Pulse shape analysis in Gerda Phase II.

The GERmanium Detector Array (Gerda) collaboration searched for neutrinoless double- ß decay in 76 Ge using isotopically enriched high purity germanium detectors at the Laboratori Nazionali del Gran Sasso of INFN. After Phase I (2011-2013), the experiment benefited from several upgrades, including an additional active veto based on LAr instrumentation and a significant increase of mass by point-contact germanium detectors that improved the half-life sensitivity of Phase II (2015-2019) by an order of magnitude. At the core of the background mitigation strategy, the analysis of the time profile of individual pulses provides a powerful topological discrimination of signal-like and background-like events. Data from regular 228 Th calibrations and physics data were both considered in the evaluation of the pulse shape discrimination performance. In this work, we describe the various methods applied to the data collected in Gerda Phase II corresponding to an exposure of 103.7 kg year. These methods suppress the background by a factor of about 5 in the region of interest around Q ß ß = 2039  keV, while preserving ( 81 ± 3 ) % of the signal. In addition, an exhaustive list of parameters is provided which were used in the final data analysis.

Effect of cilobradine in cats with a first episode of congestive heart failure due to primary cardiomyopathy.

INTRODUCTION: Heart rate (HR) is often elevated in cats with cardiomyopathies (CMPs). Pharmacologic modulation of HR may reduce cardiac morbidity and mortality. OBJECTIVES: To investigate the effects of cilobradine vs. placebo, regarding time to cardiac mortality or morbidity in cats with first episode of congestive heart failure (CHF) due to primary CMP. ANIMALS: Three hundred and sixty-seven client-owned cats with primary CMP that had presented with a first episode of CHF at 50 centers in Europe. Per-protocol population comprised 193 cats (n = 89 cilobradine, n = 104 placebo). An interim analysis for futility was planned. METHODS: Prospective, randomized, placebo-controlled, double-blinded, multicenter clinical trial. Primary outcome variable was the time to a composite of cardiac mortality or cardiac morbidity. RESULTS: Median time to primary outcome was 84 days (95% confidence interval [CI]: 63-219 days) in the cilobradine group (CG) and 203 days in the placebo group (95% CI: 145-377 days) with observed hazard ratio of 1.44, indicating a higher hazard for the CG (P = 0.057). Mean HR was 28 beats per minute (bpm) lower at Day 7 (P < 0.0001) and remained 29 bpm lower at Day 360 (P = 0.026) in the CG than that in the placebo group. Although the number of adverse events did not differ, there were more serious adverse events in the CG. CONCLUSIONS: Heart rate reduction by cilobradine in cats with a first episode of CHF due to primary CMP did not reduce cardiac mortality and morbidity.

Examining the link between thoracic rotation and scapular dyskinesis and shoulder pain amongst college swimmers.

OBJECTIVES: In National Collegiate Athletic Association Division I swimmers, we examined the differences in thoracic spine rotation in swimmers with and without scapular dyskinesis and the relationship between thoracic spine rotation and shoulder pain/dysfunction according to the Kerlan-Jobe Orthopaedic Clinic (KJOC) score. DESIGN: Cross-sectional. SETTING: Laboratory-based. PARTICIPANTS: 34 NCAA Division I swimmers (13 males, 21 females). MAIN OUTCOME MEASURES: Self-reported upper extremity function and pain assessed with the KJOC questionnaire, thoracic spine range of motion, presence of scapular dyskinesis. RESULTS: Dyskinesis was present in 15 of 34 (44%) subjects. Thoracic rotation averaged 136.7° and KJOC averaged 87.7 with no differences between swimmers with or without dyskinesis. We observed no correlation between KJOC-identified shoulder pain/dysfunction and thoracic rotation. CONCLUSIONS: In our cohort of NCAA Division 1 swimmers, no differences were found between swimmers with or without scapular dyskinesis and extent of thoracic rotation. We found no correlation between thoracic rotation and the amount of self-reported pain and dysfunction experienced in the upper extremity. The presence of scapular dyskinesis in nearly half of our subjects indicates that swimmers need to be assessed for this abnormality. If observed, rehabilitation should address the dyskinesis and improve thoracic rotation in an attempt to alleviate further upper extremity pain and dysfunction.

Probing Majorana neutrinos with double-ß decay.

A discovery that neutrinos are Majorana fermions would have profound implications for particle physics and cosmology. The Majorana character of neutrinos would make possible the neutrinoless double-ß (0νßß) decay, a matter-creating process without the balancing emission of antimatter. The GERDA Collaboration searches for the 0νßß decay of 76Ge by operating bare germanium detectors in an active liquid argon shield. With a total exposure of 82.4 kg⋅year, we observe no signal and derive a lower half-life limit of T 1/2 > 0.9 × 1026 years (90% C.L.). Our T 1/2 sensitivity, assuming no signal, is 1.1 × 1026 years. Combining the latter with those from other 0νßß decay searches yields a sensitivity to the effective Majorana neutrino mass of 0.07 to 0.16 electron volts.

[Uveal Melanoma Cell Under Oxidative Stress - Influence of VEGF and VEGF-Inhibitors]. / Uveale Melanomzellen unter oxidativem Stress ­ Einfluss von VEGF und VEGF-Inhibitoren.

BACKGROUND: The role of oxidative stress in cancer is complex. While the pathological alterations induced by oxidative stress may be involved in the induction of tumours, in the late stages of tumour development, it can facilitate the loss of tumour cells and might even prevent metastasis. Tumour cells show metabolic alterations, often inducing an increased production of reactive oxygen species, which makes these cells particularly vulnerable to additional oxidative stress. This is an important mode of action in the use of many chemotherapeutics and in the application of ionizing radiation. Uveal melanoma is the most frequent primary tumour in the adult eye. For metastasis of this tumour, which affects about 50 % of the patients, no appropriate treatment is currently available. However, the primary tumour can efficiently be treated with ionizing radiation. A frequent side effect of this treatment is radiation retinopathy, which is treated with vascular endothelial growth factor (VEGF) antagonists. A therapy of the primary tumour with VEGF antagonists is under discussion. So far, little data is available on this subject, however, a paradoxical worsening of the situation has been found in a mouse model of uveal melanoma treated with bevacizumab. METHODS: We have investigated the effect of VEGF and of the VEGF-antagonist bevacizumab on the survival of five different melanoma cell lines under oxidative stress treatment with hydrogen peroxide. In addition, we investigated the expression of relevant proteins and the effect of bevacizumab on the proliferation of the cells as well as its effect on the angiogenic behaviour of endothelial cells, co-cultured with uveal melanoma cells. RESULTS: Our study showed that not only VEGF but also, paradoxically, the VEGF-antagonist bevacizumab is able to protect uveal melanoma cells from oxidative stress-induced cell death. Bevacizumab did not influence the proliferation of the cells and showed only limited effectiveness to reduce angiogenic structures. CONCLUSION: Considering that oxidative stress is the mode of action for ionizing radiation to induce cell death, a protective effect of bevacizumab on uveal melanoma cells against oxidative stress is worrisome and argues against the use of VEGF in uveal melanoma.

Historical bibliometric analysis of the top cited articles on vesicoureteral reflux 1950-2016, and incorporation of a novel impact index.

INTRODUCTION AND OBJECTIVES: Vesicoureteral reflux (VUR) has been one of the defining conditions unique to pediatric urology since its inception. The clinical implications of this disease process depend on intrinsic patient factors such as age, genetics, epigenetics, voiding habits, anatomic anomalies, and extrinsic factors such as the pathogenicity of infectious agents. Knowledge about its natural history, the implications of conservative and surgical management, and their associated outcomes have evolved dramatically over time. This study aimed to use bibliometric analyses to summarize the evolution of VUR management over time. In order to accomplish this, the most referenced articles for VUR since 1950 were identified, and a comprehensive analysis of their impact on the management and understanding of VUR was performed by creating a novel impact index. METHODS: A reference search was carried out for indexed citations through the portal 'Science Citation Index' in the subsection 'Web of Science Core Collection' using 'vesicoureteral reflux' as a MeSH term. References were analyzed and subcategorized according to various subtopics. A unique impact index was developed to adjust the number of publications for the time since publication, in order to define the impact of the paper amongst the most frequently cited papers. Articles were analyzed and data were tabulated according to the number of citations, country and institute of origin, journal of publication, impact factor, and first authorship. RESULTS: Citation counts ranged from 43 to 510, and the mean number of citations per publication was 101.43. The most discussed topic was 'treatment'. The impact index showed that more recent publications have a higher impact. The author with the highest index impact had 271 citations in a period of 5 years. The top 150 articles were published across 23 countries, the majority being from the USA (Summary fig.). The most frequently cited institution had 12 publications. The journal with the highest publication referencing rate was the Journal of Urology. CONCLUSION: The most cited articles were valuable sources of information to describe the historical evolution of the pathophysiology and management of VUR. After adjusting for time since publication, the most recent publications (i.e. those published after 1990) had a higher impact index. Combining traditional bibliometric analysis with this novel impact index may allow researchers to optimize future literature analyses, while also assisting clinicians in understanding best practices for patient management based on the available literature.

Improved Limit on Neutrinoless Double-ß Decay of

The GERDA experiment searches for the lepton-number-violating neutrinoless double-ß decay of ^{76}Ge (^{76}Ge→^{76}Se+2e^{-}) operating bare Ge diodes with an enriched ^{76}Ge fraction in liquid argon. The exposure for broad-energy germanium type (BEGe) detectors is increased threefold with respect to our previous data release. The BEGe detectors feature an excellent background suppression from the analysis of the time profile of the detector signals. In the analysis window a background level of 1.0_{-0.4}^{+0.6}×10^{-3} counts/(keV kg yr) has been achieved; if normalized to the energy resolution this is the lowest ever achieved in any 0νßß experiment. No signal is observed and a new 90% C.L. lower limit for the half-life of 8.0×10^{25} yr is placed when combining with our previous data. The expected median sensitivity assuming no signal is 5.8×10^{25} yr.

Application of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement to publications on endoscopic treatment for vesicoureteral reflux.

OBJECTIVE: Following an increasing number of submissions on endoscopic treatment of vesicoureteral reflux (VUR), the Journal of Pediatric Urology sought to establish a quality guideline that would enable reviewers to select the best papers for publication in the journal. The "Strengthening the Reporting of Observational Studies in Epidemiology" (STROBE) Statement, established in 2007, is a 22-item checklist designed to assist with clear reporting of observational studies. This checklist includes a description of methodological items and instructions on how to use them to transparently report observational studies. The aim of the present study was to apply the STROBE principle to observational studies about endoscopic management of VUR, and to establish a "check-list" to assist authors with good-quality submissions. STUDY DESIGN: The 22 STROBE criteria were listed and applied to publications on endoscopic treatment by utilizing examples from the current literature, with additional suggestions about how future studies could build upon the information already published on the subject. RESULTS: Based on this strategy, a checklist that is particular to endoscopic treatment studies was produced as a guideline for authors and reviewers. DISCUSSION: Application of the STROBE statement principles, in combination with key VUR data, will allow better quality submissions and a higher chance of positive reviews and acceptance rates.

Final efficacy and updated safety results of the randomized phase III BEATRICE trial evaluating adjuvant bevacizumab-containing therapy in triple-negative early breast cancer.

BACKGROUND: The purpose of this analysis was to assess the long-term impact of adding bevacizumab to adjuvant chemotherapy for early triple-negative breast cancer (TNBC). METHODS: Patients eligible for the open-label randomized phase III BEATRICE trial had centrally confirmed triple-negative operable primary invasive breast cancer (pT1a-pT3). Investigators selected anthracycline- and/or taxane-based chemotherapy for each patient. After definitive surgery, patients were randomized 1:1 to receive ≥4 cycles of chemotherapy alone or with 1 year of bevacizumab (5 mg/kg/week equivalent). Stratification factors were nodal status, selected chemotherapy, hormone receptor status, and type of surgery. The primary end point was invasive disease-free survival (IDFS; previously reported). Secondary outcome measures included overall survival (OS) and safety. RESULTS: After 56 months' median follow-up, 293 of 2591 randomized patients had died. There was no statistically significant difference in OS between treatment arms in either the total population (hazard ratio 0.93, 95% confidence interval [CI] 0.74-1.17; P = 0.52) or pre-specified subgroups. The 5-year OS rate was 88% (95% CI 86-90%) in both treatment arms. Updated IDFS results were consistent with the primary IDFS analysis. Five-year IDFS rates were 77% (95% CI 75-79%) with chemotherapy alone versus 80% (95% CI 77-82%) with bevacizumab. From 18 months after first study dose to study end, new grade ≥3 adverse events occurred in 4.6% and 4.5% of patients in the two arms, respectively. CONCLUSION: Final OS results showed no significant benefit from bevacizumab therapy for early TNBC. Late-onset toxicities were rare in both groups. Five-year OS and IDFS rates suggest that the prognosis for patients with TNBC is better than previously thought. CLINICALTRIALS.GOV: NCT00528567.

MicroRNAs 223-3p and 93-5p in patients with chronic kidney disease before and after renal transplantation.

Chronic kidney disease (CKD) is associated with a multifactorial dysregulation of bone and vascular calcification and closely linked to increased cardiovascular mortality and concomitant bone disease. We aimed to investigate specific microRNA (miRNA) signatures in CKD patients to find indicators for vascular calcification and/or bone mineralization changes during CKD and after kidney transplantation (KT). A miRNA array was used to investigate serum miRNA profiles in CKD patients, then selected miRNAs were quantified in a validation cohort comprising 73 patients in CKD stages 3 to 5, 67 CKD patients after KT, and 36 healthy controls. A spectrum of biochemical parameters including markers for kidney function, inflammation, glucose, and mineral metabolism was determined. The relative expression of miR-223-3p and miR-93-5p was down-regulated in patients with CKD stage 4 and 5 compared to healthy controls. This down-regulation disappeared after kidney transplantation even when lower glomerular filtration rates (eGFR) persisted. MiR-223-3p and miR-93-5p were associated with interleukin-6 (IL-6) and eGFR levels, and by trend with interleukin-8 (IL-8), C-peptide, hematocrit, and parathyroid hormone (PTH). This study contributes new knowledge of serum miRNA expression profiles in CKD, potentially reflecting pathophysiological changes of bone and calcification pathways associated with inflammation, vascular calcification, mineral and glucose metabolism. Identified miRNA signatures can contribute to future risk markers or future therapeutic targets in bone and kidney disease.

Detailed evaluation of the upper urinary tract in patients with prune belly syndrome using magnetic resonance urography.

INTRODUCTION: Magnetic resonance urography (MRU) has proven to be useful in the setting of complex urologic anatomy. Prune belly syndrome (PBS) patients are known to have malformed and highly variable urinary tract anatomy due to significant dilation and renal dysplasia. OBJECTIVE: To further characterize the renal and ureteral anatomy and renal function in patients with PBS via MRU. STUDY DESIGN: Children with PBS undergoing MRU (2006-2011) were identified. Studies were performed to evaluate severe hydronephrosis in all patients. Demographics, previous imaging, and MRU findings were collected. A single radiologist reviewed all studies. RESULTS: MRU was performed on 13 boys, with a median age of 29.3 months (IQR 6-97). Two patients underwent >1 study for ureteropelvic junction obstruction (UPJ obstruction) and calyceal diverticulum with a solitary kidney, respectively. Hydroureteronephrosis (HUN) was identified in 12 boys (92%), while one (8%) did not have ureteral dilation. All patients demonstrated morphologic abnormalities beyond HUN as follows: five (38%) renal dysplasia; five (38%) scarring; four (31%) calyceal diverticula; and three (23%) thickened bladder. The median renal transit time (RTT) was 6 min (IQR 3.5-10.5), and >8 min (range 8.5-35) in six patients; one patient was ultimately diagnosed with obstruction. The mean serum creatinine was 0.5 ± 0.3 mg/dl. This summary figure is a coronal excretory phase T1 MRU image demonstrating absence of well-defined calyces and a 5-cm calyceal diverticulum (white arrow). DISCUSSION: This study reports significant anatomic and functional findings on MRU that were not readily apparent when using standard imaging for children with PBS. The high-resolution images and functional data obtained with MRU allowed for visualization of calyceal diverticula and abnormal renal pelvic anatomy not previously described in PBS. In addition, renal dysplasia could be identified with MRU, which is badly characterized in the PBS population outside of renal biopsy studies. Potential limitations of the study included its nature as a small retrospective case series, which limited the ability to compare imaging modalities. Imaging modalities were based on individual clinical needs; therefore, comparison with diuretic renal scintigraphy was limited. CONCLUSION: MRU provided anatomic and functional details of the urinary tract in children with PBS that allowed for characterization of new renal anatomic abnormalities, including the incidence of calyceal diverticula and renal dysplasia, which have not been previously described. While renal scarring, dysplasia and calyceal diverticula were easily discerned on MRU in ten patients, their clinical significance requires longer follow-up in a larger patient population.

Diagnostic approach in lymphoplasmacytic plaque.

BACKGROUND: Lymphoplasmacytic plaque (LPP) is a recently described rare skin disease characterized by a dense dermal lymphohistiocytic infiltrate with polyclonal plasma cells. The clinical picture is distinct with reddish to brownish plaque with a predilection for the lower leg. LPP typically affects children. OBJECTIVE: To define clinical and histologic criteria of LPP and to develop a diagnostic flow chart. METHODS: We investigated six of our own LPP cases. Immunoglobulin light chains, IgG, IgG4, CD31, CD163 as a histiocytic marker were examined by immunohistochemistry. PCR-based molecular studies were conducted for borrelia sp., mycobacterial and leishmania sp. Moreover, 10 cases, which have been reported in the literature, were checked for the same features. RESULTS: We could differentiate three main histological patterns (superficial band-like only, [deep] dermal only and mixed). Acanthosis and interface dermatitis are key features in cases with a superficial band-like or mixed infiltrate. Granulomas and giant cells could be only found in about 30% of the cases. The number of plasma cells was variable accounting for 5-40% of the infiltrate. The number of blood vessels was increased in the majority of the cases. 'Free-floating' collagen bundles surrounded by histiocytes (pseudorosettes) were identified as a new histological feature. An infectious agent could be excluded in all cases. CONCLUSIONS: LPP is a long-standing skin disease, which may also occur in adults and in other body regions than the lower leg. Reproducible clinical and histological criteria allow delineating a diagnostic work-up for LPP.

Comparison of magnetic resonance urography to dimercaptosuccinic acid scan for the identification of renal parenchyma defects in children with vesicoureteral reflux.

OBJECTIVE: The objective of this study was to compare the accuracy of dimercaptosuccinic acid (DMSA) renal scan to magnetic resonance urography (MRU) in the identification of renal parenchyma defects (RPD). MATERIALS AND METHODS: Twenty-five children with history of acute pyelonephritis and vesicoureteral reflux underwent DMSA scan and MRU to determine the presence of RPD. DMSA scans and MRUs were each evaluated by two radiologists and agreement achieved by consensus. Discordant DMSA-MRU findings were re-evaluated in a side-by-side comparison and an ultimate consensus reached. RESULTS: The ultimate consensus diagnosis was 18 kidneys with RPDs in 15 patients, of which five were classified as mild RPDs, six as moderate RPDs, and seven as severe RPDs. Although DMSA scan and MRU were similar in their ability to diagnose RPDs, MRU was considered to represent the true diagnosis in 11 of the 12 discordant cases in consensus review by four pediatric radiologists. MRU showed a much higher inter-observer agreement with a weighted kappa of 0.96 for both kidneys compared to 0.71 for the right kidney and 0.86 for the left kidney by DMSA scan. CONCLUSIONS: Our results suggest that MRU is superior to DMSA scan in the identification of renal parenchyma defects.

The mTOR-inhibitor rapamycin mediates proteinuria in nephrotoxic serum nephritis by activating the innate immune response.

Rapamycin (Rapa) is an immunosuppressant used to prevent rejection in recipients of renal transplants. Its clinical use is limited by de novo onset or exacerbation of preexisting proteinuria. In the present study, Rapa administration was started 14 days after induction of murine nephrotoxic serum nephritis (NTS) to study glomerular effects of this mammalian target of rapamycin (mTOR) inhibitor. Glomeruli were laser-microdissected, and real-time PCR was performed to assess effects on glomerular cells and the expression of inflammatory cytokines. Immunohistochemical stainings were performed to confirm mRNA data on the protein level. Compared with nephritic control animals, Rapa-treated mice developed significantly increased albuminuria. This was accompanied by a more prominent glomerular infiltration by CD4(+) T cells and macrophages. Glomerular mRNA expression profiling revealed increased levels of the proinflammatory cytokines interleukin-6 and tumor necrosis factor-α, and the chemokines monocyte chemoattractant protein-1 and macrophage inflammatory protein-1ß and their cognate macrophage-associated receptors CCR2 and CCR5 in the Rapa-treated animals. Furthermore, there were elevated glomerular transcription levels of the regulatory T cell phenotype transcription factor Foxp3. No differences in the glomerular expression of the podocyte marker nephrin or the endothelial cell marker CD31 were observed on the mRNA or protein level. In conclusion, our data indicate that Rapa-induced proteinuria in NTS is a result of the activation of the innate immune system rather than a direct toxicity to podocytes or glomerular endothelial cells.

Vesico-ureteral reflux: a critical appraisal.

It has been nearly fifty years since J.M. Smellie published a seminal work that changed the landscape of vesicoureteral reflux when he reported the outcomes of 116 children with chronic pyelonephritis and the benefits of chemoprophylaxis. Even then, he conceded "the effectiveness of any form of treatment will be known only after prolonged follow-up". Forty-six years later, the answers to many questions remain elusive. The surfeit of available information continues to provoke controversy - from the presentation of reflux to the management thereof. We endeavor to survey the rocky landscape of vesicoureteral reflux and provide a critical appraisal of the available evidence and challenges for the future.

Elastic vibrations of a fiber due to impact of an aerosol particle and their influence on the efficiency of fibrous filters.

The excitation of sound vibrations of a cylindrical fine fiber due to the impact of a spherical aerosol particle is investigated. The equations describing the dynamics of impact are derived for an arbitrary shooting parameter. The coefficient of restitution is calculated, and its analytical approximation is obtained. It is shown, for the case of long fibers, that the coefficient of restitution depends upon a single parameter λ(c). The parameter λ(c) depends on the particle radial velocity component near the fiber surface, the mass of the particle, the density of the fiber, the modulus of elasticity, and the geometric parameters of the fiber and the particle. The inertial deposition of submicron aerosol particles on fine fibers in a filter is considered. The efficiency of filtration is studied as a function of the gas flow velocity. The existence of a critical flow velocity U(*), below which the losses of particle energy during collision have no effect on the efficiency, is demonstrated. For velocities higher than the critical velocity, the filtration efficiency is dependent on the mechanisms of nonelastic losses of the particle's energy. Its value can be significantly lower than that estimated when particle rebound effects are neglected. After they have rebounded, some particles are not able to attain the initial high velocities in the stream, thus depositing on neighboring fibers. The dynamics of these particles is investigated. For this case, it is shown that the filtration efficiency is dependent on the velocity distribution of the rebounded particles and that it increases with the packing density of fibers. A qualitative difference between the asymptotic behavior of a fiber and that of a flat plate is found long after the initial impulse.

The PTH (1-84)/non-PTH (1-84) ratio is a risk factor for cardiovascular events in hemodialysis patients.

BACKGROUND: We hypothesized that the PTH (1-84)/non-PTH (1-84) ratio (PTH ratio) might help to assess cardiovascular risk in hemodialysis patients. METHODS: In this prospective cohort study 70 prevalent hemodialysis patients were followed up to 4 years. The PTH ratio was determined at baseline. Primary outcomes were cardiovascular events (CVE) and all-cause mortality. Cumulative event-free survival was compared between patients with a ratio < 1 and those with a ratio > 1. The risk-association of the PTH ratio with CVE was examined using an adjusted Multiple Cox Proportional Hazards model. RESULTS: A PTH ratio > 1 was found in 34 patients (49%). During follow-up 26 patients suffered a CVE. Patients with a CVE showed a higher ratio than patients with event-free survival (p = 0.033). In patients with a ratio > 1 a significantly higher number of CVE occurred (53 vs. 22%; p = 0.013), and these patients showed a significantly shorter event-free survival (p = 0.032). In an adjusted Cox-proportional hazards model a higher PTH ratio was found to be independently associated with an elevated risk for CVE (HR = 3.2; 95% CI 1.06 - 13.63; p = 0.04). CONCLUSIONS: A higher PTH (1-84)/non-PTH (1-84) ratio is associated with an increased risk for CVE in hemodialysis patients and might therefore be useful for cardiovascular risk estimation in this population.