Spatial Analysis of Greenspace and Mental Health in North Carolina: Consideration of Rural and Urban Communities.

Greenspace positively impacts mental health. Previous research has focused on the greenspace-mental health relationship in urban areas. Yet, little work has looked at rural areas despite rural communities reporting similar rates of poor mental health outcomes and higher rates of suicide mortality compared with urban areas. This ecological research study examined the following research questions: (1) Do public and/or private greenspaces affect the spatial distribution of mental health outcomes in North Carolina? (2) Does this relationship change with rurality? Emergency department data for 6 mental health conditions and suicide mortality data from 2009 to 2018 were included in this analysis. Spatial error and ordinary least squares regressions were used to examine the influence of public and private greenspace quantity on mental health in rural and urban communities. Results suggest greenspace benefits mental health in rural and urban communities. The strength of this relationship varies with urbanity and between public and private greenspaces, suggesting a more complex causal relationship. Given the high case counts and often lower density of mental health care facilities in rural areas, focusing attention on low-cost mental health interventions, such as greenspace, is important when considering rural mental health care.

Sustained Virologic Suppression With Dolutegravir/Lamivudine in a Test-and-Treat Setting Through 48 Weeks.

Background: We assessed the efficacy and safety of dolutegravir/lamivudine (DTG/3TC) in a US test-and-treat setting at a secondary 48-week time point of the multicenter, single-arm, phase IIIb STAT study. Methods: Participants were eligible adults newly diagnosed with human immunodeficiency virus (HIV)-1 and had started once-daily DTG/3TC within 14 days of diagnosis, before laboratory results were available. Antiretroviral therapy (ART) was modified if baseline testing indicated DTG or 3TC resistance, hepatitis B virus (HBV) coinfection, or creatinine clearance <30 mL/min per 1.73 m2, and these participants remained in the study. A proportion with HIV-1 ribonucleic acid (RNA) <50 copies/mL at Week 48 was calculated among all participants (intention-to-treat-exposed [ITT-E] missing = failure analysis) and those with available data (observed analysis). Results: At Week 48, 82% of all participants regardless of ART (107 of 131; ITT-E missing = failure) and 97% with available data (107 of 110; observed analysis) achieved HIV-1 RNA <50 copies/mL. High proportions of virologic response were seen overall, including in participants with high viral load (≥500 000 copies/mL; 89%) or low CD4+ cell count (<200 cells/mm3; 78%) at baseline. Ten participants had treatment modification (baseline HBV coinfection, n = 5; participant/proxy decision, n = 2; baseline M184V resistance mutation, adverse event [AE; rash], and pregnancy, n = 1 each) before Week 48. Two participants met confirmed virologic failure criteria. No treatment-emergent resistance was observed. Ten participants reported drug-related AEs (all grade 1-2); no serious drug-related AEs occurred. Conclusions: Results demonstrated high proportions of participants with sustained virologic suppression, no treatment-emergent resistance, and good safety over 48 weeks, supporting first-line use of DTG/3TC in a test-and-treat setting.

Pharmacokinetic and pharmacokinetic/pharmacodynamic characterization of the dolutegravir/rilpivirine two-drug regimen in SWORD-1/-2 phase 3 studies.

AIM: SWORD-1 and SWORD-2 phase 3 studies concluded that switching virologically suppressed participants with HIV-1 from their current three- or four-drug antiretroviral regimen (CAR) to the two-drug regimen of once-daily dolutegravir (DTG, 50 mg) and rilpivirine (RPV, 25 mg) was safe, well tolerated and noninferior for maintaining HIV-1 suppression at week 48 and highly efficacious to week 148. A secondary objective was to characterize drug exposure and exposure-efficacy/safety relationships. METHODS: Adults with plasma HIV-1 RNA <50 copies/mL were randomized to switch to once-daily DTG + RPV on day 1 or to continue CAR for 52 weeks before switching. Trough plasma concentrations (C0) of DTG and RPV, the proportion of participants with HIV-1 RNA <50 copies/mL and adverse events to week 100 were summarized and subjected to exposure-response analyses in the overall population, in the subset of participants who switched from CAR containing enzyme-inducing drugs and by age category (≥50 and <50 years). The relationship between C0avg (individual average C0 across visits) and efficacy/safety was investigated. RESULTS: Although week 2 DTG and RPV C0 were lower in participants switching from enzyme-inducing antiretroviral drugs, C0 and C0avg stayed above in vitro antiviral protein binding-adjusted IC90 and to week 100 with viral suppression >89%. DTG or RPV C0avg showed no relationship with virologic failures or safety. Participants ≥50 years had similar C0avg and safety response to younger participants. CONCLUSION: No clinically relevant relationship between DTG or RPV exposures and virologic or safety response was observed, confirming the DTG + RPV switch for participants as a safe and effective treatment.

Brief Report: Evaluation of Inflammation and Atherogenesis Biomarkers Through 148 Weeks Postswitch to Dolutegravir and Rilpivirine in SWORD-1/SWORD-2.

BACKGROUND: Switching to the 2-drug regimen dolutegravir + rilpivirine demonstrated noninferiority vs continuing a 3-drug or 4-drug current antiretroviral regimen (CAR) at week 48 and maintained high levels of virologic suppression to week 148 in the SWORD studies. We report inflammation and atherogenesis biomarkers postswitch to dolutegravir + rilpivirine. SETTING: SWORD-1: 65 centers, 13 countries; SWORD-2: 60 centers, 11 countries. METHODS: Virologically suppressed adults were randomized to switch to dolutegravir + rilpivirine (early-switch group; n = 513) or continue CAR (n = 511). Participants continuing CAR switched to dolutegravir + rilpivirine at week 52 (late-switch group; n = 477). Biomarkers were evaluated from Baseline to week 48 for dolutegravir + rilpivirine and CAR and noncomparatively for dolutegravir + rilpivirine postswitch through 148 weeks (early-switch) and 96 weeks (late-switch). RESULTS: Through week 48, changes in biomarkers did not significantly differ between dolutegravir + rilpivirine and CAR groups, except for increases in soluble CD14 and decreases in fatty acid-binding protein-2, which favored dolutegravir + rilpivirine. For inflammation biomarkers through week 148, there was no marked change in C-reactive protein, inconsistent changes in soluble CD14 and interleukin-6, and increases in soluble CD163. For atherogenesis biomarkers through week 148, fatty acid-binding protein-2 and soluble vascular cell adhesion molecule-1 showed sustained reductions; D-dimer showed inconsistent increases between early-switch vs late-switch groups. CONCLUSIONS: No consistent pattern of change in biomarkers postswitch to dolutegravir + rilpivirine was observed through weeks 48 and 148 in SWORD-1/SWORD-2, suggesting no association of increased inflammation or atherogenesis with the 2-drug regimen while maintaining virologic suppression.

Inter-species interactions alter antibiotic efficacy in bacterial communities.

The efficacy of antibiotic treatments targeting polymicrobial communities is not well predicted by conventional in vitro susceptibility testing based on determining minimum inhibitory concentration (MIC) in monocultures. One reason for this is that inter-species interactions can alter the community members' susceptibility to antibiotics. Here we quantify, and identify mechanisms for, community-modulated changes of efficacy for clinically relevant antibiotics against the pathogen Pseudomonas aeruginosa in model cystic fibrosis (CF) lung communities derived from clinical samples. We demonstrate that multi-drug resistant Stenotrophomonas maltophilia can provide high levels of antibiotic protection to otherwise sensitive P. aeruginosa. Exposure protection to imipenem was provided by chromosomally encoded metallo-ß-lactamase that detoxified the environment; protection was dependent upon S. maltophilia cell density and was provided by S. maltophilia strains isolated from CF sputum, increasing the MIC of P. aeruginosa by up to 16-fold. In contrast, the presence of S. maltophilia provided no protection against meropenem, another routinely used carbapenem. Mathematical ordinary differential equation modelling shows that the level of exposure protection provided against different carbapenems can be explained by differences in antibiotic efficacy and inactivation rate. Together, these findings reveal that exploitation of pre-occurring antimicrobial resistance, and inter-specific competition, can have large impacts on pathogen antibiotic susceptibility, highlighting the importance of microbial ecology for designing successful antibiotic treatments for multispecies communities.

Racial and ethnic disparities in pregnancy complications and the protective role of greenspace: A retrospective birth cohort study.

Greenspace may positively impact pregnancy health for racially and economically minoritized populations; few studies have examined local availability and accessibility of green/park space in reducing maternal morbidity. The objective of this retrospective birth cohort study was to examine the association between residential exposure to greenspace and adverse pregnancy health outcomes in a Southern US state characterized by high poverty and racial disparities in maternal health (2013-2017). National data from the Protected Area database - United States (PAD-US) and ParkServe estimated three publicly available and accessible residential greenspace measures-a more direct proxy than using remotely-sensed greenness indicators (e.g., normalized difference vegetation index (NDVI))-(a) percent area of greenspace (M1), (b) area of available greenspace per person (M2), (c) total population within a 10-minute walk (M3). Generalized Estimating Equations with logistic regression were used to examine the association between individual greenspace metrics and South Carolina hospital deliveries (n = 238,922 deliveries) for women with correlated maternal health outcomes for gestational hypertension (GHTN), gestational diabetes (GD), severe maternal morbidity (SMM), preeclampsia (PRE), mental disorders (MD), depressive disorders (DD), and preterm birth (PTB). Lowest compared to highest tertiles of all three metrics were associated with increased risk for MD, DD, and a monotonic increase in GD, particularly for black women. Women with the lowest access to M2 and M3 were more at risk for PRE, PTB, and MD. We observed that women in low-income, majority-black communities in the lowest versus highest tertile of M2 were more likely to experience a DD, MD, SMM, or PTB compared to primarily high-income majority-white communities. Available and accessible green/park space may present as an effective nature-based intervention to reduce maternal complications, particularly for gestational diabetes and other pregnancy health risks for which there are currently few known evidence-based primary prevention strategies.

Dolutegravir/lamivudine as a first-line regimen in a test-and-treat setting for newly diagnosed people living with HIV.

OBJECTIVES: Dolutegravir/lamivudine (DTG/3TC) is indicated for treatment-naive and experienced people with HIV; however, questions remain about its utility in a test-and-treat setting because of potential transmitted resistance and baseline hepatitis B virus (HBV) co-infection. We present feasibility and efficacy of DTG/3TC in newly diagnosed individuals in a test-and-treat setting. DESIGN: The single-arm STAT study evaluated DTG/3TC in a US test-and-treat setting. METHODS: Eligible adults initiated DTG/3TC 14 days or less after HIV-1 diagnosis without availability of baseline laboratory results. If baseline testing indicated DTG or 3TC resistance, HBV co-infection, or creatinine clearance less than 30 ml/min per 1.73 m2, participants remained on study with treatment modification. Efficacy endpoints included proportions of participants with HIV-1 RNA less than 50 copies/ml at Week 24, regardless of antiretroviral regimen, among all participants (intention-to-treat exposed) and those with available HIV-1 RNA data (observed). RESULTS: Of 131 participants enrolled, 8% were female and 50% were non-white. Through Week 24, treatment was modified in eight participants [five with HBV co-infection, one with baseline M184V, one for adverse event (rash), one participant decision]. At Week 24, 78% (102/131) of all participants and 92% (102/111) of those with available data achieved HIV-1 RNA less than 50 copies/ml. Incidence of drug-related adverse events was low (7%); no drug-related serious adverse events occurred. CONCLUSION: These data demonstrate the feasibility, efficacy, and safety of using DTG/3TC as a first-line regimen in a test-and-treat setting, with therapy adjustments for baseline resistance or HBV co-infection occurring safely via routine clinical care as needed [ClinicalTrials.gov, NCT03945981; see Supplemental Digital Content 1, video abstract (Video abstract summarizing the STAT study design and results), http://links.lww.com/QAD/C189].

Unpacking complexities in ethnic-racial socialization in transracial adoptive families: A process-oriented transactional system.

Over 50% of adoptions are transracial, involving primarily White parents and children of color from different ethnic or racial backgrounds. Transracial adoptive (TRA) parents are tasked with providing ethnic-racial socialization processes (ERS) to support TRA adoptees' ethnic-racial identity development and prepare them to cope with ethnic-racial discrimination. However, unlike nonadoptive families of color, TRA parents lack shared cultural history with adoptees and have limited experience navigating racial discrimination. Knowledge of ERS among TRA families has centered on unidirectional processes between parenting constructs, ERS processes, and children's functioning. However, ERS processes in this population have complexities and nuances that warrant more sensitive and robust conceptualization. This paper proposes a process-oriented dynamic ecological model of the system of ERS, situating transacting processes in and across multiple family levels (parent, adoptee, family) and incorporating developmental and contextual considerations. With its framing of the complexities in ERS among TRA families, the model offers three contributions: a conceptual organization of parenting constructs related to ERS, a more robust understanding of ERS processes that inform how parents provide ERS, and framing of transacting processes within and between parenting constructs, ERS processes, and children's functioning. Implications for research, policy, and practice are discussed.

Positive psychology in health care: defining key stakeholders and their roles.

Lifestyle-related diseases have common risk factors: physical inactivity, poor diet, inadequate sleep, high stress, substance use, and social isolation. Evidence is mounting for the benefits of incorporating effective methods that promote healthy lifestyle habits into routine health care treatments. Research has established that healthy habits foster psychological and physiological health and that emotional well-being is central to achieving total well-being. The Happiness Science and Positive Health Committee of the American College of Lifestyle Medicine aims to raise awareness about strategies for prioritizing emotional well-being. The Committee advocates for collaborative translational research to adapt the positive psychology and behavioral medicine evidence base into methodologies that address emotional well-being in nonmental health care settings. Another aim is to promote health system changes that integrate evidence-based positive-psychology interventions into health maintenance and treatment plans. Also, the Committee seeks to ameliorate health provider burnout through the application of positive psychology methods for providers' personal health. The American College of Lifestyle Medicine and Dell Medical School held an inaugural Summit on Happiness Science in Health Care in May 2018. The Summit participants recommended research, policy, and practice innovations to promote total well-being via lifestyle changes that bolster emotional well-being. These recommendations urge stakeholder collaboration to facilitate translational research for health care settings and to standardize terms, measures, and clinical approaches for implementing positive psychology interventions. Sample aims of joint collaboration include developing evidence-based, practical, low-cost behavioral and emotional assessment and monitoring tools; grants to encourage dissemination of pilot initiatives; medical record dashboards with emotional well-being and related aspects of mental health as vital signs; clinical best practices for health care teams; and automated behavioral programs to extend clinician time. However, a few simple steps for prioritizing emotional well-being can be implemented by stakeholders in the near-term.

Brief Report: Durable Suppression and Low Rate of Virologic Failure 3 Years After Switch to Dolutegravir + Rilpivirine 2-Drug Regimen: 148-Week Results From the SWORD-1 and SWORD-2 Randomized Clinical Trials.

BACKGROUND: The SWORD trials showed that in participants who achieved virologic suppression taking 3-drug or 4-drug regimens, switching to the 2-drug regimen dolutegravir plus rilpivirine was noninferior in maintaining HIV-1 RNA <50 copies/mL at the week 48 primary endpoint. We present pooled week 148 analysis results from both studies. SETTING: SWORD-1: 65 centers, 13 countries; SWORD-2: 60 centers, 11 countries. METHODS: SWORD-1 and SWORD-2 are identical, open-label, phase III studies. Participants with screening HIV-1 RNA <50 copies/mL for ≥6 months; no prior virologic failure; and no documented resistance-associated major protease inhibitor, integrase inhibitor, nucleoside reverse transcriptase inhibitor (NRTI), or non-NRTI mutations or integrase resistance-associated substitution R263K were randomly assigned 1:1 to switch to once-daily dolutegravir 50 mg plus rilpivirine 25 mg on day 1 (early-switch group) or to continue their current antiretroviral regimen and, if virologically suppressed at week 48, switch to dolutegravir plus rilpivirine at week 52 (late-switch group) until week 148. RESULTS: Using snapshot algorithm at week 148, 432 of 513 (84%) early-switch participants (148 weeks of exposure) and 428 of 477 (90%) late-switch participants (96 weeks of exposure) maintained HIV-1 RNA <50 copies/mL. Eleven participants (1%) on dolutegravir plus rilpivirine met the confirmed virologic withdrawal criterion through week 148 (early-switch group, n = 8; late-switch group, n = 3) with no integrase resistance identified. Non-NRTI resistance-associated mutations were identified in 6 participants (<1%). Drug-related adverse events (grades 2-4) were observed in 31 (6%) early-switch and 16 (3%) late-switch participants. Significant improvements in bone biomarkers were observed. Significant improvements were observed in renal biomarkers in participants taking tenofovir disoproxil fumarate pre-switch. CONCLUSION: Switching to the 2-drug regimen dolutegravir plus rilpivirine maintained virologic suppression for a high proportion of participants through 3 years, with low rates of virologic failure and a well-tolerated safety profile.

Short-term effects of specific humidity and temperature on COVID-19 morbidity in select US cities.

Little is known about the environmental conditions that drive the spatiotemporal patterns of SARS-CoV-2. Preliminary research suggests an association with meteorological parameters. However, the relationship with temperature and humidity is not yet apparent for COVID-19 cases in US cities first impacted. The objective of this study is to evaluate the association between COVID-19 cases and meteorological parameters in select US cities. A case-crossover design with a distributed lag nonlinear model was used to evaluate the contribution of ambient temperature and specific humidity on COVID-19 cases in select US cities. The case-crossover examines each COVID case as its own control at different time periods (before and after transmission occurred). We modeled the effect of temperature and humidity on COVID-19 transmission using a lag period of 7 days. A subset of 8 cities were evaluated for the relationship with meteorological parameters and 5 cities were evaluated in detail. Short-term exposure to humidity was positively associated with COVID-19 transmission in 4 cities. The associations were small with 3 out of 4 cities exhibiting higher COVID19 transmission with specific humidity that ranged from 6 to 9 g/kg. Our results suggest that weather should be considered in infectious disease modeling efforts. Future work is needed over a longer time period and across different locations to clearly establish the weather-COVID19 relationship.

Efficacy and safety of dolutegravir-rilpivirine for maintenance of virological suppression in adults with HIV-1: 100-week data from the randomised, open-label, phase 3 SWORD-1 and SWORD-2 studies.

BACKGROUND: Primary analyses of the SWORD-1 and SWORD-2 trials at 48 weeks showed that switching to a two-drug regimen of dolutegravir plus rilpivirine was non-inferior to continuing a standard three-drug or four-drug antiretroviral regimen for maintenance of virological suppression in people with HIV-1. Here, we present efficacy and safety data from the 100-week analysis of the trials. METHODS: SWORD-1 and SWORD-2 are identically designed, randomised, open-label phase 3 studies at 65 centres in 13 countries and 60 centres in 11 countries, respectively. Adults aged 18 years or older who were on a standard three-drug or four-drug antiretroviral therapy (ART) and had had fewer than 50 HIV-1 RNA copies per mL of plasma for at least 6 months were randomly assigned (1:1) to 50 mg dolutegravir plus 25 mg rilpivirine orally once daily (early-switch group) or to continue their standard regimen for 52 weeks before switching to the dolutegravir plus rilpivirine combination (ie, the late-switch group). In this analysis of week 100 data, the efficacy endpoint of interest was the proportion of participants with fewer than 50 copies of HIV-1 RNA per mL of plasma (per the US Food and Drug Administration snapshot algorithm). This outcome was assessed in all randomly assigned participants who received at least one dose of the study drug. Data were analysed after the last participant completed week 100 (Sept 15, 2017) and verified through the data cutoff (Nov 21, 2017). SWORD-1 and SWORD-2 are registered with ClinicalTrials.gov, numbers NCT02429791 and NCT02422797, respectively. FINDINGS: 513 participants were randomly assigned to dolutegravir plus rilpivirine (ie, the early-switch group) and 511 to continue their standard ART regimen, 477 of whom then switched to dolutegravir plus rilpivirine at week 52 (ie, the late-switch group). At week 100, 456 (89% [95% CI 86-92]) of 513 participants in the early-switch group and 444 (93% [91-95]) of 477 in the late-switch group had fewer than 50 HIV-1 RNA copies per mL. Drug-related adverse events occurred in 103 (20%) participants in the early-switch group and 58 (12%) in the late-switch group. The most common drug-related adverse events were headache (11 participants in the early-switch group [2%] vs eight [2%] in the late-switch group) and nausea (eight [2%] vs five [1%]). INTERPRETATION: The combination of dolutegravir plus rilpivirine sustained virological suppression of HIV-1, was associated with a low frequency of virological failure, and had a favourable safety profile, which support its use as a nucleoside reverse transcriptase inhibitor-sparing and protease inhibitor-sparing alternative to three-drug regimens that reduces overall exposure to ART. FUNDING: ViiV Healthcare and Janssen Pharmaceutica.

Speech and language therapy for management of chronic cough.

BACKGROUND: Cough both protects and clears the airway. Cough has three phases: breathing in (inspiration), closure of the glottis, and a forced expiratory effort. Chronic cough has a negative, far-reaching impact on quality of life. Few effective medical treatments for individuals with unexplained (idiopathic/refractory) chronic cough (UCC) are known. For this group, current guidelines advocate the use of gabapentin. Speech and language therapy (SLT) has been considered as a non-pharmacological option for managing UCC without the risks and side effects associated with pharmacological agents, and this review considers the evidence from randomised controlled trials (RCTs) evaluating the effectiveness of SLT in this context. OBJECTIVES: To evaluate the effectiveness of speech and language therapy for treatment of people with unexplained (idiopathic/refractory) chronic cough. SEARCH METHODS: We searched the Cochrane Airways Trials Register, CENTRAL, MEDLINE, Embase, CINAHL, trials registries, and reference lists of included studies. Our most recent search was 8 February 2019. SELECTION CRITERIA: We included RCTs in which participants had a diagnosis of UCC having undergone a full diagnostic workup to exclude an underlying cause, as per published guidelines or local protocols, and where the intervention included speech and language therapy techniques for UCC. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of 94 records. Two clinical trials, represented in 10 study reports, met our predefined inclusion criteria. Two review authors independently assessed risk of bias for each study and extracted outcome data. We analysed dichotomous data as odds ratios (ORs), and continuous data as mean differences (MDs) or geometric mean differences. We used standard methods recommended by Cochrane. Our primary outcomes were health-related quality of life (HRQoL) and serious adverse events (SAEs). MAIN RESULTS: We found two studies involving 162 adults that met our inclusion criteria. Neither of the two studies included children. The duration of treatment and length of sessions varied between studies from four sessions delivered weekly, to four sessions over two months. Similarly, length of sessions varied slightly from one 60-minute session and three 45-minute sessions to four 30-minute sessions. The control interventions were healthy lifestyle advice in both studies.One study contributed HRQoL data, using the Leicester Cough Questionnaire (LCQ), and we judged the quality of the evidence to be low using the GRADE approach. Data were reported as between-group difference from baseline to four weeks (MD 1.53, 95% confidence interval (CI) 0.21 to 2.85; participants = 71), revealing a statistically significant benefit for people receiving a physiotherapy and speech and language therapy intervention (PSALTI) versus control. However, the difference between PSALTI and control was not observed between week four and three months. The same study provided information on SAEs, and there were no SAEs in either the PSALTI or control arms. Using the GRADE approach we judged the quality of evidence for this outcome to be low.Data were also available for our prespecified secondary outcomes. In each case data were provided by only one study, therefore there were no opportunities for aggregation; we judged the quality of this evidence to be low for each outcome. A significant difference favouring therapy was demonstrated for: objective cough counts (ratio for mean coughs per hour on treatment was 59% (95% CI 37% to 95%) relative to control; participants = 71); symptom score (MD 9.80, 95% CI 4.50 to 15.10; participants = 87); and clinical improvement as defined by trialists (OR 48.13, 95% CI 13.53 to 171.25; participants = 87). There was no significant difference between therapy and control regarding subjective measures of cough (MD on visual analogue scale of cough severity: -9.72, 95% CI -20.80 to 1.36; participants = 71) and cough reflex sensitivity (capsaicin concentration to induce five coughs: 1.11 (95% CI 0.80 to 1.54; participants = 49) times higher on treatment than on control). One study reported data on adverse events, and there were no adverse events reported in either the therapy or control arms of the study. AUTHORS' CONCLUSIONS: The paucity of data in this review highlights the need for more controlled trial data examining the efficacy of SLT interventions in the management of UCC. Although a large number of studies were found in the initial search as per protocol, we could include only two studies in the review. In addition, this review highlights that endpoints vary between published studies.The improvements in HRQoL (LCQ) and reduction in 24-hour cough frequency seen with the PSALTI intervention were statistically significant but short-lived, with the between-group difference lasting up to four weeks only. Further studies are required to replicate these findings and to investigate the effects of SLT interventions over time. It is clear that SLT interventions vary between studies. Further research is needed to understand which aspects of SLT interventions are most effective in reducing cough (both objective cough frequency and subjective measures of cough) and improving HRQoL. We consider these endpoints to be clinically important. It is also important for future studies to report information on adverse events.Because of the paucity of data, we can draw no robust conclusions regarding the efficacy of SLT interventions for improving outcomes in unexplained chronic cough. Our review identifies the need for further high-quality research, with comparable endpoints to inform robust conclusions.

Postprandial plasma glucose effects of once-weekly albiglutide for the treatment of type 2 diabetes.

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) vary in their structure, duration of action, efficacy, and safety. In order to optimize glycemic control, it is important to target both fasting (FPG) and postprandial plasma (PPG) glucose. Although phase 3 trials document the effect of GLP-1 RAs on glycated hemoglobin, few data are available to assess their effect on PPG. Albiglutide is a once-weekly GLP-1 RA with a half-life of ≈ 5 days. The goal of this review is to summarize the effects of albiglutide on PPG in four phase 2 trials and to describe the PPG-lowering effects of the GLP-1 RAs. At clinically relevant doses (30-64 mg), albiglutide consistently lowered PPG after each meal in addition to its effect on lowering FPG. Multiple weekly subcutaneous injections of albiglutide led to improvements in a variety of glycemic measures, including maximal reductions in PPG from baseline, postmeal glucose excursions, and FPG. Albiglutide, a longer-acting GLP-1 RAs, provides reductions in FPG, PPG following meals, and glucose over 24 hours.

Clinical pharmacology of albiglutide, a GLP-1 receptor agonist.

UNLABELLED: Albiglutide is a glucagon-like peptide-1 analogue composed of tandem copies of modified human glucagon-like peptide-1 (7-36) coupled to recombinant human albumin that is approved in adults for the treatment of type 2 diabetes mellitus. After subcutaneous administration, albiglutide is likely primarily absorbed via the lymphatic circulation, with maximum concentrations being reached in 3 to 5 days; steady-state exposures are achieved following approximately 4 to 5 weeks of once-weekly administration. The elimination half-life of albiglutide is approximately 5 days. Clearance of albiglutide is 67 mL/h with between-subject variability of 34.9%; no covariates have been identified that would require dose adjustment of albiglutide. Albiglutide lowers the fasting plasma glucose and reduces postprandial glucose excursions. In addition, ß-cell secretion is enhanced by albiglutide during hyperglycemia, whereas secretion is suppressed during hypoglycemia; α-cell response to hypoglycemia is not impaired by albiglutide. Albiglutide does not prolong the corrected QT interval but has a modest effect on heart rate in patients with type 2 diabetes mellitus. Dose adjustment is not suggested in patients with renal impairment, but experience in patients with severe renal impairment is very limited, and it is recommended that albiglutide be used with care in such patients due to an increased frequency of diarrhea, nausea, and vomiting. No clinically relevant drug interactions have been observed in clinical trials. TRIAL REGISTRATION: NCT00938158, NCT01406262, NCT00537719, NCT01077505, NCT01147731, NCT01147718, NCT01147692, NCT00354536, NCT00394030, NCT00530309, NCT01357889, NCT00518115, NCT01098461, NCT01475734, NCT00849017, NCT00838916, NCT00839527, NCT01098539.

Effect of renal impairment on the pharmacokinetics, efficacy, and safety of albiglutide.

BACKGROUND: Chronic kidney disease is frequently present in patients with type 2 diabetes mellitus (T2DM). New therapeutic options in this patient subpopulation are needed. OBJECTIVES: Assess the effect of renal impairment on the pharmacokinetics (PK), efficacy, and safety of albiglutide in single- and multiple-dose studies. METHODS: Pharmacokinetics, safety, and efficacy of once weekly albiglutide in patients with T2DM was assessed from a single-dose (30 mg), nonrandomized, open-label study (N = 41) including subjects with normal and varying degrees of renal impairment, including hemodialysis, and a pooled analysis of 4 phase 3, randomized, double-blind (1 open-label), active or placebo-controlled multiple-dose studies. The pooled analysis of the latter 4 studies (N = 1113) was part of the population PK analysis, which included subjects with normal and varying degrees of renal impairment (mild, moderate, severe) treated with albiglutide (30 to 50 mg) to primary end points of 26 to 52 weeks. RESULTS: Single-dose PK showed area-under-the-curve ratios (and 90% CIs) of 1.32 (0.96-1.80), 1.39 (1.03-1.89), and 0.99 (0.63-1.57) for the moderate, severe, and hemodialysis groups, respectively, relative to the normal group. Results indicate that modest increases in plasma concentration of albiglutide were observed with the severity of renal impairment. There was a trend for more glycemic lowering as the estimated glomerular filtration rate decreased. The severe group had a higher frequency of gastrointestinal (eg, diarrhea, constipation, nausea, and vomiting) and hypoglycemic (with background sulfonylurea use) events compared with patients with mild or moderate renal impairment. CONCLUSION: The PK, efficacy, and safety data indicate that albiglutide has a favorable benefit/risk ratio in patients with T2DM and varying degrees of renal impairment, and the need for a dose adjustment is not suggested. Experience in patients with more severe renal impairment is very limited, so the recommendation is to use albiglutide carefully in this population. CLINICAL TRIAL REGISTRATION: (ClinicalTrials.gov):NCT00938158, NCT00849017, NCT00838916, NCT00839527, NCT0198539.

Albiglutide Does Not Prolong QTc Interval in Healthy Subjects: A Thorough ECG Study.

INTRODUCTION: Albiglutide, a selective once-weekly glucagon-like peptide-1 receptor agonist, is being developed for the treatment of type 2 diabetes mellitus. Albiglutide's effect on cardiac repolarization (QTc interval) was assessed in a randomized, double-blind, placebo-controlled, parallel-group study in healthy subjects with a nested crossover comparison for moxifloxacin. METHODS: Subjects were randomized to albiglutide (n = 85) or placebo (n = 89) and received injections of 30 mg albiglutide or placebo on Days 1 and 8 and 50 mg albiglutide or placebo on Days 15, 22, 29, and 36. In the placebo group, moxifloxacin was administered on Day -1 in half the subjects and on Day 40 in the other half. Blood samples for albiglutide plasma concentration were drawn on Days 4 and 39 and serial ECGs were extracted from continuous recordings on Days -2 (baseline), -1, 4, 39, and 40. RESULTS: Demographics were generally similar between albiglutide and placebo subjects: mean age was 29 years and BMI 25 kg/m(2). Mean change-from-baseline QTcI (∆QTcI, which was corrected for individual heart rate) on Day 4 after a single dose of albiglutide 30 mg and on Day 39 after repeat dosing with albiglutide 50 mg once weekly was similar to the placebo response. The placebo-corrected ΔQTcI (ΔΔQTcI) on both albiglutide doses was small with the largest ΔΔQTcI of 1.1 ms (upper bound of 90% CI 3.8 ms) on Day 4 and -0.6 ms (upper bound of CI 1.8 ms) on Day 39. Moxifloxacin caused the largest mean effect on ΔΔQTcI of 10.9 ms and the lower bound of the CI was above 5 ms at all preselected timepoints, thereby demonstrating assay sensitivity. Albiglutide was well tolerated and there were no clinically relevant differences in safety data between albiglutide and placebo. CONCLUSION: Albiglutide at doses up to 50 mg in healthy subjects did not prolong the QTc interval.

Physiologically based pharmacokinetic modeling of dibromoacetic acid in F344 rats.

A novel physiologically based pharmacokinetic (PBPK) model structure, which includes submodels for the common metabolites (glyoxylate (GXA) and oxalate (OXA)) that may be involved in the toxicity or carcinogenicity of dibromoacetic acid (DBA), has been developed. Particular attention is paid to the representation of hepatic metabolism, which is the primary elimination mechanism. DBA-induced suicide inhibition is modeled by irreversible covalent binding of the intermediate metabolite alpha-halocarboxymethylglutathione (alphaH1) to the glutathione-S-transferase zeta (GSTzeta) enzyme. We also present data illustrating the presence of a secondary non-GSTzeta metabolic pathway for DBA, but not dichloroacetic acid (DCA), that produces GXA. The model is calibrated with plasma and urine concentration data from DBA exposures in female F344 rats through intravenous (IV), oral gavage, and drinking water routes. Sensitivity analysis is performed to confirm identifiability of estimated parameters. Finally, model validation is performed with data sets not used during calibration. Given the structural similarity of dihaloacetates (DHAs), we hypothesize that the PBPK model presented here has the capacity to describe the kinetics of any member or mixture of members of this class in any species with the alteration of chemical-and species-specific parameters.