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Angela Yen Moore,1,2 James Del Rosso,3,4 Jodi L Johnson,5 Ayman Grada6,7 1Arlington Research Center, Inc., Arlington, TX, USA; 2Baylor University Medical Center, Dallas, TX, USA; 3JDR Dermatology Research/Thomas Dermatology, Las Vegas, NV, USA; 4Touro University Nevada, Henderson, NV, USA; 5Departments of Dermatology and Pathology, Feinberg School of Medicine, Northwestern University, Evanston, IL, USA; 6R&D and Medical Affairs, Almirall (US), Exton, PA, USA; 7Department of Dermatology, Boston University School of Medicine, Boston, MA, USACorrespondence: Angela Yen MooreArlington Research Center, Inc., 711 East Lamar, Suite 200, Arlington, TX 76011, USATel +1 817 795-7546 ext. 328Email acderm@acderm.comAbstract: Sarecycline is a tetracycline-derived oral antibiotic, specifically designed for acne, and is approved by the Food and Drug Administration (FDA) in 2018 for the treatment of inflammatory lesions of non-nodular moderate to severe acne vulgaris (AV) in patients 9 years of age and older. It has been decades since a novel systemic antibiotic was approved to treat AV, a disease that affects up to 90% of teenagers and young adults worldwide and lasts well into adulthood. Sarecycline holds promise to yield fewer side effects than other commonly used broad-spectrum tetracyclines, including minocycline and doxycycline. The narrower spectrum of antibacterial activity of sarecycline, which specifically targets C. acnes and some Gram-positive bacteria with little or no activity against Gram-negative bacteria, suggests not only the potential for reduced emergence of antibiotic-resistant bacterial strains but also less disruption of the human gut microflora. Here, we review the key preclinical and clinical evidence on sarecycline.Keywords: acne vulgaris, antibiotic, narrow spectrum, tetracycline, sarecycline

Rifapentine is a highly active antituberculosis antibiotic with treatment-shortening potential; however, exposure-response relations and the dose needed for maximal bactericidal activity have not been established. We used pharmacokinetic/pharmacodynamic data from 657 adults with pulmonary tuberculosis participating in treatment trials to compare rifapentine (n = 405) with rifampin (n = 252) as part of intensive-phase therapy. Population pharmacokinetic/pharmacodynamic analyses were performed with nonlinear mixed-effects modeling. Time to stable culture conversion of sputum to negative was determined in cultures obtained over 4 months of therapy. Rifapentine exposures were lower in participants who were coinfected with human immunodeficiency virus, black, male, or fasting when taking drug. Rifapentine exposure, large lung cavity size, and geographic region were independently associated with time to culture conversion in liquid media. Maximal treatment efficacy is likely achieved with rifapentine at 1,200 mg daily. Patients with large lung cavities appear less responsive to treatment, even at high rifapentine doses.

RationaleBiomarkers for monitoring response to anti-tuberculosis treatment are needed. We explored immune markers previously published as having predictive capability for 8 week culture status in 39 adults enrolled in a clinical trial in Kampala, Uganda.MethodsWe consecutively selected 20 HIV-negative pulmonary TB subjects with positive cultures, and 19 subjects with negative cultures at the end of intensive phase therapy. At baseline and after 8 weeks, serum was assayed for nine cytokines and soluble cytokine receptors using multiplexed platforms or ELISA. We evaluated their association with week 8 culture status first using single-variable logistic models, then using cross-validated estimates of the C-statistic, a measure of discrimination, of candidate models including 2 or 3 analytes in addition to age.ResultsAll but one analyte decreased from baseline to week 8 (all p  0.2).ConclusionExploratory post-hoc models including sTNF-R1, CRP, and age, classified 8 week culture status with promising accuracy.

Metabolite accumulation in lysosomal storage disorders (LSDs) results in impaired cell function and multi-systemic disease. Although substrate reduction and lysosomal overload-decreasing therapies can ameliorate disease progression, the significance of lysosomal overload-independent mechanisms in the development of cellular dysfunction is unknown for most LSDs. Here, we identify a mechanism of impaired chaperone-mediated autophagy (CMA) in cystinosis, a LSD caused by defects in the cystine transporter cystinosin (CTNS) and characterized by cystine lysosomal accumulation. We show that, different from other LSDs, autophagosome number is increased, but macroautophagic flux is not impaired in cystinosis while mTOR activity is not affected. Conversely, the expression and localization of the CMA receptor LAMP2A are abnormal in CTNS-deficient cells and degradation of the CMA substrate GAPDH is defective in Ctns-/- mice. Importantly, cysteamine treatment, despite decreasing lysosomal overload, did not correct defective CMA in Ctns-/- mice or LAMP2A mislocalization in cystinotic cells, which was rescued by CTNS expression instead, suggesting that cystinosin is important for CMA activity. In conclusion, CMA impairment contributes to cell malfunction in cystinosis, highlighting the need for treatments complementary to current therapies that are based on decreasing lysosomal overload.

The characterization of functionally diverse enzyme superfamilies provides the opportunity to identify evolutionarily conserved catalytic strategies, as well as amino acid substitutions responsible for the evolution of new functions or specificities. Isopr

In an unbiased approach to biomarker discovery, we applied a highly multiplexed proteomic technology (SOMAscan, SomaLogic, Inc, Boulder, CO) to understand changes in proteins from paired serum samples at enrollment and after 8 weeks of TB treatment from 39

Five experts respected for their significant contributions to the scientific literature on children of alcoholics (COA's) offer their perspectives in a panel discussion format. The panel members reflect on the historical roots of COA research and comment on its current status and future direction. Enriched by the panelists' variety of backgrounds, research interests, and approaches, the discussion emphasizes the need to consider multiple variables that influence the risk for alcoholism among COA's.

Background: Cancer and Leukemia Group B (CALGB) Study 19802, a phase 2 study, evaluated whether dose intensification of daunorubicin and cytarabine could improve disease-free survival (DFS) in adults with acute lymphoblastic leukemia (ALL) and whether high-dose systemic and intrathecal methotrexate could replace cranial radiotherapy for central nervous system (CNS) prophylaxis.Methods: One hundred sixty-one eligible, previously untreated patients ages 16 to 82 years (median age, 40 years) were enrolled, and 33 (20%) were aged ≥60 years.Results: One hundred twenty-eight patients (80%) achieved complete remission (CR). Dose intensification of daunorubicin and cytarabine was feasible. At a median follow-up of 10.4 years for surviving patients, the 5-year DFS rate was 25% (95% confidence interval, 18%-33%), and the overall survival (OS) rate was 30% (95% confidence interval, 23%-37%). Patients aged <60 years who received the 80 mg/m(2) dose of daunorubicin had a DFS of 33% (95% confidence interval, 22%-44%) and an OS of 39% (95% confidence interval, 29%-49%) at 5 years. Eighty-four patients (52%) relapsed, including 9 patients (6%) who had isolated CNS relapses. The omission of cranial irradiation did not result in higher than historic CNS relapse rates.Conclusions: Intensive systemic, oral, and intrathecal methotrexate dosing permitted the omission of CNS irradiation in adult patients with ALL. This intensive approach using higher doses of daunorubicin and cytarabine failed to result in an overall improvement in DFS or OS compared with historic CALGB studies. Future therapeutic strategies for adults with ALL should be tailored to specific age and molecular genetic subsets. [ABSTRACT FROM AUTHOR]

Background: The standard clinical approach for reducing cardiovascular disease risk due to dyslipidemia is to prescribe changes in diet and physical activity. The purpose of the current study was to determine if, across a range of dietary patterns, there were variable lipoprotein responses to an aerobic exercise training intervention.Methods: Subjects were participants in the STRRIDE I, a supervised exercise program in sedentary, overweight subjects randomized to 6 months of inactivity or 1 of 3 aerobic exercise programs. To characterize diet patterns observed during the study, we calculated a modified z-score that included intakes of total fat, saturated fat, trans fatty acids, cholesterol, omega-3 fatty acids, and fiber as compared with the 2006 American Heart Association diet recommendations. Linear models were used to evaluate relationships between diet patterns and exercise effects on lipoproteins/lipids.Results: Independent of diet, exercise had beneficial effects on low-density lipoprotein cholesterol particle number, low-density lipoprotein cholesterol size, high-density lipoprotein cholesterol, high-density lipoprotein cholesterol size, and triglycerides (P < .05 for all). However, having a diet pattern that closely adhered to American Heart Association recommendations was not related to changes in these or any other serum lipids or lipoproteins in any of the exercise groups.Conclusions: We found that even in sedentary individuals whose habitual diets vary in the extent of adherence to AHA dietary recommendations, a rigorous, supervised exercise intervention can achieve significant beneficial lipid effects. [ABSTRACT FROM AUTHOR]

The Centers for Disease Control and Prevention and National Institutes of Health convened a multidisciplinary meeting to discuss surrogate markers of treatment response in tuberculosis. The goals were to assess recent surrogate marker research and to provide specific recommendations for (1) the qualification and validation of biomarkers of treatment outcome; (2) the standardization of specimen and data collection for future clinical trials, including a minimum set of samples and collection time points; and (3) the creation ofa specimen repository to support biomarker testing. This article summarizes these recommendations and provides a roadmap for their implementation. [ABSTRACT FROM AUTHOR]

Empirical and theoretical literature suggests that stereotypical gender roles shape men's and women's health help-seeking behavior, and plays an important role in the treatment seeking delays of cardiac patients. We were interested in exploring the ways in which gender informs the experiences and help-seeking behavior of men and women who experienced the symptoms associated with acute cardiac events. We undertook 20 in-depth interviews between October 2007 and July 2008 with 11 men and 9 women recently diagnosed with an acute coronary syndrome in British Columbia, Canada. Participants were encouraged to tell their 'story' of the event that led to hospitalization and diagnosis, with a focus on the symptoms and decision making processes that occurred before and during the activation of health services: seeking the advice of others including colleagues, family members and healthcare professionals; calling 911; and attending an emergency department. Although we anticipated that distinctive patterns of help-seeking behavior aligned with stereotypical masculine and feminine ideals might emerge from our data, this was not always the case. We found some evidence of the influence of gender role ideology on the help-seeking behavior of both male and female participants. However, men's and women's experiences of seeking health care were not easily parsed into distinct binary gender patterns. Behavior that might stereotypically be considered to be 'masculine' or 'feminine' gender practice was shared by both male and female participants. Our findings undermine simple binary distinctions about gendered help-seeking prevalent in the literature, and contribute towards setting the direction of the future health policy and research agenda addressing the issue of gender and health help-seeking behavior. [ABSTRACT FROM AUTHOR]

Background: There is increasing public health evidence that women who use crack cocaine and are street-involved experience significant health problems and are more isolated with regards to accessing harm reduction and other health-related services. Simultaneously, there is growing acknowledgement that structural and 'everyday' violence are significant factors influencing the health of women who use illegal drugs. Little research has examined how these social processes play out for women who use crack cocaine. Methods: A critical ethnography informed by the theoretical constructs of structural and everyday violence and intersectionality was undertaken to explore women's use of crack cocaine within an inner-city neighbourhood in Western Canada. Data collection included baseline survey (n=126), participant observation and field notes, informal interviews (n=53), and in-depth interviews (n=13). Results: Based on thematic and theoretical analysis two interrelated themes were identified that reflected the interrelationships between women's use of crack, poverty, discrimination, racism, gendered relations of power, and legal policies and practices: (a) the context of health care; and (b) the smoking context. Conclusions: Structural inequities and 'everyday' violence are perilously damaging for women who use crack. Interventions to reduce these inequities are urgently needed if we are to reduce the significant suffering of women who are street-involved and use crack cocaine. [ABSTRACT FROM AUTHOR]

Objective: To examine the long-term safety and efficacy of three antipsychotics in early-onset schizophrenia spectrum disorders.Method: Patients (8 to 19 years old) who had improved during an 8-week, randomized, double-blind acute trial of olanzapine, risperidone, or molindone (plus benztropine) were eligible to continue on the same medication for up to 44 additional weeks under double-blind conditions. Adjunctive medications were allowed according to defined algorithms. Standardized symptom, safety, and functional assessments were conducted every 4 weeks.Results: Of the 116 youths randomized in the acute trial, 54 entered maintenance treatment (molindone, n = 20; olanzapine, n = 13; risperidone, n = 21). Fourteen (26%) completed 44 weeks of treatment. Adverse effects (n = 15), inadequate efficacy (n = 14), or study nonadherence (n = 8) were the most common reasons for discontinuation. The three treatment arms did not significantly differ in symptom decrease or time to discontinuation. Akathisia was more common with molindone and elevated prolactin concentrations more common with risperidone. Although weight gain and metabolic adverse events had occurred more often with olanzapine and risperidone during the acute trial, no significant between-drug differences emerged in most of these parameters during maintenance treatment.Conclusions: Only 12% of youths with early-onset schizophrenia spectrum disorders continued on their originally randomized treatment at 52 weeks. No agent demonstrated superior efficacy, and all were associated with side effects, including weight gain. Improved treatments are needed for early-onset schizophrenia spectrum disorders. Clinical trial registry information-Treatment of Schizophrenia and Related Disorders in Children and Adolescents; URL: http://www.clinicaltrials.gov, unique identifier: NCT00053703. [ABSTRACT FROM AUTHOR]

Introduction: This paper presents an oral history from the mid-1980s to 2009 of the start and evolution of the Multinational Association of Supportive Care in Cancer (MASCC) as seen through the recollections of the founders and early leaders. The growth of the supportive cancer care movement and MASCC's contribution to oncology supportive care is described.Discussion: As science was making progress towards better cancer treatment, a group of professionals began to research ways to prevent or mitigate the symptoms and side effects that accompany the disease and its treatments. Joining forces, they created an international, multidisciplinary organization to address and promulgate evidence-based practices of cancer supportive care. Through annual international scientific symposia, a peer-reviewed journal, an accessible website, and study group projects such as guidelines and tools, MASCC is accomplishing its mission. [ABSTRACT FROM AUTHOR]

Although nurses are encouraged to address patients' tobacco use, the integration of tobacco reduction into practice has not been consistent. An organizational behavior perspective was used to conceptualize hypothesized relationships among reported influencing factors (individual characteristics, role attitudes, perceived barriers, and workplace climate). Survey data collected at two Western Canadian hospitals (N = 214 nurses; 58% response) were used to test the model. The final model explained nearly 60% of variation in the nurses' tobacco reduction practice. Role attitude, perceived resource availability, co-worker's activities, and ability were the strongest contributors. Nurses' smoking status indirectly influenced practice through shaping role attitudes and perceived ability. Diverse leverage points to enhance nurses' involvement in patients' tobacco use were identified. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This study aimed to describe mental healthcare providers' attitudes about tobacco use, their personal smoking status, their confidence in offering smoking cessation support to clients living with severe mental illness, and the extent to which they incorporated smoking cessation interventions into their practice. The study also aimed to determine whether the providers' attitudes, smoking status, and confidence were associated with offering smoking cessation support to clients. METHODS: Self-administered questionnaires were distributed within community-based mental health agencies to those who provide care and support to adults living with severe mental illness. Outcomes measured included respondents' smoking status, attitudes related to the provision of smoking cessation support, confidence in providing smoking cessation intervention, and smoking cessation practices. We conducted multivariate analyses using logistic regression analyses to examine the factors associated with the providers' tobacco-related practices. RESULTS: In total 282 of 871 care providers responded to the survey, 22% of whom were current smokers. The providers who held sympathetic attitudes about their role and their clients' role in smoking cessation, who were never or former smokers, who were healthcare professionals rather than paraprofessionals, who had relatively more confidence, and who had more experience working in the mental health field were more likely to engage their clients in tobacco-related interventions. CONCLUSIONS: In this study the healthcare providers working in community-based mental health have a smoking prevalence rate that exceeds that of the region's general population and did not provide optimal smoking cessation support to their clients. PRACTICE IMPLICATIONS: Interventions that bolster the confidence of providers to engage is smoking cessation activities and that support a shift in attitudes about the role of tobacco use in mental health are required. [ABSTRACT FROM AUTHOR]

Rationale: Cavitary disease and delayed culture conversion have been associated with relapse. Combining patient characteristics and measures of bacteriologic response might allow treatment shortening with current drugs in some patients.Objectives: To assess whether treatment could be shortened from 6 to 4 months in patients with noncavitary tuberculosis whose sputum cultures converted to negative after 2 months.Methods: This study was a randomized, open-label equivalence trial. HIV-uninfected adults with noncavitary tuberculosis were treated daily with isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by 2 months of isoniazid and rifampin. After 4 months, patients with drug-susceptible TB whose sputum cultures on solid media were negative after 8 weeks of treatment were randomly assigned to continue treatment for 2 more months or to stop treatment. Patients were followed for relapse for 30 months after beginning treatment.Measurements and Main Results: Enrollment was stopped by the safety monitoring committee after 394 patients were enrolled due to apparent increased risk for relapse in the 4-month arm. A total of 370 patients were eligible for per protocol analysis. Thirteen patients in the 4-month arm relapsed, compared with three subjects in the 6-month arm (7.0 vs. 1.6%; risk difference, 0.054; 95% confidence interval with Hauck-Anderson correction, 0.01-0.10).Conclusion: Shortening treatment from 6 to 4 months in adults with noncavitary disease and culture conversion after 2 months using current drugs resulted in a greater relapse rate. The combination of noncavitary disease and 2-month culture conversion was insufficient to identify patients with decreased risk for relapse. [ABSTRACT FROM AUTHOR]

Background The demand for percutaneous coronary intervention (PCI) exerts constant pressure on health care systems to meet the growing needs of patients. The practice of same-day discharge PCI has emerged as a medically safe option to optimize resource utilization and improve access to care. Aim The purpose of this study was to describe elective same-day discharge PCI patients' self-care behaviour in the two to five days following their procedure, and the factors associated with cardiac self-efficacy (CSE) and self-care agency (SCA). Methods Using a cross-sectional correlational design, 98 consecutive patients were contacted by telephone, following PCI, and asked about their CSE, SCA, and adherence to discharge recommendations. Associations between selected variables were explored through multiple regression analysis. Results The findings revealed a high degree of adherence to discharge recommendations, although participants' appreciation of the long term management of their chronic disease was limited. Factors associated with lower levels of CSE and SCA included the burden of having additional chronic co-morbidities, living alone and lacking social support, and a positive screening for psychosocial distress. Conclusion Same-day discharge PCI presents a sustainable option for delivery of care for most patients. Some clients may require additional support to manage the transition between acute intervention and chronic disease management. [ABSTRACT FROM AUTHOR]