Hyper-stimulation of Pyrococcus furiosus CRISPR DNA uptake by a self-transmissible plasmid.

Pyrococcus furiosus is a hyperthermophilic archaeon with three effector CRISPR complexes (types I-A, I-B, and III-B) that each employ crRNAs derived from seven CRISPR arrays. Here, we investigate the CRISPR adaptation response to a newly discovered and self-transmissible plasmid, pT33.3. Transconjugant strains of Pyrococcus furiosus exhibited dramatically elevated levels of new spacer integration at CRISPR loci relative to the strain harboring a commonly employed, laboratory-constructed plasmid. High-throughput sequence analysis demonstrated that the vast majority of the newly acquired spacers were preferentially selected from DNA surrounding a particular region of the pT33.3 plasmid and exhibited a bi-directional pattern of strand bias that is a hallmark of primed adaptation by type I systems. We observed that one of the CRISPR arrays of our Pyrococcus furiosus laboratory strain encodes a spacer that closely matches the region of the conjugative plasmid that is targeted for adaptation. The hyper-adaptation phenotype was found to strictly depend both on the presence of this single matching spacer as well as the I-B effector complex, known to mediate primed adaptation. Our results indicate that Pyrococcus furiosus naturally encountered this conjugative plasmid or a related mobile genetic element in the past and responds to reinfection with robust primed adaptation.

Primed CRISPR DNA uptake in Pyrococcus furiosus.

CRISPR-Cas adaptive immune systems are used by prokaryotes to defend against invaders like viruses and other mobile genetic elements. Immune memories are stored in the form of 'spacers' which are short DNA sequences that are captured from invaders and added to the CRISPR array during a process called 'adaptation'. Spacers are transcribed and the resulting CRISPR (cr)RNAs assemble with different Cas proteins to form effector complexes that recognize matching nucleic acid and destroy it ('interference'). Adaptation can be 'naïve', i.e. independent of any existing spacer matches, or it can be 'primed', i.e. spurred by the crRNA-mediated detection of a complete or partial match to an invader sequence. Here we show that primed adaptation occurs in Pyrococcus furiosus. Although P. furiosus has three distinct CRISPR-Cas interference systems (I-B, I-A and III-B), only the I-B system and Cas3 were necessary for priming. Cas4, which is important for selection and processing of new spacers in naïve adaptation, was also essential for priming. Loss of either the I-B effector proteins or Cas3 reduced naïve adaptation. However, when Cas3 and all crRNP genes were deleted, uptake of correctly processed spacers was observed, indicating that none of these interference proteins are necessary for naïve adaptation.

Costs of Immunization Programs for 10 Vaccines in 94 Low- and Middle-Income Countries From 2011 to 2030.

OBJECTIVES: Understanding the level of investment needed for the 2021-2030 decade is important as the global community faces the next strategic period for vaccines and immunization programs. To assist with this goal, we estimated the aggregate costs of immunization programs for ten vaccines in 94 low- and middle-income countries from 2011 to 2030. METHOD: We calculated vaccine, immunization delivery and stockpile costs for 94 low- and middle-income countries leveraging the latest available data sources. We conducted scenario analyses to vary assumptions about the relationship between delivery cost and coverage as well as vaccine prices for fully self-financing countries. RESULTS: The total aggregate cost of immunization programs in 94 countries for 10 vaccines from 2011 to 2030 is $70.8 billion (confidence interval: $56.6-$93.3) under the base case scenario and $84.1 billion ($72.8-$102.7) under an incremental delivery cost scenario, with an increasing trend over two decades. The relative proportion of vaccine and delivery costs for pneumococcal conjugate, human papillomavirus, and rotavirus vaccines increase as more countries introduce these vaccines. Nine countries in accelerated transition phase bear the highest burden of the costs in the next decade, and uncertainty with vaccine prices for the 17 fully self-financing countries could lead to total costs that are 1.3-13.1 times higher than the base case scenario. CONCLUSION: Resource mobilization efforts at the global and country levels will be needed to reach the level of investment needed for the coming decade. Global-level initiatives and targeted strategies for transitioning countries will help ensure the sustainability of immunization programs.

Economic Benefits of Immunization for 10 Pathogens in 94 Low- and Middle-Income Countries From 2011 to 2030 Using Cost-of-Illness and Value-of-Statistical-Life Approaches.

OBJECTIVES: Vaccination has prevented millions of deaths and cases of disease in low- and middle-income countries (LMICs). During the Decade of Vaccines (2011-2020), international organizations, including the World Health Organization and Gavi, the Vaccine Alliance, focused on new vaccine introduction and expanded coverage of existing vaccines. As Gavi, other organizations, and country governments look to the future, we aimed to estimate the economic benefits of immunization programs made from 2011 to 2020 and potential gains in the future decade. METHODS: We used estimates of cases and deaths averted by vaccines against 10 pathogens in 94 LMICs to estimate the economic value of immunization. We applied 3 approaches-cost of illness averted (COI), value of statistical life (VSL), and value of statistical life-year (VSLY)-to estimate observable and unobservable economic benefits between 2011 and 2030. RESULTS: From 2011 to 2030, immunization would avert $1510.4 billion ($674.3-$2643.2 billion) (2018 USD) in costs of illness in the 94 modeled countries, compared with the counterfactual of no vaccination. Using the VSL approach, immunization would generate $3436.7 billion ($1615.8-$5657.2 billion) in benefits. Applying the VSLY approach, $5662.7 billion ($2547.2-$9719.4) in benefits would be generated. CONCLUSION: Vaccination has generated significant economic benefits in LMICs in the past decade. To reach predicted levels of economic benefits, countries and international donor organizations need to meet coverage projections outlined in the Gavi Operational Forecast. Estimates generated using the COI, VSL, or VSLY approach may be strategically used by donor agencies, decision makers, and advocates to inform investment cases and advocacy campaigns.

Social Stigma toward Persons with Opioid Use Disorder: Results from a Nationally Representative Survey of U.S. Adults.

Background: This study seeks to understand the general adult population's knowledge, attitudes, and stigma towards opioid use disorder (OUD), people with histories of opioid misuse, and policies related to OUD. Methods: We conducted a cross-sectional national survey of the U.S. adult population, using AmeriSpeak's® web, probability-based panel. The number of participants were 947 (493 females and 454 males) general population adults ages 19 -89 years old who completed a self-report survey covering: social stigma of OUD, opioid policy attitudes, perceptions of OUD as a crime, knowledge and beliefs about opioids and treatment, personal experience with opioids and the criminal justice (CJ) system, and demographics. Results: Thirteen percent self-reported ever misusing opioids, 3% reported an opioid overdose, and 14% reported personal experience with the CJ system. On average, the general adult population moderately endorses stigmatizing behaviors, agrees that OUD is a medical condition, agrees with policies to increase access to OUD treatment, and is less likely to endorse OUD as a crime. Having a disregard for OUD as a medical condition was most associated with higher levels of stigma, endorsing OUD as a crime, and disagreeing with policies to help people access OUD treatment. Conclusions: Our data provide guidance to policymakers concerning individuals with certain characteristics to target for public education efforts to reduce stigma and draw more support for public heath interventions for OUD. Our data also suggest that the content of this education should include improving understanding of OUD as a medical condition.

Race and Gender Differences in Awareness of Colorectal Cancer Screening Tests and Guidelines Among Recently Diagnosed Colon Cancer Patients in an Urban Setting.

The purpose of this study was to first characterize the prevalence of recall, recognition, and knowledge of colon cancer screening tests and guidelines (collectively, "awareness") among non-Hispanic black (NHB) and NH white (NHW) urban colon cancer patients. Second, we sought to examine whether awareness was associated with mode of cancer detection. Low awareness regarding colon cancer screening tests and guidelines may explain low screening rates and high prevalence of symptomatic detection. We examined recall, recognition, and knowledge of colorectal cancer (CRC) screening tests and guidelines and their associations with mode of cancer detection (symptomatic versus screen-detected) in 374 newly diagnosed NHB and NHW patients aged 45-79. Patients were asked to name or describe any test to screen for colon cancer (recall); next, they were given descriptions of stool testing and colonoscopy and asked if they recognized each test (recognition). Lastly, patients were asked if they knew the screening guidelines (knowledge). Overall, awareness of CRC screening guidelines was low; just 20% and 13% of patients knew colonoscopy and fecal test guidelines, respectively. Awareness of CRC screening tests and guidelines was especially low among NHB males, socioeconomically disadvantaged individuals, and those diagnosed at public healthcare facilities. Inability to name or recall a single test was associated with reduced screen-detected cancer compared with recall of at least one test (36% vs. 22%, p = 0.01). Low awareness of CRC screening tests is a risk factor for symptomatic detection of colon cancer.

A journey down to hell: new thermostable protein-tags for biotechnology at high temperatures.

The specific labelling of proteins in recent years has made use of self-labelling proteins, such as the SNAP-tag® and the Halotag®. These enzymes, by their nature or suitably engineered, have the ability to specifically react with their respective substrates, but covalently retaining a part of them in the catalytic site upon reaction. This led to the synthesis of substrates conjugated with, e.g., fluorophores (proposing them as alternatives to fluorescent proteins), but also with others chemical groups, for numerous biotechnological applications. Recently, a mutant of the OGT from Saccharolobus solfataricus (H5) very stable to high temperatures and in the presence of physical and chemical denaturing agents has been proposed as a thermostable SNAP-tag® for in vivo and in vitro harsh reaction conditions. Here, we show two new thermostable OGTs from Thermotoga neapolitana and Pyrococcus furiosus, which, respectively, display a higher catalytic activity and thermostability respect to H5, proposing them as alternatives for in vivo studies in these extreme model organisms.

100 Years of phenogenetics: Valentin Haecker and his examination of the phenotype.

Following the 'rediscovery' of Mendel's work around 1900 the study of genetics grew rapidly and multiple new inheritance theories quickly emerged such as Hugo de Vries' "Mutation Theory" (1901) and the "Boveri-Sutton Chromosome Theory" (1902). Mendel's work also caught the attention of the German geneticist Valentin Haecker, yet he was generally dissatisfied the simplicity of Mendelian genetics as he believed that inheritance and the expression of various characteristics appeared to be much more complex than the proposed "on-off hypotheses". Haecker's primary objection was that Mendelian-based theories still failed to bridge the gap between hereditary units and phenotypic traits. Haecker thus set out to bridge this gap in his research program, which he called Phänogenetik ("phenogenetics"). He outlined his work in a special study "Entwicklungsgeschichtliche Eigenschaftsanalyse (Phänogenetik)" in 1918. 2018 thus marks the 100th anniversary of Haecker's seminal publication, which was devoted to the analysis of the phenotype and highlighted the true complexity of heredity. This article takes a specific look at Haecker and his work, while also illustrating how this often forgotten scientist influenced the field of genetics and other scientists.

Prospective cohort study of the relationship between neuro-cognition, social cognition and violence in forensic patients with schizophrenia and schizoaffective disorder.

BACKGROUND: There is a broad literature suggesting that cognitive difficulties are associated with violence across a variety of groups. Although neurocognitive and social cognitive deficits are core features of schizophrenia, evidence of a relationship between cognitive impairments and violence within this patient population has been mixed. METHODS: We prospectively examined whether neurocognition and social cognition predicted inpatient violence amongst patients with schizophrenia and schizoaffective disorder (n = 89; 10 violent) over a 12 month period. Neurocognition and social cognition were assessed using the MATRICS Consensus Cognitive Battery (MCCB). RESULTS: Using multivariate analysis neurocognition and social cognition variables could account for 34 % of the variance in violent incidents after controlling for age and gender. Scores on a social cognitive reasoning task (MSCEIT) were significantly lower for the violent compared to nonviolent group and produced the largest effect size. Mediation analysis showed that the relationship between neurocognition and violence was completely mediated by each of the following variables independently: social cognition (MSCEIT), symptoms (PANSS Total Score), social functioning (SOFAS) and violence proneness (HCR-20 Total Score). There was no evidence of a serial pathway between neurocognition and multiple mediators and violence, and only social cognition and violence proneness operated in parallel as significant mediators accounting for 46 % of the variance in violent incidents. There was also no evidence that neurocogniton mediated the relationship between any of these variables and violence. CONCLUSIONS: Of all the predictors examined, neurocognition was the only variable whose effects on violence consistently showed evidence of mediation. Neurocognition operates as a distal risk factor mediated through more proximal factors. Social cognition in contrast has a direct effect on violence independent of neurocognition, violence proneness and symptom severity. The neurocognitive impairment experienced by patients with schizophrenia spectrum disorders may create the foundation for the emergence of a range of risk factors for violence including deficits in social reasoning, symptoms, social functioning, and HCR-20 risk items, which in turn are causally related to violence.

340B Contract pharmacy growth by pharmacy ownership: 2009-2022.

The 340B program grants eligible health care providers ("covered entities") access to discounted prices for outpatient prescription drugs. Covered entities frequently rely on retail pharmacies ("contract pharmacies") to dispense discounted drugs. This analysis describes contract pharmacy participation by ownership: the top 4 chains, grocery chains, small chains, and institutional independent pharmacies. We found that 71% of pharmacies in the top 4 chains were contract pharmacies. Forty one percentage of institutional pharmacies, 38% of grocery store pharmacies, and 22% of independent pharmacies participated in 340B in 2022. The median number of contracts per pharmacy was 2 among the top 4 chains and grocery store pharmacies vs 1 for all other pharmacy types. The median farthest distance in miles from contracting covered entities was largest for the top 4 chains (19 miles) and small chains (18 miles) and smallest for independent and institutional pharmacies (10 miles). The top 4 chains held the highest proportion of contracts with core safety-net providers (75% vs 61% of institutional pharmacies).

340B Participation and Safety Net Engagement Among Federally Qualified Health Centers.

Importance: The 340B program provides discounts on outpatient drugs to certain hospitals and federally supported clinics (covered entities) that can be used to generate revenue to fund safety net care. While numerous studies have found no association between 340B and safety net care provision for most hospital covered entities, less is known about whether federally qualified health centers (FQHCs), the largest group of covered entities after hospitals, use the program to enhance safety net care. Objective: To assess whether a proxy for 340B revenue was associated with increased safety net care provision among FQHCs. Design and Setting: This descriptive, retrospective cohort study examined care provided from 2005 to 2022 by 1468 FQHCs that submitted to the Health Resources and Services Administration Uniform Data System. FQHC and year-level fixed effects were included, as well as a control for differential Medicaid expansion over time. The data were analyzed between March and December 2023. Exposure: One-year lagged number of locations registered to dispense or administer 340B-discounted drugs (registered locations), which included child sites, in-house pharmacies, and contract pharmacies in the 340B Outpatient Pharmacy Affairs Database. Main outcomes: Natural logarithm of patient volume by payer, low-income status, and use of enabling services. Natural logarithm of visits in which low-profit preventive services were provided. Results: An additional registered location was associated with increased patient volume, especially for uninsured (0.4%; 95% CI, 0.3%-0.5%) and privately insured (0.4%; 95% CI, 0.2%-0.5%) patients and low-income (0.4%; 95% CI, 0.2%-0.6%), unhoused (0.3%; 95% CI, 0.1%-0.5%), and non-English-speaking (0.3%; 95% CI, 0.1%-0.5%) patients. An additional registered location was associated with increased visits with an HIV test (0.7%; 95% CI, 0.4%-0.9%), serum lead test (0.8%; 95% CI, 0.6%-1.1%), seasonal influenza shot (0.4%; 95% CI, 0.3%-0.5%), Papanicolaou smear (0.5%; 95% CI, 0.4%-0.7%), and tobacco cessation counseling (1.0%; 95% CI, 0.5%-1.4%). Across the study period, the average annual increase in locations was 1.5. Conclusions and Relevance: The results of this cohort study suggest that there are statistically significant increases in the provision of low-profit but high-value preventive services and care to safety net populations (those who lack insurance, have a low income, or require enabling services) and that, like public hospitals, FQHCs might use 340B revenues to enhance safety net care. This finding may inform debates on the 340B program by supporting differential 340B reforms across hospital and nonhospital covered entities.

SARS-CoV-2 dynamics in New York City during March 2020-August 2023.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been widespread since 2020 and will likely continue to cause substantial recurring epidemics. However, understanding the underlying infection burden (i.e., including undetected asymptomatic/mild infections) and dynamics, particularly since late 2021 when the Omicron variant emerged, is challenging due to the potential for asymptomatic and repeat SARS-CoV-2 infection, changes in testing practices, and changes in disease reporting. Here, we leverage extensive surveillance data available in New York City (NYC) and a comprehensive model-inference system to reconstruct SARS-CoV-2 dynamics therein from the pandemic onset in March 2020 to August 2023, and further validate the estimates using independent wastewater surveillance data. The validated model-inference estimates indicate a very high infection burden totaling twice the population size (>5 times documented case count) but decreasing infection-fatality risk (a >10-fold reduction) during the first 3.5 years. The detailed estimates also reveal highly complex variant dynamics and immune landscape, changing virus transmissibility, and higher infection risk during winter in NYC over this time period. These transmission dynamics and drivers, albeit based on data in NYC, may be relevant to other populations and inform future planning to help mitigate the public health burden of SARS-CoV-2.

The Use of Wastewater Surveillance to Estimate SARS-CoV-2 Fecal Viral Shedding Pattern and Identify Time Periods with Intensified Transmission.

Background: Wastewater-based surveillance is an important tool for monitoring the COVID-19 pandemic. However, it remains challenging to translate wastewater SARS-CoV-2 viral load to infection number, due to unclear shedding patterns in wastewater and potential differences between variants. Objectives: We utilized comprehensive wastewater surveillance data and estimates of infection prevalence (i.e., the source of the viral shedding) available for New York City (NYC) to characterize SARS-CoV-2 fecal shedding pattern over multiple COVID-19 waves. Methods: We collected SARS-CoV-2 viral wastewater measurements in NYC during August 31, 2020 - August 29, 2023 ( N = 3794 samples). Combining with estimates of infection prevalence (number of infectious individuals including those not detected as cases), we estimated the time-lag, duration, and per-infection fecal shedding rate for the ancestral/Iota, Delta, and Omicron variants, separately. We also developed a procedure to identify occasions with intensified transmission. Results: Models suggested fecal viral shedding likely starts around the same time as and lasts slightly longer than respiratory tract shedding. Estimated fecal viral shedding rate was highest during the ancestral/Iota variant wave, at 1.44 (95% CI: 1.35 - 1.53) billion RNA copies in wastewater per day per infection (measured by RT-qPCR), and decreased by ∼20% and 50-60% during the Delta wave and Omicron period, respectively. We identified around 200 occasions during which the wastewater SARS-CoV-2 viral load exceeded the expected level in any of 14 sewersheds. These anomalies disproportionally occurred during late January, late April - early May, early August, and from late-November to late-December, with frequencies exceeding the expectation assuming random occurrence ( P < 0.05; bootstrapping test). Discussion: These estimates may be useful in understanding changes in underlying infection rate and help quantify changes in COVID-19 transmission and severity over time. We have also demonstrated that wastewater surveillance data can support the identification of time periods with potentially intensified transmission.

Achieving immunization agenda 2030 coverage targets for 14 pathogens: Projected product and immunization delivery costs for 194 Countries, 2021-2030.

Understanding the level of investment needed for the next decade is vital to achieve the goal of Immunization Agenda 2030 (IA2030). Through the immunization funder perspective, this study estimates both global and regional economic resources required to achieve IA2030 coverage among 194 WHO member countries from 2021 to 2030, against 14 pathogens: Hepatitis B (Hep B), Haemophilus influenzae type b (Hib), Human papillomavirus (HPV), Japanese encephalitis (JE), Measles, Meningitis A (Men A), Streptococcus pneumoniae, Rotavirus, Rubella, Yellow Fever (YF), Diphtheria, Tetanus, Pertussis, and Tuberculosis. The total cost of immunization program, routine vaccine, routine delivery, and non-routine costs (SIA and stockpile) were estimated using WHO coverage forecast for IA2030. Incremental costs of achieving IA2030 for all vaccines and cost per immunized child were also assessed. All costs were calculated for each income and regional level, as well as global level. Scenario analysis and sensitivity analysis were conducted to account for uncertainty in future vaccine pricing and delivery costs. The total cost of immunization programs is $269.8 billion (95% confidence interval: $247.1 - $311.8), of which $152.8 billion is considered as routine vaccine cost, $114.9 billion is routine delivery cost. Non- routine cost for LICs and LMICs totaled $2.1 billion. The incremental cost of achieving coverage goals after 2020 is $89.9 billion ($27.7-$110.1), with upper-middle income countries requiring the largest increase in investment (56.2% of incremental costs). The average immunization cost per child across all countries is $192.6. Scenario analysis using the minimum and maximum vaccines price for fully self-financing countries resulted in total costs ranging from $193.6 and $552.2 billion. The immunization program cost among 194 WHO member countries is expected to increase during this decade. The strategy for resource mobilization and increasing investment from country governments and donors are essential to achieving IA2030 coverage and ensuring sustainable immunization programs.

Histones direct site-specific CRISPR spacer acquisition in model archaeon.

CRISPR-Cas systems provide heritable immunity against viruses and other mobile genetic elements by incorporating fragments of invader DNA into the host CRISPR array as spacers. Integration of new spacers is localized to the 5' end of the array, and in certain Gram-negative Bacteria this polarized localization is accomplished by the integration host factor. For most other Bacteria and Archaea, the mechanism for 5' end localization is unknown. Here we show that archaeal histones play a key role in directing integration of CRISPR spacers. In Pyrococcus furiosus, deletion of either histone A or B impairs integration. In vitro, purified histones are sufficient to direct integration to the 5' end of the CRISPR array. Archaeal histone tetramers and bacterial integration host factor induce similar U-turn bends in bound DNA. These findings indicate a co-evolution of CRISPR arrays with chromosomal DNA binding proteins and a widespread role for binding and bending of DNA to facilitate accurate spacer integration.

A standardized approach for measuring multivariate equity in vaccination coverage, cost-of-illness, and health outcomes: Evidence from the Vaccine Economics Research for Sustainability & Equity (VERSE) project.

Following a call from the World Health Organization in 2017 for a methodology to monitor immunization coverage equity in line with the 2030 Agenda for Sustainable Development, this study outlines a standardized approach for measuring multivariate equity in vaccine coverage, economic impact, and health outcomes. The Vaccine Economics Research for Sustainability & Equity (VERSE) composite vaccination equity measurement approach is derived from literature on the measurement of socioeconomic inequality combined with measures of direct unfairness in healthcare access. The final metrics take the form of a concentration index for vaccination coverage where individuals are ranked by multivariate unfairness in access and an absolute equity gap representing the difference in coverage between the top and bottom quintiles of individuals ranked by multivariate unfairness in access. Regression decomposition is applied to the concentration index to determine each factor's relative influence on observed inequity. These methods are applied to India's National Family Health Survey (NFHS) from 2015 to 2016 to assess the equity in being fully-immunized for age vaccination coverage and zero-dose status. The multivariate absolute equity gap is 0.120 (SE: 003) and 0.371 (SE: 0.008) for zero-dose status and fully-immunized for age, respectively. Therefore, the most disadvantaged quintile is 12 percentage points more likely to be zero-dose than the most advantaged quintile and 37.1 percentage points less likely to be fully immunized. The primary correlate of unfair disadvantage for both outcomes is maternal education accounting for 27.4% and 19.1% of observed inequality. The VERSE model provides a standardized approach for measuring multivariate vaccine coverage equity. It also allows policymakers to determine the relative magnitude of factors influencing multivariate equity rather than only the correlates of socioeconomic or bivariate equity. This framework could be adapted to track equitable progress toward Universal Health Coverage (UHC) or outcomes beyond the vaccine space.

Return on Investment of 10-Valent Pneumococcal Conjugate Vaccine in Ecuador From 2010 to 2030.

OBJECTIVES: Ecuador introduced the pneumococcal conjugate vaccine in 2010. A recent time series analysis has demonstrated the impact of 10-valent pneumococcal conjugate vaccine (PCV10) on hospitalized pneumococcal disease in children. We leveraged these estimates to calculate the return on investment (ROI) of PCV10 in Ecuador from 2010 to 2030 at the national and regional levels. METHODS: We used 2 approaches to estimate the economic benefits: (1) cost of illness, which includes treatment, transportation, and productivity loss averted, (2) and the value of statistical life, which reflects society's average willingness to pay to save one life. Costs of the immunization program include vaccine costs (doses, syringes, injection supplies) and immunization delivery costs (personnel, cold chain equipment and maintenance, transportation, distribution services, and other recurrent costs). We estimated the ROI by dividing the net benefits by costs. RESULTS: The ROI using the cost-of-illness approach was slightly negative in the introduction year. From 2011 to 2020, we estimated the ROI to be 0.45 (0.15-0.73). For the future decade, the ROI is estimated at 0.37 (-0.03 to 1.03). Using the value-of-statistical-life approach, the ROI was 1.46 (0.82-2.17) in the introduction year. In the first decade, the ROI was 1.01 (0.49-1.60); in the second decade, the ROI fell to 0.83 (0.23-1.78). CONCLUSIONS: The results of this study demonstrate the total economic benefits of PCV10 in Ecuador exceed immunization program costs after the introduction year. Estimates from this study will inform country policy makers and will contribute to efforts to mobilize resources for immunization.

On the historical roots of creationism and intelligent design: German Allmacht and Darwinian evolution in context.

As detailed in a Letter published in Science in 2017, the adherents of creationism and intelligent design are still active in promoting their biblical-literalist views of the origin and evolution of life on Earth. In this contribution, we take a look at this ideological phenomenon in the USA and analyze the philosophical roots of this ongoing movement. Specifically, we discuss Vernon Kellogg's book entitled Headquarters Nights (1917) with reference to the German 'Allmacht' (English-omnipotence) and Darwinian evolution to demonstrate how this publication bolstered the development of active anti-evolutionism in the USA among American fundamentalist Christians, inclusive of the Intelligent Design (ID)-agenda. The current activities of creationist associations in the USA and Germany are summarized, with reference to a new pro-ID-group established in Austria in 2019 that is sponsored by the Discovery Institute in Seattle, Washington (USA).

Society of Behavioral Medicine Update: retain support for the National Colorectal Cancer Roundtable's call to action to reach 80% colorectal cancer screening.

Colorectal cancer (CRC) remains the third most commonly diagnosed cancer and the third leading cause of cancer-related death in the USA. CRC can be prevented through regular screening and removal of precancerous polyps. However, roughly one third of eligible adults in the USA are not up to date with recommended CRC screening. To increase timely CRC screening uptake in the USA, in 2014, the National Colorectal Cancer Roundtable (NCCRT) launched 80% by 2018. This multilevel effort involved more than 1,500 pledged organizations targeting patients, providers, health care systems, and policymakers to increase U.S. CRC screening rates to 80% by 2018. Concurrent with this campaign, between 2012 and 2018, CRC screening rates increased nationwide by 3.6% from 65.2% to 68.8%, meaning that about 9.3 million more U.S. adults are being screened. NCCRT attributes these successes to widespread implementation of center- and system-wide evidence-based interventions to increase screening uptake, including direct patient communication, provider reminders via electronic health records, and patient navigation, among others. Moving beyond 2018, NCCRT has rebranded the initiative as the 80% Pledge and has since identified several targeted campaigns, including increased outreach to Hispanics, Latinos, and Asians, whose CRC screening uptake remains less than 50%; encouragement of Medicaid outreach activities around CRC screening in all 50 states; and advocacy for screening right at 50 years of age. Society of Behavioral Medicine continues to support NCCRT and encourages policymakers to do the same by taking legislative action to assure funding for Medicaid outreach, research innovations, and clinical quality improvement that supports the 80% Pledge.