The ortholog of human ssDNA-binding protein SSBP3 influences neurodevelopment and autism-like behaviors in Drosophila melanogaster.

1p32.3 microdeletion/duplication is implicated in many neurodevelopmental disorders-like phenotypes such as developmental delay, intellectual disability, autism, macro/microcephaly, and dysmorphic features. The 1p32.3 chromosomal region harbors several genes critical for development; however, their validation and characterization remain inadequate. One such gene is the single-stranded DNA-binding protein 3 (SSBP3) and its Drosophila melanogaster ortholog is called sequence-specific single-stranded DNA-binding protein (Ssdp). Here, we investigated consequences of Ssdp manipulations on neurodevelopment, gene expression, physiological function, and autism-associated behaviors using Drosophila models. We found that SSBP3 and Ssdp are expressed in excitatory neurons in the brain. Ssdp overexpression caused morphological alterations in Drosophila wing, mechanosensory bristles, and head. Ssdp manipulations also affected the neuropil brain volume and glial cell number in larvae and adult flies. Moreover, Ssdp overexpression led to differential changes in synaptic density in specific brain regions. We observed decreased levels of armadillo in the heads of Ssdp overexpressing flies, as well as a decrease in armadillo and wingless expression in the larval wing discs, implicating the involvement of the canonical Wnt signaling pathway in Ssdp functionality. RNA sequencing revealed perturbation of oxidative stress-related pathways in heads of Ssdp overexpressing flies. Furthermore, Ssdp overexpressing brains showed enhanced reactive oxygen species (ROS), altered neuronal mitochondrial morphology, and up-regulated fission and fusion genes. Flies with elevated levels of Ssdp exhibited heightened anxiety-like behavior, altered decisiveness, defective sensory perception and habituation, abnormal social interaction, and feeding defects, which were phenocopied in the pan-neuronal Ssdp knockdown flies, suggesting that Ssdp is dosage sensitive. Partial rescue of behavioral defects was observed upon normalization of Ssdp levels. Notably, Ssdp knockdown exclusively in adult flies did not produce behavioral and functional defects. Finally, we show that optogenetic manipulation of Ssdp-expressing neurons altered autism-associated behaviors. Collectively, our findings provide evidence that Ssdp, a dosage-sensitive gene in the 1p32.3 chromosomal region, is associated with various anatomical, physiological, and behavioral defects, which may be relevant to neurodevelopmental disorders like autism. Our study proposes SSBP3 as a critical gene in the 1p32.3 microdeletion/duplication genomic region and sheds light on the functional role of Ssdp in neurodevelopmental processes in Drosophila.

Evaluation of psychological distress, burnout and structural empowerment status of healthcare workers during the outbreak of coronavirus disease (COVID-19): a cross-sectional questionnaire-based study.

BACKGROUND: In light of several recent studies, there is evidence that the coronavirus disease 2019 (COVID-19) pandemic has caused various mental health concerns in the general population, as well as among healthcare workers (HCWs). The main aim of this study was to assess the psychological distress, burnout and structural empowerment status of HCWs during the COVID-19 outbreak, and to evaluate its predictors. METHODS: This multi-center, cross-sectional web-based questionnaire survey was conducted on HCWs during the outbreak of COVID-19 from August 2020 to January 2021. HCWs working in hospitals from 48 different countries were invited to participate in an online anonymous survey that investigated sociodemographic data, psychological distress, burnout and structural empowerment (SE) based on Depression Anxiety and Stress Scale 21 (DASS-21), Maslach Burnout Inventory (MBI) and Conditions for work effectiveness questionnaire (CWEQ_II), respectively. Predictors of the total scores of DASS-21, MBI and CWEQ-II were assessed using unadjusted and adjusted binary logistic regression analysis. RESULTS: Out of the 1030 HCWs enrolled in this survey, all completed the sociodemographic section (response rate 100%) A total of 730 (70.9%) HCWs completed the DASS-21 questionnaire, 852 (82.6%) completed the MBI questionnaire, and 712 (69.1%) completed the CWEQ-II questionnaire. The results indicate that 360 out of 730 responders (49.3%) reported severe or extremely severe levels of stress, anxiety, and depression. Additionally, 422 out of 851 responders (49.6%) reported a high level of burnout, while 268 out of 712 responders (37.6%) reported a high level of structural empowerment based on the DASS-21, MBI, and CWEQ-II scales, respectively. In addition, the analysis showed that HCWs working in the COVID-19 areas experienced significantly higher symptoms of severe stress, anxiety, depression and higher levels of burnout compared to those working in other areas. The results also revealed that direct work with COVID-19 patients, lower work experience, and high workload during the outbreak of COVID-19 increase the risks of negative psychological consequences. CONCLUSION: Health professionals had high levels of burnout and psychological symptoms during the COVID-19 emergency. Monitoring and timely treatment of these conditions is needed.

Systematic Review and Meta-analysis of the Additional Benefit of Pharmacological Thromboprophylaxis for Endovenous Varicose Vein Interventions.

OBJECTIVE: The primary objective of this systematic review and meta-analysis was to elucidate the rate of venous thromboembolism (VTE) after endovenous interventions for varicose veins in the presence of pharmacological and mechanical thromboprophylaxis versus mechanical thromboprophylaxis alone. BACKGROUND: The VTE rate after endovenous procedures for varicose veins is higher than other day-case procedures and could be reduced with pharmacological thromboprophylaxis. METHODS: The review followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines with a registered protocol (PROSPERO: CRD42021274963). Studies of endovenous intervention for superficial venous incompetence reporting the predefined outcomes with at least 30 patients were eligible. Data were pooled with a fixed effects model. RESULTS: There were 221 trials included in the review (47 randomized trial arms, 105 prospective cohort studies, and 69 retrospective studies). In randomized trial arms, the rate of deep venous thrombosis with additional pharmacological thromboprophylaxis was 0.52% (95% CI, 0.23%-1.19%) (9 studies, 1095 patients, 2 events) versus 2.26% (95% CI, 1.81%-2.82%) (38 studies, 6951 patients, 69 events) with mechanical thromboprophylaxis alone. The rate of pulmonary embolism in randomized trial arms with additional pharmacological thromboprophylaxis was 0.45% (95% CI, 0.09-2.35) (5 studies, 460 participants, 1 event) versus 0.23% (95% CI, 0.1%-0.52%) (28 studies, 4834 participants, 3 events) for mechanical measures alone. The rate of EHIT grade III to IV was 0.35% (95% CI, 0.09-1.40) versus 0.88% (95% CI, 0.28%-2.70%). There was 1 VTE-related mortality and 1 instance of major bleeding, with low rates of minor bleeding. CONCLUSIONS: There is a significant reduction in the rate of DVT with additional pharmacological thromboprophylaxis and routine prescription of anticoagulation after endovenous varicose vein intervention should be considered. VTE risk for individual study participants is heterogeneous and risk stratification in future randomized interventional studies is critical to establish the clinical effectiveness and safety of additional pharmacological thromboprophylaxis.

Physicomechanical properties of cobalt-chromium removable partial denture palatal major connectors fabricated by selective laser melting.

STATEMENT OF PROBLEM: Additive manufacturing by selective laser melting (SLM) has been claimed to be less challenging than conventional casting of cobalt-chromium (Co-Cr) removable partial dentures (RPDs), providing significant improvements. However, how the physicomechanical properties of Co-Cr RPDs fabricated by SLM compare with those fabricated by conventional casting is unclear. PURPOSE: The purpose of this in vitro study was to evaluate the physicomechanical properties of Co-Cr RPD palatal major connectors fabricated by SLM compared with those fabricated by conventional casting. MATERIAL AND METHODS: A master die simulating a maxillary arch of Kennedy class III modification 1 was scanned to create a virtual 3-dimensional (3D) cast. Two groups of 5 Co-Cr RPD major connectors were fabricated. In the 3D printing group, the Co-Cr major connector was virtually designed and exported for direct SLM 3D printing. For the conventional group, Co-Cr major connectors were constructed conventionally. The Co-Cr major connectors were virtually superimposed with the master die for surface adaptation analysis. Additional comparative analyses of surface roughness, relative density, microhardness, and microstructure of the 2 groups were performed. Data were analyzed by using independent t tests (α=.05). RESULTS: The overall volumetric and linear discrepancies were significantly higher (P<.05) in the 3D printing group. Significant differences in the surface roughness (P<.05) and microhardness (P<.05) were observed, with the 3D printing group having higher surface roughness and microhardness than the conventional group. Unlike conventional connectors, the microstructure of 3D-printed connectors showed fine homogeneous granules. CONCLUSIONS: Compared with the conventional casting technique, SLM 3D printing enabled the fabrication of Co-Cr RPD major connectors with higher microhardness and fine homogenous microstructure. However, the surface adaptation and surface roughness of SLM 3D printing Co-Cr connectors were worse than those produced conventionally. Both techniques showed similar relative densities.

Global Epidemiology of Chronic Venous Disease: A Systematic Review With Pooled Prevalence Analysis.

OBJECTIVE: To provide an updated estimate of the global prevalence of CVD and to comprehensively evaluate risk factors associated with this condition. BACKGROUND: CVD is an important cause of morbidity internationally, but the global burden of this condition is poorly characterized. The burden of CVD must be better characterized to optimize service provision and permit workforce planning to care for patients with different stages of CVD. METHODS: A systematic search in Ovid MEDLINE and Embase (1946-2019) identified 1271 articles. Full-text, English language articles reporting on the epidemiology of CVD in a general adult population were included. Data extraction was performed by 2 independent reviewers, in accordance with a preregistered protocol (PROSPERO: CRD42019153656). STATA and Review Manager were used for quantitative analysis. A crude, unadjusted pooled prevalence was calculated for each Clinical (C) stage in the Clinical, Etiologic, Anatomic, Pathophysiologic classification and across different geographical regions. Qualitative analysis was performed to evaluate associated risk factors in CVD. RESULTS: Thirty-two articles across 6 continents were identified. Nineteen studies were included in the overall pooled prevalence for each Clinical (C) stage; pooled estimates were: C0 s: 9%, C1: 26%, C2: 19%, C3: 8%, C4: 4%, C5: 1%, C6: 0.42%. The prevalence of C2 disease was highest in Western Europe and lowest in the Middle East and Africa. Commonly reported risk factors for CVD included: female sex (OR 2.26, 95% confidence intervals 2.16-2.36, P < 0.001), increasing age, obesity, prolonged standing, positive family history, parity, and Caucasian ethnicity. There was significant heterogeneity across the included studies. CONCLUSIONS: CVD affects a significant proportion of the population globally; however, there is significant heterogeneity in existing epidemiological studies.

Short- and long-term outcomes in isolated penetrating aortic ulcer disease.

BACKGROUND: The optimum management of isolated penetrating aortic ulceration (PAU), with no associated intramural hematoma or aortic dissection is not clear. We evaluate the short- and long-term outcomes in isolated PAU to better inform management strategies. METHODS: We conducted a retrospective review of 43 consecutive patients (mean age, 72.2 years; 26 men) with isolated PAU (excluding intramural hematoma/aortic dissection) managed at a single tertiary vascular unit between November 2007 and April 2019. Twenty-one percent had PAU of the arch, 62% of the thoracic aorta, and 17% of the abdominal aorta. Conservative and surgical groups were analyzed separately. Primary outcomes included mortality, PAU progression, and interventional complications. RESULTS: Initially, 67% of patients (29/43) were managed conservatively; they had significantly smaller PAU neck widths (P = .04), PAU depths (P = .004), and lower rates of associated aneurysmal change (P = .004) compared with those initially requiring surgery. Four patients (4/29) initially managed conservatively eventually required surgical management at a mean time interval of 49.75 months (range, 9.03-104.33 months) primarily owing to aneurysmal degeneration. Initially, 33% of patients (14/43) underwent surgical management; 7 of the 14 procedures were urgent. Of the 18 patients, 17 eventually managed with surgical intervention had an endovascular repair; 2 of the 17 endovascular cases involved supra-aortic debranching, six used scalloped, fenestrated, or chimney stents. The overall long-term mortality was 30% (mean follow-up, 48 months; range, 0-136 months) with no significant difference between the conservatively and surgically managed groups (P = .98). No aortic-related deaths were documented during follow-up in those managed conservatively. There was no in-hospital mortality after surgical repair. Of these 18 patients, two required reintervention within 30 days for type I or III endoleaks. Among the 18 patients, seven died during follow-up (mean survival, 90.24 months; range, 66.48-113.88) with 1 of the 18 having a confirmed aortic-related death. CONCLUSIONS: Isolated, asymptomatic, small PAUs may be safely managed conservatively with regular surveillance. Those with high-risk features or aneurysmal progression require complex strategies for successful treatment with acceptable long-term survival.

Treatment of distal deep vein thrombosis.

BACKGROUND: The treatment of distal (below the knee) deep vein thrombosis (DVT) is not clearly established. Distal DVT can either be treated with anticoagulation, or monitored with close follow-up to detect progression to the proximal veins (above the knee), which requires anticoagulation. Proponents of this monitoring strategy base their decision to withhold anticoagulation on the fact that progression is rare and most people can be spared from potential bleeding and other adverse effects of anticoagulation. OBJECTIVES: To assess the effects of different treatment interventions for people with distal (below the knee) deep vein thrombosis (DVT). SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 12 February 2019. We also undertook reference checking to identify additional studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) for the treatment of distal DVT. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials and extracted data. We resolved disagreements by discussion. Primary outcomes of interest were recurrence of venous thromboembolism (VTE), DVT and major bleeding and follow up ranged from three months to two years. We performed fixed-effect model meta-analyses with risk ratio (RRs) and 95% confidence intervals (CIs). We assessed the certainty of the evidence using GRADE. MAIN RESULTS: We identified eight RCTs reporting on 1239 participants. Five trials randomised participants to anticoagulation for up to three months versus no anticoagulation. Three trials compared anticoagulation treatment for different time periods. Anticoagulant compared to no intervention or placebo for distal DVT treatment Anticoagulation with a vitamin K antagonist (VKA) reduced the risk of recurrent VTE during follow-up compared with participants receiving no anticoagulation (RR 0.34, 95% CI 0.15 to 0.77; 5 studies, 496 participants; I2 = 3%; high-certainty evidence), and reduced the risk of recurrence of DVT (RR 0.25, 95% CI 0.10 to 0.67; 5 studies, 496 participants; I2 = 0%; high-certainty evidence). There was no clear effect on risk of pulmonary embolism (PE) (RR 0.81, 95% CI 0.18 to 3.59; 4 studies, 480 participants; I2 = 0%; low-certainty evidence). There was little to no difference in major bleeding with anticoagulation compared to placebo (RR 0.76, 95% CI 0.13 to 4.62; 4 studies, 480 participants; I2 = 26%; low-certainty evidence). There was an increase in clinically relevant non-major bleeding events in the group treated with anticoagulants (RR 3.34, 95% CI 1.07 to 10.46; 2 studies, 322 participants; I2 = 0%; high-certainty evidence). There was one death, not related to PE or major bleeding, in the anticoagulation group. Anticoagulation for three months or more compared to anticoagulation for six weeks for distal DVT treatment Three RCTs of 736 participants compared three or more months of anticoagulation with six weeks of anticoagulation. Anticoagulation with a VKA for three months or more reduced the incidence of recurrent VTE to 5.8% compared with 13.9% in participants treated for six weeks (RR 0.42, 95% CI 0.26 to 0.68; 3 studies, 736 participants; I2 = 50%; high-certainty evidence). The risk for recurrence of DVT was also reduced (RR 0.32, 95% CI 0.16 to 0.64; 2 studies, 389 participants; I2 = 48%; high-certainty evidence), but there was probably little or no difference in PE (RR 1.05, 95% CI 0.19 to 5.88; 2 studies, 389 participants; I2 = 0%; low-certainty evidence). There was no clear difference in major bleeding events (RR 3.42, 95% CI 0.36 to 32.35; 2 studies, 389 participants; I2 = 0%; low-certainty evidence) or clinically relevant non-major bleeding events (RR 1.76, 95% CI 0.90 to 3.42; 2 studies, 389 participants; I2 = 1%; low-certainty evidence) between three months or more of treatment and six weeks of treatment. There were no reports for overall mortality or PE and major bleeding-related deaths. AUTHORS' CONCLUSIONS: Our review found a benefit for people with distal DVT treated with anticoagulation therapy using VKA with little or no difference in major bleeding events although there was an increase in clinically relevant non-major bleeding when compared to no intervention or placebo. The small number of participants in this meta-analysis and strength of evidence prompts a call for more research regarding the treatment of distal DVT. RCTs comparing different treatments and different treatment periods with placebo or compression therapy, are required.

Primary care survey of venous leg ulceration management and referral pre-EVRA trial.

Venous leg ulceration (VLU) is a public health concern that is largely managed in community settings. The present study aimed to survey current VLU management in the community. A 14-question survey was distributed to primary care professionals, and 90 responses were received. Some 54% of respondents stated that they would assess ankle brachial pressure indices (ABPI) for those with VLU, while 25% reported that they would not. Additionally, 62% reported not organising duplex ultrasound scanning. Compression therapy was offered by 82% of respondents. When asked whether VLU patients were referred to specialist services in secondary or tertiary care, some 32% reported that they would. However, 57% reported that, if a study suggested that referral to specialist services was beneficial, they would change their practice. On the basis of the findings, the authors concluded that there is diversity in VLU diagnostic and treatment pathways. New, high-quality evidence may improve practice, but care delivery is influenced by local factors including time and resource distribution.

Parkinson's disease biomarkers based on α-synuclein.

Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease and is estimated to affect approximately 1-4% of individuals aged over 60 years old. Although considerable efforts have been invested into developing disease-modifying therapies for Parkinson's disease, such efforts have been confounded by the difficulty in accurately diagnosing Parkinson's disease during life to enable accurate patient stratification for clinical trialling of candidate therapeutics. Therefore, the search for effective biomarkers that can be accurately evaluated during life with non-invasive means is a pressing issue in the field. Since the discovery of α-synuclein (α-syn) as a protein linked to a familial form of Parkinson's disease, later identified as the major protein component of the neuropathological hallmark of idiopathic Parkinson's disease, considerable interest has focused on this protein and its distinct conformers. We describe here the progress that has been made in the area of Parkinson's disease biomarker discovery with a focus on α-synuclein. In particular, we highlight the novel assays that have been employed and the increasing complexity in evaluating α-synuclein with regard to the considerable diversity of conformers that exist in the biofluids and peripheral tissues under disease conditions. "This article is part of the Special Issue Synuclein."

Gut microbiome and Parkinson's disease: Perspective on pathogenesis and treatment.

BACKGROUND: Parkinson's disease (PD) is a disease of ⍺-synuclein aggregation-mediated dopaminergic neuronal loss in the substantia nigra pars compacta, which leads to motor and non-motor symptoms. Through the last two decades of research, there has been growing consensus that inflammation-mediated oxidative stress, mitochondrial dysfunction, and cytokine-induced toxicity are mainly involved in neuronal damage and loss associated with PD. However, it remains unclear how these mechanisms relate to sporadic PD, a more common form of PD. Both enteric and central nervous systems have been implicated in the pathogenesis of sporadic PD, thus highlighting the crosstalk between the gut and brain. AIM: of Review: In this review, we summarize how alterations in the gut microbiome can affect PD pathogenesis. We highlight various mechanisms increasing/decreasing the risk of PD development. Based on the previous supporting evidence, we suggest how early interventions could protect against PD development and how controlling specific factors, including our diet, could modify our perspective on disease mechanisms and therapeutics. We explain the strong relationship between the gut microbiota and the brain in PD subjects, by delineating the multiple mechanisms involved inneuroinflammation and oxidative stress. We conclude that the neurodetrimental effects of western diet (WD) and the neuroprotective effects of Mediterranean diets should be further exploredin humans through clinical trials. Key Scientific Concepts of Review: Alterations in the gut microbiome and associated metabolites may contribute to pathogenesis in PD. In some studies, probiotics have been shown to exert anti-oxidative effects in PD via improved mitochondrial dynamics and homeostasis, thus reducing PD-related consequences. However, there is a significant unmet need for randomized clinical trials to investigate the effectiveness of microbial products, probiotic-based supplementation, and dietary intervention in reversing gut microbial dysbiosis in PD.

Serotonin distinctly controls behavioral states in restrained and freely moving Drosophila.

When trapped in a physical restraint, animals must select an escape strategy to increase their chances of survival. After falling into an inescapable trap, they react with stereotypical behaviors that differ from those displayed in escapable situations. Such behaviors involve either a wriggling response to unlock the trap or feigning death to fend off a predator attack. The neural mechanisms that regulate animal behaviors have been well characterized for escapable situations but not for inescapable traps. We report that restrained vinegar flies exhibit alternating flailing and immobility to free themselves from the trap. We used optogenetics and intersectional genetic approaches to show that, while broader serotonin activation promotes immobility, serotonergic cells in the ventral nerve cord (VNC) regulate immobility states majorly via 5-HT7 receptors. Restrained and freely moving locomotor states are controlled by distinct mechanisms. Taken together, our study has identified serotonergic switches of the VNC that promote environment-specific adaptive behaviors.

Control of TGFß signalling by ubiquitination independent function of E3 ubiquitin ligase TRIP12.

Transforming growth factor ß (TGFß) pathway is a master regulator of cell proliferation, differentiation, and death. Deregulation of TGFß signalling is well established in several human diseases including autoimmune disorders and cancer. Thus, understanding molecular pathways governing TGFß signalling may help better understand the underlying causes of some of those conditions. Here, we show that a HECT domain E3 ubiquitin ligase TRIP12 controls TGFß signalling in multiple models. Interestingly, TRIP12 control of TGFß signalling is completely independent of its E3 ubiquitin ligase activity. Instead, TRIP12 recruits SMURF2 to SMAD4, which is most likely responsible for inhibitory monoubiquitination of SMAD4, since SMAD4 monoubiquitination and its interaction with SMURF2 were dramatically downregulated in TRIP12-/- cells. Additionally, genetic inhibition of TRIP12 in human and murine cells leads to robust activation of TGFß signalling which was rescued by re-introducing wildtype TRIP12 or a catalytically inactive C1959A mutant. Importantly, TRIP12 control of TGFß signalling is evolutionary conserved. Indeed, genetic inhibition of Drosophila TRIP12 orthologue, ctrip, in gut leads to a reduced number of intestinal stem cells which was compensated by the increase in differentiated enteroendocrine cells. These effects were completely normalised in Drosophila strain where ctrip was co-inhibited together with Drosophila SMAD4 orthologue, Medea. Similarly, in murine 3D intestinal organoids, CRISPR/Cas9 mediated genetic targeting of Trip12 enhances TGFß mediated proliferation arrest and cell death. Finally, CRISPR/Cas9 mediated genetic targeting of TRIP12 in MDA-MB-231 breast cancer cells enhances the TGFß induced migratory capacity of these cells which was rescued to the wildtype level by re-introducing wildtype TRIP12. Our work establishes TRIP12 as an evolutionary conserved modulator of TGFß signalling in health and disease.

Serotonergic control of feeding microstructure in Drosophila.

To survive, animals maintain energy homeostasis by seeking out food. Compared to freely feeding animals, food-deprived animals may choose different strategies to balance both energy and nutrition demands, per the metabolic state of the animal. Serotonin mediates internal states, modifies existing neural circuits, and regulates animal feeding behavior, including in humans and fruit flies. However, an in-depth study on the neuromodulatory effects of serotonin on feeding microstructure has been held back for several technical reasons. Firstly, most feeding assays lack the precision of manipulating neuronal activity only when animals start feeding, which does not separate neuronal effects on feeding from foraging and locomotion. Secondly, despite the availability of optogenetic tools, feeding in adult fruit flies has primarily been studied using thermogenetic systems, which are confounded with heat. Thirdly, most feeding assays have used food intake as a measurement, which has a low temporal resolution to dissect feeding at the microstructure level. To circumvent these problems, we utilized OptoPAD assay, which provides the precision of optogenetics to control neural activity contingent on the ongoing feeding behavior. We show that manipulating the serotonin circuit optogenetically affects multiple feeding parameters state-dependently. Food-deprived flies with optogenetically activated and suppressed serotonin systems feed with shorter and longer sip durations and longer and shorter inter-sip intervals, respectively. We further show that serotonin suppresses and enhances feeding via 5-HT1B and 5-HT7 receptors, respectively.

Abdominal aortic aneurysm clinical practice guidelines: a methodological assessment using the AGREE II instrument.

OBJECTIVES: Abdominal aortic aneurysm (AAA) clinical practice guidelines (CPGs) provide evidence-based information on patient management; however, methodological differences exist in the development of CPGs. This study examines the methodological quality of AAA CPGs using a validated assessment tool. METHODS: Medline, EMBASE and online CPG databases were searched from 1946 to 31 October 2021. Full-text, English language, evidence-based AAA CPGs were included. Consensus-based CPGs, summaries of CPGs or CPGs which were only available on purchase were excluded. Five reviewers assessed their quality using the Appraisal of Guidelines for Research and Evaluation II instrument. An overall guideline assessment scaled score of ≥80% was considered as the threshold to recommend CPG use in clinical practice. RESULTS: Seven CPGs were identified. Scores showed good inter-reviewer reliability (intraclass correlation coefficient 0.943, 95% CI 0.915 to 0.964). On average, CPGs performed adequately with mean scaled scores of over 50% in all domains. However, between CPGs, significant methodological heterogeneity was observed in all domains. Four CPGs scored ≥80% (European Society of Cardiology, the Society of Vascular Surgery, the European Society of Vascular Surgery and the National Institute of Health and Care Excellence), supporting their use in clinical practice. CONCLUSIONS: Four CPGs were considered of adequate methodological quality to recommend their use in clinical practice; nonetheless, these still showed areas for improvement, potentially through performing economic analysis and trial application of recommendations. A structured approach employing validated CPG creation tools should be used to improve rigour of AAA CPGs. Future work should also evaluate recommendation accuracy using validated appraisal tools.

Anatomy and Neural Pathways Modulating Distinct Locomotor Behaviors in Drosophila Larva.

The control of movements is a fundamental feature shared by all animals. At the most basic level, simple movements are generated by coordinated neural activity and muscle contraction patterns that are controlled by the central nervous system. How behavioral responses to various sensory inputs are processed and integrated by the downstream neural network to produce flexible and adaptive behaviors remains an intense area of investigation in many laboratories. Due to recent advances in experimental techniques, many fundamental neural pathways underlying animal movements have now been elucidated. For example, while the role of motor neurons in locomotion has been studied in great detail, the roles of interneurons in animal movements in both basic and noxious environments have only recently been realized. However, the genetic and transmitter identities of many of these interneurons remains unclear. In this review, we provide an overview of the underlying circuitry and neural pathways required by Drosophila larvae to produce successful movements. By improving our understanding of locomotor circuitry in model systems such as Drosophila, we will have a better understanding of how neural circuits in organisms with different bodies and brains lead to distinct locomotion types at the organism level. The understanding of genetic and physiological components of these movements types also provides directions to understand movements in higher organisms.

Feasibility of a 3 mm arteriotomy for brachiocephalic fistula formation.

BACKGROUND: The arteriovenous fistula is the modality of choice for long-term haemodialysis access. We describe the feasibility of routinely fashioning a brachiocephalic fistula utilising a 3 mm long arteriotomy in an attempt to reduce the incidence of symptomatic steal syndrome yet while maintaining satisfactory clinical outcomes. METHODS: All patients who underwent brachiocephalic fistula formation using a routine 3 mm long arteriotomy within Hammersmith Hospital between January 2017 and March 2018 were included. Primary outcomes included primary failure, failure of maturation, secondary patency and steal syndrome. RESULTS: Sixty-eight brachiocephalic arteriovenous fistula were fashioned utilising a 3 mm long arteriotomy during the study period. Mean age was 60.5 years with 59% having a history of diabetes mellitus. Mean followup was 368 days. Primary failure occurred in 10 (14.7%) patients. Cannulation was achieved in 67.3% of remaining fistula within 3-months, rising to 87.3% by 6-months. Primary patency at 6 and 12 months was 76% and 69%, respectively. Secondary patency at 6 and 12 months was 94% and 91%, respectively. Dialysis access steal syndrome was clinically apparent in three (4.4%) patients with all cases being managed conservatively. CONCLUSION: A 3 mm long arteriotomy may be routinely utilised for brachiocephalic fistula creation in an attempt to limit the incidence of steal syndrome yet while maintaining clinical patency outcomes.

Postsclerotherapy compression: A systematic review.

BACKGROUND: Compression after sclerotherapy is commonly used, although the evidence base for this practice is unclear. This study aims to summarize and assess the evidence for compression therapy after sclerotherapy to inform clinical practice. METHODS: A systematic review was performed according to PRISMA guidelines via Medline and EMBASE databases (1946 to December 31, 2019) by two reviewers. Full-text, English-language studies comparing compression type and/or duration in adult chronic venous disease patients undergoing liquid or foam sclerotherapy were included. RESULTS: Nine studies were identified: five using liquid sclerotherapy, three foam sclerotherapy and one using both. Studies had short follow-up periods (6-24 weeks) and reported on clinical outcomes, quality of life, side effects and complications. In C1 patients undergoing liquid sclerotherapy, any duration of stocking use significantly decreased telangiectasia and reticular vein number and size compared with no compression. No significant difference in clinical symptoms or quality of life was seen when comparing compression duration after liquid or foam sclerotherapy in tributary or truncal veins in C2 to C6 patients. Greater superficial vein resolution was seen with stockings compared with bandages in C2 patients undergoing liquid sclerotherapy to tributary veins. A comparison of stockings vs bandaging revealed differing thrombophlebitis rates but no significant difference in pigmentation. In C2 to C6 patients undergoing foam sclerotherapy, use of 35 mm Hg stockings significantly improved post-treatment symptoms compared with 23 mm Hg stockings. This review was limited by heterogeneity of outcome measurements and the variety of comparisons between compression types and durations. CONCLUSIONS: Postsclerotherapy compression may have beneficial clinical outcomes at short-term follow-up; however, evidence is lacking regarding its type, class, length, and duration. Further trials are required to guide the optimal management of postsclerotherapy patients.

A Review of Current and Future Antithrombotic Strategies in Surgical Patients-Leaving the Graduated Compression Stockings Behind?

Venous thromboembolism (VTE) remains an important consideration within surgery, with recent evidence looking to refine clinical guidance. This review provides a contemporary update of existing clinical evidence for antithrombotic regimens for surgical patients, providing future directions for prophylaxis regimens and research. For moderate to high VTE risk patients, existing evidence supports the use of heparins for prophylaxis. Direct oral anticoagulants (DOACs) have been validated within orthopaedic surgery, although there remain few completed randomised controlled trials in other surgical specialties. Recent trials have also cast doubt on the efficacy of mechanical prophylaxis, especially when adjuvant to pharmacological prophylaxis. Despite the ongoing uncertainty in higher VTE risk patients, there remains a lack of evidence for mechanical prophylaxis in low VTE risk patients, with a recent systematic search failing to identify high-quality evidence. Future research on rigorously developed and validated risk assessment models will allow the better stratification of patients for clinical and academic use. Mechanical prophylaxis' role in modern practice remains uncertain, requiring high-quality trials to investigate select populations in which it may hold benefit and to explore whether intermittent pneumatic compression is more effective. The validation of DOACs and aspirin in wider specialties may permit pharmacological thromboprophylactic regimens that are easier to administer.

UK primary care survey of venous leg ulceration management and referral - Post-EVRA trial.

OBJECTIVE: Determine standards of referral and management of patients with venous leg ulceration in primary care after the release of the EVRA (A Randomized Trial of Early Endovenous Ablation in Venous Ulceration) study results. METHODS: An online questionnaire was disseminated over four months to professionals working within primary care. RESULTS: The survey received 643 responses. Of respondents, 90 (14%) had heard of the EVRA trial and 51 (8%) were familiar with the results. Of those who answered the following questions, 410 (69.1%) stated that referral to a vascular specialist must be made by the General Practitioner and 13 (2.2%) reported that they would always refer patients for secondary care assessment before the publication of EVRA. Considering the EVRA results, 128 (29%) reported that they would change practice regarding referral and would experience no barriers and 198 (45%) reported that they would like to refer earlier but is not their decision. Barriers to changing practice included local referral policies, training and time restrictions, 266 (59%) had heard of the NICE guideline (CG168) and 194 (43%) were aware of the recommendations for referral to a vascular service within two weeks for patients with an open or healed ulcer. CONCLUSION: There is a considerable variation in local referral pathways for venous leg ulceration, and despite clinicians wanting to refer promptly, many primary care professionals are unable to. Unfortunately, the EVRA study alone may not change the overall practice, and work is needed to overcome barriers faced by primary care professionals.