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The Yesso scallop Mizuhopecten yessoensis is an important aquaculture species that was introduced to Western Canada from Japan to establish an economically viable scallop farming industry. This highly fecund species has been propagated in Canadian aquaculture hatcheries for the past 40 years, raising questions about genetic diversity and genetic differences among hatchery stocks. In this study, we compare cultured Canadian and wild Japanese populations of Yesso scallop using double-digest restriction site-associated DNA (ddRAD) sequencing to genotype 21,048 variants in 71 wild-caught scallops from Japan, 65 scallops from the Vancouver Island University breeding population, and 37 scallops obtained from a commercial farm off Vancouver Island, British Columbia. The wild scallops are largely comprised of equally unrelated individuals, whereas cultured scallops are comprised of multiple families of related individuals. The polymorphism rate estimated in wild scallops was 1.7%, whereas in the cultured strains, it ranged between 1.35 and 1.07%. Interestingly, heterozygosity rates were highest in the cultured populations, which is likely due to shellfish hatchery practices of crossing divergent strains to gain benefits of heterosis and to avoid inbreeding. Evidence of founder effects and drift was observed in the cultured strains, including high genetic differentiation between cultured populations and between cultured populations and the wild population. Cultured populations had effective population sizes ranging from 9 to 26 individuals whereas the wild population was estimated at 25,048-56,291 individuals. Further, a depletion of low-frequency variants was observed in the cultured populations. These results indicate significant genetic diversity losses in cultured scallops in Canadian breeding programs., Competing Interests: Conflicts of interest BJGS is affiliated with Sutherland Bioinformatics. The author has no competing financial interests to declare. The other authors declare that no competing interests exist., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America.)

Patients with sarcoma often report prolonged time to diagnosis, which is attributed to the rarity of sarcoma and the low awareness of pre-diagnostic signs and symptoms., Aims: To describe patients' experiences of pre-diagnostic signs/symptoms and pathways to diagnosis, including where help was sought, and the processes involved., Methods: Mixed methods involving quantitative, qualitative and inductive thematic analyses using novel process mapping of patient journey data, as reported by the patients. We examined the time from symptom onset to first professional presentation (patient interval, PI), first consultation to diagnostic biopsy, first consultation to diagnosis (diagnostic interval) and first presentation to diagnosis (total interval)., Results: A total of 87 interviews were conducted over 5 months in 2017. Of these, 78 (40 males/38 females) were included. The sarcoma subtypes were bone (n = 21), soft tissue (n = 41), head and neck (n = 9) and gastro-intestinal (GIST; n = 7). Age at diagnosis was 13-24 (n = 7), 25-39 (n = 23), 40-64 (n = 34) and 65+ (n = 14) years. The median PI was 13 days (1-4971) and similar between sarcoma subtypes, with the exception of GIST (mPI = 2 days, (1-60). The longest mPI (31 days, range 4-762) was for those aged 13-24 years. The median diagnostic interval was 87.5 (range 0-5474 days). A total of 21 patients were misdiagnosed prior to diagnosis and symptoms were commonly attributed to lifestyle factors., Conclusions: Prolonged times to diagnosis were experienced by the majority of patients in our sample. Further research into the evolution of pre-diagnostic sarcoma symptoms is required to inform awareness interventions.

Introduction: Rapid qualitative studies conducted with patient and public involvement can help promote policy-relevant and efficient research. There is a need to understand the experiences of researchers, patients, and members of the public to guide the development of good practice and to determine the extent to which rapid qualitative research can be implemented in PPIE projects., Methods: We conducted a qualitative study to explore the experiences of research teams that carried out studies using rapid techniques with patient and public involvement. We carried out 26 interviews with researchers, coordinators, patients, carers, service users and members of the public., Results: This study identified needs which related to practical and time constraints. Rapid qualitative research tends to be limited to certain PPIE groups, and particular phases of the research process. Study findings are rarely discussed with PPIE members. The educational needs of rapid qualitative research were also identified. Researchers and PPIE members considered three main issues: a lack of training on patient involvement for researchers, rapid qualitative research training for PPIE members, and the diversity of PPIE members., Conclusion: We found that rapid researchers were able to involve patients and members of the public in research despite time pressures. The challenges identified in this study can be used to plan future training programmes for researchers and PPIE panel members and develop strategies to recruit PPIE panel members from a wide range of backgrounds., Public Contribution: The research aim was to explore the experiences of those carrying out rapid qualitative studies with PPIE. As such, the participants of this study included patients, carers, service users and members of the public, who were interviewed individually. A lived experienced researcher and PPIE member for a hospital conducted the design, data collection and analysis of the study. The study brief was to interview researchers only. The lived-experience researcher initiated the inclusion of PPIE members as participants, therefore strengthening the study design. We shared the draft report with the PPIE participants for participant validation and to maintain a continuous feedback relationship. This led to addressing key issues in designing and involving PPIE members in more meaningful and equal ways. Whilst there is agreement on activities which centre on PPIE, there is no consensus on how to achieve these in high quality rapid qualitative studies., (© 2022. The Author(s).)

Abietic acid (AA), dehydroabietic acid (DHA) and triptoquinones (TQs) are bioactive abietane-type diterpenoids, which are present in many edible vegetables and medicinal herbs with health-promoting properties. Evidence suggests that beneficial effects of diterpenes operate, at least in part, through effects on cells in the immune system. Dendritic cells (DCs) are a key type of leukocyte involved in the initiation and regulation of the immune/inflammatory response and natural or synthetic compounds that modulate DC functions could be potential anti-inflammatory/immunomodulatory agents. Herein, we report the screening of 23 known semisynthetic AA and DHA derivatives, and TQs, synthesized previously by us, in a multi-analyte DC-based assay that detects inhibition of pro-inflammatory cytokine production. Based on the magnitude of the inhibitory effect observed and the number of cytokines inhibited, a variety of activities among compounds were observed, ranging from inactive/weak to very potent inhibitors. Structurally, either alcohol or methyl ester substituents on ring A along with the introduction of aromaticity and oxidation in ring C in the abietane skeleton were found in compounds with higher inhibitory properties. Two DHA derivatives and two TQs exhibited a significant inhibition in all pro-inflammatory cytokines tested and were further investigated. The results confirmed their ability to inhibit, dose dependently, LPS-stimulated expression of the co-stimulatory molecules CD40 and/or CD86 and the production of the pro-inflammatory cytokines IL-1β, IL-6, IL-12 and TNFα. Our results demonstrate that DC maturation process can be targeted by semisynthetic DHA derivatives and TQ epimers and indicate the potential of these compounds as optimizable anti-inflammatory/immunomodulatory agents.

Objectives: This study aimed to examine how Americans' opinions of the seriousness of various health-related problems have changed over time and to quantify the public's preferences for research prioritization., Methods: We conducted a survey that asked respondents to rate the seriousness of 80 health-related problems on a 4-point Likert scale ("very serious problem," "somewhat serious problem," "not too serious of a problem," or "not a problem at all"). Results were compared with past surveys from 2001 and 2013 that examined the same set of health-related problems (with the exception of COVID-19). The survey also included best-worst scaling questions that asked respondents to select, from 20 health problems, those they considered most and least important for research funding. Respondents were recruited from the KnowledgePanel, a nationally representative sample of American households., Results: A total of 768 adults completed the survey between September 3, 2020, and September 14, 2020. The health-related problems that Americans consider to be "very serious" generally align with the leading causes of death and noncommunicable diseases such as heart disease, diabetes, and mental health; nevertheless, several social determinants of health are also identified. COVID-19 was an unsurprising top priority, whereas cancer remains the highest and a persistent priority for research funding., Conclusions: Americans consider a diverse set of health-related problems to be "very serious," with recognition of social determinants of health rising. Our findings offer guidance as to the disease areas for which the public would value further public and private investment in treatment innovations., (Copyright © 2022. Published by Elsevier Inc.)

Background: Despite demonstration of bioequivalence of generics to brands and the potential for reduced costs, some patients switch back from a generic to the brand. A prior retrospective analysis suggested that this switchback rate may be lower among patients that had initially switched to authorized generics (AG), often both produced and marketed by the brand company, compared to those initially switched to another generic., Objective: Explore switching patterns of brands, AGs, and generics, switchback rates, and the potential impact of switchbacks on healthcare costs., Methods: An analysis of the Pharmetrics Plus™ database (2007-2019), a United States (US) payer administrative database, was conducted to examine the use of Upjohn medications available as AGs across multiple therapeutic areas. Patients initiating treatment with brand medication in the 6 months prior to generic market entry were identified and switch rates to generics and AGs, as well as switchback rates, were evaluated. Costs were descriptively compared between patients who switched back to brand and those who remained on any generic., Results: Across 14 brand medications, more than half of the patients initiating treatment with the brand medication were switched to a generic. Generally, switching to AG, which ranged from 0.5 to 39.6%, was lower than switching to non-AG generics (16.7-79.9%). The comparison of switchback rates from AGs to brand and non-AGs to brand showed similar results (AG:1.3-7.5%; non-AG:1.4-12.9%); however, the most substantial differences were observed where non-AG switchbacks were higher. Patients that switched back to brand remained on AG or generic for an average of 1-3 months (32-88 days). The analysis showed a tendency towards increased medical costs in the period immediately preceding switchback for all medications except sildenafil in both indications (erectile dysfunction and pulmonary arterial hypertension). For the remaining medications, medical costs ranged from $63 to $1544 higher for the switchback population. Pharmacy costs similarly tended to be higher for patients who had a switchback, with the exception of sildenafil for pulmonary arterial hypertension and sirolimus., Conclusion: Patients receiving a brand medication are likely to be switched to a generic upon market availability. Some patients switch back to the brand medication, usually within 1-3 months; this may be associated with increased medical costs. Additional research is needed to understand switching, its potential disruption to patients, and the role of brands, generics, and AGs., Competing Interests: Dr Justine Alderfer is an employee of Pfizer Inc, and holds stock from Pfizer Inc and Viatris, Inc. Ms Jyoti Aggarwal was an employee of OPEN Health at the time of research. Dr Kim Gilchrist is an employee and stockholder of Pfizer Inc. Dr Jose Maria Jimenez Alvir is an employee and stockholder of Pfizer Inc and Viatris, Inc. Dr Joseph Cook is an employee of Viatris, Inc and hold stocks from Pfizer Inc and Viatris, Inc. Ms Sang Hee Park was an employee of OPEN Health at the time of the research. Dr Jennifer M Stephens is an employee and shareholder of OPEN Health. OPEN Health received research funding from Upjohn to conduct the research. The authors report no other conflicts of interest in this work., (© 2022 Alderfer et al.)

Background: The world is experiencing local/regional hotspots and spikes in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19 disease. We aimed to formulate an applicable epidemiological model to accurately predict and forecast the impact of local outbreaks of COVID-19 to guide the local healthcare demand and capacity, policy-making and public health decisions., Methods: The model utilized the aggregated daily COVID-19 situation reports (including counts of daily admissions, discharges and bed occupancy) from the local National Health Service (NHS) hospitals and COVID-19-related weekly deaths in hospitals and other settings in Sussex (population 1.7 million), Southeast England. These data sets corresponded to the first wave of COVID-19 infections from 24 March to 15 June 2020. A novel epidemiological predictive and forecasting model was then derived based on the local/regional surveillance data. Through a rigorous inverse parameter inference approach, the model parameters were estimated by fitting the model to the data in an optimal sense and then subsequent validation., Results: The inferred parameters were physically reasonable and matched up to the widely used parameter values derived from the national data sets by Biggerstaff M, Cowling BJ, Cucunubá ZM et al. (Early insights from statistical and mathematical modeling of key epidemiologic parameters of COVID-19, Emerging infectious diseases. 2020;26(11)). We validate the predictive power of our model by using a subset of the available data and comparing the model predictions for the next 10, 20 and 30 days. The model exhibits a high accuracy in the prediction, even when using only as few as 20 data points for the fitting., Conclusions: We have demonstrated that by using local/regional data, our predictive and forecasting model can be utilized to guide the local healthcare demand and capacity, policy-making and public health decisions to mitigate the impact of COVID-19 on the local population. Understanding how future COVID-19 spikes/waves could possibly affect the regional populations empowers us to ensure the timely commissioning and organization of services. The flexibility of timings in the model, in combination with other early-warning systems, produces a time frame for these services to prepare and isolate capacity for likely and potential demand within regional hospitals. The model also allows local authorities to plan potential mortuary capacity and understand the burden on crematoria and burial services. The model algorithms have been integrated into a web-based multi-institutional toolkit, which can be used by NHS hospitals, local authorities and public health departments in other regions of the UK and elsewhere. The parameters, which are locally informed, form the basis of predicting and forecasting exercises accounting for different scenarios and impacts of COVID-19 transmission., (© The Author(s) 2021. Published by Oxford University Press on behalf of the International Epidemiological Association.)

An international online patient community, Carenity, conducted a patient study in two independent waves among adults affected by non-communicable diseases (NCDs) in Europe and in the United States of America (USA). The study aimed to assess the real time impact of the coronavirus disease 2019 (COVID-19) on the medical conditions of patients with NCDs, their access to health care, and their adaptation to daily life as well as to describe their sources of information on COVID-19 and their needs for specific information and support. During the pandemic, 50% of the patients reported a worsening of their medical condition, and 17% developed a new disease. Additionally, 26% of the respondents reported an impact of the pandemic on regular/long-term treatment intake. 54% of the patients felt very or completely socially isolated and reported a strong impact of the COVID-19 pandemic on their stress level and state of mind, with higher levels observed in the USA compared to Europe. 59% of the respondents wished to have received additional information regarding the risks associated to their medical condition during the pandemic. Television was the most used source of information, whereas physicians were the most trusted one. This study describes the substantial impact of the COVID-19 pandemic on NCD patients.

Introduction: Given the recent reports of e-cigarette, or vaping, product use-associated lung injury (EVALI) and harm of e-cigarettes, the authors evaluated changes in the use and perception of e-cigarettes as tobacco use cessation tools in 2019 relative to 2016. The authors also evaluated the sources family physicians most commonly use to receive information regarding e-cigarettes., Methods: A cross-sectional online survey of 248 community family physicians in Kansas was conducted from October 2019 to December 2019. An 11-item questionnaire measured the participants' perceptions of recommending e-cigarettes to patients for tobacco cessation. A mixed method approach was used to collect, analyze, and interpret the data. Standard descriptive statistics, Likelihood-Ratio/Fisher's exact tests, and immersion-crystallization methods were used to analyze the data., Results: The response rate was 59.3% (147/248). The proportion of the family physicians who did not recommend e-cigarettes for tobacco use cessation was significantly higher in 2019 than in 2016 (86% vs. 82%; χ 2 [1, n = 261] = 12.31; p < 0.01). Several reasons regarding respondents' perceptions of e-cigarettes as tobacco use cessation tools were reported. The medical literature and news media were the top sources where family physicians accessed e-cigarettes information., Conclusion: Most family physicians did not recommend e-cigarettes for tobacco cessation. Opinions regarding the efficacy and safety of e-cigarettes were influenced by information sources. Future, larger studies would be beneficial to further determine family physicians' beliefs and practices regarding e-cigarettes as tobacco use cessation products., (© 2020 The University of Kansas Medical Center.)

BackgroundThe first cases of extensively drug resistant gonorrhoea were recorded in the United Kingdom in 2018. There is a public health need for strategies on how to deploy existing and novel antibiotics to minimise the risk of resistance development. As rapid point-of-care tests (POCTs) to predict susceptibility are coming to clinical use, coupling the introduction of an antibiotic with diagnostics that can slow resistance emergence may offer a novel paradigm for maximising antibiotic benefits. Gepotidacin is a novel antibiotic with known resistance and resistance-predisposing mutations. In particular, a mutation that confers resistance to ciprofloxacin acts as the 'stepping-stone' mutation to gepotidacin resistance.AimTo investigate how POCTs detecting Neisseria gonorrhoeae resistance mutations for ciprofloxacin and gepotidacin can be used to minimise the risk of resistance development to gepotidacin.MethodsWe use individual-based stochastic simulations to formally investigate the aim.ResultsThe level of testing needed to reduce the risk of resistance development depends on the mutation rate under treatment and the prevalence of stepping-stone mutations. A POCT is most effective if the mutation rate under antibiotic treatment is no more than two orders of magnitude above the mutation rate without treatment and the prevalence of stepping-stone mutations is 1-13%.ConclusionMutation frequencies and rates should be considered when estimating the POCT usage required to reduce the risk of resistance development in a given population. Molecular POCTs for resistance mutations and stepping-stone mutations to resistance are likely to become important tools in antibiotic stewardship.

Objective: To determine household and health-care provider costs associated with Plasmodium vivax infection across a range of endemic settings., Methods: We collected cost data alongside three multicentre clinical trials of P. vivax treatment in Afghanistan, Brazil, Colombia, Ethiopia, Indonesia, Philippines, Peru, Thailand and Viet Nam conducted between April 2014 to December 2017. We derived household costs from trial participant surveys administered at enrolment and again 2 weeks later to determine the costs of treatment and transportation, and the number of days that patients and their household caregivers were unable to undertake their usual activities. We determined costs of routine care by health-care providers by micro-costing the resources used to diagnose and treat P. vivax at the study sites., Findings: The mean total household costs ranged from 8.7 United States dollars (US$; standard deviation, SD: 4.3) in Afghanistan to US$ 254.7 (SD: 148.4) in Colombia. Across all countries, productivity losses were the largest household cost component, resulting in mean indirect costs ranging from US$ 5.3 (SD: 3.0) to US$ 220.8 (SD: 158.40). The range of health-care provider costs for routine care was US$ 3.6-6.6. The cost of administering a glucose-6-phosphate-dehydrogenase rapid diagnostic test, ranged from US$ 0.9 to 13.5, consistently lower than the costs of the widely-used fluorescent spot test (US$ 6.3 to 17.4)., Conclusion: An episode of P. vivax malaria results in high costs to households. The costs of diagnosing and treating P. vivax are important inputs for future cost-effectiveness analyses to ensure optimal allocation of resources for malaria elimination., ((c) 2019 The authors; licensee World Health Organization.)

Background and Aims: Little is known about the prevalence or treatment of pruritus associated with primary biliary cholangitis (PBC). We analyzed data from patients with PBC recruited from all clinical centers in the United Kingdom (UK) to characterize the prevalence, severity, progression, and treatment of pruritus., Methods: We performed cross-sectional and longitudinal studies of patients in the UK-PBC cohort to assess trajectories of pruritus. Data on pruritus frequency, severity, and therapy were collected via paper questionnaires completed by 2194 patients at their initial assessment in 2011 and then again in 2014 and 2017. Self-reported treatment data were validated against the prescription record of PBC cohort in the Clinical Practice Research Datalink, a primary care database. We defined persistent pruritus as itch that occurs frequently or all the time and severe pruritus as PBC-40 pruritus domain scores of 12 or more, throughout their disease course. Latent class mixed models were used to study pruritus trajectories and identify factors associated with high pruritus., Results: At initial assessment, 1613 (73.5%) patients had experienced pruritus at some point since their development of PBC-persistent pruritus was reported by 34.5% of the patients and severe pruritus by 11.7%. Only 37.4% of patients with persistent pruritus and 50% with severe pruritus reported ever receiving cholestyramine. Frequencies of rifampicin use were 11% in patients with persistent pruritus and 23% in patients with severe pruritus. Comparison of 2011 and 2014 surveys (comprising 1423 patients) showed consistent self-reported data on pruritus. Proportions of patients in the UK-PBC cohort treated with cholestyramine or naltrexone (37.4% and 4.4%) did not differ significantly from proportions treated in the Clinical Practice Research Datalink cohort (30.4% and 4.4%) (P = .07 for cholestyramine and P = .32 for naltrexone). Latent class mixed models (n = 1753) identified 3 different groups of pruritus. Multivariable analysis identified younger age at diagnosis and higher level of alkaline phosphatase at 12 months after diagnosis as factors significantly associated with persistent high pruritus., Conclusions: In a large national cohort study of patients with PBC, we found a high prevalence of pruritus and inadequate guideline-recommended therapy. Patient-reported data used to determine pruritus prevalence and treatment are reliable. Younger age and levels of higher alkaline phosphatase were associated with persistent pruritus. We need to increase awareness and management of pruritus in PBC in the UK., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: The medical literature suggests disturbingly high rates of burnout among US physicians. The objective of this study was to determine the rates of burnout, other forms of distress, and overall quality of life among physicians in Sedgwick County., Methods: The study involved a convenience sample of 197 physicians who were active member physicians of the Medical Society of Sedgwick County (MSSC). Between July and August 2018, we surveyed 872 physicians who were active members of the MSSC. The survey assessed manifestations of burnout, symptoms of depression and suicidal ideation, fatigue, and quality of life. The authors used standard descriptive summary statistics, Mann-Whitney U test/independent samples t -Test, Fisher's exact test, and correlations to analyze the data., Results: The participation rate was 44.6%, with 49.5% of the respondents reporting manifestations of burnout. Although 85% of the participants rated their overall quality of life as good/very good, 45% screened positive for depression, 5% had thoughts of suicide during the past year, and 44% reported excessive fatigue during the past week. Those with manifestations of burnout were 2.13 (100% vs 46.9%, p < 0.01) times more likely to report thoughts of suicidal ideation, 2.43 (72.6% vs 30.4%; p < 0.001) times more likely to screen positive for depression, and 1.89 (67.5% vs 35.8%; p < 0.001) times more likely to have high degrees of fatigue. All of the participants who had suicidal ideation reported manifestations of burnout., Conclusions: Burnout was prevalent among active member physicians of the MSSC. Burnout among the participants was associated with symptoms of depression, fatigue, suicidal ideation, and intention of leaving the medical profession via early retirement and/or career change.

Background: Pruritus (itch) is a symptom commonly experienced by patients with cholestatic liver diseases such as primary biliary cholangitis (PBC, previously referred to as primary biliary cirrhosis). Bile acids (BAs) have been proposed as potential pruritogens in PBC. The ileal bile acid transporter (IBAT) protein expressed in the distal ileum plays a key role in the enterohepatic circulation of BAs. Pharmacological inhibition of IBAT with GSK2330672 may reduce BA levels in the systemic circulation and improve pruritus., Methods: This clinical study (BAT117213 study) is sponsored by GlaxoSmithKline (GSK) with associated exploratory studies supported by the National Institute for Health Research (NIHR). It is a phase 2a, multi-centre, randomised, double bind, placebo controlled, cross-over trial for PBC patients with pruritus. The primary objective is to investigate the safety and tolerability of repeat doses of GSK2330672, and explore whether GSK2330672 administration for 14 days improves pruritus compared with placebo. The key outcomes include improvement in pruritus scores evaluated on a numerical rating scale and other PBC symptoms in an electronic diary completed twice daily by the patients. The secondary outcomes include the evaluation of the effect of GSK2330672 on total serum bile acid (BA) concentrations, serum markers of BA synthesis and steady-state pharmacokinetics of ursodeoxycholic acid (UDCA)., Discussion: BAT117213 study is the first randomised controlled crossover trial of ileal bile acid transporter inhibitor, a novel class of drug to treat pruritus in PBC. The main strengths of the trial are utility of a novel, study specific, electronic symptom diary as patient reported outcome to measure the treatment response objectively and the crossover design that allows estimating the treatment effect in a smaller number of patients. The outcome of this trial will inform the trial design of future development phase of the IBAT inhibitor drug. The trial will also provide opportunity to conduct metabonomic and gut microbiome studies as explorative and mechanistic research in patients with cholestatic pruritus., Trial Registration: EudraCT number: 2012-005531-84, ClinicalTrials.gov Identifier: NCT01899703 , registered on 3(rd) July 2013.

Microsporidia are a group of intracellular pathogens causing self-limited and severe diseases in immunocompetent and immunocompromised individuals, respectively. A cellular type 1 adaptive response, mediated by IL-12, IFNγ, CD4+, and CD8+ T cells has been shown to be essential for host resistance, and dendritic cells (DC) play a key role at eliciting anti-microsporidial immunity. We investigated the in vitro response of DC and DC precursors/progenitors to infection with Encephalitozoon intestinalis (Ei), a common agent of human microsporidosis. Ei-exposed DC cultures up-regulated the surface expression of MHC class II and the costimulatory molecules CD86 and CD40, only when high loads of spores were used. A vigorous secretion of IL-6 but not of IL-1β or IL-12p70 was also observed in these cultures. Ei-exposed DC cultures consisted of immature infected and mature bystander DC, as assessed by MHC class II and costimulatory molecules expression, suggesting that intracellular Ei spores deliver inhibitory signals in DC. Moreover, Ei selectively inhibited the secretion of IL-12p70 in LPS-stimulated DC. Whereas Ei-exposed DC promoted allogeneic naïve T cell proliferation and IL-2 and IFNγ secretion in DC-CD4+ T cell co-cultures, separated co-cultures with bystander or infected DCs showed stimulation or inhibition of IFNγ secretion, respectively. When DC precursors/progenitors were exposed to Ei spores, a significant inhibition of DC differentiation was observed without shifting the development toward cells phenotypically or functionally compatible with myeloid-derived suppressor cells. Neutralization experiments demonstrated that this inhibitory effect is IL-6-dependent. Altogether this investigation reveals a novel potential mechanism of immune escape of microsporidian parasites through the modulation of DC differentiation and maturation.

Introduction: The Antiretroviral Analysis by Monte Carlo Individual Simulation (ARAMIS) model was adapted to evaluate the cost-effectiveness of dolutegravir (DTG) in Canada in treatment-naive (TN) and treatment-experienced (TE) human immunodeficiency virus (HIV)-1 patients., Methods: The ARAMIS-DTG model is a microsimulation model with a lifetime analytic time horizon and a monthly cycle length. Markov health states were defined by HIV health state (with or without opportunistic infection). DTG was compared to efavirenz (EFV), raltegravir (RAL), darunavir/ritonavir, rilpivirine (RPV), elvitegravir/cobicistat, atazanavir/ritonavir and lopinavir/ritonavir in TN patients and to RAL in TE patients. The initial cohort, the main efficacy data and safety data were derived from phase III clinical trials. Treatment algorithms were based on expert opinion. Costs normalized to the year 2013 included antiretroviral treatment cost, testing, adverse event, HIV and cardiovascular disease care and were derived from the literature., Results: Dolutegravir was estimated to be the dominant strategy compared with all comparators in both TN and TE patients. Treatment with DTG was associated with additional quality-adjusted life-years that ranged from 0.17 (vs. RAL) to 0.47 (vs. EFV) in TN patients and was 0.60 in TE patients over a lifetime. Cost savings ranged from Can$1393 (vs. RPV) to Can$28,572 (vs. RAL) in TN patients and amounted to Can$3745 in TE patients. Sensitivity analyses demonstrated the robustness of the model., Conclusions: Dolutegravir is a dominant strategy in the management of TN and TE patients when compared to recommended comparators. This is mainly related to the high efficacy and high barrier to resistance., Funding: ViiV Healthcare.

Objective: To assess individualized satisfaction with migraine treatment, patient expectations, importance rankings, treatment outcomes, and overall satisfaction were combined using a four-part conceptual model. This article describes the measurement properties of the Migraine Treatment Satisfaction Measure (MTSM) using participants from a randomized controlled trial evaluating a Headache Management Program (HMP)., Methods: Participants completed the first two parts of the MTSM upon enrollment and the final two parts at 6 months. Internal consistency reliability was computed within each of the four modules. Discriminant validity was ascertained using Migraine Disability Assessment Survey (MIDAS), Patient Health Questionnaire-9, and MSFB scores. Convergent validity was established by hypothesized positive correlations between MTSM scores, Medical Outcomes Study Short-Form (SF-36), MIDAS, and Migraine Symptom Frequency Bother (MSFB)., Results: In total, 124 participants (mean age 45.4 years, 75% women, 59.7% Caucasian) enrolled. Internal consistency for expectations, importance rankings, outcomes, and satisfaction measures was 0.83, 0.95, 0.86, and 0.95, respectively. As the severity of depression increased, MTSM scores decreased significantly. ANOVA between MTSM scores and symptom bothersomeness and symptom frequency tertiles showed a significant decrease in satisfaction in the moderate-to-severe groups. MTSM scores showed expected associations with MSFB scores (-0.301; P < 0.01), MIDAS (-0.267; P < 0.01), general health (0.253; P < 0.05), mental health (0.217; P < 0.05), and vitality subscales of SF-36 (0.214; P < 0.05). Patients in the HMP reported significantly higher MTSM scores (43.2 vs. 31.4; P < 0.001). Patients on triptans reported a significantly higher satisfaction compared to patients on analgesics (39.5 vs. 32.9; P < 0.05)., Conclusion: The MTSM is a valid and reliable patient-reported outcome that can be used to evaluate differences in treatment satisfaction associated with migraine therapies.

The role of prolactin in human breast cancer has been controversial. However, it is now apparent that human mammary epithelial cells can synthesize prolactin endogenously, permitting autocrine/paracrine actions within the mammary gland that are independent of pituitary prolactin. To model this local mammary production of prolactin (PRL), we have generated mice that overexpress prolactin within mammary epithelial cells under the control of a hormonally nonresponsive promoter, neu-related lipocalin (NRL). In each of the two examined NRL-PRL transgenic mouse lineages, female virgin mice display mammary developmental abnormalities, mammary intraepithelial neoplasias, and invasive neoplasms. Prolactin increases proliferation in morphologically normal alveoli and ducts, as well as in lesions. The tumors are of varied histotype, but papillary adenocarcinomas and adenosquamous neoplasms predominate. Neoplasms can be separated into two populations: one is estrogen receptor alpha (ERalpha) positive (greater than 15% of the cells stain for ERalpha), and the other is ERalpha- (<3%). ERalpha expression does not correlate with tumor histotype, or proliferative or apoptotic indices. These studies provide a mouse model of hormonally dependent breast cancer, and, perhaps most strikingly, a model in which some neoplasms retain ERalpha, as occurs in the human disease.

Whey acidic protein (WAP)-transforming growth factor (TGF)-alpha transgenic mice acquire both cancerous and noncancerous mammary lesions. For this study, we evaluated the effect of mouse strain background on the incidence, latency, and histotype of two noncancerous lesions, hyperplastic alveolar nodules (analogous to typical hyperplasias in women), and macrocysts. These lesions display characteristics of fibrocystic changes observed in breasts of women, and in both mice and humans are associated with an uncertain risk of progression to neoplasia. Virgin transgenic mice of the (C57BL/6J;SJL)F2 background developed very few hyperplastic alveolar nodules and no macrocysts. In contrast, when the WAP-TGF-alpha transgene was carried on the FVB/N strain, congenic virgin transgenic mice acquired both lesion types with approximately 100% penetrance. In the (FVB;C57BL/6J)F1 background, hyperplastic alveolar nodule incidence was reduced to approximately the nontransgenic mouse level, and macrocyst latency was increased dramatically. Crossing into C57BL/6 resulted in elimination of the macrocyst phenotype. Finally, FVB strain transgenic mammary epithelium transplanted into nontransgenic recipients of the FVB/N or (FVB;C57BL/6J)F1 backgrounds displayed macrocyst latency characteristic of the recipient, and not donor, mouse strain. Quantitative real-time polymerase chain reaction analysis demonstrated that, despite the difference in macrocyst incidence between (FVB;C57BL/6J)F1 and C57BL/6 virgin transgenic mice (81% versus 0%), the level of TGF-alpha expression was not different. FVB strain transgenic mice expressed only twofold more TGF-alpha than the other backgrounds. These findings indicate that C57BL/6J modifier alleles inhibit mammary lesion incidence and macrocyst latency in a semidominant manner, and that suppression of lesion development can involve host factors that are independent of mammary epithelial genotype.

The effect of a mutation affecting flocculation, differentiation into cyst-like forms, and root colonization on nitrogenase expression by Azospirillum brasilense is described. The gene flcA of strain Sp7 restored these phenotypes in spontaneous mutants of both strains Sp7 and Sp245. Employing both constitutive pLA-lacZ and nifH-lacZ reporter fusions expressed in situ, the colony morphology, colonization pattern, and potential for nitrogenase activity of spontaneous mutants and flcA Tn5-induced mutants were established. The results of this study show that the ability of Sp7 and Sp245 mutant strains to remain in a vegetative form improved their ability to express nitrogenase activity in association with wheat in a hydroponic system. Restoring the cyst formation and colonization pattern to the spontaneous mutant Sp7-S reduced nitrogenase activity rates in association with plants to that of the wild-type Sp7. Although Tn5-induced flcA mutants showed higher potentials for nitrogenase expression than Sp7, their potentials were lower than that of Sp7-S, indicating that other factors in this strain contribute to its exceptional nitrogenase activity rates on plants. The lack of lateral flagella is not one of these factors, as Sp7-PM23, a spontaneous mutant impaired in swarming and lateral-flagellum production but not in flocculation, showed wild-type nitrogenase activity and expression. The results also suggest factors of importance in evolving an effective symbiosis between Azospirillum and wheat, such as increasing the availability of microaerobic niches along the root, increased supply of carbon sources by the plant, and the retention of the bacterial cells in vegetative form for faster metabolism.