Serological investigation of SARS-CoV-2 infection in patients with suspect measles, 2017-2022.

BACKGROUND: Several studies suggested that SARS-CoV-2 was already spreading worldwide during the last months of 2019 before the first outbreak was detected in Wuhan, China. Lombardy (Northern Italy) was the first European region with sustained SARS-CoV-2 transmission and recent investigations detected SARS-CoV-2-RNA-positive patients in Lombardy since late 2019. METHODS: We tested for anti-SARS-CoV-2 IgG all serum samples available in our laboratory (N = 235, collected between March 2017 and March 2022) that we received within the framework of measles/rubella surveillance from measles and rubella virus-negative patients. RESULTS: Thirteen of 235 samples (5.5%) were IgG-positive. The positivity rate increased starting in 2019 and was significantly different from the expected false positive rate from 2019 onwards. Additionally, in 2019 the percentage of IgG-positive patients was significantly lower among SARS-CoV-2 RNA-negative patients (3/92) compared to SARS-CoV-2 RNA-positive patients (2/7, p = 0.04). The highest percentage of IgG positivity in the pre-pandemic period was recorded during the second half of 2019. This coincided with an increase in negativity for measles and a widening of the peak of the number of measles discarded cases per 100,000 inhabitants, indicating a higher-than-normal number of measles-negative patients experiencing fever and rash. This also coincided with the first patient positive for SARS-CoV-2 RNA (September 12th, 2019); this patient was also positive for anti-SARS-CoV-2 IgG and IgM. CONCLUSIONS: Although the number of samples was low and one cannot conclusively establish that the virus started circulating in Lombardy around September 2019, our findings should stimulate similar research investigating the possibility of undetected SARS-CoV-2 pre-pandemic circulation.

Political rationale, aims, and outcomes of health-related high-level meetings and special sessions at the UN General Assembly: A policy research observational study.

BACKGROUND: Recognising the substantial political weight of the United Nations General Assembly (UNGA), a UN General Assembly special session (UNGASS) and high-level meetings (HLMs) have been pursued and held for 5 health-related topics thus far. They have focused on human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS, 2001), non-communicable diseases (NCDs, 2011), antimicrobial resistance (AMR, 2016), tuberculosis (TB, 2018), and universal health coverage (UHC, 2019). This observational study presents a comprehensive analysis of the political and policy background that prompted the events, as well as an assessment of aims, approaches, and ultimate outcomes. METHODS AND FINDINGS: We investigated relevant agencies' official documents, performed a literature search, and accessed international institutions' websites for the period 1990-2020. Knowledgeable diplomatic staff and experts provided additional information. Outcomes were evaluated from a United Nations perspective based on national and international commitments, and funding trends. Eliciting an effective governmental response through UNGASSs/HLMs is a challenge. However, increased international commitment was evident after the HIV/AIDS (2001), NCDs (2011), and AMR (2016) meetings. The more recent TB (2018) and UHC (2019) HLMs have received general endorsements internationally, although concrete commitments are not yet documented. Although attribution can only be hypothesized, financial investments for HIV/AIDS following the UNGASS were remarkable, whereas following HLMs for NCDs, AMR, and TB, the financial investments remained insufficient to face the burden of these threats. Thus far, the HIV/AIDS UNGASS was the only one followed by a level of commitment that has likely contributed to the reversal of the previous burden trend. Limitations of this study include its global perspective and aerial view that cannot discern the effects at the country level. Additionally, possible peculiarities that modified the response to the meetings were not looked at in detail. Finally, we assessed a small sample of events; thus, the list of strategic characteristics for success is not exhaustive. CONCLUSIONS: Overall, UNGASSs and HLMs have the potential to lay better foundations and boldly address key health challenges. However, to succeed, they need to (i) be backed by large consensus; (ii) engage UN authorities and high-level bodies; (iii) emphasise implications for international security and the world economy; (iv) be supported by the civil society, activists, and champions; and (v) produce a political declaration containing specific, measurable, achievable, relevant, and time-bound (SMART) targets. Therefore, to ensure impact on health challenges, in addition to working with the World Health Assembly and health ministries, engaging the higher political level represented by the UNGA and heads of state and government is critical.

Molecular evidence for SARS-CoV-2 in samples collected from patients with morbilliform eruptions since late 2019 in Lombardy, northern Italy.

As a reference laboratory for measles and rubella surveillance in Lombardy, we evaluated the association between SARS-CoV-2 infection and measles-like syndromes, providing preliminary evidence for undetected early circulation of SARS-CoV-2. Overall, 435 samples from 156 cases were investigated. RNA from oropharyngeal swabs (N = 148) and urine (N = 141) was screened with four hemi-nested PCRs and molecular evidence for SARS-CoV-2 infection was found in 13 subjects. Two of the positive patients were from the pandemic period (2/12, 16.7%, March 2020-March 2021) and 11 were from the pre-pandemic period (11/44, 25%, August 2019-February 2020). Sera (N = 146) were tested for anti-SARS-CoV-2 IgG, IgM, and IgA antibodies. Five of the RNA-positive individuals also had detectable anti-SARS-CoV-2 antibodies. No strong evidence of infection was found in samples collected between August 2018 and July 2019 from 100 patients. The earliest sample with evidence of SARS-CoV-2 RNA was from September 12, 2019, and the positive patient was also positive for anti-SARS-CoV-2 antibodies (IgG and IgM). Mutations typical of B.1 strains previously reported to have emerged in January 2020 (C3037T, C14408T, and A23403G), were identified in samples collected as early as October 2019 in Lombardy. One of these mutations (C14408T) was also identified among sequences downloaded from public databases that were obtained by others from samples collected in Brazil in November 2019. We conclude that a SARS-CoV-2 progenitor capable of producing a measles-like syndrome may have emerged in late June-late July 2019 and that viruses with mutations characterizing B.1 strain may have been spreading globally before the first Wuhan outbreak. Our findings should be complemented by high-throughput sequencing to obtain additional sequence information. We highlight the importance of retrospective surveillance studies in understanding the early dynamics of COVID-19 spread and we encourage other groups to perform retrospective investigations to seek confirmatory proofs of early SARS-CoV-2 circulation.

Evidence of SARS-CoV-2 RNA in an Oropharyngeal Swab Specimen, Milan, Italy, Early December 2019.

We identified severe acute respiratory syndrome coronavirus 2 RNA in an oropharyngeal swab specimen collected from a child with suspected measles in early December 2019, ≈3 months before the first identified coronavirus disease case in Italy. This finding expands our knowledge on timing and mapping of novel coronavirus transmission pathways.

Impact of socio-economic factors on Tuberculosis treatment outcomes in north-eastern Uganda: a mixed methods study.

BACKGROUND: Tuberculosis (TB) is a major public health problem and at 48%, Karamoja in North-Eastern Uganda has the lowest treatment success rate nationally. Addressing the social determinants of TB is crucial to ending TB. This study sought to understand the extent and ways in which socio-economic factors affect TB treatment outcomes in Karamoja. METHODS: We conducted a convergent parallel mixed methods study in 10 TB Diagnostic and Treatment Units. The study enrolled former TB patients diagnosed with drug-susceptible TB between April 2018 and March 2019. Unit TB and laboratory registers were reviewed to identify pre-treatment losses to follow-up. Four focus group discussions with former TB patients and 18 key informant interviews with healthcare workers were conducted. Principle component analysis was used to generate wealth quintiles that were compared to treatment outcomes using the proportion test. The association between sociodemographic characteristics and TB treatment outcomes was evaluated using the chi-square test and multiple logistic regression. RESULTS: A total of 313 participants were randomly selected from 1184 former TB patients recorded in the unit TB registers. Of these, 264 were contacted in the community and consented to join the study: 57% were male and 156 (59.1%) participants had unsuccessful treatment outcomes. The wealthiest quintile had a 58% reduction in the risk of having an unsuccessful treatment outcome (adj OR = 0.42, 95% CI 0.18-0.99, p = 0.047). People who were employed in the informal sector (adj OR = 4.71, 95% CI 1.18-18.89, p = 0.029) and children under the age of 15 years who were not in school or employed (adj OR = 2.71, 95% CI 1.11-6.62, p = 0.029) had significantly higher odds of unsuccessful treatment outcome. Analysis of the pre-treatment loss to follow-up showed that 17.2% of patients with pulmonary bacteriologically confirmed TB did not initiate treatment with a higher proportion among females (21.7%) than males (13.5%). Inadequate food, belonging to migratory communities, stigma, lack of social protection, drug stock-outs and transport challenges affected TB treatment outcomes. CONCLUSIONS: This study confirmed that low socio-economic status is associated with poor TB treatment outcomes emphasizing the need for multi- and cross-sectoral approaches and socio-economic enablers to optimise TB care.

Use of Digital Technology to Enhance Tuberculosis Control: Scoping Review.

BACKGROUND: Tuberculosis (TB) is the leading cause of death from a single infectious agent, with around 1.5 million deaths reported in 2018, and is a major contributor to suffering worldwide, with an estimated 10 million new cases every year. In the context of the World Health Organization's End TB strategy and the quest for digital innovations, there is a need to understand what is happening around the world regarding research into the use of digital technology for better TB care and control. OBJECTIVE: The purpose of this scoping review was to summarize the state of research on the use of digital technology to enhance TB care and control. This study provides an overview of publications covering this subject and answers 3 main questions: (1) to what extent has the issue been addressed in the scientific literature between January 2016 and March 2019, (2) which countries have been investing in research in this field, and (3) what digital technologies were used? METHODS: A Web-based search was conducted on PubMed and Web of Science. Studies that describe the use of digital technology with specific reference to keywords such as TB, digital health, eHealth, and mHealth were included. Data from selected studies were synthesized into 4 functions using narrative and graphical methods. Such digital health interventions were categorized based on 2 classifications, one by function and the other by targeted user. RESULTS: A total of 145 relevant studies were identified out of the 1005 published between January 2016 and March 2019. Overall, 72.4% (105/145) of the research focused on patient care and 20.7% (30/145) on surveillance and monitoring. Other programmatic functions 4.8% (7/145) and electronic learning 2.1% (3/145) were less frequently studied. Most digital health technologies used for patient care included primarily diagnostic 59.4% (63/106) and treatment adherence tools 40.6% (43/106). On the basis of the second type of classification, 107 studies targeted health care providers (107/145, 73.8%), 20 studies targeted clients (20/145, 13.8%), 17 dealt with data services (17/145, 11.7%), and 1 study was on the health system or resource management. The first authors' affiliations were mainly from 3 countries: the United States (30/145 studies, 20.7%), China (20/145 studies, 13.8%), and India (17/145 studies, 11.7%). The researchers from the United States conducted their research both domestically and abroad, whereas researchers from China and India conducted all studies domestically. CONCLUSIONS: The majority of research conducted between January 2016 and March 2019 on digital interventions for TB focused on diagnostic tools and treatment adherence technologies, such as video-observed therapy and SMS. Only a few studies addressed interventions for data services and health system or resource management.

Variations in tuberculosis prevalence, Russian Federation: a multivariate approach.

OBJECTIVE: To analyse the epidemiological trends of tuberculosis in the Siberian and Far Eastern federal districts, the areas with the highest disease burden in the Russian Federation. METHODS: We applied principal coordinate analysis to study a total of 68 relevant variables on tuberculosis epidemiology, prevention and control. Data on these variables were collected over 2003-2016 in all 21 regions of the Siberian federal district and Far Eastern federal district (total population: 25.5 million) through the federal and departmental reporting system. We identified the regions with a favourable or unfavourable tuberculosis epidemiological profile and ranked them as low or high priority for specific interventions. FINDINGS: The median number of tuberculosis notifications in the regions was 123.3 per 100 000 population (range: 54.5-265.7) in 2003, decreasing to 82.3 per 100 000 (range: 52.9-178.3) in 2016. We found large variations in the tuberculosis epidemiological profile across different regions. The principal coordinate analysis revealed that three aggregated indicators accounted for 55% of the variation. The first coordinate corresponded to tuberculosis prevalence and case notifications in the regions; the second to the severity of the disease among patients; and the third to the percentage of multidrug-resistant tuberculosis among tuberculosis patients. The regions where intervention was most urgently needed were Chukotka Autonomous Okrug, Jewish Autonomous Oblast and Tyva Republic. CONCLUSION: The variability in tuberculosis epidemiology across regions was likely due to differences in the quality of antituberculosis services. Precision in defining necessary interventions, as determined through the principal coordinate analysis approach, can guide focused tuberculosis control efforts.

Global Epidemiology of Tuberculosis.

Tuberculosis (TB) was the underlying cause of 1.3 million deaths among human immunodeficiency virus (HIV)-negative people in 2016, exceeding the global number of HIV/acquired immune deficiency syndrome (AIDS) deaths. In addition, TB was a contributing cause of 374,000 HIV deaths. Despite the success of chemotherapy over the past seven decades, TB is the top infectious killer globally. In 2016, 10.4 million new cases arose, a number that has remained stable since the beginning of the 21th century, frustrating public health experts tasked to design and implement interventions to reduce the burden of TB disease worldwide. Ambitious targets for reductions in the epidemiological burden of TB have been set within the context of the Sustainable Development Goals (SDGs) and the End TB Strategy. Achieving these targets is the focus of national and international efforts, and demonstrating whether or not they are achieved is of major importance to guide future and sustainable investments. This article reviews epidemiological facts about TB, trends in the magnitude of the burden of TB and factors contributing to it, and the effectiveness of the public health response.

Digital health for the End TB Strategy: developing priority products and making them work.

In 2014, the World Health Organization (WHO) developed the End TB Strategy in response to a World Health Assembly Resolution requesting Member States to end the worldwide epidemic of tuberculosis (TB) by 2035. For the strategy's objectives to be realised, the next 20 years will need novel solutions to address the challenges posed by TB to health professionals, and to affected people and communities. Information and communication technology presents opportunities for innovative approaches to support TB efforts in patient care, surveillance, programme management and electronic learning. The effective application of digital health products at a large scale and their continued development need the engagement of TB patients and their caregivers, innovators, funders, policy-makers, advocacy groups, and affected communities.In April 2015, WHO established its Global Task Force on Digital Health for TB to advocate and support the development of digital health innovations in global efforts to improve TB care and prevention. We outline the group's approach to stewarding this process in alignment with the three pillars of the End TB Strategy. The supplementary material of this article includes target product profiles, as developed by early 2016, defining nine priority digital health concepts and products that are strategically positioned to enhance TB action at the country level.

WHO and the future of disease control programmes.

Huge increases in funding for international health over the past two decades have led to a proliferation of donors, partnerships, and health organisations. Over the same period, the global burden of non-communicable diseases has increased absolutely and relative to communicable diseases. In this changing landscape, national programmes for the control of HIV/AIDS, tuberculosis, malaria, and neglected tropical diseases must be reinforced and adapted for three reasons: the global burden of these communicable diseases remains enormous, disease control programmes have an integral and supporting role in developing health systems, and the health benefits of these control programmes go beyond the containment of specific infections. WHO's traditional role in promoting communicable disease control programmes must also adapt to new circumstances. Among a multiplicity of actors, WHO's task is to enhance its normative role as convenor, coordinator, monitor, and standard-setter, fostering greater coherence in global health.

Burden of Antimicrobial Resistance Among Women with Post-Partum Infections in Low-Middle Income Countries: A Systematic Review.

BACKGROUND: Due to the rising incidence of multidrug-resistant (MDR) pathogens, especially in Low-Middle-Income Countries (LMIC), post-partum infections represent a significant treatment challenge. METHODS: We performed a systematic review of the literature from January 2005 to February 2023 to quantify the frequency of maternal post-partum infections due to MDR pathogens in LMICs, focusing on methicillin-resistant Staphylococcus aureus (MRSA) and/or extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales. SECONDARY OBJECTIVES: description of antimicrobials' prescriptions. FINDINGS: We included 22 studies with 14,804 total bacterial isolates from 12 countries, mostly from WHO African-Region. Twelve papers described wound- and 10 puerperal-infections. Seven were high-quality articles. Seventeen studies reported data on MRSA, and 18 on ESBL-producing Enterobacterales. Among high-quality studies, MRSA ranged from 9.8% in Ghana to 91.2% in Uganda; ESBL-producing Enterobacterales ranged from 22.8% in Ukraine to 95.2% in Uganda. Nine articles, mostly on C-sections, described different protocols for antibiotic prophylaxis and/or post-partum treatment. INTERPRETATION: We described a high burden of post-partum infections caused by MRSA and/or ESBL-producing Enterobacterales in LMICs, but only a few studies met quality standards. There is an urgent need for high-quality studies to better describe the real burden of antimicrobial resistance in low-resource settings and inform policies to contain the spread of multidrug-resistant organisms.

Epidemiology of antituberculosis drug resistance in Saudi Arabia: findings of the first national survey.

The real magnitude of antituberculosis (anti-TB) drug resistance in Saudi Arabia is still unknown because the available data are based on retrospective laboratory studies that were limited to hospitals or cities. A representative national survey was therefore conducted to investigate the levels and patterns of anti-TB drug resistance and explore risk factors. Between August 2009 and July 2010, all culture-positive TB patients diagnosed in any of the tuberculosis reference laboratories of the country were enrolled. Isolates obtained from each patient were tested for susceptibility to first-line anti-TB drugs by the automated Bactec MGIT 960 method. Of the 2,235 patients enrolled, 75 cases (3.4%) were lost due to culture contamination and 256 (11.5%) yielded nontuberculous mycobacteria (NTM). Finally, 1,904 patients (85.2% of those enrolled) had available drug susceptibility testing results. Monoresistance to streptomycin (8.1%; 95% confidence interval [CI], 7.2 to 9.1), isoniazid (5.4%; 95% CI, 4.7 to 6.2), rifampin (1%; 95% CI, 0.7 to 1.3) and ethambutol (0.8%; 95% CI, 0.5 to 1.2) were observed. Multidrug-resistant TB (MDR-TB) was found in 1.8% (95% CI, 1.4 to 2.4) and 15.9% (95% CI, 15.4 to 16.5) of new and previously treated TB cases, respectively. A treatment history of active TB, being foreign-born, having pulmonary TB, and living in the Western part of the country were the strongest independent predictors of MDR-TB. Results from the first representative national anti-TB drug resistance survey in Saudi Arabia suggest that the proportion of MDR-TB is relatively low, though there is a higher primary drug resistance. A strengthened continuous surveillance system to monitor trends over time and second-line anti-TB drug resistance as well as implementation of innovative control measures, particularly among immigrants, is warranted.

The role of immune suppression in COVID-19 hospitalization: clinical and epidemiological trends over three years of SARS-CoV-2 epidemic.

Specific immune suppression types have been associated with a greater risk of severe COVID-19 disease and death. We analyzed data from patients >17 years that were hospitalized for COVID-19 at the "Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico" in Milan (Lombardy, Northern Italy). The study included 1727 SARS-CoV-2-positive patients (1,131 males, median age of 65 years) hospitalized between February 2020 and November 2022. Of these, 321 (18.6%, CI: 16.8-20.4%) had at least one condition defining immune suppression. Immune suppressed subjects were more likely to have other co-morbidities (80.4% vs. 69.8%, p < 0.001) and be vaccinated (37% vs. 12.7%, p < 0.001). We evaluated the contribution of immune suppression to hospitalization during the various stages of the epidemic and investigated whether immune suppression contributed to severe outcomes and death, also considering the vaccination status of the patients. The proportion of immune suppressed patients among all hospitalizations (initially stable at <20%) started to increase around December 2021, and remained high (30-50%). This change coincided with an increase in the proportions of older patients and patients with co-morbidities and with a decrease in the proportion of patients with severe outcomes. Vaccinated patients showed a lower proportion of severe outcomes; among non-vaccinated patients, severe outcomes were more common in immune suppressed individuals. Immune suppression was a significant predictor of severe outcomes, after adjusting for age, sex, co-morbidities, period of hospitalization, and vaccination status (OR: 1.64; 95% CI: 1.23-2.19), while vaccination was a protective factor (OR: 0.31; 95% IC: 0.20-0.47). However, after November 2021, differences in disease outcomes between vaccinated and non-vaccinated groups (for both immune suppressed and immune competent subjects) disappeared. Since December 2021, the spread of the less virulent Omicron variant and an overall higher level of induced and/or natural immunity likely contributed to the observed shift in hospitalized patient characteristics. Nonetheless, vaccination against SARS-CoV-2, likely in combination with naturally acquired immunity, effectively reduced severe outcomes in both immune competent (73.9% vs. 48.2%, p < 0.001) and immune suppressed (66.4% vs. 35.2%, p < 0.001) patients, confirming previous observations about the value of the vaccine in preventing serious disease.

Waiting for the truth: is reluctance in accepting an early origin hypothesis for SARS-CoV-2 delaying our understanding of viral emergence?

Two years after the start of the COVID-19 pandemic, key questions about the emergence of its aetiological agent (SARS-CoV-2) remain a matter of considerable debate. Identifying when SARS-CoV-2 began spreading among people is one of those questions. Although the current canonically accepted timeline hypothesises viral emergence in Wuhan, China, in November or December 2019, a growing body of diverse studies provides evidence that the virus may have been spreading worldwide weeks, or even months, prior to that time. However, the hypothesis of earlier SARS-CoV-2 circulation is often dismissed with prejudicial scepticism and experimental studies pointing to early origins are frequently and speculatively attributed to false-positive tests. In this paper, we critically review current evidence that SARS-CoV-2 had been circulating prior to December of 2019, and emphasise how, despite some scientific limitations, this hypothesis should no longer be ignored and considered sufficient to warrant further larger-scale studies to determine its veracity.

Tuberculosis control and elimination 2010-50: cure, care, and social development.

Rapid expansion of the standardised approach to tuberculosis diagnosis and treatment that is recommended by WHO allowed more than 36 million people to be cured between 1995 and 2008, averting up to 6 million deaths. Yet tuberculosis remains a severe global public health threat. There are more than 9 million new cases every year worldwide, and the incidence rate is falling at less than 1% per year. Although the overall target related to the Millennium Development Goals of halting and beginning to reverse the epidemic might have already been reached in 2004, the more important long-term elimination target set for 2050 will not be met with present strategies and instruments. Several key challenges persist. Many vulnerable people do not have access to affordable services of sufficient quality. Technologies for diagnosis, treatment, and prevention are old and inadequate. Multidrug-resistant tuberculosis is a serious threat in many settings. HIV/AIDS continues to fuel the tuberculosis epidemic, especially in Africa. Furthermore, other risk factors and underlying social determinants help to maintain tuberculosis in the community. Acceleration of the decline towards elimination of this disease will need invigorated actions in four broad areas: continued scale-up of early diagnosis and proper treatment for all forms of tuberculosis in line with the Stop TB Strategy; development and enforcement of bold health-system policies; establishment of links with the broader development agenda; and promotion and intensification of research towards innovations.