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EXPLORE IDM’S CURRENT RESEARCH PUBLICATIONS

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Ben J Brintz, Benjamin Haaland, Joel Howard, Dennis L Chao, Joshua L Proctor, Ashraful I Khan, Sharia M Ahmed, Lindsay T Keegan, Tom Greene

ELIFE

Traditional clinical prediction models focus on parameters of the individual patient. For infectious diseases, sources external to the patient, including characteristics of prior patients and seasonal factors, may improve predictive performance. We describe the development of a predictive model that integrates multiple sources of data in a principled statistical framework using a post-test odds formulation. Our method enables electronic real-time updating and flexibility, such that components can be included or excluded according to data availability. We apply this method to the prediction of etiology of pediatric diarrhea, where 'pre-test’ epidemiologic data may be highly informative. Diarrhea has a high burden in low-resource settings, and antibiotics are often over-prescribed. We demonstrate that our integrative method outperforms traditional prediction in accurately identifying cases with a viral etiology, and show that its clinical application, especially when used with an additional diagnostic test, could result in a 61% reduction in inappropriately prescribed antibiotics.

Edinah Mudimu, Kathryn Peebles, Zindoga Mukandavire, Emily Nightingale, Monisha Sharma, Graham F. Medley, Daniel J. Klein, Katharine Kripke, Anna Bershteyn 

PLOS ONE

Background
Pre-exposure prophylaxis (PrEP) is highly effective in preventing HIV and has the potential to significantly impact the HIV epidemic. Given limited resources for HIV prevention, identifying PrEP provision strategies that maximize impact is critical.

Methods
We used a stochastic individual-based network model to evaluate the direct (infections prevented among PrEP users) and indirect (infections prevented among non-PrEP users as a result of PrEP) benefits of PrEP, the person-years of PrEP required to prevent one HIV infection, and the community-level impact of providing PrEP to populations defined by gender and age in western Kenya and South Africa. We examined sensitivity of results to scale-up of antiretroviral therapy (ART) and voluntary medical male circumcision (VMMC) by comparing two scenarios: maintaining current coverage (“status quo”) and rapid scale-up to meet programmatic targets (“fast-track”).

Results
The community-level impact of PrEP was greatest among women aged 15–24 due to high incidence, while PrEP use among men aged 15–24 yielded the highest proportion of indirect infections prevented in the community. These indirect infections prevented continue to increase over time (western Kenya: 0.4–5.5 (status quo); 0.4–4.9 (fast-track); South Africa: 0.5–1.8 (status quo); 0.5–3.0 (fast-track)) relative to direct infections prevented among PrEP users. The number of person-years of PrEP needed to prevent one HIV infection was lower (59 western Kenya and 69 in South Africa in the status quo scenario; 201 western Kenya and 87 in South Africa in the fast-track scenario) when PrEP was provided only to women compared with only to men over time horizons of up to 5 years, as the indirect benefits of providing PrEP to men accrue in later years.

Conclusions
Providing PrEP to women aged 15–24 prevents the greatest number of HIV infections per person-year of PrEP, but PrEP provision for young men also provides indirect benefits to women and to the community overall. This finding supports existing policies that prioritize PrEP use for young women, while also illuminating the community-level benefits of PrEP availability for men when resources permit.

Monisha Sharma, PhD, Edinah Mudimu, PhD Kate Simeon, MD, Anna Bershteyn, PhD, Jienchi Dorward, MBChB, Lauren R Violette, MPH, Adam Akullian, PhD, Prof Salim S Abdool Karim, MBBCH, Prof Connie Celum, MD, Nigel Garrett, MBBS, Paul K Drain, MD

THE LANCET HIV

Background
The number of people on antiretroviral therapy (ART) requiring treatment monitoring in low-resource settings is rapidly increasing. Point-of-care (POC) testing for ART monitoring might alleviate burden on centralised laboratories and improve clinical outcomes, but its cost-effectiveness is unknown.


Methods
We used cost and effectiveness data from the STREAM trial in South Africa (February, 2017–October, 2018), which evaluated POC testing for viral load, CD4 count, and creatinine, with task shifting from professional to lower-cadre registered nurses compared with laboratory-based testing without task shifting (standard of care). We parameterised an agent-based network model, EMOD-HIV, to project the impact of implementing this intervention in South Africa over 20 years, simulating approximately 175 000 individuals per run. We assumed POC monitoring increased viral suppression by 9 percentage points, enrolment into community-based ART delivery by 25 percentage points, and switching to second-line ART by 1 percentage point compared with standard of care, as reported in the STREAM trial. We evaluated POC implementation in varying clinic sizes (10–50 patient initiating ART per month). We calculated incremental cost-effectiveness ratios (ICERs) and report the mean and 90% model variability of 250 runs, using a cost-effectiveness threshold of US$500 per disability-adjusted life-year (DALY) averted for our main analysis.


Findings
POC testing at 70% coverage of patients on ART was projected to reduce HIV infections by 4·5% (90% model variability 1·6 to 7·6) and HIV-related deaths by 3·9% (2·0 to 6·0). In clinics with 30 ART initiations per month, the intervention had an ICER of $197 (90% model variability –27 to 863) per DALY averted; results remained cost-effective when varying background viral suppression, ART dropout, intervention effectiveness, and reduction in HIV transmissibility. At higher clinic volumes (≥40 ART initiations per month), POC testing was cost-saving and at lower clinic volumes (20 ART initiations per month) the ICER was $734 (93 to 2569). A scenario that assumed POC testing did not increase enrolment into community ART delivery produced ICERs that exceeded the cost-effectiveness threshold for all clinic volumes.


Interpretation
POC testing is a promising strategy to cost-effectively improve patient outcomes in moderately sized clinics in South Africa. Results are most sensitive to changes in intervention impact on enrolment into community-based ART delivery.


Funding
National Institutes of Health.

BMC HEALTH SERVICES RESEARCH

Background

Malaria incidence has plateaued in Sub-Saharan Africa despite Seasonal Malaria Chemoprevention’s (SMC) introduction. Community health workers (CHW) use a door-to-door delivery strategy to treat children with SMC drugs, but for SMC to be as effective as in clinical trials, coverage must be high over successive seasons.

Methods

We developed and used a microplanning model that utilizes population raster to estimate population size, generates optimal households visit itinerary, and quantifies SMC coverage based on CHWs’ time investment for treatment and walking. CHWs’ performance under current SMC deployment mode was assessed using CHWs’ tracking data and compared to microplanning in villages with varying demographics and geographies.

Results

Estimates showed that microplanning significantly reduces CHWs’ walking distance by 25%, increases the number of visited households by 36% (p < 0.001) and increases SMC coverage by 21% from 37.3% under current SMC deployment mode up to 58.3% under microplanning (p < 0.001). Optimal visit itinerary alone increased SMC coverage up to 100% in small villages whereas in larger or hard-to-reach villages, filling the gap additionally needed an optimization of the CHW ratio.

Conclusion

We estimate that for a pair of CHWs, the daily optimal number of visited children (assuming 8.5mn spent per child) and walking distance should not exceed 45 (95% CI 27–62) and 5 km (95% CI 3.2–6.2) respectively. Our work contributes to extend SMC coverage by 21–63% and may have broader applicability for other community health programs.

Amelie O von Saint Andre-von Arnim, Rashmi K Kumar, Assaf P. Oron, Quynh-Uyen P Nguyen, Daniel M Mutonga, Jerry Zimmerman, Judd L Walson 

PEDIATRIC CRITICAL CARE MEDICINE

Objectives: To determine the feasibility of having caregivers assist in recognition of clinical deterioration in children hospitalized with febrile illness in a resource-limited setting.

Design: Single-center, prospective, interventional pilot study.

Setting: General pediatric wards at Kenyatta National Hospital, Nairobi, Kenya's largest public tertiary-care hospital.

Patients: Children hospitalized with acute febrile illness, accompanied by caregivers available at the bedside for 24 hours soon after hospital admission.

Interventions: Caregivers were trained to recognize signs of critical illness using the Family-Assisted Severe Febrile Illness Therapy tool, which quantifies patients' work of breathing, mental status, and perfusion, producing color-coded flags to signal illness severity. Caregivers' Family-Assisted Severe Febrile Illness Therapy assessments were compared with healthcare professional assessments and to established Pediatric Early Warning Scores (PEWS). An initial study stage was followed by refinement of training and a larger second stage with intervention/control arms.

Measurements and main results: A total of 107 patient/caregiver pairs were enrolled in the interventional arm; 106 caregivers underwent Family-Assisted Severe Febrile Illness Therapy training and were included in the analysis. Patient characteristics included median age 1.1 years (0.2-10 yr), 55 (52%) female, and diagnoses: pneumonia (64 [60%]), meningitis (38 [36%]), gastroenteritis (24 [23%]), and malaria (21 [20%]). Most caregivers had primary (34 [32%]) or secondary (53 [50%]) school education. Fourteen of 106 patients (13%) died during their stay, six within 2 days. Across all severity levels, caregiver Family-Assisted Severe Febrile Illness Therapy assessments matched professionals in 87% and 94% for stages 1 and 2, respectively. Caregiver Family-Assisted Severe Febrile Illness Therapy assessments had a moderate to strong correlation with coinciding Pediatric Early Warning Scores and were sensitive to life-threatening deterioration: for all six patients who died within 2 days of admission, caregiver assessment reached the highest alert level.

Conclusions: Caregiver involvement in recognition of critical illness in hospitalized children in low-resource settings may be feasible. This may facilitate earlier detection of clinical deterioration where staffing is severely limited by constrained resources. Further validation of the Family-Assisted Severe Febrile Illness Therapy tool is warranted, followed by its application in a larger multisite patient population to assess provider response and associated clinical outcomes.

Victoria Nembaware, Gaston K. Mazandu, Jade Hotchkiss, Jean-Michel Safari Serufuri, Jill Kent, Andre Pascal Kengne, Kofi Anie, Nchangwi Syntia Munung, Daima Bukini, Valentina Josiane Ngo Bitoungui, Deogratias Munube, Uzima Chirwa, Catherine Chunda-Liyoka, Agnes Jonathan, Miriam V. Flor-Park, Kevin Kum Esoh, Mario Jonas, Khuthala Mnika, Chandré Oosterwyk, Upendo Masamu, Jack Morrice, Annette Uwineza, Arthemon Nguweneza, Kambe Banda, Isaac Nyanor, David Nana Adjei, Nathan Edward Siebu, Malula Nkanyemka, Patience Kuona, Bamidele O. Tayo, Andrew Campbell, Assaf P. Oron, Obiageli E. Nnodu, Vivian Painstil, Julie Makani, Nicola Mulder, Ambroise Wonkam

OMICS

Sickle cell disease (SCD) is one of the most common blood disorders impacting planetary health. Over 300,000 newborns are diagnosed with SCD each year globally, with an increasing trend. The sickle cell disease ontology (SCDO) is the most comprehensive multidisciplinary SCD knowledge portal. The SCDO was collaboratively developed by the SCDO working group, which includes experts in SCD and data standards from across the globe. This expert review presents highlights and lessons learned from the fourth SCDO workshop that marked the beginning of applications toward planetary health impact, and with an eye to empower and cultivate multisite SCD collaborative research. The workshop was organized by the Sickle Africa Data Coordinating Center (SADaCC) and attended by 44 participants from 14 countries, with 2 participants connecting remotely. Notably, from the standpoint of democratizing and innovating scientific meeting design, an SCD patient advocate also presented at the workshop, giving a broader real-life perspective on patients' aspirations, needs, and challenges. A major component of the workshop was new approaches to harness SCDO to harmonize data elements used by different studies. This was facilitated by a web-based platform onto which participants uploaded data elements from previous or ongoing SCD-relevant research studies before the workshop, making multisite collaborative research studies based on existing SCD data possible, including multisite cohort, SCD global clinical trials, and SCD community engagement approaches. Trainees presented proposals for systematic literature reviews in key SCD research areas. This expert review emphasizes potential and prospects of SCDO-enabled data standards and harmonization to facilitate large-scale global SCD collaborative initiatives. As the fields of public and global health continue to broaden toward planetary health, the SCDO is well poised to play a prominent role to decipher SCD pathophysiology further, and co-design diagnostics and therapeutics innovation in the field.

INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES

Background

Absolute numbers of COVID-19 cases and deaths reported to date in the sub-Saharan Africa (SSA) region have been significantly lower than those across the Americas, Asia, and Europe. As a result, there has been limited information about the demographic and clinical characteristics of deceased cases in the region, as well as the impacts of different case management strategies.

Methods

Data from deceased cases reported across SSA through May 10, 2020 and from hospitalized cases in Burkina Faso through April 15, 2020 were analyzed. Demographic, epidemiological, and clinical information on deceased cases in SSA was derived through a line-list of publicly available information and, for cases in Burkina Faso, from aggregate records at the Centre Hospitalier Universitaire de Tengandogo in Ouagadougou. A synthetic case population was derived probabilistically using distributions of age, sex, and underlying conditions from populations of West African countries to assess individual risk factors and treatment effect sizes. Logistic regression analysis was conducted to evaluate the adjusted odds of survival for patients receiving oxygen therapy or convalescent plasma, based on therapeutic effectiveness observed for other respiratory illnesses.

Results

Across SSA, deceased cases for which demographic data are available have been predominantly male (63/103, 61.2%) and over 50 years of age (59/75, 78.7%). In Burkina Faso, specifically, the majority of deceased cases either did not seek care at all or were hospitalized for a single day (59.4%, 19/32); hypertension and diabetes were often reported as underlying conditions. After adjustment for sex, age, and underlying conditions in the synthetic case population, the odds of mortality for cases not receiving oxygen therapy was significantly higher than those receiving oxygen, such as due to disruptions to standard care (OR: 2.07; 95% CI: 1.56 – 2.75). Cases receiving convalescent plasma had 50% reduced odds of mortality than those who did not (95% CI: 0.24 – 0.93).

Conclusions

Investment in sustainable production and maintenance of supplies for oxygen therapy, along with messaging around early and appropriate use for healthcare providers, caregivers, and patients could reduce COVID-19 deaths in SSA. Further investigation into convalescent plasma is warranted, as data on its effectiveness specifically in treating COVID-19 becomes available. The success of supportive or curative clinical interventions will depend on earlier treatment seeking, such that community engagement and risk communication will be critical components of the response.

Anna Bershteyn, Monisha Sharma, Adam Akullian, Kathryn Peebles, Supriya Sarkar, R Scott Braithwaite, Edinah Mudimu

JOURNAL OF THE INTERNATIONAL AIDS SOCIETY

Introduction

Over one hundred implementation studies of HIV pre‐exposure prophylaxis (PrEP) are completed, underway or planned. We synthesized evidence from these studies to inform mathematical modelling of the prevention cascade for oral and long‐acting PrEP in the setting of western Kenya, one of the world’s most heavily HIV‐affected regions.

Methods

We incorporated steps of the PrEP prevention cascade – uptake, adherence, retention and re‐engagement after discontinuation – into EMOD‐HIV, an open‐source transmission model calibrated to the demography and HIV epidemic patterns of western Kenya. Early PrEP implementation research from East Africa was used to parameterize prevention cascades for oral PrEP as currently implemented, delivery innovations for oral PrEP, and future long‐acting PrEP. We compared infections averted by PrEP at the population level for different cascade assumptions and sub‐populations on PrEP. Analyses were conducted over the 2020 to 2040 time horizon, with additional sensitivity analyses for the time horizon of analysis and the time when long‐acting PrEP becomes available.

Results

The maximum impact of oral PrEP diminished by over 98% across all prevention cascades, with the exception of long‐acting PrEP under optimistic assumptions about uptake and re‐engagement after discontinuation. Long‐acting PrEP had the highest population‐level impact, even after accounting for possible delays in product availability, primarily because its effectiveness does not depend on drug adherence. Retention was the most significant cascade step reducing the potential impact of long‐acting PrEP. These results were robust to assumptions about the sub‐populations receiving PrEP, but were highly influenced by assumptions about re‐initiation of PrEP after discontinuation, about which evidence was sparse.

Conclusions

Implementation challenges along the prevention cascade compound to diminish the population‐level impact of oral PrEP. Long‐acting PrEP is expected to be less impacted by user uptake and adherence, but it is instead dependent on product availability in the short term and retention in the long term. To maximize the impact of long‐acting PrEP, ensuring timely product approval and rollout is critical. Research is needed on strategies to improve retention and patterns of PrEP re‐initiation.

Assaf P. Oron, Dennis L. Chao, Echezona E. Ezeanolue, Loveth N. Ezenwa, Frédéric B. Piel, Osifo Telison Ojogun, Sophie Uyoga, Thomas N. Williams & Obiageli E. Nnodu 

BMC MEDICINE

Background

Most of the world’s sickle cell disease (SCD) burden is in Africa, where it is a major contributor to child morbidity and mortality. Despite the low cost of many preventive SCD interventions, insufficient resources have been allocated, and progress in alleviating the SCD burden has lagged behind other public-health efforts in Africa. The recent announcement of massive new funding for research into curative SCD therapies is encouraging in the long term, but over the next few decades, it is unlikely to help Africa’s SCD children substantially.

Main discussion

A major barrier to progress has been the absence of large-scale early-life screening. Most SCD deaths in Africa probably occur before cases are even diagnosed. In the last few years, novel inexpensive SCD point-of-care test kits have become widely available and have been deployed successfully in African field settings. These kits could potentially enable universal early SCD screening. Other recent developments are the expansion of the pneumococcal conjugate vaccine towards near-universal coverage, and the demonstrated safety, efficacy, and increasing availability and affordability of hydroxyurea across the continent. Most elements of standard healthcare for SCD children that are already proven to work in the West, could and should now be implemented at scale in Africa. National and continental SCD research and care networks in Africa have also made substantial progress, assembling care guidelines and enabling the deployment and scale-up of SCD public-health systems. Substantial logistical, cultural, and awareness barriers remain, but with sufficient financial and political will, similar barriers have already been overcome in efforts to control other diseases in Africa.

Conclusion and recommendations

Despite remaining challenges, several high-SCD-burden African countries have the political will and infrastructure for the rapid implementation and scale-up of comprehensive SCD childcare programs. A globally funded effort starting with these countries and expanding elsewhere in Africa and to other high-burden countries, including India, could transform the lives of SCD children worldwide and help countries to attain their Sustainable Development Goals. This endeavor would also require ongoing research focused on the unique needs and challenges of SCD patients, and children in particular, in regions of high prevalence.

Laura A Skrip PhD, Jamie Bedson MSSc, Sharon Abramowitz PhD, Mohammed B Jalloh MPH, Saiku Bah MSc, Mohamed F Jalloh MPH, Ollin Demian Langle-Chimal MSc, Nicholas Cheney PhD, LaurentHébert-Dufresne PhD, Benjamin M Althouse PhD

THE LANCET PLANETARY HEALTH

Background

The west African Ebola epidemic (2014–15) necessitated behaviour change in settings with prevalent and pre-existing unmet needs as well as extensive mechanisms for local community action. We aimed to assess spatial and temporal trends in community-reported needs and associations with behaviour change, community engagement, and the overall outbreak situation in Sierra Leone.

Methods

We did a retrospective, mixed-methods study. Post-hoc analyses of data from 12 096 mobiliser visits as part of the Social Mobilization Action Consortium were used to describe the evolution of satisfied and unsatisfied needs (basic, security, autonomy, respect, and social support) between Nov 12, 2014, and Dec 18, 2015, and across 14 districts. Via Bayesian hierarchical regression modelling, we investigated associations between needs categories and behaviours (numbers of individuals referred to treatment within 24 h of symptom onset or deaths responded to with safe and dignified burials) and the role of community engagement programme status (initial vs follow-up visit) in the association between satisfied versus unsatisfied needs and behaviours.

Findings

In general, significant associations were observed between unsatisfied needs categories and both prompt referrals to treatment and safe burials. Most notably, communities expressing unsatisfied capacity needs reported fewer safe burials (relative risk [RR] 0·86, 95% credible interval [CrI] 0·82–0·91) and fewer prompt referrals to treatment (RR 0·76, 0·70–0·83) than did those without unsatisfied capacity needs. The exception was expression of unsatisfied basic needs, which was associated with significantly fewer prompt referrals only (RR 0·86, 95% CrI 0·79–0·93). Compared with triggering visits by community mobilisers, follow-up visits were associated with higher numbers of prompt referrals (RR 1·40, 95% CrI 1·30–1·50) and safe burials (RR 1·08, 1·02–1·14).

Interpretation

Community-based development of locally feasible, locally owned action plans, with the support of community mobilisers, has potential to address unmet needs for more sustained behaviour change in outbreak settings.

Funding

Bill & Melinda Gates, Bill & Melinda Gates Foundation, and National Institutes of Health.