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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.)

Objectives: To assess patient characteristics, treatment patterns, and patient-reported outcomes (PROs) associated with authorized generics (AGs) and independent generics (IGs) use., Methods: Prescription claims and National Health and Wellness Survey (NHWS) data were linked. Adults with billable national drug code (AG or IG), NHWS completion from June 2015 to July 2019, AG or IG on-hand at NHWS completion, and continuous insurance eligibility in 12 months pre- and post-NHWS completion were included. To be included, all unique medication formulations had to have at least one AG and one IG observation. PRO index date was NHWS completion; claims index date was defined as the first prescription claim identified during the 180-day period prior to NHWS completion for the same active ingredient and formulation type that was on-hand at NHWS completion., Results: Patients ( N  = 20,229; 17.2% AG users) in six therapeutic areas (attention deficit-hyperactivity disorder [ADHD], antidepressants, beta blockers [BBs], calcium channel blockers [CCBs], statins, and thyroid) were included. Generally, AG (vs. IG) users were younger and differed in regional access and insurance type (all, p  < .05). In multivariable analysis, significant differences were observed for presenteeism and overall work impairment (BBs), healthcare provider visits (BBs), and indirect costs (thyroid) (all, p  < .05). AG and IG users differed in persistence (ADHD and statins; both, p  < .05) and switch (BBs and CCBs; both, p  < .01) rates., Conclusions: PRO differences were often small in magnitude and varied by therapeutic area. The impact of switching should consider observed PRO differences, patient preferences, and market availability of AG and IG alternatives.

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.)

Objective: To evaluate the effect of providing quasi-contextualized speech therapy, defined as metacognitive, compensatory, or strategy training applied to cognitive and language impairments to facilitate the performance of future real-life activities, on functional outcomes up to 1 year following traumatic brain injury (TBI)., Setting: Acute inpatient rehabilitation., Participants: Patients enrolled during the TBI-Practice-Based Evidence (TBI-PBE) study (n = 1760), aged 14 years or older, who sustained a severe, moderate, or complicated mild TBI, received speech therapy in acute inpatient rehabilitation at one of 9 US sites, and consented to follow-up 3 and 9 months postdischarge from inpatient rehabilitation., Design: Propensity score methods applied to a database consisting of multisite, prospective, longitudinal observational data., Main Measures: Participation Assessment with Recombined Tools-Objective-17, FIM Motor and Cognitive scores, Satisfaction With Life Scale, and Patient Health Questionnaire-9., Results: When at least 5% of therapy time employed quasi-contextualized treatment, participants reported better community participation during the year following discharge. Quasi-contextualized treatment was also associated with better motor and cognitive function at discharge and during the year after discharge. The benefit, however, may be dependent upon a balance of rehabilitation time that relied on contextualized treatment., Conclusions: The use of quasi-contextualized treatment may improve outcomes. Care should be taken, however, to not provide quasi-contextualized treatment at the expense of contextualized treatment., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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.)

Objective: To use causal inference methods to determine if receipt of a greater proportion of inpatient rehabilitation treatment focused on higher level functions, for example, executive functions, ambulating over uneven surfaces (advanced therapy [AdvTx]), results in better rehabilitation outcomes., Design: A cohort study using propensity score methods applied to the traumatic brain injury practice-based evidence (TBI-PBE) database, a database consisting of multisite, prospective, longitudinal observational data., Setting: Acute inpatient rehabilitation facilities., Participants: Patients enrolled in the TBI-PBE study (N=1843), aged 14 years or older, who sustained a severe, moderate, or complicated mild TBI, receiving their first inpatient rehabilitation facility admission to 1 of 9 sites in the United States, and consented to follow-up 3 and 9 months postdischarge from inpatient rehabilitation., Interventions: Not applicable., Main Outcome Measures: Participation Assessment with Recombined Tools-Objective-17, FIM motor and cognitive scores, Satisfaction with Life Scale, and Patient Health Questionnaire-9., Results: Controlling for measured potential confounders, increasing the percentage of AdvTx during inpatient TBI rehabilitation was found to be associated with better community participation, functional independence, life satisfaction, and decreased likelihood of depression during the year after discharge from inpatient rehabilitation. Participants who began rehabilitation with greater disability experienced larger gains on some outcomes than those who began rehabilitation with more intact abilities., Conclusions: Increasing the proportion of treatment targeting higher level functions appears to have no detrimental and a small, beneficial effect on outcome. Caution should be exercised when inferring causality given that a large number of potential confounders could not be completely controlled with propensity score methods. Further, the extent to which unmeasured confounders influenced the findings is not known and could be of particular concern due to the potential for the patient's recovery trajectory to influence therapists' decisions to provide a greater amount of AdvTx., (Copyright © 2018 American Congress of Rehabilitation Medicine. All rights reserved.)

Objective: To evaluate the effect of providing a greater percentage of therapy as contextualized treatment on acute traumatic brain injury (TBI) rehabilitation outcomes., Design: Propensity score methods are applied to the TBI Practice-Based Evidence (TBI-PBE) database, a database consisting of multi-site, prospective, longitudinal observational data., Setting: Acute inpatient rehabilitation., Participants: Patients enrolled in the TBI-PBE study (N=1843), aged 14 years or older, who sustained a severe, moderate, or complicated mild TBI, received their first inpatient rehabilitation facility admission in the US, and consented to follow-up 3 and 9 months post discharge from inpatient rehabilitation., Interventions: Not applicable., Main Outcome Measures: Participation Assessment with Recombined Tools-Objective (PART-O)-17, FIM Motor and Cognitive scores, Satisfaction with Life Scale, and Patient Health Questionnaire-9., Results: Increasing the percentage of contextualized treatment during inpatient TBI rehabilitation leads to better outcomes, specifically in regard to community participation., Conclusions: Increasing the proportion of treatment provided in the context of real-life activities appears to have a beneficial effect on outcome. Although the effect sizes are small, the results are consistent with other studies supporting functional-based interventions effecting better outcomes. Furthermore, any positive findings, regardless of size or strength, are endorsed as important by consumers (survivors of TBI). While the findings do not imply that decontextualized treatment should not be used, when the therapy goal can be addressed with either approach, the findings suggest that better outcomes may result if the contextualized approach is used., (Copyright © 2019 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the effect of family attendance at inpatient rehabilitation therapy sessions on traumatic brain injury (TBI) patient outcomes at discharge and up to 9 months postdischarge., Design: Propensity score methods are applied to the TBI Practice-Based Evidence database, a database consisting of multisite, prospective, longitudinal, and observational data., Setting: Nine inpatient rehabilitation centers in the United States., Participants: Patients (N=1835) admitted for first inpatient rehabilitation after an index TBI., Intervention: Family attendance during therapy sessions., Main Outcome Measures: Participation Assessment for Recombined Tools-Objective-17 (Total scores and subdomain scores of Productivity, Out and About, and Social Relations), Functional Independence Measure, Satisfaction with Life Scale, and Patient Health Questionnaire-9., Results: Participants whose families were in attendance for at least 10% of the treatment time were more out and about in their communities at 3 and 9 months postdischarge than participants whose families attended treatment less than 10% of the time. Although findings varied by propensity score method, improved functional independence in the cognitive area at 9 months was also associated with increased family attendance., Conclusions: Family involvement during inpatient rehabilitation may improve community participation and cognitive functioning up to 9 months after discharge. Rehabilitation teams should engage patients' families in the rehabilitation process to maximize outcomes., (Copyright © 2019 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

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.

Establishing a health screening protocol is fundamental for successful captive breeding and release of wildlife. The aim of this study was to undertake a parasitological survey focusing on the presence of trypanosomes in a cohort of Regent Honeyeaters, Anthochaera phrygia, syn. Xanthomyza phrygia (Aves: Passeriformes) that are part of the breeding and reintroduction programme carried out in Australia. We describe a new blood parasite, Trypanosoma thomasbancrofti sp. n. (Kinetoplastida: Trypanosomatidae) with prevalence of 24·4% (20/81) in a captive population in 2015. The sequence of the small subunit rRNA gene (SSU rDNA) and kinetoplast ultrastructure of T. thomasbancrofti sp. n. are the key differentiating characteristics from other Trypanosoma spp. T. thomasbancrofti sp. n. is distinct from Trypanosoma cf. avium found in sympatric Noisy Miners (Manorina melanocephala). The SSU rDNA comparison suggests an intercontinental distribution of T. thomasbancrofti sp. n. and Culex mosquitoes as a suspected vector. Currently, no information exists on the effect of T. thomasbancrofti sp. n. on its hosts; however, all trypanosome-positive birds remain clinically healthy. This information is useful in establishing baseline health data and screening protocols, particularly prior to release to the wild.

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.

Bovine venereal trichomonosis caused by the flagellate Tritrichomonas foetus is a notifiable disease in Australia. While, T. foetus is pathogenic in both cattle and cats, it has long been established that the same T. foetus colonises the stomach, caecum and nasal cavity of pigs without apparent clinical significance. Multi-locus genotyping grouped the non-pathogenic porcine T. foetus with the pathogenic 'bovine genotype', rather than with the 'feline genotype' T. foetus. Bovine trichomonosis is now uncommon due to wide-spread use of artificial insemination, however, whether T. foetus remains prevalent in pigs where bovine trichomonosis has been eradicated remains unknown. We surveyed faecal samples from pigs farmed in close proximity with T. foetus-negative cattle. The Modified Diamond's Medium assay used were 77.4% (24/31) positive for trichomonads and 64.50% (20/31) were T. foetus-positive based on real-time PCR and conventional PCR. An axenic reference strain of T. foetus, designated PIG30/1 was established. In addition, a novel trichomonad ITS rDNA, PIG12, closely related to sequences from Trichomitus spp is reported. Multi-locus genotyping at nine loci matched PIG30/1 to the 'bovine genotype' T. foetus. In conclusion, cross-species transmission of T. foetus between pigs and cows from environmental exposure of T. foetus-contaminated pig faeces is unlikely. Domestic T. foetus-positive pigs possess a negligible risk of a successful T. foetus transmission event to cattle., (Copyright © 2015 Elsevier B.V. All rights reserved.)

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.

Fleas of the genus Ctenocephalides are the most common ectoparasites infesting dogs and cats world-wide. The species Ctenocephalides felis and Ctenocephalides canis are competent vectors for zoonotic pathogens such as Rickettsia felis and Bartonella spp. Improved knowledge on the diversity and phylogenetics of fleas is important for understanding flea-borne pathogen transmission cycles. Fleas infesting privately owned dogs and cats from the Czech Republic (n=97) and Romania (n=66) were subjected to morphological and molecular identification and phylogenetic analysis. There were a total of 59 (60.82%) cat fleas (Ctenocephalides felis felis), 30 (30.93%) dog fleas (Ctenocephalides canis), 7 (7.22%) European chicken fleas (Ceratophyllus gallinae) and 1 (1.03%) northern rat flea (Nosopsyllus fasciatus) collected in the Czech Republic. Both C. canis and C. felis felis were identified in Romania. Mitochondrial DNA sequencing at the cox1 gene on a cohort of 40 fleas revealed the cosmopolitan C. felis felis clade represented by cox1 haplotype 1 is present in the Czech Republic. A new C. felis felis clade from both the Czech Republic and Romania is also reported. A high proportion of C. canis was observed from dogs and cats in the current study and phylogeny revealed that C. canis forms a sister clade to the oriental cat flea Ctenocephalides orientis (syn. C. felis orientis). Out of 33 fleas tested, representing C. felis felis, C. canis and Ce. gallinae, 7 (21.2%) were positive for R. felis using diagnostic real-time PCR targeting the gltA gene and a conventional PCR targeting the ompB gene. No samples tested positive for Bartonella spp. using a diagnostic real-time PCR assay targeting ssrA gene. This study confirms high genetic diversity of C. felis felis globally and serves as a foundation to understand the implication for zoonotic disease carriage and transmission by the flea genus Ctenocephalides., (Copyright © 2015 Elsevier B.V. All rights reserved.)

This qualitative, interview-based study assessed the cultural competence of health and social service providers to meet the needs of LGBT older adults in an urban neighborhood in Denver, Colorado, known to have a large LGBT community. Only 4 of the agencies were categorized as "high competency"; 12 were felt to be "seeking improvement" and 8 were considered "not aware." These results indicate significant gaps in cultural competency for the majority of service providers. Social workers are well-suited to lead efforts directed at improving service provision and care competencies for the older LGBT community.

Objectives: Persistently impaired psychosocial functioning has been recognized in many individuals with bipolar disorder. However, existing measures of functional disability have been adapted for use in bipolar disorder based mainly on those developed for use in other conditions. The present study involved the development and validation of a new patient self-report measure specific to bipolar disorder, the Bipolar Functional Status Questionnaire (BFSQ)., Methods: Relevant constructs were identified, evaluated, and refined through an expert advisory panel in conjunction with patient interviews. Questionnaire items were vetted through iterative patient interviews. Psychometric properties were determined based on patient responses from implementation of the proposed 33-item questionnaire in an 11-site study of 596 patients with bipolar disorder across varied phases of illness., Results: Eight constructs were identified as fundamental to functional status in bipolar disorder: cognitive function, sleep, role functioning, emotional functioning, energy/vitality, social functioning, personal management, and sexual functioning. Psychometric validation supported item reduction to a 24-item unidimensional scale, with high internal consistency (coefficient alpha's = 0.93-0.95), high test-retest reliability (intraclass correlation coefficient = 0.86, 95% confidence interval = 0.82-0.89), strong convergent validity with other functional disability measures (r's > 0.70), and highly significant discriminant validity across illness phases, with large effect sizes (Cohen's d > 0.70)., Conclusions: The BFSQ is a psychometrically sound self-report measure that can be used to effectively quantify functional status across different clinical states in patients with bipolar disorder.

Healthy Colombian adult volunteers with no history of leishmaniasis were evaluated for evidence of previous subclinical infection with Leishmania based on the Montenegro skin test (MST). Twelve MST-positive subjects were enrolled in an open-label, uncontrolled clinical trial (the "MST-positive trial") and received three injections of the LEISH-F1+MPL-SE vaccine (consisting of 10 microg recombinant Leishmania polyprotein LEISH-F1 antigen [TSA+LmSTI1+LeIF]+25 microg MPL-SE adjuvant). Sixty-eight MST-negative subjects were enrolled in a randomized, double-blind, controlled trial (the "MST-negative trial") and were randomly assigned to receive three injections of either the vaccine (n=34), 10 microg LEISH-F1 protein alone (n=17), or saline placebo (n=17). In both trials, the study injections were given subcutaneously on Days 0, 28, and 56, and subjects were followed for safety and immunological endpoints. The LEISH-F1+MPL-SE vaccine was safe and well tolerated in MST-positive and MST-negative subjects. In both trials, an IFN-gamma response to the LEISH-F1 antigen at Day 84 was observed in more than half of the vaccine recipients. In the MST-negative trial, the IFN-gamma response was significantly more frequent and of greater magnitude in vaccine recipients than in protein-alone or placebo recipients. An IgG antibody response to LEISH-F1 was observed in all vaccine recipients. In both trials, delayed-type hypersensitivity (DTH) to LEISH-F1 was observed in most of the vaccine recipients. In the MST-negative trial, DTH was significantly higher in vaccine than placebo recipients. These clinical trials of the first defined vaccine for leishmaniasis show that the LEISH-F1+MPL-SE vaccine is safe and immunogenic in healthy subjects with and without evidence of previous subclinical infection with Leishmania.

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.

Assessing patient-reported outcomes (PROs) in clinical trials is of interest to clinicians, patients, regulators, and industry. The use and impact of PROs is a growing area of methodologic research, particularly as they relate to tumor types, biomarkers, and various patient populations and cultures. Both the US Food and Drug Administration (FDA) and European Agency for the Evaluation of Medicinal Products in recent guidance have acknowledged the need to account for treatment-related impact on patient symptoms and/or health-related quality of life (HRQOL). Clinical research likely reflects the informative value of PROs. A search of www.clinicaltrials.gov, the FDA Web site, and product package inserts was conducted to assess the inclusion of symptom assessment and HRQOL within industry-sponsored clinical trials in cancer and approved cancer therapies and their respective product labels. Overall, there were 2,704 industry-sponsored oncology trials, of which 322 (12%) included a PRO measure. Of the 70 FDA new or revised labels, only six package inserts include PRO data. Symptoms were assessed uniformly across the phases of clinical trials, whereas HRQOL assessment increased in the later phases of clinical trials. Collecting PRO data can enhance our understanding of cancer burden and the impact of interventions on patients' lives.

Nitrogen-fixing bacteria were isolated from the rhizosphere of different crops of Korea. A total of 16 isolates were selected and characterized. Thirteen of the isolates produced characteristics similar to those of the reference strains of Azospirillum, and the remaining 3 isolates were found to be Enterobacter spp. The isolates could be categorized into 3 groups based on their ARDRA patterns, and the first 2 groups comprised Azospirillum brasilense and Azospirillum lipoferum. The acetylene reduction activity (ARA) of these isolates was determined for free cultures and in association with wheat roots. There was no correlation between pure culture and plant-associated nitrogenase activity of the different strains. The isolates that showed higher nitrogenase activities in association with wheat roots in each group were selected and sequenced. Isolates of Azospirillum brasilense CW301, Azospirillum brasilense CW903, and Azospirillum lipoferum CW1503 were selected to study colonization in association with wheat roots. We observed higher expression of beta-galactosidase activity in A. brasilense strains than in A. lipoferum strains, which could be attributed to their higher population in association with wheat roots. All strains tested colonized and exhibited the strongest beta-galactosidase activity at the sites of lateral roots emergence.

We report the results of a double-blind, randomized, placebo-controlled clinical trial of a killed whole-cell Leishmania amazonensis candidate vaccine against American cutaneous leishmaniasis (CL) in Colombia. The trial subjects were 2597 healthy volunteers with negative leishmanin skin test (LST) selected from rural Colombian soldiers who were going to patrol endemic areas. They were randomized to receive either three doses of vaccine (n=1295) or placebo (n=1302) given at 20-day intervals. An active and passive case detection system was established to follow-up volunteers for 1 year after vaccination. Safety and efficacy of the vaccine were determined by comparing local and systemic adverse reactions after each dose and the incidence of parasitologically confirmed CL. In the vaccine and placebo groups 101 (7.7%) and 88 (6.8%) volunteers developed CL respectively. The vaccine was shown to be safe but offered no protection against CL caused by L. panamensis in the proposed vaccination schedule.

Background: The incidence of lymph node micrometastases in patients with biliary tract carcinoma is unknown. We evaluated the utility of three antibodies for immunohistochemical (IHC) detection of micrometastatic disease in patients with gallbladder and bile duct carcinoma., Materials and Methods: Surgical specimens from 35 patients with biliary tract carcinoma were evaluated. Histologically involved tissues were stained with the following antibodies using standard IHC techniques: cytokeratin (AE1:AE3), CEA (carcinoembryonic antigen), and EMA (epithelial membrane antigen). The antibodies with the greatest degree of positive staining were then used to evaluate the lymph nodes of patients with histologically negative lymph nodes. Micrometastatic disease was defined as clustered atypical cells <2 mm in size detected only with the use of IHC., Results: All of the primary tumors and histologically positive lymph nodes demonstrated staining with cytokeratin and CEA antibodies, whereas only 83% were positive for EMA. Therefore, cytokeratin and CEA antibodies were used to evaluate histologically negative lymph nodes. Anti-cytokeratin immunostaining detected micrometastatic disease in two patients. Staining with anti-CEA was negative in all specimens. Overall, two of 15 patients with histologically node negative biliary tract carcinoma had occult micrometastases., Conclusion: Cytokeratin immunostaining enables detection of micrometastases in histologically negative lymph nodes in patients with biliary tract carcinoma. Prospective protocols incorporating cytokeratin staining of the lymph nodes may help determine the incidence and clinical significance of occult micrometastatic disease in these patients.

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.

In order to test recombinant Toxoplasma as adjuvant and live vaccine carrier in the infectious disease model of murine experimental leishmaniasis, we engineered the attenuated, temperature-sensitive Toxoplasma gondii strain ts-4 to express the heterologous Leishmania antigen kinetoplastid membrane protein-11 (KMP-11). Transgenic ts-4 clones were obtained which express KMP-11 as cytoplasmatic protein or target it to the secretory pathway of the tachyzoites. Immunization of BALB/c mice with these stably transformed parasites elicited proliferative responses to both T. gondii antigen and recombinant KMP-11. When challenged with Leishmania major, we observed significant protection in animals that had been vaccinated with the KMP-11-expressing ts-4 mutants. The adjuvant attenuated only the onset of the Leishmania infection, but animals were ultimately not able to control the disease. Thus, our findings demonstrate that recombinant Toxoplasma has the potential to serve as an efficient vaccine carrier for cutaneous leishmaniasis. Furthermore, they establish a protective role for the antigen KMP-11 when given in such a vaccine formulation.

Purpose: To evaluate choroidal melanomas in enucleated eyes for the presence of type I estrogen receptors., Methods: Fourteen consecutive eyes with large choroidal melanomas (defined as >16-mm basal diameter and >8 mm thickness) from 14 patients (eight women and six men with a mean age of 57 years; range, 25--74 years) enucleated in accordance with the Collaborative Ocular Melanoma Study (COMS) protocol were investigated. Immunohistochemical techniques were employed to label the choroidal melanomas for the presence of type I estrogen receptors. Each specimen was then evaluated in a masked fashion by an experienced ophthalmic pathologist for positive nuclear staining., Results: No tumors showed immunohistochemical evidence of a type I estrogen receptor., Conclusion: Type I estrogen receptors are not present in choroidal melanoma. Estrogens are not likely to influence choroidal melanoma growth through traditional receptors.

The safety and immunogenicity of an intramuscular (i.m.) and intradermal (ID) formulation of autoclaved Leishmania (Leishmania) amazonensis vaccine was evaluated in 296 volunteers in a randomized, placebo-controlled, double-blind trial in Colombia. There were 4 vaccination groups: i.m. vaccine, i.m. placebo, ID vaccine, and ID placebo. The ID formulations were mixed with BCG as adjuvant at the time of injection. For each group, 3 vaccinations were given with a 20-day interval between injections, and adverse events were monitored at 20 min, and at 2, 7 and 21 days after each injection. BCG-induced adverse reactions resulted in cancellation of the third vaccine administration in the ID groups. Antibody titres did not differ significantly between the groups. Montenegro skin-test conversion was achieved by 86.4% and 90% of the i.m. vaccine group and by 25% and 5% of the i.m. placebo group 80 days and 1 year after vaccination, respectively. A significant increase in mean Leishmania-antigen lymphocyte proliferation indexes was observed after i.m. vaccine immunization, but not after i.m. placebo immunization, 80 days and 1 year after vaccination. Significant levels of IFN gamma but not IL-10 were observed 1 year after vaccination in the i.m. vaccine group compared to the i.m. placebo group. The good safety profile and evidence of Th1 immune reactions due to i.m. vaccination in this phase-I/II study suggest that a population-based phase-III efficacy trial of the i.m. vaccine should be initiated.

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.

Malignant testicular tumors are an important clinical problem, and ultrasound is the most frequently ordered imaging modality once a palpable scrotal mass is discovered. Numerous articles discussing the role of ultrasound in the evaluation of testicular pathology have confirmed the value of preoperative imaging. This article presents a review of imaging literature regarding testicular neoplasms, with an emphasis on correlation of gross and microscopic tumor pathology and imaging findings. Also included are sections on anatomy, epidemiology, histogenesis, and tumor markers.

Objective: To summarize the current literature on the association between biologic prognostic factors and therapeutic implications., Study Design: To illustrate how these biologic factors are determined and how they can affect treatment, three patients' biologic profiles and their implications for the patients' choice of therapeutic approaches were analyzed. Immunohistochemical techniques combined with image analysis was used to evaluate estrogen receptors, progesterone receptors, proliferation index and erbB-2. Visual assessment was used to evaluate P glycoprotein (MDR1), EGFR and p53., Results: Data from the literature stress the importance of biologic profiles for defining tumor behavior and patient management. The examples of patients' biologic factors illustrated the possible importance of these factors for helping to design treatment., Conclusion: Today the data on the association of patient response to chemotherapy and molecular markers are only starting to accumulate. A larger database is needed for a more precise estimation of response probability in order to help physicians decide between treatment options.

Twenty-one pathologists and technicians participated in a study evaluating the variation present in mitotic counts for prognostication of breast cancer. The participants counted the mitotic figures in 20 breast cancer samples from ten high power fields (mitotic activity index, MAI, giving the results in mitotic figures per 10 fields) and also made a correction for field size and area fraction of the neoplastic epithelium to get the standardized mitotic index (volume fraction corrected mitotic index, or M/VV index, giving the result in mitotic figures per square mm of neoplastic epithelium). The difference in variation between the two methods was not big, but the standardized mitotic index (SMI) showed consistently smaller variation among all participants and different subgroups. Experienced pathologists had the highest variation in mitotic counts, and specially trained technicians, the lowest. The efficiency of the mitotic counts in grading (the grading efficiency) was used to evaluate the mitotic counts. In groups without special training for mitotic counts the mean grading efficiency was lower (experienced and training pathologists both on average had the potential to grade 88% of the cases correctly) than in the group specially trained for the purpose (trained technicians had the potential to grade 95% of the cases correctly). Among the specially trained technicians, the grading efficiency was of the same magnitude as the grading efficiency achieved in determining the S-Phase fraction of cells from paraffin embedded breast cancers by flow cytometry in different laboratories. The results suggest that special training is helpful in making mitotic counts more reproducible, and that in trained hands, the mitotic counts give results comparable to more sophisticated methods of determining proliferative activity in breast cancer.

Retroperitoneal paragangliomas are uncommon neoplasms that arise from neural crest cells. Typical retroperitoneal sites of origin include adrenal medulla, organs of Zuckerkandl, and along sympathetic and parasympathetic nerves. We present a case of a woman diagnosed with retroperitoneal paraganglioma treated with debulking, intraoperative radiotherapy and external beam radiation therapy. She experienced a 7-year disease-free interval prior to symptomatic metastatic recurrence. Such remissions are consistent with the natural history for paragangliomas. The purpose of this report and literature review is to summarize the pertinent biologic and therapeutic options for these uncommon tumors.

Flow cytometric studies of archival material from 22 adrenal carcinomas demonstrated aneuploidy in 21 of 22 cases. Heterogeneity of nuclear DNA was found in 14 of the 22 cases. Eight of these showed distinct aneuploid and diploid populations, and 6 showed multiple aneuploid cell lines. The heterogeneity was detected because numerous paraffin-embedded samples of each tumor could be examined. No correlation was found between either aneuploidy or heterogeneous DNA content and patient survival, response to therapy, or hormone secretion.

The current trial was designed to assess whether the addition of prednisone or prednisone + tamoxifen would enhance the therapeutic effectiveness of 1 year of adjuvant CMF therapy. Premenopausal women with ipsilateral axillary node-positive breast carcinoma and known estrogen receptor (ER) status were randomized to receive 1 year of postoperative treatment with 12 28-day cycles of cyclophosphamide, methotrexate, 5-fluorouracil (CMF), CMF plus prednisone (CMFP), or CMFP plus tamoxifen (CMFPT). There were 553 analyzed cases with 188 receiving CMF, 183 CMFP, and 182 CMFPT. The overall time to relapse (TTR) and survival comparisons between the regimens are not statistically different at a median follow-up time of 7.7 years. The major subgroups currently with a suggestive TTR difference are greater than 3N+ (CMFPT greater than CMF, P = 0.07) and estrogen receptor-negative (ER-) greater than 3N+ (CMFPT greater than CMF, P = 0.03). Patients receiving CMFPT appeared to have a superior survival to CMF in the ER- greater than 3N+ cohort (P = 0.02). The following patient characteristics were associated with a significantly longer TTR: decreasing nodal involvement or tumor size, positive ER status, age greater than or equal to 40 years, and decreasing obesity. The favorable effects of decreasing nodal involvement, positive ER status, age 40 years or greater, and decreasing obesity carried over to survival. Development of amenorrhea was also significantly associated with improved survival (P = 0.001). Toxicity was increased by the addition of prednisone to CMF and by the addition of tamoxifen to CMFP. Overall relapse patterns were similar among the three regimens. The results of the current trial do not currently suggest an overall therapeutic benefit for adding prednisone or only 1 year of tamoxifen to CMF adjuvant treatment.

Risk factors for isolated local-regional (LR) recurrence following mastectomy for breast cancer were analyzed in a review of 627 women entered into Eastern Cooperative Oncology Group (ECOG) adjuvant chemotherapy trials between 1978 and 1982. Premenopausal patients were randomized to cyclophosphamide, methotrexate, and fluorouracil (5-FU) (CMF), cyclophosphamide, methotrexate, 5-FU, and prednisone (CMFP), or cyclophosphamide, methotrexate, 5-FU, prednisone, and tamoxifen (CMFPT). Postmenopausal patients were randomized to observation, CMFP, or CMFPT. Median follow-up time was 4.5 years. At 3 years, 225 patients relapsed and in 70 (31% of failures, 11% of all patients) the initial site was LR without distant metastases. In a multivariate analysis, the risk of an isolated LR recurrence significantly correlated with the number of positive axillary nodes, the primary tumor size, the presence of tumor necrosis, and the number of axillary nodes examined. Factors that significantly discriminated between an isolated LR recurrence and distant metastasis were the number of positive nodes and primary tumor size. Patients with four to seven positive nodes or tumor size greater than or equal to 5 cm had a chance of developing an isolated LR recurrence almost equal to the risk of distant metastases. These findings suggest a potential for improved survival in this subset of patients with the addition of postmastectomy radiation to chemotherapy, and continue to emphasize the presence of a group of patients at high risk for isolated LR recurrence despite adjuvant chemotherapy.

Metastatic Leydig cell carcinomas account for less than 0.2% of all testicular cancers, and may be associated with sex hormone production. Leydig cell carcinoma is relatively refractory to radiotherapy and chemotherapy, and median survival of patients with metastatic disease is less than 2 years. Presented are three cases of metastatic Leydig cell cancer, and a review of the literature pertaining to this rare tumor.