It's time to regulate - The importance of accurate surgical-grade tourniquet autoregulation in blood flow restriction exercise applications.

OBJECTIVE: Evaluate the efficacy of five common blood flow restriction (BFR) systems to accurately maintain and autoregulate BFR pressure in the tourniquet cuff near target pressure throughout exercise. DESIGN: Randomised crossover design. SETTING: Laboratory. PARTICIPANTS: 15 healthy individuals. OUTCOME MEASURES: 1) Percentage of total BFR time that surgical-grade tourniquet autoregulation, defined as automatic and rapid self-regulation of cuff pressure to within ±15 mmHg of initial target pressure within 1 s in the presence of transient pressure changes associated with exercise, was provided; 2) pressure change in the BFR cuff throughout exercise, by comparing the initial target pressure to the measured pressure at completion of BFR exercise. RESULTS: One BFR system could provide surgical-grade tourniquet autoregulation for the whole duration (100 ± 0%) of the BFR exercise in all subjects. In two of the five BFR systems evaluated, measured cuff pressure at the end of exercise was not different (p < 0.05) to the initial target pressure. CONCLUSIONS: Surgical-grade tourniquet autoregulation is important to consistently and reliably apply a targeted BFR pressure stimulus. This may allow BFR methodology and protocols to be accurately implemented and controlled so that the results can be more meaningfully compared, leading to the potential optimization of applications.

Alternatives to remifentanil for the analgesic component of total intravenous anaesthesia: a narrative review.

Propfol-remifentanil-based total intravenous anaesthesia has dominated recent clinical practice due to its favourable pharmacokinetic profile. Interruption in remifentanil supply has presented an opportunity to diversify or even avoid the use of opioids and consider adjuncts to propofol-based total intravenous anaesthesia. Propofol, while a potent hypnotic, is not an effective analgesic. The administration of opioids, along with other adjuncts such as α-2 adrenoceptor agonists, magnesium, lidocaine, ketamine and nitrous oxide provide surgical anaesthesia and avoids large doses of propofol being required. We provide an overview of both target-control and manual infusion regimes for the alternative opioids: alfentanil, sufentanil and fentanyl. The optimal combination of hypnotic-opioid dose, titration sequence and anticipated additional postoperative analgesia required depend on the chosen combination. In addition, we include a brief discussion on the role of non-opioid adjuncts in total intravenous anaesthesia, suggested doses and expected reduction in propofol dose.

Exploring the Relationship between Falls in Long Term Care and Psychoactive Prescribing.

Almost half of patients of nursing home residents experience one fall per year. Falls have associated significant morbidity and mortality, and a proportion of falls can be deemed avoidable. There are a variety of risk factors associated with falls, many of which are not modifiable. There has been increasing focus upon the relationship between psychotropic medications and falls as this is seen a potentially modifiable risk factor. This article reviews some of the clinical challenges about balancing falls risk mitigation strategies with the management of behavioral and psychological symptoms of dementia.

"I'm at breaking point"; Exploring pharmacists' resilience, coping and burnout during the COVID-19 pandemic.

BACKGROUND: There is a lack of evidence on how the multimodal dynamic process of resilience has impacted personal adaptation of frontline healthcare professionals, working under extreme pressure during the COVID-19 global pandemic. OBJECTIVES: To explore resilience, burnout and wellbeing for UK pharmacists in patient-facing roles, including individual and organisational factors that align to the ABC-X theoretical model of the dynamic process of resilience. METHODS: A non-experimental pragmatist research design was adopted, with a cross-sectional online survey distributed via social media and professional networks between June and July 2020. Quantitative data aligned to a positivist research paradigm was collected using validated scores, to statistically analyse wellbeing, burnout and resilience. Qualitative textual data, consistent with an interpretivist research paradigm, were analysed following an inductive thematic approach. RESULTS: A total of 199 surveys from pharmacists working within community, hospital and GP sectors were analysed. Wellbeing scores were strongly correlated to resilience scores. Wellbeing and resilience scores were both inversely correlated with burnout scores. Two-thirds of participants were classified as high-risk within the burnout scales.Key stressors were highlighted by participants, who described how individual resources and perceptions shaped their experience, which overall contributed to their burnout. Organisations that supported pharmacists embraced change and quickly adopted new ways of working, such as teleconsultations, flexible and remote working, redesign of workflow, alongside clear guidance. However, there was also reported frustration at lack of, slow or conflicting guidance from employers. CONCLUSIONS: This study adds to the growing evidence base for how individuals are affected by adverse events in a dynamic environment, alongside the role that employers can play in supporting individual and organisational resilience. It provides an opportunity to learn from pharmacists' responses to the COVID-19 pandemic, and a call to action for healthcare organisations to rebuild and invest resources into sustained support for staff wellbeing.

Phylogenomics of Piranhas and Pacus (Serrasalmidae) Uncovers How Dietary Convergence and Parallelism Obfuscate Traditional Morphological Taxonomy.

The Amazon and neighboring South American river basins harbor the world's most diverse assemblages of freshwater fishes. One of the most prominent South American fish families is the Serrasalmidae (pacus and piranhas), found in nearly every continental basin. Serrasalmids are keystone ecological taxa, being some of the top riverine predators as well as the primary seed dispersers in the flooded forest. Despite their widespread occurrence and notable ecologies, serrasalmid evolutionary history and systematics are controversial. For example, the sister taxon to serrasalmids is contentious, the relationships of major clades within the family are inconsistent across different methodologies, and half of the extant serrasalmid genera are suggested to be non-monophyletic. We analyzed exon capture to reexamine the evolutionary relationships among 63 (of 99) species across all 16 serrasalmid genera and their nearest outgroups, including multiple individuals per species to account for cryptic lineages. To reconstruct the timeline of serrasalmid diversification, we time-calibrated this phylogeny using two different fossil-calibration schemes to account for uncertainty in taxonomy with respect to fossil teeth. Finally, we analyzed diet evolution across the family and comment on associated changes in dentition, highlighting the ecomorphological diversity within serrasalmids. We document widespread non-monophyly of genera within Myleinae, as well as between Serrasalmus and Pristobrycon, and propose that reliance on traits like teeth to distinguish among genera is confounded by ecological homoplasy, especially among herbivorous and omnivorous taxa. We clarify the relationships among all serrasalmid genera, propose new subfamily affiliations, and support hemiodontids as the sister taxon to Serrasalmidae. [Characiformes; exon capture; ichthyochory; molecular time-calibration; piscivory.].

Risk factors associated with experienced stigma among people diagnosed with mental ill-health: a cross-sectional study.

PURPOSE: to examine the relationship between religiosity, social support, trauma, quality of life and experienced stigma of mental illness amongst a population diagnosed with mental ill-health. METHODS: A cross-sectional survey of day service users in Northern Ireland (n = 295) covering a range of issues including religiosity, social support, quality of life and prior experience of trauma. Stigma was measured using a recognised stigma scale. We used multinomial logistic regression to examine risk factors associated with experienced stigma. RESULTS: Univariate analysis showed significant associations between stigma and age, number of friends, social support, quality of life and prior experience of trauma. Age, quality of life, and trauma remained independently associated with stigma in a multivariate logistic regression model (x2(12) = 98.40, p < 0.001). CONCLUSION: Younger people, those with less social support, prior experience of trauma and with poorer quality of life are at increased risk of experiencing stigma related to their diagnosis of mental illness. The findings provide further understanding of stigma and are useful for those overseeing programmes to improve access to mental health treatment.

Functional organisation of the endomembrane network in the digestive gland of the Venus flytrap: revisiting an old story with a new microscopy toolbox.

Up-to-date imaging approaches were used to address the spatiotemporal organisation of the endomembrane system in secretory cells of Dionaea muscipula. Different 'slice and view' methodologies were performed on resin-embedded samples to finally achieve a 3D reconstruction of the cell architecture, using ultrastructural tomography, array tomography, serial block face-scanning electron microscopy (SBF-SEM), correlation, and volume rendering at the light microscopy level. Observations of cryo-fixed samples by high-pressure freezing revealed changes of the endomembrane system that occur after trap activation and prey digestion. They provide evidence for an original strategy that adapts the secretory machinery to a specific and unique case of stimulated exocytosis in plant cells. A first secretion peak is part of a rapid response to deliver digestive fluids to the cell surface, which delivers the needed stock of digestive materials 'on site'. The second peak of activity could then be associated with the reconstruction of the Golgi apparatus (GA), endoplasmic reticulum (ER) and vacuolar machinery, in order to prepare for a subsequent round of prey capture. Tubular continuum between ER and Golgi stacks observed on ZIO-impregnated tissues may correspond to an efficient transfer mechanism for lipids and/or proteins, especially for use in rapidly resetting the molecular GA machinery. The occurrence of one vacuolar continuum may permit continuous adjustment of cell homeostasy. The subcellular features of the secretory cells of Dionaea muscipula outline key innovations in the organisation of plant cell compartmentalisation that are used to cope with specific cell needs such as the full use of the GA as a protein factory, and the ability to create protein reservoirs in the periplasmic space. Shape-derived forces of the pleiomorphic vacuole may act as signals to accompany the sorting and entering flows of the cell.

Evaluation of a dementia awareness programme in UK schools: a qualitative study.

OBJECTIVES: 'Dementia Friends' is a programme used to raise awareness of dementia, developed by the Alzheimer's Society, which has been delivered across the UK to diverse populations, including adolescents. However, there is little evidence available with regards to adolescents' perceptions of the programme and its impact. This study aims to explore this in a group of adolescents from the south of England. STUDY DESIGN: Focus group discussions. METHODS: Thirty adolescents aged between 11 and 16 years were recruited from two schools in East Sussex, England. All had participated in a Dementia Friends session in the past month. Focus group discussions were transcribed, coded and themes were created using inductive thematic analysis. RESULTS: Four themes were identified: (1) perceptions and experiences of dementia, (2) outcomes and learning from Dementia Friends session, (3) reactions to the Dementia Friends session and (4) identified future learning needs. CONCLUSIONS: Adolescents had generally positive opinions about Dementia Friends, particularly the interactive nature of the session. Whilst they felt participating in Dementia Friends improved their attitudes and knowledge, they were often left wanting to learn more. Future research needs to empirically evaluate the extent to which Dementia Friends may improve attitudes and knowledge of dementia.

Perceptions and psychosocial impact of food, nutrition, eating and drinking in people with inflammatory bowel disease: a qualitative investigation of food-related quality of life.

INTRODUCTION: Extensive research has provided an important understanding of the impact of inflammatory bowel disease (IBD) on nutrient intake, requirements and metabolism. By contrast, there has been limited research examining the psychosocial aspects of food, eating and drinking in IBD. The present study aimed to address this unmet need. METHODS: Qualitative semi-structured interviews regarding the perceptions and psychosocial impact of food, eating and drinking were undertaken with 28 purposively selected people with IBD. Interviews were audio-recorded and transcribed verbatim. Colaizzi's framework was used to structure the data analysis. RESULTS: Five major themes were identified. IBD symptoms and both surgical and medical treatments were described as having a direct impact on eating and drinking, with participants also using different food-related strategies to control IBD symptoms. These included a process of experimentation to identify trigger foods, following a severely restricted and limited diet, eating small portions, and eating more frequently. However, their limited knowledge about if, and how, food affected their symptoms, often resulted in negative coping strategies that impacted on psychosocial functioning, including a lack of enjoyment of eating, being afraid to eat and finding social occasions stressful. Managing food and drinking also made food shopping and preparation more burdensome, creating problems with families, at work and for social life, as well as the need for careful preparation and advanced planning of activities. CONCLUSIONS: Inflammatory bowel disease has a profound impact on psychosocial aspects of food and nutrition, which impacts on 'food-related quality of life' (FRQoL). Further research is required to identify interventions that will improve FRQoL in patients with IBD.

Next generation sequencing (NGS) to improve the diagnosis and management of patients with disorders of sex development (DSD).

Disorders of sex development (DSDs) are a diverse group of conditions where the chromosomal, gonadal or anatomical sex can be atypical. The highly heterogeneous nature of this group of conditions often makes determining a genetic diagnosis challenging. Prior to next generation sequencing (NGS) technologies, genetic diagnostic tests were only available for a few of the many DSD-associated genes, which consequently had to be tested sequentially. Genetic testing is key in establishing the diagnosis, allowing for personalised management of these patients. Pinpointing the molecular cause of a patient's DSD can significantly impact patient management by informing future development needs, altering management strategies and identifying correct inheritance pattern when counselling family members. We have developed a 30-gene NGS panel, designed to be used as a frontline test for all suspected cases of DSD (both 46,XX and 46,XY cases). We have confirmed a diagnosis in 25 of the 80 patients tested to date. Confirmed diagnoses were linked to mutations in AMH, AMHR2, AR, HSD17B3, HSD3B2, MAMLD1, NR5A1, SRD5A2 and WT1 which have resulted in changes to patient management. The minimum diagnostic yield for patients with 46,XY DSD is 25/73. In 34/80 patients, only benign or likely benign variants were identified, and in 21/80 patients only variants of uncertain significance (VOUS) were identified, resulting in a diagnosis not being confirmed in these individuals. Our data support previous studies that an NGS panel approach is a clinically useful and cost-effective frontline test for patients with DSDs.

Monitoring the past and choosing the future: the prefrontal cortical influences on voluntary action.

Choosing between equivalent response options requires the resolution of ambiguity. One could facilitate such decisions by monitoring previous actions and implementing transient or arbitrary rules to differentiate response options. This would reduce the entropy of chosen actions. We examined voluntary action decisions during magnetoencephalography, identifying the spatiotemporal correlates of stimulus- and choice-entropy. Negative correlations between frontotemporal activity and entropy of past trials were observed after participants' responses, reflecting sequential monitoring of recent events. In contrast, choice entropy correlated negatively with prefrontal activity, before and after participants' response, consistent with transient activation of latent response-sets ahead of a decision and updating the monitor of recent decisions after responding. Individual differences in current choices were related to the strength of the prefrontal signals that reflect monitoring of the statistical regularities in previous events. Together, these results explain individual expressions of voluntary action, through differential engagement of prefrontal areas to guide sequential decisions.

Interface pressure, perceptual, and mean arterial pressure responses to different blood flow restriction systems.

This study examined the cuff to limb interface pressure during blood flow restriction (BFR), and the perceptual and mean arterial pressure responses, in different BFR systems. Eighteen participants attended three experimental sessions in a randomised, crossover, counterbalanced design. Participants underwent inflations at 40% and 80% limb occlusive pressure (LOP) at rest and completed 4 sets of unilateral leg press exercise at 30% of one repetition maximum with BFR at 80% LOP. Different BFR systems were used each session: an automatic rapid-inflation (RI), automatic personalized tourniquet (PT) and manual handheld pump and sphygmomanometer (HS) system. Interface pressure was measured using a universal interface device with pressure sensors. Perceived exertion and pain were measured after each set, mean arterial pressure (MAP) was measured pre-, 1-minute post- and 5-minutes post-exercise. Interface pressure was lower than the set pressure in all BFR systems at rest (P < .05). Interface pressure was, on average, 10 ± 8 and 48 ± 36 mm Hg higher than the set pressure in the RI and HS system (P < .01), with no differences observed in the PT system (P > .05), during exercise. Pain and exertion were greater in sets 3 and 4 in the RI and HS system compared to the PT system (P < .05). MAP was higher in the RI and HS system compared to the PT system at 1-minute and 5-minutes post-exercise (P < .05). BFR systems applying higher pressures amplify mean arterial pressure and perceptual responses. Automatic BFR systems appear to regulate pressure effectively within an acceptable range during BFR exercise.

Refined estimates of local recurrence risks by DCIS score adjusting for clinicopathological features: a combined analysis of ECOG-ACRIN E5194 and Ontario DCIS cohort studies.

PURPOSE: Better tools are needed to estimate local recurrence (LR) risk after breast-conserving surgery (BCS) for DCIS. The DCIS score (DS) was validated as a predictor of LR in E5194 and Ontario DCIS cohort (ODC) after BCS. We combined data from E5194 and ODC adjusting for clinicopathological factors to provide refined estimates of the 10-year risk of LR after treatment by BCS alone. METHODS: Data from E5194 and ODC were combined. Patients with positive margins or multifocality were excluded. Identical Cox regression models were fit for each study. Patient-specific meta-analysis was used to calculate precision-weighted estimates of 10-year LR risk by DS, age, tumor size and year of diagnosis. RESULTS: The combined cohort includes 773 patients. The DS and age at diagnosis, tumor size and year of diagnosis provided independent prognostic information on the 10-year LR risk (p ≤ 0.009). Hazard ratios from E5194 and ODC cohorts were similar for the DS (2.48, 1.95 per 50 units), tumor size ≤ 1 versus  > 1-2.5 cm (1.45, 1.47), age ≥ 50 versus < 50 year (0.61, 0.84) and year ≥ 2000 (0.67, 0.49). Utilization of DS combined with tumor size and age at diagnosis predicted more women with very low (≤ 8%) or higher (> 15%) 10-year LR risk after BCS alone compared to utilization of DS alone or clinicopathological factors alone. CONCLUSIONS: The combined analysis provides refined estimates of 10-year LR risk after BCS for DCIS. Adding information on tumor size and age at diagnosis to the DS adjusting for year of diagnosis provides improved LR risk estimates to guide treatment decision making.

Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a 14C-microtracer and therapeutic dose in cancer patients.

INTRODUCTION: Niraparib (Zejula™) is a poly(ADP-ribose) polymerase inhibitor recently approved by the US Food and Drug Administration for the maintenance treatment of patients with recurrent platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. The pivotal phase III clinical trial has shown improved progression-free survival in patients receiving niraparib compared with those receiving placebo. PURPOSE: Since niraparib is administered orally, it is of interest to investigate the oral bioavailability (F po) of this novel compound, which is the aim of this study. METHODS: Six patients received an oral therapeutic dose of 300 mg niraparib, followed by a 15-min intravenous infusion of 100 µg 14C-niraparib with a radioactivity of approximately 100 nCi. The niraparib therapeutic dose was measured in plasma using a validated liquid chromatography-tandem mass spectrometry method, whereas the total 14C-radioactivity and 14C-niraparib plasma levels were measured by accelerator mass spectrometry and a validated high performance liquid chromatography assay with AMS. RESULTS: The F po of niraparib was determined to be 72.7% in humans.

Correction to: Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a 14C-microtracer and therapeutic dose in cancer patients.

The article ''Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a 14C-microtracer and therapeutic dose in cancer patients'', written by L. van Andel, H. Rosing, Z. Zhang, L. Hughes, V. Kansra, M. Sanghvi, M. M. Tibben, A. Gebretensae, J. H. M. Schellens and J. H. Beijnen, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 17th October 2017 without open access.

The Impact of Cardiac Radiation Dosimetry on Survival After Radiation Therapy for Non-Small Cell Lung Cancer.

PURPOSE: The heart receives high radiation doses during radiation therapy of advanced-stage lung cancer. We have explored associations between overall survival, cardiac radiation doses, and electrocardiographic (ECG) changes in patients treated in IDEAL-CRT, a trial of isotoxically escalated concurrent chemoradiation delivering tumor doses of 63 to 73 Gy. METHODS AND MATERIALS: Dosimetric and survival data were analyzed for 78 patients. The whole heart, pericardium, AV node, and walls of left and right atria (LA/RA-Wall) and ventricles (LV/RV-Wall) were outlined on radiation therapy planning scans, and differential dose-volume histograms (dDVHs) were calculated. For each structure, dDVHs were approximated using the average dDVH and the 10 highest-ranked structure-specific principal components (PCs). ECGs at baseline and 6 months after radiation therapy were analyzed for 53 patients, dichotomizing patients according to presence or absence of "any ECG change" (conduction or ischemic/pericarditis-like change). All-cause death rate (DR) was analyzed from the start of treatment using Cox regression. RESULTS: 38% of patients had ECG changes at 6 months. On univariable analysis, higher scores for LA-Wall-PC6, Heart-PC6, "any ECG change," and larger planning target volume (PTV) were significantly associated with higher DR (P=.003, .009, .029, and .037, respectively). Heart-PC6 and LA-Wall-PC6 represent larger volumes of whole heart and left atrial wall receiving 63 to 69 Gy. Cardiac doses ≥63 Gy were concentrated in the LA-Wall, and consequently Heart-PC6 was highly correlated with LA-Wall-PC6. "Any ECG change," LA-Wall-PC6 scores, and PTV size were retained in the multivariable model. CONCLUSIONS: We found associations between higher DR and conduction or ischemic/pericarditis-like changes on ECG at 6 months, and between higher DR and higher Heart-PC6 or LA-Wall-PC6 scores, which are closely related to heart or left atrial wall volumes receiving 63 to 69 Gy in this small cohort of patients.

Mechanistic understanding of the link between Sodium Starch Glycolate properties and the performance of tablets made by wet granulation.

The impact of varying Sodium Starch Glycolate (SSG) grade and wet granulation intensity on the mechanism of disintegration and dissolution of mannitol-based Immediate Release (IR) placebo tablets was investigated. MRI and 1H NMR provided mechanistic insight, and revealed a four-fold range in both tablet disintegration and dissolution rates. MRI was used to quantify the rates of change in tablet volumes and the data fitted to a hydration/erosion model. Reduced levels of cross-linking change SSG from a swelling to a gelling matrix. The tablet hydration and dissolution rates are related to the viscosity at the tablet-solution interface, with high viscosities limiting mass transport.