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Association between non-malignant monoclonal gammopathy and adverse outcomes in chronic kidney disease: A cohort study

Ve, 28/02/2020 - 23:00

by Anthony Fenton, Rajkumar Chinnadurai, Latha Gullapudi, Petros Kampanis, Indranil Dasgupta, James Ritchie, Stephen Harding, Charles J. Ferro, Philip A. Kalra, Maarten W. Taal, Paul Cockwell

Background

In studies including the general population, the presence of non-malignant monoclonal gammopathy (MG) can be causally associated with kidney damage and shorter survival. We assessed whether the presence of an MG is associated with a higher risk of kidney failure or death in individuals with chronic kidney disease (CKD).

Methods and findings

Data were used from 3 prospective cohorts of individuals with CKD (not on dialysis or with a kidney transplant): (1) Renal Impairment in Secondary Care (RIISC, Queen Elizabeth Hospital and Heartlands Hospital, Birmingham, UK, N = 878), (2) Salford Kidney Study (SKS, Salford Royal Hospital, Salford, UK, N = 861), and (3) Renal Risk in Derby (RRID, Derby, UK, N = 1,739). Participants were excluded if they had multiple myeloma or any other B cell lymphoproliferative disorder with end-organ damage. Median age was 71.0 years, 50.6% were male, median estimated glomerular filtration rate was 42.3 ml/min/1.73 m2, and median urine albumin-to-creatinine ratio was 3.4 mg/mmol. All non-malignant MG was identified in the baseline serum of participants of RIISC. Further, light chain MG (LC-MG) was identified and studied in participants of RIISC, SKS, and RRID. Participants were followed up for kidney failure (defined as the initiation of dialysis or kidney transplantation) and death. Associations with the risk of kidney failure were estimated by competing-risks regression (handling death as a competing risk), and associations with death were estimated by Cox proportional hazards regression. In total, 102 (11.6%) of the 878 RIISC participants had an MG. During a median follow-up time of 74.0 months, there were 327 kidney failure events and 202 deaths. The presence of MG was not associated with risk of kidney failure (univariable subhazard ratio [SHR] 0.97 [95% CI 0.68 to 1.38], P = 0.85; multivariable SHR 1.16 [95% CI 0.80 to 1.69], P = 0.43), and although there was a higher risk of death in univariable analysis (hazard ratio [HR] 2.13 [95% CI 1.49 to 3.02], P < 0.001), this was not significant in multivariable analysis (HR 1.37 [95% CI 0.93 to 2.00], P = 0.11). Fifty-five (1.6%) of the 3,478 participants from all 3 studies had LC-MG. During a median follow-up time of 62.5 months, 564 of the 3,478 participants progressed to kidney failure, and 803 died. LC-MG was not associated with risk of kidney failure (univariable SHR 1.07 [95% CI 0.58 to 1.96], P = 0.82; multivariable SHR 1.42 [95% CI 0.78 to 2.57], P = 0.26). There was a higher risk of death in those with LC-MG in the univariable model (HR 2.51 [95% CI 1.59 to 3.96], P < 0.001), but not in the multivariable model (HR 1.49 [95% CI 0.93 to 2.39], P = 0.10). An important limitation of this work was that only LC-MG, rather than any MG, could be identified in participants from SKS and RRID.

Conclusions

The prevalence of MG was higher in this CKD cohort than that reported in the general population. However, the presence of an MG was not independently associated with a significantly higher risk of kidney failure or, unlike in the general population, risk of death.

An adaptable implementation package targeting evidence-based indicators in primary care: A pragmatic cluster-randomised evaluation

Ve, 28/02/2020 - 23:00

by Thomas A. Willis, Michelle Collinson, Liz Glidewell, Amanda J. Farrin, Michael Holland, David Meads, Claire Hulme, Duncan Petty, Sarah Alderson, Suzanne Hartley, Armando Vargas-Palacios, Paul Carder, Stella Johnson, Robbie Foy, on behalf of the ASPIRE programme team

Background

In primary care, multiple priorities and system pressures make closing the gap between evidence and practice challenging. Most implementation studies focus on single conditions, limiting generalisability. We compared an adaptable implementation package against an implementation control and assessed effects on adherence to four different evidence-based quality indicators.

Methods and findings

We undertook two parallel, pragmatic cluster-randomised trials using balanced incomplete block designs in general practices in West Yorkshire, England. We used ‘opt-out’ recruitment, and we randomly assigned practices that did not opt out to an implementation package targeting either diabetes control or risky prescribing (Trial 1); or blood pressure (BP) control or anticoagulation in atrial fibrillation (AF) (Trial 2). Within trials, each arm acted as the implementation control comparison for the other targeted indicator. For example, practices assigned to the diabetes control package acted as the comparison for practices assigned to the risky prescribing package. The implementation package embedded behaviour change techniques within audit and feedback, educational outreach, and computerised support, with content tailored to each indicator. Respective patient-level primary endpoints at 11 months comprised the following: achievement of all recommended levels of haemoglobin A1c (HbA1c), BP, and cholesterol; risky prescribing levels; achievement of recommended BP; and anticoagulation prescribing. Between February and March 2015, we recruited 144 general practices collectively serving over 1 million patients. We stratified computer-generated randomisation by area, list size, and pre-intervention outcome achievement. In April 2015, we randomised 80 practices to Trial 1 (40 per arm) and 64 to Trial 2 (32 per arm). Practices and trial personnel were not blind to allocation. Two practices were lost to follow-up but provided some outcome data. We analysed the intention-to-treat (ITT) population, adjusted for potential confounders at patient level (sex, age) and practice level (list size, locality, pre-intervention achievement against primary outcomes, total quality scores, and levels of patient co-morbidity), and analysed cost-effectiveness. The implementation package reduced risky prescribing (odds ratio [OR] 0.82; 97.5% confidence interval [CI] 0.67–0.99, p = 0.017) with an incremental cost-effectiveness ratio of £1,359 per quality-adjusted life year (QALY), but there was insufficient evidence of effect on other primary endpoints (diabetes control OR 1.03, 97.5% CI 0.89–1.18, p = 0.693; BP control OR 1.05, 97.5% CI 0.96–1.16, p = 0.215; anticoagulation prescribing OR 0.90, 97.5% CI 0.75–1.09, p = 0.214). No statistically significant effects were observed in any secondary outcome except for reduced co-prescription of aspirin and clopidogrel without gastro-protection in patients aged 65 and over (adjusted OR 0.62; 97.5% CI 0.39–0.99; p = 0.021). Main study limitations concern our inability to make any inferences about the relative effects of individual intervention components, given the multifaceted nature of the implementation package, and that the composite endpoint for diabetes control may have been too challenging to achieve.

Conclusions

In this study, we observed that a multifaceted implementation package was clinically and cost-effective for targeting prescribing behaviours within the control of clinicians but not for more complex behaviours that also required patient engagement.

Trial registration

The study is registered with the ISRCTN registry (ISRCTN91989345).

Advances in clinical trial design: Weaving tomorrow’s TB treatments

Gi, 27/02/2020 - 23:00

by Christian Lienhardt, Andrew Nunn, Richard Chaisson, Andrew A. Vernon, Matteo Zignol, Payam Nahid, Eric Delaporte, Tereza Kasaeva

Christian Lienhardt and co-authors discuss the conclusions of the PLOS Medicine Collection on advances in clinical trial design for development of new tuberculosis treatments.

Plans and prospects for the 2020s: Beyond peak health?

Ma, 25/02/2020 - 23:00

by The PLOS Medicine Editors

The PLOS Medicine editors discuss prospects for health and development in the coming decade.

Virological suppression and clinical management in response to viremia in South African HIV treatment program: A multicenter cohort study

Ma, 25/02/2020 - 23:00

by Lucas E. Hermans, Sergio Carmona, Monique Nijhuis, Hugo A. Tempelman, Douglas D. Richman, Michelle Moorhouse, Diederick E. Grobbee, Willem D. F. Venter, Annemarie M. J. Wensing

Background

Uptake of antiretroviral treatment (ART) is expanding rapidly in low- and middle-income countries (LMIC). Monitoring of virological suppression is recommended at 6 months of treatment and annually thereafter. In case of confirmed virological failure, a switch to second-line ART is indicated. There is a paucity of data on virological suppression and clinical management of patients experiencing viremia in clinical practice in LMIC. We report a large-scale multicenter assessment of virological suppression over time and management of viremia under programmatic conditions.

Methods and findings

Linked medical record and laboratory source data from adult patients on first-line ART at 52 South African centers between 1 January 2007 and 1 May 2018 were studied. Virological suppression, switch to second-line ART, death, and loss to follow-up were analyzed. Multistate models and Cox proportional hazard models were used to assess suppression over time and predictors of treatment outcomes. A total of 104,719 patients were included. Patients were predominantly female (67.6%). Median age was 35.7 years (interquartile range [IQR]: 29.9–43.0). In on-treatment analysis, suppression below 1,000 copies/mL was 89.0% at month 12 and 90.4% at month 72. Suppression below 50 copies/mL was 73.1% at month 12 and 77.5% at month 72. Intention-to-treat suppression was 75.0% and 64.3% below 1,000 and 50 copies/mL at month 72, respectively. Viremia occurred in 19.8% (20,766/104,719) of patients during a median follow-up of 152 (IQR: 61–265) weeks. Being male and below 35 years of age and having a CD4 count below 200 cells/μL prior to start of ART were risk factors for viremia. After detection of viremia, confirmatory testing took 29 weeks (IQR: 16–54). Viral resuppression to below 1,000 copies/mL without switch of ART occurred frequently (45.6%; 6,030/13,210) but was associated with renewed viral rebound and switch. Of patients with confirmed failure who remained in care, only 41.5% (1,872/4,510) were switched. The median time to switch was 68 weeks (IQR: 35–127), resulting in 12,325 person-years spent with a viral load above 1,000 copies/mL. Limitations of this study include potential missing data, which is in part addressed by the use of cross-matched laboratory source data, and the possibility of unmeasured confounding.

Conclusions

In this study, 90% virological suppression below the threshold of 1,000 copies/mL was observed in on-treatment analysis. However, this target was not met at the 50-copies/mL threshold or in intention-to-treat analysis. Clinical management in response to viremia was profoundly delayed, prolonging the duration of viremia and potential for transmission. Diagnostic tools to establish the cause of viremia are urgently needed to accelerate clinical decision-making.

Association of moderate alcohol intake with in vivo amyloid-beta deposition in human brain: A cross-sectional study

Ma, 25/02/2020 - 23:00

by Jee Wook Kim, Min Soo Byun, Dahyun Yi, Jun Ho Lee, Kang Ko, So Yeon Jeon, Bo Kyung Sohn, Jun-Young Lee, Yu Kyeong Kim, Seong A Shin, Chul-Ho Sohn, Dong Young Lee, for the KBASE Research Group

Background

An emerging body of literature has indicated that moderate alcohol intake may be protective against Alzheimer disease (AD) dementia. However, little information is available regarding whether moderate alcohol intake is related to reductions in amyloid-beta (Aβ) deposition, or is protective via amyloid-independent mechanisms in the living human brain. Here we examined the associations of moderate alcohol intake with in vivo AD pathologies, including cerebral Aβ deposition, neurodegeneration of AD-signature regions, and cerebral white matter hyperintensities (WMHs) in the living human brain.

Methods and findings

The present study was part of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE), an ongoing prospective cohort study that started in 2014. As of November 2016, 414 community-dwelling individuals with neither dementia nor alcohol-related disorders (280 cognitively normal [CN] individuals and 134 individuals with mild cognitive impairment [MCI]) between 56 and 90 years of age (mean age 70.9 years ± standard deviation 7.8; male, n [%] = 180 [43.5]) were recruited from 4 sites (i.e., 2 university hospitals and 2 public centers for dementia prevention and management) around Seoul, South Korea. All the participants underwent comprehensive clinical assessments comprising lifetime and current histories of alcohol intake and multimodal brain imaging, including [11C] Pittsburgh compound B positron emission tomography (PET), [18F] fluorodeoxyglucose (FDG) PET, and magnetic resonance imaging (MRI) scans. Lifetime and current alcohol intake were categorized as follows: no drinking, <1 standard drink (SD)/week, 1–13 SDs/week, and 14+ SDs/week. A moderate lifetime alcohol intake (1–13 SDs/week) was significantly associated with a lower Aβ positivity rate compared to the no drinking group, even after controlling for potential confounders (odds ratio 0.341, 95% confidence interval 0.163–0.714, p = 0.004). In contrast, current alcohol intake was not associated with amyloid deposition. Additionally, alcohol intake was not related to neurodegeneration of AD-signature regions or cerebral WMH volume. The present study had some limitations in that it had a cross-sectional design and depended on retrospective recall for alcohol drinking history.

Conclusions

In this study, we observed in middle- and old-aged individuals with neither dementia nor alcohol-related disorders that moderate lifetime alcohol intake was associated with lower cerebral Aβ deposition compared to a lifetime history of not drinking. Moderate lifetime alcohol intake may have a beneficial influence on AD by reducing pathological amyloid deposition rather than amyloid-independent neurodegeneration or cerebrovascular injury.

Changes in maternal age and prevalence of congenital anomalies during the enactment of China's universal two-child policy (2013–2017) in Zhejiang Province, China: An observational study

Lu, 24/02/2020 - 23:00

by Xiaohui Zhang, Lijin Chen, Xuemiao Wang, Xiaoyan Wang, Menghan Jia, Saili Ni, Wei He, Shankuan Zhu

Background

China implemented a partial two-child policy (2013) followed by a universal two-child policy (2015), replacing the former one-child policy mandated by the government. The changes affect many aspects of China’s population as well as maternal and infant health, but their potential impact on birth defects (BDs) remains unknown. In this study, we investigated the associations of these policy changes with BDs in Zhejiang Province, China.

Methods and findings

We used data from the BD surveillance system in Zhejiang Province, China, which covers 90 hospitals in 30 urban districts and rural counties, capturing one-third of the total births in this province. To fully consider the time interval between conception and delivery, we defined the one-child policy period as data from 2013 (births from October 2012 to September 2013), the partial two-child policy period as data from 2015 (births from October 2014 to September 2015), and the universal two-child policy period as data from 2017 (births from October 2016 to September 2017). Data from 2009 and 2011 were also used to show the changes in the proportion of births to women with advanced maternal age (35 years and older) prior to the policy changes. Main outcome measures were changes in the proportion of mothers with advanced maternal age, prevalence of BDs, rankings of BD subtypes by prevalence, prenatal diagnosis rate, and live birth rate of BDs over time. A total of 1,260,684 births (including live births, early fetal losses, stillbirths, and early neonatal deaths) were included in the analyses. Of these, 644,973 (51.16%) births were to women from urban areas, and 615,711 (48.84%) births were to women from rural areas. In total, 135,543 (10.75%) births were to women with advanced maternal age. The proportion increased by 85.68%, from 8.52% in 2013 to 15.82% in 2017. However, it had remained stable prior to policy changes. Overall, 23,095 BDs were identified over the policy changes (2013–2017). The prevalence of BDs during 2013, 2015, and 2017 was 245.95, 264.86, and 304.36 per 10,000 births, respectively. Trisomy 21 and other chromosomal defects increased in both risk and ranking from 2013 to 2017 (crude odds ratio [95% confidence interval] 2.13 [1.75–2.60], from ranking 10th to 5th, and 3.63 [2.84–4.69], from ranking 16th to 6th, respectively). The prenatal diagnosis rate increased by 3.63 (2.2–5.1) percentage points (P < 0.001), from 31.10% to 34.72%, and identification of BDs occurred 1.88 (1.81–1.95) weeks earlier (P < 0.001). The live birth rate for infants with BDs born before 28 gestational weeks increased from 1.29% to 11.45%. The major limitations of this observational study include an inability to establish causality and the possible existence of unknown confounding factors, some of which could contribute to BDs.

Conclusions

In this study, we observed significant increases in maternal age and the prevalence of total and age-related anomalies following China’s new two-child policy. Increases in live birth rate for infants with BDs born before 28 gestational weeks suggest that healthcare for very preterm births with BDs may be warranted in the future, as well as updating the definition of perinatal period.

Safety and immune responses after a 12-month booster in healthy HIV-uninfected adults in HVTN 100 in South Africa: A randomized double-blind placebo-controlled trial of ALVAC-HIV (vCP2438) and bivalent subtype C gp120/MF59 vaccines

Lu, 24/02/2020 - 23:00

by Fatima Laher, Zoe Moodie, Kristen W. Cohen, Nicole Grunenberg, Linda-Gail Bekker, Mary Allen, Nicole Frahm, Nicole L. Yates, Lynn Morris, Mookho Malahleha, Kathryn Mngadi, Brodie Daniels, Craig Innes, Kevin Saunders, Shannon Grant, Chenchen Yu, Peter B. Gilbert, Sanjay Phogat, Carlos A. DiazGranados, Marguerite Koutsoukos, Olivier Van Der Meeren, Carter Bentley, Nonhlanhla N. Mkhize, Michael N. Pensiero, Vijay L. Mehra, James G. Kublin, Lawrence Corey, David C. Montefiori, Glenda E. Gray, M. Juliana McElrath, Georgia D. Tomaras

Background

HVTN 100 evaluated the safety and immunogenicity of an HIV subtype C pox-protein vaccine regimen, investigating a 12-month booster to extend vaccine-induced immune responses.

Methods and findings

A phase 1–2 randomized double-blind placebo-controlled trial enrolled 252 participants (210 vaccine/42 placebo; median age 23 years; 43% female) between 9 February 2015 and 26 May 2015. Vaccine recipients received ALVAC-HIV (vCP2438) alone at months 0 and 1 and with bivalent subtype C gp120/MF59 at months 3, 6, and 12. Antibody (IgG, IgG3 binding, and neutralizing) and CD4+ T-cell (expressing interferon-gamma, interleukin-2, and CD40 ligand) responses were evaluated at month 6.5 for all participants and at months 12, 12.5, and 18 for a randomly selected subset. The primary analysis compared IgG binding antibody (bAb) responses and CD4+ T-cell responses to 3 vaccine-matched antigens at peak (month 6.5 versus 12.5) and durability (month 12 versus 18) timepoints; IgG responses to CaseA2_gp70_V1V2.B, a primary correlate of risk in RV144, were also compared at these same timepoints. Secondary and exploratory analyses compared IgG3 bAb responses, IgG bAb breadth scores, neutralizing antibody (nAb) responses, antibody-dependent cellular phagocytosis, CD4+ polyfunctionality responses, and CD4+ memory sub-population responses at the same timepoints. Vaccines were generally safe and well tolerated. During the study, there were 2 deaths (both in the vaccine group and both unrelated to study products). Ten participants became HIV-infected during the trial, 7% (3/42) of placebo recipients and 3% (7/210) of vaccine recipients. All 8 serious adverse events were unrelated to study products. Less waning of immune responses was seen after the fifth vaccination than after the fourth, with higher antibody and cellular response rates at month 18 than at month 12: IgG bAb response rates to 1086.C V1V2, 21.0% versus 9.7% (difference = 11.3%, 95% CI = 0.6%–22.0%, P = 0.039), and ZM96.C V1V2, 21.0% versus 6.5% (difference = 14.5%, 95% CI = 4.1%–24.9%, P = 0.004). IgG bAb response rates to all 4 primary V1V2 antigens were higher 2 weeks after the fifth vaccination than 2 weeks after the fourth vaccination: 87.7% versus 75.4% (difference = 12.3%, 95% CI = 1.7%–22.9%, P = 0.022) for 1086.C V1V2, 86.0% versus 63.2% (difference = 22.8%, 95% CI = 9.1%–36.5%, P = 0.001) for TV1c8.2.C V1V2, 67.7% versus 44.6% (difference = 23.1%, 95% CI = 10.4%–35.7%, P < 0.001) for ZM96.C V1V2, and 81.5% versus 60.0% (difference = 21.5%, 95% CI = 7.6%–35.5%, P = 0.002) for CaseA2_gp70_V1V2.B. IgG bAb response rates to the 3 primary vaccine-matched gp120 antigens were all above 90% at both peak timepoints, with no significant differences seen, except a higher response rate to ZM96.C gp120 at month 18 versus month 12: 64.5% versus 1.6% (difference = 62.9%, 95% CI = 49.3%–76.5%, P < 0.001). CD4+ T-cell response rates were higher at month 18 than month 12 for all 3 primary vaccine-matched antigens: 47.3% versus 29.1% (difference = 18.2%, 95% CI = 2.9%–33.4%, P = 0.021) for 1086.C, 61.8% versus 38.2% (difference = 23.6%, 95% CI = 9.5%–37.8%, P = 0.001) for TV1.C, and 63.6% versus 41.8% (difference = 21.8%, 95% CI = 5.1%–38.5%, P = 0.007) for ZM96.C, with no significant differences seen at the peak timepoints. Limitations were that higher doses of gp120 were not evaluated, this study was not designed to investigate HIV prevention efficacy, and the clinical significance of the observed immunological effects is uncertain.

Conclusions

In this study, a 12-month booster of subtype C pox-protein vaccines restored immune responses, and slowed response decay compared to the 6-month vaccination.

Trial registration

ClinicalTrials.gov NCT02404311.South African National Clinical Trials Registry (SANCTR number: DOH--27-0215-4796).

Secular trends in incidence of type 1 and type 2 diabetes in Hong Kong: A retrospective cohort study

Gi, 20/02/2020 - 23:00

by Andrea O. Y. Luk, Calvin Ke, Eric S. H. Lau, Hongjiang Wu, William Goggins, Ronald C. W. Ma, Elaine Chow, Alice P. S. Kong, Wing-Yee So, Juliana C. N. Chan

Background

There is very limited data on the time trend of diabetes incidence in Asia. Using population-level data, we report the secular trend of the incidence of type 1 and type 2 diabetes in Hong Kong between 2002 and 2015.

Methods and findings

The Hong Kong Diabetes Surveillance Database hosts clinical information on people with diabetes receiving care under the Hong Kong Hospital Authority, a statutory body that governs all public hospitals and clinics. Sex-specific incidence rates were standardised to the age structure of the World Health Organization population. Joinpoint regression analysis was used to describe incidence trends.A total of 562,022 cases of incident diabetes (type 1 diabetes [n = 2,426]: mean age at diagnosis is 32.5 years, 48.4% men; type 2 diabetes [n = 559,596]: mean age at diagnosis is 61.8 years, 51.9% men) were included. Among people aged <20 years, incidence of both type 1 and type 2 diabetes increased. For type 1 diabetes, the incidence increased from 3.5 (95% CI 2.2–4.9) to 5.3 (95% CI 3.4–7.1) per 100,000 person-years (average annual percentage change [AAPC] 3.6% [95% CI 0.2–7.1], p < 0.05) in boys and from 4.3 (95% CI 2.7–5.8) to 6.4 (95% CI 4.3–8.4) per 100,000 person-years (AAPC 4.7% [95% CI 1.7–7.7], p < 0.05] in girls; for type 2 diabetes, the incidence increased from 4.6 (95% CI 3.2–6.0) to 7.5 (95% CI 5.5–9.6) per 100,000 person-years (AAPC 5.9% [95% CI 3.4–8.5], p < 0.05) in boys and from 5.9 (95% CI 4.3–7.6) to 8.5 (95% CI 6.2–10.8) per 100,000 person-years (AAPC 4.8% [95% CI 2.7–7.0], p < 0.05) in girls. In people aged 20 to <40 years, incidence of type 1 diabetes remained stable, but incidence of type 2 diabetes increased over time from 75.4 (95% CI 70.1–80.7) to 110.8 (95% CI 104.1–117.5) per 100,000 person-years (AAPC 4.2% [95% CI 3.1–5.3], p < 0.05) in men and from 45.0 (95% CI 41.4–48.6) to 62.1 (95% CI 57.8–66.3) per 100,000 person-years (AAPC 3.3% [95% CI 2.3–4.2], p < 0.05) in women. In people aged 40 to <60 years, incidence of type 2 diabetes increased until 2011/2012 and then flattened. In people aged ≥60 years, incidence was stable in men and declined in women after 2011. No trend was identified in the incidence of type 1 diabetes in people aged ≥20 years. The present study is limited by its reliance on electronic medical records for identification of people with diabetes, which may result in incomplete capture of diabetes cases. The differentiation of type 1 and type 2 diabetes was based on an algorithm subject to potential misclassification.

Conclusions

There was an increase in incidence of type 2 diabetes in people aged <40 years and stabilisation in people aged ≥40 years. Incidence of type 1 diabetes continued to climb in people aged <20 years but remained constant in other age groups.

Digitally enabled aged care and neurological rehabilitation to enhance outcomes with Activity and MObility UsiNg Technology (AMOUNT) in Australia: A randomised controlled trial

Ma, 18/02/2020 - 23:00

by Leanne Hassett, Maayken van den Berg, Richard I. Lindley, Maria Crotty, Annie McCluskey, Hidde P. van der Ploeg, Stuart T. Smith, Karl Schurr, Kirsten Howard, Maree L. Hackett, Maggie Killington, Bert Bongers, Leanne Togher, Daniel Treacy, Simone Dorsch, Siobhan Wong, Katharine Scrivener, Sakina Chagpar, Heather Weber, Marina Pinheiro, Stephane Heritier, Catherine Sherrington

Background

Digitally enabled rehabilitation may lead to better outcomes but has not been tested in large pragmatic trials. We aimed to evaluate a tailored prescription of affordable digital devices in addition to usual care for people with mobility limitations admitted to aged care and neurological rehabilitation.

Methods and findings

We conducted a pragmatic, outcome-assessor-blinded, parallel-group randomised trial in 3 Australian hospitals in Sydney and Adelaide recruiting adults 18 to 101 years old with mobility limitations undertaking aged care and neurological inpatient rehabilitation. Both the intervention and control groups received usual multidisciplinary inpatient and post-hospital rehabilitation care as determined by the treating rehabilitation clinicians. In addition to usual care, the intervention group used devices to target mobility and physical activity problems, individually prescribed by a physiotherapist according to an intervention protocol, including virtual reality video games, activity monitors, and handheld computer devices for 6 months in hospital and at home. Co-primary outcomes were mobility (performance-based Short Physical Performance Battery [SPPB]; continuous version; range 0 to 3; higher score indicates better mobility) and upright time as a proxy measure of physical activity (proportion of the day upright measured with activPAL) at 6 months. The dataset was analysed using intention-to-treat principles. The trial was prospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12614000936628). Between 22 September 2014 and 10 November 2016, 300 patients (mean age 74 years, SD 14; 50% female; 54% neurological condition causing activity limitation) were randomly assigned to intervention (n = 149) or control (n = 151) using a secure online database (REDCap) to achieve allocation concealment. Six-month assessments were completed by 258 participants (129 intervention, 129 control). Intervention participants received on average 12 (SD 11) supervised inpatient sessions using 4 (SD 1) different devices and 15 (SD 5) physiotherapy contacts supporting device use after hospital discharge. Changes in mobility scores were higher in the intervention group compared to the control group from baseline (SPPB [continuous, 0–3] mean [SD]: intervention group, 1.5 [0.7]; control group, 1.5 [0.8]) to 6 months (SPPB [continuous, 0–3] mean [SD]: intervention group, 2.3 [0.6]; control group, 2.1 [0.8]; mean between-group difference 0.2 points, 95% CI 0.1 to 0.3; p = 0.006). However, there was no evidence of a difference between groups for upright time at 6 months (mean [SD] proportion of the day spent upright at 6 months: intervention group, 18.2 [9.8]; control group, 18.4 [10.2]; mean between-group difference −0.2, 95% CI −2.7 to 2.3; p = 0.87). Scores were higher in the intervention group compared to the control group across most secondary mobility outcomes, but there was no evidence of a difference between groups for most other secondary outcomes including self-reported balance confidence and quality of life. No adverse events were reported in the intervention group. Thirteen participants died while in the trial (intervention group: 9; control group: 4) due to unrelated causes, and there was no evidence of a difference between groups in fall rates (unadjusted incidence rate ratio 1.19, 95% CI 0.78 to 1.83; p = 0.43). Study limitations include 15%–19% loss to follow-up at 6 months on the co-primary outcomes, as anticipated; the number of secondary outcome measures in our trial, which may increase the risk of a type I error; and potential low statistical power to demonstrate significant between-group differences on important secondary patient-reported outcomes.

Conclusions

In this study, we observed improved mobility in people with a wide range of health conditions making use of digitally enabled rehabilitation, whereas time spent upright was not impacted.

Trial registration

The trial was prospectively registered with the Australian New Zealand Clinical Trials Register; ACTRN12614000936628

Estimating progress towards meeting women’s contraceptive needs in 185 countries: A Bayesian hierarchical modelling study

Ma, 18/02/2020 - 23:00

by Vladimíra Kantorová, Mark C. Wheldon, Philipp Ueffing, Aisha N. Z. Dasgupta

Background

Expanding access to contraception and ensuring that need for family planning is satisfied are essential for achieving universal access to reproductive healthcare services, as called for in the 2030 Agenda for Sustainable Development. Monitoring progress towards these outcomes is well established for women of reproductive age (15–49 years) who are married or in a union (MWRA). For those who are not, limited data and variability in data sources and indicator definitions make monitoring challenging. To our knowledge, this study is the first to provide data and harmonised estimates that enable monitoring for all women of reproductive age (15–49 years) (WRA), including unmarried women (UWRA). We seek to quantify the gaps that remain in meeting family-planning needs among all WRA.

Methods and findings

In a systematic analysis, we compiled a comprehensive dataset of family-planning indicators among WRA from 1,247 nationally representative surveys. We used a Bayesian hierarchical model with country-specific time trends to estimate these indicators, with 95% uncertainty intervals (UIs), for 185 countries. We produced estimates from 1990 to 2019 and projections from 2019 to 2030 of contraceptive prevalence and unmet need for family planning among MWRA, UWRA, and all WRA, taking into account the changing proportions that were married or in a union. The model accounted for differences in the prevalence of sexual activity among UWRA across countries.Among 1.9 billion WRA in 2019, 1.11 billion (95% UI 1.07–1.16) have need for family planning; of those, 842 million (95% UI 800–893) use modern contraception, and 270 million (95% UI 246–301) have unmet need for modern methods. Globally, UWRA represented 15.7% (95% UI 13.4%–19.4%) of all modern contraceptive users and 16.0% (95% UI 12.9%–22.1%) of women with unmet need for modern methods in 2019. The proportion of the need for family planning satisfied by modern methods, Sustainable Development Goals (SDG) indicator 3.7.1, was 75.7% (95% UI 73.2%–78.0%) globally, yet less than half of the need for family planning was met in Middle and Western Africa. Projections to 2030 indicate an increase in the number of women with need for family planning to 1.19 billion (95% UI 1.13–1.26) and in the number of women using modern contraception to 918 million (95% UI 840–1,001).The main limitations of the study are as follows: (i) the uncertainty surrounding estimates for countries with little or no data is large; and (ii) although some adjustments were made, underreporting of contraceptive use and needs is likely, especially among UWRA.

Conclusions

In this study, we observed that large gaps remain in meeting family-planning needs. The projected increase in the number of women with need for family planning will create challenges to expand family-planning services fast enough to fulfil the growing need. Monitoring of family-planning indicators for all women, not just MWRA, is essential for accurately monitoring progress towards universal access to sexual and reproductive healthcare services—including family planning—by 2030 in the SDG era with its emphasis on ‘leaving no one behind.’

Emerging priorities for HIV service delivery

Ve, 14/02/2020 - 23:00

by Nathan Ford, Elvin Geng, Tom Ellman, Catherine Orrell, Peter Ehrenkranz, Izukanji Sikazwe, Andreas Jahn, Miriam Rabkin, Stephen Ayisi Addo, Anna Grimsrud, Sydney Rosen, Isaac Zulu, William Reidy, Thabo Lejone, Tsitsi Apollo, Charles Holmes, Ana Francisca Kolling, Rosina Phate Lesihla, Huu Hai Nguyen, Baker Bakashaba, Lastone Chitembo, Ghion Tiriste, Meg Doherty, Helen Bygrave

Nathan Ford and co-authors discuss global priorities in the provision of HIV prevention and treatment services.

Impact of the announcement and implementation of the UK Soft Drinks Industry Levy on sugar content, price, product size and number of available soft drinks in the UK, 2015-19: A controlled interrupted time series analysis

Ma, 11/02/2020 - 23:00

by Peter Scarborough, Vyas Adhikari, Richard A. Harrington, Ahmed Elhussein, Adam Briggs, Mike Rayner, Jean Adams, Steven Cummins, Tarra Penney, Martin White

Background

Dietary sugar, especially in liquid form, increases risk of dental caries, adiposity, and type 2 diabetes. The United Kingdom Soft Drinks Industry Levy (SDIL) was announced in March 2016 and implemented in April 2018 and charges manufacturers and importers at £0.24 per litre for drinks with over 8 g sugar per 100 mL (high levy category), £0.18 per litre for drinks with 5 to 8 g sugar per 100 mL (low levy category), and no charge for drinks with less than 5 g sugar per 100 mL (no levy category). Fruit juices and milk-based drinks are exempt. We measured the impact of the SDIL on price, product size, number of soft drinks on the marketplace, and the proportion of drinks over the lower levy threshold of 5 g sugar per 100 mL.

Methods and findings

We analysed data on a total of 209,637 observations of soft drinks over 85 time points between September 2015 and February 2019, collected from the websites of the leading supermarkets in the UK. The data set was structured as a repeat cross-sectional study. We used controlled interrupted time series to assess the impact of the SDIL on changes in level and slope for the 4 outcome variables. Equivalent models were run for potentially levy-eligible drink categories (‘intervention’ drinks) and levy-exempt fruit juices and milk-based drinks (‘control’ drinks). Observed results were compared with counterfactual scenarios based on extrapolation of pre-SDIL trends. We found that in February 2019, the proportion of intervention drinks over the lower levy sugar threshold had fallen by 33.8 percentage points (95% CI: 33.3–34.4, p < 0.001). The price of intervention drinks in the high levy category had risen by £0.075 (£0.037–0.115, p < 0.001) per litre—a 31% pass through rate—whilst prices of intervention drinks in the low levy category and no levy category had fallen and risen by smaller amounts, respectively. Whilst the product size of branded high levy and low levy drinks barely changed after implementation of the SDIL (−7 mL [−23 to 11 mL] and 16 mL [6–27ml], respectively), there were large changes to product size of own-brand drinks with an increase of 172 mL (133–214 mL) for high levy drinks and a decrease of 141 mL (111–170 mL) for low levy drinks. The number of available drinks that were in the high levy category when the SDIL was announced was reduced by 3 (−6 to 12) by the implementation of the SDIL. Equivalent models for control drinks provided little evidence of impact of the SDIL. These results are not sales weighted, so do not give an account of how sugar consumption from drinks may have changed over the time period.

Conclusions

The results suggest that the SDIL incentivised many manufacturers to reduce sugar in soft drinks. Some of the cost of the levy to manufacturers and importers was passed on to consumers as higher prices but not always on targeted drinks. These changes could reduce population exposure to liquid sugars and associated health risks.

A multicomponent secondary school health promotion intervention and adolescent health: An extension of the SEHER cluster randomised controlled trial in Bihar, India

Ma, 11/02/2020 - 23:00

by Sachin Shinde, Helen A. Weiss, Prachi Khandeparkar, Bernadette Pereira, Amit Sharma, Rajesh Gupta, David A. Ross, George Patton, Vikram Patel

Background

Strengthening Evidence base on scHool-based intErventions for pRomoting adolescent health (SEHER) is a multicomponent, whole-school health promotion intervention delivered by a lay counsellor or a teacher in government-run secondary schools in Bihar, India. The objective of this study is to examine the effects of the intervention after two years of follow-up and to evaluate the consistency of the findings observed over time.

Methods and findings

We conducted a cluster randomised trial in which 75 schools were randomised (1:1:1) to receive the SEHER intervention delivered by a lay counsellor (SEHER Mitra [SM]) or a teacher (Teacher as SEHER Mitra [TSM]), respectively, alongside a standardised, classroom-based life skills Adolescence Education Program (AEP), compared to AEP alone (control group). The trial design was a repeat cross-sectional study. Students enrolled in grade 9 (aged 13–15 years) in the 2015–2016 academic year were exposed to the intervention for two years and the outcome assessment was conducted at three time points─at baseline in June 2015; 8-months follow-up in March 2016, when the students were still in grade 9; and endpoint at 17-months follow-up in December 2016 (when the students were in grade 10), the results of which are presented in this paper. The primary outcome, school climate, was measured with the Beyond Blue School Climate Questionnaire (BBSCQ). Intervention effects were estimated using mixed-effects linear or logistic regression, including a random effect to adjust for within-school clustering, minimisation variables, baseline cluster-level score of the outcome, and sociodemographic characteristics. In total, 15,232 students participated in the 17-month survey. Compared with the control group, the participants in the SM intervention group reported improvements in school climate (adjusted mean difference [aMD] = 7.33; 95% CI: 6.60–8.06; p < 0.001) and most secondary outcomes (depression: aMD = −4.64; 95% CI: −5.83–3.45; p < 0.001; attitude towards gender equity: aMD = 1.02; 95% CI: 0.65–1.40; p < 0.001; frequency of bullying: aMD = −2.77; 95% CI: −3.40 to −2.14; p < 0.001; violence victimisation: odds ratio [OR] = 0.08; 95% CI: 0.04–0.14; p < 0.001; and violence perpetration: OR = 0.16; 95% CI: 0.09–0.29; p < 0.001). There was no evidence of an intervention effect in the TSM group compared with control group. The effects of the lay counsellor–delivered intervention were larger for most outcomes at 17-months follow-up compared with those at 8 months: school climate (effect size [ES; 95% CI] = 2.23 [1.97–2.50] versus 1.88 [1.44–2.32], p < 0.001); depression (ES [95% CI] = −1.19 [−1.56 to −0.82] versus −0.27 [−0.44 to −0.11], p < 0.001); attitude towards gender equity (ES [95% CI] = 0.53 [0.27–0.79] versus 0.23 [0.10–0.36], p < 0.001); bullying (ES [95% CI] = −2.22 [−2.84 to −1.60] versus −0.47 [−0.61 to −0.33], p < 0.001); violence victimisation (OR [95% CI] = 0.08 [0.04–0.14] versus 0.62 [0.46–0.84], p < 0.001); and violence perpetration (OR [95% CI] = 0.16 [0.09–0.29] versus 0.68 [0.48–0.96], p < 0.001), suggesting incremental benefits with an extended intervention. A limitation of the study is that 27% of baseline participants did not complete the 17-month outcome assessment.

Conclusions

The trial showed that the second-year outcomes were similar to the first-year outcomes, with no effect of the teacher-led intervention and larger benefits on school climate and adolescent health accruing from extending lay counsellor–delivered intervention.

Trial registration

ClinicalTrials.gov NCT02907125.

An evaluation of Chile’s Law of Food Labeling and Advertising on sugar-sweetened beverage purchases from 2015 to 2017: A before-and-after study

Ma, 11/02/2020 - 23:00

by Lindsey Smith Taillie, Marcela Reyes, M. Arantxa Colchero, Barry Popkin, Camila Corvalán

Background

Chile’s Law of Food Labeling and Advertising, implemented in 2016, was the first national regulation to jointly mandate front-of-package warning labels, restrict child-directed marketing, and ban sales in schools of all foods and beverages containing added sugars, sodium, or saturated fats that exceed set nutrient or calorie thresholds. The objective of this study is to evaluate the impact of this package of policies on household beverage purchases.

Method and findings

In this observational study, monthly longitudinal data on packaged beverage purchases were collected from urban-dwelling households (n = 2,383) participating in the Kantar WordPanel Chile Survey from January 1, 2015, to December 31, 2017. Beverage purchases were linked to nutritional information at the product level, reviewed by a team of nutritionists, and categorized as “high-in” or “not high-in” according to whether they contained high levels of nutrients of concern (i.e., sugars, sodium, saturated fat, or energy) according to Chilean nutrient thresholds and were thus subject to the law’s warning label, marketing restriction, and school sales ban policies. The majority of high-in beverages were categorized as such because of high sugar content. We used fixed-effects models to compare the observed volume as well as calorie and sugar content of postregulation beverage purchases to a counterfactual based on preregulation trends, overall and by household-head educational attainment. Of households included in the study, 37% of household heads had low education (less than high school), 40% had medium education (graduated high school), and 23% had high education (graduated college), with the sample becoming more educated over the study period. Compared to the counterfactual, the volume of high-in beverage purchases decreased 22.8 mL/capita/day, postregulation (95% confidence interval [CI] −22.9 to −22.7; p < 0.001), or 23.7% (95% CI −23.8% to −23.7%). High-educated and low-educated households showed similar absolute reductions in high-in beverage purchases (approximately 27 mL/capita/day; p < 0.001), but for high-educated households this amounted to a larger relative decline (−28.7%, 95% CI −28.8% to −28.6%) compared to low-educated households (−21.5%, 95% CI −21.6% to −21.4%), likely because of the high-educated households’ lower level of high-in beverage purchases in the preregulation period. Calories from high-in beverage purchases decreased 11.9 kcal/capita/day (95% CI −12.0 to −11.9; p < 0.001) or 27.5% (95% CI −27.6% to −27.5%). Calories purchased from beverages classified as “not high-in” increased 5.7 kcal/capita/day (95% CI 5.7–5.7; p < 0.001), or 10.8% (10.8%–10.8%). Calories from total beverage purchases decreased 7.4 kcal/capita/day (95% CI −7.4 to −7.3; p < 0.001), or 7.5% (95% CI −7.6% to −7.5%). A key limitation of this study is the inability to assess causality because of its observational nature. We also cannot determine whether observed changes in purchases are due to reformulation or consumer behavioral change, nor can we parse out the effects of the labeling, marketing, and school sales ban policies.

Conclusions

Purchases of high-in beverages significantly declined following implementation of Chile’s Law of Food Labeling and Advertising; these reductions were larger than those observed from single, standalone policies, including sugar-sweetened-beverage taxes previously implemented in Latin America. Future research should evaluate the effects of Chile’s policies on purchases of high-in foods, dietary intake, and long-term purchasing changes.

The effect of assessing genetic risk of prostate cancer on the use of PSA tests in primary care: A cluster randomized controlled trial

Ve, 07/02/2020 - 23:00

by Jacob Fredsøe, Jan Koetsenruyter, Peter Vedsted, Pia Kirkegaard, Michael Væth, Adrian Edwards, Torben F. Ørntoft, Karina D. Sørensen, Flemming Bro

Background

Assessing genetic lifetime risk for prostate cancer has been proposed as a means of risk stratification to identify those for whom prostate-specific antigen (PSA) testing is likely to be most valuable. This project aimed to test the effect of introducing a genetic test for lifetime risk of prostate cancer in general practice on future PSA testing.

Methods and findings

We performed a cluster randomized controlled trial with randomization at the level of general practices (73 in each of two arms) in the Central Region (Region Midtjylland) of Denmark. In intervention practices, men were offered a genetic test (based on genotyping of 33 risk-associated single nucleotide polymorphisms) in addition to the standard PSA test that informed them about lifetime genetic risk of prostate cancer and distinguished between “normal” and “high” risk. The primary outcome was the proportion of men having a repeated PSA test within 2 years. A multilevel logistic regression model was used to test the association.After applying the exclusion criteria, 3,558 men were recruited in intervention practices, with 1,235 (34.7%) receiving the genetic test, and 4,242 men were recruited in control practices. Men with high genetic risk had a higher propensity for repeated PSA testing within 2 years than men with normal genetic risk (odds ratio [OR] = 8.94, p < 0.01). The study was conducted in routine practice and had some selection bias, which is evidenced by the relatively large proportion of younger and higher income participants taking the genetic test.

Conclusions

Providing general practitioners (GPs) with access to a genetic test to assess lifetime risk of prostate cancer did not reduce the overall number of future PSA tests. However, among men who had a genetic test, knowledge of genetic risk significantly influenced future PSA testing.

Trial registration

This study is registered with ClinicalTrials.gov, number NCT01739062.

Improving air quality needs to be a policy priority for governments globally

Gi, 06/02/2020 - 23:00

by Aziz Sheikh

In this Perspective, Aziz Sheikh discusses the importance of research to understand the impact of air pollution on human health, commenting on a study by Yaohua Tian and colleagues that examined associations between ambient air quality and risk of hospitalization for pneumonia in adults in China

Improving air quality needs to be a policy priority for governments globally

Gi, 06/02/2020 - 23:00

by Aziz Sheikh

In this Perspective, Aziz Sheikh discusses the importance of research to understand the impact of air pollution on human health, commenting on a study by Yaohua Tian and colleagues that examined associations between ambient air quality and risk of hospitalization for pneumonia in adults in China

Association of coincident self-reported mental health problems and alcohol intake with all-cause and cardiovascular disease mortality: A Norwegian pooled population analysis

Lu, 03/02/2020 - 23:00

by Eirik Degerud, Gudrun Høiseth, Jørg Mørland, Inger Ariansen, Sidsel Graff-Iversen, Eivind Ystrom, Luisa Zuccolo, Øyvind Næss

Background

The disease burden attributable to mental health problems and to excess or harmful alcohol use is considerable. Despite a strong relationship between these 2 important factors in population health, there are few studies quantifying the mortality risk associated with their co-occurrence in the general population. The aim of this study was therefore to investigate cardiovascular disease (CVD) and all-cause mortality according to self-reported mental health problems and alcohol intake in the general population.

Methods and findings

We followed 243,372 participants in Norwegian health surveys (1994–2002) through 2014 for all-cause and CVD mortality by data linkage to national registries. The mean (SD) age at the time of participation in the survey was 43.9 (10.6) years, and 47.8% were men. During a mean (SD) follow-up period of 16.7 (3.2) years, 6,587 participants died from CVD, and 21,376 died from all causes. Cox models estimated hazard ratios (HRs) with 95% CIs according to a mental health index (low, 1.00–1.50; high, 2.01–4.00; low score is favourable) based on the General Health Questionnaire and the Hopkins Symptom Checklist, and according to self-reported alcohol intake (low, <2; light, 2–11.99; moderate, 12–23.99; high, ≥24 grams/day). HRs were adjusted for age, sex, educational level, marital status, and CVD risk factors. Compared to a reference group with low mental health index score and low alcohol intake, HRs (95% CIs) for all-cause mortality were 0.93 (0.89, 0.97; p = 0.001), 1.00 (0.92, 1.09; p = 0.926), and 1.14 (0.96, 1.35; p = 0.119) for low index score combined with light, moderate, and high alcohol intake, respectively. HRs (95% CIs) were 1.22 (1.14, 1.31; p < 0.001), 1.24 (1.15, 1.33; p < 0.001), 1.43 (1.23, 1.66; p < 0.001), and 2.29 (1.87, 2.80; p < 0.001) for high index score combined with low, light, moderate, and high alcohol intake, respectively. For CVD mortality, HRs (95% CIs) were 0.93 (0.86, 1.00; p = 0.058), 0.90 (0.76, 1.07; p = 0.225), and 0.95 (0.67, 1.33; p = 0.760) for a low index score combined with light, moderate, and high alcohol intake, respectively, and 1.11 (0.98, 1.25; p = 0.102), 0.97 (0.83, 1.13; p = 0.689), 1.01 (0.71, 1.44; p = 0.956), and 1.78 (1.14, 2.78; p = 0.011) for high index score combined with low, light, moderate, and high alcohol intake, respectively. HRs for the combination of a high index score and high alcohol intake (HRs: 2.29 for all-cause and 1.78 for CVD mortality) were 64% (95% CI 53%, 74%; p < 0.001) and 69% (95% CI 42%, 97%; p < 0.001) higher than expected for all-cause mortality and CVD mortality, respectively, under the assumption of a multiplicative interaction structure. A limitation of our study is that the findings were based on average reported intake of alcohol without accounting for the drinking pattern.

Conclusions

In the general population, the mortality rates associated with more mental health problems and a high alcohol intake were increased when the risk factors occurred together.

Evaluation of a clinical decision rule to guide antibiotic prescription in children with suspected lower respiratory tract infection in The Netherlands: A stepped-wedge cluster randomised trial

Ve, 31/01/2020 - 23:00

by Josephine S. van de Maat, Daphne Peeters, Daan Nieboer, Anne-Marie van Wermeskerken, Frank J. Smit, Jeroen G. Noordzij, Gerdien Tramper-Stranders, Gertjan J. A. Driessen, Charlie C. Obihara, Jeanine Punt, Johan van der Lei, Suzanne Polinder, Henriette A. Moll, Rianne Oostenbrink

Background

Optimising the use of antibiotics is a key component of antibiotic stewardship. Respiratory tract infections (RTIs) are the most common reason for antibiotic prescription in children, even though most of these infections in children under 5 years are viral. This study aims to safely reduce antibiotic prescriptions in children under 5 years with suspected lower RTI at the emergency department (ED), by implementing a clinical decision rule.

Methods and findings

In a stepped-wedge cluster randomised trial, we included children aged 1–60 months presenting with fever and cough or dyspnoea to 8 EDs in The Netherlands. The EDs were of varying sizes, from diverse geographic and demographic regions, and of different hospital types (tertiary versus general). In the pre-intervention phase, children received usual care, according to the Dutch and NICE guidelines for febrile children. During the intervention phase, a validated clinical prediction model (Feverkidstool) including clinical characteristics and C-reactive protein (CRP) was implemented as a decision rule guiding antibiotic prescription. The intervention was that antibiotics were withheld in children with a low or intermediate predicted risk of bacterial pneumonia (≤10%, based on Feverkidstool). Co-primary outcomes were antibiotic prescription rate and strategy failure. Strategy failure was defined as secondary antibiotic prescriptions or hospitalisations, persistence of fever or oxygen dependency up to day 7, or complications. Hospitals were randomly allocated to 1 sequence of treatment each, using computer randomisation. The trial could not be blinded. We used multilevel logistic regression to estimate the effect of the intervention, clustered by hospital and adjusted for time period, age, sex, season, ill appearance, and fever duration; predicted risk was included in exploratory analysis. We included 999 children (61% male, median age 17 months [IQR 9 to 30]) between 1 January 2016 and 30 September 2018: 597 during the pre-intervention phase and 402 during the intervention phase. Most children (77%) were referred by a general practitioner, and half of children were hospitalised. Intention-to-treat analyses showed that overall antibiotic prescription was not reduced (30% to 25%, adjusted odds ratio [aOR] 1.07 [95% CI 0.57 to 2.01, p = 0.75]); strategy failure reduced from 23% to 16% (aOR 0.53 [95% CI 0.32 to 0.88, p = 0.01]). Exploratory analyses showed that the intervention influenced risk groups differently (p < 0.01), resulting in a reduction in antibiotic prescriptions in low/intermediate-risk children (17% to 6%; aOR 0.31 [95% CI 0.12 to 0.81, p = 0.02]) and a non-significant increase in the high-risk group (47% to 59%; aOR 2.28 [95% CI 0.84 to 6.17, p = 0.09]). Two complications occurred during the trial: 1 admission to the intensive care unit during follow-up and 1 pleural empyema at day 10 (both unrelated to the study intervention). Main limitations of the study were missing CRP values in the pre-intervention phase and a prolonged baseline period due to logistical issues, potentially affecting the power of our study.

Conclusions

In this multicentre ED study, we observed that a clinical decision rule for childhood pneumonia did not reduce overall antibiotic prescription, but that it was non-inferior to usual care. Exploratory analyses showed fewer strategy failures and that fewer antibiotics were prescribed in low/intermediate-risk children, suggesting improved targeting of antibiotics by the decision rule.

Trial registration

Netherlands Trial Register NTR5326.