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Long-standing research in animal models and humans with stroke or incomplete spinal cord injury (iSCI) indicate that specific physical training variables, such as the specificity and amount of practice, may influence neurologic recovery and locomotor function. More recent data highlight the contributions of exercise intensity, as estimated indirectly by cardiovascular exertion, as potentially more important than previously considered. The effects of exercise intensity are well described in neurologically intact individuals, although confusion regarding the definitions of intensity and safety concerns have limited its implementation during physical rehabilitation of patients with neurologic injury. The purpose of this review is to delineate some of the evidence regarding the effects of exercise intensity during locomotor training in patients with stroke and iSCI. We provide specific definitions of exercise intensity used within the literature, describe methods used to ensure appropriate levels of exertion, and discuss potential adverse events and safety concerns during its application. Further details on the effects of locomotor training intensity on clinical outcomes, and on neuromuscular and cardiovascular function will be addressed as available. Existing literature across multiple studies and meta-analyses reveals that exercise training intensity is likely a major factor that can influence locomotor function after neurologic injury. To extend these findings, we describe previous attempts to implement moderate to high intensity interventions during physical rehabilitation of patients with neurologic injury, including the utility of specific strategies to facilitate implementation, and to navigate potential barriers that may arise during implementation efforts.

OBJECTIVES: Three-dimensional transesophageal echocardiography (TEE) is widely used to guide decision-making for mitral repair - relative impact of surgical mitral valve repair (MVr) and MitraClip on annular remodeling is unknown. The aim was to determine the impact of both mitral repair strategies on annular geometry, including the primary outcome of annular circumference and area. DESIGN: This was a retrospective observational study of patients who underwent mitral intervention between 2016 and 2020. SETTING: Weill Cornell Medicine, a single large academic medical center. PARTICIPANTS: The population comprised of 50 degenerative mitral regurgitation (MR) patients undergoing MVr. INTERVENTIONS: Elective MVr and transesophageal echocardiography (TEE) MEASUREMENTS AND MAIN RESULTS: MitraClip or surgical MVr patients were matched (1:1) for gender and CAD. Mitral annular geometry indices were quantified on intra-procedural 3D TEE. Mild or less MR on follow-up TTE defined optimal response. MitraClip patients were older (80±8 vs. 66±6;p

BACKGROUND: A set of enduring conditions have been reported in the literature involving persistent sexual dysfunction after discontinuation of serotonin reuptake inhibiting antidepressants, 5 alpha-reductase inhibitors and isotretinoin.OBJECTIVE: To develop diagnostic criteria for post-SSRI sexual dysfunction (PSSD), persistent genital arousal disorder (PGAD) following serotonin reuptake inhibitors, post-finasteride syndrome (PFS) and post-retinoid sexual dysfunction (PRSD).METHODS: The original draft was designed using data from two published case series (Hogan et al., 2014 and Healy et al., 2018), which represent the largest public collections of data on these enduring conditions. It was further developed with the involvement of a multidisciplinary panel of experts.RESULTS: A set of criteria were agreed upon for each of the above conditions. Features of PSSD, PFS and PRSD commonly include decreased genital and orgasmic sensation, decreased sexual desire and erectile dysfunction. Ancillary non-sexual symptoms vary depending on the specific condition but can include emotional blunting and cognitive impairment. PGAD presents with an almost mirror image of unwanted sensations of genital arousal or irritability in the absence of sexual desire. A new term, post-SSRI asexuality, is introduced to describe a dampening of sexual interest and pleasure resulting from a pre-natal or pre-teen exposure to a serotonin reuptake inhibitor.CONCLUSIONS: These criteria will help in both clinical and research settings. As with all criteria, they will likely need modification in the light of developments.

BackgroundOver 400 variants in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) are CF-causing. CFTR modulators target variants to improve lung function, but marked variability in response exists and current therapies do not address all CF-causing variants highlighting unmet needs. Alternative epithelial ion channel/transporters such as SLC26A9 could compensate for CFTR dysfunction, providing therapeutic targets that may benefit all individuals with CF.MethodWe investigate the relationship between rs7512462, a marker ofSLC26A9activity, and lung function pre- and post-treatment with CFTR modulators in Canadian and US CF cohorts, in the general population, and in those with chronic obstructive pulmonary disease (COPD).ResultsRs7512462 CC genotype is associated with greater lung function in CF individuals with minimal function variants (for which there are currently no approved therapies; p=0.008); and for gating (p=0.033) and p.Phe508del/ p.Phe508del (p=0.006) genotypes upon treatment with CFTR modulators. In parallel, human nasal epithelia with CC and p.Phe508del/p.Phe508del after Ussing chamber analysis of a combination of approved and experimental modulator treatments show greater CFTR function (p=0.0022). Beyond CF, rs7512462 is associated with lung function in a meta-analysis of the UK Biobank and Spirometa Consortium (min p=2.74×0-44) and provides p=0.0891 in an analysis of COPD case-control status in the UK Biobank defined by spirometry.ConclusionThese findings support SLC26A9 as a therapeutic target to improve lung function for all people with CF and in individuals with other obstructive lung diseases.

Introduction Patients with Peyronie's disease may experience significat distress. The choice of treatment depends on a variety of factors, including the stage of the disease, the presence of pain, severity and direction of the curvature, penile length and the quality of erectile function. Aim To review the evidence associated with surgical treatment of Peyronie‘s Disease and provide clinical recommendations on behalf of the European Society for Sexual Medicine. 131 peer-reviewed studies and systematic reviews, which were published from 2009 to 2019 in the English language, were included. Methods MEDLINE, Google Scholar and EMBASE were searched for randomized clinical trials, meta-analyses, open-label prospective and retrospective studies. Main Outcome Measure The panel provided statements on clinically relevant questions including patient involvement in the decision process, indications for surgery, choice of the approach, and the management of patient expectations. A comparison of the different grafts used in patients who have undergone plaque incision/excision and grafting in order to identify an ideal graft, has been carried out. The prevalence of postoperative complications has been summarized. Levels of evidence were provided according to the Oxford 2011 criteria and Oxford Centre for Evidence-Based Medicine recommendations. Results In order to allow shared decision making, a patient preoperative counselling regarding the pros and cons of each intervention is recommended. In particular, adverse effects of surgical treatments should be discussed to set realistic understanding and expectations of surgical outcomes and ultimately improve postoperative satisfaction rates. Surgical treatment should be only offered in the chronic phase of the condition, when the deformity and/or degree of erectile dysfunction, prevent patients from engaging in satisfying sexual interaction, or if the deformity is the cause of severe bother. Conclusions Current European Society for Sexual Medicine recommendations cover several aspects of Peyronie's disease treatment. These recommendations aim both to ensure patients and partners have accurate and realistic expectations of their treatment options, as well as to formulate algorithms to guide clinician management pathways. Osmonov D, Ragheb A, Ward S et al, ESSM Position Statement on Surgical Treatment of Peyronie's Disease. Sex Med 2022;10:100459.

BACKGROUND AND PURPOSE The ability to switch between walking patterns (ie, locomotor switching) is vital for successful community navigation and may be impacted by poststroke impairments. Thus, the purpose of this work was to examine locomotor switching and the relationship between locomotor switching and fluid cognition in individuals after stroke compared with neurotypical adults. METHODS Twenty-nine individuals more than 6 months after stroke and 18 neurotypical adults participated in a 2-day study. On day 1, participants were taught a new walking pattern on the treadmill and then locomotor switching was assessed by instructing participants to switch between the new walking pattern and their usual walking pattern. The change between these 2 patterns was calculated as the switching index. On day 2, the NIH Toolbox Cognition Battery was administered to obtain the Fluid Cognition Composite Score (FCCS), which reflected fluid cognition. The switching index was compared between groups using an analysis of covariance, and the relationship between locomotor switching and fluid cognition was assessed with regression. RESULTS Individuals after stroke had significantly lower switching indexes compared with neurotypical adults (P = 0.03). The regression showed a significant interaction between group and FCCS (P = 0.002), with the FCCS predicting the switching index in neurotypical adults but not in individuals after stroke. DISCUSSION AND CONCLUSIONS Individuals after stroke appear to have deficits in locomotor switching compared with neurotypical adults. The relationship between fluid cognition and locomotor switching was significant in neurotypical adults but not in individuals after stroke. Future work to understand the relationship between specific cognitive domains and locomotor switching is needed (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A361).

This document incorporates recommendations from the 2021 Canadian Thoracic Society (CTS) Guideline – A Focused Update on the Management of Very Mild and Mild Asthma1 with previous statements and re...

ObjectiveTo evaluate the frequency of and risk factors for stroke as a presenting feature in adult patients with secundum atrial septal defect (ASD); rates of post-closure atrial fibrillation (AF) and stroke were also assessed.MethodsWe retrospectively reviewed adult patients who presented with an ASD between 2002 and 2018, excluding those with known atrial arrhythmias. Risk factors for stroke were identified using multivariable logistic regression. Post-closure stroke was evaluated using survival analysis stratified by the presence of post-procedure AF.ResultsOf 346 patients with ASD (median age 44 years), 34 (10%) presented with a history of stroke. Independent risk factors included elevated body mass index over 25 (OR: 18.2; 95% CI: 4.0 to 82.2; pConclusionsIn this study population, the incidence of stroke prior to ASD closure among patients without atrial arrhythmias was 10%. Risk factors included obesity, smoking and prominent Eustachian valve anatomy. Lifestyle changes should be recommended for at-risk patients, and it may be reasonable to consider ASD closure in the absence of haemodynamic indications in patients at increased risk of stroke.

Tetyana Kendzerska,1– 3 Carl van Walraven,1– 3 Daniel I McIsaac,1,3,4 Marcus Povitz,5,6 Sunita Mulpuru,1,2 Isac Lima,1,3 Robert Talarico,1,3 Shawn D Aaron,1,2 William Reisman,5,7 Andrea S Gershon3,8,9 1Department of Medicine, The Ottawa Hospital Research Institute/The Ottawa Hospital, Ottawa, Ontario, Canada; 2Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada; 3ICES, Ottawa, Toronto, Ontario, Canada; 4Departments of Anesthesiology & Pain Medicine, University of Ottawa and Ottawa Hospital, Ottawa, Ontario, Canada; 5Department of Medicine at Schulich School of Medicine and Dentistry at Western University, London, Ontario, Canada; 6Cumming School of Medicine, Department of Medicine, University of Calgary, Calgary, Alberta, Canada; 7Department of Medicine, London Health Sciences Centre, London, Ontario, Canada; 8Faculty of Medicine, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; 9Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, CanadaCorrespondence: Tetyana KendzerskaOttawa Hospital Research Institute, Division of Respirology, University of Ottawa, The Ottawa Hospital, Civic Campus, 1053 Carling Ave, Ottawa, ON, K1Y 4E9, CanadaEmail tkendzerska@toh.caBackground: There is limited evidence on whether obstructive sleep apnea (OSA) can be accurately identified using health administrative data.Study Design and Methods: We derived and validated a case-ascertainment model to identify OSA using linked provincial health administrative and clinical data from all consecutive adults who underwent a diagnostic sleep study (index date) at two large academic centers (Ontario, Canada) from 2007 to 2017. The presence of moderate/severe OSA (an apnea–hypopnea index≥ 15) was defined using clinical data. Of 39 candidate health administrative variables considered, 32 were tested. We used classification and regression tree (CART) methods to identify the most parsimonious models via cost-complexity pruning. Identified variables were also used to create parsimonious logistic regression models. All individuals with an estimated probability of 0.5 or greater using the predictive models were classified as having OSA.Results: The case-ascertainment models were derived and validated internally through bootstrapping on 5099 individuals from one center (33% moderate/severe OSA) and validated externally on 13,486 adults from the other (45% moderate/severe OSA). On the external cohort, parsimonious models demonstrated c-statistics of 0.75– 0.81, sensitivities of 59– 60%, specificities of 87– 88%, positive predictive values of 79%, negative predictive values of 73%, positive likelihood ratios (+LRs) of 4.5– 5.0 and –LRs of 0.5. Logistic models performed better than CART models (mean integrated calibration indices of 0.02– 0.03 and 0.06– 0.12, respectively). The best model included: sex, age, and hypertension at the index date, as well as an outpatient specialty physician visit for OSA, a repeated sleep study, and a positive airway pressure treatment claim within 1 year since the index date.Interpretation: Among adults who underwent a sleep study, case-ascertainment models for identifying moderate/severe OSA using health administrative data had relatively low sensitivity but high specificity and good discriminative ability. These findings could help study trends and outcomes of OSA individuals using routinely collected health care data.Keywords: obstructive sleep apnea, case-ascertainment modelling, health administrative data

OBJECTIVE. The purpose of this article is to review the clinical and imaging features of diffuse pulmonary hemorrhage. CONCLUSION. Diffuse pulmonary hemorrhage is a life-threatening syndrome associated with a wide variety of underlying pathologic categories. Nonspecific clinical and imaging features pose challenges to promptly diagnosing this condition. Chest radiography commonly shows alveolar opacification, and CT reveals the extent of disease. Integration of clinical, radiologic, laboratory, and pathologic findings facilitates timely diagnosis and etiologic identification.

Purpose Cystic fibrosis (CF), caused by pathogenic variants in the CF transmembrane conductance regulator (CFTR), affects multiple organs including the exocrine pancreas, which is a causal contributor to cystic fibrosis–related diabetes (CFRD). Untreated CFRD causes increased CF-related mortality whereas early detection can improve outcomes. Methods Using genetic and easily accessible clinical measures available at birth, we constructed a CFRD prediction model using the Canadian CF Gene Modifier Study (CGS; n = 1,958) and validated it in the French CF Gene Modifier Study (FGMS; n = 1,003). We investigated genetic variants shown to associate with CF disease severity across multiple organs in genome-wide association studies. Results The strongest predictors included sex, CFTR severity score, and several genetic variants including one annotated to PRSS1, which encodes cationic trypsinogen. The final model defined in the CGS shows excellent agreement when validated on the FGMS, and the risk classifier shows slightly better performance at predicting CFRD risk later in life in both studies. Conclusion We demonstrated clinical utility by comparing CFRD prevalence rates between the top 10% of individuals with the highest risk and the bottom 10% with the lowest risk. A web-based application was developed to provide practitioners with patient-specific CFRD risk to guide CFRD monitoring and treatment.

BACKGROUND Passive-dynamic ankle-foot orthosis (PD-AFO) bending stiffness, which assists plantar flexor function, can be prescribed to improve poststroke gait. However, outcomes with PD-AFOs are variable likely because of improper personalization. We implemented a prescription model that objectively personalizes PD-AFO bending stiffness based on each individual's level of plantar flexor weakness (quantitatively prescribed PD-AFO). OBJECTIVES To evaluate whether a quantitatively prescribed PD-AFO improves peak paretic plantar flexion moment compared with the original AFO for individuals after stroke and to examine the immediate effects of wearing a quantitatively prescribed PD-AFO. STUDY DESIGN This is a repeated-measures study. METHODS PD-AFO bending stiffness was personalized for 10 individuals after stroke through the previously developed prescription model. Participants underwent an instrumented gait analysis while wearing their original AFO and the quantitatively prescribed PD-AFO. RESULTS Participants' peak paretic plantar flexion moment significantly increased while wearing the quantitatively prescribed PD-AFO compared with the original AFO. In addition, participants showed different levels of improvements in a series of other key biomechanical and walking performance parameters with PD-AFO use. Some participants showed improvements in all parameters, whereas others showed moderate to no improvements. CONCLUSIONS Quantitatively prescribed PD-AFO bending stiffness resulted in inconsistent improvements in biomechanical and walking performance parameters, which warrants further investigation. Future work should investigate whether more consistent benefits are seen with faster walking speeds and longer-term PD-AFO use. In addition, future work should conduct larger-scale studies that aim to understand and optimize orthosis-patient matching for all AFO designs/characteristics.

Objectives The aim of this study was to assess 1-year clinical outcomes among high-risk patients with failed surgical mitral bioprostheses who underwent transseptal mitral valve-in-valve (MViV) with the SAPIEN 3 aortic transcatheter heart valve (THV) in the MITRAL (Mitral Implantation of Transcatheter Valves) trial. Background The MITRAL trial is the first prospective study evaluating transseptal MViV with the SAPIEN 3 aortic THV in high-risk patients with failed surgical mitral bioprostheses. Methods High-risk patients with symptomatic moderate to severe or severe mitral regurgitation (MR) or severe mitral stenosis due to failed surgical mitral bioprostheses were prospectively enrolled. The primary safety endpoint was technical success. The primary THV performance endpoint was absence of MR grade ≥2+ or mean mitral valve gradient ≥10 mm Hg (30 days and 1 year). Secondary endpoints included procedural success and all-cause mortality (30 days and 1 year). Results Thirty patients were enrolled between July 2016 and October 2017 (median age 77.5 years [interquartile range (IQR): 70.3 to 82.8 years], 63.3% women, median Society of Thoracic Surgeons score 9.4% [IQR: 5.8% to 12.0%], 80% in New York Heart Association functional class III or IV). The technical success rate was 100%. The primary performance endpoint in survivors was achieved in 96.6% (28 of 29) at 30 days and 82.8% (24 of 29) at 1 year. Thirty-day all-cause mortality was 3.3% and was unchanged at 1 year. The only death was due to airway obstruction after swallowing several pills simultaneously 29 days post-MViV. At 1-year follow-up, 89.3% of patients were in New York Heart Association functional class I or II, the median mean mitral valve gradient was 6.6 mm Hg (interquartile range: 5.5 to 8.9 mm Hg), and all patients had MR grade ≤1+. Conclusions Transseptal MViV in high-risk patients was associated with 100% technical success, low procedural complication rates, and very low mortality at 1 year. The vast majority of patients experienced significant symptom alleviation, and THV performance remained stable at 1 year.

Objectives The authors report 1-year outcomes of high-risk patients with failed surgical annuloplasty rings undergoing transseptal mitral valve–in–ring (MViR) with the SAPIEN 3 aortic transcatheter heart valve (THV). Background The MITRAL (Mitral Implantation of Transcatheter Valves) trial is the first prospective study evaluating transseptal MViR with the SAPIEN 3 aortic THV in high-risk patients with failed surgical annuloplasty rings. Methods Prospective enrollment of high-risk patients with symptomatic moderate to severe or severe mitral regurgitation (MR) or severe mitral stenosis and failed annuloplasty rings at 13 U.S. sites. The primary safety endpoint was technical success. The primary THV performance endpoint was absence of MR grade ≥2+ or mean mitral valve gradient ≥10 mm Hg (30 days and 1 year). Secondary endpoints included procedural success and all-cause mortality (30 days and 1 year). Results Thirty patients were enrolled between January 2016 and October 2017 (median age 71.5 years [interquartile range: 67.0 to 76.8 years], 36.7% women, median Society of Thoracic Surgeons score 7.6% [interquartile range: 5.1% to 11.8%], 76.7% in New York Heart Association functional class III or IV). Technical success was 66.7% (driven primarily by need for a second valve in 6 patients). There was no intraprocedural mortality or conversion to surgery. The primary performance endpoint was achieved in 85.7% of survivors at 30 days (24 of 28) and 89.5% of patients alive at 1 year with echocardiographic data available (17 of 19). All-cause mortality at 30 days was 6.7% and at 1 year was 23.3%. Among survivors at 1-year follow-up, 84.2% were in New York Heart Association functional class I or II, the median mean mitral valve gradient was 6.0 mm Hg (interquartile range: 4.7 to 7.3 mm Hg), and all had ≤1+ MR. Conclusions Transseptal MViR was associated with a 30-day mortality rate lower than predicted by the Society of Thoracic Surgeons score. At 1 year, transseptal MViR was associated with symptom improvement and stable THV performance.

Background There is significant variability in poststroke locomotor learning that is poorly understood and affects individual responses to rehabilitation interventions. Cognitive abilities relate to upper extremity motor learning in neurologically intact adults, but have not been studied in poststroke locomotor learning. Objective To understand the relationship between locomotor learning and retention and cognition after stroke. Methods Participants with chronic (>6 months) stroke participated in 3 testing sessions. During the first session, participants walked on a treadmill and learned a new walking pattern through visual feedback about their step length. During the second session, participants walked on a treadmill and 24-hour retention was assessed. Physical and cognitive tests, including the Fugl-Meyer-Lower Extremity (FM-LE), Fluid Cognition Composite Score (FCCS) from the NIH Toolbox -Cognition Battery, and Spatial Addition from the Wechsler Memory Scale-IV, were completed in the third session. Two sequential regression models were completed: one with learning and one with retention as the dependent variables. Age, physical impairment (ie, FM-LE), and cognitive measures (ie, FCCS and Spatial Addition) were the independent variables. Results Forty-nine and 34 participants were included in the learning and retention models, respectively. After accounting for age and FM-LE, cognitive measures explained a significant portion of variability in learning ( R2 = 0.17, P = .008; overall model R2 = 0.31, P = .002) and retention (Δ R2 = 0.17, P = .023; overall model R2 = 0.44, P = .002). Conclusions Cognitive abilities appear to be an important factor for understanding locomotor learning and retention after stroke. This has significant implications for incorporating locomotor learning principles into the development of personalized rehabilitation interventions after stroke.

The COVID19 pandemic brought unprecedented disruption to healthcare. Staggering morbidity, mortality, and economic losses prompted the review and refinement of care for structural heart disease (SHD). To mitigate negative impacts in the face of crisis or capacity constraints, this paper offers best practice recommendations for Planning Efficient and Resource Leveraging Systems (PEARLS) in structural heart programs. A systematic assessment is recommended for hospital capacity, Heart Team roles and functions, and patient and procedural risks associated with increased resource utilization. Strategies, tactics, and pathways are provided for the delivery of patient-centered, efficient and resource-leveraging care from referral to follow-up. Through the optimal use of capacity and resources, paired with dynamic triage, forecasting, and surveillance, Heart Teams may aspire to plan and implement an optimized system of care for SHD.

Aim: Patient-reported symptoms, functioning and overall quality of life (QoL) were compared between dacomitinib and gefitinib in ARCHER 1050. Patients & methods: Patients (n = 448) with advanced EGFR mutation-positive non-small-cell lung cancer completed the EORTC-QLQ-C30 questionnaire and its lung-specific module, LC-13. Mean scores over time were analyzed using a mixed model for repeated measures. Results: Both treatments showed early improvement in disease-related symptoms that was maintained during treatment. Treatment-related diarrhea and sore mouth decreased following dose reduction with dacomitinib. There were no clinically meaningful changes in functioning and overall QoL in either treatment group. Conclusion: Longer treatment duration, enabled by dose reduction, allowed patients on dacomitinib to improve treatment-related symptoms and maintain functioning and overall QoL for longer than gefitinib.

Highlights • This review presents a conceptual framework linking motor control impairments after sport-related concussion (SRC) to elevated risk for lower extremity musculoskeletal injury. • Athletes with SRC demonstrate neuroanatomic and neurophysiologic changes relevant to motor control and altered motor function that support the conceptual framework. • Alterations in motor function after SRC include decreased muscle activation and force production, modified movement patterns, poor balance, and impaired motor task performance with or without a simultaneous cognitive task. • These deficits indicate a need to evaluate for and rehabilitate motor control impairments after SRC through the return to sport continuum to mitigate musculoskeletal injury risk., This review presents a conceptual framework and supporting evidence that links impaired motor control after sport-related concussion (SRC) to increased risk for musculoskeletal injury. Multiple studies have found that athletes who are post-SRC have higher risk for musculoskeletal injury compared to their counterparts. A small body of research suggests that impairments in motor control are associated with musculoskeletal injury risk. Motor control involves the perception and processing of sensory information and subsequent coordination of motor output within the central nervous system to perform a motor task. Motor control is inclusive of motor planning and motor learning. If sensory information is not accurately perceived or there is interference with sensory information processing and cognition, motor function will be altered, and an athlete may become vulnerable to injury during sport participation. Athletes with SRC show neuroanatomic and neurophysiological changes relevant to motor control even after meeting return to sport criteria, including a normal neurological examination, resolution of symptoms, and return to baseline function on traditional concussion testing. In conjunction, altered motor function is demonstrated after SRC in muscle activation and force production, movement patterns, balance/postural stability, and motor task performance, especially performance of a motor task paired with a cognitive task (i.e., dual-task condition). The clinical implications of this conceptual framework include a need to intentionally address motor control impairments after SRC to mitigate musculoskeletal injury risk and to monitor motor control as the athlete progresses through the return to sport continuum., Graphical abstract Image, graphical abstract

This asthma guideline update focuses on the management of individuals with asthma at the mild end of the spectrum. It applies to children 1 year of age and over and adults. This update was initiate...

This study aimed to evaluate short- and long-term outcomes of kidney transplantation over 37 years in a national referral center and compare outcomes between Israeli Jewish and Arab children. Data on 599 pediatric transplantations performed in 545 children during 1981–2017, including demographic parameters, kidney failure disease profile, and pre-transplant dialysis duration, were retrieved from our computerized database and patient files. Patient and graft survival were estimated using the Kaplan-Meier method. Twenty-year patient survival was 91.4% for live donor (LD) and 80.2% for deceased donor (DD) kidney recipients. Respective 10-year and 20-year graft survival rates for first kidney-only transplants were 75.2% and 47.0% for LD and 60.7% and 38.4% for DD grafts. Long-term graft survival improved significantly (p < 0.001) over the study period for recipients of both LD and DD allografts and reached 7-year graft survival of 92.0% and 71.3%, respectively. The proportion of DD transplantations was higher in the Arab subpopulation: 73.8% vs. 48.4% (p < 0.001). Graft survival was not associated with age at transplantation and did not differ between the Arab (N = 202) and Jewish children (N = 343). Median (IQR) waiting time on dialysis did not differ significantly between the Arab and Jewish children: 18 (10–30) and 15 (9–30) months, respectively (p Mann-Whitney = 0.312). Good and progressively improving long-term results were obtained in pediatric kidney transplantation at our national referral center, apparently due to expertise gained over time and advances in immunosuppression. Equal access to DD kidney transplant and similar graft survival were found between ethnic groups.

Understanding the Anthropocene—as both a set of physiological phenomena and as an existential crisis of modernity—requires interrogating Earth-changing transformations in food and agriculture. Agri...

Background Eccentricity of coronary ostial positions in relation to the aortic valve cusp may influence the target laceration location in BASILICA (Bioprosthetic or native Aortic Scallop Intentional Laceration to prevent Coronary Artery obstruction). Eccentricity of the coronary ostia in relation to coronary cusps of native and valve-in-valve transcatheter aortic valve replacement (TAVR) was not well described before. Methods A total of 121 pre-TAVR patients’ CT data (72 native valves TAVR and 49 bioprosthetic surgical valves TAVR) was included and coronary ostial eccentricity angles were measured and compared. Coronary ostial angles were measured between mid-cusp line to coronary ostium in CT perpendicular images. Results In the overall cohort, the right coronary artery (RCA) had an eccentric origin in the majority of cases, favoring the commissure between the right and the non coronary cusp (17.0°, IQR; 10–25). On the other hand, the left coronary artery (LCA) originated most commonly near center of the cusp position (0°, IQR; -8 -7.5) In comparison of native and bioprosthetic valves, RCA ostial angles were more eccentric in native valves (19.0°, IQR; 12–26) than in bioprosthetic valves (14.0°, IQR; 3–20) (p = 0.004). Whereas, LCA ostial angle has no significant differences between native valves (−2.0°, IQR;-7.75-5.75) and bioprosthetic valves (1°, IQR;-8-13), (p = 0.6). Conclusion RCA ostia often have an eccentric origin towards the non-coronary cusp, especially in native aortic valves, while LCA ostia commonly originate near the center of the cusp. This finding may contribute to better performance of BASILICA procedures.

Introduction Rodent animal models are currently the most used in vivo model in translational studies looking into the pathophysiology of erectile dysfunction after nerve-sparing radical prostatectomy. Aim This European Society for Sexual Medicine (ESSM) statement aims to guide scientists toward utilization of the rodent model in an appropriate, timely, and proficient fashion. Methods MEDLINE and EMBASE databases were searched for basic science studies, using a rodent animal model, looking into the consequence of pelvic nerve injury on erectile function. Main outcome measures The authors present a consensus on how to best perform experiments with this rodent model, the details of the technique, and highlight possible pitfalls. Results Owing to the specific issue—basic science—Oxford 2011 Levels of Evidence criteria cannot be applied. However, ESSM statements on this topic will be provided in which we summarize the ESSM position on various aspects of the model such as the use of the Animal Research Reporting In Vivo Experiments guideline and the of common range parameter for nerve stimulation. We also highlighted the translational limits of the model. Conclusion The following statements were formulated as a suggestive guidance for scientists using the cavernous nerve injury model. With this, we hope to standardize and further improve the quality of research in this field. It must be noted that this model has its limitations.

BACKGROUND, PURPOSE/OBJECTIVE: Walking behavior in the chronic stroke population is multi-factorial. Previous work focused on the role of physical and biopsychosocial factors in understanding daily stepping post stroke. However, qualitative evidence suggests that social and physical environmental factors also affect daily stepping in those with stroke. The purpose of this study was to understand the role of social and physical environmental factors in daily stepping after stroke. METHODS: 249 individuals ≥ 6 months post stroke were included in this cross-sectional analysis (129 females, mean age 62.98 years, SD 11.94). The social environment included living situation, work status, and marital status. The physical environment included the Area Deprivation Index (ADI) and Walk Score. At least three days of stepping was collected using an accelerometry-based device. Predictors were entered sequentially into a regression model: demographic characteristics, social environmental factors, and physical environmental factors. RESULTS: After adjusting for demographic factors, social environmental factors explained 6.2% (p= .017) of the variance in post stroke daily stepping. The addition of physical environmental factors improved the model (ΔR(2) = .029, p = .024). The final model explained 9.2% (p=.003) of the variance in daily stepping. Lower area deprivation (ADI β= −0.178, p= .015) and working (working vs. retired β= −0.187, p= 0.029 and working vs. unemployed β= −0.227, p=.008) were associated with greater daily stepping. DISCUSSION/CONCLUSION: Social and physical environmental factors predicted daily stepping and should be considered when setting expectations relative to the effects of rehabilitation on daily stepping in individuals poststroke.

Joint dislocations account for a small but important portion of all athletic injuries, with most occurring at the glenohumeral, patellofemoral, and interphalangeal joints. Athletic trainers are responsible for managing acute joint-dislocation injuries, which may include performing closed-reduction techniques when appropriate. To achieve optimal patient outcomes, the clinician should be formally trained and skilled in performing various techniques and familiar with the evidence supporting the selection of each technique. In this clinical review, we outline general reduction procedures and then summarize and synthesize the existing literature on common closed-reduction techniques for glenohumeral-, patellofemoral-, and interphalangeal-joint dislocations. When appropriate, the content has been adapted to be specific to the athletic trainer's scope of practice.

Over the past few years, an increase use of low-intensity shockwave therapy (LISWT) for the treatment of erectile dysfunction (ED) has been observed. However, many controversies in the scientific literature about its efficacy still exist. We aimed to investigate changes in the pattern of usage and attitudes toward LISWT for ED among experts over the last years. A dedicated online survey was sent to delegates at the Congress for the EAU Section of Andrological Urology (ESAU) in Prague from 31st October to 1st November 2019. The survey captured demographic data, professional background, and the experience and personal knowledge about LISWT. The results were compared with a previous survey conducted in 2016 and investigating the same topics in order to assess changes in the knowledge and opinion on LISWT over time. Overall, 172 and 192 questionnaires were available from 2019 and 2016, respectively. Participants in the 2019 survey were 80 (45.7%) urologists, 52 (29.7%) uro-andrologists, and 34 (19.4%) residents in urology, from 30 different countries. Compared to the past, we observed an increase of respondents who were familiar with LISWT (75 vs. 95%; p < 0.0001) and who performed LISWT in their routine practice (38% in 2019 vs. 14% in 2016; p < 0.0001). Conversely, no changes in terms of overall perception of treatment efficacy were registered over time (68% in 2019 vs. 72% in 2016 considered LISWT as an effective treatment, respectively (p = 0.5)). An increased proportion of physicians had suggested a wider application of LISWT, and some even advocated its use in nonvasculogenic ED (33% in 2019 vs. 5.9% in 2016; p < 0.0001). The awareness and clinical application of LISWT for ED have increased over time, despite the lack of robust evidence in terms of effectiveness. Further research on the benefit of LISWT is needed to guide physicians in the therapeutic management of ED patients.

IntroductionLocomotor high-intensity interval training (HIIT) is a promising intervention for stroke rehabilitation that typically involves bursts of fast treadmill walking alternated with recovery periods. However, overground translation of treadmill speed gains has been somewhat limited, some important outcomes have not been tested and baseline response predictors are poorly understood. This pilot study aimed to guide future research by assessing preliminary outcomes of combined overground and treadmill HIIT.MethodsTen participants >6 months post stroke completed a multi-domain assessment battery before and after a 4-week no-intervention control phase, then again after a 4-week treatment phase involving 12 sessions of overground and treadmill HIIT. The primary analyses assessed relative changes in overground and treadmill walking speeds after HIIT, evaluated responsiveness of different outcome measures and estimated effects of baseline gait speed on treatment response.ResultsOverground and treadmill gait function both improved during the treatment phase relative to the control phase, with overground speed changes averaging 61% of treadmill speed changes (95% CI: 33-89%). Moderate or larger effect sizes were observed for measures of gait performance, balance, fitness, cognition, fatigue, perceived change and brain volume. Participants with baseline comfortable gait speed DiscussionFuture locomotor HIIT studies should consider including: 1) both overground and treadmill training; 2) measures of cognition, fatigue and brain volume, to complement typical motor & fitness assessment; and 3) baseline gait speed as a covariate.

Objective It was previously found that balance self-efficacy mediated the relationship between physical capacity and participation after stroke. The effect of other factors that influence participation, such as depression, on this relationship has not been explored. This study examined the effect of symptoms of depression on the mediated relationship between physical capacity and participation by balance self-efficacy in individuals after stroke. Methods In this cross-sectional study, 282 persons with chronic stroke (>6 months) were classified as having either low or high Geriatric Depression Scale scores. This study used a multiple group structural equation model to test moderated mediation by comparing a constrained model (indicating no effect of depression on the mediation) and an unconstrained model (indicating an effect of depression on the mediation). The models were compared using a chi-squared difference test. Results The chi-squared difference test suggested that the unconstrained model was a better fit, indicating that depressive symptoms moderated the mediated relationship between physical capacity and participation (χ2(3, N = 282) = 9.0). In the Low Depression group, a significant indirect effect indicated that balance self-efficacy did mediate the relationship between physical capacity and participation. There was no significant indirect effect in the High Depression group. Conclusion The results suggest the relationship between physical capacity and participation appears to be mediated by balance self-efficacy in individuals after stroke with low reports of depressive symptoms, but in those with high reports of depressive symptoms, physical capacity and balance self-efficacy are unrelated to participation. Impact Targeting balance self-efficacy to improve post-stroke participation may be beneficial only for individuals with low reports of depression. In individuals after stroke with high reports of depression, treatment should include and emphasize the treatment of those depressive symptoms. Additional work further examining these complex relationships is warranted.

Introduction Radiofrequency (RF)-based treatment has been introduced as an esthetic alternative treatment for various medical indications without the scientific backup of a satisfactory body of evidence. Furthermore, the United States Food and Drug Administration issued a warning regarding the safety of energy-based technologies for indications such as vaginal “rejuvenation," cosmetic vaginal treatment, vaginal conditions related to menopause, and symptoms of urinary incontinence and sexual function on July 30, 2018. Aim To perform a thorough review of the existing literature regarding RF-based vaginal devices for the treatment of female genitourinary indications and summarize the evidence available in a few short statements. Methods A thorough review of the literature regarding RF treatments for gynecological indications was performed based on several databases. Studies that included at least 15 patients were eligible for analysis. Main Outcome Measure Efficacy of RF devices for different genitourinary indications. Results Although a high level of heterogeneity of studies poses a serious challenge, the committee reached a decision on several statements related to the use of RF-based devices for genitourinary indications. Clinical Implications RF-based vaginal treatments have not been studied thoroughly enough in order to establish decisive recommendations regarding their safety and efficacy. Strength & Limitations These position statements have been established by a group of experts. The lack of strong evidence makes it difficult to give decisive recommendations. Conclusions Further randomized controlled trials with proper methodology and design are required to establish both benefits and possible harm these treatments may have in both short and long term for all the different indications studied.

BACKGROUND AND OBJECTIVES: High-intensity interval training (HIIT) is a promising strategy for improving gait and fitness after stroke, but optimal parameters remain unknown. We tested the effects of short vs long interval type and over-ground vs treadmill mode on training intensity. METHODS: Using a repeated measures design, 10 participants with chronic hemiparetic gait performed 12 HIIT sessions over 4 weeks, alternating between short and long-interval HIIT sessions. Both protocols included 10 minutes of over-ground HIIT, then 20 minutes of treadmill HIIT and another 10 minutes over-ground. Short-interval HIIT involved 30 second bursts at maximum safe speed and 30–60 second rest periods. Long-interval HIIT involved 4-minute bursts at ~90% of peak heart rate (HR(peak)) and 3-minute recovery periods at ~70% HR(peak). RESULTS: Compared with long-interval HIIT, short-interval HIIT had significantly faster mean overground speeds (0.75 vs 0.67 m/s) and treadmill speeds (0.90 vs 0.51 m/s), with similar mean treadmill HR (82.9 vs 81.8 %HR(peak)) and session perceived exertion (16.3 vs 16.3), but lower overground HR (78.4 vs 81.1 %HR(peak)) and session step counts (1481 vs 1672). For short-interval HIIT, training speeds and HR were significantly higher on the treadmill vs. overground. For long-interval HIIT, the treadmill elicited HR similar to overground training at significantly slower speeds. CONCLUSIONS: Both short and long-interval HIIT elicit high intensities but emphasize different dosing parameters. Based on these preliminary findings and previous studies, we hypothesize that overground and treadmill short-interval HIIT could be optimal for improving gait speed and overground long-interval HIIT could be optimal for improving gait endurance.

Purpose To describe and compare associations with macular retinal nerve fiber layer (mRNFL), ganglion cell complex (GCC), and ganglion cell–inner plexiform layer (GCIPL) thicknesses in a large cohort. Design Cross-sectional study. Participants We included 42 044 participants in the UK Biobank. The mean age was 56 years. Methods Spectral-domain OCT macular images were segmented and analyzed. Corneal-compensated intraocular pressure (IOPcc) was measured with the Ocular Response Analyzer (Reichert, Corp., Buffalo, NY). Multivariable linear regression was used to examine associations with mean mRNFL, GCC, and GCIPL thicknesses. Factors examined were age, sex, ethnicity, height, body mass index (BMI), smoking status, alcohol intake, Townsend deprivation index, education level, diabetes status, spherical equivalent, and IOPcc. Main Outcome Measures Thicknesses of mRNFL, GCC, and GCIPL. Results We identified several novel independent associations with thinner inner retinal thickness. Thinner inner retina was associated with alcohol intake (most significant for GCIPL: –0.46 μm for daily or almost daily intake compared with special occasion only or never [95% confidence interval (CI), 0.61–0.30]; P = 1.1×10–8), greater social deprivation (most significant for GCIPL: –0.28 μm for most deprived quartile compared with least deprived quartile [95% CI, –0.42 to –0.14]; P = 6.6×10–5), lower educational attainment (most significant for mRNFL: –0.36 μm for less than O level compared with degree level [95% CI, –0.45 to 0.26]; P = 2.3×10–14), and nonwhite ethnicity (most significant for mRNFL comparing blacks with whites: –1.65 μm [95% CI, –1.86 to –1.43]; P = 2.4×10–50). Corneal-compensated intraocular pressure was associated most significantly with GCIPL (–0.04 μm/mmHg [95% CI, –0.05 to –0.03]; P = 4.0×10–10) and was not associated significantly with mRNFL (0.00 μm/mmHg [95% CI, –0.01 to 0.01]; P = 0.77). The variables examined explained a greater proportion of the variance of GCIPL (11%) than GCC (6%) or mRNFL (7%). Conclusions The novel associations we identified may be important to consider when using inner retinal parameters as a diagnostic tool. Associations generally were strongest with GCIPL, particularly for IOP. This suggests that GCIPL may be the superior inner retinal biomarker for macular pathophysiologic processes and especially for glaucoma.

Background Individuals with acute-onset central nervous system (CNS) injury, including stroke, motor incomplete spinal cord injury, or traumatic brain injury, often experience lasting locomotor deficits, as quantified by decreases in gait speed and distance walked over a specific duration (timed distance). The goal of the present clinical practice guideline was to delineate the relative efficacy of various interventions to improve walking speed and timed distance in ambulatory individuals greater than 6 months following these specific diagnoses. Methods A systematic review of the literature published between 1995 and 2016 was performed in 4 databases for randomized controlled clinical trials focused on these specific patient populations, at least 6 months postinjury and with specific outcomes of walking speed and timed distance. For all studies, specific parameters of training interventions including frequency, intensity, time, and type were detailed as possible. Recommendations were determined on the basis of the strength of the evidence and the potential harm, risks, or costs of providing a specific training paradigm, particularly when another intervention may be available and can provide greater benefit. Results Strong evidence indicates that clinicians should offer walking training at moderate to high intensities or virtual reality-based training to ambulatory individuals greater than 6 months following acute-onset CNS injury to improve walking speed or distance. In contrast, weak evidence suggests that strength training, circuit (ie, combined) training or cycling training at moderate to high intensities, and virtual reality-based balance training may improve walking speed and distance in these patient groups. Finally, strong evidence suggests that body weight-supported treadmill training, robotic-assisted training, or sitting/standing balance training without virtual reality should not be performed to improve walking speed or distance in ambulatory individuals greater than 6 months following acute-onset CNS injury to improve walking speed or distance. Discussion The collective findings suggest that large amounts of task-specific (ie, locomotor) practice may be critical for improvements in walking function, although only at higher cardiovascular intensities or with augmented feedback to increase patient's engagement. Lower-intensity walking interventions or impairment-based training strategies demonstrated equivocal or limited efficacy. Limitations As walking speed and distance were primary outcomes, the research participants included in the studies walked without substantial physical assistance. This guideline may not apply to patients with limited ambulatory function, where provision of walking training may require substantial physical assistance. Summary The guideline suggests that task-specific walking training should be performed to improve walking speed and distance in those with acute-onset CNS injury although only at higher intensities or with augmented feedback. Future studies should clarify the potential utility of specific training parameters that lead to improved walking speed and distance in these populations in both chronic and subacute stages following injury. Disclaimer These recommendations are intended as a guide for clinicians to optimize rehabilitation outcomes for persons with chronic stroke, incomplete spinal cord injury, and traumatic brain injury to improve walking speed and distance.

Objectives To evaluate possible discrepancies between patients’ expectations concerning sexual side effects related to prostate cancer treatment, based on the obtained information prior to treatment. Moreover, to determine if demographic or clinical factors may have an effect on the accuracy of patients’ expectations concerning sexual side effects after treatment. Methods A multicenter, cross-sectional survey was performed among men treated with prostatectomy, brachytherapy, external-beam radiotherapy and/or hormonal therapy. Results In total, 412 questionnaires were analyzed. Of men with sexual side effects after treatment, 1 in 3 (32.5%, n = 109) reported their complaints as worse than expected; significantly more often reported by men treated surgically (P = .001), men with a local stage tumor (P = .005) and by men with a lower prostate-specific antigen level at diagnosis (P = .046). It was significantly less often reported by men treated with radiotherapy combined with hormonal therapy (P = .031). Men who used brochures as an information source reported their sexual side effects significantly less often as worse than expected (P Conclusion One in three men with sexual side effects after prostate cancer treatment, experienced their complaints as worse than expected based on the obtained information prior to treatment. Men treated with radiotherapy combined with hormonal therapy indicated less discrepancy between expectations and developed sexual side effects, whereas prostatectomy, low stage tumor and low prostate-specific antigen level were associated with more discrepancy. Brochures should be administered additionally to verbal information to improve patients’ understanding of possible sexual side effects and to enhance the accuracy of patients’ expectations.

Objective. To identify outcomes of patients undergoing emergency transcatheter aortic valve replacement (TAVR) and determine predictors of in-hospital mortality. Background. Emergency TAVR has emerged as a viable treatment strategy for patients with decompensated severe aortic stenosis and/or regurgitation; however, data on patients undergoing emergency TAVR are limited. Methods. All emergency TAVR procedures were identified from a single tertiary academic center between January 2015 and August 2018. Results. 31 patients underwent emergency TAVR due to cardiogenic shock (26 patients), electrical instability with incessant ventricular tachycardia (2 patients), severe refractory angina (2 patients), and decompensated heart failure with hypoxemic respiratory failure requiring mechanical ventilation (1 patient). Mechanical circulatory support (MCS) was used in 16 (51.6%). MCS initiation occurred immediately prior to TAVR in 10 patients and placed post-TAVR in 6 patients. 6 patients died before hospital discharge (in-hospital mortality 19.4%). 1-year and 2-year survival rates were 61.0% and 55.9%, respectively. Univariate predictors of in-hospital mortality were preprocedural pulmonary artery pulsatility index (PAPi) ≤1.8 (66.7% vs. 20.0%, p=0.01), intraprocedural cardiopulmonary resuscitation (CPR) (83.3% vs 4.0%, p≤0.001), acute kidney injury post-TAVR (80.0% vs. 4.2%, p≤0.001), initiation of dialysis post-TAVR (60.0% vs. 4.2%, p≤0.001), and MCS initiation post-TAVR (50.0% vs. 12.0%, p=0.03). MCS initiation before TAVR was associated with improved survival compared with post-TAVR initiation. Conclusion. Emergency TAVR in extreme risk patients with acute decompensated heart failure or cardiogenic shock secondary to severe aortic valve disease is associated with high in-hospital mortality rates. Careful patient selection taking into account right heart function, assessed by PAPi, and early utilization of MCS may improve survival following emergency TAVR.

Background Newborn screening (NBS) for cystic fibrosis (CF) not only identifies infants with a diagnosis of CF, but also those with an uncertain diagnosis of cystic fibrosis (CF), i.e. CF transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS) or CF screen positive inconclusive diagnosis (CFSPID). These infants have an uncertain long-term outcome and it is currently unclear around time of diagnosis, which infants are at higher risk of later fulfilling a CF diagnosis. In this study, we hypothesised that immunoreactive trypsinogen (IRT) levels, used in NBS as a marker of pancreatic disease and function, may reflect the degree of CFTR dysfunction in each individual and therefore would help to identify those with CRMS/CSPID who are later at risk for meeting the criteria of CF. Methods In this longitudinal, prospective study, infants with CRMS/CFSPID and CF were recruited and followed in 9 CF clinics (Canada and Italy). We compared NBS IRT levels between CF and CRMS/CFSPID, and between children with CRMS/CFSPID→CF and CRMS/CFSPID→CRMS/CFSPID during the period of June 2007 to April 2016. Results Ninety eight CRMS/CFSPID and 120 CF subjects were enrolled. During the study period, 14 (14.3%) CRMS/CFSPID subjects fulfilled the diagnostic criteria for CF (CRMS/CFSPID→CF), while the diagnosis remained uncertain (CRMS/CFSPID→ CRMS/CFSPID) in 84 (85.7%) subjects. Significantly higher NBS IRT concentrations (ng/ml) were present in CF than CRMS/CFPSID (median (interquartile range): 143.8 (99.8–206.2) vs. 75.0 (61.0–105.9); P n = 14) had significantly higher NBS IRT concentrations (ng/ml) than CRMS/CFSPID→ CRMS/CFSPID (n = 83) (median (interquartile range): 108.9 (72.3–126.8) vs. 73.7(60.0–96.0); P = 0.02). Conclusions Amongst infants who tested positive on NBS for CF, there is a gradation of elevated NBS IRT concentrations. Infants with CF have higher NBS IRT levels than CRMS/CFPSID, and higher NBS IRT concentrations were present in infants with CRMS/CFSPID→CF than CRMS/CFSPID→ CRMS/CFSPID. NBS IRT concentrations, in concert with other factors, may have the potential to predict the likelihood of CF amongst infants with CRMS/CFSPID.

Introduction Hormonal contraception is available worldwide in many different forms. Fear of side effects and health concerns are among the main reasons for not using contraceptives or discontinuing their use. Although the safety and efficacy of contraceptives have been extensively examined, little is known about their impact on female sexual function, and the evidence on the topic is controversial. Aim To review the available evidence about the effects of hormonal contraceptives on female sexuality in order to provide a position statement and clinical practice recommendations on behalf of the European Society of Sexual Medicine. Methods A comprehensive review of the literature was performed. Main Outcome Measure Several aspects of female sexuality have been investigated, including desire, orgasmic function, lubrication and vulvovaginal symptoms, pelvic floor and urological symptoms, partner preference, and relationship and sexual satisfaction. For each topic, data were analyzed according to the different types of hormonal contraceptives (combined estrogen-progestin methods, progestin-only methods, and oral or non-oral options). Results Recommendations according to the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence criteria and specific statements on this topic, summarizing the European Society of Sexual Medicine position, were developed. Clinical Implications There is not enough evidence to draw a clear algorithm for the management of hormonal contraception-induced sexual dysfunction, and further studies are warranted before conclusions can be drawn. A careful baseline psychological, sexual, and relational assessment is necessary for the health care provider to evaluate eventual effects of hormonal contraceptives at follow-up. Strengths & Limitations All studies have been evaluated by a panel of experts who have provided recommendations for clinical practice. Conclusion The effects of hormonal contraceptives on sexual function have not been well studied and remain controversial. Available evidence indicates that a minority of women experience a change in sexual functioning with regard to general sexual response, desire, lubrication, orgasm, and relationship satisfaction. The pathophysiological mechanisms leading to reported sexual difficulties such as reduced desire and vulvovaginal atrophy remain unclear. Insufficient evidence is available on the correlation between hormonal contraceptives and pelvic floor function and urological symptoms.

Introduction: Metabolically unhealthy obesity (MUHO) is the most important preventable cardiovascular (CV) risk factor. Recently, the significance of metabolically healthy obesity (MHO) as a CV ris...

Background Although the pathogenic role of metabolically complicated obesity (MCO) in erectile dysfunction (ED), major adverse cardiovascular events (MACE), and male infertility has been widely studied, that of metabolically healthy obesity (MHO) has been poorly investigated. Aim To assess the role of MHO in the pathogenesis of ED, prediction of MACE, and male reproductive health. Methods A consecutive series of 4,945 men (mean age, 50.5 ± 13.5 years) with sexual dysfunction (SD) (cohort 1) and 231 male partners of infertile couples (mean age, 37.9 ± 9.1 years; cohort 2) were studied. A subset of men with SD (n = 1,687) was longitudinally investigated to evaluate MACE. All patients underwent clinical, biochemical, erectile function, and flaccid penile color Doppler ultrasound (PCDU) assessment. Infertile men also underwent scrotal and transrectal ultrasound; semen analysis, including interleukin (IL-) 8; and prostatitis-like symptom assessment. MHO was defined as body mass index >30 kg/m2 with high-density lipoprotein cholesterol level >40 mg/dL and absence of diabetes or hypertension. The rest of the obesity sample was defined as MCO. MHO or MCO were compared with the rest of the sample, defined as normal weight (NW) individuals. Outcomes Clinical, biochemical, erectile, and PCDU assessment in MHO, MCO and NW men in both cohorts; longitudinal MACE incidence assessment in cohort 1. Results In cohort 1, 816 men (16.5%) were obese, 181 (3.7%) were MHO, and 635 (12.8%) were MCO. In cohort 2, 68 men (28.4%) were obese, 19 (8.2%) were MHO, and 49 (21.2%) were MCO. After adjusting for confounders, in both samples, the men with MHO and MCO had lower total testosterone levels and worse PCDU parameters compared with the NW men. However, only MCO men had worse erectile function compared with NW men. In the longitudinal study, both MHO and MCO men independently had a higher incidence of MACE compared with NW men (P < .05 for both). In cohort 2, MHO and MCO men had a larger prostate volume, and MCO men also had higher ultrasound and biochemical (IL-8) features of prostatic inflammation compared with NW men, but no differences in prostatitis-like symptoms or seminal parameters. Clinical implications MHO men should be considered at high cardiovascular risk like MCO men and followed-up for erectile dysfunction and prostate abnormalities overtime. Strengths & Limitations The study simultaneously examined several endpoints with validated instruments within 2 different male populations, 1 with SD and 1 with infertility. As for limitations, there is no consensus in the scientific community regarding the definition of MHO, and the results are derived from patients with SD or infertility, which could have different characteristics than the general male population. Conclusion MHO is associated with subclinical ED, increased cardiovascular risk, and prostate enlargement.

Introdução: De acordo com o Instituto Nacional do Câncer (INCA) a estimativa de novos casos de câncer do colo do útero (CCU) para o Estado do Espírito Santo, no triênio 2020-2022, é de 11,65 por 100.000 habitantes. Objetivos: Traçar o perfil clínico-epidemiológico das usuárias do serviço de atenção integral à saúde da mulher da policlínica da Universidade Vila Velha (UVV), a partir dos determinantes da consulta ginecológica, e correlacionar aos achados citológicos e histológicos. Métodos: Estudo de corte transversal, observacional e retrospectivo envolvendo 590 prontuários de pacientes, atendidas entre fevereiro de 2011 e julho de 2016 no serviço de atenção integral à saúde da mulher na policlínica/UVV. Resultados: A média de idade das mulheres incluídas nesse estudo foi de 39,5 anos (DP± 16,2). Os fatores de risco como estado civil e tempo de relacionamento conjugal, multiparidade, e uso de contraceptivos hormonais orais foram associados a maior chance de CCU. Associação estatística da variável idade não evidenciou risco de CCU. Conclusões: Os resultados vão de acordo com os preconizados pelo INCA e Ministério da Saúde. Isso reforça a importância da rastreabilidade na atenção primária e os fatores que interferem na mesma.

BACKGROUND AND OBJECTIVES Cystic fibrosis (CF) screen–positive infants with an inconclusive diagnosis (CFSPID) are infants in whom sweat testing and genetic analysis does not resolve a CF diagnosis. Lack of knowledge about the health outcome of these children who require clinical follow-up challenges effective consultation. Early predictive biomarkers to delineate the CF risk would allow a more targeted approach to these children. METHODS Prospective, longitudinal, multicenter, Canada-wide cohort study of CF positive–screened newborns with 1 to 2 cystic fibrosis transmembrane conductance regulator gene variants, of which at least 1 is not known to be CF-causing and/or a sweat chloride between 30 and 59 mmol/L. These were monitored for conversion to a CF diagnosis, pulmonary, and nutritional outcomes. RESULTS The mean observation period was 7.7 (95% confidence interval 7.1 to 8.4) years. A CF diagnosis was established for 24 of the 115 children with CFSPID (21%) either because of reinterpretation of the cystic fibrosis transmembrane conductance regulator genotype or because of increase in sweat chloride concentration ≥60 mmol/L. An initial sweat chloride of ≥40 mmol/l predicted conversion to CF on the basis of sweat testing. The 91 remaining children with CFSPID were pancreatic sufficient and showed normal growth until school age. Pulmonary function as well as lung clearance index in a subgroup of children with CFSPID were similar to that of healthy controls. CONCLUSIONS Children with CFSPID have good nutritional and pulmonary outcomes at school age, but rates of reclassifying the diagnosis are high. The initial sweat chloride test can be used as a biomarker to predict the risk for CF in CFSPID.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder whose most debilitating pathology is progressive and cumulative heterotopic ossification (HO) of skeletal muscles, ligaments, tendons, and fascia. FOP is caused by mutations in the type I BMP receptor gene ACVR1, which enable ACVR1 to utilize its natural antagonist, Activin A, as an agonistic ligand. The physiological relevance of this property is underscored by the fact that HO in FOP is exquisitely dependent on activation of FOP-mutant ACVR1 by Activin A, an effect countered by inhibition of Activin A via monoclonal antibody treatment. Hence, we surmised that ACVR1 antibodies that block activation of ACVR1 by ligand should also inhibit HO in FOP and provide an additional therapeutic option for this condition. Therefore, we generated ACVR1 monoclonal antibodies that block ACVR1’s activation by its ligands. Surprisingly, in vivo, these ACVR1 antibodies stimulate HO and activate signaling of FOP-mutant ACVR1. This property is restricted to FOP-mutant ACVR1 and results from ACVR1 antibody-mediated dimerization of ACVR1. Conversely, wild type ACVR1 is inhibited by ACVR1 antibodies. These results uncover an additional novel property of FOP-mutant ACVR1 and indicate that ACVR1 antibodies should not be considered as therapeutics for FOP.

Background Stroke results in neurologic impairments and aerobic deconditioning that contribute to limited walking capacity which is a major barrier post-stroke. Current exercise recommendations and stroke rehabilitation guidelines recommend moderate-intensity aerobic training post-stroke. Locomotor high-intensity interval training is a promising new strategy that has shown significantly greater improvements in aerobic fitness and motor performance than moderate-intensity aerobic training in other populations. However, the relative benefits and risks of high-intensity interval training and moderate-intensity aerobic training remain poorly understood following stroke. In this study, we hypothesize that locomotor high-intensity interval training will result in greater improvements in walking capacity than moderate-intensity aerobic training. Methods Using a single-blind, 3-site randomized controlled trial, 50 chronic (> 6 months) stroke survivors are randomly assigned to complete 36 locomotor training sessions of either high-intensity interval training or moderate-intensity aerobic training. Main eligibility criteria are age 40–80 years, single stroke for which the participant received treatment (experienced 6 months to 5 years prior to consent), walking speed ≤ 1.0 m/s, able to walk at least 3 min on the treadmill at ≥ 0.13 m/s (0.3 mph), stable cardiovascular condition (American Heart Association class B), and the ability to walk 10 m overground without continuous physical assistance. The primary outcome (walking capacity) and secondary outcomes (self-selected and fast gait speed, aerobic fitness, and fatigue) are assessed prior to initiating training and after 4 weeks, 8 weeks, and 12 weeks of training. Discussion This study will provide fundamental new knowledge to inform the selection of intensity and duration dosing parameters for gait recovery and optimization of aerobic training interventions in chronic stroke. Data needed to justify and design a subsequent definitive trial will also be obtained. Thus, the results of this study will inform future stroke rehabilitation guidelines on how to optimally improve walking capacity following stroke. Trial registration ClinicalTrials.govNCT03760016. Registered on November 30, 2018.

Introduction Penile traction therapy (PTT) aims to non-surgically reduce curvature, enhance girth, and recover lost length. Available clinical practice guidelines however lack clear recommendations regarding their use. Aim To present a comprehensive review and recommendation regarding the available evidence to the use of PTT in Peyronie's disease (PD). Methods A systematic literature search was performed on Pubmed and Medline for relevant studies from all times until 2019. Studies of PTT (monotherapy and in combination) in patients with PD with any documented degree of curvature and in either the acute or chronic phase of the disease were included. Full texts not published in English language were excluded. Main outcomes measures Several scenarios, including preclinical data have been investigated. For each topic covered evidence was analyzed and expert opinion was stated. Results The paucity of high-level studies precluded any strong recommendations, however, specific statements on this topic, summarizing the ESSM position, were provided. The available data about the use of PTT in PD are still poor, and the impact of this therapy for the treatment of PD has not been clearly stablished. Available data in the clinical setting are still poor, and the impact of these devices on PD evolution has not been clearly established. Conclusion PTT seems to be a valid treatment option for PD, although there is not enough evidence to give any definitive recommendation in any clinical scenario. García-Gómez B, Aversa A, Alonso-Isa M et al. The Use of Penile Traction Devices for Peyronie's Disease: Position Statements from the European Society for Sexual Medicine. Sex Med 2021;9:100387.

Background Androgen deprivation therapy (ADT) for prostate cancer with luteinizing hormone-releasing hormone (LHRH) agonists can be improved. Objective To assess safety, the frequency and severity of hot flushes (HFs), bone health, and antitumor effects of high-dose estetrol (HDE4) when combined with ADT. Design, setting and participants A phase II, double-blind, randomized, placebo-controlled study was conducted in advanced prostate cancer patients requiring ADT (the PCombi study). Intervention Patients receiving LHRH agonist treatment were randomized 2:1 to 40 mg HDE4 (n = 41) or placebo (n = 21) cotreatment for 24 wk. Outcome measurements and statistical analysis Coprimary endpoints were frequency/severity of HFs and levels of total and free testosterone (T). Secondary endpoints included assessments of bone metabolism (osteocalcin and type I collagen telopeptide [CTX1]), prostate-specific antigen (PSA), and follicle-stimulating hormone (FSH). Efficacy analysis was based on the selected per-protocol (PP) population. Results and limitations Of 62 patients included in the study, 57 were suitable for a PP analysis (37 HDE4; 20 placebo). No E4-related serious cardiovascular adverse events occurred at 24 wk. Weekly HFs were reported by 13.5% of patients with HDE4 and 60.0% with placebo (p, Take Home Message Androgen-deprivation therapy (ADT) for prostate cancer with luteinizing hormone-releasing hormone (LHRH) agonists can be improved. Cotreatment of ADT with high-dose estetrol in advanced prostate cancer patients results in fewer occurrences of hot flushes, bone protection, and other antitumor benefits.

Cancer cells have long been recognized to exhibit unique bioenergetic requirements. The apoptolidin family of glycomacrolides are distinguished by their selective cytotoxicity towards oncogene transformed cells, yet their molecular mechanism remains uncertain. We used photoaffinity analogs of the apoptolidins to identify the F1 subcomplex of mitochondrial ATP synthase as the target of apoptolidin A. CryoEM of apoptolidin and ammocidin-ATP synthase complexes revealed a novel shared mode of inhibition that was confirmed by deep mutational scanning of the binding interface to reveal resistance mutations which were confirmed using CRISPR-Cas9. Ammocidin A was found to suppress leukemia progression in vivo at doses that were tolerated with minimal toxicity. The combination of cellular, structural, mutagenesis, and in vivo evidence define the mechanism of action of apoptolidin family glycomacrolides and establish a path to address OXPHOS-dependent cancers.

Cancer cells have long been recognized to exhibit unique bioenergetic requirements. The apoptolidin family of glycomacrolides are distinguished by their selective cytotoxicity towards oncogene-transformed cells, yet their molecular mechanism remains uncertain. We used photoaffinity analogs of the apoptolidins to identify the F1 subcomplex of mitochondrial ATP synthase as the target of apoptolidin A. Cryogenic electron microscopy (cryo-EM) of apoptolidin and ammocidin–ATP synthase complexes revealed a novel shared mode of inhibition that was confirmed by deep mutational scanning of the binding interface to reveal resistance mutations which were confirmed using CRISPR–Cas9. Ammocidin A was found to suppress leukemia progression in vivo at doses that were tolerated with minimal toxicity. The combination of cellular, structural, mutagenesis, and in vivo evidence defines the mechanism of action of apoptolidin family glycomacrolides and establishes a path to address oxidative phosphorylation-dependent cancers. Photoaffinity analogs of a family of glycosylated macrolides, apoptolidins, revealed the F1 subcomplex of mitochondrial ATP synthase as the target. Cryo-EM analysis of the apoptolidin–ATP synthase complex enabled identification of resistance mutations.

PURPOSE The use of genomics within cancer research and clinical oncology practice has become commonplace. Efforts such as The Cancer Genome Atlas have characterized the cancer genome and suggested a wealth of targets for implementing precision medicine strategies for patients with cancer. The data produced from research studies and clinical care have many potential secondary uses beyond their originally intended purpose. Effective storage, query, retrieval, and visualization of these data are essential to create an infrastructure to enable new discoveries in cancer research. METHODS Moffitt Cancer Center implemented a molecular data warehouse to complement the extensive enterprise clinical data warehouse (Health and Research Informatics). Seven different sequencing experiment types were included in the warehouse, with data from institutional research studies and clinical sequencing. RESULTS The implementation of the molecular warehouse involved the close collaboration of many teams with different expertise and a use case–focused approach. Cornerstones of project success included project planning, open communication, institutional buy-in, piloting the implementation, implementing custom solutions to address specific problems, data quality improvement, and data governance, unique aspects of which are featured here. We describe our experience in selecting, configuring, and loading molecular data into the molecular data warehouse. Specifically, we developed solutions for heterogeneous genomic sequencing cohorts (many different platforms) and integration with our existing clinical data warehouse. CONCLUSION The implementation was ultimately successful despite challenges encountered, many of which can be generalized to other research cancer centers.

Background: Coronary artery obstruction is a rare, devastating complication of transcatheter aortic valve replacement. Transcatheter electrosurgical aortic leaflet laceration (Bioprosthetic or Native Aortic Scallop Intentional Laceration to Prevent Iatrogenic Coronary Artery Obstruction [BASILICA]) is a novel technique to prevent coronary artery obstruction. We report the 1-year outcomes of the BASILICA trial. Primary end points of 30-day success and safety have been reported previously. Methods: The BASILICA trial was a prospective, multicenter, single-arm safety and feasibility study. Subjects with severe native or bioprosthetic aortic valve disease at high or extreme risk for surgery, and high risk of coronary artery obstruction, were included. End points at 1 year included death, stroke, and myocardial infarction. Source data was independently verified and end points independently adjudicated. Results: Thirty subjects were enrolled between February 2018 and July 2018. At 30 days, BASILICA was successful in 28 subjects (93.3%), there were 3 strokes (10%), including 1 disabling stroke (3.3%), 1 death (3.3%), and 1 periprocedural myocardial infarction (3.3%). Between 30 days and 1 year, there were no additional strokes, no myocardial infarction, and 2 deaths (10% 1-year mortality). No subject needed repeat intervention for aortic valve or coronary disease. Two subjects had infective endocarditis (6.7%), but neither was isolated to the aortic valve. There were no hospital admissions for heart failure. Fourteen (46.7%) subjects required repeat hospital admission for other causes. Aortic valve gradients on echocardiography, New York Heart Association functional class, and Kansas City Cardiomyopathy Questionnaire scores improved from baseline to 30 days and were maintained at 1 year. Conclusions: In these subjects with multiple comorbidities and restrictive anatomy that underwent transcatheter aortic valve replacement, there was no late stroke, myocardial infarction, or death related to BASILICA. Mitigation of coronary obstruction remained intact at 1 year and was not related to recurrent readmission. These results are reassuring for patients and physicians who wish to avoid the long-term complications related to snorkel stenting. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03381989.

Objectives We present our initial experience with the fourth-generation MitraClip™ (G4) system and propose preliminary criteria for device selection. Background The MitraClip™ G4 system recently underwent a "controlled release" for transcatheter edge-to-edge mitral valve repair. The four new devices include technical improvements such as controlled gripper actuation (independent leaflet capture) and continuous left atrial pressure monitoring. To date, a patient-specific device selection algorithm, and the technology's impact on procedural times and success, have not been described. Methods We present an initial multi-center experience and short-term outcomes with the new system, suggest procedural and imaging considerations, and propose initial guidance for device selection. Results Sixty-one procedures performed by three operators at two centers between November 2019 and May 2020 were analyzed. At 30-day follow-up, there were three deaths (4.9%), four neurological events (6.6%), and seven re-hospitalizations (11.5%). Fifty-nine patients achieved device and procedural success (96.7%), and there was one device-related technical issue (1.6%). Compared to the same operators utilizing the third generation MitraClip™, the G4 system resulted in a significant reduction in the median number of clips used per patient (1 IQR 1-2 vs. 2 IQR 1-3, p = .023) and a trend toward shorter device times. Conclusion Based on our initial experience, we found that the MitraClip™ G4 system is associated with high procedural success and fewer devices needed per procedure. The expanded device options may allow a more targeted approach to the myriad of pathologic presentations of mitral regurgitation. This early experience should provide a foundational opportunity for further refinement.