Discovery of JNJ-1802, a First-in-Class Pan-Serotype Dengue Virus NS4B Inhibitor.

Dengue is a global public health threat, with about half of the world's population at risk of contracting this mosquito-borne viral disease. Climate change, urbanization, and global travel accelerate the spread of dengue virus (DENV) to new areas, including southern parts of Europe and the US. Currently, no dengue-specific small-molecule antiviral for prophylaxis or treatment is available. Here, we report the discovery of JNJ-1802 as a potent, pan-serotype DENV inhibitor (EC50's ranging from 0.057 to 11 nM against the four DENV serotypes). The observed oral bioavailability of JNJ-1802 across preclinical species, its low clearance in human hepatocytes, the absence of major in vitro pharmacology safety alerts, and a dose-proportional increase in efficacy against DENV-2 infection in mice were all supportive of its selection as a development candidate against dengue. JNJ-1802 is being progressed in clinical studies for the prevention or treatment of dengue.

Call for the application of a biopsychosocial and interdisciplinary approach to the return-to-sport framework of snow sports athletes.

Snow sports such as alpine skiing or snowboarding are associated with a high risk of injury and reinjury and are subject to a very special environment with specific rehabilitation challenges that must be addressed. Due to geographic decentralisation, seasonal climatic limitations, alternation of training in off-snow and on-snow settings and unique loading patterns of practising these sports, special rehabilitation structures and processes are required compared with other sports. In addition, returning to preinjury performance requires a high level of confidence and a resumption of risk-taking in demanding situations such as high-speed skiing and high-amplitude jumps. A biopsychosocial and interdisciplinary approach can be viewed as a holistic, athlete-centred approach that promotes interprofessional communication and collaboration. This is particularly central for managing the physical/biological, psychological and social demands of injury management for snow sports. It can help ensure that rehabilitation content is well coordinated and tailored to individual needs. This is because transitions between different rehabilitation phases and caring professionals are well aligned, and rehabilitation is understood not only as purely 'physical recovery' but also as 'psychological recovery' considering the snow sports-specific setting with specific social norms. Ultimately, this may improve the rehabilitation success of snow sports athletes.

Response to 'Eruptive keratoacanthomas associated with dupilumab therapy'.

Case of a patient developing multiple rashes of squamous cell carcinoma 6 weeks after the introduction of dupilumab due to atopic eczema.

Discovery of Acyl-Indole Derivatives as Pan-Serotype Dengue Virus NS4B Inhibitors.

In the absence of any approved dengue-specific treatment, the discovery and development of a novel small-molecule antiviral for the prevention or treatment of dengue are critical. We previously reported the identification of a novel series of 3-acyl-indole derivatives as potent and pan-serotype dengue virus inhibitors. We herein describe our optimization efforts toward preclinical candidates 24a and 28a with improved pan-serotype coverage (EC50's against the four DENV serotypes ranging from 0.0011 to 0.24 µM for 24a and from 0.00060 to 0.084 µM for 28a), chiral stability, and oral bioavailability in preclinical species, as well as showing a dose-proportional increase in efficacy against DENV-2 infection in vivo in mice.

Potential determinants of unfavourable healthcare utilisation trajectories during the last year of life of people with incident Alzheimer Disease or Related Syndromes: a nationwide cohort study using administrative data.

BACKGROUND: people approaching the end-of-life frequently face inappropriate care. With Alzheimer Disease or Related Syndromes (ADRS), end-of-life is characterised by progressive decline, but this period remains difficult to identify. This leads to a lack of anticipation and sometimes with unfavourable healthcare utilisation trajectories (HUTs). OBJECTIVE: to quantify unfavourable HUTs during the last year of life and identify their potential determinants in both community and nursing-home settings. DESIGN: nationwide cohort study using administrative database. SETTING: French community and nursing-home residents. SUBJECTS: incident ADRS people identified in 2012, who died up to 31 December 2017. METHODS: we used multidimensional clustering to identify 15 clusters of HUTs, using 11 longitudinal healthcare dimensions during the last year of life. Clusters were qualitatively assessed by pluri-disciplinary experts as favourable or unfavourable HUTs. Individual and contextual potential determinants of unfavourable HUTs were studied by setting using logistic random-effect regression models. RESULTS: 62,243 individuals died before 31 December 2017; 46.8% faced unfavourable end-of-life HUTs: 55.2% in the community and 31.8% in nursing-homes. Individual potential determinants were identified: younger age, male gender, ADRS identification through hospitalisation, shorter survival, life-limiting comorbidities, psychiatric disorders, acute hospitalisations and polypharmacy. In the community, deprivation and autonomy were identified as potential determinants. Contextual potential determinants raised mostly in the community, such as low nurse or physiotherapist accessibilities. CONCLUSIONS: Nearly half of people with ADRS faced unfavourable HUTs during their last year of life. Individual potential determinants should help anticipate advance care planning and palliative care needs assessment. Contextual potential determinants suggest geographical disparities and health inequalities.

Clustering 5-Year Multidimensional Health Care Trajectory Patterns in Alzheimer's Disease and Related Syndromes.

OBJECTIVE: After diagnosis of Alzheimer's disease and related syndromes (ADRS), personalized care adapted to each patient's needs is recommended to provide a care plan and start symptomatic treatments according to guidelines. Over the past decade, dedicated structures and care have been implemented in various settings. Equal access to ADRS care, health care providers and services is crucial to ensure potential health benefits for everyone. However, the extent of use of recommended services and favorable health care utilization trajectories (HUT) may vary according to individual and contextual characteristics. The aim of this article was to (1) describe HUT patterns after multidimensional clustering of similar trajectories, (2) assess the proportion of individuals presenting favorable HUTs, and (3) identify factors associated with favorable HUTs. DESIGN: Cohort study. SETTING AND PARTICIPANTS: A cohort of 103,317 people newly diagnosed with ADRS identified in the French health reimbursement system (SNDS) was followed for 5 years with their monthly utilization on 11 health care dimensions. METHODS: For 3 age groups (65-74, 75-84, ≥85 years), 15 clusters of patients were identified using partitioning around medoids applied to Levenshtein distances. They were qualitatively assessed by pluridisciplinary experts. Individual and contextual determinants of clusters denoting favorable trajectories were identified using mixed random effects multivariable logistic regression models. RESULTS: Clusters with favorable HUTs denoting slow, progressive trajectories centered on at-home care, represented approximatively 25% of the patients. Determinants of favorable HUTs were mostly individual (age, female gender, absence of certain comorbidities, circumstances of ADRS identification, lower deprivation). Contextual determinants were also identified, in particular accessibility to nurses and nursing homes. Inter-territories variance was small but significant in all age groups (from 0.9% to 1.8%). CONCLUSION AND IMPLICATIONS: Favorable HUTs remain the minority and many efforts can still be made to improve HUTs. Qualitative studies could help understanding underlying barriers to favorable HUTs.

Final five-year results of the REMEDEE Registry: Real-world experience with the dual-therapy COMBO stent.

OBJECTIVES: This final report from the REMEDEE Registry assessed the long-term safety and efficacy of the dual-therapy COMBO stent in a large unselected patient population. BACKGROUND: The bio-engineered COMBO stent (OrbusNeich Medical BV, The Netherlands) is a dual-therapy pro-healing stent. Data of long-term safety and efficacy of the this stent is lacking. METHODS: The prospective, multicenter, investigator-initiated REMEDEE Registry evaluated clinical outcomes after COMBO stent implantation in daily clinical practice. One thousand patients were enrolled between June 2013 and March 2014. RESULTS: Five-year follow-up data were obtained in 97.2% of patients. At 5-years, target lesion failure (TLF) (composite of cardiac death, target-vessel myocardial infarction, or target lesion revascularization) was present in 145 patients (14.8%). Definite or probable stent thrombosis (ST) occurred in 0.9%, with no additional case beyond 3-years of follow-up. In males, 5-year TLF-rate was 15.6 versus 12.6% in females (p = .22). Patients without diabetes mellitus (DM) had TLF-rate of 11.4%, noninsulin-treated DM 22.7% (p = .001) and insulin-treated DM 41.2% (p < .001). Patients presenting with non-ST segment elevation acute coronary syndrome (NSTE-ACS) had higher incidence of TLF compared to non-ACS (20.4 vs. 13.3%; p = .008), while incidence with STE-ACS was comparable to non-ACS (10.7 vs. 13.3%; p = .43). CONCLUSION: Percutaneous coronary intervention with the dual-therapy COMBO stent in unselected patient population shows low rates of TLF and ST to 5 years. Remarkably, no case of ST was noted beyond 3 years.

[Older people in Ehpad, representations of young adults]. / Personnes âgées en Ehpad, représentations des jeunes adultes.

Studies on social representations of older persons are numerous and come mainly from American literature. However, few studies have examined young people's viewpoint. This article focuses on the representations of older patients among students in Bac Professionnel.

A High-Fidelity Phantom for the Simulation and Quantitative Evaluation of Transurethral Resection of the Prostate.

Transurethral resection of the prostate (TURP) is a minimally invasive endoscopic procedure that requires experience and skill of the surgeon. To permit surgical training under realistic conditions we report a novel phantom of the human prostate that can be resected with TURP. The phantom mirrors the anatomy and haptic properties of the gland and permits quantitative evaluation of important surgical performance indicators. Mixtures of soft materials are engineered to mimic the physical properties of the human tissue, including the mechanical strength, the electrical and thermal conductivity, and the appearance under an endoscope. Electrocautery resection of the phantom closely resembles the procedure on human tissue. Ultrasound contrast agent was applied to the central zone, which was not detectable by the surgeon during the surgery but showed high contrast when imaged after the surgery, to serve as a label for the quantitative evaluation of the surgery. Quantitative criteria for performance assessment are established and evaluated by automated image analysis. We present the workflow of a surgical simulation on a prostate phantom followed by quantitative evaluation of the surgical performance. Surgery on the phantom is useful for medical training, and enables the development and testing of endoscopic and minimally invasive surgical instruments.

Thermal effects of Ho:YAG laser lithotripsy during retrograde intrarenal surgery and percutaneous nephrolithotomy in an ex vivo porcine kidney model.

PURPOSE: To evaluate the thermal effect of high-power holmium:yttrium-aluminum-garnet (Ho:YAG) laser lithotripsy in flexible/semirigid ureteroscopy (fURS/sURS) and percutaneous nephrolithotomy (PNL) in a standardized ex vivo porcine kidney model with real-time temperature assessment. METHODS: The experimental setup consisted of three models designed to evaluate the thermal effects of Ho:YAG laser lithotripsy in fURS, sURS and PNL, respectively. In all setups, a postmortem porcine kidney was placed in a 37 °C water bath. Three thermocouples were inserted into the renal parenchyma while a flexible thermocouple was placed 3-4 mm proximal to the laser fiber to measure temperature variations in the collecting system. The thermal impact was evaluated in relation to laser power between 5 and 100 W and various irrigation rates (37 °C, 0-100 ml/min). RESULTS: In all three experimental setups, sufficient irrigation was required to prevent potentially damaging temperatures into the renal pelvis and parenchyma. Even 5 W in fURS can lead to a potentially harming temperature rise if insufficient irrigation is applied. Particularly, high-power settings ≥ 30 W carry an elevated risk for critical temperature rises. The results allow the definition of a specific irrigation threshold for any power setting to prevent critical temperatures in the present study design. CONCLUSIONS: Ho:YAG laser lithotripsy bears the risk of thermal damages to the urinary tract even at low-power settings if inadequate irrigation is applied. Sufficient irrigation is mandatory to perform safe Ho:YAG laser lithotripsy. Based on the results, we developed a formula calculating the approximate ΔT for irrigation rates ≥ 30 ml/min: ΔT = 15 K × (power [W]/irrigation [ml/min]).

Long-Term Performance of the COMBO Dual-Therapy Stent: Results from the REMEDEE Registry.

BACKGROUND: Data of long-term safety and efficacy of the COMBO dual-therapy stent is lacking. REMEDEE Registry evaluated the COMBO stent and showed low clinical event rates up to 3 year. We report the clinical outcomes at 4-year follow-up of this registry. METHODS: The REMEDEE Registry is a prospective, multicenter registry with minimal exclusion criteria, evaluating clinical outcomes after treatment with the COMBO stent. A 1000 patients were enrolled between June 2013 and March 2014. Target lesion failure (TLF), defined as a composite of cardiac death, target-vessel myocardial infarction (TV-MI) and target lesion revascularization (TLR), at 4-year follow-up was the primary focus of this analysis. RESULTS: Four-year follow-up data were obtained in 97.3% of patients. TLF was present in 117 patients (11.9%). Cardiac death occurred in 45 patients (4.6%), TV-MI was observed in 25 patients (2.6%) and TLR was performed in 73 patients (7.5%). Of the 7.5% TLR at 4 years, 1.5% were beyond 2 years. Definite ST was seen in 7 patients (0.7%) and probable ST in 1 (0.1%). No definite or probable ST occurred between 3 and 4 years follow-up. At 4-year follow-up, 93.1% of patients were free of ischemic symptoms. CONCLUSION: This registry showed excellent 4-year results after COMBO stent placement, with no ST beyond 3 years.

Characterization of Flow-Caused Intrarenal Pressure Conditions During Percutaneous Nephrolithotomy In Vitro.

PURPOSE: To investigate renal pelvic pressures during percutaneous nephrolithotomy (PCNL) in the standard, mini, and ultramini PCNL systems. METHODS: We studied an ultramini PCNL system (UMP, outer shaft diameter 13F), a mini PCNL system (MPCNL, shaft 18F, nephroscope 12F), and a standard PCNL system (SPCNL, shaft 27F, nephroscope 24F). Pressure profiles were first investigated in an open model setup, subsequently in a closed model, and finally in an ex vivo porcine kidney. Measurements were determined with the nephroscope in an advanced and pulled-back position for all models. RESULTS: In the advanced position, maximum pressures of 41.61 ± 0.20 mmHg (UMP), 15.61 ± 0.15 mmHg (MPCNL), and 15.46 ± 0.14 mmHg (SPCNL) were measured in the closed model. In the pulled-back position, maximum pressures were 16.04 ± 0.22 mmHg (UMP), 17.02 ± 0.11 mmHg (MPCNL), and 20.50 ± 0.11 mmHg (SPCNL). In the ex vivo porcine kidney model, maximum pressures were 13.81 ± 6.04 mmHg (UMP), 5.64 ± 0.21 (MPCNL), and 9.21 ± 0.52 (SPCNL) with the nephroscope pushed to end position. After retracting the nephroscope from the outer shaft, pressures in all systems did not exceed 10 mmHg. CONCLUSIONS: The maximum pressures achieved with the three PCNL systems in all three models were kept below the 30 mmHg critical threshold value. High pressures were only determined for the UMP system with the nephroscope pushed to its end position. This was attributed to the conical shape of the nephroscope, which occupies the space between the nephroscope and outer shaft, resulting in outflow obstruction.

Risk Factors for Ureteral Damage in Ureteroscopic stone Treatment: Results of the German Prospective Multicentre Benchmarks of Ureterorenoscopic Stone Treatment-Results in Terms of Complications, Quality of Life, and Stone-Free Rates Project.

BACKGROUND: The Post-Ureteroscopic Lesion Scale (PULS) is a validated, standardised scale that classifies iatrogenic ureteral lesions during ureteroscopy (URS). OBJECTIVE: To determine risk factors for the various PULS-grades caused by URS. METHOD: We prospectively investigated the independent influence of various risk factors in correlation with PULS-Grade 1+ and 2+ on 307 patients with ureterorenoscopic stone treatment from 14 German urologic departments. RESULTS: The following are the outcomes of the study: 117 (38.4%) and 188 (61.6%) of the calculi (median stone size 6 mm) were found in the kidney or ureter; 70% and 82.4% underwent preoperative or postoperative ureteral stenting; 44.3 and 7.2% received laser or ballistic lithotripsy; 60% of the patients presented with PULS grade 1+ and 8% with PULS grade of 2+. Only intracorporal lithotripsy revealed a significant independent risk factor for PULS grade 1+ or 2+. Both laser and ballistic therapies raised the probability of PULS grade 1+ by the factors 3.6 (p < 0.001) and 3.9 (p = 0.021), respectively. The ORs in conjunction with PULS grade 2+ were 3.1 (p = 0.038) and 5.8 (p = 0.014) respectively. Neither endpoint exhibited a significant difference regarding the lithotripsic procedure (laser vs. ballistic). CONCLUSION: Intracorporal lithotripsy is associated with a significant increase in damage to the ureter; further research is needed to determine its long-term effects.

[Uro mHealth: health apps in urology]. / Uro mHealth: Gesundheits-Apps in der Urologie.

The use of readily available mHealth apps on smartphones and tablets is increasing worldwide, including the field of urology. Access to knowledge, data collection and communication are thus simplified and accelerated. A wide range of health apps exists for the public, patients, health professionals and medical education. In particular, in the field of urology, several high quality mHealth contents have been created in recent years. Nevertheless, there is still need for improvement and development.The ubiquity of health apps might also bring particular risks. Healthcare professionals can use their private electronic devices when dealing with patients or patient data, and thus risk violations of patient and data protection rights.There are no universal quality standards or legal certification requirements for mHealth apps. Private (mostly commercial) app developers and providers possess quasi-proprietary rights concerning user data. Politics, scientific funding agencies and medical societies are therefore urgently needed to set standards and to promote and fund open-source key projects providing quality benchmarks within the field.

[Current trends in flexible ureteroscopy: an update]. / Aktuelle Trends in der flexiblen Ureterorenoskopie ­ ein Update.

Flexible ureteroscopy (fURS) has become a success story in urology. Since its implementation into the treatment of urolithiasis, fURS has demonstrated excellent clinical performance and safety. In recent years, the spread of disposable ureteroscopes has shaped the field of endoscopic stone treatment. However, the primary advantage of these devices is that they improve the workflow in urology theatres (no sterilisation, no repair costs) and possibly minimise bacteria transfer in working channels rather than being a real technological "game changer". Novel disruptive improvements such as automatic laser lithotripsy or intrarenal pressure and temperature control in real time are still waiting to enter the clinical routine. These innovations might take fURS to the next level and disruptively change endoscopic stone treatment.

Three-year clinical outcomes after dual-therapy COMBO stent placement: Insights from the REMEDEE registry.

BACKGROUND: The bio-engineered COMBO stent (OrbusNeich Medical BV, The Netherlands) is a dual-therapy pro-healing stent. This novel technology may allow a shorter duration of dual antiplatelet therapy (DAPT) after stenting. We present the first 3 year clinical outcomes of patients treated with COMBO stent. METHODS AND RESULTS: The prospective, multicenter, investigator-initiated, all-comers REMEDEE Registry evaluates clinical outcomes after COMBO stent treatment. A 1,000 patients were enrolled between June 2013 and March 2014. Patients had a mean of 65 years ±11, 26% of the patients were females and 18% diabetics. More than 50% of patients presented with acute coronary syndrome, 60% of treated lesions were AHA/ACC lesion type B2 or C. Target lesion failure (TLF) at 3 year follow-up occurred in 10.7% of patients (N = 105). The separate components cardiac death, target vessel myocardial infarction and target lesion revascularization occurred in 4.1%, 2.0%, and 7.1%, respectively of patients. Definite stent thrombosis (ST) was observed in 0.7% of all patients. At 3-year follow-up there were only 73 patients taking DAPT. CONCLUSIONS: At 3-year follow-up, patients treated with COMBO stent in the present large prospective all-comers cohort, continue to show good clinical outcomes. Clinicaltrials.gov identifier: NCT01874002. CONDENSED ABSTRACT: The COMBO stent is a sirolimus-eluting stent with a luminal anti-CD34-antibody layer, that binds endothelial progenitor cells. These cells can differentiate to endothelial cells and stimulate early endothelialization of the stent. The REMEDEE Registry is the first large, multicenter, prospective, cohort study evaluating the clinical outcomes of 1,000 all-comers patients treated with COMBO stent. Target lesion failure at 3 year follow-up was 10.7% and the rate of definite ST was 0.7%.

Robotic waterjet wound debridement - Workflow adaption for clinical application and systematic evaluation of a novel technology.

OBJECTIVE: We evaluated the clinical potential of a novel robotic system for autonomous performance of waterjet wound debridement. SUMMARY BACKGROUND DATA: Within the last decade, waterjet wound debridement has proven to be a valid alternative to the conventional approach using sharp spoons and scalpel. METHODS: The DLR MIRO robot using the DLR MICA instrument for robotic surgery was adapted for actuation of an ERBEJET 2 flexible endoscopic waterjet probe. Waterjet debridement of various wound shapes and sizes using a porcine skin model was compared between this novel robotic system and a control group of human medical professionals with regard to wound area cleaned by the waterjet, off-target area, and procedural time. RESULTS: After the wound area was registered in the robotic system, it automatically generated a cleaning path and performed debridement based on generated surface model. While the robotic system demonstrated a significant advantage for the covered wound area (p = 0.031), the average off-target area was not significantly different from human controls. Human participants had high variability in cleaning quality across users and trials, while the robotic system provided stable results. Overall procedural time was significantly lower in trials performed by humans. CONCLUSIONS: Robotic waterjet wound debridement is a promising new technological approach compared to the current clinical standard of interventional wound therapy, providing higher efficiency and quality of wound cleaning compared to human performance. Additional trials on more complicated wound shapes and in vivo tissue are necessary to more thoroughly evaluate the clinical potential of this technology.

Robotic stone surgery - Current state and future prospects: A systematic review.

OBJECTIVE: To provide a comprehensive review of robot-assisted surgery in urolithiasis and to consider the future prospects of robotic approaches in stone surgery. MATERIALS AND METHODS: We performed a systematic PubMed© literature search using predefined Medical Subject Headings search terms to identify PubMed-listed clinical research studies on robotic stone surgery. All authors screened the results for eligibility and two independent reviewers performed the data extraction. RESULTS: The most common approach in robotic stone surgery is a robot-assisted pyelolithotomy using the da Vinci™ system (Intuitive Surgical Inc., Sunnyvale, CA, USA). Several studies show this technique to be comparable to classic laparoscopic and open surgical interventions. One study that focused on ureteric stones showed a similar result. In recent years, promising data on robotic intrarenal surgery have been reported (Roboflex Avicenna™; Elmed Medical Systems, Ankara, Turkey). Initial studies have shown its feasibility and high stone-free rates and prove that this novel endoscopic approach is safe for the patient and comfortable for the surgeon. CONCLUSIONS: The benefits of robotic devices in stone surgery in existing endourological, laparoscopic, and open treatment strategies still need elucidation. Although recent data are promising, more prospective randomised controlled studies are necessary to clarify the impact of this technique on patient safety and stone-free rates.

[The Old-Age Heart]. / Das Herz im Alter.

The Old-Age Heart Abstract. Knowledge of cardiovascular changes in old age and their therapeutic options is important. Old age can lead to hypertrophy of the left ventricle, diastolic dysfunction, heart valve changes and pulmonary hypertension. Patients often develop arterial hypertension. Valvular changes are common in people over 100 years of age (aortic stenosis and mitral insufficiency). The risk of coronary heart disease is 35 % for men and 24 % for women. In old age, sinus node dysfunction and atrial fibrillation are common. 25 % of all strokes are cardiac embolisms in atrial fibrillation. Cardiac interventions in the elderly are increasingly frequent and include coronary catheter revascularization or valve interventions (percutaneous aortic valve replacement or MitraClip). Optimal therapy in old age includes not only cardiovascular interventions also include drugs and a lifestyle modification and mainly serves to improve the quality of life.