Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders.

Clozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity (p = 1.03 × 10-3; R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score (p = 0.01; R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times (p = 6.84×10-4) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44×10-3). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78×10-7) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP-activity in schizophrenia.

High-quality endoscope reprocessing decreases endoscope contamination.

OBJECTIVES: Several outbreaks of severe infections due to contamination of gastrointestinal (GI) endoscopes, mainly duodenoscopes, have been described. The rate of microbial endoscope contamination varies dramatically in literature. The aim of this multicentre prospective study was to evaluate the hygiene quality of endoscopes and automated endoscope reprocessors (AERs) in Tyrol/Austria. METHODS: In 2015 and 2016, a total of 463 GI endoscopes and 105 AERs from 29 endoscopy centres were analysed by a routine (R) and a combined routine and advanced (CRA) sampling procedure and investigated for microbial contamination by culture-based and molecular-based analyses. RESULTS: The contamination rate of GI endoscopes was 1.3%-4.6% according to the national guideline, suggesting that 1.3-4.6 patients out of 100 could have had contacts with hygiene-relevant microorganisms through an endoscopic intervention. Comparison of R and CRA sampling showed 1.8% of R versus 4.6% of CRA failing the acceptance criteria in phase I and 1.3% of R versus 3.0% of CRA samples failing in phase II. The most commonly identified indicator organism was Pseudomonas spp., mainly Pseudomonas oleovorans. None of the tested viruses were detected in 40 samples. While AERs in phase I failed (n = 9, 17.6%) mainly due to technical faults, phase II revealed lapses (n = 6, 11.5%) only on account of microbial contamination of the last rinsing water, mainly with Pseudomonas spp. CONCLUSIONS: In the present study the contamination rate of endoscopes was low compared with results from other European countries, possibly due to the high quality of endoscope reprocessing, drying and storage.

A prospective international Aspergillus terreus survey: an EFISG, ISHAM and ECMM joint study.

OBJECTIVES: A prospective international multicentre surveillance study was conducted to investigate the prevalence and amphotericin B susceptibility of Aspergillus terreus species complex infections. METHODS: A total of 370 cases from 21 countries were evaluated. RESULTS: The overall prevalence of A. terreus species complex among the investigated patients with mould-positive cultures was 5.2% (370/7116). Amphotericin B MICs ranged from 0.125 to 32 mg/L, (median 8 mg/L). CONCLUSIONS: Aspergillus terreus species complex infections cause a wide spectrum of aspergillosis and the majority of cryptic species display high amphotericin B MICs.

Reduction in advanced breast cancer after introduction of a mammography screening program in Tyrol/Austria.

BACKGROUND: We analysed all female breast cancer (BC) cases in Tyrol/Austria regarding the shift in cancer characteristics, especially the shift in advanced BC, for the group exposed to screening as compared to the group unexposed to screening. METHODS: The analysis was based on all BC cases diagnosed in women aged 40-69 years, resident in Tyrol, and diagnosed between 2009 and 2013. The data were linked to the Tyrolean mammography screening programme database to classify BC cases as "exposed to screening" or "unexposed to screening". Age-adjusted relative risks (RR) were estimated by relating the exposed to the unexposed group. RESULTS: In a total of about 145,000 women aged 40-69 years living in Tyrol during the study period, 1475 invasive BC cases were registered. We estimated an age-adjusted relative risk (RR) for tumour size ≥ 21 mm of 0.72 (95% confidence interval (CI) 0.60 to 0.86), for metastatic BC of 0.27 (95% CI 0.17 to 0.46) and for advanced BC of 0.83 (95% CI 0.71 to 0.96), each comparing those exposed to those unexposed to screening, respectively. CONCLUSION: In our population-based registry analysis we observed that participation in the mammography screening programme in Tyrol is associated with a 28% decrease in risk for BC cases with tumour size ≥ 21 mm and a 17% decrease in risk for advanced BC. We therefore expect the Tyrolean mammography programme to show a reduction in BC mortality.

Frequency of dermatological side effects of continuous subcutaneous insulin infusion in children and adolescents with type 1 diabetes.

BACKGROUND: The incidence of type 1 diabetes is rising, particularly in young infants. The treatment with continuous subcutaneous insulin infusion (CSII) offers certain benefits and has gained popularity. Insulin-pump therapy could be associated with cutaneous-adverse effects. The purpose of our study was to investigate the frequency and characterization of skin-related complications in patients with CSII. METHODS: In a single center setting, 54 patients (28 male, 26 female) on CSII therapy aged between 3 and 20 years participated in our study. Data including duration of diabetes, duration of CSII, pump model, catheter material, frequency of catheter switch and hygiene procedures at time of puncture were collected through a standardized questionnaire and photographs of affected areas of the skin were made. Statistical analysis was done to verify an association with gender, patients' age, HbA1c values, and body mass index. RESULTS: Our observation revealed skin complications at the site of catheter insertion in 43% (8 f, 15 m) of our patients. A frequent occurrence of scars (24%, 6 f, 7 m), lipohypertrophic areas (20%, 4 f, 7 m) and eczema (11%, 1 f, 5 m) was observed. Furthermore, 6% (1 f, 2 m) showed changes in pigmentation and 6% (1 f, 2 m) lipoatrophy. The catheter localization had to be switched due to skin-complications in 24% (6 f, 7 m) whereas none of our patients discontinued insulin-pump therapy. CONCLUSION: Skin-related complications during CSII are frequent and regular examination of the insertion sites is crucial. To verify the occurrence of lipoatrophy associated with insulin pump therapy - an otherwise rare complication - larger studies would be needed.

Differences between patients and medical professionals in the evaluation of aesthetic outcome following breast reconstruction with implants.

BACKGROUND AND AIM: Most studies on breast reconstruction evaluate different surgical techniques, types of implant or time of reconstruction. Moreover, evaluations are usually performed either by surgeons or by patients, but are rarely compared. We conducted a study on aesthetic outcome following breast reconstruction with implants comparing the evaluation by patients versus medical professionals. METHODS: Forty-seven patients, who had a breast reconstruction with implants between 2001 and 2010 (median follow-up 71 months), underwent a clinical examination, standardized photo documentation and filled out a questionnaire to evaluate their aesthetic result (rate 1 very good to 5 very poor). Photo documentation was independently evaluated by 18 medical professionals using the same evaluation instrument and the results were compared. Gender and patient aspects were taken into account. RESULTS: We found statistically significant differences between patients and medical professional ratings. The patient evaluation was better through all categories as compared to the evaluation by medical personnel. The degree of medical education or gender aspects did not significantly affect the professional ratings. Age at reconstruction, length of follow-up or primary versus secondary reconstruction did not seem to make a difference in the evaluations of the patients versus the medical professionals.. CONCLUSION: The differences between patient and expert opinion in rating of aesthetic results indicate that patient satisfaction is influenced by multiple factors and not only by good aesthetic outcome. Patient evaluation should therefore be carefully considered in treatment and outcome studies of breast reconstruction..

Metabolic risk factors and skin cancer in the Metabolic Syndrome and Cancer Project (Me-Can).

BACKGROUND: Little is known about the associations of metabolic aberrations with malignant melanoma (MM) and nonmelanoma skin cancer (NMSC). OBJECTIVES: To assess the associations between metabolic factors (both individually and combined) and the risk of skin cancer in the large prospective Metabolic Syndrome and Cancer Project (Me-Can). METHODS: During a mean follow-up of 12 years of the Me-Can cohort, 1728 (41% women) incident MM, 230 (23% women) fatal MM and 1145 (33% women) NMSC were identified. Most NMSC cases (76%) were squamous cell carcinoma (SCC) (873, 33% women). Hazard ratios (HRs) were estimated by Cox proportional hazards regression for quintiles and standardized z-scores (with a mean of 0 and SD of 1) of body mass index (BMI), blood pressure, glucose, cholesterol, triglycerides and for a combined metabolic syndrome score. Risk estimates were corrected for random error in the measurements. RESULTS: Blood pressure per unit increase of z-score was associated with an increased risk of incident MM cases in men and women [HR 1·17, 95% confidence interval (CI) 1·04-1·31 and HR 1·18, 95% CI 1·03-1·36, respectively] and fatal MM cases among women (HR 2·39, 95% CI 1·58-3·64). In men, all quintiles for BMI above the reference were associated with a higher risk of incident MM. In women, SCC NMSC risk increased across quintiles for glucose levels (P-trend 0·02) and there was a trend with triglyceride concentration (P-trend 0·09). CONCLUSION: These findings suggest that mechanisms linked to blood pressure may be involved in the pathogenesis of MM. SCC NMSC in women could be related to glucose and lipid metabolism.

Effects of six second generation antipsychotics on body weight and metabolism - risk assessment and results from a prospective study.

BACKGROUND: Due to the association of second generation antipsychotics (SGAs) with weight gain and alterations of glucose and lipid homeostasis, we aimed to group six commonly prescribed SGAs into classes of differing risks. METHODS: Twenty-eight patients meeting the criteria for a diagnosis of schizophrenic disorder according to ICD-10 were assigned to monotherapy with olanzapine, clozapine, quetiapine, amisulpride, ziprasidone or risperidone. The levels of glucose and lipid metabolism were assessed before and after 28 days of treatment. RESULTS: Based on cluster analysis, olanzapine and clozapine were found to constitute a high-risk group for metabolic dysregulation while amisulpride, quetiapine, risperidone and ziprasidone could be assigned to a non-high-risk group. Subjects from the high-risk group displayed significant weight gain with concomitant increases of HOMA-IR, levels of insulin, total cholesterol, TG, LDL-C and leptin. No significant changes were observed in the non-high-risk group. CONCLUSION: The results of this study support the conclusion of the Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes that certain SGAs are associated with a higher risk for weight gain, insulin resistance and dyslipidemia.

Subjective response and attitudes toward antipsychotic drug therapy during the initial treatment period: a prospective follow-up study in patients with schizophrenia.

OBJECTIVE: In this prospective study, patients with schizophrenia were followed up for 3 months to investigate the impact of sociodemographic factors, psychopathology, change in psychopathology and side effects on subjective response and attitudes toward antipsychotics during the initial treatment period. METHOD: We investigated 42 patients starting treatment with a new-generation antipsychotic. Next to the registration of demographic data various rating scales were used: the Positive and Negative Syndrome Scale (PANSS), the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale and the Drug Attitude Inventory (DAI). RESULTS: Two patients experienced a first episode of the illness and were neuroleptic naïve, and 40 had suffered from at least one prior episode of schizophrenia. Longer duration of illness as well as the amelioration of psychopathological symptoms had a positive impact on subjective response to treatment. Correlations between antipsychotic-induced side effects and drug attitude tended to be weak. CONCLUSION: Our results emphasize the necessity of improving psychopathological symptoms during the initial treatment period to improve attitudes toward and compliance with treatment.

Outcomes in schizophrenia outpatients treated with amisulpride or olanzapine.

INTRODUCTION: We compared stable patients with schizophrenia who were treated with either amisulpride or olanzapine in terms of symptomatic outcome, neurocognitive functioning, functionality, and subjective outcome. METHODS: Sixty outpatients with chronic schizophrenia who had been treated with either amisulpride or olanzapine for at least six months were investigated. RESULTS: The scores of positive, negative, and cognitive symptoms did not differ between the two groups, but patients treated with olanzapine had significantly lower scores on the excitement and depression/anxiety components of the PANSS. With regard to cognitive variables, patients treated with amisulpride showed significantly lower values regarding verbal fluency and significantly better verbal memory than patients treated with olanzapine. Both treatment groups were comparable with respect to functional and subjective outcome variables. DISCUSSION: These observations add to the evidence that continuous treatment with different second-generation antipsychotics with relatively few side effects leads to comparable outcomes in patients with schizophrenia.

Prediction of serious complications in patients admitted to a surgical ward.

BACKGROUND: Prediction of complications is an essential part of risk management in surgery. Knowing which patients are at high risk of developing complications will contribute to the quality and cost reduction of surgery. METHODS: All patients admitted to a general surgical ward during a 1-year interval were followed until 30 days after discharge. Complications and data on potential risk factors were recorded prospectively. Relative risks were calculated for each risk factor and predictive values for the development of a serious or minor complication were computed using logistic regression analysis. The predictive values of different combinations of variables were expressed as receiver operating characteristic curves. RESULTS: Of 3075 patients, 375 suffered one or more serious complications and 319 experienced a minor complication. A model was developed for prediction of serious complications, consisting of 11 variables, with an area under the curve (AUC) of 0.79 (95 per cent confidence interval (c.i.) 0.76 to 0.81). The prognostic value of the model for minor complications (seven variables) was lower (AUC 0.68 (95 per cent c.i. 0.65 to 0.71)). CONCLUSION: Serious complications in patients admitted to a surgical ward can be predicted using a model consisting of 11 variables. The risk score can be used in the decision-making process before surgery.

Seasonality of schizophrenia and stillbirths in The Netherlands.

Studies from Denmark and the USA have reported a strong correlation between the seasonal pattern for stillbirths and the seasonal birth pattern for people who develop schizophrenia. It has been suggested that the correlation could be caused by a common seasonal factor (e. g. intra-uterine infections during the third trimester of pregnancy), which produces death in some fetuses and nonfatal brain changes in others, changes that are manifested in later life as schizophrenia. The aims of our study were (i) to assess the seasonal patterns for stillbirths and for pre-schizophrenic births in The Netherlands and (ii) to examine their relationship. The Dutch psychiatric registry provided data on all Dutch-born subjects who had been hospitalized at least once with a diagnosis of schizophrenia in the period 1970-1994. We selected data on patients born in the period 1926-1970 (n=29891). The government provided monthly numbers of live births and stillbirths in the latter period. Seasonality of birth was examined using Poisson regression analysis. The risk of an admission for schizophrenia was highest for people born in the months of May and June and lowest for those born in August and September. When the risk for subjects born in June was compared with the risk for subjects born in September, the Relative Risk was 1.14 [95% confidence interval (CI): 1.07 to 1.22]. The seasonal pattern of stillbirths was different, in that it showed a peak in the month of January. The low, however, as in schizophrenia, occurred in the months of August and September. The two seasonal patterns were found to be weakly correlated: Spearman's rank correlation coefficient rho=0.41 (95% CI: -0.22 to 0.80). This was the largest European study on birth seasonality in schizophrenia. The hypothesis that a common factor is responsible for a seasonal excess of stillbirths and for a seasonal birth excess of people who develop schizophrenia was not supported. The possibility remains, however, that a common factor explains seasonal (birth rate) deficits in these disorders.