CCX559 is a potent, orally-administered small molecule PD-L1 inhibitor that induces anti-tumor immunity.

The interaction of PD-L1 with PD-1 is a major immune checkpoint that limits effector T cell function against cancer cells; monoclonal antibodies that block this pathway have been approved in multiple tumor indications. As a next generation therapy, small molecule inhibitors of PD-L1 have inherent drug properties that may be advantageous for certain patient populations compared to antibody therapies. In this report we present the pharmacology of the orally-available, small molecule PD-L1 inhibitor CCX559 for cancer immunotherapy. CCX559 potently and selectively inhibited PD-L1 binding to PD-1 and CD80 in vitro, and increased activation of primary human T cells in a T cell receptor-dependent fashion. Oral administration of CCX559 demonstrated anti-tumor activity similar to an anti-human PD-L1 antibody in two murine tumor models. Treatment of cells with CCX559 induced PD-L1 dimer formation and internalization, which prevented interaction with PD-1. Cell surface PD-L1 expression recovered in MC38 tumors upon CCX559 clearance post dosing. In a cynomolgus monkey pharmacodynamic study, CCX559 increased plasma levels of soluble PD-L1. These results support the clinical development of CCX559 for solid tumors; CCX559 is currently in a Phase 1, first in patient, multicenter, open-label, dose-escalation study (ACTRN12621001342808).

Postmarketing Colitis Cases Associated With Alpelisib Use Reported to the US Food and Drug Administration.

This case series investigates reports of 20 patients with colitis temporally associated with alpelisib use.

A Pilot Screen of a Novel Peptide Hormone Library Identified Candidate GPR83 Ligands.

The identification of novel peptide hormones by functional screening is challenging because posttranslational processing is frequently required to generate biologically active hormones from inactive precursors. We developed an approach for functional screening of novel potential hormones by expressing them in endocrine host cells competent for posttranslational processing. Candidate preprohormones were selected by bioinformatics analysis, and stable endocrine host cell lines were engineered to express the preprohormones. The production of mature hormones was demonstrated by including the preprohormones insulin and glucagon, which require the regulated secretory pathway for production of the active forms. As proof of concept, we screened a set of G-protein-coupled receptors (GPCRs) and identified protein FAM237A as a specific activator of GPR83, a GPCR implicated in central nervous system and regulatory T-cell function. We identified the active form of FAM237A as a C-terminally cleaved, amidated 9 kDa secreted protein. The related protein FAM237B, which is 64% homologous to FAM237A, demonstrated similar posttranslational modification and activation of GPR83, albeit with reduced potency. These results demonstrate that our approach is capable of identifying and characterizing novel hormones that require processing for activity.

High tempo music prolongs high intensity exercise.

Music has been shown to reduce rating of perceived exertion, increase exercise enjoyment and enhance exercise performance, mainly in low-moderate intensity exercises. However, the effects of music are less conclusive with high-intensity activities. The purpose of this with-participant design study was to compare the effects of high tempo music (130 bpm) to a no-music condition during repeated high intensity cycling bouts (80% of peak power output (PPO)) on the following measures: time to exercise end-point, rating of perceived exertion (RPE), heart rate (HR), breathing frequency, ventilatory kinetics and blood lactate (BL). Under the music condition, participants exercised 10.7% longer (p = 0.035; Effect size (ES) = 0.28) (increase of 1 min) and had higher HR (4%; p = 0.043; ES = 0.25), breathing frequency (11.6%; p < 0.001; ES = 0.57), and RER (7% at TTF; p = 0.021; ES = 1.1) during exercise, as measured at the exercise end-point. Trivial differences were observed between conditions in RPE and other ventilatory kinetics during exercise. Interestingly, 5 min post-exercise termination, HR recovery was 13.0% faster following the music condition (p < 0.05) despite that music was not played during this period. These results strengthen the notion that music can alter the association between central motor drive, central cardiovascular command and perceived exertion, and contribute to prolonged exercise durations at higher intensities along with a quicken HR recovery.

Repeated-Dose Oral N-Acetylcysteine in Parkinson's Disease: Pharmacokinetics and Effect on Brain Glutathione and Oxidative Stress.

Parkinson's disease (PD) is associated with oxidative stress and decreased nigral glutathione (GSH), suggesting that therapies that boost GSH may have a disease-modifying effect. Intravenous administration of a high dose of N-acetylcysteine (NAC), a well-known antioxidant and GSH precursor, increases blood and brain GSH in individuals with PD and with Gaucher disease and in healthy controls. To characterize the pharmacokinetics of repeated high oral doses of NAC and their effect on brain and blood oxidative stress measures, we conducted a 4-week open-label prospective study of oral NAC in individuals with PD (n = 5) and in healthy controls (n = 3). Brain GSH was measured in the occipital cortex using 1 H-MRS at 3 and 7 tesla before and after 28 days of 6000 mg NAC/day. Blood was collected prior to dosing and at predetermined collection times before and after the last dose to assess NAC, cysteine, GSH, catalase, malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) concentrations and the reduced-to-oxidized GSH ratio (GSH/ glutathione disulfide [GSSG]). Symptomatic adverse events were reported by 3 of the 5 subjects with PD. NAC plasma concentration-time profiles were described by a first-order absorption, 1-compartment pharmacokinetic model. Although peripheral antioxidant measures (catalase and GSH/GSSG) increased significantly relative to baseline, indicators of oxidative damage, that is, measures of lipid peroxidation (4-HNE and MDA) were unchanged. There were no significant increases in brain GSH, which may be related to low oral NAC bioavailability and small fractional GSH/GSSG blood responses. Additional studies are needed to further characterize side effects and explore the differential effects of NAC on measures of antioxidant defense and oxidative damage.

90-90-90-Plus: Maintaining Adherence to Antiretroviral Therapies.

Medication adherence is the "Plus" in the global challenge to have 90% of HIV-infected individuals tested, 90% of those who are HIV positive treated, and 90% of those treated achieve an undetectable viral load. The latter indicates viral suppression, the goal for clinicians treating people living with HIV (PLWH). The comparative importance of different psychosocial scales in predicting the level of antiretroviral adherence, however, has been little studied. Using data from a cross-sectional study of medication adherence with an international convenience sample of 1811 PLWH, we categorized respondent medication adherence as None (0%), Low (1-60%), Moderate (61-94%), and High (95-100%) adherence based on self-report. The survey contained 13 psychosocial scales/indices, all of which were correlated with one another (p < 0.05 or less) and had differing degrees of association with the levels of adherence. Controlling for the influence of race, gender, education, and ability to pay for care, all scales/indices were associated with adherence, with the exception of Berger's perceived stigma scale. Using forward selection stepwise regression, we found that adherence self-efficacy, depression, stressful life events, and perceived stigma were significant predictors of medication adherence. Among the demographic variables entered into the model, nonwhite race was associated with double the odds of being in the None rather than in the High adherence category, suggesting these individuals may require additional support. In addition, asking about self-efficacy, depression, stigma, and stressful life events also will be beneficial in identifying patients requiring greater adherence support. This support is essential to medication adherence, the Plus to 90-90-90.

Prior Military Service, Identity Stigma, and Mental Health Among Transgender Older Adults.

PURPOSE OF THE STUDY: Converging evidence from large community-based samples, Internet studies, and Veterans Health Administration data suggest that transgender adults have high rates of U.S. military service. However, little is known about the role of prior military service in their mental health later in life, particularly in relation to identity stigma. In this article, we examine relationships between prior military service, identity stigma, and mental health among transgender older adults. DESIGN AND METHODS: We used a subsample of transgender older adults (n = 183) from the 2014 survey of Aging with Pride: National Health, Aging, and Sexuality/Gender Study (NHAS). We employed weighted multivariate linear models to evaluate the relationships between psychological health-related quality of life (HRQOL), depressive symptomatology (Center for Epidemiological Studies Depression Scale [CES-D] scores), identity stigma, and prior military service, controlling for background characteristics. RESULTS: Identity stigma was significantly related with higher depressive symptomatology and lower psychological HRQOL. Having a history of prior military service significantly predicted lower depressive symptomatology and higher psychological HRQOL. The relationships between psychological HRQOL, identity stigma, and prior military service were largely explained by depressive symptomatology. Prior military service significantly attenuated the relationship between identity stigma and depressive symptomatology. IMPLICATIONS: By identifying the role of military service in the mental health of transgender older adults, this study provides insights into how prior military service may contribute to resilience and positive mental health outcomes. Directions for future research are discussed.

Sexual transmission-risk behaviour among HIV-positive persons: a multisite study using social action theory.

AIM: Sexual risk behaviour was explored and described using Social Action Theory. BACKGROUND: The sexual transmission of HIV is complex and multi-factorial. Social Action Theory provides a framework for viewing self-regulation of modifiable behaviour such as condom use. Condom use is viewed within the context of social interaction and interdependence. DESIGN: Cross-sectional survey. METHODS: Self-report questionnaire administered to adults living with HIV/AIDS, recruited from clinics, service organizations and by active outreach, between 2010 - 2011. FINDINGS: Having multiple sex partners with inconsistent condom use during a 3-month recall period was associated with being male, younger age, having more years of education,substance use frequency and men having sex with men being a mode of acquiring HIV. In addition, lower self-efficacy for condom use scores were associated with having multiple sex partners and inconsistent condom use. CONCLUSION: Social Action Theory provided a framework for organizing data from an international sample of seropositive persons. Interventions for sexually active, younger, HIV positive men who have sex with men, that strengthen perceived efficacy for condom use, and reduce the frequency of substance use, may contribute to reducing HIV-transmission risk.

Roller-massager application to the quadriceps and knee-joint range of motion and neuromuscular efficiency during a lunge.

CONTEXT: Roller massagers are used as a recovery and rehabilitative tool to initiate muscle relaxation and improve range of motion (ROM) and muscular performance. However, research demonstrating such effects is lacking. OBJECTIVE: To determine the effects of applying a roller massager for 20 and 60 seconds on knee-joint ROM and dynamic muscular performance. DESIGN: Randomized controlled clinical trial. SETTING: University laboratory. PATIENTS OR OTHER PARTICIPANTS: Ten recreationally active men (age = 26.6 ± 5.2 years, height = 175.3 ± 4.3 cm, mass = 84.4 ± 8.8 kg). INTERVENTION(S): Participants performed 3 randomized experimental conditions separated by 24 to 48 hours. In condition 1 (5 repetitions of 20 seconds) and condition 2 (5 repetitions of 60 seconds), they applied a roller massager to the quadriceps muscles. Condition 3 served as a control condition in which participants sat quietly. MAIN OUTCOME MEASURE(S): Visual analog pain scale, electromyography (EMG) of the vastus lateralis (VL) and biceps femoris during roller massage and lunge, and knee-joint ROM. RESULTS: We found no differences in pain between the 20-second and 60-second roller-massager conditions. During 60 seconds of roller massage, pain was 13.5% (5.7 ± 0.70) and 20.6% (6.2 ± 0.70) greater at 40 seconds and 60 seconds, respectively, than at 20 seconds (P < .05). During roller massage, VL and biceps femoris root mean square (RMS) EMG was 8% and 7%, respectively, of RMS EMG recorded during maximal voluntary isometric contraction. Knee-joint ROM was 10% and 16% greater in the 20-second and 60-second roller-massager conditions, respectively, than the control condition (P < .05). Finally, average lunge VL RMS EMG decreased as roller-massage time increased (P < .05). CONCLUSIONS: Roller massage was painful and induced muscle activity, but it increased knee-joint ROM and neuromuscular efficiency during a lunge.

Discovery of MK-4409, a Novel Oxazole FAAH Inhibitor for the Treatment of Inflammatory and Neuropathic Pain.

We report herein the identification of MK-4409, a potent and selective fatty acid amide hydrolase (FAAH) inhibitor. Starting from a high throughput screening (HTS) hit, medicinal chemistry efforts focused on optimizing of FAAH inhibition in vitro potency, improving the pharmacokinetic (PK) profile, and increasing in vivo efficacy in rodent inflammatory and neuropathic pain assays.

Predictors of medication adherence among HIV-positive women in North America.

OBJECTIVE: To explore the relationships among contextual, environmental, and regulatory factors with antiretroviral (ARV) medication adherence to assist care providers in improving care for women living with HIV. DESIGN: Descriptive, multicenter study. SETTING: Sixteen HIV clinics and service organizations in North America. PARTICIPANTS: This convenience sample was drawn from a larger study of 2,182 persons living with HIV recruited from clinics and service from September 2009 to January 2011. We included 383 women living with HIV who were taking ARV medications. METHODS: We assessed the relationship of contextual, environmental, and psychological factors specific to women living with HIV in relation to adherence to ARV medication. Descriptive and multivariate statistics were used to examine the effects of these factors on self-reported ARV drug adherence. RESULTS: Age, depression symptoms, stigma, engagement with health care provider, and four psychological factors were correlated with self-reported ARV medication adherence (p = .01). Regression analysis indicated that adherence self-efficacy and depression symptoms accounted for 19% for 3-day and 22% for 30-day self-reported medication adherence. CONCLUSIONS: Adherence self-efficacy and depression symptoms predict ARV medication adherence in women and should be evaluated by nurses. Future research is needed to identify antecedents to and interventions that support adherence self-efficacy and decrease depression symptoms.

Self-compassion and risk behavior among people living with HIV/AIDS.

Sexual risk behavior and illicit drug use among people living with HIV/AIDS (PLWHA) contribute to poor health and onward transmission of HIV. The aim of this collaborative multi-site nursing research study was to explore the association between self-compassion and risk behaviors in PLWHA. As part of a larger project, nurse researchers in Canada, China, Namibia, Puerto Rico, Thailand and the US enrolled 1211 sexually active PLWHA using convenience sampling. The majority of the sample was male, middle-aged, and from the US. Illicit drug use was strongly associated with sexual risk behavior, but participants with higher self-compassion were less likely to report sexual risk behavior, even in the presence of illicit drug use. Self-compassion may be a novel area for behavioral intervention development for PLWHA.

Acceptance in the domestic environment: the experience of senior housing for lesbian, gay, bisexual, and transgender seniors.

The social environment impacts the ability of older adults to interact successfully with their community and age-in-place. This study asked, for the first time, residents of existing Lesbian, Gay, Bisexual, and Transgender (LGBT) senior living communities to explain why they chose to live in those communities and what, if any, benefit the community afforded them. Focus groups were conducted at 3 retirement communities. Analysis found common categories across focus groups that explain the phenomenon of LGBT senior housing. Acceptance is paramount for LGBT seniors and social networks expanded, contrary to socioemotional selectivity theory. Providers are encouraged to develop safe spaces for LGBT seniors.

Associations between the legal context of HIV, perceived social capital, and HIV antiretroviral adherence in North America.

BACKGROUND: Human rights approaches to manage HIV and efforts to decriminalize HIV exposure/transmission globally offer hope to persons living with HIV (PLWH). However, among vulnerable populations of PLWH, substantial human rights and structural challenges (disadvantage and injustice that results from everyday practices of a well-intentioned liberal society) must be addressed. These challenges span all ecosocial context levels and in North America (Canada and the United States) can include prosecution for HIV nondisclosure and HIV exposure/transmission. Our aims were to: 1) Determine if there were associations between the social structural factor of criminalization of HIV exposure/transmission, the individual factor of perceived social capital (resources to support one's life chances and overcome life's challenges), and HIV antiretroviral therapy (ART) adherence among PLWH and 2) describe the nature of associations between the social structural factor of criminalization of HIV exposure/transmission, the individual factor of perceived social capital, and HIV ART adherence among PLWH. METHODS: We used ecosocial theory and social epidemiology to guide our study. HIV related criminal law data were obtained from published literature. Perceived social capital and HIV ART adherence data were collected from adult PLWH. Correlation and logistic regression were used to identify and characterize observed associations. RESULTS: Among a sample of adult PLWH (n = 1873), significant positive associations were observed between perceived social capital, HIV disclosure required by law, and self-reported HIV ART adherence. We observed that PLWH who have higher levels of perceived social capital and who live in areas where HIV disclosure is required by law reported better average adherence. In contrast, PLWH who live in areas where HIV transmission/exposure is a crime reported lower 30-day medication adherence. Among our North American participants, being of older age, of White or Hispanic ancestry, and having higher perceived social capital, were significant predictors of better HIV ART adherence. CONCLUSIONS: Treatment approaches offer clear advantages in controlling HIV and reducing HIV transmission at the population level. These advantages, however, will have limited benefit for adherence to treatments without also addressing the social and structural challenges that allow HIV to continue to spread among society's most vulnerable populations.

Roller-massager application to the hamstrings increases sit-and-reach range of motion within five to ten seconds without performance impairments.

BACKGROUND: Foam rollers are used to mimic myofascial release techniques and have been used by therapists, athletes, and the general public alike to increase range of motion (ROM) and alleviate pressure points. The roller-massager was designed to serve a similar purpose but is a more portable device that uses the upper body rather than body mass to provide the rolling force. OBJECTIVES/PURPOSE: A roller massager was used in this study to examine the acute effects on lower extremity ROM and subsequent muscle length performance. METHODS: Seven male and ten female volunteers took part in 4 trials of hamstrings roller-massager rolling (1 set - 5 seconds, 1 set - 10 seconds, 2 sets - 5 seconds, and 2 sets - 10 seconds) at a constant pressure (13 kgs) and a constant rate (120 bpm). A group of 9 participants (three male, six female) also performed a control testing session with no rolling intervention. A sit and reach test for ROM, along with a maximal voluntary contraction (MVC) force and muscle activation of the hamstrings were measured before and after each session of rolling. RESULTS: A main effect for testing time (p<0.0001) illustrated that the use of the roller-massager resulted in a 4.3% increase in ROM. There was a trend (p=0.069) for 10s of rolling duration to increase ROM more than 5s rolling duration. There were no significant changes in MVC force or MVC EMG activity after the rolling intervention. CONCLUSIONS: The use of the roller-massager had no significant effect on muscle strength, and can provide statistically significant increases in ROM, particularly when used for a longer duration.

Engagement with Health Care Providers Affects Self- Efficacy, Self-Esteem, Medication Adherence and Quality of Life in People Living with HIV.

The engagement of patients with their health care providers (HCP) improves patients' quality of life (QOL), adherence to antiretroviral therapy, and life satisfaction. Engagement with HCP includes access to HCP as needed, information sharing, involvement of client in decision making and self-care activities, respect and support of the HCP for the client's choices, and management of client concerns. This study compares country-level differences in patients' engagement with HCP and assesses statistical associations relative to adherence rates, self-efficacy, self-esteem, QOL, and symptom self-reporting by people living with HIV (PLHIV). A convenience sample of 2,182 PLHIV was enrolled in the United States, Canada, Puerto Rico, Namibia, and China. Cross-sectional data were collected between September 2009 and January 2011. Inclusion criteria were being at least 18 years of age, diagnosed with HIV, able to provide informed consent, and able to communicate in the local language with site researchers. In the HCP scale, a low score indicated greater provider engagement. Country comparisons showed that PLHIV in Namibia had the most HCP engagement (OR 2.80, p < 0.001) and that PLHIV in China had the least engagement (OR -7.03, p < 0.0001) compared to the PLHIV in the Western countries. Individuals having better HCP engagement showed better self-efficacy for adherence (t = -5.22, p < 0.0001), missed fewer medication doses (t = 1.92, p ≤ 0.05), had lower self-esteem ratings (t = 2.67, p < 0.01), fewer self-reported symptoms (t = 3.25, p < 0.0001), and better overall QOL physical condition (t = -3.39, p < 0.001). This study suggests that promoting engagement with the HCP is necessary to facilitate skills that help PLHIV manage their HIV. To improve ART adherence, HCPs should work on strategies to enhance self-efficacy and self-esteem, therefore, exhibiting fewer HIV-related symptoms and missing less medication doses to achieve better QOL.

Disclosure of serostatus to sex partners among HIV-positive men and women in Hawaii.

The HIV epidemic in the United States is not abating, and sexual activity is the transmission-risk factor most frequently reported among those newly infected. Many HIV-positive persons have difficulty disclosing their serostatus to sex partners (SPs) and may not use condoms consistently. The aims of the research were to explore patterns of disclosure to SPs among HIV-positive men (N = 93) and women (N = 23) living in Hawaii, and to explore factors influencing disclosure and condom use. Using a survey design, participants were asked about their sexual activity during a three-month recall period, including detailed information for up-to-three most recent SPs. A variety of demographic, HIV-illness, self-efficacy, and contextual variables were examined as potential factors influencing disclosure. A total of 278 SPs were reported with rates of disclosure and of condom use near 50% for both genders. Perceived self-efficacy (SE) for disclosure decision-making was associated with disclosure for both men and women. Not discussing a SP's serostatus was associated with nondisclosure for both men and women. Additional factors influencing disclosure for men included cocaine and marijuana use, and years since diagnosis. Being transgendered was associated with less disclosure, but the small sample size for women precludes generalization of findings. There was an association between disclosure and condom use for men but not for women. Nurses must routinely assess for client HIV transmission-risk behaviors, and encourage disclosure of serostatus to SPs. It is also essential to offer clients behavioral strategies that can enhance their intentions to use condoms.

HIV/AIDS in Hawai'i: state of the state.

This paper describes the HIV/AIDS epidemic in Hawai'i over the last decade and identifies characteristics of those infected, including race/ethnicity, age, and risk behaviors related to HIV acquisition. State-based HIV/AIDS surveillance and counseling and testing data were reviewed, along with a comprehensive review of HIV/AIDS-related literature and reports emerging from agencies in Hawai'i. Recent legislative measures concerning HIV testing, counseling and HIV reporting were reviewed and summarized. Hawai'i continues to have low HIV/AIDS prevalence compared to other US states. There have been continuing changes in the face of HIV/AIDS in Hawai'i over the last decade, including increased number of AIDS cases among Hispanics and African Americans and a decreased percentage of cases among Caucasians and also among men who have sex with men. Legislative and policy changes have been implemented with the intent of enhancing the efficiency and quantity of HIV testing, and of strengthening the HIV prevention and care services offered in the State.

Male self-disclosure of HIV-positive serostatus to sex partners: a review of the literature.

HIV-positive men face multiple challenges when deciding whether to disclose their serostatus to sex partners. The purpose of this literature review (1996-2004) is to identify valid and reliable research results that identify factors influencing serostatus disclosure to sex partners by men who are HIV-positive. Articles included in the review were identified through an electronic search using pertinent terms related to disclosure to sex partners, followed by a search of references for additional articles. A compilation of research results for 17 articles is presented under the headings of background, contextual, and psychosocial factors influencing disclosure. An analysis of the data suggests that differences in disclosure rates vary based on sex partner factors including serostatus, relationship status, and number of sex partners. Rates of disclosure to primary sex partners ranged from 67% to 88%, suggesting that nearly one third of main sex partners were not disclosed to and were at risk of contracting HIV, whereas a pattern of lower disclosure among casual partners was evident. As the number of sex partners increased, the likelihood of disclosure to all sex partners decreased, ranging from one quarter (25%) to slightly over half (58%). In addition, perceived efficaciousness and positive outcome expectations were the most frequent theoretical constructs embedded in the research associated with disclosure, suggesting that these factors play an important role in the process of disclosure to sex partners. Interpersonal factors that positively influenced self-disclosure included spousal support, emotional investment, and communication about safe sex, including asking about a partner's serostatus. Self-disclosure was not consistently associated with safer sex. Recommendations for future research are presented, based on the results included in this review.

Drosophila calmodulin mutants with specific defects in the musculature or in the nervous system.

We have studied lethal mutations in the single calmodulin gene (Cam) of Drosophila to gain insight into the in vivo functions of this important calcium sensor. As a result of maternal calmodulin (CaM) in the mature egg, lethality is delayed until the postembryonic stages. Prior to death in the first larval instar, Cam nulls show a striking behavioral abnormality (spontaneous backward movement) whereas a mutation, Cam7, that results in a single amino acid change (V91G) produces a very different phenotype: short indented pupal cases and pupal death with head eversion defects. We show here that the null behavioral phenotype originates in the nervous system and involves a CaM function that requires calcium binding to all four sites of the protein. Further, backward movement can be induced in hypomorphic mutants by exposure to high light levels. In contrast, the V91G mutation specifically affects the musculature and causes abnormal calcium release in response to depolarization of the muscles. Genetic interaction studies suggest that failed regulation of the muscle calcium release channel, the ryanodine receptor, is the major defect underlying the Cam7 phenotype.