Strong isolation by distance and evidence of population microstructure reflect ongoing transmission in Zanzibar.

Background: The Zanzibar archipelago of Tanzania has become a low-transmission area for . Despite being considered an area of pre-elimination for years, achieving elimination has been difficult, likely due to a combination of imported infections from mainland Tanzania and continued local transmission.

Methods: To shed light on these sources of transmission, we applied highly multiplexed genotyping utilizing molecular inversion probes to characterize the genetic relatedness of 282 isolates collected across Zanzibar and in Bagamoyo district on the coastal mainland from 2016 to 2018.

The Journey of Zanzibar's Digitally Enabled Community Health Program to National Scale: Implementation Report.

Background: While high-quality primary health care services can meet 80%-90% of health needs over a person's lifetime, this potential is severely hindered in many low-resource countries by a constrained health care system. There is a growing consensus that effectively designed, resourced, and managed community health worker programs are a critical component of a well-functioning primary health system, and digital technology is recognized as an important enabler of health systems transformation.

Objective: In this implementation report, we describe the design and rollout of Zanzibar's national, digitally enabled community health program-Jamii ni Afya.

Strong isolation by distance and evidence of population microstructure reflect ongoing transmission in Zanzibar.

The Zanzibar archipelago of Tanzania has become a low-transmission area for Despite being considered an area of pre-elimination for years, achieving elimination has been difficult, likely due to a combination of imported infections from mainland Tanzania, and continued local transmission. To shed light on these sources of transmission, we applied highly multiplexed genotyping utilizing molecular inversion probes to characterize the genetic relatedness of 282 isolates collected across Zanzibar and in Bagamoyo District on the coastal mainland from 2016-2018. Overall, parasite populations on the coastal mainland and Zanzibar archipelago remain highly related.

Pneumococcal concentration and serotype distribution in preschool children with radiologically confirmed pneumonia compared to healthy controls prior to introduction of pneumococcal vaccination in Zanzibar: an observational study.

Background: The World Health Organization recommends pneumococcal vaccination (PCV) in the first year of life. We investigated pneumococcal serotypes in children with clinical or radiologically confirmed pneumonia and healthy controls prior to PCV13 vaccine introduction in Zanzibar.

Methods: Children (n = 677) with non-severe acute febrile illness aged 2-59 months presenting to a health centre in Zanzibar, Tanzania April-July 2011 were included.

Evaluation of a Neonatal Resuscitation Training Programme for Healthcare Professionals in Zanzibar, Tanzania: A Pre-post Intervention Study.

Neonatal mortality rates remain high in Sub-Saharan African countries. Improving the newborn resuscitation skills of healthcare professionals is important in addressing this challenge. The aim of this study was to evaluate a neonatal resuscitation training programme delivered over a two-year period for healthcare professionals in Zanzibar, Tanzania.

Influence of cytochrome P450 (CYP) 2C8 polymorphisms on the efficacy and tolerability of artesunate-amodiaquine treatment of uncomplicated Plasmodium falciparum malaria in Zanzibar.

Background: The anti-malarial drug, amodiaquine, a commonly used, long-acting partner drug in artemisinin-based combination therapy, is metabolized to active desethyl-amodiaquine (DEAQ) by cytochrome P450 2C8 (CYP2C8). The CYP2C8 gene carries several polymorphisms including the more frequent minor alleles, CYP2C8*2 and CYP2C8*3. These minor alleles have been associated with decreased enzymatic activity, slowing the amodiaquine biotransformation towards DEAQ.

Increased Sensitivity of Plasmodium falciparum to Artesunate/Amodiaquine Despite 14 Years as First-Line Malaria Treatment, Zanzibar.

Artemisinin-based combination therapies (ACTs) are first-line treatments for uncomplicated Plasmodium falciparum malaria. ACT resistance is spreading in Asia but not yet in Africa. Reduced effects of ACT partner drugs have been reported but with little information regarding widely used artesunate/amodiaquine (ASAQ).

Falciparum malaria from coastal Tanzania and Zanzibar remains highly connected despite effective control efforts on the archipelago.

Background: Tanzania's Zanzibar archipelago has made significant gains in malaria control over the last decade and is a target for malaria elimination. Despite consistent implementation of effective tools since 2002, elimination has not been achieved. Importation of parasites from outside of the archipelago is thought to be an important cause of malaria's persistence, but this paradigm has not been studied using modern genetic tools.

Use of Routine Health Information System Data to Evaluate Impact of Malaria Control Interventions in Zanzibar, Tanzania from 2000 to 2015.

Background: Impact evaluations allow countries to assess public health gains achieved through malaria investments. This study uses routine health management information system (HMIS) data from Zanzibar to describe changes in confirmed malaria incidence and impact of case management and vector control interventions during 2000-2015.

Methods: HMIS data from 129 (82%) public outpatient facilities were analyzed using interrupted time series models to estimate the impact of artemisinin-based combination therapy (ACT), indoor residual spray, and long-lasting insecticidal nets.

Author Correction: The temporal dynamics and infectiousness of subpatent Plasmodium falciparum infections in relation to parasite density.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The temporal dynamics and infectiousness of subpatent Plasmodium falciparum infections in relation to parasite density.

Malaria infections occurring below the limit of detection of standard diagnostics are common in all endemic settings. However, key questions remain surrounding their contribution to sustaining transmission and whether they need to be detected and targeted to achieve malaria elimination. In this study we analyse a range of malaria datasets to quantify the density, detectability, course of infection and infectiousness of subpatent infections.

A cluster randomised controlled trial of two rounds of mass drug administration in Zanzibar, a malaria pre-elimination setting-high coverage and safety, but no significant impact on transmission.

Background: Mass drug administration (MDA) has the potential to interrupt malaria transmission and has been suggested as a tool for malaria elimination in low-endemic settings. This study aimed to determine the effectiveness and safety of two rounds of MDA in Zanzibar, a pre-elimination setting.

Methods: A cluster randomised controlled trial was conducted in 16 areas considered as malaria hotspots, with an annual parasite index of > 0.

Pathogen Clearance and New Respiratory Tract Infections Among Febrile Children in Zanzibar Investigated With Multitargeting Real-Time Polymerase Chain Reaction on Paired Nasopharyngeal Swab Samples.

Background: New molecular methods have revealed frequent and often polymicrobial respiratory infections in children in low-income settings. It is not known whether presence of multiple pathogens is due to prolonged infections or to frequent exposure. The aim of this study was to analyze short-term pathogen clearance from nasopharynx and the rate of new respiratory tract infections in febrile preschool children.

Coinfection with Enteric Pathogens in East African Children with Acute Gastroenteritis-Associations and Interpretations.

Enteric coinfections among children in low-income countries are very common, but it is not well known if specific pathogen combinations are associated or have clinical importance. In this analysis, feces samples from children in Rwanda and Zanzibar less than 5 years of age, with ( = 994) or without ( = 324) acute diarrhea, were analyzed by real-time polymerase chain reaction targeting a wide range of pathogens. Associations were investigated by comparing co-detection and mono-detection frequencies for all pairwise pathogen combinations.

Rapid Clearance and Frequent Reinfection With Enteric Pathogens Among Children With Acute Diarrhea in Zanzibar.

Background: Acute infectious gastroenteritis is an important cause of illness and death among children in low-income countries. In addition to rotavirus vaccination, actions to improve nutrition status, sanitation, and water quality are important to reduce enteric infections, which are frequent also among asymptomatic children. The aim of this study was to investigate if the high prevalence of these infections reflects that they often are not cleared properly by the immune response or rather is due to frequent pathogen exposure.

The Impact of Introducing Malaria Rapid Diagnostic Tests on Fever Case Management: A Synthesis of Ten Studies from the ACT Consortium.

Since 2010, the World Health Organization has been recommending that all suspected cases of malaria be confirmed with parasite-based diagnosis before treatment. These guidelines represent a paradigm shift away from presumptive antimalarial treatment of fever. Malaria rapid diagnostic tests (mRDTs) are central to implementing this policy, intended to target artemisinin-based combination therapies (ACT) to patients with confirmed malaria and to improve management of patients with nonmalarial fevers.

Artemisinin combination therapy mass drug administration in a setting of low malaria endemicity: programmatic coverage and adherence during an observational study in Zanzibar.

Background: Mass drug administration (MDA) appears to be effective in reducing the risk of malaria parasitaemia. This study reports on programmatic coverage and compliance of MDA using artemisinin-based combination therapy (ACT) in four shehias (smallest administration unit) that had been identified as hotspots through Zanzibar's malaria case notification surveillance system.

Methods: Mass drug administration was done in four shehias selected on the basis of: being an established malaria hot spot; having had mass screening and treatment (MSaT) 2-6 weeks previously; and exceeding the epidemic alert threshold of 5 cases within a week even after MSaT.

Spatial Distribution of Falciparum Malaria Infections in Zanzibar: Implications for Focal Drug Administration Strategies Targeting Asymptomatic Parasite Carriers.

Background: Optimal use of mass/targeted screen-and-treat or mass or focal drug administration as malaria elimination strategies remains unclear. We therefore studied spatial distribution of Plasmodium falciparum infections to compare simulated effects of these strategies on reducing the parasite reservoir in a pre-elimination setting.

Methods: P.

Impact of introduction of rapid diagnostic tests for malaria on antibiotic prescribing: analysis of observational and randomised studies in public and private healthcare settings.

 To examine the impact of use of rapid diagnostic tests for malaria on prescribing of antimicrobials, specifically antibiotics, for acute febrile illness in Africa and Asia. Analysisof nine preselected linked and codesigned observational and randomised studies (eight cluster or individually randomised trials and one observational study). Public and private healthcare settings, 2007-13, in Afghanistan, Cameroon, Ghana, Nigeria, Tanzania, and Uganda.

Field Evaluation of a High Throughput Loop Mediated Isothermal Amplification Test for the Detection of Asymptomatic Plasmodium Infections in Zanzibar.

Background: New field applicable diagnostic tools are needed for highly sensitive detection of residual malaria infections in pre-elimination settings. Field performance of a high throughput DNA extraction system for loop mediated isothermal amplification (HTP-LAMP) was therefore evaluated for detecting malaria parasites among asymptomatic individuals in Zanzibar.

Methods: HTP-LAMP performance was evaluated against real-time PCR on 3008 paired blood samples collected on filter papers in a community-based survey in 2015.

Using low-cost drones to map malaria vector habitats.

Background: There is a growing awareness that if we are to achieve the ambitious goal of malaria elimination, we must compliment indoor-based vector control interventions (such as bednets and indoor spraying) with outdoor-based interventions such as larval source management (LSM). The effectiveness of LSM is limited by our capacity to identify and map mosquito aquatic habitats. This study provides a proof of concept for the use of a low-cost (< $1000) drone (DJI Phantom) for mapping water bodies in seven sites across Zanzibar including natural water bodies, irrigated and non-irrigated rice paddies, peri-urban and urban locations.

Acute Uncomplicated Febrile Illness in Children Aged 2-59 months in Zanzibar - Aetiologies, Antibiotic Treatment and Outcome.

Background: Despite the fact that a large proportion of children with fever in Africa present at primary health care facilities, few studies have been designed to specifically study the causes of uncomplicated childhood febrile illness at this level of care, especially in areas like Zanzibar that has recently undergone a dramatic change from high to low malaria transmission.

Methods: We prospectively studied the aetiology of febrile illness in 677 children aged 2-59 months with acute uncomplicated fever managed by IMCI (Integrated Management of Childhood Illness) guidelines in Zanzibar, using point-of-care tests, urine culture, blood-PCR, chest X-ray (CXR) of IMCI-pneumonia classified patients, and multiple quantitative (q)PCR investigations of nasopharyngeal (NPH) (all patients) and rectal (GE) swabs (diarrhoea patients). For comparison, we also performed NPH and GE qPCR analyses in 167 healthy community controls.

Field deployment of loop-mediated isothermal amplification for centralized mass-screening of asymptomatic malaria in Zanzibar: a pre-elimination setting.

Background: Molecular tools for detection of low-density asymptomatic Plasmodium infections are needed in malaria elimination efforts. This study reports results from the hitherto largest implementation of loop-mediated isothermal amplification (LAMP) for centralized mass screening of asymptomatic malaria in Zanzibar.

Methods: Healthy individuals present and willing to participate in randomly selected households in 60 villages throughout Zanzibar were screened for malaria by rapid diagnostic tests (RDT).

Characterising temporal trends in asymptomatic Plasmodium infections and transporter polymorphisms during transition from high to low transmission in Zanzibar, 2005-2013.

Background: Improved understanding of the asymptomatic malaria parasite reservoir is a prerequisite to pursue malaria elimination efforts. We therefore characterised temporal trends and transporter polymorphisms in asymptomatic Plasmodium infections during the transition from high to low transmission in Zanzibar.

Methods: Healthy individuals participating in cross-sectional surveys conducted 2005-2013 were screened for asymptomatic malaria by PCR.

SYBR Green real-time PCR-RFLP assay targeting the plasmodium cytochrome B gene--a highly sensitive molecular tool for malaria parasite detection and species determination.

A prerequisite for reliable detection of low-density Plasmodium infections in malaria pre-elimination settings is the availability of ultra-sensitive and high-throughput molecular tools. We developed a SYBR Green real-time PCR restriction fragment length polymorphism assay (cytb-qPCR) targeting the cytochrome b gene of the four major human Plasmodium species (P. falciparum, P.