Background: Treatment for localized prostate cancer (PCa) can cause long-term changes in erectile functioning. However, data on the importance of sexuality and possible consequences of altered erectile functioning on selfesteem in men with localized PCa are lacking.
Methods: Self-report questionnaires were completed by 292 men with PCa, initially managed with active surveillance (AS) or radical prostatectomy (RP). Independent t-tests were conducted to evaluate group differences. A sequential multiple regression model was fitted to analyze the associations between the importance of sexuality, changes in erectile functioning and impairment of self-esteem. Interaction effects were tested using simple slope analyses.
Results: Participants were 70 ± 7.2 years old and 66.5% rated sex as being “rather/very important”. The two groups differed markedly in changes in erectile functioning, importance of sexuality and impairment of selfesteem (p < .001), with higher values in RP patients. Regression analysis showed that after adjustment for control variables and importance of sexuality, changes in erectile functioning were still associated with impairment of selfesteem (B = .668, SE = .069, p < .001). The interaction of changes in erectile functioning and importance of sexuality reached significance (B = .318, SE = .062, p < .001).
Conclusions: RP patients report more changes in erectile functioning than AS patients. Moreover, in men with localized PCa, erectile functioning and self-esteem are closely related. Sexuality seems to be important for the majority of these men. Physicians should address the possibility of erectile dysfunction and its potential effects on psychological well-being before the treatment decision.View less
Background: Systemic autoinflammatory diseases (SAIDs) are rare debilitating disorders of which there is limited awareness and a significant delay in diagnosis. There is no uniform approach in the diagnosis and treatment of these disorders and the real life state of SAID patient care is poorly characterized. The aim of this study was to obtain data on the epidemiology, state of care and the perception of physicians who are involved in the care of SAID patients.
Methods: We performed a questionnaire-based survey and contacted 134 university departments of dermatology, pediatrics, rheumatology and other SAID departments of tertiary care in German-speaking countries.
Results: A total of 37 departments participated in the survey. The majority of departments managed both adult and pediatric patients with a variety of monogenic and polygenic/acquired SAIDs. For monogenic SAIDs such as cryopyrin-associated periodic syndromes (CAPS) and familial Mediterranean fever (FMF), the diagnostic and treatment strategies were similar among the departments. The diagnostic work-up included inflammatory markers and genetic testing, the first line treatment interleukin-1 (IL-1) blockers for CAPS and colchicine for FMF. For polygenic/acquired SAIDs, we observed a significant heterogeneity in diagnostic and therapeutic approaches. As a major unmet need, diagnostic delay was identified with a median time to diagnosis of 2 (range 1–5) years. The overall state of care for SAID patients was rated to be excellent or good by only 12% of departments, and to be poor or non-sufficient by 40% of departments.
Conclusion: This study demonstrates a high need to improve the state of care and to harmonize diagnostic and treatment strategies for SAID patients.View less
Omega-3 fatty acids have long been ascribed a positive cardiovascular function. However, the plasma measurements invariably ignore 40% of the blood specimen, cells that engage in continuous exchange with their environment. In our study, we included all components of the circulating blood. Erythrocyte or red-blood-cell (RBC) n–3 fatty acid status has been linked to cardiovascular disease and death. A low omega-3 index is an independent risk factor for cardiovascular disease and mortality. We tested the hypothesis that acute, maximal exercise would influence the relationship between RBC and serum fatty acids. RBC fatty acids profiling was achieved using targeted HPLC-MS mass spectrometry. Healthy volunteers performed maximal treadmill exercise testing using the modified Bruce protocol. Central hemodynamics were monitored and maximal workload was assessed in metabolic equivalents (METs). Venous blood was obtained for RBC lipidomics. With the incremental exercise test, no fatty acid-level variations were found in RBCs, while heart rate and arterial blood pressure increased significantly. No changes occurred in the omega-3 quotient, namely the percentage of eicosapentaenoic acid and docosahexaenoic acid in RBC fatty acids in the RBC membrane. Nonetheless, maximal (13.50 ± 1.97 METs) exercise intensity led to a decrease of RBC lauric acid (C12:0) in the recovery period. These data suggest that despite significant hemodynamic effects, short-term maximal exercise is insufficient to alter RBC n–3 and other fatty-acid status, including the omega-3 quotient, in healthy individuals. RBC lauric acid deserves further scrutiny as a potential regulator of cardiovascular and metabolic functions.View less
Background: An early detection of Osteoarthritis is urgently needed and still not possible until today. The aim of the study was to assess whether molecular biomarkers of cartilage turnover are associated with longitudinal change in knee cartilage thickness during a 2 year period in individuals with increased risk of developing knee osteoarthritis. A secondary aim was to assess whether prior knee injury or subjective patient-reported outcomes at baseline (BL) were associated with articular cartilage changes. Nineteen volleyball players (mean age 46.5 ± 4.9 years, 47% male) with a 30-year history of regular high impact training were recruited. The serum biomarkers Cpropeptide of type II procollagen (CPII), cartilage oligomeric matrix protein (COMP), collagenase generated carboxy-terminal neoepitope of type II collagen (sC2C), cartilage intermediate layer protein 2 (CILP-2), and the urine biomarkers Ctelopeptide of type II collagen (CTX-II) and collagenase-generated peptide(s) of type II collagen (C2C-HUSA) were assessed at BL and at 2 year follow up (FU). Femorotibial cartilage thinning, thickening and absolute thickness change between BL and FU was evaluated from magnetic resonance imaging. Subjective clinical status at BL was evaluated by the International Knee Documentation Committee Subjective Knee Form and the Short-Form 36 Physical Component Score. Results: CILP-2 was significantly higher at FU and linearly associated with the absolute cartilage thickness change during the experimental period. Prior injury was a predictor of increased absolute cartilage thickness change. Conclusion: Measuring the change in the cartilage biomarker CILP-2 might be a valid and sensitive method to detect early development of knee osteoarthritis as CILP-2 appears to be related to cartilage thickness loss in certain individuals with increased risk of developing knee osteoarthritis. Prior knee injury may be predictive of increased articular cartilage thickness change.View less
We aimed to explore left atrial (LA) remodeling in the patients with solid cancer before initiation of chemo- or radiotherapy. This retrospective investigation included 92 chemo- and radiotherapy-naive cancer patients and 40 age- and gender-matched controls with a similar cardiovascular risk profile as the cancer group. All participants underwent comprehensive echocardiographic examination before the start of chemo- or radiotherapy. LA phasic function was evaluated in volumetric and strain method. Indexed minimal and pre-A LA volumes were significantly higher in the cancer patients. Total and passive LA emptying fraction (EF) were significantly lower, whereas active LAEF was significantly higher in the cancer patients. LA total longitudinal strain was significantly lower in the cancer patients. Strain rate analysis of LA phasic function showed that LA function during systole and early diastole was reduced in the cancer group, while it was increased during late diastole. These findings indicated that LA reservoir and conduit functions, assessed with LA volumetric and strain analysis, were deteriorated in the cancer group. On the other hand, LA booster pump function was elevated in the cancer group in comparison with the controls. In the whole population, cancer was associated with reduced LA total longitudinal strain independently of age, gender, BMI, LV hypertrophy, E/e’ ratio, diabetes, and hypertension. LA phasic function was impaired in the chemo- and radiotherapy-naive cancer patients in comparison with the control group. Cancer, LV hypertrophy, and hypertension were associated with reduced LA longitudinal strain independently of other important clinical parameters.View less
Persistent Human Papillomavirus (HPV) infection is a prerequisite for cervical cancer development. Few studies investigated clearance of high-risk HPV in low-and-middle-income countries. Our study investigated HPV clearance and persistence over four years in women from North Tongu District, Ghana. In 2010/2011, cervical swabs of 500 patients were collected and HPV genotyped (nested multiplex PCR) in Accra, Ghana. In 2014, 104 women who previously tested positive for high-risk HPV and remained untreated were re-tested for HPV. Cytobrush samples were genotyped (GP5+/6+ PCR & Luminex-MPG readout) in Berlin, Germany. Positively tested patients underwent colposcopy and treatment if indicated. Of 104 women, who tested high-risk HPV+ in 2010/2011, seven (6,7%; 95%CI: 2.7-13.4%) had ≥1 persistent high-risk-infection after ~4 years (mean age 39 years). Ninety-seven (93,3%; 95%CI: 86.6-97.3%) had cleared the original infection, while 22 (21.2%; 95%CI: 13.8-30.3%) had acquired new high-risk infections with other genotypes. Persistent types found were HPV 16, 18, 35, 39, 51, 52, 58, and 68. Among those patients, one case of CIN2 (HPV 68) and one micro-invasive cervical cancer (HPV 16) were detected. This longitudinal observational data suggest that single HPV screening rounds may lead to over-referral. Including type-specific HPV re-testing or additional triage methods could help reduce follow-up rates.View less
Osseointegration of dental implants can be promoted by implant-surface modifications using bisphosphonate coatings. In addition, it is of clinical interest to promote peri-implant bone formation and to restore bony structure in low bone-mass patients. The present study evaluated a combination of an anti-resorptive zoledronic acid (ZOL) implant-coating and a systemically applied sclerostin antibody, a known bone anabolic treatment principle, versus sole sclerostin antibody treatment or ZOL implant-coating in a rat osteoporosis model. Uncoated reference surface implants or ZOL-coated implants (n = 64/group) were inserted into the proximal tibia of aged osteoporotic rats three months following ovariectomy. 32 animals of each group received once weekly sclerostin antibody therapy. Osseointegration was assessed 2 or 4 weeks post-implantation by ex vivo μCT, histology and biomechanical testing. Overall implant survival rate was 97 %. Histomorphology revealed pronounced bone formation along the entire implant length of ZOL-coated implants. At 4 weeks following implant insertion, bone-implant contact, cancellous bone mineral density and bone volume/tissue volume were significantly increased for the combination of ZOL and sclerostin antibody as compared to sclerostin antibody or ZOL implant-coating alone. Removal torque was also significantly increased in the combination therapy group relative to animals receiving only sclerostin antibody therapy or ZOL-coated implants. In an osteoporotic rat model, the combination of anti-resorptive ZOL implant-coating and systemically applied sclerostin antibody led to significantly increased peri-implant bone formation. Therefore, the combination of ZOL and the osteoanabolic sclerostin antibody was more effective than either agent alone.View less
INTRODUCTION: Childhood vaccination programmes have been established in all Organisation for Economic Co-operation and Development (OECD) countries; however, measles, mumps and rubella (MMR) as well as diphtheria, tetanus, pertussis and polio (Tdap-IPV) vaccination rates are not optimal in adolescents. Education in combination with easy access vaccination may be a promising approach to improve vaccination rates. We aim at improving MMR and Tdap-IPV rates in a school setting in the context of a planned cluster randomised controlled trial (cRCT), the present paper describes the detailed protocol of this trial.
METHODS AND ANALYSIS: We will conduct a school-based cRCT, where schools will be randomised to either an educational condition addressing knowledge, risk communication and enhancing self-efficacy regarding vaccination or a low-intensity information condition. In both conditions, a bus equipped with medical staff and materials, will be delivering MMR and Tdap-IPV vaccine directly after the intervention. Schools in the city centre of Berlin, Germany, will be stratified by percentage of migration and type of school. Primary outcome is the number of students who receive vaccination in the bus. Secondary outcomes are knowledge and self-efficacy. An estimated sample size of 355 school classes with approximately 25 students per class is required. The planned analyses will take the nested structure of students, classes and schools into account.
ETHICS AND DISSEMINATION: The study will be performed according to the principles of Good Clinical Practice and the Declaration of Helsinki. Approval was obtained by the local ethics committee. Parents of all students will be informed in advance. Their written consent will be obtained, in case students are underage. For dissemination, we will engage with governmental organisations to create potential of our educational unit to be included in future public health prevention schemes.View less
The global burden of chronic kidney disease is rising. The etiologies, heterogeneous, and arterial hypertension, are key factors contributing to the development and progression of chronic kidney disease. Arterial hypertension is induced and maintained by a complex network of systemic signaling pathways, such as the hormonal axis of the renin-angiotensin-aldosterone system, hemodynamic alterations affecting blood flow, oxygen supply, and the immune system. This review summarizes the clinical and histopathological features of hypertensive kidney injury and focusses on the interplay of distinct systemic signaling pathways, which drive hypertensive kidney injury in distinct cell types of the kidney. There are several parallels between hypertension-induced molecular signaling cascades in the renal epithelial, endothelial, interstitial, and immune cells. Angiotensin II signaling via the AT1R, hypoxia induced HIFα activation and mechanotransduction are closely interacting and further triggering the adaptions of metabolism, cytoskeletal rearrangement, and profibrotic TGF signaling. The interplay of these, and other cellular pathways, is crucial to balancing the injury and repair of the kidneys and determines the progression of hypertensive kidney disease.View less
We applied deep convolutional neural networks (CNNs) to detect periodontal bone loss (PBL) on panoramic dental radiographs. We synthesized a set of 2001 image segments from panoramic radiographs. Our reference test was the measured % of PBL. A deep feed-forward CNN was trained and validated via 10-times repeated group shuffling. Model architectures and hyperparameters were tuned using grid search. The final model was a seven-layer deep neural network, parameterized by a total number of 4,299,651 weights. For comparison, six dentists assessed the image segments for PBL. Averaged over 10 validation folds the mean (SD) classification accuracy of the CNN was 0.81 (0.02). Mean (SD) sensitivity and specificity were 0.81 (0.04), 0.81 (0.05), respectively. The mean (SD) accuracy of the dentists was 0.76 (0.06), but the CNN was not statistically significant superior compared to the examiners (p = 0.067/t-test). Mean sensitivity and specificity of the dentists was 0.92 (0.02) and 0.63 (0.14), respectively. A CNN trained on a limited amount of radiographic image segments showed at least similar discrimination ability as dentists for assessing PBL on panoramic radiographs. Dentists’ diagnostic efforts when using radiographs may be reduced by applying machine-learning based technologies.View less
Especially patients older than 65 years undergoing surgery are prone to develop frailty-related complications that may go far beyond the index hospitalization (e.g., cognitive impairment following postoperative delirium). However, aging-relevant information are currently not fully integrated into hospitals' perioperative processes.
We introduce a temporal perspective, which focuses on the social construction of time, to better understand existing barriers to the exchange of frailty-related data, targeting complexity research. Our chosen context is perioperative care provided by a tertiary hospital in Germany that has implemented a special track for patients over 65 years old undergoing elective surgery. The research followed a participatory modelling approach between domain and modelling experts with the goal of creating a feedback loop model of the relevant system relationships and dynamics.
The results of the study show how disparate temporal regimes, understood as frameworks for organizing actions in the light of time constraints, time pressure, and deadlines, across different clinical, ambulant, and geriatric care sectors create disincentives to cooperate in frailty-related data exchanges. Moreover, we find that shifting baselines, meaning continuous increases in cost and time pressure in individual sectors, may unintentionally reinforce - rather than discourage - disparate temporal regimes.
Together, these results may (1) help to increase awareness of the importance of frailty-related data exchanges, and (2) impel efforts aiming to transform treatment processes to go beyond sectoral boundaries, taking into account the potential benefits for frail patients arising from integrated care processes using information technology.View less
Background: Hybrid positron emission tomography and magnetic resonance imaging (PET/MRI) scanners are increasingly used for both clinical and preclinical imaging. Especially functional MRI sequences such as diffusionweighted imaging (DWI) are of great interest as they provide information on a molecular level, thus, can be used as surrogate biomarkers. Due to technical restrictions, MR sequences need to be adapted for each system to perform reliable imaging. There is, to our knowledge, no suitable DWI protocol for 1 Tesla PET/MRI scanners. We aimed to establish such DWI protocol with focus on the choice of b values, suitable for longitudinal monitoring of tumor characteristics in a rat liver tumor model.
Material and methods: DWI was first performed in 18 healthy rat livers using the scanner-dependent maximum of 4 b values (0, 100, 200, 300 s/mm2). Apparent diffusion coefficients (ADC) were calculated from different b value combinations and compared to the reference measurement with four b values. T2-weighted MRI and optimized DWI with best agreement between accuracy, scanning time, and system performance stability were used to monitor orthotopic hepatocellular carcinomas (HCC) in five rats of which three underwent additional 2-deoxy-2-(18F)fluoro-D-glucose(FDG)-PET imaging. ADCs were calculated for the tumor and the surrounding liver parenchyma and verified by histopathological analysis.
Results: Compared to the reference measurements, the combination b = 0, 200, 300 s/mm2 showed the highest correlation coefficient (rs = 0.92) and agreement while reducing the acquisition time. However, measurements with less than four b values yielded significantly higher ADCs (p < 0.001). When monitoring the HCC, an expected drop of the ADC was observed over time. These findings were paralleled by FDG-PET showing both an increase in tumor size and uptake heterogeneity. Interestingly, surrounding liver parenchyma also showed a change in ADC values revealing varying levels of inflammation by immunohistochemistry.
Conclusion: We established a respiratory-gated DWI protocol for a preclinical 1 T PET/MRI scanner allowing to monitor growth-related changes in ADC values of orthotopic HCC liver tumors. By monitoring the changes in tumor ADCs over time, different cellular stages were described. However, each study needs to adapt the protocol further according to their question to generate best possible results.View less
Background: Previously, we found that patients with borderline personality disorder (BPD) but not healthy controls (HC) showed improved memory retrieval after hydrocortisone administration.
Objective: In this study, we examined whether increases in endogenous cortisol after psychosocial stress are associated with memory function in patients with BPD and in healthy individuals.
Methods: We recruited 49 female patients with BPD and 49 female HC. All participants were exposed to a psychosocial stressor, the Trier Social Stress Test (TSST) and a control condition (Placebo (P-)TSST) in randomized order. Salivary cortisol, alpha amylase (sAA) and blood pressure were measured in response to stress. Subsequently, we examined free recall of a previously learned word list, autobiographical memory, and working memory.
Results: We found a stress*time*group interaction effect for the cortisol response and for sAA to stress, which is mainly triggered by a slightly different increase in cortisol between groups from pre to post TSST. Furthermore, BPD patients showed a less pronounced increase in diastolic blood pressure compared to HC after stress. There was no effect of stress on memory performance in any tests, either in healthy controls or in patients with BPD.
Conclusion: Our results suggest a slightly blunted response of the HPA axis and the sympathetic nervous system to stress in BPD compared to healthy women. In contrast to hydrocortisone administration, psychosocial stress did not improve memory retrieval in BPD patients. This might be explained by lower cortisol concentrations and parallel increases in norepinephrine and negative affect after stress.View less
Viral infections have a major impact on morbidity and mortality of immunosuppressed solid organ transplant (SOT) patients because of missing or failure of adequate pharmacologic antiviral treatment. Adoptive antiviral T-cell therapy (AVTT), regenerating disturbed endogenous T-cell immunity, emerged as an attractive alternative approach to combat severe viral complications in immunocompromised patients. AVTT is successful in patients after hematopoietic stem cell transplantation where T-cell products (TCPs) are manufactured from healthy donors. In contrast, in the SOT setting TCPs are derived from/applied back to immunosuppressed patients.We and others demonstrated feasibility of TCP generation from SOT patients and first clinical proof-of-concept trials revealing promising data. However, the initial efficacy is frequently lost longterm, because of limited survival of transferred short-lived T-cells indicating a need for next-generation TCPs. Our recent data suggest that Rapamycin treatment during TCP manufacture, conferring partial inhibition of mTOR, might improve its composition. The aim of this study was to confirm these promising observations in a setting closer to clinical challenges and to deeply characterize the next-generation TCPs. Using cytomegalovirus (CMV) as model, our next-generation Rapamycin-treated (Rapa-)TCP showed consistently increased proportions of CD4+ T-cells as well as CD4+ and CD8+ central-memory T-cells (TCM). In addition, Rapamycin sustained T-cell function despite withdrawal of Rapamycin, showed superior T-cell viability and resistance to apoptosis, stable metabolism upon activation, preferential expansion of TCM, partial conversion of other memory T-cell subsets to TCM and increased clonal diversity. On transcriptome level, we observed a gene expression profile denoting long-lived early memory T-cells with potent effector functions. Furthermore, we successfully applied the novel protocol for the generation of Rapa-TCPs to 19/19 SOT patients in a comparative study, irrespective Amini et al. Advanced CMV-Specific T-Cell Therapy for SOT of their history of CMV reactivation. Moreover, comparison of paired TCPs generated before/after transplantation did not reveal inferiority of the latter despite exposition to maintenance immunosuppression post-SOT. Our data imply that the Rapa-TCPs, exhibiting longevity and sustained T-cell memory, are a reasonable treatment option for SOT patients. Based on our success to manufacture Rapa-TCPs from SOT patients under maintenance immunosuppression, now, we seek ultimate clinical proof of efficacy in a clinical study.View less
All memory T cells mount an accelerated response on antigen reencounter, but significant functional heterogeneity is present within the respective memory T-cell subsets as defined by CCR7 and CD45RA expression, thereby warranting further stratification. Here we show that several surface markers, including KLRB1, KLRG1, GPR56, and KLRF1, help define low, high, or exhausted cytokine producers within human peripheral and intrahepatic CD4+ memory T-cell populations. Highest simultaneous production of TNF and IFN-γ is observed in KLRB1+KLRG1+GPR56+ CD4 T cells. By contrast, KLRF1 expression is associated with T-cell exhaustion and reduced TNF/IFN-γ production. Lastly, TCRβ repertoire analysis and in vitro differentiation support a regulated, progressive expression for these markers during CD4+ memory T-cell differentiation. Our results thus help refine the classification of human memory T cells to provide insights on inflammatory disease progression and immunotherapy development.View less
Clinically relevant exocytosis of mast cell (MC) mediators can be triggered by high-affinity IgE receptor (FcεRI)-aggregation (allergic route) or by the so-called pseudo-allergic pathway elicited via MAS-related G protein-coupled receptor-X2 (MRGPRX2). The latter is activated by drugs and endogenous neuropeptides. We recently reported that FcεRI-triggered degranulation is attenuated when human skin mast cells are chronically exposed to IL-33. Here, we were interested in the regulation of the MRGPRX2-route. Chronic exposure of skin MCs to IL-33 basically eliminated the pseudo-allergic/neurogenic route as a result of massive MRGPRX2 reduction. This downregulation seemed to partially require c-Jun N-terminal Kinase (JNK), but not p38, the two kinases activated by IL-33 in skin MCs. Surprisingly, however, JNK had a positive effect on MRGPRX2 expression in the absence of IL-33. This was evidenced by Accell®-mediated JNK knockdown and JNK inhibition. In stark contrast to the dampening effect upon prolonged exposure, IL-33 was able to prime for increased degranulation by MRGPRX2 ligands when administered directly before stimulation. This supportive effect depended on p38, but not on JNK activity. Our data reinforce the concept that exposure length dictates whether IL-33 will enhance or attenuate secretion. IL-33 is, thus, the first factor to acutely enhance MRGPRX2-triggered degranulation. Finally, we reveal that p38, rarely associated with MC degranulation, can positively affect exocytosis in a context-dependent manner.View less
To investigate whether nasal high-frequency oscillatory ventilation (nHFOV) started immediately after extubation of mechanically ventilated very low birth weight infants reduces the partial pressure of carbon dioxide at 72 h after extubation in comparison with nasal continuous positive airway pressure. This randomised controlled single-centre trial aimed to include 68 preterm infants at high risk of extubation failure.
Implementation of the study protocol was feasible. However, from 2015 to 2017, only six patients could be recruited, leading to early termination of the trial. The slow recruitment was due to the introduction of new strategies to avoid endotracheal mechanical ventilation, which reduced the number of eligible infants. Moreover, the included infants failed their extubation more often than anticipated, thereby increasing the required sample size. Based on our single-centre experience, we provide information for study planning and discuss the specific requirements for future trial protocols on nHFOV. The extubation of high-risk infants into nHFOV could well be beneficial, but a multicentric approach is necessary to investigate this hypothesis.
Trial Registration Clinicaltrials.gov NCT02340299, on 16 January 2015.View less
Background: Anti-tumour immune competence has an impact in hepatocarcinogenesis and success of anti-cancer therapies. Tumour-infiltrating lymphocytes (TILs) and monocytes/macrophages (TAMs) are proposed to have significance in cancer. However, there is only limited data concerning their impact on patient outcome and survival in hepatocellular carcinoma (HCC). Methods: Frequencies of CD68+, CD163+M2-polarized TAMs and TILs were measured in de novo HCC tumours in noncirrhosis (n = 58) using immunohistology and correlated to patients’ clinicopathological characteristics and survival rates. Results: Patients with tumours marked by appearance of TILs and CD68+ TAMs showed an improved 1-, 3- and 5-year recurrence-free survival (all p ≤ 0.05). CD68+ TAMs were associated with reduced incidence of recurrent and multifocal disease. Conversely, CD163+ TAMs were associated with multifocal HCC and lymphangiosis carcinomatosa (all p ≤ 0.05). Conclusions: TILs and CD68+ TAMs are associated with multiple tumour characteristics and patient survival in HCC. However, there is only scarce data about the biology underlying their mechanistic involvement in human tumour progression. Thus, experimental data on functional links might help develop novel immunologic checkpoint inhibitor targets for liver cancer.View less
Background: While literature on the theoretical value of entrustable professional activities (EPAs) for assessment is rapidly expanding, little experience exists on its application. The aims of this study are to develop and explore the utility of an EPA-based assessment tool for capturing the workplace performance of final-year medical students based on a full set of end-of-training EPAs.
Methods: The tool was developed in a systematic iterative process. Twelve 12 end-of-undergraduate medical training EPAs were nested into 72 smaller EPAs and cross-mapped onto a 6-point supervision level scale, both adjusted to the context of final-year clerkships. One version was created for students’ self-assessment of their ability to carry out tasks and their history of carrying out tasks, and another version was created for supervisors’ assessment of students’ ability to carry out tasks. The tool was administered to final-year clerkship students and their clinical supervisors to explore its utility as an assessment approach. The results were analysed using descriptive and interferential statistics.
Results: We enrolled a total of 60 final-year medical students. For 33 students, ratings were provided from one supervisor and for 27 students from two supervisors. With regard to the reliability and validity of the tool, students’ and supervisors’ ratings showed an overall good internal consistency as well as variability between and within the EPAs. Over the full EPA range, students rated their ability to perform a task slightly higher than their task performance history and slightly lower than the supervisors’ ratings. Students’ self-ratings of their ability to perform a task correlated with their history in performing the task. Supervisors’ ratings correlated among supervisors and not with students’ ratings. Concerning educational outcomes, supervisors’ average rating of students’ ability to perform the EPAs without direct supervision was 64%, and key findings being double-checked.
Conclusions: This study introduces a tool that is adjusted to the final-year clerkship context and can assess the workplace performance of trainees based on a full set of end-of-training EPAs. Its utility characteristics suggest that the tool may be employed as a formative and outcome-aligned approach to the assessment of final-year students before entering into residency.View less
The transient receptor potential cation channel subfamily C member 6 (TRPC6) is a Ca2+-permeable nonselective cation channel and has received recent attention because of its capability to promote chronic kidney disease (CKD). The aims of this study were (i) to examine whether deletion of TRPC6 impacts on renal fibrosis and inflammatory cell infiltration in an early CKD model of unilateral ureter obstruction (UUO) in mice; and (ii) whether TRPC6-deficiency as well as UUO affect the regulation of TRPC expression in murine kidneys.
Wild-type (WT), Trpc6-knockout (Trpc6-/-) and New Zealand obese (NZO) mice underwent sham operation or unilateral ureteral obstruction (UUO). The kidneys were harvested 7 days after surgery. We examined renal fibrosis and inflammatory cell infiltration by histological and immunohistochemical staining. The mRNA expression of TRPC members and markers of fibrosis and inflammation in kidney were assessed by using real-time quantitative reverse transcription PCR.
Histological and immunohistochemical analyses revealed less inflammatory cell infiltration (F4/80 and CD3) in UUO kidneys of Trpc6-/- mice compared to UUO kidneys of WT mice as well as less fibrosis. Genomic deletion of TRPC6 also affected the expression of pro-fibrotic genes in UUO Trpc6-/- kidneys compared to UUO WT kidneys while the expression of pro-inflammatory genes did not differ. UUO caused marked up-regulation of Trpc6 and down-regulation of Trpc1 mRNA in kidneys of WT and NZO mice. Trpc3 mRNA expression was significantly elevated in kidneys of Trpc6-/- mice underwent UUO while the levels did not change in kidneys of neither WT nor in NZO mice underwent UUO.
TRPC6 contributes to renal fibrosis and immune cell infiltration in the UUO mouse model. Therefore, inhibition of TRPC6 emerges as a promising novel therapeutic strategy for treatment of chronic kidney failure in chronic obstructive nephropathy. However, confounding genomic and non-genomic effects of other TRPC channels should be taken into consideration to fully comprehend the renoprotective potential of targeting TRPC6 therapeutically under chronic kidney damaging conditions.View less