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The objective of this report was to determine the pharmacokinetic properties, safety, and tolerability of single and multiple doses of intravenous delafloxacin. In addition, the absolute bioavailability (BA) of the 450-mg tablet formulation of delafloxacin was determined. Three clinical trials are summarized. The first study was a randomized, double-blind, placebo-controlled, single- (300, 450, 600, 750, 900, and 1200 mg) ascending-dose study of IV delafloxacin in 62 (52 active, 10 placebo) healthy volunteers. The second study was a randomized, double-blind, placebo-controlled study of IV delafloxacin (300 mg) given as a single dose on day 1, followed by twice-daily dosing on days 2 through 14; 12 (8 active, 4 placebo) healthy volunteers were enrolled. The third study was an open-label, randomized, 2-period, 2-sequence crossover study in which 56 healthy volunteers were randomly assigned to 1 of 2 sequences of a single oral dose of delafloxacin (450-mg tablet) or IV delafloxacin (300 mg). Serial blood samples were collected, and plasma pharmacokinetic parameters of delafloxacin were calculated. Delafloxacin Cmax values increased proportionally with increasing single IV dose for the dose range of 300 to 1200 mg, whereas the AUC values increased more than proportionally to dose for the same dose range. The mean terminal half-life of delafloxacin was approximately 12 hours (ranging from 8 to 17 hours). The volume of distribution (Vd) at steady state was approximately 35 L, which is similar to the volume of total body water. There was minimal accumulation of delafloxacin after twice-daily IV administration of 300 mg with an accumulation ratio of 1.09. The delafloxacin total exposure after a single 1-hour IV infusion of 300 mg and a single oral dose of a 450-mg tablet were equivalent with geometric least square mean ratio (90% CI) of 0.8768 (0.8356–0.9200) for AUC0–∞ and 0.8445 (0.8090–0.8815) for AUC0–t, respectively. The Cmax values of delafloxacin were not equivalent for the 2 formulations with a ratio (90% CI) of 0.5516 (0.5150–0.5908), respectively. The mean absolute bioavailability of delafloxacin was 58.8%. Delafloxacin was well tolerated in healthy volunteers after single and multiple IV doses. The total systemic exposure to IV (300 mg) and oral (450 mg) delafloxacin is comparable, supporting that a switch between the 2 formulations is appropriate.

The objective of this report is describe the results of 2 studies that examined the pharmacokinetic parameters, safety profile, and tolerability of single and multiple ascending doses of oral delafloxacin and the effects of food, sex, and age on oral delafloxacin pharmacokinetic parameters, safety profile, and tolerability. The first study contained 3 parts and used unformulated delafloxacin in a capsule. Part 1 was a randomized, double-blind, placebo-controlled, single (50, 100, 200, 400, 800, 1200, and 1600 mg) ascending-dose study of oral delafloxacin in healthy men. Part 2 was a single-dose crossover study in which 20 men received 250 mg delafloxacin with or without food. Part 2 also included a parallel group, double-blind, placebo-controlled study in 16 women and 16 elderly men and women who were randomized (3:1) to receive 250 mg delafloxacin or placebo. Part 3 was a randomized, double-blind, placebo-controlled, multiple (100, 200, 400, 800, 1200 mg once daily for 5 days) ascending-dose study of oral delafloxacin in healthy men. The second study was a single-dose, randomized, 3-period crossover study in which participants received 900 mg delafloxacin (2 × 450-mg tablets) under fasted conditions, with a high-fat meal, or fasted with a high-fat meal 2 hours after dosing. Serial blood samples were collected, and plasma pharmacokinetic parameters of delafloxacin were determined. Delafloxacin Cmax and AUC0–∞ increased with increasing oral dose over the dose range of 50 to 1600 mg. The increases in delafloxacin AUC0–∞ were dose proportional at doses of ≥200 mg. Steady state was reached by day 3 of dosing with minimal accumulation of delafloxacin. The Cmax of delafloxacin was decreased slightly in the presence of food. No sex difference in delafloxacin pharmacokinetic parameters was observed. In the elderly men and women, mean delafloxacin Cmax and AUC0–∞ were 35% higher than observed for young adults, which could be partially explained by a decrease in the creatinine clearance in the elderly men and women. Delafloxacin was well tolerated at the tested doses, with gastrointestinal adverse effects observed more commonly at doses ≥1200 mg. Delafloxacin exhibits linear pharmacokinetic parameters that reached steady state after 3 days of daily oral dosing with minimal accumulation. Delafloxacin was well tolerated throughout both studies, with gastrointestinal effects observed at the higher doses (≥1200 mg).

The applications of ultrasound in managing the clinical care of athletes have been expanding over the past decade. This review provides an analysis of the research that has been published regarding the use of ultrasound in athletes and focuses on how these emerging techniques can impact the clinical management of athletes by sports medicine physicians. Electronic database literature searches were performed using the subject terms ‘ultrasound’ and ‘athletes’ from the years 2003 to 2012. The following databases were searched: PubMed, Web of Science, Cochrane Library, CINAHL, and SPORTDiscus™. The search produced 617 articles in total, with a predominance of articles focused on cardiac and musculoskeletal ultrasound. 266 of the studies involved application of ultrasound in evaluating the cardiovascular properties of athletes, and 151 studies involved musculoskeletal ultrasound. Other applications of ultrasound included abdominal, vascular, bone density and volume status. New techniques in echocardiography have made significant contributions to the understanding of the physiological changes that occur in the athlete’s heart in response to the haemodynamic stress associated with different types of activity. The likely application of these techniques will be in managing athletes with hypertrophic cardiomyopathy, and the techniques are near ready for application into clinical practice. These techniques are highly specialized, however, and will require referral to dedicated laboratories to influence the clinical management of athletes. Investigation of aortic root pathology and pulmonary vascular haemodynamics are also emerging, but will require additional studies with larger numbers and outcomes analysis to validate their clinical utility. Some of these techniques are relatively simple, and thus hold the potential to enter clinical management in a point-of-care fashion. Musculoskeletal ultrasound has demonstrated a number of diagnostic and therapeutic techniques applicable to pathology of the shoulder, elbow, wrist, hand, hip, knee and ankle. These techniques have been applied mainly to the management of impingement syndromes, tendinopathies and arthritis. Many of these techniques have been validated and have entered clinical practice, while more recently developed techniques (such as dynamic ultrasound and platelet-rich plasma injections) will require further research to verify efficacy. Research in musculoskeletal ultrasound has also been helpful in identifying risk factors for injury and, thus, serving as a focus for developing interventions. Research in abdominal ultrasound has investigated the potential role of ultrasound imaging in assessing splenomegaly in athletes with mononucleosis, in an attempt to inform decisions and policies regarding return to play. Future research will have to demonstrate a reduction in adverse events in order to justify the application of such a technique into policy. The role of ultrasound in assessing groin pain and abdominal pain in ultraendurance athletes has also been investigated, providing promising areas of focus for the development of treatment interventions and physical therapy. Finally, preliminary research has also identified the role of ultrasound in addressing vascular disease, bone density and volume status in athletes. The potential applications of ultrasound in athletes are broad, and continuing research, including larger outcome studies, will be required to establish the clinical utility of these techniques in the care of athletes.

A randomized trial of bedaquiline–pretomanid–linezolid for highly drug-resistant tuberculosis assessed the use of linezolid at 600 or 1200 mg for 9 or 26 weeks; the 600-mg dose for 26 weeks had a favorable profile.

Two professional athletes in the US National Basketball Association required surgery for aortic root dilation in 2012. These cases have attracted attention in sports medicine to the importance of aortic root disease in athletes. In addition to aortic root dilation, other forms of aortic disease include anomalous coronary artery, bicuspid aortic valve, and Marfan’s syndrome. In this review, electronic database literature searches were performed using the terms “aortic root” and “athletes.” The literature search produced 122 manuscripts. Of these, 22 were on aortic root dilation, 21 on anomalous coronary arteries, 12 on bicuspid aortic valves, and 8 on Marfan’s syndrome. Aortic root dilation is a condition involving pathologic dilation of the aortic root, which can lead to life-threatening sequelae. Prevalence of the condition among athletes and higher risk athletes in particular sports needs to be better delineated. Normative parameters for aortic root diameter in the general population are proportionate to anthropomorphic variables, but this has not been validated for athletes at the extremes of anthropomorphic indices. Although echocardiography is the favored screening modality, computed tomography (CT) and cardiac magnetic resonance imaging (MRI) are also used for diagnosis and surgical planning. Medical management has utilized beta-blockers, with more recent use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and statins. Indications for surgery are based on comorbidities, degree of dilation, and rate of progression. Management decisions for aortic root dilation in athletes are nuanced and will benefit from the development of evidence-based guidelines. Anomalous coronary artery is another form of aortic disease with relevance in athletes. Diagnosis has traditionally been through cardiac catheterization, but more recently has included evaluation with echocardiography, multislice CT, and MRI. Athletes with this condition should be restricted from participation in competitive sports, but can be cleared for participation 6 months after surgical repair. Bicuspid aortic valve is another form of aortic root disease with significance in athletes. Although echocardiography has traditionally been used for diagnosis, CT and MRI have proven more sensitive and specific. Management of bicuspid aortic valve consists of surveillance through echocardiography, medical therapy with beta-blockers and ARBs, and surgery. Guidelines for sports participation are based on the presence of aortic stenosis, aortic regurgitation, and aortic root dilation. Marfan’s syndrome is a genetic disorder with a number of cardiac manifestations including aortic root dilation, aneurysm, and dissection. Medical management involves beta-blockers and ARBs. Thresholds for surgical management differ from the general population. With regard to sports participation, the most important consideration is early detection. Athletes with the stigmata of Marfan’s syndrome or with family history should be tested. Further research should determine whether more aggressive screening is warranted in sports with taller athletes. Athletes with Marfan’s syndrome should be restricted from activities involving collision and heavy contact, avoid isometric exercise, and only participate in activities with low intensity, low dynamic, and low static components. In summary, many forms of aortic root disease afflict athletes and need to be appreciated by sports medicine practitioners because of their potential to lead to tragic but preventable deaths in an otherwise healthy population.

Detailed ex-situ electron microscopy and atom probe tomography (APT) were combined with in-situ synchrotron diffraction to systematically quantify the chemical, morphological, and lattice instabilities that occur during aging of a polycrystalline high-refractory content Ni-base superalloy. The morphological changes and splitting phenomenon associated with the secondary γ′ precipitates were related to a combination of discrete chemical composition variations at the secondary γ′/γ interfaces and additional chemical energy arising from γ precipitates that form within the secondary γ′ particles. The compositional phase inhomogeneities led to the precipitation of finely dispersed tertiary γ′ particles within the γ matrix and secondary γ particles within the secondary γ′ precipitates, which, along with surface grooving of the secondary γ′ particles, likely due to a spike in the lattice misfit at the particle interfaces, contributed to the splitting of the precipitates during aging.

To the Editor: Conradie et al. (Sept. 1 issue) 1 report impressive results of the ZeNix trial of a bedaquiline–pretomanid–linezolid regimen for drug-resistant tuberculosis, with doses of linezolid that were lower than the 1200-mg dose that has been associated with adverse events. In this trial performed in South Africa, the country of Georgia, Moldova, and Russia, 9 of the 181 participants (5.0%) had bedaquiline resistance (minimum inhibitory concentration, 2 to 4 μg per milliliter) at baseline. Despite reported 99.8% adherence to the trial regimen, 6 of 9 participants (67%) with bedaquiline-resistant tuberculosis at baseline had a favorable outcome, as compared with . . .

The applications of ultrasound in managing the clinical care of athletes have been expanding over the past decade. This review provides an analysis of the research that has been published regarding the use of ultrasound in athletes and focuses on how these emerging techniques can impact the clinical management of athletes by sports medicine physicians. Electronic database literature searches were performed using the subject terms 'ultrasound' and 'athletes' from the years 2003 to 2012. The following databases were searched: PubMed, Web of Science, Cochrane Library, CINAHL, and SPORTDiscus™. The search produced 617 articles in total, with a predominance of articles focused on cardiac and musculoskeletal ultrasound. 266 of the studies involved application of ultrasound in evaluating the cardiovascular properties of athletes, and 151 studies involved musculoskeletal ultrasound. Other applications of ultrasound included abdominal, vascular, bone density and volume status. New techniques in echocardiography have made significant contributions to the understanding of the physiological changes that occur in the athlete's heart in response to the haemodynamic stress associated with different types of activity. The likely application of these techniques will be in managing athletes with hypertrophic cardiomyopathy, and the techniques are near ready for application into clinical practice. These techniques are highly specialized, however, and will require referral to dedicated laboratories to influence the clinical management of athletes. Investigation of aortic root pathology and pulmonary vascular haemodynamics are also emerging, but will require additional studies with larger numbers and outcomes analysis to validate their clinical utility. Some of these techniques are relatively simple, and thus hold the potential to enter clinical management in a point-of-care fashion. Musculoskeletal ultrasound has demonstrated a number of diagnostic and therapeutic techniques applicable to pathology of the shoulder, elbow, wrist, hand, hip, knee and ankle. These techniques have been applied mainly to the management of impingement syndromes, tendinopathies and arthritis. Many of these techniques have been validated and have entered clinical practice, while more recently developed techniques (such as dynamic ultrasound and platelet-rich plasma injections) will require further research to verify efficacy. Research in musculoskeletal ultrasound has also been helpful in identifying risk factors for injury and, thus, serving as a focus for developing interventions. Research in abdominal ultrasound has investigated the potential role of ultrasound imaging in assessing splenomegaly in athletes with mononucleosis, in an attempt to inform decisions and policies regarding return to play. Future research will have to demonstrate a reduction in adverse events in order to justify the application of such a technique into policy. The role of ultrasound in assessing groin pain and abdominal pain in ultraendurance athletes has also been investigated, providing promising areas of focus for the development of treatment interventions and physical therapy. Finally, preliminary research has also identified the role of ultrasound in addressing vascular disease, bone density and volume status in athletes. The potential applications of ultrasound in athletes are broad, and continuing research, including larger outcome studies, will be required to establish the clinical utility of these techniques in the care of athletes.