Supporting the Art: Medication Adherence Patterns in Persons Prescribed Ingestible Sensor-enabled Oral Pre-Exposure Prophylaxis to Prevent Human Immunodeficiency Virus Infection.

BACKGROUND: Timely, accurate adherence data may support oral pre-exposure prophylaxis (PrEP) success and inform prophylaxis choice. We evaluated a Food and Drug Administration (FDA)-approved digital health feedback system (DHFS) with ingestible-sensor-enabled (IS) tenofovir-disoproxil-fumarate plus emtricitabine (Truvada®) in persons starting oral PrEP. METHODS: Human immunodeficiency virus (HIV)-negative adults were prescribed IS-Truvada® with DHFS for 12 weeks to observe medication taking behavior. Baseline demographics, urine toxicology, and self-report questionnaires were obtained. Positive detection accuracy and adverse events were computed as percentages, with Kaplan Meier Estimate for persistence-of-use. In participants persisting ≥28 days, adherence patterns (taking and timing) were analyzed, and mixed-effects logistic regression modeled characteristics associated with treatment adherence. RESULTS: Seventy-one participants were enrolled, mean age 37.6 years (range 18-69), 90.1% male, 77.5% White, 33.8% Hispanic, 95.8% housed, and 74.6% employed. Sixty-three participants (88.7%) persisted ≥28 days, generating 4987 observation days, average 79.2 (29-105). Total confirmed doses were 86.2% (95% confidence interval [CI] 82.5, 89.4), decreasing over time, odds ratio (OR) 0.899 (95% CI .876, .923) per week, P < .001; 79.4% (95% CI 66.7%, 87.3%) of participants had ≥80% adherence. Pattern analysis showed days without confirmed doses clustered (P = .003); regular dose timing was higher among participants with ≥80% confirmed doses (0.828, 95% CI .796 to .859) than among those with <80% (0.542, 95% CI95 .405 to .679) P < .001. In multi-predictor models, better adherence was associated with older age, OR 1.060 (95% CI 1.033, 1.091) per year, P < .001; negative vs positive methamphetamine screen, OR 5.051 (95% CI 2.252, 11.494), P < .001. CONCLUSIONS: DHFS with IS-Truvada® distinguished adherent persons from those potentially at risk of prophylactic failure. Ongoing methamphetamine substance use may impact oral PrEP success.

Lung function tracking in children with perinatally acquired HIV following early antiretroviral therapy initiation.

INTRODUCTION: Lung disease remains a frequent complication in children with perinatal HIV infection (CHIV) and exposure without infection (CHEU), resulting in diminished lung function. In CHIV, early antiretroviral therapy (ART) initiation improves survival and extrapulmonary outcomes. However, it is unknown if there is benefit to lung function. METHODS: Cohorts of CHIV (ART initiated at median 4.0 months), CHEU and HIV-unexposed children (CHU) prospectively performed pulmonary function testing (PFT) consisting of spirometry, plethysmography and diffusing capacity from 2013 to 2020. We determined lung function trajectories for PFT outcomes comparing CHIV to CHU and CHEU to CHU, using linear mixed effects models with multiple imputation. Potential confounders included sex, age, height, weight, body mass index z-score, urine cotinine and Tanner stage. RESULTS: 328 participants (122 CHIV, 126 CHEU, 80 CHU) performed PFT (ages 6.6-15.6 years). Spirometry (forced expiratory volume in 1 s, FEV1, forced vital capacity (FVC), FEV1/FVC) outcomes were similar between groups. In plethysmography, the mean residual volume (RV) z-score was 17% greater in CHIV than CHU (95% CI 1% to 33%, p=0.042). There was no difference in total lung capacity (TLC) or RV/TLC z-scores between groups. Diffusing capacity for carbon monoxide was similar in all groups, while alveolar volume (VA) differed between HIV groups by sex. CONCLUSION: Our study indicates that early ART initiation can mitigate the loss of lung function in CHIV with lasting benefit through childhood; however, there remains concern of small airway disease. CHEU does not appear to disrupt childhood lung function trajectory.

Wirelessly observed therapy compared to directly observed therapy to confirm and support tuberculosis treatment adherence: A randomized controlled trial.

BACKGROUND: Excellent adherence to tuberculosis (TB) treatment is critical to cure TB and avoid the emergence of resistance. Wirelessly observed therapy (WOT) is a novel patient self-management system consisting of an edible ingestion sensor (IS), external wearable patch, and paired mobile device that can detect and digitally record medication ingestions. Our study determined the accuracy of ingestion detection in clinical and home settings using WOT and subsequently compared, in a randomized control trial (RCT), confirmed daily adherence to medication in persons using WOT or directly observed therapy (DOT) during TB treatment. METHODS AND FINDINGS: We evaluated WOT in persons with active Mycobacterium tuberculosis complex disease using IS-enabled combination isoniazid 150 mg/rifampin 300 mg (IS-Rifamate). Seventy-seven participants with drug-susceptible TB in the continuation phase of treatment, prescribed daily isoniazid 300 mg and rifampin 600 mg, used IS-Rifamate. The primary endpoints of the trial were determination of the positive detection accuracy (PDA) of WOT, defined as the percentage of ingestions detected by WOT administered under direct observation, and subsequently the proportion of prescribed doses confirmed by WOT compared to DOT. Initially participants received DOT and WOT simultaneously for 2-3 weeks to allow calculation of WOT PDA, and the 95% confidence interval (CI) was estimated using the bootstrap method with 10,000 samples. Sixty-one participants subsequently participated in an RCT to compare the proportion of prescribed doses confirmed by WOT and DOT. Participants were randomized 2:1 to receive WOT or maximal in-person DOT. In the WOT arm, if ingestions were not remotely confirmed, the participant was contacted within 24 hours by text or cell phone to provide support. The number of doses confirmed was collected, and nonparametric methods were used for group and individual comparisons to estimate the proportions of confirmed doses in each randomized arm with 95% CIs. Sensitivity analyses, not prespecified in the trial registration, were also performed, removing all nonworking (weekend and public holiday) and held-dose days. Participants, recruited from San Diego (SD) and Orange County (OC) Divisions of TB Control and Refugee Health, were 43.1 (range 18-80) years old, 57% male, 42% Asian, and 39% white with 49% Hispanic ethnicity. The PDA of WOT was 99.3% (CI 98.1; 100). Intent-to-treat (ITT) analysis within the RCT showed WOT confirmed 93% versus 63% DOT (p < 0.001) of daily doses prescribed. Secondary analysis removing all nonworking days (weekends and public holidays) and held doses from each arm showed WOT confirmed 95.6% versus 92.7% (p = 0.31); WOT was non-inferior to DOT (difference 2.8% CI [-1.8%, 9.1%]). One hundred percent of participants preferred using WOT. WOT associated adverse events were <10%, consisting of minor skin rash and pruritus associated with the patch. WOT provided longitudinal digital reporting in near real time, supporting patient self-management and allowing rapid remote identification of those who needed more support to maintain adherence. This study was conducted during the continuation phase of TB treatment, limiting its generalizability to the entire TB treatment course. CONCLUSIONS: In terms of accuracy, WOT was equivalent to DOT. WOT was superior to DOT in supporting confirmed daily adherence to TB medications during the continuation phase of TB treatment and was overwhelmingly preferred by participants. WOT should be tested in high-burden TB settings, where it may substantially support low- and middle-income country (LMIC) TB programs. TRIAL REGISTRATION: ClinicalTrials.gov NCT01960257.

Performance of a commercial smart watch compared to polysomnography reference for overnight continuous oximetry measurement and sleep apnea evaluation.

STUDY OBJECTIVES: To evaluate the accuracy and precision of continuous overnight oxygen saturation (SpO2) measurement by a commercial wrist device (WD) incorporating high-grade sensors, and investigate WD estimation of sleep-disordered breathing by quantifying overnight oxygen desaturation index (ODI) compared to polysomnography (PSG) ODI and apnea-hypopnea index (AHI) with and without sleep questionnaire data, to assess WD ability to detect obstructive sleep apnea (OSA) and determine its severity. METHODS: Participants completed sleep questionnaires, had a WD (Samsung Galaxy Watch 4) placed on their wrist, and underwent attending, in-lab overnight PSG (Nihon Kohden) with pulse oximetry probe secured either to a finger or ear lobe. PSG data was scored by a single experienced registered PSG technologist. Statistical analysis included demographic characteristics, continuous SpO2 measurement WD vs PSG root mean square error (RMSE) with Bland Altman plot and linear regression associations. Predictive models for PSG ODI and AHI severity were built using logistic regression with probability cutoffs determined via receiver operating curve (ROC) characteristics. RESULTS: The 51 participants analyzed had median age of 49 (range 22-78) years, 66.7% were male, with median body mass index (BMI) 28.1 (range 20.1, 47.3) kg/m2 with race/ethnicity distribution of 49.0% Caucasian, 25.5% Hispanic, 9.8% African-American, 9.8% Asian, and 5.9% Middle Eastern. WD vs PSG continuous SpO2 measurement in percentage points demonstrated bias of 0.91 (CI95 0.38, 1.45), standard deviation 2.37 (CI95 2.36, 2.38), and RMSE 2.54 (CI95 2.34, 2.73). WD area under the curve (AUC) ROC characteristics for predicting PSG were 0.882 ODI>15/h, 0.894 AHI>30/h, 0.800 AHI>15/h, and 0.803 AHI>5/h. WD plus select sleep questionnaire AUCs for predicting PSG were 0.943 AHI>30/h, 0.868 AHI>15/h, and 0.863 AHI>5/h. CONCLUSIONS: The WD conducted reliable overnight continuous SpO2 monitoring with RMSE <3% vs PSG. Predictive models of PSG AHI based on WD measurements alone, or plus sleep questionnaires, demonstrated excellent to outstanding discrimination for OSA identification and severity. Longitudinal WD use should be evaluated promptly based on WD potential to improve accessibility and accuracy of OSA testing, as well as support treatment follow-up.

Longitudinal controlled attenuation parameter and liver stiffness in children with and without perinatal HIV infection in South Africa.

OBJECTIVES: Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging cause of liver disease in HIV. Transient elastography (TE) with controlled attenuation parameter (CAP) measures liver stiffness as a marker of liver fibrosis and CAP as a measure of hepatic steatosis. Our aim was to evaluate longitudinal CAP and liver stiffness in children with perinatally acquired HIV (PHIV) on antiretroviral therapy (ART) from early life compared to HIV-uninfected children (HU). DESIGN: Prospective cohort study. METHODS: PHIV and HU were followed annually for two years. During the study, 60% of PHIV switched from older ART regimens to tenofovir disoproxil, lamivudine and dolutegravir (TLD). Longitudinal evolution of CAP and liver stiffness were investigated in two PHIV groups - on older ART and on TLD - compared to HU children using linear mixed effects models. RESULTS: 263 children and adolescents (112 PHIV, 151 HU) aged 7-20 years were followed. PHIV on older ART had CAP 8.61% (95% CI 4.42% to 12.97%, p < 0.001) greater than HU and no significant difference in CAP between PHIV on TLD and HU. No significant difference in liver stiffness was found between PHIV on older ART regimens and PHIV on TLD compared to HU. CONCLUSION: PHIV on older ART had higher CAP than HU, whereas in PHIV switched to TLD there was no difference in CAP compared to HU. There was no difference in liver stiffness between either PHIV group and HU. This suggests starting ART early in life might protect PHIV from developing hepatic fibrosis.

Pulse wave velocity in early-treated children living with perinatal HIV infection is similar to uninfected children.

INTRODUCTION: HIV is associated with accelerated cardiovascular disease, due to HIV-associated metabolic abnormalities, antiretroviral therapy (ART), and HIV itself. Carotid-femoral pulse wave velocity (PWV) is the noninvasive gold standard measurement of arterial stiffness, and associated with incident vascular events in adults. It is unclear if arterial stiffness is accelerated in children living with perinatal HIV (CHIV) who initiate ART early in life. We compared the longitudinal trajectory of PWV in CHIV to children unexposed to HIV. A secondary comparison compared HIV exposed uninfected children (CHEU) to unexposed children. METHODS: Four hundred and sixty-five children (141 CHIV, 160 CHEU, 164 unexposed) previously in the children with HIV early antiretroviral therapy (ART) (CHER) and P1060 trials were followed annually at Tygerberg Children's Hospital, South Africa between 2014 and 2020. CHIV initiated ART in infancy or early childhood, with excellent ART adherence and largely sustained viral suppression. The primary outcome was PWV, measured using the Vicorder system, and evaluated using linear mixed effects models. RESULTS: Median (interquartile range) age at first PWV measurement was 8.64 (7.7-9.1) years, and median follow-up time 2.9 (1.6-4.0) years. Adjusted analyses showed no significant mean difference in PWV in CHIV and CHEU compared to unexposed [CHIV: 0.101 m/s, 95% confidence interval (CI) -0.012 to 0.214; CHEU: 0.068 m/s, 95% CI -0.047 to 0.183], after adjusting for gender, age, ethnicity, mean arterial pressure, resting average heart rate and family history of cardiovascular disease. CONCLUSIONS: Early-treated CHIV with sustained viral suppression have similar PWV to unexposed children. Excellent adherence and early ART initiation may protect against cardiovascular disease.

Decreased Hepatic Steatosis in South African Adolescents With Perinatal HIV Switching to Dolutegravir-containing Regimens.

BACKGROUND: Although dolutegravir (DTG) has a favorable metabolic profile, it has been linked to excess weight gain. We evaluated changes in hepatic steatosis in adolescents with perinatally acquired HIV switching to DTG-containing antiretroviral therapy (ART). METHODS: Virologically suppressed adolescents switched to dolutegravir for a minimum of 4 months or on unchanged ART (84% protease inhibitor) were assessed prospectively with anthropometry, transient elastography with controlled attenuation parameter (CAP) and fasting metabolic profiles. ART regimens were determined independently of the study. RESULTS: In total 68 adolescents [baseline median age 13.5 years [interquartile range (IQR): 12.5-14.4 years]; 42 (62%) female] were recruited. However, 38 remained on the same regimen and were followed for a median of 98 weeks (IQR: 48-108 weeks), and 30 switched to DTG and were followed for a median of 52 weeks (IQR: 49-101). There was no baseline difference in CAP between groups. There was no significant change in body mass index z-score in either group, but the median CAP in the DTG group decreased by -40dB/m (IQR: -51 to -31 dB/m) after a median of 44 weeks (IQR: 28-50 weeks) on DTG, compared to +1dB/m (IQR: -29 to +14 dB/m) in adolescents not switched ( P < 0 .01). Cholesterol and triglycerides were lower in those switched. Whereas hepatic steatosis prevalence decreased from 17% to 3% in adolescents who switched to dolutegravir, its prevalence doubled from 8% to 16% in those not switched ( P = 0.1). CONCLUSIONS: In this exploratory study, adolescents switched to DTG-containing regimens had reduced hepatic steatosis, cholesterol and triglycerides with no excess weight gain compared to those on unchanged ART.

Microbiological analysis of nontyphoidal Salmonella strains causing distinct syndromes of bacteremia or enteritis in HIV/AIDS patients in San Diego, California.

Recurrent invasive nontyphoidal Salmonella (NTS) infection is an AIDS-defining illness that has become less common in the developed world in the era of highly active antiretroviral therapy (HAART), while it has emerged as a major public health problem in developing countries, particularly sub-Saharan Africa. We retrospectively analyzed Salmonella (NTS) infection in HIV/AIDS patients from June 2003 until December 2009 at the University of California, San Diego (UCSD), Medical Center. Bacterial isolates from all patients were tested for selected microbiological properties, including major Salmonella (NTS) virulence loci rpoS, sodCI, spvB, and sseI. Fourteen percent of all Salmonella (NTS) cases recorded at the UCSD Medical Center during this period occurred in known HIV/AIDS patients. The clinical presentations in HIV patients fell into two distinct groups, bacteremia and enteritis. There was little clinical overlap between these two syndromes. All strains were positive for the presence of the rpoS and sodCI virulence loci, and 75% of strains were positive for the presence of the spvB and sseI loci. Antibiotic susceptibility assay showed that all strains were susceptible to trimethoprim-sulfamethoxazole and ciprofloxacin. The clinical presentation did not have a clear relationship to the CD4(+) cell count. Of the bacteremic isolates, all but one isolate, drawn from a patient with substantial enteric comorbidities, had all of the virulence genes tested, but 66% of nonbacteremic, enteritis strains also contained all the tested virulence loci. In conclusion, neither patients' CD4(+) cell count nor bacterial strain properties necessarily predicted the clinical presentation of HIV/AIDS patients with Salmonella (NTS) infection, and AIDS patients can have episodes of Salmonella enteritis without dissemination.

High prevalence of lipoatrophy in pre-pubertal South African children on antiretroviral therapy: a cross-sectional study.

BACKGROUND: Despite changes in WHO guidelines, stavudine is still used extensively for treatment of pediatric HIV in the developing world. Lipoatrophy in sub-Saharan African children can be stigmatizing and have far-reaching consequences. The severity and extent of lipoatrophy in pre-pubertal children living in sub-Saharan Africa is unknown. METHODS: In this cross-sectional study, children who were 3-12 years old, on antiretroviral therapy and pre-pubertal were recruited from a Family HIV Clinic in South Africa. Lipoatrophy was identified and graded by consensus between two HIV pediatricians using a standardized grading scale. A professional dietician performed formal dietary assessment and anthropometric measurements of trunk and limb fat. Previous antiretroviral exposures were recorded. In a Dual-Energy X-ray Absorbtiometry (DXA) substudy body composition was determined in 42 participants. RESULTS: Among 100 recruits, the prevalence of visually obvious lipoatrophy was 36% (95% CI: 27%-45%). Anthropometry and DXA measurements corroborated the clinical diagnosis of lipoatrophy: Both confirmed significant, substantial extremity fat loss in children with visually obvious lipoatrophy, when adjusted for age and sex. Adjusted odds ratio for developing lipoatrophy was 1.9 (95% CI: 1.3 - 2.9) for each additional year of accumulated exposure to standard dose stavudine. Cumulative time on standard dose stavudine was significantly associated with reductions in biceps and triceps skin-fold thickness (p=0.008). CONCLUSIONS: The prevalence of visually obvious lipoatrophy in pre-pubertal South African children on antiretroviral therapy is high. The amount of stavudine that children are exposed to needs review. Resources are needed to enable low-and-middle-income countries to provide suitable pediatric-formulated alternatives to stavudine-based pediatric regimens. The standard stavudine dose for children may need to be reduced. Diagnosis of lipoatrophy at an early stage is important to allow timeous antiretroviral switching to arrest progression and avoid stigmatization. Diagnosis using visual grading requires training and experience, and DXA and comprehensive anthropometry are not commonly available. A simple objective screening tool is needed to identify early lipoatrophy in resource-limited settings where specialized skills and equipment are not available.

Penetration and activation of brain endothelium by Salmonella enterica serovar Typhimurium.

Salmonella meningitis is a serious disease of the central nervous system, common particularly in Africa. Here, we show that Salmonella enterica serovar Typhimurium is able to adhere, invade, and penetrate human brain microvascular endothelial cells (hBMECs), the single-cell layer constituting the blood-brain barrier (BBB). Cellular invasion was dependent on host actin cytoskeleton rearrangements, while expression of a functional type III secretion system was not essential. In addition, Salmonella infection activated a proinflammatory immune response targeting neutrophil signaling and recruitment. Salmonella invasion and immune activation may represent a crucial step in the penetration of the BBB and development of Salmonella meningitis.

Prevalence and Risk Factors for Hepatic Steatosis in Children With Perinatal HIV on Early Antiretroviral Therapy Compared to HIV-Exposed Uninfected and HIV-Unexposed Children.

Objectives: We evaluated the prevalence and risk factors for hepatic steatosis in South African children with perinatally acquired HIV (PHIV) who started treatment early and remain on long-term antiretroviral therapy (ART) compared to HIV-uninfected children. Design: A cross-sectional study from April 2019 to October 2021. PHIV, HIV-exposed uninfected (HEU) and HIV-unexposed (HU) children were enrolled from an ongoing cohort study. Methods: All children had transient elastography (TE) with controlled attenuation parameter (CAP). Liver enzymes, lipogram, insulin and glucose were sent after an overnight fast. Multivariable linear regression analyses identified predictors of CAP. Hepatic steatosis was defined as CAP>248kPa. Results: 215 children (111 [52%] male; median age 14.1 years; IQR 12.7-14.9) participated in the study, 110 PHIV, 105 HIV-uninfected (36 HEU, 69 HU). PHIV initiated ART at a median age of 2.7 months (IQR 1.8-8.5). Hepatic steatosis prevalence was 9% in PHIV, 3% in HEU and 1% in HU children (p = 0.08). However, 8% of lean (body mass index z-score ≤ +1) PHIV had hepatic steatosis compared to zero lean HEU or HU children (p = 0.03). In multivariable linear regression analysis of all PHIV, body mass index (BMI) z-score was positively associated with CAP (p = 0.001) while CD4 count (p = 0.02) and duration of suppression of HIV viraemia (p = 0.009) were negatively associated with CAP, adjusting for age, sex and ethnicity. Conclusions: Hepatic steatosis prevalence was higher in lean PHIV than lean HIV-uninfected South African children. Longer suppression of HIV viraemia and higher CD4 count were associated with lower CAP and might be protective factors for hepatic steatosis in PHIV children.

Childhood lung function following perinatal HIV infection and early antiretroviral therapy initiation: a cross-sectional study.

Despite the introduction of antiretroviral therapy (ART), HIV-associated pulmonary complications remain prevalent in children following perinatal HIV infection. In the post-ART era the incidence of opportunistic infections has decreased; however, non-infectious complications including diminished lung function are common. It is unclear whether early initiation of ART influences lung function later in life. We performed a cross-sectional study examining pulmonary function tests (PFT) (spirometry, plethysmography, carbon monoxide diffusing capacity) in HIV-unexposed (HU), HIV-exposed-uninfected (HEU) and perinatally HIV-infected children on early ART (HIV+) recruited from the Cape Town arms of the CHER and IMPAACT 1060 trials. PFT was performed once children could participate (October 2013 to January 2020). Global Lung Initiative reference software was used for Z-standardisation of lung function by sex, age and height. In total 394 children (HU n=90, HEU n=162, HIV+ n=142) underwent PFT, median age 8.7 (IQR 7.7-9.8) years. HIV+ had ART initiated at a median age of 17.6 (8.0-36.7) weeks. Forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC Z-scores were similar in all groups. Plethysmography demonstrated air-trapping with increased total lung capacity (TLC), functional residual capacity, residual volume (RV) and RV/TLC Z-scores in HIV+. There were no differences in alveolar volume; however, diffusing capacity was increased in HIV+. Our findings indicate that following perinatal HIV infection, early ART may attenuate HIV-associated lung disease and is associated with normal childhood spirometry. However plethysmography demonstrates that small airway dysfunction is more pronounced in HIV+. Longitudinal follow-up is required to assess if these children are at risk of obstructive airway disease later in life.

Accuracy of Samsung Smartphone Integrated Pulse Oximetry Meets Full FDA Clearance Standards for Clinical Use.

Background: Pulse oximetry is used as an assessment tool to gauge the severity of COVID-19 infection and identify patients at risk of poor outcomes.1,2,3,4 The pandemic highlights the need for accurate pulse oximetry, particularly at home, as infection rates increase in multiple global regions including the UK, USA and South Africa5. Over 100 million Samsung smartphones containing dedicated biosensors (Maxim Integrated Inc, San Jose, CA) and preloaded Apps to perform pulse oximetry, are in use globally. We performed detailed in human hypoxia testing on the Samsung S9 smartphone to determine if this integrated hardware meets full FDA/ISO requirements for clinical pulse oximetry. Methods: The accuracy of integrated pulse oximetry in the Samsung 9 smartphone during stable arterial oxygen saturations (SaO2) between 70% and 100% was evaluated in 12 healthy subjects. Inspired oxygen, nitrogen, and carbon dioxide partial pressures were monitored and adjusted via a partial rebreathing circuit to achieve stable target SaO2 plateaus between 70% and 100%. Arterial blood samples were taken at each plateau and saturation measured on each blood sample using ABL-90FLEX blood gas analyzer. Bias, calculated from smartphone readings minus the corresponding arterial blood sample, was reported as root mean square deviation (RMSD). Findings: The RMSD of the over 257 data points based on blood sample analysis obtained from 12 human volunteers tested was 2.6%. Interpretation: Evaluation of the smartphone pulse oximeter performance is within requirements of <3.5% RMSD blood oxygen saturation (SpO2) value for FDA/ISO clearance for clinical pulse oximetry. This is the first report of smartphone derived pulse oximetry measurements that meet full FDA/ISO accuracy certification requirements. Both Samsung S9 and S10 contain the same integrated pulse oximeter, thus over 100 million smartphones in current global circulation could be used to obtain clinically accurate spot SpO2 measurements to support at home assessment of COVID-19 patients.

Earlier antiretroviral initiation is independently associated with better arterial stiffness in children living with perinatally acquired HIV with sustained viral suppression in Mozambique.

BACKGROUND: Cardiovascular disease is a major driver of morbidity and mortality in adults living with HIV. The drivers of cardiovascular disease in children living with perinatally acquired HIV (PHIV) with sustained HIV viral suppression are unclear. OBJECTIVES: We explored the contribution of HIV-specific risk factors to arterial stiffness independently of traditional risk factors (metabolic syndrome [MetS]) in prepubertal children with PHIV with sustained viral suppression in a low-income country in Africa. METHOD: For this cross-sectional analysis, arterial stiffness was assessed by pulse wave velocity z-score (PWVz), measured using a Vicorder device. Metabolic syndrome components were measured. We retrospectively collected the antiretroviral therapy (ART) exposures, HIV stage, CD4 count and HIV viral load. A multivariate linear regression model was constructed for MetS components, retaining age and gender as obligatory variables. We then added HIV-related metrics to assess whether these had an independent or additive effect. RESULTS: We studied 77 virally suppressed children with PHIV without evidence of cardiovascular disease (from medical history and physical examination). In the initial model, the PWVz was independently associated with each MetS component. The PWVz was higher in participants with proportionally greater visceral fat (waist/height ratio), elevated lipids (triglyceride/high-density lipoprotein ratio) and insulin resistance (log homeostatic model assessment [HOMA]). The addition of age at ART initiation increased the model R 2 value from 0.36 to 0.43. In the resulting model, younger age at ART initiation was independently associated with a better PWVz (P < 0.001). CONCLUSION: Earlier ART initiation was independently associated with lower large artery stiffness. This effect was independent of the effect of elevated lipids, visceral fat and insulin resistance.

Smartphone Biosensor With App Meets FDA/ISO Standards for Clinical Pulse Oximetry and Can Be Reliably Used by a Wide Range of Patients.

BACKGROUND: Millions of smartphones contain a photoplethysmography (PPG) biosensor (Maxim Integrated) that accurately measures pulse oximetry. No clinical use of these embedded sensors is currently being made, despite the relevance of remote clinical pulse oximetry to the management of chronic cardiopulmonary disease, and the triage, initial management, and remote monitoring of people affected by respiratory viral pandemics, such as severe acute respiratory syndrome coronavirus 2 or influenza. To be used for clinical pulse oximetry the embedded PPG system must be paired with an application (app) and meet US Food and Drug Administration (FDA) and International Organization for Standardization (ISO) requirements. RESEARCH QUESTION: Does this smartphone sensor with app meet FDA/ISO requirements? Are measurements obtained using this system comparable to those of hospital reference devices, across a wide range of people? STUDY DESIGN AND METHODS: We performed laboratory testing addressing ISO and FDA requirements in 10 participants using the smartphone sensor with app. Subsequently, we performed an open-label clinical study on 320 participants with widely varying characteristics, to compare the accuracy and precision of readings obtained by patients with those of hospital reference devices, using rigorous statistical methodology. RESULTS: "Breathe down" testing in the laboratory showed that the total root-mean-square deviation of oxygen saturation (Spo2) measurement was 2.2%, meeting FDA/ISO standards. Clinical comparison of the smartphone sensor with app vs hospital reference devices determined that Spo2 and heart rate accuracy were 0.48% points (95% CI, 0.38-0.58; P < .001) and 0.73 bpm (95% CI, 0.33-1.14; P < .001), respectively; Spo2 and heart rate precision were 1.25 vs reference 0.95% points (P < .001) and 5.99 vs reference 3.80 bpm (P < .001), respectively. These small differences were similar to the variation found between two FDA-approved reference instruments for Spo2: accuracy, 0.52% points (95% CI, 0.41-0.64; P < .001) and precision, 1.01 vs 0.86% points (P < .001). INTERPRETATION: Our findings support the application for full FDA/ISO approval of the smartphone sensor with app tested for use in clinical pulse oximetry. Given the immense and immediate practical medical importance of remote intermittent clinical pulse oximetry to both chronic disease management and the global ability to respond to respiratory viral pandemics, the smartphone sensor with app should be prioritized and fast-tracked for FDA/ISO approval to allow clinical use. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04233827; URL: www.clinicaltrials.gov.

Identification of Salmonella SPI-2 secretion system components required for SpvB-mediated cytotoxicity in macrophages and virulence in mice.

The Salmonella SpvB protein possesses ADP-ribosyl transferase activity. SpvB, acting as an intracellular toxin, covalently modifies monomeric actin, leading to loss of F-actin filaments in Salmonella-infected human macrophages. Using defined Salmonella mutants, different functional components of the SPI-2 type three secretion system (TTSS), ssaV, spiC, sseB, sseC, and sseD, were found to be required for SpvB-mediated actin depolymerization in human macrophages. Expression of SpvB protein in Salmonella was not affected by any of the SPI-2 mutants and the effects of these loci were not due to reduced numbers of intracellular bacteria. Interestingly, the major SPI-2 virulence effector, SifA, is not required for SpvB action. Further, caspase-3 activation is an additional marker of cytotoxicity in Salmonella-infected human macrophages. Caspase-3 activity depended on SpvB and SPI-2 TTSS function, but not on SifA. These human macrophage cell culture results were corroborated by virulence studies in mice. Using competitive infection of mice with mixed inocula of single and double mutants, spvBmut1 mutation did not have an effect independent of ssaJ mutation, essential for SPI-2 TTSS function. In contrast, competitive infection studies in mice confirmed that SpvB and SifA have independent virulence effects, as predicted by the macrophage studies.

mTOR activity in AIDS-related diffuse large B-cell lymphoma.

BACKGROUND: Patients infected with HIV have a significantly increased risk of developing non-Hodgkin lymphomas despite the widespread use of HAART. To investigate mTOR pathway activity in acquired immunodeficiency syndrome (AIDS) related diffuse large B-cell lymphoma AR-DLBCL, we used immunohistochemistry to examine the presence of the phosphorylated 70 ribosomal S6 protein-kinase (p70S6K), an extensively studied effector of mTOR Complex 1 (mTORC1) and the phosphorylated phosphatase and tensin homolog (pPTEN), a negative regulator of mTORC1 pathway. MATERIALS AND METHODS: We evaluated tissue samples from 126 patients with AR-DLBCL. Among them, 98 samples were from tissue microarrays (TMAs) supplied by the Aids and Cancer Specimen Resource (ACSR), the remaining 28 samples were from cases diagnosed and treated at the University of California, San Diego (UCSD). The presence of p70S6K was evaluated with two antibodies directed against the combined epitopes Ser235/236 and Ser240/244, respectively; and additional monoclonal anti-bodies were used to identify pPTEN and phosphorylated proline-rich Akt substrate of 40kDa (pPRAS40). The degree of intensity and percentage of cells positive for p70S6K and pPTEN were assessed in all the samples. In addition, a subgroup of 28 patients from UCSD was studied to assess the presence of pPRAS40, an insulin-regulated activator of the mTORC1. The expression of each of these markers was correlated with clinical and histopathologic features. RESULTS: The majority of the patients evaluated were males (88%); only two cases (1.6%) were older than 65 years of age. We found high levels of both p70S6K-paired epitopes studied, 48% positivity against Ser235/236 (44% in ACSR and 64% in UCSD group), and 86% positivity against Ser240/244 (82% in ACSR and 100% in UCSD group). We observed more positive cells and stronger intensity with epitope Ser240/244 in comparison to Ser235/236 (p<0.0001). The degree of intensity and percentage of cells positive for pPTEN was positively correlated with p70S6K levels (p = 0.016 for 235/236 and p = 0.007 for 240/244). High levels of pPRAS40 were observed in the majority of the cases evaluated (64.3%), but no correlation was found with either pPTEN (p = 0.9) or p70S6K (p = 0.9) levels. CONCLUSION: AR-DLBCL frequently contain p70S6K, a main downstream effector of the mTOR pathway. The presence of p70S6K is positively correlated with pPTEN, an inactive form of PTEN, which makes mTORC1 activated. The presence of p70S6K was independent of HIV viral load or CD4 (+) counts. These results suggest that the mTOR pathway is active in the majority of AR-DLBCL, and p70S6K, particularly the Ser240/244 epitope immunohistochemistry is an excellent surrogate biomarker, which could be used to identify cases expected to be responsive to mTOR inhibitors.

High Prevalence of Dyslipidemia and Insulin Resistance in HIV-infected Prepubertal African Children on Antiretroviral Therapy.

BACKGROUND: Data describing the true extent of antiretroviral therapy (ART)-induced dyslipidemia and insulin resistance in perinatally infected children on ART in Africa are sparse. METHODS: Fasting total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, insulin and glucose were performed on the first 100 of 190 pediatric ART clinic attendees. Diet assessment was performed by a trained dietician. Lipoatrophy was formally graded by consensus between 2 expert HIV pediatricians. Durations of previous ART exposures, clinical stage, pre-ART viral load, nadir and current CD4 were recorded. Dual-energy X-ray absorptiometry was performed on a subset of 42 patients selected semi-randomly. RESULTS: Prevalences of insulin resistance, abnormal total cholesterol, LDL, HDL and triglyceride were 10%, 13%, 12%, 13% and 9%, respectively. Overall, 40% had at least 1 lipid abnormality or insulin resistance. Adjusted mean LDL cholesterol increased by 0.24 mmol/L for each additional year of cumulative lopinavir/r exposure (P = 0.03) after correcting for age, gender, body mass index, previous stavudine exposure, age at ART initiation, dietary fat and refined carbohydrate, whereas adjusted mean LDL cholesterol was 0.9 mmol/L higher in children exposed to efavirenz within the previous 6 months (P = 0.02). Adjusting for age, gender and ethnicity, dual-energy X-ray absorptiometry revealed that greater trunk fat and lower peripheral subcutaneous fat were associated with elevated triglycerides but not with total cholesterol, LDL, HDL or homeostatic model assessment. Similarly, the presence of visually obvious lipoatrophy was associated with elevated triglycerides but not with total cholesterol, LDL, HDL, homeostatic model assessment or lactate. CONCLUSIONS: Prevalences of insulin resistance and dyslipidemia were high. Cumulative lopinavir is an independent risk factor for dyslipidemia, with efavirenz exposure having only transitory effect.

Let Visuals Tell the Story: Medication Adherence in Patients with Type II Diabetes Captured by a Novel Ingestion Sensor Platform.

BACKGROUND: Chronic diseases such as diabetes require high levels of medication adherence and patient self-management for optimal health outcomes. A novel sensing platform, Digital Health Feedback System (Proteus Digital Health, Redwood City, CA), can for the first time detect medication ingestion events and physiological measures simultaneously, using an edible sensor, personal monitor patch, and paired mobile device. The Digital Health Feedback System (DHFS) generates a large amount of data. Visual analytics of this rich dataset may provide insights into longitudinal patterns of medication adherence in the natural setting and potential relationships between medication adherence and physiological measures that were previously unknown. OBJECTIVE: Our aim was to use modern methods of visual analytics to represent continuous and discrete data from the DHFS, plotting multiple different data types simultaneously to evaluate the potential of the DHFS to capture longitudinal patterns of medication-taking behavior and self-management in individual patients with type II diabetes. METHODS: Visualizations were generated using time domain methods of oral metformin medication adherence and physiological data obtained by the DHFS use in 5 patients with type II diabetes over 37-42 days. The DHFS captured at-home metformin adherence, heart rate, activity, and sleep/rest. A mobile glucose monitor captured glucose testing and level (mg/dl). Algorithms were developed to analyze data over varying time periods: across the entire study, daily, and weekly. Following visualization analysis, correlations between sleep/rest and medication ingestion were calculated across all subjects. RESULTS: A total of 197 subject days, encompassing 141,840 data events were analyzed. Individual continuous patch use varied between 87-98%. On average, the cohort took 78% (SD 12) of prescribed medication and took 77% (SD 26) within the prescribed ±2-hour time window. Average activity levels per subjects ranged from 4000-12,000 steps per day. The combination of activity level and heart rate indicated different levels of cardiovascular fitness between subjects. Visualizations over the entire study captured the longitudinal pattern of missed doses (the majority of which took place in the evening), the timing of ingestions in individual subjects, and the range of medication ingestion timing, which varied from 1.5-2.4 hours (Subject 3) to 11 hours (Subject 2). Individual morning self-management patterns over the study period were obtained by combining the times of waking, metformin ingestion, and glucose measurement. Visualizations combining multiple data streams over a 24-hour period captured patterns of broad daily events: when subjects rose in the morning, tested their blood glucose, took their medications, went to bed, hours of sleep/rest, and level of activity during the day. Visualizations identified highly consistent daily patterns in Subject 3, the most adherent participant. Erratic daily patterns including sleep/rest were demonstrated in Subject 2, the least adherent subject. Correlation between sleep /rest and medication ingestion in each individual subject was evaluated. Subjects 2 and 4 showed correlation between amount of sleep/rest over a 24-hour period and medication-taking the following day (Subject 2: r=.47, P<.02; Subject 4: r=.35, P<.05). With Subject 2, sleep/rest disruptions during the night were highly correlated (r=.47, P<.009) with missing doses the following day. CONCLUSIONS: Visualizations integrating medication ingestion and physiological data from the DHFS over varying time intervals captured detailed individual longitudinal patterns of medication adherence and self-management in the natural setting. Visualizing multiple data streams simultaneously, providing a data-rich representation, revealed information that would not have been shown by plotting data streams individually. Such analyses provided data far beyond traditional adherence summary statistics and may form the foundation of future personalized predictive interventions to drive longitudinal adherence and support optimal self-management in chronic diseases such as diabetes.