Biological warfare: Implications for antimicrobial use

Biological warfare is intended to incapacitate a large number of individuals at a single exposure, creating epidemictype disease, death, and social chaos. The organisms with potential for immediate use as bacteriologic weapons are Bacillus anthracis, Brucella melitensis, Yersinia pestis, and Vibrio cholera, all necessitating antibiotic therapy for a cure. It is reasonable, therefore, to assume that a biological attack, or even a hoax, would requiure thousands of individuals over a large area to begin antibiotic therapy. Issues such as antibiotic availability, logistical problems in antibiotic distribution, development of drug resistance, side effects influencing the individual, and adverse effects on the community due to the impact of mass therapy on the ecology, make biological warfare the most apocalyptic scenario for the creation of a "postantibiotic era."     

Applications of In Vitro–In Vivo Correlations in Generic Drug Development: Case Studies

In vitro–in vivo correlation (IVIVC) is a predictive mathematical model describing the relationship between an in vitro property and a relevant in vivo response. The main objective of an IVIVC is to serve as a surrogate for human bioequivalence (BE) studies, which may reduce the number of BE studies performed during the initial approval process as well as with certain scale-up and postapproval changes. The US Food and Drug Administration (FDA) published a regulatory guidance related to development, evaluation, and applications of IVIVC for extended-release (ER) oral dosage forms in September 1997. Despite the publication of this guidance, the deficiencies related to IVIVC are still identified by the Division of Bioequivalence in the process of Abbreviated New Drug Application (ANDA) review. Thus, the main objective of this article is to present the most commonly occurring deficiencies associated with IVIVCs via selected case studies from the ANDAs for oral ER drug products only. We searched internal FDA databases from January 1996 to December 2014 to identify the ANDAs for proposed generic oral ER drug products containing IVIVC. Only 14 ANDA submissions had IVIVC data, and most were not acceptable. Only one ANDA submission included adequate information related to IVIVC data enabling the completion of BE review within first review cycle. It is hoped that awareness of the deficiencies presented in our article would help the generic drug applicants to submit complete and appropriate information related to IVIVC data, ultimately, resulting in a more timely approval of ANDAs.KEY WORDS: bioequivalence, extended-release drug products, generics, IVIVC, SUPAC     

Brief Report: Educational attainment does not influence brain aging

Education has been related to various advantageous lifetime outcomes. Here, using longitudinal structural MRI data (4,422 observations), we tested the influential hypothesis that higher education translates into slower rates of brain aging. Cross-sectionally, education was modestly associated with regional cortical volume. However, despite marked mean atrophy in the cortex and hippocampus, education did not influence rates of change. The results were replicated across two independent samples. Our findings challenge the view that higher education slows brain aging.     

Overestimation of postischemic myocardial stunning on gated SPECT imaging: correlation with echocardiography.

BACKGROUND: Postischemic global and regional left ventricular (LV) dysfunction on stress-gated single photon emission computed tomography (SPECT) imaging is attributed widely to myocardial stunning. We sought to determine the specificity of gated SPECT for the detection of myocardial stunning after ischemic stress. METHODS AND RESULTS: Twenty-seven patients with an ischemic response to stress on dual-isotope exercise SPECT were enrolled prospectively. Transthoracic echocardiography was performed just before stress gated SPECT for assessment of regional wall motion and quantitative LV ejection fraction (LVEF). The 17 myocardial segments for each patient were scored for myocardial perfusion by stress gated SPECT, and regional wall motion by stress gated SPECT and echo. Of the 459 myocardial segments, 41% had perfusion defects, 15% had stress gated SPECT regional wall motion abnormality, 4.8% had poststress echo regional wall motion abnormality, and 3.9% had baseline regional wall motion abnormality. Overall, a stress gated SPECT regional wall motion abnormality had a sensitivity of 100% and a specificity of 89%. Among reversible perfusion defects of moderate severity or more, a stress gated SPECT regional wall motion abnormality had a specificity of 41% and a positive predictive value of 8%. Stress gated SPECT LVEF was similar to poststress echo LVEF for all patients, but significantly lower in patients with reversible perfusion defects of moderate severity or more. CONCLUSION: Post-stress gated SPECT imaging overestimates global and regional myocardial stunning. Caution should be exercised in interpreting poststress global or regional LV function on stress gated SPECT in scans with reversible ischemia.     

Let’s Get Physical: Sexual Orientation Disparities in Physical Activity,Sports Involvement,and Obesity Among a Population-Based Sample of Adolescents

Objectives. We examined sexual orientation disparities in physical activity, sports involvement, and obesity among a population-based adolescent sample.Methods. We analyzed data from the 2012 Dane County Youth Assessment for 13 933 students in grades 9 through 12 in 22 Wisconsin high schools. We conducted logistic regressions to examine sexual orientation disparities in physical activity, sports involvement, and body mass index among male and female adolescents.Results. When we accounted for several covariates, compared with heterosexual females, sexual minority females were less likely to participate in team sports (adjusted odds ratio [AOR] = 0.44; 95% confidence interval [CI] = 0.37, 0.53) and more likely to be overweight (AOR = 1.28; 95% CI = 1.02, 1.62) or obese (AOR = 1.88; 95% CI = 1.43, 2.48). Sexual minority males were less likely than heterosexual males to be physically active (AOR = 0.62; 95% CI = 0.46, 0.83) or to participate in team sports (AOR = 0.26; 95% CI = 0.20, 0.32), but the 2 groups did not differ in their risk of obesity.Conclusions. Sexual orientation health disparities in physical activity and obesity are evident during adolescence. Culturally affirming research, interventions, and policies are needed for sexual minority youths.Obesity is an increasing and serious health problem among adolescents.1,2 This is of major concern because obesity has many health and social consequences and it affects adolescents’ overall well-being.3,4 Obesity among adolescents also has a high likelihood of continuing into adulthood.5 Recent population-based and longitudinal research has demonstrated that there are disparities in obesity between sexual minority and heterosexual adolescents.6–8 Research has also documented sexual orientation disparities in physical activity and sports involvement in adolescence.9,10 Despite this increased attention, the overall empirical base remains limited, and findings also suggest some gender nuances that need further exploration. More population-based research is needed to investigate these disparities, consistent with federal health priorities.7,11There are sexual orientation–based disparities in physical activity and sports involvement among adolescents; however, there are mixed findings for females. One study reported that sexual minority females are less likely than heterosexual females to participate in moderate to vigorous physical activity and team sports,9 whereas another study found no such differences in physical activity.10 Findings are more consistent for sexual minority male adolescents, who are less likely than heterosexual males to engage in moderate to vigorous physical activity, to engage in recommended levels of physical activity, and to participate in team sports.9,10 More research is needed because of the paucity of studies and mixed results. This is especially important given that adolescents’ physical activity has been shown to relieve stress and protect against many mental and physical health conditions, including obesity,12,13 for which sexual minority adolescents are at greater risk.Research on sexual orientation disparities in obesity suggests that there are some gender nuances. Many studies have found that sexual minority female adolescents have higher risk of obesity than heterosexual females (e.g., higher body mass index [BMI], defined as weight in kilograms divided by the square of height in meters).6,8,10,14 These sexual orientation disparities in obesity among adolescent females parallel those among sexual minority adult women.15,16Findings of elevated obesity risk among sexual minority male adolescents are mixed. Some studies show that sexual minority males, specifically bisexual males, have higher odds of obesity than heterosexuals,14 whereas other studies have documented no differences.10 By contrast, some studies have found that heterosexual males have increases in BMI during adolescence compared with sexual minority males.6,8 These mixed findings for sexual minority males might be attributed to physical maturation and developmental changes in adolescence that some of the cross-sectional studies could not examine.10,14 Specifically, one study found that sexual minority males had higher obesity risk than heterosexual males in early adolescence, but their risk of obesity became lower than for heterosexual males later in adolescence.6 The authors postulated that, compared with heterosexual males, sexual minority males reach puberty maturation earlier in adolescence but make less substantial weight gains later in adolescence.6Sexual orientation health disparities have been explained through the minority stress model: sexual minority youths experience unique stressors and stigma related to their sexual identity (e.g., homophobic bullying), which lead to poorer health.17 Sexual minority adolescents might therefore be less likely to be physically active or involved in team sports because of potential minority stressors that they often experience at school, especially bias and heightened discrimination experienced in the context of sports or in their communities.18–20 More recently, the negative effects of minority stress and stigma on physical health disparities have been documented,21,22 including their effects on obesity for sexual minority women.23 However, the minority stress model is not sufficient in explaining how sexual minority adolescent females, but not males, are at greater risk for obesity compared with their heterosexual peers.Another potential explanation of these obesity disparities is related to cultural norms and sexual minority females’ experiences of internalizing ideals for femininity and appearance8 and sexual minority males’ ideals for muscularity and body image.24 For instance, compared with heterosexual women, sexual minority women are more likely to be satisfied with their bodies and attracted to women with greater body mass,25,26 whereas sexual minority men are less likely to be satisfied with their bodies compared with heterosexual men and are more likely to be attracted to muscular men.25,27 Therefore, these 2 groups might engage (or not engage) in differing body weight management and dieting behaviors compared with their heterosexual peers; concomitantly, these behaviors might render differing risks for obesity.Sexual minority adolescents’ lack of physical activity and sports involvement might be influenced by traditional gender norms associated with athleticism and sports, which has implications for their athletic self-esteem and involvement. For adolescent males, team sports are a means to define masculinity28; however, adolescent males often engage in homophobic banter to prove their masculinity and heterosexuality and to enforce traditional gender norms.29,30 Sexual prejudice is pervasive in athletic settings,19,20 making sports contexts unwelcoming and unsafe for many sexual minority males. Traditional feminine gender norms and homophobia also affect sexual minority females’ involvement in sports.31 However, sexual minority adolescent females have unique gendered experiences in relation to sports. Because women’s athleticism can be a stereotype for being a lesbian,32 sexual minority females might avoid sports involvement. Expecting or experiencing exclusion in sports settings might also affect sexual minority adolescents’ athletic self-esteem, consequently preventing them from engaging in future sports or physical activity.9 In fact, athletic self-esteem has been found to contribute to sexual orientation disparities in sports involvement and physical activity.9Emerging evidence of sexual orientation disparities in physical activity, sports involvement, and obesity among adolescents, in addition to potential gender nuances in these disparities, points to the need for more population-based research in this area. We therefore examined sexual orientation disparities among a large adolescent population-based sample and tested for gender differences. While accounting for variables commonly associated with physical activity and obesity among adolescents,4,33 we hypothesized that sexual minority adolescents would be less likely to report physical activity and sports involvement than would their heterosexual peers. We also hypothesized that sexual minority females would be at higher risk for being overweight and obese than their heterosexual peers. Because of mixed findings in existing sexual orientation disparities research among adolescent males, we hypothesized that sexual minority males would be at equal risk for being overweight and obese than their heterosexual male peers.     

Guidelines for Community-Acquired Pneumonia

Community-acquired pneumonia (CAP) is common, costly, and clinically serious. Several national and international practice guidelines have been developed to promote more appropriate, cost-effective care for patients with CAP. This article compares and contrasts eight international practice guidelines for the management of CAP, describes the extent to which recommendations are reflected in practice, and proposes explanations for non-adherence to guidelines. We found consistency in recommendations across all the guidelines for the management of patients with CAP requiring intensive care. In this setting, all guidelines recommend chest radiography, sputum Gram stain and culture, blood cultures, testing for Legionella pneumophila, and timely administration of antibiotics active against both typical (i.e. Streptococcus pneumoniae, Hemophilus influenzae) and atypical organisms (i.e. Legionella spp., Mycoplasma pneumoniae, and Chlamydia pneumoniae). Recommendations for the management of the average inpatient with pneumonia were more variable, with the greatest differences between the North American and European guidelines. The North American guidelines (in contrast to European ones), recommended empiric treatment of typical and atypical organisms in all inpatients. There were also differences in policies regarding the necessity of chest radiography, sputum studies, and serologic testing. Some guidelines explicitly embrace the use of prediction rules to inform the decision to hospitalize, while others do not. Some of these admission decision algorithms focus on identifying low risk patients, while others are most concerned with high risk patients. There was also considerable variation in the specificity and operationalization of clinical criteria for switching from parenteral to oral antibiotics or judging appropriateness for discharge. Many recommendations for key management decisions tended to lack explicit, objective, and actionable criteria that could be easily implemented in real world practice. Review of the pneumonia literature revealed that physician performance of guideline-recommended best practices is often suboptimal. Administration of timely antibiotics (< or =8 hours of presentation) and use of first-line antibiotics occurred in 75-85% and 18-79% of cases, respectively. Collection of blood cultures within 24 hours of presentation and prior to administration of antibiotics was achieved in 69-83% and 63-82% of cases, respectively. Screening the eligibility of CAP patients for hospital-based pneumococcal and influenza vaccination occurred on average in 11 and 14% of hospitalizations, respectively, in the US. Lack of awareness of guidelines, conflicting advice among them, and lack of specific, objective, actionable recommendations most likely contribute to nonadherence to CAP guidelines. Increased attention to these factors will be needed if professional society practice guidelines are to fulfill their promise as tools for improving the quality and outcomes of care for patients with pneumonia.     

Physical therapy and mobility 2 and 6 months after hip fracture

OBJECTIVES: To examine the relationship between early physical therapy (PT), later therapy, and mobility 2 and 6 months after hip fracture. DESIGN: Prospective, multisite observational study. SETTING: Four hospitals in the New York City area. PARTICIPANTS: Four hundred forty-three hospitalized older patients discharged after surgery for hip fracture in 1997-98. MEASUREMENTS: Patient demographics, fracture type, comorbidities, dementia, number of new impairments at discharge, amount of PT between day of surgery and postoperative day (POD) 3, amount of therapy between POD4 and 8 weeks later, and prefracture, 2-, and 6-month mobility measured using the Functional Independence Measure. RESULTS: More PT immediately after hip fracture surgery was associated with significantly better locomotion 2 months later. Each additional session from the day of surgery through POD3 was associated with an increase of 0.4 points (P=.032) on the 14-point locomotion scale, but the positive relationship between early PT and mobility was attenuated by 6 months postfracture. There was no association between later therapy and 2- or 6-month mobility. CONCLUSION: PT immediately after hip fracture surgery is beneficial. The effects of later therapy on mobility were difficult to assess because of limitations of the data. Well-designed randomized, controlled trials of the effect of varying schedules and amounts of therapy on functional status after hip fracture would be informative.