New frontiers in the cGAS-STING intracellular DNA-sensing pathway.

The cGAS-STING intracellular DNA-sensing pathway has emerged as a key element of innate antiviral immunity and a promising therapeutic target. The existence of an innate immune sensor that can be activated by any double-stranded DNA (dsDNA) of any origin raises fundamental questions about how cGAS is regulated and how it responds to "foreign" DNA while maintaining tolerance to ubiquitous self-DNA. In this review, we summarize recent evidence implicating important roles for cGAS in the detection of foreign and self-DNA. We describe two recent and surprising insights into cGAS-STING biology: that cGAS is tightly tethered to the nucleosome and that the cGAMP product of cGAS is an immunotransmitter acting at a distance to control innate immunity. We consider how these advances influence our understanding of the emerging roles of cGAS in the DNA damage response (DDR), senescence, aging, and cancer biology. Finally, we describe emerging approaches to harness cGAS-STING biology for therapeutic benefit.

COVID-19-related work absenteeism and associated lost productivity cost in Germany: a population-based study.

OBJECTIVE: To estimate COVID-19 absenteeism and indirect costs, by care setting. METHODS: A population-based retrospective cohort study using data from the German Statutory Health Insurance (SHI) database to define outpatient (April 2020-December 2021) and hospitalized (April 2020-October 2022) cohorts of employed working-aged individuals. RESULTS: In the outpatient cohort (n = 369,220) median absenteeism duration and associated cost was 10.0 (IQR: 5.0, 15.0) days and €1,061 (530, 1,591), respectively. In the hospitalized cohort (n = 20,687), median absenteeism and associated cost was 15.0 (7.0, 32.0) days and €1,591 (743, 3,394), respectively. Stratified analyses showed greater absenteeism in older workers, those at risk and those with severe disease. CONCLUSIONS: The hospitalized cohort had longer absenteeism resulting in higher productivity loss. Being older, at risk of severe COVID-19 and higher disease severity during hospitalization were important drivers of higher absenteeism duration.

Travel-Associated Dengue Cases - United States, 2010-2021.

Dengue, the leading cause of arboviral disease worldwide, can be fatal without appropriate treatment. Among 7,528 confirmed or probable travel-associated U.S. dengue cases reported during 2010-2021, one in five (1,474, 20%) was reported in 2019. This is 168% higher than the annual average number of cases reported during 2010-2018 and 2020-2021 (approximately 550 per year) and 61% higher than the 913 cases reported in 2016, the second highest year on record. The number of cases as a fraction of air traffic volume to international destinations outside North America or Europe was also highest in 2019, with 41.9 cases per million trips, compared with 21.0 per million in other years during 2010-2021. This report compares the number and characteristics of travel-associated dengue cases reported to national surveillance in the United States in 2019 with cases reported during 2010-2018 and 2020-2021. Areas with conditions suitable for dengue transmission as well as the population at risk for dengue are expected to increase, placing U.S. travelers at higher risk for infection. Health care providers should be aware that dengue is a common cause of fever in the returning traveler and be familiar with its signs and symptoms, testing, and management. Dengue vaccines are not currently recommended for U.S. travelers; therefore, persons should review areas of dengue risk and follow guidance for preventing mosquito bites.

Travel-Associated Dengue Cases - United States, 2010-2021.

Dengue, the leading cause of arboviral disease worldwide, can be fatal without appropriate treatment. Among 7,528 confirmed or probable travel-associated U.S. dengue cases reported during 2010-2021, one in five (1,474, 20%) was reported in 2019. This is 168% higher than the annual average number of cases reported during 2010-2018 and 2020-2021 (approximately 550 per year) and 61% higher than the 913 cases reported in 2016, the second highest year on record. The number of cases as a fraction of air traffic volume to international destinations outside North America or Europe was also highest in 2019, with 41.9 cases per million trips, compared with 21.0 per million in other years during 2010-2021. This report compares the number and characteristics of travel-associated dengue cases reported to national surveillance in the United States in 2019 with cases reported during 2010-2018 and 2020-2021. Areas with conditions suitable for dengue transmission as well as the population at risk for dengue are expected to increase, placing U.S. travelers at higher risk for infection. Health care providers should be aware that dengue is a common cause of fever in the returning traveler and be familiar with its signs and symptoms, testing, and management. Dengue vaccines are not currently recommended for U.S. travelers; therefore, persons should review areas of dengue risk and follow guidance for preventing mosquito bites.

SARS-CoV-2 Omicron Replacement of Delta as Predominant Variant, Puerto Rico.

We reconstructed the SARS-CoV-2 epidemic caused by Omicron variant in Puerto Rico by sampling genomes collected during October 2021-May 2022. Our study revealed that Omicron BA.1 emerged and replaced Delta as the predominant variant in December 2021. Increased transmission rates and a dynamic landscape of Omicron sublineage infections followed.

Hepatitis C Screening and Antibody Prevalence Among Newly Arrived Refugees to the United States, 2010-2017.

Six refugee screening sites collaborated to estimate the prevalence of hepatitis C virus (HCV) antibodies among newly arrived refugees in the United States from 2010 to 2017, identify demographic characteristics associated with HCV antibody positivity, and estimate missed HCV antibody-positive adults among unscreened refugees. We utilized a cross-sectional study to examine HCV prevalence among refugees (N = 144,752). A predictive logistic regression model was constructed to determine the effectiveness of current screening practices at identifying cases. The prevalence of HCV antibodies among the 64,703 refugees screened was 1.6%. Refugees from Burundi (5.4%), Moldova (3.8%), Democratic Republic of Congo (3.2%), Burma (2.8%), and Ukraine (2.0%) had the highest positivity among refugee arrivals. An estimated 498 (0.7%) cases of HCV antibody positivity were missed among 67,787 unscreened adults. The domestic medical examination represents an opportunity to screen all adult refugees for HCV to ensure timely diagnosis and treatment.

Computational design of constitutively active cGAS.

Cyclic GMP-AMP synthase (cGAS) is a pattern recognition receptor critical for the innate immune response to intracellular pathogens, DNA damage, tumorigenesis and senescence. Binding to double-stranded DNA (dsDNA) induces conformational changes in cGAS that activate the enzyme to produce 2'-3' cyclic GMP-AMP (cGAMP), a second messenger that initiates a potent interferon (IFN) response through its receptor, STING. Here, we combined two-state computational design with informatics-guided design to create constitutively active, dsDNA ligand-independent cGAS (CA-cGAS). We identified CA-cGAS mutants with IFN-stimulating activity approaching that of dsDNA-stimulated wild-type cGAS. DNA-independent adoption of the active conformation was directly confirmed by X-ray crystallography. In vivo expression of CA-cGAS in tumor cells resulted in STING-dependent tumor regression, demonstrating that the designed proteins have therapeutically relevant biological activity. Our work provides a general framework for stabilizing active conformations of enzymes and provides CA-cGAS variants that could be useful as genetically encoded adjuvants and tools for understanding inflammatory diseases.

Clinical Features of COVID-19, Dengue, and Influenza among Adults Presenting to Emergency Departments and Urgent Care Clinics-Puerto Rico, 2012-2021.

Dengue and influenza are pathogens of global concern and cause febrile illness similar to COVID-19. We analyzed data from an enhanced surveillance system operating from three emergency departments and an urgent care clinic in Puerto Rico to identify clinical features predictive of influenza or dengue compared with COVID-19. Participants with fever or respiratory symptoms and aged ≥18 years enrolled May 2012-January 2021 with dengue, influenza, or SARS-CoV-2 confirmed by reverse transcriptase polymerase chain reaction were included. We calculated adjusted odds ratios (aORs) and 95% CIs using logistic regression to assess clinical characteristics of participants with COVID-19 compared to those with dengue or influenza, adjusting for age, subregion, and days from illness onset to presentation for clinical care. Among 13,431 participants, we identified 2,643 with dengue (N = 303), influenza (N = 2,064), or COVID-19 (N = 276). We found differences in days from onset to presentation among influenza (2 days [interquartile range: 1-3]), dengue (3 days [2-4]), and COVID-19 cases (4 days [2-7]; P < 0.001). Cough (aOR: 0.12 [95% CI: 0.07-0.19]) and shortness of breath (0.18 [0.08-0.44]) were less common in dengue compared with COVID-19. Facial flushing (20.6 [9.8-43.5]) and thrombocytopenia (24.4 [13.3-45.0]) were more common in dengue. Runny nose was more common in influenza compared with COVID-19 (8.3 [5.8-12.1]). In summary, cough, shortness of breath, facial flushing, and thrombocytopenia helped distinguish between dengue and COVID-19. Although few features distinguished influenza from COVID-19, presentation > 4 days after symptom onset suggests COVID-19. These findings may assist clinicians making time-sensitive decisions regarding triage, isolation, and management while awaiting pathogen-specific testing.

Genomic surveillance of SARS-CoV-2 in Puerto Rico enabled early detection and tracking of variants.

Background: Puerto Rico has experienced the full impact of the COVID-19 pandemic. Since SARS-CoV-2, the virus that causes COVID-19, was first detected on the island in March of 2020, it spread rapidly though the island's population and became a critical threat to public health. Methods: We conducted a genomic surveillance study through a partnership with health agencies and academic institutions to understand the emergence and molecular epidemiology of the virus on the island. We sampled COVID-19 cases monthly over 19 months and sequenced a total of 753 SARS-CoV-2 genomes between March 2020 and September 2021 to reconstruct the local epidemic in a regional context using phylogenetic inference. Results: Our analyses reveal that multiple importation events propelled the emergence and spread of the virus throughout the study period, including the introduction and spread of most SARS-CoV-2 variants detected world-wide. Lineage turnover cycles through various phases of the local epidemic were observed, where the predominant lineage was replaced by the next competing lineage or variant after ~4 months of circulation locally. We also identified the emergence of lineage B.1.588, an autochthonous lineage that predominated in Puerto Rico from September to December 2020 and subsequently spread to the United States. Conclusions: The results of this collaborative approach highlight the importance of timely collection and analysis of SARS-CoV-2 genomic surveillance data to inform public health responses.

Dengue: A Growing Problem With New Interventions.

Dengue is the disease caused by 1 of 4 distinct, but closely related dengue viruses (DENV-1-4) that are transmitted by Aedes spp. mosquito vectors. It is the most common arboviral disease worldwide, with the greatest burden in tropical and sub-tropical regions. In the absence of effective prevention and control measures, dengue is projected to increase in both disease burden and geographic range. Given its increasing importance as an etiology of fever in the returning traveler or the possibility of local transmission in regions in the United States with competent vectors, as well as the risk for large outbreaks in endemic US territories and associated states, clinicians should understand its clinical presentation and be familiar with appropriate testing, triage, and management of patients with dengue. Control and prevention efforts reached a milestone in June 2021 when the Advisory Committee on Immunization Practices (ACIP) recommended Dengvaxia for routine use in children aged 9 to 16 years living in endemic areas with laboratory confirmation of previous dengue virus infection. Dengvaxia is the first vaccine against dengue to be recommended for use in the United States and one of the first to require laboratory testing of potential recipients to be eligible for vaccination. In this review, we outline dengue pathogenesis, epidemiology, and key clinical features for front-line clinicians evaluating patients presenting with dengue. We also provide a summary of Dengvaxia efficacy, safety, and considerations for use as well as an overview of other potential new tools to control and prevent the growing threat of dengue .

Genomic surveillance of SARS-CoV-2 in Puerto Rico reveals emergence of an autochthonous lineage and early detection of variants.

Puerto Rico has experienced the full impact of the COVID-19 pandemic. Since SARS-CoV-2, the virus that causes COVID-19, was first detected on the island in March of 2020, it spread rapidly though the island’s population and became a critical threat to public health. We conducted a genomic surveillance study through a partnership with health agencies and academic institutions to understand the emergence and molecular epidemiology of the virus on the island. We sampled COVID-19 cases monthly over 19 months and sequenced a total of 753 SARS-CoV-2 genomes between March 2020 and September 2021 to reconstruct the local epidemic in a regional context using phylogenetic inference. Our analyses revealed that multiple importation events propelled the emergence and spread of the virus throughout the study period, including the introduction and spread of most SARS-CoV-2 variants detected world-wide. Lineage turnover cycles through various phases of the local epidemic were observed, where the predominant lineage was replaced by the next competing lineage or variant after approximately 4 months of circulation locally. We also identified the emergence of lineage B.1.588, an autochthonous lineage that predominated circulation in Puerto Rico from September to December 2020 and subsequently spread to the United States. The results of this collaborative approach highlight the importance of timely collection and analysis of SARS-CoV-2 genomic surveillance data to inform public health responses.

Characteristics and clinical outcomes of patients hospitalized with laboratory-confirmed COVID-19-Puerto Rico, March-August 2020.

Hispanics are the majority ethnic population in Puerto Rico where we reviewed charts of 109 hospitalized COVID-19 patients to better understand demographic and clinical characteristics of COVID-19 and determine risk factors for poor outcomes. Eligible medical records of hospitalized patients with confirmed COVID-19 illnesses were reviewed at four participating hospitals in population centers across Puerto Rico and data were abstracted that described the clinical course, interventions, and outcomes. We found hospitalized patients had a median of 3 underlying conditions with obesity and diabetes as the most frequently reported conditions. Intensive care unit (ICU) admission occurred among 28% of patients and 18% of patients died during the hospitalization. Patients 65 or older or with immune deficiencies had a higher risk for death. Common symptoms included cough, dyspnea, and fatigue; less than half of patients in the study reported fever which was less frequent than reported elsewhere in the literature. It is important for interventions within Hispanic communities to protect high-risk groups.

Impact of Anthelmintic Price Increases on Practice Patterns of Healthcare Providers Caring for Immigrant and Refugee Populations in the United States.

In the United States, prices of long-established, generic anthelmintic medications have markedly risen. In the past decade, albendazole and mebendazole have increased in price by > 8,000%, whereas praziquantel has increased by > 500%. To determine the effect of these price increases on the practice patterns of healthcare providers, we conducted a cross-sectional electronic survey of clinics in the United States that primarily care for immigrant and refugee patient populations. Among 32 clinics, 53.1% reported that price increases impacted how providers diagnosed and treated helminth infections. A third (34.4%) of clinics reported that price increases have left them unable to treat known helminth infections. Other ways in which price increases impacted practice patterns included prescribing anthelmintics other than albendazole, mebendazole, or praziquantel when possible (34.4%); avoiding screening asymptomatic patients for helminth infections (15.6%); advising patients to acquire medications from another country (15.6%) or the patient's home country (9.4%); reducing anthelmintic dosing regimens to fewer pills (9.4%); and advising patients to purchase medications on the Internet (6.3%). These findings suggest price increases have negatively impacted the diagnosis and treatment of helminth infections in this population, and have resulted in the inability to treat known helminth infections. These findings have significant implications for the morbidity and mortality of infected individuals, as well as for public health in the United States.

Barriers to malaria prevention among immigrant travelers in the United States who visit friends and relatives in sub-Saharan Africa: A cross-sectional, multi-setting survey of knowledge, attitudes, and practices.

BACKGROUND: Despite achievements in the reduction of malaria globally, imported malaria cases to the United States by returning international travelers continue to increase. Immigrants to the United States from sub-Saharan Africa (SSA) who then travel back to their homelands to visit friends and relatives (VFRs) experience a disproportionate burden of malaria illness. Various studies have explored barriers to malaria prevention among VFRs and non-VFRs-travelers to the same destinations with other purpose for travel-but few employed robust epidemiologic study designs or performed comparative analyses of these two groups. To better quantify the key barriers that VFRs face to implement effective malaria prevention measures, we conducted a comprehensive community-based, cross-sectional, survey to identify differences in malaria prevention knowledge, attitudes, and practices (KAP) among VFRs and others traveling to Africa and describe the differences between VFRs and other types of international travelers. METHODS AND FINDINGS: Three distinct populations of travelers with past or planned travel to malaria-endemic countries of SSA were surveyed: VFRs diagnosed with malaria as reported through a state health department; members of the general VFR population (community); and VFR and non-VFR travelers presenting to a travel health clinic, both before their pretravel consultation and again, after return from travel. A Community Advisory Board of African immigrants and prior qualitative research informed survey development and dissemination. Across the three groups, 489 travelers completed surveys: 351 VFRs and 138 non-VFRs. VFRs who reported taking antimalarials on their last trip rated their concern about malaria higher than those who did not. Having taken five or more trips to SSA was reported more commonly among VFRs diagnosed with malaria than community VFRs (44.0% versus 20.4%; p = 0.008). Among travel health clinic patients surveyed before and after travel, VFR travelers were less successful than non-VFRs in adhering to their planned use of antimalarials (82.2% versus 98.7%; p = 0.001) and employing mosquito bite avoidance techniques (e.g., using bed nets: 56.8% versus 81.8%; p = 0.009). VFRs who visited the travel health clinic were more likely than VFR respondents from the community to report taking an antimalarial (83.0% versus 61.9%; p = 0.009), or to report bite avoidance behaviors (e.g., staying indoors when mosquitoes were out: 80.9% versus 59.5%; p = 0.009). CONCLUSIONS: We observed heterogeneity in malaria prevention behaviors among VFRs and between VFR and non-VFR traveler populations. Although VFRs attending the travel health clinic appear to demonstrate better adherence to malaria prevention measures than VFR counterparts surveyed in the community, specialized pretravel care is not sufficient to ensure chemoprophylaxis use and bite avoidance behaviors among VFRs. Even when seeking specialized pretravel care, VFRs experience greater barriers to the use of malaria prevention than non-VFRs. Addressing access to health care and upstream barrier reduction strategies that make intended prevention more achievable, affordable, easier, and resonant among VFRs may improve malaria prevention intervention effectiveness.

Tight nuclear tethering of cGAS is essential for preventing autoreactivity.

cGAS is an intracellular innate immune sensor that detects double-stranded DNA. The presence of billions of base pairs of genomic DNA in all nucleated cells raises the question of how cGAS is not constitutively activated. A widely accepted explanation for this is the sequestration of cGAS in the cytosol, which is thought to prevent cGAS from accessing nuclear DNA. Here, we demonstrate that endogenous cGAS is predominantly a nuclear protein, regardless of cell cycle phase or cGAS activation status. We show that nuclear cGAS is tethered tightly by a salt-resistant interaction. This tight tethering is independent of the domains required for cGAS activation, and it requires intact nuclear chromatin. We identify the evolutionarily conserved tethering surface on cGAS and we show that mutation of single amino acids within this surface renders cGAS massively and constitutively active against self-DNA. Thus, tight nuclear tethering maintains the resting state of cGAS and prevents autoreactivity.

Barriers to malaria prevention in US-based travellers visiting friends and relatives abroad: a qualitative study of West African immigrant travellers†.

BACKGROUND: Over half of malaria cases reported in the USA occur among people travelling to visit friends and relatives (VFRs), predominantly to West Africa. Few studies have queried VFR travellers directly on barriers to seeking pre-travel care. We aim to describe the knowledge, attitudes and practices of VFRs travelling to malaria-endemic countries from the USA. With these findings, we aim to design interventions to encourage preventive behaviours before and during travel. METHODS: Sixteen focus groups were held in two US metropolitan areas with West African immigrant populations: Minneapolis-St. Paul, MN, and New York City, NY. A total of 172 people from 13 African countries participated. Focus group discussions were audio-recorded and transcribed, and modified grounded theory analysis was performed. Participants reviewed themes to verify intent of statements. RESULTS: Participants described the high cost of provider visits and chemoprophylaxis, challenges in advocating for themselves in healthcare settings and concerns about offending or inconveniencing hosts as barriers to malaria prevention. Cultural barriers to accessing pre-travel care included competing priorities when trip planning, such as purchasing gifts for family, travel logistics and safety concerns. When participants sought pre-travel care, most consulted their primary care provider. Participants expressed low confidence in US providers' knowledge and training about malaria and other tropical diseases. CONCLUSION: Barriers to pre-travel care for VFR travellers are multifaceted and extend beyond their perception of disease risk. Only some barriers previously reported in anecdotal and qualitative literature were supported in our findings. Future interventions should be aimed at barriers identified by individual communities and involve primary and travel specialist healthcare providers. Additional work is needed to address systems-level barriers to accessing care and establishing community-based programs to support West African VFR traveller health.