7 fold increased risk of developing an MPN among first degree relatives of MPN patients. While familial MDS appears to be less common, identification of multiple predisposition genes has led to the incorporation of this entity into the most recent WHO classification of myeloid neoplasms. Identification of predisposing germline mutations in the myeloid malignancies has led to a better understanding of the pathophysiology of these diseases and improved clinical care. However, many familial MDS and MPN cases exist in which the inherited genetic lesion is unknown. Our recent investigation of a multigenerational family with inherited MDS/AML marked by erythroid hyperplasia identified a missense variant in ERBB3 that co-segregated with the disease phenotype (1). In this study, we investigated a kindred with an autosomal dominant familial cancer syndrome characterized by both MPN and solid tumor malignancies.Methods: Whole exome sequencing was performed via the Baylor-Hopkins Center for Mendelian Genomics at Center for Inherited Disease Research at Johns Hopkins University. Saliva or peripheral blood samples were used as source DNA. Sequence analysis and variant calling/filtering was performed as previously described (1). Targeted sequencing of the ERBB genes was performed via MiSeq using an Illumina TruSeq Custom Amplicon (v1.5) designed to sequence the entire open reading frame of selected genes. Analysis was performed using Illumina BaseSpace TruSeq applications. Germline variants were identified via variant allele frequency and heterozygous, nonsynonymous variants with a minor allele frequency < 0.01 and a depth > 40x were prioritized.Results: The proband was diagnosed with a JAK2 V617F positive MPN at age 37. Subsequent personal cancer history included melanoma and renal carcinoma. Family history was significant for ovarian cancer and melanoma in her mother, MPN and melanoma in her maternal aunt, and bladder cancer in her maternal uncle (Figure 1A). Exome sequencing of the three family members affected with melanoma was performed in order to identify the predisposing inherited variant in this family. Sequence analysis produced 71 candidate rare, heterozygous, nonsynonymous single nucleotide variants (SNV), including one in the gene ERBB2 . Genotyping of 2 additional family members for the ERBB2 c.3182T>C;p.L1061P SNV established that it co-segregates with disease (Figure 1A). To further investigate the prevalence of rare germline ERBB2 and ERBB3 variants in both MPN and MDS, we performed targeted sequencing of these genes in two discovery cohorts: 1) 96 cases of MPN, of which 63 had a 1st or 2nd degree relative with a family history of MPN and 2) 19 cases of erythroid MDS/AML. Five out of 96 (5.2%) cases of MPN were found to have ERBB2 variants, while 3 of 96 (3.1%) had ERBB3 variants. Of the 19 erythroid MDS/AML cases, no ERBB2 variants were identified, while 1 had an ERBB3 variant. Further, one MPN case with a germline ERBB2 c.G3250T:p.D1084Y variant had a family history of breast cancer in her mother, who also carried this variant (Figure 1B). We analyzed a validation cohort of 630 cases of hematologic malignancies (approximately 20% MPN) sequenced as part of their clinical evaluation at the Sidney Kimmel Cancer Center. Similar to the findings in our discovery cohorts, rare germline ERBB2 variants were enriched in MPN, found in approximately 5% of MPN compared to only 1.8% of all other myeloid disorder diagnoses. In contrast, germline ERBB3 variants were present in 1.6% of MPN compared to 1.8% of the other myeloid disorders (Table).Conclusions: We have identified germline ERBB2 variants that co-segregate with disease in two kindreds with familial cancer syndromes manifesting as a mixed MPN and solid tumor phenotype. In addition, we show that germline ERBB2 and ERBB3 variants are present in patients with hematologic malignancies at a higher incidence than expected in the general population, and ERBB2 variants are associated with an MPN phenotype. Together, these data implicate these genes in the predisposition to myeloid malignancy as well as other familial cancer syndromes. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Rare Germline Variant in NFATC4 Associated with Familial Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) has one of the highest familial risks of any cancer, with up to eightfold increased risk in first degree relatives of CLL patients. Genome-wide association studies (GWAS) have identified multiple common single nucleotide polymorphisms (SNPs) associated with risk, but these have modest effect. Similarly, identified germline variants associated with disease account for just a small minority of CLL patients, making familial CLL an attractive target for research, that could provide direct insight into pathobiology.We used whole exome sequencing (WES; Illumina) to search for rare germline variants (<1% Minor Allele Frequency) in 36 patients from 17 families with Mendelian-like CLL inheritance, where at least two affected family members were sequenced. Median age at diagnosis was 56.4 (range 41-72), 61% were male, 10/23 (43%) were IGHV -unmutated, and 5/24 (21%) had del17p and/or TP53 mutation. We found 3819 rare variants shared within all affected members of a given family. Of those, 71 non-synonymous variants were shared across at least 2 families, and 39 of these were predicted to be pathogenic by at least two commonly-used phenotype prediction tools. None of these variants are within known somatic CLL driver genes, nor were any found in genes near known CLL GWAS SNPs. In order to prioritize these variants, we assessed whether they were enriched among CLL cases (n = 646) as compared to ethnically matched normal population controls (n=8,920), a dataset we have recently reported (Tiao, Improgo et al, Leukemia). Using Fisher's exact test with Benjamini-Hochberg (BH) correction for multiple tests, we found that 27 of the 71 shared variants across multiple families were also enriched in unrelated CLL patients compared to controls. Among those, a rare variant of nuclear factor of activated T-cells 4 (NFATC4), rs200328372, was the most highly enriched in CLL (OR 20.8, Fisher-q-BH 0.026). This variant affects a splice acceptor site predicted to have a deleterious effect on the protein (FATHMM for non-coding variants). In a pathway analysis (MSigDB, DAVID) of genes carrying shared variants across families, NFATC4 together with SOS1 and PTPN7 were associated with the T-cell receptor, B-cell receptor, and MAP-kinase pathways, suggesting a possible role in CLL pathogenesis.The NFATC4 protein, also known as NFAT3, is part of a DNA-binding transcriptional complex that translocates to the nucleus after activation through dephosphorylation by calcineurin. This complex is involved in the inducible expression of cytokine genes in T cells, including interleukin (IL)-2 and IL-4. While NFATC1 has been implicated in CLL pathogenesis and was associated with more aggressive disease in a mouse model of CLL, the role of NFATC4 has not been elucidated. To further investigate this as well as its association with familial CLL, we compared gene expression profiling (GEP; Affymetrix U133 plus 2.0 array) data between familial and sporadic CLL patients and normal B-cells. While NFATC4 expression did not differ between normal B-cells (n=16) and CLL (n=143), it was significantly down-regulated in familial (n=47) as compared to sporadic (n=96) CLL cases (Mann-Whitney, p=0.005). In the 4 cases that harbor the shared risk variant, GEP results showed additional significant down-regulation of NFATC4 expression (Kruskal-Wallis, p=0.003 for all comparisons) (Figure 1).RNA sequencing (Illumina) demonstrated NFATC4 down-regulation in all CLL samples (not specifically in familial CLL as with GEP; n=100) versus normal B-cells (n=6; Mann-Whitney, p=-0.00024), suggesting a putative role for NFATC4 as a tumor suppressor. Since NFATC4 has over 30 alternatively spliced transcripts potentially affected by the rs200328372 variant, we used Cufflinks software to look at isoform-level RNA sequencing data, available on two relatives who carried this variant, compared to CLL cases and controls. Both relatives had reduced expression of all isoforms (Figure 2), suggesting that this mutation may reduce NFATC4 expression altogether. Studies of protein expression are ongoing.In conclusion, through rare germline variant analysis in familial CLL, we found a potentially deleterious variant of NFATC4 that is enriched in CLL. Subsequently, we used RNA sequencing data to show, for the first time, that NFATC4 expression is decreased in CLL versus normal B-cells, revealing a potential tumor suppressor mechanism in CLL. [Display omitted] DisclosuresBrown:Sun BioPharma: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Pharmacyclics: Consultancy; Redx: Consultancy; AstraZeneca: Consultancy; Pfizer: Consultancy; Janssen Oncology: Honoraria; AbbVie: Consultancy, Honoraria; Roche/Genentech: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Infinity Pharmaceuticals: Consultancy; Astellas Pharma: Consultancy.

Phenotype and progression among patients with dilated cardiomyopathy and RBM20 mutations

BackgroundOver 70 genes that encode different cell components have been involved in the aetiology of dilated cardiomyopathy. Genotype-phenotype interactions are an unsolved problem, and to a large extent the effects of mutations in the expression mechanisms involved in the disease remain unknown, although associations are increasingly being established which have clinical and prognostic implications. Methods and resultsThe objective of our work was to describe our population that has cardiomyopathy associated with mutations in the gene RBM20, and study the genotype-phenotype relationship. We studied 8 cases undergoing follow-up at our Unit, and collected data for demographic, clinical and diagnostic testing variables. The mean age on diagnosis was 55 years [52–59], with a median follow-up of 31.5 months [26.0–67.3]. It is worth noting that 62.5% of the patients in our group had a history of cardiomyopathy in first degree relatives, and 37.5% of them had a family history of sudden death. One of the genetic variations of the sample was shared by three subjects who had no apparent family relationship with each other, and this variation had not been described in controls. It is also interesting that arrhythmic events were found in 37.5% of the sample, and 50% of patients had an indication for implantable cardiac defibrillator. ConclusionThis is the first analysis of patients with RBM20 mutations conducted in our country, and it indicates a profile with prominent arrhythmogenesis, a high penetrance of familial cardiomyopathy, and sudden death.

Coexistence of Autoantibodies and Other Autoimmune Diseases with Multiple Sclerosis and Related Disorders - Experience from the Mangalore Demyelinating Disease Registry (MANDDIR).

Background:Co-occurrence of other autoimmune disorders (AID) and autoantibodies in patients with autoimmune demyelinating CNS disorders have not been studied previously in patients of Indian origin.Objective:To determine the frequency of concomitant autoimmune disorders, anti-nuclear antibody (ANA) and antithyroid antibody (ATAb) and to evaluate the impact on clinical course of disease.Materials and Methods:A total of 111 patients with MS and 152 patients with non-MS demyelinating disorders were included. Demographics, clinical course and disability were recorded. History of other autoimmune disorders (AIDs) in patients and first degree relatives was noted. Serum ANA and ATAb were tested.Results:Concomitant AIDs were seen in 21% of MS and 19% of non-MS patients. Autoimmune thyroid disease was most frequent and seen in 10.8% of MS and 6.6% of non-MS disorders. Frequency of ATAb was significantly higher among MS group (MS 25.5% vs non-MS 13.2% P = 0.04) but that of ANA was similar between the 2 groups (MS 19.8% vs non-MS 26.9% P = 0.17). A positive family history of autoimmune disorders was noted in 20% of MS and 15.1% of non-MS disorders. Clinical course was unaffected by presence of concomitant AID and autoantibodies.Conclusion:Cooccurrence of autoantibodies and AID are seen in a significant number of patients with MS and non-MS disorders and influences clinical management.

High Familial Recurrence of Congenital Heart Defects in Laterality Defects Patients: An Evaluation of 184 Families

As a rare disease with genetic pathogenesis, observational study about familial CHD recurrence risk on CHD patients with laterality defects is lacking. This study aimed to investigate familial recurrence among families of patients with CHD and laterality defects, and compare them with CHD patients without laterality defects. A total of 184 patients with CHD and laterality defects treated in Cardiovascular Center, Children’s Hospital of Fudan University were observed from 2008 to 2019. A detailed family history was documented by trained staff using questionnaires, and information about the subtypes of CHD and laterality defects was also collected. In addition, positive family history information, including all three degrees relatives and all affected family members, was reconfirmed by trained medical staff through face-to-face interviews, telephone interviews, and letter return visits. Of the 184 included patients, 30 had at least one family member (from among three linear generations and distant relatives) with CHD. The familial recurrence rate of CHD in our cohort was 16.3% (30/184), which was higher than the 3.3% (67/2024) of patients with CHD without laterality defects. This result shows that the recurrence rate among the first-, second-, and third-degree relatives was 11.7% (11/94), 1.5% (3/204), and 3.1% (6/91) and that the recurrence rate among siblings (21.4%, 9/42) was higher than that among parents (3.8%, 2/52). The familial recurrence risk of CHD among patients with CHD and laterality defects is high, which is consistent with the previous study that reported a high familial recurrence of heterotaxy of 10%. First-degree relatives have a higher recurrence rate than second- and third-degree relatives, especially siblings. These findings have important significance for prenatal screening, intervention, and genetic counseling in the Chinese population, but may not be generalizable to other populations that may have different rates of familial and sporadic cases.

Complicated Grief, Depression, Health and Attachment Style in First Degree Relatives of Individuals with a Chronic Psychotic Disorders.

Complicated grief (CG) is a form of unrelenting grief after the death of a loved one. However, family members of individuals who suffer from Schizophrenia, Schizoaffective disorders and Bipolar disorder may experience symptoms of CG even though their loved one is still alive. The present study assessed CG and risk factors for CG in first degree relatives of individuals with severe chronic mental illness. The incidence of CG was examined in 78 parents, siblings, adult children and spouses recruited through organizations and social media that provide support services for individuals suffering from mental illness and their families. High rates of CG (39.7%) were found in this group. CG was associated with a higher prevalence of posttraumatic and depression symptoms and poorer physical health. These findings may contribute to heightening therapists' awareness of the importance of assessing, acknowledging and resolving CG in the family members of patients with chronic psychotic disorders.

Echocardiography for latent rheumatic heart disease in first degree relatives of children with acute rheumatic fever: Implications for active case finding in family members.

BackgroundIndividuals with Acute Rheumatic Fever (ARF) often report a family history of ARF or Rheumatic Heart Disease (RHD) however the degree of familial susceptibility to RHD is poorly defined. This study aimed to determine RHD prevalence among first degree relatives of ARF patients using echocardiography.MethodsChildren with ARF were recruited from Auckland, New Zealand. Parents and siblings ≥ 4years were offered echocardiography. Echocardiograms were reported according to World Heart Federation 2012 criteria. RHD prevalence in first degree relatives was compared to previously established population rates in the region.FindingsIn total, 70 index cases with ARF were recruited. Echocardiography was performed in 94 parents and 132 siblings. There were 3 siblings with definite RHD and 9 with borderline RHD. There were 4 parents with definite RHD. Overall prevalence of RHD (definite and borderline) in siblings was 90/1,000 (95% CI 45–143/1,000) compared to 36/1,000 (95% CI 30–42/1,000) in New Zealand children from high ARF incidence populations (p 0.001). Prevalence of definite RHD in parents was 42/1,000 (95% CI 7–87/1,000) compared to 22/1,000 (95% CI 9–36/1,000) in adults from a high ARF incidence New Zealand population (p 0.249).InterpretationRHD prevalence in siblings and parents of ARF cases is significantly greater than in comparable background populations. The contribution of hereditary versus environmental risk factors remains uncertain. We recommend targeted echocardiographic case-finding among siblings and parents of ARF/RHD cases in order to detect previously unrecognized latent RHD.

The Role of Ultrasound Guided IVC-CI versus Central Venous Pressure in Assessment of Critically Ill Patients

Abstract Background: Both hypovolemia and volume over load increase the morbidity and mortality of patients. So evaluation of intravascular volume status is the first important step in patients with signs of shock. Use of non invasive method as Inferior Vena Cava (IVC) measurements is one of methods to avoid complications of invasive procedure as central venous pressure monitoring. Aim of Study: This study aimed to provide a useful guide for noninvasive intravascular volume status (as diagnosed and manage) and to evaluating the correlation between Inferior Vena Cava-Collapsibility Index (IVC-CI) measured with ultrasonography versus central venous pressure. Patients and Methods: This study was a prospective observation study that was conducted on forty critically ill patients of both sexes, aging >!21 years old of ASA (III & IV) with signs of shock, admitted in the ICU at Al-Zahraa Uni-versity Hospitals during the last two year (October 2018 till October 2020), were enrolled in the non probability consecutive sampling after approval of the Al-Azhar University Ethical Committee and written informed consent from the patient or the 1st degree relatives in case of comatosed patient. After were screened for signs of shock, hemodynamic parameters were monitored continuously then 500ml of Nacl 0.9% was administered in 15 minutes and clinical response was observed with measures taken by using ultrasound. Then the patients were divided into responder and non responder. Results: In our study there was 24 patients of 40 patients (60%) responded to volume resuscitation. While 16 patients of 40 patients (40%) did not respond to volume resuscitation regimen and then blood pressure improved only after intro-duction of vasopressor as regarding to demographic data, there was no significant difference between two groups, as regarding to heart rate, MAP, and central venous pressure was no significant difference between two groups. In responder group there was strongly correlated that was highly significant of CVP and IVC-CI, in non responder group, there was no correlation between CVP and IVP-CI throughout the study. Conclusion: Inferior vena cava collapsibility index as-sessment is relatively safe option and sensitive at least when compared to measuring CVP.

Coronary Disease Risk in Asymptomatic Patients with Left Ventricular Moderate Dilatation

Goal of the Study is to assess the risk of coronary disease of asymptomatic ischemia in patients with left ventricular moderate dilatation. Methods: The work was based on the results of investigation of 185patients with left ventricular moderate dilatation, aged 35-55 years from the “Tbilisi Heart and Vascular Clinic” contingent. Among them, there are 159 men and 26 women. Results: Patients who suffer from left ventricular moderate dilatation and don’t expose typical symptom of ischemia possibly are in risk of carrying damaged coronary artery. the LV moderate dilatation of the left ventricle can be used for primary diagnosing of silent ischemia. Sensitivity - 0.867(95%CI:0.806-0.927); Specificity – 0.800(95%CI:0.703-0.897); Prognostic value of positive results; 0.889(95%CI:0.832-0.946); Prognostic value of negative results - 0.765(95%CI:0.664-0.866); diagnostic value - 0.843(95%CI:0.791-0.896). Conclusions: In patients with silent ischemia, the coronary disease predictors are: left ventricular moderate dilatation, male gender, dyslipidemia, arterial hypertension, smoking, positive treadmill test, ischemic disease in 1st degree relatives, low tolerance to treadmill test. Thus, we can use the moderate dilatation of the left ventricle for the primary diagnosing of silent ischemia. The test is simple and non-invasive. It is characterized by high sensitivity and specificity and can be used for early diagnosing of silent ischemia and the prevention of cardiac cases.

Assessment of vascular function in complete glycaemic spectrum

ABSTRACT Purpose: The present study was conceived to delineate the point of vascular dysfunction along the glycemic spectrum (normoglycemic individuals with no family history of diabetes, normoglycemic individuals with family history of diabetes, prediabetic individuals, and diabetic individuals). Materials and Methods: In this cross-sectional comparative study, we enrolled 252 participants of both gender in the age group of 30–50 years. They were classified based on their family history of diabetes and glycemic status into four groups along the glycemic spectrum as mentioned above. We measured flow-mediated dilation (FMD) from brachial artery and vascular function biomarkers such as enthothelin-1 (ET-1), von Willbrand Factor (vWF), Vascular Endothelial Growth Factor (VEGF) to assess the vascular function. The comparison of data between groups were done using One Way ANOVA/Kruskal–Wallis followed by post-hoc analysis using LSD/Mann–Whitney U Test depending on the normality of the data. Spearman correlation was done between vascular function and plasma glucose levels to identify its relationship. Linear regression was carried out to identify the factors influencing the FMD across the glycemic spectrum. Results: We observed that vascular function negatively correlated with blood glucose levels. However, endothelin-1 and vWF derangement was there even in normoglycemic first degree relatives of diabetes (FDRD) and the derangement increased in prediabetes and diabetes. Physiological dysfunction in terms of decreased flow-mediated dilation starts from prediabetes only. VEGF derangement is found only in diabetic individuals. Conclusion: Vascular dysfunction is found even in normoglycemic FDRD and the derangement increased and compounded with the advancement of disease.

The patterns of family genetic risk scores for eleven major psychiatric and substance use disorders in a Swedish national sample

To clarify the structure of genetic risks for 11 major psychiatric disorders, we calculated, from morbidity risks for disorders in 1st–5th degree relatives controlling for cohabitation effects, in the Swedish population born between 1932 and 1995 (n = 5,830,014), the family genetic risk scores (FGRS) for major depression (MD), anxiety disorders (AD), obsessive-compulsive disorder (OCD), bipolar disorder (BD), schizophrenia (SZ), bulimia (BUL), anorexia nervosa (AN), alcohol use disorder (AUD), drug use disorder (DUD), ADHD, and autism-spectrum disorder (ASD). For all affected individuals, we calculated their mean standardized FGRS for each disorder. The patterns of FGRS were quite similar for MD and AD, and for AUD and DUD, but substantially less similar for BUL and AN, BD and SZ, and ADHD and ASD. While OCD had high levels of FGRS for MD and AD, the overall FGRS profile differed considerably from MD and AD. ADHD FGRS scores were substantially elevated in AUD and DUD. FGRS scores for BD, OCD, AN, ASD, ADHD, and especially SZ were relatively disorder-specific while genetic risk for MD and AD had more generalized effects. The levels of FGRS for BMI, coronary artery disease, and educational attainment across our disorders replicated prior associations found using molecular genetic methods. All diagnostic categories examined had elevated FGRS for many disorders producing, for each condition, an informative FGRS profile. Using a novel method which approximates, from pedigree data, aggregate genetic risk, we have replicated and extended prior insights into the structure of genetic risk factors for key psychiatric illnesses.

Concealed cardiomyopathy as a frequent cause of idiopathic ventricular fibrillation in a representative Czech cohort of survivors of sudden cardiac arrest (SCA)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministry of Health of the Czech Republic Introduction The complex diagnostic work up in SCA survivors often does not yield a concrete cardiological diagnosis. Moreover, there is conflicting evidence whether genetic testing could support or guide clinical diagnostics. Purpose To assess the molecular architecture of idiopathic ventricular fibrillation in cases without apparent evidence of specific structural or arrhythmic cardiac disease at initial diagnostic work up in a representative Czech cohort. Patients and Methods Between 2013 - 2020 we have ascertained 100 SCA survivors (54 M / 46 F; age range at cardiac arrest 5-69 years). Genetic counselling was followed by massively parallel DNA sequencing using custom-made panels comprising 100 cardiac conditions-related genes. Subsequently, thorough cardiological screening examinations in first degree relatives were carried out. Presence of pathogenic variants was validated by Sanger DNA sequencing and through family segregation analyses. Results Highly likely or certain molecular aetiology (i.e. based on the presence of Class 4 or 5 variants) was disclosed in 20/100 (20%) in PKP2 (3x), SCN5A (4x), RYR2 (3x), TTN (2x), PLN, FLNC, PRKAG2, KCNH2, KCNQ1, SLC4A, TNNT2, and DSP. Interestingly, the KCNE1 p.Asp85Asn (LQT 5 lite) variant, was detected in further 3/100 cases, representing a recognized risk factor for ventricular arrhythmias. Conclusions Genetic testing facilitates stratification of the cause of arrhythmia in a substantial portion of SCA survivors. The utility of positive outcomes of genetic testing was substantiated in 10/20 gene positive patients, where the genetic stratification led to diagnosis of concealed arrhythmogenic cardiomyopathy, whose extent of morphological changes was under the diagnostic sensibility of imaging modalities or ECG. Our results enable individualized care in SCA survivors and assure targeted preventive approaches in their relatives.