Blood Inflammatory Biomarkers Differentiate Inpatient and Outpatient Coronavirus Disease 2019 From Influenza.

Background: The ongoing circulation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a diagnostic challenge because symptoms of coronavirus disease 2019 (COVID-19) are difficult to distinguish from other respiratory diseases. Our goal was to use statistical analyses and machine learning to identify biomarkers that distinguish patients with COVID-19 from patients with influenza. Methods: Cytokine levels were analyzed in plasma and serum samples from patients with influenza and COVID-19, which were collected as part of the Centers for Disease Control and Prevention's Hospitalized Adult Influenza Vaccine Effectiveness Network (inpatient network) and the US Flu Vaccine Effectiveness (outpatient network). Results: We determined that interleukin (IL)-10 family cytokines are significantly different between COVID-19 and influenza patients. The results suggest that the IL-10 family cytokines are a potential diagnostic biomarker to distinguish COVID-19 and influenza infection, especially for inpatients. We also demonstrate that cytokine combinations, consisting of up to 3 cytokines, can distinguish SARS-CoV-2 and influenza infection with high accuracy in both inpatient (area under the receiver operating characteristics curve [AUC] = 0.84) and outpatient (AUC = 0.81) groups, revealing another potential screening tool for SARS-CoV-2 infection. Conclusions: This study not only reveals prospective screening tools for COVID-19 infections that are independent of polymerase chain reaction testing or clinical condition, but it also emphasizes potential pathways involved in disease pathogenesis that act as potential targets for future mechanistic studies.

Hazardous alcohol use and HIV indicators in six African countries: results from the Population-based HIV Impact Assessments, 2015-2017.

INTRODUCTION: Hazardous alcohol use (HAU), defined as a pattern of alcohol consumption that increases the risk of harmful consequences for the user or others, is associated with an elevated risk of human immunodeficiency virus (HIV) infection and poor health outcomes. We describe the association between people living with HIV (PLHIV) who report HAU and key HIV indicators. Gaps in current literature in estimating HAU on HIV outcomes at the regional level of Eastern and Southern Africa still exist and our analysis aims to address this issue. METHODS: We used weighted pooled data (2015-2017) from the nationally representative Population-based HIV Impact Assessments among adults who provided written consent aged 18-59 years from Eswatini, Malawi, Namibia, Tanzania, Zambia and Zimbabwe. We estimated differences in the prevalence of HIV infection and The Joint United Nations Programme on HIV and AIDS (UNAIDS) 90-90-90 indicators between PLHIV by HAU status using log-binomial regression, stratified by sex. HAU was determined using the Alcohol Use Identification Test-Consumption. RESULTS: Among the 9755 women and 4444 men who tested HIV positive, 6.6% of women and 21.8% of men engaged in HAU. Women who reported HAU were more likely to be HIV positive (adjusted prevalence ratio [aPR] = 1.31, 95% CI: 1.18-1.46) compared to those who did not report HAU. For the UNAIDS 90-90-90 targets, women who engaged in HAU were more likely to be unaware of their HIV-positive status (aPR = 1.22, 95% CI: 1.01-1.47) and not on antiretroviral therapy (ART) (aPR = 1.73, 95% CI: 1.26-2.37). Men who engaged in HAU were more likely to be unaware of their HIV-positive status (aPR = 1.56, 95% CI 1.39-1.76) and not on ART (aPR = 1.72, 95% CI: 1.30-2.29). No difference in viral load suppression, defined as <1000 copies/ml of HIV RNA, was seen by sex. CONCLUSIONS: PLHIV who engage in HAU were more likely to have suboptimal outcomes along the HIV care continuum when compared to those who did not engage in HAU. Targeted interventions, such as alcohol screening for HAU in HIV testing and treatment settings and HIV prevention efforts in alcohol-based venues, may help countries reach HIV epidemic control by 2030.

Associations Between Mobility, Food Insecurity, and Transactional Sex Among Women in Cohabitating Partnerships: An Analysis From 6 African Countries 2016-2017.

BACKGROUND: Mobile women are at risk of HIV infection in sub-Saharan Africa, although we lack evidence for HIV risk among women in mobile partnerships, especially in the context of household food insecurity, a growing concern in the region. SETTING: Women aged 15-59 years with a cohabitating male partner who participated in population-based HIV impact assessment surveys in Eswatini, Lesotho, Namibia, Tanzania, Uganda, and Zambia. METHODS: We evaluated the association between women's and their partner's mobility (being away from home for more than 1 month or staying elsewhere) and transactional sex (selling sex or receiving money or goods in exchange for sex). We examined associations for effect measure modification by food insecurity level in the household in the past month. We used survey-weighted logistic regression, pooled and by country, adjusting for individual, partner, and household-level variables. RESULTS: Among women with a cohabitating male partner, 8.0% reported transactional sex, ranging from 2.7% in Lesotho to 13.4% in Uganda. Women's mobility [aOR 1.35 (95% CI: 1.08 to 1.68)], but not their partner's mobility [aOR 0.91 (0.74-1.12)], was associated with transactional sex. Food insecurity was associated with transactional sex independent of mobility [aOR 1.29 (1.10-1.52)]. Among those who were food insecure, mobility was not associated with increased odds of transactional sex. CONCLUSION: Food insecurity and women's mobility each increased the odds of transactional sex. Because transactional sex is associated with HIV risk, prevention programs can address the needs of mobile and food-insecure women, including those in cohabitating relationships.

Migration in Namibia and its association with HIV acquisition and treatment outcomes.

BACKGROUND: In the 21st century, understanding how population migration impacts human health is critical. Namibia has high migration rates and HIV prevalence, but little is known about how these intersect. We examined the association between migration and HIV-related outcomes using data from the 2017 Namibia Population-based HIV Impact Assessment (NAMPHIA). METHODS AND FINDINGS: The NAMPHIA survey selected a nationally representative sample of adults in 2017. All adults aged 15-64 years were invited to complete an interview and home-based HIV test. Recent infection (<130 days) was measured using HIV-1 LAg avidity combined with viral load (>1000 copies/mL) and antiretroviral analyte data. Awareness of HIV status and antiretroviral use were based on self-report and/or detectable antiretrovirals in blood. Viremia was defined as having a viral load ≥1000 copies/mL, including all participants in the denominator regardless of serostatus. We generated community viremia values as a weighted proportion at the EA level, excluding those classified as recently infected. Significant migrants were those who had lived outside their current region or away from home >one month in the past three years. Recent cross-community in-migrants were those who had moved to the community two years ago to determine the association of migration and timing with recent infection or viral load suppression (VLS). All proportions are weighted. Of eligible adults, we had HIV results and migration data on 9,625 (83.9%) of 11,474 women and 7,291 (73.0%) of 9,990 men. Most respondents (62.5%) reported significant migration. Of cross-community in-migrants, 15.3% were recent. HIV prevalence was 12.6% and did not differ by migration status. Population VLS was 77.4%. Recent cross-community in-migration was associated with recent HIV infection (aOR: 4.01, 95% CI 0.99-16.22) after adjusting for community viremia. Significant migration (aOR 0.73, 95% CI: 0.55-0.97) and recent cross-community in-migration (aOR 0.57, 95% CI: 0.35-0.92) were associated with lower VLS, primarily due to lack of awareness of HIV infection. The study was limited by lack of precise data on trajectory of migration. CONCLUSIONS: Despite a high population-level VLS, Namibia still has migrant populations that are not accessing effective treatment for HIV. Targeting migrants with effective prevention and testing programs in communities with viremia could enable further epidemic control.

The role of Namibia Field Epidemiology and Laboratory Training Programme in strengthening the public health workforce in Namibia, 2012-2019.

Namibia faces a critical shortage of skilled public health workers to perform emergency response operations, preparedness activities and real-time surveillance. The Namibia Field Epidemiology and Laboratory Training Programme (NamFELTP) increases the number of skilled public health professionals and strengthens the public health system in Namibia. We describe the NamFELTP during its first 7 years, assess its impact on the public health workforce and provide recommendations to further strengthen the workforce. We reviewed disease outbreak investigations and response reports, field projects and epidemiological investigations conducted during 2012-2019. The data were analysed using descriptive methods such as frequencies and rates. Maps representing the geographical distribution of NamFELTP workforce were produced using QGIS software V.3.2. There were no formally trained field epidemiologists working in Namibia before the NamFELTP. In its 7 years of operation, the programme graduated 189 field epidemiologists, of which 28 have completed the Advanced FELTP. The graduates increased epidemiological capacity for surveillance and response in Namibia at the national and provincial levels, and enhanced epidemiologist-led outbreak responses on 35 occasions, including responses to outbreaks of human and zoonotic diseases. Trainees analysed data from 51 surveillance systems and completed 31 epidemiological studies. The NamFELTP improved outcomes in the Namibia's public health systems; including functional and robust public health surveillance systems that timely and effectively respond to public health emergencies. However, the current epidemiological capacity is insufficient and there is a need to continue training and mentorship to fill key leadership and strategic roles in the public health system.

Analysis of Glyphosate Residues in Foods from the Canadian Retail Markets between 2015 and 2017.

Underlying the risk management of pesticides to protect human health and to facilitate trade among nations are sound scientific data on the levels of compliance with standards set by governments and internationally from monitoring of the levels of pesticides in foods. Although glyphosate is among the universally used pesticides in the world, monitoring has been hampered by the analytical difficulties in dealing with this highly polar compound. Starting in 2015, using liquid chromatography/tandem mass spectrometry (LC-MS/MS) that permits accurate and reproducible determination of glyphosate, the prevalence, concentrations, and compliance rates were determined. In this work, the glyphosate residues contents of 7955 samples of fresh fruits and vegetables, milled grain products, pulse products, and finished foods collected from April 2015 to March 2017 in the Canadian retail market are reported. A total of 3366 samples (42.3%) contained detectable glyphosate residues. The compliance rate with Canadian regulations was 99.4%. There were 46 noncompliant samples. Health Canada determined that there was no long-term health risk to Canadian consumers from exposure to the levels of glyphosate found in the samples of a variety of foods surveyed. The high level of compliance (99.4% of samples with the Canadian regulatory limits) and the lack of a health risk for noncompliant samples indicate that, with respect to glyphosates, the food available for sale in Canada is safe.

Scaling Up Testing for Human Immunodeficiency Virus Infection Among Contacts of Index Patients - 20 Countries, 2016-2018.

In 2017, the Joint United Nations Programme on HIV/AIDS (UNAIDS) estimated that worldwide, 36.9 million persons were living with human immunodeficiency virus (HIV) infection, the virus infection that causes acquired immunodeficiency syndrome (AIDS). Among persons with HIV infection, approximately 75% were aware of their HIV status, leaving 9.4 million persons with undiagnosed infection (1). Index testing, also known as partner notification or contact tracing, is an effective case-finding strategy that targets the exposed contacts of HIV-positive persons for HIV testing services. This report summarizes data from HIV tests using index testing in 20 countries supported by CDC through the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) during October 1, 2016-March 31, 2018. During this 18-month period, 1,700,998 HIV tests with 99,201 (5.8%) positive results were reported using index testing. The positivity rate for index testing was 9.8% among persons aged ≥15 years and 1.5% among persons aged <15 years. During the reporting period, HIV positivity increased 64% among persons aged ≥15 years (from 7.6% to 12.5%) and 67% among persons aged <15 years (from 1.2% to 2.0%). Expanding index testing services could help increase the number of persons with HIV infection who know their status, are initiated onto antiretroviral treatment, and consequently reduce the number of persons who can transmit the virus.

Anthrax Epizootic in Wildlife, Bwabwata National Park, Namibia, 2017.

In late September 2017, Bwabwata National Park in Namibia experienced a sudden die-off of hippopotamuses and Cape buffalo. A multiorganizational response was initiated, involving several ministries within Namibia and the US Centers for Disease Control and Prevention. Rapid interventions resulted in zero human or livestock cases associated with this epizootic.

Establishment of CDC Global Rapid Response Team to Ensure Global Health Security.

The 2014-2016 Ebola virus disease epidemic in West Africa highlighted challenges faced by the global response to a large public health emergency. Consequently, the US Centers for Disease Control and Prevention established the Global Rapid Response Team (GRRT) to strengthen emergency response capacity to global health threats, thereby ensuring global health security. Dedicated GRRT staff can be rapidly mobilized for extended missions, improving partner coordination and the continuity of response operations. A large, agencywide roster of surge staff enables rapid mobilization of qualified responders with wide-ranging experience and expertise. Team members are offered emergency response training, technical training, foreign language training, and responder readiness support. Recent response missions illustrate the breadth of support the team provides. GRRT serves as a model for other countries and is committed to strengthening emergency response capacity to respond to outbreaks and emergencies worldwide, thereby enhancing global health security.

Use of a nationwide call center for Ebola response and monitoring during a 3-day house-to-house campaign - Sierra Leone, September 2014.

During May 23, 2014-January 10, 2015, Sierra Leone reported 7,777 confirmed cases of Ebola virus disease (Ebola). In response to the epidemic, on August 5, Sierra Leone's Emergency Operations Center established a toll-free, nationwide Ebola call center. The purpose of the call center is to encourage public reporting of possible Ebola cases and deaths to public health officials and to provide health education about Ebola to callers. This information also functions as an "alert" system for public health officials and supports surveillance efforts for the response. National call center dispatchers call district-level response teams composed of surveillance officers and burial teams to inform them of reported deaths and possible Ebola cases. Members of these response teams investigate cases and conduct follow-up actions such as transporting ill persons to Ebola treatment units or providing safe, dignified medical burials as resources permit. The call center continues to operate. This report describes calls received during a 3-day national campaign and reports the results of an assessment of the call center operation during the campaign.

Ascariasis in humans and pigs on small-scale farms, Maine, USA, 2010-2013.

Ascaris is a genus of parasitic nematodes that can cause infections in humans and pigs. During 2010-2013, we identified 14 cases of ascariasis in persons who had contact with pigs in Maine, USA. Ascaris spp. are important zoonotic pathogens, and prevention measures are needed, including health education, farming practice improvements, and personal and food hygiene.

HIV and related risk behavior among men who have sex with men in Zanzibar, Tanzania: results of a behavioral surveillance survey.

We conducted a respondent driven sampling survey to estimate HIV prevalence and risk behavior among men who have sex with men (MSM) in Unguja, Zanzibar. Men aged ≥ 15 years living in Unguja and reporting anal sex with another man in the past 3 months were asked to complete a questionnaire and provide specimens for biologic testing. HIV prevalence was 12.3% (95% confidence interval 8.7, 16.3). HIV infection was associated with injecting drugs in the past 3 months, Hepatitis C virus infection and being paid for sex in the past year. Interventions for MSM in Zanzibar are needed and should include linkages to prevention, care and treatment services.

HIV risk and the overlap of injecting drug use and high-risk sexual behaviours among men who have sex with men in Zanzibar (Unguja), Tanzania.

BACKGROUND: Men who have sex with men and inject drugs (MSM-IDU) are particularly vulnerable to HIV infection and have the potential to transmit HIV across multiple populations through their male and female sexual partners and injection drug-using partners. METHODS: Respondent-driven sampling was used to recruit men who reported engaging in anal sex with another man in the past 3 months, aged ≥15 years, and living in Unguja, Zanzibar. Participants responded to a face-to-face interview about their HIV and injecting risk behaviours and were tested for HIV, Hepatitis B (HBV) and C (HCV) and syphilis. RESULTS: Among the 509 MSM who enrolled in the survey, 14% (n=66) reported injecting drugs in the past 3 months among which 66% used heroin, 60% used a needle after someone else had and 68% passed a needle to someone else after using it. MSM-IDU were significantly more likely to have two or more non-paying male receptive sex partners and to have engaged in group sex in the past month, to have symptoms of a sexually transmitted infection in past 6 months, to have been arrested or beaten in the past 12 months and to be infected with HIV and co-infected with HIV and HCV compared to MSM who did not inject drugs. MSM-IDU were less likely to have used a condom at last sex with a non-paid female partner, to know where to get a confidential HIV test and to have ever been tested for HIV compared to MSM who did not inject drugs. CONCLUSION: MSM-IDU, and MSM in general, in Unguja practice multiple high-risk behaviours that put them at risk for blood-borne and sexual transmission of HIV and HCV infection. Targeted interventions for MSM-IDU must account for the overlap of high-risk sexual and drug-using networks and integrate injection drug use and HIV services.

Stage-dependent modes of Pax6-Sox2 epistasis regulate lens development and eye morphogenesis.

The transcription factors Pax6 and Sox2 have been implicated in early events in lens induction and have been proposed to cooperate functionally. Here, we investigated the activity of Sox2 in lens induction and its genetic relationship to Pax6 in the mouse. Conditional deletion of Sox2 in the lens placode arrests lens development at the pit stage. As previously shown, conditional deletion of Pax6 in the placode eliminates placodal thickening and lens pit invagination. The cooperative activity of Sox2 and Pax6 is illustrated by the dramatic failure of lens and eye development in presumptive lens conditional, compound Sox2, Pax6 heterozygotes. The resulting phenotype resembles that of germ line Pax6 inactivation, and the failure of optic cup morphogenesis indicates the importance of ectoderm-derived signals for all aspects of eye development. We further assessed whether Sox2 and Pax6 were required for N-cadherin expression at different stages of lens development. N-cadherin was lost in Sox2-deficient but not Pax6-deficient pre-placodal ectoderm. By contrast, after the lens pit has formed, N-cadherin expression is dependent on Pax6. These data support a model in which the mode of Pax6-Sox2 inter-regulation is stage-dependent and suggest an underlying mechanism in which DNA binding site availability is regulated.

Co-operative roles for E-cadherin and N-cadherin during lens vesicle separation and lens epithelial cell survival.

The classical cadherins are known to have both adhesive and signaling functions. It has also been proposed that localized regulation of cadherin activity may be important in cell assortment during development. In the context of eye development, it has been suggested that cadherins are important for separation of the invaginated lens vesicle from the surface ectoderm. To test this hypothesis, we conditionally deleted N-cadherin or E-cadherin from the presumptive lens ectoderm of the mouse. Conditional deletion of either cadherin alone did not produce a lens vesicle separation defect. However, these conditional mutants did exhibit common structural deficits, including microphthalmia, severe iris hyperplasia, persistent vacuolization within the fibre cell region, and eventual lens epithelial cell deterioration. To assess the co-operative roles of E-cadherin and N-cadherin within the developing lens, double conditional knockout embryos were generated. These mice displayed distinct defects in lens vesicle separation and persistent expression of another classical cadherin, P-cadherin, within the cells of the persistent lens stalk. Double mutant lenses also exhibited severe defects in lens epithelial cell adhesion and survival. Finally, the severity of the lens phenotype was shown to be sensitive to the number of wild-type E- and N-cadherin alleles. These data suggest that the co-operative expression of both E- and N-cadherin during lens development is essential for normal cell sorting and subsequent lens vesicle separation.

Optic cup and facial patterning defects in ocular ectoderm beta-catenin gain-of-function mice.

BACKGROUND: The canonical Wnt signaling pathway has a number of critical functions during embryonic development and, when activated aberrantly, in the genesis of cancer. Current evidence suggests that during eye development, regulation of Wnt signaling is critical for patterning the surface ectoderm that will contribute to multiple components of the eye. Wnt signaling loss-of-function experiments show that a region of periocular ectoderm will form ectopic lentoid bodies unless the Wnt pathway modifies its fate towards other structures. Consistent with this, Wnt signaling gain of function in the ocular region ectoderm results in a suppression of lens fate. RESULTS: Here we demonstrate that ectoderm-specific Wnt signaling gain-of-function embryos exhibit additional defects besides those noted in the lens. There are profound facial defects including a foreshortened snout, malformation of the nasal region, and clefting of the epidermis along the ocular-nasal axis. Furthermore, despite the restriction of Wnt pathway gain-of-function to the surface ectoderm, the optic cup is inappropriately patterned and ultimately forms a highly convoluted, disorganized array of epithelium with the characteristics of retina and retinal pigmented epithelium. CONCLUSION: We suggest that activation of the Wnt pathway in surface ectoderm may disrupt the normal exchange of signals between the presumptive lens and retina that coordinate development of a functional eye.

Canonical Wnt signaling negatively regulates branching morphogenesis of the lung and lacrimal gland.

Key gene families such as FGFs and BMPs are important mediators of branching morphogenesis. To understand whether Wnt genes, and in particular, the canonical Wnt signaling pathway also function in the branching process, we have used a combination of experimental and genetic gain and loss of function approaches to perturb the levels of canonical Wnt signaling in two arborized structures, the lung and the lacrimal gland. Here, we show that the addition of Wnt3a conditioned medium or LiCl strongly represses growth and proliferation of the lung and lacrimal gland, a result that was confirmed in vivo using a dominant stable mutation of beta-catenin conditionally expressed in the lacrimal gland epithelium. In agreement with these data, knockdown of Wnt signaling with beta-catenin morpholinos results in a greater number of branches and increased cell proliferation. In addition, we show that canonical Wnt signaling is able to modulate the levels of Fgf10 and suppress BMP-induced proliferation in the lacrimal gland. Thus, canonical Wnt signaling negatively regulates branching morphogenesis providing a balance to FGFs and BMPs which positively regulate this process. This multilayered control of growth and proliferation ensures that branched structures attain the morphology required to function efficiently.

The duality of beta-catenin function: a requirement in lens morphogenesis and signaling suppression of lens fate in periocular ectoderm.

In the current analysis, we have investigated both the cytoskeletal and signaling roles of beta-catenin during the early phases of lens development using conditional loss- and gain-of-function strategies. Conditional loss of beta-catenin in the presumptive lens does not perturb the normal sequential appearance of lens fate markers but results in a dramatic failure of the coordinated epithelial cell behavior that constitutes lens morphogenesis. Similarly, loss-of-function for Lrp6, the Wnt pathway coreceptor expressed in the eye primordium, does not prevent expression of lens induction markers. Surprisingly, conditional deletion of beta-catenin in periocular ectoderm results in the formation of Prox-1 and beta-crystallin-positive ectopic lentoid bodies. Combined with the observation that the Wnt pathway reporter TOPGAL is expressed in nasal periocular ectoderm, these data suggest that, in this location, the canonical Wnt signaling pathway normally suppresses lens fate in favor of other structures. Consistent with this proposal, a dominant-active form of beta-catenin causes a loss of lens fate and a complete absence of lens development when expressed in the presumptive lens ectoderm.

Vesicular stomatitis virus: a potential therapeutic virus for the treatment of hematologic malignancy.

Certain strains of vesicular stomatitis virus (VSV) have been shown to be oncolytic in a wide variety of solid tumors. In the present study, we tested the leukemolytic properties of VSV using established leukemia cell lines and primary patient material. VSV efficiently killed essentially all leukemic cell lines. In contrast, however, normal clonogenic bone marrow progenitor cells and peripheral blood cells were remarkably refractory to infection by VSV. By exploiting this large difference in susceptibility to infection we successfully purged contaminating leukemic cells from cultures of peripheral blood progenitor cells (PBPC) using VSV. VSV was also able to infect and kill leukemic cells in primary samples taken from patients with multiple myeloma (MM). This study demonstrates the potential utility of VSV in the treatment, both ex vivo and in vivo, of hematologic malignancies.