The majority of studies on prevalence and characteristics of residents in difficulty have been conducted in English-speaking countries and the existing literature may not reflect the prevalence and characteristics of residents in difficulty in other parts of the world such as the Scandinavian countries, where healthcare systems are slightly different. The aim of this study was to examine prevalence and characteristics of residents in difficulty in one out of three postgraduate medical training regions in Denmark, and to produce both a quantifiable overview and in-depth understanding of the topic.N = 157) were invited to participate in an e-survey about residents in difficulty. Survey data were combined with database data on demographical characteristics of the background population (N = 2399) of residents, and analyzed statistically (Chi-squared test (Χ2) or Fisher’s exact test). Secondly, we performed a qualitative interview study involving three focus group interviews with residency program directors. The analysis of the interview data employed qualitative content analysis.We performed a mixed methods study. All regional residency program directors  belated and inconsistent feedback on the resident’s inadequate performance, and 2) the perceived culturally rooted priority of efficient patient care before education in the workplace. These two themes were emphasized by the program directors as the primary underlying causes of the residents’ difficulty.More work is needed in order to clarify the link between, on the one hand, observable markers of residents in difficulty and, on the other hand, immanent processes and logics of practice in a healthcare system. From our perspective, further sociological and pedagogical investigations in educational cultures across settings and specialties could inform our understanding of and knowledge about pitfalls in residents’ and doctors’ socialization into the healthcare system. International literature reports that 3–10 % of doctors in postgraduate medical education struggle to comply with educational requirements and occupational adaptation . These rWhat are the demographic characteristics of the residents in difficulty?What are the reported behavioral problems and the presumed contributory causes of the residents in difficulty as they are perceived by the residency program directors?In this paper, we will examine the prevalence and characteristics of residents in difficulty in Denmark across hospital specialties. The main research questions addressed are:We will begin the paper with a description of the methods and the context of the study. Then we will present the results of the data collection, and finally we will discuss the results in relation to two particular issues: 1) the personal characteristics of residents in difficulty; and 2) malfunctioning of the healthcare system as an educational arena. The paper is based on the results from a mixed methods study across all specialties in hospitals in the region sampled. Although Denmark is a small country, the results from this study may shed light on the apparent discrepancy between two components of residency training in hospitals: the strong emphasis on individual attributes as explanations for the resident’s difficulty and the culturally rooted anticipated social relationship between the resident and the workplace environment.The study was designed as a mixed methods study. The study comprised of an e- survey, a database study, and a qualitative interview study. A mixed methods strategy is appropriate when a researcher intends to approach a research question or a topic from different angles . In thisPostgraduate medical education in Denmark is governed by the Danish National Board of Health and amounts to 8–9 years of enrolment in a residency program. The program includes two parts: 1) 1 year in basic programs in which the resident is employed in different clinical departments for a period of 6 months in each department; and 2) 5–6 years in a specialist program in which the resident is employed in alternating clinical departments for a period of 6–36 months in each. Most residents start at a regional hospital and then after 12–24 months they shift to a university hospital department. A typical residency program introduces the resident to a variety of clinical specialties and after 2 years it centres around one specialty. The completion of the specialist program, including approved competencies and mandatory courses, authorizes the resident to practice as a specialist doctor. The Danish healthcare system is dependent on most residents in Denmark eventually becoming specialist doctors and, accordingly, most residents anticipate reaching a specialist doctor position after the completion of the residency program. Because the residency program takes place in clinical departments, each participating department is obliged to nominate one of the clinical consultants in the department to direct and manage the residency program in the department . These rn = 157) across all specialties appointed in the northern postgraduate medical training region in Denmark.Participants in the study were all residency program directors (Permission for data extraction and handling was sought and approved by the Danish Data Protection Agency (J.nr. 2013-41-1794), and due to the non-biological and non-sensitive nature of the data it is exempted from the rules of the Danish Research Ethics Committee.The e-survey study consisted of a questionnaire that was distributed to all 157 residency program directors in the above-mentioned region. The questionnaire was divided into three parts. In the first part, the residency program directors were asked about department demographics and how many residents in difficulty were identified in their departments in 2012. In the second part, the residency program directors were asked to respond to a sequence of questions regarding their most recent experience with a resident in difficulty. The questions concerned: 1) demographic characteristics of the resident in difficulty ; 2) the residency program directors’ perception of the resident’s behaviour; and 3) the residency program directors’ perception of contributory causes to the resident’s difficulties. Similar to the studies of Tabby and colleagues  and Yao Χ2) or Fisher’s exact test statistics.In order to be able to compare residents in difficulty with the background population , we collected database data on demographics of all residents in the region for the calendar year 2012. We extracted information from the database ‘Evaluer.dk’ on selected variables such as age, gender, and specialty. Hence, in the following paragraphs of the paper we refer to two groups: 1) the population in focus: the residents in difficulty in 2012 (the e-survey data); and 2) the background population: all residents in 2012 (the database data). The differences in distributions in the two groups  were tested using either a Chi-squared test  the different types of interventions applied in the remediation of a trainee in difficulty and 6) the emotional strains  on the residency program director, is located elsewhere. Finally, we will compare the quantitative and qualitative data.Of the 157 invited respondents, 115 73.2 %) completed the e-survey. The respondents reported the prevalence of residents in difficulty in the region to be 6.8 %  in 2012. There were no statistically significant differences in the prevalence of residents in difficulty by type of specialty, when specialty was categorized into four main groups – internal medicine, surgery, general practice, other . The respondents saw between zero and nine residents in difficulty in their departments in 2012, with a median of one problem resident per department. Whilst there were no differences in the gender distribution between residents in difficulty and the background population  of the most recent residents in difficulty respondents had had experience with were identified as having difficulties within the first 3 months in the department, and 16 % (16/100) were identified as struggling even before their first day in the department. However, the difficulties were not acted upon by the departments until the third or fourth year in specialty training.According to the respondents, the most common behavioural characteristics of residents in difficulty related to lack of competence in the leader/administrator role and in the professional role. More specifically, these residents had difficulty in completing tasks within a reasonable time frame; they did not take sufficient leadership in collaborative situations: they did not show an adequate understanding of their own role and abilities; and they did not act adequately in stressful situations Table .Table 3BWhen asked about the perceived causes for the resident being in difficulty, the respondents generally tended to list personal attributes of the residents, such as insecure/nervous behaviour and lack of necessary motivation, as the main causes. Less frequent causes identified were lack of basic knowledge and skills, and stressors in the personal life of the resident Table .Table 4AThe types of interventions used to help residents in difficulty in the respondents’ departments are listed in Table In addition to the general findings from the e-survey and database study, the focus group interviews unveiled another important layer of details about residents in difficulty.“They enjoy their work”; “They take responsibility for their own learning”; “They quickly become a part of the team” and “They easily readjust and adapt to new demands” (focus group 1).“They are curious, investigative, and willing to learn” and “They have to be bold, because they need to cross their own comfort zone in order to learn something” (focus group 2).“They are professional”; “They are able to communicate with everybody about everything, and they show that they are able to pick up new things” and “They have the will and the motivation to learn” (focus group 3).In total, 22 residency program directors  participated in the focus group interviews. We invited the residency program directors to compare behaviours and characteristics of residents in difficulty and successful residents. Similar to the results of the e-survey and database study, the residency program directors highlighted differences in personal attributes of residents in difficulty. Furthermore, the program directors described the successful residents in shorter sentences and with keywords, whereas the descriptions of residents in difficulty were longer and included more complex explanations concerning contextual characteristics of each resident’s workplace. The extracts below summarize the residency program directors’ descriptions of the successful residents  as persons who are willing to learn and are able to adapt to new circumstances and surroundings.Laying low or vanishing while on duty: “Some residents hide while on duty; they lay low and stay anonymous for some time until they find out what’s going on here” (focus group 3).Poor patient communication skills: “I gave feedback to some of the residents at the emergency course because their professionalism and their patient communication skills were poor: ‘Now, let’s bang the venous catheter into your arm’, one of them said, and also even more crude things. This is not the way to communicate with patients! But surprisingly, the residents were stunned by my feedback” (focus group 2).Inflated confidence: “Soon we became aware that this resident had a quite different self-image and much grander thoughts about own skills and capacities than we had. And it took a long time before we managed to evaluate this problem. We discovered that the resident had been allowed to skim over his previous appointments without any consequences. Although the previous places of appointment have had some conversations with him, he wouldn’t comply with the suggested changes (focus group 2).Emotionally affected by the job: “For some residents, the distinction between being a professional and being personal had disappeared. When you ask them, for instance, how they perceive the word empathy, some of the residents have not considered that the capacity to understand a person does not include being compassionate and emotional about this person. When you engage emotionally with your patients you risk acting inappropriately” (focus group 3).Cannot prioritize the daily tasks: “Some residents try to keep several balls in the air, but they cannot complete anything, because they always take on new tasks. And then you discover that they have not managed to complete half of the tasks of the daily program, because they took on too many tasks” (focus group 3).Lack key competences and skills: “You may have a problem in the department when a resident apparently complete the outpatient clinic with a large number of patients on schedule, but nobody really knows what is going in there…I think many colleagues have troubles about the dilemma figuring out exactly how skilled the resident is or if the resident is too hasty and slipshod in the outpatient clinic” (focus group 3).Lack of cooperative skills that are relevant in the local setting: “[It has been difficult to cooperate with] a few residents with a background in other cultural settings where you don’t …  … where you have a power relation between doctors and nurses and other staff, so that for instance a doctor does not act on nurses’ instructions or on female doctors’ instructions for that matter (focus group 2).In comparison, the residency program directors’ descriptions of the behavioural characteristics of residents in difficulty (code 2: behaviours and characteristics of residents in difficulty) were more complex; thus the analysis of code 2 resulted in seven subcodes that sum up the residency program directors’ accounts. Below, each of the seven subcodes are illustrated by an extract from the focus group interviews.In the focus group interviews, the residency program directors were offered the opportunity to explain their accounts by exemplifying specific cases of residents in difficulty. These cases  illustrated that most residents in difficulty exhibit several of the above-mentioned behavioral characteristics in different combinations. The described diversity and complexity of the residents in difficulty accentuates the fact that identifying one exact difficulty and designing adequate remediation is indeed perceived as a multifaceted challenge by the residency program directors we interviewed.The presumed contributory causes of the difficulties (code 4: contributory causes to the residents’ difficulty) were many and diverse. Thus, the analysis of code 4 resulted in 10 subcodes that sum up the residency program directors’ accounts. The subcodes are related to personal attributes similar to the above-mentioned behavioural characteristics and to social, cultural, and/or organizational matters. For example, they include workplace-related traumatic episodes, illnesses (own or in the family), cultural differences (residents from other countries), a generation gap, and many short-term appointments in different departments during residency training. However, two of the ten contributory causes were mentioned numerous times in all focus group interviews and stood out as prime underlying reasons for residents ending up in difficulty. The extracts below illustrate these two causes:Cause 1:Belated and inconsistent feedback on the resident’s inadequate performance“But it’s also much easier to just send the doctor back in the system to the next appointment. So, it is very hard for us to start this thing about a resident in difficulty, and in general, actually to terminate the resident’s training. So, everything calls for closing your eyes and letting time pass” (focus group 1).“We are simply too nice and too neat, and it is inappropriate in this context because we do not dare tell the truth” (focus group 1).“The question is: Does it become a threat to the resident if you say it early in the appointment?” (focus group 2).so much trouble accepting that this is a resident that just cannot make it here” (focus group 3).“Well, it took 6 months before the residency program director dared mention that there could be a problem, and it’s really, really hard. We have “And residents who are helpful and always get up and take the call, and always assume an extra call and make the outpatient clinic work smoothly – these residents are very useful for our system, but sometimes we (the senior doctors) don’t know the quality of their work or what is really happening in the outpatient clinic when we are not there. And then it can be difficult to argue for your concerns, if you are the only one saying that ‘I have a feeling that there is something wrong professionally with that resident’. Then the collective acknowledgements are delayed, because the resident in difficulty is nice to have in the ward [because the person is helpful] regardless of his or her lack of competencies” (focus group 3).Cause 2:The perceived culturally rooted priority of efficient patient care before education in the workplacenot supposed to [swear word] educate people, I’ll join you when I’m finish operating’” (focus group 1).“Being a culture bearer (as we are) may also be in this respect to ensure to create enough time for training. Who would otherwise create it than ourselves? The problem is that we may not just agree on how much time for training, because we might consider our own and our department’s interests to be more important. So when you go to meetings, then you’ll hear sometimes … and it is not because it is only surgeons, but it can often be surgeons, and they do not come to our supervisory meetings because ‘I don’t have [swear word] time, I am supposed to [swear word] operate, and I am “But changing a culture, that’s really what the problem is. The departments have a huge responsibility for those so-called ‘residents in difficulty’. The residents all have high GPA’s from high school, they have undergone the longest of the hardest education at university, so it’s not real jerks we receive from medical school, but they may have some personality weaknesses and infirmities, which means that they must be guided along the way” (focus group 2).“If the surgical training, for instance, is not sufficiently systematic, then the residents risk ending up in difficulty without necessarily self-inducing the situation. You have to know how the education system in that surgical department is running, otherwise remediation does not help, because if things [training and educational activities] are too sloppy in a department, you will come up with a plan that runs just as sloppily, and nobody is helped by that” (focus group 3).Both of these causes (cause 1 and cause 2) relate to sociocultural challenges that involve workplace culture including social relationships among colleagues, ingrained habits in the department, and cases of consultants de-emphasizing their educational responsibilities.Problem residents are found across most specialties in different countries at a prevalence of about 3–10 % , 4–6, 24The findings seemed to disclose a discrepancy between, on the one hand, the reported behavioural problems, being a matter of the expected social relationship between the doctor and his/her workplace environment, and, on the other hand, the strong emphasis on individual attributes as the explaining causes of the difficulties. Previous studies also emphasize individual attributes as the explaining causes of difficulties. For example, Long  listed sIn addition, supervisors may feel that they lack sufficient skills to approach the resident in difficulty effectively, i.e. that they could be opening a can of worms which could potentially make things worse , 36, 37,Our study cannot determine the reason for the belated and inconsistent feedback on residents’ inadequate performance and unprofessional behavior. However, belated and inconsistent feedback may be caused by inadequate evaluation systems; for example, Adams and colleagues  showed tWe must emphasize that identifying individual characteristics in a resident does not solve the problem of residents in difficulty in general. Hence, we agree with Tabby and colleagues : “We do When we teach, in addition to the knowledge and skills we intend to convey, we also transmit a vast array of behaviours, beliefs, and attitudes we never intended to share, or even recognized we were imparting—the so-called “hidden curriculum”. […] Nevertheless, it is important to recognize that trainees and physicians in all training and practice settings at times display unprofessional behaviors, including those designated as role models.Considering all the findings in our study, residents in difficulty seem to be a sociocultural challenge that exists because of immanent processes and complications at an individual level  and a systemic level (in the workplace culture) respectively. As shown in our study, two contributory causes were mentioned numerous times in all focus group interviews and stood out as prime underlying reasons for residents ending up in difficulty: belated and inconsistent feedback on the residents’ inadequate performance and the perceived culturally rooted priority of patient care before education in the workplace. These two causes seem to be embedded in a workplace culture and at a system level. Thus they demand a sociocultural rather than an individualistic approach in order to be explained and eventually solved. However, research on the perceived underlying causes of residents in difficulty mainly concern personal attributes of the resident, whereas the workplace culture is rarely examined. Only a few previous studies report that sociocultural challenges at a system level are prior causes of individually based causes of difficulty in medical education , 32. In doxa (from Greek: common belief) of a system, that is the common sense “accepted by all as self-evident” and the dominant social norm  in a system such as the healthcare system, appears to resist change even if change seems to be required, because doxa is closely connected to powerful positions and intractable traditions in the system. If this is the case, and if we intend to prevent systems from contributing to causes that generate residents in difficulty, then the remediation of ‘a workplace culture in difficulty’ seems as imperative as the remediation of individual residents in difficulty.Most interestingly, the authors found that the majority of program directors felt that their efforts at remediation aimed at the individual level of the resident were only somewhat successful. An important question left unanswered by the abovementioned studies is the option of remedying ‘a workplace culture in difficulty’, since these studies did not examine residents’ workplace cultures. Our results indicate that program directors were well aware of the influence of disturbing workplace cultures on the socialization of residents. Thus our results support a most interesting ethnographical study by Szymczak and Bosk  that demOur study has limitations. The main weaknesses include the limited population in the study. We only included program directors from one of three postgraduate medical training regions in Denmark, and although we had a relatively high response rate (73.2 %), we cannot conclude that our results represent Danish program directors’ perceptions of residents in difficulty in general. Also, the limited number of focus group interviews may pose a restriction to our aim to grasp the general perceptions among program directors across different specialties and regions in Denmark. However, we consider data gathered in this way to be worthwhile to pursue and include in examinations of respondents’ beliefs and experiences of complex phenomena, such as residents in difficulty.Despite these limitations, out study provides important insights into the dual nature of difficulties for residents in the healthcare system: while personal attributes and behavioural characteristics of the individual resident may serve as observable markers in the process of identifying a resident needing remediation and support, sociocultural problems in terms of belated feedback on inadequate performance and a perceived priority of efficient patient care before education in the workplace may well explain why some residents end up in difficulty.The results of this mixed method study showed the prevalence of residents in difficulty was 6.8 %. We found no statistically significant differences in the prevalence of residents in difficulty by type of specialty. According to the residency program directors, the most common behavioural characteristics of residents in difficulty are related to lack of competence in both the role as leader/administrator and the professional role. The results also showed that two important themes related to the workplace culture of the resident in difficulty were belated and inconsistent feedback on the resident’s inadequate performance, and the perceived culturally rooted priority of efficient patient care before education in the workplace. These two themes were emphasized by the program directors as the primary underlying causes of the residents’ difficulty. More work is needed in order to clarify the link between, on the one hand, observable markers of residents in difficulty and, on the other hand, immanent processes and logics of practice in a healthcare system. From our perspective, further sociological and pedagogical investigations in educational cultures across settings and specialties could inform our understanding of and knowledge about pitfalls in residents’ and doctors’ socialization into the healthcare system.


In addition, this biosensor exhibited satisfactory repeatability, reproducibility, anti-interference properties and stability. Besides, the sensor achieved the detection of hydroquinone in lake water.NiCu alloy nanoparticle-loaded carbon nanofibers (NiCuCNFs) were fabricated by a combination of electrospinning and carbonization methods. A series of characterizations, including SEM, TEM and XRD, were employed to study the NiCuCNFs. The as-prepared NiCuCNFs were then mixed with laccase (Lac) and Nafion to form a novel biosensor. NiCuCNFs successfully achieved the direct electron transfer of Lac. Cyclic voltammetry and linear sweep voltammetry were used to study the electrochemical properties of the biosensor. The finally prepared biosensor showed favorable electrocatalytic effects toward hydroquinone. The detection limit was 90 nM (S/N = 3), the sensitivity was 1.5 µA µM Nowadays, metal nanoparticles have become widely utilized in electrochemical sensing and biosensing applications, which can be attributed to their rich electronic properties, high surface area, great mechanical properties, and excellent chemical stability . Among vet al. prepared Pd-Ni/CNF composites and found that Pd-Ni alloy showed improved electrocatalytic activity for sugar oxidation [Various techniques have been employed to prepare alloy nanoparticles, including electrodeposition , laser axidation .in situ detection.Hydroquinone is a type of environmental pollutant that can be found in the human diet, medicines and cosmetics . It is vIn this study, we prepared NiCu alloy nanoparticle-loaded carbon nanofibers (NiCuCNFs) by a combined electrospinning and thermal treatment method. Then, a NiCuCNFs, Lac and Nafion mixture was deposited on a glass carbon electrode (GCE) surface to construct a novel biosensing platform. The NiCuCNFs helped achieve the direct electron transfer (DET) of Lac. Meanwhile, the obtained biosensor was used to detect hydroquinone and showed low detection limit, high sensitivity, good selectivity, and excellent stability. Moreover, the biosensor demonstrated that it can be applied to the detection of hydroquinone in real water environments.w = 150,000 g·mol−1) was obtained from Pfaltz & Bauer Inc. . N,N-dimethylformamide (DMF), hydroquinone, Nafion (10 wt % dispersion in water), copper acetate and nickel nitrate were also all obtained from Sigma-Aldrich . PH 5.0 0.1 M acetate buffer solution was prepared as the test solution.Laccase was purchased from Sigma-Aldrich . Polyacrylonitrile , Nafion (1.5 wt %) and NiCuCNFs (0.3 mg·mL−1) were mixed together and coated onto a polished GCE surface to fabricated the biosensor. During the process, NiCuCNFs were firstly dispersed into acetate buffer with the help of ultrasonication. NiCuCNFs suspension, 40 µL of Nafion and 15 mg of Lac was then mixed and magnetically stirred for 1 h. Eventually, 10 µL of the mixture was coated onto the polished GCE surface to fabricate a Lac-NiCuCNF-Nafion modified GCE (Lac-NiCuCNF-Nafion/GCE). The dried Lac-NiCuCNF-Nafion/GCE was stored at 4 °C.Lac  and a high-resolution transmission electron microscope  were employed to observe the morphology of NiCuCNFs. A SuperX Energy Dispersive Spectrometry  was used to characterize the elemental mapping of NiCuCNFs. X-ray diffraction  in a 2θ range of 10°–80°) was employed to analyze the chemical compositions of NiCuCNFs.−1, and sensitivity 1 × 10−5 A·V−1. The buffer solution was deoxidized for 20 min before all of electrochemical experiments to create a nitrogen ambient except the linear sweep voltammetry experiments for the biosensor.Electrochemical experiments were conducted using a DY2300 potentiostat . The electrochemical tests were carried out by using a three-electrode cell, the biosensor electrode was used as the work electrode, platinum wire was used as auxiliary electrode and Ag/AgCl electrode was used as reference electrode. For the linear sweep voltammetry experiments, the experiment parameter was set as following: linear frequency 60 Hz, scan rate 0.1 V·sca. 310 nm (. 310 nm c.ca. 25.6° was ascribed to the (002) plane of carbon [ca. 44.1° and 50.9° were respectively assigned to the crystal planes (111) and (200) of NiCu alloy, which was identical with the reported result [XRD characterization was used to characterize the chemical constitution of NiCuCNF. f carbon . The pead result . Besidesl planes 1 and ca. 0.4 V and 0.1 V (vs. Ag/AgCl), respectively, which could be ascribed to the direct electrochemistry behavior of Lac. The formal potential (E°′) is around 0.25 V and the peak-to-peak separation (ΔEp) is 300 mV at 100 mV·s−1. This demonstrated that the DET of Lac was achieved by the NiCuCNFs by linking Lac active center to GCE surface.Epa) and cathodic peak potentials (Epc) shifted to more positive positions and more negative positions, respectively, with the change of scan rate, indicating the quasi-reversible electrochemical reaction process. Based on the Laviron equation [vs. log(scan rate) , R is the thermodynamic gas constant (8.314 J·K−1·mol−1), T is the temperature (298 K). From the above equations, α was calculated to be 0.5, n was 1. The electron transfer rate constant  c. Besiden = 1, α = 0.5, the value of −1. The surface coverage  of electroactive species on the electrode was calculated by the formula Q = nFAГ, Q is the charge (C), F is the Faraday constant, A is the electrode area (cm2), and n is the transfer electron number. The surface coverage of electroactive laccase was calculated to be 2.38 × 10−10 mol·cm−2. This value is larger than the value reported in literature (1.3 × 10−11 mol·cm−2) [ol·cm−2) , which sLinear sweep voltammetry (LSV) was applied to study the biosensor response to hydroquinone. −1, the detection limit (S/N = 3) was 90 nM. The detection linear range was 4 × 10−7–2.37 × 10−6 M (ΔI = 2.8(±0.1) + 1.5(±0.065)C; r2 = 0.9902), here ΔI is the peak current (µA) and C is the concentration (µM). The repeatability, reproducibility, anti-interference and stability of Lac-NiCuCNF-Nafion/GCE was investigated by adding 1.5 µM hydroquinone in acetate buffer solution by LSV. The relative standard deviation (RSD) value for six successive measurements was 1.8%, implying a good repeatability. To study the reproducibility of biosensor, five Lac-NiCuCNF-Nafion/GCE modified electrodes were respectively prepared under the same condition and the RSD value was calculated to be 3.7%, which demonstrated that the Lac-NiCuCNF-Nafion/GCE possessed acceptable reproducibility.To investigate the anti-interference properties of Lac-NiCuCNF-Nafion/GCE, its LSV response towards different phenolic compounds were examined. It can be seen from The stability of Lac-NiCuCNF-Nafion/GCE biosensor was also studied, and the result is shown in The practical application of the Lac-NiCuCNF-Nafion/GCE biosensor was also investigated by using untreated water from Lake Raleigh . Herein, a recovery experiment was used and repeated for five times and the results are displayed in In summary, NiCuCNFs were synthesized by a combined method of electrospinning and thermal treatment. Subsequently, NiCuCNFs with Lac, Nafion and a GCE were integrated to construct a novel biosensing platform. The electrochemical experiments indicated that the DETof Lac could be achieved by NiCuCNFs. The resultant Lac-NiCuCNF-Nafion/GCE biosensor showed stronger electrocatalysis toward hydroquinone than Lac-CuCNF-Nafion/GCE and Lac-NiCNF-Nafion/GCE due to the better sensibilization of NiCuCNFs. The as-prepared biosensor was employed to detect hydroquinone and showed satisfactory detection results with a low detection limit, high sensitivity and wide linear range. Besides, the biosensor also showed good repeatability, reproducibility, anti-interference properties and stability. The biosensor was further employed to detect hydroquinone in lake water samples and achieved satisfactory recoveries. NiCuCNFs thus offer new opportunities for the construction of other enzyme-based biosensors for the analysis of environmental pollutants in the future.


Objectives: To determine Internal Medicine residency program compliance with the Accreditation Council for Graduate Medical Education 80% pass-rate standard and the correlation between residency program size and performance on the American Board of Internal Medicine Certifying Examination.Using a cross-sectional study design from 2010-2012 American Board of Internal Medicine Certifying Examination data of all Internal Medicine residency programs, comparisons were made between program pass rates to the Accreditation Council for Graduate Medical Education pass-rate standard. To assess the correlation between program size and performance, a Spearman’s rho was calculated. To evaluate program size and its relationship to the pass-rate standard, receiver operative characteristic curves were calculated.Of 372 Internal Medicine residency programs, 276 programs (74%) achieved a pass rate of ≥80%, surpassing the Accreditation Council for Graduate Medical Education minimum standard. A weak correlation was found between residency program size and pass rate for the three-year period . The area underneath the receiver operative characteristic curve was 0.69 , suggesting programs with less than 12 examinees/year are less likely to meet the minimum Accreditation Council for Graduate Medical Education pass-rate standard .Although a majority of Internal Medicine residency programs complied with Accreditation Council for Graduate Medical Education pass-rate standards, a quarter of the programs failed to meet this requirement. Program size is positively but weakly associated with American Board of Internal Medicine Certifying Examination performance, suggesting other unidentified variables significantly contribute to program performance. Electronically published data were obtained from the ABIM website, with permission to use the data granted from the Director of Research Analysis at the ABIM. This study was evaluated by the University of Pittsburgh IRB for ethical approval, and was deemed non-human-subject research.Data were directly obtained from the ABIM website.Descriptive statistics were performed to compare Internal Medicine residency program performance with the ACGME 80% pass-rate standard. To assess for differences in program pass rates for Internal Medicine and Internal Medicine-Pediatrics examinees, a Chi-square test was used.To determine the correlation between residency program size and program performance, a Spearman’s rank correlation was used. The number of program examinees during the three-year study period was used as a representation of program size since the overall number of trainees in each program could not be identified in the ABIM database. The proportion of trainees in each program during the three-year period who passed the examination was used as the measure of program performance.To further evaluate the relationship between program size and examination performance, receiver operating characteristic (ROC) curves were prepared. An ROC curve is a plot of the sensitivity and 1-specificity across the range of residency size cutoff points derived from 2 x 2 matrices.A total of 424 training programs were included in the analysis, including 372 (87.7%) Internal Medicine residency programs  and 52 (12.3%) combined Internal Medicine-Pediatrics residency programs (756 examinees), for a combined total of 20,654 examinees. All (100%) of the programs met the inclusion criterion.In total, 17,867 of 20,654 examinees passed the ABIM Certifying Examination, with an overall pass rate of 86.5% There was no difference in performance between Internal Medicine examinees (pass rate = 86.5%) and combined Internal Medicine-Pediatrics examinees . Of the 372 Internal Medicine residency programs, 276 (74.2%) had a three-year ABIM Certifying Examination pass rate of at least 80% while 96 (25.8%) programs had a pass rate of less than 80%. The mean pass rate for Internal Medicine Residency programs was 85% ± 10%. The mean number of examinees per program during the study period was 53 ± 34. A scatter plot of program pass rates and program size with the resultant compliance with the ACGME 80% pass-rate standard is shown in The Spearman’s rank correlation (ρ) between program size and performance was 0.19 (p < 0.001). The ROC analysis is graphically shown in There were 118 unique program sizes used in generating the nonparametric ROC curve during the study period (range [10-164]). The area underneath the nonparametric ROC curve was 0.69  (p < 0.001). The residency program size cutoff point that maximized sensitivity and specificity was 12 examinees per year. The optimal 2 x 2 matrix is shown in In this study investigating the relationship between the ABIM Certifying Examination with Internal Medicine residency program compliance with the ACGME 80% pass-rate standard and program size, 74% of programs were compliant and 26% were not compliant with the minimum standard. The percentage of both Internal Medicine and combined Internal Medicine-Pediatrics residency programs achieving the minimum ACGME 80% pass-rate standard is consistent with prior work in Pediatrics.,We also found a weak correlation was found between ABIM Certifying Examination scores and program size, suggesting a number of additional unidentified programmatic variables are contributing to the variation in program success with the ABIM Certifying Examination. We identified an association between performance on the ABIM Certifying Examination and Internal Medicine residency program size, similar to our prior work in Pediatrics and Surgery, revealing that larger program size is associated with improved performance.,Additionally, our results showed that programs with less than12 examinees/year are statistically less likely to meet the minimum ACGME 80% pass-rate standard. Using the area underneath the ROC results, we identified statistically significant discrimination between the ABIM certifying examination and program size in relation to the ACGME 80% pass-rate standard - this means that size can be used as an independent predictor of ABIM certifying examination pass rates. This size cut-off is identical to a recent study in Pediatrics that showed residency programs with 12 or more examinees/year satisfied the ACGME pass-rate standard.These findings are important. In the context of the changing “milestone” evaluations, duty hour reform, and resultant changes in clinical care delivery models, understanding residency program factors that may be associated with high or low performance on the ABIM certifying examination are vital to improve the overall education and training of our future healthcare workforce.We found that a majority of Internal Medicine residency programs were compliant with the ACGME 80% pass-rate standard on the ABIM Certifying Examination. Larger residency programs were associated with increased pass rates and programs with less than 12 examinees per year were less likely to comply with the ACGME pass-rate standard. Although program size is associated with performance on the ABIM certifying examination, several other currently unidentified factors are contributing to high performance. Additional studies are required to identify these additional factors to inform strategies implemented by applicants, current resident trainees, and residency programs to improve the quality of performance on this examination.The authors declare that they have no conflict of interest.


In example, a total of 15.482 individuals died from road traffic accidents in Iran between 1999 and 2000.3 To decrease the number of accidents and death among all ages around the World the World Health Organization (WHO) focuses on this problem and set up the „Decade of Action for Road Safety 2011-2020“ in May 2011.Trauma remains the number one cause of death for the youngest half of the population and is responsible for more productive years of life lost than cancer, stroke, and heart disease combined.4 It was first set up in 1986 in Canada to act against the high and increasing number of road traffic victims. The program brings together groups within the hospital, from external agencies and victims of previous injuries, exposing youth to the potential physical and psychological impact that results from a traumatic injury. As the first center in the European Union (EU) this systematic approach to injury prevention was implemented into a trauma center in Germany in 2011. We like to introduce a 1-day in-hospital injury awareness and prevention program for youth aged 15 years and older called: The P.A.R.T.Y. program (Prevent Alcohol and Risk-Related Trauma in Youth).In a three month proof-of-concept we invited three different school classes to join the P.A.R.T.Y. program at our trauma center over a period of three month (one class per month) and raised a questionnaire including 6 different questions about the setting of our program and additionally we wanted all students to grade each station of the program. Fifty-eight students between fifteen and sixteen years of age attended the program during the pilot strategy in 2011. After attending the program the students evaluated it by giving each part of the trauma circle a grade between 1 and 6 . 58% (n= 34) of all students rated the program best grade (1) and 41 % (n= 24) with second grade. Grades between three and six were not awarded by the students who attended the program. Injury prevention strategies are shown to reduce the number of road traffic injuries in youth. The program is already part of injury prevention strategies in North America, Australia, Japan and Brazil. We proofed, that this program can also be set up in a level one trauma unit in Germany. We think that the P.A.R.T.Y. program can be integrated into the daily routine of trauma centers around the world to address the important topic of injury prevention.


Parental well-being can be seriously impacted during the challenging perinatal period. Most research and support services focus on perinatal psychopathology, leaving a need for programs that recognize and enhance the strengths and well-being of parents. Furthermore, fathers have received minimal attention and support relative to mothers, despite experiencing perinatal distress. New parents have limited time and energy to invest in program attendance, and web-based programs provide an ideal platform for delivering perinatal well-being programs. Such programs are globally accessible, available at any time, and can be accessed anywhere with an Internet connection.This paper describes the protocol of a randomized controlled trial investigating the effects on first-time parents’ perinatal well-being, comparing two versions of the online program Baby Steps.The clinical trial will randomize 240 primiparous mother-father couples to either (1) Babycare, an online information-only program providing tips on selected childcare issues, or (2) Well-being, an online interactive program including all content from the Babycare program, plus parental well-being-focused content with tools for goal-setting and problem solving. Both programs will be supported by short message service (SMS) texts at two, four, seven, and ten weeks to encourage continued use of the program. Primary outcomes will be measures of perinatal distress and quality of life. Secondary outcomes will be couple relationship satisfaction, parent self-efficacy, and social support. Cost-effectiveness will also be measured for each Baby Steps program.Participant recruitment commenced March, 2015 and continued until October, 2015. Follow-up data collection has commenced and will be completed May, 2016 with results expected in July, 2016.Perinatal distress has substantial impacts on parents and their infants, with potential to affect later childhood adjustment, relationships, and development. This study aims to test the impact of a highly accessible online program to support parental coping, and maximize the well-being of both parents. By including fathers in the program, Baby Steps has the potential to engage and support this often neglected group who can make a substantial contribution to familial well-being.Australian & New Zealand Clinical Trials Registry: ANZCTR12614001256662; https://www.anzctr.org.au/ Trial/Registration/TrialReview.aspx?id=367277 (Archived by WebCite at http://www.webcitation.org/6ibUsjFIL) However, screening and preventive programs for perinatal depression have not been universally available [The perinatal period is challenging for parents, and the changes and demands encountered during this life transition can seriously impair parents’ well-being. The impact of these challenges is well-recognized in mothers with postpartum depression rates of approximately 20% in Australian women . Most nevailable , and havvailable . Lack ofvailable . An accePostpartum distress has significant and wide-ranging consequences. In mothers, postpartum distress affects attachment , child dIn addition to significant costs to family well-being, perinatal distress has high economic costs. The annual health costs associated with perinatal depression and anxiety could be up to AUD $70 million in new mothers and AUD $16 million in new fathers, if their baby was delivered in 2012 . The cosMany mothers prefer psychosocial treatments during the postpartum period, especially while breastfeeding . Rapid aThere is growing evidence, however, that interventions may not always require substantial clinician involvement to reduce distress. A single face-to-face psychoeducational session with a maternal and child health nurse was found to reduce depression and anxiety in women without psychiatric histories . AnotherOnline interventions may overcome these uptake barriers, as the Internet is a highly accessible and cost-effective vehicle for the delivery of flexible and sustainable support. In 2012-2013, 83% of Australian households had Internet access , and 89%The Internet has already proven feasible for screening postpartum depression in mothers . Further. However, few universal strategies for preventing perinatal distress and enhancing well-being have been evaluated in rigorous, large-scale studies [The perinatal period is a time of transition , offerin studies .Online programs targeting prevention of postpartum depression are in their infancy. A fully-automated program developed for pregnant women presented psychological strategies across 44 short sessions . InformaAlthough some programs addressing the prevention of postpartum depression in women have succeeded in engaging fathers ,44,45, fTo date, no study has trialed a web-based intervention targeting perinatal well-being in both mothers and fathers, nor has a related cost-effectiveness analysis been conducted. This proposed study addresses these gaps, and constitutes one of few trials that focus on well-being and universal prevention, rather than the treatment of established depression. Due to this novelty, our results are likely to have wide application. Electronic programs have the potential to alleviate maternal and paternal distress, and help recent parents enjoy the enriching and exciting experience of early parenthood by increasing access to effective support at minimal cost. By addressing parents’ well-being and supporting childcare, participants may also assist in promoting positive parenting, offering potentially long-range benefits for this and future generations of Australian children.Baby Steps, that targets perinatal well-being in both mothers and fathers . Specifically, the first aim is to compare the effectiveness on indices of well-being using two versions of the Baby Steps program for first-time parents: Babycare (an online information-only program providing information and tips on selected childcare issues) and Well-being . The second aim is to assess the cost-effectiveness of the Well-being program compared to the Babycare program.The aim of this trial is to conduct the first RCT of a web-based intervention, Well-being program will show lower levels of distress and a higher level of quality of life at 13 and 26 weeks post-baseline, compared to participants receiving the Babycare program. In addition, couple relationship satisfaction, parental self-efficacy, social support, and cost-effectiveness are predicted to be greater at 13 and 26 weeks post-baseline for participants receiving the Well-being program, compared to participants receiving the Babycare program.It is predicted that participants receiving the Babycare program or the Well-being program. This study is an RCT designed to evaluate the effectiveness of an online intervention targeting perinatal well-being in first-time mothers and fathers. After baseline data are collected, participating couples will be randomly allocated to receive either the A total sample of 240 primiparous mother-father couples will be recruited. Participants will primarily be recruited through private and public antenatal parent education classes at the Mater Mothers’ Hospital, Brisbane, Australia. A member of the research team will visit the class immediately before the session commences to inform participants about the study and program. Couples will have the opportunity to ask questions and those interested in participating will be assisted with registration for the study. Participants will also be recruited through an exposition targeting expectant parents, and nationally through advertisements on social media and parenting forums, which will direct couples to the program website. Interested couples will be given the opportunity to ask further questions of the research team via email or telephone. During registration, all participants will be asked to select from a dropdown box regarding how they were first informed about the research trial.Participants will be included in the trial if they are a co-parenting male-female couple aged 18 years or older, this is the first child for both parents, gestation is between 26 and 38 weeks at registration (couples registering before 26 weeks of gestation will be reminded by email to retake the screening survey when they reach the 26-week time point), and the pregnancy involves a single child. Participants must also be literate in English, have Internet and mobile phone access, and complete the baseline assessment. Both parents must be eligible for the couple to participate. Exclusion criteria are presented in Babycare program.Couples will register for the study by creating a website account for each user with email addresses and passwords. Registrants will then be individually emailed with a link to the screening survey, in which the trial information statement is provided. Participants will confirm that they have read and understood the statement, and that they consent to participate in the research before continuing. Participants will then complete the screening survey to confirm that they meet the study inclusion criteria. Eligible participants will be directed to the online baseline assessment survey, and both parents must complete the survey before the couple is randomly assigned to an intervention condition. Registrants who are not eligible for the study will still be able to access the Babycare program. After completion of the baseline assessment and randomization, couples will be telephoned by a researcher  to welcome them to the study, collect postal address details, and provide the research team’s contact information.Reminder emails will be sent to registered participants on an automated schedule if they or their partner have not completed the screening survey three days post-registration, or the baseline survey three days post-screening. If the survey is still not complete 10 days post-registration, participants will be contacted by a research officer to assist with completion of the survey (if the couple gives ongoing consent to participate). If both individuals have not completed the baseline assessment four weeks after eligibility is confirmed, couples will be withdrawn from the study and offered access to the Follow-up assessments will be at 13 and 26 weeks post-baseline. For the purposes of these assessments, couples will be treated as individual participants and emailed an individualized online survey link. To maximize retention, participants will be reminded to complete the survey via scheduled emails. If the participant has not responded within two weeks of the due date, a researcher  will phone the participant, establish ongoing consent from the participant, and attempt to obtain the assessment over the phone. Participants will be offered an AUD $20 gift voucher (AUD $40 per couple) for completing each follow-up assessment.Given the high frequency of perinatal distress, it is expected that some participants will experience distress during the study. Although the program focuses on well-being and does not specifically address depression, participants will be monitored for signs of elevated distress through their responses on the EPDS, and will be followed-up with according to the protocol outlined in Baby Steps programs. When the researcher notifies Goji that a participating couple has completed their baseline assessment, Goji will allocate the participants to a research group, randomizing couples as a unit. Randomizations will be in permuted blocks, and stratified by scores on the EPDS: neither parent distressed  versus either parent distressed . These cut-off scores represent optimum screening levels for depressive or anxiety disorders in fathers and mothers [Allocations will be generated by the Goji program, a web-based research trials management system developed at Queensland University of Technology, Australia, by the same web developers who programmed the Couples will be randomized as a unit but may elect to withdraw individually or as a couple. An individual will be able to continue participating in the trial if their partner withdraws, and this will not have any effect on their participation in the trial.Time x Condition interaction (P<.05) over three occasions of measurement, with a small effect size of f=0.082 [A total of 240 couples (120 couples per group) will be recruited. A sample size of 240 will give a power of .80 for detecting a significant  f=0.082 ,51.Baby Steps programs, Babycare and Well-being, was developed by a team comprised of clinical psychologists, midwives, and a neonatologist. Baby Steps is a modular, self-paced program designed to provide infant care and well-being information, and tools relevant for mothers and fathers during late pregnancy until their infant is approximately six months of age. Each module contains 4-8 categories that help to guide program users through the information contained within the module, or information presented through external websites and programs. Suggestions are offered for employing the information and tips individually, as parent and infant, as a couple, or as a family. A Get Help tab includes links to other parenting websites and programs, and links to face-to-face, telephone, or online health service providers.The content of the Program information is written in an encouraging and non-judgmental tone, designed to create an empathic environment in which new parents can access information and tools. Inclusive language is used to aid engagement of both mothers and fathers in the program and gender role assumptions have deliberately been avoided when presenting the content. For example, information about returning to work after a brief leave is provided for both mothers and fathers, as are tips and suggestions for helping to feed an infant. Photos and images of both men and women interacting with their infants are used throughout the program.Babycare program is comprised of four modules: (1) Getting Prepared – practical tools to help expectant parents prepare for the arrival of an infant, (2) Feeding – information about breastfeeding, formula feeding, and combined feeding, (3) Improving Baby’s Sleeping Habits – information for understanding the patterns of infants’ sleep and sleep cues, plus practical tools for creating a sleep routine, and (4) Soothing – information and practical techniques to calm a crying infant.The Babycare participants two, four, seven, and ten weeks after program allocation to remind them to log into the program.Automated short message service (SMS) texts will be sent to Babycare is an information-only program, while Well-being is an interactive program including the four Babycare program modules along with five additional modules promoting parental well-being, and utilizes interactive tools for the enhancement of well-being. The five additional modules are: (1) Self-Care – information and tips to assist new parents to look after their physical and mental health, (2) Relationships – tools for working through changes in the romantic relationship after an infant is born, (3) Interacting with Baby – information to assist new parents to understand, bond with, and play with their infant, (4) Changing Roles – tips to assist new parents to adjust to the new roles that parenthood brings, and (5) Especially for Fathers – well-being and infant care information targeted specifically to fathers.Baby Steps programs, the Especially for Fathers module was developed to provide additional father-targeted information. However, this module is also available to mothers who may wish to understand the role of fathers, and provides useful tips for his well-being.After qualitative interviews with mothers and fathers who trialed the Well-being participants can choose tips to send to the My Plans tool, which functions as a goal-setting, problem-solving, and behavioral activation tool. Participants are encouraged to develop plans to incorporate the chosen tips into their lives, including setting a specific date and time when the plan will be attempted, or a regular frequency at which they will complete the plan. Example suggestions for plans that may be attractive to mothers, fathers, or both parents are distributed throughout the modules. A participant using the Self-Care module could select the Talk to someone about what’s stressing you tip, and choose to develop a plan to Book an appointment with my General Practitioner and to complete the plan on November 10th. Participants are able to review and update their plans throughout their use of the program, and can mark plans as completed.Within each module, Well-being program also includes a Scrapbook tool, in which participants can upload and view photos that remind them of pleasure and success. The participant’s personalized Dashboard displays Scrapbook photos, upcoming plan due dates, rotating module tips, and light-hearted, infant-specific trivia questions.The Well-being program will also receive automated SMS texts two, four, seven, and ten weeks after allocation, reminding them to log into the program, select useful tips, develop plans to enhance well-being, and regularly review the progress of their plans.Participants allocated to the Reporting of this study is guided by the Consolidated Standards of Reporting Trials statement  and inteMeasures will be restricted to minimize the burden on participants. Demographics collected will include details of income and occupational engagement. Economic information including healthcare data, work time/productivity data, and intervention establishment/delivery data will also be collected. Past and recent psychiatric history will also be assessed. Information concerning the outcome of the pregnancy will be collected 13 weeks post-baseline. The EPDS  will be feeding your baby, putting your baby to sleep, settling your baby, providing support to your partner), will be assessed on an 11-point scale. The scale increases in 10-point increments, and ranges from 0  to 100 (extremely confident). Current satisfaction with participants’ parenting role and skills, and with relationships and social support , will be rated on a similar 11-point scale from 0  to 100 (extremely satisfied). The same rating scale will be used for program satisfaction at 13 weeks post-baseline . Timing of the assessments is presented in Three measures were designed specifically for this study. These measures were created to be brief, as to minimize time burden on participants, and designed to directly measure certain program components. Self-efficacy over the initial 13 weeks of child-rearing, and providing support to a partner .Both Version 22 of the IBM SPSS Statistics program will be used to perform all data analyses.Baseline data from the two program groups will be compared to check for comparability of the groups. Chi-square tests will be used for categorical variables, ANOVA tests for normally distributed continuous variables, and Kruskal-Wallis tests for non-parametric data. Any differences detected will be controlled for during the subsequent analyses.All data analyses will be based on the intention-to-treat principle . ContinuThe evaluation will examine the perspectives of costs to health services and to society. Unit costs will be applied to resource-use data collected on health care , work time/productivity, and intervention establishment/delivery. The AQol-8D , a multiThis trial received ethical approval from the Human Research Ethics Committees of Queensland University of Technology (No. 1400000687) and the Mater Health Services (No. HREC/14/MHS/166). The trial will be implemented in compliance with this protocol and the Australian National Statement on Ethical Conduct in Human Research .Participant recruitment commenced March, 2015 and continued until October, 2015. Follow-up data collection has commenced and will be completed May, 2016 with results expected in July, 2016.Depression and distress have substantial impacts on new parents and their babies, with potential to affect later adjustment, relationships, and child development -16. The Baby Steps screens for distress and depression, provides childcare resources and interactive tools, and addresses emotional and physical well-being of both fathers and mothers. Key foci are self-selected childcare issues and maintaining pleasurable physical and social activity. Personal tailoring, after-hours availability, rural accessibility, and low cost per user allow the platform to be easily disseminated to large numbers of people across Australia. This study conducts the first perinatal trial to differentiate component effects from a combined intervention of this type, examining distress, functioning, and childcare confidence, and is the first to compare cost-effectiveness of such interventions. As such, this project helps to facilitate the translation of research into policy and practice at state and national levels. Baby Steps is one of few trials that focuses on well-being and prevention rather than established depression (thereby having wide applicability), and is also one of the few trials to focus on the well-being of new fathers.The current research addresses several issues. This project has developed an innovative program with a unique combination of modules, based on several related programs designed by the authors. Baby Steps offers a strategy to engage and support fathers, improving their own outcomes as well as their support of mothers, and potentially preventing losses in work time and productivity associated with depression. In concert with other strategies to address the causes of depression and anxiety, this project assists in promoting the long-term emotional and physical health and well-being of Australian children and their families.This project has the potential to influence standard services to support parents, thereby increasing their effectiveness, with minimal increases in cost.


Scientific Reports5: Article number: 1551210.1038/srep15512; published online: 10222015; updated: 04132016The Acknowledgements section in this Article is incomplete.“This study was supported by National 973 Program (2012CBA01305); National Science Fund for Outstanding Young Scholars (81322039); National Natural Science Foundation (31371524); Distinguished Young Scholars of Jiangsu Province (BK20130041); Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD); New Century Excellent Talents in University (NCET-13-0870) and the California Tobacco-Related Disease Research Program (TRDRP) Grant 19XT-0070 (to B.H.) under U.S. Department of Energy (Contract no. DE-AC02-05CH11231).”should read:“This study was supported by National 973 Program (2012CBA01305); National Science Fund for Outstanding Young Scholars (81322039); National Natural Science Foundation (31371524); Distinguished Young Scholars of Jiangsu Province (BK20130041); Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD); New Century Excellent Talents in University (NCET-13-0870) and the California Tobacco-Related Disease Research Program (TRDRP) Grant 19XT-0070 (to B.H.) under U.S. Department of Energy (Contract no. DE-AC02-05CH11231); The California Consortium on Thirdhand Smoke, California Tobacco-Related Disease Research Program (trdrp.org) grant 20PT-0184 and California Tobacco-Related Disease Research Program grant 21 ST-011).”


Quaking (QKI) is a tumor-suppressor gene encoding a conserved RNA-binding protein, whose expression is downregulated in several solid tumors. Here we report that QKI plays an important role in the immune response and suppression of leukemogenesis. We show that the expression of Qki is reduced in lipopolysaccharide (LPS)-challenged macrophages, suggesting that Qki is a key regulator of LPS signaling pathway. Furthermore, LPS-induced downregulation of Qki expression is miR-155-dependent. Qki overexpression impairs LPS-induced phosphorylation of JNK and particularly p38 MAPKs, in addition to increasing the production of anti-inflammatory cytokine IL-10. In contrast, Qki ablation decreases Fas expression and the rate of Caspase3/7 activity, while increasing the levels of IL-1α, IL-1β and IL-6, and p38 phosphorylation. Similarly, the p38 pathway is also a target of QKI activity in chronic lymphocytic leukemia (CLL)-derived MEC2 cells. Finally, B-CLL patients show lower levels of QKI expression compared with B cells from healthy donor, and Qki is similarily downregulated with the progression of leukemia in Eμ-miR-155 transgenic mice. Altogether, these data implicate QKI in the pathophysiology of inflammation and oncogenesis where miR-155 is involved. High lerognosis –5. Targelymphoma . Furtheractivity . In hema signals . Thus, Ln origin –9. The oly Ship1 –12, Socs1 [Socs1 .QKI, KH domain containing, RNA binding) is a member of the signal transduction and activation of RNA (STAR) family of RNA-binding proteins. Three major QKI isoforms , each with a specific carboxy-terminal end, are produced through alternative splicing both in mouse and human [QKI behaves as a tumor suppressor gene (TSG) in glioblastoma multiforme (GBM) [miR-20a, thus, increasing miR-20a down-regulatory effects on TGF-β receptor type II (TGF-βR2), whose activity is oncogenic in gliomagenesis [Quaking (nd human . QKI-5 cnd human –16. QKI me (GBM) . QKI, unme (GBM) , is alsome (GBM) –19. In Gagenesis .QKI is the first most probable target of miR-155 in apes and human (targetscan.org), and that the expression of miR-155 is upregulated in glioblastomas [miR-155 might carry out its oncogenic and pro-inflammatory functions at least in part by targeting QKI. In the present study, we show that (i) QKI is indeed a target of miR-155 in B cells; (ii) the expression of QKI is lower in B-cells from CLL patients compare to B cells from healthy donors, and acts as TSG also in CLL; (iii) Qki is a target of LPS signaling, and its expression is downregulated following LPS challenge of macrophages; (iv) Qki modulates downstream LPS signaling in return; particularly p38 MAPK activation and IL-10 production, thus presenting with anti-inflammatory properties. We propose that miR-155 and QKI form a critical regulatory component downstream of TLR4 in target hematopoietic cells, and that miR-155 exerts its pro-inflammatory and oncogenic activities at least in part through the downregulation of QKI expression.As lastomas –21, the miR-155 is upregulated in mouse RAW-264.7 macrophages treated with LPS [miR-155, we monitored the expression of Qki, using a probe spanning exons 4 and 5 that recognizes all Qki isoforms, as well as of miR-155 and Tnf in mouse RAW-264.7 macrophages following LPS stimulation. Qki expression decreased 2-fold within 4 hours, while the expression of miR-155 as well as that of Tnf, both immediate downstream targets of LPS signaling, increased significantly , further confirming our hypothesis. On Western blots, Qki levels also decreased significantly only for a short period of time (data not shown), suggesting that Qki might be a critical component of LPS signaling, potentially involved in preventing the initiation of an unnecessary innate immune response, assuring the robustness of the response at its onset, and resolving and terminating the response later on. Our pan-Qki antibody detected one Qki isoform only, and QKI-5 being the main isoform expressed in hematopoietic cells [We have previously shown that the expression of with LPS . As Qki y Figure –1C. Beyoe Figure . This inic cells , this ismiR-155 inhibitory RNA (155-I) protected Qki transcript from downregulation only during the first 4 hours of LPS challenge, while remaining without effects later on . To determine whether miR-155 could directly target QKI transcripts, we prepared three Luciferase reporter constructs from human QKI-3′-UTR, each containing one miR-155 target site  that bind to this particular region of Qki-3′-UTR, given that the stability of several immune transcripts is regulated by the fixation of RNA binding proteins on their 3′-UTR, and that we observed a similar phenomenon in RAW264.7 macrophages, but not in HEK-293 kidney cells (not shown).Human e Figure . A miR-1e Figure . FinallyS Figure , giving l Figure , 2C. ThiQki being a target of LPS signaling suggested that Qki itself might be a modulator of the innate immune response. We thus transfected RAW-246.7 cells with a construct expressing QKI-5 (hereafter referred to as QKI), chosen because: (i) it is the only QKI isoform that contains a nuclear localization signal and functions in pre-miRNA splicing and/or RNA retention [QKI-5 doubled the level of anti-inflammatory IL-10 in cell supernatant , lead to higher levels of inflammatory IL-1α, IL-1β, IL-6 and GM-CSF  and by 177% at 1-hour (P = 0.0789)  Figure , as deted Figure . As the miR-155 is high in B-CLL-derived cell lines as well as in CLL patients [QKI and miR-155 expression well discriminate Burkitt's cell lines, all with lower miR-155 and higher QKI levels, from CLL cell lines, all with higher miR-155 but lower QKI levels  and Ingenuity software. Expectedly, pathways implicated in the regulation of lymphocyte differentiation, proliferation, function and/or signaling were affected in both cell lines (not shown). However, siQKI had also cell specific effects . Finally, Qki levels were also lower in B cells of Eμ-miR-155 transgenic mice at the most advanced stage of leukemia . Thus, QKI may represents a regulatory hub directing many cellular processes. As human QKI 3′-UTR contains three miR-155 target site, the third one being present only in apes, where QKI came to represent the first most probable target of miR-155, one can expect miR-155-QKI cross-regulatory interactions to have gained a critical importance in this group.Finally, Qki have marked rapid tremor and seizures, and their entire central nervous system is severely depleted in myelin [miR-155 expression is elevated in neuro-inflammatory pathologies such as MS or ALS [miR-155 activity, therefore, miR-155-QKI interactions could prove to be significantly important for future therapies aimed at neuro-degenerative pathologies presented with high levels of miR-155.Mice with spontaneous deletion of n myelin . As miR-S or ALS , 42, ourmiR-155 is critical for mounting an effective immune response, its prolonged expression under chronic inflammatory conditions drives immune pathologies and leukemias. Therefore, a better understanding of miR-155/QKI functions and their control of expression in immune cells should allow to design new miR-155-based cancer immunotherapies. Our findings suggest that when QKI-miR-155 reciprocal regulation becomes dysfunctional, enhanced miR-155 activity drives tumor development and evasion of the immune response.In conclusion, while Supplementary information is available at Oncotarget website.+ B cells were purchased from Sanguine BioSciences . Eμ-miR-155 transgenic mice were previously described [Affymetrix microarray  analyses were submitted to the MIAME database (accession number E-MTAB-2375). Purified CD19escribed . B cellsQKI 3′UTR and the Luciferase reporter construct containing the promoter of QKI gene were purchased from SwitchGear. Each miR-155 site was subsequently mutated using the Quick-Exchange Mutagenesis kit . Human QKI-5 cDNA was purchased from Genecopeia  and recloned into the pCMV-HA expression vector.Cells were grown following standard procedures. Information for miRNAs and siRNAs is found in Luciferase assays were run 48 hours after transfection as previously described . CaspaseRNU-44, RNU-48, RNU-6B or U6 for MiRNA assays and OAZ1, β-Actin or GAPDH for Gene Expression assays.RNAs were extracted either with TRIzol (Life Technologies) or the RNA purification kit from Norgen . They were subsequently subjected to DNase digestion (Turbo-DNase-Life Technologies). MiRNA and gene qRT-PCRs were respectively performed using the corresponding Assays from Life Technologies . RT-PCRst test, and P values are provided in the Figure legends.Antibodies and other related information are listed in


Every day rheumatoid arthritis (RA) patients make many decisions about managing their disease. An online, computer-tailored, self-management program can support this decision making, but development of such a program requires the active participation of patients.To develop an online, computer-tailored, self-management program integrated with the nursing care, as nurses have an important role in supporting self-management behavior.The intervention mapping framework was used to develop the program. Development was a multistep process: (1) needs assessment; (2) developing program and change objectives in a matrix; (3) selecting theory-based intervention methods and practical application strategies; (4) producing program components; (5) planning and adoption, implementation, and sustainability; and (6) planning for evaluation.After conducting the needs assessment (step 1), nine health-related problems were identified: (1) balancing rest and activity, (2) setting boundaries, (3) asking for help and support, (4) use of medicines, (5) communicating with health professionals, (6) use of assistive devices, (7) performing physical exercises, (8) coping with worries, and (9) coping with RA. After defining performance and change objectives (step 2), we identified a number of methods which could be used to achieve them (step 3), such as provision of general information about health-related behavior, self-monitoring of behavior, persuasive communication, modeling, and self-persuasion and tailoring. We described and operationalized these methods in texts, videos, exercises, and a medication intake schedule. The resulting program (step 4) consisted of an introduction module and nine modules dealing with health-related problems. The content of these modules is tailored to the user’s self-efficacy, and patients can use the online program as often as they want, working through a module or modules at their own speed. After implementation (step 5), the program will be evaluated in a two-center pilot trial involving 200 RA patients. Log-in data and qualitative interviews will used for a process evaluation.The intervention mapping framework was used to guide development of an online computer-tailored self-management program via a process which could serve as a model for the development of other interventions. A pilot randomized controlled trial (RCT) will provide insight into the important outcome measures in preparation for a larger RCT. The process evaluation will provide insight into how RA patients use the program and the attrition rate.Netherlands Trial Register (NTR): NTR4871; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4871 [accessed 13-NOV-15]http://www.webcitation.org/6d1ZyIoEy Rheumatoid arthritis (RA) is a chronic autoimmune disease which predominantly affects the joints. Many RA patients face physical problems such as pain, stiffness, and fatigue which cause difficulties in everyday life . RA has Although healthcare professionals can give patients advice and support during visits and appointments, patients have to make day-to-day decisions about management of their disease by themselves. Self-management programs can help RA patients to take an active role in the everyday management of their disease -9. Self-In the Netherlands, 2 studies, one in adolescent RA patients  and the An online self-management program is a complex intervention. First, it should include a variety of components, such as information provision, management of symptoms, social support, and communication strategies . Second,To ensure that our development process took account of these 3 overarching requirements, we used the intervention mapping framework. We chose to develop a tailored intervention because adapting communications and behavioral change strategies to patient needs  means thThis article describes the development of an online computer-tailored program and the design of an evaluation procedure using the intervention mapping framework which could serve as a guide for the development and testing of other interventions.The intervention mapping framework is designed to ensure that development work is focused on the most important determinants of behavior. Intervention mapping has been used successfully to develop health programs related to, for instance, medication adherence , promotiFirst we recruited a multidisciplinary panel of 5 RA patients, 2 rheumatologists, one rheumatology nurse, a psychologist, a physiotherapist, an occupational therapist, and 3 researchers . The rheumatology nurse and rheumatologist played a crucial role in the development and implementation of the program.Our needs assessment comprised two components: (1) a literature search for information on health problems, problems affecting health-related behaviors, and determinants of problems and (2) input from 2 meetings of the multidisciplinary panel. During the first meeting, we held a brainstorming session to identify the main health problems affecting RA patients. To select the most important health problems for RA patients, we coded health problems found in literature and discussed this among the multidisciplinary panel. Selection was further based on recognizability and importance of the health problems. In the second meeting, we identified problems affecting health-related behaviors and their determinants based on the literature and discussed the following questions among RA patients and health professionals: (1) why do patients have problems and (2) why do patients have problems with this behavior? In the third meeting, we asked the multidisciplinary panel whether the listed problems in health-related behavior were easily changeable or not. After these meetings, the researchers listed and coded the health problems, the problems affecting health-related behaviors, and their determinants manually.In the second step, we organized the performance objectives and change objectives as a matrix to indicate which behaviors needed to change to achieve the overall goal of the program, which was to enhance patients’ ability to self-manage their disease and thus improve their quality of life. The performance objectives formalized the behavioral changes RA patients needed to make to achieve the behavioral goals of the program. The change objectives were performance objectives linked to changeable determinants of behavior. Thus, change objectives state what needs to change in determinants to achieve the performance objectives. Researcher RMZ constructed a matrix of the relationships between performance and change objectives which was subsequently validated by the multidisciplinary panel.After defining the matrix we selected theory-driven methods on the basis of behavioral change theories. In this study, 2 independent researchers linked methods from the classification of the behavior change techniques to the problems affecting health-related behaviors and their determinants in order to select methods which could be used to achieve our overall goal. The behavior change technique classification defines strategies used in supportive programs . Using aProgram development was based on the change objectives and the selected theory-driven methods and consisted of composing program materials and pretesting these materials. Our research group worked with an information and communications technology partner to produce the program materials. The research group developed the content, including textual material, and our information and communications technology partner incorporated this material into an online program.Our pretest of the online program comprised testing of the program materials by the multidisciplinary panel and testing of the program by 3 RA patients not involved in its development using the “think aloud” method .Intervention mapping steps 1 through 4 formed the basis of the implementation. Meetings of the multidisciplinary panel were held to identify and categorize barriers and facilitators to implementation of the online program. The rheumatologist and specialist rheumatology nurse played a crucial role in the implementation process.In the final intervention mapping step we planned to evaluate the feasibility of the study design and the online self-management program by conducting an exploratory randomized controlled trial (RCT) and a process evaluation . To do tWe selected the 8 most important health problems in daily life for RA patients: pain, fatigue, stiffness, daily functioning, sexuality, work, social activities, and coping with RA.We identified 9 general problems affecting health-related behavior from our literature review and through discussions among the multidisciplinary panel: (1) balancing rest and activity, (2) setting boundaries, (3) asking for help and support, (4) use of medicines, (5) communicating with health professionals, (6) use of assistive devices, (7) performing physical exercises, (8) coping with worries, and (9) coping with RA.Our literature search determined that the following factors were relevant to problems affecting health-related behavior: knowledge, awareness, risk perception, social influence, attitude, self-efficacy, and habits. Patients confirmed the relevance of these determinants.The results of the needs assessment were used to draw up a matrix of performance and change objectives. One of the performance objectives was “the patient is able to set her or his boundaries.” This performance objective was relevant to the following health problems in daily life: pain, fatigue, social activities, and work.Next we formulated change objectives relevant to the determinants knowledge, attitude, self-efficacy, and risk perception; for example, the patient knows the consequences of not setting his or her boundaries (knowledge), and the patient is conscious of the positive consequences of setting boundaries (attitude).We used our matrix of change objectives to select a theory on which to base our intervention. The matrix placed the most emphasis on self-efficacy, attitude, and subjective norms. The theory of planned behavior posits that these constructs are the most important determinants of behavior, so we based our interventions on this theory. We also emphasize knowledge and awareness in our matrix, as these are preconditions for self-efficacy, attitude, and subjective norms. We then made a list of techniques which could be used to improve self-efficacy, attitude, subjective norms, and their preconditions.Determinant knowledge: provide general information about health behavior, increase memory and/or understanding of transferred information. Determinant awareness: risk-communication, self-monitoring of behavior, self-report of behavior. Determinant social influence: provide information about peer behavior. Determinant attitude: persuasive communications, belief selection, reinforcement on behavioral progress, providing contingent rewards. Determinant self-efficacy: modeling, practice, plan coping responses. Determinant intention of behavior: develop medication intake schedule. Determinant action control: use of social support, use of cues, self-persuasion. We operationalized these methods as follows: we used texts to increase knowledge, awareness, attitude, social influence, and action control; we used videos and exercises with feedback options to increase self-efficacy; and we encouraged patients to keep a diary within the online program to increase their awareness of their own health status and use an intake schedule to increase intention of behavior. We also tailored the program to the user’s self-reported level of self-efficacy, because self-efficacy has been found to predict changes in various health-related behaviors [For this, we derived the following methods per determinant from the coding manual for behavioral change techniques . Determiehaviors .We used the change objectives and the practical applications as the basis for the online program, “Reuma zelf te lijf,” which has 10 modules consisting of 2-5 sessions each. During the pretest the collaborative multidisciplinary panel found that the information and the exercises provided in the modules were understandable/readable and applicable. The layout and structure of the modules were described as attractive and clear. The 3 patients who tested the program using the “think aloud” method found it difficult to navigate through the program. In response to this, we adjusted the program to make navigation easier.We have planned a trial which will be conducted in 2 Dutch hospitals. The managers of the 2 rheumatology departments met regularly with the researchers to discuss trial procedures. The multidisciplinary panel identified barriers and facilitators relevant for the implementation of the online program. This information was used to design an implementation plan for the 2 hospitals which focuses on dissemination of the online program and the user's experience of interacting with the online program. We asked the specialist nurses to bring the online program to the attention of their patients during appointments. For this, a researcher explained the modules and exercises in the program to specialist RA nurses to facilitate integration of the online program with nursing care. To ensure that users’ first experiences of the program were positive, we sent potential users a written instruction manual for the program. To encourage repeated use of the program, users will be sent reminders via email.To evaluate the feasibility, we plan to do an exploratory RCT as advised by the Medical Research Council's framework for the development and evaluation of complex interventions . The aimTo explore which outcome measures are most likely to capture patient potential benefits, we chose the following potential outcomes: (1) the Patient Activation Measurement (PAM-13), which assesses the knowledge, skills, and confidence for self-management ; (2) theIn the process evaluation we will use the framework of Saunders et al  to evaluFinally, to get insight into whether the online program changes the roles of patients and nurses in management of RA we have made a checklist to be completed after nursing appointments with patients in both the control group and the intervention group that covers what topics were discussed during the nursing consultation and whether it was the nurse or the patient who raised a particular topic.This article describes the systematically developed generic online, computer-tailored self-management supportive program for adult RA patients.Using intervention mapping to structure the development process is a strength of this program. In the needs assessment, we successfully defined health problems, problems affecting health-related behaviors, and determinants of problems with health-related behavior which were relevant to RA patients. Extending the needs assessment to encompass determinants of behavior gave us a good understanding of the causes of problems with health-related behaviors. The online program uses tailored behavioral change strategies too, which should improve the likelihood of RA patients’ ability to manage their disease. Another strength of intervention mapping is the use which is made of input from patients and health professionals. Integrating the experiences, knowledge, and visions of these diverse groups with scientific insights enabled us to develop a well-grounded intervention, tailored to the preferences and support needs of RA patients.A second expected strength of the program is that the program is computer-tailored to the user’s level of self-efficacy. This ensures that RA patients receive material which is suited to their personal needs, and this may increase motivation to persist with exercises and strategies recommended therein. The online format has the further advantage that patients can use the program as often as they want or need. They can choose which modules to work through and can do so at their own speed, whenever they want.A third expected strength of the program is the extent to which the online program can be integrated with regular nursing care. All the topics covered in the program fall within the scope of a specialist RA nurse’s expertise and can be discussed during appointments with a nurse. Specialist RA nurses can encourage RA patients to use the program and hopefully benefit by continuing to practice self-management.The composition of the multidisciplinary panel might be considered a limitation of the study. All 5 RA patients had long disease duration and had found ways to cope with their illness and may not have been able to recall the problems they had in the early phase of the disease. However, in each meeting we asked the patients to try to remember how things had been when they were first diagnosed.Another limitation might be the choice of the channel for communication relatively early in the development process. Instead of in step 4, we decided in step 1 to use an online program as communication channel. This influenced our choices at certain points in the development process, for example the choice for behavioral change strategies. This is in conflict with the concept of intervention mapping as an iterative process. However, choosing to use eHealth early on gave us the opportunity to learn about its pros and cons and how to deal with them during implementation.This article describes how to develop a self-management program in a structured way and could serve as a guide for the development of similar interventions. The study yielded an online, computer-tailored self-management program suitable for all RA patients. In the planned exploratory RCT, we will assess important outcomes and estimate the relevant effect sizes; this should be useful preparation for a larger RCT. The process evaluation will give us more insight into how RA patients use the program, which will inform future development of the program. We hope that this online self-management program will become one of the treatment options available to RA patients as part of an integrated disease management plan.