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Context Silver-Russell syndrome (SRS) is a clinical and molecular heterogeneous disorder associated with short stature, typical facial gestalt, and body asymmetry. Though molecular causes of SRS can be identified in a significant number of patients, about one-half of patients currently remain without a molecular diagnosis. However, determination of the molecular cause is required for a targeted treatment and genetic counselling. Objective The aim of this study was to corroborate the role of HMGA2 as an SRS-causing gene and reevaluate its mode of inheritance. Design, Setting, Patients Patients were part of an ongoing study aiming on SRS-causing genes. They were classified according to the Netchine-Harbison clinical scoring system, and DNA samples were investigated by whole exome sequencing. Common molecular causes of SRS were excluded before. Results Three novel pathogenic HMGA2 variants were identified in 5 patients from 3 SRS families, and fulfilling diagnostic criteria of SRS. For the first time, homozygosity for a variant in HMGA2 could be identified in a severely affected sibpair, whereas parents carrying heterozygous variants had a mild phenotype. Treatment with recombinant growth hormone led to a catch-up growth in 1 patient, whereas all others did not receive growth hormone and stayed small. One patient developed type 2 diabetes at age 30 years. Conclusions Identification of novel pathogenic variants confirms HMGA2 as an SRS-causing gene; thus, HMGA2 testing should be implemented in molecular SRS diagnostic workup. Furthermore, inheritance of HMGA2 is variable depending on the severity of the variant and its consequence for protein function.

Most genetic variants are rare and specific to the population, highlighting the importance of characterizing local population genetic diversity. Many countries have initiated population-based whole-genome sequencing (WGS) studies. Genomic variation within Lithuanian families are not available in the public databases. Here, we describe initial findings of a high-coverage (an average of 36.27×) whole genome sequencing for 25 trios of the Lithuanian population. Each genome on average carried approximately 4,701,473 (±28,255) variants, where 80.6% (3,787,626) were single nucleotide polymorphisms (SNPs), and the rest 19.4% were indels. An average of 12.45% was novel according to dbSNP (build 150). The WGS structural variation (SV) analysis identified on average 9133 (±85.10) SVs, of which 95.85% were novel. De novo single nucleotide variation (SNV) analysis identified 4417 variants, where 1.1% de novo SNVs were exonic, 43.9% intronic, 51.9% intergenic, and the rest 3.13% in UTR or downstream sequence. Three potential pathogenic de novo variants in the ZSWIM8, CDC42EP1, and RELA genes were identified. Our findings provide useful information on local human population genomic variation, especially for de novo variants, and will be a valuable resource for further genetic studies, and medical implications.

As global and local crises continue to destabilize stakeholders' trust in organizations, they need to find a long-term solution to the problem of declining trust. A critical marketing task for the sustainability of any business is to focus on the organization's reputation as a valuable, sustainable, and intangible asset of the organization. Growing trust in business is associated with corporate reputation that highlights company’s values and beliefs, shows the ways the company is trying to achieve its goals, to fulfil consumers’ expectations and its commitments. In some cases, a company does not even have to try to earn stakeholder trust as this function is performed by corporate reputation that develops positive stakeholders’ attitude towards the company as a reliable subject in the relationship. An analysis of the organization’s reputation and stakeholder trust in the organization revealed a lack of a systematic approach to how the reputation of one organization affects the trust of customers. The research focuses on the issue of consumer trust, consumer being one of the most important stakeholders. Differences in the impact of corporate reputation dimensions on consumer trust are noticed in different sectors, which creates the need for in-depth study of the issue. The aim of the article is to estimate the impact of corporate reputation on consumer trust and to determine which dimensions of corporate reputation affect different types of consumer trust. Empirical research findings are based on the case of pharmacy network in Lithuania. The pharmacy network is chosen for analysis due to the phenomenon that has appeared in the market, i.e., over the years decreasing trust in companies of one sector (pharmaceutical, in this case) has been unjustly identified with the situation in the other sector (pharmacy), which results in difficulties faced when building corporate reputation.

Poster-Abstract

Background: According to the National Diabetes Register (NDR) report (2016), 21.2% of adults with type 1 diabetes (T1D) achieve glycaemic targets measured with HbA1c (52 mmol / mol) and 20.1% of patients have very poor glycaemic control (HbA1c> 70 mmol / mol). In recent years, a positive trend in improving HbA1c has been observed; despite it, there is a great need to understand how diabetes care can be improved. Thus, the following questions were formulated: To what extent are international guidelines for visits with HbA1c controls in T1D followed? (Study I) Which of the two most commonly used CGM sensors is most accurate in estimating blood glucose levels and which CGM system is most user-friendly? (Study II) Can some patient subgroups have greater effect on insulin pump treatment than others? (Study III) What is the excess risk of acute coronary events for persons with T1D compared to persons without T1D in Sweden, when modern guidelines have been implemented? How does this risk differ for people with T1D in relation to glycaemic control and renal complications? (Study IV) Material and methods: To calculate the HbA1c yearly measurement rate, we included patients from 10 diabetes clinics in Sweden. Data were collected via the Diab-Base electronic record system (study I). Persons with T1D and insulin pump use for at least 5 years who had HbA1c measurement at the beginning and end of the period and patients with insulin injections were included from Dia-Base in study III. In an economically independent clinical trial on precision and treatment satisfaction with 2 different CGM (Dexcom G4 and Enlite) systems, ambulatory patients with T1D were included (study II). All patients arrived at three scheduled visits for blood sampling and filled in a questionnaire regarding treatment satisfaction. In a study of risk of myocardial infarction in persons with T1D compared to controls (study IV), we included patients registered in NDR (n = 33 886) and 5 randomly selected matched controls (n = 169 223). Through interaction with data from the National Board of Social Services, data were collected on cardiovascular disease, death date and causes of death. Results and conclusions: Persons with T1D, get fewer than 2 HbA1c controls per year on average in Sweden against recommended 4 controls per year. Patients with insulin injections receive fewer HbA1c controls and need extra focus (study I). We found that DexCom G4 had a higher precision and treatment satisfaction, which is likely to make adequate decisions on treatment (study II). We found no strong predictors for the greater effect of insulin pump on lowering HbA1c. The decrease was 2.5 mmol / mol at very high HbA1c compared with about 2 mmol / mol on average. However, insulin pump treatment has a value since a certain decrease in HbA1c occurs (study III). Persons with T1D had about 4 times the risk of cardiac infarction than persons without diabetes in Sweden. The risk is significantly lower for people with good glycaemic control and absence of renal complications. Continued focus on better methods for improving HbA1c, as well as primary and secondary prevention of coronary artery disease are essential for reducing the risk of coronary complications in T1D.

Human ciliopathies are hereditary conditions caused by defects of proteins expressed at the primary cilium. Among ciliopathies, Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS) and nephronophthisis (NPH) present clinical and genetic overlap, being allelic at several loci. One of the most interesting gene is TMEM67, encoding the transmembrane protein meckelin. We performed mutation analysis of TMEM67 in 341 probands, including 265 JSRD representative of all clinical subgroups and 76 MKS fetuses. We identified 33 distinct mutations, of which 20 were novel, in 8/10 (80%) JS with liver involvement (COACH phenotype) and 12/76 (16%) MKS fetuses. No mutations were found in other JSRD subtypes, confirming the strong association between TMEM67 mutations and liver involvement. Literature review of all published TMEM67 mutated cases was performed to delineate genotype-phenotype correlates. In particular, comparison of the types of mutations and their distribution along the gene in lethal versus non lethal phenotypes showed in MKS patients a significant enrichment of missense mutations falling in TMEM67 exons 8 to 15, especially when in combination with a truncating mutation. These exons encode for a region of unknown function in the extracellular domain of meckelin.

Multicenter long-term studies of predictors for the effectiveness of continuous subcutaneous insulin infusion (CSII) in clinical practice are lacking. We hypothesized that there are substantially greater reductions in hemoglobin A1c (HbA1c) in patients with poor glycemic control and that other predictors may also exist.We used data from 10 outpatient diabetic clinics in Sweden and studied CSII treatment over 5 years. Patients with HbA1c values available ≤ 6 months before starting CSII and at 5 years were included (n = 272, 82% of CSII patients) along with 2,437 contemporaneous controls on multiple daily insulin injections (MDI). Baseline variables evaluated were age, sex, diabetes duration, insulin dose, body mass index (BMI), HbA1c at baseline, and outpatient clinical care unit.At 5 years, significantly greater reductions in HbA1c by CSII compared with MDI were found for patients with higher baseline HbA1c (P = 0.032) and lower baseline BMI (P = 0.013). For baseline HbA1c levels of 7.0%, 8.0%, and 9.0% and a BMI of 25 kg/m(2), the reduction in HbA1c level by CSII was 0.08% (difference not significant), 0.16% (95% confidence interval, 0.03-0.29%), and 0.25% (95% confidence interval, 0.11-0.39%), respectively. Corresponding analyses for the change in HbA1c level from start to 1 and 2 years revealed a significant interaction of insulin pump therapy only with baseline HbA1c levels (P0.001 and P = 0.030, respectively). The interaction term between outpatient clinical care unit and CSII treatment was statistically significant for some care units, with some care units demonstrating a benefit from CSII and others demonstrating a detriment.Patients with high HbA1c levels have a greater probability of improved HbA1c after initiating pump therapy, but effects remain relatively modest even for patients with poor control. Factors predicting successful insulin pump use need further study.

Continuous glucose monitoring (CGM) is a tool widely used in the treatment of patients with type 1 diabetes. The purpose of the current study was to evaluate whether accuracy and patient treatment satisfaction differ between the Enlite™ (Medtronic MiniMed, Inc., Northridge, CA) and Dexcom(®) (San Diego, CA) G4 PLATINUM CGM sensors.Thirty-eight ambulatory patients with type 1 diabetes used the Dexcom G4 and Enlite sensors simultaneously for a minimum of 4 and maximum of 6 days. Patients measured capillary glucose levels with a HemoCue(®) (Ängelholm, Sweden) system six to 10 times a day. In addition, two inpatient studies were performed between Days 1-3 and 4-6.The mean absolute relative difference (MARD) in blood glucose for the Dexcom G4 was significantly lower (13.9%) than for the Enlite sensor (17.8%) (P0.0001). The corresponding MARDs for Days 1-3 were 15.0% versus 19.4% (P=0.0027) and 13.6% versus 15.9% (P=0.026) for Days 4-6. For glucose levels in the hypoglycemic range (4.0 mmol/L), the MARD for the Dexcom G4 was 20.0% compared with 34.7% for the Enlite (P=0.0041). On a visual analog scale (VAS) (0-100), patients rated the Dexcom G4 more favorably than the Enlite in 12 out of the 13 user experience questions. For example, more patients rated their experience with the Dexcom G4 as positive (VAS, 79.7 vs. 46.6; P0.0001) and preferred to use it in their daily lives (VAS, 79.1 vs. 42.1; P0.0001).The Dexcom G4 sensor was associated with greater overall accuracy than the Enlite sensor during initial (Days 1-3) and later (Days 4-6) use and for glucose levels in the hypoglycemic range. Patients reported a significantly more positive experience using the Dexcom G4 than the Enlite.

The excess risk of major coronary events (acute myocardial infarction (AMI) or death from coronary heart disease (CHD)) in individuals with type 1 diabetes (T1D) in relation to glycaemic control and renal complications is not known.Individuals with T1D in the Swedish National Diabetes Registry after 1 January 1998, without a previous MI (n=33 170) and 1 64 698 controls matched on age, sex and county were followed with respect to non-fatal AMI or death from CHD. Data were censored at death due to any cause until 31 December 2011.During median follow-up of 8.3 and 8.9 years for individuals with T1D and controls, respectively, 1500 (4.5%) and 1925 (1.2%), experienced non-fatal AMI or died from CHD, adjusted HR 4.07 (95% CI 3.79 to 4.36). This excess risk increased with younger age, female sex, worse glycaemic control and severity of renal complications.The adjusted HR in men with T1D with updated mean haemoglobin A1c (HbA1c)6.9% (52 mmol/mol) and normoalbuminuria was 1.30 (95% CI 0.90 to 1.88) and in women 3.16 (95% CI 2.14 to 4.65). HRs increased to 10.7 (95% CI 8.0 to 14.3) and 31.8 (95% CI 23.6 to 42.8) in men and women, respectively, with HbA1c9.7% and renal complications.The excess risk of AMI in T1D is substantially lower with good glycaemic control, absence of renal complications and men compared with women. In women, the excess risk of AMI or CHD death persists even among patients with good glycaemic control and no renal complications.

Background: Using the standard venous reference for the evaluation of continuous glucose monitoring (CGM) systems could possibly negatively affect measured CGM accuracy since CGM are generally calibrated with capillary glucose and venous and capillary glucose concentrations differ. We therefore aimed to quantify the effect of using capillary versus venous glucose reference samples on estimated accuracy in capillary calibrated CGM. Methods: We evaluated 41 individuals with type 1 diabetes mellitus (T1DM) using the Dexcom G4 CGM system over 6 days. Patients calibrated their CGM devices with capillary glucose by means of the HemoCue system. During 2 visits, capillary and venous samples were simultaneously measured by HemoCue and compared to concomitantly obtained CGM readings. The mean absolute relative difference (MARD) was calculated using capillary and venous reference samples. Results: Venous glucose values were 0.83 mmol/L (15.0 mg/dl) lower than capillary values over all glycemic ranges, P < .0001. Below 4 mmol/l (72 mg/dl), the difference was 1.25 mmol/l (22.5 mg/dl), P = .0001, at 4-10 mmol/l (72-180 mg/dl), 0.67 mmol/l (12.0 mg/dl), P < .0001 and above 10 mmol/l (180 mg/dl), 0.95 mmol/l (17.1 mg/dl), P < .0001. MARD was 11.7% using capillary values as reference compared to 13.7% using venous samples, P = .037. Below 4 mmol/l (72 mg/dl) MARD was 16.6% and 31.8%, P = .048, at 4-10 mmol/l (72-180 mg/dl) 12.1% and 12.6%, P = .32, above 10 mmol/l (180 mg/dl) 8.7% and 9.2%, P = .82. Conclusion: Using capillary glucose concentrations as reference to evaluate the accuracy of CGM calibrated with capillary samples is associated with a lower MARD than using venous glucose as the reference. Capillary glucose concentrations were significantly higher than venous in all glycemic ranges.

Dataset of the group of ethnic Lithuanian population (LITGEN project). (PDF 138Â kb)

Background Congenital hearing loss (CHL) is diagnosed in 1 – 2 newborns in 1000, genetic factors contribute to two thirds of CHL cases in industrialised countries. Mutations of the GJB2 gene located in the DFNB1 locus (13q11-12) are a major cause of CHL worldwide. The aim of this cross-sectional study was to assess the contribution of the DFNB1 locus containing the GJB2 and GJB6 genes in the development of early onset hearing loss in the affected group of participants, to determine the population-specific mutational profile and DFNB1-related HL burden in Lithuanian population. Methods Clinical data were obtained from a collection of 158 affected participants (146 unrelated probands) with early onset non-syndromic HL. GJB2 and GJB6 gene sequencing and GJB6 gene deletion testing were performed. The data of GJB2 and GJB6 gene sequencing in 98 participants in group of self-reported healthy Lithuanian inhabitants were analysed. Statistic summary, homogeneity tests, and logistic regression analysis were used for the assessment of genotype-phenotype correlation. Results Our findings show 57.5 % of affected participants with two pathogenic GJB2 gene mutations identified. The most prevalent GJB2 mutations were c.35delG, p. (Gly12Valfs*2) (rs80338939) and c.313_326del14, p. (Lys105Glyfs*5) (rs111033253) with allele frequencies 64.7 % and 28.3 % respectively. GJB6 gene mutations were not identified in the affected group of participants. The statistical analysis revealed significant differences between GJB2(−) and GJB2(+) groups in disease severity (p = 0.001), and family history (p = 0.01). The probability of identification of GJB2 mutations in patients with various HL characteristics was estimated. The carrier rate of GJB2 gene mutations – 7.1 % (~1 in 14) was identified in the group of healthy participants and a high frequency of GJB2-related hearing loss was estimated in our population. Discussion The results show a very high proportion of GJB2-positive individuals in the research group affected with sensorineural HL. The allele frequency of c.35delG mutation (64.7 %) is consistent with many previously published studies in groups of affected individuals of Caucasian populations. The high frequency of the c.313_326del14 (28.3 % of pathogenic alleles) mutation in affected group of participants was an unexpected finding in our study suggesting not only a high frequency of carriers of this mutation in our population but also its possible origin in Lithuanian ancestors. The high frequency of carriers of the c.313_326del14 mutation in the entire Lithuanian population is supported by it being identified twice in the ethnic Lithuanian group of healthy participants (a frequency 2.0 % of carriers in the study group). Conclusion Analysis of the allele frequency of GJB2 gene mutations revealed a high proportion of c. 313_326del14 (rs111033253) mutations in the GJB2-positive group suggesting its possible origin in Lithuanian forebears. The high frequency of carriers of GJB2 gene mutations in the group of healthy participants corresponds to the substantial frequency of GJB2-associated HL in Lithuania. The observations of the study indicate the significant contribution of GJB2 gene mutations to the pathogenesis of the disorder in the Lithuanian population and will contribute to introducing principles to predict the characteristics of the disease in patients. Electronic supplementary material The online version of this article (doi:10.1186/s12863-016-0354-9) contains supplementary material, which is available to authorized users.

Quality parameters and description of all mutations analyzed with Illumina VeraCode GoldenGate assay. (DOCX 69 kb)

Dataset of the group of affected individuals (DEAFGEN project). (PDF 191Â kb)

The conditions for PCR amplification of GJB2 and GJB6 genes coding sequences (primer sequences, annealing temperature, lengths of the amplicons). (PDF 8Â kb)

Many scientists analysed the importance of stakeholders on the ground of the interrelationship between an organization and stakeholders. Nevertheless, scientists do not define which stakeholders should be considered as the most or the least important. For this reason, the stakeholder grouping in accordance with their importance to the organization has been done. Stakeholders are divided into internal and external; primary and secondary; normative, functional, diffused and customers; regulatory, organizational, community and media; groups in the order of power and interest. In this paper, we also highlighted another stakeholder group, which we call a shadow group due to its illegal impact on the organization or industry. The analysis of stakeholder grouping initiated that while grouping stakeholders in accordance with their importance to the organization, it is worth to divide them into primary and secondary. Allocating the stakeholders to the primary and secondary groups unconsciously leads to the conclusion that primary stakeholders take the first, i.e. the most important place with regard to secondary stakeholders. It was observed that the scientists, acting on business interests, propose that even these stakeholders who find themselves in the same stakeholder group have unequal importance - the organizations give the priority to stakeholders, previously considered as the secondary. Consequently, because of these two different mainstream approaches of the theorists and the scientists, acting on business interests, it remains unclear what stakeholders should be attributed to which groups considering their importance to organization. DOI: http://dx.doi.org/10.5755/j01.ee.26.1.6921

Cleft lip with or without cleft palate (CL/P) is one of the mostcommonhumanbirthdefects.CL/Pmayoccuraspartofacomplexmalformation syndrome or, as is more commonly the case, as anonsyndromic malformation. In European populations non-syndromic cleft lip with or without cleft palate (NSCL/P) has abirth prevalence of 1/700–1/1,000. NSCL/P has a multifactorialetiology resulting from interactions between multiple genetic andenvironmentalfactors.Nonsyndromiccleftpalateonly(NSCPO)isthe second most common form of nonsyndromic clefting, with aprevalence of 1/2,000 in most European populations. AlthoughNSCL/P and NSCPO are generally considered to be develop-mentally and genetically distinct entities, there is evidence thatthey may have an etiological overlap [Kondo et al., 2002; Sivertsenet al., 2008].The identification of susceptibility genes for NSCL/P has beenthe subject of extensive research. Of the many candidate genesinvestigated, however, only the IRF6 gene has shown a convincingdegreeofconsistencyacrossstudies[Zuccheroetal.,2004;Rahimovet al., 2008]. The first genome-wide association scan (GWAS)recently reported a new major susceptibility locus at chromosome8q24.21,with the strongestassociationsignal having been observedfor rs987525 (P¼3.34 10

Aim: Guidelines for the treatment of type 1 diabetes generally recommend quarterly or more frequent Haemoglobin A1c (HbA1c) assessment in patients with inadequate glycaemic control. The purpose of the current study was to evaluate to what extent these guidelines are followed in clinical practice in Sweden. Method: We studied 5989 patients with type 1 diabetes from 10 outpatient diabetes clinics in Sweden from 1 January 2005 to 31 December 2009. Data on HbA1c measurement frequency were obtained from the Diab-Base electronic medical records database, where HbA1c measurements are recorded together with other patient characteristics, including treatment and other general risk factors for diabetic complications. The frequency of HbA1c measurements was obtained for all patients by calendar year, care unit, and during time periods where glucose was classified as well controlled (HbA1c7% was performed within 4 months. The probability of a subsequent assessment in the 4 months following an HbA1c value>7.0% increase in patients treated with continuous subcutaneous insulin infusion (CSII), OR=1.57 (1.46-1.69). Differences were also noted by care unit, age, gender, glycaemic control, calendar year, and weight and diabetes duration. Conclusion: In patients with type 1 diabetes, HbA1c is measured less frequently in clinical practice in Sweden than guidelines recommend, although patients with CSII and treated in certain care units receive more frequent assessments.

This paper investigates the impact of shocking advertising to consumer buying behavior. Scientists proved that shock tactics in advertising influences consumer buying behavior. The paper analyses the main components of shocking advertising, which cause positive or negative attitude to shocking advertising, influencing consumer buying behavior. Theoretical research studies confirmed that positive or negative consumer attitudes to shocking advertising is influenced by socio-demographic and cultural-social factors - religiosity, moral principles, age, gender, individualism-collectivism, high-low context language. Developed theoretical model of the link among the socio-demographic and cultural-social factors, consumer perception of shocking advertising and consumer buying behavior, which can be used for further practical studies. DOI: http://dx.doi.org/10.5755/j01.em.18.1.3643

Background Limb-girdle muscular dystrophies are characterized by predominant involvement of the shoulder and pelvic girdle and trunk muscle groups. Currently, there are 31 genes implicated in the different forms of limb-girdle muscular dystrophies, which exhibit similar phenotypes and clinical overlap; therefore, advanced molecular techniques are required to achieve differential diagnosis. Methods We investigated 26 patients from Latvia and 34 patients from Lithuania with clinical symptoms of limb-girdle muscular dystrophies, along with 565 healthy unrelated controls from general and ethnic populations using our developed test kit based on the Illumina VeraCode GoldenGate genotyping platform, Ion AmpliSeq Inherited Disease Panel and direct sequencing of mutations in calpain 3 (CAPN3), anoctamin 5 (ANO5) and fukutin related protein (FKRP) genes. Results Analysis revealed a homozygous CAPN3 c.550delA mutation in eight patients and three heterozygous variants in controls: dysferlin (DYSF) c.5028delG, CAPN3 c.2288A > G, and FKRP c.135C > T. Additionally, three mutations within FKRP gene were found: homozygous c.826C > A, and two compound – c.826C > A/c.404_405insT and c.826C > A/c.204_206delCTC mutations, and one mutation within CLCN1 gene – c.2680C > T p.Arg894Ter. ANO5 c.191dupA was not present. Conclusions Genetic diagnosis was possible in 12 of 60 patients (20 %). The allele frequency of CAPN3 gene mutation c.550delA in Latvia is 0.0016 and in Lithuania - 0.0029. The allele frequencies of CAPN3 gene mutation c.2288A > G and DYSF gene mutation c.4872delG are 0.003. Electronic supplementary material The online version of this article (doi:10.1186/s12891-016-1058-z) contains supplementary material, which is available to authorized users.