Development of an Animal Model of Military-Relevant Traumatic Stress.

INTRODUCTION: Acute Stress Reactions (ASRs) affect a subgroup of individuals who experience traumatic stress. In the context of military operations, such reactions are often termed Combat and Operational Stress Reactions (COSRs). COSRs not only encompass all symptoms of ASRs but also include additional symptoms related to military combat and may develop at a rate higher than the general public experiences ASRs. Despite an obvious need, there are currently no approved pharmacologic treatments or guidelines for ASR and/or COSR. Preclinical rodent stress models and behavioral assessments are used to evaluate pharmacotherapies and elucidate underlying mechanisms. Here, we combined established traumatic stress models to develop a model of traumatic stress relevant to military trauma exposure and measured behavioral outcomes that reflect outcomes observed in ASRs and COSRs. MATERIALS AND METHODS: Adult male rats underwent exposure to either a combination of two or three traumatic stress exposures (e.g., predator exposure, underwater trauma (UWT), and/or inescapable shock) or control procedures. Behavioral performance on the open field, elevated plus maze, and acoustic startle response (SR) was then assessed 24- and 48-hours following stress/control procedures. RESULTS: In Experiment 1, rats were exposed to a two-stressor model, where predator exposure was coupled with UWT. Minor behavioral deficits were observed in SR for stress-exposed rats as compared to controls. In Experiment 2, inescapable shock was added to predator exposure and UWT. Behavioral performance deficits were observed across all behavioral tests. In Experiment 3, procedures from Experiment 2 were repeated with the only major modification being a shortened predator exposure duration, which resulted in performance deficits in SR only. CONCLUSIONS: We found that the three-stressor model of Experiment 2 resulted in the greatest overall behavioral disturbance (both in the number of variables and magnitude of stress effects). Interestingly, behavioral deficits elicited from the shorter predator exposure were distinct from those observed with longer predator exposure times. Together, these results generally suggest that combined preclinical stressors with military-relevant elements result in behavioral performance deficits reflective of post-trauma phenotypes in Soldiers. The present findings support the use of both physical and psychological stressors to model operationally relevant traumatic stress exposure.

Variation in trauma-related behavioral effects using a preclinical rat model of three predator exposure stress.

The underlying mechanisms of trauma-related disorders are challenging to discover and the disorders are difficult to treat, in part due to the complex and varied expressions of response to traumatic stress. These challenges will be easier to overcome as more is understood about the variability in response to trauma. Incorporating assessment of variability into animal models of traumatic stress may allow better translation to clinical research and treatment development. In this study, we characterized variability in behavioral responses following traumatic stress exposure using a predator exposure (PE) animal model. Elevated plus maze (EPM) and acoustic startle response (SR) were used to study avoidance and arousal symptoms in male Sprague-Dawley rats. Behavioral data were compared between control (n = 31) and predator-exposed (n = 30) rats. PE behavior was clustered using k-means principal components analysis. Four clusters and three distinct subgroups were identified and were characterized as avoidant (Cluster 4, 30%), moderately avoidant (Clusters 2 and 3, 49%), and unaffected (Cluster 1, 17%). These results demonstrate that rodent responses to PE are varied, similar to human presentations following traumatic stress, suggesting it may be possible to develop treatment strategies for varied symptom presentations using a preclinical animal model.

Clinical practice and volume trends of inferior vena cava filter usage at a single tertiary care center during a 19-year period.

BACKGROUND: We investigated the clinical practice and volume trends of inferior vena cava filter (IVCF) usage at a single institution for an extended period and identified the potential factors affecting the clinical decision for placement, follow-up, and retrieval. METHODS: An institutional database was queried for IVCFs placed from 2000 to 2018 using the Current Procedural Terminology codes. The medical records were reviewed to evaluate the demographics, economic status, placement indication, IVCF type, follow-up evaluation for retrieval, and retrieval success rates. Statistical analysis was performed using SPSS, and t tests for continuous and χ2 for categorical variables. RESULTS: A total of 3915 IVCFs were placed from 2000 to 2018. The placement of IVCFs had increased steadily from 2000 (127 IVCFs/y), peaking in 2010 at 371 IVCFs/y and representing a 292% increase in IVCF usage. Since 2010, the number of IVCFs placed has steadily declined until 2016 to 2018, with a 426% decrease from the peak. In a subgroup of IVCFs placed for prophylaxis, the total volume trends paralleled a shift in clinical indications, peaking in 2010 and accounting for 45% of all IVCFs placed and then decreasing from 2013 to 2018 to ≤10%. Overall, 989 permanent IVCFs (25.3%) and 2926 retrievable IVCFs (74.7%) were placed during the entire study period. Before dedicated efforts to implement retrieval follow-up visits, the successful retrieval rate was ∼1% from 2000 to 2006 and had increased to ∼10% to 15% from 2007 to 2015, 36.7% in 2016, 40.2% in 2017, and 40.3% in 2018 after implementation of more active retrieval follow-up protocols. The predictors for the lack of evaluation for IVCF retrieval included an extended length of stay (P = .004) and geographic distance (P < .001). CONCLUSIONS: The use of IVCFs during the past 19 years at our institution reflected increased usage from 2000 to 2010, corresponding to an increase in prophylactic placement, followed by a decreasing total volume from 2011 to 2018, largely attributable to decreased prophylactic IVCF placement. Improved retrieval rates were seen after implementation of an active IVCF retrieval program.

Integration of Arts and Humanities in Medical Education: a Narrative Review.

This narrative review aims to identify and review the extant literature describing methods and outcomes of embedding the arts and humanities (AH) into medical school curricula. The Association of American Medical Colleges changed the Medical College Admission Test (MCAT) in 2015 to place new emphasis on the role of liberal arts in the process of developing well-rounded physicians. Consequently, medical schools have been implementing more connections to creative writing, literature, theater, movies, music, and the visual arts into their curricula. To review the current literature, we focused on methods medical educators used to embed content related to AH into their curricula to shape and drive associated learning outcomes. We conducted searches in PubMed, CINAHL, PsycINFO, and ERIC for peer-reviewed articles from 2011 to 2020. The authors selected three dyads in medical humanities and reviewed articles independently followed by discussion to identify thematic links to major findings. Out of 261 articles, a total of 177 full-text articles were reviewed with 34 selected for final inclusion. Our review included articles describing curriculum development and delivery in publications from Australia, Canada, India, New Zealand, and the USA. This review showed medical educators are implementing didactic and experiential instructional approaches to embedding the arts, humanities, and social sciences into the medical school classroom. Medical educators' attempts to embed AH into medical school curricula show promising results. Unfortunately, small sample sizes, short-term interventions, and an over-reliance of subjective assessment measures limit our knowledge of the true impact of these interventions. More rigorous assessments of required and longitudinal coursework are necessary to know the true impact of participation in AH coursework for medical students.

Response and recovery of endocrine, behavioral, and neuronal morphology outcomes after different traumatic stressor exposures in male rats.

Preclinical models of organismal response to traumatic stress (threat of death or serious injury) can be monitored using neuroendocrine, behavioral, and structural metrics. While many rodent models of traumatic stress have provided a glimpse into select components of the physiological response to acute and chronic stressors, few studies have directly examined the potential differences between stressors and their potential outcomes. To address this gap, we conducted a multi-level comparison of the immediate and longer-term effects of two types of acute traumatic stressors. Adult male rats were exposed to either underwater trauma (UWT), predator exposure (PE), or control procedural handling conditions. Over the next 7 days, yoked cohorts underwent either serial blood sampling for neuroendocrine evaluation across the circadian cycle, or repeated behavioral testing in the elevated plus maze. In addition, a subset of brains from the latter cohort were assessed for dendritic spine changes in the prefrontal cortex and basolateral amygdala. We observed stressor-dependent patterns of response and recovery across all measures, with divergence between endocrine responses despite similar behavioral outcomes. These results demonstrate that different stressors elicit unique behavioral, neuroendocrine, and neuro-structural response profiles and suggest that specific stress models can be used to model desired responses for specific preclinical applications, such as evaluations of underlying mechanisms or therapeutic candidates.

Cost and clinical outcomes of postoperative intensive care unit versus general floor management in head and neck free flap reconstructive surgery patients.

PURPOSE: To compare clinical, surgical, and cost outcomes in patients undergoing head and neck free-flap reconstructive surgery in the setting of postoperative intensive care unit (ICU) against general floor management. METHODS: Retrospective analysis of head and neck free-flap reconstructive surgery patients at a single tertiary academic medical center. Clinical data was obtained from medical records. Cost data was obtained via the Mayo Clinic Rochester Cost Data Warehouse, which assigns Medicare reimbursement rates to all professional billed services. RESULTS: A total of 502 patients were included, with 82 managed postoperatively in the ICU and 420 on the general floor. Major postoperative outcomes did not differ significantly between groups (Odds Ratio[OR] 1.54; p = 0.41). After covariate adjustments, patients managed in the ICU had a 3.29 day increased average length of hospital stay (Standard Error 0.71; p < 0.0001) and increased need for take-back surgery (OR 2.35; p = 0.02) when compared to the general floor. No significant differences were noted between groups in terms of early free-flap complications (OR 1.38;p = 0.35) or late free-flap complications (Hazard Ratio 0.81; p = 0.61). Short-term cost was $8772 higher in the ICU (range = $5640-$11,903; p < 0.01). Long-term cost did not differ significantly. CONCLUSION: Postoperative management of head and neck oncologic free-flap patients in the ICU does not significantly improve major postoperative outcomes or free-flap complications when compared to general floor care, but does increase short-term costs. General floor management may be appropriate when cardiopulmonary compromise is not present.

Short and long-term outcomes of three-dimensional printed surgical guides and virtual surgical planning versus conventional methods for fibula free flap reconstruction of the mandible: Decreased nonunion and complication rates.

BACKGROUND: To determine whether virtual surgical planning and three-dimensional printed cutting guides (3D/VSP) improved radiographic bone union compared to conventional methods (CM) in fibula free flap (FFF) reconstruction of the mandibles. METHODS: Retrospective study from the years 2000-2018 at a tertiary hospital. Osseous union was evaluated by a radiologist blinded to each patient's treatment. RESULTS: Two hundred sixty patients who underwent FFF tissue transfer, 28 with VSP and 3D cutting guides. Bony union was not achieved in 46 (20%) patients who underwent CM compared to 1 (4%) of patients with VSP and guides (p = 0.036). FFF complication was significantly higher in CM with 87 patients (38%) compared to three patients (11%) in 3D/VSP (p = 0.005). Median time to bony union for patients who underwent CM was 1.4 years compared to 0.8 years in 3D/VSP. CONCLUSIONS: 3D/VSP reduced the rate of radiographic nonunion and flap-related complications in FFF reconstruction for mandibular defects.

Acute Sialadenitis After Skull Base Surgery: Systematic Review and Summative Practice Recommendations.

BACKGROUND: Sialadenitis is a rare complication of skull base neurosurgery, in which the submandibular gland undergoes acute inflammation with edema after surgery. Although attributable to transient obstruction or manual compression, presentation may be rapidly life-threatening as a result of airway obstruction. Understanding risk factors is limited at present, and no practical management guidelines have been reported. Our objective was to survey the literature and to characterize the associated risk factors, treatment considerations, and overall trends in outcomes for patients experiencing post skull base neurosurgery sialadenitis. METHODS: A search of the Ovid EMBASE, SCOPUS, and PubMed databases from inception through August 2020 was performed via Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Systematic review identified 13 publications describing 18 cases of acute sialadenitis after skull base surgery. We describe the 19th reported case. Commonalities include the need for aggressive respiratory support as intubation or emergent tracheostomy is almost universally required. Risk factors are poorly understood but may include extreme flexion and/or rotation of the head and neck. Outcomes are favorable overall, although secondary complications have been described. CONCLUSIONS: Sialadenitis is a rare but potentially life-threatening complication of skull base neurosurgery, owing to acute loss of airway and the potential for a diverse array of secondary complications.

Prevalence of Surgical, Anesthetic, and Device-related Complications Among Infants Implanted Before 9 and 12 Months of Age Versus Older Children: Evidence for the Continued Expansion of Pediatric Cochlear Implant Candidacy Criteria.

OBJECTIVE: To compare the prevalence of surgical, anesthetic, and device-related complications among infants and older children receiving cochlear implantation (CI). STUDY DESIGN: Retrospective chart review. SETTING: Tertiary academic referral center. PATIENTS: Pediatric patients who underwent CI from November 1990 to January 2020. INTERVENTION: CI. MAIN OUTCOME MEASURES: Surgical, anesthetic, and device-related complication rates were compared by age group (<12 versus 12-23 versus 24+ months with subset analysis of <9 versus 9-11 months). RESULTS: A total of 406 primary pediatric CI surgeries encompassing 482 ears were analyzed, including 45 ears in 23 patients implanted less than 9 months and 89 ears in 49 patients less than 12 months. No anesthetic complications occurred. Postoperative surgical and device-related complication rates were not significantly different among the less than 12, 12 to 23, and 24+ month groups (16% versus 16% versus 12%; p = 0.23) or between the less than 9 and 9 to 11 month groups (22% versus 9%; p = 0.09). Thirty-day readmission was significantly higher for patients less than 12 months compared with patients 24+ months (6% versus <1%; p = 0.011), but was not significantly higher compared with patients 12 to 23 months (6% versus 3%; p = 0.65). Reoperation rates did not differ significantly among the less than 12, 12 to 23, and 24+ month groups (10% versus 7% versus 6%; p = 0.31). CONCLUSIONS: The prevalence of surgical, anesthetic, and device related complications was not significantly different among infants implanted less than 9 or less than 12 months of age when compared with older children. These data provide evidence for the continued expansion of pediatric cochlear implant candidacy criteria to include appropriately selected infants less than 9 months of age.

Language and Audiological Outcomes Among Infants Implanted Before 9 and 12 Months of Age Versus Older Children: A Continuum of Benefit Associated With Cochlear Implantation at Successively Younger Ages.

OBJECTIVE: To compare language and audiological outcomes among infants (<9 and <12 mo) and older children receiving cochlear implantation (CI). STUDY DESIGN: Retrospective chart review. SETTING: Tertiary academic referral center. PATIENTS: Pediatric patients receiving CI between October 1995 and October 2019. INTERVENTION: Cochlear implantation. MAIN OUTCOME MEASURES: Most recent language and audiological assessment scores were evaluated by age group. RESULTS: A total of 118 children were studied, including 19 who were implanted <9 months of age, 19 implanted 9 to <12 months of age, and 80 implanted 12 to <36 months of age. The mean duration of follow-up was 7.4 ±â€Š5.0 years. Most recent REEL-3 receptive (88 ±â€Š12 vs. 73 ±â€Š15; p = 0.020) and expressive (95 ±â€Š13 vs. 79 ±â€Š12; p = 0.013) communication scores were significantly higher in the <9 months group compared to the 9 to <12 months group. PLS and OWLS auditory comprehension and oral expression scores were significantly higher in the <12 months group compared to the 12 to <36 months group. The difference in NU-CHIPS scores between <12 and 12 to <36 months was statistically significant (89% ±â€Š6 vs. 83% ±â€Š12; p = 0.009). LNT scores differed significantly between <9 and 9 to <12 months (94% ±â€Š4 vs. 86% ±â€Š10; p = 0.028). CONCLUSIONS: The recent FDA expansion of pediatric CI eligibility criteria to include infants as young as 9 months of age should not serve as a strict clinical cutoff. Rather, CI can be pursued in appropriately selected younger infants to optimize language and audiological outcomes.

Characterization of novel neutralizing mouse monoclonal antibody JM1-24-3 developed against MUC18 in metastatic melanoma.

BACKGROUND: MUC18 is a glycoprotein highly expressed on the surface of melanoma and other cancers which promotes tumor progression and metastasis. However, its mechanism of action and suitability as a therapeutic target are unknown. METHODS: A monoclonal antibody (mAb) (JM1-24-3) was generated from metastatic melanoma tumor live cell immunization, and high-throughput screening identified MUC18 as the target. RESULTS: Analysis of molecular interactions between MUC18 and JM1-24-3 revealed that the downstream signaling events depended on binding of the mAb to a conformational epitope on the extracellular domain of MUC18. JM1-24-3 inhibited melanoma cell proliferation, migration and invasion in vitro and reduced tumor growth and metastasis in vivo. CONCLUSION: These results confirm that MUC18 is mechanistically important in melanoma growth and metastasis, suggest that the MUC18 epitope identified is a promising therapeutic target, and that the JM1-24-3 mAb may serve as the basis for a potential therapeutic agent.

Fear expression is reduced after acute and repeated nociceptin/orphanin FQ (NOP) receptor antagonism in rats: therapeutic implications for traumatic stress exposure.

RATIONALE: Evaluation of pharmacotherapies for acute stress disorder (ASD) or post-traumatic stress disorder (PTSD) is challenging due to robust heterogeneity of trauma histories and limited efficacy of any single candidate to reduce all stress-induced effects. Pursuing novel mechanisms, such as the nociceptin/orphanin FQ (NOP) system, may be a viable path for therapeutic development and of interest as it is involved in regulation of relevant behaviors and recently implicated in PTSD and ASD. OBJECTIVES: First, we evaluated NOP receptor antagonism on general behavioral performance and again following a three-species predator exposure model (Experiment 1). Then, we evaluated effects of NOP antagonism on fear memory expression (Experiment 2). METHODS: Adult, male rats underwent daily administration of NOP antagonists (J-113397 or SB-612,111; 0-20 mg/kg, i.p.) and testing in acoustic startle, elevated plus maze, tail-flick, and open field tests. Effects of acute NOP antagonism on behavioral performance following predator exposure were then assessed. Separately, rats underwent fear conditioning and were later administered SB-612,111 (0-3 mg/kg, i.p.) prior to fear memory expression tests. RESULTS: J-113397 and SB-612,111 did not significantly alter most general behavioral performance measures alone, suggesting minimal off-target behavioral effects of NOP antagonism. J-113397 and SB-612,111 restored performance in measures of exploratory behavior (basic movements on the elevated plus maze and total distance in the open field) following predator exposure. Additionally, SB-612,111 significantly reduced freezing behavior relative to control groups across repeated fear memory expression tests, suggesting NOP antagonism may be useful in dampening fear responses. Other measures of general behavioral performance were not significantly altered following predator exposure. CONCLUSIONS: NOP antagonists may be useful as pharmacotherapeutics for dampening fear responses to trauma reminders, and the present results provide supporting evidence for the implication of the NOP system in the neuropathophysiology of dysregulations in fear learning and memory processes observed in trauma- and stress-related disorders.

Wide local excision prior to sentinel lymph node biopsy for primary melanoma of the head and neck.

BACKGROUND: Previous wide local excision prior to sentinel lymph node biopsy (SLNB) may have the potential to disrupt lymphatic channels, thus incorrectly identifying the sentinel node. The purpose of this study was to investigate: (1) regional recurrence rates of prior wide local excision compared to other biopsy techniques and (2) survival outcomes in patients with melanoma of the head and neck. METHODS: Between the years 2000 and 2016, 391 cases were reviewed with a median follow-up time of 30 months in a large tertiary care center. Biopsy practices included shave, punch, wide local excision, and narrow margin excisional/Mohs, and associations with time to local or regional relapse and death from melanoma were evaluated. Main outcomes included identification of sentinel lymph nodes, overall survival, and melanoma-specific survival. RESULTS: Of the 391 patients, biopsy patterns were as follows: 77 (19%) unknown biopsy, 30 (8%) prior wide local excision (WLE), 105 (27%) narrow margin excisional biopsy, 69 (18%) punch biopsy, and 110 (28%) shave biopsy. SLNB was successfully identified in all 30 patients whom had a prior WLE. There were 50 regional recurrences in the neck and 27 local recurrences with the median (IQR) at 1.2 years and 1.0 years, respectively. Multivariable associations of type of prior biopsy, depth of invasion, and nodal status with time to regional recurrence, local recurrence, overall survival, and melanoma-specific survival were not significantly different. CONCLUSIONS: Sentinel lymph node biopsy for melanoma of the head and neck can be successfully performed in patients after previous wide local excision.

EUPATI Guidance for Patient Involvement in Medicines Research and Development (R&D); Guidance for Pharmaceutical Industry-Led Medicines R&D.

The importance and merits of greater patient involvement in medicines research and development (R&D) are commonly acknowledged and are thought to offer benefits for all involved parties. It helps to improve discovery, development, and evaluation of new effective medicines, based on the collaborative identification and understanding of unmet needs, research priorities, optimization of clinical study design, outcome measures, and endpoint development. It can result in increased transparency, trust and mutual respect between patients and other stakeholders. This applies to all stages of medicines R&D, from industry-led research, to regulation and licensing of medicines, to appraisal by health technology assessment (HTA) bodies. Integration of patients into the medicines development process needs to be structured and governed by clear rules and modes of operation to be effective and yield the best results for all stakeholders. Existing codes of practice for patient involvement with various stakeholders do not comprehensively cover the full scope of R&D, with the exception of more general statements applicable to interaction. Overarching guidance on meaningful and ethical interaction is missing. One specific aim of the European Patients' Academy on Therapeutic Innovation (EUPATI) was to close this gap through the development of guidance documents for selected stakeholders. Four separate guidance documents were developed, incorporating the results from comprehensive internal and external consultation. They cover patient involvement in: pharmaceutical industry-led medicines R&D; ethics committees; regulatory authorities; HTA. Each guidance suggests where patient involvement could be adopted or strengthened. The EUPATI guidance document for patient involvement in industry-led medicines research and development covers the interaction between patients and the pharmaceutical industry within all functions throughout the medicines R&D lifecycle in relation to medicines for human use. It relates to activities pre-approval and post approval, involving individuals and groups of patients. The guideline distinguishes between the level of expertise in a disease area that is required and the different areas where patient involvement can take place; however, this is not meant to limit involvement, and these opportunities may change and increase over time. This EUPATI guidance document is aimed at the pharmaceutical industry who want to engage patients in R&D activities, however all stakeholders involving patients in pharmaceutical-led medicines R&D should understand and use this EUPATI guidance document.

EUPATI and Patients in Medicines Research and Development: Guidance for Patient Involvement in Regulatory Processes.

The importance and merits of greater patient involvement in medicines research and development (R&D) are commonly acknowledged and is thought to offer benefits for all involved parties. It improves discovery, development, and evaluation of new effective medicines, based, among others, on the collaborative identification and understanding of unmet needs, research priorities, optimization of clinical study design, as well as incorporating patient views in regulatory activities. It fosters increased transparency, trust and mutual respect between patients and other stakeholders and applies to all stages of medicines R&D, inclusive of regulation and licensing of medicines and appraisal by health technology assessment (HTA) bodies. In order to be effective and beneficial for all stakeholders, patient engagement as an integral part of medicines R&D needs clear and mutually agreed rules. Existing codes of practice for patient involvement do not comprehensively cover the full scope of patient engagement in all processes related to R&D. One specific aim of the European Patients' Academy on Therapeutic Innovation (EUPATI) was to close this gap through the development of guidance documents for pharmaceutical industry-led medicines R&D, ethics committees, regulatory authorities and health technology assessment (HTA). The guidance in this article covers patient involvement in the regulatory field and draws on the mature "Framework for interaction between the European Medicines Agency and patients and consumers and their organizations." It expands on the EMA framework, specifically including National Competent Authorities (NCAs). It sets out objectives for patient involvement in medicines regulation and recommends concrete suggested working practices. It is primarily aimed at regulatory authorities wishing to interact with patients or their organizations in their activities but should also be considered by patients/patient organizations planning to collaborate with regulatory authorities.

EUPATI and Patients in Medicines Research and Development: Guidance for Patient Involvement in Ethical Review of Clinical Trials.

Involvement of patients in the research and development process (R&D) of new medicines-in all areas of indications-today is a widely accepted strategy in pharmaceutical industry to ensure relevance and suitability of the treatment under development. This may consist in, but is not limited to, patient input to achieve more patient-friendly protocol design, endpoint, and comparator selection as well as disease-adapted study conditions in a pre- or post-marketing clinical trial. Ethical aspects and especially the balance of benefit and risk in a clinical trial are frequently judged differently by clinical researchers, regulators, ethics committees, and patients due to their different focus. The final assessment of the ethical aspects of a planned clinical trial is provided by an independent ethics committee consisting of physicians and other experts in healthcare and clinical trial methodology as well as of lay persons. The participation of patients in ethics committees is a much-discussed concept, its suitability disputed in many countries, and only limited experience on best practices is available. In order to be effective and yield the best results for all stakeholders, integration of patients into the medicines development process needs to be structured and governed by clear, mutually agreed rules and modes of operation. Communication and collaboration processes need to be systematically implemented to establish transparency, trust and respect between those developing new medicines and their users, respectively between those involved in design and approval of clinical trials and participants. In particular agreement on the ethical aspects of a clinical trial and/or its overall ethical acceptability is a prerequisite before the start of a clinical trial. Existing codes of practice for patient involvement with various stakeholders do not comprehensively cover the full scope of R&D, with the exception of more general statements on interaction. Overarching guidance on meaningful and ethical interaction is missing. One specific aim of the European Patients' Academy on Therapeutic Innovation (EUPATI) was to close this gap through the development of guidance documents for ethics committees, pharmaceutical industry-led medicines R&D, regulatory authorities, and health technology assessment (HTA). This EUPATI "Guidance for patient involvement in ethical review of clinical trials" gives practical recommendations for ground rules and lists options for conditions and practices for involving patients in the work of ethics committees to enable trustful and constructive collaboration whatever the national (legal) framework for patient involvement in ethics committees might be. The guidance sets the collaboration of patients in ethics committees in the broader context of relevance and opportunities for patient input on ethics in the overall medicines R&D and specifically the overall clinical trial process from concept development to trial result reporting in lay summaries. In addition to a presentation of the full text of the Guidance, this article aims at providing additional background information on the development process of the Guidance, as well as insight into the current debate on this topic.

EUPATI Guidance for Patient Involvement in Medicines Research and Development: Health Technology Assessment.

The main aim of health technology assessment (HTA) is to inform decision making by health care policy makers. It is a systematic process that evaluates the use of health technologies and generally involves a critical review of international evidence related to clinical effectiveness of the health technology vs. the best standard of care. It can also include an evaluation of cost effectiveness, and social and ethical impacts in the local health care system. The HTA process advises whether or not a health technology should be used, and if so, how it is best used and which patients are most likely to benefit from it. The importance of patient involvement in HTA is becoming widely recognized, for scientific and democratic reasons. The extent of patient involvement in HTA varies considerably across Europe. Commonly HTA is still focused on quantitative evidence to determine clinical and/or cost effectiveness, but the interest in understanding patients' experiences and preferences is increasing. Some HTA bodies provide support for participation in their processes, but again this varies widely across Europe. The involvement of patients in HTA is determined at the national and regional level, and is not subject to any European-wide legislation. The guidance text presented in this article was developed as part of the work of the European Patients' Academy on Therapeutic Innovation (EUPATI) and covers the interaction between HTA bodies and patients and their representatives when medicines are being assessed. Other EUPATI guidance documents relate to patient involvement in pharmaceutical industry-led research and development, ethics committees, and regulatory authorities. The guidance provides recommendations for activities to support patient involvement in HTA bodies and specific guidance for individual HTA processes. It seeks to improve patient involvement, using the outcomes of published research and consensus-building exercises. It also draws on good practice examples from individual HTA bodies. The guidance is not intended to be prescriptive and should be used according to specific circumstances, national legislation, or the unique needs of each interaction. This article represents the formal publication of the HTA guidance text with discussion about recent progress in, and continuing barriers to, patient involvement in HTA.

Impact of Providing Feed and/or Water on Performance, Physiology, and Behavior of Weaned Pigs during a 32-h Transport.

Transportation at weaning is a complex stressor made up of many factors, including withdrawal from feed and water, which can potentially negatively affect the health and welfare of pigs, especially those already experiencing weaning stress. The objective of this study was to evaluate the effect of weaning and extended transport durations (up to 32 h), with and without the provision of feed and/or water, on pig welfare. Treatment groups included: pigs neither weaned nor transported, control (CON); weaned pigs transported and provided with feed and water (T+); weaned pigs transported without feed and water (T-); weaned pigs transported with only feed (T+F); and weaned pigs transported with only water provided (TRAN+W). The effect of transport (with and without feed and/or water) on weaned pigs was assessed using behavior, performance, and physiology. After a 32-h transport period, pigs transported without water lost markedly more weight than those transported with water ( p < 0.01). Furthermore, the neutrophil to lymphocyte ratio was markedly higher in male pigs transported without water ( p < 0.05). Overall, transportation had a negative effect on pig well-being, especially when water was not provided.

Minority Participation and Well-Being in Majority Catholic Nations: What Does it Mean to be a Religious Minority?

This paper examines the effect of religious majority size on religious minority well-being. Religious minorities face a number of challenges ranging from deliberate discrimination to inadequate worship space and accommodations. Yet for many of the members of religious minority groups, religion remains an important part of community organizing and individual well-being. Given this paradox, it is important to consider the ways that minority status is experienced in different contexts and by different groups. Using data on non-Catholics in majority Catholic nations, this paper demonstrates that the personal benefits of participation in a minority religion are dependent on the size of the Catholic majority. Although religious minorities generally experience health and wellness gains via their engagement with religious communities, the non-Catholic residents of some Catholic nations score higher on self-reports of mental and physical health when they are not actively engaged with their religious tradition. Explanations for this conditional relationship are considered in the discussion of the results.

Effect of Provision of Feed and Water during Transport on the Welfare of Weaned Pigs.

Transportation is a complex stressor made up of factors including weaning itself and withdrawal from feed and water. Therefore, transportation has the potential to negatively impact the health and welfare of weaned pigs. Pigs were transported for 32 h and measures of performance, physiology, and behavior were taken to assess piglet welfare. Treatment groups included pigs not weaned or transported (CON), weaned pigs provided with feed and water (WEAN+), weaned pigs not provided with feed and water (WEAN-), weaned and transported pigs provided with feed and water (TRANS+), and weaned and transported pigs not provided with feed and water (TRANS-). Body weight loss was different among treatments (p < 0.01). CON pigs had a 6.5% ± 0.45% gain in body weight after 32 h. WEAN+, WEAN-, TRANS+, and TRANS- groups all had a loss in body weight of 5.9% ± 0.45%, 7.8% ± 0.45%, 6.5% ± 0.45% and 9.1% ± 0.46%, respectively. The N:L was greater in all weaned pigs at 8 h compared to CON pigs (p < 0.01). WEAN- and transported pigs had significantly higher N:L than CON pigs from 8 h through 16 h, however, all treatment groups were similar to CON pigs after 16 h irrespective of provision of feed and water. Blood glucose levels were lower in transported and/or weaned pigs than CON pigs after 16 h irrespective of the provision of feed and water. TRANS+ females had higher creatine kinase (CK) levels than males (p < 0.05). After a 16 h transport period, TRANS- pigs had higher total plasma protein (TP) levels than all other treatment groups (p < 0.05). Significant changes in behavior were observed during and after transportation, which could also be indicative of stress. Overall, transportation and weaning had a negative effect on performance, physiology and behavior (both during and post-weaning) of pigs, especially when feed and water was not provided. Transporting pigs without feed and water for more than 24 h was a welfare concern as indicated by changes in body weight and physiology measures of stress.