MDA5-autoimmunity and interstitial pneumonitis contemporaneous with the COVID-19 pandemic (MIP-C).

BACKGROUND: Anti-MDA5 (Melanoma differentiation-associated protein-5) positive dermatomyositis (MDA5+-DM) is characterised by rapidly progressive interstitial lung disease (ILD) and high mortality. MDA5 is an RNA sensor and a key pattern recognition receptor for the SARS-CoV-2 virus. METHODS: This is a retrospective observational study of a surge in MDA5 autoimmunity, as determined using a 15 muscle-specific autoantibodies (MSAs) panel, between Janurary 2018 and December 2022 in Yorkshire, UK. MDA5-positivity was correlated with clinical features and outcome, and regional SARS-CoV-2 positivity and vaccination rates. Gene expression patterns in COVID-19 were compared with autoimmune lung disease and idiopathic pulmonary fibrosis (IPF) to gain clues into the genesis of the observed MDA5+-DM outbreak. FINDINGS: Sixty new anti-MDA5+, but not other MSAs surged between 2020 and 2022, increasing from 0.4% in 2019 to 2.1% (2020), 4.8% (2021) and 1.7% (2022). Few (8/60) had a prior history of confirmed COVID-19, peak rates overlapped with regional SARS-COV-2 community positivity rates in 2021, and 58% (35/60) had received anti-SARS-CoV-2 vaccines. 25/60 cases developed ILD which rapidly progression with death in 8 cases. Among the 35/60 non-ILD cases, 14 had myositis, 17 Raynaud phenomena and 10 had dermatomyositis spectrum rashes. Transcriptomic studies showed strong IFIH1 (gene encoding for MDA5) induction in COVID-19 and autoimmune-ILD, but not IPF, and IFIH1 strongly correlated with an IL-15-centric type-1 interferon response and an activated CD8+ T cell signature that is an immunologic hallmark of progressive ILD in the setting of systemic autoimmune rheumatic diseases. The IFIH1 rs1990760TT variant blunted such response. INTERPRETATION: A distinct pattern of MDA5-autoimmunity cases surged contemporaneously with circulation of the SARS-COV-2 virus during COVID-19. Bioinformatic insights suggest a shared immunopathology with known autoimmune lung disease mechanisms. FUNDING: This work was supported in part by the National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC), and in part by the National Institutes of Health (NIH) grant R01-AI155696 and pilot awards from the UC Office of the President (UCOP)-RGPO (R00RG2628, R00RG2642 and R01RG3780) to P.G. S.S was supported in part by R01-AI141630 (to P.G) and in part through funds from the American Association of Immunologists (AAI) Intersect Fellowship Program for Computational Scientists and Immunologists.

The Risk of Adhesive Bowel Obstruction in Children With Appendicitis: A Systematic Review.

OBJECTIVE: Complicated appendicitis is associated with a higher risk of postoperative complications, including adhesive bowel obstruction. The aim of this meta-analysis is to investigate the difference in rates of postoperative bowel obstruction in paediatric patients with complicated versus simple appendicitis and whether this is influenced by the surgical approach. METHODS: A systematic literature search following PRISMA guidelines was conducted using MEDLINE, Embase and Cochrane Library for studies that analysed incidence of adhesive bowel obstruction in paediatric patients after appendicectomy. Studies from 1998 to 2022 were included in analysis. The study protocol was registered on PROSPERO (ID CRD42022309769). RESULTS: Pooled analysis of 6 studies with low risk of bias and adequate follow up periods, considering 58,962 cases of appendicectomy, revealed complex appendicitis was associated with a near two-fold increase in incidence of SBO (pooled odds ratio 2.02 (95% CI 1.35-2.69)). Interestingly, a similar pooled analysis of 10 studies, considering 62,433 cases of appendicectomy, revealed no significant difference between open and laparoscopic management of complex appendicitis (pooled odds ratio 0.93 (95% CI 0.24 to 1.62)). CONCLUSION: Complex appendicitis is associated with a two-fold increase in the rates of adhesive bowel obstruction. Whilst there are cosmetic advantages of a laparoscopic approach, surgical expertise should be favoured in decision making relating to surgical approach (laparoscopic versus open) as the evidence for a laparoscopic approach reducing risks of adhesive bowel obstruction is not convincing. LEVEL OF EVIDENCE: Level II.

Interactions between integrin α9ß1 and VCAM-1 promote neutrophil hyperactivation and mediate poststroke DVT.

ABSTRACT: Venous thromboembolic events are significant contributors to morbidity and mortality in patients with stroke. Neutrophils are among the first cells in the blood to respond to stroke and are known to promote deep vein thrombosis (DVT). Integrin α9 is a transmembrane glycoprotein highly expressed on neutrophils and stabilizes neutrophil adhesion to activated endothelium via vascular cell adhesion molecule 1 (VCAM-1). Nevertheless, the causative role of neutrophil integrin α9 in poststroke DVT remains unknown. Here, we found higher neutrophil integrin α9 and plasma VCAM-1 levels in humans and mice with stroke. Using mice with embolic stroke, we observed enhanced DVT severity in a novel model of poststroke DVT. Neutrophil-specific integrin α9-deficient mice (α9fl/flMrp8Cre+/-) exhibited a significant reduction in poststroke DVT severity along with decreased neutrophils and citrullinated histone H3 in thrombi. Unbiased transcriptomics indicated that α9/VCAM-1 interactions induced pathways related to neutrophil inflammation, exocytosis, NF-κB signaling, and chemotaxis. Mechanistic studies revealed that integrin α9/VCAM-1 interactions mediate neutrophil adhesion at the venous shear rate, promote neutrophil hyperactivation, increase phosphorylation of extracellular signal-regulated kinase, and induce endothelial cell apoptosis. Using pharmacogenomic profiling, virtual screening, and in vitro assays, we identified macitentan as a potent inhibitor of integrin α9/VCAM-1 interactions and neutrophil adhesion to activated endothelial cells. Macitentan reduced DVT severity in control mice with and without stroke, but not in α9fl/flMrp8Cre+/- mice, suggesting that macitentan improves DVT outcomes by inhibiting neutrophil integrin α9. Collectively, we uncovered a previously unrecognized and critical pathway involving the α9/VCAM-1 axis in neutrophil hyperactivation and DVT.

Bailout Options for Intra-operative Implant and Instrumentation Related Incidents and Complications During Arthroscopic Knee Surgery-A Retrospective Study.

Background: Arthroscopic knee procedures are one amongst the common surgical interventions for problems in the knee. It is technically more demanding than an open procedure and is associated with several potential complications. During arthroscopy procedures, several technical challenges may arise, and even experienced surgeons may encounter new issues. However, careful attention to the surgical technique can help prevent or resolve them. Methodology: The study was conducted on all patients who underwent knee arthroscopy procedure during study period. We recorded details of the implants used and any unexpected situations related to them, as well as how they were managed. Instrumentation-related parameters such as screwdriver issues, radiofrequency ablator issues, scope damages, shaver complications, probe complications, and meniscus suture passing devices were also assessed. Results: In total, there were 12 (3.73%) implant and instrument-related incidents and complications, of which 5 (1.55%) were implant-related and 7 (2.17%) were instrument related. Among the instrumentation-related incidents and complications, two (0.62%) were screwdriver breakage incidents, two (0.62%) were radiofrequency ablator-related incidents, one was arthroscopic probe (0.31%) related incident, one (0.31%) was meniscus suture passing device related complication and one (0.31%) was arthroscope related incident. Conclusion: Surgeons must be ready to anticipate and effectively manage any technical difficulties that may arise during the procedure, maintaining composure in the face of unexpected challenges and guiding the team. In most cases, incidents can be addressed intra operatively and may not have long-term effects on patient outcomes. It is crucial to have multiple implant and instrument backup options available for successful surgery.

Mid-term Results of Total Hip Arthroplasty for Posttraumatic Osteoarthritis after Acetabular Fracture.

Purpose: The prognosis of total hip replacement (THR) after open reduction and internal fixation (ORIF) versus THR following non-operative treatment of acetabular fractures is unclear. Few studies have been conducted in this regard. Therefore, the purpose of the current study was to perform an assessment and compare the functional outcomes for study subjects in the ORIF and non-ORIF groups during the follow-up period compared to baseline. Materials and Methods: This longitudinal comparative study, which included 40 patients who underwent THR for either posttraumatic arthritis after fixation of an acetabular fracture or arthritis following conservative management of a fracture, was conducted for 60 months. Twenty-four patients had undergone ORIF, and 16 patients had undergone nonoperative/conservative management for acetabular fractures. Following THR, the patients were followed up for monitoring of functional outcomes for the Harris hip score (HHS) and comparison between the ORIF and non-ORIF groups was performed. Results: The HHS showed significant improvement in both ORIF and non-ORIF groups. At the end of the mean follow-up period, no significant variation in scores was observed between the groups, i.e., ORIF group (91.61±6.64) compared to non-ORIF group (85.74±11.56). A significantly higher number of re-interventions were required for medial wall fractures and combined fractures compared to posterior fractures (P<0.05). Conclusion: THR resulted in improved functional outcome during follow-up in both the groups; however, the ORIF group was observed to have better functional outcome. Re-intervention was not required for any of the posterior fractures at the end of the mean follow-up period.

Can ChatGPT help patients answer their otolaryngology questions?

Background: Over the past year, the world has been captivated by the potential of artificial intelligence (AI). The appetite for AI in science, specifically healthcare is huge. It is imperative to understand the credibility of large language models in assisting the public in medical queries. Objective: To evaluate the ability of ChatGPT to provide reasonably accurate answers to public queries within the domain of Otolaryngology. Methods: Two board-certified otolaryngologists (HZ, RS) inputted 30 text-based patient queries into the ChatGPT-3.5 model. ChatGPT responses were rated by physicians on a scale (accurate, partially accurate, incorrect), while a similar 3-point scale involving confidence was given to layperson reviewers. Demographic data involving gender and education level was recorded for the public reviewers. Inter-rater agreement percentage was based on binomial distribution for calculating the 95% confidence intervals and performing significance tests. Statistical significance was defined as p < .05 for two-sided tests. Results: In testing patient queries, both Otolaryngology physicians found that ChatGPT answered 98.3% of questions correctly, but only 79.8% (range 51.7%-100%) of patients were confident that the AI model was accurate in its responses (corrected agreement = 0.682; p < .001). Among the layperson responses, the corrected coefficient was of moderate agreement (0.571; p < .001). No correlation was noted among age, gender, or education level for the layperson responses. Conclusion: ChatGPT is highly accurate in responding to questions posed by the public with regards to Otolaryngology from a physician standpoint. Public reviewers were not fully confident in believing the AI model, with subjective concerns related to less trust in AI answers compared to physician explanation. Larger evaluations with a representative public sample and broader medical questions should immediately be conducted by appropriate organizations, governing bodies, and/or governmental agencies to instill public confidence in AI and ChatGPT as a medical resource. Level of Evidence: 4.

Cellular Senescence Program is Sensitive to Physical Differences in Polymeric Tissue Scaffolds.

A typical cellular senescence program involves exposing cells to DNA-damaging agents such as ionization radiation or chemotherapeutic drugs, which cause multipronged changes, including increased cell size and volume, the onset of enhanced oxidative stress, and inflammation. In the present study, we examined if the senescence onset decision is sensitive to the design, porosity, and architecture of the substrate. To address this, we generated a library of polymeric scaffolds widely used in tissue engineering of varied stiffness, architecture, and porosity. Using irradiated A549 lung cancer cells, we examined the differences between cellular responses in these 3D scaffold systems and observed that senescence onset is equally diminished. When compared to the two-dimensional (2D) culture formats, there were profound changes in cell size and senescence induction in three-dimensional (3D) scaffolds. We further establish that these observed differences in the senescence state can be attributed to the altered cell spreading and cellular interactions on these substrates. This study elucidates the role of scaffold architecture in the cellular senescence program.

Pediatric Airway Balloon Dilation: Urge for Safety Redesign.

Airway balloons are widely used by otolaryngologists to treat laryngotracheal stenosis. We review an adverse event and interventions that may prevent similar occurrences. There are no other reports of similar incidents in the Food and Drug Administration Manufacturer and User Facility Device Experience. We implore Acclarent to redesign their airway balloon device to prevent accidental airway irrigation.

Novel technique of predicting the dimensions of 5-stranded hamstring grafts for anterior cruciate ligament reconstruction: A descriptive study.

Background: Prediction of hamstring tendon autografts is essential when planning a ligament reconstruction surgery. This is especially important in cases of multiple ligament reconstruction surgeries. This study was designed to predict the dimensions of 5-stranded hamstring grafts from anthropometric parameters in patients undergoing anterior cruciate ligament (ACL) reconstruction surgery. Methods: 172 patients undergoing ACL reconstruction with hamstring autografts were included in the study. Preoperative parameters included age, gender, height, weight, body mass index (BMI), thigh length, thigh circumference, and tibia length; intraoperative parameters included semitendinosus (ST) and gracilis (G) length and diameter, final 5-stranded graft length and diameter. Pre-operative data was correlated with intra-operative data using tests of significance. Results: Height, tibia and thigh length were greater in males (p < 0.05) whereas BMI was greater in females (p < 0.05). G and ST length alongwith 5-stranded graft length and diameter were significantly greater in males (p < 0.05). The graft dimensions could be correlated with the pre-operative anthropometric parameters using specific equations. This was applicable to the lengths and diameters of ST, G and 5-stranded grafts. We also noted that an increase in age was associated with a reduction in graft dimensions except for the diameter of G graft in females and length of 5-stranded grafts in males. Conclusion: 5-stranded hamstring graft dimensions can be reliably predicted using anthropometric parameters and this eases surgical planning.

The use of artificial dermal substitutes for repair of the donor site following harvesting of a radial forearm free flap: A systematic review.

BACKGROUND: Artificial dermal substitutes (ADMs) have been trialled to improve outcomes at the donor site following the harvesting of a radial forearm free flap (RFFF). This systematic review compares donor site aesthetic and functional outcomes, with the use of an ADM versus conventional practice. METHODS: The databases Medline, Embase, Cochrane Library, Web of Science (Core Collection), and Scopus were searched for retrospective, prospective, and case-control studies and randomised control trials (RCTs) involving any ADM. Studies with adult patients having undergone RFFF harvesting and donor site repair with an ADM, commenting on appropriate clinical outcomes and without high risk of bias, were included. Direction-of-effect analysis was performed on relevant groupings of studies since heterogeneity in outcome measurement precluded meta-analyses. RESULTS: Across eight non-comparative studies included, 132 patients had donor site coverage with AlloDerm™, Integra™, Matriderm™, or Rapiderm. Across 11 comparative studies included, 240 patients had donor site coverage with fish-skin matrix, AlloDerm™, amniotic membrane, MegaDerm™, Hyalomatrix, Integra™, or Matriderm™. Five out of 11 comparative studies demonstrated superior aesthetic outcomes with ADMs according to at least one aesthetic metric compared to controls, whilst 6/11 demonstrated superior functional outcomes with ADMs. No study demonstrated poorer aesthetic or functional outcomes with an ADM compared to conventional practice. CONCLUSIONS: In summary, the lack of studies reporting poorer outcomes with them compared to conventional practices, and a cumulative effect direction in their favour, provide strong indications in support of the use of AlloDerm™, Integra™, or Matriderm™ grafts. Further comparative studies, including RCTs, are needed to reinforce these initial indications.

MDA5-autoimmunity and Interstitial Pneumonitis Contemporaneous with the COVID-19 Pandemic (MIP-C).

Background: Anti-MDA5 (Melanoma differentiation-associated protein-5) positive dermatomyositis (MDA5 + -DM) is characterised by rapidly progressive interstitial lung disease (ILD) and high mortality. MDA5 senses single-stranded RNA and is a key pattern recognition receptor for the SARS-CoV-2 virus. Methods: This is a retrospective observational study of a surge in MDA5 autoimmunity, as determined using a 15 muscle-specific autoantibodies (MSAs) panel, between Janurary 2018-December 2022 in Yorkshire, UK. MDA5-positivity was correlated with clinical features and outcome, and regional SARS-CoV-2 positivity and vaccination rates. Gene expression patterns in COVID-19 were compared with autoimmune lung disease and idiopathic pulmonary fibrosis (IPF) to gain clues into the genesis of the observed MDA5 + -DM outbreak. Results: Sixty new anti-MDA5+, but not other MSAs surged between 2020-2022, increasing from 0.4% in 2019 to 2.1% (2020), 4.8% (2021) and 1.7% (2022). Few (8/60) had a prior history of confirmed COVID-19, peak rates overlapped with regional SARS-COV-2 community positivity rates in 2021, and 58% (35/60) had received anti-SARS-CoV-2 RNA vaccines. Few (8/60) had a prior history of COVID-19, whereas 58% (35/60) had received anti-SARS-CoV-2 RNA vaccines. 25/60 cases developed ILD which rapidly progression with death in 8 cases. Among the 35/60 non-ILD cases, 14 had myositis, 17 Raynaud phenomena and 10 had dermatomyositis spectrum rashes. Transcriptomic studies showed strong IFIH1 (gene encoding for MDA5) induction in COVID-19 and autoimmune-ILD, but not IPF, and IFIH1 strongly correlated with an IL-15-centric type-1 interferon response and an activated CD8+ T cell signature that is an immunologic hallmark of progressive ILD in the setting of systemic autoimmune rheumatic diseases. The IFIH1 rs1990760TT variant blunted such response. Conclusions: A distinct pattern of MDA5-autoimmunity cases surged contemporaneously with circulation of the SARS-COV-2 virus during COVID-19. Bioinformatic insights suggest a shared immunopathology with known autoimmune lung disease mechanisms.

Evaluating the Current Ability of ChatGPT to Assist in Professional Otolaryngology Education.

Objective: To quantify ChatGPT's concordance with expert Otolaryngologists when posed with high-level questions that require blending rote memorization and critical thinking. Study Design: Cross-sectional survey. Setting: OpenAI's ChatGPT-3.5 Platform. Methods: Two board-certified otolaryngologists (HZ, RS) input 2 sets of 30 text-based questions (open-ended and single-answer multiple-choice) into the ChatGPT-3.5 model. Responses were rated on a scale (correct, partially correct, incorrect) by each Otolaryngologist working simultaneously with the AI model. Interrater agreement percentage was based on binomial distribution for calculating the 95% confidence intervals and performing significance tests. Statistical significance was defined as P < .05 for 2-sided tests. Results: In testing open-ended questions, the ChatGPT model had 56.7% of initially answering questions with complete accuracy, and 86.7% chance of answer with some accuracy (corrected agreement = 80.1%; P < .001). For repeat questions, ChatGPT improved to 73.3% with complete accuracy and 96.7% with some accuracy (corrected agreement = 88.8%; P < .001). For multiple-choice questions, the ChatGPT model performed substantially worse (43.3% correct). Conclusion: ChatGPT currently does not provide reliably accurate responses to sophisticated questions in Otolaryngology. Professional societies must be aware of the potential of this tool and prevent unscrupulous use during test-taking situations and consider guidelines for clinical scenarios. Expert clinical oversight is still necessary for myriad use cases (eg, hallucination).

Exploring the Theranostic Applications and Prospects of Nanobubbles.

Anticancer medications as well as additional therapeutic compounds, have poor clinical effectiveness due to their diverse distribution, non-selectivity for malignant cells, and undesirable off-target side effects. As a result, ultrasound-based targeted delivery of therapeutic compounds carried in sophisticated nanocarriers has grown in favor of cancer therapy and control. Nanobubbles are nanoscale bubbles that exhibit unique physiochemical properties in both their inner core and outer shell. Manufacturing nanobubbles primarily aims to enhance therapeutic agents' bioavailability, stability, and targeted delivery. The small size of nanobubbles allows for their extravasation from blood vessels into surrounding tissues and site-specific release through ultrasound targeting. Ultrasound technology is widely utilized for therapy due to its speed, safety, and cost-effectiveness, and micro/nanobubbles, as ultrasound contrast agents, have numerous potential applications in disease treatment. Thus, combining ultrasound applications with NBs has recently demonstrated increased localization of anticancer molecules in tumor tissues with triggered release behavior. Consequently, an effective therapeutic concentration of drugs/genes is achieved in target tumor tissues with ultimately increased therapeutic efficacy and minimal side effects on other non-cancerous tissues. This paper provides a brief overview of the production processes for nanobubbles, along with their key characteristics and potential therapeutic uses.

Revision of Failed Medial Meniscus Posterior Root Repair: A Case Report.

Introduction: Meniscal root tear decreases the ability of the meniscus to convert the axial load to radially directed hoop stress. This leads to a decreased contact area and increased contact pressures, leading to early osteoarthrosis of the knee and eventually higher chances of undergoing total knee replacement. Meniscal root repair helps to restore normal knee kinematics; however, non-anatomical repair results in increased strain in the repair and causes early failure of the repair, leading to abnormal knee kinematics. Case Report: A 45-year-old female with a body mass index of 40.6, hypothyroid, and type II diabetes mellitus presented to the outpatient department with the complaints of left knee pain and difficulty in walking. She had undergone an arthroscopic medial meniscus posterior root repair 1 year back. Clinical and radiological examinations helped to diagnose a re-tear of the medial meniscus root with a non-anatomic tibial tunnel. She then underwent arthroscopic revision root repair surgery. Currently, the patient is at a 1-year follow-up and has resumed her activities of daily living. Conclusion: Anatomical repair of the posterior horn of the medial meniscus is important in restoring normal knee kinematics and for the ability of the meniscus to maintain the hoop stress. Non-anatomic repair leads to early failure and progression to rapid cartilage degeneration, resulting in early osteoarthritis and eventual knee replacement. Any revision surgery presents its own different set of challenges. The basic principles must be adhered to while addressing any failure of the primary surgery.

NICE 2022 guidelines on the management of melanoma: Update and implications.

AIMS: In July 2022, NICE updated the guidelines on the management of melanoma by lowering the number of follow-up appointments and sentinel lymph node biopsy (SLNB) but increasing the number of scans. This study aims to evaluate the implications of executing the new guidelines in terms of cost-effectiveness and personnel. METHODS: All patients newly diagnosed with melanoma in 2019 at a regional skin cancer specialist center were reviewed. Data were analyzed for their journey on an idealized pathway modeled over a 5-year follow-up period when adhering to both the previous and new guidelines. Differences in the management of melanoma were elucidated by comparing these changes. The cost was quantified on a perpatient basis and the financial implication on each department was considered. RESULTS: One hundred and ten patients were diagnosed with melanoma in 2019, stages I-III. The changes ease the burden on plastic surgery and dermatology; however, increased pressure is faced by radiologists and histopathologists. An overall cost benefit of £141.85 perpatient was calculated, resulting in a decrease of 1.22 hospital visits on average and an increase in the time spent there (19.55 min). The additional expenses of implementing the new guidelines due to the added BRAF tests, CT, and ultrasound scans are outweighed by savings from the reduction in follow-up appointments and SLNB. CONCLUSION: The focus has shifted to less invasive procedures for lower melanoma stages and fewer follow-up appointments, at the expense of more genetic testing and imaging. This paper serves as a useful baseline for other centers to plan their service provision and resource allocation to adhere to the updated guidelines.

Ensuring tympanostomy tube follow-up during the COVID-19 pandemic.

OBJECTIVES: The impact of the COVID-19 pandemic on surgical practice was widespread. Local health restrictions in many communities limited the number and types of patients seen and treated. Our goal is to understand the discrepancies in follow-up for bilateral myringotomy with tubes (BMT) and understand whether the pandemic made it more difficult for certain patient populations to continue routine follow up. METHODS: This cross-sectional study abstracted demographic and clinical data from the medical charts of randomized pediatric patients who underwent a BMT procedure between 2017 and 2022 at a tertiary pediatric academic care center site. Suboptimal follow-up was defined as no clinic visits within the first 6 months of surgery, and less than 3 follow-ups within a 24-month period after surgery. Data regarding secondary surgeries, clinical variables, race, zip code, and dates and number follow-ups were recorded from randomly chosen eligible charts. Complications were defined as need for revision surgery or development of post-tympanostomy sequalae such as perforation, cholesteatoma, or granuloma. RESULTS: Pre-pandemic (N = 150) patients from 2017 to 2019 and post-pandemic (N = 150) patients from 2020 to 2022 cohorts were analyzed. No significant differences were identified between the groups regarding age, presence of combined surgery, anesthesia class, diagnosis, or race. There was no significant difference in rate of complications or need for revision surgery between either cohort nor when stratified for demographics. CONCLUSION: Limitations imposed upon medical care including outpatient clinics due COVID restrictions did not have an impact on tympanostomy tube follow-up regarding frequency of visits and risk of complication or revision surgery. LEVEL OF EVIDENCE: IV.