Comparison of two multi-trait association testing methods and sequence-based fine mapping of six additive QTL in Swiss Large White pigs.

BACKGROUND: Genetic correlations between complex traits suggest that pleiotropic variants contribute to trait variation. Genome-wide association studies (GWAS) aim to uncover the genetic underpinnings of traits. Multivariate association testing and the meta-analysis of summary statistics from single-trait GWAS enable detecting variants associated with multiple phenotypes. In this study, we used array-derived genotypes and phenotypes for 24 reproduction, production, and conformation traits to explore differences between the two methods and used imputed sequence variant genotypes to fine-map six quantitative trait loci (QTL). RESULTS: We considered genotypes at 44,733 SNPs for 5,753 pigs from the Swiss Large White breed that had deregressed breeding values for 24 traits. Single-trait association analyses revealed eleven QTL that affected 15 traits. Multi-trait association testing and the meta-analysis of the single-trait GWAS revealed between 3 and 6 QTL, respectively, in three groups of traits. The multi-trait methods revealed three loci that were not detected in the single-trait GWAS. Four QTL that were identified in the single-trait GWAS, remained undetected in the multi-trait analyses. To pinpoint candidate causal variants for the QTL, we imputed the array-derived genotypes to the sequence level using a sequenced reference panel consisting of 421 pigs. This approach provided genotypes at 16 million imputed sequence variants with a mean accuracy of imputation of 0.94. The fine-mapping of six QTL with imputed sequence variant genotypes revealed four previously proposed causal mutations among the top variants. CONCLUSIONS: Our findings in a medium-size cohort of pigs suggest that multivariate association testing and the meta-analysis of summary statistics from single-trait GWAS provide very similar results. Although multi-trait association methods provide a useful overview of pleiotropic loci segregating in mapping populations, the investigation of single-trait association studies is still advised, as multi-trait methods may miss QTL that are uncovered in single-trait GWAS.

A photogrammetric method for target monitoring inside the MEG II detector.

An automatic target monitoring method based on photographs taken by a CMOS photo-camera has been developed for the MEG II detector. The technique could be adapted for other fixed-target experiments requiring good knowledge of their target position to avoid biases and systematic errors in measuring the trajectories of the outcoming particles. A CMOS-based, high resolution, high radiation tolerant, and high magnetic field resistant photo-camera was mounted inside the MEG II detector at the Paul Scherrer Institute (Switzerland). MEG II is used to search for lepton flavor violation in muon decays. The photogrammetric method's challenges, affecting measurements of low momentum particles' tracks, are the high magnetic field of the spectrometer, high radiation levels, tight space constraints, and the need to limit the material budget in the tracking volume. The camera is focused on the dot pattern drawn on the thin MEG II target, about 1 m away from the detector endcaps where the photo-camera is placed. Target movements and deformations are monitored by comparing images of the dots taken at various times during the measurement. The images are acquired with a Raspberry board and analyzed using custom software. Global alignment to the spectrometer is guaranteed by corner cubes placed on the target support. As a result, the target monitoring fulfills the needs of the experiment.

Biologic drug survival rates in the era of anti-interleukin-17 antibodies: a time-period-adjusted registry analysis.

BACKGROUND: Drug survival rates reflect efficacy and safety and may be influenced by the availability of alternative treatment options. Little is known about time-dependent drug survival in psoriasis and the effect of increasing numbers of biologic treatment options. OBJECTIVES: To determine whether drug survival is influenced by the availability of treatment options and by factors such as gender, psoriatic arthritis or previous biologic treatment. METHODS: This observational, retrospective, multicentre cohort study analysed data from patients registered in the Austrian Psoriasis Registry (PsoRA) who were treated with biologics between 1 January 2015 and 30 November 2019. RESULTS: A total of 1572 patients who received 1848 treatment cycles were included in this analysis. The highest long-term Psoriasis Area and Severity Index improvement was observed after treatment with ixekizumab, followed by ustekinumab and secukinumab, adalimumab and etanercept. Overall, ustekinumab surpassed all other biologics in drug survival up to 48 months. However, when adjusted for biologic naïvety, its superiority vanished and drug survival rates were similar for ixekizumab (91·6%), secukinumab (90·2%) and ustekinumab (92·8%), all of them superior to adalimumab (76·5%) and etanercept (71·9%) at 12 months and beyond. Besides biologic non-naïvety (2·10, P < 0·001), the introduction of a new drug such as secukinumab or ixekizumab (relative hazard ratio 1·6, P = 0·001) and female gender (1·50, P = 0·019) increased the risk of treatment discontinuation overall, whereas psoriatic arthritis did not (1·12, P = 0·21). CONCLUSIONS: The time-dependent availability of drugs should be considered when analysing and comparing drug survival. Previous biologic exposure significantly influences drug survival. Women are more likely to stop treatment.

[Risk factors and management strategies for early and late infections following reconstruction with special tumour endoprostheses]. / Risikofaktoren und Managementstrategien des Früh- und Spätinfektes nach Rekonstruktion mit Tumorspezialendoprothesen.

BACKGROUND: Periprosthetic joint infection (PJI) of megaprostheses occur in about 10% of all cases. The criteria for PJI are defined by the "Musculoskleletal Infection Society" (MSIS) and apply to both primary arthroplasty and megaprostheses. MANAGEMENT: The management strategies of PJI in megaprostheses are dependent on the duration of infection and the maturity of the bacterial biofilm. Implant retention with an exchange of the mobile components is only possible in the presence of an immature biofilm. In the presence of a mature biofilm, a one- or two-stage exchange must be performed. A complete exchange of all endoprosthetic components should be performed, if possible, since a partial retention of isolated components results in inferior treatment success rates. RESULTS: The highest success rates are achievable with two-stage exchanges. Multiple risk factors such as skin necrosis, postoperative haematoma, prolonged wound secretion and operative times ≥ 2.5 h are risk factors for the development of PJI in megaprostheses. Knowledge regarding these risk factors allows for an identification of high-risk patients and early management of PJI.

Effective genetic markers for identifying the Escherichia coli F4ac receptor status of pigs.

The F4ac receptor locus (F4acR), which encodes susceptibility or resistance to Escherichia coli diarrhoea, is inherited as an autosomal recessive monogenetic trait. F4acR is localized on pig chromosome 13 (SSC13q41-q44) near the MUC13 gene. Two flanking markers (CHCF1 and ALGA0106330) with a high linkage disequilibrium (LD) with F4acR were found to be effective for the genetic identification of F4ac-resistant pigs in the Swiss Large White breed (one recombinant out of 2034 genotyped pigs). Three recombinant boars, one each from the Duroc, Swiss Landrace and Piétrain breeds, were genotyped with seven different markers and phenotyped by means of a microscopic adhesion test. Only ALGA0072075, CHCF1 and CHCF3 indicated the correct phenotype. To test the effect of the resistance allele on production traits, 530 Large White pigs from the national test station were investigated. A significant difference existed among the F4acR locus genotypes in the intramuscular fat content of the longissimus dorsi muscle, whereas no other production traits were influenced by the resistance allele. The frequency of the CHCF1-C and ALGA0106330-A alleles associated with resistance in the Swiss Large White population was 60%, which is advantageous for implementing this trait in a breeding programme to select for E. coli F4ac-resistant animals. The selection of resistant pigs should start on the male side due to the inability of resistant sows to produce sufficient amounts of protecting antibodies in the colostrum. Selection of genetically F4ac-resistant pigs is a sustainable and suitable alternative to decreasing animal loss and antibiotic use due to diarrhoea.

Religiosity and psychological resilience in patients with schizophrenia and bipolar disorder: an international cross-sectional study.

OBJECTIVE: The impact of religious/spiritual activities on clinical outcomes in patients with serious mental illnesses remains controversial, which was addressed in this international cross-sectional study. METHOD: Three-hundred sixty-nine subjects were recruited from Austria (n = 189) and Japan (n = 180), consisting of 112 outpatients with paranoid schizophrenia, 120 with bipolar I disorder (DSM-IV), and 137 healthy controls. Religiosity was assessed in terms of attendance and importance of religious/spiritual activities, while resilience was assessed using the 25-item Resilience Scale. General linear models were used to test whether higher religiosity will be associated with higher resilience, higher social functioning, and lower psychopathology. The association between levels of spiritual well-being and resilience was also examined. RESULTS: Attendance of religious services (F[4,365] = 0.827, P = 0.509) and importance of religion/spirituality (F[3,365] = 1.513, P = 0.211) did not show significant associations with resilience. Regarding clinical measures, a modest association between higher importance of religion/spirituality and residual manic symptoms was observed in bipolar patients (F[3,118] = 3.120, P = 0.029). In contrast to the findings regarding religiosity, spiritual well-being showed a strong positive correlation with resilience (r = 0.584, P < 0.001). CONCLUSION: The protective effect of religiosity in terms of resilience, social functioning, and psychopathology was not evident in our sample. Spiritual well-being appears more relevant to resilience than religiosity.

Quality of life in schizophrenia and bipolar disorder: The impact of symptomatic remission and resilience.

BACKGROUND: Health-related quality of life (HRQOL) is significantly affected in individuals with schizophrenia or bipolar I disorder (BD-I). The current study investigated whether symptomatic remission and resilience might differently impact HRQOL in these patients. METHODS: Fifty-two patients with schizophrenia and 60 patients suffering from BD-I from outpatient mental health services as well as 77 healthy control subjects from the general community were included into a cross-sectional study. HRQOL and resilience were assessed using the WHOQOL-BREF and the Resilience Scale. In patients, psychopathology was quantified by the Positive and Negative Syndrome Scale or the Montgomery Asberg Depression Rating Scale and the Young Mania Rating Scale, respectively. RESULTS: Notably, both patient groups showed lower HRQOL and resilience compared to control subjects, non-remitted patients indicated lower HRQOL than remitted ones. The effect of remission on HRQOL was significantly larger in patients with BD-I than in those with schizophrenia but did not explain the difference in HRQOL between groups. Resilience predicted HRQOL in all three groups. When accounting for the effect of resilience among remitted patients, only the difference in HRQOL between schizophrenia patients and control subjects was significant. CONCLUSION: These findings demonstrate the impact of symptomatic remission and resilience on HRQOL of both patients suffering from schizophrenia and BD-I and indicate that these factors are especially relevant for HRQOL of patients with BD-I.

Emotional intelligence and non-social cognition in schizophrenia and bipolar I disorder.

BACKGROUND: The different patterns of Emotional Intelligence (EI) deficits in schizophrenia and bipolar I disorder are are not yet well understood. This study compares EI levels among these groups and highlights the potential impact of non-social cognition on EI. METHOD: Fifty-eight schizophrenia and 60 bipolar outpatients were investigated using the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) and the Brief Assessment of Cognition in Schizophrenia (BACS). Analyses of covariance were performed with adjustment for the BACS composite score. RESULTS: Compared to bipolar subjects, schizophrenia patients showed significantly lower levels in both EI and non-social cognition. After adjustment for the BACS composite score, the difference in EI was lost. The mediation analysis revealed that differences between schizophrenia and bipolar patients in strategic EI are almost fully attributable to the mediating effect of non-social cognition. CONCLUSIONS: Our findings suggest that in both schizophrenia and bipolar patients EI is strongly influenced by non-social cognitive functioning. This has to be taken into account when interpreting MSCEIT data in comparative studies in serious mental illness and emphasizes the importance of cognitive remediation.

Quality of life in stabilized patients with schizophrenia is mainly associated with resilience and self-esteem.

OBJECTIVE: Improving quality of life (QoL) is an important objective in the treatment of schizophrenia. The aim of the current study was to examine to what extent resilience, self-esteem, hopelessness, and psychopathology are correlated with QoL. METHOD: We recruited 52 out-patients diagnosed with schizophrenia according to DSM-IV criteria and 77 healthy control subjects from the general community. In patients, psychopathology was quantified by the Positive and Negative Syndrome Scale. The following scales were used in both patients and control subjects: the Berliner Lebensqualitätsprofil, the Resilience Scale, the Rosenberg Self-Esteem Scale, and the Beck Hopelessness Scale to assess QoL, resilience, self-esteem, and hopelessness respectively. RESULTS: Patients with schizophrenia presented with significantly less QoL, resilience, self-esteem, and hope compared to healthy control subjects. In patients, QoL correlated moderately with resilience, self-esteem, and hopelessness and weakly with symptoms. With respect to the latter, particularly depression and positive symptoms were negatively correlated with QoL. CONCLUSION: Our results highlight the complex nature of QoL in patients suffering from schizophrenia. They underscore that significant efforts are necessary to enhance resilience and self-esteem and to diminish hopelessness as well as affective and positive symptoms in patients with schizophrenia.

Economic analysis of two-stage septic revision after total hip arthroplasty: What are the relevant costs for the hospital's orthopedic department?

BACKGROUND: The number of septic total hip arthroplasty (THA) revisions is increasing continuously, placing a growing financial burden on hospitals. Orthopedic departments performing septic THA revisions have no basis for decision making regarding resource allocation as the costs of this procedure for the departments are unknown. It is widely assumed that septic THA procedures can only be performed at a loss for the department. Therefore, the purpose of this study was to investigate whether this assumption is true by performing a detailed analysis of the costs and revenues for two-stage septic THA revision. METHODS: Patients who underwent revision THA for septic loosening in two sessions from January 2009 through March 2012 were included in this retrospective, consecutive cost study from the orthopedic department's point of view. We analyzed variable and case-fixed costs for septic revision THA with special regard to implantation and explantation stay. By using marginal costing approach we neglected hospital-fixed costs. Outcome measures include reimbursement and daily contribution margins. RESULTS: The average direct costs (reimbursement) incurred for septic two-stage revision THA was €10,828 (€24,201). The difference in cost and contribution margins per day was significant (p < .001 and p = 0.019) for ex- and implantation (€4147 vs. €6680 and €429 vs. €306) while length of stay and reimbursement were comparable. CONCLUSIONS: This is the first detailed analysis of the hospital department's cost for septic revision THA performed in two sessions. Disregarding hospital-fixed costs the included variable and case fixed-costs were covered by revenues. This study provides cost data, which will be guidance for health care decision makers.

Deficient interference control during working memory updating in adults with ADHD: An event-related potential study.

OBJECTIVE: Little is known about the underlying mechanisms of poor working memory (WM) performance of adults with attention deficit hyperactivity disorder (ADHD). This study investigates interference and load effects during WM updating by use of event-related potentials. METHOD: Forty ADHD patients and 41 controls performed verbal n-back tasks under conditions of low and high WM load. Intrusion probes, i.e., lures, were implemented to challenge interference control abilities during WM processing. RESULTS: Stimulus-dependent N200 amplitude modulation and behavioral performance in lure trials were reduced in adults with ADHD compared to healthy controls. Also, P300 amplitudes tended to be less sensitive to WM load in patients with ADHD. CONCLUSION: Our findings provide electrophysiological evidence for inaccurate discrimination of stimulus categories. Particularly, deficient interference control may lead to overt WM deficits in adult subjects with ADHD. SIGNIFICANCE: The current findings contribute to a deeper understanding of the neural substrates of executive dysfunction in adult ADHD, focusing on the domain of WM.

Psychiatric misdiagnoses in Dandy-Walker variant.

Cases of intellectual impairment and aberrant behavior in patients with cerebellar diseases have been described since the early nineteenth century. Here, we report on a patient suffering from Dandy-Walker variant who presented with symptoms of obsessive compulsive disorder and delusional disorder. The current findings emphasize the potential relevance of focal cerebellar lesions as organic correlates of these disorders.

Detection of necrosis of the gastric fundus after blunt abdominal trauma by PET-CT.

Positron emission tomography with [(18)F]-fluorodeoxyglucose provides functional and anatomic information by visualising the uptake of radiolabelled glucose in tumour and inflammatory cells. We report delayed diagnosis of necrosis of the gastric fundus after blunt abdominal trauma in a 73-year-old man. After a car accident with head-on collision, the patient was stabilised in our emergency room. His femur was treated by internal fixation, his ellbow was stabilised by a fixateur externe. During surgery his status deteriorated. The patient was in need of high dosage of inotrops during the following days. He had a biventricular pacemaker implanted because of ischemic myocardiopathy, and he suffered from renal insufficiency. Over the next days, his haemodynamics improved. A central venous line had to be removed because of ensuing septic fever. The patient complained of upper abdominal pain and nausea. A sonography and computer tomography without contrast medium were performed with negative result. Because of contamination of the central venous line with Staphylococcus epidermidis the pacemaker was evaluated for infection by transoesophageal echocardiography, again without any findings. Because of ongoing fever and positive inflammatory markers a positron emission tomography was indicated, as a contrast examination and a magnetic resonance examination were not feasible because of the renal insufficiency and the pacemaker, respectively. Prophylactic removal of the pacemaker would have been a substantial risk for the patient due to his underlying myocardiopathy. Positron emission tomography showed an increased tracer uptake in the gastric fundus, which turned out to be necrotic by endoscopy. A laparoscopic resection followed, and drainage of an abscess, which had evolved subsequently between stomach and spleen stopped the inflammatory process. This case report demonstrates that positron emission tomography may be an alternative to computer tomography with contrast medium and magnetic resonance imaging to detect an inflammatory process in patients with pre-existing disease.

Mortality attributable to rheumatic heart disease in the Kimberley: a data linkage approach.

BACKGROUND: Acute rheumatic fever (ARF) and its sequelae, rheumatic heart disease (RHD) are now uncommon in the general Australian population. However, these preventable and treatable diseases continue to affect Aboriginal Australians disproportionately, especially in remote communities. In the Kimberley region of Western Australia (WA), the prevalence of RHD is approximately 1% among Aboriginal residents. Yet an accurate and comprehensive picture of RHD-related mortality is lacking. AIM: This study aims to determine the mortality burden attributable to ARF and RHD in the Kimberley using linked hospitalisation and death registry data. METHODS: A retrospective cohort study was undertaken comprising all Kimberley residents with a WA hospital admission for ARF or RHD between 1970 and 2010, linked with the WA Death Register. We manually classified RHD-attributable deaths ('definite' or 'probable') to determine mortality burden. Hospitalisation prior to death, including valvular surgery was also ascertained. RESULTS: There were 35 RHD-attributable deaths in the Kimberley between 1990 and 2010, with 94% occurring in Aboriginal people. Their median age of death was 40 years. The age-standardised RHD annual death rate was 15.6 per 100 000 with a total of 1100 premature years of life lost before age of 75 within this group. Conventional International Classification of Diseases-generated mortality data underestimated mortality burden. CONCLUSION: RHD remains a significant cause of premature mortality for Aboriginal people in the Kimberley, with mortality rates unmatched in the general Australian population since the first half of the 20th century. Efforts to reduce progression of this disease through RHD Register and Control Programs are crucial alongside action to address underlying socioeconomic and environmental inequities.

An economic analysis of aseptic revision hip arthroplasty: calculation of partial hospital costs in relation to reimbursement.

INTRODUCTION: Aseptic loosening is one of the most common intermediate and long-term complications after total hip replacement (THR). These complications cause suffering and require expensive revision surgery. Little concrete data on direct costs are available from the hospital's, moreover operating department's perspective. We here provide a detailed analysis of the costs of THR revision and relate them to reimbursement underlying the German diagnosis-related groups (DRG) system. MATERIALS AND METHODS: Major cost parameters were identified using for orientation the cost matrix of the German Institute for Hospital Reimbursement (InEK GmbH). We then retrospectively analysed the major direct costs of aseptic revision THR in terms of contribution margins I and II. The analysis included a total of 114 patients who underwent aseptic revision from 1 January 2009 to 31 March 2012. Data were retrieved from the hospital information system and patient records. All costs of surgery, diagnostic tests, and other treatments were calculated as purchase prices in EUR. The comparative analysis of direct costs and reimbursements was done for DRG I46A and I46B from the hospital's, especially treating department's rather than the society or healthcare insurance's perspective. RESULTS: The average direct cost incurred by the hospital for a THR revision was 4,380.0. The largest share was accounted for surgical costs (62.7 % of total). Implant and staff costs were identified as the most important factors that can be influenced. The proportion of the daily contribution margin that was left to cover the hospital's indirect cost decreased with the relative cost weight of the DRG to which a patient was assigned. CONCLUSION: Our study for the first time provides a detailed analysis of the major direct case costs of THR revision for aseptic loosening from the provider's perspective. Our findings suggest that these revision operations could be performed cost-beneficially by the operating unit. From an economic perspective, cases with higher cost weights are more favorable for a hospital. These results need to be confirmed in multicenter studies.

Efficiency of different selection strategies against boar taint in pigs.

The breeding scheme of a Swiss sire line was modeled to compare different target traits and information sources for selection against boar taint. The impact of selection against boar taint on production traits was assessed for different economic weights of boar taint compounds. Genetic gain and breeding costs were evaluated using ZPlan+, a software based on selection index theory, gene flow method and economic modeling. Scenario I reflected the currently practiced breeding strategy as a reference scenario without selection against boar taint. Scenario II incorporated selection against the chemical compounds of boar taint, androstenone (AND), skatole (SKA) and indole (IND) with economic weights of -2.74, -1.69 and -0.99 Euro per unit of the log transformed trait, respectively. As information sources, biopsy-based performance testing of live boars (BPT) was compared with genomic selection (GS) and a combination of both. Scenario III included selection against the subjectively assessed human nose score (HNS) of boar taint. Information sources were either station testing of full and half sibs of the selection candidate or GS against HNS of boar taint compounds. In scenario I, annual genetic gain of log-transformed AND (SKA; IND) was 0.06 (0.09; 0.02) Euro, which was because of favorable genetic correlations with lean meat percentage and meat surface. In scenario II, genetic gain increased to 0.28 (0.20; 0.09) Euro per year when conducting BPT. Compared with BPT, genetic gain was smaller with GS. A combination of BPT and GS only marginally increased annual genetic gain, whereas variable costs per selection candidate augmented from 230 Euro (BPT) to 330 Euro (GS) or 380 Euro (both). The potential of GS was found to be higher when selecting against HNS, which has a low heritability. Annual genetic gain from GS was higher than from station testing of 4 full sibs and 76 half sibs with one or two measurements. The most effective strategy to reduce HNS was selecting against chemical compounds by conducting BPT. Because of heritabilities higher than 0.45 for AND, SKA and IND and high genetic correlations to HNS, the (correlated) response in units of the trait could be increased by 62% compared with scenario III with GS and even by 79% compared with scenario III, with station testing of siblings with two measurements. Increasing the economic weights of boar taint compounds amplified negative effects on average daily gain, drip loss and intramuscular fat percentage.

A performance test for boar taint compounds in live boars.

Genetically reducing boar taint using low-taint lines is considered the most sustainable and economic long-term alternative to surgical castration of male pigs. Owing to the high heritability of the main boar taint components (androstenone, skatole and indole), breeding is an excellent tool for reducing the number of tainted carcasses. To incorporate boar taint into breeding programmes, standardized performance testing is required. The objective of this study was to develop and formally present a performance test for the main boar taint compounds on live breeding candidates. First, a standardized performance test for boar taint was established. A biopsy device was developed to extract small tissue samples (200 to 300 mg) from breeding candidates. Quantification of boar taint components from these small samples using specialized chemical extraction methods proved accurate and repeatable (r = 0.938). Following establishment of the method, biopsy samples of 516 live boars (100 to 130 kg live weight) were collected in the second step. Various mixed linear models were tested for each boar taint compound; models were ranked in terms of their information content. Pedigree information of 2245 ancestors of biopsied animals was included, and genetic parameters were estimated using univariate and multivariate models. Androstenone (in µg/g liquid fat (LF): mean = 0.578, σ = 0.527), skatole (in µg/g LF: mean = 0.033, σ = 0.002) and indole (in µg/g LF: mean = 0.032, σ = 0.002) levels obtained by biopsy were plausible. Heritability estimates for androstenone calculated with univariate (0.453) and multivariate (0.452) analyses were comparable to those in the literature. Heritabilities for skatole (0.495) and indole (0.550) were higher than that for androstenone. Genetic and phenotypic correlations were similar to those published previously. Our results show that data on boar taint compounds from small adipose samples obtained by biopsy provide similar genetic parameters as that described in the literature for larger samples and are therefore a reliable performance test for boar taint in live breeding candidates.