Targeting myostatin/activin A protects against skeletal muscle and bone loss during spaceflight.

Among the physiological consequences of extended spaceflight are loss of skeletal muscle and bone mass. One signaling pathway that plays an important role in maintaining muscle and bone homeostasis is that regulated by the secreted signaling proteins, myostatin (MSTN) and activin A. Here, we used both genetic and pharmacological approaches to investigate the effect of targeting MSTN/activin A signaling in mice that were sent to the International Space Station. Wild type mice lost significant muscle and bone mass during the 33 d spent in microgravity. Muscle weights of Mstn-/- mice, which are about twice those of wild type mice, were largely maintained during spaceflight. Systemic inhibition of MSTN/activin A signaling using a soluble form of the activin type IIB receptor (ACVR2B), which can bind each of these ligands, led to dramatic increases in both muscle and bone mass, with effects being comparable in ground and flight mice. Exposure to microgravity and treatment with the soluble receptor each led to alterations in numerous signaling pathways, which were reflected in changes in levels of key signaling components in the blood as well as their RNA expression levels in muscle and bone. These findings have implications for therapeutic strategies to combat the concomitant muscle and bone loss occurring in people afflicted with disuse atrophy on Earth as well as in astronauts in space, especially during prolonged missions.

Game-based learning to improve diagnostic accuracy: a pilot randomized-controlled trial.

OBJECTIVES: Perform a pilot study of online game-based learning (GBL) using natural frequencies and feedback to teach diagnostic reasoning. METHODS: We conducted a multicenter randomized-controlled trial of computer-based training. We enrolled medical students, residents, practicing physicians and nurse practitioners. The intervention was a 45 min online GBL training vs. control education with a primary outcome of score on a scale of diagnostic accuracy (composed of 10 realistic case vignettes, requesting estimates of probability of disease after a test result, 0-100 points total). RESULTS: Of 90 participants there were 30 students, 30 residents and 30 practicing clinicians. Of these 62 % (56/90) were female and 52 % (47/90) were white. Sixty were randomized to GBL intervention and 30 to control. The primary outcome of diagnostic accuracy immediately after training was better in GBL (mean accuracy score 59.4) vs. control (37.6), p=0.0005. The GBL group was then split evenly (30, 30) into no further intervention or weekly emails with case studies. Both GBL groups performed better than control at one-month and some continued effect at three-month follow up. Scores at one-month GBL (59.2) GBL plus emails (54.2) vs. control (33.9), p=0.024; three-months GBL (56.2), GBL plus emails (42.9) vs. control (35.1), p=0.076. Most participants would recommend GBL to colleagues (73 %), believed it was enjoyable (92 %) and believed it improves test interpretation (95 %). CONCLUSIONS: In this pilot study, a single session with GBL nearly doubled score on a scale of diagnostic accuracy in medical trainees and practicing clinicians. The impact of GBL persisted after three months.

[Case report: Purulent pericarditis caused by candida species--a rare but life-threatening disease in intensive care medicine]. / Kasuistik: Die purulente Candida-Perikarditis--Ein seltenes, aber lebensbedrohliches Krankheitsbild in der Intensivmedizin.

We report a case of a male patient with drug abuse in his medical history who was hospitalized because of a community acquired pneumonia. Subsequently the patient developed an acute lung injury (ARDS) and a fulminant purulent pericarditis accompanied by a pericardial effusion. Caused by the pericardial tamponade cardiac function was severely restricted. Due to fast diagnosis and immediate adequate therapy such as systemic anti-fungal treatment, pericardiocentesis, percutaneous drainage, and later surgical intervention the patient was treated successfully. This article describes etiology, pathophysiology and symptoms of purulent Candida-pericarditis and gives a review of existing literature regarding this extremely rare disease. In addition therapeutic options are discussed.

Genomic amplification and oncogenic properties of the KCNK9 potassium channel gene.

Representational difference analysis (RDA) of human breast cancer was used to discover a novel amplicon located at chromosomal region 8q24.3. We examined a series of breast cancer samples harboring amplification of this region and determined that KCNK9 is the sole overexpressed gene within the amplification epicenter. KCNK9 encodes a potassium channel that is amplified from 3-fold to 10-fold in 10% of breast tumors and overexpressed from 5-fold to over 100-fold in 44% of breast tumors. Overexpression of KCNK9 in cell lines promotes tumor formation and confers resistance to both hypoxia and serum deprivation, suggesting that its amplification and overexpression plays a physiologically important role in human breast cancer.

Parenting and caregiving duties as career challenges among clinical microbiologists: a cross-sectional survey.

Aim: To estimate the burden of parenting and caregiving duties among clinical microbiologists in Germany and to identify workplace-related support systems and barriers to engaging in career-relevant activities. Methods: A cross-sectional web-based survey was conducted. Participants were asked to answer 37 questions, of which 24 specifically addressed parenting and caregiving duties. Results: Only few workplace-related support systems are currently available, and experiences of job-related disadvantages were frequently reported (27 of 47; 57.4%). Main barriers were a lack of flexible working hours and reliable childcare. Sociocultural norms and a lack of role models were perceived as detrimental. Conclusion: More support systems and a credible culture of family friendliness are needed to prevent jeopardizing the academic potential of young parents.

Innovate to eliminate: a prerequisite in NTD programmes.

Innovation plays a critical role in progress towards achievement of the World Health Organization's road map for neglected tropical diseases 2021-2030. As disease prevalence decreases, the cost to identify and treat remaining cases goes up. Additionally, as programmes move to the surveillance phase, diagnostic tests need to be highly sensitive and affordable. Until the early end to the Ascend West and Central Africa programme, the Ascend Learning and Innovation Fund supported five projects from 2019 to 2021. Designed for innovation, the fund encompassed a range of activities, including operational research, product development and social behavioural change. This flexibility allowed innovation to bridge the gap between strategic policy and practical implementation, piloting and proving business models to respond to information found through Ascend.

Clinician Conceptualization of the Benefits of Treatments for Individual Patients.

Importance: Knowing the expected effect of treatment on an individual patient is essential for patient care. Objective: To explore clinicians' conceptualizations of the chance that treatments will decrease the risk of disease outcomes. Design, Setting, and Participants: This survey study of attending and resident physicians, nurse practitioners, and physician assistants was conducted in outpatient clinical settings in 8 US states from June 2018 to November 2019. The survey was an in-person, paper, 26-item survey in which clinicians were asked to estimate the probability of adverse disease outcomes and expected effects of therapies for diseases common in primary care. Main Outcomes and Measures: Estimated chance that treatments would benefit an individual patient. Results: Of 723 clinicians, 585 (81%) responded, and 542 completed all the questions necessary for analysis, with a median (interquartile range [IQR]) age of 32 (29-44) years, 287 (53%) women, and 294 (54%) White participants. Clinicians consistently overestimated the chance that treatments would benefit an individual patient. The median (IQR) estimated chance that warfarin would prevent a stroke in the next year was 50% (5%-80%) compared with scientific evidence, which indicates an absolute risk reduction (ARR) of 0.2% to 1.0% based on a relative risk reduction (RRR) of 39% to 50%. The median (IQR) estimated chance that antihypertensive therapy would prevent a cardiovascular event within 5 years was 30% (10%-70%) vs evidence of an ARR of 0% to 3% based on an RRR of 0% to 28%. The median (IQR) estimated chance that bisphosphonate therapy would prevent a hip fracture in the next 5 years was 40% (10%-60%) vs evidence of ARR of 0.1% to 0.4% based on an RRR of 20% to 40%. The median (IQR) estimated chance that moderate-intensity statin therapy would prevent a cardiovascular event in the next 5 years was 20% (IQR 5%-50%) vs evidence of an ARR of 0.3% to 2% based on an RRR of 19% to 33%. Estimates of the chance that a treatment would prevent an adverse outcome exceeded estimates of the absolute chance of that outcome for 60% to 70% of clinicians. Clinicians whose overestimations were greater were more likely to report using that treatment for patients in their practice (eg, use of warfarin: correlation coefficient, 0.46; 95% CI, 0.40-0.53; P < .001). Conclusions and Relevance: In this survey study, clinicians significantly overestimated the benefits of treatment to individual patients. Clinicians with greater overestimates were more likely to report using treatments in actual patients.

Accuracy of Practitioner Estimates of Probability of Diagnosis Before and After Testing.

Importance: Accurate diagnosis is essential to proper patient care. Objective: To explore practitioner understanding of diagnostic reasoning. Design, Setting, and Participants: In this survey study, 723 practitioners at outpatient clinics in 8 US states were asked to estimate the probability of disease for 4 scenarios common in primary care (pneumonia, cardiac ischemia, breast cancer screening, and urinary tract infection) and the association of positive and negative test results with disease probability from June 1, 2018, to November 26, 2019. Of these practitioners, 585 responded to the survey, and 553 answered all of the questions. An expert panel developed the survey and determined correct responses based on literature review. Results: A total of 553 (290 resident physicians, 202 attending physicians, and 61 nurse practitioners and physician assistants) of 723 practitioners (76.5%) fully completed the survey (median age, 32 years; interquartile range, 29-44 years; 293 female [53.0%]; 296 [53.5%] White). Pretest probability was overestimated in all scenarios. Probabilities of disease after positive results were overestimated as follows: pneumonia after positive radiology results, 95% (evidence range, 46%-65%; comparison P < .001); breast cancer after positive mammography results, 50% (evidence range, 3%-9%; P < .001); cardiac ischemia after positive stress test result, 70% (evidence range, 2%-11%; P < .001); and urinary tract infection after positive urine culture result, 80% (evidence range, 0%-8.3%; P < .001). Overestimates of probability of disease with negative results were also observed as follows: pneumonia after negative radiography results, 50% (evidence range, 10%-19%; P < .001); breast cancer after negative mammography results, 5% (evidence range, <0.05%; P < .001); cardiac ischemia after negative stress test result, 5% (evidence range, 0.43%-2.5%; P < .001); and urinary tract infection after negative urine culture result, 5% (evidence range, 0%-0.11%; P < .001). Probability adjustments in response to test results varied from accurate to overestimates of risk by type of test (imputed median positive and negative likelihood ratios [LRs] for practitioners for chest radiography for pneumonia: positive LR, 4.8; evidence, 2.6; negative LR, 0.3; evidence, 0.3; mammography for breast cancer: positive LR, 44.3; evidence range, 13.0-33.0; negative LR, 1.0; evidence range, 0.05-0.24; exercise stress test for cardiac ischemia: positive LR, 21.0; evidence range, 2.0-2.7; negative LR, 0.6; evidence range, 0.5-0.6; urine culture for urinary tract infection: positive LR, 9.0; evidence, 9.0; negative LR, 0.1; evidence, 0.1). Conclusions and Relevance: This survey study suggests that for common diseases and tests, practitioners overestimate the probability of disease before and after testing. Pretest probability was overestimated in all scenarios, whereas adjustment in probability after a positive or negative result varied by test. Widespread overestimates of the probability of disease likely contribute to overdiagnosis and overuse.

Children's interpretations of general quantifiers, specific quantifiers, and generics.

Recently, several scholars have hypothesized that generics are a default mode of generalization, and thus that young children may at first treat quantifiers as if they were generic in meaning. To address this issue, the present experiment provides the first in-depth, controlled examination of the interpretation of generics compared to both general quantifiers ("all Xs", "some Xs") and specific quantifiers ("all of these Xs", "some of these Xs"). We provided children (3 and 5 years) and adults with explicit frequency information regarding properties of novel categories, to chart when "some", "all", and generics are deemed appropriate. The data reveal three main findings. First, even 3-year-olds distinguish generics from quantifiers. Second, when children make errors, they tend to be in the direction of treating quantifiers like generics. Third, children were more accurate when interpreting specific versus general quantifiers. We interpret these data as providing evidence for the position that generics are a default mode of generalization, especially when reasoning about kinds.

Reducing the incidence and severity of pericardial adhesions with a sprayable polymeric matrix.

PURPOSE: This study was undertaken to evaluate the antiadhesive properties of a polymeric agent in infants undergoing staged surgical correction of congenital heart abnormalities. DESCRIPTION: Sixteen infants having staged surgical repair were treated with a polymeric matrix at the completion of the initial surgery. There were 5 untreated controls. The tenacity and extent of adhesions at five separate regions of the heart were evaluated at the follow-up surgery. EVALUATION: For all sites combined, there was a threefold difference in median tenacity scores in favor of the experimental treatment (1.0 vs 3.0, p < 0.01). Significant differences were achieved separately at the right ventricle and the anterior surface of the great vessels (p = 0.02 for both comparisons). Analysis of adhesion scores reflecting the extent of adhesions similarly favored the experimental treatment for all sites (80 vs 270, p < 0.01), with significant differences persisting at the right atrium (p < 0.01) and the anterior surface of the great vessels (p = 0.04). There were no treatment-related adverse events. CONCLUSIONS: Use of this polymeric agent at the completion of open cardiac surgery may prevent the occurrence or reduce the severity of pericardial adhesions.

[Certification and quality management of a complex university cardiac center according to law EN ISO 9001: 2000]. / Zertifizierung von Teileinrichtungen komplexer Grosskliniken nach DIN EN ISO 9001: 2000 dargestellt am Beispiel einer herzchirurgischen Universitätsklinik.

Quality management systems can improve quality in health care units. The introduction of a quality management system according to ISO 9001: 2000 in a university department of cardiovascular surgery is described. First a thorough analysis of all processes of patient treatment and clinical research was obtained. Multiple interfaces had to be defined to different departments as well as to administration units. All necessary resources were evaluated and optimised. Customer satisfaction was evaluated by surveys of patients and collaborating physicians. Quality rounds including physicians, nurses and technicians were instituted. Based on these preparatory works all processes including their responsibilities and necessary resources were redefined and described in the quality manual. After 18 months' of certification of our quality management system according to ISO 9001: 2000 was recommended by an independent, accredited organisation. In summary, certification of a university department of cardiovascular surgery according to ISO 9001: 2000 is possible and may represent the first step towards total quality management. In complex health care units the certification of individual departments may help to generate a consciousness for quality on the road to total quality management.

Six years of clinical follow-up with endothelial cell-seeded small-diameter vascular grafts during coronary bypass surgery.

This clinical study was performed to investigate the patency rate of endothelial cell-seeded small-diameter expanded polytetrafluoroethylene grafts during coronary artery bypass surgery. Between September 1995 and December 1998, 14 patients (median age: 71 years, range: 61-79 years) received 21 endothelial cell-seeded small-diameter grafts. In all, 43% of the performed implantations were reoperations. Endothelial cells were harvested from a forearm vein, cultured and characterized in the laboratory until a sufficient number was available. After in vitro seeding, the grafts were allowed to mature for another 10 days, prior to implantation. Graft patency was investigated with angiography, angioscopy, and intravascular ultrasonography during follow-up. Cumulative data represented 58 patients' years and was 100% complete. The seeded autologous vascular endothelial cell density was 1.05 × 10(5) ± 0.12 × 10(5) cells/cm(2) with a cell viability of 95.5 ± 1.5%. Operative mortality was 7.1% (one patient). Patency rate at discharge was 95.2%, and at a mean follow-up of 27 months was 90.5%. The proven patency rate at up to 72 months was at least 50.0%, as five patients refused angiographic evaluation. None of these five patients suffered from angina pectoris and so the best scenario would have shown a patency rate of 85.7%. Angioscopy and intravascular ultrasonography showed absence of atheroma or stenosis in the investigated patent grafts. Autologous vascular endothelial cell seeding improves patency rate of small-caliber expanded polytetrafluoroethylene grafts in patients without suitable autologous graft material.

Aortocoronary endothelial cell-seeded polytetrafluoroethylene graft: 9-year patency.

We report a 71-year old man with coronary artery disease. Complete coronary revascularization was not possible with autologous grafts; therefore, a 4-mm expanded polytetrafluoroethylene graft was implanted that had been seeded preoperatively with autologous vascular endothelial cells. At 9-year follow-up, the patient is asymptomatic and shows a patent graft.

Electrocardiographic-gated multislice computed tomography for visualization of cardiac morphology in congenitally corrected transposition of the great arteries.

A case of congenitally corrected transposition of the great arteries in a 64-old-woman is presented. Diagnosis was missed by invasive angiocardiography. Electrocardiographic-gated multislice computed tomography not only demonstrated switching of the aortic root and pulmonary trunk but clearly identified fine morphologic details of the cardiac chambers, including the atypical coronary artery pattern.