Observational study of the effects of traumatic injury, haemorrhagic shock and resuscitation on the microcirculation: a protocol for the MICROSHOCK study

Introduction: The microcirculation is the physiological site of oxygen and substrate exchange. Its effectiveness during circulatory shock is vital for the perfusion of tissues, and has a bearing on subsequent organ function and prognosis. Microcirculatory dysfunction following traumatic haemorrhagic shock (THS) has been understudied compared with other pathologies such as sepsis. The aim of the MICROSHOCK study is to investigate changes seen in the microcirculation of patients following THS, and to assess its response to resuscitation. A greater understanding of the behaviour and mechanisms of microcirculatory dysfunction in this context may direct future avenues of goal-directed resuscitation for these patients. Methods and analysis: This multicentre prospective longitudinal observational study includes patients who present as an emergency with THS. Microcirculatory parameters are recorded using sublingual incident dark field microscopy alongside measurements of global flow (oesophageal Doppler and transthoracic echocardiography). Patients are enrolled into the study as soon as feasible after they arrive in hospital, and then at subsequent daily time points. Blood samples are taken for investigation into the mechanisms of microcirculatory dysfunction. Sequential Organ Failure Assessment scores will be analysed with microcirculatory parameters to determine whether they correlate with greater fidelity than more conventional, global circulatory parameters. Ethics and dissemination: Research Ethics Committee approval has been granted for this study (Reference: 14/YH/0078). Owing to the nature of THS, capacity for informed consent will be absent on patient enrolment. This will be addressed according to the Mental Health Capacity Act 2005. The physician in charge of the patient's care (nominated consultee) may consent on behalf of the patient. Consent will also be sought from a personal consultee (close relative or friend). After capacity is regained, the participant will be asked for their consent. Results will be submitted for publication in peer-reviewed journal format and presented at relevant academic meetings

Determination of clinical competencies for exercise physiology students

Introduction: Clinical placements and assessment are a key part of health professional education. However, quality assessment in a clinical environment is difficult to achieve without a clear picture of what constitutes competence. The aim of this study was to establish a set of competencies that describe the attributes considered critical to ensuring an entry-level exercise physiologist (EP) can practice safely and effectively with a client-centred philosophy. Methods: This study used a mixed methods, multiphase approach. The competencies, which are organised into units of competency with underlying elements, were developed following online surveys and focus groups involving those with expertise in the area, with additional refinement provided by the project team. A first-stage validation was conducted via electronic survey where (i) participants rated the importance of each unit of competency to practice as an entry-level EP; and (ii) those participants who were recently graduated EPs rated the extent to which they perceived they were competent in each unit. Results: The final set of competencies is described as 19 elements organised into 6 units. The units are: (i) Communication, (ii) Professionalism, (iii) Assessment and Interpretation, (iv) Planning and delivery of an exercise and/or physical activity intervention, (v) Lifestyle Modification and (vi) Risk Management. The majority of survey participants (93-97%) considered each unit of competency as being important to practice successfully as an entry-level EP. The majority (78-95%) of the sub-group who identified as new EPs considered themselves competent in each unit, suggesting the competencies are articulated at the level of a new EP. Conclusion: The competencies resulted from an extensive, iterative process involving those with expertise in the area followed by initial validation. The competencies will have a range of applications, including informing the development of a student placement assessment tool

Determination of clinical competencies for exercise physiology students

Introduction: Clinical placements and assessment are a key part of health professional education. However, quality assessment in a clinical environment is difficult to achieve without a clear picture of what constitutes competence. The aim of this study was to establish a set of competencies that describe the attributes considered critical to ensuring an entry-level exercise physiologist (EP) can practice safely and effectively with a client-centred philosophy. Methods: This study used a mixed methods, multiphase approach. The competencies, which are organised into units of competency with underlying elements, were developed following online surveys and focus groups involving those with expertise in the area, with additional refinement provided by the project team. A first-stage validation was conducted via electronic survey where (i) participants rated the importance of each unit of competency to practice as an entry-level EP; and (ii) those participants who were recently graduated EPs rated the extent to which they perceived they were competent in each unit. Results: The final set of competencies is described as 19 elements organised into 6 units. The units are: (i) Communication, (ii) Professionalism, (iii) Assessment and Interpretation, (iv) Planning and delivery of an exercise and/or physical activity intervention, (v) Lifestyle Modification and (vi) Risk Management. The majority of survey participants (93-97%) considered each unit of competency as being important to practice successfully as an entry-level EP. The majority (78-95%) of the sub-group who identified as new EPs considered themselves competent in each unit, suggesting the competencies are articulated at the level of a new EP. Conclusion: The competencies resulted from an extensive, iterative process involving those with expertise in the area followed by initial validation. The competencies will have a range of applications, including informing the development of a student placement assessment tool

Safety and Efficacy of Nivolumab Monotherapy in Recurrent or Metastatic Cervical, Vaginal, or Vulvar Carcinoma: Results From the Phase I/II CheckMate 358 Trial

Nivolumab; Carcinoma cervical, vaginal o vulvar; Carcinoma metastàticNivolumab; Cervical, vaginal, or vulvar carcinoma; Metastatic carcinomaNivolumab; Carcinoma de cuello uterino, vaginal o vulvar; Carcinoma metastáticoPURPOSE Nivolumab was assessed in patients with virus-associated tumors in the phase I/II CheckMate 358 trial (ClinicalTrials.gov identifier: NCT02488759). We report on patients with recurrent/metastatic cervical, vaginal, or vulvar cancers. PATIENTS AND METHODS Patients received nivolumab 240 mg every 2 weeks. Although patients with unknown human papillomavirus status were enrolled, patients known to have human papillomavirus–negative tumors were ineligible. The primary end point was objective response rate. Duration of response (DOR), progression-free survival, and overall survival were secondary end points. Safety and patient-reported outcomes were exploratory end points. RESULTS Twenty-four patients (cervical, n = 19; vaginal/vulvar, n = 5) were enrolled. Most patients had received prior systemic therapy for metastatic disease (cervical, 78.9%; vaginal/vulvar, 80.0%). Objective response rates were 26.3% (95% CI, 9.1 to 51.2) for cervical cancer and 20.0% (95% CI, 0.5 to 71.6) for vaginal/vulvar cancers. At a median follow-up of 19.2 months, median DOR was not reached (range, 23.3 to 29.5+ months; + indicates a censored observation) in the five responding patients in the cervical cohort; the DOR was 5.0 months in the single responding patient in the vaginal/vulvar cohort. Median overall survival was 21.9 months (95% CI, 15.1 months to not reached) among patients with cervical cancer. Any-grade treatment-related adverse events were reported in 12 of 19 patients (63.2%) in the cervical cohort and all five patients in the vaginal/vulvar cohort; there were no treatment-related deaths. In the cervical cohort, nivolumab treatment generally resulted in stabilization of patient-reported outcomes associated with health status and health-related quality of life. CONCLUSION The efficacy of nivolumab in patients with recurrent/metastatic cervical and vaginal or vulvar cancers is promising and warrants additional investigation. No new safety signals were identified with nivolumab treatment in this population

The influence of expertise on brain activation of the action observation network during anticipation of tennis and volleyball serves

In many daily activities, and especially in sport, it is necessary to predict the effects of others´ actions in order to initiate appropriate responses. Recently, researchers have suggested that the action–observation network (AON) including the cerebellum plays an essential role during such anticipation, particularly in sport expert performers. In the present study, we examined the influence of task-specific expertise on the AON by investigating differences between two expert groups trained in different sports while anticipating action effects. Altogether, 15 tennis and 16 volleyball experts anticipated the direction of observed tennis and volleyball serves while undergoing functional magnetic resonance imaging (fMRI). The expert group in each sport acted as novice controls in the other sport with which they had only little experience. When contrasting anticipation in both expertise conditions with the corresponding untrained sport, a stronger activation of AON areas (SPL, SMA), and particularly of cerebellar structures, was observed. Furthermore, the neural activation within the cerebellum and the SPL was linearly correlated with participant´s anticipation performance, irrespective of the specific expertise. For the SPL, this relationship also holds when an expert performs a domain-specific anticipation task. Notably, the stronger activation of the cerebellum as well as of the SMA and the SPL in the expertise conditions suggests that experts rely on their more fine-tuned perceptual-motor representations that have improved during years of training when anticipating the effects of others´ actions in their preferred sport. The association of activation within the SPL and the cerebellum with the task achievement suggests that these areas are the predominant brain sites involved in fast motor predictions. The SPL reflects the processing of domain-specific contextual information and the cerebellum the usage of a predictive internal model to solve the anticipation task

Aquilegia, Vol. 18 No. 1, January- February 1994: Newsletter of the Colorado Native Plant Society

https://epublications.regis.edu/aquilegia/1069/thumbnail.jp

Safety and Efficacy of Nivolumab Monotherapy in Recurrent or Metastatic Cervical, Vaginal, or Vulvar Carcinoma: Results From the Phase I/II CheckMate 358 Trial

Purpose: Nivolumab was assessed in patients with virus-associated tumors in the phase I/II CheckMate 358 trial (ClinicalTrials.gov identifier: NCT02488759). We report on patients with recurrent/metastatic cervical, vaginal, or vulvar cancers. Patients and methods: Patients received nivolumab 240 mg every 2 weeks. Although patients with unknown human papillomavirus status were enrolled, patients known to have human papillomavirus-negative tumors were ineligible. The primary end point was objective response rate. Duration of response (DOR), progression-free survival, and overall survival were secondary end points. Safety and patient-reported outcomes were exploratory end points. Results: Twenty-four patients (cervical, n = 19; vaginal/vulvar, n = 5) were enrolled. Most patients had received prior systemic therapy for metastatic disease (cervical, 78.9%; vaginal/vulvar, 80.0%). Objective response rates were 26.3% (95% CI, 9.1 to 51.2) for cervical cancer and 20.0% (95% CI, 0.5 to 71.6) for vaginal/vulvar cancers. At a median follow-up of 19.2 months, median DOR was not reached (range, 23.3 to 29.5+ months; + indicates a censored observation) in the five responding patients in the cervical cohort; the DOR was 5.0 months in the single responding patient in the vaginal/vulvar cohort. Median overall survival was 21.9 months (95% CI, 15.1 months to not reached) among patients with cervical cancer. Any-grade treatment-related adverse events were reported in 12 of 19 patients (63.2%) in the cervical cohort and all five patients in the vaginal/vulvar cohort; there were no treatment-related deaths. In the cervical cohort, nivolumab treatment generally resulted in stabilization of patient-reported outcomes associated with health status and health-related quality of life. Conclusion: The efficacy of nivolumab in patients with recurrent/metastatic cervical and vaginal or vulvar cancers is promising and warrants additional investigation. No new safety signals were identified with nivolumab treatment in this population

Shuffled ATG8 interacting motifs form an ancestral bridge between UFMylation and autophagy

UFMylation involves the covalent modification of substrate proteins with UFM1 (Ubiquitin‐fold modifier 1) and is important for maintaining ER homeostasis. Stalled translation triggers the UFMylation of ER‐bound ribosomes and activates C53‐mediated autophagy to clear toxic polypeptides. C53 contains noncanonical shuffled ATG8‐interacting motifs (sAIMs) that are essential for ATG8 interaction and autophagy initiation. However, the mechanistic basis of sAIM‐mediated ATG8 interaction remains unknown. Here, we show that C53 and sAIMs are conserved across eukaryotes but secondarily lost in fungi and various algal lineages. Biochemical assays showed that the unicellular alga Chlamydomonas reinhardtii has a functional UFMylation pathway, refuting the assumption that UFMylation is linked to multicellularity. Comparative structural analyses revealed that both UFM1 and ATG8 bind sAIMs in C53, but in a distinct way. Conversion of sAIMs into canonical AIMs impaired binding of C53 to UFM1, while strengthening ATG8 binding. Increased ATG8 binding led to the autoactivation of the C53 pathway and sensitization of Arabidopsis thaliana to ER stress. Altogether, our findings reveal an ancestral role of sAIMs in UFMylation‐dependent fine‐tuning of C53‐mediated autophagy activation

The German National Registry of Primary Immunodeficiencies (2012-2017)

Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment