Effect of azithromycin on incidence of acute respiratory exacerbations in children with HIV taking antiretroviral therapy and co-morbid chronic lung disease: a secondary analysis of the BREATHE trial

Background - In the BREATHE trial weekly azithromycin decreased the rate of acute respiratory exacerbations (AREs) compared to placebo among children and adolescents with HIV-associated chronic lung disease (CLD) taking antiretroviral therapy (ART). The aim of this analysis was to identify risk factors associated with AREs and mediators of the effect of azithromycin on AREs. Methods - The primary outcome of this analysis was the rate of AREs by study arm up to 49 weeks. We analysed rates using Poisson regression with random intercepts. Interaction terms were fitted for potential effect modifiers. Participants were recruited from Zimbabwe and Malawi between15 June 2016 and 4 September 2018. Findings - We analysed data from 345 participants (171 allocated to azithromycin and 174 allocated to placebo). Rates of AREs were higher among those with an abnormally high respiratory rate at baseline (adjusted rate ratio (aRR) 2.08 95% CI 1.10-3.95 p-value 0.02) and among those with a CD4 cell count -2 and participants without baseline resistance to azithromycin. However, there was no statistical evidence for interaction due to low statistical power. Interpretation - These may represent subgroups who may benefit the most from treatment with weekly azithromycin, which could help guide targeted treatment. Funding - There was no funding source for this post hoc analysis

The impact of long-term azithromycin on antibiotic resistance in HIV-associated chronic lung disease

Selection for resistance to azithromycin (AZM) and other antibiotics such as tetracyclines and lincosamides remains a concern with long-term AZM use for treatment of chronic lung diseases (CLD). We investigated the impact of 48 weeks of AZM on the carriage and antibiotic resistance of common respiratory bacteria among children with HIV-associated CLD. Nasopharyngeal (NP) swabs and sputa were collected at baseline, 48 and 72 weeks from participants with HIV-associated CLD randomised to receive weekly AZM or placebo for 48 weeks and followed postintervention until 72 weeks. The primary outcomes were prevalence and antibiotic resistance of Streptococcus pneumoniae (SP), Staphylococcus aureus (SA), Haemophilus influenzae (HI) and Moraxella catarrhalis (MC) at these timepoints. Mixed-effects logistic regression and Fisher’s exact test were used to compare carriage and resistance, respectively. Of 347 (174 AZM, 173 placebo) participants (median age 15 years (IQR 13–18), female 49%), NP carriage was significantly lower in the AZM (n=159) compared to placebo (n=153) arm for SP (18% versus 41%, p<0.001), HI (7% versus 16%, p=0.01) and MC (4% versus 11%, p=0.02); SP resistance to AZM (62% (18 out of 29) versus 13% (8 out of 63), p<0.0001) or tetracycline (60% (18 out of 29) versus 21% (13 out of 63), p<0.0001) was higher in the AZM arm. Carriage of SA resistant to AZM (91% (31 out of 34) versus 3% (1 out of 31), p<0.0001), tetracycline (35% (12 out of 34) versus 13% (4 out of 31), p=0.05) and clindamycin (79% (27 out of 34) versus 3% (1 out of 31), p<0.0001) was also significantly higher in the AZM arm and persisted at 72 weeks. Similar findings were observed for sputa. The persistence of antibiotic resistance and its clinical relevance for future infectious episodes requiring treatment needs further investigation

Incidence and progression of echocardiographic abnormalities in HIV-infected older children and adolescents taking antiretroviral therapy: A prospective cohort study

BACKGROUND: A high prevalence of cardiac abnormalities has been reported in children with HIV taking ART in sub-Saharan Africa. We investigated the incidence and progression of cardiac abnormalities among children taking ART in Zimbabwe. METHODS: A prospective cohort study was conducted at a paediatric HIV clinic from 2014 to 2017. Children with HIV aged between 6 and 16 years and taking ART ≥6 months were enrolled. Transthoracic echocardiography was performed at baseline and 18 months. RESULTS: Of 197 participants recruited at baseline, 175 [(89%), 48% female, median age 12 (IQR, 10-14) years] were followed up. The incidence of left and right heart abnormalities was 3.52 and 5.64 per 100 pys, respectively. Stunting was associated with the development of any cardiac abnormality [adjusted OR 2.59 (95% CI, 1.03-6.49); p=0.043]. Right ventricular (RV) dilatation persisted at follow up in 92% and left ventricular (LV) diastolic dysfunction in 88%. Cardiac abnormalities present at baseline reverted to normal over the follow up period in 11(6%). There was an overall increase in mean z-scores for LV, left atrium (LA), RV, interventricular septum and LV posterior wall diameters at 18 months (p<0.001). CONCLUSIONS: Despite ART, children with HIV have a high incidence of cardiac abnormalities, with only a minority being transient. Mean z-scores for LV, LA, RV, interventricular septum and LV posterior wall diameters increased over a relatively short follow up period, suggesting the potential for progression of cardiac abnormalities. Longer follow up is required to understand the clinical implications of these abnormalities

Ejection Time-Corrected Systolic Velocity Improves Accuracy in the Evaluation of Myocardial Dysfunction: A Study in Piglets

This study aimed to assess the effect of correcting for the impact of heart rate (HR) or ejection time (ET) on myocardial velocities in the long axis in piglets undergoing hypoxia. The ability to eject a higher volume at a fixed ET is a characteristic of contractility in the heart. Systolic velocity of the atrioventricular annulus displacement is directly related to volume changes of the ventricle. Both ET and systolic velocity may be measured in a single heartbeat. In 29 neonatal pigs, systolic velocity and ET were measured with tissue Doppler techniques in the mitral valve annulus, the tricuspid valve annulus, and the septum. All ejection time corrected velocities (S(ET), mean ± SEM, cm/s) decreased significantly during hypoxia (Smva(ET) 15.5 ± 0.2 to 13.2 ± 0.3 (p < 0.001), Sseptal(ET) 9.9 ± 0.1 to 7.8 ± 0.2 (p < 0.001), Stva(ET) 12.1 ± 0.2 to 9.8 ± 0.3 (p < 0.001)). The magnitude of change from baseline to hypoxia was greater for ejection time corrected systolic velocities than for RR-interval corrected velocities (mean ± SEM, cm/s); ΔSmva(ET) 2.3 ± 2.0 vs. ΔSmva(RR) 1.6 ± 1.1 (p = 0.02), ΔSseptal(ET) 2.1 ± 1.0 vs. ΔSseptal(RR) 1.6 ± 1.0 (p < 0.01), ΔStva(ET) 2.3 ± 1.1 vs. ΔStva(RR) 1.8 ± 1.3 (p = 0.04). The receiver operator characteristic (ROC) showed superior performance of S(ET) compared with uncorrected velocities. The decrease in S(ET) during hypoxia was not influenced by important hemodynamic determinants. ET-corrected systolic velocity improves accuracy and decreases variability in the evaluation of systolic longitudinal function and contractility during global hypoxia in neonatal pigs compared with systolic velocity alone. It is robust toward hemodynamic changes. This novel method has the potential of becoming a useful tool in clinical practice

History of tuberculosis is associated with lower exhaled nitric oxide levels in HIV-infected children

Objective: HIV disrupts host defense mechanisms and maintains chronic inflammation in the lung. Nitric oxide is a marker of lung inflammation and can be measured in the exhaled air. We investigated the relationship between exhaled nitric oxide (eNO), HIV status and airway abnormalities in perinatally HIV-infected children aged 6–19 years. Design: A cross-sectional study. Methods: HIV-infected individuals on antiretroviral therapy and HIV-uninfected children with no active tuberculosis (TB) or acute respiratory tract infection were recruited from a public hospital in Harare, Zimbabwe. Clinical history was collected and eNO testing and spirometry was performed. The association between eNO and explanatory variables (HIV, FEV1 z-score, CD4+ cell count, viral load, history of TB) was investigated using linear regression analysis adjusted for age, sex and time of eNO testing. Results: In total, 222 HIV-infected and 97 HIV-uninfected participants were included. Among HIV-infected participants, 57 (25.7%) had a history of past TB; 56 (25.2%) had airway obstruction, but no prior TB. HIV status was associated with lower eNO level [mean ratio 0.79 (95% confidence interval, 95% CI 0.65–0.97), P = 0.03]. Within the HIV-infected group, history of past TB was associated with lower eNO levels after controlling for age, sex and time of eNO testing [0.79 (95% CI 0.67–0.94), P = 0.007]. Conclusion: HIV infection and history of TB were associated with lower eNO levels. eNO levels may be a marker of HIV and TB-induced alteration in pulmonary physiology; further studies focused on potential causes for lower eNO levels in HIV and TB are warranted

Adherence to additional medication for management of HIV-associated comorbidities among older children and adolescents taking antiretroviral therapy

BACKGROUND : Management of co-morbidities among persons living with HIV is an emerging priority, which may require additional medication over and above life-long antiretroviral therapy (ART). We explored factors associated with adherence to the trial drug among children and adolescents with perinatally acquired HIV taking antiretroviral therapy (ART) in the Bronchopulmonary Function in Response to Azithromycin Treatment for Chronic Lung Disease in HIV-Infected Children (BREATHE) trial. METHODS : The BREATHE trial recruited 6–19 year olds with perinatally acquired HIV and co-morbid chronic lung disease as measured by FEV1. This two-site trial was individually randomised (1:1), double-blind and placebo-controlled. Participants received a once-weekly weightbased dose of 1–5 tablets of azithromycin (AZM: 250mg) or placebo, taken orally. We used pharmacy dispensing records and count of returned pills to measure adherence to study medication. Logistic regression was used to explore factors associated with adherence coverage. Poisson regression with Lexis expansion for time was used to explore whether adherence modified the effect of azithromycin on the incidence of acute respiratory exacerbation, a secondary outcome of the trial. Trial registration: ClinicalTrials.gov NCT02426112. RESULTS : The 347 participants (median age 15.3, 51% male) consumed 14,622 doses of study medication over 16,220 person-weeks under study. Adherence was higher for those randomised to AZM (73.4%) than placebo (68.4%) and declined over the 48 weeks of the study (Score test for trend <0.02). Those with unsuppressed HIV viral load at baseline had 2.08 (95% CI: 1.19, 3.63) times the odds of non-adherence than those with viral suppression. Differences were also observed between trial sites. CONCLUSION : The majority of children and adolescents tolerated the addition of a once-weekly dose of medication to their pill burden. Barriers in adhering to treatment for co-morbid conditions are likely common to barriers in adhering to ART. Control of co-morbidities will therefore present additional challenges in HIV care.The Global Health and Vaccination Research (GLOBVAC) Programme of the Medical Research Council of Norway, the Wellcome Trust, the Medical Research Council (MRC) and the Department for International Development (DFID UK).http://www.plosone.orgdm2022School of Health Systems and Public Health (SHSPH

Adherence to additional medication for management of HIV-associated comorbidities among older children and adolescents taking antiretroviral therapy.

BACKGROUND: Management of co-morbidities among persons living with HIV is an emerging priority, which may require additional medication over and above life-long antiretroviral therapy (ART). We explored factors associated with adherence to the trial drug among children and adolescents with perinatally acquired HIV taking antiretroviral therapy (ART) in the Bronchopulmonary Function in Response to Azithromycin Treatment for Chronic Lung Disease in HIV-Infected Children (BREATHE) trial. METHODS: The BREATHE trial recruited 6-19 year olds with perinatally acquired HIV and co-morbid chronic lung disease as measured by FEV1. This two-site trial was individually randomised (1:1), double-blind and placebo-controlled. Participants received a once-weekly weight-based dose of 1-5 tablets of azithromycin (AZM: 250mg) or placebo, taken orally. We used pharmacy dispensing records and count of returned pills to measure adherence to study medication. Logistic regression was used to explore factors associated with adherence coverage. Poisson regression with Lexis expansion for time was used to explore whether adherence modified the effect of azithromycin on the incidence of acute respiratory exacerbation, a secondary outcome of the trial. Trial registration: ClinicalTrials.gov NCT02426112. RESULTS: The 347 participants (median age 15.3, 51% male) consumed 14,622 doses of study medication over 16,220 person-weeks under study. Adherence was higher for those randomised to AZM (73.4%) than placebo (68.4%) and declined over the 48 weeks of the study (Score test for trend <0.02). Those with unsuppressed HIV viral load at baseline had 2.08 (95% CI: 1.19, 3.63) times the odds of non-adherence than those with viral suppression. Differences were also observed between trial sites. CONCLUSION: The majority of children and adolescents tolerated the addition of a once-weekly dose of medication to their pill burden. Barriers in adhering to treatment for co-morbid conditions are likely common to barriers in adhering to ART. Control of co-morbidities will therefore present additional challenges in HIV care

Multimorbidity and associations with clinical outcomes in a middle-aged population in Iran: a longitudinal cohort study

BACKGROUND: As the populations of lower-income and middle-income countries age, multimorbidity is increasing, but there is little information on its long-term consequences. We aimed to show associations between multimorbidity and outcomes of mortality and hospitalisation in Iran, a middle-income country undergoing rapid economic transition. METHODS: We conducted a secondary analysis of longitudinal data collected in the Golestan Cohort Study. Data on demographics, morbidities and lifestyle factors were collected at baseline, and information on hospitalisations or deaths was captured annually. Logistic regression was used to analyse the association between baseline multimorbidity and 10-year mortality, Cox-proportional hazard models to measure lifetime risk of mortality and zero-inflation models to investigate the association between hospitalisation and multimorbidity. Multimorbidity was classified as ≥2 conditions or number of conditions. Demographic, lifestyle and socioeconomic variables were included as covariables. RESULTS: The study recruited 50 045 participants aged 40–75 years between 2004 and 2008, 47 883 were available for analysis, 416 (57.3%) were female and 12 736 (27.94%) were multimorbid. The odds of dying at 10 years for multimorbidity defined as ≥2 conditions was 1.99 (95% CI 1.86 to 2.12, p<0.001), and it increased with increasing number of conditions (OR of 3.57; 95% CI 3.12 to 4.08, p<0.001 for ≥4 conditions). The survival analysis showed the hazard of death for those with ≥4 conditions was 3.06 (95% CI 2.74 to 3.43, p<0.001). The number of hospital admissions increased with number of conditions (OR of not being hospitalised of 0.36; 95% CI 0.31 to 0.52, p<0.001, for ≥4 conditions). CONCLUSION: The long-terms effects of multimorbidity on mortality and hospitalisation are similar in this population to those seen in high-income countries

Mass Measurements near N=Z

Abstract After an outline of the physics motivations, that illustrate why we think it is important to measure masses in the region N≈Z, we report on on experiments performed at Ganil. An experiment aimed at measuring the masses of proton-rich nuclei in the mass region A ≈ 60–80 has been performed, using a direct time-of-flight technique in conjunction with SISSI and the SPEG spectrometer at GANIL. The nuclei were produced via the fragmentation of a 78 Kr beam (73 meV/nucleon). A novel technique for the purification of the secondary beams, based on the stripping of the ions and using the α and the SPEG spectrometers, was succesfully checked. It allows for good selectivity without altering the beam quality. Secondary ions of 100 Ag, 100 Cd, 100 In and 100 Sn were produced via the fusion-evaporation reaction 50 Cr + 58 Ni at an energy of 5.1 MeV/nucleon, and were accelerated simultaneously in the second cyclotron of GANIL (CSS2). About 10 counts were observed from the production and acceleration of 100 Sn 22+ . The masses of 100 Cd, 100 In and 100 Sn were measured with respect to 100 Ag using the CSS2 cyclotron, with precisions of 2 × 10 −6 , 3 × 10 −6 and 10 −5 respectively