Incidence of emergency calls and out-of-hospital cardiac arrest deaths during the COVID-19 pandemic: findings from a cross-sectional study in a UK ambulance service.

BACKGROUND: In response to the COVID-19 pandemic, a national lockdown was introduced on 23 March 2020. In the following weeks, emergency departments in the UK reported a reduction in attendances. We aimed to explore the incidence of emergency calls across North East England, as well as the number of out-of-hospital cardiac arrest (OHCA) deaths. METHODS: Data were collected for all patients who contacted North East Ambulance Service between 4 March 2019-2 June 2019 and 2 March 2020-31 May 2020 suffering stroke, ST elevation myocardial infarction, allergy, asthma, chronic obstructive pulmonary disease, falls, intoxication, seizure, sepsis, acute coronary syndrome and OHCA. RESULTS: There were a reduction in incidence of calls, excluding OHCA, resulting in ambulance activation during the pandemic compared with same period in 2019, 16 743 versus 19 639, respectively (-14.74%). The decline in calls was partially reversed by the end of May 2020. Incidence of OHCA at the time of the national lockdown had increased by 13.79% with a peak increase of 73.56% in the second week in April 2020. OHCA deaths peaked in the first 2 weeks in April 2020, 95.65% and 90.07%, respectively, but by the end May 2020, incidence of OHCA and OHCA deaths had returned to prelockdown levels. CONCLUSION: Incidence of emergency calls were reduced during the pandemic compared with 2019. There was a rise in incidence of OHCA and OHCA deaths during the same period; however, these changes appear transient. Further research is required to understand patient behaviour towards seeking help during the pandemic and the long-term consequences of not doing so.

Flap Endonuclease 1 Limits Telomere Fragility on the Leading Strand.

The existence of redundant replication and repair systems that ensure genome stability underscores the importance of faithful DNA replication. Nowhere is this complexity more evident than in challenging DNA templates, including highly repetitive or transcribed sequences. Here, we demonstrate that flap endonuclease 1 (FEN1), a canonical lagging strand DNA replication protein, is required for normal, complete leading strand replication at telomeres. We find that the loss of FEN1 nuclease activity, but not DNA repair activities, results in leading strand-specific telomere fragility. Furthermore, we show that FEN1 depletion-induced telomere fragility is increased by RNA polymerase II inhibition and is rescued by ectopic RNase H1 expression. These data suggest that FEN1 limits leading strand-specific telomere fragility by processing RNA:DNA hybrid/flap intermediates that arise from co-directional collisions occurring between the replisome and RNA polymerase. Our data reveal the first molecular mechanism for leading strand-specific telomere fragility and the first known role for FEN1 in leading strand DNA replication. Because FEN1 mutations have been identified in human cancers, our findings raise the possibility that unresolved RNA:DNA hybrid structures contribute to the genomic instability associated with cancer.

Lymphoedema management with the LymphFlow Advance pneumatic compression pump.

There are many intermittent pneumatic compression devices available for use in the management and adjunct treatment of lymphatic, venous and arterial disease. This article discusses the development of a new advanced pneumatic compression device, the LymphFlow Advance, which can perform focussed treatment on the lymphoedematous area using a variety of different cycles. Case studies with therapist and patient feedback are used to demonstrate the use of the LymphFlow Advance in the lymphoedema clinic, with a discussion of the evidence to underpin recommended treatment regimes.

Inferior vena cava filters for prevention of venous thromboembolism in obese patients undergoing bariatric surgery: a systematic review.

OBJECTIVE: The use of inferior vena cava (IVC) filters for prevention of venous thromboembolism (VTE) in bariatric surgery is a contentious issue. We aim to review the evidence for the use of IVC filters in bariatric surgical patients, describe trends in practice, and discuss challenges in developing evidence-based guidelines. BACKGROUND: The incidence of VTE in modern bariatric procedures with traditional methods of thromboprophylaxis, such as sequential calf compression devices and perioperative low molecular weight heparin, is approximately 2%. METHODS: A systematic review of the literature was conducted according to PRISMA guidelines. We searched Medline up until July 2013 with the terms "bariatric filter" and "gastric bypass filter." Two investigators independently screened search results according to an agreed list of eligibility criteria. RESULTS: Eighteen studies were included. There were no randomized controlled trials. Data from controlled cohort studies suggest that those who undergo IVC filter insertion preoperatively may be at higher risk of developing deep vein thrombosis (DVT) and pulmonary embolism (PE). A small cohort of patients with multiple risk factors for VTE benefitted from reduced PE-related mortality after preoperative IVC filter insertion. Data from 12 case series reporting VTE outcomes from a total of 497 patients who underwent preoperative IVC filter insertion demonstrated DVT rates of 0% to 20.8% and PE rates ranging from 0% to 6.4%. CONCLUSIONS: Published data reporting the safety and efficacy of IVC filter use in bariatric surgical patients is highly heterogeneous. There is no evidence to suggest that the potential benefits of IVC filters outweigh the significant risks of therapy.

Retrograde mechanochemical ablation of the small saphenous vein for the treatment of a venous ulcer.

We present the first case of retrograde ablation of the small saphenous vein to treat active venous ulceration. A 73-year-old gentleman with complicated varicose veins of the left leg and a non-healing venous ulcer despite previous successful endovenous treatment to his left great saphenous vein underwent mechanochemical ablation of his small saphenous vein with the ClariVein® system, under local anaesthetic, using a retrograde cannulation technique. Post-operatively the patient had improved symptomatically and the ulcer size had reduced. This report highlights that patients with small saphenous vein incompetence and active ulceration can be treated successfully with retrograde mechanochemical ablation.

The moderating effect of social support on the effectiveness of a web-based, computer-tailored physical activity intervention for older adults.

This study aimed to assess the moderating effect of social support on the effectiveness of a web-based, computer-tailored physical activity intervention for older adults. In the Active for Life trial, 243 inactive adults aged 65+ years were randomised into: (1) tailoring + Fitbit (n = 78), (2) tailoring-only (n = 96) or (3) control (n = 69). For the current study, participants were categorised as having higher (n = 146) or lower (n = 97) social support based on the Duke Social Support Index (DSSI_10). Moderate-to-vigorous physical activity (MVPA) was measured through accelerometers at baseline and post-intervention. A linear mixed model analysis demonstrated that among participants with lower social support, the tailoring + Fitbit participants, but not the tailoring only participants increased their MVPA more than the control. Among participants with higher social support, no differences in MVPA changes were observed between groups. Web-based computer-tailored interventions with Fitbit integration may be more effective in older adults with lower levels of social support.

Okazaki fragment processing-independent role for human Dna2 enzyme during DNA replication.

Dna2 is an essential helicase/nuclease that is postulated to cleave long DNA flaps that escape FEN1 activity during Okazaki fragment (OF) maturation in yeast. We previously demonstrated that the human Dna2 orthologue (hDna2) localizes to the nucleus and contributes to genomic stability. Here we investigated the role hDna2 plays in DNA replication. We show that Dna2 associates with the replisome protein And-1 in a cell cycle-dependent manner. Depletion of hDna2 resulted in S/G(2) phase-specific DNA damage as evidenced by increased γ-H2AX, replication protein A foci, and Chk1 kinase phosphorylation, a readout for activation of the ATR-mediated S phase checkpoint. In addition, we observed reduced origin firing in hDna2-depleted cells consistent with Chk1 activation. We next examined the impact of hDna2 on OF maturation and replication fork progression in human cells. As expected, FEN1 depletion led to a significant reduction in OF maturation. Strikingly, the reduction in OF maturation had no impact on replication fork progression, indicating that fork movement is not tightly coupled to lagging strand maturation. Analysis of hDna2-depleted cells failed to reveal a defect in OF maturation or replication fork progression. Prior work in yeast demonstrated that ectopic expression of FEN1 rescues Dna2 defects. In contrast, we found that FEN1 expression in hDna2-depleted cells failed to rescue genomic instability. These findings suggest that the genomic instability observed in hDna2-depleted cells does not arise from defective OF maturation and that hDna2 plays a role in DNA replication that is distinct from FEN1 and OF maturation.

An evolutionarily conserved, alternatively spliced, intron in the p68/DDX5 DEAD-box RNA helicase gene encodes a novel miRNA.

The DEAD-box RNA helicase p68 (DDX5) plays important roles in several cellular processes, including transcription, pre-mRNA processing, and microRNA (miRNA) processing. p68 expression is growth and developmentally regulated, and alterations in p68 expression and/or function have been implicated in tumor development. The p68 gene encodes an evolutionarily conserved, alternatively spliced, intron the function of which has to date remained unclear. Although the intron-containing p68 RNA does not appear to yield an alternative p68 protein, it is differentially expressed in cell lines and tissues, indicating regulation of expression. Here we show that the p68 conserved intron encodes a novel putative miRNA, suggesting a previously unknown possible regulatory function for the p68 intron. We show that this miRNA (referred to as p68 miRNA) is processed from the intron via the canonical miRNA-processing pathway and that it associates with the Argonaute protein Ago2. Finally we show that the p68 miRNA suppresses an mRNA bearing complementary target sequences, suggesting that it is functional. These findings suggest a novel mechanism by which alterations in p68 expression may impact on the cell.

Scoring systems for the post-thrombotic syndrome.

OBJECTIVE: To assess each of the scoring systems used to diagnose and classify post-thrombotic syndrome, a common chronic complication of deep vein thrombosis. The design of the study was a systematic review of the literature pertaining to post-thrombotic syndrome. METHODS: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines by a search of PubMed (1948 to September 2011) using the search terms "post-thrombotic syndrome," "postthrombotic syndrome," "post-phlebitic syndrome," and "postphlebitic syndrome." A manual reference list search was also carried out to identify further studies that would be appropriate for inclusion. The various scoring systems in use were identified and assessed against a list of criteria to determine their validity for use. For outcome measures, each scoring system was assessed for specific criteria, including interobserver reliability, association with ambulatory venous pressures, ability to assess severity of post-thrombotic syndrome, ability to assess change in condition over time, and association with patient-reported symptom severity. RESULTS: The Villalta, Ginsberg, Brandjes, Widmer, CEAP, and Venous Clinical Severity Score systems all were assessed for the stated outcome measures. From their use in the literature, only the Villalta score was able to fulfill all the criteria described. The main criticism of the Villalta score in the literature appears to be its use of subjective measures. To that end, we propose that use of a venous disease-specific quality-of-life questionnaire in combination with the Villalta score may help standardize the subjective criteria. CONCLUSIONS: The Villalta score, combined with a venous disease-specific quality-of-life questionnaire, should be considered the "gold standard" for the diagnosis and classification of post-thrombotic syndrome.

Investigating the relationship between bullying involvement and self-harmful thoughts and behaviour in young people: A systematic review.

BACKGROUND: There is a complex and inconsistent relationship between bullying involvement and self-harmful thoughts and behaviour (SHTB) in young people. This novel systematic review aims to establish key interacting, moderating and mediating variables associated with SHTB in young people involved in bullying. METHODS: The systematic review was registered with PROSPERO: CRD42020192023. A search was conducted (until February 2021) across databases: PubMed/MEDLINE, EMBASE, PsycINFO (Ovid), Cochrane Library, Scopus (Elsevier), Web of Science, ERIC and CINAHL (EBSCOhost). Observational studies containing quantitative primary or secondary data analyses were included in the review, on the basis that they examined interactions, moderators, or mediators between bullying involvement and SHTB in young people. Versions of the Newcastle-Ottawa Scale were used to assess risk of bias in the included studies. RESULTS: A total of 57 studies were included. Overall, 3 studies identified interactions, 25 studies identified moderators and 21 studies identified mediators. 9 studies identified moderator-mediators. The findings were categorised as either self-harmful thoughts or self-harmful behaviours and synthesised under the following themes: socio-demographic; depression; parental; personality/psychological; and social/environmental. LIMITATIONS: This review uncovered significant heterogeneity and a paucity of replicated studies in the field, therefore, tentative conclusions have been drawn. CONCLUSIONS: This comprehensive review highlights the key role of depression as a mediator between traditional/cyber victimisation and SHTB in young people. The moderating effects of gender on mediation models investigating the role of depression suggest the possibility that females involved in bullying may be at increased suicide risk.

RNA helicases p68 and p72: multifunctional proteins with important implications for cancer development.

The DEAD box RNA helicases p68 (DDX5) and p72 (DDX17) play important roles in multiple cellular processes that are commonly dysregulated in cancers, including transcription, pre-mRNA processing/alternative splicing and miRNA processing. Although p68 and p72 appear to have some overlapping functions, they clearly also have distinct, nonredundant functions. Furthermore, their ability to interact with a variety of different factors and act as multifunctional proteins has the potential to impact on several different processes, and alterations in expression or function of p68 and/or p72 could have profound implications for cancer development. However, their roles are likely to be context-dependent and both proteins have been reported to have pro-proliferation or even oncogenic functions as well as antiproliferative or tumor cosuppressor roles. Therefore, eludicating the precise role of these proteins in cancer is likely to be complex and to depend on the cellular environment and interacting factors. In this article, we review the many functions that have been attributed to p68 and p72 and discuss their potential roles in cancer development.

Pilot Trial of Neuromuscular Stimulation in Human Subjects with Chronic Venous Disease.

INTRODUCTION: Neuromuscular stimulation (NMES) has been shown to improve peripheral blood flow in healthy people. We investigated the effect of bilateral leg NMES on the symptoms of chronic venous disease. METHODS: Forty subjects were recruited from four groups: healthy, superficial insufficiency, deep insufficiency, and deep obstruction. Haemodynamic venous measurements were taken from the right femoral vein with ultrasound, laser Doppler fluximetry from the left hand and foot. Devices were then worn for 4-6 hours per day, for 6 weeks. Haemodynamic measurements were repeated at week 6. Quality of life questionnaires were taken at week 0, 6 and 8. RESULTS: The mean age was 48.7, BMI 28.6kg/m2, and maximum calf circumference 39.0 cm. Twenty-four subjects were men. NMES increased femoral vein peak velocity, TAMV and volume flow by 55%, 20%, 36% at 20 minutes (all p<0.05), which was enhanced at week 6 (PV and TAMV p<0.05). Mean increases in arm and leg fluximetry were 71% and 194% (both p<0.01). Leg swelling was reduced by mean 252.7 mL (13%, p<0.05) overall; 338.9 mL (16%, p<0.05) in venous disease. For those with venous pathology, scores for disease specific and generic quality of life questionnaires improved. Those with C4-6 disease benefitted the most, with improvements in VDS score of 1, AVVQ of 6, and SF-12 of 10. CONCLUSION: NMES improves venous haemodynamic parameters in chronic venous disease, which is enhanced by regular use. NMES reduces leg oedema, improves blood supply to the skin of the foot, and may positively affect quality of life. CLINICAL TRIALS: This trial was registered with www.clinicaltrials.org.uk (NCT02137499).

The ObgE/CgtA GTPase influences the stringent response to amino acid starvation in Escherichia coli.

The stringent response is important for bacterial survival under stressful conditions, such as amino acid starvation, and is characterized by the accumulation of ppGpp and pppGpp. ObgE (CgtA, YhbZ) is an essential conserved GTPase in Escherichia coli and several observations have implicated the protein in the control of the stringent response. However, consequences of the protein on specific responses to amino acid starvation have not been noted. We show that ObgE binds to ppGpp with biologically relevant affinity in vitro, implicating ppGpp as an in vivo ligand of ObgE. ObgE mutants increase the ratio of pppGpp to ppGpp within the cell during the stringent response. These changes are correlated with a delayed inhibition of DNA replication by the stringent response, delayed resumption of DNA replication after release, as well as a decreased survival after amino acid deprivation. With these data, we place ObgE as an active effector of the response to amino acid starvation in vivo. Our data correlate the pppGpp/ppGpp ratio with DNA replication control under bacterial starvation conditions, suggesting a possible role for the relative balance of these two nucleotides.

Cell cycle synchronization of Escherichia coli using the stringent response, with fluorescence labeling assays for DNA content and replication.

We describe a method for synchronization of the cell cycle in the bacterium Escherichia coli. Treatment of asynchronous cultures with the amino acid analog, dl-serine hydroxamate, induces the stringent response, with concomitant arrest of DNA replication at initiation. Following release of the stringent response, cells initiate DNA replication in synchrony, as determined by flow cytometry for DNA content, Southern blotting and microscopy. This method has the advantage that it can be used in fully wild-type cells, at different growth rates, and may be applicable to other bacterial species with replication control by the stringent response. We also elaborate other methods useful for establishing cell cycle parameters in bacterial populations. We describe flow cytometric methods for analyzing bacterial populations for DNA content using the DNA-specific dye PicoGreen, readily detected by most commercial flow cytometers. We also present an method for incorporation of the nucleotide ethynyl-deoxyuridine, EdU, followed by "click" labeling with fluorescent dyes, which allows us to measure and visualize newly replicated DNA in fixed E. coli K-12 cells under non-denaturing conditions.

Intravenous versus oral paracetamol in a UK ambulance service: a case control study.

OBJECTIVES: To determine the effectiveness of intravenous versus oral paracetamol (acetaminophen) in the management of acute pain in the out-of-hospital setting. METHODS: We extracted ambulance electronic patient care records for all patients who received 1 g intravenous paracetamol throughout January 2019, and case matched these by sex and age with consecutive patients who received 1 g oral paracetamol over the same time period. Eligible for inclusion were all patients aged ≥ 18 who received 1 g paracetamol for acute pain and who were transported to the emergency department (ED). The primary outcome was the mean reduction in pain score using the numeric rating scale (NRS), with a reduction of 2 or more accepted as clinically significant. RESULTS: 80 care records were eligible for analysis; 40 patients received intravenous and 40 patients received oral paracetamol. The mean age of both groups was 54 years (± 3 years) and 67.5% (n = 54) were female. Patients receiving intravenous paracetamol had a clinically significant mean (SD) improved pain score compared to those receiving oral paracetamol, 2.02 (1.64) versus 0.75 (1.76), respectively [p = 0.0013]. 13/40 (32.5%) patients who received intravenous paracetamol saw an improved pain score of ≥ 2 compared to 8/40 (20%) who received oral paracetamol. No patients received additional analgesia or reported any adverse symptoms. Abdominal pain, infection and trauma were the most common causes of pain in both groups. CONCLUSION: Our study suggests that intravenous paracetamol is more effective than oral paracetamol when managing acute pain in the out-of-hospital setting. Our findings support further investigation of the role of paracetamol in paramedic practice using more robust methods.

Cyanoacrylate glue embolisation for varicose veins - A novel complication.

BACKGROUND: Non-thermal non-tumescent methods for varicose vein treatment have rapidly gained popularity in recent years due to clinical efficacy comparable to other endovenous methods, but with a superior safety and tolerability profile. Cyanoacrylate is an adhesive that rapidly polymerises during endovenous treatment to cause rapid occlusion of veins and initiate vein fibrosis. METHOD: Cyanoacrylate glue treatment is known to cause complications such as phlebitis, cellulitis and deep vein thrombosis in rare instances. We present the first reported case of cyanoacrylate extravasation with chronic foreign body reaction in a patient nine months after initial treatment. RESULTS: We discuss the aetiology of this complication, its treatment, patient outcome and its significance to both clinicians and patients. CONCLUSION: Cyanoacrylate glue embolisation can, in rare instances, lead to extravasation and chronic foreign body reaction, necessitating surgical intervention. The relative novelty of cyanoacrylate glue embolisation in the treatment of varicose veins requires clinicians to monitor for rare complications during its use in clinical practice. Patients should be aware of the rare risk of glue extravasation and foreign body reaction for fully informed consent prior to treatment.

Management of acute and chronic iliofemoral venous outflow obstruction: a multidisciplinary team consensus.

The aim of this manuscript was to establish a consensus for the management of acute and chronic venous obstruction among specialists in the UK. Specialist physicians representing vascular surgery, interventional radiology and hematology were invited to 3 meetings to discuss management of acute and chronic iliofemoral obstruction. The meetings outlined controversial areas, included a topic-by-topic review; and on completion reached a consensus when greater than 80% agreement was reached on each topic. Physicians from 19 UK hospitals agreed on treatment protocols and highlighted areas that need development. Potential standard treatment algorithms were created. It was decided to establish a national registry of venous patients led by representatives from the treating multidisciplinary teams. Technical improvements have facilitated invasive treatment of patients with acute and chronic venous obstruction; however, the evidence guiding treatment is weak. Treatment should be conducted in centers with multi-disciplinary input; robust, coordinated data collection; and regular outcome analysis to ensure safe and effective treatment and a basis for future evolvement.

Reducing the risk of venous thromboembolism following superficial endovenous treatment: A UK and Republic of Ireland consensus study.

OBJECTIVES: Venous thromboembolism is a potentially fatal complication of superficial endovenous treatment. Proper risk assessment and thromboprophylaxis could mitigate this hazard; however, there are currently no evidence-based or consensus guidelines. This study surveyed UK and Republic of Ireland vascular consultants to determine areas of consensus. METHODS: A 32-item survey was sent to vascular consultants via the Vascular and Endovascular Research Network (phase 1). These results generated 10 consensus statements which were redistributed (phase 2). 'Good' and 'very good' consensus were defined as endorsement/rejection of statements by >67% and >85% of respondents, respectively. RESULTS: Forty-two consultants completed phase 1. This generated seven statements regarding risk factors mandating peri-procedural pharmacoprophylaxis and three statements regarding specific pharmacoprophylaxis regimes. Forty-seven consultants completed phase 2. Regarding venous thromboembolism risk factors mandating pharmacoprophylaxis, 'good' and 'very good' consensus was achieved for 5/7 and 2/7 statements, respectively. Regarding specific regimens, 'very good' consensus was achieved for 3/3 statements. CONCLUSIONS: The main findings from this study were that there was 'good' or 'very good' consensus that patients with any of the seven surveyed risk factors should be given pharmacoprophylaxis with low-molecular-weight heparin. High-risk patients should receive one to two weeks of pharmacoprophylaxis rather than a single dose.

Neuromuscular electrical stimulation for the prevention of venous thromboembolism.

Objective Venous thromboembolism, encompassing deep vein thrombosis and pulmonary embolism, is a significant cause of morbidity and mortality, affecting one in 1000 adults per year. Neuromuscular electrical stimulation is the transcutaneous application of electrical impulses to elicit muscle contraction, preventing venous stasis. This review aims to investigate the evidence underlying the use of neuromuscular electrical stimulation in thromboprophylaxis. Methods The Medline and Embase databases were systematically searched, adhering to PRISMA guidelines, for articles relating to electrical stimulation and thromboprophylaxis. Articles were screened according to a priori inclusion and exclusion criteria. Results The search strategy identified 10 randomised controlled trials, which were used in three separate meta-analyses: five trials compared neuromuscular electrical stimulation to control, favouring neuromuscular electrical stimulation (odds ratio of deep vein thrombosis 0.29, 95% confidence interval 0.13-0.65; P = .003); three trials compared neuromuscular electrical stimulation to heparin, favouring heparin (odds ratio of deep vein thrombosis 2.00, 95% confidence interval 1.13-3.52; P = .02); three trials compared neuromuscular electrical stimulation as an adjunct to heparin versus heparin only, demonstrating no significant difference (odds ratio of deep vein thrombosis 0.33, 95% confidence interval 0.10-1.14; P = .08). Conclusion Neuromuscular electrical stimulation significantly reduces the risk of deep vein thrombosis compared to no prophylaxis. It is inferior to heparin in preventing deep vein thrombosis and there is no evidence for its use as an adjunct to heparin.