Preimplantation Genetic Testing within the Public Healthcare System in Slovenia.

Preimplantation genetic testing (PGT) is the earliest form of prenatal diagnosis that has become an established procedure for couples at risk of passing a severe genetic disease to their offspring. At UMC Ljubljana, we conducted a retrospective register-based study to present 15 years of PGT service within the public healthcare system in Slovenia. We collected the data of the PGT cycles from 2004 to 2019 and compared clinical outcomes for chromosomal and monogenic diseases using different embryo biopsy and testing approaches. In addition, we assessed the extent to which PGT has become the preferred option compared to classic prenatal diagnostics. We treated 211 couples, 110 with single gene disorder, 88 with structural chromosome rearrangement and 13 for numerical chromosome aberration. There were 375 PGT cycles with oocyte retrieval, while embryo transfer was possible in 263 cases resulting in 78 deliveries and 84 children. Altogether, the clinical pregnancy rate per embryo transfer was 31% in 2004-2016 (blastomere biopsy) and 43% in 2017-19 (blastocyst biopsy), respectively. We assessed that approximately a third of couples would opt for PGT, while the rest preferred natural conception with prenatal diagnosis. Our results show that providing a PGT service within the public healthcare system has become a considerable option in pregnancy planning for couples at risk of transmitting a severe genetic disease to their offspring. In Slovenia, approximately a third of couples would opt for PGT. Although the number of cycles is small, our clinical results are comparable to larger centres.

Modeling Water Quality in Watersheds: From Here to the Next Generation.

In this synthesis, we assess present research and anticipate future development needs in modeling water quality in watersheds. We first discuss areas of potential improvement in the representation of freshwater systems pertaining to water quality, including representation of environmental interfaces, in-stream water quality and process interactions, soil health and land management, and (peri-)urban areas. In addition, we provide insights into the contemporary challenges in the practices of watershed water quality modeling, including quality control of monitoring data, model parameterization and calibration, uncertainty management, scale mismatches, and provisioning of modeling tools. Finally, we make three recommendations to provide a path forward for improving watershed water quality modeling science, infrastructure, and practices. These include building stronger collaborations between experimentalists and modelers, bridging gaps between modelers and stakeholders, and cultivating and applying procedural knowledge to better govern and support water quality modeling processes within organizations.

A Systematic Clinical Review of Prenatally Diagnosed Tetrasomy 9p.

Tetrasomy 9p was first described in 1973 and approximately 68 cases with a variable phenotype have been reported to date with 22 of them being detected prenatally. The objective of this study was to review prenatally-reported cases of tetrasomy 9p thus far and to identify ultrasound phenotypes that may be suggestive of this specific syndrome. A PubMed database search was done in February 2018 without any restriction of publication date orjournals, with the use of the following keywords: tetrasomy 9p, tetrasomy 9p prenatal, mosaic tetrasomy 9p, mosaic tetrasomy 9p prenatal, isochromosome 9p, duplication 9p prenatal, trisomy 9p prenatal. Reported cases were included if the clinical presentation and diagnostic approach of each case was clearly described. The most common characteristics of prenatally-detected tetrasomy 9p are intrauterine growth retardation (IUGR, 57.0%), central nervous system (CNS) abnormalities (59.0%), skeletal anomalies (29.0%), genitourinary and renal anomalies (29.0%) and cardiac defects (29.0%). The phenotypic spectrum of tetrasomy 9p is rather unspecific as these findings are commonly associated with other chromosome anomalies, as well as microdeletion/microduplication or monogenic syndromes. The combination of early fetal morphology and diagnostic genetic testing enables a definite tetrasomy 9p diagnosis and effective further pregnancy management.

The American Society of Transplantation Consensus Conference on the Use of Hepatitis C Viremic Donors in Solid Organ Transplantation.

The availability of direct-acting antiviral agents for the treatment of hepatitis C virus (HCV) infection has resulted in a profound shift in the approach to the management of this infection. These changes have affected the practice of solid organ transplantation by altering the framework by which patients with end-stage organ disease are managed and receive organ transplants. The high level of safety and efficacy of these medications in patients with chronic HCV infection provides the opportunity to explore their use in the setting of transplanting organs from HCV-viremic patients into non-HCV-viremic recipients. Because these organs are frequently discarded and typically come from younger donors, this approach has the potential to save lives on the solid organ transplant waitlist. Therefore, an urgent need exists for prospective research protocols that study the risk versus benefit of using organs for hepatitis C-infected donors. In response to this rapidly changing practice and the need for scientific study and consensus, the American Society of Transplantation convened a meeting of experts to review current data and develop the framework for the study of using HCV viremic organs in solid organ transplantation.

[What are the Prerequisites for a Successful Cooperation between Nursing Homes and Physicians? - Results of a Mixed-methods Cross-Sectional Study in Bavarian Nursing Homes]. / Was sind die Voraussetzungen für eine erfolgreiche Zusammenarbeit zwischen Pflegeeinrichtung und Ärzten? ­ Ergebnisse einer Mixed Methods Querschnittserhebung in bayerischen Pflegeeinrichtungen.

Aim: This mixed-methods cross-sectional study examined the cooperation between nursing home staff and physicians in Bavarian nursing homes in order to understand which organisational and communication measures are resulting in satisfying teamwork among professional groups in nursing homes. Methods: In 3 interview rounds nursing home staff, general practitioners, medical specialists, dentists, nursing home residents, and relatives in 52 nursing homes were interviewed using a questionnaire that was enhanced after every round. Additionally, focus group interviews have been performed in 2 nursing homes. Results: 443 persons involved in patient care, 50 residents and 47 relatives participated in the structured interviews. 22 persons attended the focus group interviews. 65% of the nursing homes required regular visits of general practitioners and 36% or, respectively, 27% required regular or on demand visits of specialists. 47% of the nursing home staff that was asked about this issue stated that it would make their work easier if only a small number of physicians were in charge of their institution. Measures for improvement of medical care in nursing homes most frequently suggested by interview partners responsible for patient care were: better communication (9%), better remuneration of physicians' nursing home visits (7%, nurses and physicians) and less bureaucracy and regular physicians' visits (5% in each question). Conclusion: Because of the composition of our study sample it cannot be assumed that the results are representative for all Bavarian nursing homes. Confidence in one another, low number of persons in charge, binding agreements and regular physicians' nursing home visits are essential for a successful cooperation between providing physicians and nursing home staff.

A critical update on endothelial nitric oxide synthase gene variations in women with idiopathic recurrent spontaneous abortion: genetic association study, systematic review and meta-analyses.

A number of case-control studies investigated the association between idiopathic recurrent spontaneous abortion (IRSA) and variations in the gene encoding endothelial nitric oxide synthase (NOS3), but yielded contradictory results. Our aim was to test the association of the NOS3 variable number of tandem repeats (VNTR) in intron 4 and +894 G/T single-nucleotide polymorphism (SNP) with IRSA in Slovenian women (148 IRSA and 149 control women), conduct a systematic review of literature on the association between NOS3 gene variations and IRSA, and perform meta-analyses of studies that met the inclusion criteria, defined by virtue of the European Society for Human Reproduction and Embryology evidence-based guidelines for recurrent spontaneous abortion. Genotyping was performed using PCR and restriction fragment length polymorphism methods. The systematic review of literature (English language) was conducted using PubMed and Scopus databases, to 1 November 2014. We determined no association of IRSA with the VNTR in intron 4 and +894 G/T SNP in Slovenian women. Furthermore, 16 case-control studies were identified on the association between 15 NOS3 gene variations and IRSA. However, significant inconsistencies exist in the selection criteria of patients and controls between studies. The meta-analysis of VNTR in intron 4 was performed on five studies (894 patients, 944 controls), whereas the meta-analysis of +894 G/T SNP included six studies (1111 patients, 1121 controls). The association with IRSA was significant for the +894 G/T SNP under the dominant genetic model (GT+TT versus GG) based on fixed (odds ratio (OR) = 1.54, 95% confidence interval (CI) = 1.28-1.86, P = <0.01) and random effects models (OR = 1.54, 95% CI = 1.03-2.31, P = 0.03). In conclusion, the GT and TT genotypes of the +894 G/T SNP in women might contribute to a predisposition to IRSA. Additional genetic association and functional studies in different populations with larger numbers of participants and a uniformly defined IRSA are needed to clarify the contribution of NOS3 +894 G/T gene variation to IRSA.

[PREDICTING FACTORS OF THE LIFE SPAN IN PATIENTS, SUFFERING METASTATIC COLORECTAL CANCER AND SYNCHRONOUS HEPATIC AFFECTION AFTER SURGICAL TREATMENT].

The results of treatment of 125 patients, suffering metastatic hepatic affection in colorectal cancer (pT1--4N0--2M1--in colonic cancer and pT1--3N0--2M1--in cancer recti), to whom in 2008-2015 yrs a one-staged (Group 1) or two-staged (Group II) surgical treatment was done. In affection of 4 regional lymph nodes and more (pN2) late results were less favorable, than in pN1 or pN0, not depending from surgical approach choosed. In 48 (38.4%) patients with one syndromal hepatic metastatic focus, the indices of general three-year and five-year cumulative survival were the best, than in other groups--82 and 63% (p = 0.001) accordingly; in monolobar affection--68 and 49%, and in bilobar--23 and 0%, not depending from method of surgical treatment (p < 0.001) choosed. Predictive factors were established, which impact negatively the indices of general survival in patients, suffering metastatic hepatic affection in colorectal cancer: hepatic metastatic foci number 4 and more, bilobar hepatic metastatic affection.

[The influence of fibroblast growth factor (FGF2) on cardiomyocytes differentiation of mesenchymal stem cells of bone marrow ex vivo].

The influence of FGF2 on the efficiency of cardiomyocytes differentiation of mesenchymal stem cells (MSC) of bone marrow induced by 5-azacetidine (5-aza) was studied. The effect of FGF2 developing by the 14th day after the combined action of a differentiating agent and growth factor was manifested in an increase in Mef2A, Mef2D and gene transcription and a rise of ionized Ca2+ concentration in cytoplasm keeping cell viability and proliferation activity. In the presence of FGF2 this approach provided cardiomyogenesis and the increase in the formation of early precursors of cardiomyocytes.

[Challenges for medical staff and local authorities in an aging population in a German rural area]. / Medizinische und kommunale Herausforderungen einer alternden Gesellschaft im ländlichen Bereich.

OBJECTIVE: The aim of this survey is the assessment of health and social situation of elderly persons in rural regions as well as their requests and needs concerning accommodation and medical care in the old age. METHODS: In a cross-sectional survey, inhabitants of the rural commune Markt Heiligenstadt, Upper Franconia, aged over 50 years were interviewed. Sixty-eight questions were asked regarding wishes and needs concerning accommodation and living in the old age. RESULTS: 513 (39%) inhabitants participated. Their mean age was 66 years (± 11 years) and 53% were female. 49% are suffering from hypertension and 17% from diabetes mellitus. Reduced autonomy in everyday life is predominantly caused by diseases of the musculoskeletal system. 40% of the respondents aged over 70 years reported hearing and visual impairments. Most of the participants are living in their privately owned home (81%) despite their comparatively low income and express their wish to live and be cared for in their own home in old age (90%). 75% of the respondents are married or living in a partnership. 90% have children and in 55% the children are living in the same house or in the commune. There are 2 local family doctors' practices, but no specialists' practices and no hospitals in the commune. Almost all the respondents (98%) have a regular family doctor. 17% of the participants would relocate if there was no family doctor nearby, 6% if there was no specialist and 4% if there was no hospital nearby. CONCLUSION: Health problems and functional limitations among the inhabitants of Markt Heiligenstadt are similar to those reported in German nationwide surveys. Medical care is strongly depending on general practitioners. The strong social networks of the participants and the predominant presence of residential property are important resources needed to accomplish the preference for home care in old age. This implies increasing challenges for the primary care providers. In future, the general practitioner will be a central coordinator of medical care and professional nursing together with the care by family members.

Variation in organ quality between liver transplant centers.

A wide spectrum of quality exists among deceased donor organs available for liver transplantation. It is unknown whether some transplant centers systematically use more low quality organs, and what factors might influence these decisions. We used hierarchical regression to measure variation in donor risk index (DRI) in the United States by region, organ procurement organization (OPO) and transplant center. The sample included all adults who underwent deceased donor liver transplantation between January 12, 2005 and February 1, 2009 (n = 23,810). Despite adjusting for the geographic region and OPO, transplant centers' mean DRI ranged from 1.27 to 1.74, and could not be explained by differences in patient populations such as disease severity. Larger volume centers and those having competing centers within their OPO were more likely to use higher risk organs, particularly among recipients with lower model for end-stage liver disease (MELD) scores. Centers using higher risk organs had equivalent waiting list mortality rates, but tended to have higher post-transplant mortality (hazard ratio 1.10 per 0.1 increase in mean DRI). In conclusion, the quality of deceased donor organ patients receive is variable and depends in part on the characteristics of the transplant center they visit.

Centers for Disease Control 'high-risk' donors and kidney utilization.

The aims of this study were to determine whether Centers for Disease Control high risk (CDCHR) status of organ donors affects kidney utilization and recipient survival. Data from the Scientific Registry of Transplant Recipients were used to examine utilization rates of 45,112 standard criteria donor (SCD) deceased donor kidneys from January 1, 2005, and February 2, 2009. Utilization rates for transplantation were compared between CDCHR and non-CDCHR kidneys, using logistic regression to control for possible confounders. Cox regression was used to determine whether CDCHR status independently affected posttransplant survival among 25,158 recipients of SCD deceased donor kidneys between January 1, 2005, and February 1, 2008. CDCHR kidneys were 8.2% (95% CI 6.9-9.5) less likely to be used for transplantation than non-CDCHR kidneys; after adjusting for other factors, CDCHR was associated with an odds ratio of utilization of 0.67 (95% CI 0.61-0.74). After a median 2 years follow-up, recipients of CDCHR kidneys had similar posttransplant survival compared to recipients of non-CDCHR kidneys (hazard ratio 1.06, 95% CI 0.89-1.26). These findings suggest that labeling donor organs as 'high risk' may result in wastage of approximately 41 otherwise standard kidneys per year.

Foreigners traveling to the U.S. for transplantation may adversely affect organ donation: a national survey.

The aims of this study were (1) to determine attitudes among the American public regarding foreigners coming to the United States for the purposes of transplantation, and (2) to investigate the impact this practice might have on the public's willingness to donate organs. A probability-based national sample of adults age > or =18 was asked whether people should be allowed to travel to the United States to receive a transplant, and whether this practice would discourage the respondents from becoming an organ donor. Among 1049 participants, 30% (95% CI 25-34%) felt that people should not be allowed to travel to the United States to receive a deceased donor transplant, whereas 28% felt this would be acceptable in some cases. Thirty-eight percent (95% CI 33-42%) indicated that this practice might prevent them from becoming an organ donor. In conclusion, deceased-donor transplantation of foreigners is opposed by many Americans. Media coverage of this practice has the potential to adversely affect organ donation.

Attitudes of the American public toward organ donation after uncontrolled (sudden) cardiac death.

Concerns about public support for organ donation after cardiac death have hindered expansion of this practice, particularly rapid organ recovery in the context of uncontrolled (sudden) cardiac death (uDCD). A nationally representative Internet-based panel was provided scenarios describing donation in the context of brain death, controlled cardiac death and uncontrolled cardiac death. Participants were randomized to receive questions about trust in the medical system before or after the rapid organ recovery scenario. Among 1631 panelists, 1049 (64%) completed the survey. Participants expressed slightly more willingness to donate in the context of controlled and uncontrolled cardiac death than after brain death (70% and 69% vs. 66%, respectively, p < 0.01). Eighty percent of subjects (95% CI 77-84%) would support having a rapid organ recovery program in their community, though 83% would require family consent or a signed donor card prior to invasive procedures for organ preservation. The idea of uDCD slightly decreased trust in the medical system from 59% expressing trust to 51% (p = 0.02), but did not increase belief that a signed donor card would interfere with medical care (28% vs. 32%, p = 0.37). These findings provide support for the careful expansion of uDCD, albeit with formal consent prior to organ preservation.

Ultrasound characteristics of breast fibroadenomas are related to clinical and histological parameters.

PURPOSE: We hypothesized that ultrasound characteristics of breast fibroadenomas (FA) vary in relation to the clinical and histological parameters: patient age, tumor size and histological classification. MATERIALS AND METHODS: Eleven ultrasound characteristics frequently observed in breast tumors were defined before the onset of our study. These characteristics, as well as a semi-quantitative score for vascularization on color-coded Doppler ultrasound, were analyzed in a retrospective study. Histology revealed adult type differentiation in all FA. They were divided into florid, regressive and mixed subtypes. The examiner was blinded for the histological classification during image analysis. RESULTS: Histological type: florid FA: more frequent in younger women (age group < 30 years; p < 0.001), and bigger than regressive FA (larger than 16 mm: p = 0.007). Statistically significant differences between florid and regressive FA regarding the ultrasound features: enhanced posterior ultrasound transmission (p < 0.001), homogenous echo pattern (p = 0.003) and lobulated margin contour (p = 0.042). Tumor size: patients with larger tumors (> 16 mm) were younger (mean age 35 vs. 43 years, p < 0.001). More often in bigger FA: enhanced dorsal ultrasound transmission (p < 0.001), hyperechoic spots (p < 0.001), strong vascularization (p < 0.001), inhomogeneous echo pattern (p = 0.001), horizontal axis (p = 0.009), lobulated margin contour (p = 0.009), lateral shadowing (p = 0.047). Age: more often in older patients (age group > 30 years): dorsal ultrasound shadowing (p = 0.008), irregular margin contour (p = 0.038), homogenous echo pattern (p = 0.047). CONCLUSION: Histological type, tumor size and patient age significantly influence ultrasound characteristics of breast FA. This might be helpful to consider when breast lesions are classified and decisions for biopsies are made.

Magnetoelastic properties and behaviour of 4C pyrrhotite, Fe7S8, through the Besnus transition.

Pyrrhotite, Fe7S8, is a commonly occurring carrier of magnetic remanence and has a low temperature transition, the Besnus transition, involving a change in spin state. Variations of the thermodynamic, magnetic and elastic properties through this transition at ∼33 K in a natural sample of 4C pyrrhotite have been tested against a group theoretical model for coupling between order parameters relating to Fe/vacancy ordering (irrep U 1(1/2,0,1/4)) and magnetic ordering (irreps m[Formula: see text] and m[Formula: see text]). Magnetoelastic coupling is weak but the pre-existing microstructure of ferroelastic and magnetic domains, that develop as a consequence of Fe/vacancy and ferrimagnetic ordering during slow cooling in nature (P63/mmc → C2'/c'), causes subtle changes in the low temperature transition (C2'/c' → P [Formula: see text]). The Besnus transition involves a rotation of magnetic moments out of the a-c plane of the monoclinic structure, but it appears that the transition temperature might vary locally according to whether it is taking place within the pre-existing domain walls or in the domains that they separate. Evidence of metamagnetic transitions suggests that the magnetic field-temperature phase diagram will display some interesting diversity. Low temperature magnetic transitions in minerals of importance to the palaeomagnetism community have been used to identify the presence of magnetite and haematite in rocks and the Besnus transition is diagnostic of the existence of pyrrhotite, Fe7S8.

Intraepithelial CD8-positive T lymphocytes predict survival for patients with serous stage III ovarian carcinomas: relevance of clonal selection of T lymphocytes.

BACKGROUND: The aim of this study was to investigate the prognostic effect of tumour-infiltrating lymphocytes (TILs) in serous stage III ovarian carcinoma to determine TIL clonality and to correlate this to Her2/neu expression. METHODS: Formalin-fixed and paraffin-embedded ovarian carcinomas were examined for CD20-, CD3-, CD4- and CD8-positive lymphocytes (n=100), and for Her2/neu-positive tumour cells (n=55/100) by immunohistochemistry. Clonality analysis was carried out by T-cell receptor gamma (TCRgamma) gene rearrangements (n=93/100). Statistical analyses included experimental and clinico-pathological variables, as well as disease-free (DFS) and overall (OS) survival. RESULTS: CD20-positive B lymphocytes were present in 57.7% (stromal)/33.0% (intraepithelial) and CD3-positive T lymphocytes in 99.0% (stromal)/90.2% (intraepithelial) of ovarian carcinomas. Intraepithelial CD3-positive T lymphocytes were correlated with improved DFS in optimally debulked patients (P=0.0402). Intraepithelial CD8-positive T lymphocytes were correlated with improved OS in all optimally debulked patients (P=0.0201) and in those undergoing paclitaxel/carboplatin therapy (P=0.0092). Finally, rarified and clonal TCRgamma gene rearrangements were detected in 37 out of 93 (39.8%) and 15 out of 93 (16.1%) cases, respectively. This was marginally associated with improved DFS (P=0.0873). Despite a significant correlation of HER2/neu status and intraepithelial CD8-positive lymphocytes (P=0.0264), this was non-directional (R=-0.257; P=0.0626). CONCLUSION: Improved survival of ovarian cancer patients is related to the infiltration, clonal selection and intraepithelial persistence of T lymphocytes.

Geographic variation in organ availability is responsible for disparities in liver transplantation between Hispanics and Caucasians.

The aims of this study were to determine whether disparities in waiting list outcomes exist for Hispanics and African Americans during the post-MELD era, and to investigate interactions between disparities and geography. Scientific Registry of Transplant Recipients data were used to compare Hispanics and African Americans to Caucasians listed between 2003 and 2008. Endpoints included (i) receipt of a liver transplant and (ii) death or removal from the waiting list for being too sick or medically unsuitable. Adjustment for possible confounders was performed using multivariate Cox regression, with adjustment for geographic variation using a fixed-effects multilevel model. In multivariate analysis, African Americans have similar hazard of transplantation and death/removal as Caucasians during the post-MELD era. However, Hispanics are less likely to receive a transplant than Caucasians despite adjustment for potential confounders (HR 0.80, 95% CI 0.77-0.83), while having a similar hazard of death/removal. This effect disappeared after adjusting for unequal regional distribution of Hispanics, who represent 8% of patients in donation service areas (DSAs) having median waiting times of < or = 155 days versus 19% in DSAs with median waiting times of >155 days. In conclusion, disparities in liver transplantation exist for Hispanics during the post-MELD era, caused by geographic variation in organ availability.

Heart-hand syndrome of Slovenian type: a new kind of laminopathy.

BACKGROUND: Heart-hand syndromes are a heterogeneous group of genetic disorders characterised by the association of congenital cardiac disease and limb deformities. Laminopathies are a group of diseases caused by mutations in the LMNA gene encoding A-type lamins. RESULTS: We report a new LMNA mutation (c.1609-12T>G, IVS9-12 T>G) that creates a new cryptic splicing site with the retention of 11 intronic nucleotides in the mRNA. This LMNA mutation segregates with a new type of heart-hand syndrome in a previously reported family suffering from adult onset progressive conduction system disease, atrial and ventricular tachyarrhythmias, sudden death, dilated cardiomyopathy, and brachydactyly with predominant foot involvement. Analysis of the fibroblasts of two affected family members identified for the first time a truncated lamin A/C protein resulting from the frame shift created by the new splicing site, together with nuclear envelope abnormalities confirming that this LMNA mutation is pathogenic. CONCLUSIONS: This new heart-hand syndrome should therefore be considered as a new kind of laminopathy. As part of laminopathies with heart involvement, patients presenting with this phenotype and their relatives are at risk for developing sudden cardiac death and should beneficiate from appropriate LMNA genetic diagnosis.

[A 74-year-old female patient with histologically proven carcinoid of the lungs and pulmonary mosaic pattern]. / 74-jährige Patientin mit histologisch gesichertem Karzinoid der Lunge und pulmonalem Mosaikmuster.

Diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH) can be idiopathic or reactive to chronic airway disease, then termed pulmonary neuroendocrine cell hyperplasia (PNECH). DIPNECH can be complicated by obliterative bronchiolitis and is presumably often misdiagnosed because the clinical symptoms are unspecific, the entity is relatively unknown and high-resolution computed tomography (HRCT) in inspiration and expiration is necessary for the diagnosis. However, the HRCT findings of air-trapping in combination with nodules are very characteristic and should raise suspicion of this entity. DIPNECH is thought to be a precursor of tumorlets and carcinoids and usually runs a benign course. The diagnosis is confirmed by histology.