In adult lung transplant recipients who have received 3 months of valganciclovir, extending prophylaxis by an additional 9 months significantly reduces CMV infection, disease, and disease severity without increased ganciclovir resistance or toxicity. A beneficial effect with regard to prevention of CMV disease seems to extend at least through 18 months after transplantation.

IMPORTANCE The left atrial appendage is a key site of thrombus formation in atrial fibrillation (AF) and can be occluded or removed at the time of cardiac surgery. There is limited evidence regarding the effectiveness of surgical left atrial appendage occlusion (S-LAAO) for reducing the risk of thromboembolism. OBJECTIVE To evaluate the association of S-LAAO vs no receipt of S-LAAO with risk of thromboembolism among older patients undergoing cardiac surgery. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study of a nationally representative Medicare-linked cohort from the Society of Thoracic Surgeons Adult Cardiac Surgery Database (2011–2012). Patients ≥65 years old with AF undergoing cardiac surgery (coronary artery bypass grafting [CABG], mitral valve surgery ± CABG, aortic valve surgery ± CABG) with and without concomitant S-LAAO were followed until December 31, 2014. EXPOSURE S-LAAO vs. no S-LAAO. MAIN OUTCOME MEASURES Primary outcome was readmission for thromboembolism (stroke, transient ischemic attack, or systemic embolism) at up to 3 years follow-up, as defined by Medicare claims data. Secondary endpoints included hemorrhagic stroke, all-cause mortality, and a composite endpoint (thromboembolism, hemorrhagic stroke, all-cause mortality). RESULTS Among 10,524 patients undergoing surgery (median age of 76 years; 39% female; median CHA2DS2-VASc score of 4), 3,892 (37%) underwent S-LAAO. Overall, at a mean follow-up of 2.6 years, thromboembolism occurred in 5.4%, hemorrhagic stroke in 0.9%, death in 21.5%, and the composite endpoint in 25.7%. S-LAAO, compared with no S-LAAO, was associated with lower unadjusted rates of thromboembolism (4.2% vs. 6.2%), all-cause mortality (17.3% vs. 23.9%), and the composite endpoint (20.5% vs. 28.7%), but no significance difference in rates of hemorrhagic stroke (0.9% vs. 0.9%). After inverse probability-weighted adjustment, S-LAAO was associated with a significantly lower rate of thromboembolism (subdistribution hazard ratio [HR] 0.67, confidence interval [CI] 0.56–0.81, p<0.0001), death (HR 0.88, CI 0.79–0.97, p=0.001), and the composite endpoint (HR 0.83, CI 0.76–0.91, p<0.001), but not hemorrhagic stroke (subdistribution HR 0.84, 0.53–1.32, p=0.44). S-LAAO, compared with no S-LAAO, was associated with a lower risk of thromboembolism among those discharged without anticoagulation (unadjusted rate 4.2% vs. 6.0%, adjusted subdistribution HR 0.26, CI 0.17–0.40, p<0.001), but not among those discharged with anticoagulation (unadjusted rate 4.1% vs. 6.3%, adjusted subdistribution HR 0.88, CI 0.56–1.39, p=0.59). CONCLUSIONS AND RELEVANCE Among older patients with AF undergoing concomitant cardiac surgery, S-LAAO compared with no S-LAAO, was associated with a lower risk of readmission for thromboembolism over the three years. These findings are supportive of S-LAAO, but randomized trials are necessary to provide definitive evidence.

Summary OBJECTIVE To describe the contribution of paediatric HIV and of HIV co-infections to admissions to a hospital in Moshi, Tanzania, using contemporary laboratory methods. METHODS During 1 year, we enrolled consecutively admitted patients aged ≥2 months and <13 years with current or recent fever. All patients underwent standardized clinical history taking, a physical examination and HIV antibody testing; standard aerobic blood cultures and malaria film were also done, and hospital outcome was recorded. Early infant HIV diagnosis by HIV-1 RNA PCR was performed on those aged <18 months. HIV-infected patients also received serum cryptococcal antigen testing and had their CD4-positive T-lymphocyte count and percent determined. RESULTS A total of 467 patients were enrolled whose median age was 2 years (range 2 months–13 years); Of those patients, 57.2% were female and 12.2% were HIV-infected. Admission clinical diagnosis of HIV disease was made in 10.7% and of malaria in 60.4%. Of blood cultures, 5.8% grew pathogens; of these 25.9% were Salmonella enterica (including 6 Salmonella Typhi) and 22.2% Streptococcus pneumoniae. Plasmodium falciparum was identified on blood film of 1.3%. HIV infection was associated with S. pneumoniae (odds ratio 25.7, 95% CI 2.8, 234.0) bloodstream infection (BSI), but there was no evidence of an association with Escherichia coli or P. falciparum; Salmonella Typhi BSI occurred only among HIV-uninfected participants. The sensitivity and specificity of an admission clinical diagnosis of malaria were 100% and 40.3%; and for an admission diagnosis of bloodstream infection, they were 9.1% and 86.4%, respectively. CONCLUSION Streptococcus pneumoniae is a leading cause of bloodstream infection among paediatric admissions in Tanzania and is closely associated with HIV infection. Malaria was over-diagnosed clinically, whereas invasive bacterial disease was underestimated. HIV and HIV co-infections contribute to a substantial proportion of paediatric febrile admissions, underscoring the value of routine HIV testing.

Biosimilars (or follow-on biologics) are a new class of medicine which enters the market subsequent to a previously approved version. They have demonstrated similarity to innovator biologic products in terms of quality, safety, and efficacy. The EMA has taken the lead in the regulatory approval framework for biosimilar products, and WHO has published guidelines on the evaluation of biosimilars in order to facilitate the global harmonization. Based on EMA and WHO guidelines, many other countries such as Canada, Japan and Korea have also issued their own guidance for evaluating follow-on biologics. The US FDA was authorized to approve follow-on biologics by the BPCI Act passed by the US Congress on March 23, 2010, and has just issued a draft guidance in early 2012. The basic concepts and main principles of approving biosimilars are similar among various nations, notwithstanding some differences in regard to the scope, the choice of reference product, and the data requirement. This article reviews the regulatory approval pathway of biosimilar products in different regions.

The appropriate duration of antibiotics for staphylococcal bacteremia is unknown. OBJECTIVE To test whether an algorithm that defines treatment duration for staphylococcal bacteremiavsstandardofcareprovidesnoninferiorefficacywithoutincreasingsevereadverseevents. DESIGN, SETTING, AND PARTICIPANTS A randomized trial involving adults with staphylococcal bacteremia was conducted at 16 academic medical centers in the United States (n = 15) and Spain (n = 1) from April 2011 to March 2017. Patients were followed up for 42 days beyond end of therapy for those with Staphylococcus aureus and 28 days for those with coagulase-negative staphylococcal bacteremia. Eligible patients were 18 years or older and had 1 or more blood cultures positive for S aureus or coagulase-negative staphylococci. Patients were excluded if they had known or suspected complicated infection at the time of randomization. INTERVENTIONS Patients were randomized to algorithm-based therapy (n = 255) or usual practice (n = 254). Diagnostic evaluation, antibiotic selection, and duration of therapy were predefined for the algorithm group, whereas clinicians caring for patients in the usual practice group had unrestricted choice of antibiotics, duration, and other aspects of clinical care. MAIN OUTCOMES AND MEASURES Coprimary outcomes were (1) clinical success, as determined by a blinded adjudication committee and tested for noninferiority within a 15% margin; and (2) serious adverse event rates in the intention-to-treat population, tested for superiority. The prespecified secondary outcome measure, tested for superiority, was antibiotic days among per-protocol patients with simple or uncomplicated bacteremia. RESULTS Among the 509 patients randomized (mean age, 56.6 [SD, 16.8] years; 226 [44.4%] women), 480 (94.3%) completed the trial. Clinical success was documented in 209 of 255 patients assigned to algorithm-based therapy and 207 of 254 randomized to usual practice (82.0% vs 81.5%; difference, 0.5% [1-sided 97.5% CI, −6.2% to ϱ]). Serious adverse events were reported in 32.5% of algorithm-based therapy patients and 28.3% of usual practice patients (difference, 4.2% [95% CI, −3.8% to 12.2%]). Among per-protocol patients with simple or uncomplicated bacteremia, mean duration of therapy was 4.4 days for algorithm-based therapy vs 6.2 days for usual practice (difference, −1.8 days [95% CI, −3.1 to −0.6]). CONCLUSIONS AND RELEVANCE Among patients with staphylococcal bacteremia, the use of an algorithm to guide testing and treatment compared with usual care resulted in a noninferior rate of clinical success. Rates of serious adverse events were not significantly different, but interpretation is limited by wide confidence intervals. Further research is needed to assess the utility of the algorithm.

In this paper, we propose a new three-arm parallel design to investigate biosimilarity between a biosimilar product and an innovator biological product by using relative distance based on the absolute mean differences. In the proposed design, one arm is for the biosimilar product and the other two arms are for the innovator biological product. The distance between the biosimilar product and the innovator biological product is defined by the absolute mean different between two products. Similarly, the distance between the innovator biological products from two difference batches is defined. The relative distance is defined as the ratio of the two distances whose denominator is the distance between the innovator biological products from two different batches. In the proposed design, if the relative distance is less than a prespecified margin, we claim that the two products are claimed to be biosimilar. The statistical test based on the ratio estimator and the linearization method are developed to assess biosimilarity. The power functions of two tests are derived in large sample and compared numerically. Because the statistical test based on the ratio estimator is more powerful than the linearization method, we recommend the statistical test based on the ratio estimator.

In pharmaceutical industry, the sponsors are interested in bringing their drug products from one region (e.g., the United States of America) to another region (e.g., Asian Pacific) to increase the exclusivity of the drug products in the marketplace. However, it is a concern whether the clinical results can be extrapolated from the target patient population in one region to a similar but different patient population in a new region due to a possible difference in ethnic factors. The International Conference on Harmonization (ICH) recommends that a bridging study may be necessarily conducted to extrapolate the clinical results between regions. However, little or no information regarding the criterion for determining whether a bridging study is necessary based on the evaluation of the complete clinical data package is provided by the ICH. Furthermore, no criterion on the assessment of similarity of clinical results between regions is given. In this paper, we propose the use of a sensitivity index as a possible criterion for regulatory authorities in the new region to evaluate whether a bridging clinical study should be conducted and the sample size of such a bridging clinical study. A criterion and a statistical method for assessment of similarity of clinical results between regions are also proposed, using the concept of population bioequivalence [FDA. Guidance for Industry--Statistical Approaches to Establishing Bioequivalence, Center for Drug Evaluation and Research, Food and Drug Administration: Rockville, MD, 2001] assuming that study site is random.

When the patent of a brand-name, marketed drug expires, new, generic products are usually offered. Small-molecule generic and originator drug products are expected to be chemically identical. Their pharmaceutical similarity can be typically assessed by simple regulatory criteria such as the expectation that the 90 % confidence interval for the ratio of geometric means of some pharmacokinetic parameters be between 0.80 and 1.25. When such criteria are satisfied, the drug products are generally considered to exhibit therapeutic equivalence. They are then usually interchanged freely within individual patients. Biological drugs are complex proteins, for instance, because of their large size, intricate structure, sensitivity to environmental conditions, difficult manufacturing procedures, and the possibility of immunogenicity. Generic and brand-name biologic products can be expected to show only similarity but not identity in their various features and clinical effects. Consequently, the determination of biosimilarity is also a complicated process which involves assessment of the totality of the evidence for the close similarity of the two products. Moreover, even when biosimilarity has been established, it may not be assumed that the two biosimilar products can be automatically substituted by pharmacists. This generally requires additional, careful considerations. Without declaring interchangeability, a new product could be prescribed, i.e. it is prescribable. However, two products can be automatically substituted only if they are interchangeable. Interchangeability is a statistical term and it means that products can be used in any order in the same patient without considering the treatment history. The concepts of interchangeability and prescribability have been widely discussed in the past but only in relation to small molecule generics. In this paper we apply these concepts to biosimilars and we discuss: definitions of prescribability and interchangeability and their statistical implementation; the relation between bioequivalence and interchangeability for small-molecule drug products; regulatory requirements and expectations of biosimilar products in various jurisdictions; possible statistical approaches to establish the similarity and interchangeability of biologic drug products; definition of other technical terms such as switchability and automatic substitution. The paper will be concluded with a discussion of the anticipated future use of interchangeability of biological drug products.