A Cross-Sectional Study of Symptom Prevalence, Frequency, Severity, and Impact of Long-COVID in Scotland: Part I.

BACKGROUND: Commonly reported symptoms of long COVID may have different patterns of prevalence and presentation across different countries. While some limited data have been reported for the United Kingdom, national specificity for Scotland is less clear. We present a cross-sectional survey to examine the symptom prevalence, frequency, and severity of long COVID for people living with the condition in Scotland. METHODS: An online survey was created in the English language and was available between April 21, 2022 and August 5, 2022. Participants were included if they were ≥18 years old, living in Scotland, and had self-diagnosed or confirmed long COVID; and excluded if they were hospitalized during their initial infection. Within this article we quantify symptom prevalence, frequency, severity, and duration. RESULTS: Participants (n = 253) reported the most prevalent long-COVID symptoms to be post-exertional malaise (95%), fatigue/tiredness (85%), and cognitive impairment (68%). Fatigue/tiredness, problems with activities of daily living (ADL), and general pain were most frequently occurring, while sleep difficulties, problems with ADL, and nausea were the most severe. Scottish Index of Multiple Deprivation associated with symptom number, severity, and frequency, whereas vaccine status, age, sex, and smoking status had limited or no association. CONCLUSIONS: These findings outline the challenges faced for those living with long COVID and highlight the need for longitudinal research to ascertain a better understanding of the condition and its longer-term societal impact.

A Cross-Sectional Study of Symptom Prevalence, Frequency, Severity, and Impact of Long COVID in Scotland: Part II.

BACKGROUND: There has been some effort to map the prevalence, frequency, and severity of symptoms of long COVID at local and national levels. However, what is frequently absent from such accounts is details of the impact the disease and its symptoms have had on those living with the condition. In this article, we present details of the impact on work, caring, and mental health gathered using a cross-sectional survey. METHODS: Data were collected using an online survey that was available from April 21, 2022, to August 5, 2022. Included participants had either self-diagnosed or confirmed long COVID, were living in Scotland, and were aged ≥18 years. Hospitalization during initial COVID-19 infection was an exclusion criterion. Participants were asked to report on the impact of their illness on everyday activities such as working, studying, or caring. They also completed an assessment of their current mood. RESULTS: People with long COVID were often severely impacted in their ability to work and study. Severe impact on work and study were predicted by more severe and more frequent fatigue, more severe pain, and more severe cognitive impairment. Respondents' ability to care for child dependents was also associated with more severe and more frequent fatigue, and more severe cognitive impairments. More severe pain associated with greater impact on adult care. Negative mood correlated most strongly with frequency and severity of neurological symptoms, including lack of attention, loss of smell, impaired sense of smell, loss of taste, impaired sense of taste, and loss of appetite. CONCLUSIONS: Long COVID has a significant impact on ability to work, study, and care for dependents. The severity of this impact is associated with specific symptom burden, including fatigue, pain, and cognitive impairment.

Ribonucleicacid interference or small molecule inhibition of Runx1 in the border zone prevents cardiac contractile dysfunction following myocardial infarction.

AIMS: Myocardial infarction (MI) is a major cause of death worldwide. Effective treatments are required to improve recovery of cardiac function following MI, with the aim of improving patient outcomes and preventing progression to heart failure. The perfused but hypocontractile region bordering an infarct is functionally distinct from the remote surviving myocardium and is a determinant of adverse remodelling and cardiac contractility. Expression of the transcription factor RUNX1 is increased in the border zone 1-day after MI, suggesting potential for targeted therapeutic intervention. OBJECTIVE: This study sought to investigate whether an increase in RUNX1 in the border zone can be therapeutically targeted to preserve contractility following MI. METHODS AND RESULTS: In this work we demonstrate that Runx1 drives reductions in cardiomyocyte contractility, calcium handling, mitochondrial density, and expression of genes important for oxidative phosphorylation. Both tamoxifen-inducible Runx1-deficient and essential co-factor common ß subunit (Cbfß)-deficient cardiomyocyte-specific mouse models demonstrated that antagonizing RUNX1 function preserves the expression of genes important for oxidative phosphorylation following MI. Antagonizing RUNX1 expression via short-hairpin RNA interference preserved contractile function following MI. Equivalent effects were obtained with a small molecule inhibitor (Ro5-3335) that reduces RUNX1 function by blocking its interaction with CBFß. CONCLUSIONS: Our results confirm the translational potential of RUNX1 as a novel therapeutic target in MI, with wider opportunities for use across a range of cardiac diseases where RUNX1 drives adverse cardiac remodelling.

Defining blood-induced microglia functions in neurodegeneration through multiomic profiling.

Blood protein extravasation through a disrupted blood-brain barrier and innate immune activation are hallmarks of neurological diseases and emerging therapeutic targets. However, how blood proteins polarize innate immune cells remains largely unknown. Here, we established an unbiased blood-innate immunity multiomic and genetic loss-of-function pipeline to define the transcriptome and global phosphoproteome of blood-induced innate immune polarization and its role in microglia neurotoxicity. Blood induced widespread microglial transcriptional changes, including changes involving oxidative stress and neurodegenerative genes. Comparative functional multiomics showed that blood proteins induce distinct receptor-mediated transcriptional programs in microglia and macrophages, such as redox, type I interferon and lymphocyte recruitment. Deletion of the blood coagulation factor fibrinogen largely reversed blood-induced microglia neurodegenerative signatures. Genetic elimination of the fibrinogen-binding motif to CD11b in Alzheimer's disease mice reduced microglial lipid metabolism and neurodegenerative signatures that were shared with autoimmune-driven neuroinflammation in multiple sclerosis mice. Our data provide an interactive resource for investigation of the immunology of blood proteins that could support therapeutic targeting of microglia activation by immune and vascular signals.

Accelerometer measured physical activity and sedentary time in individuals with multiple sclerosis versus age matched controls: A systematic review and meta-analysis.

BACKGROUND: People with Multiple Sclerosis (PwMS) find it more difficult to engage in physical activity (PA) than healthy controls. Accelerometers can be used to measure sedentary time and free-living physical activity, understanding the differences between PwMS and controls can help inform changes such as interventions to promote a more active lifestyle. This in turn will help prevent secondary conditions and reduce symptom progression. OBJECTIVE: To conduct a systematic review and meta-analysis on accelerometer measured sedentary behavior and physical activity between PwMS and healthy controls. METHODS: A systematic search of five databases (PubMed, Web of Science, Ovid, Science Direct and CINAHIL) from inception until 22nd November 2019. Inclusion criteria was (1) included a group of participants with a definite diagnosis of multiple sclerosis of any type; (2) have 3 or more days of PA monitoring using accelerometers during free living conditions; (3) include age matched healthy controls; (4) assess adults over the age of 18; (5) reported data had to have been reported in a manner suitable for quantitative pooling including: percent of time spent sedentary, minutes per day of sedentary, light, moderate, vigorous activity (moderate and vigorous totaled together), steps per day or counts per day. RESULTS: Initial search produced 9021 papers, after applying inclusion criteria 21 eligible papers were included in the study. One paper was a longitudinal study from which only baseline data was included. One paper was a reliability and validity study, with data for PwMS versus controls in the validity section. All other papers are cross sectional, with one being a pilot study and another a random control study. One paper used two devices in unison, only one set of data is included in the statistics. Outcome data was available for 1098 participants, 579 PwMS and 519 healthy controls. Significant differences were seen in all categories tested: (1) sedentary time (min/day), standard mean difference -0.286, P = 0.044, n = 4 studies; (2) relative sedentary time (%/day), standard mean difference -0.646, P = 0.000, n = 5 studies; (3) LPA (min/day), standard mean difference 0.337, P = 0.039, n = 5 studies; (4) relative LPA (%/day), standard mean difference 0.211, P = 0.152, n = studies; (5) MVPA (min/day), standard mean difference 0.801, P = 0.000, n = 8 studies; (6) relative MVPA (%/day), mean difference 0.914, P = 0.000, n = 5 studies; (7) step count, standard mean difference 0.894, P = 0.000, n = 8 studies; (8) activity count, standard mean difference 0.693, P = 0.000, n = 13 studies. CONCLUSION: PwMS are more sedentary and engage in less LPA, MVPA, steps per day and accelerometer counts per day than healthy controls when measured using accelerometers during free-living conditions.

Drivers of Sinoatrial Node Automaticity in Zebrafish: Comparison With Mechanisms of Mammalian Pacemaker Function.

Cardiac excitation originates in the sinoatrial node (SAN), due to the automaticity of this distinct region of the heart. SAN automaticity is the result of a gradual depolarisation of the membrane potential in diastole, driven by a coupled system of transarcolemmal ion currents and intracellular Ca2+ cycling. The frequency of SAN excitation determines heart rate and is under the control of extra- and intracardiac (extrinsic and intrinsic) factors, including neural inputs and responses to tissue stretch. While the structure, function, and control of the SAN have been extensively studied in mammals, and some critical aspects have been shown to be similar in zebrafish, the specific drivers of zebrafish SAN automaticity and the response of its excitation to vagal nerve stimulation and mechanical preload remain incompletely understood. As the zebrafish represents an important alternative experimental model for the study of cardiac (patho-) physiology, we sought to determine its drivers of SAN automaticity and the response to nerve stimulation and baseline stretch. Using a pharmacological approach mirroring classic mammalian experiments, along with electrical stimulation of intact cardiac vagal nerves and the application of mechanical preload to the SAN, we demonstrate that the principal components of the coupled membrane- Ca2+ pacemaker system that drives automaticity in mammals are also active in the zebrafish, and that the effects of extra- and intracardiac control of heart rate seen in mammals are also present. Overall, these results, combined with previously published work, support the utility of the zebrafish as a novel experimental model for studies of SAN (patho-) physiological function.

A Systematic Review of Randomised Control Trials Evaluating the Efficacy and Safety of Open and Endoscopic Carpal Tunnel Release.

INTRODUCTION: Carpal tunnel syndrome is the most prevalent form of nerve compression syndrome of the upper limb; therefore, it is of clinical significance to critique treatment methods. There is an ongoing debate amongst clinicians as to which surgical method-open or endoscopic carpal tunnel release-provides better overall symptom relief and faster recovery time. This systematic review aimed to investigate the evidence from randomised control trials to evaluate the effectiveness and safety of open and endoscopic carpal tunnel release surgery. METHODS: Database searches were carried out to identify literature. An inclusion and exclusion criteria was applied to only include randomised control trials which compared open and endoscopic surgery. Publications were then selected according to PRISMA guidelines, risk of bias was assessed and patient outcome was assessed. RESULTS: Twenty-three studies were selected for this systematic review. It was found that for improvement to grip strength and symptom severity, the endoscopic group had more significant improvement in the short term, resulting in a quicker return to work time compared to the open group. The complication rate for both intervention groups was low despite more severe and irreversible complications such as prolonged pain and wound infections being observed in the open group; however, the endoscopic group reported a higher risk of needing repeat surgery. CONCLUSION: The quicker recovery time, improved cosmetic result and less severe complications observed with the endoscopic technique suggest that it should be used more often. However, this review found no convincing evidence of a significantly superior technique in the long term.

Preclinical models of myocardial infarction: from mechanism to translation.

Approximately 7 million people are affected by acute myocardial infarction (MI) each year, and despite significant therapeutic and diagnostic advancements, MI remains a leading cause of mortality worldwide. Preclinical animal models have significantly advanced our understanding of MI and have enabled the development of therapeutic strategies to combat this debilitating disease. Notably, some drugs currently used to treat MI and heart failure (HF) in patients had initially been studied in preclinical animal models. Despite this, preclinical models are limited in their ability to fully reproduce the complexity of MI in humans. The preclinical model must be carefully selected to maximise the translational potential of experimental findings. This review describes current experimental models of MI and considers how they have been used to understand drug mechanisms of action and support translational medicine development. LINKED ARTICLES: This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc.

Blood lactate concentrations during rest and exercise in people with Multiple Sclerosis: A systematic review and meta-analysis.

BACKGROUND: Multiple Sclerosis (MS) is a chronic disorder which irreversibly damages axons within brain matter. Blood lactate concentration could be a biomarker of MS onset and progression, but no systematic review has yet sought to confirm or dispute the elevation and biomarker potential of blood lactate in people with MS (PwMS) or to consolidate understanding of lactate production during exercise in PwMS. OBJECTIVE: To perform a systematic review and meta-analysis on blood lactate in PwMS during rest and exertion compared to Healthy Controls (HC) and following chronic exercise intervention. METHODS: A systematic search of six electronic databases (PubMed, CINAHL, Science Direct, Cochrane Library, SPORTDiscus and PEDro) was performed on 10th April 2020. Mean, standard deviation and sample size for lactate measures at rest and during exercise were pooled to determine overall effect size using a random effects model.  The 20-point Appraisal tool for Cross-Sectional Studies was utilised to assess study quality and inherent risk of bias. To qualify for inclusion, studies had to include human adults (>18 years) with a confirmed clinical diagnosis of MS, be published in English, have undergone peer review, report absolute blood lactate values for data extraction, and if involving testing during/after exercise, to do so during bilateral exercise methods. RESULTS: 18 studies were qualitatively analysed and 15 studies quantitatively analysed. Outcome data was available for 1986 participants (nMS = 1129). A total of 7 papers tested blood lactate during rest (LactateREST), 7 papers tested during sub-maximal intensity exercise (LactateSUB-MAX), and 8 papers tested during maximal intensity exercise (LactateMAX). Meta analyses showed elevated LactateREST and reduced LactateMAX in PwMS compared to HC, higher LactateMAX in lower EDSS-scoring PwMS compared to higher EDSS-scoring PwMS, and that LactateSUB-MAX decreases and LactateMAX increases in PwMS following a chronic exercise intervention. Qualitative analysis reported LactateREST to be reduced in PwMS following a chronic exercise intervention. CONCLUSIONS: LactateREST is elevated in PwMS compared to HC. LactateMAX is lower in PwMS compared to HC and lower still in higher compared to lower EDSS-scoring groups of PwMS. Chronic exercise interventions have the potential to reduce LacatateSUB-MAX for a given power output and increase LactateMAX in PwMS compared to baseline values. LactateREST may be reduced in PwMS following a chronic exercise intervention but more research is required for confirmation. The results of this review were limited by small sample sizes and number of studies available for each testing condition, limited data available for potentially confounding/correlating factors (eg. VO2 and power output) as well as heterogeneity of methodology adopted across studies, often due to lactate testing being a secondary outcome measure. PLS: Lactate levels in the blood are different during rest and at intense exercise levels in people with Multiple Sclerosis (MS) compared to healthy counterparts, with people with MS showing a smaller jump in lactate during intense exercise from a higher resting level. After exercising for at least 3 months, blood lactate levels during exercise may become more similar to the levels seen in people without Multiple Sclerosis, but more research is required to give a clearer picture of this. We can hopefully use blood lactate in future to measure the progression of MS in an individual as well as the effectiveness of their exercise programme.

What keeps us ticking? Sinoatrial node mechano-sensitivity: the grandfather clock of cardiac rhythm.

The rhythmic and spontaneously generated electrical excitation that triggers the heartbeat originates in the sinoatrial node (SAN). SAN automaticity has been thoroughly investigated, which has uncovered fundamental mechanisms involved in cardiac pacemaking that are generally categorised into two interacting and overlapping systems: the 'membrane' and 'Ca2+ clock'. The principal focus of research has been on these two systems of oscillators, which have been studied primarily in single cells and isolated tissue, experimental preparations that do not consider mechanical factors present in the whole heart. SAN mechano-sensitivity has long been known to be a contributor to SAN pacemaking-both as a driver and regulator of automaticity-but its essential nature has been underappreciated. In this review, following a description of the traditional 'clocks' of SAN automaticity, we describe mechanisms of SAN mechano-sensitivity and its vital role for SAN function, making the argument that the 'mechanics oscillator' is, in fact, the 'grandfather clock' of cardiac rhythm.

Sinoatrial Node Structure, Mechanics, Electrophysiology and the Chronotropic Response to Stretch in Rabbit and Mouse.

The rhythmic electrical activity of the heart's natural pacemaker, the sinoatrial node (SAN), determines cardiac beating rate (BR). SAN electrical activity is tightly controlled by multiple factors, including tissue stretch, which may contribute to adaptation of BR to changes in venous return. In most animals, including human, there is a robust increase in BR when the SAN is stretched. However, the chronotropic response to sustained stretch differs in mouse SAN, where it causes variable responses, including decreased BR. The reasons for this species difference are unclear. They are thought to relate to dissimilarities in SAN electrophysiology (particularly action potential morphology) between mouse and other species and to how these interact with subcellular stretch-activated mechanisms. Furthermore, species-related differences in structural and mechanical properties of the SAN may influence the chronotropic response to SAN stretch. Here we assess (i) how the BR response to sustained stretch of rabbit and mouse isolated SAN relates to tissue stiffness, (ii) whether structural differences could account for observed differences in BR responsiveness to stretch, and (iii) whether pharmacological modification of mouse SAN electrophysiology alters stretch-induced chronotropy. We found disparities in the relationship between SAN stiffness and the magnitude of the chronotropic response to stretch between rabbit and mouse along with differences in SAN collagen structure, alignment, and changes with stretch. We further observed that pharmacological modification to prolong mouse SAN action potential plateau duration rectified the direction of BR changes during sustained stretch, resulting in a positive chronotropic response akin to that of other species. Overall, our results suggest that structural, mechanical, and background electrophysiological properties of the SAN influence the chronotropic response to stretch. Improved insight into the biophysical determinants of stretch effects on SAN pacemaking is essential for a comprehensive understanding of SAN regulation with important implications for studies of SAN physiology and its dysfunction, such as in the aging and fibrotic heart.

Neurohumoral Control of Sinoatrial Node Activity and Heart Rate: Insight From Experimental Models and Findings From Humans.

The sinoatrial node is perhaps one of the most important tissues in the entire body: it is the natural pacemaker of the heart, making it responsible for initiating each-and-every normal heartbeat. As such, its activity is heavily controlled, allowing heart rate to rapidly adapt to changes in physiological demand. Control of sinoatrial node activity, however, is complex, occurring through the autonomic nervous system and various circulating and locally released factors. In this review we discuss the coupled-clock pacemaker system and how its manipulation by neurohumoral signaling alters heart rate, considering the multitude of canonical and non-canonical agents that are known to modulate sinoatrial node activity. For each, we discuss the principal receptors involved and known intracellular signaling and protein targets, highlighting gaps in our knowledge and understanding from experimental models and human studies that represent areas for future research.

Intrinsic regulation of sinoatrial node function and the zebrafish as a model of stretch effects on pacemaking.

Excitation of the heart occurs in a specialised region known as the sinoatrial node (SAN). Tight regulation of SAN function is essential for the maintenance of normal heart rhythm and the response to (patho-)physiological changes. The SAN is regulated by extrinsic (central nervous system) and intrinsic (neurons, peptides, mechanics) factors. The positive chronotropic response to stretch in particular is essential for beat-by-beat adaptation to changes in hemodynamic load. Yet, the mechanism of this stretch response is unknown, due in part to the lack of an appropriate experimental model for targeted investigations. We have been investigating the zebrafish as a model for the study of intrinsic regulation of SAN function. In this paper, we first briefly review current knowledge of the principal components of extrinsic and intrinsic SAN regulation, derived primarily from experiments in mammals, followed by a description of the zebrafish as a novel experimental model for studies of intrinsic SAN regulation. This mini-review is followed by an original investigation of the response of the zebrafish isolated SAN to controlled stretch. Stretch causes an immediate and continuous increase in beating rate in the zebrafish isolated SAN. This increase reaches a maximum part way through a period of sustained stretch, with the total change dependent on the magnitude and direction of stretch. This is comparable to what occurs in isolated SAN from most mammals (including human), suggesting that the zebrafish is a novel experimental model for the study of mechanisms involved in the intrinsic regulation of SAN function by mechanical effects.