Tardigrade secretory proteins protect biological structures from desiccation.

Tardigrades, microscopic animals that survive a broad range of environmental stresses, express a unique set of proteins termed tardigrade-specific intrinsically disordered proteins (TDPs). TDPs are often expressed at high levels in tardigrades upon desiccation, and appear to mediate stress adaptation. Here, we focus on the proteins belonging to the secreted family of tardigrade proteins termed secretory-abundant heat soluble ("SAHS") proteins, and investigate their ability to protect diverse biological structures. Recombinantly expressed SAHS proteins prevent desiccated liposomes from fusion, and enhance desiccation tolerance of E. coli and Rhizobium tropici upon extracellular application. Molecular dynamics simulation and comparative structural analysis suggest a model by which SAHS proteins may undergo a structural transition upon desiccation, in which removal of water and solutes from a large internal cavity in SAHS proteins destabilizes the beta-sheet structure. These results highlight the potential application of SAHS proteins as stabilizing molecules for preservation of cells.

European Respiratory Society clinical practice guideline on symptom management for adults with serious respiratory illness.

Respiratory symptoms are ubiquitous and impair health-related quality of life in people with respiratory disease. This European Respiratory Society (ERS) task force aimed to provide recommendations for symptomatic treatment in people with serious respiratory illness. The ERS task force comprised 16 members, including representatives of people with serious respiratory illness and informal caregivers. Seven questions were formulated, six in the PICO (Population, Intervention, Comparison, Outcome) format, which were addressed with full systematic reviews and evidence assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation). One question was addressed narratively. An "evidence-to-decision" framework was used to formulate recommendations. To treat symptoms in people with serious respiratory illness, the task force suggests the use of graded exercise therapy (conditional recommendation, low certainty of evidence); and suggests the use of a multicomponent services, handheld fan and breathing techniques (conditional recommendations, very low certainty of evidence). The task force suggests not to use opioids (conditional recommendation, very low certainty of evidence); and suggests either administering or not administering supplemental oxygen therapy (conditional recommendation, low certainty of evidence). The task force suggests that needs assessment tools may be used as part of a comprehensive needs assessment, but do not replace patient-centred care and shared decision making (conditional recommendation, low certainty of evidence). The low certainty of evidence, modest impact of interventions on patient-centred outcomes, and absence of effective strategies to ameliorate cough highlight the need for new approaches to reduce symptoms and enhance wellbeing for individuals who live with serious respiratory illness.

Illness perceptions, cognitive and behavioural responses to chronic breathlessness in individuals living with advanced respiratory disease: an observational study.

Background: Understanding the complexity and multidimensional nature of chronic breathlessness is key to its successful management. The aim of this study was to explore illness perceptions, cognitive and behavioural responses to chronic breathlessness in individuals living with advanced respiratory disease. Methods: This was a cross-sectional secondary analysis of data from a feasibility randomised control trial (SELF-BREATHE) for individuals living with chronic breathlessness due to advanced disease. All participants completed the following questionnaires: numerical rating scale (NRS) breathlessness severity, NRS distress due to breathlessness, NRS self-efficacy for managing breathlessness, Dyspnea-12 (D-12), Chronic Respiratory Disease Questionnaire (CRQ), Brief Illness Perception Questionnaire (Brief IPQ) and the Cognitive and Behavioural Responses Questionnaire, short version (CBRQ-S). The associations between the Brief IPQ and CBRQ-S with NRS breathlessness severity, distress and self-efficacy, D-12 and CRQ were examined using Spearman's rho correlation coefficient rs. A Spearman's rs of ≥0.50 was predefined as the threshold to denote important associations between variables. A p-value of <0.008 was considered statistically significant, to account for the number of comparisons performed. Results: The illness perception items consequences, identity, concern and emotional response were associated with increased breathlessness severity, increased distress, reduced breathlessness self-management ability and lower health-related quality of life. Symptom focusing and embarrassment avoidance were identified as important cognitive responses to chronic breathlessness. Conclusion: Interventions that directly target illness perceptions, cognitive and behavioural responses to chronic breathlessness may improve symptom burden, self-efficacy and health-related quality of life.

The clinical utility of the Breathing Pattern Assessment Tool (BPAT) to identify dysfunctional breathing (DB) in individuals living with postural orthostatic tachycardia syndrome (POTS).

BACKGROUND: Dysfunctional breathing (DB) resulting in inappropriate breathlessness is common in individuals living with postural orthostatic tachycardia syndrome (POTS). DB in POTS is complex, multifactorial, and not routinely assessed clinically outside of specialist centres. To date DB in POTS has been identified and diagnosed predominately via cardiopulmonary exercise testing (CPEX), hyperventilation provocation testing and/or specialist respiratory physiotherapy assessment. The Breathing Pattern Assessment Tool (BPAT) is a clinically validated diagnostic tool for DB in Asthma. There are, however, no published data regarding the use of the BPAT in POTS. The aim of this study was therefore to assess the potential clinic utility of the BPAT in the diagnosis of DB in individuals with POTS. METHODS: A retrospective observational cohort study of individuals with POTS referred to respiratory physiotherapy for formal assessment of DB. DB was determined by specialist respiratory physiotherapist assessment which included physical assessment of chest wall movement/breathing pattern. The BPAT and Nijgmegen questionnaire were also completed. Receiver operating characteristics (ROC) analysis was used to compare the physiotherapy assessment based diagnosis of DB to the BPAT score. RESULTS: Seventy-seven individuals with POTS [mean (sd) age 32 (11) years, 71 (92 %) female] were assessed by a specialist respiratory physiotherapist, with 65 (84 %) being diagnosed with DB. Using the established BPAT cut off of four or more, receiver operating characteristics (ROC) analysis indicated a sensitivity of 87 % and specificity of 75 % for diagnosing DB in individuals with POTS with an area under the curve (AUC) of 0.901 (95 % CI 0.803-0.999), demonstrating excellent discriminatory ability. CONCLUSION: BPAT has high sensitivity and moderate specificity for identifying DB in individuals living with POTS.

A randomised, controlled, feasibility trial of an online, self-guided breathlessness supportive intervention (SELF-BREATHE) for individuals with chronic breathlessness due to advanced disease.

Introduction: SELF-BREATHE is a complex, transdiagnostic, supportive, digital breathlessness intervention co-developed with patients. SELF-BREATHE seeks to build capacity and resilience within health services by improving the lives of people with chronic breathlessness using nonpharmacological, self-management approaches. This study aimed to determine whether SELF-BREATHE is feasible to deliver and acceptable to patients living with chronic breathlessness. Methods: A parallel, two-arm, single-blind, single-centre, randomised controlled, mixed-methods feasibility trial with participants allocated to 1) intervention group (SELF-BREATHE) or 2) control group (usual National Health Service (NHS) care). The setting was a large multisite NHS foundation trust in south-east London, UK. The participants were patients living with chronic breathlessness due to advanced malignant or nonmalignant disease(s). Participants were randomly allocated (1:1) to an online, self-guided, breathlessness supportive intervention (SELF-BREATHE) and usual care or usual care alone, over 6 weeks. The a priori progression criteria were ≥30% of eligible patients given an information sheet consented to participate; ≥60% of participants logged on and accessed SELF-BREATHE within 2 weeks; and ≥70% of patients reported the methodology and intervention as acceptable. Results: Between January 2021 and January 2022, 52 (47%) out of 110 eligible patients consented and were randomised. Of those randomised to SELF-BREATHE, 19 (73%) out of 26 logged on and used SELF-BREATHE for a mean±sd (range) 9±8 (1-33) times over 6 weeks. 36 (70%) of the 52 randomised participants completed and returned the end-of-study postal questionnaires. SELF-BREATHE users reported it to be acceptable. Post-intervention qualitative interviews demonstrated that SELF-BREATHE was acceptable and valued by users, improving breathlessness during daily life and at points of breathlessness crisis. Conclusion: These data support the feasibility of moving to a fully powered, randomised controlled efficacy trial with minor modifications to minimise missing data (i.e. multiple methods of data collection: face-to-face, telephone, video assessment and by post).

The evolution of the British Journal of Anaesthesia: the first 100 years.

At this centenary of the British Journal of Anaesthesia (BJA) in 2023, six of its 12 editors/editors-in-chief detail developments over the decades that have led to the BJA becoming a high-impact international scientific journal. As a charity, the BJA supports academic research and training in anaesthesia, critical care, and pain medicine including funding of research grants and postgraduate education. Building on this foundation, the BJA continues to innovate as it aims to become fully electronic, expand into open access publishing, and increase the diversity of its editorial board.

Optimising breathlessness triggered services for older people with advanced diseases: a multicentre economic study (OPTBreathe).

BACKGROUND: In advanced disease, breathlessness becomes severe, increasing health services use. Breathlessness triggered services demonstrate effectiveness in trials and meta-analyses but lack health economic assessment. METHODS: Our economic study included a discrete choice experiment (DCE), followed by a cost-effectiveness analysis modelling. The DCE comprised face-to-face interviews with older patients with chronic breathlessness and their carers across nine UK centres. Conditional logistic regression analysis of DCE data determined the preferences (or not, indicated by negative ß coefficients) for service attributes. Economic modelling estimated the costs and quality-adjusted life years (QALYs) over 5 years. FINDINGS: The DCE recruited 190 patients and 68 carers. Offering breathlessness services in person from general practitioner (GP) surgeries was not preferred (ß=-0.30, 95% CI -0.40 to -0.21); hospital outpatient clinics (0.16, 0.06 to 0.25) or via home visits (0.15, 0.06 to 0.24) were preferred. Inperson services with comprehensive treatment review (0.15, 0.07 to 0.21) and holistic support (0.19, 0.07 to 0.31) were preferred to those without. Cost-effectiveness analysis found the most and the least preferred models of breathlessness services were cost-effective compared with usual care. The most preferred service had £5719 lower costs (95% CI -6043 to 5395), with 0.004 (95% CI -0.003 to 0.011) QALY benefits per patient. Uptake was higher when attributes were tailored to individual preferences (86% vs 40%). CONCLUSION: Breathlessness services are cost-effective compared with usual care for health and social care, giving cost savings and better quality of life. Uptake of breathlessness services is higher when service attributes are individually tailored.

"The whole of humanity has lungs, doesn't it? We are not all the same sort of people": patient preferences and choices for an online, self-guided chronic breathlessness supportive intervention: SELF-BREATHE.

Introduction: The burden of chronic breathlessness on individuals, family, society and health systems is significant and set to increase exponentially with an ageing population with complex multimorbidity, yet there is a lack of services. This has been further amplified by the coronavirus disease 2019 pandemic. Online breathlessness interventions have been proposed to fill this gap, but need development and evaluation based on patient preferences and choices. This study aimed to explore the preferences and choices of patients regarding the content of an online self-guided chronic breathlessness supportive intervention (SELF-BREATHE). Methods: Semi-structured telephone interviews were conducted with adults living with advanced malignant and nonmalignant disease and chronic breathlessness (July to November 2020). Interviews were analysed using conventional and summative content analysis. Results: 25 patients with advanced disease and chronic breathlessness (COPD n=13, lung cancer n=8, interstitial lung disease n=3, bronchiectasis n=1; 17 male; median (range) age 70 (47-86) years; median (range) Medical Research Council dyspnoea score 3 (2-5)) were interviewed. Individuals highlighted strong preferences for focused education, methods to increase self-motivation and engagement, interventions targeting breathing and physical function, software capability to personalise the content of SELF-BREATHE to make it more meaningful to the user, and aesthetically designed content using various communication methods including written, video and audio content. Furthermore, they identified the need to address motivation as a key potential determinant of the success of SELF-BREATHE. Conclusion: Our findings provide an essential foundation for future digital intervention development (SELF-BREATHE) and scaled research.

Single-molecule studies reveal method for tuning the heterogeneous activity of alkaline phosphatase.

Single-molecule-enzymology (SME) methods have enabled the observation of heterogeneous catalytic activities within a single enzyme population. Heterogeneous activity is hypothesized to originate from conformational changes in the enzyme that result from changes in the local environment leading to catalytically active substates. Here, we use SME to investigate the mechanisms of heterogeneous activity exhibited by tissue nonspecific alkaline phosphatase (TNSALP), which reveals two subpopulations with different catalytic activities. We show the effect of pH and temperature on the distribution of TNSALP activity and confirm the presence of two subpopulations attributed to half- and fully active TNSALP substates. We provide mechanistic insight about protein structure using molecular dynamic simulations and show pH- and temperature-dependent conformational transitions that corroborate experimentally observed changes in TNSALP activity. These results show the utility of SME to understand heterogeneous enzyme activity and demonstrate a simple approach using pH and temperature to tune catalytic activity within an enzyme population.

"You can do it yourself and you can do it at your convenience": internet accessibility and willingness of people with chronic breathlessness to use an internet-based breathlessness self-management intervention during the COVID-19 pandemic.

INTRODUCTION: The burden of chronic breathlessness on individuals, family, society and health systems is significant, and set to increase exponentially with population ageing, complex multimorbidity and coronavirus disease 2019 (COVID-19)-related disability. Breathlessness support services are effective; however, reach and access are limited. Delivering online breathlessness interventions may build capacity and resilience within health systems to tackle chronic breathlessness through supported self-management. The aim of this study was to explore accessibility and willingness of patients with chronic breathlessness to use an internet-based breathlessness self-management intervention (SELF-BREATHE). METHODS: Semi-structured telephone interviews were conducted with adults living with advanced malignant and non-malignant disease and chronic breathlessness (July to November 2020). Interviews were analysed using conventional and summative content analysis. RESULTS: 25 patients (COPD: n=13; lung cancer: n=8; interstitial lung disease (ILD): n=3; bronchiectasis: n=1) were interviewed: 17 male, median (range) age 70 (47-86) years and Medical Research Council dyspnoea score 3 (2-5). 21 patients had internet access. Participants described greater use, acceptance and normalisation of the internet since the advent of the COVID-19 pandemic. They described multifaceted internet use: functional, self-investment (improving health and wellbeing) and social. The concept of SELF-BREATHE was highly valued, and most participants with internet access were willing to use it. In addition to technical limitations, personal choice and perceived value of the internet were important factors that underpinned readiness to use online resources. CONCLUSION: These findings suggest that patients living with chronic breathlessness that have access to the internet would have the potential to benefit from the online SELF-BREATHE intervention, if given the opportunity.

Impact of fan therapy during exercise on breathlessness and recovery time in patients with COPD: a pilot randomised controlled crossover trial.

BACKGROUND: Patients with COPD reduce physical activity to avoid the onset of breathlessness. Fan therapy can reduce breathlessness at rest, but the efficacy of fan therapy during exercise remains unknown in this population. The aim of the present study was to investigate 1) the effect of fan therapy on exercise-induced breathlessness and post-exercise recovery time in patients with COPD and 2) the acceptability of fan therapy during exercise; and 3) to assess the reproducibility of any observed improvements in outcome measures. METHODS: A pilot single-centre, randomised, controlled, crossover open (nonmasked) trial (clinicaltrials.gov NCT03137524) of fan therapy versus no fan therapy during 6-min walk test (6MWT) in patients with COPD and a modified Medical Research Council (mMRC) dyspnoea score ≥2. Breathlessness intensity was quantified before and on termination of the 6MWT, using the numerical rating scale (NRS) (0-10). Post-exertional recovery time was measured, defined as the time taken to return to baseline NRS breathlessness score. Oxygen saturation and heart rate were measure pre- and post-6MWT. RESULTS: 14 patients with COPD completed the trial per protocol (four male, 10 female; median (interquartile range (IQR)) age 66.50 (60.75 to 73.50) years); mMRC dyspnoea 3 (2 to 3)). Fan therapy resulted in lower exercise-induced breathlessness (ΔNRS; Δ modified Borg scale) (within-individual differences in medians (WIDiM) -1.00, IQR -2.00 to -0.50; p<0.01; WIDiM -0.25, IQR -2.00 to 0.00; p=0.02), greater distance walked (metres) during the 6MWT (WIDiM 21.25, IQR 12.75 to 31.88; p<0.01), and improved post-exertional breathlessness (NRS) recovery time (WIDiM -10.00, IQR -78.75 to 50.00; p<0.01). Fan therapy was deemed to be acceptable by 92% of participants. CONCLUSION: Fan therapy was acceptable and provided symptomatic relief to patients with COPD during exercise. These data will inform larger pilot studies and efficacy studies of fan therapy during exercise.

A demand-capacity mismatch between rehabilitation need and service provision as a result of the COVID-19 pandemic? Early clinical observations from a large teaching hospital in London.

In this short report the authors characterise inpatient bed occupancy and predicted rehabilitation need of patients cared for in two acute hospitals of a large London NHS Trust during the first wave of the COVID-19 pandemic, including 394 people with confirmed COVID-19. Data were captured on a single day (17th April 2020) from the two Trust hospitals to inform discharge planning in line with national COVID-19 Hospital Discharge Service policy guidance. Our data suggests that the proportion of COVID-19 patients predicted to require rehabilitation upon hospital discharge may be greater than the estimates described in the national COVID-19 Hospital Discharge Service policy guidance; posing the question is there a demand-capacity mismatch between rehabilitation need and service provision as a result of the COVID-19 pandemic?

Grandiose narcissists and decision making: Impulsive, overconfident, and skeptical of experts-but seldom in doubt.

A substantial body of research has documented that grandiose narcissists are characterized by high self-esteem, a sense of personal superiority and entitlement, overconfidence, a willingness to exploit others for self-gain, and hostility and aggression when challenged. We report two studies (N = 452) that explore how these dispositions affect their decision making. We show that grandiose narcissists' overconfidence, impulsivity, and a willingness to ignore expert advice results in a higher likelihood of making a bad decision. In addition, after getting the wrong answer, grandiose narcissists are more likely to blame others and remain self-confident in their judgment.

Treatment of psoriasis with NFKBIZ siRNA using topical ionic liquid formulations.

Systemic antibodies targeting tumor necrosis factor-α (TNF-α) and interleukin-17A (IL-17A) are effective in plaque psoriasis. Despite their popularity, safety concerns pose a challenge for systemic biologics. While anti-TNF-α and anti-IL-17A antibodies effectively inhibit respective proteins, we hypothesize that an approach based on local silencing of an upstream target such as NFKBIZ can be advantageous for treating psoriasis. However, effective delivery of small interfering RNA (siRNA) into the skin is a substantial hurdle due to skin's barrier function and poor stability of siRNA. Using ionic liquids as an enabling technology, we report on the effective delivery of NFKBIZ siRNA into the skin and its therapeutic efficacy in a psoriasis model. Treatment with IL-siRNA suppressed aberrant gene expression and resulted in down-regulation of psoriasis-related signals including TNF-α and IL-17A. These results provide a framework for a topical delivery platform for siRNA.

Breathlessness and dysfunctional breathing in patients with postural orthostatic tachycardia syndrome (POTS): The impact of a physiotherapy intervention.

Postural orthostatic tachycardia syndrome (POTS) is a chronic, multifactorial syndrome with complex symptoms of orthostatic intolerance. Breathlessness is a prevalent symptom, however little is known about the aetiology. Anecdotal evidence suggests that breathless POTS patients commonly demonstrate dysfunctional breathing/hyperventilation syndrome (DB/HVS). There are, however, no published data regarding DB/HVS in POTS, and whether physiotherapy/breathing retraining may improve patients' breathing pattern and symptoms. The aim of this study was to explore the potential impact of a physiotherapy intervention involving education and breathing control on DB/HVS in POTS. A retrospective observational cohort study of all patients with POTS referred to respiratory physiotherapy for treatment of DB/HVS over a 20-month period was undertaken. 100 patients (99 female, mean (standard deviation) age 31 (12) years) with a clinical diagnosis of DB/HV were referred, of which data was available for 66 patients pre - post intervention. Significant improvements in Nijmegen score, respiratory rate and breath hold time (seconds) were observed following treatment. These data provide a testable hypothesis that breathing retraining may provide breathless POTS patients with some symptomatic relief, thus improving their health-related quality of life. The intervention can be easily protocolised to ensure treatment fidelity. Our preliminary findings provide a platform for a subsequent randomised controlled trial of breathing retraining in POTS.

Single-Molecule Mechanistic Study of Enzyme Hysteresis.

Hysteresis is an important feature of enzyme-catalyzed reactions, as it reflects the influence of enzyme regulation in the presence of ligands such as substrates or allosteric molecules. In typical kinetic studies of enzyme activity, hysteretic behavior is observed as a "lag" or "burst" in the time course of the catalyzed reaction. These lags and bursts are due to the relatively slow transition from one state to another state of the enzyme molecule, with different states having different kinetic properties. However, it is difficult to understand the underlying mechanism of hysteresis by observing bulk reactions because the different enzyme molecules in the population behave stochastically. In this work, we studied the hysteretic behavior of mutant ß-glucuronidase (GUS) using a high-throughput single-molecule array platform and investigated the effect of thermal treatment on the hysteresis.

A home-based lower limb-specific resistance training programme for patients with COPD: an explorative feasibility study.

It is feasible and acceptable to deliver a home-based lower limb-specific resistance training (LLSRT) programme to patients with COPD. Individual patient improvements in walking distance and breathlessness severity were observed post-LLSRT intervention. http://bit.ly/30xYpWI.