Стратегия развития организационной культуры как фактор эффективности деятельности организации

В работе были рассмотрены функции и элементы организационной культуры и её влияние на эффективность деятельности организации. В результате исследования были предложены рекомендации и мероприятия по совершенствованию организационной культуры.The word considered the functions and elements of organizational culture and its influence on the effectiveness of the organization. As a result of the study, recommendations and measures were proposed to improve the organizational culture

SNP array typing provides new insights in chromosomal nondisjunction

Background Maternal uniparental disomy (UPD) of chromosome 7 (upd(7)mat) accounts for approximately 10% of patients with Silver-Russell syndrome (SRS). For upd(7)mat and trisomy 7, a significant number of mechanisms have been proposed to explain the postzygotic formation of these chromosomal compositions, but all have been based on as small number of cases. To obtain the ratio of isodisomy and heterodisomy in UPDs (hUPD, iUPD) and to determine the underlying formation mechanisms, we analysed a large cohort of upd(7)mat patients (n = 73) by SNP array typing. Based on these data, we discuss the UPDs and their underlying trisomy 7 formation mechanisms. Results A whole chromosome 7 maternal iUPD was confirmed in 28.8%, a mixture or complete maternal hUPD in 71.2% of patients. Conclusions We could demonstrate that nondisjunction mechanism affecting chromosome 7 are similar to that of the chromosomes more frequently involved in trisomy (and/or UPD), and that mechanisms other than trisomic rescue have a lower significance than previously suspected. Furthermore, we suggest SNP array typing for future parent- and cell-stage-of origin studies in human aneuploidies as they allow the definite classification of trisomies and UPDs, and provide information on recombinational events and their suggested association with aneuploidy formation

Not Fit for Hire: The United States and France on Weight Discrimination in Employment

Part I will examine past and present attitudes regarding obesity in US society and will discuss the employment challenges obese individuals face because of weight discrimination. Further, Part I will survey US statutory laws at the federal, state, and local levels that currently protect against particular instances of weight discrimination. In sum, this Part aims to provide the current legal and social landscape in the United States for protecting individuals against employment discrimination based on their weight. Part II will look at France’s cultural bias against obesity and its laws against physical appearance discrimination. Part II then will analyze French statutory law and legislative history. This Part will ground the discussion in cases that have arisen in French media involving physical appearance discrimination based on weight, including an investigation by France’s human rights watch institution, Le Défenseur des droits. Overall, this perspective on French law will form the foundation for analyzing the extent of protection that the United States may feasibly adopt to protect individuals against weight discrimination. Part III juxtaposes France’s laws prohibiting physical appearance discrimination with current US federal law to highlight the ways in which the United States falls short of its promise of equal protection for all by permitting employment discrimination based on an individual’s weight. This Part posits that US law may serve as a tool to catalyze important social change in the public’s perception of obesity, based on a similar shift in public perception that occurred in France following the adoption of its laws prohibiting physical appearance discrimination. Ultimately, this Note argues that the United States must act to eliminate the pervasive discrimination against obese individuals by passing national legislation making employment decisions based on weight unlawful

Holoprosencephaly–polydactyly/pseudotrisomy 13: a presentation of two new cases and a review of the literature

Patients with a combination of holoprosencephaly and polydactyly, but with apparently normal chromosomes, may be clinically diagnosed with holoprosencephaly–polydactyly syndrome (HPS), also termed pseudotrisomy 13. However, the criteria for HPS have been controversial since the advent of the diagnostic term, and a clear understanding of the condition lacks definitive delineation. We review the historical and current perspectives on the condition and analyze findings in 40 patients with apparent HPS, including cases from the literature and two previously unreported patients. Overall, our analysis suggests previously unrecognized trends in patients diagnosed with HPS. Specifically, there appears to be a higher prevalence of visceral anomalies, most significantly cardiac and genitourinary, but also with increased gastrointestinal, pulmonary, adrenal, skeletal, and renal abnormalities, in patients with HPS. Although these visceral anomalies may not be essential for the identification of HPS, clinicians should be aware of the presence of such characteristics in these patients to optimize management and help establish etiologies

clinical homogeneity and allelic heterogeneity in seven patients

Background Larsen syndrome is an autosomal dominant skeletal dysplasia characterized by large joint dislocations and craniofacial dysmorphism. It is caused by missense or small in-frame deletions in the FLNB gene. To further characterize the phenotype and the mutation spectrum of this condition, we investigated seven probands, five sporadic individuals and a mother-son-duo with Larsen syndrome. Methods The seven patients from six unrelated families were clinically and radiologically evaluated. All patients were screened for mutations in selected exons and exon-intron boundaries of the FLNB gene by Sanger sequencing. FLNB transcript analysis was carried out in one patient to analyse the effect of the sequence variant on pre-mRNA splicing. Results All patients exhibited typical facial features and joint dislocations. Contrary to the widely described advanced carpal ossification, we noted delay in two patients. We identified the five novel mutations c.4927G > A/p.(Gly1643Ser), c.4876G > T / p.(Gly1626Trp), c.4664G > A / p.(Gly1555Asp), c.2055G > C / p.Gln685delins10 and c.5021C > T / p.(Ala1674Val) as well as a frequently observed mutation in Larsen syndrome [c.5164G > A/p.(Gly1722Ser)] in the hotspot regions. FLNB transcript analysis of the c.2055G > C variant revealed insertion of 27 bp intronic sequence between exon 13 and 14 which gives rise to in-frame deletion of glutamine 685 and insertion of ten novel amino acid residues (p.Gln685delins10). Conclusions All seven individuals with Larsen syndrome had a uniform clinical phenotype except for delayed carpal ossification in two of them. Our study reveals five novel FLNB mutations and confirms immunoglobulin-like (Ig) repeats 14 and 15 as major hotspot regions. The p.Gln685delins10 mutation is the first Larsen syndrome-associated alteration located in Ig repeat 5. All mutations reported so far leave the filamin B protein intact in accordance with a gain-of-function effect. Our findings underscore the characteristic clinical picture of FLNB-associated Larsen syndrome and add Ig repeat 5 to the filamin B domains affected by the clustered mutations

47 patients with FLNA associated periventricular nodular heterotopia

Background: Heterozygous loss of function mutations within the Filamin A gene in Xq28 are the most frequent cause of bilateral neuronal periventricular nodular heterotopia (PVNH). Most affected females are reported to initially present with difficult to treat seizures at variable age of onset. Psychomotor development and cognition may be normal or mildly to moderately impaired. Distinct associated extracerebral findings have been observed and may help to establish the diagnosis including patent ductus arteriosus Botalli, progressive dystrophic cardiac valve disease and aortic dissection, chronic obstructive lung disease or chronic constipation. Genotype-phenotype correlations could not yet be established. Methods: Sanger sequencing and MLPA was performed for a large cohort of 47 patients with Filamin A associated PVNH (age range 1 to 65 years). For 34 patients more detailed clinical information was available from a structured questionnaire and medical charts on family history, development, epileptologic findings, neurological examination, cognition and associated clinical findings. Available detailed cerebral MR imaging was assessed for 20 patients. Results: Thirty-nine different FLNA mutations were observed, they are mainly truncating (37/39) and distributed throughout the entire coding region. No obvious correlation between the number and extend of PVNH and the severity of the individual clinical manifestation was observed. 10 of the mutation carriers so far are without seizures at a median age of 19.7 years. 22 of 24 patients with available educational data were able to attend regular school and obtain professional education according to age. Conclusions: We report the clinical and mutation spectrum as well as MR imaging for a large cohort of 47 patients with Filamin A associated PVNH including two adult males. Our data are reassuring in regard to psychomotor and cognitive development, which is within normal range for the majority of patients. However, a concerning median diagnostic latency of 17 to 20 years was noted between seizure onset and the genetic diagnosis, intensely delaying appropriate medical surveillance for potentially life threatening cardiovascular complications as well as genetic risk assessment and counseling prior to family planning for this X-linked dominant inherited disorder with high perinatal lethality in hemizygous males

Pubertal presentation in seven patients with congenital adrenal hyperplasia due to P450 Oxidoreductase deficiency

Context: P450 oxidoreductase (POR) is a crucial electron donor to all microsomal P450 cytochrome (CYP) enzymes including 17α-hydroxylase (CYP17A1), 21-hydroxylase (CYP21A2) and P450 aromatase. Mutant POR causes congenital adrenal hyperplasia with combined glucocorticoid and sex steroid deficiency. P450 oxidoreductase deficiency (ORD) commonly presents neonatally, with disordered sex development in both sexes, skeletal malformations, and glucocorticoid deficiency. \ud \ud Objective: The aim of the study was to describe the clinical and biochemical characteristics of ORD during puberty. \ud \ud Design: Clinical, biochemical, and genetic assessment of seven ORD patients (five females, two males) presenting during puberty was conducted. \ud \ud Results: Predominant findings in females were incomplete pubertal development (four of five) and large ovarian cysts (five of five) prone to spontaneous rupture, in some only resolving after combined treatment with estrogen/progestin, GnRH superagonists, and glucocorticoids. Pubertal development in the two boys was more mildly affected, with some spontaneous progression. Urinary steroid profiling revealed combined CYP17A1 and CYP21A2 deficiencies indicative of ORD in all patients; all but one failed to mount an appropriate cortisol response to ACTH stimulation indicative of adrenal insufficiency. Diagnosis of ORD was confirmed by direct sequencing, demonstrating disease-causing POR mutations. \ud \ud Conclusion: Delayed and disordered puberty can be the first sign leading to a diagnosis of ORD. Appropriate testosterone production during puberty in affected boys but manifest primary hypogonadism in girls with ORD may indicate that testicular steroidogenesis is less dependent on POR than adrenal and ovarian steroidogenesis. Ovarian cysts in pubertal girls may be driven not only by high gonadotropins but possibly also by impaired CYP51A1-mediated production of meiosis-activating sterols due to mutant POR

Genome sequencing in families with congenital limb malformations

The extensive clinical and genetic heterogeneity of congenital limb malformation calls for comprehensive genome-wide analysis of genetic variation. Genome sequencing (GS) has the potential to identify all genetic variants. Here we aim to determine the diagnostic potential of GS as a comprehensive one-test-for-all strategy in a cohort of undiagnosed patients with congenital limb malformations. We collected 69 cases (64 trios, 1 duo, 5 singletons) with congenital limb malformations with no molecular diagnosis after standard clinical genetic testing and performed genome sequencing. We also developed a framework to identify potential noncoding pathogenic variants. We identified likely pathogenic/disease-associated variants in 12 cases (17.4%) including four in known disease genes, and one repeat expansion in HOXD13. In three unrelated cases with ectrodactyly, we identified likely pathogenic variants in UBA2, establishing it as a novel disease gene. In addition, we found two complex structural variants (3%). We also identified likely causative variants in three novel high confidence candidate genes. We were not able to identify any noncoding variants. GS is a powerful strategy to identify all types of genomic variants associated with congenital limb malformation, including repeat expansions and complex structural variants missed by standard diagnostic approaches. In this cohort, no causative noncoding SNVs could be identified. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00439-021-02295-y

PEDIA: prioritization of exome data by image analysis.

PURPOSE: Phenotype information is crucial for the interpretation of genomic variants. So far it has only been accessible for bioinformatics workflows after encoding into clinical terms by expert dysmorphologists. METHODS: Here, we introduce an approach driven by artificial intelligence that uses portrait photographs for the interpretation of clinical exome data. We measured the value added by computer-assisted image analysis to the diagnostic yield on a cohort consisting of 679 individuals with 105 different monogenic disorders. For each case in the cohort we compiled frontal photos, clinical features, and the disease-causing variants, and simulated multiple exomes of different ethnic backgrounds. RESULTS: The additional use of similarity scores from computer-assisted analysis of frontal photos improved the top 1 accuracy rate by more than 20-89% and the top 10 accuracy rate by more than 5-99% for the disease-causing gene. CONCLUSION: Image analysis by deep-learning algorithms can be used to quantify the phenotypic similarity (PP4 criterion of the American College of Medical Genetics and Genomics guidelines) and to advance the performance of bioinformatics pipelines for exome analysis