Propionibacterium acnes susceptibility to low-level 449 nm blue light photobiomodulation.

BACKGROUND AND OBJECTIVE: Recent advances in low-level light devices have opened new treatment options for mild to moderate acne patients. Light therapies have been used to treat a variety of skin conditions over the years but were typically only available as treatments provided by professional clinicians. Clinical application of blue light has proven to be effective for a broader spectral range and at lower fluences than previously utilized. Herein, we tested the hypothesis that sub-milliwatt/cm2 levels of long-wave blue light (449 nm) effectively kills Propionibacterium acnes, a causative agent of acne vulgaris, in vitro. MATERIALS AND METHODS: Two types of LED light boards were designed to facilitate in vitro blue light irradiation to either six-well plates containing fluid culture or a petri plate containing solid medium. P. acnes. Survival was determined by counting colony forming units (CFU) following irradiation. P. acnes was exposed in the presence and absence of oxygen. Coproporphyrin III (CPIII) photoexcitation was spectrophotometrically evaluated at 415 and 440 nm to compare the relative photochemical activities of these wavelengths. RESULTS: 422 and 449 nm blue light killed P. acnes in planktonic culture. Irradiation with 449 nm light also effectively killed P. acnes on a solid agar surface. Variation of time or intensity of light exposure resulted in a fluence-dependent improvement of antimicrobial activity. The presence of oxygen was necessary for killing of P. acnes with 449 nm light. CPIII displayed clear photoexcitation at both 415 and 440 nm, indicating that both wavelengths are capable of initiating CPIII photoexcitation at low incident light intensities (50 uW/cm2 ). CONCLUSION: Herein we demonstrate that sub-milliwatt/cm2 levels of long-wave blue light (449 nm) effectively kill P. acnes. The methods and results presented allow for deeper exploration and design of light therapy treatments. Results from these studies are expanding our understanding of the mode of action and functionality of blue light, allowing for improved options for acne patients. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Fast Click Rate Electrocochleography and Auditory Brainstem Response in Normal-Hearing Adults Using Continuous Loop Averaging Deconvolution.

OBJECTIVES: Using the continuous loop averaging deconvolution (CLAD) technique for conventional electrocochleography (ECochG) and auditory brainstem response (ABR) recordings, the effects of testing at high stimulus rates may have the potential to diagnose disorders of the inner ear and auditory nerve. First, a body of normative data using the CLAD technique must be established. DESIGN: Extratympanic click ECochG and ABR to seven stimulus rates using CLAD were measured simultaneously from a tympanic membrane electrode and surface electrodes on the forehead and mastoid of 42 healthy individuals. RESULTS: Results showed that the compound action potential (AP) of the ECochG and waves I, III, and V of the ABR decreased in amplitude and increased in latency as stimulus rate was increased from standard 7.1 clicks/s up to 507.81 clicks/s, with sharp reduction in AP amplitude at 97.66 clicks/s and reaching asymptote at 292.97 clicks/s. The summating potential (SP) of the ECochG, however, stayed relatively stable, resulting in increased SP/AP ratios with increasing rate. The SP/AP amplitude ratio showed more stability than AP amplitude findings, thus it is recommended for use in evaluation of cochlear and neural response. CONCLUSIONS: Results of both amplitude and latency data from this normative neural adaptation function of the auditory pathway serves as guide for improving diagnostic utility of both ECochG and ABR using CLAD as a reliable technique in distinguishing inner ear and auditory nerve disorders.

The Three-Decade Long Journey in Heart Failure Drug Development.

Heart failure is a global disease with increasing prevalence due to an aging worldwide population with increasing co-morbidities. Despite several therapeutic options available to treat HFrEF, morbidity and mortality remain high. Importantly, no approved therapies are available to treat HFpEF. This paper will briefly summarize the burden of disease, HF classification and definitions and the landmark clinical trials in both HFrEF and HFpEF. Given the increasing incidence and prevalence of HF and the high morbidity and mortality associated with this disease, continued development efforts are essential to address the unmet needs of these patients.

Novel sGC Stimulators and sGC Activators for the Treatment of Heart Failure.

The burden of heart failure (HF) increases worldwide with an aging population, and there is a high unmet medical need in both, heart failure with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). The nitric oxide (NO) pathway is a key regulator in the cardiovascular system and modulates vascular tone and myocardial performance. Disruption of the NO-cyclic guanosine monophosphate (cGMP) signaling axis and impaired cGMP formation by endothelial dysfunction could lead to vasotone dysregulation, vascular and ventricular stiffening, fibrosis, and hypertrophy resulting in a decline of heart as well as kidney function. Therefore, the NO-cGMP pathway is a treatment target in heart failure. Exogenous NO donors such as nitrates have long been used for treatment of cardiovascular diseases but turned out to be limited by increased oxidative stress and tolerance. More recently, novel classes of drugs were discovered which enhance cGMP production by targeting the NO receptor soluble guanylate cyclase (sGC). These compounds, the so-called sGC stimulators and sGC activators, are able to increase the enzymatic activity of sGC to generate cGMP independently of NO and have been developed to target this important signaling cascade in the cardiovascular system.This review will focus on the role of sGC in cardiovascular (CV) physiology and disease and the pharmacological potential of sGC stimulators and sGC activators therein. Preclinical data will be reviewed and summarized, and available clinical data with riociguat and vericiguat, novel direct sGC stimulators, will be presented. Vericiguat is currently being studied in a Phase III clinical program for the treatment of heart failure with reduced ejection fraction (HFrEF).

Closed vitrification of human oocytes and blastocysts: outcomes from a series of clinical cases.

PURPOSE: High survival rates and clinical outcomes similar to those from fresh oocytes and blastocysts have been observed with open oocyte vitrification systems. It has been suggested that the extremely fast cooling rates that are only achieved with open systems are necessary for human oocyte and blastocyst vitrification. However, there is a potential risk of introducing contamination with open systems. The aim of this study was to assess whether similar survival and subsequent implantation rates could be achieved using a closed vitrification system for human oocytes and blastocysts. METHODS: Initially, donated immature oocytes that were matured in vitro were vitrified using the cryoprotectants ethylene glycol (EG) + dimethyl sulphoxide (DMSO) + sucrose and either a closed system (Rapid-i®) or an open system (Cryolock). The closed system was subsequently introduced clinically for mature oocyte cryopreservation cases and blastocyst vitrification. RESULTS: Using in vitro matured oocytes, a similar survival was achieved with the open system of 92.4 % (73/79) and with the closed system of 89.7 % (35/39). For clinical oocyte closed vitrification, high survival rate of 90.5 % (374/413) and an implantation rate of 32.7 % (18/55) from the transfer of day 2 embryos was achieved, which is similar to fresh day 2 embryo transfers. Blastocysts have also been successfully cryopreserved using the Rapid-i closed vitrification system with 94 % of blastocysts having an estimated ≥75 % of cells intact and a similar implantation rate (31.5 %) to fresh single blastocyst transfers. CONCLUSION: Closed vitrification can achieve high survival and similar implantation rates to fresh for both oocytes and blastocysts.

Developing a prevention synthesis and translation system to promote science-based approaches to teen pregnancy, HIV and STI prevention.

The Interactive Systems Framework for Dissemination and Implementation (ISF) is a multi-system framework that can guide research-to-practice efforts by building and supporting the work of three interacting systems: the Prevention Delivery, Support, and Synthesis and Translation Systems. The Synthesis and Translation system is vital to bridging science and practice, yet how to develop it and train support system partners to use it is under-researched. This article bridges this gap by offering a case example of the planning, development, and use of a synthesis and translation product called Promoting Science-based Approaches to Teen Pregnancy Prevention using Getting To Outcomes. The case presented documents the process used for developing the synthesis and translation product, reports on efforts to engage the Prevention Support system to use the product, and how we approached building interaction between the Synthesis and Translation System and the Support System partners. Practice-oriented evaluation data are also presented. Implications for practice, policy and research are discussed.

Breast and cervical cancer screening and health beliefs among African American women attending educational programs.

This article assessed the relationship between breast and cervical cancer screening rates and health beliefs in African American women participating in Witness Project of Harlem (WPH) education sessions. WPH is a culturally sensitive, faith-based breast and cervical cancer screening education program targeting African American women in medically underserved New York City communities. A questionnaire administered to women participating for the first time in a Witness Project education session collected demographics, adherence to breast and cervical cancer screening, and information about health beliefs related to cancer worry, medical mistrust, and religious faith. Screening adherence guidelines applied were as per the American Cancer Society recommendations. No statistically significant relationship was found between worry about getting breast or cervical cancer and screening adherence, or between screening adherence and agreement with statements about medical mistrust and religious beliefs. The low screening mammography and monthly breast self-exam rates emphasize the utility of programs like WPH that teach the importance of screening mammography and breast self-exam and point to the need for increased access to quality health care and cancer screening in underserved populations.

Quaternary Phosphonium Compound Unveiled as a Potent Disinfectant against Highly Resistant Acinetobacter baumannii Clinical Isolates.

Acinetobacter baumannii is classified as a highest threat pathogen, urgently necessitating novel antimicrobials that evade resistance to combat its spread. Quaternary ammonium compounds (QACs) have afforded a valuable first line of defense against antimicrobial resistant pathogens as broad-spectrum amphiphilic disinfectant molecules. However, a paucity of innovation in this space has driven the emergence of QAC resistance. Through this work, we sought to identify next-generation disinfectant molecules with efficacy against highly resistant A. baumannii clinical isolates. We selected 12 best-in-class molecules from our previous investigations of quaternary ammonium and quaternary phosphonium compounds (QPCs) to test against a panel of 35 resistant A. baumannii clinical isolates. The results highlighted the efficacy of our next-generation compounds over leading commercial QACs, with our best-in-class QAC (2Pyr-11,11) and QPC (P6P-10,10) displaying improved activities with a few exceptions. Furthermore, we elucidated a correlation between colistin resistance and QAC resistance, wherein the only pan-resistant isolate of the panel, also harboring colistin resistance, exhibited resistance to all tested QACs. Notably, P6P-10,10 maintained efficacy against this strain with an IC90 of 3 µM. In addition, P6P-10,10 displayed minimum biofilm eradication concentrations as low as 32 µM against extensively drug resistant clinical isolates. Lastly, examining the development of disinfectant resistance and cross-resistance, we generated QAC-resistant A. baumannii mutants and observed the development of QAC cross-resistance. In contrast, neither disinfectant resistance nor cross-resistance was observed in A. baumannii under P6P-10,10 treatment. Taken together, the results of this work illustrate the need for novel disinfectant compounds to treat resistant pathogens, such as A. baumannii, and underscore the promise of QPCs, such as P6P-10,10, as viable next-generation disinfectant molecules.

Validation of a claims-based algorithm to identify patients with chronic thromboembolic pulmonary hypertension using electronic health record data.

This study aimed to validate an algorithm developed to identify chronic thromboembolic pulmonary hypertension (CTEPH) among patients with a history of pulmonary embolism. Validation was halted because too few patients had gold-standard evidence of CTEPH in the administrative claims/electronic health records database, suggesting that CTEPH is underdiagnosed.

Measuring social change preferences in African American adolescents: development of the Measure of Social Change for Adolescents (MOSC-A).

Studies addressing Black adolescents' social change strategies are nonexistent and might be associated with the absence of social change measures for Black adolescents. In an effort to begin addressing this concern, the 30-item Measure of Social Change for Adolescents (MOSC-A) was designed to measure Black adolescents' first- (i.e., within the system) and second- (outside of the system) order social change strategies. Factor analysis of responses that 226 Black adolescents gave to the MOSC-A revealed first- and second-order social change factors. Item response theory analyses revealed that 65% of the items on the former factor adequately discriminate across different trait levels, but those of the latter were less promising. Scaffolded on this study, future research might refine the MOSC-A's psychometric properties and improve its utility.

Design and methods for the Better Resiliency Among Veterans and non-Veterans with Omega-3's (BRAVO) study: A double blind, placebo-controlled trial of omega-3 fatty acid supplementation among adult individuals at risk of suicide.

Suicide remains the 10th leading cause of death among adults in the United States (U.S.). Annually, approximately 30 per 100,000 U.S. military Veterans commit suicide, compared to 14 per 100,000 U.S. civilians. Symptoms associated with suicidality can be treatment resistant and proven-effective pharmaceuticals may have adverse side-effects. Thus, a critical need remains to identify effective approaches for building psychological resiliency in at-risk individuals. Omega-3 highly unsaturated fatty acids (n-3 HUFAs) are essential nutrients, which must be consumed in the diet. N-3 HUFAs have been demonstrated to reduce symptoms of depression, anxiety, and impulsivity - which are associated with suicide risk. Here we present the design and methods for the Better Resiliency Among Veterans and non-Veterans with Omega-3's (BRAVO) study, which is a double blind, randomized, controlled trial among individuals at risk of suicide of an n-3 HUFA versus placebo supplementation in the form of all natural fruit juice beverages. The BRAVO study seeks to determine if dietary supplementation with n-3 HUFAs reduces the risk for serious suicidal behaviors, suicidal thinking, negative emotions, and symptoms associated with suicide risk. Sub-analyses will evaluate efficacy in reducing depressive symptoms, alcohol, and nicotine use. A sub-study utilizes functional magnetic resonance imaging (fMRI) to evaluate the neuropsychological and neurophysiological effects of n-3 HUFAs. We also outline selection of appropriate proxy outcome measures for detecting response to treatment and collection of ancillary data, such as diet and substance use, that are critical for interpretation of results.

Exploring New Endpoints for Patients With Heart Failure With Preserved Ejection Fraction.

The epidemiological, clinical, and societal implications of the heart failure (HF) epidemic cannot be overemphasized. Approximately half of all HF patients have HF with preserved ejection fraction (HFpEF). HFpEF is largely a syndrome of the elderly, and with aging of the population, the proportion of patients with HFpEF is expected to grow. Currently, there is no drug known to improve mortality or hospitalization risk for these patients. Besides mortality and hospitalization, it is imperative to realize that patients with HFpEF have significant impairment in their functional capacity and their quality of life on a daily basis, underscoring the need for these parameters to ideally be incorporated within a regulatory pathway for drug approval. Although attempts should continue to explore therapies to reduce the risk of mortality or hospitalization for these patients, efforts should also be directed to improve other patient-centric concerns, such as functional capacity and quality of life. To initiate a dialogue about the compelling need for and the challenges in developing such alternative endpoints for patients with HFpEF, the US Food and Drug Administration on November 12, 2015, facilitated a meeting represented by clinicians, academia, industry, and regulatory agencies. This document summarizes the discussion from this meeting.

Rest-activity cycles in childhood and adolescent depression.

OBJECTIVE: To quantify circadian rhythms in rest-activity cycles in depressed children and adolescents. METHOD: Rest-activity cycles were evaluated by actigraphy over five consecutive 24-hour periods in 100 children and adolescents, including 59 outpatients with major depressive disorder (MDD) and 41 healthy normal controls. Total activity, total light exposure, and time spent in light at more than 1,000 lux were averaged over the recording period for each participant. Time series analysis was used to determine the amplitude and period length of circadian rhythms in rest-activity. RESULTS: Overall, adolescents with MDD had lower activity levels, damped circadian amplitude, and lower light exposure and spent less time in bright light than healthy controls. Among children, those with MDD showed lower light exposure and spent less time in bright light, but only depressed girls showed damped circadian amplitude. The sex differences were substantially greater in the MDD group than in the normal control group. CONCLUSIONS: These results confirm damped circadian rhythms in children and adolescents with MDD and highlight the influence of gender and age on these measures.

Pharmacotherapy of obesity: clinical treatments and considerations.

Obesity is a world-wide epidemic associated with significant morbidity and mortality which costs billions of dollars per year. The associated related conditions are many and include heart disease, stroke, type II diabetes mellitus, sleep apnea and certain types of cancer. Given that it is a multifactorial problem, the treatments must also address the numerous causes associated with the development of obesity. The neurohormonal regulation of feeding and energy is a complex system often necessitating modification through more than 1 pathway to achieve weight loss. Therefore, in addition to lifestyle changes, attenuation of caloric intake and increase in caloric expenditure, pharmacotherapies, including combination medications, may prove beneficial in its treatment. Adding to the current available pharmacotherapies for obesity, the Food and Drug Administration has recently approved 2 new combination medications known as lorcaserin (Belviq) and phentermine-topiramate (Qsymia). As with these and other medications used for weight loss, clinical cautions, side effects, precise review of patients' medical history and selecting the appropriate medication are imperative. Additionally, close follow-up is necessary in patients undergoing treatment for weight loss. As weight loss progresses, patients who are currently undergoing concomitant treatment for comorbid diabetes and hypertension need to be monitored for appropriate changes in medications used to treat those conditions. Weight loss is often accompanied by improvement in blood pressure and glucose levels and therefore resting blood pressure and fasting and/or postprandial plasma glucose levels should be monitored at follow-up. Although unique to each individual, the benefits of weight loss are substantial and can improve well-being and physical health.

Promoting science-based approaches to teen pregnancy prevention: proactively engaging the three systems of the interactive systems framework.

In the field of teen pregnancy prevention many efficacious prevention programs are available but adoption of these programs is slow at the community level. In this article, we present a multi-site, capacity-building effort called the Promoting Science-based Approaches to Teen Pregnancy Prevention project (PSBA) as a case example of a proactive application of the Interactive System Framework (ISF) for dissemination and implementation. The ISF is a multi-system model leading to dissemination and implementation of science-based prevention programming through the work of three interactive systems: The "Prevention Delivery," "Prevention Support," and "Prevention Synthesis & Translation" Systems. This article describes the proactive use of the ISF to conceptualize and bolster the PSBA program's goal of assisting local prevention partners in the use of science-based approaches (SBA) to prevent teen pregnancy. PSBA uses all three systems of the ISF to facilitate practice improvements and offers valuable research opportunities to investigate factors related to dissemination and implementation processes across these systems. Describing our application of this framework highlights the feasibility of actively using the ISF to build prevention infrastructure and to guide large-scale prevention promotion strategies in the area of teen pregnancy prevention. The program's ongoing evaluation is presented as an example of early efforts to develop an evidence base around the ISF. Research implications are discussed.

Intensive insulin therapy for critically ill patients.

OBJECTIVE: To evaluate the clinical outcomes of glycemic control of intensive insulin therapy and recommend its place in the management of critically ill patients. DATA SOURCES: Searches of MEDLINE (1966-March 2004) and Cochrane Library, as well as an extensive manual review of abstracts were performed using the key search terms hyperglycemia, insulin, intensive care unit, critically ill, outcomes, and guidelines and algorithms. STUDY SELECTION AND DATA EXTRACTION: All articles identified from the data sources were evaluated and deemed relevant if they included and assessed clinical outcomes. DATA SYNTHESIS: Mortality among patients with prolonged critical illness exceeds 20%, and most deaths are attributable to sepsis and multisystem organ failure. Hyperglycemia is common in critically ill patients, even in those with no history of diabetes mellitus. Maintaining normoglycemia with insulin in critically ill patients has been shown to improve neurologic, cardiovascular, and infectious outcomes. Most importantly, morbidity and mortality are reduced with aggressive insulin therapy. This information can be implemented into protocols to maintain strict control of glucose. CONCLUSIONS: Use of insulin protocols in critically ill patients improves blood glucose control and reduces morbidity and mortality in critically ill populations. Glucose levels in critically ill patients should be controlled through implementation of insulin protocols with the goal to achieve normoglycemia, regardless of a history of diabetes. Frequent monitoring is imperative to avoid hypoglycemia.