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Urinary tract infections (UTI) affect a large proportion of the population, causing among other symptoms, more frequent and urgent micturition. Previous studies reported that the gram-negative bacterial wall component lipopolysaccharides (LPS) trigger acute epithelial and bladder voiding responses, but the underlying mechanisms remain unknown. The cation channel TRPV4 is implicated in the regulation of the bladder voiding. Since TRPV4 is activated by LPS in airway epithelial cells, we sought to determine whether this channel plays a role in LPS-induced responses in urothelial cells (UCs). We found that human-derived UCs display a fast increase in intracellular Ca2+ concentration upon acute application of Escherichia coli LPS. Such responses were detected also in freshly isolated mouse UCs, and found to be dependent on TRPV4, but not to require the canonical TLR4 signaling pathway of LPS detection. Confocal microscopy experiments revealed that TRPV4 is dispensable for LPS-induced nuclear translocation of NF-κB in mouse UCs. On the other hand, quantitative RT PCR determinations showed an enhanced LPS-induced production of proinflammatory cytokines in TRPV4-deficient UCs. Cystometry experiments in anesthetized wild type mice revealed that acute intravesical instillation of LPS rapidly increases voiding frequency. This effect was not observed in TRPV4-deficient animals, but was largely preserved in Tlr4 KO and Trpa1 KO mice. Our results suggest that activation of TRPV4 by LPS in UCs regulates the proinflammatory response and contributes to LPS-induced increase in voiding frequency. These findings further support the concept that TRP channels are sensors of LPS, mediating fast innate immunity mechanisms against gram-negative bacteria. ispartof: FRONTIERS IN IMMUNOLOGY vol:11 ispartof: location:Switzerland status: published

Although hearing aids (HAs) are sometimes efficacious in abating tinnitus, the precise mechanism underlying their effect is unclear and predictors of symptom improvement have not been determined. Here, we examined the correlation between the amount of tinnitus improvement and pre-HA quantitative electroencephalography (qEEG) findings to investigate cortical predictors of improvement after wearing HAs. QEEG data of thirty-three patients with debilitating tinnitus were retrospectively correlated with the percentage improvements in tinnitus handicap inventory and the numerical rating scale scores of tinnitus. Activation of brain areas involved in the default mode network (DMN; inferior parietal lobule, parahippocampus, and posterior cingulate cortex) were found to be a negative predictor of improvement in tinnitus-related distress after wearing HAs. In addition, higher pre-HA cortical power at the medial auditory processing system or higher functional connectivity of the lateral/medial auditory pathway to the DMN was found to serve as a positive prognostic indicator with regard to improvement of tinnitus-related distress. In addition, insufficient activity of the pre-treatment noise canceling system tended to be a negative predictor of tinnitus perception improvement after wearing HAs. The current study may serve as a milestone toward a pre-HAs prediction strategy for tinnitus improvements in subjects with hearing loss and severe tinnitus.

OBJECTIVES: To create a rat model for neurogenic detrusor underactivity (DU) by bilateral pelvic nerve crush injury (BPNI) and to study temporal changes in detrusor contractility and morphology. METHODS: Male Sprague-Dawley rats were subjected to BPNI or sham surgery and evaluated 1, 3 and 9 weeks after surgery. Bladder function was determined in vivo by awake cystometry, micturition pattern analysis and 24-hours urine collection. Bladders were harvested for in vitro pharmacological investigation by isometric tension recording. Bladders and major pelvic ganglia were investigated by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and histochemistry. RESULTS: Overflow incontinence was observed 1 week after BPNI. At 3 and 9 weeks after BPNI, rats showed a bladder phenotype characteristic for DU with increased post-void residuals, reduced voiding efficiencies and lower maximum pressures. In isolated bladder strips, contractile responses to potassium chloride (KCl), carbachol and α,β-methylene adenosine 5'-triphosphate (α,β-mATP) were preserved. On the other hand, neural induced contractility was reduced after BPNI, in line with reduced expression of protein gene product 9.5 and choline acetyltransferase in the major pelvic ganglion 1 week after BPNI. Bladder-to-body weight ratio and detrusor thickness increased following BPNI, indicating detrusor hypertrophy to compensate for the reduced neural input. CONCLUSIONS: BPNI induces a rat model for neurogenic DU. In this model, the detrusor maintains its contractility but denervation of the detrusor was observed. This article is protected by copyright. All rights reserved. ispartof: BJU Int vol:123 issue:5A pages:E86-E96 ispartof: location:England status: Published online

In the present study, we use resting state fMRI to investigate whether nucleus accumbens (NAc) and extended frontostriatal networks are involved in the pathology of auditory phantom perception, i.e., tinnitus, through a study of functional connectivity. We hypothesize that resting state functional connectivity involving NAc will be increased relative to what is observed in healthy subjects and that this connectivity will correlate with clinical measures of tinnitus such as percept loudness, duration of symptoms, etc. We show that a large sample of patients with chronic tinnitus (n = 90) features extensive functional connectivity involving NAc that is largely absent in healthy subjects (n = 94). We further show that connectivity involving NAc correlates significantly with tinnitus percept loudness and the duration of tinnitus symptoms, even after controlling for the effects of age and hearing loss. The loudness correlation, which involves NAc and parahippocampal cortex, is consistent with existing literature identifying the parahippocampus as a tinnitus generator. Our results further suggest that frontostriatal connectivity may predict the transition from acute to chronic tinnitus, analogous to what is seen in the pain literature. We discuss these ideas and suggest fruitful avenues for future research.

INTRODUCTION: Clinical Networks are complex interventions that enable healthcare professionals from various disciplines to work in a coordinated manner in the context of multiple care settings, to provide a high quality response to a specific disease. The aim of this study was to evaluate if clinical networks are able to improve effectiveness, efficiency, patients' satisfaction and professionals' behavior in the health care settings, namely the "quadruple aim" quality goals. MATERIALS AND METHODS: A systematic review of documents published until February 28, 2018, in Medline, Embase and CINAHL was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses approach. A specific research strategy was created to identify studies evaluating effectiveness, efficiency, patient satisfaction and professionals well-being obtained through clinical networks implementation. RESULTS: 14249 studies were identified; 12 of these were eligible to the evaluation of "Quadruple Aim" outcomes. 9 studies focused on patients' outcomes improvement and 4 on network efficiency. Professionals' and patients' experience were not considered in any study. CONCLUSIONS: There are some evidences that clinical network can improve patients' outcomes and health funds allocation in a small number of moderate-low quality studies. Further rigorous studies are needed to confirm these findings and to evaluate patients' and professionals' experience, taking into account also networks' structural features that could influence outcomes achievement. ispartof: Journal of Healthcare Quality Research vol:34 issue:1 pages:29-39 ispartof: location:Spain status: published

ZusammenfassungMutationen des hepatocyte nuclear factor 1 α-(HNF1α) Gens lösen einen MODY3-Diabetes aus und sind mit einer hepatozellulären Adenomatose assoziiert. Eine maligne Transformation von HNF1α-mutierten hepatozellulären Adenomen ist selten. Wir beschreiben hier den Fall eines 28-jährigen Mannes mit heterozygoter HNF1α-Keimbahnmutation mit MODY3-Diabetes und einer hepatozellulären Adenomatose mit multiplen, HNF1α-inaktivierten Adenomen, der ein inflammatorisches Adenom mit β-Catenin-Mutation mit maligner Transformation in ein gut differenziertes hepatozelluläres Karzinom (HCC) entwickelte.

The recent trend is towards value-based healthcare, which is characterized by the relationship between quality of care and the associated costs. However, value in healthcare is a largely unmeasured and misunderstood concept. In particular, a definition of multi-stakeholder value in healthcare decision-making is missing. In this case study, we review the radical prostatectomy procedure because previous studies have shown discrepancies between what the patient’s value most and what the experts think the patient’s value most. The objective of this research is to address this gap by identifying a multi-stakeholder definition of value which will improve healthcare decision-making. Multi-criteria decision-making (MCDM) techniques, more specifically the Analytic Hierarchy Process (AHP), are applied to prioritize the quality of care indicators according to the following six pillars of quality: safety, effectiveness, efficiency, timeliness, patient-centeredness and equity. In addition, the average cost of a radical prostatectomy is estimated. A distinction is made between three treatment stages in order to calculate the overall quality score by assigning weights to criteria in each treatment stage. According to the AHP weights, the pillars of effective, patient-centered and equitable care contribute the most to value creation. Finally, some of the challenges of MCDM studies are addressed, such as conflicting preferences between stakeholder groups. In conclusion, this case study stresses the need to adapt operational research methods and knowledge to be applied in value-based healthcare. The AHP is a suitable approach to address the needs of healthcare decision-makers, to set priorities, and to identify value improvement opportunities while considering all of the stakeholders involved in the full care cycle.

INTRODUCTION AND OBJECTIVE:Membranous urethral length (MUL), measured via MRI, is one of the variables that can contribute to continence recovery (CR). However, to date, there is lack of consensus ...

INTRODUCTION AND OBJECTIVE:Molecular classification of muscle invasive bladder cancer (MIBC) has revealed several subtypes, with luminal and basal as most distinct. A consensus is arising that at I...

INTRODUCTION AND OBJECTIVE:The efficacy of NoS for treatment of stress urinary incontinence (SUI) after prostatic surgery (PS) has been well established in patients not exposed to radiotherapy (RT)...

Neurofeedback is going through a renaissance. Advances in brain imaging and computing have renewed efforts to modify brain activity and behaviour using this technique. Here, over 80 neurofeedback researchers present a consensus-derived checklist – CRED-nf – for reporting and experimental design standards in the field., Neurofeedback has begun to attract the attention and scrutiny of the scientific and medical mainstream. Here, neurofeedback researchers present a consensus-derived checklist that aims to improve the reporting and experimental design standards in the field.

Tinnitus, the perception of a phantom sound, is accompanied by loudness and distress components. Distress however accompanies not just tinnitus, but several disorders. Several functional connectivity studies show that distress is characterized by disconnectivity of fronto-limbic circuits or hyperconnectivity of default mode/salience networks. The drawback, however, is that it considers only the magnitude of connectivity, not the direction. Thus, the current study aims to identify the core network of the domain-general distress component in tinnitus by comparing whole brain directed functional networks calculated from 5 min of resting state EEG data collected from 310 tinnitus patients and 256 non-tinnitus controls. We observe a reorganization of the overall tinnitus network, reflected by a decrease in strength and efficiency of information transfer between fronto-limbic and medial temporal regions, forming the main hubs of the tinnitus network. Further, a disconnection amongst a subset of these connections was observed to correlate with distress, forming a core distress network. The core distress network showed a decrease in strength of connections specifically going from the left hippocampus/parahippocampus to the subgenual anterior cingulate cortex. Such a disconnection suggests that the parahippocampal contextual memory has little influence on the (paradoxical) value that is attached to the phantom sound and that distress is the consequence of the absence of modulation of the phantom sound.

Auditory phantom percepts such as tinnitus are associated with auditory deafferentation. The idea is that auditory deafferentation limits the amount of information the brain can acquire to make sense of the world. Because of this, auditory deafferentation increases the uncertainty of the auditory environment. To minimize uncertainty, the deafferented brain will attempt to obtain or fill in the missing information. A proposed multiphase compensation model suggests two distinct types of bottom-up related tinnitus: an auditory cortex related tinnitus and a parahippocampal cortex related tinnitus. The weakness of this model is that it cannot explain why some people without hearing loss develop tinnitus, whereas conversely others with hearing loss do not develop tinnitus. In this human study, we provide evidence for a top-down type of tinnitus associated with a deficient noise-cancelling mechanism. A total of 72 participants (age: 40.96 ± 7.67 years; males: 48; females: 24) were recruited for this study. We demonstrate that top-down related tinnitus is related to a change in the pregenual anterior cingulate cortex that corresponds to increased activity in the auditory cortex. This is in accordance with the idea that tinnitus can have different generators as proposed in a recent model that suggests that different compensation mechanisms at a cortical level can be linked to phantom percepts.SIGNIFICANCE STATEMENTChronic tinnitus affects 15% of the population worldwide. The term “tinnitus” however represents a highly heterogeneous condition, as evidenced by the fact that there are no effective treatments or even an adequate understanding of the underlying neural mechanisms. Consistent with this idea, our research shows that tinnitus indeed has different subtypes related to hearing loss. In a human study tightly controlled for hearing loss, we establish a tinnitus subtype associated with a deficient top-down noise-cancelling mechanism, which distinguishes it from bottom-up subtypes. We demonstrate that top-down related tinnitus relates to a change in the pregenual anterior cingulate cortex that corresponds to increased activity in the auditory cortex, whereas bottom-up tinnitus instead relates to changes in the parahippocampal cortex.

BACKGROUND: Fibromyalgia is a chronic disorder characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, memory, and mood problems. Recently, occipital nerve field stimulation (ONS) has been proposed as an effective potential treatment for fibromyalgia-related pain. The aim of this study is to unravel the neural mechanism behind occipital nerve stimulation's ability to suppress pain in fibromyalgia patients. MATERIALS AND METHODS: Seven patients implanted with subcutaneous electrodes in the C2 dermatoma were enrolled for a Positron Emission Tomography (PET) H215O activation study. These seven patients were selected from a cohort of 40 patients who were part of a double blind, placebo-controlled study followed by an open label follow up at six months. The H215O PET scans were taken during both the "ON" (active stimulation) and "OFF" (stimulating device turned off) conditions. Electroencephalogram (EEG) data were also recorded for the implanted fibromyalgia patients during both the "ON" and "OFF" conditions. RESULTS: Relative to the "OFF" condition, ONS stimulation resulted in activation in the dorsal lateral prefrontal cortex, comprising the medial pain pathway, the ventral medial prefrontal cortex, and the bilateral anterior cingulate cortex as well as parahippocampal area, the latter two of which comprise the descending pain pathway. Relative deactivation was observed in the left somatosensory cortex, constituting the lateral pain pathway as well as other sensory areas such as the visual and auditory cortex. The EEG results also showed increased activity in the descending pain pathway. The pregenual anterior cingulate cortex extending into the ventral medial prefrontal cortex displayed this increase in the theta, alpha1, alpha2, beta1, and beta2 frequency bands. CONCLUSION: PET shows that ONS exerts its effect via activation of the descending pain inhibitory pathway and the lateral pain pathway in fibromyalgia, while EEG shows activation of those cortical areas that could be responsible for descending inhibition system recruitment. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov , number NCT00917176 (June 10, 2009). ispartof: BMC NEUROLOGY vol:18 issue:1 ispartof: location:England status: published

The posteromedial cortex (PMC)-comprising posterior cingulate cortex (PCC), retrosplenial cortex (RSC), and the precuneus (PrC)-is perhaps best known for its involvement in the default mode network. There is no consensus regarding the specific functions of PMC, however, and its component regions each exhibit distinct, but partially overlapping functional profiles. To date, there has been minimal effort to disentangle the functions of these regions. In the present study, we use Neurosynth ( http://neurosynth.org ) to conduct an unbiased meta-analysis of the PMC based on fMRI coactivation and semantic information extracted from 11,406 studies. Our analyses revealed six PMC clusters with distinct functional profiles: superior and inferior dorsal PCC, anterior and posterior PrC, ventral PCC, and RSC. We discuss these findings in the context of the existing literature and suggest several fruitful avenues for continued research.

OBJECTIVE To evaluate the effectiveness and tolerance of the AdVance Male Sling System for the treatment of male stress urinary incontinence in patients after prostatic surgery. METHODS An international, observational, prospective, multicenter study was conducted on male patients with urinary incontinence after prostatic surgery. Patients underwent a 24-hour pad test with a threshold at 250 g. All patients were operated with the same AdVance implant procedure. They were seen 6 weeks later, and examined again at 3, 6, 12, and 24 months. Incontinence was measured using 1-hour and 24-hour pad tests, the number of protective pads used, ICIQ-SF and IQoL questionnaires. Success was defined as no urinary leakage and no pad use. Patient improvement was defined as a reduction of more than 50% in leakage and no more than one pad used per day. Any perioperative and late complications were documented. RESULTS From January 2007 to November 2012, 113 patients were successfully operated on. At 24 months after surgery, the mean weight of the 1-hour pad test had decreased from 48.7 g to 6.6 g (P < 0.001) while that of the 24-hour pad test decreased to 45.0 g from 113.9 g (P < 0.001). Success and improvement occurred in 22.6% and 58.0% of the patients, respectively. Seventy-five patients (80.6%) used none or one protective pad daily, and the IQoL and ICIQ-SF scores were both significantly improved. Fourteen patients (12.4%) required a second intervention. Three patients (2.7%) had a Clavien IIIb complication. CONCLUSION The AdVance Male Sling System is an effective treatment for mild to moderate male stress urinary incontinence. Complications from its use are rare and 24-month results are satisfactory.

BACKGROUND: Improvement of bladder emptying by modulating afferent nerve activity is an attractive therapeutic strategy for detrusor underactivity. Transient receptor potential vanilloid 4 (TRPV4) is a sensory ion channel in urothelial cells that contribute to the detection of bladder filling. OBJECTIVE: To investigate the potential benefit of intravesical TRPV4 agonists in a pelvic nerve injury rat model for detrusor underactivity. DESIGN, SETTING, AND PARTICIPANTS: Female wild-type and Trpv4 knockout rats underwent sham surgery or bilateral pelvic nerve injury (bPNI). Four weeks later, rats underwent cystometry with infusion of the TRPV4 agonist GSK1016790A. Bladders were harvested for in vitro pharmacological studies, quantitative reverse polymerase chain reaction and immunohistochemistry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Data are expressed as median ± interquartile range. Statistical comparisons were made using the Mann-Witney U test and Wilcoxon signed rank test as appropriate. RESULTS AND LIMITATIONS: Rats with bPNI showed a phenotype characteristic of detrusor underactivity with lower-amplitude voiding contractions, decreased voiding frequency, and increased postvoid residual. Intravesical application of GSK1016790A increased voiding frequency and reduced postvoid residual in wild-type, but not Trpv4-/-, rats. In isolated bladder strips, GSK1016790A did not induce relevant contractions, indicating that the observed improvements in bladder function are the result of increased afferent signalling through TRPV4 activation, rather than a local effect on the detrusor. The altered urinary phenotype of Trpv4-/- mice was not apparent in the Trpv4-/- rat model, suggesting species-related functional variations. Our results are limited to the preclinical setting in rodents. CONCLUSIONS: Intravesical activation of TRPV4 improves bladder dysfunction after bPNI by increasing afferent signalling. PATIENT SUMMARY: We demonstrate that the sensory protein transient receptor potential vanilloid 4 (TRPV4) can be targeted to improve bladder function in animals that have iatrogenic injury to the nerves innervating the bladder. Further research is required to determine whether these results can be translated to patients with an underactive bladder. ispartof: EUROPEAN UROLOGY vol:74 issue:3 pages:336-345 ispartof: location:Switzerland status: published

Early and moderate Parkinson’s disease patients seem to have attention dysfunctions manifested differentially in separate attention streams: top-down and bottom-up. With a focus on the neurophysiological underpinnings of such differences, this study evaluated source-localized regional activity and functional connectivity of regions in the top-down and bottom-up streams as well as any discordance between the two streams. Resting state electroencephalography was used for 36 Parkinson’s disease patients and 36 healthy controls matched for age and gender. Parkinson’s disease patients showed disproportionally higher bilateral gamma activity in the bottom-up stream and higher left alpha2 connectivity in the top-down stream when compared to age-matched controls. An additional cross-frequency coupling analysis showed that Parkinson’s patients have higher alpha2-gamma coupling in the right posterior parietal cortex, which is part of the top-down stream. Higher coupling in this region was also associated with lower severity of motor symptoms in Parkinson’s disease. This study provides evidence that in Parkinson’s disease, the activity in gamma frequency band and connectivity in alpha2 frequency band is discordant between top-down and bottom-up attention streams.

Tinnitus is the perception of a phantom sound characterized behaviorally by a loudness and a distress component. Although a wealth of information is available about the relationship between these behavioral correlates and changes in static functional connectivity, its relationship with dynamic changes in network connectivity is yet unexplored. The aim of this study was thus to investigate changes in the flexibility and stability of temporal variability in tinnitus and its relation to loudness and distress using continuous resting-state EEG. We observe an increase in temporal variability at the whole-brain level in tinnitus, which is spatiotemporally distributed at the nodal level. Behaviorally, we observe changes in the relationship between temporal variability and loudness and distress depending on the amount of distress experienced. In patients with low distress, there is no relationship between temporal variability and loudness or distress, demonstrating a resilience in dynamic connectivity of the brain. However, patients with high distress exhibit a direct relationship with increasing loudness in the primary auditory cortex and parahippocampus, and an inverse relationship with increasing distress in the parahippocampus. In tinnitus, the specific sensory (loudness) component related to increased temporal variability possibly reflects a Bayesian search for updating deafferentation-based missing information. On the other hand, the decreased temporal variability related to the nonspecific distress component possibly reflects a more hard-wired or less adaptive contextual processing. Therefore, our findings may reveal a way to understand the changes in network dynamics not just in tinnitus, but also in other brain disorders.

The pelvic floor is at an increased risk of damage during the lifespan of women. Pregnancy, vaginal delivery, aging, menopause, previous pelvic surgery, and lifestyle factors have a negative influence on the connective tissue and muscular components of the pelvic floor leading to urinary incontinence (UI). Pregnancy and vaginal delivery have been identified as the most important risk factors for incontinence. Cystocele, rectocele, uterine, vault prolapse, and/or incontinence can occur due to lacerations of the connective tissue support at different levels. Moreover, muscular damage of the levator complex can lead to widening of the levator hiatus, giving way to the descent of pelvic organs resulting in UI. Although some genetic abnormalities have been identified, their clinical implications remain unclear. Diagnostic evaluations should be performed in accordance with established evidence-based guidelines. Although short-term results of single-incision midurethral slings indicate similar efficacy to conventional midurethral slings, their long-term outcome is still not determined. Scientists continue to investigate the exact causes of stress UI as well as the optimum substitute material using the best surgical reconstructive approach. The recent European Association of Urology consensus statement underlines an imperative requirement for an optimal solution using minimal amount of material related to the indication and higher competence of surgeons for this surgery. High-quality trials with a longer follow-up are currently an unmet need.

Thalamocortical dysrhythmia (TCD) is a model proposed to explain divergent neurological disorders. It is characterized by a common oscillatory pattern in which resting-state alpha activity is replaced by cross-frequency coupling of low- and high-frequency oscillations. We undertook a data-driven approach using support vector machine learning for analyzing resting-state electroencephalography oscillatory patterns in patients with Parkinson’s disease, neuropathic pain, tinnitus, and depression. We show a spectrally equivalent but spatially distinct form of TCD that depends on the specific disorder. However, we also identify brain areas that are common to the pathology of Parkinson’s disease, pain, tinnitus, and depression. This study therefore supports the validity of TCD as an oscillatory mechanism underlying diverse neurological disorders., Thalamocortical dysrhythmia has been proposed to occur in a number of neurological and psychiatric disorders. Here, the authors use a data-driven approach to demonstrate thalamocortical dysrhythmia occurs in individuals with Parkinson’s disease, neuropathic pain, tinnitus, and depression.

Context Neuromodulation is considered in patients with non-neurogenic lower urinary tract dysfunction (LUTD) not responsive to conservative treatment. Objective To systematically review the available studies on efficacy and safety of sacral neuromodulation (SNM) and percutaneous tibial nerve stimulation (PTNS) in non-neurogenic LUTDs not responsive to conservative treatments. Evidence acquisition A literature research was conducted in PubMed/Medline and Scopus, restricted to articles in English, published between January 1998 and June 2017, with at least 20 patients and 6 mo of follow-up. Evidence synthesis Twenty-one reports were identified. Concerning SNM, the improvement of ≥50% in leakage episodes ranged widely between 29% and 76%. Overall dry rate ranged between 43% and 56%. Overall success/improvement rate in PTNS varied between 54% and 59%. Symptom improvement or efficacy in interstitial cystitis/bladder pain syndrome patients appeared to be lower compared with other indications in both techniques. Safety data showed fewer side effects in patients submitted to PTNS. Conclusions Neuromodulation gives good results and is a safe therapy for patients with overactive bladder or chronic nonobstructive urinary retention with long-lasting efficacy. Moreover, PTNS has been shown to have good success rates and fewer side effects compared with SNM. These data have to be confirmed with long-term follow-up. Patient summary Sacral neuromodulation can improve low urinary tract symptoms in selected patients; it appears to be a safe therapy for nonresponders to standard medical therapies. Percutaneous tibial nerve stimulation (PTNS) is a less invasive technique that gives good results in short time with fewer side effects. However, we must consider that PTNS has not been tested in the long term and results are lower if compared with SNM.

Simple Summary Chronic inflammation is known to drive cancer initiation and progression in the liver and other organs. In different genetic mouse models, the role of the pro-inflammatory kinase Tak1 in liver cancer development has been controversial so far. To clarify the role of Tak1 in human hepatocellular carcinoma (HCC), we investigated the expression of Tak1 in a large and clinicopathologically well-characterized patient cohort with HCC. In human livers and HCCs, Tak1 is predominantly present in its isoform Tak1A localizing to the cell nucleus. Tak1 is upregulated in HCCs of the diethylnitrosamine mouse model as well as in human HCCs, independent of etiology, and is further induced in distant metastases. Overexpression of the isoform Tak1A in the HCC cell line Huh7 resulted in increased tumor cell migration, whereas overexpression of full-length Tak1 had no significant effect. In human HCCs, high nuclear Tak1 expression is associated with vascular invasion and short overall survival. Abstract Although knowledge on inflammatory signaling pathways driving cancer initiation and progression has been increasing, molecular mechanisms in hepatocarcinogenesis are still far from being completely understood. Hepatocyte-specific deletion of the MAPKKK Tak1 in mice recapitulates important steps of hepatocellular carcinoma (HCC) development, including the occurrence of cell death, steatohepatitis, dysplastic nodules, and HCCs. However, overactivation of Tak1 in mice upon deletion of its deubiquitinase Cyld also results in steatohepatitis and HCC development. To investigate Tak1 and Cyld in human HCCs, we created a tissue microarray to analyze their expression by immunohistochemistry in a large and well-characterized cohort of 871 HCCs of 561 patients. In the human liver and HCC, Tak1 is predominantly present as its isoform Tak1A and predominantly localizes to cell nuclei. Tak1 is upregulated in diethylnitrosamine-induced mouse HCCs as well as in human HCCs independent of etiology and is further induced in distant metastases. A high nuclear Tak1 expression is associated with short survival and vascular invasion. When we overexpressed Tak1A in Huh7 cells, we observed increased tumor cell migration, whereas overexpression of full-length Tak1 had no significant effect. A combined score of low Cyld and high Tak1 expression was an independent prognostic marker in a multivariate Cox regression model.

Interstitial cells (ICs) are thought to play a functional role in urinary bladder. Animal models are commonly used to elucidate bladder physiology and pathophysiology. However, inter-species comparative studies on ICs are rare. We therefore analyzed ICs and their distribution in the upper lamina propria (ULP), the deeper lamina propria (DLP) and the detrusor muscular layer (DET) of human, guinea pig (GP) and pig. Paraffin slices were examined by immunohistochemistry and 3D confocal immunofluorescence of the mesenchymal intermediate filament vimentin (VIM), alpha-smooth muscle actin (αSMA), platelet-derived growth factor receptor alpha (PDGFRα) and transient receptor potential cation channel A1 (TRPA1). Image stacks were processed for analysis using Huygens software; quantitative analysis was performed with Fiji macros. ICs were identified by immunoreactivity for VIM (excluding blood vessels). In all species ≥ 75% of ULP ICs were VIM+/PDGFRα+ and ≥ 90% were VIM+/TRPA1+. In human and pig ≥ 74% of ULP ICs were VIM+/αSMA+, while in GP the percentage differed significantly with only 37% VIM+/αSMA+ ICs. Additionally, over 90% of αSMA+ ICs were also TRPA1+ and PDGFRα+ in human, GP and pig. In all three species, TRPA1+ and PDGFRα+ ICs point to an active role for these cells in bladder physiology, regarding afferent signaling processes and signal modification. We hypothesize that decline in αSMA-positivity in GP reflects adaptation of bladder histology to smaller bladder size. In our experiments, pig bladder proved to be highly comparable to human urinary bladder and seems to provide safer interpretation of experimental findings than GP.

OBJECTIVES: To create an animal model for neurogenic underactive bladder disease (UAB) and identify markers to describe secondary myogenic changes in the bladder wall. MATERIALS AND METHODS: Male rats underwent either bilateral pelvic nerve injury or sham surgery. Four weeks after surgery functional evaluation was performed and tissue was harvested. Functional evaluation consisted of analysis of voiding pattern, 24-h urine collection in a metabolic cage, in vivo cystometry and in-vitro contractile function assessment. PCR and immunohistochemical localization of different smooth muscle cell and extracellular matrix markers was performed on bladder strips. RESULTS: After pelvic nerve injury, dry bladder weight increased and voiding contractions were absent, resulting in overflow incontinence. In-vitro contractile response to carbachol was decreased. This was paired with an upregulation of synthetic smooth muscle cell (SMC) markers mRNA expression such as retinol binding protein 1 (RBP1), myosin 10 (MYH10) and osteopontin (OPN), and a downregulation of contractile SMC marker smoothelin (SMTL). The SMTL/OPN mRNA ratio was 50 times higher in sham bladders compared to PNI bladders. CONCLUSIONS: The loss of in-vivo and in-vitro contractile function following pelvic nerve transection is characterized by a switch from a contractile to synthetic SMC phenotype, which is best characterized by the ratio SMTL/OPN mRNA expression. Modulating this phenotypical switch is a potential target for the development of UAB therapy. We suggest for the first time a set of markers that may be useful to evaluate therapeutic strategies on improvements in bladder wall structure. ispartof: NEUROUROLOGY AND URODYNAMICS vol:37 issue:5 pages:1594-1604 ispartof: location:United States status: published

Background In this study we are using source localized neurofeedback to moderate tinnitus related distress by influencing neural activity of the target region as well as the connectivity within the default network. Hypothesis We hypothesize that up-training alpha and down-training beta and gamma activity in the posterior cingulate cortex has a moderating effect on tinnitus related distress by influencing neural activity of the target region as well as the connectivity within the default network and other functionally connected brain areas. Methods Fifty-eight patients with chronic tinnitus were included in the study. Twenty-three tinnitus patients received neurofeedback training of the posterior cingulate cortex with the aim of up-training alpha and down-training beta and gamma activity, while 17 patients underwent training of the lingual gyrus as a control situation. A second control group consisted of 18 tinnitus patients on a waiting list for future tinnitus treatment. Results This study revealed that neurofeedback training of the posterior cingulate cortex results in a significant decrease of tinnitus related distress. No significant effect on neural activity of the target region could be obtained. However, functional and effectivity connectivity changes were demonstrated between remote brain regions or functional networks as well as by altering cross frequency coupling of the posterior cingulate cortex. Conclusion This suggests that neurofeedback could remove the information, processed in beta and gamma, from the carrier wave, alpha, which transports the high frequency information and influences the salience attributed to the tinnitus sound. Based on the observation that much pathology is the result of an abnormal functional connectivity within and between neural networks various pathologies should be considered eligible candidates for the application of source localized EEG based neurofeedback training., Graphical abstract Image 1

Immunotherapy is gradually becoming a key factor in the therapeutic algorithm for patients with genito-urinary (GU) cancers at different stages of disease. Robust and reliable biomarkers are crucial for an appropriate inclusion of patients in clinical trials and for a reliable patient selection for treatments with immunomodulatory drugs. The increasing knowledge on the genomic landscape of GU cancers supports stratification of patients for targeted therapies. This review focusses on emerging biomarkers and the role of genomics in predicting clinical benefit to immunomodulatory agents in GU cancers. Based on cancer incidences and available data we restricted this overview to bladder, prostate and renal cancer.

Dysfunctional neural activity in the cortical reward system network has been implicated in food addiction. This is the first study exploring the potential therapeutic effects of high definition transcranial pink noise stimulation (HD-tPNS) targeted at the anterior cingulate cortex (ACC) on craving and brain activity in women with obesity who showed features of food addiction (Yale Food Addiction Scale score of ≥3). Sixteen eligible females participated in a randomized, double-blind, parallel group study. Participants received six 20-minute sessions of either 1 mA (n = 8) or sham (n = 8) stimulation with HD-tPNS over two weeks. Anode was placed above the ACC (Fz) with 4 cathodes (F7, T3, F8, and T4). Food craving was assessed using the Food Cravings Questionnaire State (FCQ-S) and brain activity was measured using electroencephalogram (EEG). Assessments were at baseline, and two days, four weeks, and six weeks after stimulation. A 22% decrease (mean decrease of −1.11, 95% CI -2.09, −0.14) was observed on the 5-point ‘intense desire to eat’ subscale two days after stimulation in the HD-tPNS group compared to sham. Furthermore, whole brain analysis showed a significant decrease in beta 1 activity in the ACC in the stimulation group compared to sham (threshold 0.38, p = 0.04). These preliminary findings suggest HD-tPNS of the ACC transiently inhibits the desire to eat and, thus, warrants further examination as a potential tool in combating food craving.

Objective: Incontinentia pigmenti (IP) is a genetic disease leading to severe neurological symptoms, such as epileptic seizures, but no specific treatment is available. IP is caused by pathogenic variants that inactivate the Nemo gene. Replacing Nemo through gene therapy might provide therapeutic benefits. Methods: In a mouse model of IP we administered a single intravenous dose of the AAV vector AAV-BR1-CAG-NEMO delivering the Nemo gene to the brain endothelium. Spontaneous epileptic seizures and the integrity of the BBB were monitored. Results: The endothelium-targeted gene therapy improved the integrity of the blood-brain barrier. In parallel, it reduced the incidence of seizures and delayed their occurrence. Neonate mice intravenously injected with the AAV-BR1-CAG-NEMO vector developed no hepatocellular carcinoma or other major adverse effects 11 months after vector injection, demonstrating that the vector has a favorable safety profile. Interpretation: The data show that the blood-brain barrier is a target of antiepileptic treatment and more specifically provide evidence for the therapeutic benefit of a brain endothelial-targeted gene therapy in IP. This article is protected by copyright. All rights reserved.

Midurethral sling procedures are the first surgical option in women undergoing surgery for stress urinary incontinence (SUI). Single-incision midurethral-slings (SIMS) were designed to provide similar efficacy to traditional midurethral slings but with reduced morbidity. In this international trial we compared the efficacy of a SIMS (MiniArc) and a transobturator standard midurethral sling (SMUS; Monarc) in the treatment of SUI in terms of subjective and objective cure rates and morbidity over a long-term follow-up. This was a randomized controlled nonblinded extended trial with a follow-up period of 36 months. Women with symptomatic SUI were eligible. The primary outcome was subjective cure, defined as an improvement in the Patient Global Impression of Improvement (PGI-I) score. Secondary outcomes were objective cure (negative cough stress test), disease-specific quality of life, surgical parameters and morbidity. An intention to treat analysis was performed. Differences in dichotomous variables were tested using the chi-squared test. Differences in continuous variables were tested using Student’s t test or the Mann-Whitney U test. We hypothesized that MiniArc would be noninferior to Monarc concerning subjective cure. We randomized 97 women to the MiniArc group and 96 to the Monarc group. The attrition rate was 23% in the MiniArc group and 22% in the Monarc group after 3 years. At 36 months, the subjective cure rates were 86% in the MiniArc group and 87% in the Monarc group (risk difference −0.6%, 95% CI −12 to 11%). The objective cure rates were 89% and 88%, respectively (risk difference 1.3%, 95% CI −9 to 11%). Both procedures were associated with low complication rates. After a follow-up of 36 months, MiniArc (SIMS) is non-inferior to Monarc (SMUS) with respect to subjective and objective cure.

Fibromyalgia is a disorder characterized by widespread musculoskeletal pain frequently accompanied by other symptoms such as fatigue. Moderate improvement from pharmacological and non-pharmacological treatments have proposed non-invasive brain stimulation techniques such as transcranial direct current stimulation (tDCS) to the occipital nerve (more specifically the C2 area) or to the dorsolateral prefrontal cortex (DLPFC) as potential treatments. We aimed to explore the effectiveness of repeated sessions of tDCS (eight sessions) targeting the C2 area and DLPFC in reducing fibromyalgia symptoms, more specifically pain and fatigue. Forty-two fibromyalgia patients received either C2 tDCS, DLPFC tDCS or sham procedure (15 C2 tDCS-11 DLPFC tDCS-16 sham). All groups were treated with eight sessions (two times a week for 4 weeks). Our results show that repeated sessions of C2 tDCS significantly improved pain, but not fatigue, in fibromyalgia patients, whereas repeated sessions of DLPFC tDCS significantly improved pain as well as fatigue. This study shows that eight sessions of tDCS targeting the DLPFC have a more general relief in fibromyalgia patients than when targeting the C2 area, suggesting that stimulating different targets with eight sessions of tDCS can lead to benefits on different symptom dimensions of fibromyalgia.

Ensuring cost containment while providing high quality patient care is of paramount concern to hospitals. The operating theater in particular is a major cost driver for any hospital, and is among the most critical resources in terms of both capacity and patient care. Effective inventory and distribution systems are a prerequisite for realizing efficiency improvements in the internal operating theater supply chain. In this work, discrete-event simulation is used to model part of the internal distribution process in the operating theater at a Belgian Hospital and to identify improvements by focusing on the replenishment process. A logistics performance measurement framework based on Analytic Network Process (ANP), as a popular Multi-Criteria Decision-Making (MCDM) technique, is adopted to assess three replenishment scenarios. The best performing scenario is selected using the Internal Logistics Efficiency Performance (ILEP) index as an evaluation basis. This research indicates that industrial engineering techniques, such as simulation and MCDM, which are successfully applied in industrial sectors, can also be adopted to realize efficiency opportunities in healthcare logistics.

Manufacturing and maintenance processes significantly benefit from effective and integrated Supply Chain Management (SCM). Recently, hospitals start to recognize the importance of these logistics initiatives to improve their operational performance while also maintaining high quality of patient care. Patient care processes are supported by a range of supply chain activities including inventory management and distribution of medical supplies to point-of-care locations. At the operating room for instance, the logistics staff’s goal is managing materials and information flows to have the requested materials at the right operating room at the right time, in the most efficient way. However, poor inventory management, lack of standardization and lack of coordination between departments complicate healthcare logistics processes, and hence result in many waste. Opportunities for efficiency gains in these logistics processes can be identified by measuring the performance of the internal supply chain. This paper presents a rigorously defined logistics performance measurement framework to evaluate the efficiency of logistics processes in operating rooms. The Analytic Network Process (ANP) is utilized as a popular Multi-Criteria Decision-Making (MCDM) technique to provide effective decision-support models. The proposed ANP-based framework is a first step towards measuring the performance of operating room supply chain processes by selecting and prioritizing logistics objectives and associated Key Performance Indicators (KPIs). Further research is required to validate the ANP framework by including multiple stakeholders’ preferences, as they may have conflicting views on performance definitions. The final goal of the framework is to support hospital logistics managers in making transparent and informed decisions to improve inventory and distribution policies in the operating room while considering all stakeholders’ preferences.

Objectives To test the hypothesis that an implantable sensing system containing accelerometers can detect small‐scale autonomous movements, also termed micromotions, which might be relevant to bladder physiology. Methods We developed a 6‐mm submucosal implant containing a pressure sensor (MS5637) and a triaxial accelerometer (BMA280). Sensor prototypes were tested by implantation in the bladders of Gottingen minipigs. Repeated awake voiding cystometry was carried out with air‐charged catheters in a standard urodynamic set‐up as comparators. We identified four phases of voiding similar to cystometry in other animal models based on submucosal pressure. Acceleration signals were separated by frequency characteristics to isolate linear acceleration from the baseline acceleration. The total linear acceleration was calculated by the root mean square of the three measurement axes. Acceleration activity during voiding was investigated to adjacent 1‐s windows and was compared with the registered pressure. Results We observed a total of 19 consecutive voids in five measurement sessions. A good correlation (r > 0.75) was observed between submucosal and catheter pressure in 14 of 19 premicturition traces. The peak‐to‐peak interval between maximum total linear acceleration was correlated with the interval between submucosal voiding pressure peaks (r = 0.760, P < 0.001). The total linear acceleration was higher during voiding compared with pre‐ and postmicturition periods (start of voiding/phase 1). Conclusions To the best of our knowledge, this is the first report of bladder wall acceleration, a novel metric that reflects bladder wall movement. Submucosal sensors containing accelerometers can measure bladder pressure and acceleration.

Although tinnitus retraining therapy (TRT) based on Jastreboff's classical neurophysiological model is efficacious in most patients, its effects on the cortical activity changes responsible for the improvement of tinnitus are still unclear. In this study, we compared pre- and post-TRT resting-state quantitative electroencephalography (rs-qEEG) findings to identify power changes that could explain TRT-induced improvements. Thirty-seven patients with severe tinnitus were enrolled in the study, and rs-qEEG data recorded before the initial TRT sessions and 6 months after TRT were compared. In addition, associations between the changes in qEEG and percentage improvements in Tinnitus Handicap Inventory (THI) scores and numeric rating scale (NRS) scores of tinnitus loudness and tinnitus perception were examined. The mean THI score decreased significantly 6 months after the initial TRT session. Also, significant improvements were observed 6 months after the initial TRT session compared with the pre-treatment scores in NRS loudness, distress, and perception. As compared with the pre-TRT status, post-TRT 6 months status showed significantly decreased powers in the left primary and secondary auditory cortices for the gamma frequency band. Changes in the alpha 1 frequency band power in the right insula and orbitofrontal cortex (OFC) appeared to be positively correlated with the percentage changes in NRS distress. These results suggested that TRT improved tinnitus-related distress by reducing the power of the top-down autonomic response modulator or peripheral physiological responses to emotional experiences. That is, TRT induced habituation via modulation of functional connections between the auditory system and the limbic and autonomic nervous systems. Our results confer additional basis for understanding the neurophysiological model and the newly suggested integrative model of tinnitus by De Ridder et al. (2014) in the context of the long-term efficacy of TRT.

Background The SUNBURST Study, a USA-based controlled cross-over trial demonstrated that burst spinal cord stimulation was superior compared to tonic stimulation in suppressing chronic intractable pain. However, when on burst stimulation, participants preferred lower to higher amplitudes. This led to the hypothesis that lower burst amplitudes will correlate with lower pain scores while higher amplitudes will be associated with higher pain scores. Objective To investigate correlations between burst amplitude and self-reported pain and different psychosocial measures. Materials and methods One hundred participants in the SUNBURST study were randomized to receive burst or tonic stimulation, each for 12 weeks in a cross-over manner. Complete data of 99 participants were used in this secondary analysis. Pearson correlations were conducted at 6-, 12-, 18-, and 24-weeks postactivation to determine the strength of linear relationships between burst amplitude and (1) the average seven-day daily pain Visual Analogue Scale (VAS), (2) the different domains of the Pain Catastrophizing Scale (PCS), (3) the different domains of the SF-36v2 (Quality Metric Incorporated, Lincoln, RI) Health Survey. In addition, correlations between tonic stimulation amplitude and the above-mentioned outcome measures were examined. Results Significant positive correlations were identified between burst amplitude and total, "worst," and "trunk" pain for VAS; all domains for PCS; and "Role-Physical," "Bodily Pain," and "General Health" for SF-36v2™ after 12-weeks of burst stimulation. Conclusions In burst spinal cord stimulation, in contrast to tonic stimulation, lower amplitudes are more effective in suppressing pain than high amplitudes.

ObjectiveTo illustrate the development and use of standardised mortality rates (SMRs) as a trigger for quality improvement in a network of 27 hospitals.DesignThis research was a retrospective observational study. The primary outcome was in-hospital mortality. SMRs were calculated for All Patient Refined—Diagnosis-Related Groups (APR-DRGs) that reflect 80% of the Flemish hospital network mortality. Hospital mortality was modelled using logistic regression. The metrics were communicated to the member hospitals using a custom-made R-Shiny web application showing results at the level of the hospital, patient groups and individual patients. Experiences with the metric and strategies for improvement were shared in chief medical officer meetings organised by the Flemish hospital network.Setting27 Belgian hospitals.Participants1 198 717 hospital admissions for registration years 2009–2016.ResultsPatient gender, age, comorbidity as well as admission source and type were important predictors of mortality. Altogether the SMR models had a C-statistic of 88%, indicating good discriminatory capability. Seven out of ten APR-DRGs with the highest percentage of hospitals statistically significantly deviating from the benchmark involved malignancy. The custom-built web application and the trusted environment of the Flemish hospital network created an interoperable strategy to get to work with SMR findings. Use of the web application increased over time, with peaks before and after key discussion meetings within the Flemish hospital network. A concomitant reduction in crude mortality for the selected APR-DRGs from 6.7% in 2009 to 5.9% in 2016 was observed.ConclusionsThis study reported on the phased approach for introducing SMR reporting to trigger quality improvement. Prerequisites for the successful use of quality metrics in hospital benchmarks are a collaborative approach based on trust among the participants and a reporting platform that allows stakeholders to interpret and analyse the results at multiple levels.