Impact and cost-effectiveness of SARS-CoV-2 self-testing strategies in schools: a multicountry modelling analysis.

OBJECTIVES: To determine the most epidemiologically effective and cost-effective school-based SARS-CoV-2 antigen-detection rapid diagnostic test (Ag-RDT) self-testing strategies among teachers and students. DESIGN: Mathematical modelling and economic evaluation. SETTING AND PARTICIPANTS: Simulated school and community populations were parameterised to Brazil, Georgia and Zambia, with SARS-CoV-2 self-testing strategies targeted to teachers and students in primary and secondary schools under varying epidemic conditions. INTERVENTIONS: SARS-CoV-2 Ag-RDT self-testing strategies for only teachers or teachers and students-only symptomatically or symptomatically and asymptomatically at 5%, 10%, 40% or 100% of schools at varying frequencies. OUTCOME MEASURES: Outcomes were assessed in terms of total infections and symptomatic days among teachers and students, as well as total infections and deaths within the community under the intervention compared with baseline. The incremental cost-effectiveness ratios (ICERs) were calculated for infections prevented among teachers and students. RESULTS: With respect to both the reduction in infections and total cost, symptomatic testing of all teachers and students appears to be the most cost-effective strategy. Symptomatic testing can prevent up to 69·3%, 64·5% and 75·5% of school infections in Brazil, Georgia and Zambia, respectively, depending on the epidemic conditions, with additional reductions in community infections. ICERs for symptomatic testing range from US$2 to US$19 per additional school infection averted as compared with symptomatic testing of teachers alone. CONCLUSIONS: Symptomatic testing of teachers and students has the potential to cost-effectively reduce a substantial number of school and community infections.

Metatranscriptomics reveals diversity of symbiotic interaction and mechanisms of carbon exchange in the marine cyanolichen Lichina pygmaea.

Lichens are exemplar symbioses based upon carbon exchange between photobionts and their mycobiont hosts. Historically considered a two-way relationship, some lichen symbioses have been shown to contain multiple photobiont partners; however, the way in which these photobiont communities react to environmental change is poorly understood. Lichina pygmaea is a marine cyanolichen that inhabits rocky seashores where it is submerged in seawater during every tidal cycle. Recent work has indicated that L. pygmaea has a complex photobiont community including the cyanobionts Rivularia and Pleurocapsa. We performed rRNA-based metabarcoding and mRNA metatranscriptomics of the L. pygmaea holobiont at high and low tide to investigate community response to immersion in seawater. Carbon exchange in L. pygmaea is a dynamic process, influenced by both tidal cycle and the biology of the individual symbiotic components. The mycobiont and two cyanobiont partners exhibit distinct transcriptional responses to seawater hydration. Sugar-based compatible solutes produced by Rivularia and Pleurocapsa in response to seawater are a potential source of carbon to the mycobiont. We propose that extracellular processing of photobiont-derived polysaccharides is a fundamental step in carbon acquisition by L. pygmaea and is analogous to uptake of plant-derived carbon in ectomycorrhizal symbioses.

Multiple evolutionary transitions of reproductive strategies in a phylum of aquatic colonial invertebrates.

Parental care is considered crucial for the enhanced survival of offspring and evolutionary success of many metazoan groups. Most bryozoans incubate their young in brood chambers or intracoelomically. Based on the drastic morphological differences in incubation chambers across members of the order Cheilostomatida (class Gymnolaemata), multiple origins of incubation were predicted in this group. This hypothesis was tested by constructing a molecular phylogeny based on mitogenome data and nuclear rRNA genes 18S and 28S with the most complete sampling of taxa with various incubation devices to date. Ancestral character estimation suggested that distinct types of brood chambers evolved at least 10 times in Cheilostomatida. In Eucratea loricata and Aetea spp. brooding evolved unambiguously from a zygote-spawning ancestral state, as it probably did in Tendra zostericola, Neocheilostomata, and 'Carbasea' indivisa. In two further instances, brooders with different incubation chamber types, skeletal and non-skeletal, formed clades (Scruparia spp., Leiosalpinx australis) and (Catenicula corbulifera (Steginoporella spp. (Labioporella spp., Thalamoporella californica))), each also probably evolved from a zygote-spawning ancestral state. The modular nature of bryozoans probably contributed to the evolution of such a diverse array of embryonic incubation chambers, which included complex constructions made of polymorphic heterozooids, and maternal zooidal invaginations and outgrowths.

Tuberculosis testing patterns in South Africa to identify groups that would benefit from increased investigation.

The National Health Laboratory Service (NHLS) collects all public health laboratory test results in South Africa, providing a cohort from which to identify groups, by age, sex, HIV, and viral suppression status, that would benefit from increased tuberculosis (TB) testing. Using NHLS data (2012-2016), we assessed levels and trends over time in TB diagnostic tests performed (count and per capita) and TB test positivity. Estimates were stratified by HIV status, viral suppression, age, sex, and province. We used logistic regression to estimate the odds of testing positive for TB by viral suppression status. Nineteen million TB diagnostic tests were conducted during period 2012-2016. Testing per capita was lower among PLHIV with viral suppression than those with unsuppressed HIV (0.08 vs 0.32) but lowest among people without HIV (0.03). Test positivity was highest among young adults (aged 15-35 years), males of all age groups, and people with unsuppressed HIV. Test positivity was higher for males without laboratory evidence of HIV than those with HIV viral suppression, despite similar individual odds of TB. Our results are an important national baseline characterizing who received TB testing in South Africa. People without evidence of HIV, young adults, and males would benefit from increased TB screening given their lower testing rates and higher test positivity. These high-test positivity groups can be used to guide future expansions of TB screening.

Integrating Molecular Diagnostics and GIS Mapping: A Multidisciplinary Approach to Understanding Tuberculosis Disease Dynamics in South Africa Using Xpert MTB/RIF.

An investigation was carried out to examine the use of national Xpert MTB/RIF data (2013-2017) and GIS technology for MTB/RIF surveillance in South Africa. The aim was to exhibit the potential of using molecular diagnostics for TB surveillance across the country. The variables analysed include Mycobacterium tuberculosis (Mtb) positivity, the mycobacterial proportion of rifampicin-resistant Mtb (RIF), and probe frequency. The summary statistics of these variables were generated and aggregated at the facility and municipal level. The spatial distribution patterns of the indicators across municipalities were determined using the Moran's I and Getis Ord (Gi) statistics. A case-control study was conducted to investigate factors associated with a high mycobacterial load. Logistic regression was used to analyse this study's results. There was striking spatial heterogeneity in the distribution of Mtb and RIF across South Africa. The median patient age, urban setting classification, and number of health care workers were found to be associated with the mycobacterial load. This study illustrates the potential of using data generated from molecular diagnostics in combination with GIS technology for Mtb surveillance in South Africa. Spatially targeted interventions can be implemented in areas where high-burden Mtb persists.

The genome sequence of the sea mat, Membranipora membranacea (Linnaeus, 1767).

We present a genome assembly from an adult colony of Membranipora membranacea (the sea mat; Bryozoa; Gymnolaemata; Cheilostomatida; Membraniporidae). The genome sequence is 339 megabases in span. Most of the assembly (99.95%) is scaffolded into 11 chromosomal pseudomolecules. The mitochondrial genome has also been assembled and is 14.7 kilobases in length.

The genome sequence of an erect bryozoan, Bugulina stolonifera (Ryland, 1960).

We present a genome assembly from a Bugulina stolonifera colony (an erect bryozoan; Bryozoa; Gymnolaemata; Cheilostomatida; Bugulidae). The genome sequence is 235 megabases in span. Most of the assembly (99.85%) is scaffolded into 11 chromosomal pseudomolecules. The mitochondrial genome was also assembled and is 14.4 kilobases long.

Cross-municipality migration and spread of tuberculosis in South Africa.

Human migration facilitates the spread of infectious disease. However, little is known about the contribution of migration to the spread of tuberculosis in South Africa. We analyzed longitudinal data on all tuberculosis test results recorded by South Africa's National Health Laboratory Service (NHLS), January 2011-July 2017, alongside municipality-level migration flows estimated from the 2016 South African Community Survey. We first assessed migration patterns in people with laboratory-diagnosed tuberculosis and analyzed demographic predictors. We then quantified the impact of cross-municipality migration on tuberculosis incidence in municipality-level regression models. The NHLS database included 921,888 patients with multiple clinic visits with TB tests. Of these, 147,513 (16%) had tests in different municipalities. The median (IQR) distance travelled was 304 (163 to 536) km. Migration was most common at ages 20-39 years and rates were similar for men and women. In municipality-level regression models, each 1% increase in migration-adjusted tuberculosis prevalence was associated with a 0.47% (95% CI: 0.03% to 0.90%) increase in the incidence of drug-susceptible tuberculosis two years later, even after controlling for baseline prevalence. Similar results were found for rifampicin-resistant tuberculosis. Accounting for migration improved our ability to predict future incidence of tuberculosis.

Contribution of Reinfection to Annual Rate of Tuberculosis Infection (ARI) and Incidence of Tuberculosis Disease.

BACKGROUND: Modeling studies have concluded that 60-80% of tuberculosis (TB) infections result from reinfection of previously infected persons. The annual rate of infection (ARI), a standard measure of the risk of TB infection in a community, may not accurately reflect the true risk of infection among previously infected persons. We constructed a model of infection and reinfection with Mycobacterium tuberculosis to explore the predictive accuracy of ARI and its effect on disease incidence. METHODS: We created a deterministic simulation of the progression from TB infection to disease and simulated the prevalence of TB infection at the beginning and end of a theoretical year of infection. We considered 10 disease prevalence scenarios ranging from 100/100 000 to 1000/100 000 in simulations where TB exposure probability was homogeneous across the whole simulated population or heterogeneously stratified into high-risk and low-risk groups. ARI values, rates of progression from infection to disease, and the effect of multiple reinfections were obtained from published studies. RESULTS: With homogeneous exposure risk, observed ARI values produced expected numbers of infections. However, when heterogeneous risk was introduced, observed ARI was seen to underestimate true ARI by 25-58%. Of the cases of TB disease that occurred, 36% were among previously infected persons when prevalence was 100/100 000, increasing to 79% of cases when prevalence was 1000/100 000. CONCLUSIONS: Measured ARI underestimates true ARI as a result of heterogeneous population mixing. The true force of infection in a community may be greater than previously appreciated. Hyperendemic communities likely contribute disproportionally to the global TB disease burden.

Geospatial analysis of reported activity locations to identify sites for tuberculosis screening.

Mobile screening units can help close tuberculosis case detection gaps. Placing screening units where people at high risk for undiagnosed tuberculosis preferentially spend time could make screening more resource-effective. We conducted a case-control study in Lima, Peru to identify locations where people with tuberculosis were more likely to spend time than community controls. We surveyed participants about activity locations over the past 6 months. We used density-based clustering to assess how patient and control activity locations differed, and logistic regression to compare location-based exposures. We included 109 tuberculosis patients and 79 controls. In density-based clustering analysis, the two groups had similar patterns of living locations, but their work locations clustered in distinct areas. Both groups were similarly likely to use public transit, but patients predominantly used buses and were less likely to use rapid transit (adjusted odds ratio [aOR] 0.31, 95% confidence interval [CI] 0.10-0.96) or taxis (aOR 0.42, 95% CI 0.21-0.85). Patients were more likely to have spent time in prison (aOR 11.55, 95% CI 1.48-90.13). Placing mobile screening units at bus terminals serving locations where tuberculosis patients have worked and within and around prisons could help reach people with undiagnosed tuberculosis.

Spatial heterogeneity of extensively drug resistant-tuberculosis in Western Cape Province, South Africa.

Tuberculosis (TB) remains a leading infectious disease killer globally. Treatment outcomes are especially poor among people with extensively drug-resistant (XDR) TB, until recently defined as rifampicin-resistant (RR) TB with resistance to an aminoglycoside (amikacin) and a fluoroquinolone (ofloxacin). We used laboratory TB test results from Western Cape province, South Africa between 2012 and 2015 to identify XDR-TB and pre-XDR-TB (RR-TB with resistance to one second-line drug) spatial hotspots. We mapped the percentage and count of individuals with RR-TB that had XDR-TB and pre-XDR-TB across the province and in Cape Town, as well as amikacin-resistant and ofloxacin-resistant TB. We found the percentage of pre-XDR-TB and the count of XDR-TB/pre-XDR-TB highly heterogeneous with geographic hotspots within RR-TB high burden areas, and found hotspots in both percentage and count of amikacin-resistant and ofloxacin-resistant TB. The spatial distribution of percentage ofloxacin-resistant TB hotspots was similar to XDR-TB hotspots, suggesting that fluoroquinolone-resistace is often the first step to additional resistance. Our work shows that interventions used to reduce XDR-TB incidence may need to be targeted within spatial locations of RR-TB, and further research is required to understand underlying drivers of XDR-TB transmission in these locations.

Unprecedented frequency of mitochondrial introns in colonial bilaterians.

Animal mitogenomes are typically devoid of introns. Here, we report the largest number of mitochondrial introns ever recorded from bilaterian animals. Mitochondrial introns were identified for the first time from the phylum Bryozoa. They were found in four species from three families (Order Cheilostomatida). A total of eight introns were found in the complete mitogenome of Exechonella vieirai, and five, 17 and 18 introns were found in the partial mitogenomes of Parantropora penelope, Discoporella cookae and Cupuladria biporosa, respectively. Intron-encoded protein domains reverse transcriptase and intron maturase (RVT-IM) were identified in all species. Introns in E. vieirai and P. penelope had conserved Group II intron ribozyme domains V and VI. Conserved domains were lacking from introns in D. cookae and C. biporosa, preventing their further categorization. Putative origins of metazoan introns were explored in a phylogenetic context, using an up-to-date alignment of mitochondrial RVT-IM domains. Results confirmed previous findings of multiple origins of annelid, placozoan and sponge RVT-IM domains and provided evidence for common intron donor sources across metazoan phyla. Our results corroborate growing evidence that some metazoans with regenerative abilities (i.e. placozoans, sponges, annelids and bryozoans) are susceptible to intron integration, most likely via horizontal gene transfer.

Geographic accessibility to health facilities predicts uptake of community-based tuberculosis screening in an urban setting.

OBJECTIVES: Annually, more than 30% of individuals with tuberculosis (TB) remain undiagnosed. We aimed to assess whether geographic accessibility measures can identify neighborhoods that would benefit from TB screening services targeted toward closing the diagnosis gap. METHODS: We used data from a community-based mobile TB screening program in Carabayllo district, Lima, Peru. We constructed four accessibility measures from the geographic center of neighborhoods to health facilities. We used logistic regression to assess the association between these measures and screening uptake in one's residential neighborhood versus elsewhere, with quasi-information criterion values to assess the association. RESULTS: We analyzed the screening locations for 25,000 Carabayllo residents from 49 neighborhoods. Pedestrian walk time was preferable to Euclidean distance or vehicular time in our models. For each additional 12 minutes walking time between the neighborhood and the health facility, the odds of residents using TB screening units located in their neighborhoods increased by 50% (95% CI: 26%-78%). Females had 9% (95% CI: 3%-16%) increased odds versus males of using a screening unit in their own neighborhood. CONCLUSION: Placing mobile TB screening units in neighborhoods with longer pedestrian time to access health facilities could benefit individuals who face more acute access barriers to health care.

Tuberculous Meningitis in Children: A Forgotten Public Health Emergency.

Tuberculous meningitis (TBM) remains a major cause of morbidity and mortality in children with tuberculosis (TB), yet there are currently no estimates of the global burden of pediatric TBM. Due to frequent non-specific clinical presentation and limited and inadequate diagnostic tests, children with TBM are often diagnosed late or die undiagnosed. Even when diagnosed and treated, 20% of children with TBM die. Of survivors, the majority have substantial neurological disability with significant negative impact on children and their families. Surveillance data on this devastating form of TB can help to quantify the contribution of TBM to the overall burden, morbidity and mortality of TB in children and the epidemiology of TB more broadly. Pediatric TBM usually occurs shortly after primary infection with Mycobacterium tuberculosis and reflects ongoing TB transmission to children. In this article we explain the public health importance of pediatric TBM, discuss the epidemiology within the context of overall TB control and health system functioning and the limitations of current surveillance strategies. We provide a clear rationale for the benefit of improved surveillance of pediatric TBM using a TB care cascade framework to support monitoring and evaluation of pediatric TB, and TB control more broadly. Considering the public health implications of a diagnosis of TBM in children, we provide recommendations to strengthen pediatric TBM surveillance and outline how improved surveillance can help us identify opportunities for prevention, earlier diagnosis and improved care to minimize the impact of TBM on children globally.

Missed Tuberculosis Diagnoses: Analysis of Pediatric Autopsy Data From General Hospitals in Lviv, Ukraine.

We reviewed autopsy data from general hospitals in Lviv, Ukraine to understand pediatric mortality due to tuberculosis (TB). We identified 14 (0.6%) of 2345 autopsied children with unrecognized or untreated TB. More sensitive TB diagnostics for children and improved strategies for identifying which children require TB evaluation are urgently needed.

Paleozoic origins of cheilostome bryozoans and their parental care inferred by a new genome-skimmed phylogeny.

Phylogenetic relationships and the timing of evolutionary events are essential for understanding evolution on longer time scales. Cheilostome bryozoans are a group of ubiquitous, species-rich, marine colonial organisms with an excellent fossil record but lack phylogenetic relationships inferred from molecular data. We present genome-skimmed data for 395 cheilostomes and combine these with 315 published sequences to infer relationships and the timing of key events among c. 500 cheilostome species. We find that named cheilostome genera and species are phylogenetically coherent, rendering fossil or contemporary specimens readily delimited using only skeletal morphology. Our phylogeny shows that parental care in the form of brooding evolved several times independently but was never lost in cheilostomes. Our fossil calibration, robust to varied assumptions, indicates that the cheilostome lineage and parental care therein could have Paleozoic origins, much older than the first known fossil record of cheilostomes in the Late Jurassic.

Mapping local hot spots with routine tuberculosis data: A pragmatic approach to identify spatial variability.

OBJECTIVE: To use routinely collected data, with the addition of geographic information and census data, to identify local hot spots of rates of reported tuberculosis cases. DESIGN: Residential locations of tuberculosis cases identified from eight public health facilities in Lima, Peru (2013-2018) were linked to census data to calculate neighborhood-level annual case rates. Heat maps of tuberculosis case rates by neighborhood were created. Local indicators of spatial autocorrelation, Moran's I, were used to identify where in the study area spatial clusters and outliers of tuberculosis case rates were occurring. Age- and sex-stratified case rates were also assessed. RESULTS: We identified reports of 1,295 TB cases across 74 neighborhoods during the five-year study period, for an average annual rate of 124.2 reported TB cases per 100,000 population. In evaluating case rates by individual neighborhood, we identified a median rate of reported cases of 123.6 and a range from 0 to 800 cases per 100,000 population. Individuals aged 15-44 years old and men had higher case rates than other age groups and women. Locations of both hot and cold spots overlapped across age- and gender-specific maps. CONCLUSIONS: There is significant geographic heterogeneity in rates of reported TB cases and evident hot and cold spots within the study area. Characterization of the spatial distribution of these rates and local hot spots may be one practical tool to inform the work of local coalitions to target TB interventions in their zones.

Addressing the Data Gaps on Child and Adolescent Tuberculosis.

The burden of tuberculosis (TB) among children and young adolescents (<15 years old) is estimated at 1.1 million; however, only 400,000 are treated for TB, indicating a large gap between the number who are cared for and the number estimated to have TB. Accurate data on the burden of pediatric TB is essential to guide action. Despite several improvements in estimating the burden of pediatric TB in the last decade, as well as enhanced data collection efforts, several data gaps remain, both at the global level, but also at the national level where surveillance systems and collaborative research are critical. In this article, we describe recent advances in data collection and burden estimates for TB among children and adolescents, and the remaining gaps. While data collection continues to improve, burden estimates must evolve in parallel, both in terms of their frequency and the methods used. Currently, at the global level, there is a focus on age-disaggregation of TB notifications, the collection of data on TB-HIV, multi-drug resistant (MDR)-TB and treatment outcomes, as well as estimates of the disease burden. Additional data from national surveillance systems or research projects on TB meningitis, as well as other forms of extra-pulmonary TB, would be useful. We must capitalize on the current momentum in child and adolescent TB to close the remaining data gaps for these age groups to better understand the epidemic and further reduce morbidity and mortality due to TB.