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Abstract Background Peer tutorials are widely used in medical and health professions education. Some evidence suggests that peer tutorials can have positive effects for student peer tutors and tutees alike. To promote these positive effects, peer tutors are often prepared for their tasks. However, detailed information about this preparation is missing in the literature. The present study thus examines from the tutors’ perspective how peer tutor preparation is conducted, both in interprofessional and uniprofessional contexts, and how this preparation affects peer relations. Methods A qualitative design was used for the study. For data gathering, three online focus group discussions were conducted with student peer tutors from uniprofessional and interprofessional settings who had a background in health professions. Data were analysed inductively via thematic analysis. Results A total of 19 individuals participated in three focus group discussions (n = 6/n = 6/n = 7). From the participants’ perspective, preparation measures were heterogenous. Of a wide range of different measures, some were perceived as more helpful, others as less helpful. In analysing the data, three relevant themes came up which were dereived from the peer tutors’ perspective: roles, eye level, and (self-)trust. All three themes were found to be closely related and appeared to have a direct influence on peer relations. This influence on the learning/teaching process was either positive or negative depending on the respondents’ experiences. Conclusion From the peer tutors’ perspective, the preparation they received affected their relationships with their peers in a variety of ways, influenced by the context and the peer tutors’ needs. This finding should be taken into account when planning and implementing future preparatory activities. In addition, further pedagogical considerations and discussions about preparatory activities for peer tutors and their potential impact on social and cognitive congruence are needed.

Abstract Background Evaluations of continuing professional development programs typically focus on short-term knowledge and skill acquisition. There is a need for more comprehensive program evaluation methods that assess a broader range of impacts and can elicit how and why these outcomes occurred. We conducted a qualitative study to investigate the impacts of a multidisciplinary, online health professional postgraduate degree and to gain insights into the factors that led to these impacts. Methods Participants were graduates of the University of Melbourne’s Master of Cancer Sciences who could participate in an online interview. Semi-structured, qualitative interviews were conducted exploring a broad range of impacts, including changes in professional practice and career trajectory since graduation, and how the degree influenced these impacts. Data were analysed inductively. Results Fifteen participants (female: 80%, 31–50 years old: 67%) from a range of professions were interviewed. A number of major themes were uncovered. Impacts on career trajectory included expanded career horizons (e.g. increased role diversity and complexity), and increased confidence in their professional identity. Impacts on professional practice included individual improvements in patient care and research, as well as changes in organisational practice. Factors identified as leading to these impacts were: (i) active, interactive and interprofessional learning; (ii) networking, informal mentoring, and role-modelling; and (iii) support at multiple levels. Conclusion This study provides preliminary evidence of the positive impact of a Master of Cancer Sciences on graduate career trajectory and professional practice. In addition, the inductive methodology enabled identification of the curricular features (both planned and emergent) that influenced these impacts, facilitating potential transferability of learnings to other teaching programs.

Abstract Bio-based fertilizers (BBFs) recovered from animal manure are promising products to optimise resources recovery and generate high agricultural yields. However, their fertilization value may be limited and it is necessary to enrich BBFs with microbial consortia to enhance their fertilization value. Three specific microbial consortia were developed according to the characteristics of three different BBFs produced from manure (bio-dried solid fraction, solid fraction of digestate and biochar) to enhance plant growth and product quality. A greenhouse pot experiment was carried out with tomato plants grown with microbiologically activated BBFs applied either as N-organic fertilizers or as an organic amendment. A next generation sequencing analysis was used to characterise the development of each rhizospheric community. All the activated BBFs gave enhanced tomato yields (fresh and dry weight) compared with the non-activated treatments and similar to, or higher than, chemical fertilization. Concerning the tomato fruits’ organoleptic quality, lycopene and carotenoids concentrations were improved by biological activation. Metagenomic analysis points at Trichoderma as the main driver of the positive effects, with the effects of added bacteria being negligible or limited at the early stages after fertilization. In the context of the circular economy, the activated BBFs could be used to replace synthetic fertilisers, reducing costs and environmental burdens and increasing production.

Abstract Background Improving oncology-specific knowledge and skills of healthcare professionals is critical for improving the outcomes of people with cancer. Many current postgraduate education offerings may be inaccessible to busy professionals, contain minimal consumer input or do not focus on the multidisciplinary nature of cancer care. In response to these needs, a Master of Cancer Sciences degree was developed. Our aim is to describe the development of the Master of Cancer Sciences. Methods We describe the development of the Master of Cancer Sciences, including its theoretical and its pedagogical underpinnings. Results Our approach to curriculum design was guided by Kern’s Six-Step Approach to Medical Curriculum and underpinned by the Seven Principles of Online Learning. These approaches were further underpinned by the Cognitive Theory of Multimedia Learning which informed our approach to audio and visual information design. The pedagogy is interactive, experiential, interprofessional and importantly, includes consumers as educators. In practice, learning activities include peer feedback, multidisciplinary team meeting simulations, group work and clinical role plays. The online environment was visually shaped through infographics, high-quality educational videos and gamification. Conclusion We have designed a Master of Cancer Sciences that is one of the first wholly online, cancer-specific Masters’ programs. Its industry-led curriculum using evidence-based pedagogical choices utilises a range of novel digital formats and integrates the consumer perspective to provide a holistic overview of the field. Quantitative and qualitative evaluation of learning outcomes is ongoing.

Background: Castleman disease (CD) is a rare lymphoproliferative disorder with various subtypes, including the HHV-8-negative/idiopathic multicentric CD (iMCD). The diagnosis of iMCD remains challenging due to its non-specific presentation, in the form of generalised lymphadenopathies and inflammation. Two clinical presentations have been recently defined: a severe form iMCD-TAFRO and a milder form of iMCD not otherwise specified (iMCD-NOS). identification of interleukin-6 (IL-6) as a major culprit of inflammatory symptoms led to the development of anti-IL-6 therapies, with siltuximab being the approved first-line treatment. Case description: A 16-year-old male presented with recurrent fever, night sweats and several other non-specific symptoms. After extensive evaluations, an excisional lymph node biopsy confirmed the iMCD-NOS diagnosis. The patient received high-dose steroid therapy followed by siltuximab for four years. This treatment was well tolerated with only mild neutropenia not leading to dose adjustment. On siltuximab, the patient developed two mild COVID-19 episodes. His response to siltuximab remained effective throughout four years. Discussion: The absence of biomarker or causal agent identification poses a diagnostic challenge requiring lymph node histopathology for a definitive diagnosis of iMCD. Anti-IL 6 (siltuximab) is the recommended frontline therapy, suppressing inflammation and halting disease progression. Intravenous administration every 3 to 6 weeks can impact patient quality of life, prompting further research for alternative treatments. High-dose steroids, rituximab, cyclosporine, tacrolimus, lenalidomide or combined chemotherapy such as rituximab-bortezomib-dexamethasone are among the considered options according to disease severity. Conclusion: Overall, long-term siltuximab effectively controlled iMCD symptoms and was well tolerated by this young adult, who endured two mild COVID-19 episodes.

BackgroundCommunication is a critical component of the patient-provider relationship; however, limited research exists on the role of nonverbal communication. Virtual human training is an informatics-based educational strategy that offers various benefits in communication skill training directed at providers. Recent informatics-based interventions aimed at improving communication have mainly focused on verbal communication, yet research is needed to better understand how virtual humans can improve verbal and nonverbal communication and further elucidate the patient-provider dyad. ObjectiveThe purpose of this study is to enhance a conceptual model that incorporates technology to examine verbal and nonverbal components of communication and develop a nonverbal assessment that will be included in the virtual simulation for further testing. MethodsThis study will consist of a multistage mixed methods design, including convergent and exploratory sequential components. A convergent mixed methods study will be conducted to examine the mediating effects of nonverbal communication. Quantitative (eg, MPathic game scores, Kinect nonverbal data, objective structured clinical examination communication score, and Roter Interaction Analysis System and Facial Action Coding System coding of video) and qualitative data (eg, video recordings of MPathic–virtual reality [VR] interventions and student reflections) will be collected simultaneously. Data will be merged to determine the most crucial components of nonverbal behavior in human-computer interaction. An exploratory sequential design will proceed, consisting of a grounded theory qualitative phase. Using theoretical, purposeful sampling, interviews will be conducted with oncology providers probing intentional nonverbal behaviors. The qualitative findings will aid the development of a nonverbal communication model that will be included in a virtual human. The subsequent quantitative strand will incorporate and validate a new automated nonverbal communication behavior assessment into the virtual human simulation, MPathic-VR, by assessing interrater reliability, code interactions, and dyadic data analysis by comparing Kinect responses (system recorded) to manually scored records for specific nonverbal behaviors. Data will be integrated using building integration to develop the automated nonverbal communication behavior assessment and conduct a quality check of these nonverbal features. ResultsSecondary data from the MPathic-VR randomized controlled trial data set (210 medical students and 840 video recordings of interactions) were analyzed in the first part of this study. Results showed differential experiences by performance in the intervention group. Following the analysis of the convergent design, participants consisting of medical providers (n=30) will be recruited for the qualitative phase of the subsequent exploratory sequential design. We plan to complete data collection by July 2023 to analyze and integrate these findings. ConclusionsThe results from this study contribute to the improvement of patient-provider communication, both verbal and nonverbal, including the dissemination of health information and health outcomes for patients. Further, this research aims to transfer to various topical areas, including medication safety, informed consent processes, patient instructions, and treatment adherence between patients and providers. International Registered Report Identifier (IRRID)DERR1-10.2196/46601

Abstract Artificial intelligence and radiomics have the potential to revolutionise cancer prognostication and personalised treatment. Manual outlining of the tumour volume for extraction of radiomics features (RF) is a subjective process. This study investigates robustness of RF to inter-observer variation (IOV) in contouring in lung cancer. We utilised two public imaging datasets: ‘NSCLC-Radiomics’ and ‘NSCLC-Radiomics-Interobserver1’ (‘Interobserver’). For ‘NSCLC-Radiomics’, we created an additional set of manual contours for 92 patients, and for ‘Interobserver’, there were five manual and five semi-automated contours available for 20 patients. Dice coefficients (DC) were calculated for contours. 1113 RF were extracted including shape, first order and texture features. Intraclass correlation coefficient (ICC) was computed to assess robustness of RF to IOV. Cox regression analysis for overall survival (OS) was performed with a previously published radiomics signature. The median DC ranged from 0.81 (‘NSCLC-Radiomics’) to 0.85 (‘Interobserver’—semi-automated). The median ICC for the ‘NSCLC-Radiomics’, ‘Interobserver’ (manual) and ‘Interobserver’ (semi-automated) were 0.90, 0.88 and 0.93 respectively. The ICC varied by feature type and was lower for first order and gray level co-occurrence matrix (GLCM) features. Shape features had a lower median ICC in the ‘NSCLC-Radiomics’ dataset compared to the ‘Interobserver’ dataset. Survival analysis showed similar separation of curves for three of four RF apart from ‘original_shape_Compactness2’, a feature with low ICC (0.61). The majority of RF are robust to IOV, with first order, GLCM and shape features being the least robust. Semi-automated contouring improves feature stability. Decreased robustness of a feature is significant as it may impact upon the features’ prognostic capability.

Abstract Background Students may be the first to recognise and respond to psychological distress in other students. Peer support could overcome medical student reluctance to seek help despite their high rates of mental ill-health. Yet, despite the adoption of peer support programs, there is little evidence of impact on students. Peer support programs may assume that medical students accept and view peer support positively. We explored these assumptions by asking students about their experiences and views on peer support. Methods Qualitative semi-structured interviews exploring peer support experiences and views on peer support were conducted with ten medical students at two contrasting medical schools. Informed by a constructivist stance, interview transcripts underwent thematic analysis. Results Three groups of themes were identified: participants’ experiences of peer support encounters, concerns about providing support, and views on students’ roles in peer support. Participants readily recalled signs of peer distress. Encounters were ad hoc, informal, and occurred within relationships based on friendship or by being co-located in the same classes or placements. Concerns about initiating and offering support included lack of expertise, maintaining confidentiality, stigma from a mental health diagnosis, and unclear role boundaries, with implications for acceptance of student roles in peer support. Conclusions Our study emphasised the centrality of social relationships in enabling or discouraging peer support. Relationships developed during medical studies may anticipate the collegial relationships between medical professionals. Nevertheless, only some students are willing to undertake peer support roles. We suggest different strategies for promoting informal peer support that can be offered by any student, to those promoting formal support roles for selected students. Future research focusing on the impact for both the students who receive, and on the students who provide peer support is called for.

Abstract CUX1, encoding a homeodomain-containing transcription factor, is recurrently deleted or mutated in multiple tumor types. In myeloid neoplasms, CUX1 deletion or mutation carries a poor prognosis. We have previously established that CUX1 functions as a tumor suppressor in hematopoietic cells across multiple organisms. Others, however, have described oncogenic functions of CUX1 in solid tumors, often attributed to truncated CUX1 isoforms, p75 and p110, generated by an alternative transcriptional start site or post-translational cleavage, respectively. Given the clinical relevance, it is imperative to clarify these discrepant activities. Herein, we sought to determine the CUX1 isoforms expressed in hematopoietic cells and find that they express the full-length p200 isoform. Through the course of this analysis, we found no evidence of the p75 alternative transcript in any cell type examined. Using an array of orthogonal approaches, including biochemistry, proteomics, CRISPR/Cas9 genomic editing, and analysis of functional genomics datasets across a spectrum of normal and malignant tissue types, we found no data to support the existence of the CUX1 p75 isoform as previously described. Based on these results, prior studies of p75 require reevaluation, including the interpretation of oncogenic roles attributed to CUX1.

Technological advances have yielded new molecular biology-based methods for the diagnosis of infectious diseases. The newest and most powerful molecular diagnostic tests are available at regional and national reference laboratories, as well as at specialized centers that are certified to conduct metagenomic testing. Metagenomic assays utilize advances in DNA extraction technology, DNA sequence library construction, high throughput DNA sequencing and automated data analysis to identify millions of individual strands of DNA extracted from clinical samples. At present, metagenomic assays are only possible at a small number of special research, academic and commercial laboratories. Continued research in human and pathogen genomic organization and host-pathogen interactions, represent important future goals that will maximize the information obtained from metagenomic assays. To illustrate the power and limitations of metagenomics, we report on a previously healthy 27 year old woman with work related exposure to ill animals, and who developed a rapidly progressive, severe diffuse interstitial pneumonitis that ultimately ended in the need for a double lung transplant. Metagenomic testing on DNA extracted from pleural fluid and nasopharyngeal swabs demonstrated the presence of expected normal bacterial flora along with some unexpected herpesvirus and non-HIV retroviral elements integrated into the patients DNA. Although no specific pathogen was ultimately identified to explain this patient’s severe disease, the sample preparation and data analysis methods detailed herein illustrate the powerful benefits and limitations of metagenomic testing.

Abstract Background Sarcoidosis is an inflammatory disease characterized by the formation of granulomas, which involve the heart in up to 25% of patients. Cardiac sarcoidosis can lead to life threatening arrhythmias and heart failure. While corticosteroids have been used as a treatment for over 50 years, they are associated with hypertension, diabetes, and weight gain, further increasing cardiovascular risk. Interleukin-1 (IL-1) is the prototypical proinflammatory cytokine that works to activate the nuclear transcription factor NF-kB, one of the targets of glucocorticoids. IL-1 also plays an important role also in the pathophysiology of heart disease including atherosclerosis, myocardial infarction, and myocarditis. Methods Building on a network of research collaborators developed in the Cardiac Sarcoidosis Consortium, we will investigate the feasibility and tolerability of treatment of CS with anakinra at two National Institute of Health Clinical and Translational Science Award (CTSA) hubs with expertise in cardiac sarcoidosis. In this pilot study, up to 28 patients with cardiac sarcoidosis will be recruited to compare the administration of an IL-1 blocker, anakinra, 100 mg daily on top of standard of care versus standard of care only for 28 days and followed for 180 days. Utilizing surrogate endpoints of changes in systemic inflammatory biomarkers and cardiac imaging, we aim to determine whether IL-1 blockade with anakinra can combat systemic and cardiac inflammation in patients with cardiac sarcoidosis. Discussion The current trial demonstrates an innovative collaborative approach to clinical trial development in a rare, understudied disease that disproportionately affects females and minorities. Trial Registration The trial was registered prospectively with ClinicalTrials.gov on July 12, 2019, identifier NCT04017936.

Abstract Radiomics is a promising technique for discovering image based biomarkers of therapy response in cancer. Reproducibility of radiomics features is a known issue that is addressed by the image biomarker standardisation initiative (IBSI), but it remains challenging to interpret previously published radiomics signatures. This study investigates the reproducibility of radiomics features calculated with two widely used radiomics software packages (IBEX, MaZda) in comparison to an IBSI compliant software package (PyRadiomics). Intensity histogram, shape and textural features were extracted from 334 diffusion weighted magnetic resonance images of 59 head and neck cancer (HNC) patients from the PREDICT-HN observational radiotherapy study. Based on name and linear correlation, PyRadiomics shares 83 features with IBEX and 49 features with MaZda, a sub-set of well correlated features are considered reproducible (IBEX: 15 features, MaZda: 18 features). We explore the impact of including non-reproducible radiomics features in a HNC radiotherapy response model. It is possible to classify equivalent patient groups using radiomic features from either software, but only when restricting the model to reliable features using a correlation threshold method. This is relevant for clinical biomarker validation trials as it provides a framework to assess the reproducibility of reported radiomic signatures from existing trials.

There is a global shortage of health care providers needed to address all levels of primary and specialty care. The recent COVID-19 pandemic also highlights the importance and added value of health professionals with specialty training in infectious diseases. In the United States, advanced practice providers (APPs) are being engaged to meet the expanding demand for generalist and specialist patient care. The history and development of advanced practice registered nurses (APRNs) and physician assistants (PAs), are discussed as collaborative healthcare providers to promote better understanding of the ways they can be incorporated into a healthcare system. An example of how APPs are utilized to provide both inpatient and outpatient care of persons with infectious diseases is illustrated at our midwestern United States regional medical center. Especially relevant for regions of the world where both nurses and physicians are in short supply, this paper identifies ways that healthcare leaders can support, develop and strategically utilize APPs to provide critically necessary functions and achieve excellent outcomes. Challenges to future healthcare administration are articulated and compared with World Health Organization roadmap objectives for nursing that can be expanded to better utilize all APPS as valuable healthcare professionals.

Peer-assisted learning (PAL)-especially peer tutorials-are gaining momentum in health professions education, particularly in interprofessional education. As little is known about the use of peer tutorials or the preparation of tutors in this context in Germany and in other countries, this study aims to provide an overview of these interventions. A cross-sectional study with a descriptive-exploratory design was conducted. German institutions for health professions education were contacted, and individuals with pedagogical responsibilities were invited to participate in an online survey. The survey was informed by two studies in which seven domains were identified as important. These included facts about the institution, the offer of PAL, the use of tutorials, and the design of tutor training. The survey used mostly closed-ended questions. The questionnaire was completed by n = 100 participants. Overall, n = 46 participants indicated that PAL was offered at their institution. Of these 46 participants, 32 (70%) indicated that uniprofessional PAL was offered, 2 (4%) indicated that interprofessional PAL was offered, and 12 (26%) indicated that both forms of PAL were offered. Peer tutoring was the most common format in both cases (73% for uniprofessional and 64% for interprofessional PAL), and mandatory interventions were mostly used to prepare the tutors. These interventions were held by educators or lecturers and were offered mostly face-to-face as workshops or as discussions. Deepening the tutors' social competencies through training was given high relevance. Regarding content, focus was placed on communication, (self-)reflection, and group management. Eighty-eight participants expressed recommendations for future directions in terms of preparing tutors for interprofessional PAL. Minor differences between the use of uniprofessional and interprofessional PAL and tutor training were found. Nevertheless, implementation strategies varied. In future, preparatory measures for tutors should be more uniformly designed and geared to the specific requirements of uniprofessional and interprofessional learning, and that at best on an empirical basis.

Cancer: Proteins that work together could reveal drug targets Studying the activity of proteins that work together to control cell division is revealing several that might be suitable targets for new drugs to fight cancer. Researchers led by Josep Clotet and Mariana Ribeiro at the International University of Catalonia, Barcelona, Spain, investigated the activities of the complex formed between two proteins, CDK16 and CCNY. CDK16 is an enzyme that modifies other molecules by adding phosphate groups (PO4) to them. CCNY is a protein that controls the activity of CDK16 and other proteins. Previous research has suggested a role for the complex in the development of cancer, but the mechanism has been unclear. The researchers found that the CDK16/CCNY complex activates proteins that control the network of microtubules in cells known as the cytoskeleton. One of these proteins, PRC1, is essential for cell division.

Background: Erectile dysfunction (ED) is a common public health issue with a significant impact on quality of life. The associations between ED and several risk factors have been reported previously. The continuously increasing incidence of these factors is contributing to the increasing prevalence of ED. Aim: To assess ED prevalence and severity in a representative sample of 45-year-old German men and to analyze the association with risk factors (lifestyle risk factors/comorbidities). Methods: Data were collected within the German Male Sex-Study. Randomly selected 45-year-old men were invited. A total of 10,135 Caucasian, heterosexual, sexually active men were included in this analysis. The self-reported prevalence of ED was assessed using the Erectile Function domain of the International Index of Erectile Function. Risk factors for ED were ascertained using self-report questionnaires. An anamnesis interview and a short physical examination were performed. Main Outcome Measure: ED prevalence and severity were evaluated in a cross-sectional design. The associations of ED with comorbidities (eg, depression, diabetes, hypertension, lower urinary tract symptoms) and lifestyle factors (ie, smoking, obesity, central obesity, physical inactivity, and poor self-perceived health-status) were analyzed by logistic regression. Results: The overall prevalence of ED was 25.2% (severe, 3.1%; moderate, 9.2%; mild to moderate, 4.2%; mild, 8.7%). Among the men with ED, 48.8% had moderate or severe symptoms. ED prevalence increased with the number of risk factors, to as high as 68.7% in men with 5–8 risk factors. In multiple logistic regression with backward elimination, the strongest associations with ED were found for depression (odds ratio [OR] = 1.87), poor self-perceived health status (OR = 1.72), lower urinary tract symptoms (OR = 1.68), and diabetes (OR = 1.38). Conclusion: One out of 4 men already had symptoms of ED at age 45. Almost one-half of the men with ED had moderate to severe symptoms. ED was strongly associated with each analyzed risk factor, and the prevalence and severity of ED increased with an increasing number of risk factors.Hallanzy J, Kron M, Goethe VE, et al. Erectile Dysfunction in 45-Year-Old Heterosexual German Men and Associated Lifestyle Risk Factors and Comorbidities: Results From the German Male Sex Study. Sex Med 2019;7:26–34. Key Words: Erectile Dysfunction, Prevalence, Severity, Risk Factors, Middle-Aged Men, German Male Sex-Study

Aging of the nervous system is typified by depressed metabolism, compromised proteostasis, and increased inflammation that results in cognitive impairment. Differential expression analysis is a popular technique for exploring the molecular underpinnings of neural aging, but technical drawbacks of the methodology often obscure larger expression patterns. Co-expression analysis offers a robust alternative that allows for identification of networks of genes and their putative central regulators. In an effort to expand upon previous work exploring neural aging in the marine model Aplysia californica, we used weighted gene correlation network analysis to identify co-expression networks in a targeted set of aging sensory neurons in these animals. We identified twelve modules, six of which were strongly positively or negatively associated with aging. Kyoto Encyclopedia of Genes analysis and investigation of central module transcripts identified signatures of metabolic impairment, increased reactive oxygen species, compromised proteostasis, disrupted signaling, and increased inflammation. Although modules with immune character were identified, there was no correlation between genes in Aplysia that increased in expression with aging and the orthologous genes in oyster displaying long-term increases in expression after a virus-like challenge. This suggests anti-viral response is not a driver of Aplysia sensory neuron aging.

Background In the curative-intent treatment of locally advanced lung cancer, significant morbidity and mortality can result from thoracic radiation therapy. Symptomatic radiation pneumonitis occurs in one in three patients and can lead to radiation-induced fibrosis. Local failure occurs in one in three patients due to the lungs being a dose-limiting organ, conventionally restricting tumour doses to around 60 Gy. Functional lung imaging using positron emission tomography (PET)/CT provides a geographic map of regional lung function and preclinical studies suggest this enables personalised lung radiotherapy. This map of lung function can be integrated into Volumetric Modulated Arc Therapy (VMAT) radiotherapy planning systems, enabling conformal avoidance of highly functioning regions of lung, thereby facilitating increased doses to tumour while reducing normal tissue doses.Methods and analysis This prospective interventional study will investigate the use of ventilation and perfusion PET/CT to identify highly functioning lung volumes and avoidance of these using VMAT planning. This single-arm trial will be conducted across two large public teaching hospitals in Australia. Twenty patients with stage III non-small cell lung cancer will be recruited. All patients enrolled will receive dose-escalated (69 Gy) functional avoidance radiation therapy. The primary endpoint is feasibility with this achieved if ≥15 out of 20 patients meet pre-defined feasibility criteria. Patients will be followed for 12 months post-treatment with serial imaging, biomarkers, toxicity assessment and quality of life assessment.Discussion Using advanced techniques such as VMAT functionally adapted radiation therapy may enable safe moderate dose escalation with an aim of improving local control and concurrently decreasing treatment related toxicity. If this technique is proven feasible, it will inform the design of a prospective randomised trial to assess the clinical benefits of functional lung avoidance radiation therapy.Ethics and dissemination This study was approved by the Peter MacCallum Human Research Ethics Committee. All participants will provide written informed consent. Results will be disseminated via publications.Trials registration number NCT03569072; Pre-results

Introduction Daily radiotherapy delivered with radiosensitisation offers patients with muscle invasive bladder cancer (MIBC) comparable outcomes to cystectomy with functional organ preservation. Most recurrences following radiotherapy occur within the bladder. Increasing the delivered radiotherapy dose to the tumour may further improve local control. Developments in image-guided radiotherapy have allowed bladder tumour-focused ‘plan of the day’ radiotherapy delivery. We aim to test within a randomised multicentre phase II trial whether this technique will enable dose escalation with acceptable rates of toxicity.Methods and analysis Patients with T2-T4aN0M0 unifocal MIBC will be randomised (1:1:2) between standard/control whole bladder single plan radiotherapy, standard dose adaptive tumour-focused radiotherapy or dose-escalated adaptive tumour-focused radiotherapy (DART). Adaptive tumour-focused radiotherapy will use a library of three plans (small, medium and large) for treatment. A cone beam CT taken prior to each treatment will be used to visualise the anatomy and inform selection of the most appropriate plan for treatment.Two radiotherapy fractionation schedules (32f and 20f) are permitted. A minimum of 120 participants will be randomised in each fractionation cohort (to ensure 57 evaluable DART patients per cohort).A comprehensive radiotherapy quality assurance programme including pretrial and on-trial components is instituted to ensure standardisation of radiotherapy planning and delivery.The trial has a two-stage non-comparative design. The primary end point of stage I is the proportion of patients meeting predefined normal tissue constraints in the DART group. The primary end point of stage II is late Common Terminology Criteria for Adverse Events grade 3 or worse toxicity aiming to exclude a rate of >20% (80% power and 5% alpha, one sided) in each DART fractionation cohort. Secondary end points include locoregional MIBC control, progression-free survival overall survival and patient-reported outcomes.Ethics and dissemination This clinical trial is approved by the London-Surrey Borders Research Ethics Committee (15/LO/0539). The results when available will be disseminated via peer-reviewed scientific journals, conference presentations and submission to regulatory authorities.Trial registration number NCT02447549; Pre-results

Background: Mitochondrial succinate accumulation has been suggested as key event for ischemia reperfusion injury in mice. No specific data are however available on behavior of liver mitochondria during ex situ machine perfusion in clinical transplant models. Methods: We investigated mitochondrial metabolism of isolated perfused rat livers before transplantation. Livers were exposed to warm and cold ischemia to simulate donation after circulatory death (DCD) and organ transport. Subsequently, livers were perfused with oxygenated Belzer-MPS for 1h, at hypothermic or normothermic conditions. Various experiments were performed with supplemented succinate and/or mitochondrial inhibitors. The perfusate, liver tissues, and isolated mitochondria were analyzed by mass-spectroscopy and fluorimetry. Additionally, rat DCD livers were transplanted after 1h hypothermic or normothermic oxygenated perfusion. In parallel, perfusate samples were analysed during HOPE-treatment of human DCD livers before transplantation. Findings: Succinate exposure during rat liver perfusion triggered a dose-dependent release of mitochondrial Flavin-Mononucleotide (FMN) and NADH in perfusates under normothermic conditions. In contrast, perfusate FMN was 3-8 fold lower under hypothermic conditions, suggesting less mitochondrial injury during cold re-oxygenation compared to normothermic conditions. HOPE-treatment induced a mitochondrial reprogramming with uploading of the nucleotide pool and effective succinate metabolism. This resulted in a clear superiority after liver transplantation compared to normothermic perfusion. Finally, the degree of mitochondrial injury during HOPE of human DCD livers, quantified by perfusate FMN and NADH, was predictive for liver function. Interpretation: Mitochondrial injury determines outcome of transplanted rodent and human livers. Hypothermic oxygenated perfusion improves mitochondrial function, and allows viability assessment of liver grafts before implantation. Funding: detailed information can be found in Acknowledgments.

Introduction: Decades of political and social unrest negatively impacted medical education in Iraq. Recently, new opportunities arose for medical schools to engage international education organizations and the World Health Organization to implement medical school curriculum changes, replacing older discipline-based, teacher-focused systems with a systems-based, student-focused reformed curriculum. Methods: A descriptive, cross sectional quantitative study was designed to survey medical students near the beginning (years 2-3) and at near the end (years 5-6) of their six-year program at the Al Kindy College of Medicine, University of Baghdad, Iraq. Results: A validated questionnaire collected data on thirty-two issues, including student perception of learning, student perception of teachers, academic self-perception and student self-perception. Seven of the thirty-two questions included in this survey resulted in significantly different responses from group 1 (second and third year) vs group 2 (fifth and sixth year) students. Conclusions: This study concluded that the two student groups were significantly different in their awareness of the need for curriculum change, but that student self-perception in both groups was less than ideal at present. In the future, studies are planned to assess student confidence in their professional development, as teaching institutions advance toward broader accreditation and thus opportunities for their students.

BackgroundComplications after surgery for esophageal cancer are associated with significant resource utilization. The aim of this study was to analyze the economic burden of two frequently used endoscopic treatments for anastomotic leak management after esophageal surgery: Treatment with a Self-expanding Metal Stent (SEMS) and Endoscopic Vacuum Therapy (EVT).Materials and methodsBetween January 2012 and December 2016, we identified 60 German-Diagnosis Related Group (G-DRG) cases of patients who received a SEMS and / or EVT for esophageal anastomotic leaks. Direct costs per case were analyzed according to the Institute for Remuneration System in Hospitals (InEK) cost-accounting approach by comparing DRG payments on the case level, including all extra fees per DRG catalogue.ResultsIn total, 60 DRG cases were identified. Of these, 15 patients were excluded because they received a combination of SEMS and EVT. Another 6 cases could not be included due to incomplete DRG data. Finally, N = 39 DRG cases were analyzed from a profit-center perspective. A further analysis of the most frequent DRG code -G03- including InEK cost accounting, revealed almost twice the deficit for the EVT group (N = 13 cases, € - 9.282 per average case) compared to that for the SEMS group (N = 9 cases, € - 5.156 per average case).ConclusionEndoscopic treatments with SEMS and EVT for anastomotic leaks following oncological Ivor Lewis esophagectomies are not cost-efficient for German hospitals. Due to longer hospitalization and insufficient reimbursements, EVT is twice as costly as SEMS treatment. An adequate DRG cost compensation is needed for SEMS and EVT.

Abstract Candida albicans is an opportunistic pathogen, typically found as a benign commensal yeast living on skin and mucosa, but poised to invade injured tissue to cause local infections. In debilitated and immunocompromised individuals, C. albicans may spread to cause life-threatening systemic infections. Upon contact with serum and at body temperature, C. albicans performs a regulated switch to filamentous morphology, characterized by emergence of a germ tube from the yeast cell followed by mold-like growth of branching hyphae. The ability to switch between growth morphologies is an important virulence factor of C. albicans. To identify compounds able to inhibit hyphal morphogenesis, we screened libraries of existing drugs for inhibition of the hyphal switch under stringent conditions. Several compounds that specifically inhibited hyphal morphogenesis were identified. Chemogenomic analysis suggested an interaction with the endocytic pathway, which was confirmed by direct measurement of fluid-phase endocytosis in the presence of these compounds. These results suggest that the activity of the endocytic pathway, which is known to be particularly important for hyphal growth, represents an effective target for hyphae-inhibiting drugs.

ABSTRACT CONTEXT AND OBJECTIVE: This systematic review compared reiki and prayer with drug use for relieving pain during hospitalization for cesarean, given that the popularity of integrative medicine and spiritual healing has been increasing. It had the aim of evaluating whether reiki or prayer is effective in relieving pain during cesarean section. DESIGN AND SETTING: Systematic review with meta-analysis conducted at Botucatu Medical School, UNESP, São Paulo, Brazil. METHODS: The following databases were searched up to March 2016: MEDLINE, Embase, LILACS and CENTRAL. Randomized controlled trials published in English or Portuguese were included in the review. Two reviewers independently screened eligible articles, extracted data and assessed the risk of bias. A GRADE table was produced to evaluate the risk of bias. RESULTS: There was evidence with a high risk of bias showing a statistically significant decrease in pain score through use of reiki and prayer, in relation to the protocol group: mean difference = -1.68; 95% confidence interval: -1.92 to -1.43; P < 0.00001; I2 = 92%. Furthermore, there was no statistically significant difference in heart rate or systolic or diastolic blood pressure. CONCLUSION: Evidence with a high risk of bias suggested that reiki and prayer meditation might be associated with pain reduction.

Spissistilus festinus (Say) (Hemiptera: Membracidae) was shown to transmit Grapevine red blotch virus (GRBV) in a greenhouse study. Grapevines infected with GRBV exhibit reduced sugar accumulation, altered secondary metabolite production and delayed berry maturation that negatively impacts wine quality and economics. Augmentative biocontrol may be a useful integrated pest management (IPM) tool for suppressing S. festinus populations in vineyards, but minimal research has been conducted on testing potential predators against the different life stages of S. festinus. The susceptibility of S. festinus adults and nymphs (1st through 5th instar) to predation by six commercially available biocontrol agents in petri dish and bell bean plant arenas was determined under greenhouse conditions. No significant mortality of S. festinus nymphs or adults occurred when exposed to Cryptolaemus montrouzieri adults, C. montrouzieri larvae and Sympherobius barberi adults in petri dish or bell bean plant arenas. Significant mortality of 1st and 2nd instar nymphs of S. festinus in the presence of Zelus renardii nymphs was observed in petri dish but not in bell bean arenas. Hippodamia convergens adults and Chrysoperla rufilabris larvae both consumed a significant number of S. festinus nymphs in petri dish and bell bean arenas. No significant predation of S. festinus adults was documented in this experiment. Results of this study aid in identifying predators that may be suitable candidates for additional field testing to determine their potential efficacy as biocontrol agents of S. festinus in a vineyard setting.

BackgroundThere is ample evidence that gestational diabetes mellitus has a direct influence on urinary incontinence and pelvic floor muscles. There are no standardized pelvic floor muscle exercise programs in the literature for the physiotherapy and differ in the type of exercise, intensity, type and duration of application, and the frequency and duration of treatment sessions. The aim of this systematic review will be to investigate that Pelvic Floor Muscle Training can prevent and/or decrease the pregnancy specific urinary incontinence in women with gestational diabetes mellitus or gestational hyperglycemia.MethodsWe will perform a systematic review according to the Cochrane methodology of Randomized Controlled Trials. An overall search strategy will be developed and adapted for Embase, MEDLINE, LILACS, and CENTRAL databases, with the date of consultation until June 2020. The MeSH terms used will be "Pregnancy", "Hyperglycemia", "Diabetes Mellitus, Type 2", "Diabetes Mellitus, Type 1", "Pregnancy in Diabetics", "Diabetes, Gestational", "Urinary Incontinence", "Pelvic Floor Muscle Strength". Primary outcomes: improvement or cure of pregnancy specific urinary incontinence (which can be assessed by questionnaires, and tools such as tampon test, voiding diary, urodynamic study). Secondary outcomes: improvement of pelvic floor muscle strength (pelvic floor functional assessment, perineometer, electromyography, functional ultrasonography), improved quality of life (questionnaires), presence or absence of postpartum Urinary Incontinence and adverse effects. Quality assessment by Cochrane instrument. Metanalysis if plausible, will be performed by the software Review Manager 5.3.DiscussionThe present study will be the first to analyze the effectiveness of pelvic floor exercises in pregnant women with Gestational Diabetes Mellitus or Hyperglycemia, who suffer from pregnancy specific urinary incontinence. Randomized Controlled Trials design will be chosen because they present the highest level of evidence. It is expected to obtain robust and conclusive evidence to support clinical practice, in addition to promoting studies on the theme and contributing to new studies.Trial registrationSystematic review registration: PROSPERO CRD42017065281.

Objectives Patients suitable for radical chemoradiotherapy for lung cancer routinely have radiotherapy (planning) volumes based on positron emission tomography (PET)-computed tomography (CT) imaging alone. Endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) can identify PET-occult malignancy and benign PET-avid regions. We investigated the impact of EBUS-TBNA on curative-intent radiotherapy in non-small cell lung cancer (NSCLC). Methods A prospective multicentre trial was undertaken, investigating the impact of systematic EBUS-TBNA in addition to PET-CT for patients considered for radical chemoradiotherapy with NSCLC. A subset analysis of patients with discordant findings between PET-CT and EBUS-TBNA was performed. Radiotherapy plans investigated tumour coverage and dose to critical organs at risk (OARs) using PET-CT alone in comparison to PET-CT and EBUS-TBNA. Results Of 30 patients enrolled, 10 had discordant findings between PET-CT and EBUS-TBNA. EBUS-TBNA-derived plans allowed for reduction in dose to OARs in patients downstaged by EBUS-TBNA, and reduced the risk of geographic miss in treating PET-occult disease in four patients where EBUS-TBNA identified malignant involvement of PET-negative lymphadenopathy. With the addition of EBUS-TBNA to radiotherapy planning, reductions were noted of 5.7%, 3.7% and 12.5% for the risks of symptomatic pneumonitis, mean heart dose and mean oesophageal dose, respectively. Conclusions This study demonstrates for the first time that systematic EBUS-TBNA prior to radical-intent radiotherapy significantly improves coverage of subclinical disease through detection of PET-occult metastases. Identification of false-positive lymph node involvement in highly selected cases may reduce radiation dose to critical structures, and risk of organ toxicity.

BackgroundTrials have examined on the benefits of vitamin D supplementation in pregnant women.ObjectiveThis review aimed to evaluate whether oral vitamin D supplements, when given to pregnant women with gestational diabetes mellitus (GDM), would improve maternal and neonatal outcomes, compared with no treatment or placebo.MethodWe performed a systematic review following Cochrane methodology, and randomized trials were included where pregnant women with GDM received vitamin D supplementation versus placebo/no treatment or vitamin D and calcium versus placebo/no treatment. Primary outcomes were preeclampsia, preterm birth, cesarean delivery, gestational hypertension, and adverse events related to vitamin D supplementation. The search strategies were applied to the following databases: MEDLINE, Embase, LILACS, and CENTRAL. Similar outcomes in at least two trials were plotted using Review Manager 5.3 software. The quality of evidence was generated according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE).ResultsThe total of 1224 references were identified, eleven trials were potentially eligible, and six were included in this review (totaling 456 women). The meta-analysis of frequency of cesarean deliveries did not show significant differences between groups, none of the trials evaluated the remaining primary outcomes. For secondary outcomes, our results suggest that vitamin D supplementation in pregnant women with GDM may reduce newborn complications such as hyperbilirubinemia, polyhydramnios (RR: 0.40, 95% CI: 0.23 to 0.68; RR: 0.17, 95% CI: 0.03 to 0.89; respectively), and the need for maternal or infant hospitalization (RR: 0.13; 95% CI: 0.02 to 0.98; RR: 0.40, 95% CI: 0.23 to 0.69). However, the evidence was of low or very low quality.ConclusionWe did not find moderate or high quality evidence indicating that vitamin D supplementation, when compared with placebo, improves glucose metabolism, adverse maternal and neonatal outcomes related to GDM in pregnant women.

PURPOSE:To explore the utility of diffusion and perfusion changes in primary renal cell carcinoma (RCC) after stereotactic ablative body radiotherapy (SABR) as an early biomarker of treatment response, using diffusion weighted (DWI) and dynamic contrast enhanced (DCE) MRI. METHODS:Patients enrolled in a prospective pilot clinical trial received SABR for primary RCC, and had DWI and DCE MRI scheduled at baseline, 14 days and 70 days after SABR. Tumours

Antenatal stress is linked to fetal risks that increase the chances of neonatal complications and reduction of child cognitive ability. Therefore, we aimed to evaluate if maternal stress affects fetal, neonatal or child development. The following databases were searched: MEDLINE (1966 to May 2016), Embase (1980 to May 2016), LILACS (1982 to May 2016) and CENTRAL (1972 to May 2016). Observational studies published in English and Portuguese were included whether there was any relationship between fetal and neonatal outcome, such as birth weight, preterm labor, child development with pregnant women that were subjected to any stress type during at least one month of follow-up. Two independent reviewers screened eligible articles, extracted data and assessed the risk of bias. Thus, 8 cohort studies with about 8,271 pregnant women and 1,081,151 children proved eligible. Results suggested a significant association between antenatal stress exposure and increasing rates of low birth weight (Odds ratio (OR) 1.68 [95% Confidential Interval (CI) 1.19, 2.38]). However, there was no statistically significance difference between non-exposed and exposed groups related to preterm labor (OR 1.98 [95% CI 0.91 to 4.31]; I2 = 68%, p = 0.04). Although, results were inconsistent with primary analysis suggesting a significant association between antenatal stress exposure and the occurrence of higher rates of preterm birth (OR 1.42 [95% CI 1.05 to 1.91]; I2 = 68%, p = 0.04) in the sensitivity analysis. Furthermore, the current review has suggested that stress perceived during antenatal negatively influences fetal life and child development. Yet, further studies are necessary with adequate sample size and longer follow-up time to confirm our findings.

Reduced levels of brain-derived neurotrophic factor (BDNF) are thought to contribute to the pathophysiology of Rett syndrome (RTT), a severe neurodevelopmental disorder caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). In Mecp2 mutant mice, BDNF deficits have been associated with breathing abnormalities, a core feature of RTT, as well as with synaptic hyperexcitability within the brainstem respiratory network. Application of BDNF can reverse hyperexcitability in acute brainstem slices from Mecp2-null mice, suggesting that therapies targeting BDNF or its receptor, TrkB, could be effective at acute reversal of respiratory abnormalities in RTT. Therefore, we examined the ability of LM22A-4, a small-molecule BDNF loop-domain mimetic and TrkB partial agonist, to modulate synaptic excitability within respiratory cell groups in the brainstem nucleus tractus solitarius (nTS) and to acutely reverse abnormalities in breathing at rest and during behavioral arousal in Mecp2 mutants. Patch-clamp recordings in Mecp2-null brainstem slices demonstrated that LM22A-4 decreases excitability at primary afferent synapses in the nTS by reducing the amplitude of evoked excitatory postsynaptic currents and the frequency of spontaneous and miniature excitatory postsynaptic currents. In vivo, acute treatment of Mecp2-null and -heterozygous mutants with LM22A-4 completely eliminated spontaneous apneas in resting animals, without sedation. Moreover, we demonstrate that respiratory dysregulation during behavioral arousal, a feature of human RTT, is also reversed in Mecp2 mutants by acute treatment with LM22A-4. Together, these data support the hypothesis that reduced BDNF signaling and respiratory dysfunction in RTT are linked, and establish the proof-of-concept that treatment with a small-molecule structural mimetic of a BDNF loop domain and a TrkB partial agonist can acutely reverse abnormal breathing at rest and in response to behavioral arousal in symptomatic RTT mice.