The World Health Organization's public health intelligence activities during the COVID-19 pandemic response, December 2019 to December 2021.

The coronavirus disease (COVID-19) presented a unique opportunity for the World Health Organization (WHO) to utilise public health intelligence (PHI) for pandemic response. WHO systematically captured mainly unstructured information (e.g. media articles, listservs, community-based reporting) for public health intelligence purposes. WHO used the Epidemic Intelligence from Open Sources (EIOS) system as one of the information sources for PHI. The processes and scope for PHI were adapted as the pandemic evolved and tailored to regional response needs. During the early months of the pandemic, media monitoring complemented official case and death reporting through the International Health Regulations mechanism and triggered alerts. As the pandemic evolved, PHI activities prioritised identifying epidemiological trends to supplement the information available through indicator-based surveillance reported to WHO. The PHI scope evolved over time to include vaccine introduction, emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, unusual clinical manifestations and upsurges in cases, hospitalisation and death incidences at subnational levels. Triaging the unprecedented high volume of information challenged surveillance activities but was managed by collaborative information sharing. The evolution of PHI activities using multiple sources in WHO's response to the COVID-19 pandemic illustrates the future directions in which PHI methodologies could be developed and used.

Implications of differentiated care for successful ART scale-up in a concentrated HIV epidemic in Yangon, Myanmar.

INTRODUCTION: National AIDS Programme in Myanmar has made significant progress in scaling up antiretroviral treatment (ART) services and recognizes the importance of differentiated care for people living with HIV. Indeed, long centred around the hospital and reliant on physicians, the country's HIV response is undergoing a process of successful decentralization with HIV care increasingly being integrated into other health services as part of a systematic effort to expand access to HIV treatment. This study describes implementation of differentiated care in Médecins Sans Frontières (MSF)-supported programmes and reports its outcomes. METHODS: A descriptive cohort analysis of adult patients on antiretroviral treatment was performed. We assessed stability of patients as of 31 December 2014 and introduced an intervention of reduced frequency of physicians' consultations for stable patients, and fast tract ART refills. We measured a number of saved physician's visits as the result of this intervention. Main outcomes, remained under care, death, lost to follow up, treatment failure, were assessed on 31 December 2015 and reported as rates for different stable groups. RESULTS: On 31 December 2014, our programme counted 16, 272 adult patients enrolled in HIV care, of whom 80.34% were stable. The model allowed for an increase in the average number of patients one medical team could care for - from 745 patients in 2011 to 1, 627 in 2014 - and, thus, a reduction in the number of teams needed. An assessment of stable patients enrolled on ART one year after the implementation of the new model revealed excellent outcomes, aggregated for stable patients as 98.7% remaining in care, 0.4% dead, 0.8% lost to follow-up, 0.8% clinical treatment failure and 5.8% with immunological treatment failure. CONCLUSIONS: Implementation of a differentiated model reduced the number of visits between stable clients and physicians, reduced the medical resources required for treatment and enabled integrated treatment of the main co-morbidities. We hope that these findings will encourage other stakeholders to implement innovative models of HIV care in Myanmar, further expediting the scale up of ART services, the decentralization of treatment and the integration of care for the main HIV co-morbidities in this context.

HIV Nef promotes expression of B-lymphocyte stimulator by blood dendritic cells during HIV infection in humans.

Dendritic cells (DCs) modulate B-cell survival and differentiation, mainly through production of growth factors such as B lymphocyte stimulator (BLyS; also known as "B-cell factor belonging to the tumor necrosis factor family" [BAFF]). We have recently shown that, in human immunodeficiency virus (HIV)-infected individuals with rapid and those with classic disease progression, B-cell dysregulations were associated with increased BLyS expression in plasma and by blood myeloid DCs (mDCs), in contrast to aviremic HIV-infected individuals with slow disease progression (also known as "elite controllers"). In previous work with transgenic mice expressing HIV genes, B-cell dysregulations were concomitant with altered mDCs and dependent on HIV negative factor (Nef). We now report that HIV Nef is detected early after infection and despite successful therapy in plasma and BLyS-overexpressing blood mDCs of HIV-infected rapid and classic progressors, whereas it is low to undetectable in aviremic slow progressors. In vitro, HIV Nef drives monocyte-derived DCs toward BLyS overexpression through a process involving STAT1. Importantly, this is counteracted in the presence of all-trans retinoic acid. Nef thus contributes to high BLyS proinflammatory profiles in HIV-infected individuals.

IL-10 and lymphotoxin-α expression profiles within marginal zone-like B-cell populations are associated with control of HIV-1 disease progression.

Understanding how the immune system facilitates or controls HIV-1 disease progression has important implications for the design of effective interventions. We report that although B-cell dysregulations associated with HIV-1 disease progression are accompanied by an overall decrease in the percentage of total blood B-cells, we observe an increase in relative frequencies of cells presenting characteristics of both transitional immature and first-line marginal zone (MZ) B-cell populations, we designated as precursor MZ-like B-cells. B-cells with similar attributes have been associated with IL-10 expression and "regulatory" potential. As such, the relative frequencies of precursor MZ-like B-cells expressing IL-10 are increased in the blood of viremic HIV-1-infected individuals when compared to HIV-negative subjects. Importantly, in aviremic HIV-1 Elite-Controllers (EC), we found unaltered relative percentages of precursor MZ-like B-cells which presented normal IL-10 expression patterns. Furthermore, EC had increased relative frequencies of blood MZ-like B-cells expressing LT-α. Thus in contrast to viremic HIV-1-infected individuals, EC present MZ-like B-cell populations which IL-10 and LT-α expression profiles may favour homeostasis of immune responses and lymphoid microenvironments.

Investigation of a pandemic H1N1 influenza outbreak in a remote First Nations community in northern Manitoba, 2009.

OBJECTIVES: First Nations communities in Manitoba were significantly affected by the pandemic H1N1 influenza virus (pH1N1) in 2009. Our objective was to conduct an epidemiologic investigation of a pH1N1 outbreak in one remote First Nations community (population 3,300) in northern Manitoba to inform a timely public health response and provide recommendations for preventing future outbreaks. METHODS: Chart reviews were conducted at the nursing station for patients meeting the influenza-like illness (ILI) case definition during the study period (April 20 to June 11, 2009). Descriptive analyses examined age, gender, clinical presentation, management, outcomes and risk factors. Comparisons were made for hospitalized versus non-hospitalized cases and laboratory-confirmed versus possible cases using Pearson's chi-square test for gender and symptoms and using a t-test for age. RESULTS: There were 180 ILI cases, including 23 laboratory-confirmed cases of pH1N1. Forty percent of children < 1 year old in the community and 9.4% of pregnant women presented to the nursing station with ILI. Most ILI cases were managed through the community nursing station, although 18.3% of cases (n = 33) were medically evacuated and 16.1% (n = 29) were hospitalized. There were no differences between hospitalized versus non-hospitalized or laboratory-confirmed versus possible cases. Risk factors identified in a subset of cases included exposure to an individual with ILI prior to illness onset, overcrowding and inadequate access to household water. CONCLUSIONS: Early arrival and rapid transmission of pH1N1 rendered usual non-pharmacological control measures largely ineffective. Recommendations for prevention of future outbreaks include an effective communications strategy and daily surveillance for disease detection and monitoring. Key determinants of health should be addressed in remote First Nations communities to prevent disease and protect the health of these populations.

Short communication: persistence of high blood levels of the chemokines CCL2, CCL19, and CCL20 during the course of HIV infection.

Dendritic cells (DCs) are important mediators of the immune response against HIV and yet blood DC numbers fall substantially during HIV infection. Here we report that blood levels of the DC-tissue tropic chemokines monocyte chemotactic protein (MCP-1/CCL2), macrophage inflammatory proteins (MIP-3α/CCL20), and MIP-3ß/CCL19 remained elevated throughout the course of HIV infection suggesting that the relatively low levels of blood circulating DCs may be due to active recruitment of these cells to peripheral sites to fight disease progression.

High expression levels of B lymphocyte stimulator (BLyS) by dendritic cells correlate with HIV-related B-cell disease progression in humans.

In view of assessing the possible contribution of dendritic cells (DCs) to HIV-related B-cell disorders, we have longitudinally measured B lymphocyte stimulator (BLyS) surface expression by myeloid DCs (mDCs) and concentrations of B-cell growth factors in the blood of subjects undergoing primary HIV infection with different rates of disease progression. We report that BLyS surface expression by mature mDCs and precursors as well as blood levels of BLyS, a proliferation-inducing ligand (APRIL), interleukin-6 (IL-6), and IL-10 increased above normal levels in both rapid and normal HIV progressors as quickly as in the acute phase of infection and persisting throughout the course of disease despite successful therapy. Consequently, hyperglobulinemia and high blood levels of circulating activated mature B cells and precursor/activated marginal zone (MZ)-like B cells were found throughout follow-up for both rapid and normal progressors. In contrast, mDC cell-surface expression of BLyS as well as blood levels of BLyS, immunoglobulin, activated mature B cells, and precursor/activated MZ-like B cells in aviremic slow progressors were similar to those observed in healthy donors. Interestingly, the levels of mature MZ B cells were significantly reduced in slow progressors. Our results suggest that DCs might modulate the outcome of the HIV-related B-cell disease progression through the expression of BLyS.

Persistence of high levels of blood soluble human leukocyte antigen-G is associated with rapid progression of HIV infection.

Human leukocyte antigen-G is an important suppressor of the immune response, and HIV can modulate its expression. Longitudinal monitoring of soluble human leukocyte antigen-G plasma levels in patients with primary HIV infection undergoing different rates of disease progression showed that levels were elevated in the early phases of infection and remained high throughout follow-up in rapid progressors who responded to antiretroviral therapy but were restored to normal levels in the chronic phase of infection in both untreated normal progressors and long-term nonprogressors.

HIV infection affects blood myeloid dendritic cells after successful therapy and despite nonprogressing clinical disease.

We assessed the longitudinal changes in blood myeloid dendritic cell (mDC) and plasmacytoid dendritic cell (pDC) populations in subjects with primary human immunodeficiency virus (HIV) infection undergoing different rates of disease progression. The relative level and degree of maturation of all cell populations decreased significantly in untreated individuals with acute infection. The most dramatic changes were observed in the rapid progressor group, correlating with their rate of clinical progression. Levels of mDCs remained lower than normal throughout follow-up for both rapid progressors who responded to antiretroviral therapy (ART) and untreated normal progressors. In contrast, mDC precursors were restored to normal levels during subsequent phases of infection in both rapid and normal progressors, and these levels were increased in long-term nonprogressors. pDC levels followed the pattern of CD4+ T cell fluctuations. These findings provide evidence for an ongoing process affecting mDCs after successful ART and despite nonprogressing clinical disease following HIV infection.

Human papillomavirus type 16 (HPV-16) viral load and persistence of HPV-16 infection in women infected or at risk for HIV.

BACKGROUND: Persistent HPV-16 infection is a marker for risk of progression to high-grade cervical lesions. The predictive value of HPV-16 viral loads for persistent HPV-16 infection was assessed longitudinally in a cohort of 1055 sexually active women. METHODS: HPV-16 viral loads were measured with real-time PCR targeting the E6 gene in 948 genital specimens collected from 139 women (100 HIV-seropositive, 39 HIV-seronegative). RESULTS: Forty of 139 participants were classified as having persistent HPV-16 infection (lasting more than 12 months) and 27 women had transient infection. CD4 counts were negatively correlated with HPV-16 loads (R=-0.29, p=0.02). In multivariate analysis controlling for age, HIV, race and CD4 counts, peak HPV-16 viral loads (odds ratio (OR) 1.3, 95% confidence interval (CI) 1.0-1.7) and CD4 cell counts (OR 2.0, 95% CI 1.1-3.6) were associated with persistence of HPV-16 infection. Women with > or =10(7) HPV-16copies/microg cellular DNA were infected for a longer period of time than women with a lower viral load after controlling for age, CD4 count and HIV status (p=0.01). CONCLUSION: Higher HPV-16 viral loads were predictive of persistence of HPV-16 infection, a marker risk for potential progression to high-grade pre-cancerous and cancerous lesions of the cervix.

Re-evaluation of blood mercury, lead and cadmium concentrations in the Inuit population of Nunavik (Québec): a cross-sectional study.

BACKGROUND: Arctic populations are exposed to mercury, lead and cadmium through their traditional diet. Studies have however shown that cadmium exposure is most often attributable to tobacco smoking. The aim of this study is to examine the trends in mercury, lead and cadmium exposure between 1992 and 2004 in the Inuit population of Nunavik (Northern Québec, Canada) using the data obtained from two broad scale health surveys, and to identify sources of exposure in 2004. METHODS: In 2004, 917 adults aged between 18 and 74 were recruited in the 14 communities of Nunavik to participate to a broad scale health survey. Blood samples were collected and analysed for metals by inductively coupled plasma mass spectrometry, and dietary and life-style characteristics were documented by questionnaires. Results were compared with data obtained in 1992, where 492 people were recruited for a similar survey in the same population. RESULTS: Mean blood concentration of mercury was 51.2 nmol/L, which represent a 32% decrease (p < 0.001) between 1992 and 2004. Mercury blood concentrations were mainly explained by age (partial r2 = 0.20; p < 0.0001), and the most important source of exposure to mercury was marine mammal meat consumption (partial r2 = 0.04; p < 0.0001). In 2004, mean blood concentration of lead was 0.19 mumol/L and showed a 55% decrease since 1992. No strong associations were observed with any dietary source, and lead concentrations were mainly explained by age (partial r2 = 0.20.; p < 0.001). Blood cadmium concentrations showed a 22% decrease (p < 0.001) between 1992 and 2004. Once stratified according to tobacco use, means varied between 5.3 nmol/L in never-smokers and 40.4 nmol/L in smokers. Blood cadmium concentrations were mainly associated with tobacco smoking (partial r2 = 0.56; p < 0.0001), while consumption of caribou liver and kidney remain a minor source of cadmium exposure among never-smokers. CONCLUSION: Important decreases in mercury, lead and cadmium exposure were observed. Mercury decrease could be explained by dietary changes and the ban of lead cartridges use likely contributed to the decrease in lead exposure. Blood cadmium concentrations remain high and, underscoring the need for intensive tobacco smoking prevention campaigns in the Nunavik population.

Influence of human papillomavirus type 16 (HPV-16) E2 polymorphism on quantification of HPV-16 episomal and integrated DNA in cervicovaginal lavages from women with cervical intraepithelial neoplasia.

Integrated human papillomavirus type 16 (HPV-16) viral loads are currently estimated by quantification with real-time PCR of HPV-16 E6 (RT-E6 and HPV-16 PG) and E2 (RT-E2-1) DNA. We assessed the influence of HPV-16 E2 polymorphism on quantification of integrated HPV-16 DNA in anogenital specimens. HPV-16 E2 was sequenced from 135 isolates (123 from European and 12 from non-European lineages). An assay targeting conserved HPV-16 E2 sequences (RT-E2-2) was optimized and applied with RT-E6 and RT-E2-1 on 139 HPV-16-positive cervicovaginal lavages collected from 74 women [58 human immunodeficiency virus (HIV)-seropositive and 16 HIV-seronegative]. Ratios of HPV-16 copies measured with RT-E2-2 and RT-E2-1 obtained with African 2 (median=3.23, range=1.92-3.49) or Asian-American (median=3.78, range=1.47-37) isolates were greater than those obtained with European isolates (median=1.02, range=0.64-1.80; P<0.02 for each comparison). The distribution of HPV-16 E2 copies measured in 139 samples with RT-E2-2 (median=6150) and RT-E2-1 (median=8960) were different (P<0.0001). The risk of high-grade cervical intraepithelial neoplasia (CIN-2,3) compared with women without CIN was increased with higher HPV-16 total [odds ratio (OR)=2.17, 95 % confidence interval (CI)=1.11-4.23], episomal (OR=2.14, 95 % CI=1.09-4.19), but not for HPV-16 integrated viral load (OR=1.71, 95 % CI=0.90-3.26), after controlling for age, race, CD4 count, HIV and HPV-16 polymorphism. The proportion of samples with an E6/E2 ratio >2 in women without squamous intraepithelial lesion (7 of 35) was similar to that of women with CIN-2,3 (5 of 11, P=0.24) or CIN-1 (5 of 14, P=0.50). HPV-16 E2 polymorphism was a significant factor that influenced measures of HPV-16 integrated viral load.

High level of correlation of human papillomavirus-16 DNA viral load estimates generated by three real-time PCR assays applied on genital specimens.

Human papillomavirus-16 (HPV-16) viral load could be a biomarker predictive of the presence of high-grade cervical lesions. Recently, several real-time PCR assays have been developed to accurately measure HPV-16 viral load. However, results from various reports using these assays cannot be compared because interassay test correlation has not been documented. The variability of HPV-16 DNA quantitation was assessed by comparing three real-time PCR assays (HPV-16 L1, HPV-16 E6, and HPV-16 E6 PG) applied on 144 genital samples (125 cervicovaginal lavages and 19 specimens collected using vaginal tampons) obtained from 84 women (66 HIV seropositive and 18 HIV seronegative). Correlation was greater between the HPV-16 E6 assays [correlation coefficient (rho) = 0.92] than between each E6 assay and HPV-16 L1 assay (rho = 0.83 and 0.84, respectively). The median HPV-16 copies measured by HPV-16 E6 PG (14,609 HPV-16 copies/2 muL sample) and HPV-16 E6 (18,846 HPV-16 copies/2 muL) were similar (P = 0.27) but were both greater than the median HPV-16 copies measured with the L1 assay (4,124 HPV-16 copies/2 muL; P < 0.001). Correlations between HPV-16 E6 assays were similar for samples containing non-European (rho = 0.93) or European (rho = 0.95) variants. However, the correlation between HPV-16 L1 and HPV-16 E6 PG or HPV-16 E6 was lower for specimens containing non-European variants (rho = 0.80 and 0.76, respectively) compared with specimens containing European variants (rho > 0.85). HPV-16 DNA quantity estimated with the three assays was comparable although lower with the HPV-16 L1 assay. The level of correlation depended on viral polymorphism, viral load, and cervical disease status.

High levels of HPV-16 DNA are associated with high-grade cervical lesions in women at risk or infected with HIV.

OBJECTIVE: To examine associations between levels of episomal and integrated human papillomavirus (HPV) 16 DNA and the grade of cervical disease. DESIGN: Cross-sectional data were obtained from a cohort of women with and without HIV infection and with high-risk sexual behaviour. METHODS: Episomal and integrated HPV-16 DNA loads were measured in cervicovaginal lavages collected from 75 women (58 HIV seropositive, 17 HIV seronegative) using real-time polymerase chain reaction assays, controlling for cell content and the presence of inhibitors. RESULTS: HPV-16 viral loads were significantly higher in women with high-grade squamous intraepithelial lesions (n = 6) than in women with normal cytology (n = 44), whether total (10(8.28) versus 10(5.10) HPV-16 DNA copies/microg DNA), episomal (10(7.99) versus 10(4.61)) or integrated (10(7.95) versus 10(4.77)) HPV-16 viral loads were measured (P < 0.02 for each comparison). Thirty-nine women had colposcopy [11 normal cervix, 16 cervical intraepithelial neoplasia (CIN) 1, six CIN 2, six CIN 3] and 24 additional women had three consecutive normal cytology smears. Controlling for age, race, CD4 cell count and HIV status, total (OR 3.5, 95% CI 1.2-10.4; P = 0.02), episomal (OR 2.9, 95% CI 1.2-7.4; P = 0.02,) and integrated (OR 1.6, 95% CI 1-2.6; P = 0.05) HPV-16 DNA loads were significantly associated with CIN 2,3, but the differences between CIN 1 and CIN 2,3 were not significant (P > 0.06). A greater amount of cellular DNA was collected from women with CIN 2,3 (P = 0.007). CONCLUSION: Higher HPV-16 DNA loads are associated with cervical lesions detected by either histology or cytology. No additional information is gained by measuring integrated or episomal over total HPV-16 DNA loads.

Age and ovarian reserve are distinct predictive factors of cycle outcome in low responders.

The respective roles of age and ovarian reserve in predicting IVF outcome do not seem to be equivalent, as a high pregnancy rate seems to be preserved in the youngest women, despite low ovarian recruitment. The purpose of this study was to analyse the outcome of IVF/intracytoplasmic sperm injection (ICSI) procedures according to both age and ovarian reserve of patients with a low ovarian response to stimulation. A total of 163 IVF/ICSI cycles selected by a low response were analysed. The IVF outcome differed according to the women's age, with a cut-off value at 36 years. While the number of transferred embryos was similar, the pregnancy rate (PR) was 14.6% in younger patients but 4.9% (P < 0.04) in older ones. An elevated FSH was constantly associated with a poor cycle outcome. In contrast, when the FSH was normal, PR was significantly higher (P < 0.05) in women aged <36 (23.8%) than in women aged > or =36 (6.5%). This study shows that assisted reproduction outcome in women with a low ovarian response is primarily dependent on the ovarian status. The negative influence of age is relevant in patients with normal FSH. Therefore, even if the ovarian response to stimulation is low, patients aged <36 years with a normal FSH should proceed to oocyte retrieval.

Determination of Viable Bacterial Populations in Raw Milk within 20 Minutes by Using a Direct Epifluorescent Filter Technique.

The results from a shortened procedure for the direct epifluorescent filter technique (DEFT) determination of viable bacterial populations in raw milk were compared to standard plate counts. Shortening the prefiltration trypsin-Triton X-100 incubation period from 10 to 3 min enabled the completion of the analysis within 20 min. The short DEFT method results had a correlation coefficient (r) of 0.81 with plate counts. With respect to precision, the average difference between values of duplicate plate count analyses was 0.16 log units; that of the short DEFT was 0.14 log units. The slopes of the regressions equations were less than 1, indicating that a direct correlation is not achieved. Short DEFT values were 0.17 log units higher than those of plate counts on milk samples containing less than 10,000 CFU/ml. For milk samples containing counts over 10,000 CFU/ml, short DEFT values averaged only 0.05 log units above plate count readings. Daily preparation of the stain appears unnecessary since acridine orange solutions stored for up to 2 days at 4°C did not produce results significantly (P > 0.05) different from those obtained with fresh solutions. The short DEFT method has potential for the assessment of the bacteriological quality of raw milk in tanker deliveries.