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A five-time Olympic gold medalist and a U.S. Olympic team physician present a fitness program based on a philosophy of applying exercise as a prescription medication, in a guide that discusses key principles in fitness and weight loss.

Tibetans and Sherpas have long been revered for their physical aptitude at high altitude, and are thought to have lived at high altitude longer than any other culture. We performed physiologic testing on 2 Sherpas who currently hold world records for: (1) most number of ascents of Mt Everest and (2) speed ascent of Mt Everest from base camp to the summit. In doing so, we describe certain physiological aspects of these individuals that may contribute to their abilities at altitude. Anthropometric measurements, blood testing, and electro- and echocardiographic examination as well as pulmonary function tests were performed. Exercise testing consisted of treadmill climbing at increasing incline and speed while wearing a 22 kg backpack in Salt Lake City (1325 m) and Park City (2063 m). Anthropometry, electrocardiography, pulmonary function, strength, and echocardiography were consistent with predicted parameters for the general population. The Sherpas demonstrated appropriate cardiopulmonary response to dynamic exercise similar to moderately fit individuals while performing treadmill testing, both at moderate and high altitude. As expected, the energetic cost increased at higher altitude, likely due to increased respiratory work. The 2 world-record Sherpa climbers were within normal ranges for the specific measurements that were tested. They displayed appropriate cardiopulmonary and physiological responses and exercise performance profiles at moderate and high altitude.

Conduction disorders and permanent pacemaker implantation are common complications in patients who undergo transcatheter aortic valve implantation (TAVI). The aim of this study was to assess the incidence and clinical significance of new bundle branch block in patients who underwent TAVI with the Medtronic CoreValve Revalving System (MCRS) or the Edwards SAPIEN valve (ESV). Data from 238 patients with no previous pacemaker implantation, left bundle branch block (LBBB) or right bundle branch block at baseline electrocardiography who underwent TAVI with either MCRS (n = 87) or ESV (n = 151) bioprostheses from 2007 to 2011 were analyzed. New-onset LBBB occurred in 26.5% patients (n = 63): 13.5% with the ESV (n = 20) and 50.0% with the MCRS (n = 43) (p = 0.001). Permanent pacemaker implantation was required in 12.7% of patients (n = 8) because of complete atrioventricular block (ESV n = 2, MCRS n = 4), LBBB and first degree atrioventricular block (MCRS n = 1) and new-onset LBBB associated with sinus bradycardia (MCRS n = 1). At discharge, LBBB persisted in 8.6% of ESV patients (n = 13) and 32.2% of MCRS patients (n = 28) (p = 0.001). On multivariate analysis, the only predictor of LBBB was MCRS use (odds ratio 7.2, 95% confidence interval 2.9 to 17.4, p <0.001). Persistent new-onset LBBB at discharge was not associated with overall (log-rank p = 0.42) or cardiovascular (log-rank p = 0.46) mortality. New-onset right bundle branch block was documented in 4.6% of patients (n = 11), with no statistically significant differences between the ESV and MCRS. In conclusion, new-onset LBBB is a frequent intraventricular conduction disturbance after TAVI with a higher incidence with the MCRS compared with the ESV. LBBB persists in most patients, but in this cohort, it was not a predictor of overall or cardiovascular mortality or permanent pacemaker implantation.

MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression post-transcriptionally, are involved in many complex cellular processes. Several miRNAs are differentially expressed in hematopoietic tissues and play important roles in normal differentiation, but, when aberrantly regulated, contribute to the abnormal proliferation and differentiation of leukemic cells. Recently, we reported that a small subset of miRNAs is differentially expressed in acute promyelocytic leukemia (APL) blasts and is modulated by treatment with all-trans-retinoic acid (ATRA). In particular, PML/RARα-positive blasts from APL patients display lower levels of miRNA let-7c, a member of the let-7 family, than normal promyelocytes and its expression increases after ATRA treatment. In this study, we investigated the effects of let-7c in acute myeloid leukemia (AML) cells. We found that ectopic expression of let-7c promotes granulocytic differentiation of AML cell lines and primary blasts. Moreover, we identified PBX2, a well-known homeodomain protein whose aberrant expression enhances HoxA9-dependent leukemogenesis, as a novel let-7c target that may contribute to the AML phenotype. Together, these studies raise the possibility that perturbation of the let-7c-PBX2 pathway may have a therapeutic value in AML.

Objectives To assess the frequency of loss of smell and taste in children during Covid-19 infection and their prevalence along with other symptoms, as well as the recovery of chemosensory function once healed. Methods To evaluate symptoms during infection, we adapted the Scandinavian adaptation of the Multi-Clinic Smell and Taste Questionnaire and the modified Monel-Jefferson questionnaire. For smell analysis we used Odor Identification (OI) and two variants of the Odor Discrimination (OD) test, and we compared the results with those of a control group. Results We enrolled nine patients in our experimental group and nine in our control group. Fever was the most frequent symptom (55% of cases), followed by anosmia and ageusia (44% of cases), muscle pain and asthenia (22% of cases) and diarrhea, abdominal pain, cough, and headache (11% of cases). In 11% of cases, olfactory symptoms were the only manifestation of the disease. There was no statistically significant difference in OI test and OD tests between the two groups (Children healed from Covid-19 and Control Group). Conclusion Loss of smell and taste are the second most common symptoms of pediatric Covid-19, and they should always be tested because they can be the only manifestations of infection. Olfactory function in Covid-19 children decreases with increasing age and improves with the passage of time after illness.

The addition of cyclo-oxygenase-2 (COX-2) inhibitors and prolonged constant infusion (PCI) of gemcitabine to treatment for advanced non-small-cell lung cancer (NSCLC) might improve treatment efficacy. We aimed to assess whether the addition of rofecoxib or PCI gemcitabine could improve overall survival compared with first-line treatment with cisplatin plus gemcitabine given by standard infusion. Patients with stage IV or IIIb (with supraclavicular nodes or pleural effusion) NSCLC who were under 70 years of age and who had performance status 0 or 1 were eligible for this multicentre, prospective, open-label, randomised phase III trial with 2×2 factorial design. Patients were randomly assigned to one of four treatment groups: group A, gemcitabine 1200 mg/m 2 in a 30-min intravenous infusion on days 1 and 8 and intravenous cisplatin 80 mg/m 2 on day 1, every 21 days for six cycles; group B, the same treatments as group A plus oral rofecoxib 50 mg/day until disease progression; group C, intravenous PCI gemcitabine 1200 mg/m 2 in a 120-min infusion on days 1 and 8 and intravenous cisplatin 80 mg/m 2 on day 1, every 21 days for six cycles; group D, the same drugs as group C plus oral rofecoxib 50 mg/day until disease progression. The primary endpoint was overall survival; secondary endpoints were progression-free survival, response rate, quality of life, and toxicity. Analyses were intention-to-treat. This trial is registered on the clinical trials site of the US National Institutes of Health website http://clinicaltrials.gov/ct/show/NCT00385606. Between Jan 30, 2003, and May 3, 2005, 400 patients were enrolled. Median age was 60 years (range 29–71). PCI gemcitabine did not improve overall survival (median 47 weeks [95% CI 40–55] vs 44 [36–52], with standard gemcitabine infusion, hazard ratio (HR) of death 0·93 [0·74–1·17], p=0·41), progression-free survival, nor any other secondary endpoint. Vomiting and fatigue were significantly worse with PCI gemcitabine. The two rofecoxib groups were closed early (on Oct 1, 2004) due to withdrawal of the drug because of safety issues. With intention-to-treat statistical analyses limited to 240 patients (ie, those randomised before July 1, 2004) who had at least 3 months of treatment, rofecoxib did not prolong overall survival (median 44 weeks [CI 36–55] vs 44 [40–54] without rofecoxib, and HR of death 1·00 [0·75–1·34], p=0·85), or progression-free survival, but did improve response rate (41% vs 26%, p=0·02), global quality of life, physical, emotional and role functioning, fatigue, and sleeping. Rofecoxib significantly increased the incidence of diarrhoea and decreased constipation, fatigue, fever, weight loss, and pain, and analgesic consumption. Severe cardiac ischaemia was more frequent with rofecoxib than without; however, the difference was not statistically significant in the primary analysis (p=0·06) and became significant when patients who were randomised between July 1, 2004, and Sept 30, 2004, were included in the analysis (p=0·03). Neither PCI gemcitabine nor rofecoxib prolonged survival in the patients in this study. Rofecoxib improved response rate and several quality-of-life items, including pain-related items and global quality of life. Further studies with less cardiotoxic COX-2 inhibitors are needed in NSCLC.

In the last decades, advances in percutaneous coronary intervention (PCI) strategies have significantly reduced the risk of procedural complications and in-hospital mortality of patients with acute coronary syndromes (ACS), thus increasing the population of stable post-ACS patients. This novel epidemiological scenario emphasizes the importance of implementing secondary preventive and follow-up strategies. The follow-up of patients after ACS or elective PCI should be based on common pathways and on the close collaboration between hospital cardiologists and primary care physicians. However, the follow-up strategies of these patients are still poorly standardized. This SICI-GISE/SICOA consensus document was conceived as a proposal for the long-term management of post-ACS or post-PCI patients based on their individual residual risk of cardiovascular adverse events. We defined five patient risk classes and five follow-up strategies including medical visits and examinations according to a specific time schedule. We also provided a short guidance for the selection of the appropriate imaging technique for the assessment of left ventricular ejection fraction and of non-invasive anatomical or functional tests for the detection of obstructive coronary artery disease. Physical and pharmacological stress echocardiography was identified as the first-line imaging technique in most of cases, while cardiovascular magnetic resonance should be preferred when an accurate evaluation of left ventricular ejection fraction is needed. The standardization of the follow-up pathways of patients with a history of ACS or elective PCI, shared between hospital doctors and primary care physicians, could result in a more cost-effective use of resources and potentially improve patient's long-term outcome.

Abstract Aims The number of patients undergoing percutaneous coronary interventions (PCI) after transcatheter aortic valve replacement (TAVR) is expected to increase, but their prognosis remains poorly understood. Methods and results Consecutive PCI patients with prior TAVR were compared to patients without prior TAVR between 2008 and 2023. The Kaplan–Meier method was used to estimate the 1-year incidence of major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death or myocardial infarction. An entropy balance approach was implemented to adjust for imbalances in patient and procedural characteristics. Adjusted hazard ratios (HRs) were estimated using weighted Cox regression models. Comparing 420 PCI patients with prior TAVR (mean age 80.8 years, 37.1% women) to 1197 without (mean age 70.4 years, 24.6% women), 1-year MACE was higher in the prior TAVR group (8.7 vs. 3.7%; unadjusted HR 2.35, 95% CI 1.49–3.69; P < 0.001). After adjustment for clinical and procedural characteristics, prior TAVR remained associated with an increased risk of MACE (adjusted HR 2.36, 95% CI 1.08–5.16; P = 0.032). This was primarily driven by higher cardiovascular death (adjusted HR 3.12, 95% CI 1.10–8.79, P = 0.032), while the association with myocardial infarction was attenuated post-adjustment and no longer statistically significant. Conclusion Patients undergoing PCI after TAVR experience a higher incidence of MACE compared to those undergoing PCI without prior TAVR, underscoring the importance of accurate patient selection before performing PCI in patients with chronic coronary syndrome and history of TAVR. Graphical Abstract Graphical Abstract

. Bile duct leaks and stenosis, although greatly reduced in their incidence, still play a major role in early and late graft loss. Their pathogenesis is multifactorial, being related to graft quality, ischemia time, arterial blood flow, and, of course, technical mishaps. The diagnosis and treatment of biliary complications is nowadays a joint effort among surgeons, interventional radiologists, and gastroenterologists. The correct algorithm in obtaining a fast diagnosis and the correct therapeutic approach are necessary to save the graft, avoid retransplantation or recipient death. Although this may seem to be a simple and basic concept, it assumes tremendous importance in liver transplantation in which the differential diagnosis between biliary and arterial complications or graft rejection and malfunctioning is often a difficult one.

The main obstacle to a expansion of human liver transplantation is the lack of donor organs. At present mortality reported for pediatric and adult patients on the waiting list is 10%to 20%. This article focuses on several techniques to alleviate this problem. Several years ago, application of reduced-size liver transplantation overcame the donor shortage among small infants through the use of grafts shaped to almost any size needed. Today reduced-size grafts are only rarely used, most commonly with traumatized donor livers or particularly small pediatric donor livers. Split liver transplantation also yields a net gain of organs, in that it uses one organ to save either an adult and a child or, recently, two adults. The technique of ex situ splitting is progressively being replaced by the in situ splitting technique, which yields better preserved grafts,optimization of graft/donor matching by pretransplant manipulation(preconditioning), avoidance of early rejection in the recipient,portal decompression, temporary liver support, if necessary, and induction of fast regeneration. In acute hepatic failure, auxiliary heterotopic liver transplantation might be sufficient to support liver function until regeneration of the native liver has begun. Domino transplantation in some patients with inborn errors of metabolism or storage disease should be considered. This article focuses on increasing the organ supply by using split liver transplantation techniques and living-donor liver transplantation.