A molecular switch controls the impact of cholesterol on a Kir channel.

SignificanceCholesterol is one of the main components found in plasma membranes and is involved in lipid-dependent signaling enabled by integral membrane proteins such as inwardly rectifying potassium (Kir) channels. Similar to other ion channels, most of the Kir channels are down-regulated by cholesterol. One of the very few notable exceptions is Kir3.4, which is up-regulated by this important lipid. Here, we discovered and characterized a molecular switch that controls the impact (up-regulation vs. down-regulation) of cholesterol on Kir3.4. Our results provide a detailed molecular mechanism of tunable cholesterol regulation of a potassium channel.

A practical evidence-based approach to management of type 2 diabetes in children and young people (CYP): UK consensus.

BACKGROUND: Type 2 diabetes in young people is an aggressive disease with a greater risk of complications leading to increased morbidity and mortality during the most productive years of life. Prevalence in the UK and globally is rising yet experience in managing this condition is limited. There are no consensus guidelines in the UK for the assessment and management of paediatric type 2 diabetes. METHODS: Multidisciplinary professionals from The Association of Children's Diabetes Clinicians (ACDC) and the National Type 2 Diabetes Working Group reviewed the evidence base and made recommendations using the Grading Of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. RESULTS AND DISCUSSION: Young people with type 2 diabetes should be managed within a paediatric diabetes team with close working with adult diabetes specialists, primary care and other paediatric specialties. Diagnosis of diabetes type can be challenging with many overlapping features. Diabetes antibodies may be needed to aid diagnosis. Co-morbidities and complications are frequently present at diagnosis and should be managed holistically. Lifestyle change and metformin are the mainstay of early treatment, with some needing additional basal insulin. GLP1 agonists should be used as second-line agents once early ketosis and symptoms are controlled. Glycaemic control improves microvascular but not cardiovascular risk. Reduction in excess adiposity, smoking prevention, increased physical activity and reduction of hypertension and dyslipidaemia are essential to reduce major adverse cardiovascular events. CONCLUSIONS: This evidence-based guideline aims to provide a practical approach in managing this condition in the UK.

Should AMOC observations continue: how and why?

The Atlantic meridional overturning circulation (AMOC) is a large-scale circulation pattern responsible for northward heat transport in the Atlantic and is associated with climate variations on a wide range of time scales. Observing the time-varying AMOC has fundamentally changed our understanding of the large-scale ocean circulation and its interaction with the climate system, as well as identified shortcomings in numerical simulations. With a wide range of gains already achieved, some now ask whether AMOC observations should continue. A measured approach is required for a future observing system that addresses identified gaps in understanding, accounts for shortcomings in observing methods and maximizes the potential to guide improvements in ocean and climate models. Here, we outline a perspective on future AMOC observing and steps that the community should consider to move forward. This article is part of a discussion meeting issue 'Atlantic overturning: new observations and challenges'.

Selectivity filter modalities and rapid inactivation of the hERG1 channel.

The human ether-á-go-go-related gene (hERG1) channel conducts small outward K+ currents that are critical for cardiomyocyte membrane repolarization. The gain-of-function mutation N629D at the outer mouth of the selectivity filter (SF) disrupts inactivation and K+-selective transport in hERG1, leading to arrhythmogenic phenotypes associated with long-QT syndrome. Here, we combined computational electrophysiology with Markov state model analysis to investigate how SF-level gating modalities control selective cation transport in wild-type (WT) and mutant (N629D) hERG1 variants. Starting from the recently reported cryogenic electron microscopy (cryo-EM) open-state channel structure, multiple microseconds-long molecular-dynamics (MD) trajectories were generated using different cation configurations at the filter, voltages, electrolyte concentrations, and force-field parameters. Most of the K+ permeation events observed in hERG1-WT simulations occurred at microsecond timescales, influenced by the spontaneous dehydration/rehydration dynamics at the filter. The SF region displayed conductive, constricted, occluded, and dilated states, in qualitative agreement with the well-documented flickering conductance of hERG1. In line with mutagenesis studies, these gating modalities resulted from dynamic interaction networks involving residues from the SF, outer-mouth vestibule, P-helices, and S5-P segments. We found that N629D mutation significantly stabilizes the SF in a state that is permeable to both K+ and Na+, which is reminiscent of the SF in the nonselective bacterial NaK channel. Increasing the external K+ concentration induced "WT-like" SF dynamics in N629D, in qualitative agreement with the recovery of flickering currents in experiments. Overall, our findings provide an understanding of the molecular mechanisms controlling selective transport in K+ channels with a nonconventional SF sequence.

Skin biomechanical properties and leg volume in aging healthy adults.

BACKGROUND: In adults ageing is accompanied by changes in limb volume and skin biomechanical properties. OBJECTIVES: To explore the relationship between body size, aging, skin biomechanics, and leg volume, VLeg and to define predictive equations linking leg volume with these properties. METHODS: Sixty-two healthy adults (Age 18-80 years, M:F 45:55) were recruited. Anthropomorphic measures were recorded along with VLeg (via circumferential method) and skin tone, stiffness, and elastance (via tonometry). Regression analysis was performed to define relationship between the measured parameters. RESULTS: In healthy adults bilateral VLeg were the same regardless of leg or sex, 5791 ± 1363 for females and 6151 ± 1203 mls for males. VLeg was positively correlated to body weight, where VLeg (mls) = 1058 + 69 × Wt (kg) for females and VLeg (mls) = 539 + 65 × Wt (Kg) of body weight for males. Skin surface biomechanical properties varied with sex, leg volume, and location on the leg with the malleolus exhibiting the stiffest surface. CONCLUSION: The study shows that anthropometric measures change with sex and leg size are multifactorial and body weight, sex, and skin condition as important determinant factors of leg volume.

I22: SAXS/WAXS beamline at Diamond Light Source - an overview of 10 years operation.

Beamline I22 at Diamond Light Source is dedicated to the study of soft-matter systems from both biological and materials science. The beamline can operate in the range 3.7 keV to 22 keV for transmission SAXS and 14 keV to 20 keV for microfocus SAXS with beam sizes of 240 µm × 60 µm [full width half-maximum (FWHM) horizontal (H) × vertical (V)] at the sample for the main beamline, and approximately 10 µm × 10 µm for the dedicated microfocusing platform. There is a versatile sample platform for accommodating a range of facilities and user-developed sample environments. The high brilliance of the insertion device source on I22 allows structural investigation of materials under extreme environments (for example, fluid flow at high pressures and temperatures). I22 provides reliable access to millisecond data acquisition timescales, essential to understanding kinetic processes such as protein folding or structural evolution in polymers and colloids.

Mass Equilibration and Fluctuations in the Angular Momentum Dependent Dynamics of Heavy Element Synthesis Reactions.

Mass and angle distributions for the ^{52}Cr+^{198}Pt and ^{54}Cr+^{196}Pt reactions (both forming ^{250}No) were measured and subtracted, giving new information on fast quasifission mass evolution, and the first direct determination of the dependence of sticking times on angular momentum. TDHF calculations showed good agreement with average experimental values, but experimental mass distributions unexpectedly extended to symmetric splits while the peak yield remained close to the initial masses. This implies a strong role of fluctuations in mass division early in the collision, giving insights into the transition from fast energy dissipative deep-inelastic collisions to quasifission.

Toward Reducing hERG Affinities for DAT Inhibitors with a Combined Machine Learning and Molecular Modeling Approach.

Psychostimulant drugs, such as cocaine, inhibit dopamine reuptake via blockading the dopamine transporter (DAT), which is the primary mechanism underpinning their abuse. Atypical DAT inhibitors are dissimilar to cocaine and can block cocaine- or methamphetamine-induced behaviors, supporting their development as part of a treatment regimen for psychostimulant use disorders. When developing these atypical DAT inhibitors as medications, it is necessary to avoid off-target binding that can produce unwanted side effects or toxicities. In particular, the blockade of a potassium channel, human ether-a-go-go (hERG), can lead to potentially lethal ventricular tachycardia. In this study, we established a counter screening platform for DAT and against hERG binding by combining machine learning-based quantitative structure-activity relationship (QSAR) modeling, experimental validation, and molecular modeling and simulations. Our results show that the available data are adequate to establish robust QSAR models, as validated by chemical synthesis and pharmacological evaluation of a validation set of DAT inhibitors. Furthermore, the QSAR models based on subsets of the data according to experimental approaches used have predictive power as well, which opens the door to target specific functional states of a protein. Complementarily, our molecular modeling and simulations identified the structural elements responsible for a pair of DAT inhibitors having opposite binding affinity trends at DAT and hERG, which can be leveraged for rational optimization of lead atypical DAT inhibitors with desired pharmacological properties.

Cost-effectiveness of mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage: an economic evaluation based on the MifeMiso trial.

OBJECTIVE: To assess the cost-effectiveness of mifepristone and misoprostol (MifeMiso) compared with misoprostol only for the medical management of a missed miscarriage. DESIGN: Within-trial economic evaluation and model-based analysis to set the findings in the context of the wider economic evidence for a range of comparators. Incremental costs and outcomes were calculated using nonparametric bootstrapping and reported using cost-effectiveness acceptability curves. Analyses were performed from the perspective of the UK's National Health Service (NHS). SETTING: Twenty-eight UK NHS early pregnancy units. SAMPLE: A cohort of 711 women aged 16-39 years with ultrasound evidence of a missed miscarriage. METHODS: Treatment with mifepristone and misoprostol or with matched placebo and misoprostol tablets. MAIN OUTCOME MEASURES: Cost per additional successfully managed miscarriage and quality-adjusted life years (QALYs). RESULTS: For the within-trial analysis, MifeMiso intervention resulted in an absolute effect difference of 6.6% (95% CI 0.7-12.5%) per successfully managed miscarriage and a QALYs difference of 0.04% (95% CI -0.01 to 0.1%). The average cost per successfully managed miscarriage was lower in the MifeMiso arm than in the placebo and misoprostol arm, with a cost saving of £182 (95% CI £26-£338). Hence, the MifeMiso intervention dominated the use of misoprostol alone. The model-based analysis showed that the MifeMiso intervention is preferable, compared with expectant management, and this is the current medical management strategy. However, the model-based evidence suggests that the intervention is a less effective but less costly strategy than surgical management. CONCLUSIONS: The within-trial analysis found that based on cost-effectiveness grounds, the MifeMiso intervention is likely to be recommended by decision makers for the medical management of women presenting with a missed miscarriage. TWEETABLE ABSTRACT: The combination of mifepristone and misoprostol is more effective and less costly than misoprostol alone for the management of missed miscarriages.

Barriers to Prescribing Opioids in the Management of Chronic Breathlessness in COPD: A Review.

In people with COPD breathlessness is a common symptom and if mistreated can result in poor physical health and reduced quality of life. While it is important to manage the breathlessness using non-pharmacological management, persistent breathlessness may be treated with opioids. However, some physicians are reluctant to prescribe opioids to manage breathlessness in COPD. The aim of this review is to report the views, attitudes and barriers (if any) of healthcare professionals towards using opioids to manage chronic breathlessness in COPD. A review of the relevant literature was undertaken, using CINAHL, ScienceDirect and PubMed databases. The selected literature was assessed for quality of study design and methods used. Eleven studies (three qualitative, three mixed-methods and five quantitative) were reviewed and three themes were identified. Opioid use for refractory breathlessness in COPD is likely under prescribed by health care professionals working in areas other than palliative care. Additionally, there is a lack of confidence in using opioids except in those with palliative care experience, who are more likely to believe opioids may be helpful. Barriers identified are a lack of training, education, inadequate guidelines and concerns surrounding respiratory depression and other side effects. Research on this topic is mainly comprised of interviews or surveys and is low to moderate quality. Further clinical trials are needed on this topic including the opinions of all prescribing health care professionals involved in the care of these patients. Additionally, guidelines should offer further advice on when to start opioids and which patients would benefit most from opioids.

Artificial intelligence using convolutional neural networks for real-time detection of early esophageal neoplasia in Barrett's esophagus (with video).

BACKGROUND AND AIMS: The visual detection of early esophageal neoplasia (high-grade dysplasia and T1 cancer) in Barrett's esophagus (BE) with white-light and virtual chromoendoscopy still remains challenging. The aim of this study was to assess whether a convolutional neural artificial intelligence network can aid in the recognition of early esophageal neoplasia in BE. METHODS: Nine hundred sixteen images from 65 patients of histology-proven early esophageal neoplasia in BE containing high-grade dysplasia or T1 cancer were collected. The area of neoplasia was masked using image annotation software. Nine hundred nineteen control images were collected of BE without high-grade dysplasia. A convolutional neural network (CNN) algorithm was pretrained on ImageNet and then fine-tuned with the goal of providing the correct binary classification of "dysplastic" or "nondysplastic." We developed an object detection algorithm that drew localization boxes around regions classified as dysplasia. RESULTS: The CNN analyzed 458 test images (225 dysplasia and 233 nondysplasia) and correctly detected early neoplasia with sensitivity of 96.4%, specificity of 94.2%, and accuracy of 95.4%. With regard to the object detection algorithm for all images in the validation set, the system was able to achieve a mean average precision of .7533 at an intersection over union of .3 CONCLUSIONS: In this pilot study, our artificial intelligence model was able to detect early esophageal neoplasia in BE images with high accuracy. In addition, the object detection algorithm was able to draw a localization box around the areas of dysplasia with high precision and at a speed that allows for real-time implementation.

"I can guess the month but beyond that, I can't tell" an exploratory qualitative study of health care provider perspectives on gestational age estimation in Rajasthan, India.

BACKGROUND: Accurately estimating gestational age is essential to the provision of time-sensitive maternal and neonatal interventions, including lifesaving measures for imminent preterm birth and trimester-specific health messaging. METHODS: We explored healthcare provider perspectives on gestational age estimation in the state of Rajasthan, India, including the methods they use (last menstrual period [LMP] dating, ultrasound, or fundal height measurement); barriers to making accurate estimates; how gestational age estimates are documented and used for clinical decision-making; and what could help improve the accuracy and use of these estimates. We interviewed 20 frontline healthcare providers and 10 key informants. Thematic network analysis guided our coding and synthesis of findings. RESULTS: Health care providers reported that they determined gestational age using some combination of LMP, fundal height, and ultrasound. Their description of their practices showed a lack of standard protocol, varying levels of confidence in their capacity to make accurate estimates, and differing strategies for managing inconsistencies between estimates derived from different methods. Many frontline healthcare providers valued gestational age estimation more to help women prepare for childbirth than as a tool for clinical decision making. Feedback on accuracy was rare. The providers sampled could not offer ultrasound directly, and instead could only refer women to ultrasound at higher level facilities, and usually only in the second or third trimesters because of late antenatal care-seeking. Low recall among pregnant women limited the accuracy of LMP. Fundal height was heavily relied upon, despite its lack of precision. CONCLUSION: The accuracy of gestational age estimates is influenced by factors at four levels: 1. health system (protocols to guide frontline workers, interventions that make use of gestational age, work environment, and equipment); 2. healthcare provider (technical understanding of and capacity to apply the gestational age estimation methods, communication and rapport with clients, and value assessment of gestational age); 3. client (time of first antenatal care, migration status, language, education, cognitive approach to recalling dates, and experience with biomedical services); and, 4. the inherent limitations and ease of application of the methods themselves.

Investigating the nutritional advice and support given to colorectal cancer survivors in the UK: is it fit for purpose and does it address their needs?

BACKGROUND: The present study assessed the quantity and quality of nutritional advice and support given to colorectal cancer survivors in the UK. METHODS: A descriptive cross-sectional survey was completed by 75 colorectal cancer survivors recruited through social media and bowel cancer support groups in the UK. The survey consisted of open-ended and closed questions that aimed to explore the nutritional needs, nutritional advice given and other sources of information accessed by colorectal cancer survivors. RESULTS: Sixty-nine percent of respondents reported that they did not receive any nutritional advice or support from their healthcare team throughout diagnosis, treatment and post-treatment. Colorectal cancer survivors accessed nutritional advice from a variety of sources, mainly cancer charity websites. Respondents expressed their desire for individualised advice relating to their nutritional problems. CONCLUSIONS: The results obtained in the present study indicate that a high proportion of colorectal cancer patients are not receiving the nutritional support that they need to overcome nutritional difficulties. There is an urgent need to improve clinical practice to ensure colorectal patients receive nutritional advice that is both consistent between healthcare professionals and personalised throughout each stage of diagnosis, treatment and post-treatment.

Clinician perception of a novel cardiovascular lifestyle prescription form in the primary and secondary care setting in Wales, UK.

ISSUES ADDRESSED: To establish the views of clinicians on the feasibility and effectiveness of using a novel lifestyle prescription form (LRx) which requires co-signing by clinician and patient and is uniquely based on the design of the standard drug prescription form, in the primary and secondary health care settings. METHODS: Thirty-six participants were issued with a "prescription" pad, of 20 LRx scripts, for 1 month and requested to issue an LRx prescription to patients they deemed suitable during their consultation, recording their reason for use of the LRx. Each clinician was then asked to complete a comprehensive feedback questionnaire. RESULTS: Feedback of the LRx was overwhelmingly positive. The script was viewed as a more effective way to convey and support cardiovascular lifestyle advice, than usual care. Forty per cent (196 of 480) of the LRx scripts that were provided to primary and secondary care clinicians during the study period were issued. In most consultations, the LRx script was issued to reaffirm dietary advice. Nurses and health care assistants were more likely than doctors to use the LRx in response to a request for lifestyle advice from a patient. CONCLUSIONS: The LRx may be a useful addition to the clinician's communication toolkit to stimulate lifestyle behaviour changes in their patients. The main barrier to use in the study was lack of consultation time. SO WHAT?: Issuing the LRx is a method of solidifying lifestyle advice that clinicians could utilise, providing them with another tool in their behaviour change arsenal, particularly with familiarity with the tool.

Mechanisms Suppressing Superheavy Element Yields in Cold Fusion Reactions.

Superheavy elements are formed in fusion reactions which are hindered by fast nonequilibrium processes. To quantify these, mass-angle distributions and cross sections have been measured, at beam energies from below-barrier to 25% above, for the reactions of ^{48}Ca, ^{50}Ti, and ^{54}Cr with ^{208}Pb. Moving from ^{48}Ca to ^{54}Cr leads to a drastic fall in the symmetric fission yield, which is reflected in the measured mass-angle distribution by the presence of competing fast nonequilibrium deep inelastic and quasifission processes. These are responsible for reduction of the compound nucleus formation probablity P_{CN} (as measured by the symmetric-peaked fission cross section), by a factor of 2.5 for ^{50}Ti and 15 for ^{54}Cr in comparison to ^{48}Ca. The energy dependence of P_{CN} indicates that cold fusion reactions (involving ^{208}Pb) are not driven by a diffusion process.

Cost-effectiveness of a peer mentoring intervention to improve disease self-management practices and self-efficacy among African American women with systemic lupus erythematosus: analysis of the Peer Approaches to Lupus Self-management (PALS) pilot study.

OBJECTIVE: The Peer Approaches to Lupus Self-management (PALS) program was developed as a peer mentoring tool to improve health behaviors, beliefs, and outcomes in African American women with systemic lupus erythematosus (SLE). This study aims to assess the cost of the PALS intervention and determine its effectiveness when compared to existing treatments. METHODS: Peer mentors and mentees were paired on shared criteria such as life stage, marital status, or whether they were mothers. This 12-week program consisted of a weekly peer mentoring session by telephone. Cost of healthcare utilization was evaluated by assessing the healthcare costs pre- and post-intervention. Validated measures of quality of life, self-management, disease activity, depression, and anxiety were collected. Total direct program costs per participant were totaled and used to determine average per unit improvement in outcome measures. The benefit-cost ratio and pre- versus post-intervention hospital charges were examined. RESULTS: A total of 20 mentees and 7 mentors were enrolled in the PALS program. All PALS pairs completed 12 sessions lasting an average of 54 minutes. Mentees reported statistically significant decreases in patient-reported disease activity, depression, and anxiety, with improved trends in patient activation or patient engagement in their disease and management. The total cost per patient was $1291.50, which was $107.62 per patient per week. There was a savings of $23,417 per individual receiving the intervention with a benefit-cost ratio of 18.13 per patient. CONCLUSION: These findings suggest that the PALS intervention was effective in improving patient-level factors and was cost-effective. Future research will need to validate these findings in a larger sample.

Exploring Zeptosecond Quantum Equilibration Dynamics: From Deep-Inelastic to Fusion-Fission Outcomes in

Energy dissipative processes play a key role in how quantum many-body systems dynamically evolve toward equilibrium. In closed quantum systems, such processes are attributed to the transfer of energy from collective motion to single-particle degrees of freedom; however, the quantum many-body dynamics of this evolutionary process is poorly understood. To explore energy dissipative phenomena and equilibration dynamics in one such system, an experimental investigation of deep-inelastic and fusion-fission outcomes in the ^{58}Ni+^{60}Ni reaction has been carried out. Experimental outcomes have been compared to theoretical predictions using time dependent Hartree-Fock and time dependent random phase approximation approaches, which, respectively, incorporate one-body energy dissipation and fluctuations. Excellent quantitative agreement has been found between experiment and calculations, indicating that microscopic models incorporating one-body dissipation and fluctuations provide a potential tool for exploring dissipation in low-energy heavy ion collisions.

Vedolizumab as a rescue therapy for patients with medically refractory Crohn's disease.

AIM: Vedolizumab, a monoclonal antibody resulting in gut-selective anti-inflammatory activity, was approved by the US Food and Drug Administration in 2014 for use in patients with Crohn's disease (CD). The aim of this study was to investigate the efficacy of vedolizumab as a rescue therapy when other medical therapies have failed. METHOD: A retrospective review was performed on consecutive patients with CD receiving vedolizumab at the Penn State Hershey IBD Center between May 2014 and March 2016. These patients were unresponsive or intolerant to tumour necrosis factor (TNF) antagonist therapy, and previously would have been candidates for surgery. Outcomes included surgical intervention, clinical response and endoscopic improvement. RESULTS: A total of 48 patients with medically refractory CD receiving vedolizumab were included. The median length of follow-up was 69 weeks (range 15-113 weeks). A majority (81%) of patients previously failed at least two TNF antagonists, and 77% had prior surgery for CD. Surgical intervention was required in 21 (44%) patients and 13 (27%) patients required intra-abdominal operations. At the conclusion of the study, 23 (48%) patients reported continued improvement of symptoms, and 22 of 37 (59%) patients undergoing endoscopy showed improvement. Patients with the inflammatory CD phenotype were more likely to improve clinically and avoid surgery. CONCLUSION: Vedolizumab alone or in combination with immunomodulators or steroids may be used as a rescue therapy in patients with medically refractory CD and may decrease the rate of surgical intervention. Patients with the inflammatory CD phenotype had the best clinical response and decreased need for surgery, suggesting that vedolizumab is most effective in the inflammatory phenotype.