Early-stage photodegradation of aromatic poly(urethane-urea) elastomers

The photooxidative stability of an aromatic segmented poly(urethane-urea) (PUU) elastomer, stabilised with a range of carbon black fillers, was assessed after very low UVA doses as a means to identify components that are highly susceptible to UV degradation, and suggest better design of such materials. Fourier-transform infrared (FTIR) analysis indicated rapid degradation of the urea bonds in the hard segments, followed by chain scission and photo-Fries reaction of the urethane linkages. In the soft segments, the oxidation of the original ether groups resulted in the formation of large amounts of ester groups, while some crosslinking of the ether groups was also evident. Carbon black provided moderate protection against degradation, with the smallest-sized particles being the most effective. Protection was evidenced by reduced surface cracking as well as an increased resistance to chemical changes in both the soft segments and hard segments. Even so, significant degradation was still evident at low UV doses suggesting that further stabilisation is required to increase the UV durability of these elastomers and improve their long-term performance

Experiential Exposure as the Key to Recruiting Medical Students Into Pathology

Medical student interest and pursuit of a career in pathology have been steadily declining since 2015. We conducted three separate surveys of medical students to better understand these trends. In our first survey, we focused on assessing U.S. allopathic medical students understanding and perceptions of pathology. We later surveyed U.S. osteopathic medical students as a companion to the allopathic medical student survey, in which many similarities were discovered with some key differences. In our final survey, we specifically looked at curriculum differences between the U.S. allopathic medical schools that graduate the most students who enter pathology training programs (Group 1) versus those schools that graduate the fewest future pathologists (Group 2) to determine if the curriculum had an impact on medical student matriculation into pathology. Together, through these surveys, we were able to identify several remarkable recurring trends, presenting areas of targetable action. Here, we summarize themes from the three studies as well as a review of pertinent literature to offer best practices for exposing and engaging medical students to pathology and possibly recruiting students to consider pathology as a career

How Influential Are Medical School Curriculum and Other Medical School Characteristics in Students’ Selecting Pathology as a Specialty?

There has been a significant decline in the number of United States allopathic medical students matching to pathology residency programs. Data acquired from the American Association of Medical Colleges (AAMC) show sustained variation in the medical school production of students who go on to pathology residency. When divided into groups based on the medical school\u27s historical volume of graduates entering pathology, the schools in groups labeled Group 1 and Group 2 produced significantly higher and lower proportions of pathology residents, respectively. This study aimed to identify what medical school curriculum elements and other medical school characteristics might explain the differences observed in the AAMC data. The Dean or another undergraduate medical education contact from the Group 1 and Group 2 schools was invited to participate in an interview. Pathology Program Directors and Pathology Department Chairs were also included in communications. Thirty interviews were completed with equal numbers from each group. Interview questions probed pathology experiences, existence, and structure of a pathology interest group, options for post-sophomore fellowships, recent curriculum changes, and the extent of mentoring programs. Surprisingly, the curriculum does not appear to be a predictor of a medical school\u27s production of students who enter pathology residency. A significantly greater percentage of Group 1 schools are public institutions compared to Group 2 schools. Other factors that may increase the number of students who go into pathology include mentoring, active learning versus observation, and post-sophomore fellowships or other opportunities to work in the capacity of a new pathology resident

Informing the development of Australia's national eating disorders research and translation strategy : a rapid review methodology

Background Eating disorders (EDs) are highly complex mental illnesses associated with significant medical complications. There are currently knowledge gaps in research relating to the epidemiology, aetiology, treatment, burden, and outcomes of eating disorders. To clearly identify and begin addressing the major deficits in the scientific, medical, and clinical understanding of these mental illnesses, the Australian Government Department of Health in 2019 funded the InsideOut Institute (IOI) to develop the Australian Eating Disorder Research and Translation Strategy, the primary aim of which was to identify priorities and targets for building research capacity and outputs. A series of rapid reviews (RR) were conducted to map the current state of knowledge, identify evidence gaps, and inform development of the national research strategy. Published peer-reviewed literature on DSM-5 listed EDs, across eight knowledge domains was reviewed: (1) population, prevalence, disease burden, Quality of Life in Western developed countries; (2) risk factors; (3) co-occurring conditions and medical complications; (4) screening and diagnosis; (5) prevention and early intervention; (6) psychotherapies and relapse prevention; (7) models of care; (8) pharmacotherapies, alternative and adjunctive therapies; and (9) outcomes (including mortality). While RRs are systematic in nature, they are distinct from systematic reviews in their aim to gather evidence in a timely manner to support decision-making on urgent or high-priority health concerns at the national level. Results Three medical science databases were searched as the primary source of literature for the RRs: Science Direct, PubMed and OVID (Medline). The search was completed on 31st May 2021 (spanning January 2009-May 2021). At writing, a total of 1,320 articles met eligibility criteria and were included in the final review. Conclusions For each RR, the evidence has been organised to review the knowledge area and identify gaps for further research and investment. The series of RRs (published separately within the current series) are designed to support the development of research and translation practice in the field of EDs. They highlight areas for investment and investigation, and provide researchers, service planners and providers, and research funders rapid access to quality current evidence, which has been synthesised and organised to assist decision-making

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Degradation and stabilization of polyurethane elastomers

Polyurethane elastomers have a combination of excellent mechanical, physical and chemical properties along with exceptional biocompatibility. Therefore, these elastomeric systems are used in a diverse range of indoor, outdoor, underwater and biomedical applications. However, under certain conditions polyurethane elastomers undergo degradation, resulting in modified properties during usage or even complete failure. The degradation will not only severely affect the quality of the associated items, devices, or instruments, but may also cause catastrophic outcomes risking people’s safety and health. This review presents a comprehensive survey of the literature regarding various types of degradation of polyurethane elastomers, including photo-, thermal, ozonolytic, hydrolytic, chemical, enzymatic, in-vivo/in-vitro oxidative, biological, and mechanical degradation. The stability of polyurethane elastomers based on different building blocks of macrodiols (polyester, polyether, polycarbonate, polybutadiene, and polyisobutylene), isocyanates (aromatic and aliphatic), and chain extenders (diols, triols, and diamines) are summarised, and the mechanisms of different types of degradation are presented. The chemical components significantly influence not only the material structure and properties but also the degradative stability. Focussing on the components, we explore strategies for the enhancement of polyurethane stability through chemistry and engineering. A range of stabilizers, including both organic and inorganic additives for better stability against different types of degradation, are discussed, with a focus on their efficacy and mechanisms of action. A perspective on novel polyurethane materials with desired structures and properties combined with exceptional stability is also provided

Dysphagia and quality of life, participation, and inclusion experiences and outcomes for adults and children with dysphagia : a scoping review

Purpose: Research shows that dysphagia impacts quality of life negatively, but the nature of these impacts is not well understood. This review article aims to examine the impacts of dysphagia and its interventions on mealtime-related quality of life, participation, and inclusion for people with dysphagia. Method: The protocol for this scoping review was published in July 2019 and involved a search of five scientific databases using dysphagia and quality of life–related terms. Results: In total, 106 studies were included in this review article. A qualitative metasynthesis demonstrated that dysphagia had various negative impacts on quality of life, particularly in populations with severe dysphagia. Dysphagia interventions had a range of positive impacts on quality of life; however, modifying food texture also had negative impacts. Most studies (n = 95) included adults with acquired dysphagia. Only seven studies included people with lifelong conditions, including cerebral palsy or intellectual disability, and only four studies included children. Almost half of the studies (n = 44) used quantitative instruments, including the Swallowing Quality of Life questionnaire or the Eating Assessment Tool, to measure the impact of dysphagia on quality of life, and few studies used qualitative approaches. Conclusions: There are both positive and negative impacts of dysphagia and dysphagia-related interventions on quality of life, participation, and inclusion. Most research is quantitative and limited to adults with acquired dysphagia. Qualitative and longitudinal studies that include populations with lifelong disability and children are needed to determine how dysphagia and its interventions impact quality of life across conditions and over the life span