SARS-CoV-2 papain-like protease activates nociceptors to drive sneeze and pain.

SARS-CoV-2, the virus responsible for COVID-19, triggers symptoms such as sneezing, aches and pain.1 These symptoms are mediated by a subset of sensory neurons, known as nociceptors, that detect noxious stimuli, densely innervate the airway epithelium, and interact with airway resident epithelial and immune cells.2-6 However, the mechanisms by which viral infection activates these neurons to trigger pain and airway reflexes are unknown. Here, we show that the coronavirus papain-like protease (PLpro) directly activates airway-innervating trigeminal and vagal nociceptors in mice and human iPSC-derived nociceptors. PLpro elicits sneezing and acute pain in mice and triggers the release of neuropeptide calcitonin gene-related peptide (CGRP) from airway afferents. We find that PLpro-induced sneeze and pain requires the host TRPA1 ion channel that has been previously demonstrated to mediate pain, cough, and airway inflammation.7-9 Our findings are the first demonstration of a viral product that directly activates sensory neurons to trigger pain and airway reflexes and highlight a new role for PLpro and nociceptors in COVID-19.

Emergency Endovascular Repair of Thoracic Aorta Via a Percutaneous Popliteal Approach Following an Iatrogenic Injury.

Iatrogenic arterial injuries are rare but well-recognised complications of spinal surgery. This paper presents a case of an iatrogenic arterial injury during a total en bloc spondylectomy resulting in significant haemorrhage and the patient's haemodynamic instability. The devastating complication was successfully treated with an emergency thoracic endovascular aortic repair via a percutaneous popliteal approach, while the patient remained in prone position. The patient had an uneventful recovery with no subsequent arterial injury or pseudoaneurysm to the access vessel.

Hemodynamic Implications of STABILISE Technique for Aortic Dissection Repair.

BACKGROUND: The stent-assisted balloon-induced intimal disruption and relamination (STABILISE) technique for treatment of type B dissection has shown promising clinical results at mid-term. Computational modeling is a way of noninvasively obtaining hemodynamic effects, such as pressure and wall shear stress, leading to a better understanding of potential benefits. Particular areas of interest are (1) the effect of intimal disruption and re-lamination and (2) the effect of the bare metal stent in the visceral aortic segment. METHODS: Single-center prospective case series. Data from 5 consecutive locally performed cases of STABILISE technique were analyzed. Included cases were type B aortic dissection with or without prior de-branching. The STABILISE procedure had to be performed without 30-day major complications. Preoperative and postoperative imaging data for each patient were transferred to the biomedical engineering team. Each case was reconstructed, meshed, and simulated with computational fluid dynamics using patient-specific data (heart rate, blood pressure, height, and weight). Hemodynamic parameters were then extracted from the simulations. RESULTS: In all cases, computational analysis showed for postoperative patients: (1) a drop in pressure difference between lumina and (2) lower wall shear stress effects, compared to their preoperative status. These observations were most pronounced in the visceral aortic segment. CONCLUSIONS: Computational modeling shows favourable changes in the flow dynamics of type B dissection treated using the STABILISE technique. This may suggest protective effects of this technique for long-term aortic healing and cicatrization.

Dietary and lifestyle factors associated with troublesome gastroesophageal reflux symptoms in Vietnamese adults.

Background: Dietary and lifestyle habits related to troublesome gastroesophageal reflux symptoms (tGERS) differ significantly across populations. There have yet to be studies on the Vietnamese population. Aims: To identify dietary and lifestyle habits associated with tGERS in Vietnamese adults. Methods: A cross-sectional survey was conducted among Vietnamese adults aged 18 years and older from March 2023 to May 2023. Participants were recruited online through a widely read national newspaper and Facebook, one of Vietnam's most popular social media platforms. The survey questionnaire comprised 27 questions covering participants' basic demographic information, dietary and lifestyle habits, the presence and characteristics of tGERS, and inquiries about specific dietary and lifestyle patterns, foods, and beverages associated with tGERS. Results: A total of 4,400 valid responses were collected, including 2050 participants without tGERS and 2,350 participants with tGERS. Multivariate analysis showed several factors associated with tGERS, including eating beyond fullness (OR 1.383, CI95% 1.127-1.698), tight clothing (OR 1.627, CI95% 1.256-2.107), stress (OR 1.566, CI95% 1.363-1.800), and insomnia (OR 1.321, CI95% 1.129-1.546). Among habits associated with tGERS, eating beyond fullness was the most frequently reported (64.6%). Interestingly, although a short meal-to-bed time and staying up late after midnight were not risk factors for tGERS, they were two common factors associated with tGERS in symptomatic participants, particularly those with nocturnal reflux symptoms. For food triggers, the three most common ones were greasy foods (71.9%), sour/spicy soups (64.7%), and citrus fruits (36.0%). In terms of beverages, carbonated soft drinks were at the top of triggering tGERS (40.3%), and beer and orange juice were the second and third most common triggers, accounting for 35.7 and 30.6%, respectively. Conclusion: We reported the dietary and lifestyle habits associated with tGERS in Vietnamese adults for the first time. These findings will serve as a basis for future studies on the primary prevention and nondrug management of tGERS in Vietnam.

The meaning of self-acceptance.

A research technician describes how receiving an ADHD diagnosis allowed her to re-examine how she sees herself and her work.

Controlling the controls: what is negative pressure wound therapy compared to in clinical trials?

AIM: Surgical site infections (SSIs) are common following colorectal operations. Clinical trials suggest that closed incision negative pressure wound therapy (ciNPWT) may reduce SSIs compared to a 'standard of care' group. However, wound management in the standard of care group may vary. The aim of this review was to assess the control arms in trials of ciNPWT for potential confounding variables that could influence the rates of SSI and therefore the trial outcomes. METHODS: A mapping review of the PubMed database was undertaken in the English language for randomized controlled trials that assessed, in closed surgical wounds, the use of ciNPWT compared to standard of care with SSI as an outcome. Data regarding wound care to assess potential confounding factors that may influence SSI rates were compared between the ciNPWT and standard of care groups. Included were the method of wound closure, control dressing type, frequency of dressing changes and postoperative wound care (washing). RESULTS: Twenty-seven trials were included in the mapping review. There was heterogeneity in ciNPWT duration. There was little control in the comparator standard of care groups with a variety of wound closure techniques and different control dressings used. Overall standard of care dressings were changed more frequently than the ciNPWT dressing and there was no control over wound care or washing. No standard for 'standard of care' was apparent. CONCLUSION: In randomized trials assessing the intervention of ciNPWT compared to standard of care there was considerable heterogeneity in the comparator groups and no standard of care was apparent. Heterogeneity in dressing protocols for standard of care groups could introduce potential confounders impacting SSI rates. There is a need to standardize care in ciNPWT trials to assess potential meaningful differences in SSI prevention.

Routine bacterial culture of proximal bone specimens during minor amputation in patients with diabetes-related foot infections has little clinical utility in predicting re-operation or ulcer healing.

BACKGROUND: Trans-phalangeal and trans-metatarsal amputation, collectively termed 'minor amputations' are important procedures for managing infections of diabetes-related foot ulcers (DFU). Following minor amputation, international guidelines recommend a prolonged course of antibiotics if residual infected bone on intra-operative bone samples are identified, but the quality of the evidence underpinning these guidelines is low. In this study, we examined the concordance of microbiological results from proximal bone cultures compared to results from superficial wound swabs in relation to patient outcomes; with the aim of determining the utility of routinely obtaining marginal bone specimens. METHODS: Data was retrospectively collected on 144 individuals who underwent minor amputations for infected DFU at a large Australian tertiary hospital. Concordance was identified for patients with both superficial wound swabs and intra-operative bone samples available. Patient outcomes were monitored up to 6 months post-amputation. The primary outcome was complete healing at 6 months; and secondary outcome measures included further surgery and death. Mann Whitney U testing was performed for bivariate analyses of continuous variables, Chi-Squared testing used for categorical variables and a logistic regression was performed with healing as the dependent variable. RESULTS: A moderate-high degree of concordance was observed between microbiological samples, with 38/111 (35%) of patients having discordant wound swab and bone sample microbiology. Discordant results were not associated with adverse outcomes (67.2% with concordant results achieved complete healing compared with 68.6% patients with discordant results; P = 0.89). Revascularisation during admission (0.37 [0.13-0.96], P = 0.04) and amputation of the 5th ray (0.45 [0.21-0.94], P = 0.03) were independent risk factors for non-healing. CONCLUSION: There was a moderate-high degree of concordance between superficial wound swab results and intra-operative bone sample microbiology in this patient cohort. Discordance was not associated with adverse outcomes. These results suggest there is little clinical utility in routinely collecting proximal bone as an adjunct to routine wound swabs for culture during minor amputation for an infected DFU.

Feasibility of the Complete Endovascular Reconstruction of the Trifurcation (CERT) Technique for Revascularisation in Chronic Limb Threatening Ischemia.

BackgroundRevascularisation of patients with chronic limb threatening ischaemia due to arterial lesions in the below the knee segment can be challenging. This study describes a novel technique that allows a complete endovascular reconstruction of the trifurcation (CERT) utilising stents in the below the knee segment when conventional techniques are exhausted, or have failed to deliver an acceptable result, leading to remaining outflow compromise. Methods: Eight patients with Rutherford 5 chronic limb threatening ischaemia underwent CERT between January 1st, 2018 and January 1st, 2020. All patients underwent ultrasound at 6 weeks post operatively and then at variable intervals until the completion of the follow up period in March 2020. Results: Technical success of the CERT technique was achieved in all patients. Six patients had anterior tibial artery/Tibioperoneal trunk reconstructions, whilst 2 patients were stented directly into posterior tibial and peroneal artery. Five patients (63%) achieved wound healing. All-cause mortality was 25% (2 patients) with 1 patient achieving wound healing prior to death. Two stents were occluded during the follow up period. The first was asymptomatic and had achieved wound healing. The second was symptomatic with stent occlusion and a delayed presentation with Rutherford 3 acute limb ischaemia. Conclusions: Complete endovascular reconstruction of the trifurcation is a feasible option to achieve revascularisation in patients with tissue loss and below the knee arterial lesions allowing a continuous reconstruction of the trifurcation segment keeping the anatomical configuration intact. Clinical outcomes appear acceptable however larger series are needed.

Frail patients having vascular surgery during the early COVID-19 pandemic experienced high rates of adverse perioperative events and amputation.

BACKGROUND: Frailty predicts adverse perioperative outcomes and increased mortality in patients having vascular surgery. Frailty assessment is a potential tool to inform resource allocation, and shared decision-making about vascular surgery in the resource constrained COVID-19 pandemic environment. This cohort study describes the prevalence of frailty in patients having vascular surgery and the association between frailty, mortality and perioperative outcomes. METHODS: The COVID-19 Vascular Service in Australia (COVER-AU) prospective cohort study evaluates 30-day and six-month outcomes for consecutive patients having vascular surgery in 11 Australian vascular units, March-July 2020. The primary outcome was mortality, with secondary outcomes procedure-related outcomes and hospital utilization. Frailty was assessed using the nine-point visual Clinical Frailty Score, scores of 5 or more considered frail. RESULTS: Of the 917 patients enrolled, 203 were frail (22.1%). The 30 day and 6 month mortality was 2.0% (n = 20) and 5.9% (n = 35) respectively with no significant difference between frail and non-frail patients (OR 1.68, 95%CI 0.79-3.54). However, frail patients stayed longer in hospital, had more perioperative complications, and were more likely to be readmitted or have a reoperation when compared to non-frail patients. At 6 months, frail patients had twice the odds of major amputation compared to non-frail patients, after adjustment (OR 2.01; 95% CI 1.17-3.78), driven by a high rate of amputation during the period of reduced surgical activity. CONCLUSION: Our findings highlight that older, frail patients, experience potentially preventable adverse outcomes and there is a need for targeted interventions to optimize care, especially in times of healthcare stress.

Safe endoscopic removal of ingested fish bone with esophageal perforation and impingement on the aortic wall.

Esophageal foreign bodies are common conditions that may lead to serious complications, such as esophageal perforation, neck abscess, mediastinitis, arterial injury, and lung damage. We report a rare case of esophageal fish bone impingement on the aorta that was managed without complication by endoscopic removal.

Uterine Arteriovenous Malformation: A Pictorial Review of Diagnosis and Management.

Uterine arteriovenous malformation (UAVM) is a rare condition and is classified as either congenital or acquired UAVM. Patients with UAVMs usually experience miscarriages or recurrent menorrhagia. Ultrasound is used for the initial estimation of UAVMs. Computed tomography and magnetic resonance imaging are noninvasive and valuable methods that provide good compatibility with digital subtraction angiography to support the diagnosis and treatment of UAVM. Timely diagnosis is crucial to provide appropriate treatment for alleviating complications. This article presents a pictorial and literature review of the current evidence of the diagnosis and management of UAVM.

Availability and service provision of multidisciplinary diabetes foot units in Australia: a cross-sectional survey.

BACKGROUND: With growing global prevalence of diabetes mellitus, diabetes-related foot disease (DFD) is contributing significantly to disease burden. As more healthcare resources are being dedicated to the management of DFD, service design and delivery is being scrutinised. Through a national survey, this study aimed to investigate the current characteristics of services which treat patients with DFD in Australia. METHODS: An online survey was distributed to all 195 Australian members of the Australian and New Zealand Society for Vascular Surgery investigating aspects of DFD management in each member's institution. RESULTS: From the survey, 52 responses were received (26.7%). A multidisciplinary diabetes foot unit (MDFU) was available in more than half of respondent's institutions, most of which were tertiary hospitals. The common components of MDFU were identified as podiatrists, endocrinologists, vascular surgeons and infectious disease physicians. Many respondents identified vascular surgery as being the primary admitting specialty for DFD patients that require hospitalisation (33/52, 63.5%). This finding was consistent even in centres with MDFU clinics. Less than one third of MDFUs had independent admission rights. CONCLUSIONS: The present study suggests that many tertiary centres in Australia provide their diabetic foot service in a multidisciplinary environment however their composition and function remain heterogeneous. These findings provide an opportunity to evaluate current practice and, to initiate strategies aimed to improve outcomes of patients with DFD.

An External Validation Study of the Oakland and Glasgow-Blatchford Scores for Predicting Adverse Outcomes of Acute Lower Gastrointestinal Bleeding in an Asian Population.

AIMS: This study is aimed at (1) validating the performance of Oakland and Glasgow-Blatchford (GBS) scores and (2) comparing these scores with the SALGIB score in predicting adverse outcomes of acute lower gastrointestinal bleeding (ALGIB) in a Vietnamese population. METHODS: A multicenter cohort study was conducted on ALGIB patients admitted to seven hospitals across Vietnam. The adverse outcomes of ALGIB consisted of blood transfusion; endoscopic, radiologic, or surgical interventions; severe bleeding; and in-hospital death. The Oakland and GBS scores were calculated, and their performance was compared with that of SALGIB, a locally developed prediction score for adverse outcomes of ALGIB in Vietnamese, based on the data at admission. The accuracy of these scores was measured using the area under the receiver operating characteristic curve (AUC) and compared by the chi-squared test. RESULTS: There were 414 patients with a median age of 60 (48-71). The rates of blood transfusion, hemostatic intervention, severe bleeding, and in-hospital death were 26.8%, 15.2%, 16.4, and 1.4%, respectively. The SALGIB score had comparable performance with the Oakland score (AUC: 0.81 and 0.81, respectively; p = 0.631) and outperformed the GBS score (AUC: 0.81 and 0.76, respectively; p = 0.002) for predicting the presence of any adverse outcomes of ALGIB. All of the three scores had acceptable and comparable performance for in-hospital death but poor performance for hemostatic intervention. The Oakland score had the best performance for predicting severe bleeding. CONCLUSIONS: The Oakland and SALGIB scores had excellent and comparable performance and outperformed the GBS score for predicting adverse outcomes of ALGIB in Vietnamese.

Development and Validation of a Scoring System to Predict Severe Acute Lower Gastrointestinal Bleeding in Vietnamese.

BACKGROUND/AIMS: The prevalence of acute lower gastrointestinal bleeding (ALGIB) has progressively increased worldwide but there are few studies in Asian populations. This study aimed to develop and validate a scoring system to predict severe ALGIB in Vietnamese. METHODS: Risk factors for severe ALGIB were identified by multiple logistic regression analysis using data from a retrospective cohort of 357 patients admitted to a tertiary hospital. These factors were weighted to develop the severe acute lower gastrointestinal bleeding (SALGIB) score to predict severe ALGIB. The performance of SALGIB was validated in a prospective cohort of 324 patients admitted to 6 other hospitals using area under the receiver operating characteristics curve (AUC) analysis. RESULTS: There were four factors at admission independently associated with severe ALGIB in the derivation cohort: heart rate ≥ 100/min, systolic blood pressure < 100 mmHg, hematocrit < 35%, and platelets ≤ 150 × 103/µL. The SALGIB score determined severe ALGIB with AUC values of 0.91 and 0.86 in the derivation and validation cohorts, respectively. A SALGIB score < 2 associated with low risk of severe ALGIB in both cohorts (3.7% and 1.2%; respectively). CONCLUSIONS: The SALGIB score has good performance in discriminating risk of severe ALGIB in Vietnamese.

iBRAB: In silico based-designed broad-spectrum Fab against H1N1 influenza A virus.

Influenza virus A is a significant agent involved in the outbreak of worldwide epidemics, causing millions of fatalities around the world by respiratory diseases and seasonal illness. Many projects had been conducting to investigate recovered infected patients for therapeutic vaccines that have broad-spectrum activity. With the aid of the computational approach in biology, the designation for a vaccine model is more accessible. We developed an in silico protocol called iBRAB to design a broad-reactive Fab on a wide range of influenza A virus. The Fab model was constructed based on sequences and structures of available broad-spectrum Abs or Fabs against a wide range of H1N1 influenza A virus. As a result, the proposed Fab model followed iBRAB has good binding affinity over 27 selected HA of different strains of H1 influenza A virus, including wild-type and mutated ones. The examination also took by computational tools to fasten the procedure. This protocol could be applied for a fast-designed therapeutic vaccine against different types of threats.

Pharmacological and Toxicological Properties of the Potent Oral γ-Secretase Modulator BPN-15606.

Alzheimer's disease (AD) is characterized neuropathologically by an abundance of 1) neuritic plaques, which are primarily composed of a fibrillar 42-amino-acid amyloid-ß peptide (Aß), as well as 2) neurofibrillary tangles composed of aggregates of hyperphosporylated tau. Elevations in the concentrations of the Aß42 peptide in the brain, as a result of either increased production or decreased clearance, are postulated to initiate and drive the AD pathologic process. We initially introduced a novel class of bridged aromatics referred tγ-secretase modulatoro as γ-secretase modulators that inhibited the production of the Aß42 peptide and to a lesser degree the Aß40 peptide while concomitantly increasing the production of the carboxyl-truncated Aß38 and Aß37 peptides. These modulators potently lower Aß42 levels without inhibiting the γ-secretase-mediated proteolysis of Notch or causing accumulation of carboxyl-terminal fragments of APP. In this study, we report a large number of pharmacological studies and early assessment of toxicology characterizing a highly potent γ-secretase modulator (GSM), (S)-N-(1-(4-fluorophenyl)ethyl)-6-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-4-methylpyridazin-3-amine (BPN-15606). BPN-15606 displayed the ability to significantly lower Aß42 levels in the central nervous system of rats and mice at doses as low as 5-10 mg/kg, significantly reduce Aß neuritic plaque load in an AD transgenic mouse model, and significantly reduce levels of insoluble Aß42 and pThr181 tau in a three-dimensional human neural cell culture model. Results from repeat-dose toxicity studies in rats and dose escalation/repeat-dose toxicity studies in nonhuman primates have designated this GSM for 28-day Investigational New Drug-enabling good laboratory practice studies and positioned it as a candidate for human clinical trials.