Predicting the effect of fresh gas flow on tidal volume in volume-controlled mechanically ventilated dogs.

OBJECTIVES: To determine if the tidal volume (VT) delivered (VTDEL) to canine patients being mechanically ventilated by a volume-controlled ventilator differed from the volume set on the ventilator (VTSET) at three fresh gas flow (FGF) rates. To determine if VTDEL could be accurately predicted by an FGF-based mathematical model. STUDY DESIGN: Prospective proof-of-concept study. ANIMALS: A total of 23 adult client-owned dogs undergoing elective orthopedic surgery. METHODS: Dogs were anesthetized and ventilated with a volume-controlled mechanical ventilator with constant respiratory rate (fR) of 10 breaths minute-1, inspiratory-to-expiratory ratio of 1:2 [fraction of inspiratory time (TI) in one respiratory cycle (Ttot) 1:3], and VTSET as body weight (kg) × 15 (mL kg-1). VTDEL was measured in 20 dogs at three FGF (500, 1000 and 4000 mL minute-1). A mathematical model was used to calculate predicted volume (VTPRED) for each animal at each FGF: VTSET + {FGF × [(TI/Ttot)/fR]}. Linear repeated measures models were fit comparing VTDEL to VTSET and to VTPRED by FGF. RESULTS: VTDEL was significantly higher than VTSET at every FGF (p < 0.05), and differences were larger at higher FGF (p < 0.001). There were no statistically significant differences between VTDEL and VTPRED at FGF rates of 500 and 4000 mL minute-1 and, although the mean VTDEL was statistically significantly higher than VTPRED at FGF 1000 mL minute-1 (p = 0.017), the mean difference of 9 mL was not clinically significant. CONCLUSIONS AND CLINICAL RELEVANCE: Dogs on volume-controlled ventilators may be ventilated at a higher VTDEL than intended depending on the FGF settings. Ventilation of small animals at high FGF could inadvertently induce pulmonary damage. A mathematical equation can be used to achieve a desired VTDEL by adjusting VTSET values based on FGF, fR and TI/Ttot.

Randomized Controlled Trial of a Remote Coaching mHealth Adherence Intervention in Youth Living with HIV.

Youth living with HIV (YLWH) in the US have low rates of viral suppression (VS). In a prospective randomized clinical trial (ATN152) that enrolled 89 YLWH on antiretroviral therapy (ART) with detectable viral load, we evaluated a 12 week triggered escalating real-time adherence (TERA) intervention with remote coaching, electronic dose monitoring (EDM), and outreach for missed/delayed doses compared to standard of care (SOC). Median [Q1, Q3] percent days with EDM opening was higher in TERA (72% (47%, 89%)) versus SOC (41% (21%, 59%); p < 0.001) and incidence of numbers of 7 day gaps between openings were lower (TERA to SOC ratio: 0.40; 95% CI 0.30, 0.53; p < 0.001). There were no differences in VS at week 12 (TERA 35%; 95% CI 21%, 51% versus SOC 36%; 95% CI 22%, 51%; p > 0.99) or later time-points. The intervention improved adherence but not VS in heavily ART-experienced YLWH. Remote coaching more closely tailored to the unique dosing patterns and duration of need for youth struggling to reach VS warrants further investigation.

Incorporating estimands into clinical trial statistical analysis plans.

BACKGROUND: International Council for Harmonisation (ICH) E9 Statistical Principles for Clinical Trials was developed as a consensus guidance document to encourage worldwide harmonization of the principles of statistical methodology in clinical trials. Addendum E9 (R1) clarified and extended ICH E9 with a focus on estimands and sensitivity analyses. Since the release of E9 (R1), clinical trial protocols have included estimands, but there is variation in how they are presented. Statistical analysis plans (SAPs) are increasingly becoming publicly available (e.g. posting on ClinicalTrials.gov) and present an opportunity to link estimands with planned analyses to present the alignment of trial objectives, design, conduct, and analysis. METHODS: A table format was used to create a template for inclusion in SAPs that satisfies ICH E9 (R1) guidance to align statistical analysis to the estimand. The template provides a consistent structure for presentation of estimands and the associated analysis, and is applicable to a wide range of trial designs. We illustrate use of the template with a hypothetical clinical trial in HIV-1. RESULTS: The estimand-to-analysis table template starts with the study objective describing the clinical question of interest as written in the trial protocol. The remainder of the table describes each attribute of the estimand (treatment, target population, variable, intercurrent events, and population-level summary) in the left column (ESTIMAND), while the right column describes how each attribute will be handled using the data collected in the clinical trial (ANALYSIS). The template was applied to a hypothetical, early-phase single-arm trial, modeled after a pediatric trial in HIV, where the objective was to determine the safety of a new antiretroviral drug as part of a combination antiretroviral treatment regimen in the pediatric population. Three intercurrent events were illustrated in the table: death, premature treatment discontinuation before 24 weeks, and pregnancy. An estimand-to-analysis table from a grant application that addresses the primary objective of a placebo-controlled randomized trial is also presented to demonstrate an alternative usage. CONCLUSION: We found the template to be useful in study design, providing a snapshot of the objective, target population, potential intercurrent events, analysis plan, and considerations for missing data in one place and facilitating discussion among stakeholders. The proposed standardized presentation of estimand attributes and analysis considerations in SAPs will provide guidance to SAP authors and consistency across studies to facilitate reviews.

Safety and Efficacy of 48 and 96 Weeks of Alendronate in Children and Adolescents With Perinatal Human Immunodeficiency Virus Infection and Low Bone Mineral Density for Age.

No safety concerns were identified in a randomized, crossover study of alendronate/placebo in youth with perinatal HIV infection and low bone mineral density (BMD). BMD improved with 48 weeks of alendronate and continued to improve with an additional 48 weeks of therapy. Gains were largely maintained 48 weeks after stopping alendronate.

Alendronate Improves Bone Mineral Density in Children and Adolescents Perinatally Infected With Human Immunodeficiency Virus With Low Bone Mineral Density for Age.

BACKGROUND: Children and adolescents with perinatal human immunodeficiency virus (HIV) infection and with low bone mineral density (BMD) may be at higher risk of osteoporosis and fractures in later life than their uninfected peers. Bisphosphonate therapy has been shown to reduce fractures in adults with osteoporosis, but has not been formally studied in youths living with HIV. METHODS: Fifty-two children and adolescents (aged 11-24 years) perinatally infected with HIV with low lumbar spine (LS) BMD (Z score < -1.5) were randomized to receive once-weekly alendronate or placebo in a double-blind cross-over study designed to assess the safety and efficacy of 48 and 96 weeks of alendronate in the United States and Brazil. All participants received daily calcium carbonate and vitamin D supplementation and were asked to engage in regular weight-bearing exercise. Safety and efficacy are summarized for the initial 48 weeks of the trial. RESULTS: Grade 3 or higher abnormal laboratory values, signs, or symptoms developed in 5 of 32 (16%) participants on alendronate and 2 of 18 (11%) on placebo (P > .99). No cases of jaw osteonecrosis, atrial fibrillation, or nonhealing fractures were reported. Mean increases (95% confidence interval) in LS BMD over 48 weeks were significantly larger on alendronate (20% [14%-25%]) than placebo (7% [5%-9%]) (P < .001). Similar improvements were seen for whole body BMD. CONCLUSIONS: In this small study in children and adolescents perinatally infected with HIV with low LS BMD, 48 weeks of alendronate was well-tolerated, showed no safety concerns, and significantly improved LS and whole body BMD compared to participants on vitamin D/calcium supplementation and exercise alone. CLINICAL TRIALS REGISTRATION: NCT00921557.

Intestinal Integrity Biomarkers in Early Antiretroviral-Treated Perinatally HIV-1-Infected Infants.

Intestinal fatty acid binding protein (iFABP) levels did not differ between human immunodeficiency virus type 1 (HIV-1)- infected infants and uninfected infants exposed to HIV-1, but those who breastfed had substantially lower levels. Zonulin levels increased from 3 to 5.3 months of age with perinatal acquisition of HIV-1 despite early antiretroviral treatment. Biomarkers of intestinal integrity (ie, iFABP and zonulin) were compared in 56 HIV-1-positive African infants who received early antiretroviral treatment and 53 HIV-1-exposed but uninfected (HEU) controls. Despite heightened inflammation and immune activation in HIV-positive infants, iFABP and zonulin levels at 3 months of age were not different from those in HEU infants and largely were not correlated with inflammatory and immune activation biomarkers. However, zonulin levels increased and became significantly higher in HIV-positive infants as compared to HEU infants by 5 months of age, despite viral suppression due to antiretroviral treatment. These findings have implications for intestinal integrity biomarker profiling in perinatal HIV-1 infection.

Inflammation and Immune Activation in Antiretroviral-Treated Human Immunodeficiency Virus Type 1-Infected African Infants and Rotavirus Vaccine Responses.

Biomarkers of inflammation and immune activation were correlated with rotavirus vaccine responses in 68 human immunodeficiency virus type 1 (HIV-1)­infected (and 116 HIV-exposed but uninfected (HEU) African infants receiving pentavalent rotavirus vaccine (RV5) in a clinical trial. Prevaccination, HIV-1+ infants had significantly higher concentrations of interferon γ (IFNγ), interleukin1ß, interleukin 2, interleukin 6, interleukin 10 (IL-10), and soluble CD14 compared with HEU infants. Postvaccination concentrations of neutralizing antibodies to RV5 were negatively correlated with prevaccination concentrations of IL-10 (RV5 surface proteins G1 and P1) and IFNγ (G1) in the HIV-1+ infants, whereas antirotavirus immunoglobulin A (IgA) levels were not. Heightened inflammation and immune activation in HIV-1+ infants did not alter IgA responses associated with protection from rotavirus disease.

Nevirapine- Versus Lopinavir/Ritonavir-Based Antiretroviral Therapy in HIV-Infected Infants and Young Children: Long-term Follow-up of the IMPAACT P1060 Randomized Trial.

BACKGROUND: The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) P1060 study demonstrated short-term superiority of lopinavir/ritonavir (LPV/r) over nevirapine (NVP) in antiretroviral therapy (ART), regardless of prior NVP exposure. However, NVP-based ART had a marginal benefit in CD4 percentage (CD4%) and growth. We compared 5-year outcomes from this clinical trial. METHODS: Human immunodeficiency virus (HIV)-infected, ART-eligible children were enrolled into 2 cohorts based on prior NVP exposure and randomized to NVP- or LPV/r-based ART. The data safety monitoring board recommended unblinding results in both cohorts due to superiority of LPV/r for the primary endpoint: stopping randomized treatment, virologic failure (VF), or death by 6 months. Participants were offered a switch in regimens (if on NVP) and continued observational follow-up. We compared time to VF or death, death, and CD4% and growth changes using intention-to-treat analyses. Additionally, inverse probability weights were used to account for treatment switching and censoring. RESULTS: As of September 2014, 329 of the 451 (73%) enrolled participants were still in follow-up (median, 5.3 years; interquartile range [IQR], 4.3-6.4), with 52% on NVP and 88% on LPV/r as originally randomized. NVP arm participants had significantly higher risk of VF or death (adjusted hazard ratio [aHR], 1.90; 95% confidence interval [CI], 1.37-2.65) but not death alone (aHR, 1.65; 95% CI, .72-3.76) compared with participants randomized to LPV/r. Mean CD4% was significantly higher in the NVP arm up to 1 year after ART initiation, but not beyond. Mean weight-for-age z scores were marginally higher in the NVP arm, but height-for-age z scores did not differ. Similar trends were observed in sensitivity analyses. CONCLUSIONS: These findings support the current World Health Organization recommendation of LPV/r in first-line ART regimens for HIV-infected children. CLINICAL TRIALS REGISTRATION: NCT00307151.

Nevirapine versus ritonavir-boosted lopinavir for HIV-infected children.

BACKGROUND: Nevirapine-based antiretroviral therapy is the predominant (and often the only) regimen available for children in resource-limited settings. Nevirapine resistance after exposure to the drug for prevention of maternal-to-child human immunodeficiency virus (HIV) transmission is common, a problem that has led to the recommendation of ritonavir-boosted lopinavir in such settings. Regardless of whether there has been prior exposure to nevirapine, the performance of nevirapine versus ritonavir-boosted lopinavir in young children has not been rigorously established. METHODS: In a randomized trial conducted in six African countries and India, we compared the initiation of HIV treatment with zidovudine, lamivudine, and either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 2 to 36 months of age who had no prior exposure to nevirapine. The primary end point was virologic failure or discontinuation of treatment by study week 24. RESULTS: A total of 288 children were enrolled; the median percentage of CD4+ T cells was 15%, and the median plasma HIV type 1 (HIV-1) RNA level was 5.7 log(10) copies per milliliter. The percentage of children who reached the primary end point was significantly higher in the nevirapine group than in the ritonavir-boosted lopinavir group (40.8% vs. 19.3%; P<0.001). Among the nevirapine-treated children with virologic failure for whom data on resistance were available, more than half (19 of 32) had resistance at the time of virologic failure. In addition, the time to a protocol-defined toxicity end point was shorter in the nevirapine group (P=0.04), as was the time to death (P=0.06). CONCLUSIONS: Outcomes were superior with ritonavir-boosted lopinavir among young children with no prior exposure to nevirapine. Factors that may have contributed to the suboptimal results with nevirapine include elevated viral load at baseline, selection for nevirapine resistance, background regimen of nucleoside reverse-transcriptase inhibitors, and the standard ramp-up dosing strategy. The results of this trial present policymakers with difficult choices. (Funded by the National Institute of Allergy and Infectious Diseases and others; P1060 ClinicalTrials.gov number, NCT00307151.).

Antiretroviral treatment for children with peripartum nevirapine exposure.

BACKGROUND: Single-dose nevirapine is the cornerstone of the regimen for prevention of mother-to-child transmission of human immunodeficiency virus (HIV) in resource-limited settings, but nevirapine frequently selects for resistant virus in mothers and children who become infected despite prophylaxis. The optimal antiretroviral treatment strategy for children who have had prior exposure to single-dose nevirapine is unknown. METHODS: We conducted a randomized trial of initial therapy with zidovudine and lamivudine plus either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 6 to 36 months of age, in six African countries, who qualified for treatment according to World Health Organization (WHO) criteria. Results are reported for the cohort that included children exposed to single-dose nevirapine prophylaxis. The primary end point was virologic failure or discontinuation of treatment by study week 24. Enrollment in this cohort was terminated early on the recommendation of the data and safety monitoring board. RESULTS: A total of 164 children were enrolled. The median percentage of CD4+ lymphocytes was 19%; a total of 56% of the children had WHO stage 3 or 4 disease. More children in the nevirapine group than in the ritonavir-boosted lopinavir group reached a primary end point (39.6% vs. 21.7%; weighted difference, 18.6 percentage-points; 95% confidence interval, 3.7 to 33.6; nominal P=0.02). Baseline resistance to nevirapine was detected in 18 of 148 children (12%) and was predictive of treatment failure. No significant between-group differences were seen in the rate of adverse events. CONCLUSIONS: Among children with prior exposure to single-dose nevirapine for perinatal prevention of HIV transmission, antiretroviral treatment consisting of zidovudine and lamivudine plus ritonavir-boosted lopinavir resulted in better outcomes than did treatment with zidovudine and lamivudine plus nevirapine. Since nevirapine is used for both treatment and perinatal prevention of HIV infection in resource-limited settings, alternative strategies for the prevention of HIV transmission from mother to child, as well as for the treatment of HIV infection, are urgently required. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00307151.).

Electronic Dose Monitoring Device Patterns in Youth Living With HIV Enrolled in an Adherence Intervention Clinical Trial.

INTRODUCTION: Youth living with HIV in the US have low rates of viral suppression, in part because of challenges with antiretroviral therapy adherence. METHODS: Daily dosing in the Adolescent Medicine Trials Network for HIV/AIDS Interventions 152 study, a randomized controlled trial of a 12-week adherence intervention (triggered escalating real-time adherence intervention) for viremic youth, compared with standard of care (SOC), was measured by electronic dose monitoring (EDM) throughout 48 weeks of follow-up. EDM data collected over the first 24 weeks were used to characterize patterns of antiretroviral therapy adherence with group-based trajectory models. RESULTS: Four trajectory groups were identified among the 85 participants included in the analysis during the intervention phase of the study: (Worst) no interaction with EDM, (Declining) initially moderate EDM-based adherence followed by steep declines, (Good) initially high EDM-based adherence with modest declines, and (Best) consistently high EDM-based adherence. Being in the SOC arm, not being in school, higher evasiveness and panic decision-making scores, and lower adherence motivation were associated with higher odds of being in a worse trajectory group ( P < 0.05). A general decline in dosing was observed in the 12 weeks postintervention, when all participants were managed using SOC. CONCLUSIONS: Use of group-based trajectory models allowed a more nuanced understanding of EDM-based adherence over time compared with collapsed summary measures. In addition to the study intervention, other factors influencing EDM-based adherence included being in school, decision-making styles, and adherence-related motivation. This information can be used to design better intervention services for youth living with HIV.

DNA Barcoding Medicinal Plant Species from Indonesia.

Over the past decade, plant DNA barcoding has emerged as a scientific breakthrough and is often used to help with species identification or as a taxonomical tool. DNA barcoding is very important in medicinal plant use, not only for identification purposes but also for the authentication of medicinal products. Here, a total of 61 Indonesian medicinal plant species from 30 families and a pair of ITS2, matK, rbcL, and trnL primers were used for a DNA barcoding study consisting of molecular and sequence analyses. This study aimed to analyze how the four identified DNA barcoding regions (ITS2, matK, rbcL, and trnL) aid identification and conservation and to investigate their effectiveness for DNA barcoding for the studied species. This study resulted in 212 DNA barcoding sequences and identified new ones for the studied medicinal plant species. Though there is no ideal or perfect region for DNA barcoding of the target species, we recommend matK as the main region for Indonesian medicinal plant identification, with ITS2 and rbcL as alternative or complementary regions. These findings will be useful for forensic studies that support the conservation of medicinal plants and their national and global use.

A comparison of epidural morphine with low dose bupivacaine versus epidural morphine alone on motor and respiratory function in dogs following splenectomy.

OBJECTIVE: To compare post-operative motor function in dogs that received epidural morphine and low dose bupivacaine versus epidural morphine alone following splenectomy. STUDY DESIGN: Prospective, randomized study. ANIMALS: 16 client owned dogs undergoing routine splenectomy. METHODS: Following splenectomy dogs were randomly allocated into one of two groups. The morphine group (MOR) was administered epidural morphine (0.1 mg kg(-1)); the morphine-bupivacaine group (MORB) received epidural morphine (0.1 mg kg(-1)) and low dose bupivacaine [0.25 mg kg(-1), (0.167%)]. The adjusted final volume was 0.15 mL kg(-1) in both groups. Motor function and pain assessment were performed at pre-determined times using a simple numerical motor score and the University of Melbourne Pain Scale (UMPS) respectively. An arterial blood gas was performed 2 hours following epidural administration to check for respiratory compromise. If patients scored >7 on the UMPS or were deemed painful by the observer they were administered hydromorphone intravenously and dose and time of rescue analgesia were recorded. RESULTS: There were no statistically significant differences in motor scores, pain scores, amount of rescue analgesia administered or PaCO2 between treatment groups. No dogs demonstrated respiratory depression or profound motor dysfunction at any time point during the study. 9/16 (56%) dogs did not require rescue analgesia during the first 18 hours following splenectomy. CONCLUSIONS AND CLINICAL RELEVANCE: The combination of low dose bupivacaine (0.25 mg kg(-1)) and morphine (0.1 mg kg(-1)) when administered epidurally has little effect on post-operative motor function. This combination can be used without concern of motor paralysis in healthy animals.

Immune Markers and Their Association with Bone Density in Children, Adolescents, and Young Adults with Perinatally Acquired HIV.

To describe distributions of immune markers in children and young adults by sex and HIV status, and within groups, investigate associations of immune markers with bone density across Tanner stage. Using data and samples from 353 participants in a cross-sectional study in youth with perinatally acquired HIV (PHIV) and matched HIV-negative controls, distributions of inflammation and activation immune markers were described by sex and HIV status. Correlations and structural equation models (SEM) were used to explore marginal and multivariable associations of the immune markers with bone density and to assess whether patterns of association varied by sex and HIV status. Immune marker distributions did not differ by sex, but there were some differences by HIV status. Correlation patterns among bone, body composition, and immune markers were similar across the sex and HIV status groups. Conclusions from SEMs were limited by small sample sizes, but there was some indication that patterns of association between bone density and certain immune markers differed in male PHIV with more advanced Tanner stage compared to the other three groups. In conclusion, distributions of bone density, body composition, and immune markers may vary by sex and HIV status, although associations among these outcomes within sex and HIV status groups appear similar. Bone density of male PHIV appears to be more negatively affected than females, regardless of female HIV status. Larger longitudinal studies across Tanner stages are needed to further explore potential biological relationships between immune markers and bone density in youth living with HIV.

Sedative effects of alfaxalone and hydromorphone with or without midazolam in cats: a pilot study.

OBJECTIVES: The aim of this pilot study was to compare the quality of sedation and ease of intravenous (IV) catheter placement following sedation using two intramuscular (IM) sedation protocols in cats: hydromorphone, alfaxalone and midazolam vs hydromorphone and alfaxalone. METHODS: This was a prospective, randomized and blinded study. Cats were randomly assigned to receive an IM injection of hydromorphone (0.1 mg/kg), alfaxalone (1.5 mg/kg) and midazolam (0.2 mg/kg; HAM group), or hydromorphone (0.1 mg/kg) and alfaxalone (1.5 mg/kg; HA group). Sedation scoring (0-9, where 9 indicated maximum sedation) was performed at 0, 5, 10, 15 and 20 mins from the time of injection. At 20 mins, an IV catheter placement score (0-10, where 10 indicated least resistance) was performed. RESULTS: Twenty-one client-owned adult cats were included in this study. Sedation and IV catheter placement scores were compared between groups using Wilcoxon rank sum tests. Peak sedation was significantly higher (P = 0.002) in the HAM group (median 9; range 7-9) than in the HA group (median 7; range 3-9), and IV catheter placement scores were significantly higher (P = 0.001) in the HAM group (median 9.5; range 7-10) compared with the HA group (median 7; range 4-9). Spearman correlations were calculated between IV catheter placement score and sedation scores. There was a significant positive correlation of average sedation over time (correlation 0.83; P <0.001) and sedation at 20 mins (correlation 0.76; P <0.001) with a higher, more favorable IV catheter placement score. CONCLUSIONS AND RELEVANCE: These preliminary results suggest that the addition of midazolam to IM alfaxalone and hydromorphone produced more profound sedation and greater ease of IV catheter placement than IM alfaxalone and hydromorphone alone.

Plasma biomarker factors associated with neurodevelopmental outcomes in children with perinatal HIV infection and controlled viremia.

OBJECTIVE: We examined relationships between plasma biomarkers and neurodevelopment in children from sub-Saharan Africa with perinatal HIV (PHIV) with controlled viremia on antiretroviral therapy (ART). DESIGN: Longitudinal retrospective cohort study of children with controlled blood HIV replication. METHODS: Children (N = 213; 57% girls) started ART at less than 3 years of age, had neurodevelopmental assessments (cognition, attention/impulsivity, motor proficiency, global executive functions) at 5-11 years, and achieved controlled viremia (HIV-1 RNA <400 copies/ml for ≥9 months before initial assessment). Twenty-three plasma biomarkers were measured at onset of controlled viremia, week 0 (first neurodevelopmental assessment), and week 48 (second neurodevelopmental assessment). Factor analysis was conducted at each time point. Multivariable linear regressions assessed associations between factors and neurodevelopmental scores. RESULTS: Median age at week 0 was 7.0 years. Eighteen biomarkers loaded on six factors: a (L-10, IFNγ, IFNα2, IL-1ß, IL-6, IP-10, TNFα); B (sCD163, sICAM-1, sVCAM-1, CRP); C (sE-selectin, sP-selectin); D [MIP-1ß, vascular endothelial growth factor (VEGF)-A]; E (sCD14, CRP); and F (CX3CL1, MCP-1). Higher factor B scores were consistently associated with worse cognition and attention/impulsivity, and higher factor D scores with better attention/impulsivity. CONCLUSION: These results suggest a detrimental effect of increased endothelial cell activation (sICAM-1, sVCAM-1) and monocyte/macrophage scavenger function (sCD163) and a beneficial effect of increased CCR5 ligand and HIV entry blocker MIP-1ß and angiogenesis stimulant-VEGF concentrations on the neurodevelopment of children with PHIV. The model that emerges is of vascular inflammation leading to neurodevelopmental deficits. The role of persistent HIV replication in the central nervous system also needs to be further explored.

Correlates of High HIV Viral Load and Antiretroviral Therapy Adherence Among Viremic Youth in the United States Enrolled in an Adherence Improvement Intervention.

A sizable portion of youth (ages 13-24) living with HIV in the United States have unsuppressed viral load. The AIDS Interventions (ATN) 152 study [evaluating the Triggered Escalating Real-Time Adherence (TERA) intervention] baseline data were examined to identify correlates of high viremia (>5000 copies/mL) and self-reported adherence, which can help in planning of differentiated services for viremic youth. Depression, HIV-stigma, and cannabis use were common in this sample of 87 youth. Almost half (48%) had high viremia, which associated with enacted stigma, moderate- to high-risk alcohol use, mental health diagnosis, and age ≥21. Self-reported adherence was related to viral load and associated with mental and physical health functioning, depression, social support, self-confident decision-making, total and internalized stigma, adherence motivation, and report of a missed a care visit in the past 6 months. Mental health emerged as a common correlate of viral load and adherence. Clinical Trial Registration number: NCT03292432.

Implications of discrimination based on sexuality, gender, and race/ethnicity for psychological distress among working-class sexual minorities: the United for Health Study, 2003-2004.

This study investigated the distribution of demographic characteristics, the prevalence of discrimination based on sexuality, gender, and race, and relationships with psychological distress among 178 working-class sexual minorities (i.e., who identified as lesbian, gay, or bisexual (LGB) or had ever engaged in same-sex sexual behaviors) recruited to the United for Health Study (2003-2004). The results indicated considerable heterogeneity in responses to items assessing sexual orientation and sexual behavior, with a majority of sexual minority participants not identifying as LGB (74.2%). The authors found significant demographic differences in LGB identification by gender, race/ethnicity, nativity, and socioeconomic factors. In addition, LGB participants had higher levels of psychological distress than non-LGB-identified sexual minorities. Linear regression analyses revealed that reports of racial/ethnic discrimination and sexuality discrimination were associated with higher levels of psychological distress among sexual minority participants. The results underscore the need to collect multiple measures of sexuality in conducting research on racially diverse working-class communities; to consider demographic factors in collecting sexuality data; and to disaggregate information on sexuality by LGB identification. Findings also highlight the importance of addressing discrimination in ameliorating problematic mental health outcomes among working-class sexual minorities.

Postoperative regurgitation and respiratory complications in brachycephalic dogs undergoing airway surgery before and after implementation of a standardized perianesthetic protocol.

OBJECTIVE: To determine whether implementation of a standardized perianesthetic protocol was associated with reduced incidence of postoperative regurgitation, pneumonia, and respiratory distress in brachycephalic dogs undergoing general anesthesia for airway surgery. ANIMALS: 84 client-owned dogs. PROCEDURES: A perianesthetic protocol that included preoperative administration of metoclopramide and famotidine, restrictive use of opioids, and recovery of patients in the intensive care unit was fully implemented for brachycephalic dogs in July 2014. Medical records of brachycephalic dogs (specifically Boston Terriers, French Bulldogs, English Bulldogs, and Pugs) undergoing anesthesia for airway surgery before (group A) and after (group B) protocol implementation were reviewed. Patient characteristics, administration of medications described in the protocol, surgical procedures performed, anesthesia duration, recovery location, and postoperative development of regurgitation, pneumonia, and respiratory distress were recorded. Data were compared between groups. RESULTS: The proportion of dogs with postoperative regurgitation in group B (4/44 [9%]) was significantly lower than that in group A (14/40 [35%]). No intergroup differences in patient characteristics (including history of regurgitation), procedures performed, or anesthesia duration were found. Rates of development of postoperative pneumonia and respiratory distress did not differ between groups. A history of regurgitation was associated with development of postoperative regurgitation. CONCLUSIONS AND CLINICAL RELEVANCE: Implementation of the described protocol was associated with decreased incidence of postoperative regurgitation in brachycephalic dogs undergoing anesthesia. Prospective studies are warranted to elucidate specific causes of this finding.

Triggered Escalating Real-Time Adherence Intervention to Promote Rapid HIV Viral Suppression Among Youth Living With HIV Failing Antiretroviral Therapy: Protocol for a Triggered Escalating Real-Time Adherence Intervention.

BACKGROUND: Youth living with HIV (YLWH) are confronted with many self-care challenges that can be experienced as overwhelming in the context of normal developmental processes that characterize adolescence and young adulthood. A sizable minority of YLWH have unsuppressed viral loads in the United States attributable to antiretroviral therapy (ART) nonadherence. Interventions to promote sustained viral suppression in YLWH are needed. OBJECTIVE: The aim of this study is to evaluate the efficacy of the Triggered Escalating Real-Time Adherence (TERA) intervention in comparison with standard of care (SOC) in YLWH (aged 13-24 years) failing ART on (1) primary outcome measures-HIV viral suppression (VLS), defined as both <200 copies/ml and <50 copies/ml at 12 weeks, and (2) secondary outcome measures-VLS rates and rates of ART adherence at 24, 36, and 48 weeks as well as patterns of adherence over time as measured by an electronic dose monitoring (EDM) device. METHODS: The TERA study is a phase 2, multisite clinical trial conducted with 120 YLWH failing ART (randomized 1:1 to TERA or SOC) at participating clinical sites within the Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN). Participants are followed for a total of 48 weeks. For TERA arm participants, the first 12 weeks involve delivery of the intervention. For all participants, clinical outcomes are collected throughout follow-up, and adherence is assessed using EDM over the full 48 weeks. During the 12-week intervention period, TERA arm participants receive 3 remote coaching sessions delivered in clinic via videoconferencing timed to coincide with baseline and follow-up clinical visits, text message reminders when the EDM has not been opened at dose time (which escalate to 2-way theory-informed short message service coaching interactions in response to real-time nonadherence), and review of dosing graphs produced by EDM at follow-up visits. RESULTS: Launch dates for enrollment varied by site. Enrollment began in April 2018 and is expected to be completed by August 2019, with results presented by the second quarter of 2021. CONCLUSIONS: Effective, generalizable, and scalable approaches to rapidly assist YLWH failing to achieve and sustain VLS may have a substantial impact on individual health and efforts to curb transmission. Coaching for a brief but intensive period from remote coaches and using communication channels common to youth may offer multiple unique advantages in promoting self-care. TRIAL REGISTRATION: ClinicalTrials.gov NCT03292432; https://clinicaltrials.gov/ct2/show/NCT03292432 (Archived by WebCite at http://www.webcitation.org/768J8ijjp). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/11416.