Phylogenetic inference of inter-population transmission rates for infectious diseases.

Estimating transmission rates is a challenging yet essential aspect of comprehending and controlling the spread of infectious diseases. Various methods exist for estimating transmission rates, each with distinct assumptions, data needs, and constraints. This study introduces a novel phylogenetic approach called transRate, which integrates genetic information with traditional epidemiological approaches to estimate inter-population transmission rates. The phylogenetic method is statistically consistent as the sample size (i.e. the number of pathogen genomes) approaches infinity under the multi-population susceptible-infected-recovered model. Simulation analyses indicate that transRate can accurately estimate the transmission rate with a sample size of 200 ~ 400 pathogen genomes. Using transRate, we analyzed 40,028 high-quality sequences of SARS-CoV-2 in human hosts during the early pandemic. Our analysis uncovered significant transmission between populations even before widespread travel restrictions were implemented. The development of transRate provides valuable insights for scientists and public health officials to enhance their understanding of the pandemic's progression and aiding in preparedness for future viral outbreaks. As public databases for genomic sequences continue to expand, transRate is increasingly vital for tracking and mitigating the spread of infectious diseases.

Bioinformatics mentorship in a resource limited setting.

BACKGROUND: The two recent simultaneous developments of high-throughput sequencing and increased computational power have brought bioinformatics to the forefront as an important tool for effective and efficient biomedical research. Consequently, there have been multiple approaches to developing bioinformatics skills. In resource rich environments, it has been possible to develop and implement formal fully accredited graduate degree training programs in bioinformatics. In resource limited settings with a paucity of expert bioinformaticians, infrastructure and financial resources, the task has been approached by delivering short courses on bioinformatics-lasting only a few days to a couple of weeks. Alternatively, courses are offered online, usually over a period of a few months. These approaches are limited by both the lack of sustained in-person trainer-trainee interactions, which is a key part of quality mentorships and short durations which constrain the amount of learning that can be achieved. METHODS: Here, we pioneered and tested a bioinformatics training/mentorship model that effectively uses the available expertise and computational infrastructure to deliver an in-person hands-on skills training experience. This is done through a few physical lecture hours each week, guided personal coursework over the rest of the week, group discussions and continuous close mentorship and assessment of trainees over a period of 1 year. RESULTS: This model has now completed its third iteration at Makerere University and has successfully mentored trainees, who have progressed to a variety of viable career paths. CONCLUSIONS: One-year (intermediate) skills based in-person bioinformatics training and mentorships are viable, effective and particularly appropriate for resource limited settings.

The 'Tully monster' is a vertebrate.

Problematic fossils, extinct taxa of enigmatic morphology that cannot be assigned to a known major group, were once a major issue in palaeontology. A long-favoured solution to the 'problem of the problematica', particularly the 'weird wonders' of the Cambrian Burgess Shale, was to consider them representatives of extinct phyla. A combination of new evidence and modern approaches to phylogenetic analysis has now resolved the affinities of most of these forms. Perhaps the most notable exception is Tullimonstrum gregarium, popularly known as the Tully monster, a large soft-bodied organism from the late Carboniferous Mazon Creek biota (approximately 309-307 million years ago) of Illinois, USA, which was designated the official state fossil of Illinois in 1989. Its phylogenetic position has remained uncertain and it has been compared with nemerteans, polychaetes, gastropods, conodonts, and the stem arthropod Opabinia. Here we review the morphology of Tullimonstrum based on an analysis of more than 1,200 specimens. We find that the anterior proboscis ends in a buccal apparatus containing teeth, the eyes project laterally on a long rigid bar, and the elongate segmented body bears a caudal fin with dorsal and ventral lobes. We describe new evidence for a notochord, cartilaginous arcualia, gill pouches, articulations within the proboscis, and multiple tooth rows adjacent to the mouth. This combination of characters, supported by phylogenetic analysis, identifies Tullimonstrum as a vertebrate, and places it on the stem lineage to lampreys (Petromyzontida). In addition to increasing the known morphological disparity of extinct lampreys, a chordate affinity for T. gregarium resolves the nature of a soft-bodied fossil which has been debated for more than 50 years.

Transmission Dynamics in Tuberculosis Patients With Human Immunodeficiency Virus: A Systematic Review and Meta-analysis of 32 Observational Studies.

BACKGROUND: There are large knowledge gaps on the transmission dynamics of Mycobacterium tuberculosis in settings where both tuberculosis and human immunodeficiency virus (HIV) are endemic. We aimed to assess the infectiousness of tuberculosis patients coinfected with HIV. METHODS: We systematically searched for studies of contacts of both HIV-positive and HIV-negative tuberculosis index cases. Our primary outcome was Mycobacterium tuberculosis infection in contacts. Data on sputum smear and lung cavitation status of index cases were extracted from each study to assess effect modification. Secondary outcomes included prevalent tuberculosis and HIV in contacts of HIV-positive and HIV-negative index cases. RESULTS: Of 5255 original citations identified, 32 studies met inclusion criteria, including 25 studies investigating M. tuberculosis infection (Nparticipants = 36 893), 13 on tuberculosis (Nparticipants = 18 853), and 12 on HIV positivity (Nparticipants = 18 424). Risk of M. tuberculosis infection was lower in contacts of HIV-positive index cases (odds ratio [OR], 0.67, 95% confidence interval [CI], .58-.77) but was heterogeneous (I2 = 75.1%). Two factors modified this relationship: the lung cavitary status of the index case and immunosuppression (measured through CD4 counts or HIV or acquired immunodeficiency syndrome diagnoses) among index people living with HIV. Rates of HIV were consistently higher in contacts of coinfected index cases (OR, 4.9; 95% CI, 3.0-8.0). This was modified by whether the study was in sub-Saharan Africa (OR, 2.8; 95% CI, 1.6-4.9) or in another global region (OR, 9.8; 95% CI, 5.9-16.3). CONCLUSIONS: Tuberculosis patients coinfected with HIV are less infectious than HIV-uninfected cases when they have severe immunosuppression or paucibacillary disease. Contacts of coinfected index cases are almost 5 times more likely to also have HIV.

Excess Risk of Tuberculosis Infection Among Extra-household Contacts of Tuberculosis Cases in an African City.

BACKGROUND: Although households of tuberculosis (TB) cases represent a setting for intense transmission of Mycobacterium tuberculosis, household exposure accounts for <20% of transmission within a community. The aim of this study was to estimate excess risk of M. tuberculosis infection among household and extra-household contacts of index cases. METHODS: We performed a cross-sectional study in Kampala, Uganda, to delineate social networks of TB cases and matched controls without TB. We estimated the age-stratified prevalence difference of TB infection between case and control networks, partitioned as household and extra-household contacts. RESULTS: We enrolled 123 index cases, 124 index controls, and 2415 first-degree network contacts. The prevalence of infection was highest among household contacts of cases (61.5%), lowest among household contacts of controls (25.2%), and intermediary among extra-household TB contacts (44.9%) and extra-household control contacts (41.2%). The age-adjusted prevalence difference between extra-household contacts of cases and their controls was 5.4%. The prevalence of infection was similar among the majority of extra-household case contacts and corresponding controls (47%). CONCLUSIONS: Most first-degree social network members of TB cases do not have adequate contact with the index case to experience additional risk for infection, but appear instead to acquire infection through unrecognized exposures with infectious cases in the community.

Community drivers of tuberculosis diagnostic delay in Kampala, Uganda: a retrospective cohort study.

BACKGROUND: Recent approaches to TB control have focused on identifying and treating active cases to halt further transmission. Patients with TB symptoms often delay to seek care, get appropriate diagnosis, and initiate effective treatment. These delays are partly influenced by whom the patients contact within their community network. We aimed to evaluate the community drivers of diagnostic delay in an urban setting in Uganda. METHODS: In this study we analyze data from a retrospective cohort of 194 TB patients in Kampala, Uganda. We characterized the patterns of contacts made by patients seeking care for TB symptoms. The main outcome of interest was total community contact delay, defined as the time patients spent seeking care before visiting a provider capable of diagnosing TB. RESULTS: Visits to health providers without access to appropriate diagnostic services accounted for 56% of contacts made by cohort members, and were significantly associated with community contact delay, as were symptoms common to other prevalent illnesses, such as bone and joint pain. CONCLUSIONS: Education programs aimed at primary care providers, as well as other community members, may benefit case identification, by informing them of rarer symptoms of TB, potential for co-infections of TB and other prevalent diseases, and the availability of diagnostic services.

Association between tuberculosis in men and social network structure in Kampala, Uganda.

BACKGROUND: Globally, tuberculosis disease (TB) is more common among males than females. Recent research proposes that differences in social mixing by sex could alter infection patterns in TB. We examine evidence for two mechanisms by which social-mixing could increase men's contact rates with TB cases. First, men could be positioned in social networks such that they contact more people or social groups. Second, preferential mixing by sex could prime men to have more exposure to TB cases. METHODS: We compared the networks of male and female TB cases and healthy matched controls living in Kampala, Uganda. Specifically, we estimated their positions in social networks (network distance to TB cases, degree, betweenness, and closeness) and assortativity patterns (mixing with adult men, women, and children inside and outside the household). RESULTS: The observed network consisted of 11,840 individuals. There were few differences in estimates of node position by sex. We found distinct mixing patterns by sex and TB disease status including that TB cases have proportionally more adult male contacts and fewer contacts with children. CONCLUSIONS: This analysis used a network approach to study how social mixing patterns are associated with TB disease. Understanding these mechanisms may have implications for designing targeted intervention strategies in high-burden populations.

Heme oxygenase-1 and neopterin plasma/serum levels and their role in diagnosing active and latent TB among HIV/TB co-infected patients: a cross sectional study.

BACKGROUND: Tuberculosis (TB) diagnosis in the context of HIV co-infection remains challenging. Heme oxygenase 1 (HO-1) and neopterin have been validated as potential biomarkers for TB diagnosis. Latent TB infection (LTBI) is diagnosed using tuberculin skin test (TST) and interferon gamma release assays (T-Spot and QuantiFERON TB gold tests, respectively). However, these tests have shown challenges and yet diagnosing LTBI is important for the overall control of TB. This study was conducted to determine the levels of H0-1 and neopterin, and their role in the diagnosis of TB among individuals enrolled in the Community Health and Social Network of Tuberculosis (COHSONET) study and the Kampala TB Drug Resistance Survey (KDRS). METHODS: This was a nested cross-sectional study. Plasma and serum samples collected from 140 patients at Mulago National Referral Hospital, Kampala Uganda were used. M.tb culture was performed on sputum to confirm active TB(ATB) and QuantiFERON TB gold test to confirm latent TB infection (LTBI). ELISAs were performed to determine the levels of HO-1 and neopterin. Data analysis was done using t-test and Receiver Operating Characteristic curves to determine the diagnostic accuracy. RESULTS: HO-1 levels among active tuberculosis (ATB)/HIV-infected patients and LTBI/HIV-infected patients were 10.7 ng/ml (IQR: 7.3-12.7 ng/ml) and 7.5 ng/ml (IQR: 5.4-14.1 ng/ml) respectively. Neopterin levels among ATB/HIV-positive patients and LTBI/HIV-positive patients were 11.7 ng/ml (IQR: 5.2.4 ng/ml) and 8.8 ng/ml (IQR: 2.4-19.8 ng/ml), respectively. HO-1 showed a sensitivity of 58.57% and a specificity of 67.14% with area under the curve (AUC) of 0.57 when used to discriminate between ATB and LTB. Neopterin showed an AUC of 0.62 with a sensitivity of 57.14% and a specificity of 60.0% when used to distinguish ATB from LTB. CONCLUSION: There was no in significant difference in HO-1 concentration levels of ATB individuals compared to LTB individuals. There was a significant difference in neopterin concentrations levels of ATB individuals compared to latently infected individuals. Findings from this study, show that HO-1 and neopterin have poor ability to distinguish between ATB and LTB.

Neuraxial Anesthesia Is Associated With Decreased Pain Scores and Post-Anesthesia Care Unit Opioid Requirement Compared With General Anesthesia in Hip Arthroscopy.

PURPOSE: We sought to identify the immediate postoperative differences in opioid use, pain scores, and post-anesthesia care unit (PACU) length of stay (LOS) after hip arthroscopy related to the type of anesthesia used for the surgical procedure. METHODS: Patients undergoing hip arthroscopy for femoroacetabular impingement syndrome with labral tears by a single surgeon at an academic center between October 2017 and July 2019 were reviewed retrospectively. The primary outcome was PACU opioid administration, measured by morphine equivalents. Secondary parameters included total LOS, postincision LOS, PACU LOS, and PACU arrival/discharge pain scores. Analyses conducted were t tests, Wilcoxon rank sum tests, or χ2 tests. RESULTS: A total of 129 patients met inclusion criteria for this study; 54 male and 75 female, with an average age of 28 (±10.1) years. In total, 52 (40.3%) had general anesthesia and 77 (59.7%) had neuraxial anesthesia, including spinal, epidural, and combined spinal-epidural anesthesia, which were intermixed throughout the study period. Intraoperative and PACU opioid administration demonstrated a significant difference in medians. Neuraxial methods required a lower morphine equivalents in both the operating room (30.0 vs 53.9, P = .001) and PACU (18.2 vs 31.2, P = 0.002). Neuraxial anesthesia had lower median PACU arrival and discharge pain scores (0.0 vs. 5.0, P = .001, 3.0 vs. 4.0, P = .013). There was no statistically significant difference in postincision LOS or traction time. General anesthesia was associated with a longer PACU phase 1 time (1.0 vs 1.3 hours, P = .005). No major adverse events such as death, disability, or prolonged hospitalization occurred in either group. CONCLUSIONS: Neuraxial anesthesia use in routine hip arthroscopy was associated with lower immediate postoperative pain scores, lower intraoperative and immediate postoperative opioid requirements, and may be associated with shorter anesthesia recovery time without any major adverse events when compared with general anesthesia. LEVEL OF EVIDENCE: III, Retrospective Comparative Study.

Modeling Approaches to Predicting Persistent Hotspots in SCORE Studies for Gaining Control of Schistosomiasis Mansoni in Kenya and Tanzania.

BACKGROUND: Some villages, labeled "persistent hotspots (PHS)," fail to respond adequately in regard to prevalence and intensity of infection to mass drug administration (MDA) for schistosomiasis. Early identification of PHS, for example, before initiating or after 1 or 2 years of MDA could help guide programmatic decision making. METHODS: In a study with multiple rounds of MDA, data collected before the third MDA were used to predict PHS. We assessed 6 predictive approaches using data from before MDA and after 2 rounds of annual MDA from Kenya and Tanzania. RESULTS: Generalized linear models with variable selection possessed relatively stable performance compared with tree-based methods. Models applied to Kenya data alone or combined data from Kenya and Tanzania could reach over 80% predictive accuracy, whereas predicting PHS for Tanzania was challenging. Models developed from one country and validated in another failed to achieve satisfactory performance. Several Year-3 variables were identified as key predictors. CONCLUSIONS: Statistical models applied to Year-3 data could help predict PHS and guide program decisions, with infection intensity, prevalence of heavy infections (≥400 eggs/gram of feces), and total prevalence being particularly important factors. Additional studies including more variables and locations could help in developing generalizable models.

Defining adequate contact for transmission of Mycobacterium tuberculosis in an African urban environment.

BACKGROUND: The risk of infection from respiratory pathogens increases according to the contact rate between the infectious case and susceptible contact, but the definition of adequate contact for transmission is not standard. In this study we aimed to identify factors that can explain the level of contact between tuberculosis cases and their social networks in an African urban environment. METHODS: This was a cross-sectional study conducted in Kampala, Uganda from 2013 to 2017. We carried out an exploratory factor analysis (EFA) in social network data from tuberculosis cases and their contacts. We evaluated the factorability of the data to EFA using the Kaiser-Meyer-Olkin Measure of Sampling Adequacy (KMO). We used principal axis factoring with oblique rotation to extract and rotate the factors, then we calculated factor scores for each using the weighted sum scores method. We assessed construct validity of the factors by associating the factors with other variables related to social mixing. RESULTS: Tuberculosis cases (N = 120) listed their encounters with 1154 members of their social networks. Two factors were identified, the first named "Setting" captured 61% of the variance whereas the second, named 'Relationship' captured 21%. Median scores for the setting and relationship factors were 10.2 (IQR 7.0, 13.6) and 7.7 (IQR 6.4, 10.1) respectively. Setting and Relationship scores varied according to the age, gender, and nature of the relationship among tuberculosis cases and their contacts. Family members had a higher median setting score (13.8, IQR 11.6, 15.7) than non-family members (7.2, IQR 6.2, 9.4). The median relationship score in family members (9.9, IQR 7.6, 11.5) was also higher than in non-family members (6.9, IQR 5.6, 8.1). For both factors, household contacts had higher scores than extra-household contacts (p < .0001). Contacts of male cases had a lower setting score as opposed to contacts of female cases. In contrast, contacts of male and female cases had similar relationship scores. CONCLUSIONS: In this large cross-sectional study from an urban African setting, we identified two factors that can assess adequate contact between tuberculosis cases and their social network members. These findings also confirm the complexity and heterogeneity of social mixing.

Tracking Progress Toward Elimination of Mother to Child Transmission of HIV in Zambia: Findings from the Early Infant Diagnosis of HIV Program (2009-2017).

BACKGROUND: We carried out analyses of early infant testing results at Livingstone Central Hospital in Zambia to assess time of testing, linkages to care and availability of test results for clinical decision making. METHODS: We abstracted data from registers of HIV-exposed infants who had dried blood spots cards (DBS) collected for DNA-PCR from January 2009 to December 2017. Only those tested from 2014 to 2017 had additional data which were used to estimate risk factors for mother-to-child HIV transmission using logistic regression models. RESULTS: DBS were collected from 2630 children. The proportion of HIV-positive tests decreased from 21% in 2009 to 2% in 2016 and 2017. Median turnaround time for results was 9 weeks (IQR: 5, 15) for HIV-negative, 7 weeks (IQR: 5, 13) for HIV-positive children. Only 2% of infants whose mothers took antiretroviral therapy (ART) were HIV positive, while 18% of infants whose mothers took short course antiretroviral drugs (ARVs) were infected. Infants of mothers who did not take ARVs had 9 times the odds of an HIV positive test (OR = 8.9, 95% CI: 3.6, 22.6). Infants of mothers who received short course ARVs were 40% less likely to get an HIV test within the first 2 months of life (OR = 0.6, 95% CI: 0.4, 0.9) compared to infants of mothers who received ART. Only 52% had a third test at median age 52 weeks (IQR: 50, 54). CONCLUSIONS: Long turnaround time for test results and low retention in care after the initial HIV test were critical challenges to clinical decision making.

Urban-rural disparities in treatment outcomes among recurrent TB cases in Southern Province, Zambia.

BACKGROUND: At least 13-20% of all Tuberculosis (TB) cases are recurrent TB. Recurrent TB has critical public health importance because recurrent TB patients have high risk of Multi-Drug Resistant TB (MDR-TB). It is critical to understand variations in the prevalence and treatment outcomes of recurrent TB between different geographical settings. The objective of our study was to estimate the prevalence of recurrent TB among TB cases and compare risk of unfavorable treatment outcomes between rural and urban settings. METHODS: In a retrospective cohort study conducted in southern province of Zambia, we used mixed effects logistic regression to asses associations between explanatory and outcome variables. Primary outcome was all-cause mortality and exposure was setting (rural/urban). Data was abstracted from the facility TB registers. RESULTS: Overall 3566 recurrent TB cases were diagnosed among 25,533 TB patients. The prevalence of recurrent TB was 15.3% (95% CI: 14.8 15.9) in urban and 11.3% (95% CI: 10.7 12.0) in rural areas. Death occurred in 197 (5.5%), 103 (2.9%) were lost to follow-up, and 113 (3.2%) failed treatment. Rural settings had 70% higher risk of death (adjusted OR: 1.7; 95% CI: 1.2 2.7). Risk of lost to follow-up was twice higher in rural than urban (adjusted OR: 2.0 95% CI: 1.3 3.0). Compared to HIV-uninfected, HIV-infected individuals on Antiretroviral Treatment (ART) were 70% more likely to die (adjusted OR: 1.7; 95% CI: 1.2 3.1). CONCLUSION: Recurrent TB prevalence was generally high in both urban and rural settings. The risk of mortality and lost to follow-up was higher among rural patients. We recommend a well-organized Directly Observed Therapy strategy adapted to setting where heightened TB control activities are focused on areas with poor treatment outcomes.

Clinical management decisions for adults with prolonged acute cough: Frequency and associated factors.

BACKGROUND: Uncomplicated episodes of prolonged acute cough are usually viral and self-limited, but despite evidence and recommendations to the contrary, they are often treated with antibiotics. METHODS: Mixed cross-sectional and prospective observational study of adults 18 years or older presenting to two urgent care centers with a cough of 7 to 56 days as their chief complaint. Factors associated with cough duration and clinical decisions were analyzed by univariate and multivariate logistic regression. RESULTS: Of the 125 enrolled patients, 118 (94%) received an antibiotic, 97 (78%) a cough suppressant, 87 (70%) a systemic corticosteroid, and 39 (31%) a chest X-ray (CXR). Longer duration of cough was associated with the presence of self-reported wheezing or noises (adjusted odds ratio 6.29, 95% CI 1.36-29.16) while the presence of both wheezing and crackles on a clinician chest exam was associated with shorter duration (aOR 0.03, 95% CI 0.00-0.27). A clinician was more likely to order a CXR in patients with dyspnea (aOR 3.01, 95% CI 1.21-7.49), less likely to prescribe a systemic corticosteroid in patients with crackles (aOR 0.27, 95% CI 0.09-0.82), and more likely to prescribe a cough suppressant to older patients (1.04 per additional year of age, 95% CI 1.01-1.07). CONCLUSIONS: Systemic corticosteroids and cough suppressants are being prescribed at high rates in patients with uncomplicated acute cough in the urgent care setting. Additional studies to determine if similar rates are seen in other urgent care centers, or in other contemporary ambulatory settings are warranted.

Predictors of loss to follow-up among children on long-term antiretroviral therapy in Zambia (2003-2015).

BACKGROUND: Retention in care is critical for children living with HIV taking antiretroviral therapy (ART). Loss to follow-up (LTFU) is high in HIV treatment programs in resource limited settings. We estimated the cumulative incidence of LTFU and identified associated risk factors among children on ART at Livingstone Central Hospital (LCH), Zambia. METHODS: Using a retrospective cohort study design, we abstracted data from medical records of children who received ART between 2003 and 2015. Loss to follow-up was defined as no clinical and pharmacy contact for at least 90 days after the child missed their last scheduled clinical visit. Non-parametric competing risks models were used to estimate the cumulative incidence of death, LTFU and transfer. Cause-specific Cox regression was used to estimate the hazard ratios of the risk factors of LTFU. RESULTS: A total of 1039 children aged 0-15 years commenced ART at LCH between 2003 and 2015. Median duration of follow-up was 3.8 years (95% CI: 1.2-6.5), median age at ART initiation was 3.6 years (IQR: 1.3-8.6), 179 (17%) started treatment during their first year of life. At least 167 (16%) were LTFU and we traced 151 (90%). Of those we traced, 39 (26%) had died, 71 (47%) defaulted, 20 (13%) continued ART at other clinics and 21 (14%) continued treatment with gaps. The cumulative incidence of LTFU for the entire cohort was 2.7% (95% CI: 1.9-3.9) at 3 months, 4.1% (95% CI: 2.9-5.4) at 6 months and 14.1% (95% CI: 12.4-16.9) after 5 years on ART. Associated risk factors were: 1) non-disclosure of HIV status at baseline, aHR = 1.9 (1.2-2.9), 2) No phone ownership, aHR = 2.1 (1.6-2.9), 3) starting treatment between 2013 to 2015, aHR = 5.6 (2.2-14.1). CONCLUSION: Among the children LTFU mortality and default were substantially high. Children who started treatment in recent years (2013-2015) had the highest hazard of LTFU. Lack of access to a phone and non-disclosure of HIV-status to the index child was associated with higher hazards of LTFU. We recommend re-enforcement of client counselling and focused follow-up strategies using modern technology such as mobile phones as adjunct to current approaches.

Long-term survival outcomes of HIV infected children receiving antiretroviral therapy: an observational study from Zambia (2003-2015).

BACKGROUND: In 2017, 64% of children living with HIV in Zambia accessed Antiretroviral Therapy (ART). Despite expanded ART coverage, there is paucity of information on effectiveness of pediatric ART in reducing mortality. The aim of this research is to describe treatment outcomes, measure mortality rates and assess predictors of mortality among children receiving ART. METHODS: Using a retrospective cohort study design, we abstracted routinely collected clinical data from medical records of children from birth to 15 years old, who had received ART for at least 6 months at Livingstone Central Hospital in Southern Province Zambia, between January 2003 and June 2015. The primary outcome was death. Cause of death was ascertained from medical records and death certificates. Distribution of survival times according to baseline covariates were estimated using Kaplan Meier and Cox Proportional Hazards methods. RESULTS: Overall, 1039 children were commenced on ART during the study period. The median age at treatment initiation was 3.6 years (IQR: 1.3-8.6) and 520 (50%) children were female. Of these, 71 (7%) died, 164 (16%) were lost to follow-up, 210 (20%) transferred and 594 (56%) were actively on treatment. After 4450 person years, mortality rate was 1.6/100 (95% CI: 1.4-1.8). Mortality was highest during the first 3 months of treatment (11.7/100 (95% CI: 7.6-16.3). In multivariable proportional hazards regression, the adjusted hazards of death were highest among children aged < 1 year (aHR = 3.1 (95% CI: 1.3-6.4), compared to those aged 6-15 years, WHO stage 4 (aHR =4.8 (95% CI: 2.3-10), compared to WHO stage 1 and 2. In the sensitivity analysis to address bias due to loss to follow-up, mortality increased 5 times when we assumed that all the children who were lost to follow up died within 90 days of their last visit. CONCLUSION: We observed low attrition due to mortality among children on ART. Loss to follow-up was high (16%). Mortality was highest during the first 3 months of treatment. Children aged less than one year and those with advanced WHO disease stage had higher mortality. We recommend effective interventions to improve retention in care and early diagnosis of HIV in children.

Resistance and Susceptibility to Mycobacterium tuberculosis Infection and Disease in Tuberculosis Households in Kampala, Uganda.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major public health problem. Household contact studies identify children and adults along the spectrum from Mtb exposure to disease. In the Kawempe Community Health Study (conducted in Kampala, Uganda), 872 culture-confirmed pulmonary TB cases and their 2,585 contacts were enrolled during 2002-2012 and followed for up to 2 years each. Risk factors identified by time-to-event analysis for secondary TB differed among children, women, and men. Younger age (P = 0.0061), human immunodeficiency virus (HIV) (P = 0.0002), thinness (P = 0.01), absent bacille Calmette-Guérin vaccination (P = 0.002), and epidemiologic risk score (P < 0.0001) were risks for children. For women, risks were HIV (P < 0.0001), thinness (World Health Organization criteria; P < 0.0001), and epidemiologic risk score (P = 0.003). For men, HIV (P = 0.0007) and low body mass index (P = 0.008) resulted in faster progression to TB. Tuberculin skin testing (TST) identified contacts with Mtb infection and those with persistently negative TST. Risks for faster time to Mtb infection were identified, and included age (P = 0.0007), baseline TST induration (P < 0.0001), and epidemiologic risk score (P < 0.0001) only in children. Those with persistently negative TST comprised 10% of contacts but had no unique epidemiologic characteristics among adults. The burden of Mtb infection and disease is high in TB households, and risk factors for progression from exposure to infection and disease differ among children, women, and men.

The Palaeozoic colonization of the water column and the rise of global nekton.

The colonization of the water column is among the most important transformations in the evolution of animal life and global ecosystems. The Devonian nekton revolution has been identified as a major macroevolutionary event signifying the rapid occupation of the water column by independent radiations of swimming animals. Using new data, an expanded taxonomic coverage, sample standardization and increased ecological resolution, we analysed patterns of nektonization during the Palaeozoic. We find that nekton and eunekton were well established prior to the Devonian and did not diversify dramatically during any Palaeozoic interval. Relative nektic diversity and occurrences decreased rather than increased during the Devonian. Eunektic diversity and occurrences increased throughout the Palaeozoic, but this rise was protracted and cannot be attributed to any single interval. Our new data indicate that the metazoan colonization of the water column was considerably more complex and gradual than previously understood.

Glycemic Control and the Prevalence of Tuberculosis Infection: A Population-based Observational Study.

BACKGROUND: Several cohort studies demonstrate that diabetics are at increased risk for active tuberculosis, and poor glycemic control may exacerbate this risk. A higher prevalence of tuberculosis infection at baseline among diabetics may partially explain these results; however, no population-based studies have investigated this association. Furthermore, whether glycemic control modifies the relationship between diabetes and tuberculosis infection, as it does with active tuberculosis, is unknown. METHODS: Diabetics were diagnosed through physician evaluation and using 3 laboratory tests including hemoglobin A1C (HbA1C), fasting plasma glucose (FPG), or 2-hour plasma glucose (PG). Tuberculosis infection was diagnosed through tuberculin skin tests, and glycemic control was assessed linearly and categorically using recommended targets. RESULTS: Among 4215 participants, the prevalence of tuberculosis infection was 4.1%, 5.5%, and 7.6% in nondiabetic, prediabetic, and diabetic participants (Ptrend = .012). In multivariate analysis, diabetes was associated with tuberculosis infection (adjusted odds ratio [AOR], 1.5; 95% confidence interval [CI], 1.0-2.2). Compared to nondiabetics, diabetics who were undiagnosed (AOR, 2.2 and 1.2 in diagnosed diabetics), FPG >130 mg/dL (AOR, 2.6 and 1.3 in diabetics with FPG ≤130 mg/dL), or not on insulin (AOR, 1.7 and 0.8 in diabetics on insulin) had elevated tuberculosis infection rates. In a linear dose-response analysis, increasing values of FPG (AOR, 1.02 per 1-mg/dL; 95% CI, 1.01-1.03), PG (AOR, 1.02 per 1-mg/dL; 95% CI, 1.01-1.04), and HbA1C (AOR, 1.13 per 1%; 95% CI, 1.04-1.22) all predicted tuberculosis infection. CONCLUSIONS: Our results suggest glycemic control may modify the relationship between tuberculosis infection and diabetes.

Transmission of Mycobacterium Tuberculosis in Households and the Community: A Systematic Review and Meta-Analysis.

The individual- and population-level impact of household tuberculosis exposure on transmission is unclear but may have implications for the effectiveness and implementation of control interventions. We systematically searched for and included studies in which latent tuberculosis infection was assessed in 2 groups: children exposed and unexposed to a household member with tuberculosis. We also extracted data on the smear and culture status of index cases, the age and bacillus Calmette-Guérin vaccination status of contacts, and study design characteristics. Of 6,176 citations identified from our search strategy, 26 studies (13,999 children with household exposure to tuberculosis and 174,097 children without) from 1929-2015 met inclusion criteria. Exposed children were 3.79 (95% confidence interval (CI): 3.01, 4.78) times more likely to be infected than were their community counterparts. Metaregression demonstrated higher infection among children aged 0-4 years of age compared with children aged 10-14 years (ratio of odds ratios = 2.24, 95% CI: 1.43, 3.51) and among smear-positive versus smear-negative index cases (ratio of odds ratios = 5.45, 95% CI: 3.43, 8.64). At the population level, we estimated that a small proportion (<20%) of transmission was attributable to household exposure. Our results suggest that targeting tuberculosis prevention efforts to household contacts is highly effective. However, a large proportion of transmission at the population level may occur outside the household.