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Functional Apis mellifera honey bee colonies rely on collaborative brood care typically performed by nurse bees with well-developed hypopharyngeal glands (HPGs). Neonicotinoids, widely used insecticides, have been shown to negatively affect HPG development when worker bees were exposed to field-realistic concentrations either as brood or adults. To date, it is unknown whether timing of neonicotinoid exposure influences the severity of these observed negative effects on HPGs. To address this, we conducted a fully-crossed field experiment assessing potential effects of a neonicotinoid blend (clothianidin and thiamethoxam combined) on worker HPGs when exposed during different life stages. We found that neonicotinoid exposure during the brood stage, but not the adult stage, significantly influenced subsequent HPG development. Since HPG morphogenesis begins during the brood stage, neonicotinoid-induced stress possibly impaired this process, resulting in smaller glands once these individuals became adult nurses. Because HPG productivity is correlated to their size, smaller glands as a result of neonicotinoid exposure could negatively affect colony functionality., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

This study argues that value assessment conducted from a societal perspective should rely on the Generalized Cost-Effectiveness Analysis (GCEA) framework proposed herein. Recently developed value assessment inventories - such as the Second Panel on Cost-Effectiveness's "impact inventory" and International Society of Pharmacoeconomics Outcomes Research (ISPOR) "value flower" - aimed to more comprehensively capture the benefits and costs of new health technologies from a societal perspective. Nevertheless, application of broader value elements in practice has been limited in part because quantifying these elements can be complex, but also because there have been numerous methodological advances since these value inventories have been released (e.g. generalized and risk-adjusted cost effectiveness). To facilitate estimation of treatment value from a societal perspective, this paper provides an updated value inventory - called the GCEA value flower - and a user guide for implementing GCEA for health economics researchers and practitioners. GCEA considers 15 broader value elements across four categories: (i) uncertainty, (ii) dynamics, (iii) beneficiary, and (iv) additional value components. The uncertainty category incorporates patient risk preferences into value assessment. The dynamics category petals account for the evolution of real-world treatment value (e.g. option value) and includes drug pricing trends (e.g. future genericization). The beneficiary category accounts for the fact health technologies can benefit others (e.g. caregivers) and also that society may care to whom health benefits accrue (e.g. equity). Finally, GCEA incorporates additional broader sources of value (e.g. community spillovers, productivity losses). This GCEA user guide aims to facilitate both the estimation of each of these value elements and the incorporation of these values into health technology assessment when conducted from a societal perspective., (© 2024 the author(s), published by De Gruyter, Berlin/Boston.)

The Inflation Reduction Act of 2022 requires that Medicare negotiate a Maximum Fair Price for selected small-molecule drugs nine years after their Food and Drug Administration (FDA) approval and thirteen years postapproval for selected biologics. The discrepancy between these time frames raises questions about the relative value of small-molecule drugs versus biologics. We compared the incremental quality-adjusted life-year (QALY) gains, incremental costs, and incremental cost-effectiveness ratios (ICERs) of small-molecule drugs and biologics approved by the FDA during the period 1999-2018. We used the Mann-Whitney U test (to compare medians) and Kolmogorov-Smirnov test (to compare the distributions). We found that small-molecule drugs and biologics offer similar magnitudes of incremental QALY gains (0.08 versus 0.10). Small-molecule drugs tend to be associated with lower additional costs ($4,738 versus $16,020) and more favorable cost-effectiveness ($108,314 per QALY versus $228,286 per QALY). Creating parity regarding time to Medicare price negotiation may be appropriate.

Virus spillovers from managed honey bees, Apis mellifera, are thought to contribute to the decline of wild pollinators, including bumble bees. However, data on the impact of such viruses on wild pollinators remain scarce, and the influence of landscape structure on virus dynamics is poorly understood. In this study, we deployed bumble bee colonies in an agricultural landscape and studied changes in the bumble bee virome during field placement under varying habitat composition and configuration using a multiscale analytical framework. We estimated prevalence of viruses and viral loads (i.e. number of viral genomic equivalent copies) in bumble bees before and after placing them in the field using next generation sequencing and quantitative PCR. The results show that viral loads and number of different viruses present increased during placement in the field and that the virus composition of the colonies shifted from an initial dominance of honey bee associated viruses to a higher number (in both viral loads and number of viruses present) of bumble bee associated viruses. Especially DWV-B, typical for honey bees, drastically decreased after the time in the field. Viral loads prior to placing colonies in the field showed no effect on colony development, suggesting low impacts of these viruses in field settings. Notably, we further demonstrate that increased habitat diversity results in a lower number of different viruses present in Bombus colonies, while colonies in areas with well-connected farmland patches decreased in their total viral load after field placement. Our results emphasize the importance of landscape heterogeneity and connectivity for wild pollinator health and that these influences predominate at fine spatial scales., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Emerging infectious diseases pose a threat to pollinators. Virus transmission among pollinators via flowers may be reinforced by anthropogenic land-use change and concomitant alteration of plant-pollinator interactions. Here, we examine how species' traits and roles in flower-visitation networks and landscape-scale factors drive key honeybee viruses-black queen cell virus (BQCV) and deformed wing virus-in 19 wild bee and hoverfly species, across 12 landscapes varying in pollinator-friendly (flower-rich) habitat. Viral loads were on average more than ten times higher in managed honeybees than in wild pollinators. Viral loads in wild pollinators were higher when floral resource use overlapped with honeybees, suggesting these as reservoir hosts, and increased with pollinator abundance and viral loads in honeybees. Viral prevalence decreased with the amount of pollinator-friendly habitat in a landscape, which was partly driven by reduced floral resource overlap with honeybees. Black queen cell virus loads decreased with a wild pollinator's centrality in the network and the proportion of visited dish-shaped flowers. Our findings highlight the complex interplay of resource overlap with honeybees, species traits and roles in flower-visitation networks and flower-rich pollinator habitat shaping virus transmission., (© 2024. The Author(s).)

The Centers for Medicare and Medicaid Services' coverage with evidence development (CED) policy allows the agency to provide coverage for an item or service through a National Coverage Determination (NCD), conditional upon an agreement to collect evidence designed to address specific questions or uncertainties. The goals of this policy are to expedite beneficiary access to new items and services and to generate additional evidence on the impact of these items or services for Medicare beneficiaries. However, these goals have not been fully realized because of several issues with the way the policy has been implemented, including (1) a lack of clear criteria for when CED will be applied, (2) examples of CED data collection activities placing unnecessary burdens on clinicians and the potential for undue inducement on beneficiaries, and (3) a lack of clarity around the process and timeline for reconsidering and ending CED requirements. Additionally, there are cases in which the application of CED has failed to improve access to services for certain Medicare beneficiaries because no data collection activity was implemented in response to the CED requirement or because the NCD only allows the technology to be provided and studied in certain centers of excellence. We describe a roadmap for addressing these issues, which includes, for example, developing a framework to guide the application of coverage constraints in NCDs with CED requirements. Once these issues are addressed, the Centers for Medicare and Medicaid Services could consider expanding the use of CED to technologies that are not subject to NCDs., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: Traditional value assessment frameworks are challenged in comprehensively assessing the societal value new therapies bring to individuals with rare, progressive, genetic, fatal, neuromuscular diseases such as Duchenne muscular dystrophy (DMD). The objective of this study was to identify how value assessment frameworks may need to be adapted to measure the value to society of DMD therapies., Patients and Methods: Three stakeholder groups (6 patient advocates, 4 clinicians, 3 health economists; N = 13) participated in semi-structured interviews around the International Society for Pharmacoeconomics and Outcomes Research's Value Flower, which includes elements to consider within value assessments of healthcare technologies., Results: All stakeholders agreed that traditional value assessment frameworks based on the quality-adjusted life year (QALY) are narrow and will undervalue new DMD therapies. All stakeholders expressed some level of concern that using the QALY as a key metric of value discriminates against patients with severe progressive diseases and disabilities. Some stakeholders saw value in using the QALY for cross-disease comparisons in resource-constrained environments if the methodology was appropriate. All stakeholders recommended considering additional elements of value in decision-making around new DMD therapies. These elements reflect: economic and humanistic costs incurred by patients, caregivers, and families with Duchenne, such as indirect out-of-pocket costs, lost productivity, and family spillovers; meaningful attributes for individuals with disabilities and high unmet need, such as severity of disease, value of hope, and real option value; and factors that contribute to improvements in population health, such as insurance value, equity, and scientific spillovers., Conclusion: These findings highlight the need to expand traditional value assessment frameworks and take a holistic approach that incorporates the perspectives of individuals with Duchenne, caregivers, clinicians, and health economists when assessing the societal value of new DMD therapies. Broadening value assessment will prevent restricted or delayed access to therapies for individuals with Duchenne., Competing Interests: RF, PF, AK, and DM have no conflicts of interest to report for this work. KM reports grants from Sarepta, outside the submitted work. MP reports grants from Sarepta Therapeutics, PTC Therapeutics, Pfizer, Edgewise Therapeutics, and NS Pharma, outside the submitted work. CGL serves on advisory boards/consults with Avidity, Biogen, Roche, Novartis, and Sarepta Therapeutics. LL provides training for Sarepta Therapeutics and reports personal fees from Sarepta Therapeutics and Atom International for training services. NLK serves on advisory boards/consults with Astellas, Argenx, Biogen, Novartis, Roche, and Sarepta Therapeutics. PBS has served as a consultant to Novartis Gene Therapies, Biogen, Genentech, Sarepta Therapeutics, Pfizer, Solid Biosciences, Astellas Gene Therapies, Argenx, Alexion, Catalyst Pharma, Grifols, Avidity, Dyne, AMO Pharma, Abcuro, UCB, and CSL Behring. JK is an employee of SNELL Medical Communication, Inc., which has received funding from Sarepta Therapeutics. PJN has consulted and participated on advisory boards for Sarepta Therapeutics and reports personal fees from Roche Holding AG. JS is an employee of FTI Consulting, a consulting firm to healthcare, life sciences, and other industries. RJW served as a consultant to Sarepta Therapeutics in the work leading to the creation of this manuscript and has served on advisory boards and as a consultant on projects sponsored by several other biopharmaceutical companies. RJW also reports personal fees from Sarepta Therapeutics. The authors report no other conflicts of interest in this work., (© 2024 Fischer et al.)

In eusocial insects, worker longevity is essential to ensure colony survival in brood-free periods. Trade-offs between longevity and other traits may render long-living workers in brood-free periods more susceptible to pesticides compared to short-lived ones. Further, colony environment (e.g., adequate nutrition) may enable workers to better cope with pesticides, yet data comparing long vs. short-living workers and the role of the colony environment for pesticide tolerance are scarce. Here, we show that long-living honey bee workers, Apis mellifera, are less susceptible to the neonicotinoid thiamethoxam than short-lived workers, and that susceptibility was further reduced when workers were acclimatized under colony compared to laboratory conditions. Following an OECD protocol, freshly-emerged workers were exposed to thiamethoxam in summer and winter and either acclimatized within their colony or in the laboratory. Mortality and sucrose consumption were measured daily and revealed that winter workers were significantly less susceptible than summer workers, despite being exposed to higher thiamethoxam dosages due to increased food consumption. Disparencies in fat body activity, which is key for detoxification, may explain why winter bees were less susceptible. Furthermore, colony acclimatization significantly reduced susceptibility towards thiamethoxam in winter workers likely due to enhanced protein nutrition. Brood absence and colony environment seem to govern workers' ability to cope with pesticides, which should be considered in risk assessments. Since honey bee colony losses occur mostly over winter, long-term studies assessing the effects of pesticide exposure on winter bees are required to better understand the underlying mechanisms., (© 2024. The Author(s).)

Objectives: To examine ultraorphan drugs in terms of incremental health, costs, and cost-effectiveness compared with more prevalent disease drugs., Methods: We identified Food and Drug Administration drug approvals from 1999 to 2019. For drugs approved for multiple indications, we considered each drug-indication pair separately. Utilizing Food and Drug Administration's orphan drug designation and US disease prevalence, we categorized drug-indication pairs as: ultraorphan (<10 000 patients), "other" orphan (≥10 000 and <200 000), and nonorphan (≥200 000). We searched the PubMed database for cost-effectiveness analyses and comparative effectiveness studies. We excluded manufacturer-funded studies. We extracted estimates of incremental health gains in terms of quality-adjusted life-years (QALYs) and incremental costs associated with drug-indication pairs compared with the standard of care at the time of their approval. We compared QALY gains, added costs, and incremental cost-effectiveness ratios (ICERs) using the Kruskal-Wallis, Mann-Whitney U (MWU), and Kolmogorov-Smirnov (KS) tests., Results: Median incremental QALYs, costs, and ICERs differed across nonorphan, "other" orphan, and ultraorphan categories (Kruskal-Wallis P < .01). Compared with nonorphan drugs, ultraorphan drugs had larger QALY gains (0.700 vs 0.050, MWU P < .01, KS P < .01), larger costs ($172 231 vs $3360, MWU P < .01, KS P < .01), and larger ICERs ($1 216 184/QALY vs $114 061/QALY, MWU P < .01, KS P <.01). Compared with "other" orphan drugs, ultraorphan drugs had larger QALY gains (0.700 vs 0.310, MWU P =.65, KS P =.32), larger costs ($172 231 vs $69 308, MWU P = .03, KS P = .03), and larger ICERs ($1 216 184/QALY vs $223 472/QALY, MWU P <.01, KS P <.01)., Conclusions: Novel ultraorphan drugs typically offer larger incremental health gains than drugs for more prevalent diseases, but because of their substantial added costs, are typically less cost-effective., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2024. Published by Elsevier Inc.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

The guideline update outlines the advantages as well as the limitations of NIV in the treatment of acute respiratory failure in daily clinical practice and in different indications.Non-invasive ventilation (NIV) has a high value in therapy of hypercapnic acute respiratory failure, as it significantly reduces the length of ICU stay and hospitalization as well as mortality.Patients with cardiopulmonary edema and acute respiratory failure should be treated with continuous positive airway pressure (CPAP) and oxygen in addition to necessary cardiological interventions. This should be done already prehospital and in the emergency department.In case of other forms of acute hypoxaemic respiratory failure with only mild or moderately disturbed gas exchange (PaO 2 /FiO 2  > 150 mmHg) there is no significant advantage or disadvantage compared to high flow nasal oxygen (HFNO). In severe forms of ARDS NIV is associated with high rates of treatment failure and mortality, especially in cases with NIV-failure and delayed intubation.NIV should be used for preoxygenation before intubation. In patients at risk, NIV is recommended to reduce extubation failure. In the weaning process from invasive ventilation NIV essentially reduces the risk of reintubation in hypercapnic patients. NIV is regarded useful within palliative care for reduction of dyspnea and improving quality of life, but here in concurrence to HFNO, which is regarded as more comfortable. Meanwhile NIV is also recommended in prehospital setting, especially in hypercapnic respiratory failure and pulmonary edema.With appropriate monitoring in an intensive care unit NIV can also be successfully applied in pediatric patients with acute respiratory insufficiency., Competing Interests: Eine Übersicht der Interessenkonflikt findet sich im Internet unter http://awmf.org; AWMF-Registernummer 020-004., (Thieme. All rights reserved.)

The spread of invasive species often follows a jump-dispersal pattern. While jumps are typically fostered by humans, local dispersal can occur due to the specific traits of a species, which are often poorly understood. This holds true for small hive beetles (Aethina tumida), which are parasites of social bee colonies native to sub-Saharan Africa. They have become a widespread invasive species. In 2017, a mark-release-recapture experiment was conducted in six replicates (A-F) using laboratory reared, dye-fed adults (N = 15,690). Honey bee colonies were used to attract flying small hive beetles at fixed spatial intervals from a central release point. Small hive beetles were recaptured (N = 770) at a maximum distance of 3.2 km after 24 h and 12 km after 1 week. Most small hive beetles were collected closest to the release point at 0 m (76%, replicate A) and 50 m (52%, replicates B to F). Temperature and wind deviation had significant effects on dispersal, with more small hive beetles being recaptured when temperatures were high (GLMM: slope = 0.99, SE = 0.17, Z = 5.72, P < 0.001) and confirming the role of wind for odour modulated dispersal of flying insects (GLMM: slope = - 0.39, SE = 0.14, Z = - 2.90, P = 0.004). Our findings show that the small hive beetles is capable of long-distance flights, and highlights the need to understand species specific traits to be considered for monitoring and mitigation efforts regarding invasive alien species., (© 2024. The Author(s).)

Introduction: Studies have reported health-related quality-of-life impacts of Duchenne muscular dystrophy (DMD); however, further research is needed to understand how those with DMD experience their condition and how psychosocial impacts evolve over time in response to disease progression. This qualitative study explores the social and emotional implications of key transitions, challenges and adaptations throughout the disease course from the perspective of patients and family caregivers., Methods: Semi-structured interviews were conducted with men and boys with DMD, and/or their caregivers, in the USA. Thematic analysis was used to examine patterns in data collected across the interviews., Results: Nineteen participants were included. Three major themes were identified: (1) barriers to participation are multifaceted; (2) an emotional journey shaped by 'inevitable progression;' (3) family provides critical tangible and emotional support. This study illustrates that psychosocial impacts of DMD are shaped by knowledge of the condition's natural history alongside other factors including the extent of social barriers, personal growth and adaptation, and family support., Conclusions: Findings provide insight into the strength and resilience with which individuals and their families respond to daily challenges and major clinical milestones and highlight the relative importance of loss of upper limb function as a transition in DMD affecting health-related quality-of-life., (© 2024. The Author(s).)

Objectives: Critics of quality-adjusted life-years argue that it discriminates against older individuals. However, little empirical evidence has been produced to inform this debate. This study aimed to compare published cost-effectiveness analyses (CEAs) on patients aged ≥65 years and those aged <65 years., Methods: We used the Tufts Cost-Effectiveness Analysis Registry to identify CEAs published in MEDLINE between 1976 and 2021. Eligible CEAs were categorized according to age (≥65 years vs <65 years). The distributions of incremental cost-effectiveness ratios (ICERs) were compared between the age groups. We used logistic regression to assess the association between age groups and the cost-effectiveness conclusion adjusted for confounding factors. We conducted sensitivity analyses to explore the impact of mixed age and age-unknown groups and all ICERs from the same CEAs. Subgroup analyses were also conducted., Results: A total of 4445 CEAs categorized according to age <65 years (n = 3784) and age ≥65 years (n = 661) were included in the primary analysis. The distributions of ICERs and the likelihood of concluding that the intervention was cost-effective were similar between the 2 age groups. Adjusted odds ratios ranged from 1.132 (95% CI 0.930-1.377) to 1.248 (95% CI 0.970-1.606) (odds ratio >1 indicating that CEAs for age ≥65 years were more likely to conclude the intervention was cost-effective than those for age <65 years). Sensitivity and subgroup analyses found similar results., Conclusion: Our analysis found no systematic differences in published ICERs using quality-adjusted life-years between CEAs for individuals aged ≥65 years and those for individuals aged <65 years., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2024. Published by Elsevier Inc.)

Objectives: There is increasing interest in expanding the elements of value to be considered when making health policy decisions. To help inform value frameworks, this study quantified preferences for disease attributes in a general public sample and examined which combination of attributes (disease profiles) are considered most important for research and treatment., Methods: A discrete choice experiment (DCE) was conducted in a US general population sample, recruited through online consumer panels. Respondents were asked to select one of a set of health conditions they believed to be most important, characterized by attributes defined by a previous qualitative study: onset age; cause of disease; life expectancy; caregiver requirement; symptom burden (characterized by the Health Utilities Index with varying levels of ambulation independence, dexterity limitations, and degree of pain and discomfort); and disease prevalence. A fractional factorial DCE design was implemented using R, and 60 choice sets were generated (separated into blocks of 10 per participant). Data were analyzed using a mixed-logit regression model, and results used to assess the likelihood of preferring disease profiles. Based on individual attribute preferences, overall preferences for disease profiles, including a profile aligned with Duchenne muscular dystrophy (DMD), were compared., Results: Fifty-two percent of respondents (n = 537) were female, and 70.6% were aged 18-54 years. Attributes considered most important were those related to life expectancy (odds ratio [OR], 95% confidence interval [CI] 1.88 [1.56-2.27] for a 50% reduction in remaining life expectancy vs no impact), and symptom burden (OR [95% CI] 1.84 [1.47-2.31] for severe vs mild burden). Greater importance was also found for pediatric onset, caregiver requirement, and diseases affecting more people. As an example of disease profile preferences, a DMD-like pediatric inherited disease with 50% reduction in life expectancy, extensive caregiver requirement, severe symptom burden, and 1:5000 prevalence had 2.37-fold higher odds of being selected as important versus an equivalent disease with adult onset and no life expectancy reduction., Conclusions: Of disease attributes included in this DCE, respondents valued higher prevalence of disease, life expectancy and symptom burden as most important for prioritizing research and treatment. Based on expressed attribute preferences, a case study of an inherited pediatric disease involving substantial reductions to length and quality of life and requiring caregiver support has relatively high odds of being identified as important compared to diseases reflecting differing attribute profiles. These findings can help inform expansions of value frameworks by identifying important attributes from the societal perspective., (© 2024. The Author(s).)

Health technology assessment (HTA) decisions for pharmaceuticals are complex and evolving. New rare disease treatments are often approved more quickly through accelerated approval schemes, creating more uncertainties about clinical evidence and budget impact at the time of market entry. The use of real-world evidence (RWE), including early coverage with evidence development, has been suggested as a means to support HTA decisions for rare disease treatments. However, the collection and use of RWE poses substantial challenges. These challenges are compounded when considered in the context of treatments for rare diseases. In this paper, we describe the methodological challenges to developing and using prospective and retrospective RWE for HTA decisions, for rare diseases in particular. We focus attention on key elements of study design and analyses, including patient selection and recruitment, appropriate adjustment for confounding and other sources of bias, outcome selection, and data quality monitoring. We conclude by offering suggestions to help address some of the most vexing challenges. The role of RWE in coverage and pricing determination will grow. It is, therefore, necessary for researchers, manufacturers, HTA agencies, and payers to ensure that rigorous and appropriate scientific principles are followed when using RWE as part of decision-making., (© 2024. The Author(s).)

Invasive vectors can induce dramatic changes in disease epidemiology. While viral emergence following geographical range expansion of a vector is well known, the influence a vector can have at the level of the host's pathobiome is less well understood. Taking advantage of the formerly heterogeneous spatial distribution of the ectoparasitic mite Varroa destructor that acts as potent virus vector among honeybees Apis mellifera , we investigated the impact of its recent global spread on the viral community of honeybees in a retrospective study of historical samples. We hypothesized that the vector has had an effect on the epidemiology of several bee viruses, potentially altering their transmissibility and/or virulence, and consequently their prevalence, abundance, or both. To test this, we quantified the prevalence and loads of 14 viruses from honeybee samples collected in mite-free and mite-infested populations in four independent geographical regions. The presence of the mite dramatically increased the prevalence and load of deformed wing virus, a cause of unsustainably high colony losses. In addition, several other viruses became more prevalent or were found at higher load in mite-infested areas, including viruses not known to be actively varroa-transmitted, but which may increase opportunistically in varroa-parasitized bees., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors.)

Background: Professional roles within a hospital system may influence attitudes behind clinical decisions., Objective: To determine participants' preferences about clinical decisions that either value equal health care access or efficiency., Design: Deidentified survey asking participants to choose between offering a low-cost screening test to a whole population ("equal access") or a more sensitive, expensive test that could be given to only half of the population but resulting in 10% more avoided deaths ("efficient"). Data collection took place from August 18, 2021, to January 24, 2022. Study 1644 was determined to be exempt by Tufts Health Sciences Institutional Review Board (IRB)., Setting: Tufts Medicine Healthcare System., Participants: Approximately 15,000 hospital employees received an e-mail from the Tufts Medicine Senior Vice President of Academic Integration., Measurements: Analysis of survey responses with chi-square and 1-sample t tests to determine the proportion who chose each option. Logistic regression models fit to examine relationships between professional role and test choice., Results: A total of 1,346 participants completed the survey (∼9.0% response rate). Overall, approximately equal percentages of respondents chose the "equal access" (48%) and "efficient" option (52%). However, gender, professional role (categorical), and clinical role (dichotomous) were significantly associated with test choice. For example, among those in nonclinical roles, women were more likely than men to choose equal health care access. In multivariable analyses, having clinical roles was significantly associated with 1.73 times the likelihood of choosing equal access (95% confidence interval = 1.33-2.25)., Limitations: Generalizability concerns and survey question wording limit the study results., Conclusion: Clinicians were more likely than nonclinicians to choose the equal health care access option, and health care administrators were more likely to choose efficiency. These differing attitudes can affect patient care and health care quality., Highlights: Divergent preferences of valuing equal health care access and efficiency may be in conflict during clinical decision making.In this cross-sectional study that included 1,346 participants, approximately equal percentages of respondents chose the "equal access" (48%) and "efficient" option (52%), a nonsignificant difference. However, gender, professional role (categorical), and clinical role (dichotomous) were significantly associated with test choiceSince clinicians were more likely than nonclinicians to choose the equal health care access option and health care administrators were more likely to choose efficiency, these differing attitudes can affect patient care and health care quality., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: LC is supported by Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) grant number K12HD092535 and by Tufts University. PRB is supported by the Clinical and Translational Science Awards, National Institutes of Health (award No. UL1TR002544). He has also received compensation as a topic editor for Clinical Therapeutics (Elsevier) 2016–2022 and as co-editor-in-chief beginning in 2022, as a subject matter expert for AAAS in 2019, and as a training consultant for small pharmaceutical companies in 2020–2022 for less than 5% of compensation. DNS receives support from the Tupper Research Institute.

Western honeybee populations, Apis mellifera, in Europe have been known to survive infestations of the ectoparasitic mite, Varroa destructor, by means of natural selection. Proposed mechanisms in literature have been focused on the management of this parasite, however literature remains scare on the differences in viral ecology between colonies that have adapted to V. destructor and those that are consistently treated for it. Samples were collected from both a mite-surviving and a sympatric mite-susceptible honeybee population in Norway. The prevalence and abundances of 10 viruses, vectored by the parasite or not, were investigated in adult host workers and pupae as well as in V. destructor mites. Here we show that the mite-vectored Deformed wing virus (DWV-A) is often lower in both abundance and prevalence in the mite-surviving population in tandem with lower phoretic mite infestations compared to the mite susceptible population. However, the non-mite-vectored Black queen cell virus (BQCV), had both a higher abundance and prevalence in the mite-surviving population compared to the susceptible population. The data therefore suggest that general adaptations to virus infections may be unlikely to explain colony survival. Instead, mechanisms suppressing mite reproduction and therefore the impact seem to be more important., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Oddie 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.)

Background: The progression of Duchenne muscular dystrophy (DMD) is characterized by loss of ambulation, respiratory insufficiency, cardiomyopathy, and early mortality. DMD profoundly impacts health-related quality-of-life (HRQoL). However, few health state utility data exist; published utilities tend to be derived from small samples for a limited number of health states and are often based on caregiver-reported patient health status. This study estimated utility values for varied clinical and functional health states in DMD, based on patient-reported health status., Methods: Individuals with DMD in the US aged 12-40 years completed the EQ-5D (5-level) and Health Utilities Index (HUI) preference-based instruments. Based on responses to a clinical questionnaire, participants self-classified into functional health states according to level of lower and upper limb function, use of respiratory support, and presence of cardiomyopathy. Mean [standard deviation (SD)] utility and EQ-5D visual analogue scale (VAS) scores were estimated according to health state; and median (interquartile range) attribute levels calculated to understand which domains of health are most severely affected in DMD., Results: Of 63 males with DMD, mean (SD) age was 19.8 (6.1) years and 11 (17.5%) were ambulatory. Mean (SD) utility values were 0.92 (0.08; HUI2), 0.84 (0.20; HUI3), and 0.84 (0.13; EQ-5D) for ambulatory patients without cardiomyopathy (n = 10). For non-ambulatory patients with moderately impaired upper limb function, night and daytime ventilation without cardiomyopathy, mean (SD) utilities were 0.49 (0.07) for the HUI2, 0.16 (0.15) for the HUI3 and 025 (0.14) for the EQ-5D. Mean (SD) VAS scores for the same health states were 91 (9) and 83 (21), respectively. In addition to impairments in mobility/ambulation, and self-care, attributes like usual activities and pain also showed notable effects of DMD., Conclusions: In DMD, although a relationship between disease progression and HRQoL is observed, there is large variability in utility within functional health states, and across instruments. Utility values for less severe non-ambulatory health states described by level of upper limb function are novel. These utility values, derived based on direct patient feedback rather than from caregiver report, are relevant to individuals of varying functional statuses and augment scarce DMD-specific utility data., (© 2023. The Author(s).)

Competing Interests: The authors declare no conflict of interest.

Policy Points The increasing number of drugs granted accelerated approval by the Food and Drug Administration (FDA) has challenged the Medicare program, which often pays for expensive therapies despite substantial uncertainty about benefits and risks to Medicare beneficiaries. We recommend several administrative and legislative approaches for improving FDA-Centers for Medicare and Medicaid Services (CMS) coordination around accelerated-approval drugs, including promoting earlier discussions among the FDA, the CMS, and drug companies; strengthening Medicare's coverage with evidence development program; linking Medicare payment to evidence generation milestones; and ensuring that the CMS has adequate staffing and resources to evaluate new therapies. These activities can help improve the integrity; transparency; and efficiency of approval, coverage, and payment processes for drugs granted accelerated approval., Context: The Food and Drug Administration (FDA)'s accelerated-approval pathway expedites patient access to promising treatments. However, increasing use of this pathway has challenged the Medicare program, which often pays for expensive therapies despite substantial uncertainty about benefits and risks to Medicare beneficiaries. We examined approaches to improve coordination between the FDA and Centers for Medicare and Medicaid Services (CMS) for drugs granted accelerated approval., Methods: We argue that policymakers have focused on expedited pathways at the FDA without sufficient attention to complementary policies at the CMS. Although differences between the FDA and CMS decisions are to be expected given the agencies' different missions and statutory obligations, procedural improvements can ensure that Medicare beneficiaries have timely access to novel therapies that are likely to improve health outcomes. To inform policy options and recommendations, we conducted semistructured interviews with stakeholders to capture diverse perspectives on the topic., Findings: We recommend ten areas for consideration: clarifying the FDA's evidentiary standards; strengthening FDA authorities; promoting earlier discussions among the FDA, the CMS, and drug companies; improving Medicare's coverage with evidence development program; tying Medicare payment for accelerated-approval drugs to evidence generation milestones; issuing CMS guidance on real-world evidence; clarifying Medicare's "reasonable and necessary" criteria; adopting lessons from international regulatory-reimbursement harmonization efforts; ensuring that the CMS has adequate staffing and expertise; and emphasizing equity., Conclusions: Better coordination between the FDA and CMS could improve the transparency and predictability of drug approval and coverage around accelerated-approval drugs, with important implications for patient outcomes, health spending, and evidence generation processes. Improved coordination will require reforms at both the FDA and CMS, with special attention to honoring the agencies' distinct authorities. It will require administrative and legislative actions, new resources, and strong leadership at both agencies., (© 2023 Milbank Memorial Fund.)

There in increasing evidence for recent global insect declines. This is of major concern as insects play a critical role in ecosystem functionality and human food security. Even though environmental pollutants are known to reduce insect fertility, their potential effects on insect fitness remain poorly understood - especially for soil-dwelling species. Here, we show that fertility of soil-dwelling beetles, Aethina tumida, is reduced, on average, by half due to field-realistic neonicotinoid soil contaminations. In the laboratory, pupating beetles were exposed via soil to concentrations of the neonicotinoid thiamethoxam that reflect global pollution of agricultural and natural habitats. Emerged adult phenotypes and reproduction were measured, and even the lowest concentration reported from natural habitats reduced subsequent reproduction by 50%. The data are most likely a conservative estimate as the beetles were only exposed during pupation. Since the tested concentrations reflect ubiquitous soil pollution, the data reveal a plausible mechanism for ongoing insect declines. An immediate reduction in environmental pollutants is urgently required if our aim is to mitigate the prevailing loss of species biodiversity., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lars Straub reports financial support was provided by Vinetum Foundation., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Declaration of interests The authors declare no competing interests.

A range of different genetic architectures underpin local adaptation in nature. Honey bees (Apis mellifera) in the Eastern African Mountains harbor high frequencies of two chromosomal inversions that likely govern adaptation to this high-elevation habitat. In the Americas, honey bees are hybrids of European and African ancestries and adaptation to latitudinal variation in climate correlates with the proportion of these ancestries across the genome. It is unknown which, if either, of these forms of genetic variation governs adaptation in honey bees living at high elevations in the Americas. Here, we performed whole-genome sequencing of 29 honey bees from both high- and low-elevation populations in Colombia. Analysis of genetic ancestry indicated that both populations were predominantly of African ancestry, but the East African inversions were not detected. However, individuals in the higher elevation population had significantly higher proportions of European ancestry, likely reflecting local adaptation. Several genomic regions exhibited particularly high differentiation between highland and lowland bees, containing candidate loci for local adaptation. Genes that were highly differentiated between highland and lowland populations were enriched for functions related to reproduction and sperm competition. Furthermore, variation in levels of European ancestry across the genome was correlated between populations of honey bees in the highland population and populations at higher latitudes in South America. The results are consistent with the hypothesis that adaptation to both latitude and elevation in these hybrid honey bees are mediated by variation in ancestry at many loci across the genome., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

The ectoparasitic mite Varroa destructor is an invasive species of Western honey bees (Apis mellifera) and the largest pathogenic threat to their health world-wide. Its successful invasion and expansion is related to its ability to exploit the worker brood for reproduction, which results in an exponential population growth rate in the new host. With invasion of the mite, wild honeybee populations have been nearly eradicated from Europe and North America, and the survival of managed honeybee populations relies on mite population control treatments. However, there are a few documented honeybee populations surviving extended periods without control treatments due to adapted host traits that directly impact Varroa mite fitness. The aim of this study was to investigate if Varroa mite reproductive success was affected by traits of adult bee behaviours or by traits of the worker brood, in three mite-resistant honey bee populations from Sweden, France and Norway. The mite's reproductive success was measured and compared in broods that were either exposed to, or excluded from, adult bee access. Mite-resistant bee populations were also compared with a local mite-susceptible population, as a control group. Our results show that mite reproductive success rates and mite fecundity in the three mite-resistant populations were significantly different from the control population, with the French and Swedish populations having significantly lower reproductive rates than the Norwegian population. When comparing mite reproduction in exposed or excluded brood treatments, no differences were observed, regardless of population. This result clearly demonstrates that Varroa mite reproductive success can be suppressed by traits of the brood, independent of adult worker bees., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: Because existing publication guidelines and checklists have limitations when used to assess the quality of cost-effectiveness analysis, we developed a novel quality assessment tool for cost-effectiveness analyses, differentiating methods and reporting quality and incorporating the relative importance of different quality attributes., Methods: We defined 15 quality domains from a scoping review and identified 72 methods and reporting quality attributes (36 each). After designing a best-worst scaling survey, we fielded an online survey to researchers and practitioners to estimate the relative importance of the attributes in February 2021. We analyzed the survey data using a sequential conditional logit model. The final tool included 48 quality attributes deemed most important for assessing methods and reporting quality (24 each), accompanied by a free and web-based scoring system., Results: A total of 524 participants completed the methodology section, and 372 completed both methodology and reporting sections. Quality attributes pertaining to the "modeling" and "data inputs and evidence synthesis" domains were deemed most important for methods quality, including "structure of the model reflects the underlying condition and intervention's impact" and "model validation is conducted." Quality attributes pertaining to "modeling" and "Intervention/comparator(s)" domains were considered most important for reporting quality, including "model descriptions are detailed enough for replication." Despite its growing prominence, "equity considerations" were not deemed as important as other quality attributes., Conclusions: The Criteria for Health Economic Quality Evaluation tool allows users to differentiate methods and reporting as well as quantifies the relative importance of quality attributes. Alongside other considerations, it could help assess and improve the quality of cost-effectiveness evidence to inform value-based decisions., (Copyright © 2023. Published by Elsevier Inc.)

Objectives: Health technology assessment (HTA) organizations vary in terms of how they conduct assessments. We assess whether and to what extent HTA bodies have adopted societal and novel elements of value in their economic evaluations., Methods: After categorizing "societal" and "novel" elements of value, we reviewed fifty-three HTA guidelines. We collected data on whether each guideline mentioned each societal or novel element of value, and if so, whether the guideline recommended the element's inclusion in the base case, sensitivity analysis, or qualitative discussion in the HTA., Results: The HTA guidelines mention on average 5.9 of the twenty-one societal and novel value elements we identified (range 0-16), including 2.3 of the ten societal elements and 3.3 of the eleven novel value elements. Only four value elements (productivity, family spillover, equity, and transportation) appear in over half of the HTA guidelines, whereas thirteen value elements are mentioned in fewer than one-sixth of the guidelines, and two elements receive no mention. Most guidelines do not recommend value element inclusion in the base case, sensitivity analysis, or qualitative discussion in the HTA., Conclusions: Ideally, more HTA organizations will adopt guidelines for measuring societal and novel value elements, including analytic considerations. Importantly, simply recommending in guidelines that HTA bodies consider novel elements may not lead to their incorporation into assessments or ultimate decision making.

Multiple mating by both sexes is common among sexually reproducing animals. Small hive beetles (SHB), Aethina tumida, are parasites of bee nests endemic to sub-Saharan Africa and have become a widespread invasive species. Despite the considerable economic damages they can cause, their basic biology remains poorly understood. Here we show that male and female small hive beetles can mate multiple times, suggesting that costs for mating are low in this species. In an invasive A. tumida population in the United States, a combination of laboratory experiments for males and paternity analysis with eight polymorphic DNA microsatellite markers for field-caught females were used to estimate the number of mating by both sexes. The data show that females and males can mate multiple times-females mated with up to eight males, whereas males mated with at least seven females. The results also showed that A. tumida displayed a skewed paternity, although this was not consistent among the tested females. Thus, first or last male advantage seem to be unlikely in A. tumida. Our observations that individuals of both sexes of A. tumida can mate multiple times opens new research avenues for examining drivers of multiple mating and determining the role it may play in promoting biological invasions., (© 2022 The Authors. Insect Science published by John Wiley & Sons Australia, Ltd on behalf of Institute of Zoology, Chinese Academy of Sciences.)

Background: We examined racial and ethnic differences in medication use for a representative US population of patients with Alzheimer's disease and related dementias (ADRD)., Methods: We examined cholinesterase inhibitors and memantine initiation, non-adherence, and discontinuation by race and ethnicity, using data from the 2000-2016 Health and Retirement Study linked with Medicare and Medicaid claims., Results: Among newly diagnosed ADRD patients (n = 1299), 26% filled an ADRD prescription ≤90 days and 36% ≤365 days after diagnosis. Among individuals initiating ADRD-targeted treatment (n = 1343), 44% were non-adherent and 24% discontinued the medication during the year after treatment initiation. Non-Hispanic Blacks were more likely than Whites to not adhere to ADRD medication therapy (odds ratio: 1.50 [95% confidence interval: 1.07-2.09])., Discussion: Initiation of ADRD-targeted medications did not vary by ethnoracial group, but non-Hispanic Blacks had lower adherence than Whites. ADRD medication non-adherence and discontinuation were substantial and may relate to cost and access to care., Highlights: Initiation of anti-dementia medications among newly diagnosed Alzheimer's disease and related dementias (ADRD) patients was low in all ethnoracial groups. ADRD medication non-adherence and discontinuation were substantial and may relate to cost and access to care. Compared to Whites, Blacks and Hispanics had lower use, poorer treatment adherence, and more frequent discontinuation of ADRD medication, but when controlling for disease severity and socioeconomic factors, racial disparities diminish. Our findings demonstrate the importance of adjusting for socioeconomic characteristics and disease severity when studying medication use and adherence in ADRD patients., (© 2022 the Alzheimer's Association.)

Introduction: Assessing medical technologies for Alzheimer's disease (AD) creates challenges for current methods of value assessment. New value assessment approaches for AD are also needed., Methods: We adapted concepts from health economics to help guide decision makers to more informed decisions about AD therapies and diagnostics., Results: We propose a value framework based on five categories: perspective, value elements, analysis, reporting, and decision making. AD value assessments should include the perspective of the patient-caregiver dyad. We propose a broader array of value elements than currently used. Analytics and decision methods can synthesize evidence for all elements of value. Decisions should use a "deliberative appraisal" approach informed by the composite evidence and be transparently reported., Discussion: Using the proposed framework, the value of forthcoming innovations for AD may be more thoroughly assessed for and by all stakeholders. It can guide decision makers to carefully consider all relevant elements of value contributing to more holistic and transparent decision making., Research Highlights: Alzheimer's disease challenges common methods of evaluating medical technology. Using current methods, new AD innovations might not be appropriately valued. Poor value assessments will adversely affect patient access to AD innovations. A full AD value framework expands perspective, elements, analysis, decision-making, reporting., (© 2022 Eli Lilly and Company and The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Alzheimer's disease (AD) is a major global health crisis in need of more effective therapies. However, difficult choices to optimize value-based care will need to be made. While identifying preferred therapeutic attributes of new AD therapies is necessary, few studies have explored how preferences may vary between the stakeholders. In this study, the trade-offs among key attributes of amyloid plaque-lowering therapies for AD were assessed using a discrete choice experiment (DCE) and compared between caregivers and neurologists., Methods: An initial pilot study was conducted to identify the potentially relevant features of a new therapy. The DCE evaluated seven drug attributes: clinical effects in terms of delay in AD progression over the standard of care (SOC), variation in clinical effects, biomarker response (achieving amyloid plaque clearance on PET scan), amyloid-related imaging abnormalities-edema (ARIA-E), duration of therapy, need for treatment titration as well as route, and frequency of drug administration. Respondents were then randomly presented with 12 choice sets of treatment options and asked to select their preferred option in each choice set. Hierarchical Bayesian regression modeling was used to estimate weighted preference attributes, which were presented as mean partial utility scores (pUS), with higher scores suggesting an increased preference., Results: Both caregivers (n = 137) and neurologists (n = 161) considered clinical effects (mean pUS = 0.47 and 0.82) and a 5% incremental in ARIA-E (mean pUS =  - 0.26 and - 0.52) to be highly impactful determinants of therapeutic choice. In contrast, variation in clinical effects (mean pUS = 0.12 and 0.14) and treatment duration (mean pUS =  - 0.02 and - 0.13) were the least important characteristics of any new treatment. Neurologists' also indicated that subcutaneous drug delivery (mean pUS = 0.42 vs. 0.07) and administration every 4 weeks (mean pUS = 1.0 vs. 0.20) are highly desirable therapeutic features. Respondents were willing to accept up to a 9% increment in ARIA-E for one additional year of delayed progression., Conclusions: Caregivers and neurologists considered incremental clinical benefit over SOC and safety to be highly desirable qualities for a new drug that could clear amyloid plaques and delay clinical progression and indicated a willingness to accept incremental ARIA-E to achieve additional clinical benefits., (© 2023. The Author(s).)

The complete genome sequence of Lactobacillus melliventris strain IBH004, isolated from the gut of a honeybee worker (Apis mellifera) and containing two plasmids and a temperate phage, was determined using hybrid assembly of Oxford Nanopore and Illumina reads. Phage-sequence relationships were identified from the coding sequences, and a proteomic tree was constructed.

BACKGROUND: The Institute for Clinical and Economic Review (ICER) has emerged in a visible role in US health care. However, it is unclear to what extent US commercial health plans use ICER value assessments in their specialty drug coverage decisions. OBJECTIVE: To evaluate the relationship between ICER's reported cost-effectiveness ratios (CERs) and coverage restrictiveness. Also, to examine the frequency with which plans have cited ICER in their coverage policies and to investigate how frequently health plans adjusted their drug coverage criteria in the 12 months after ICER's assessments. METHODS: We analyzed the Tufts Medical Center Specialty Drug Evidence and Coverage Database, which includes specialty drug coverage decisions issued by 17 large US commercial health plans. For ICER-assessed drugs, we recorded ICER's estimated CERs in the form of cost per quality-adjusted life-year (QALY) gained. First, we used multivariate logistic regression to examine the association between ICER's reported CERs and plan coverage restrictiveness, when controlling for other factors that were likely to affect decision-making. Next, we examined how often plans cited ICER's assessments in coverage decisions issued in years 2017-2020. Lastly, we examined whether plans added or removed coverage restrictions (eg, patient subgroup restrictions or step therapy protocols) in the 12 months following ICER's assessment. RESULTS: Plans tended to cover drugs with higher (less favorable) CERs more restrictively than drugs with CERs less than $100,000 per QALY: odds ratio (OR) = 4.48 if $100,000-$175,000 per QALY; OR = 2.00 if $175,000-$500,000 per QALY; and OR = 2.10 if $500,000 or more per QALY (all P < 0.01). Plans cited ICER in 0.8% (5/622) of coverage policies in 2017, 0.6% (5/833) in 2018, 1.7% (19/1,139) in 2019, and 2.4% (33/1,406) in 2020. For drugs with CERs less than $175,000 per QALY, plans adjusted coverage in 37% of cases: added restrictions in 20%, removed restrictions in 15%, and added one restriction but removed another in 2%. For drugs with CERs of $175,000 or more, plans changed coverage criteria in 29% of cases: added restrictions in 21%, removed restrictions in 5%, and added one restriction but removed another in 4%. CONCLUSIONS: We found that when controlling for other factors, health plans' specialty drug coverage decisions were associated with ICER's estimated CERs. Plans infrequently cited ICER value assessments. We did not observe a trend for plans more often narrowing coverage criteria for drugs with CERs $175,000 or more compared with drugs with CERs less than $175,000. DISCLOSURES: This research study was supported by a consortium of funders: Amgen, Genen-tech, Janssen Pharmaceuticals, Otsuka, and GSK.

Interspecies transmission of RNA viruses is a major concern for human and animal health. However, host-range, transmission routes and especially the possible impact of these viruses on alternative hosts are often poorly understood. Here, we investigated the role of the labyrinth spider, Agelena labyrinthica, as a potential alternative host of viruses commonly known from western honey bees, Apis mellifera. Field-collected spiders were screened for Acute bee paralysis virus (ABPV), Black queen cell virus, Chronic bee paralysis virus, Deformed wing virus type A and B (DWV-B), Israeli acute paralysis virus, Lake Sinai virus and Sacbrood virus. In a laboratory experiment, labyrinth spiders were fed with ABPV and DWV-B infected honey bees or virus free control food. Our results show that natural infections of A. labyrinthica with these viruses are common in the field, as 62.5% of the samples were positive for at least one virus, supporting their wide host range. For DWV-B, the laboratory data indicate that foodborne transmission occurs and that high virus titres may reduce cocoon building, which would be the first report of clinical symptoms of DWV in Araneae. Since cocoons are tokens of fitness, virus transmission from honey bees might affect spider populations, which would constitute a concern for nature conservation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Schläppi 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.)

Insects constitute vital components of ecosystems. There is alarming evidence for global declines in insect species diversity, abundance, and biomass caused by anthropogenic drivers such as habitat degradation or loss, agricultural practices, climate change, and environmental pollution. This raises important concerns about human food security and ecosystem functionality and calls for more research to assess insect population trends and identify threatened species and the causes of declines to inform conservation strategies. Analysis of genetic diversity is a powerful tool to address these goals, but so far animal conservation genetics research has focused strongly on endangered vertebrates, devoting less attention to invertebrates, such as insects, that constitute most biodiversity. Insects' shorter generation times and larger population sizes likely necessitate different analytical methods and management strategies. The availability of high-quality reference genome assemblies enables population genomics to address several key issues. These include precise inference of past demographic fluctuations and recent declines, measurement of genetic load levels, delineation of evolutionarily significant units and cryptic species, and analysis of genetic adaptation to stressors. This enables identification of populations that are particularly vulnerable to future threats, considering their potential to adapt and evolve. We review the application of population genomics to insect conservation and the outlook for averting insect declines.

Introduction: Host shift of parasites may have devastating effects on the novel hosts. One remarkable example is that of the ectoparasitic mite Varroa destructor, which has shifted its host from Eastern honey bees (Apis cerana) to Western honey bees (Apis mellifera) and posed a global threat to apiculture., Objectives: To identify the genetic factors underlying the reproduction of host-shifted V. destructor on the new host., Methods: Genome sequencing was conducted to construct the phylogeny of the host-shifted and non-shifted mites and to screen for genomic signatures that differentiated them. Artificial infestation experiment was conducted to compare the reproductive difference between the mites, and transcriptome sequencing was conducted to find differentially expressed genes (DEGs) during the reproduction process., Results: The host-shifted and non-shifted V. destructor mites constituted two genetically distinct lineages, with 15,362 high-F ST SNPs identified between them. Oogenesis was upregulated in host-shifted mites on the new host A. mellifera relative to non-shifted mites. The transcriptomes of the host-shifted and non-shifted mites differed significantly as early as 1h post-infestation. The DEGs were associated with nine genes carrying nonsynonymous high-F ST SNPs, including mGluR2-like, Lamb2-like and Vitellogenin 6-like, which were also differentially expressed, and eIF4G, CG5800, Dap160 and Sas10, which were located in the center of the networks regulating the DEGs based on protein-protein interaction analysis., Conclusions: The annotated functions of these genes were all associated with oogenesis. These genes appear to be the key genetic determinants of the oogenesis of host-shifted mites on the new host. Further study of these candidate genes will help elucidate the key mechanism underlying the success of host shifts of V. destructor., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Production and hosting by Elsevier B.V.)

Collaborative brood care by workers is essential for the functionality of eusocial Apis mellifera honey bee colonies. The hypopharyngeal food glands of workers play a crucial role in this context. Even though there is consensus that ubiquitous ectoparasitic mites Varroa destructor and widespread insecticides, such as neonicotinoids, are major stressors for honey bee health, their impact alone and in combination on the feeding glands of workers is poorly understood. Here, we show that combined exposure to V. destructor and neonicotinoids antagonistically interacted on hypopharyngeal gland size, yet they did not interact on emergence body mass or survival. While the observed effects of the antagonistic interaction were less negative than expected based on the sum of the individual effects, hypopharyngeal gland size was still significantly reduced. Alone, V. destructor parasitism negatively affected emergence body mass, survival, and hypopharyngeal gland size, whereas neonicotinoid exposure reduced hypopharyngeal gland size only. Since size is associated with hypopharyngeal gland functionality, a reduction could result in inadequate brood care. As cooperative brood care is a cornerstone of eusociality, smaller glands could have adverse down-stream effects on inclusive fitness of honey bee colonies. Therefore, our findings highlight the need to further study how ubiquitous stressors like V. destructor and neonicotinoids interact to affect honey bees., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Alzheimer's disease (AD) is a chronic neurodegenerative disorder associated with a high burden of illness. New therapies under development include agents that target amyloid-beta (Aβ), a key component in AD pathogenesis. Understanding the decision-making process for new AD drugs would help determine if such therapies should be adopted by society. Multicriteria decision analysis (MCDA) was applied to three key stakeholder groups to assess treatment alternatives for AD based on a multitude of decision trade-offs covering main components of care., Methods: AD caregivers (n = 117), neurologists (n = 90), and payors (n = 90) from the USA received an online survey. The decision problem was broken down into four decision criterion and 12 subcriteria for two treatment scenarios: an Aβ-targeted therapy vs. the standard of care (SOC). Respondents were asked to indicate how much they preferred one option over another on a scale from 1 (equal preference) to 9 (high preference) based on each criterion and subcriterion. The decision criteria and subcriteria were weighted and presented as partial utility scores (pUS), with higher scores suggesting an increased preference for that decision-making component., Results: Caregivers and payors applied the highest value to need for intervention (mean pUS = 0.303 and 0.259) and clinical outcomes (mean pUS = 0.286 and 0.377). In contrast, neurologists placed the highest value on clinical outcomes and types of benefits (mean pUS = 0.436 and 0.248). When decision subcriteria were examined, efficacy (mean pUS = 0.115, 0.219, and 0.166) and the type of patient benefits (mean pUS = 0.135, 0.178, and 0.126) were among the most valued by caregivers, neurologists, and payors., Conclusion: All groups placed the highest value on drug efficacy and types of benefit derived by patients. In contrast, cost implications were among the least important aspects in their decision-making., (© 2022. The Author(s).)

Background: Older adults with dementia including Alzheimer's disease may have difficulty communicating their treatment preferences and thus may receive intensive end-of-life (EOL) care that confers limited benefits., Objective: This study compared the use of life-sustaining interventions during the last 90 days of life among Medicare beneficiaries with and without dementia., Methods: This cohort study utilized population-based national survey data from the 2000-2016 Health and Retirement Study linked with Medicare and Medicaid claims. Our sample included Medicare fee-for-service beneficiaries aged 65 years or older deceased between 2000 and 2016. The main outcome was receipt of any life-sustaining interventions during the last 90 days of life, including mechanical ventilation, tracheostomy, tube feeding, and cardiopulmonary resuscitation. We used logistic regression, stratified by nursing home use, to examine dementia status (no dementia, non-advanced dementia, advanced dementia) and patient characteristics associated with receiving those interventions., Results: Community dwellers with dementia were more likely than those without dementia to receive life-sustaining treatments in their last 90 days of life (advanced dementia: OR = 1.83 [1.42-2.35]; non-advanced dementia: OR = 1.16 [1.01-1.32]). Advance care planning was associated with lower odds of receiving life-sustaining treatments in the community (OR = 0.84 [0.74-0.96]) and in nursing homes (OR = 0.68 [0.53-0.86]). More beneficiaries with advanced dementia received interventions discordant with their EOL treatment preferences., Conclusions: Community dwellers with advanced dementia were more likely to receive life-sustaining treatments at the end of life and such treatments may be discordant with their EOL wishes. Enhancing advance care planning and patient-physician communication may improve EOL care quality for persons with dementia.

Social isolation during opioid withdrawal is a major contributor to the current opioid addiction crisis. We find that sociability deficits during protracted opioid withdrawal in mice require activation of kappa opioid receptors (KORs) in the nucleus accumbens (NAc) medial shell. Blockade of release from dynorphin (Pdyn)-expressing dorsal raphe neurons (DR Pdyn ), but not from NAc Pdyn neurons, prevents these deficits in prosocial behaviors. Conversely, optogenetic activation of DR Pdyn neurons reproduced NAc KOR-dependent decreases in sociability. Deletion of KORs from serotonin (5-HT) neurons, but not from NAc neurons or dopamine (DA) neurons, prevented sociability deficits during withdrawal. Finally, measurements with the genetically encoded GRAB 5-HT sensor revealed that during withdrawal KORs block the NAc 5-HT release that normally occurs during social interactions. These results define a neuromodulatory mechanism that is engaged during protracted opioid withdrawal to induce maladaptive deficits in prosocial behaviors, which in humans contribute to relapse., Competing Interests: Declaration of interests R.C.M. is on the scientific advisory boards of MapLight Therapeutics, Bright Minds, MindMed, Cyclerion, AZTherapies, and Aelis Farma. B.D.H. is on the scientific advisory boards of Osmind and Journey Clinical and is a consultant for Clairvoyant Therapeutics and Vine Ventures. N.E. is a consultant for Boehringer Ingelheim., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: We aimed to investigate patient and caregiver views on the relative importance of traditional and nontraditional domains of value, and to determine if these views differed according to key demographic characteristics., Patients and Methods: We conducted a modified Delphi approach using a web-based survey of adult patients managing a chronic condition or caregivers of a patient with chronic illness who were recruited using purposive sampling focused on demographic and clinical characteristics. The first survey round asked participants to rate the 13 domains of value on a 5-point Likert scale and rank each domain that they rated as important or very important. In the second survey round, participants reconsidered their own and aggregated round 1 results. New questions were added, including "rescuing" domains, challenges faced in taking medication, and a free-text option to add domains not already captured., Results: Initial recruitment resulted in 79 participants. Sixty-three (79.7%) completed the first round, and 58 participants completed both rounds. Overall ratings and rankings were consistent between survey rounds, and respondents ranked most highly domains considered traditional domains of value (for example, survival, costs). Patient activists were about six times more likely to rate each domain as important or very important compared to general disease advocates. Significant factors associated with a higher odds of rating a domain as important or very important were age 35-54 and 55-64 compared to 18-34, while factors associated with a decreased odds were males and patients compared to caregivers., Conclusion: Patients and caregivers place significant emphasis on traditional measures of value compared to nontraditional measures, and participants' prior beliefs impact what aspects of value they deem important., Competing Interests: Mr. Voehler, Dr. Neumann, and Dr. Ollendorf are employed by the Tufts Center for the Evaluation of Value and Risk in Health, which maintains a variety of databases that are sponsored by life sciences companies, government agencies, and academic institutions. However, neither our principal funder nor any of our center’s sponsors had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. In addition, Dr. Neumann also reports grants from NPC, NIH, Alzheimer’s Association, Arnold Ventures, BMS, Otsuka, and Travere; funding to The CEA registry from NSF, NLM, AHRQ, CDC, and a variety of pharmaceutical and device companies and non-profits which subscribe to the data (https://cevr.tuftsmedicalcenter.org/sponsorship); personal fees from CBO, Bayer, Panalgo, Merck, ArgenX, and Novartis Gene Therapy Sarepta (consulting), outside the submitted work. Dr. Ollendorf reports grants from PhRMA Foundation, during the conduct of the study; grants from Merck Sharp & Dohme and Commonwealth Fund; personal fees from GlaxoSmithKline and University of Colorado, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2022 Voehler et al.)