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BackgroundOver the past 30 years, the healthcare industry has increasingly turned its attention to rare diseases. Regulators have emphasized the need for clinical research in this area to be patient-centered. However, there is a lack of evidence concerning whether this need is actually met. In this paper, we aim to address this gap.MethodsFirst, we describe the state of patient-centricity in clinical research in rare diseases based on a targeted literature review. Second, we discuss recommendations from scientific bodies on patient-reported outcome (PRO) measures in rare diseases. Third, we analyze data collected from EMA’s and FDA’s websites concerning rare disease labeling claims and data fromClinicaltrials.govconcerning the use of PRO measures in rare disease pivotal trials. Fourth, we perform an exhaustive literature review on the use of PRO measures in the pharmaceutical industry, including all phases of clinical research, observational/registry studies, and instrument development and validation.ResultsThere is limited information on rare disease patient engagement in study design, recruitment, and retention. None of the initiatives describing methods for developing PRO measures in rare diseases provide the clear guidance clinical researchers need. Only 17.4% of orphan drug labels contain a PRO measure. Less than half of pivotal trials in orphan drugs have a PRO measure as a primary or a secondary endpoint. Although the number of publications about PRO measures in rare diseases has risen in the past fifteen years, our results indicate that substantial improvements are needed to achieve patient-centricity.ConclusionsThe nature and extent of patient engagement in rare disease research is under-documented. The current paradigm for developing and using PRO measures in clinical research is failing to meet the needs of rare disease patients. Not only are PROs rarely used as high-level endpoints in clinical trials or taken into account in labeling claims, they are also under-researched overall – there are too few measures for the multitude of rare diseases. We call for a clear guidance on patient engagement and suggest a realistic approach to the adaptation of PRO strategy to the specific context of clinical research in rare diseases.

Introduction BAY 94-9027 is a newly developed extended half-life product to treat haemophilia, allowing for fewer injections than with standard products. This post hoc analysis aimed to compare physicians’ and patients’ opinions on BAY 94-9027 prophylaxis, and explore how qualitative interview data is aligned with the data from the Haemophilia-specific Quality of Life questionnaire for Adults (Haemo-QoL-A). Methods Exploratory qualitative interviews were conducted with physicians and patients by phone upon the exit of patients from the PROTECT VIII extension phase following a semi-directed guide. In this post hoc analysis, all transcripts were reviewed and reported concepts were compared to assess the level of concordance between physicians and patients. These qualitative data were compared with the Haemo-QoL-A mean global and subscale scores at baseline and end of main phase (36 weeks later). Results Ten physicians and 16 patients (mean age 47 years) from Israel, the Netherlands and the USA were interviewed. Significant improvements were reported by all physicians from baseline [e.g. lower frequency of bleeds (80%), improvement in emotional functioning (90%)], which is in concordance with patients’ reports. The improved confidence reported by physicians cascaded to greater participation in various activities, resulting in a better perceived emotional state and a significant improvement on the Haemo-QoL-A emotional impact subscale score (p = 0.04) between baseline and end of main phase. Most physicians (80%) reported improvement in bleed frequency, as patients did (88%). Improvement in physical functioning or mobility was not consistently reported in this 8-month study. Conclusion Interviewed physicians and patients generally agreed on the beneficial impact of BAY 94-9027, specifically regarding the increased level of self-confidence in patients and its subsequent positive impact on patients’ lives. These findings supported the observed improvement on the Haemo-QoL-A emotional impact subscale. Overall, this study highlights the concordance between physician and patient perspective on the positive experience with BAY 94-9027.

Distress is a factor that can adversely affect quality of life in breast cancer patients. A rapid and non-invasive tool to accurately detect distress is therefore important. The aims of the study were (1) to describe the women’s experiences after having received a breast cancer diagnosis and while awaiting primary surgery, in terms of anxiety and depression, (2) to evaluate the use of the Distress Thermometer (DT) in newly diagnosed breast cancer patients, and (3) to define an optimal cutoff score for the DT for this population. This study involved 436 newly diagnosed patients in the pre-surgery phase. Consent forms and questionnaires were delivered by nurses during the pre-surgery check-ups, in the time between the 4 weeks post-diagnosis and the 2 weeks before surgery. Receiver operating characteristic analysis was used to evaluate the diagnostic accuracy of the DT compared to the Hospital Anxiety and Depression Scale (HADS) and to define an optimal cutoff score for the DT in this specific population. The results showed that the DT is a fast, easy, and well-accepted screening tool in the Italian context of women newly diagnosed with breast cancer, performing well in relation to the HADS. The proposed cutoff score for DT screening in the clinical setting is 4 versus 5. The DT is recommended as a first step in screening, always followed by a more detailed evaluation of psychological functioning.

The aim of this study was to investigate health care professionals’ level of in-depth understanding about the various types and characteristics of stalking. In particular, the study examines knowledge on the characteristics of stalkers and their victims, acted behaviors, and coping strategies used to stop the harassment. The data were collected by means of an ad hoc questionnaire. The sample comprised 210 participants working in local health units in Turin, a large city located in the northern part of Italy. The majority were women (160, 76.2%). The participants were aged 20–64 years, and the mean age was 41.63 years (SD = 11.18). The majority of participants were psychologists (99, 47.1%), 31 (14.8%) were nurses, 31 (14.8%) had an unspecified medical profession, 29 (13.8%) were psychiatrists, and 20 (9.5%) were general practitioners. According to the findings, interventions with male victims of stalking, especially when the stalker is a woman, require attention in particular. Underestimating the stalking experience is a risk, so health care professionals in their interventions must explain to the men the emotive and physical consequences of the victimization. Moreover, in suggesting coping strategies, health care professionals must consider the victim’s fear of reporting the incident not only to law enforcement authorities but also to family and friends. The findings showed that health care professionals need a better understanding of the stalking phenomenon. Education courses are a valuable tool to identify characteristics of the phenomenon, validate existing knowledge, and decrease the level of missing information to develop the skills needed to take appropriate action in cases of stalking.

Background The assessment of health-related quality of life (HRQoL) has seen exponential growth in oncology clinical trials. However, the measurement of HRQoL has yet to be optimised in routine clinical practice. This study aimed at exploring the operationalisation of HRQoL in clinical practice with the goal of reaching a consensus from a panel of physicians. Materials and methods Physicians involved in the management of lung cancer patients in France were recruited to participate in a Delphi study. The study involved three rounds of iterated queries to gain consensus on management aspects of HRQoL, including timing of discussion on HRQoL, which specific domains of HRQoL should be discussed, and what was the most appropriate method of assessment. The threshold adopted for consensus was at least 70% agreement among physicians. A scientific committee reviewed results following each round of the Delphi study. Results A representative panel of 60 physicians participated in this study. Consensus was obtained for HRQoL management at all time points in the patient care pathway. Panellists agreed that HRQoL discussions should occur during routine visits and hospitalisation. The involvement of patients' relatives was also recognised as important, except when discussing side-effects and involvement of a multidisciplinary team. There was a lack of consensus on a systematic assessment for all patients at each visit and no consensus on how HRQoL should be measured in clinical practice. Conclusions HRQoL discussions are considered an integral part in the management of lung cancer patients, and are deemed key to success in patient–physician interaction. Further research is required to harmonise how best to implement HRQoL assessment., Highlights • HRQoL was considered part of routine clinical visits in thoracic oncology by French physicians. • HRQoL was deemed key in the patient–physician interaction during the patient care pathway. • The implementation of the quality-of-life assessment is not yet in place, and the tools to assess it are not yet identified. • Further work should be conducted to harmonise how to best implement and use quality-of-life assessment in routine practice.

Much information is known about the long-term consequences of separation and divorce, whereas there is a paucity of studies about the short-term consequences of such experiences. This study investigates the adoption of dysfunctional behaviors (e.g., insistent telephone calls and text messages, verbal threats, and sending unwanted objects) shortly after a relationship dissolution. A total of 136 participants who declared to have been left by their former partner in the previous 6 months were included in this study (i.e., females: n = 84; males: n = 52; mean age = 30.38; SD = 4.19). Attachment styles were evaluated as explanatory variables when facing a relationship dissolution, in connection with a set of (1) demographic variables (i.e., gender, education, and current marital/relationship status), (2) dysfunctional behaviors, and (3) motivations on the basis of those behaviors. Results showed that a secure or dismissing attachment style, a higher education, and currently married (but awaiting separation) status were the protective factors in adopting such dysfunctional behaviors, while the preoccupied and fearful-avoidant subjects, especially females, tended to adopt dysfunctional behaviors (i.e., communication attempts and defamation) and reported fear of abandonment and need for attention as underlying motivations. Future study on longitudinal aspects of the relationship dissolution processes is required to have deeper insights into this phenomenon. This study sheds light on the relationship between adult attachment styles and the motivations behind the adoption of dysfunctional behaviors after a relationship dissolution.

Background Hazelnut allergy, which is characterized by symptoms that range from mild to severe, is one of the most common allergies in children throughout Europe, and an accurate diagnosis of this allergy is therefore essential. However, lipophilic allergens, such as oleosins, are generally underrepresented in diagnostic tests. We therefore sought to characterize the IgE reactivity of raw and roasted hazelnut oleosins, using the sera of hazelnut‐allergic pediatric patients. Methods Raw and roasted hazelnut oil body–associated proteins were analyzed by means of 1D and 2D electrophoresis and MS. Oleosin IgE reactivity was assessed by immunoblotting with the sera of 27 children who have confirmed hazelnut allergies and from 10 tolerant subjects. A molecular characterization of the oleosins was performed by interrogating the C. avellana cv. Jefferson and cv. TGL genomes, and through expression and purification of the recombinant new allergen. Results A proteomic and genomic investigation allowed two new oleosins to be identified, in addition to Cor a 12 and Cor a 13, in hazelnut oil bodies. One of the new oleosins was registered as a new allergen, according to the WHO/IUIS Allergen Nomenclature Subcommittee criteria, and termed Cor a 15. Cor a 15 was the most frequently immunorecognized oleosin in our cohort. Oleosins resulted to be the only immunorecognized allergens in a subgroup of allergic patients who showed low ImmunoCAP assay IgE values and positive OFC and PbP. Hazelnut roasting resulted in an increase in oleosin immunoreactivity. Conclusion A novel hazelnut oleosin, named Cor a 15, has been discovered. Cor a 15 could play a role in eliciting an allergic reaction in a subgroup of pediatric patients that exclusively immunorecognize oleosins. The high prevalence of hazelnut oleosin sensitization here reported further confirms the need to include oleosins in routine diagnostic procedures.

The strategies that non-profit organizations choose for volunteer engagement and financial sustainability are of the utmost importance for successful work. The main purpose of this study was to investigate feasible strategies for volunteer engagement and financial sustainability. Interviews were conducted to obtain data on the experience of volunteer managers in dealing with volunteers and financial matters together. Qualitative data analysis methods were used to code and analyze the data. Significant themes emerged from the data gathered through interviews that highlighted the strategies for volunteer engagement and financial sustainability chosen by the managers of non-profit organizations. From the manager&rsquo, s perspective, the following strategies were considered important for engaging volunteers at non-profit organizations (NPOs): &lsquo, building the skill sets of volunteers&rsquo, &lsquo, fulfilling ulterior motives&rsquo, and &lsquo, administering a culture of administrative support&rsquo, Moreover, &lsquo, local fundraising preference&rsquo, transparency&rsquo, building trust&rsquo, were regarded as successful strategies for maintaining financial sustainability. The findings of this study showed that, to function smoothly, non-profit organizations need to follow certain strategies to be cautious about volunteers as well as finance. The findings provide fruitful implications for practitioners and policy makers, and these are discussed in the paper. Furthermore, the limitations addressed in the study suggest a future direction for research in terms of study design and more focus on study informants.

The COVID-19 pandemic influenced the work of employees across all continents. This article presents raw data that may be used to describe how the pandemic affected the work of employees in four European countries and how it influenced their job attitudes, feelings and work performance. In total, 726 respondents from Germany, the Czech Republic, Slovakia and Italy filled out an extensive online survey and provided information about changes in their workload, work difficulty, income, social contact, work from home, task performance and organizational commitment during the pandemic, and about the risk of being infected by COVID-19 during their workday. The employees also reported their actual work performance, organizational commitment, job satisfaction, intention to leave and irritation in the time of the pandemic. To reveal factors that might help employees cope with pandemic, the respondents filled out established questionnaires measuring servant leadership of their supervisor, perceived organizational support, social support provided by colleagues, their own occupational self-efficacy, resilience, job crafting and readiness for change. The data is unique as it was collected in a specific situation during the pandemic, when the work of employees was affected by security measures and lockdown introduced by governments in countries where they worked.

Background Patients with chronic conditions are required to take long-term treatments for their disease itself or to prevent any potential health risks. Measuring patient acceptance of their medication should help to better understand and predict patients’ behavior toward treatment. This study aimed to describe the level of patient acceptance toward various long-term treatments in real life using an online patient community. Methods This was an observational, cross-sectional study conducted through the French Carenity platform. All Carenity patient members were invited to complete an online questionnaire including the 25-item ACCEptance by the Patients of their Treatment (ACCEPT©) questionnaire. ACCEPT© measures patient acceptance toward their medication and includes one general acceptance dimension (Acceptance/General) and six treatment-attribute specific dimensions (scores 0–100; lowest to highest acceptance): Acceptance/Medication Inconvenience, Acceptance/Long-term Treatment, Acceptance/Regimen Constraints, Acceptance/Side effects, Acceptance/Effectiveness, and Acceptance/Numerous Medications. Patients included in the analysis were treated adults experiencing any chronic diseases and who responded to at least one ACCEPT© item. Results Among the 4193 patients included in the analysis, more than 270 chronic diseases were represented, amidst which 19 included more than 30 patients. Mean ACCEPT© Acceptance/General score for those 19 diseases were 61.2 (SD = 31.9) for type 1 diabetes, 59.8 (SD = 32.3) for asthma, 56.3 (SD = 34.3) for hypertension, 52.0 (SD = 32.2) for chronic obstructive pulmonary disease, 51.7 (SD = 27.0) for epilepsy, 50.1 (SD = 33.1) for bipolar disorder, 49.9 (SD = 33.1) for type 2 diabetes, 48.6 (SD = 31.6) for multiple sclerosis, 46.1 (SD = 34.5) for Crohn’s disease/ulcerative colitis, 44.3 (SD = 31.5) for depression, 42.8 (SD = 31.5) for lupus, 42.3 (SD = 33.0) for arthrosis, 41.8 (SD = 32.6) for Parkinson’s disease, 40.5 (SD = 32.2) for rheumatoid arthritis, 38.6 (SD = 31.7) for breast cancer, 36.4 (SD = 36.4) for myocardial infarction, 35.8 (SD = 32.0) for ankylosing spondylitis, 34.1 (SD = 32.3) for psoriasis, and 33.7 (SD = 31.7) for fibromyalgia. Conclusions This first of its kind study enabled ACCEPT© data to be collected in real life for a variety of chronic diseases. These data may help in evaluating and interpreting levels of acceptance in future studies and provide valuable insights about patient priorities and current unmet needs.

Globe artichoke (Cynara cardunculus var. scolymus) is a cross-pollinated, highly heterozygous species, which is conventionally propagated vegetatively. A scheme is described here which combines phenotypic with genotypic selection to fast track the development of a seed-propagated variety. The scheme was tested by making three selections, on a phenotypic basis, from a Brazilian seed-propagated variety showing an high phenotypic variation. The genetic relatedness as well as the heterozygosity of the material in study, in respect to standard variety representatives, was initially assessed with a wide set of microsatellite markers. Afterwards, an AFLP-based selection demonstrated to provide a practical and cheap means of conducting marker assisted breeding, which can be easily adopted also in laboratories of small seed companies. The selection approach described here could be readily adopted also to convert current vegetatively propagated landraces into seed-propagated varieties.

BACKGROUND: Interferon-induced expression of programmed cell death ligands (PD-L1/PD-L2) may sustain tumour immuneevasion. Patients featuring MET amplification, a genetic lesion driving transformation, may benefit from anti-MET treatment. We explored if MET-targeted therapy interferes with Interferon-gamma modulation of PD-L1/PD-L2 in MET-amplified tumours.METHODS: PD-L1/PD-L2 expression and signalling pathways downstream of MET or Interferon-gamma were analysed in MET-amplified tumour cell lines and in patient-derived tumour organoids, in basal condition, upon Interferon-gamma stimulation, and after anti-MET therapy.RESULTS: PD-L1 and PD-L2 were upregulated in MET-amplified tumour cells upon Interferon-gamma treatment. This induction was impaired by JNJ-605, a selective inhibitor of MET kinase activity, and MvDN30, an antibody inducing MET proteolytic cleavage. We found that activation of JAKs/STAT1, signal transducers downstream of the Interferon-gamma receptor, was neutralised by MET inhibitors. Moreover, JAK2 and MET associated in the same signalling complex depending on MET phosphorylation. Results were confirmed in MET-amplified organoids derived from human colorectal tumours, where JNJ-605 treatment revoked Interferon-gamma induced PD-L1 expression.CONCLUSIONS: These data show that in MET-amplified cancers, treatment with MET inhibitors counteracts the induction of PD-1 ligands by Interferon-gamma. Thus, therapeutic use of anti-MET drugs may provide additional clinical benefit over and above the intended inhibition of the target oncogene.

Interest in the phenomenon of workplace violence has increased in recent years because such violence is evident in the healthcare sector. The prevalence and consequences of victimization among heal...

To meet the growing social service needs of our societies, the social services and other Volunteer organizations need to understand the needs and motives of their volunteers to keep them retained. ...

Police officers are among the workers most exposed to acute or chronic stressful events, which compromises their psychosocial well-being and physical health. Exposure to traumatic events, human suffering, problematic situations and episodes of violence can cause psychological damage and lead to the development of secondary traumatic stress. The aim of this research is to explore the effect of job demands and job resources on secondary traumatic stress in police officers. To better understand this phenomenon and its consequences in this population, police officers were compared with health care professionals working as first responders. An ad hoc questionnaire was administered to 112 and 286 health care professionals. The findings showed that compared with health care workers, police officers suffer from secondary traumatic stress to a greater extent. Moreover, the results showed that some police officers suffered more than health care professionals regarding certain consequences of secondary traumatic stress, such as negative emotions and burnout. This study suggests implications and offers insights for both police officers and the organizations in which they work: police officer organizations should contribute to preventing the phenomenon of secondary traumatic stress by proposing programmes that implement resilience training and adaptive coping strategies.

ObjectivesThis study aims to analyse, from a descriptive and qualitative point of view, the episodes of violence reported by healthcare workers (HCWs) in a large public Italian hospital. Qualitative analysis permits us to collect the victims’ words used to describe the event and the ways in which they dealt with it. A comparison between genders was performed to better understand what type of different strategies could be used to improve the prevention of workplace violence for HCWs.Design and settingThe retrospective observational study was carried out in ‘Città della Salute e della Scienza’, a complex of four interconnected hospitals situated in Northern Italy. This study analysed aggression data from the 4-year period of 2015–2018 that included all HCW categories. The data were obtained from the aggression reporting form.ParticipantsThe analysed records were supplied by 396 HCWs (3.6% of all HCWs in the hospital).ResultsMale HCWs aged ConclusionsThe findings from this explorative study suggest that there is a gender difference in the characteristics of workplace violence perpetrated by patients, patients’ relatives and visitors and in the way in which these episodes are described. Consequently, it is important for informative and preventive courses to consider gender differences in experiencing a violent episode.

Aims: The aim of this study was to compare victims of one type of cyberstalking (OneType) with victims of more than one type of cyberstalking (MoreType) regarding (1) the impact of cyberstalking and (2) attitudes related to telling someone about the experience of cyberstalking and the coping strategies used by victims. Methods: A self-administered questionnaire was distributed to over 250 students at the University of Torino. Results: About half of the participants experienced at least one incident of cyberstalking. Among them, more than half experienced more than one type of cyberstalking. Victims suffered from depression more than those who had never experienced cyberstalking. No statistically significant difference emerged for anxiety. The coping strategies used by MoreType were more varied than those used by OneType victims of cyberstalking. Moreover, MoreType victims told someone about their victimization more than OneType victims. Conclusion: The work presented suggests implications for health care professionals, police officers, and government. For example, our suggestion is to pay attention to cyberstalking victims and provide flyers in schools, universities, and cafeterias that explain the risk of certain online behaviors and their consequences in physical and emotional spheres.

Background and Objectives: Cancer is a threatening-life disease with a significant psychological burden. The psychological morbidity varies according to the phases of the illness and is influenced by multiple socio-demographic factors, that are useful to consider in order to identify the categories of patients most at risk of developing psychiatric disorders. The present study analyzes, in a sample of women newly diagnosed with breast cancer, the relationships between their levels of anxiety and depression and several socio-demographic characteristics. The study was cross-sectional. Materials and Methods: Four hundred and seventy eight women newly diagnosed with breast cancer completed the Hospital Anxiety and Depression Scale during the pre-surgical phase. Results: Findings show that almost 40% of the sample had clinically relevant anxious symptoms and about a quarter of the sample had significant depressive symptoms. Their prevalence was higher in widows. Moreover, depressive symptoms were higher in older women and anxious symptoms were higher in patients with a lower educational level. In the pre-surgical phase, women can suffer from clinically relevant anxiety and depression, especially the widows, older women, and women with a lower educational level. Conclusions: Identifying the most psychologically vulnerable patients, due to specific socio-demographic characteristics, is essential in order to provide adequate psycho-oncological treatments to the categories of patients, who are most at risk of developing psychopathological concerns.

Understanding the population genetic structure of crop gene pool is a fundamental prerequisite in plant evolutionary biology and plant breeding. Based on this consideration, in this chapter we pursued two main aims. The first was to review the status of the research pointed at deciphering the population structure of the gene pools of globe artichoke. The second was to show how the use of a well-characterized germplasm collection together with deep genotyping could serve the identification of QTLs for traits of agronomic and economic relevance in globe artichoke.

With the growth of patient-reported outcome (PRO) measurement, questions arise regarding how copyright protection applies to PRO instruments in general and to their translations in particular. The main objectives of this reflection paper are: 1) to help authors of PRO instruments understand basic rules of intellectual property and copyright that protect the integrity of their instruments and derivatives; and 2) to provide recommendations to authors and users of PRO instruments to prevent misuse or abuse. National laws on intellectual property (IP) and the international Berne Convention fully apply to PRO instruments since they are creations of the mind. Therefore, the copyright holder / owner / claimant of a PRO instrument, i.e., the person or legal entity who owns the copyright of the instrument, is granted exclusive rights that are divided into two main categories: moral and economic rights. Moral rights are: 1) the right of attribution (or right of paternity), i.e., the right to claim authorship of the work, 2) the right against false attribution, and 3) the right of integrity, i.e., the right to object to any mutilation, deformation or modification of the work. Economic rights represent the exclusive rights of the author to make or authorize reproduction, development of derivative works, distribution and communication to the public. In other words, the PRO instrument’s copyright holder controls access (distribution, reproduction), and authorizes all derivative works, i.e., adaptations (e.g., electronic formats), modifications (e.g., shorter versions), and translations. Hence, the access to and use of an original PRO instrument and its derivatives in any kind of research should always be associated with the identification of its copyright holder. However, in some cases, this identification may be challenging, in particular when copyright ownership is not clearly defined. To prevent ownership conflicts as well as misuse or abuse of PRO instruments, the ISOQOL Translation and Cultural Adaptation Special Interest Group (TCA-SIG) provides recommendations to authors of PRO instruments and their users. In particular, the TCA-SIG recommends that the ownership of PRO instruments and their derivatives should be defined from the beginning (i.e., from the development of the instrument) and along the life cycle of the instrument between all parties involved. These recommendations apply not only to PRO instruments but also to all the other clinical outcome assessments (COAs), since they are also creations of the mind.

Introduction Despite being reported since 1943 as well as being the subject of a large body of literature since that time, no consensus has been reached regarding the etiology of opioid induced hyperalgesia (OIH). It is often described as a paradoxical increased pain response to noxious stimuli due to increased sensitization or an acute tolerance to opioids. Case We report the case of a 60 year old patient on chronic Intrathecal combined fentanyl and Bupivacaine who had worsening pain with increasing doses and improved after weaning off intrathecal opioids. Conclusion OIH has been described in various settings including patients on methadone maintenance therapy, perioperative opioid administration, cancer patients on opioids, and healthy volunteers who are acutely exposed to opioids, including high dose intrathecal opioids such as Morphine and Sufentanil. To our knowledge, no cases of opioid induced hyperalgesia was previously reported in the case of intrathecal Fentanyl.

Background The disability assessment component of the Health Assessment Questionnaire, the HAQ-DI,1 developed in US English, assesses a patient‘s level of functional ability and includes questions of fine movements of the upper extremity, locomotor activities of the lower extremity, and activities that involve both upper and lower extremities. There are 20 questions in eight categories of functioning which represent a comprehensive set of functional activities – dressing, rising, eating, walking, hygiene, reach, grip, and usual activities. The stem of each item asks over the past week ”Are you able to …” perform a particular task. The patient‘s responses are made on a scale from zero (no disability) to three (completely disabled). Objectives To explore the challenges faced during the cultural adaptation of the HAQ-DI, focusing on one simple task, i.e., “Are you able to cut your meat?” in the eating category. Methods The archives of Mapi Language Services were searched and 130 translations were retrieved, representing 13 language families. The translation methods followed either the standard linguistic validation process [i.e., conceptual analysis, dual translation process (forward, backward translation into English), test with patients and clinician review] or the adjusted process in case of countries using national variants of the same language (i.e., Australian English or English used in India).2 Results In most of the target languages, cutting a whole piece of meat presented in one plate was not a cultural issue. However, in vegetarian-driven cultures or countries where cutting meat was performed while cooking, the item had to be adapted and changed to comply both with the local culture and the concept explored by the item (i.e., fine movement of the upper extremity). For instance, an equivalent of “to cut meat while cooking” was chosen in Korean; “to cut meat (when eating or preparing food),” in Bahasa (Indonesia); “to cut raw vegetables,” in Gujarati (India); or “make bite size pieces of your food (e.g., chapatis)” in English for India. Conclusions The close collaboration between the developer and the translation teams was essential in finding appropriate conceptual equivalents of the simple task of cutting meat in 13 different language families. References [1] Bruce B, Fries JF. The Stanford Health Assessment Questionnaire: dimensions and practical applications. Health Qual Life Outcomes. 2003Jun 9;1:20. [2] Mear I, Giroudet C. Chapter 1: Linguistic Validation Procedures. In: Acquadro C, Conway K, Giroudet C, Mear I, editors. Linguistic Validation Manual for Health Outcome Assessments. Lyon, France: Mapi Institute; 2012. p. 15–117. Disclosure of Interest None declared

The purpose of the study is to evaluate the extent to which a retrospectively conducted translatability assessment (TA) could identify the items previously singled out during the validation study as having poor content validity or poor measurement performance. This study was performed with the intent of supporting evidence of the usefulness of TA early in the PRO development process. The Weight module of the Youth Quality-of-Life Instrument (YQOL-W) was used for this appraisal of translatability.Two linguists, blinded to the design and results of content validation and psychometric analyses, conducted a TA on the 32-item version of the YQOL-W taken into cross-sectional validation for item reduction. TA results were categorized into (1) issues relating to target culture (cross-cultural issues) and (2) issues relating to the structure of the original questionnaire (structural issues). Items for possible revision or deletion were identified. We compared the results of the TA with the content validity and psychometric results and decisions to eliminate items after cross-sectional validation.Content validation identified seven of the 32 items to be dropped, and psychometric analyses including the 25 remaining items highlighted an additional four to be eliminated, yielding a final instrument with 21 items. Out of these 11 dropped items, TA had identified nine as problematic (82 %) and the developer was advised to drop five of them (45.4 %). In addition, TA results highlighted the need to change the original formulation of eight items for semantic reasons and identified two instances where alternative wording should be used for translation purposes without any change to the original formulation.Our study showed that translatability assessment confirmed problematic issues in items previously identified as having poor content validity or poor measurement performance. In general, a translatability assessment offers the possibility for the identification of alternative formulations for translation purposes, modifications of original formulations to optimize subsequent translations efforts, and the early detection and discussion of irrelevant or inappropriate items.

Background Phenylketonuria (PKU) is a rare genetic disorder caused by a defect in the metabolism of phenylalanine (PHE) resulting in elevated blood and brain PHE levels, and leading to cognitive, emotional, and psychosocial problems. The phenylketonuria – quality of life (PKU-QOL) questionnaire was the first self-administered disease-specific instrument developed to assess the impact of PKU and its treatment on the health-related quality of life (HRQL) of patients and their caregivers. Available in four versions (child, adolescent, adult and parent), the PKU-QOL was simultaneously developed and validated in seven countries [i.e., France, Germany, Italy, The Netherlands, Spain, Turkey and the United Kingdom (UK)]. The objectives of our study were to develop and linguistically validate the PKU-QOL questionnaire for use in the United States (US). Methods The UK versions served as a basis for the development of the US English PKU-QOL questionnaire. The linguistic validation process consisted of 4 steps: 1) adaptation of the UK versions into US English by a translator native of US English and living in the US; 2) a clinician review; 3) cognitive interviews with patients and caregivers to test the appropriateness, understandability and clarity of the US translations; and 4) two proof-readings. Results The adaptation from UK to US English revealed the usual syntactic and idiomatic differences between the two languages, such as differences in: 1) Spelling, e.g., “dietician” (UK) vs. “dietitian” (US), or “mum” (UK) vs. “mom” (US); 2) Syntax or punctuation; and 3) Words/expressions use, e.g., “holidays” (UK) vs. “vacation” (US), or “biscuits” (UK) vs. “crackers” (US). The major issue was cultural, and consisted of using a different terminology to describe PKU treatment throughout the questionnaires. The clinician, with the patients and the caregivers, during the interviews suggested to replace “supplement and amino-acid mixture” or “supplements” with “medical formula.” This wording was later changed to “medical food” to be consistent with the terminology used in current US published guidelines. Conclusions The translation of the UK English PKU-QOL questionnaire into US English did not raise critical semantic and cultural issues. The PKU-QOL will be valuable for US healthcare providers in individualizing treatment and managing patients with PKU.

Aims: Liver steatosis is the most common benign form of non-alcoholic fatty liver disease. It might be a risk factor for hepatocellular carcinoma, either (i) by causing fibrosis, which highly predisposes to hepatoma, or (ii) by being an early precursor of carcinoma, although it is usually considered not to be pre-neoplastic. We investigated Research Article British Journal of Medicine & Medical Research, 3(4): 1773-1785, 2013 1774 the genomic profile of liver samples from patients with fatty liver disease. Study Design & Methodology: Copy number variation was investigated by array-CGH, using the Human Genome 244K catalogue array (Agilent Technologies), and changes validated by quantitative polymerase chain reaction analysis. Results: The analysis of liver biopsies from 17 patients, 10 of whom had histological diagnosis of non-alcoholic fatty liver disease, showed differences in the type of variants in patients with steatosis compared to those without steatosis at several chromosome bands, including 3q29, 6p2, 11q11 and 22q11. Conclusion: The genomic copy number changes we have demonstrated suggest that genomic structural variations may be associated with the pathogenesis or the evolution of steatosis.

A simple validated LC-MS/MS-based method was set up to detect milk contamination in bakery products, taking the effects of food processing into account for the evaluation of allergen recovery and quantification. Incurred cookies were prepared at eight levels of milk contamination and were cooked to expose all milk components, including allergenic proteins, to food processing conditions. Remarkable results were obtained in term of sufficiently low LOD and LOQ (1.3 and 4 mg/kg cookies, respectively). Precision was calculated as intra-day repeatability (RSD in the 5-20% range) and inter-day repeatability (4 days; RSD never exceeded 12%). The extraction recovery values ranged from 20% to 26%. Method applicability was evaluated by analysing commercial cookies labelled either as "milk-free" or "may contain milk". Although the ELISA methodology is considered the gold standard for detecting allergens in foods, this robust LC-MS/MS approach should be a useful confirmatory method for assessing and certifying "milk-free" food products.

Background: The BHQ is a new health-related quality of life questionnaire, developed in British English for patients with bronchiectasis. Objectives: The objectives of this study were to present the results of the translation of the BHQ into 11 languages, i.e., 9 Indo-European (Dutch for Belgium and The Netherlands, English for the USA, French for Belgium and France, German, Italian, and Spanish for Spain and the USA), one Japonic (Japanese), and one Sino-Tibetan (Mandarin). Methods: In each country, the following translation method (i.e., linguistic validation) was used: 1. In-depth analysis of the original (i.e., concept definition) and suggestion of translation alternatives; 2. Forward/backward translation step (or adaptation for English and Spanish versions); and 3. Review by a clinician. Results: The translation process did not reveal any cultural issues since most of the concepts assessed were cross-culturally relevant. The main difficulties consisted in finding conceptual equivalents to the response choices designed as Likert-type scales in 7 points (e.g., “All of the time” to “None of the time”). In all countries, translators ensured that the continuity of time was kept between all versions using either adverbs or synonyms (e.g., “Always” for “All of the time”). Items 2, 5 and 10 generated most discussion across languages for idiomatic or syntactic reasons. The clinicians9 review proved useful to clarify the concept of “clear chest” in item 4, i.e., meaning “chest clear of sputum or congestion,” and led to changes in wording. Conclusion: The rigorous translation methodology was essential in producing 11 translations of the BHQ conceptually equivalent to the original.

The objectives of this study were to finalize, develop the scoring, and explore the psychometric properties of the ACCEPTance by the Patients of their Treatment (ACCEPT©) questionnaire, as well as to provide the first elements for its interpretation and guidance for its future use. ACCEPT© was finalized according to reference methods including testing in a pilot study, i.e., a multi-center, observational, longitudinal study conducted in France, in collaboration with a network of pharmacists. Principal component analysis using Varimax rotation was performed. The loadings of items on components in the principal component analysis were used to inform item selection. Validity of the measurement model of ACCEPT© was confirmed using Multi-trait/Multi-item Analysis based on item-scale Spearman correlations. Internal consistency reliability of the questionnaire was assessed by determining the Cronbach’s α coefficient. Linear and logistic regressions were used to identify predictors of general acceptance, and to study predictors of persistence. A total of 189 patients were included. The final version of ACCEPT© is composed of 25 items, distributed in seven dimensions providing a comprehensive appraisal of acceptance of long-term medication, with six scores measuring acceptance of treatment specific attributes and one score measuring general treatment acceptance. The measurement properties of ACCEPT© were overall fairly satisfactory. Regressions showed that Acceptance/Effectiveness is a predictor of general acceptance. However, no predictor of persistence could be identified. The self-administered ACCEPT© questionnaire is a valid and reliable instrument for the assessment of patients’ acceptance of long-term medication. Disease-specific and large prospective studies are needed to assess the ability of ACCEPT© to predict persistence with treatment.

For more information, please contact: Caroline Anfray canfray@mapigroup.com  It is worth mentioning that, in 2007, of 3,000 occasions on which developers, publishers, or users of PRO instruments submitted requests for information or asked for help from the Mapi Research Trust’s PRO Information Support Team,1 38% were questions about copyright or conditions of use. The most frequently asked questions were: “Who should be contacted to get permission to use a questionnaire, an existing translation or to develop a new translation of a PRO questionnaire?” or “Who is the copyright holder?” Thirty-four percent were about practical information about the instruments with questions such as: “Is this the latest version of the instrument?”, “Does the translation reflect the original questionnaire?” or “Is the translation validated?”

Currently, haemophilia care aims to provide the best possible quality of life for individuals living with this chronic disease. Many factors are known to influence treatment adherence, including treatment satisfaction. Health-related quality of life (HRQoL) and treatment satisfaction are, therefore, important outcomes in clinical trials and clinical practice. As individuals' perception of their well-being often differs from that of their physician, it is recommended that self-report instruments are used to assess patient-reported outcomes (PROs). The way that the impact of haemophilia is perceived by the patient and their family can be different, so it is important to assess how parents perceive the impact on their children. A series of PRO instruments have been developed, adapted to different age groups and parents of patients with haemophilia. To allow the instruments to be used internationally, culturally adapted and linguistically validated translations have been developed; some instruments have been translated into 61 languages. Here, we report the process used for cultural adaptation of the Haemo-QoL, Haem-A-QoL and Hemo-Sat into 28 languages. Equivalent concepts for 22 items that were difficult to adapt culturally for particular languages were identified and classed as semantic/conceptual (17 items), cultural (three items), idiomatic (one item), and grammatical (one item) problems. This has resulted in linguistically validated versions of these instruments, which can be used to assess HRQoL and treatment satisfaction in clinical trials and clinical practice. They will provide new insights into areas of haemophilia that remain poorly understood today.

Resumen El dermatofibrosarcoma protuberans (DFSP) es un tumor cutaneo, localmente agresivo, que afecta a adultos jovenes o de edad media. Se han descrito diferentes formas histologicas, siendo la mixoide una de las mas infrecuentes. Microscopicamente esta constituido por una neoformacion que ocupa la dermis e hipodermis, de predominio mixoide, con areas perifericas conformadas por haces de celulas fusiformes, de crecimiento infiltrativo, que expresan el marcador inmunohistoquimico CD34 de forma difusa. Presentamos por primera vez un DFSP mixoide en un dedo de la mano izquierda de una nina de 14 anos, de mas de 10 anos de evolucion. Se trata del primer caso infantil de DFSP mixoide en dicha localizacion. Este subtipo histologico se ha descrito fundamentalmente en las extremidades de adultos, siendo excepcional en ninos. Se comenta el diagnostico diferencial con otros tumores mesenquimales mixoides CD34 positivos.

Multiplex ligation-dependent probe amplification (MLPA) and array- comparative genomic hybridization analysis have been proven to be useful in the identification of submicroscopic copy-number imbalances in families with nonsyndromic X-linked intellectual disability (NS-XLID). Here we report the first description of a child with mild intellectual disability and a submicroscopic duplication at Xp22.12 identified by MLPA with a P106 MRX kit (MRC-Holland, Amsterdam, Netherlands) and further confirmed and characterized with a custom 244-k oligo-array, fluorescence in situ hybridization, quantitative polymerase chain reaction (qPCR), and immunoblotting. This 1.05-megabase duplication encompasses 7 genes, RPS6KA3 being the only of these genes known to be related to ID. The proband was an 8-year-old boy referred to the genetics unit for psychomotor retardation and learning disabilities. Both maternal brothers also showed learning difficulties and delayed language during childhood in a similar way to the proband. These boys also carried the duplication, as did the healthy mother and grandmother of the proband. The same duplication was also observed in the 5-year-old younger brother who presented with features of developmental delay and learning disabilities during the previous year. Increased RPS6KA3/RSK2 levels were demonstrated in the proband by qPCR and immunoblotting. To our knowledge, this is the first family identified with a submicroscopic duplication including the entire RPS6KA3/RSK2 gene, and our findings suggest that an increased dose of this gene is responsible for a mild form of NS-XLID.

Background: We describe a 65-year-old patient with adult attention deficit hyperactivity disorder [ADHD], poorly controlled by adderall XR, and generalized pain from fibromyalgia syndrome [FMS]. The patient's pain did not respond to amitriyptyline, lidoderm patch, percocet, diazepam, metaxalone, ibuprofen, or gabapentin.Findings: Her pain related to FMS responded dramatically to atomoxetine, a selective norepinephrine reuptake inhibitor approved by the Food and Drug Administration for ADHD treatment, which was substituted for adderall XR in this patient. The patient reported a 60 percent pain reduction and marked improvement of her functional status, as well as improvement regarding her ADHD.Conclusions: We suggest that atomoxetine might be a useful adjunct in the treatment of FMS, and possibly neuropathic pain conditions.

The importance of patient perspectives on disease impact and response to therapy is increasingly recognized. Patient-reported outcomes (PROs), including health-related quality of life (HRQL), provide information on the effectiveness of medical interventions that cannot be obtained using objective clinical measures. For drug development, PROs such as symptom questionnaires are accepted by the European Medicines Agency (EMEA) and US Food and Drug Administration (FDA) in the approval process. HRQL assessments can help to establish the niche for a new product to support marketing efforts. Utilities can also be derived from health outcomes measures for cost-effectiveness analyses required by health plans for granting drug reimbursement. Because they more closely reflect routine clinical care, effectiveness studies are often a superior setting than traditional randomized controlled trials (RCTs) for conducting comprehensive PRO assessments to determine the real-world impact of therapy on symptoms and other aspects of everyday life. Screening, quality of care, self-reported adherence to treatment, and patient monitoring are important potential applications of PROs in effectiveness studies. However, well-known limitations of effectiveness studies also apply to PROs; these sometimes include a lack of randomization, controls, and blinding. It may be difficult to obtain patient compliance and clinician assistance with PRO assessments in a real-world setting. PRO data may be biased by nonrandom patient dropout, errors in timing of PRO assessments, and the environment in which questionnaires are administered. Additionally, the drug development schedule often requires outcomes results before effectiveness studies can be conducted. Addressing these difficulties during study design and the use of short and targeted questionnaires will improve the usefulness and feasibility of PRO measures in effectiveness studies. Drug Dev. Res. 67:193–201, 2006. © 2006 Wiley-Liss, Inc.