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Background: Recent evidence suggests that 1 dose of the human papillomavirus (HPV) vaccine may have similar effectiveness in reducing HPV infection risk compared to 2 or 3 doses., Objective: To evaluate the public health impact and cost-effectiveness of implementing a 1-dose or a 2-dose program of the 9-valent HPV vaccine in a low- and middle-income country (LMIC)., Methods: We adapted a dynamic transmission model to the Indonesia setting, and conducted a probabilistic sensitivity analysis using distributions reflecting the uncertainty in levels and durability of protection of a 1-dose that were estimated under a Bayesian framework incorporating 3-year vaccine efficacy data from the KEN SHE trial (base-case) and 10 year effectiveness data from the India IARC study (alternative analysis). Scenarios included different coverage levels targeted at girls-only, or girls and boys. Costs and benefits were computed over 100 years from a national single-payer perspective., Results: Depending on the coverage and target population, the median number of cancer cases avoided in 2-dose programs ranged between 600,000-2,100,000, compared to 200,000-600,000 in 1-dose programs. The 1-dose programs are unlikely to be cost-effective compared to 2-dose programs even at low willingness-to-pay (WTP) thresholds. The girls-only 2-dose program tends to be cost-effective at lower WTP thresholds, particularly in scenarios with high coverage, dose price and discount rate, while the girls and boys 2-dose program is cost-effective at higher WTP thresholds. In the alternative analysis, 1-dose programs have higher probability of being cost-effective compared to the base-case, particularly for low WTP thresholds (less than 0.5 GDP) and for high coverage, dose price and discount rate., Conclusion: Adoption of 1-dose programs with 9-valent vaccine in an LMIC resulted in more vaccine-preventable HPV-related cancer cases than 2-dose programs. The 2-dose programs were more likely to be cost-effective than 1-dose programs for a wide range of WTP thresholds and scenarios., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Vincent Daniels and Kunal Saxena are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and shareholders in Merck & Co., Inc., Rahway, NJ, USA. Oscar Patterson-Lomba and Andres Gomez-Lievano are employees of Analysis Group, Inc., a consulting company that has provided paid consulting services to Merck & Co., Inc, which funded the development and conduct of this study and manuscript. Jarir At Thobari, Nancy Durand, and Evan Myers have received consultancy fees from Merck & Co., Inc., (Copyright: © 2024 Daniels et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: Human papillomavirus (HPV) is a prevalent sexually transmitted infection with significant implications for public health. In Poland, a nationwide vaccination program offers a choice between the 9-valent (9v) and 2-valent (2v) HPV vaccines. We aimed to assess the cost-effectiveness of the 9v vs 2v vaccine from the public payer perspective in Poland., Material and Methods: A cost-effectiveness analysis was conducted to compare the public health and economic benefits of using 9v vs 2v vaccine in Poland over 100-year horizon using a previously published deterministic dynamic transmission model. A target population of girls and boys aged 12-13 years was considered. The model was populated with local epidemiological inputs, utilities, and costs, including vaccine and administration costs, as well as costs related to medical procedures for HPV-related diseases., Results: The 9v vaccine reduced the prevalence of HPV infections and HPV-related diseases substantially more than 2v vaccine when both are compared to no vaccination strategy. The total discounted cost savings of using the 9v vaccine instead of 2v, excluding the vaccine costs, amounted to EUR 66 million. The incremental cost-effectiveness ratio amounted to 8094 EUR per quality-adjusted life year, much below the official cost-effectiveness threshold in Poland set up at the three times the annual gross domestic product per capita. 9v cost-effectiveness ratio remained unchanged when shorter time-horizons of 20, 40, 60, or 80 years were considered., Conclusions: Using 9v HPV vaccine in Poland is highly cost-effective compared to the 2v vaccine.

Importance: Patients who have been treated for high-grade cervical intraepithelial neoplasia (CIN grade ≥2) are at a high risk for subsequent CIN and other cancers and diseases related to human papillomavirus (HPV). HPV vaccination can reduce the risk of subsequent disease in patients surgically treated for grade 2 or greater CIN; however, there is no formal recommendation for prophylactic HPV vaccination in this high-risk population, and the cost-effectiveness is unknown., Objective: To assess the incremental lifetime outcomes, costs, and cost-effectiveness of integrating peritreatment 9-valent HPV (9vHPV) vaccination in combination with posttreatment surveillance for the prevention of cervical cancer and other HPV-attributable diseases in patients surgically treated for grade 2 or greater CIN vs posttreatment surveillance alone from a UK payer perspective., Design, Setting, and Participants: This economic evaluation used 3 independent Markov model structures. Model inputs for vaccine efficacy, utilities, and costs were obtained from published sources, and cervical cancer screening data were obtained from the National Health Service Cervical Screening Program. Costs were adjusted to 2022 to 2023 reference years. Data were analyzed from October 2022 to September 2023., Exposure: Peritreatment vaccination with 9vHPV in combination with posttreatment surveillance compared with posttreatment surveillance alone., Main Outcomes and Measures: Clinical outcomes included grade 1, 2, or 3 CIN; cervical cancer; vaginal cancer; vulvar cancer; anal cancer; head and neck cancer; genital warts; and recurrent respiratory papillomatosis. Incremental cost-effectiveness ratios (ICERs) using a willingness-to-pay threshold (WTP) of £20 000 (US $26 200) per quality-adjusted life-year (QALY) were estimated. Deterministic sensitivity analysis and probabilistic sensitivity analysis were performed., Results: Vaccination with 9vHPV in conjunction with posttreatment surveillance was cost-effective, with a favorable ICER of £13 789.07 (US $18 064.68) per QALY gained (ie, below the WTP of £20 000 per QALY) vs posttreatment surveillance alone. The resulting ICER was £52 358.01 (US $68 588.99) per HPV-related cancer averted and £64 090 (US $83 958.18) per HPV-related cancer death averted. The ICER was most sensitive to discount rate, incidence of HPV infection, vaccine price, and age at initial treatment for grade 2 or greater CIN. Results of the probabilistic sensitivity analysis showed peritreatment 9vHPV vaccination was cost-effective at the WTP recommended by the UK's Joint Committee on Vaccination and Immunisation (90% of iterations <£30 000 [US $39 300] per QALY) in 100% of iterations., Conclusions and Relevance: These findings suggest that peritreatment prophylactic 9vHPV vaccination is a cost-effective option for preventing subsequent HPV-attributable diseases in patients surgically treated for grade 2 or greater CIN.

Background: Poly ADP-ribose polymerase (PARP) inhibitors are approved for the treatment of some men with advanced prostate cancer. Rare but serious side effects include myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The impact of PARP inhibitors on clonal hematopoiesis (CH), a potential precursor lesion associated with MDS and AML, is incompletely understood in prostate cancer. We hypothesized that PARP inhibitors would increase CH prevalence and abundance., Methods: We prospectively enrolled participants with advanced prostate cancer treated with PARP inhibitors. The presence of CH was assessed from leukocytes using an ultra-deep error-corrected dual unique molecular identifiers sequencing method targeting 49 genes most commonly mutated in CH and myeloid malignancies. Variant allele frequencies (VAF) of ≥0.5% were considered clinically significant. Blood samples were collected before and after PARP inhibitor treatment., Results: Ten men were enrolled; mean age of 67 years. Six patients had Gleason 7 disease, and four had Gleason ≥8 disease at diagnosis. Nine had localized disease at diagnosis, and eight had prior treatment with radiation. The mean time between pre- and post-treatment blood samples was 11 months (range 2.6-31 months). Six patients (60%) had CH identified prior to PARP inhibitor treatment, three with multiple clones. Of 11 CH clones identified in follow-up, 5 (45%) appeared or increased after treatment. DNMT3A, TET2, and PPM1D were the most common CH alterations observed. The largest post-treatment increase involved the PPM1D gene., Conclusion: CH alterations are frequently found after treatment with PARP inhibitors in patients with prostate cancer and this may be one mechanism by which PARP inhibitors lead to increased risk of MDS/AML., (© 2024 Wiley Periodicals LLC.)

Human papillomavirus (HPV) is a common sexually transmitted virus that can cause cervical cancer and other diseases. Dynamic transmission models (DTMs) have been developed to evaluate the health and economic impacts of HPV vaccination. These models typically include many parameters, such as natural history of the disease, transmission, demographic, behavioral, and screening. To ensure the accuracy of DTM projections, it is important to parameterize them with the best available evidence. This study aimed to identify and synthesize data needed to parametrize DTMs on the natural history of HPV infection and related diseases. Parameters describing data of interest were grouped by their anatomical location (genital warts, recurrent respiratory papillomatosis, and cervical, anal, vaginal, vulvar, head and neck, and penile cancers), and natural history (progression, regression, death, cure, recurrence, detection), and were identified through a systematic literature review (SLR) and complementary targeted literature reviews (TLRs). The extracted data were then synthesized by pooling parameter values across publications, and summarized using the range of values across studies reporting each parameter and the median value from the most relevant study. Data were extracted and synthesized from 223 studies identified in the SLR and TLRs. Parameters frequently reported pertained to cervical cancer outcomes, while data for other anatomical locations were less available. The synthesis of the data provides a large volume of parameter values to inform HPV DTMs, such as annual progression rates from cervical intraepithelial neoplasia (CIN) 1 to CIN 2+ (median of highest quality estimate 0.0836), CIN 2 to CIN 3+ (0.0418), carcinoma in situ (CIS) 2 to local cancer+ (0.0396), and regional to distant cancer (0.0474). Our findings suggest that while there is a large body of evidence on cervical cancer, parameter values featured substantial heterogeneity across studies, and further studies are needed to better parametrize the non-cervical components of HPV DTMs., (© 2024. The Author(s).)

The high prevalence of human papillomavirus (HPV) infection in China suggests there would be a substantial positive health impact of widespread vaccination against HPV. We adapted a previously described dynamic transmission model of the natural history of HPV infection and related diseases to the Chinese setting to estimate the public health impact in China of 2-valent (with and without cross-protection), 4-valent, and 9-valent HPV vaccination strategies. The model predicted the incidence and mortality associated with HPV-related diseases, including cervical and noncervical cancers, genital warts, and recurrent respiratory papillomatosis (RRP), based on the various vaccination coverage rate (VCR) scenarios, over a 100-year time horizon. The public health impact of the 4 vaccination strategies was estimated in terms of cases and deaths averted compared to a scenario with no vaccination. Under the assumption of various primary and catch-up VCR scenarios, all 4 vaccination strategies reduced the incidence of cervical cancer in females and noncervical cancers in both sexes, and the 4-valent and 9-valent vaccines reduced the incidence of genital warts and RRP in both sexes. The 9-valent vaccination strategy was superior on all outcomes. The number of cervical cancer cases averted over 100 years ranged from ~ 1 million to ~ 5 million while the number of cervical cancer deaths averted was ~ 345,000 to ~ 1.9 million cases, depending on the VCR scenario. The VCR for primary vaccination was the major driver of cases averted.

Competing Interests: The authors declare no conflict of interest.

Background: The United Kingdom (UK) switched from using the 4-valent human papillomavirus (HPV) vaccine (Gardasil®) to the 9-valent vaccine (Gardasil 9®) in 2021. Objective: To estimate and compare the health and economic outcomes of 2 HPV vaccination programs in the UK targeting girls and boys aged 12-13 years from the perspective of the UK National Health Service. The 2 vaccination strategies were (1) universal vaccination 4-valent (UV4V), using the 4-valent HPV vaccine (4vHPV), and (2) universal vaccination 9-valent (UV9V), using the 9-valent HPV vaccine (9vHPV). Methods: A deterministic heterosexual compartmental disease transmission model was used to track health and economic outcomes over a 100-year time horizon. Outcomes were discounted at an annual rate of 3.5% and 1.5%. All costs were adjusted to 2020 British pounds (£). Health outcomes were measured in quality-adjusted life-years (QALYs), and the summary results were presented as incremental cost-effectiveness ratios (£/QALY gained) when comparing UV4V with UV9V. Results: Using the same vaccine coverage for both programs, the total cumulative cases of HPV-related health outcomes tracked over the 100-year horizon indicated that the relative number of cases averted (UV9V vs UV4V) ranged from 4% (anal male cancers and deaths) to 56% (cervical intraepithelial neoplasia [CIN1]). Assuming that 9vHPV cost £15.18 more than 4vHPV (a cost differential based on discounted list prices), the estimated incremental cost-effectiveness ratio was £8600/QALY gained when discounted at 3.5%, and £3300/QALY gained when discounted at 1.5%. The estimated incremental cost-effectiveness ratios from the sensitivity analyses remained <£28000/QALY over a wide range of parameter inputs and demonstrated that disease utilities, discount rate, and vaccine efficacy were the 3 most influential parameters. Discussion: Consistent with other published studies, the results from this study found that the 9vHPV vaccine prevented a substantial number of cases when compared with the 4vHPV vaccine and was highly cost-effective. Conclusions: These results demonstrate that replacing universal 4vHPV with 9vHPV can prevent a substantial additional number of HPV-related cases/deaths (in both women and men) and remain cost-effective over a range of 9vHPV price premiums., Competing Interests: This study was performed by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co, Inc, Kenilworth, New Jersey. KOE, CP, OO, and VD are employees of Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, New Jersey, and may hold stock or stock options in Merck & Co, Inc, Kenilworth, New Jersey.

The profound transformation of medical libraries over the last twenty years reflects the advancements in medical education and health care delivery, increased expectations of users, and accelerated evolution of technology. The Harvey Cushing/John Hay Whitney Medical Library (CWML) used this opportunity to rethink how staffing could be redeployed to accommodate these new developments. After assessing processes, workflows, and individual responsibilities, library administration devised a novel team approach that would allow clerical & technical (C&T) staff to work across departmental lines to provide a broader variety of in-depth and frontline services. This paper will share how the C&T staff at the CWML developed a broader skill set, while providing library services to users in the rapidly changing field of medical education and health care services.

Although no human papillomavirus (HPV) vaccine is indicated for single-dose administration, some observational evidence suggests that a 1-dose regimen might reduce HPV infection risk to that achieved with 2 doses. This study estimated the potential health and economic outcomes associated with switching from a 2-dose HPV vaccination program for girls and boys aged 13-14 years to an off-label 9-valent (9vHPV), 1-dose regimen, accounting for the uncertainty of the effectiveness and durability of a single dose. A dynamic HPV transmission infection and disease model was adapted to the United Kingdom and included a probabilistic sensitivity analysis using estimated distributions for duration of protection of 1-dose and degree of protection of 1 relative to 2 doses. One-way sensitivity analyses of key inputs were performed. Outcomes included additional cancer and disease cases and the difference in net monetary benefit (NMB). The 1-dose program was predicted to result in 81,738 additional HPV-related cancer cases in males and females over 100 years compared to the 2-dose program, ranging from 36,673 to 134,347 additional cases (2.5% and 97.5% quantiles, respectively), and had a 7.8% probability of being cost-effective at the £20,000/quality-adjusted life years willingness-to-pay (WTP) threshold. In one-way sensitivity analyses, the number of additional cancer cases was sensitive to the median of the duration of protection distribution and coverage rates. The differences in NMBs were sensitive to the median of the duration of protection distribution, dose price and discount rate, but not coverage variations. Across sensitivity analyses, the probability of 1 dose being cost-effective vs 2 doses was < 50% at the standard WTP threshold. Adoption of a 1-dose 9vHPV vaccination program resulted in more vaccine-preventable HPV-related cancer and disease cases in males and females, introduced substantial uncertainty in health and economic outcomes, and had a low probability of being cost-effective compared to the 2-dose program., Competing Interests: Declaration of Competing Interest V Daniels, K Saxena, A Saah, A Luxembourg, C Velicer, Y Chen, and E Elbasha, are employees of Merck & Co., Inc., a manufacturer of HPV vaccines, and may own stocks and/or stock options. O Petterson-Lomba and  A Gomez-Lievano are employees of Analysis Group, Inc.  who were paid consultants to Merck & Co., Inc. in connection with the development of this manuscript., (Copyright © 2022 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA and The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Despite routine vaccination of children against hepatitis A (HepA), a large segment of the United States population remains unvaccinated, imposing a risk of hepatitis A virus (HAV) to adolescents and adults. In July of 2020, the Advisory Committee on Immunization Practices recommended that all children and adolescents aged 2-18 years who have not previously received a HepA vaccine be vaccinated. We evaluated the public health impact and cost-effectiveness of this HepA catch-up vaccination strategy., Methods: We used a dynamic transmission model to compare adding a HepA catch-up vaccination of persons age 2-18 years to a routine vaccination of children 12-23 months of age with routine vaccination only in the United States. The model included various health compartments: maternal antibodies, susceptible, exposed, asymptomatic infectious, symptomatic infectious (outpatient, hospitalized, liver transplant, post- liver transplant, death), recovered, and vaccinated with and without immunity. Using a 3% annual discount rate, we estimated the incremental cost per quality-adjusted life year (QALY) gained from a societal perspective over a 100-year time horizon. All costs were converted into 2020 US dollars., Findings: Compared with the routine vaccination policy at 12-23 months of age over 100 years, the catch-up program for unvaccinated children and adolescents aged 2-18 years, prevented 70,072 additional symptomatic infections, 51,391 outpatient visits, 16,575 hospitalizations, and 413 deaths. The catch-up vaccination strategy was cost-saving when compared with the routine vaccination strategy. In scenario analysis allowing administering a second dose to partially vaccinated children, the cost-effectiveness of was not favorable at a higher vaccination coverage ($196,701/QALY at 5% and $476,241/QALY at 50%)., Interpretation: HepA catch-up vaccination in the United States is expected to reduce HepA morbidity and mortality and save cost. The catch-up program would be optimized when focusing on unvaccinated children and adolescents and maximizing their first dose coverage., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. The HepA vaccine, VAQTA® (Hepatitis A Vaccine, Inactivated) was developed and is currently marketed by Merck & Co., Inc., Kenilworth, NJ, USA., (Copyright © 2021 Merck Sharp and Dohme Corp. Published by Elsevier Ltd.. All rights reserved.)

The Advisory Committee on Immunization Practices (ACIP) recommended catch-up 9-valent Human Papillomavirus (HPV) vaccination through age 26 years, and shared clinical decision-making for adults aged 27-45 years, compared with catch-up through age 26 years and 21 years for females and males, respectively (status quo; pre-June-2019 recommendations). This study assessed the public health impact and cost-effectiveness of expanded catch-up vaccination through age 45 years (expanded catch-up) compared with status quo. We used an HPV dynamic transmission infection and disease model to assess disease outcomes and incremental cost-effectiveness ratio (ICER) of expanded catch-up compared with status quo. Costs (2018 USD), calculated from a healthcare sector perspective, and quality-adjusted life years (QALY) were discounted at 3% annually. Historical vaccination coverage was estimated using NIS-TEEN survey data (NHANES data for sensitivity analysis). Alternative scenario analyses included restricting upper age of expanded catch-up through 26 years (June-2019 ACIP recommendation), 29 years, and further 5-year increments. Our results show expanded catch-up vaccination would prevent additional 37,856 cancers, 314,468 cervical intraepithelial neoplasia-2/3s, 1,743,461 genital warts, and 10,698 deaths compared with status quo over 100 years at cost of $141,000/QALY. With NHANES coverage, the ICER was $96,000/QALY. The June-2019 ACIP recommendation also provided public health benefits with an ICER of $117,000/QALY, compared with status quo. The ICER for expanded vaccination through age 34 years was $107,000/QALY. Expanding catch-up vaccination program through age 45 years-old in the US is expected to provide public health benefits, and cost-effectiveness improves with expanding catch-up through age 34.

The coronavirus disease 2019 (COVID-19) pandemic has significantly affected utilization of preventative health care, including vaccines. We aimed to assess HPV vaccination rates during the pandemic, and conduct a simulation model-based analysis to estimate the impact of current coverage and future pandemic recovery scenarios on disease outcomes. The model population included females and males of all ages in the US. The model compares pre-COVID vaccine uptake to 3 reduced coverage scenarios with varying recovery speed. Vaccine coverage was obtained from Truven Marketscan™. Substantially reduced coverage between March-August 2020 was observed compared to 2018-2019. The model predicted that 130,853 to 213,926 additional cases of genital warts; 22,503 to 48,157 cases of CIN1; 48,682 to 110,192 cases of CIN2/3; and 2,882 to 6,487 cases of cervical cancer will occur over the next 100 years, compared to status quo. Providers should plan efforts to recover HPV vaccination and minimize potential long-term consequences., Competing Interests: Declaration of Competing Interest Vincent Daniels, Kunal Saxena, Craig Roberts, Lixia Yao, and Smita Kothari are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and may own Merck & Co., Inc., Kenilworth, NJ, USA restricted stock units and/or stock options. Shelby Corman is an employee of Pharmerit – an OPEN Health Company, which received consulting fees in conjunction with this work. Linda Niccolai is a Scientific Advisor for Merck and Scientific Advisory Board member for Moderna., (Copyright © 2021. Published by Elsevier Ltd.)

Objectives: This study sought to establish by expert review a consensus-based, focused ultrasound curriculum, consisting of a foundational set of focused ultrasound skills that all Canadian medical students would be expected to attain at the end of the medical school program., Methods: An expert panel of 21 point-of-care ultrasound and educational leaders representing 15 of 17 (88%) Canadian medical schools was formed and participated in a modified Delphi consensus method. Experts anonymously rated 195 curricular elements on their appropriateness to include in a medical school curriculum using a 5-point Likert scale. The group defined consensus as 70% or more experts agreeing to include or exclude an element. We determined a priori that no more than 3 rounds of voting would be performed., Results: Of the 195 curricular elements considered in the first round of voting, the group reached consensus to include 78 and exclude 24. In the second round, consensus was reached to include 4 and exclude 63 elements. In our final round, with 1 additional item added to the survey, the group reached consensus to include an additional 3 and exclude 8 elements. A total of 85 curricular elements reached consensus to be included, with 95 to be excluded. Sixteen elements did not reach consensus to be included or excluded., Conclusions: By expert opinion-based consensus, the Canadian Ultrasound Consensus for Undergraduate Medical Education Group recommends that 85 curricular elements be considered for inclusion for teaching in the Canadian medical school focused ultrasound curricula., (© 2020 The Authors. Journal of Ultrasound in Medicine published by Wiley Periodicals, Inc. on behalf of the American Institute of Ultrasound in Medicine.)

Background: In 2017, varicella vaccination became mandatory for all children in Italy, based on a two-dose schedule administered at 12-15 months of age and 5 to 6 years of age. Varicella vaccines are available in different formulations (as a single vaccine or as a combination vaccine together with measles, mumps, and rubella) and are made by multiple manufacturers with different effectiveness profiles. This study calculates the cost-effectiveness of a range of varicella vaccination strategies to identify the optimal strategy for Italy., Methods: A dynamic transmission cost-effectiveness model was applied in Italy to simulate the long-term (50 years) costs and outcomes associated with different varicella vaccination strategies. Five vaccination strategies were evaluated using the model: two doses of two different combination Measles-Mumps-Rubella-Varicella vaccines (either Vaccine A (MSD) [denoted QQVa] or Vaccine B (GSK) [denoted QQVb]); a first dose of a single Varicella vaccine followed by a second dose of a combination vaccine (either Vaccine C (MSD) followed by Vaccine A [denoted MQVa] or Vaccine D (GSK) followed by Vaccine B [denoted MQVb]); or no vaccine at all (NV). The model was adapted for Italy using publicly available Italian data and expert opinion., Results: Over the 50-year time-horizon, in the absence of universal varicella vaccination, there would be 34.8 million varicella cases, 142 varicella-infection-related deaths, and €23 billion in societal costs. The cost per capita from a societal perspective ranged from €164.55 to €392.18 with NV being the most expensive and QQVa the least expensive. The most effective strategy was QQVa, which resulted in a 66% decrease in varicella cases and 30% reduction in varicella-related deaths compared to NV strategy. QQVa led to a net saving in societal cost around €13 billion compared to NV as the cost of vaccination was more than offset by the savings that resulted from the reduced burden of illness., Conclusion: Varicella vaccination has a major impact on reducing varicella incidence, prevalence, and societal costs. This analysis supports the policy for universal varicella vaccination in Italy as the NV strategy was the most expensive and resulted in the poorest outcomes. QQVa offers the greatest benefits at the lowest cost and should be considered as a potential priority strategy for Italian population., Competing Interests: CA, VB, and SG report financial support from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, RG and EOB are employees of Evidera, Modelling and Simulation, Inc, and participated in the study under contract to Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USAND (at the time of the study), VJD and LJW are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, who may own stock and/or hold stock options in Merck & Co., Inc., Kenilworth, NJ, USA. The authors report no other conflicts of interest in this work., (© 2020 Azzari et al.)

Padsevonil is an antiepileptic drug (AED) candidate synthesized in a medicinal chemistry program initiated to rationally design compounds with high affinity for synaptic vesicle 2 (SV2) proteins and low-to-moderate affinity for the benzodiazepine binding site on GABA A receptors. The pharmacological profile of padsevonil was characterized in binding and electrophysiological experiments. At recombinant SV2 proteins, padsevonil's affinity for SV2A was greater than that of levetiracetam and brivaracetam (pKi 8.5, 5.2, and 6.6, respectively). Unlike the latter AEDs, both selective SV2A ligands, padsevonil also displayed high affinity for the SV2B and SV2C isoforms (pKi 7.9 and 8.5, respectively). Padsevonil's interaction with SV2A differed from that of levetiracetam and brivaracetam; it exhibited slower binding kinetics: dissociation t 1/2 30 minutes from the human protein at 37°C compared with <0.5 minute for levetiracetam and brivaracetam. In addition, its binding was not potentiated by the allosteric modulator UCB1244283. At recombinant GABA A receptors, padsevonil displayed low to moderate affinity (pIC 50 ≤6.1) for the benzodiazepine site, and in electrophysiological studies, its relative efficacy compared with zolpidem (full-agonist reference drug) was 40%, indicating partial agonist properties. In in vivo (mice) receptor occupancy studies, padsevonil exhibited SV2A occupancy at low ED 50 (0.2 mg/kg) and benzodiazepine site occupancy at higher doses (ED 50 36 mg/kg), supporting in vitro results. Padsevonil's selectivity for its intended targets was confirmed in profiling studies, where it lacked significant effects on a wide variety of ion channels, receptors, transporters, and enzymes. Padsevonil is a first-in-class AED candidate with a unique target profile allowing for presynaptic and postsynaptic activity. SIGNIFICANCE STATEMENT: Padsevonil is an antiepileptic drug candidate developed as a single molecular entity interacting with both presynaptic and postsynaptic targets. Results of in vitro and in vivo radioligand binding assays confirmed this target profile: padsevonil displayed nanomolar affinity for the three synaptic vesicle 2 protein isoforms (SV2A, B, and C) and micromolar affinity for the benzodiazepine binding site on GABA A receptors. Furthermore, padsevonil showed greater affinity for and slower binding kinetics at SV2A than the selective SV2A ligands, levetiracetam, and brivaracetam., (Copyright © 2019 The Author(s).)

Background: Achievement goal theory is consistently associated with specific cognitions, emotions, and behaviours that support learning in many domains, but has not been examined in postgraduate medical education. The purpose of this research was to examine internal medicine residents' achievement goals, and how these relate to their sense of self-efficacy, epistemic emotions, and valuing of formative compared to summative assessments. These outcomes will be important as programs transition more to competency based education that is characterized by ongoing formative assessments., Methods: Using a correlational design, we distributed a self-report questionnaire containing 49 items measuring achievement goals, self-efficacy, emotions, and response to assessments to internal medicine residents. We used Pearson correlations to examine associations between all variables., Results: Mastery-approach goals were positively associated with self-efficacy and curiosity and negatively correlated with frustration and anxiety. Mastery-approach goals were associated with a greater value for feedback derived from annual ACP exams, end-of-rotation written exams, and annual OSCEs. Performance-approach goals were only associated with valuing ACP exams., Conclusion: Mastery-approach goals were associated with self-efficacy and epistemic emotions among residents, two constructs that facilitate autonomous learning. Residents with mastery-approach goals also appeared to value a wider range of types of assessment data. This profile will likely be beneficial for learners in a competency-based environment that involves high levels of formative feedback., Competing Interests: Conflicts of interest: There are no conflicts of interest for any of the authors.

Introduction: The exogenous boosting (EB) hypothesis posits that cell-mediated immunity is boosted for individuals reexposed to varicella-zoster virus (VZV). Historically, mathematical models of the impact of universal childhood varicella vaccination (UVV) have used limited data to capture EB and often conclude that UVV will temporarily increase herpes zoster (HZ) incidence., Areas Covered: We updated a 2013 systematic literature review of 40 studies to summarize new evidence from observational or modeling studies related to EB and its parameterization. We abstracted data on observational study designs and mathematical model structures, EB frameworks, and HZ-related parameter values., Expert Commentary: This review identified an additional 41 studies: 22 observational and 19 modeling studies. Observational analyses generally reported pre-UVV increases in HZ incidence, making it difficult to attribute post-UVV increases to UVV versus other causes. Modeling studies considered a range of EB frameworks, from no boosting to full permanent immunity. Mathematical modeling efforts are needed in countries with long-standing vaccination programs to capture the dynamics of VZV transmission and temporal changes that may affect HZ incidence. Use of real-world pre-/postvaccination data on varicella and HZ incidence to validate model predictions may improve approaches to EB parameterization and understanding of the effects of varicella vaccination programs.

Context: The concept of entrustment has garnered significant attention in medical specialties, despite variability in supervision styles and entrustment decisions. There is a need to further study the enactment of supervision on inpatient wards to inform competency-based assessment design., Methods: Attending physicians, while supervising on clinical teaching inpatient wards, were invited to describe a recent moment of enacting supervision with an internal medicine resident. Constructivist grounded theory guided data collection and analysis. Interview transcripts were analysed in iterative cycles to inform data collection. Constant comparison was used to build a theory of supervision from the identified themes., Results: In 2016-2017, 23 supervisors from two Canadian universities with supervision reputations ranging from very involved to less involved participated in one or two interviews (total: 28). Supervisors were not easily dichotomised into styles based on behaviour because all used similar oversight strategies. Supervisors described adjusting between 'hands-on' (e.g. detail oriented) and 'hands-off' (e.g. less visible on ward) styles depending on the context. All also contended with the competing roles of clinical teacher and care provider. Supervisors made a distinction between the terms `entrust' and `trust', and did not grant complete entrustment to senior residents., Conclusions: We propose that a supervisor's perceived responsibility for the ward underlies adjustments between 'hands-on' (i.e. personal ward responsibility) and 'hands-off' (i.e. shared ward responsibility) styles. Our approaches to clinical supervision model combines this responsibility tension with the tension between patient care and teaching to illustrate four supervisory approaches, each with unique priorities influencing entrustment. Given the fluidity in supervision, documenting changes in oversight strategies, rather than absolute levels of entrustment, may be more informative for assessment purposes. Research is needed to determine if there is sufficient association between the supervision provided, the entrustment decision made and the supervisor's trust in a trainee to use these as proxies in assessing a trainee's competence., (© 2018 John Wiley & Sons Ltd and The Association for the Study of Medical Education.)

Algal blooms, including those containing cyanobacteria, are of environmental concern due to the toxicities of some of the constituent microorganisms. This compromises the safety of freshwater causing illness in livestock and humans. We present historical accounts of algal blooms occurring during the 18th and 19th centuries indicating that the advent of intensive farming in the 17th century provided nutrients for promoting harmful algal blooms., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: Lifelong learning is an integral part of health professionals' maintenance of competence. Several studies have examined the orientation toward lifelong learning at various stages of the education and career continuum; however, none has looked at changes throughout training and practice. The objective of the present study was to determine if there are differences between groups defined by their places on the education and career continuum., Methods: The authors performed a group-level meta-analysis on studies that used the 14-item Jefferson Scale of Physician Lifelong Learning or its variants. Eleven published articles, which reported on studies with post-secondary health professions students, residents, and practicing health professionals met the inclusion criteria. In total, there were 12 independent data sets, with four data sets per group., Results: In total, over seven thousand students, residents, and practicing health professionals responded to the Jefferson Scale (N=7.269). Individual study means tendency to be high, suggesting a high orientation toward lifelong learning among the trainees (students and residents) and practicing health professionals. Meta-analysis results indicated that the orientation toward lifelong learning tended to increase gradually along the education and career continuum. Significant differences in the group means were found between the trainees and practicing health professionals., Conclusion: In the reviewed studies, the orientation toward lifelong learning among students, residents, and practicing professionals was high. Nonetheless, although based on separate cohorts, it appears that the orientation toward lifelong learning continues to develop even after the completion of formal training., Competing Interests: Funding/Support:This research was supported by the Social Sciences and Humanities Research Council (SSHRC), Grant # 430-2016-00267. Conflict of interests: None declared.

The putative Major Facilitator Superfamily (MFS) transporter, SV2A, is the target for levetiracetam (LEV), which is a successful anti-epileptic drug. Furthermore, SV2A knock out mice display a severe seizure phenotype and die after a few weeks. Despite this, the mode of action of LEV is not known at the molecular level. It would be extremely desirable to understand this more fully in order to aid the design of improved anti-epileptic compounds. Since there is no structure for SV2A, homology modelling can provide insight into the ligand-binding site. However, it is not a trivial process to build such models, since SV2A has low sequence identity to those MFS transporters whose structures are known. A further level of complexity is added by the fact that it is not known which conformational state of the receptor LEV binds to, as multiple conformational states have been inferred by tomography and ligand binding assays or indeed, if binding is exclusive to a single state. Here, we explore models of both the inward and outward facing conformational states of SV2A (according to the alternating access mechanism for MFS transporters). We use a sequence conservation analysis to help guide the homology modelling process and generate the models, which we assess further with Molecular Dynamics (MD). By comparing the MD results in conjunction with docking and simulation of a LEV-analogue used in radioligand binding assays, we were able to suggest further residues that line the binding pocket. These were confirmed experimentally. In particular, mutation of D670 leads to a complete loss of binding. The results shed light on the way LEV analogues may interact with SV2A and may help with the on-going design of improved anti-epileptic compounds.

Astronauts experience Space Motion Sickness requiring treatment with an anti-motion sickness medication, scopolamine during space missions. Bioavailability after oral administration of scopolamine is low and variable, and absorption form transdermal patch is slow and prolonged. Intranasal administration achieves faster absorption and higher bioavailability of drugs that are subject to extrahepatic, first pass metabolism after oral dosing. We examined pharmacokinetics of 0.1, 0.2, and 0.4 mg doses of the Investigational New Drug formulation of intranasal scopolamine gel (INSCOP) in 12 healthy subjects using a randomized, double-blind cross-over study design. Subjects received one squirt of 0.1 g of gel containing either 0.1 mg or 0.2 mg/0.1 mL scopolamine or placebo in each nostril. Serial blood samples and total urine voids were collected after dosing and drug concentrations were determined using a modified LC-MS-MS method. Results indicate dose-linear pharmacokinetics of scopolamine with linear increases in Cmax and AUC within the dose range tested. Plasma drug concentrations were significantly lower in females than in males after administration of 0.4 dose. All three doses were well tolerated with no unexpected or serious adverse side effects reported. These results suggest that intranasal scopolamine gel formulation (INSCOP) offers a fast, reliable, and safe alternative for the treatment of motion sickness., (© 2014, The American College of Clinical Pharmacology.)

Synaptic vesicle glycoprotein (SV)2A is a transmembrane protein found in secretory vesicles and is critical for Ca(2+) -dependent exocytosis in central neurons, although its mechanism of action remains uncertain. Previous studies have proposed, variously, a role of SV2 in the maintenance and formation of the readily releasable pool (RRP) or in the regulation of Ca(2+) responsiveness of primed vesicles. Such previous studies have typically used genetic approaches to ablate SV2 levels; here, we used a strategy involving small interference RNA (siRNA) injection to knockdown solely presynaptic SV2A levels in rat superior cervical ganglion (SCG) neuron synapses. Moreover, we investigated the effects of SV2A knockdown on voltage-dependent Ca(2+) channel (VDCC) function in SCG neurons. Thus, we extended the studies of SV2A mechanisms by investigating the effects on vesicular transmitter release and VDCC function in peripheral sympathetic neurons. We first demonstrated an siRNA-mediated SV2A knockdown. We showed that this SV2A knockdown markedly affected presynaptic function, causing an attenuated RRP size, increased paired-pulse depression and delayed RRP recovery after stimulus-dependent depletion. We further demonstrated that the SV2A-siRNA-mediated effects on vesicular release were accompanied by a reduction in VDCC current density in isolated SCG neurons. Together, our data showed that SV2A is required for correct transmitter release at sympathetic neurons. Mechanistically, we demonstrated that presynaptic SV2A: (i) acted to direct normal synaptic transmission by maintaining RRP size, (ii) had a facilitatory role in recovery from synaptic depression, and that (iii) SV2A deficits were associated with aberrant Ca(2+) current density, which may contribute to the secretory phenotype in sympathetic peripheral neurons., (© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)