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[This corrects the article DOI: 10.1017/cts.2020.23.].

A primary barrier to translation of clinical research discoveries into care delivery and population health is the lack of sustainable infrastructure bringing researchers, policymakers, practitioners, and communities together to reduce silos in knowledge and action. As National Institutes of Health's (NIH) mechanism to advance translational research, Clinical and Translational Science Award (CTSA) awardees are uniquely positioned to bridge this gap. Delivering on this promise requires sustained collaboration and alignment between research institutions and public health and healthcare programs and services. We describe the collaboration of seven CTSA hubs with city, county, and state healthcare and public health organizations striving to realize this vision together. Partnership representatives convened monthly to identify key components, common and unique themes, and barriers in academic-public collaborations. All partnerships aligned the activities of the CTSA programs with the needs of the city/county/state partners, by sharing resources, responding to real-time policy questions and training needs, promoting best practices, and advancing community-engaged research, and dissemination and implementation science to narrow the knowledge-to-practice gap. Barriers included competing priorities, differing timelines, bureaucratic hurdles, and unstable funding. Academic-public health/health system partnerships represent a unique and underutilized model with potential to enhance community and population health.

A study published in the journal Translational Neurodegeneration examines the role of the integrated stress response (ISR) in amyotrophic lateral sclerosis (ALS). The researchers specifically investigate the impact of inhibiting the ISR kinase GCN2 on the clustering and toxicity of mutant SOD1, a protein associated with ALS. The study finds that inhibiting GCN2 delays disease progression in a mouse model of ALS by reducing mutant SOD1 clustering. These findings suggest that targeting the ISR pathway, particularly GCN2, may hold promise for ALS treatment. [Extracted from the article]

BackgroundThe San Francisco Health Improvement Partnership (SFHIP) promotes health equity by using a novel collective impact model that blends community engagement with evidence-to-policy translational science. The model involves diverse stakeholders, including ethnic-based community health equity coalitions, the local public health department, hospitals and health systems, a health sciences university, a school district, the faith community, and others sectors.Community contextWe report on 3 SFHIP prevention initiatives: reducing consumption of sugar sweetened beverages (SSBs), regulating retail alcohol sales, and eliminating disparities in children's oral health.MethodsSFHIP is governed by a steering committee. Partnership working groups for each initiative collaborate to 1) develop and implement action plans emphasizing feasible, scalable, translational-science-informed interventions and 2) consider sustainability early in the planning process by including policy and structural interventions.OutcomeThrough SFHIP's efforts, San Francisco enacted ordinances regulating sale and advertising of SSBs and a ballot measure establishing a soda tax. Most San Francisco hospitals implemented or committed to implementing healthy-beverage policies that prohibited serving or selling SSBs. SFHIP helped prevent Starbucks and Taco Bell from receiving alcohol licenses in San Francisco and helped prevent state authorization of sale of powdered alcohol. SFHIP increased the number of primary care clinics providing fluoride varnish at routine well-child visits from 3 to 14 and acquired a state waiver to allow dental clinics to be paid for dental services delivered in schools.InterpretationThe SFHIP model of collective impact emphasizing community engagement and policy change accomplished many of its intermediate goals to create an environment promoting health and health equity.

Abstract Background Public health surveillance and epidemiologic investigations are critical public health functions for identifying threats to the health of a community. Very little is known about how these functions are conducted at the local level. The purpose of the Epidemiology Networks in Action (EpiNet) Study was to describe the epidemiology and surveillance response to the 2009 pandemic influenza A (H1N1) by city and county health departments in the San Francisco Bay Area in California. The study also documented lessons learned from the response in order to strengthen future public health preparedness and response planning efforts in the region. Methods In order to characterize the epidemiology and surveillance response, we conducted key informant interviews with public health professionals from twelve local health departments in the San Francisco Bay Area. In order to contextualize aspects of organizational response and performance, we recruited two types of key informants: public health professionals who were involved with the epidemiology and surveillance response for each jurisdiction, as well as the health officer or his/her designee responsible for H1N1 response activities. Information about the organization, data sources for situation awareness, decision-making, and issues related to surge capacity, continuity of operations, and sustainability were collected during the key informant interviews. Content and interpretive analyses were conducted using ATLAS.ti software. Results The study found that disease investigations were important in the first months of the pandemic, often requiring additional staff support and sometimes forcing other public health activities to be put on hold. We also found that while the Incident Command System (ICS) was used by all participating agencies to manage the response, the manner in which it was implemented and utilized varied. Each local health department (LHD) in the study collected epidemiologic data from a variety of sources, but only case reports (including hospitalized and fatal cases) and laboratory testing data were used by all organizations. While almost every LHD attempted to collect school absenteeism data, many respondents reported problems in collecting and analyzing these data. Laboratory capacity to test influenza specimens often aided an LHD’s ability to conduct disease investigations and implement control measures, but the ability to test specimens varied across the region and even well-equipped laboratories exceeded their capacity. As a whole, the health jurisdictions in the region communicated regularly about key decision-making (continued on next page) (continued from previous page) related to the response, and prior regional collaboration on pandemic influenza planning helped to prepare the region for the novel H1N1 influenza pandemic. The study did find, however, that many respondents (including the majority of epidemiologists interviewed) desired an increase in regional communication about epidemiology and surveillance issues. Conclusion The study collected information about the epidemiology and surveillance response among LHDs in the San Francisco Bay Area that has implications for public health preparedness and emergency response training, public health best practices, regional public health collaboration, and a perceived need for information sharing.

Abstract Background Due to the uncommon nature of large-scale disasters and emergencies, public health practitioners often turn to simulated emergencies, known as “exercises”, for preparedness assessment and improvement. Under the right conditions, exercises can also be used to conduct original public health systems research. This paper describes the integration of a research framework into a statewide operations-based exercise program in California as a systems-based approach for studying public health emergency preparedness and response. Methods We developed a research framework based on the premise that operations-based exercises conducted by medical and public health agencies can be described using epidemiologic concepts. Using this framework, we conducted a survey of key local and regional medical and health agencies throughout California following the 2010 Statewide Medical and Health Exercise. The survey evaluated: (1) the emergency preparedness capabilities activated and functions performed in response to the emergency scenario, and (2) the major challenges to inter-organizational communications and information management. Results Thirty-five local health departments (LHDs), 24 local emergency medical services (EMS) agencies, 121 hospitals, and 5 Regional Disaster Medical and Health Coordinators/Specialists (RDMHC) responded to our survey, representing 57%, 77%, 26% and 83%, respectively, of target agencies in California. We found two sets of response capabilities were activated during the 2010 Statewide Exercise: a set of core capabilities that were common across all agencies, and a set of agency-specific capabilities that were more common among certain agency types. With respect to one response capability in particular, inter-organizational information sharing, we found that the majority of respondents’ comments were related to the complete or partial failure of communications equipment or systems. Conclusions Using the 2010 Statewide Exercise in California as an opportunity to develop our research framework, we characterized several aspects of the public health and medical system’s response to a standardized emergency scenario. From a research perspective, this study provides a potential new framework for conducting exercise-based research. From a practitioner’s perspective, our results provide a starting point for preparedness professionals’ dialogue about expected and actual organizational roles, responsibilities, and resource capacities within the public health system. Additionally, the identification of specific challenges to inter-organizational communications and information management offer specific areas for intervention.

Abstract Background The large-scale deployment of antiviral drugs from the Strategic National Stockpile during the 2009 H1N1 influenza response provides a unique opportunity to study local public health implementation of the medical countermeasure dispensing capability in a prolonged event of national significance. This study aims to describe the range of methods used by local health departments (LHDs) in California to manage antiviral activities and to gain a better understanding of the related challenges experienced by health departments and their community partners. Methods This research employed a mixed-methods approach. First, a multi-disciplinary focus group of pandemic influenza planners from key stakeholder groups in California was convened in order to generate ideas and identify critical themes related to the local implementation of antiviral activities during the H1N1 influenza response. These qualitative data informed the development of a web-based survey, which was distributed to all 61 LHDs in California for the purpose of assessing the experiences of a representative sample of local health agencies in a large region. Results Forty-four LHDs participated in this study, representing 72% of the local public health agencies in California. While most communities dispensed a modest number of publicly purchased antivirals, LHDs nevertheless drew on their previous work and engaged in a number of antiviral activities, including: acquiring, allocating, distributing, dispensing, tracking, developing guidance, and communicating to the public and clinical community. LHDs also identified specific antiviral challenges presented by the H1N1 pandemic, including: reconciling multiple sources and versions of antiviral guidance, determining appropriate uses and recipients of publicly purchased antivirals, and staffing shortages. Conclusions The 2009 H1N1 influenza pandemic presented an unusual opportunity to learn about the role of local public health in the management of antiviral response activities during a real public health emergency. Results of this study offer an important descriptive account of LHD management of publicly purchased antivirals, and provide practitioners, policy makers, and academics with a practice-based assessment of these events. The issues raised and the challenges faced by LHDs should be leveraged to inform public health planning for future pandemics and other emergency events that require medical countermeasure dispensing activities.

Abstract Background In recent years, national and global mortality data have been characterized in terms of well-established risk factors. In this regard, alcohol consumption has been called the third leading "actual cause of death" (modifiable behavioral risk factor) in the United States, after tobacco use and the combination of poor diet and physical inactivity. Globally and in various regions of the world, alcohol use has been established as a leading contributor to the overall burden of disease and as a major determinant of health disparities, but, to our knowledge, no one has characterized alcohol-related harm in such broad terms at the local level. We asked how alcohol-related premature mortality in San Francisco, measured in years of life lost (YLLs), compares with other well-known causes of premature mortality, such as ischemic heart disease or HIV/AIDS. Methods We applied sex- and cause-specific population-attributable fractions (PAFs) of years of life lost (YLLs) from the Global Burden of Disease Study to 17 comparable outcomes among San Francisco males and females during 2004-2007. We did this in three ways: Method 1 assumed that all San Franciscans drink like populations in developed economies. These estimates were limited to alcohol-related harm. Method 2 modified these estimates by including several beneficial effects. Method 3 assumed that Latino and Asian San Franciscans drink alcohol like populations in the global regions related to their ethnicity. Results By any of these three methods, alcohol-related premature mortality accounts for roughly a tenth of all YLLs among males. Alcohol-related YLLs among males are comparable to YLLs for leading causes such as ischemic heart disease and HIV/AIDS, in some instances exceeding them. Latino and black males bear a disproportionate burden of harm. Among females, for whom estimates differed more by method and were smaller than those for males, alcohol-related YLLs are comparable to leading causes which rank somewhere between fifth and fourteenth. Conclusions Alcohol consumption is a major contributor to premature mortality in San Francisco, especially among males. Interventions to avert alcohol-related harm in San Francisco should be taken at the population level and deserve the same attention that is given to other major risk factors, such as smoking or obesity.

Deficiencies in the protein-folding capacity of the endoplasmic reticulum (ER) in all eukaryotic cells lead to ER stress and trigger the unfolded protein response (UPR). ER stress is sensed by Ire1, a transmembrane kinase/endoribonuclease, which initiates the non-conventional splicing of the messenger RNA encoding a key transcription activator, Hac1 in yeast or XBP1 in metazoans. In the absence of ER stress, ribosomes are stalled on unspliced HAC1 mRNA. The translational control is imposed by a base-pairing interaction between the HAC1 intron and the HAC1 5' untranslated region. After excision of the intron, transfer RNA ligase joins the severed exons, lifting the translational block and allowing synthesis of Hac1 from the spliced HAC1 mRNA to ensue. Hac1 in turn drives the UPR gene expression program comprising 7-8% of the yeast genome to counteract ER stress. Here we show that, on activation, Ire1 molecules cluster in the ER membrane into discrete foci of higher-order oligomers, to which unspliced HAC1 mRNA is recruited by means of a conserved bipartite targeting element contained in the 3' untranslated region. Disruption of either Ire1 clustering or HAC1 mRNA recruitment impairs UPR signalling. The HAC1 3' untranslated region element is sufficient to target other mRNAs to Ire1 foci, as long as their translation is repressed. Translational repression afforded by the intron fulfils this requirement for HAC1 mRNA. Recruitment of mRNA to signalling centres provides a new paradigm for the control of eukaryotic gene expression.

BACKGROUND: A core function of local health departments is to conduct health assessments. The analysis of death certificates provides information on diseases, conditions, and injuries that are likely to cause death - an important outcome indicator of population health. The expected years of life lost (YLL) measure is a valid, stand-alone measure for identifying and ranking the underlying causes of premature death. The purpose of this study was to rank the leading causes of premature death among San Francisco residents, and to share detailed methods so that these analyses can be used in other local health jurisdictions. METHODS: Using death registry data and population estimates for San Francisco deaths in 2003-2004, we calculated the number of deaths, YLL, and age-standardized YLL rates (ASYRs). The results were stratified by sex, ethnicity, and underlying cause of death. The YLL values were used to rank the leading causes of premature death for men and women, and by ethnicity. RESULTS: In the years 2003-2004, 6312 men died (73,627 years of life lost), and 5726 women died (51,194 years of life lost). The ASYR for men was 65% higher compared to the ASYR for women (8971.1 vs. 5438.6 per 100,000 persons per year). The leading causes of premature deaths are those with the largest average YLLs and are largely preventable. Among men, these were HIV/AIDS, suicide, drug overdose, homicide, and alcohol use disorder; and among women, these were lung cancer, breast cancer, hypertensive heart disease, colon cancer, and diabetes mellitus. A large health disparity exists between African Americans and other ethnic groups: African American age-adjusted overall and cause-specific YLL rates were higher, especially for homicide among men. Except for homicide among Latino men, Latinos and Asians have comparable or lower YLL rates among the leading causes of death compared to whites. CONCLUSION: Local death registry data can be used to measure, rank, and monitor the leading causes of premature death, and to measure and monitor ethnic health disparities.

Background and Purpose: The integrated stress response (ISR) regulates translation in response to diverse stresses. ISR activation has been documented in amyotrophic lateral sclerosis (ALS) patients and ALS experimental models. In experimental models, both ISR stimulation and inhibition prevented ALS neurodegeneration; however, which mode of ISR regulation would work in patients is still debated. We previously demonstrated that the ISR modulator ISRIB (Integrated Stress Response InhiBitor, an eIF2B activator) enhances survival of neurons expressing the ALS neurotoxic allele SOD1 G93A. Here, we tested the effect of two ISRIB‐like eIF2B activators (2BAct and PRXS571) in the disease progression of transgenic SOD1G93A mice. Experimental Approach: After biochemical characterization in primary neurons, SOD1G93A mice were treated with 2BAct and PRXS571. Muscle denervation of vulnerable motor units was monitored with a longitudinal electromyographic test. We used a clinical score to document disease onset and progression; force loss was determined with the hanging wire motor test. Motor neuronal survival was assessed by immunohistochemistry. Key Results: In primary neurons, 2BAct and PRXS571 relieve the ISR‐imposed translational inhibition while maintaining high ATF4 levels. Electromyographic recordings evidenced an earlier and more dramatic muscle denervation in treated SOD1G93A mice that correlated with a decrease in motor neuron survival. Both compounds anticipated disease onset and shortened survival time. Conclusion and Implications: 2BAct and PRXS571 anticipate disease onset, aggravating muscle denervation and motor neuronal death of SOD1G93A mice. This study reveals that the ISR works as a neuroprotective pathway in ALS motor neurons and reveals the toxicity that eIF2B activators may display in ALS patients. [ABSTRACT FROM AUTHOR]

Abstract Background In recent years, national and global mortality data have been characterized in terms of well-established risk factors. In this regard, alcohol consumption has been called the third leading "actual cause of death" (modifiable behavioral risk factor) in the United States, after tobacco use and the combination of poor diet and physical inactivity. Globally and in various regions of the world, alcohol use has been established as a leading contributor to the overall burden of disease and as a major determinant of health disparities, but, to our knowledge, no one has characterized alcohol-related harm in such broad terms at the local level. We asked how alcohol-related premature mortality in San Francisco, measured in years of life lost (YLLs), compares with other well-known causes of premature mortality, such as ischemic heart disease or HIV/AIDS. Methods We applied sex- and cause-specific population-attributable fractions (PAFs) of years of life lost (YLLs) from the Global Burden of Disease Study to 17 comparable outcomes among San Francisco males and females during 2004-2007. We did this in three ways: Method 1 assumed that all San Franciscans drink like populations in developed economies. These estimates were limited to alcohol-related harm. Method 2 modified these estimates by including several beneficial effects. Method 3 assumed that Latino and Asian San Franciscans drink alcohol like populations in the global regions related to their ethnicity. Results By any of these three methods, alcohol-related premature mortality accounts for roughly a tenth of all YLLs among males. Alcohol-related YLLs among males are comparable to YLLs for leading causes such as ischemic heart disease and HIV/AIDS, in some instances exceeding them. Latino and black males bear a disproportionate burden of harm. Among females, for whom estimates differed more by method and were smaller than those for males, alcohol-related YLLs are comparable to leading causes which rank somewhere between fifth and fourteenth. Conclusions Alcohol consumption is a major contributor to premature mortality in San Francisco, especially among males. Interventions to avert alcohol-related harm in San Francisco should be taken at the population level and deserve the same attention that is given to other major risk factors, such as smoking or obesity.

Abstract Background A core function of local health departments is to conduct health assessments. The analysis of death certificates provides information on diseases, conditions, and injuries that are likely to cause death – an important outcome indicator of population health. The expected years of life lost (YLL) measure is a valid, stand-alone measure for identifying and ranking the underlying causes of premature death. The purpose of this study was to rank the leading causes of premature death among San Francisco residents, and to share detailed methods so that these analyses can be used in other local health jurisdictions. Methods Using death registry data and population estimates for San Francisco deaths in 2003–2004, we calculated the number of deaths, YLL, and age-standardized YLL rates (ASYRs). The results were stratified by sex, ethnicity, and underlying cause of death. The YLL values were used to rank the leading causes of premature death for men and women, and by ethnicity. Results In the years 2003–2004, 6312 men died (73,627 years of life lost), and 5726 women died (51,194 years of life lost). The ASYR for men was 65% higher compared to the ASYR for women (8971.1 vs. 5438.6 per 100,000 persons per year). The leading causes of premature deaths are those with the largest average YLLs and are largely preventable. Among men, these were HIV/AIDS, suicide, drug overdose, homicide, and alcohol use disorder; and among women, these were lung cancer, breast cancer, hypertensive heart disease, colon cancer, and diabetes mellitus. A large health disparity exists between African Americans and other ethnic groups: African American age-adjusted overall and cause-specific YLL rates were higher, especially for homicide among men. Except for homicide among Latino men, Latinos and Asians have comparable or lower YLL rates among the leading causes of death compared to whites. Conclusion Local death registry data can be used to measure, rank, and monitor the leading causes of premature death, and to measure and monitor ethnic health disparities.

Abstract Background Previous smallpox ring vaccination models based on contact tracing over a network suggest that ring vaccination would be effective, but have not explicitly included response logistics and limited numbers of vaccinators. Methods We developed a continuous-time stochastic simulation of smallpox transmission, including network structure, post-exposure vaccination, vaccination of contacts of contacts, limited response capacity, heterogeneity in symptoms and infectiousness, vaccination prior to the discontinuation of routine vaccination, more rapid diagnosis due to public awareness, surveillance of asymptomatic contacts, and isolation of cases. Results We found that even in cases of very rapidly spreading smallpox, ring vaccination (when coupled with surveillance) is sufficient in most cases to eliminate smallpox quickly, assuming that 95% of household contacts are traced, 80% of workplace or social contacts are traced, and no casual contacts are traced, and that in most cases the ability to trace 1–5 individuals per day per index case is sufficient. If smallpox is assumed to be transmitted very quickly to contacts, it may at times escape containment by ring vaccination, but could be controlled in these circumstances by mass vaccination. Conclusions Small introductions of smallpox are likely to be easily contained by ring vaccination, provided contact tracing is feasible. Uncertainties in the nature of bioterrorist smallpox (infectiousness, vaccine efficacy) support continued planning for ring vaccination as well as mass vaccination. If initiated, ring vaccination should be conducted without delays in vaccination, should include contacts of contacts (whenever there is sufficient capacity) and should be accompanied by increased public awareness and surveillance.

Abstract Background The United States (US) has re-instituted smallpox vaccinations to prepare for an intentional release of the smallpox virus into the civilian population. In an outbreak, people of all ages will be vaccinated. To prepare for the impact of large-scale ring and mass vaccinations, we conducted a systematic review of the complication and mortality risks of smallpox vaccination. We summarized these risks for post-vaccinial encephalitis, vaccinia necrosum (progressive vaccinia), eczema vaccinatum, generalized vaccinia, and accidental infection (inadvertant autoinoculation). Methods Using a MEDLINE search strategy, we identified 348 articles, of which seven studies met our inclusion criteria (the number of primary vaccinations and re-vaccinations were reported, sufficient data were provided to calculate complication or case-fatality risks, and comparable case definitions were used). For each complication, we estimated of the complication, death, and case-fatality risks. Results The life-threatening complications of post-vaccinial encephalitis and vaccinia necrosum were at least 3 and 1 per million primary vaccinations, respectively. Twenty-nine percent of vaccinees with post-vaccinial encephalitis died and 15% with vaccinia necrosum died. There were no deaths among vaccinees that developed eczema vaccinatum; however, 2.3% of non-vaccinated contacts with eczema vaccinatum died. Among re-vaccinees, the risk of post-vaccinial encephalitis was reduced 26-fold, the risk of generalized vaccinia was reduced 29-fold, and the risk of eczema vaccinatum was reduced 12-fold. However, the risk reductions of accidental infection and vaccinia necrosum were modest (3.8 and 1.5 fold respectively).

Abstract Background In persons with acquired immunodeficiency syndrome (AIDS), Cryptosporidium parvum causes a prolonged, severe diarrheal illness to which there is no effective treatment, and the risk of developing cryptosporidiosis from drinking tap water in non-outbreak settings remains uncertain. To test the hypothesis that drinking tap water was associated with developing cryptosporidiosis, we conducted a matched case-control study among persons with AIDS in San Francisco. Methods Among patients reported to the San Francisco AIDS Registry from May 1996 through September 1998, we compared patients who developed cryptosporidiosis to those who did not. Cases were individually matched to controls based on age, sex, race/ethnicity, CD4+ T lymphocyte count, date of CD4+ count, and date of case diagnosis. Population attributable fractions (PAFs) were calculated. Results The study consisted of 49 cases and 99 matched controls. In the multivariable analysis with adjustments for confounders, tap water consumption inside and outside the home at the highest exposure categories was associated with the occurrence of cryptosporidiosis (inside the home: odds ratio (OR), 6.76; 95% CI 1.37–33.5, and outside the home: OR 3.16; 95% CI 1.23–8.13). The PAF was 85%; that is, the proportion of cases of cryptosporidiosis in San Francisco AIDS patients attributable to tap water consumption could have been as high as 85%. Conclusions Although the results from this observational study cannot be considered definitive, until there is more data, we recommend persons with AIDS, especially those with compromised immune systems, consider avoiding tap water.