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).

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.

Trends in 340B Drug Pricing Program Contract Growth Among Retail Pharmacies From 2009 to 2022.

This cross-sectional study assesses the increases and decreases over time in the number of pharmacy contracts, distance from contracting pharmacies, and proportion of pharmacy contracts with safety-net practices in the US.

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.

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.

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.

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.

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.

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).

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.

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.

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.

Return On Investment From Immunization Against 10 Pathogens In 94 Low- And Middle-Income Countries, 2011-30.

Estimating the value of global investment in immunization programs is critical to helping decision makers plan and mobilize immunization programs and allocate resources required to realize their full benefits. We estimated economic benefits using cost-of-illness and value-of-a-statistical-life approaches and combined this estimation with immunization program costs to derive the return on investment from immunization programs against ten pathogens for ninety-four low- and middle-income countries for the period 2011-30. Using the cost-of-illness approach, return on investment for one dollar invested in immunization against our ten pathogens was 26.1 for the ninety-four countries from 2011 to 2020 and 19.8 from 2021 to 2030. Using the value-of-a-statistical-life approach, return on investment was 51.0 from 2011 to 2020 and 52.2 from 2021 to 2030. The results demonstrate continued high return on investment from immunization programs. The return-on-investment estimates from this study will inform country policy makers and decision makers in funding agencies and will contribute to efforts to mobilize resources for immunization. Realization of the full benefits of immunization will depend on sustained investment in and commitment to immunization programs.

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.

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.

Ecology and Evolution: Haeckel's Darwinian Paradigm.

Ernst Haeckel coined the term ecology in the process of Darwinizing our understanding of nature. His concept of ecology was part of a theoretical system embracing development, evolution, and environment. We outline Haeckel's views on ecology as an evolutionary science and demonstrate their importance for current theoretical developments.

Ernst Haeckel's contribution to Evo-Devo and scientific debate: a re-evaluation of Haeckel's controversial illustrations in US textbooks in response to creationist accusations.

As Blackwell (Am Biol Teach 69:135-136, 2007) pointed out, multiple authors have attempted to discredit Haeckel, stating that modern embryological studies have shown that Haeckel's drawings are stylized or embellished. More importantly, though, it has been shown that the discussion within the scientific community concerning Haeckel's drawings and the question of whether embryonic similarities are convergent or conserved have been extrapolated outside the science community in an attempt to discredit Darwin and evolutionary theory in general (Behe in Science 281:347-351, 1998; Blackwell in Am Biol Teach 69:135-136, 2007; Pickett et al. in Am Biol Teach 67:275, 2005; Wells in Am Biol Teach 61:345-349, 1999; Icons of evolution: science or myth? Why much of what we teach about evolution is wrong. Regnery Publishing, Washington, 2002). In this paper, we address the controversy surrounding Haeckel and his work in order to clarify the line between the shortcomings and the benefits of his research and illustrations. Specifically, we show that while his illustrations were not perfect anatomical representations, they were useful educational visualizations and did serve an important role in furthering studies in embryology.