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Enterprise asset management (EAM) systems are used by asset owners and/or operators to manage the maintenance of their physical assets. These assets, including equipment, facilities, vehicles, and infrastructure, need maintenance to sustain their operations. An EAM system provides the means to have less unplanned downtime and extended asset longevity, which offers clear business benefits that improve the profit and loss statement and balance sheet. Particularly for capital-intensive industries, like drilling and exploration, the failure of on-time delivery of critical equipment or processes is disruptive and costs nonproductive time and customer satisfaction. Organizations understand these issues and employ an appropriate asset management system to engineer their asset maintenance and management. An EAM system is needed to manage the people, assets/equipment, and processes. EAMs are used to plan, optimize, execute, and track the needed maintenance activities with associated priorities, skills, materials, tools, and information. Similarly, nondestructive testing (NDT) is used as a tool for integrity assessment of assets in drilling and exploration. The main advantage of using NDT is that the item’s intended use or serviceability is not affected. The selection of a specific technique should be based on knowledge and skills that include design, material processing, and material evaluation. Validating the purpose of this paper, we emphasize the importance of optimizing the asset utilization and serviceability to enhance overall efficiency by integrating EAM software that manages assets, the operation management system (OMS) controlling the processes, and asset inspection management systems (AIMSs).

Introduction: Transgender includes trans-men and trans-women, persons with intersex variations, gender-queers, and persons with socio-cultural identities. Any normal parent expects a binary outcome out of the nine months long pregnancy, however, for some, life changes when the expected outcome is different. Objective: The article tends to understand the life of transgender/Hijra in India with respect to specific healthcare needs along with constitutional mechanism to extend them their legal rights. Method: The researcher reviewed available literature to analyse the issues and challenges in accessing healthcare services by the transgender community. Grey literature and qualitative methods like consultation/ interviews with communities and subject experts were also done to supplement the study outcomes. Results: The study shows that after a long movement, transgender were formally given recognition in 21st century in India. Currently, we have a number to begin with. WHO’s ICD-11 included “gender identity disorders” as “gender incongruence” in its new chapter on sexual health. Interactions with key experts and community reveals different specific needs of transgender population. Conclusion: Five points as way forward to improve health care accessibility of transgender in India: Creating an enabling environment before the next Census in India; addressing stigma and other issues that make transgender people vulnerable to health risks; extending equal human and legal rights to transgender; revising the medical curriculum so as to include a chapter on transgender health; and No Me Without Me.

Engineering Asset Management(EAM) is management of engineering assets and it provides guidelines on the effective usage of all the physical engineered assets within the organization. Similarly, Non-Destructive Testing [NDT] is used as a handy tool for integrity assessment of Assets in scheduled maintenance & inspection program. Though Asset Inspection in Oil & Gas Industry were using conventional NDT methods, now ASME, API and others came up with inspection procedures based on fracture mechanics, where each user to ascertain how their tool/regional operating condition deviate from the assumptions herein, then employ their engineering and technical judgment in deciding how and when to employ any part of these standard. Till recent past, there were no regular validation for these procedures being performed as presumed; benchmark for Severity of failure in North Sea offshore and that in MENA Onshore are set as same. Integration of Operations Management System [OMS] based in Asset Inspection with the EAM allows the Asset Owner/Custodian to consistently monitor each Asset, Acquire monitoring / measurement data in common platform using standardized operating procedures, Measure / Analyze Longevity of each Asset and enable the end user to validate their Service Quality Plan and inspection procedures, as per applicable operating limits and risks. The purpose of this paper to emphasize the importance of optimizing the Asset utilization and serviceability to enhance overall efficiency by integrating; (1)EAM software that manages Assets, (2)OMS controlling the process and (3)Asset Inspection Management System[AIMS]. Case study refer our AIMS, a tool to track all Equipment data [Images, OEM/CoC Document, Inspection Reports/Certificates, track analysis of major attributes] through a single channel - Master Asset [Inspection] Register. Uniquely numbered Assets in each category Drilling Tubulars, Hosting &Handling Equipment and/or Lifting Equipment Item is captured in respective Master Asset Inspection Register with all related Equipment data & Inspection records. Inspection records provides all its inspection related history since its commissioning and manufacturing OEM/CoC Documents. Our cloud based AIMS-App's compliance to API Q2, ISO9001:2015 and ISO17020:2012 ensures its certifying requirements to, (1)relevant Industry standard and bench mark (2)Competence of Inspection Personnel and (3)Compliance of Measuring Devices & Equipment. In last two years [2016-2018] by ensuring Acceptance Benchmark only, more than 70% reduction in premature failure [Crack in Thread Connection; where 50% of those are potential NPT cases] in drilling Tools achieved. Our App provide the user to analyze Inspection data. The trend analysis of tools helps in its planning and utilization plus the data can be directly input to modify Service Quality Plan to optimizing the asset utilization & serviceability. The above are some of the immediate befit to Oil Company and Drilling Contractor by AIMS. This paper also discusses one more dimension of it, Reliability in Service Quality. As this AIMS Tool is synchronized with our, (1)EAM software that manages company's all assets and resources, and (2)OMS controlling the process, the integration of all three increase the overall efficiency of the service and results in profitability of a business.

Commercial Pure (CP) grade-2 titanium is a choice material for the construction of Silver Oxide Zinc reserve-battery components like battery containers, cell casings, electrolyte bladder housings, etc. The above-said components are either not directly exposed to electrolyte or have limited duration exposure, e.g., the cell-case is filled with electrolyte just before operational use, by transferring the stored electrolyte from the electrolyte tanks, using pressurized gas. There is a need to widen the application CP grade-2 titanium material for the construction of electrolyte tank-reservoir in reserve batteries, where long storage requirement exists. Therefore, a study was undertaken on the corrosion behavior of CP grade-2 titanium material, with the known concentration of Potassium Hydroxide (KOH), as used in reserve battery applications. The samples for the conduct of the experiment were carefully prepared by TIG welding procedure. Material characterization studies were undertaken by macro and microstructural analysis using optical microscope (OM), phase analysis by X-ray diffraction (XRD), and Scanning Electron Microscope (SEM). Further, different corrosion studies like immersion test, salt spray test, potentiodynamic polarization studies, and surface morphology studies were undertaken. The results of all the above studies revealed that CP grade-2 titanium material with weld joints if prepared with the standardized procedure, can be effectively used in the construction of electrolyte tanks for Silver Oxide Zinc based Reserve Batteries for meeting strategic defense applications.

Objectives This review summarized the applicability of various decision-making tools for helping people with dementia or mild cognitive impairment (MCI) and their families make decisions. Design This study was a narrative literature review. The protocol of this review was registered in the International Prospective Register of Systematic Reviews (PROSPERO ID: CRD42020182259). Setting and Participants People with dementia or MCI and their families were included in this study. Methods This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. We searched the Cochrane Library, PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, and Chinese Electronic Periodical Services databases from inception to May 2021. The Joanna Briggs Institute Critical Appraisal Checklists for a variety of study designs were used. Results Topics related to decision-making were categorized as everyday activity decisions or medical treatment decisions. Various types of decision-making tools were identified, and we observed that decision aids can be modified and used for both everyday activity decisions and medical treatment decisions. In addition to highlighting decision aids for specific decisional issues and topics, we also elucidated other validated tools that can be used to facilitate the decision-making process. Conclusions and Implications This study highlighted the topics involved in decision-making and using decision-making tools. The current review provides information that can help individuals and health care professionals choose optimal decision-making tools. On the basis of our findings, future studies can determine the most appropriate tools for intervention or outcome measures.

Dropped Objects pose the number-one risk of serious injuries, fatalities, and equipment damage in several industries across the globe and is more prominent in Off shore drilling condition, where more personnel perform their duties within a confined space. Dropped Object Prevention Scheme [DROPS] is intended to be applied to operations in which Dropped Objects could cause harm to people, equipment, and/or the environment. Though Companies develop documented DROPS at relevant levels/departments within the organization as per objectives and targets developed as part of their company's existing Health, Safety, and Environment and/or operational goal-setting processes. Third Party DROPS Survey and Reporting is a catalyst to integrate & guide the scheme to meet its objectives. This paper emphasizes the importance of a robust DROPS, reinforced by repeatable and reliable DROPS Survey & Reporting, in compliance with present industry standard and at the end extend its SMARTER possibilities of expansion with use of RFID Tags and Artificial Intelligence. Our cloud-based Asset Inspection Management System "SOSINSPECTIONEERING" through which (1)Each individually identified DROPS Item shall have a Unique Asset ID,(2)Generate individual DROPS Report for each DROPS Asset, (3)Generate a DROPS Master Asset Register capturing the main features of DROPS Reports and linking it to the latest DROPS Report, (4)Option for Client to download a excel picture book with all 3 levels of Securing and a detailed item specific checklist, (5)The Check list downloaded to ‘Tab’ or any equivalent device provides the work site supervisor to use it in his/her regular verification inspection and report compliance/non-compliance report for further analysis. We are also developing the system to next level of application such as, (a)Tagging each DROPS Asset with RFID Tags, (b) RFID Tag to load with latest DROPS Report for that Asset ID, (c)Each DROPS Reports of the Asset to linked to its other documentation like (i)Manufacture Certificate; (ii)OEM/Other DATA Sheets; (iii)Latest Lifting Certificate &NDT Inspection, (d)RFID scanner with the Work Site Supervisor to Download the DROPS Report or ‘Drone’ to scan the RFID Tag to Down load the latest DROPS Report to the Remote System for verification, (e)Work Site Supervisor of Third Party DROPS Surveyor with Camera can take real time Photos to edit the DROPS Report and modify the ‘Photo Book’ in real time, (f)similarly Camera fitted in a ‘Drone’ can go one step beyond the checklist to use artificial intelligence to recognize patterns and takes a probabilistic approach to verify the compliance by using more historical data.

Despite evidence about the value of high quality postnatal services for the survival, health and wellbeing of the mother and neonate, sub-optimal use of the available services delivered through public sector remains a persistent challenge in India and most low-middle income countries. An extensive search till Dec 31, 2017 in databases including PubMed, Scopus and Science Direct was conducted and selected studies were organized, categorized and summarized for integrated review. Of the 3463 studies screened, 47 relevant studies were identified through integrated systematic process. The ‘nexus’ framework consisting of four domains namely: social-cultural, educational, organizational and economic-physical were used to determine the promoters and inhibitors of postnatal care-utilization. The important inhibitory factors at household and community context were myths-cultural practices, gaps in the awareness of mother and families regarding danger signs and postnatal complications and hesitancy to contact health workers due to trust deficit. There were lack of clarity about job responsibilities, poor quality of training, skills building and supervision of front line workers. Quality of home visits, and irregular incentives to health workers were other factors. The facilitating factors were mother’s autonomy, young mothers, access to media and repeated and timely contact with the health worker, antenatal care (ANC) attendance and institutional deliveries, conditional cash transfer and availability of health insurance. Several factors like social mobilization, skill building and training cut across the domains of the nexus framework. The review suggested a multi-dimensional focus on implementing integrated continuum of care models covering prenatal-postnatal and infancy period.

Objective Clinicians are challenged to decide when and how to conduct decision-making capacity assessment and guardianship applications for confused hospitalised older patients. This study aimed to understand the characteristics of confused hospitalised older patients who require decision-making capacity assessment and guardianship applications and to determine the impact of a locally introduced capacity testing procedure on the conduct of decision-making capacity assessment and guardianship application in a regional hospital setting. Design Before and after study. Setting Regional New South Wales hospital. Participants Twenty-four confused hospitalised older patients who had decision-making capacity assessment during November 2014-April 2015 and November 2015-April 2016. Main outcome measure The impact of a standardised capacity testing procedure on the conduct of decision-making capacity assessment. Results After capacity testing procedure implementation, there were significant improvements in the number of multidisciplinary team meetings, documentation of decision-making capacity assessment process and length of stay. The majority of patients who required guardianship application was aged over 70 years, had a medical history of dementia, >20 days of acute hospital admission and had no evidence of future care-planning. Conclusion Implementation of capacity testing procedure is likely to have contributed to the positive changes in the conduct of decision-making capacity assessment and guardianship application process for confused hospitalised older patients. This study provides some evidence of decision-making capacity assessment process gaps; and indicates clinical and demographic characteristics of confused hospitalised older patients who might require decision-making capacity assessment and guardianship applications. The evidence of lack of appropriate future care-planning for ageing patients and increasing hospital admissions of confused hospitalised older patients presents future challenges in rural health.

Objective Decision-making capacity assessments for hospital settings are challenging as it is dominated by the ethical and legal principles of maintaining autonomy and protection. Health clinicians, especially in rural areas, are challenged with a lack of a standardised processes and pathways for decision-making capacity assessment. A literature review was conducted to determine what measurement tools clinicians are utilising in the hospital setting for decision-making capacity assessment and how decisions relating to consent to treatment, independent living and finances are made. Design Literature review. Method A search of MEDLINE, EMBASE and PsycINFO databases from January 2006 to April 2019 was conducted for peer-reviewed articles to determine how decision-making capacity assessments are conducted and the tools clinicians are utilising in the hospital setting. Results Five main themes were identified from this review: (a) domains of capacity; (b) capacity assessment; (c) capacity assessment instruments; (d) who performs capacity assessment; and (e) challenges and limitations to capacity assessment in the hospital setting. Currently, there is no gold standard for capacity assessment. Conclusion This review shows that there is currently a lack of a uniform approach or a singular test to determine capacity. It is proposed that a multidisciplinary approach to decision-making capacity assessment could be an effective model in the hospital setting, especially in rural health due to limited access to aged care specialists. It is important that clinicians receive ongoing training in decision-making capacity assessment and further research is recommended in this specialised area of practice.

Tables and References supporting ACMG classification of variants identified. (PDF 811 kb)

The proposed study is an attempt to understand the link between Outpatient Department (OPD) patient satisfaction and job satisfaction among front office executives of the OPD. The study was conducted in a 300 bedded multispecialty hospital in Delhi. The study is very important as the OPD is considered to be the mirror of any hospital, which reflects the functioning of the hospital being the first point of contact between the patient and the hospital staff. A structured questionnaire was used in conducting the study. Total 158 patients were interviewed during 2 months period. Stratified random sampling technique used in selecting the samples. Both type of patients, first timers and old patient participated in the study. As second part of the study, all 22 front office executives from the above-mentioned three concerned departments were participated. The age group of the employees ranged from 20 to 50 years. How to cite this article John S, Sharma R, Dhingra MK. Role of Employee Satisfaction in Influencing Patient Satisfaction. Int J Res Foundation Hosp Healthc Adm 2013;1(1):13-18.

Aim Hypertrophic cardiomyopathy (HCM) exhibits genetic heterogeneity that is dominated by variation in eight sarcomeric genes. Genetic variation in a large number of non-sarcomeric genes has also been implicated in HCM but not formally assessed. Here we used very large case and control cohorts to determine the extent to which variation in non-sarcomeric genes contributes to HCM. Methods and results We sequenced known and putative HCM genes in a new large prospective HCM cohort (n = 804) and analysed data alongside the largest published series of clinically genotyped HCM patients (n = 6179), previously published HCM cohorts and reference population samples from the exome aggregation consortium (ExAC, n = 60 706) to assess variation in 31 genes implicated in HCM. We found no significant excess of rare (minor allele frequency

The paper describes the social entrepreneurship (S-ENT) critical success factors (CSFs) identified from a survey study carried out in India. The ranking analysis of the survey results shows that 28 factors are rated as critical for determining the S-ENT success of a social enterprise. Further, the factor analysis revealed that the identified CSFs can be grouped into seven clusters, namely leadership, social enterprise planning, community engagement, innovative financing, human capital, legal support, and social enterprise marketing. The outcome of the thesis provides pioneering insights through a structured framework for investigating the individual CSFs and their different levels of contribution to S-ENT success. The inventive knowledge generated out of the thesis work, can be specifically fruitful for practitioners and other stakeholders in identifying the areas of their social enterprise functioning that demand their utmost priority and attention, in identifying the skills and resources required for their venture success, in assessing their competitive advantage and in helping to setup evaluation mechanism of their ventures etc. The pioneering insights can also be utilised by academicians for theory building and further analysis in the field.

We investigated the promoter polymorphisms of the pituitary growth hormone gene (GH1) and exon 3 deletion polymorphism (GHRd3) in its receptor gene (GHR) in 299 angiographically proven patients with coronary artery disease (CAD) and 231 asymptomatic controls enrolled in the ongoing Indian Atherosclerosis Research Study. Real time PCR based analysis of the GHR variant showed significant association of the GHRd3 deletion allele with CAD (OR 0.48, 95% CI: 0.30–0.76, P = 0.0014) and a dominant model of inheritance (Akaike information criterion = 482). The deletion allele showed significant association with high plasma HDL-c levels (P = 0.001). Sequencing of the proximal promoter region of GH1 revealed 12 novel polymorphisms and a TAGA haplotype constituted by the functional SNPs rs2005171, rs11568828, rs2005172 and rs6171, that showed significant association with CAD alone (adjusted OR of 3.31 (95% CI = 1.33–8.29, P = 0.011) and in CAD patients with diabetes (P = 0.019). Mean standardized height was associated with three of the four haplotype-tagging SNPs in the cohort (P ≤ 0.03). Eleven of the 12 polymorphic promoter SNPs contributed to 14.7% of variation in height in females in the whole dataset (P = 0.029). CAD patients with history of stroke exhibited marginally significantly lower mean height as compared to rest of the cohort (P < 0.006). In conclusion, genetic polymorphisms in the GHR gene and its ligand, GH1, may modulate the risk of CAD in the Asian Indian population.

Clinical genetic testing for inherited cardiac conditions (ICC) began in the late twentieth century and has since rapidly expanded from single gene testing via Sanger sequencing to routinely interrogating large numbers of genes via nextgeneration sequencing (NGS). Catalyzed by the disruptive innovation of NGS, major paradigm changes have taken place in the medical genetics field. Historically, genetic tests were configured for a single disorder and testing was typically performed after a clinical diagnosis had been established. As genetic testing is more widely adopted in the clinic, it has been increasingly recognized that the phenotypic spectrum of many disorders is larger than appreciated and that sequencing a broader array of genes covering related clinical entities can aid in establishing or refining a clinical diagnosis [1]. For this reason, large multi-disease gene panels are now frequently utilized for disorders with clinical and genetic heterogeneity including many inherited cardiac conditions. For example, gene panels for dilated cardiomyopathy (DCM) now typically also include genes associated with hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) as these disorders can be the primary genetic etiology in a patient with DCM [2]. Similarly, sequencing tests for Noonan syndrome initially included only Noonan syndrome genes but today cover overlapping rasopathies [3]. With NGS prices continuing to drop, molecular genetic testing laboratories are beginning to adopt whole-exome and whole-genome sequencing (WES, WGS). Using those assays as a first-line genetic test seems to be within reach, which has recently spurred a debate as to what NGS test is appropriate for which clinical scenario. WES andWGS have thus far been mostly used for patients with complex diagnoses or for patients where other testing options yielded no result. However, these assays still have important drawbacks such as incomplete coverage of critical genes. This tends to be a lesser problem for most gene panels, which may therefore still be the better choice for patients with a well-established diagnosis where complete coverage of the main disease associated genes is paramount. In this issue of the journal, Pua et al. describe a targeted gene capture panel covering 174 genes for the most prevalent inherited cardiac conditions (including arrhythmias, cardiomyopathies, aortopathies, and hyperlipidemias). Genes were selected to cast a wide net and include well-known disease genes and also genes whose disease association is less well established at this point. An in-depth curation of the level of evidence behind each gene is beyond the scope of this work but is being addressed by expert-driven community efforts such as the Clinical Genome Resource (ClinGen) [4]. The authors describe the analytic performance of this panel using Illumina’s Nextera capture assay followed by sequencing on the widely used MiSeq (∼300× mean depth) in addition to the NextSeq500 instrument (∼600×). Additionally, the completeness of coverage of the main disease genes was compared to standard WES (∼70× mean depth), deep WES (∼500×), and WGS (∼70×). At a very high analytical accuracy, their panel clearly (and expectedly) outperformed WES and WGS in terms of completeness of the main disease genes though this difference was less pronounced for deep WES and WGS. Part of the debate on whether exome sequencing can soon replace gene panels has focused on the increasing rate of disease gene discovery our community has been experiencing, Editor-in-Chief Jennifer L. Hall oversaw the review of this article

The recent discovery of heterozygous human mutations that truncate full-length titin (TTN, an abundant structural, sensory, and signaling filament in muscle) as a common cause of end-stage dilated cardiomyopathy (DCM) promises new prospects for improving heart failure management. However, realization of this opportunity has been hindered by the burden of TTN-truncating variants (TTNtv) in the general population and uncertainty about their consequences in health or disease. To elucidate the effects of TTNtv, we coupled TTN gene sequencing with cardiac phenotyping in 5267 individuals across the spectrum of cardiac physiology and integrated these data with RNA and protein analyses of human heart tissues. We report diversity of TTN isoform expression in the heart, define the relative inclusion of TTN exons in different isoforms (using the TTN transcript annotations available at http://cardiodb.org/titin), and demonstrate that these data, coupled with the position of the TTNtv, provide a robust strategy to discriminate pathogenic from benign TTNtv. We show that TTNtv is the most common genetic cause of DCM in ambulant patients in the community, identify clinically important manifestations of TTNtv-positive DCM, and define the penetrance and outcomes of TTNtv in the general population. By integrating genetic, transcriptome, and protein analyses, we provide evidence for a length-dependent mechanism of disease. These data inform diagnostic criteria and management strategies for TTNtv-positive DCM patients and for TTNtv that are identified as incidental findings.

The titingene ( TTN ) is a major determinant of myocardial function, its importance in both familial and ‘idiopathic’ Dilated Cardiomyopathy (DCM) has recently been ascertained. In some instances a second genetic mutation or a physiological perturbation (e.g. pregnancy) may reveal otherwise latent TTN mutation effects. We hypothesise that patients with pronounced LV dysfunction following MI, when controlling for infarct parameters and coronary anatomy, may have a high burden of TTN truncating variants (TTNtvs). We studied a large cohort of post-MI patients prospectively recruited at the Royal Brompton and Harefield NHS Foundation Trust. Gadolinium-enhanced Cardiac Magnetic Resonance was used to characterise cardiac dimensions, function and tissue properties. The size and thickness of MI, wall motion and number of hibernating segments were quantified by two experts blinded to genotype using a standard 17-segment model. Targeted re-sequencing of TTN and other key DCM genes was performed. Genetic variation in DCM genes in 530ethnically matchedhealthy volunteers along with public repositories was used for variant annotation and comparison. Our initial analyses show that out of the 336 post-MI patients, nine (2.7%) had a TTNtv. As hypothesised, TTNtv were significantly enriched in patients with LV ejection fraction (LVEF) TTNtv , in post-MI systolic dysfunction. Based on these findings it will be important to explore if genetic stratification of the post-MI patient can inform medical or revascularisation strategies.

Next-generation sequencing (NGS) provides an unprecedented opportunity to assess genetic variation underlying human disease. Here, we compared two NGS approaches for diagnostic sequencing in inherited arrhythmia syndromes. We compared PCR-based target enrichment and long-read sequencing (PCR-LR) with in-solution hybridization-based enrichment and short-read sequencing (Hyb-SR). The PCR-LR assay comprehensively assessed five long-QT genes routinely sequenced in diagnostic laboratories and "hot spots" in RYR2. The Hyb-SR assay targeted 49 genes, including those in the PCR-LR assay. The sensitivity for detection of control variants did not differ between approaches. In both assays, the major limitation was upstream target capture, particular in regions of extreme GC content. These initial experiences with NGS cardiovascular diagnostics achieved up to 89 % sensitivity at a fraction of current costs. In the next iteration of these assays we anticipate sensitivity above 97 % for all LQT genes. NGS assays will soon replace conventional sequencing for LQT diagnostics and molecular pathology.

Introduction The common heritable condition of Bicuspid Aortic Valve (BAV) is phenotypically heterogeneous, with valve dysfunction and aortopathy the major complications. We report overrepresentation of rare, likely pathogenic variants in target genes in a large cohort of 176 patients with BAV. We also describe a more severe aortic phenotype in patients with more than one known or likely pathogenic variant, supporting a multi-hit hypothesis for development of complications of BAV. Methods We recruited 176 patients with BAV without known syndromic basis from two large tertiary referral centres. Phenotyping was performed with routine clinical MRI and/or echocardiography. We identified 63 genes of interest with known or suspected links to BAV or to aortic /aortic valve (AV) pathology. We used genomic DNA from our patients for NGS of these target genes. Control populations were provided by the Exome Variant Server (EVS; 6503 samples) and 1000 genomes project. We analysed called variants in silico , usingSIFT, Polyphen2, Grantham scoring and phastCONS, and categorised variants into the following groups based on likely pathogenicity using a combination of in silico tools: known links with disease, likely, possible, and unlikely pathogenicity. Results 10 patients (5.7% of our cohort) had variants previously associated with aortic or AV pathology or with abnormalities of smooth muscle function; 3 in GATA5, 2 in FBN1, 2 in MYH11, 1 in NOTCH1 and 1 in COL3A1. In silico analysis identified 45 further instances of 31 likely pathogenic, rare variants in 33 patients (a further 19% of our cohort), in 11 different genes: GATA5 (see Table 1), NOTCH1 (see Figure 1), MYH11, PLOD3, FBN1, MMP9, NKX2–5, JAG1, ACE, ENG, PDIA2 and KCNJ2. The combined prevalence of these known or likely pathogenic variants in our cohort was significantly greater than in the EVS control populations (p 10 patients had known or likely pathogenic variants in more than one gene of interest. These 10 patients had a significantly higher prevalence of significant aortopathy and/or coarctation of the aorta than the rest of our cohort (6/10 vs 20/176; p = 0.0006). Conclusions We identified known or likely pathogenic genetic variants in nearly a quarter of our BAV cohort. Some of these (eg the c.698T >C variant in GATA5) may be common polymorphisms, wrongly classified by in silico tools. However, many are undoubtedly genuine determinants of phenotype, as evidenced by their overrepresentation in our cohort, and the finding of a more severe aortic phenotype in patients with more than one presumed pathogenic variant. Further research, including our own control population and family studies, is planned. This is also the first study, to our knowledge, to correlate BAV aortopathy with more complex genotypes, and lends support to a multi-hit genetic hypothesis for development of aortic complications of BAV.

Elevated factor VII (FVII) level is a risk factor for coronary artery disease (CAD). We investigated the role of R353Q polymorphism in the F7 gene in 139 Indian families with CAD, comprising of 222 affected subjects, 105 unaffected subjects and 126 affected sibling pairs. Plasma per cent FVIIc activity (FVII.c activity) differed significantly across R353Q genotype (P < 0.0001). Frequency of subjects with RR and QQ genotypes were higher in 4th quartile and 1st quartile of FVII.c activity, respectively (P < 0.0001). F7 R353Q SNP was able to explain up to 7% of variation in FVII.c activity by regression analysis and an additive genetic component of variance of 28.04% by heritability analysis. Quantitative trait loci analysis showed suggestive linkage evidence of F7 SNP with per cent FVII.c activity (LOD score −1.82; P = 0.002). Individuals with RR and RQ genotypes carried an OR of 2.071 (95% c.i. = 1.506−2.850) and 2.472 (95% c.i. = 1.679−3.641), respectively, towards CAD risk. There was significant correlation of FVII.c activity with lipid markers, particularly among those with RR and RQ genotype after covariate adjustment. In conclusion, the F7 R353Q SNP appears to moderately influence plasma FVII.c activity and risk of CAD in Indians.

Table 3. Analysis of variance of the plasma lipid biomarkers and rs10757278 SNP. AA AG GG Plasma lipid Mean ± s.e. [mg/dl] Mean ± s.e. [mg/dl] Mean ± s.e. [mg/dl] P value Total cholesterol 5.09 ± 0.05 (164.02) 5.11 ± 0.02 (165.67) 5.13 ± 0.03 (169.02) 0.828 Triglycerides 4.75 ± 0.09 (115.58) 4.89 ± 0.04 (132.95) 4.93 ± 0.06 (138.38) 0.261 HDL cholesterol 3.7 ± 0.04 (40.45) 3.7 ± 0.02 (40.45) 3.78 ± 0.03 (43.82) 0.085 LDL cholesterol 4.55 ± 0.07 (94.63) 4.53 ± 0.03 (92.76) 4.51 ± 0.05 (90.92) 0.888

SummaryInflammation plays a major role in coronary artery disease (CAD). We investigated the polymorphisms in the interleukin 6 (IL6) gene and their effect on the expression of acute-phase proteins in premature CAD in Asian Indian families. One hundred and ninety affected sibling pairs (ASPs) were genotyped for three tag single nucleotide polymorphisms (SNPs) in the IL6 gene for linkage analysis. We observed suggestive logarithm of odds (LOD) score for one SNP (rs2066992) in a subset of 62 ASPs with the age at onset less than 45 years (LOD score = 1.114, p = 0.011 in linkage analysis; pi = 0.55, p = 0.008 in identity by descent; LOD score = 1.06, p = 0.014 in quantitative trait locus for plasma levels of high sensitivity C-reactive protein, hsCRP). This was followed by sequencing of the promoter region and haplotype analysis in 46 probands and 40 controls. Five out of the eight previously reported promoter SNPs were found to be polymorphic (rs1800797, rs1800796, rs7802307, rs7802308, rs1800795). Two novel sequence variants were also found. One promoter haplotype (GGAAG) was detected with an odds ratio (OR) of 3.676 (p = 0.0017, 95% confidence interval [CI]: 1.68 – 8.045) and population attributable risk of 21.1% (95%CI: 9.2%-31.5%). The plasma levels of both hsCRP and fibrinogen exhibited significant association with these promoter SNP genotypes (p < 0.001). In conclusion, IL6 gene polymorphisms appear to be important genetic factors in premature CAD, and in the regulation of key atherogenic markers in Asian Indian families.

Background The APOA1-C3-A5 gene cluster plays an important role in the regulation of lipids. Asian Indians have an increased tendency for abnormal lipid levels and high risk of Coronary Artery Disease (CAD). Therefore, the present study aimed to elucidate the relationship of four single nucleotide polymorphisms (SNPs) in the Apo11q cluster, namely the -75G>A, +83C>T SNPs in the APOA1 gene, the Sac1 SNP in the APOC3 gene and the S19W variant in the APOA5 gene to plasma lipids and CAD in 190 affected sibling pairs (ASPs) belonging to Asian Indian families with a strong CAD history. Methods & results Genotyping and lipid assays were carried out using standard protocols. Plasma lipids showed a strong heritability (h2 48% – 70%; P < 0.0001). A subset of 77 ASPs with positive sign of Logarithm of Odds (LOD) score showed significant linkage to CAD trait by multi-point analysis (LOD score 7.42, P < 0.001) and to Sac1 (LOD score 4.49) and -75G>A (LOD score 2.77) SNPs by single-point analysis (P < 0.001). There was significant proportion of mean allele sharing (pi) for the Sac1 (pi 0.59), -75G>A (pi 0.56) and +83C>T (pi 0.52) (P < 0.001) SNPs, respectively. QTL analysis showed suggestive evidence of linkage of the Sac1 SNP to Total Cholesterol (TC), High Density Lipoprotein-cholesterol (HDL-C) and Apolipoprotein B (ApoB) with LOD scores of 1.42, 1.72 and 1.19, respectively (P < 0.01). The Sac1 and -75G>A SNPs along with hypertension showed maximized correlations with TC, TG and Apo B by association analysis. Conclusion The APOC3-Sac1 SNP is an important genetic variant that is associated with CAD through its interaction with plasma lipids and other standard risk factors among Asian Indians.

Social entrepreneurship is relatively a new concept within social sciences. Like the case with any newly emerging field, social entrepreneurship is confronting the challenges of justifying the use of new constructs and hence the challenge of generating new knowledge and insights. Till date, the field of social entrepreneurship has majorly been consented as a multidisciplinary approach to social problem solving. In this regard, researchers are attempting to take insights from different disciplines in an effort towards delimiting the scope and context of social entrepreneurship. However, social entrepreneurship is projected or seen as sharing much in common with business management and entrepreneurship. As such, the different approaches of management domain find high appropriateness for application, explanation and further expansion of this field. In light of the above and on the basis of a few qualitative case studies conducted in the western countries till date, the paper attempts to gain critical insights about the use of marketing concepts in social enterprises.

Introduction As gene sequencing becomes more widespread, the clinical implications of incidental findings in patients’ genomes are becoming more complex. We identified healthy volunteers with mutations known to cause penetrant, Mendelian aortic disease, and examined the association of these mutations with aortic pulse wave velocity (PWV); a key marker of cardiovascular risk and aortic elastic function. Methods We recruited 476 healthy volunteers with no known history of cardiovascular risk factors or disease for aortic phenotyping and gene sequencing. We measured aortic arch pulse wave velocity derived from Cardiovascular MRI (CMR) using ArtFun software and performed whole exome sequencing (Illumina HiSeq 2000). Sequence was alignedto hg19 reference using BWA v0.7.10 and variants were called using GATK and validated using IGV. Variants that are presumed causative for aortic disease were prioritised using HGMD and were further annotated by literature review. A binary variable, "AOV status" reflected the presence or absence of a variant linked with aortopathy by this approach. Statistical analysis was performed using linear regression modelling, Mann-Whitney U tests and bootstrapping in R. For Mann-Whitney U tests, we used age-corrected PWV [=PWV/log (Age)]. Results 17 of our healthy volunteers (3%) had previously reported pathogenic mutations in seven aortopathy genes ( COL1A2 , COL3A1 , FBN1 , MYH11 , MYLK , TGFBR1 and TGFBR2 ; see Table 1). Three mutations (in 4 individuals; 0.8% of our cohort) had evidence for pathogenicity (eg family linkage analysis) beyond just a single case report; two in TGFBR2 (3 individuals) and one in COL1A2 . These four subjects had significantly higher aPWVs than control cases (Mann-Whitney U test; U=235, p = 0.01; see Figure 1), and than those cases where the evidence for variant pathogenicity was limited (p = 0.02). Linear regression modelling of PWV was significantly improved by the addition of AOV status (ANOVA of nested linear models; p = 0.03; F=5.56(1), R 2 =0.07; multiple R 2 =0.57; p Discussion It is not unusual to find “disease-causing” variants in an apparently healthy population. Sometimes this is used to argue against the pathogenicity of a particular variant. However, our results imply that some of these “healthy” individuals may have penetrant aortic disease but of limited expressivity. These individuals may have increased risk of cardiovascular events, and so-called “spontaneous” aortic aneurysm and dissection. This finding therefore has implications for genetic counselling, as well as for the conduct of gene sequencing studies.

Tables and References supporting ACMG classification of variants identified. (PDF 811 kb)

Background Cardiovascular magnetic resonance (CMR) imaging is the gold standard imaging modality for characterization of dilated cardiomyopathy (DCM). We recently identified genetic variants that truncate the giant protein Titin (TTN) accounting for up to 25% of DCM cases: a discovery that will increase the utility of genetic testing and family screening in DCM. However, the clinical consequences of TTN truncating variants (TTNtv) are unknown. Here, we integrated the power of CMR and capacity of next generation sequencing (NGS) to assess the relationship between genotype and phenotype in a non-ischemic DCM population. Methods 319 patients referred for characterization of DCM were recruited and underwent quantitative CMR study with detailed phenotyping (Siemens Avanto or Siemens Sonata 1.5T scanners). Additional clinical data were collected. TTN genotypes were determined by target enrichment using SureSelect and NGS sequencing using the SOLiD 5500 platform. Results TTN truncating variants (TTNtv) were identified in 13% (n = 42) of cases, the commonest genetic cause of DCM. Table 1 compares the CMR and clinical characteristics of TTNtv-positive and TTNtv-negative cohorts. TTNtv-positive DCM patients had lower left ventricular (LV) ejection fraction (EF) (p = 0.02), thinner LV walls (p < 0.02) and higher incidence of sustained ventricular tachycardia (VT) (p = 0.001) which was independent of EF. No statistically significant difference in the prevalence of midwall fibrosis existed between the two groups. Multivariate linear regression models that considered age, sex, TTNtv presence and position (distance from the protein N-terminus) indicated that TTNtv position was significantly correlated with biventricular ejection fraction and indexed stroke volumes such that more distal truncations had worse indices of cardiac function. For example, a C-terminal TTNtv would be associated with an absolute reduction in LV EF of 18 ± 7%, (p = 0.005), as compared with an N-terminal TTNtv. Conclusions These data highlight the prevalence of TTNtv in this unselected DCM cohort and suggest that TTNtvpositive DCM patients may benefit from tailored clinical management. Sustained VT, LV wall thickness and LVEF influence DCM outcomes. The increased risk of sustained VT in TTNtv-positive DCM may warrant a lower threshold for device therapy, as recommended for DCM caused by LMNA mutations. As distal TTNtv were associated with worse LV function, more aggressive clinical management may be appropriate in patients carrying these variants. The phenotypic expression of genetic substrates can be highly variable, and CMR is central to the accurate phenotypic description of this common yet heterogenous condition. Enhanced molecular understanding may lead to strategies to alter disease course beyond current pharmacological and device based therapy.