A probabilistic-deterministic approach for assessing climate change effects on infection risks downstream of sewage emissions from CSOs.

The discharge of pathogens into urban recreational water bodies during combined sewer overflows (CSOs) pose a potential threat for public health which may increase in the future due to climate change. Improved methods are needed for predicting the impact of these effects on the microbiological urban river water quality and infection risks during recreational use. The aim of this study was to develop a novel probabilistic-deterministic modelling approach for this purpose building on physically plausible generated future rainfall time series. The approach consists of disaggregation and validation of daily precipitation time series from 21 regional climate models for a reference period (1971-2000, C20), a near-term future period (2021-2050, NTF) and a long-term future period (2071-2100, LTF) into sub-daily scale, and predicting the concentrations of enterococci and Giardia and Cryptosporidium, and infection risks during recreational use in the river downstream of the sewage emissions from CSOs. The approach was tested for an urban river catchment in Austria which is used for recreational activities (i.e. swimming, playing, wading, hand-to-mouth contact). According to a worst-case scenario (i.e. children bathing in the river), the 95th percentile infection risks for Giardia and Cryptosporidium range from 0.08 % in winter to 8 % per person and exposure event in summer for C20. The infection risk increase in the future is up to 0.8 log10 for individual scenarios. The results imply that measures to prevent CSOs may be needed to ensure sustainable water safety. The approach is promising for predicting the effect of climate change on urban water safety requirements and for supporting the selection of sustainable mitigation measures. Future studies should focus on reducing the uncertainty of the predictions at local scale.

Automated detection of poor-quality data: case studies in healthcare.

The detection and removal of poor-quality data in a training set is crucial to achieve high-performing AI models. In healthcare, data can be inherently poor-quality due to uncertainty or subjectivity, but as is often the case, the requirement for data privacy restricts AI practitioners from accessing raw training data, meaning manual visual verification of private patient data is not possible. Here we describe a novel method for automated identification of poor-quality data, called Untrainable Data Cleansing. This method is shown to have numerous benefits including protection of private patient data; improvement in AI generalizability; reduction in time, cost, and data needed for training; all while offering a truer reporting of AI performance itself. Additionally, results show that Untrainable Data Cleansing could be useful as a triage tool to identify difficult clinical cases that may warrant in-depth evaluation or additional testing to support a diagnosis.

ATLAS trial of adjuvant axitinib in patients with renal cell carcinoma: subgroup analyses with focus on axitinib dosing and racial groups.

BACKGROUND: The ATLAS trial, investigating adjuvant axitinib versus placebo in renal cell carcinoma (RCC), was stopped for futility at a preplanned interim analysis. We report subgroup outcome analyses by ethnicity, time on treatment, dose modification and toxicity. PATIENTS AND METHODS: Patient demographics, baseline characteristics, treatment duration and exposure and safety were analysed for Asian versus non-Asian patients treated with axitinib versus placebo. Disease-free survival (DFS) was analysed by ethnicity, treatment duration (≥1 versus <1 year), dose modification and adverse event (AE) grade. RESULTS: No DFS benefit was observed for Asian {hazard ratio (HR) 0.883 [95% confidence interval (CI) 0.638-1.220]} or non-Asian [HR 0.828 (95% CI 0.490-1.400)] patients treated with axitinib or placebo. Fewer Asian versus non-Asian patients were in the highest-risk group in axitinib (51.9% versus 72.3%) or placebo (51.5% versus 66.0%) arm. Highest-risk patients in both subgroups had no DFS benefit with either treatment. More axitinib-treated Asian versus non-Asian patients had dose reductions due to AEs (58.8% versus 46.0%; P = 0.028). Asian patients experienced more nasopharyngitis but less fatigue or asthenia than non-Asians. Among Asian patients, proteinuria, hypothyroidism, nasopharyngitis, and hypertension were more common in Japanese patients than Korean patients and more common in Korean patients than Chinese patients. Patients receiving axitinib >1 year versus ≤1 year did not have different DFS: HR 0.572 (95% CI 0.247-1.327); P = 0.1874. Compared with patients on stable axitinib dose, DFS was longer in patients with dose reduction [HR 0.458 (95% CI 0.305-0.687); P = 0.0001], whereas DFS was not different in those with dose escalation [HR 1.936 (95% CI 0.937-3.997); P = 0.0685]. DFS was not different in patients experiencing grade ≥2 versus <2 AEs within 6 months of initiating axitinib: HR 0.885 (95% CI 0.419-1.869); P = 0.7488. CONCLUSIONS: Asian versus non-Asian subgroup analysis revealed differences in AE experience and drug exposure. There were no DFS differences based on ethnicity or treatment duration, but axitinib dose reduction led to longer DFS.

Assessing the faecal source sensitivity and specificity of ruminant and human genetic microbial source tracking markers in the central Ethiopian highlands.

This study tested genetic microbial source tracking (MST) methods for identifying ruminant- (BacR) and human-associated (HF183/BacR287, BacHum) bacterial faecal contaminants in Ethiopia in a newly created regional faecal sample bank (n = 173). BacR performed well, and its marker abundance was high (100% sensitivity (Sens), 95% specificity (Spec), median log10 8·1 marker equivalents (ME) g-1 ruminant faeces). Human-associated markers tested were less abundant in individual human samples (median: log10 5·4 and 4·2 (ME + 1) g-1 ) and were not continuously detected (81% Sens, 91% Spec for BacHum; 77% Sens, 91% Spec for HF183/BacR287). Furthermore, the pig-associated Pig2Bac assay was included and performed excellent (100% Sens, 100% Spec). To evaluate the presence of MST targets in the soil microbiome, representative soil samples were tested during a whole seasonal cycle (n = 60). Only BacR could be detected, but was limited to the dry season and to sites of higher anthropogenic influence (log10 3·0 to 4·9 (ME + 1) g-1 soil). In conclusion, the large differences in marker abundances between target and non-target faecal samples (median distances between distributions ≥log10 3 to ≥log10 7) and their absence in pristine soil indicate that all tested assays are suitable candidates for diverse MST applications in the Ethiopian area.

Pancreas size and exocrine function is decreased in young children with recent-onset Type 1 diabetes.

AIMS: To measure pancreatic area and exocrine function in young children with recent-onset Type 1 diabetes to determine whether the exocrine pancreas is also affected in the pathophysiology of early childhood diabetes. METHODS: Thirty-two children (14 boys) aged 5.5 (4.5, 7.3) median (IQR) years presenting with recent-onset Type 1 diabetes and 90 controls (44 boys) of similar age had ultrasound imaging of the pancreas. Children with Type 1 diabetes were receiving insulin and were without ketosis. Transverse and longitudinal areas of the pancreas were measured by digitalized outline. Pancreatic faecal elastase-1 was analysed using an enzyme-linked immunosorbent assay kit in recent-onset Type 1 diabetes and 38 first-degree relative control children. RESULTS: Pancreatic area and exocrine function were reduced in Type 1 diabetes. Mean transverse area (SD) in Type 1 diabetes was 6.82 cm2 (1.61) vs. 8.31 cm2 (1.74) in controls, adjusted estimate (95% CI) 1.45 (-2.12, -0.79), P < 0.001; longitudinal area was 1.28 cm2 (0.44) vs. 1.55 cm2 (0.43), adjusted estimate (95% CI) -0.27 (-0.45, -0.09), P = 0.003. Faecal elastase-1 levels in Type 1 diabetes were 455 (323, 833) ug/g, median (IQR) vs. 1408 µg/g (1031, 1989) in controls, P < 0.001. CONCLUSION: Pancreatic area and accompanying subclinical exocrine function were reduced in very young children with recent-onset Type 1 diabetes. This supports changes in the exocrine pancreas in the pathophysiology of Type 1 diabetes presenting in early life.

Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase III, randomized ATLAS trial.

Background: The ATLAS trial compared axitinib versus placebo in patients with locoregional renal cell carcinoma (RCC) at risk of recurrence after nephrectomy. Patients and methods: In a phase III, randomized, double-blind trial, patients had >50% clear-cell RCC, had undergone nephrectomy, and had no evidence of macroscopic residual or metastatic disease [independent review committee (IRC) confirmed]. The intent-to-treat population included all randomized patients [≥pT2 and/or N+, any Fuhrman grade (FG), Eastern Cooperative Oncology Group status 0/1]. Patients (stratified by risk group/country) received (1 : 1) oral twice-daily axitinib 5 mg or placebo for ≤3 years, with a 1-year minimum unless recurrence, occurrence of second primary malignancy, significant toxicity, or consent withdrawal. The primary end point was disease-free survival (DFS) per IRC. A prespecified DFS analysis in the highest-risk subpopulation (pT3, FG ≥ 3 or pT4 and/or N+, any T, any FG) was conducted. Results: A total of 724 patients (363 versus 361, axitinib versus placebo) were randomized from 8 May 2012, to 1 July 2016. The trial was stopped due to futility at a preplanned interim analysis at 203 DFS events. There was no significant difference in DFS per IRC [hazard ratio (HR) = 0.870; 95% confidence interval (CI) : 0.660-1.147; P = 0.3211). In the highest-risk subpopulation, a 36% and 27% reduction in risk of a DFS event (HR; 95% CI) was observed per investigator (0.641; 0.468-0.879; P = 0.0051), and by IRC (0.735; 0.525-1.028; P = 0.0704), respectively. Overall survival data were not mature. Similar adverse events (AEs; 99% versus 92%) and serious AEs (19% versus 14%), but more grade 3/4 AEs (61% versus 30%) were reported for axitinib versus placebo. Conclusions: ATLAS did not meet its primary end point; however, improvement in DFS per investigator was seen in the highest-risk subpopulation. No new safety signals were reported. Trial registration number: NCT01599754.

Multiparametric monitoring of microbial faecal pollution reveals the dominance of human contamination along the whole Danube River.

The microbial faecal pollution of rivers has wide-ranging impacts on a variety of human activities that rely on appropriate river water quality. Thus, detailed knowledge of the extent and origin of microbial faecal pollution is crucial for watershed management activities to maintain safe water use. In this study, the microbial faecal pollution levels were monitored by standard faecal indicator bacteria (SFIB) along a 2580 km stretch of the Danube, the world's most international river, as well as the Danube's most important tributaries. To track the origin of faecal pollution, host-associated Bacteroidetes genetic faecal marker qPCR assays for different host groups were applied in concert with SFIB. The spatial resolution analysis was followed by a time resolution analysis of faecal pollution patterns over 1 year at three selected sites. In this way, a comprehensive faecal pollution map of the total length of the Danube was created, combining substantiated information on both the extent and origin of microbial faecal pollution. Within the environmental data matrix for the river, microbial faecal pollution constituted an independent component and did not cluster with any other measured environmental parameters. Generally, midstream samples representatively depicted the microbial pollution levels at the respective river sites. However, at a few, somewhat unexpected sites, high pollution levels occurred in the lateral zones of the river while the midstream zone had good water quality. Human faecal pollution was demonstrated as the primary pollution source along the whole river, while animal faecal pollution was of minor importance. This study demonstrates that the application of host-associated genetic microbial source tracking markers in concert with the traditional concept of microbial faecal pollution monitoring based on SFIB significantly enhances the knowledge of the extent and origin of microbial faecal pollution patterns in large rivers. It constitutes a powerful tool to guide target-oriented water quality management in large river basins.

Micturating cystourethrogram as a tool for investigating UTI in children - An institutional audit.

BACKGROUND: Micturating cystourethrograms (MCUG) are the gold standard for evaluating vesicoureteric reflux (VUR). There is a growing consensus for increasing the threshold for performing MCUGs following urinary tract infections (UTI) in children. There are several varying guidelines. It is important to detect high-grade reflux in the setting of an UTI because of potential long-term complications. OBJECTIVE: This audit aimed to retrospectively: (1) identify the conformance rate of local guidelines at the Women's and Children's Hospital (WCH); (2) assess predictors for an abnormal MCUG; and (3) compare local guidelines against the Royal Children's Hospital, Melbourne (RCH), National Institute for Healthcare and Excellence (NICE), and American Academy of Pediatrics (AAP) guidelines for selectively detecting high-grade reflux. METHOD: The number of MCUGs performed from 2008 to 2012 at the WCH radiology department was collected. Patients undergoing MCUG during the 2012 calendar year were identified. Only children having an initial MCUG as part of an UTI investigation with prerequisite imaging as per guidelines were included. Each child's age, sex, referral source, reason, renal ultrasound (RUS) prior to the MCUG, MCUG result and VUR grade were recorded. The WCH guidelines were applied to determine conformance, to evaluate predictors for an abnormal MCUG, and compared against other retrospectively applied guidelines (RCH, NICE, AAP). RESULTS/DISCUSSION: There was complete data for 168 children who underwent MCUG as part of an UTI investigation (median age 0.79 years, range 0.12-8.74, male:female 67:101). There were 67/168 abnormal MCUGs (62 children with VUR, five bladder diverticulum), and 97 refluxing renal units (43 high-grade VUR units). No posterior urethral valves (PUV) were identified as part of the UTI investigation. A total of 143/168 patients had prior RUS (normal:abnormal 67:76). The WCH guidelines had 82% conformance. There was no statistically significant association between an abnormal MCUG and age, sex, referral source, reason, or prior RUS result. The WCH guidelines may have missed five children with high-grade VUR (four children had surgery), compared with RCH, APP and NICE, with 8, 15, and 17 children, respectively, having high-grade VUR (two, five, and five children had surgery, respectively) show in the Summary Table. The retrospective study had limitations and possible selection bias (children with UTI without a MCUG). There were no standard treatment approaches for VUR; hence establishing a MCUG guideline is difficult. An alternative is the top-down approach. CONCLUSION: Current institutional guidelines for considering MCUG following UTI in children vary considerably. The MCUG guidelines at any institution must take into account the local management guidelines for high-grade VUR.

Thoracic non-osseous lesions in cancer patients detected in low-dose CT images acquired as part of skeletal SPECT/CT examinations.

AIM: Hybrid single-photon emission tomographic (SPECT) and X-ray computed tomography (CT) systems are increasingly used in oncologic imaging. With SPECT/CT not only the thoracic spine but also the surrounding soft tissue needs to be evaluated for pathological findings. The purpose of this study was to assess the prevalence of non-osseous findings detectable on low-dose CT datasets from patients studied by thoracic 99mTc-dicarboxypropane diphosphonate (DPD)-SPECT/CT. PATIENTS, METHODS: 119 consecutive oncologic patients (81 breast cancer, 38 with other cancer) who underwent DPD-SPECT CT of the thoracic region were included in this study. Non-osseous findings on CT were classified as either probably benign or suspicious. Suspicious findings were correlated with retrievable previous imaging and if performed with follow up imaging (MRI, CT with contrast medium, Ultrasound) or biopsy results. RESULTS: In 80/119 (67%) patients no imaging was performed before SPECT/CT. Only 7/119 subjects (6%) had no other lesions than bone lesions. In 101/119 (85%) patients lesions found on SPECT/CT images were rated as benign and in 65/119 (55%) patients as suspicious. In 8/119 (7%) patients with previously unknown suspicious lesions on SPECT/CT images suspicious findings were confirmed by biopsy. CONCLUSION: 7% of patients referred to SPECT/CT of the thoracic spine for staging of malignant disease had previously unknown suspicious non-osseous lesions detectable on the low-dose CT images which were confirmed by biopsy. This could be especially relevant for cancer entities like breast and prostate, in which no thorax-CT is routinely intended for staging.

Paediatric CT dose: a multicentre audit of subspecialty practice in Australia and New Zealand.

OBJECTIVES: To evaluate paediatric CT dosimetry in Australia and New Zealand and calculate size-specific dose estimates (SSDEs) for chest and abdominal examinations. METHODS: Eight hospitals provided data from 12 CT systems for 1462 CTs in children aged 0-15. Imaging data were recorded for eight examinations: head (trauma, shunt), temporal bone, paranasal sinuses, chest (mass) and chest HRCT (high-resolution CT), and abdomen/pelvis (mass/inflammation). Dose data for cranial examinations were categorised by age and SSDEs by lateral dimension. Diagnostic reference ranges (DRRs) were defined by the 25th and 75th percentiles. Centralised image quality assessment was not undertaken. RESULTS: DRRs for 201 abdominopelvic SSDEs were: 2.8-4.7, 3.6-11.5, 8.5-15.0, 7.6-15, and 10.6-16.2 for the <15 cm, 15-19 cm, 20-24 cm, 25-29 cm and >30 cm groups, respectively. For 147 chest examinations using these body width categories, SSDE DRRs were 2.0-4.4, 3.3-7.9, 4.0-9.4, 4.5-12, and 6.5-12. Kilovoltage peak (kVp), but not AEC or IR, was associated with SSDE (parameter estimate [standard error]: 0.12 (0.03); p < 0.0001). CONCLUSIONS: Australian and New Zealand paediatric CT DRRs and abdominal SSDEs are comparable to international data. SSDEs for chest examinations are proposed. Dose variations could be reduced by adjusting kVp. KEY POINTS: • SSDEs can be calculated for all patients, CT systems, and practices • Kilovoltage peak (kVp) has the greatest association with dose in similar-sized patients • Paediatric DRRs for CT are now available for use internationally.

Assessment of skills using a virtual reality temporal bone surgery simulator.

Surgery on the temporal bone is technically challenging due to its complex anatomy. Precise anatomical dissection of the human temporal bone is essential and is fundamental for middle ear surgery. We assessed the possible application of a virtual reality temporal bone surgery simulator to the education of ear surgeons. Seventeen ENT physicians with different levels of surgical training and 20 medical students performed an antrotomy with a computer-based virtual temporal bone surgery simulator. The ease, accuracy and timing of the simulated temporal bone surgery were assessed using the automatic assessment software provided by the simulator device and additionally with a modified Final Product Analysis Scale. Trained ENT surgeons, physicians without temporal bone surgical training and medical students were all able to perform the antrotomy. However, the highly trained ENT surgeons were able to complete the surgery in approximately half the time, with better handling and accuracy as assessed by the significant reduction in injury to important middle ear structures. Trained ENT surgeons achieved significantly higher scores using both dissection analysis methods. Surprisingly, there were no significant differences in the results between medical students and physicians without experience in ear surgery. The virtual temporal bone training system can stratify users of known levels of experience. This system can be used not only to improve the surgical skills of trained ENT surgeons for more successful and injury-free surgeries, but also to train inexperienced physicians/medical students in developing their surgical skills for the ear.

[Treatment of chronic rhinosinusitis using balloon sinuplasty. A quality of life analysis]. / Behandlung chronischer Rhinosinusitis mit der Ballon-Sinuplastik. Eine Lebensqualitätsanalyse.

BACKGROUND: Balloon sinuplasty (functional endoscopic dilation surgery, FEDS) has become established as a safe therapeutic procedure for treatment of chronic rhinosinusitis. Our goal was to assess the effect on quality of life (QoL) using validated tools and identify predictive factors. MATERIALS AND METHODS: A consecutive cohort of 14 patients was evaluated using the disease-specific QoL questionnaire Sino-Nasal Outcome Test 20 (SNOT-20). The measured postoperative changes were then correlated to the results of preoperative CT scan analyses performed according to Lund. RESULTS: Both the overall SNOT-20 scores and those corresponding to subsections regarding primary nasal symptoms (PNS) and secondary rhinogenic symptoms (SRS) showed a highly significant improvement (p < 0.01). Changes in PNS but not in SRS correlated with the CT scan analyses (p < 0.05). Eighty five percent of patients said that they would choose to undergo FEDS again. CONCLUSIONS: FEDS is an effective technique that can alleviate symptoms and improve QoL. Patient selection should not be based on CT data alone but a CT scan can be used to determine whether or not the FEDS technique is applicable to the individual patient.

[Diagnosis and management of pain syndromes following parotidectomy]. / Diagnostik und Management von Schmerzsyndromen nach Parotidektomie.

The preservation of the great auricular nerve in parotid gland surgery for benign disease is discussed controversially. The negative impact on quality of life due to lack of sensation in the auricle was underestimated in former times. Thus, more and more surgeons try to preserve the nerve with rising incidence of possible complications like neuralgia. We report on three patients with postoperative neuralgia of the great auricular nerve. Two patients experienced a long lasting remission of their neuralgia after an infiltration of the punctum nervosum with a local anesthetic. In a third patient the great auricular nerve had to be resected 6 months after parotidectomy. Other options of therapy are described.

[The indication for radiosynoviorthesis. From the perspective of the nuclear medicine expert, rheumatic orthopedist and internist]. / Indikation zur Radiosynoviorthese. Aus Sicht des Nuklearmediziners, Rheumaorthopäden und Internisten.

Radiosynovectomy or radiosynoviorthesis (RSO), the intra-articular injection of beta-emitting radionuclides (e.g. colloidal preparations of 90-Yttrium, 186-Rhenium or 169-Erbium), is an approved, reliable and easily performed therapy for the treatment of chronic synovitis without harmful side effects. The best clinical results have been obtained in patients with predominantly inflammatory joint disease such as rheumatoid arthritis or reactive arthritis. But RSO is also established to treat pain and persistent effusions after total knee replacement. It also represents an adjuvant therapy in patients with pigmented villonodular synovitis to protect against recurrence following synovectomy. In patients with hemophilia and arthropathy a reduction in joint bleeding is seen and the use of coagulation factor is reduced. The indication for RSO should be made in close cooperation between the referring physician, the rheumatologist and the nuclear medicine expert in the context of a multimodal therapy concept. In this way, success rates of over 80%, with only few side effects, can be achieved, particularly in rheumatoid arthritis, reactive arthritis and hemophilic arthropathy.

Species-relevant inescapable stress differently influences memory consolidation and retrieval of mice in a spatial radial arm maze.

Stress affects learning and there are both facilitating and impairing actions of stressors on memory processes. Here we investigated the influence of acute exposure to 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), an ethological relevant stressor for rodents, on spatial memory formation and performance in a radial arm maze (RAM) task and studied TMT effects on corticosterone levels in GAD67-GFP knock-in mice and their wildtype littermates. Our results suggest that predator odor-exposure differently affects consolidation and retrieval of memory in a hippocampus-dependent spatial learning task in adult male mice, independently from their genotypes. Acute TMT-stress before retrieval facilitates performance, whereas repeated TMT-stress during consolidation exerts no influence. Additionally, we found genotype specific effects of TMT on corticosterone release. While TMT-stress tend to result in increased corticosterone release in wildtypes there was a significant decrease in transgenic mice. Taken together, these findings indicate that biologically significant predator odor-induced stress can have different actions on the strength of spatial memory formation depending on the timing with regard to memory phases. Furthermore, we suppose an impact of GABAergic mechanisms on HPA-stress axis activation to TMT resulting in absent peripheral corticosterone release of GAD67-GFP mice.

HERG1 gene expression as a specific tumor marker in colorectal tissues.

INTRODUCTION: Colorectal carcinomas exhibit a frequent recurrence after curative surgery, which may partially be due to histopathologically inconspicuous minimal residual disease. Reliable markers for tumor cells in colorectal tissue are still missing. Therefore, in this study we compared the predictive value of the putative tumor markers carcinoembryonic antigen (CEA), cytokeratin-19 (CK19) and cytokeratin-20 (CK20) to that of a novel marker, the human ether-a-go-go-related gene (HERG1) K(+) channel, a suggested regulator of tumor cell proliferation. MATERIALS AND METHODS: Using RT-PCR we studied HERG, CEA, CK19 and CK20 expression in colorectal carcinomas and non-carcinoma controls. HERG1 immunhistochemistry was performed in a total of 66 specimens, in colorectal carcinoma (n = 23), in matched histopathologically negative samples (n = 23) taken near the excision site from the same tumor patients and in healthy control biopsies (n = 20). In order to verify the relevance of HERG1 for tumor proliferation we studied the effect of HERG1 inhibition in the Colo-205 colon cancer carcinoma cell line using the MTT-assay. RESULTS: HERG1 was expressed in all tumor samples regardless of their stage and in adenomas larger than 0.4 cm, but absent in small adenomas, sigmadiverticulitis specimen and healthy histopathologically negative samples, except for one which developed a tumor recurrence. In contrast, CEA, CK19 and CK20 were absent in some tumors. The selective HERG1 inhibitor E-4031 dose-dependently impaired tumor growth in the proliferation assays. DISCUSSION: Our data indicate that HERG1, but not CEA, CK19 or CK20, is a highly sensitive and reliable tumor biomarker that may constitute a novel molecular target for tumor treatment.