The COVID-19 Pandemic: Effects on Civil Registration of Births and Deaths and on Availability and Utility of Vital Events Data.

The complex and evolving picture of COVID-19-related mortality highlights the need for data to guide the response. Yet many countries are struggling to maintain their data systems, including the civil registration system, which is the foundation for detailed and continuously available mortality statistics. We conducted a search of country and development agency Web sites and partner and media reports describing disruptions to the civil registration of births and deaths associated with COVID-19 related restrictions.We found considerable intercountry variation and grouped countries according to the level of disruption to birth and particularly death registration. Only a minority of the 66 countries were able to maintain service continuity during the COVID-19 restrictions. In the majority, a combination of legal and operational challenges resulted in declines in birth and death registration. Few countries established business continuity plans or developed strategies to deal with the backlog when restrictions are lifted.Civil registration systems and the vital statistics they generate must be strengthened as essential services during health emergencies and as core components of the response to COVID-19.

Improving quality of medical certification of causes of death in health facilities in Tanzania 2014-2019.

BACKGROUND: Monitoring medically certified causes of death is essential to shape national health policies, track progress to Sustainable Development Goals, and gauge responses to epidemic and pandemic disease. The combination of electronic health information systems with new methods for data quality monitoring can facilitate quality assessments and help target quality improvement. Since 2015, Tanzania has been upgrading its Civil Registration and Vital Statistics system including efforts to improve the availability and quality of mortality data. METHODS: We used a computer application (ANACONDA v4.01) to assess the quality of medical certification of cause of death (MCCD) and ICD-10 coding for the underlying cause of death for 155,461 deaths from health facilities from 2014 to 2018. From 2018 to 2019, we continued quality analysis for 2690 deaths in one large administrative region 9 months before, and 9 months following MCCD quality improvement interventions. Interventions addressed governance, training, process, and practice. We assessed changes in the levels, distributions, and nature of unusable and insufficiently specified codes, and how these influenced estimates of the leading causes of death. RESULTS: 9.7% of expected annual deaths in Tanzania obtained a medically certified cause of death. Of these, 52% of MCCD ICD-10 codes were usable for health policy and planning, with no significant improvement over 5 years. Of certified deaths, 25% had unusable codes, 17% had insufficiently specified codes, and 6% were undetermined causes. Comparing the before and after intervention periods in one Region, codes usable for public health policy purposes improved from 48 to 65% within 1 year and the resulting distortions in the top twenty cause-specific mortality fractions due to unusable causes reduced from 27.4 to 13.5%. CONCLUSION: Data from less than 5% of annual deaths in Tanzania are usable for informing policy. For deaths with medical certification, errors were prevalent in almost half. This constrains capacity to monitor the 15 SDG indicators that require cause-specific mortality. Sustainable quality assurance mechanisms and interventions can result in rapid improvements in the quality of medically certified causes of death. ANACONDA provides an effective means for evaluation of such changes and helps target interventions to remaining weaknesses.

Improving coverage of civil registration and vital statistics, Bangladesh.

PROBLEM: Bangladesh has no national system for registering deaths and determining their causes. As a result, policy-makers lack reliable and complete data to inform public health decisions. APPROACH: In 2016, the government of Bangladesh introduced a pilot project to strengthen the civil registration and vital statistics system and generate cause of death data in Kaliganj Upazila. Community-based health workers were trained to notify births and deaths to the civil registrar, and to conduct verbal autopsy interviews with family members of a deceased person. International experts in cause-of-death certification and coding trained master trainers on how to complete the international medical certificate of cause of death. These trainers then trained physicians and coders. LOCAL SETTING: Kaliganj Upazila has an estimated population of 304 600, and 5600 births and 1550 deaths annually. Health assistants and family welfare assistants make regular visits to households to track certain health outcomes. RELEVANT CHANGES: Following the start of the project in 2016, the number of births registered within 45 days rose from 873 to 4630 in 2018. The number of deaths registered within 45 days increased from 458 to 1404. During this period, health assistants conducted 7837 verbal autopsy interviews. Between January 2017 and December 2018, 105 master trainers and more than 7000 physicians were trained to complete the international medical certificate of cause of death and they completed more than 12 000 certificates. LESSONS LEARNT: Training community-based health workers, physicians and coders were successful approaches to improve death registration completeness and availability of cause-of-death data.

Local Heat Application for the Treatment of Buruli Ulcer: Results of a Phase II Open Label Single Center Non Comparative Clinical Trial.

BACKGROUND: Buruli ulcer (BU) is a necrotizing skin disease most prevalent among West African children. The causative organism, Mycobacterium ulcerans, is sensitive to temperatures above 37°C. We investigated the safety and efficacy of a local heat application device based on phase change material. METHODS: In a phase II open label single center noncomparative clinical trial (ISRCTN 72102977) under GCP standards in Cameroon, laboratory confirmed BU patients received up to 8 weeks of heat treatment. We assessed efficacy based on the endpoints 'absence of clinical BU specific features' or 'wound closure' within 6 months ("primary cure"), and 'absence of clinical recurrence within 24 month' ("definite cure"). RESULTS: Of 53 patients 51 (96%) had ulcerative disease. 62% were classified as World Health Organization category II, 19% each as category I and III. The average lesion size was 45 cm(2). Within 6 months after completion of heat treatment 92.4% (49 of 53, 95% confidence interval [CI], 81.8% to 98.0%) achieved cure of their primary lesion. At 24 months follow-up 83.7% (41 of 49, 95% CI, 70.3% to 92.7%) of patients with primary cure remained free of recurrence. Heat treatment was well tolerated; adverse effects were occasional mild local skin reactions. CONCLUSIONS: Local thermotherapy is a highly effective, simple, cheap and safe treatment for M. ulcerans disease. It has in particular potential as home-based remedy for BU suspicious lesions at community level where laboratory confirmation is not available. CLINICAL TRIALS REGISTRATION: ISRCT 72102977.

Diagnosis of neglected tropical diseases among patients with persistent digestive disorders (diarrhoea and/or abdominal pain ≥14 days): Pierrea multi-country, prospective, non-experimental case-control study.

BACKGROUND: Diarrhoea still accounts for considerable mortality and morbidity worldwide. The highest burden is concentrated in tropical areas where populations lack access to clean water, adequate sanitation and hygiene. In contrast to acute diarrhoea (<14 days), the spectrum of pathogens that may give rise to persistent diarrhoea (≥14 days) and persistent abdominal pain is poorly understood. It is conceivable that pathogens causing neglected tropical diseases play a major role, but few studies investigated this issue. Clinical management and diagnostic work-up of persistent digestive disorders in the tropics therefore remain inadequate. Hence, important aspects regarding the pathogenesis, epidemiology, clinical symptomatology and treatment options for patients presenting with persistent diarrhoea and persistent abdominal pain should be investigated in multi-centric clinical studies. METHODS/DESIGN: This multi-country, prospective, non-experimental case-control study will assess persistent diarrhoea (≥14 days; in individuals aged ≥1 year) and persistent abdominal pain (≥14 days; in children/adolescents aged 1-18 years) in up to 2000 symptomatic patients and 2000 matched controls. Subjects from Côte d'Ivoire, Indonesia, Mali and Nepal will be clinically examined and interviewed using a detailed case report form. Additionally, each participant will provide a stool sample that will be examined using a suite of diagnostic methods (i.e., microscopic techniques, rapid diagnostic tests, stool culture and polymerase chain reaction) for the presence of bacterial and parasitic pathogens. Treatment will be offered to all infected participants and the clinical treatment response will be recorded. Data obtained will be utilised to develop patient-centred clinical algorithms that will be validated in primary health care centres in the four study countries in subsequent studies. DISCUSSION: Our research will deepen the understanding of the importance of persistent diarrhoea and related digestive disorders in the tropics. A diversity of intestinal pathogens will be assessed for potential associations with persistent diarrhoea and persistent abdominal pain. Different diagnostic methods will be compared, clinical symptoms investigated and diagnosis-treatment algorithms developed for validation in selected primary health care centres. The findings from this study will improve differential diagnosis and evidence-based clinical management of digestive syndromes in the tropics. TRIAL REGISTRATION: ClinicalTrials.gov; identifier: NCT02105714 .

Current knowledge on Mycobacterium leprae transmission: a systematic literature review.

UNLABELLED: Summary BACKGROUND: The transmission pathways of Mycobacterium leprae are not fully understood. Solid evidence exists for an increased risk for individuals living in close contact with leprosy patients but the existence of zoonotic leprosy, environmental reservoirs and trauma-related transmission has also been established. PURPOSE: To assess the current state of knowledge on M. leprae transmission, we conducted a systematic review of the peer-reviewed literature pertaining to this topic. METHOD: Major electronic bibliographic databases were searched for relevant peer-reviewed articles published up to January 2014. No restrictions on study types, participants and location were applied, and all outcomes demonstrated to contribute to the transmission of M. leprae were considered. Included studies were grouped by mode of transmission, namely (i) human-to-human via aerosols or direct contact; (ii) direct inoculation (e.g. injury); and (iii) transmission to humans from environmental or zoonotic reservoirs, and by insects. The importance of the different transmission pathways and the strength of the evidence were assessed considering the number of publications describing similar findings, the consistency of the findings and the methodological quality of the studies. RESULTS: A total of 79 relevant articles were retained out of 3,805 hits resulting from the application of the search strategy. Solid evidence for transmission among contacts exists, and for zoonotic leprosy in the southern States of the USA. Based on the extant evidence, skin-to-skin contact, aerosols/droplets and shedding of bacteria into the environment and subsequent infection, e.g. through dust or small wounds, all remain possible options. CONCLUSION: No study has unequivocally demonstrated the mechanisms by which M. leprae bacteria travel from one case of leprosy to another.

Primary cultivation: factors affecting contamination and Mycobacterium ulcerans growth after long turnover time of clinical specimens.

BACKGROUND: While cultivation of pathogens represents a foundational diagnostic approach in the study of infectious diseases, its value for the confirmation of clinical diagnosis of Buruli ulcer is limited by the fact that colonies of Mycobacterium ulcerans appear only after about eight weeks of incubation at 30°C. However, for molecular epidemiological and drug sensitivity studies, primary isolation of M. ulcerans remains an essential tool. Since for most of the remote Buruli ulcer endemic regions of Africa cultivation laboratories are not easily accessible, samples from lesions often have to be stored for extended periods of time prior to processing. The objective of the current study therefore was to determine which transport medium, decontamination method or other factors decrease the contamination rate and increase the chance of primary isolation of M. ulcerans bacilli after long turnover time. METHODS: Swab and fine needle aspirate (FNA) samples for the primary cultivation were collected from clinically confirmed Buruli ulcer patients in the Mapé Basin of Cameroon. The samples were either stored in the semi-solid transport media 7H9 or Amies or dry for extended period of time prior to processing. In the laboratory, four decontamination methods and two inoculation media were evaluated and statistical methods applied to identify factors that decrease culture contamination and factors that increase the probability of M. ulcerans recovery. RESULTS: The analysis showed: i) that the use of moist transport media significantly increased the recovery rate of M. ulcerans compared to samples kept dry; ii) that the choice of the decontamination method had no significant effect on the chance of M. ulcerans isolation; and iii) that Löwenstein-Jensen supplemented with antibiotics as inoculation medium yielded the best results. We further found that, ten extra days between sampling and inoculation lead to a relative decrease in the isolation rate of M. ulcerans by nearly 20%. Finally, collection and processing of multiple samples per patient was found to significantly increase the M. ulcerans isolation rate. CONCLUSIONS: Based on our analysis we suggest a procedure suitable for the primary isolation of M. ulcerans strains from patients following long delay between sample collection and processing to establish a M. ulcerans strain collection for research purposes.

Are cause of death data for Shanghai fit for purpose? A retrospective study of medical records.

OBJECTIVES: To assess the quality of cause of death reporting in Shanghai for both hospital and home deaths. DESIGN AND SETTING: Medical records review (MRR) to independently establish a reference data set against which to compare original and adjusted diagnoses from a sample of three tertiary hospitals, one secondary level hospital and nine community health centres in Shanghai. PARTICIPANTS: 1757 medical records (61% males, 39% females) of deaths that occurred in these sample sites in 2017 were reviewed using established diagnostic standards. INTERVENTIONS: None. PRIMARY OUTCOME: Original underlying cause of death (UCOD) from medical facilities. SECONDARY OUTCOME: Routine UCOD assigned from the Shanghai Civil Registration and Vital Statistics (CRVS) system and MRR UCODs from MRR. RESULTS: The original UCODs as assigned by doctors in the study facilities were of relatively low quality, reduced to 31% of deaths assigned to garbage codes, reduced to 2.3% following data quality and follow back procedures routinely applied by the Shanghai CRVS system. The original UCOD had lower chance-corrected concordance and cause-specific mortality fraction accuracy of 0.57 (0.44, 0.70) and 0.66, respectively, compared with 0.75 (0.66, 0.85) and 0.96, respectively, after routine data checking procedures had been applied. CONCLUSIONS: Training in correct death certification for clinical doctors, especially tertiary hospital doctors, is essential to improve UCOD quality in Shanghai. A routine quality control system should be established to actively track diagnostic performance and provide feedback to individual doctors or facilities as needed.

Glycerol-3-phosphate acyltransferases gat1p and gat2p are microsomal phosphoproteins with differential contributions to polarized cell growth.

Glycerol-3-phosphate acyltransferase (GPAT) catalyzes the initial step in the synthesis of all glycerolipids. It is the committed and rate-limiting step and is redundant in Saccharomyces cerevisiae, mammals, and plants. GPAT controls the formation of lipid intermediates that serve not only as precursors of more-complex lipids but also as intracellular signaling molecules. Saccharomyces cerevisiae possesses two GPATs, encoded by the GAT1 and GAT2 genes. Metabolic analysis of yeast lacking either GAT1 or GAT2 indicated partitioning of the two main branches of phospholipid synthesis at the initial and rate-limiting GPAT step. We are particularly interested in identifying molecular determinants mediating lipid metabolic pathway partitioning; therefore, as a starting point, we have performed a detailed study of Gat1p and Gat2p cellular localization. We have compared Gat1p and Gat2p localization by fluorescence microscopy and subcellular fractionation using equilibrium density gradients. Our results indicate Gat1p and Gat2p overlap mostly in their localization and are in fact microsomal GPATs, localized to both perinuclear and cortical endoplasmic reticula in actively proliferating cells. A more detailed analysis suggests a differential enrichment of Gat1p and Gat2p in distinct ER fractions. Furthermore, overexpression of these enzymes in the absence of endogenous GPATs induces proliferation of distinct ER arrays, differentially affecting cortical ER morphology and polarized cell growth. In addition, our studies also uncovered a dynamic posttranslational regulation of Gat1p and Gat2p and a compensation mechanism through phosphorylation that responds to a cellular GPAT imbalance.

Introduction of Mycobacterium ulcerans disease in the Bankim Health District of Cameroon follows damming of the Mapé River.

Buruli ulcer (BU) is an emerging ulcerative skin disease caused by infection with Mycobacterium ulcerans. Efforts to control its spread have been hampered by our limited understanding of M. ulcerans reservoirs and transmission, and the factors leading to the emergence of BU disease in a particular region. In this report we investigate an anecdotal link between damming the Mapé River in Cameroon and the emergence of BU in the Health Districts bordering Lake Bankim, the impoundment created by the Mapé dam. We used bacterial population genomics and molecular dating to find compelling support for a 2000 M. ulcerans introduction event that followed about 10 years after the filling of the newly created impoundment in 1988. We compared the genomic reconstructions with high-resolution satellite imagery to investigate what major environmental alterations might have driven the emergence of the new focus.

Transmission of Hepatitis B and D Viruses in an African Rural Community.

According to the World Health Organization (WHO), an estimated 257 million people worldwide are chronically infected with hepatitis B virus (HBV), with approximately 15 million of them being coinfected with hepatitis D virus (HDV). To investigate the prevalence and transmission of HBV and HDV within the general population of a rural village in Cameroon, we analyzed serum samples from most (401/448) of the villagers. HBV surface antigen (HBsAg) was detected in 54 (13.5%) of the 401 samples, with 15% of them also containing anti-HDV antibodies. Although Cameroon has integrated HBV vaccination into their Expanded Program on Immunization for newborns in 2005, an HBsAg carriage rate of 5% was found in children below the age of 5 years. Of the 54 HBsAg-positive samples, 49 HBV pre-S/S sequences (7 genotype A and 42 genotype E sequences) could be amplified by PCR. In spite of the extreme geographical restriction in the recruitment of study participants, a remarkable genetic diversity within HBV genotypes was observed. Phylogenetic analysis of the sequences obtained from PCR products combined with demographic information revealed that the presence of some genetic variants was restricted to members of one household, indicative of intrafamilial transmission, which appears to take place at least in part perinatally from mother to child. Other genetic variants were more widely distributed, reflecting horizontal interhousehold transmission. Data for two households with more than one HBV-HDV-coinfected individual indicate that the two viruses are not necessarily transmitted together, as family members with identical HBV sequences had different HDV statuses. IMPORTANCE This study revealed that the prevalence of HBV and HDV in a rural area of Cameroon is extremely high, underlining the pressing need for the improvement of control strategies. Systematic serological and phylogenetic analyses of HBV sequences turned out to be useful tools to identify networks of virus transmission within and between households. The high HBsAg carriage rate found among children demonstrates that implementation of the HBV birth dose vaccine and improvement of vaccine coverage will be key elements in preventing both HBV and HDV infections. In addition, the high HBsAg carriage rate in adolescents and adults emphasizes the need for identification of chronically infected individuals and linkage to WHO-recommended treatment to prevent progression to liver cirrhosis and hepatocellular carcinoma.

Correction: The Burden of Leprosy in Cameroon: Fifteen Years into the Post-elimination Era.

[This corrects the article DOI: 10.1371/journal.pntd.0005012.].

Susceptibility to Mycobacterium ulcerans Disease (Buruli ulcer) Is Associated with IFNG and iNOS Gene Polymorphisms.

Buruli ulcer (BU) is a chronic necrotizing disease of the skin and subcutaneous fat tissue. The causative agent, Mycobacterium ulcerans, produces mycolactone, a macrolide toxin, which causes apoptosis of mammalian cells. Only a small proportion of individuals exposed to M. ulcerans develop clinical disease, as surrounding macrophages may control the infection by bacterial killing at an early stage, while mycolactone concentration is still low. Otherwise, bacterial multiplication leads to in higher concentrations of mycolactone, with formation of necrotizing lesions that are no more accessible to immune cells. By typing a cohort of 96 Ghanaian BU patients and 384 endemic controls without BU, we show an association between BU and single nucleotide polymorphisms (SNPs) in iNOS (rs9282799) and IFNG (rs2069705). Both polymorphisms influence promoter activity in vitro. A previously reported SNP in SLC11A1 (NRAMP, rs17235409) tended to be associated with BU. Altogether, these data reflect the importance of IFNG signaling in early defense against M. ulcerans infection.

Spatial Distribution of Mycobacterium ulcerans in Buruli Ulcer Lesions: Implications for Laboratory Diagnosis.

BACKGROUND: Current laboratory diagnosis of Buruli ulcer (BU) is based on microscopic detection of acid fast bacilli, quantitative real-time PCR (qPCR), histopathology or cultivation. Insertion sequence (IS) 2404 qPCR, the most sensitive method, is usually only available at reference laboratories. The only currently available point-of-care test, microscopic detection of acid fast bacilli (AFB), has limited sensitivity and specificity. METHODOLOGY/ PRINCIPAL FINDINGS: Here we analyzed AFB positive tissue samples (n = 83) for the presence, distribution and amount of AFB. AFB were nearly exclusively present in the subcutis with large extracellular clusters being most frequently (67%) found in plaque lesions. In ulcerative lesions small clusters and dispersed AFB were more common. Beside this, 151 swab samples from 37 BU patients were analyzed by IS2404 qPCR and ZN staining in parallel. The amount of M. ulcerans DNA in extracts from swabs correlated well with the probability of finding AFB in direct smear microscopy, with 56.1% of the samples being positive in both methods and 43.9% being positive only in qPCR. By analyzing three swabs per patient instead of one, the probability to have at least one positive swab increased from 80.2% to 97.1% for qPCR and from 45% to 66.1% for AFB smear examination. CONCLUSION / SIGNIFICANCE: Our data show that M. ulcerans bacteria are primarily located in the subcutis of BU lesions, making the retrieval of the deep subcutis mandatory for examination of tissue samples for AFB. When laboratory diagnosis is based on the recommended less invasive collection of swab samples, analysis of three swabs from different areas of ulcerative lesions instead of one increases the sensitivity of both qPCR and of smear microscopy substantially.