Serotonin reduction in post-acute sequelae of viral infection.

Post-acute sequelae of COVID-19 (PASC, "Long COVID") pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses have been formulated to explain the etiology of PASC, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction. Here, we propose a mechanism that links all four hypotheses in a single pathway and provides actionable insights for therapeutic interventions. We find that PASC are associated with serotonin reduction. Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover. Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. These findings provide a possible explanation for neurocognitive symptoms associated with viral persistence in Long COVID, which may extend to other post-viral syndromes.

Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade.

Therapeutic blocking of the PD1 pathway results in significant tumor responses, but resistance is common. We demonstrate that prolonged interferon signaling orchestrates PDL1-dependent and PDL1-independent resistance to immune checkpoint blockade (ICB) and to combinations such as radiation plus anti-CTLA4. Persistent type II interferon signaling allows tumors to acquire STAT1-related epigenomic changes and augments expression of interferon-stimulated genes and ligands for multiple T cell inhibitory receptors. Both type I and II interferons maintain this resistance program. Crippling the program genetically or pharmacologically interferes with multiple inhibitory pathways and expands distinct T cell populations with improved function despite expressing markers of severe exhaustion. Consequently, tumors resistant to multi-agent ICB are rendered responsive to ICB monotherapy. Finally, we observe that biomarkers for interferon-driven resistance associate with clinical progression after anti-PD1 therapy. Thus, the duration of tumor interferon signaling augments adaptive resistance and inhibition of the interferon response bypasses requirements for combinatorial ICB therapies.

Defibrillation Strategies for Refractory Ventricular Fibrillation.

BACKGROUND: Despite advances in defibrillation technology, shock-refractory ventricular fibrillation remains common during out-of-hospital cardiac arrest. Double sequential external defibrillation (DSED; rapid sequential shocks from two defibrillators) and vector-change (VC) defibrillation (switching defibrillation pads to an anterior-posterior position) have been proposed as defibrillation strategies to improve outcomes in patients with refractory ventricular fibrillation. METHODS: We conducted a cluster-randomized trial with crossover among six Canadian paramedic services to evaluate DSED and VC defibrillation as compared with standard defibrillation in adult patients with refractory ventricular fibrillation during out-of-hospital cardiac arrest. Patients were treated with one of these three techniques according to the strategy that was randomly assigned to the paramedic service. The primary outcome was survival to hospital discharge. Secondary outcomes included termination of ventricular fibrillation, return of spontaneous circulation, and a good neurologic outcome, defined as a modified Rankin scale score of 2 or lower (indicating no symptoms to slight disability) at hospital discharge. RESULTS: A total of 405 patients were enrolled before the data and safety monitoring board stopped the trial because of the coronavirus disease 2019 pandemic. A total of 136 patients (33.6%) were assigned to receive standard defibrillation, 144 (35.6%) to receive VC defibrillation, and 125 (30.9%) to receive DSED. Survival to hospital discharge was more common in the DSED group than in the standard group (30.4% vs. 13.3%; relative risk, 2.21; 95% confidence interval [CI], 1.33 to 3.67) and more common in the VC group than in the standard group (21.7% vs. 13.3%; relative risk, 1.71; 95% CI, 1.01 to 2.88). DSED but not VC defibrillation was associated with a higher percentage of patients having a good neurologic outcome than standard defibrillation (relative risk, 2.21 [95% CI, 1.26 to 3.88] and 1.48 [95% CI, 0.81 to 2.71], respectively). CONCLUSIONS: Among patients with refractory ventricular fibrillation, survival to hospital discharge occurred more frequently among those who received DSED or VC defibrillation than among those who received standard defibrillation. (Funded by the Heart and Stroke Foundation of Canada; DOSE VF ClinicalTrials.gov number, NCT04080986.).

Engineered CAR T Cells Targeting the Cancer-Associated Tn-Glycoform of the Membrane Mucin MUC1 Control Adenocarcinoma.

Genetically modified T cells expressing chimeric antigen receptors (CARs) demonstrate robust responses against lineage restricted, non-essential targets in hematologic cancers. However, in solid tumors, the full potential of CAR T cell therapy is limited by the availability of cell surface antigens with sufficient cancer-specific expression. The majority of CAR targets have been normal self-antigens on dispensable hematopoietic tissues or overexpressed shared antigens. Here, we established that abnormal self-antigens can serve as targets for tumor rejection. We developed a CAR that recognized cancer-associated Tn glycoform of MUC1, a neoantigen expressed in a variety of cancers. Anti-Tn-MUC1 CAR T cells demonstrated target-specific cytotoxicity and successfully controlled tumor growth in xenograft models of T cell leukemia and pancreatic cancer. These findings demonstrate the therapeutic efficacy of CAR T cells directed against Tn-MUC1 and present aberrantly glycosylated antigens as a novel class of targets for tumor therapy with engineered T cells.

Safety and Adverse Events During Primary Care Paramedic Interfacility Transfer of Stable STEMI Patients.

OBJECTIVE: Current guidelines recommend that patients presenting with ST-elevation myocardial infarction (STEMI) to hospitals not capable of performing primary percutaneous coronary intervention (PCI) be transferred to a PCI-capable hospital if reperfusion can be accomplished within 120 min. Most STEMI patients are accompanied by an advanced care paramedic (ACP, equivalent to EMT-P), nurse, or physician who can manage complications should they arise. In our region, stable STEMI patients are transported by primary care paramedics (PCPs, similar scope of practice to advanced EMT) in cases where a nurse, physician, or ACP paramedic is not available. Our goal was to describe adverse events and need for advanced interventions among initially stable STEMI patients during interfacility transfer by PCPs. METHODS: We reviewed ambulance and hospital records of initially stable STEMI patients (as determined by first set of vital signs documented by paramedics) transferred to a PCI-capable hospital by PCPs between March 1, 2014, and December 31, 2019. We identified whether pre-determined adverse clinical events occurred during the transport as well as the potential need for advanced care interventions not within the PCP scope of practice. Adverse events upon arrival in the PCI lab were also identified. RESULTS: Of 346 STEMI patients transferred, 179 met inclusion criteria. The mean age of included patients was 61 years (SD 12.1) and 74.9% (134/179) were male. Median transport interval was 36 min (IQR 3.0). During transport, 47/179 (26.0%) patients experienced pre-defined adverse events; for 16/47 (34%), one or more adverse events was major. Three patients met criteria for ACP interventions. One patient suffered a cardiac arrest and was promptly resuscitated with defibrillation by the PCPs. CONCLUSIONS: We found PCP-interfacility transport of initially stable STEMI patients was safe and associated with a moderate proportion of adverse events, the majority of which did not require an advanced care intervention. These findings may help decision-making to avoid delays transferring stable patients to PCI-capable centers.

Global Economic Evaluation of the Reported Costs of Deep Brain Stimulation.

INTRODUCTION: Despite the known benefits of deep brain stimulation (DBS), the cost of the procedure can limit access and can vary widely. Our aim was to conduct a systematic review of the reported costs associated with DBS, as well as the variability in reporting cost-associated factors to ultimately increase patient access to this therapy. METHODS: A systematic review of the literature for cost of DBS treatment was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed and Embase databases were queried. Olsen & Associates (OANDA) was used to convert all reported rates to USD. Cost was corrected for inflation using the US Bureau of Labor Statistics Inflation Calculator, correcting to April 2022. RESULTS: Twenty-six articles on the cost of DBS surgery from 2001 to 2021 were included. The median number of patients across studies was 193, the mean reported age was 60.5 ± 5.6 years, and median female prevalence was 38.9%. The inflation- and currency-adjusted mean cost of the DBS device was USD 21,496.07 ± USD 8,944.16, the cost of surgery alone was USD 14,685.22 ± USD 8,479.66, the total cost of surgery was USD 40,942.85 ± USD 17,987.43, and the total cost of treatment until 1 year of follow-up was USD 47,632.27 ± USD 23,067.08. There were no differences in costs observed across surgical indication or country. CONCLUSION: Our report describes the large variation in DBS costs and the manner of reporting costs. The current lack of standardization impedes productive discourse as comparisons are hindered by both geographic and chronological variations. Emphasis should be put on standardized reporting and analysis of reimbursement costs to better assess the variability of DBS-associated costs in order to make this procedure more cost-effective and address areas for improvement to increase patient access to DBS.

Endovascular balloon usage in endoscopic third ventriculostomy for hydrocephalus during a national shortage: case series and technical note.

Endoscopic third ventriculostomy (ETV) is a well-established surgical technique for treating hydrocephalus. Many providers have transitioned to utilizing the specialized Neuroballoon for the stoma dilation in ETV; however, these devices are intermittently unavailable during supply chain shortages. We present the experience of employing cardiac angioplasty and neurovascular balloons as substitutes for the Neuroballoon in 3 patients. The scepter balloon (Microvention), priced at $1800 compared to the standard $300 Neuroballoon (Integra), proved effective, but its pliability presented technical challenges. The substantial cost differential compared to a Neuroballoon ($300) raises economic considerations. The Cardiac TREK balloon (Abbott) was similarly effective, while also being easier to manage endoscopically and cheaper at $158. These experiences support the viability of non-neuroendoscopic specialized balloons as alternatives for ETV dilation of the floor of tuber cinereum.

Pediatric non-galenic pial arteriovenous fistula's characteristics and outcomes: a systematic review.

INTRODUCTION: Pediatric non-galenic pial arteriovenous fistulas (pAVFs) are rare vascular malformations that are characterized by a pial arterial-venous connection without an intervening capillary bed. Outcomes and treatment strategies for pAVFs are highly individualized, owing to the rarity of the disease and lack of large-scale data guiding optimal treatment approaches. METHODS: We performed a systematic review of pediatric patients (< 18 years at diagnosis) diagnosed with a pAVF by digital subtraction angiogram (DSA). The demographics, treatment modalities, and outcomes were documented for each patient and clinical outcome data was collected. Descriptive information stratified by outcome scores were classified as follows: 1 = excellent (no deficit and full premorbid activity), 2 = good (mild deficit and full premorbid activity), 3 = fair (moderate deficit and impaired activity), 4 = poor (severe deficit and dependent on others), 5 = death. RESULTS: A total of 87 studies involving 231 patients were identified. Median age at diagnosis was 3 years (neonates to 18 years). There was slight male preponderance (55.4%), and 150 subjects (81.1%*) experienced excellent outcomes after treatment. Of the 189 patients treated using endovascular approaches, 80.3% experienced excellent outcomes and of the 15 patients surgically treated subjects 75% had an excellent outcome. The highest rate of excellent outcomes was achieved in patients treated with Onyx (95.2%) and other forms of EvOH (100%). High output heart failure and comorbid vascular lesions tended to result in worse outcomes, with only 54.2% and 68% of subjects experiencing an excellent outcome, respectively. *Outcomes were reported in only 185 patients. CONCLUSION: pAVFs are rare lesions, necessitating aggregation of patient data to inform natural history and optimal treatment strategies. This review summarizes the current literature on pAVF in children, where children presenting with heart failure as a result of high flow through the lesion were less likely to experience an excellent outcome. Prospective, large-scale studies would further characterize pediatric pAVFs and enable quantitative analysis of outcomes to inform best treatment practices.

Cost considerations for vestibular schwannoma screening and imaging: a systematic review.

Vestibular schwannomas (VS) account for approximately 8% of all intracranial neoplasms. Importantly, the cost of the diagnostic workup for VS, including the screening modalities most commonly used, has not been thoroughly investigated. Our aim is to conduct a systematic review of the published literature on costs associated with VS screening. A systematic review of the literature for cost of VS treatment was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The terms "vestibular schwannoma," "acoustic neuroma," and "cost" were queried using the PubMed and Embase databases. Studies from all countries were considered. Cost was then corrected for inflation using the US Bureau of Labor Statistics Inflation Calculator, correcting to April 2022. The search resulted in an initial review of 483 articles, of which 12 articles were included in the final analysis. Screening criteria were used for non-neurofibromatosis type I and II patients who complained of asymmetric hearing loss, tinnitus, or vertigo. Patients included in the studies ranged from 72 to 1249. The currency and inflation-adjusted mean cost was $418.40 (range, $21.81 to $487.03, n = 5) for auditory brainstem reflex and $1433.87 (range, $511.64 to $1762.15, n = 3) for non-contrasted computed tomography. A contrasted magnetic resonance imaging (MRI) scan was found to have a median cost of $913.27 (range, $172.25-$2733.99; n = 8) whereas a non-contrasted MRI was found to have a median cost of $478.62 (range, $116.61-$3256.38, n = 4). In terms of cost reporting, of the 12 articles, 1 (8.3%) of them separated out the cost elements, and 10 (83%) of them used local prices, which include institutional costs and/or average costs of multiple institutions. Our findings describe the limited data on published costs for screening and imaging of VS. The paucity of data and significant variability of costs between studies indicates that this endpoint is relatively unexplored, and the cost of screening is poorly understood.

Editorial Commentary: Biceps Management During Rotator Cuff Tear: Confounding Variables Result in Unclear Indications.

Is "killing the biceps" during rotator cuff repair a capital crime or a lawful act? One of the most passionately debated topics in shoulder surgery is what to do with the biceps during rotator cuff repair: save it, tenotomize it, or perform tenodesis. Results of repair are not very successful, and given that repair of massive rotator cuff tears shows a 40% to 57% failure rate, there is renewed interest in sparing the biceps tendon as a humeral head depressor-or so that it may be used as a local graft for revision rotator cuff repair. The literature regarding tenodesis versus biceps sparing during rotator cuff repair is controversial. There are so many confounding variables affecting rotator cuff repair outcomes (tear size, comorbidities, age, tissue quality, etc.) that we do not believe that anything less than a randomized, prospective study that matches groups is likely to provide a conclusive verdict.

Clinically Significant Outcome Scores in Orthopaedic Sports Medicine Shoulder and Knee Surgery Are Increasing in Prevalence but Often Reported Incorrectly.

PURPOSE: To study the prevalence and quality of application of minimal clinically important difference (MCID), substantial clinical benefit (SCB), patient-acceptable symptomatic state (PASS), and maximum outcome improvement (MOI), reported in the orthopaedic sports medicine knee and shoulder literature in recent years and to bring awareness of proper use of such metrics. METHODS: A literature review of all shoulder and knee articles published from the American Journal of Sports Medicine (AJSM), Journal of Shoulder and Elbow Surgery (JSES), and Arthroscopy from 2016 to 2020 was performed, specifically investigating whether MCID, SCB, PASS, or MOI were used or reported. Additionally, the way these metrics were reported and interpreted was recorded. RESULTS: Out of 5,039 studies, 889 shoulder and knee studies met the inclusion criteria. Overall, 16.7% reported either MCID, PASS, or SCB. MCID was the most reported across all 3 journals. MCID was reported 12.4% of the time throughout the 5 years. PASS was reported 3.2% and SCB 1.1% of the time over the 5 years. MOI was not reported by any of the journals during this period. There was a statistically significant increase in MCID reporting in 2 of the 3 journals over the 5-year course, Arthroscopy (P = .02) and AJSM (P = .05). There was no statistically significant increase in PASS or SCB reporting rates in all 3 journals. Only 39.1% of studies reported MCID correctly (i.e., defined as the number of individual patients meeting MCID/total patients in the study). CONCLUSIONS: This study shows an increasing trend in the use of clinically significant outcome metrics, such as MCID, for interpretation of patient-reported outcomes; however, these individual metrics are often not being used on the individual level and subsequently not reported accurately. We recommend determining whether the specific metric met the threshold per individual patient and then reporting those as a percentage of the sample population to achieve the full potential of these metrics and translate them accurately across various studies. CLINICAL RELEVANCE: As the usage of clinically significant outcome metrics rises, so does the need for accurate reporting. These findings will encourage future studies to follow a more standardized format.

STAT3 mutation-associated airway epithelial defects in Job syndrome.

BACKGROUND: Job syndrome is a disease of autosomal dominant hyper-IgE syndrome (AD-HIES). Patients harboring STAT3 mutation are particularly prone to airway remodeling and airway infections. OBJECTIVES: Airway epithelial cells play a central role as the first line of defense against pathogenic infection and express high levels of STAT3. This study thus interrogates how AD-HIES STAT3 mutations impact the physiological functions of airway epithelial cells. METHODS: This study created human airway basal cells expressing 4 common AD-HIES STAT3 mutants (R382W, V463del, V637M, and Y657S). In addition, primary airway epithelial cells were isolated from a patient with Job syndrome who was harboring a STAT3-S560del mutation and from mice harboring a STAT3-V463del mutation. Cell proliferation, differentiation, barrier function, bacterial elimination, and innate immune responses to pathogenic infection were quantitatively analyzed. RESULTS: STAT3 mutations reduce STAT3 protein phosphorylation, nuclear translocation, transcription activity, and protein stability in airway basal cells. As a consequence, STAT3-mutated airway basal cells give rise to airway epithelial cells with abnormal cellular composition and loss of coordinated mucociliary clearance. Notably, AD-HIES STAT3 airway epithelial cells are defective in bacterial killing and fail to initiate vigorous proinflammatory responses and neutrophil transepithelial migration in response to an experimental model of Pseudomonas aeruginosa infection. CONCLUSIONS: AD-HIES STAT3 mutations confer numerous abnormalities to airway epithelial cells in cell differentiation and host innate immunity, emphasizing their involvement in the pathogenesis of lung complications in Job syndrome. Therefore, therapies must address the epithelial defects as well as the previously noted immune cell defects to alleviate chronic infections in patients with Job syndrome.

Impact of fludrocortisone on the outcomes of subarachnoid hemorrhage patients: A retrospective analysis.

BACKGROUND: Whether the use of fludrocortisone affects outcomes of patients with aneurysmal subarachnoid hemorrhage (aSAH). METHODS: We conducted a retrospective analysis of 78 consecutive patients with a ruptured aSAH at a single academic center in the United States. The primary outcome was the score on the modified Rankin scale (mRS, range, 0 [no symptoms] to 6 [death]) at 90 days. The primary outcome was adjusted for age, hypertension, aSAH grade, and time from aSAH onset to aneurysm treatment. Secondary outcomes were neurologic and cardiopulmonary dysfunction events. RESULTS: Among 78 patients at a single center, the median age was 58 years [IQR, 49 to 64.5]; 64 % were female, and 41 (53 %) received fludrocortisone. The adjusted common odds ratio, aOR, of a proportional odds regression model of fludrocortisone use with mRS was 0.33 (95 % CI, 0.14-0.80; P = 0.02), with values <1.0 favoring fludrocortisone. Organ-specific dysfunction events were not statistically different: delayed cerebral ischemia (22 % vs. 39 %, P = 0.16); cardiac dysfunction (0 % vs. 11 %; P = 0.10); and pulmonary edema (15 % vs. 8 %; P = 0.59). CONCLUSIONS: The risk of disability or death at 90 days was lower with the use of fludrocortisone in aSAH patients.

Computational Analysis of Routine Biopsies Improves Diagnosis and Prediction of Cardiac Allograft Vasculopathy.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is a leading cause of morbidity and mortality for heart transplant recipients. Although clinical risk factors for CAV have been established, no personalized prognostic test exists to confidently identify patients at high versus low risk of developing aggressive CAV. This investigation aimed to leverage computational methods for analyzing digital pathology images from routine endomyocardial biopsies (EMBs) to develop a precision medicine tool for predicting CAV years before overt clinical presentation. METHODS: Clinical data from 1 year after transplant were collected on 302 transplant recipients from the University of Pennsylvania, including 53 patients with early-onset CAV and 249 no early-onset CAV controls. These data were used to generate a clinical model (Clinical Risk Factor Future Cardiac Allograft Vasculopathy Prediction Model [ClinCAV-Pr]) for predicting future CAV development. From this cohort, 183 archived EMBs were collected for CD31 and modified trichrome staining and then digitally scanned. These included 1-year posttransplant EMBs from 50 patients with early-onset CAV and 82 patients with no early-onset CAV, as well as 51 EMBs from disease control patients obtained at the time of definitive coronary angiography confirming CAV. Using biologically inspired, handcrafted features extracted from digitized EMBs, quantitative histological models for differentiating no early-onset CAV from disease controls (Histological Cardiac Allograft Vasculopathy Diagnostic Model [HistoCAV-Dx]) and for predicting future CAV from 1-year posttransplant EMBs were developed (Histological Future Cardiac Allograft Vasculopathy Prediction Model [HistoCAV-Pr]). The performance of histological and clinical models for predicting future CAV (ie, HistoCAV-Pr and ClinCAV-Pr, respectively) were compared in a held-out validation set before being combined to assess the added predictive value of an integrated predictive model (Integrated Histological/Clinical Risk Factor Future Cardiac Allograft Vasculopathy Prediction Model [iCAV-Pr]). RESULTS: ClinCAV-Pr achieved modest performance on the independent test set, with an area under the receiver operating curve (AUROC) of 0.70. The HistoCAV-Dx model for diagnosing CAV achieved excellent discrimination, with an AUROC of 0.91, whereas the HistoCAV-Pr model for predicting CAV achieved good performance with an AUROC of 0.80. The integrated iCAV-Pr model achieved excellent predictive performance, with an AUROC of 0.93 on the held-out test set. CONCLUSIONS: Prediction of future CAV development is greatly improved by incorporation of computationally extracted histological features. These results suggest morphological details contained within regularly obtained biopsy tissue have the potential to enhance precision and personalization of treatment plans for patients after heart transplant.

Impact of integrating genomic data into the electronic health record on genetics care delivery.

PURPOSE: Integrating genomic data into the electronic health record (EHR) is key for optimally delivering genomic medicine. METHODS: The PennChart Genomics Initiative (PGI) at the University of Pennsylvania is a multidisciplinary collaborative that has successfully linked orders and results from genetic testing laboratories with discrete genetic data in the EHR. We quantified the use of the genomic data within the EHR, performed a time study with genetic counselors, and conducted key informant interviews with PGI members to evaluate the effect of the PGI's efforts on genetics care delivery. RESULTS: The PGI has interfaced with 4 genetic testing laboratories, resulting in the creation of 420 unique computerized genetic testing orders that have been used 4073 times to date. In a time study of 96 genetic testing activities, EHR use was associated with significant reductions in time spent ordering (2 vs 8 minutes, P < .001) and managing (1 vs 5 minutes, P < .001) genetic results compared with the use of online laboratory-specific portals. In key informant interviews, multidisciplinary collaboration and institutional buy-in were identified as key ingredients for the PGI's success. CONCLUSION: The PGI's efforts to integrate genomic medicine into the EHR have substantially streamlined the delivery of genomic medicine.

Pulmonary vascular inflammation with fatal coronavirus disease 2019 (COVID-19): possible role for the NLRP3 inflammasome.

BACKGROUND: Pulmonary hyperinflammation is a key event with SARS-CoV-2 infection. Acute respiratory distress syndrome (ARDS) that often accompanies COVID-19 appears to have worse outcomes than ARDS from other causes. To date, numerous lung histological studies in cases of COVID-19 have shown extensive inflammation and injury, but the extent to which these are a COVID-19 specific, or are an ARDS and/or mechanical ventilation (MV) related phenomenon is not clear. Furthermore, while lung hyperinflammation with ARDS (COVID-19 or from other causes) has been well studied, there is scarce documentation of vascular inflammation in COVID-19 lungs. METHODS: Lung sections from 8 COVID-19 affected and 11 non-COVID-19 subjects, of which 8 were acute respiratory disease syndrome (ARDS) affected (non-COVID-19 ARDS) and 3 were from subjects with non-respiratory diseases (non-COVID-19 non-ARDS) were H&E stained to ascertain histopathological features. Inflammation along the vessel wall was also monitored by expression of NLRP3 and caspase 1. RESULTS: In lungs from COVID-19 affected subjects, vascular changes in the form of microthrombi in small vessels, arterial thrombosis, and organization were extensive as compared to lungs from non-COVID-19 (i.e., non-COVID-19 ARDS and non-COVID-19 non-ARDS) affected subjects. The expression of NLRP3 pathway components was higher in lungs from COVID-19 ARDS subjects as compared to non-COVID-19 non-ARDS cases. No differences were observed between COVID-19 ARDS and non-COVID-19 ARDS lungs. CONCLUSION: Vascular changes as well as NLRP3 inflammasome pathway activation were not different between COVID-19 and non-COVID-19 ARDS suggesting that these responses are not a COVID-19 specific phenomenon and are possibly more related to respiratory distress and associated strategies (such as MV) for treatment.

COVID-19 mortality prediction in the intensive care unit with deep learning based on longitudinal chest X-rays and clinical data.

OBJECTIVES: We aimed to develop deep learning models using longitudinal chest X-rays (CXRs) and clinical data to predict in-hospital mortality of COVID-19 patients in the intensive care unit (ICU). METHODS: Six hundred fifty-four patients (212 deceased, 442 alive, 5645 total CXRs) were identified across two institutions. Imaging and clinical data from one institution were used to train five longitudinal transformer-based networks applying five-fold cross-validation. The models were tested on data from the other institution, and pairwise comparisons were used to determine the best-performing models. RESULTS: A higher proportion of deceased patients had elevated white blood cell count, decreased absolute lymphocyte count, elevated creatine concentration, and incidence of cardiovascular and chronic kidney disease. A model based on pre-ICU CXRs achieved an AUC of 0.632 and an accuracy of 0.593, and a model based on ICU CXRs achieved an AUC of 0.697 and an accuracy of 0.657. A model based on all longitudinal CXRs (both pre-ICU and ICU) achieved an AUC of 0.702 and an accuracy of 0.694. A model based on clinical data alone achieved an AUC of 0.653 and an accuracy of 0.657. The addition of longitudinal imaging to clinical data in a combined model significantly improved performance, reaching an AUC of 0.727 (p = 0.039) and an accuracy of 0.732. CONCLUSIONS: The addition of longitudinal CXRs to clinical data significantly improves mortality prediction with deep learning for COVID-19 patients in the ICU. KEY POINTS: • Deep learning was used to predict mortality in COVID-19 ICU patients. • Serial radiographs and clinical data were used. • The models could inform clinical decision-making and resource allocation.

Formation of a de novo intracranial arteriovenous fistula in a child with PTEN hamartoma tumor syndrome.

PURPOSE: Dural arteriovenous fistulae (dAVF) are an uncommon feature of PTEN hamartoma tumor syndrome (PHTS). We report a case of an adolescent male diagnosed with PHTS following the treatment of multiple intracranial dAVF to emphasize the association of vascular anomalies with this disorder and discuss potential implications. CASE REPORT: An adolescent male presented with bilateral proptosis secondary to intracranial venous hypertension. Workup revealed the presence of a complex intracranial dAVF which was treated with several embolization procedures. Following treatment, a de novo dAVF was identified on surveillance imaging. A genetic workup revealed a pathogenic mutation in PTEN consistent with a diagnosis of PHTS. CONCLUSIONS: Recognition that PHTS may be associated with dAVF, and potentially delayed spontaneous formation of dAVF, is critically important due to the potential for devastating yet preventable neurologic sequelae.

Editorial Commentary: Indications for Shoulder SLAP Lesion Repair Versus Biceps Tenodesis Depend on Patient Age, Tear Type and Location, and Quality of Tissue.

Whether to repair a shoulder SLAP lesion or perform a biceps tenodesis depends on a multitude of factors: patient age, activity or work level, type of SLAP tear, location of SLAP tear, and quality of labral tissue. Determining which procedure to perform does not have such a simple, one-size-fits-all solution. For patients younger than 40 years, repair of type 2 SLAP tears that do not directly affect the biceps anchor (i.e., those tears from the 12:30 clock-face position to the 2-o'clock position or from the 10-o'clock position to the 11:30 clock-face position) is generally successful. For tears at the biceps anchor in patients younger than 40 years, repair the SLAP tear but perform tenodesis of the biceps. For type 3 SLAP tears, debride the bucket-handle component and spare the biceps because it usually is not involved. For type 4 tears, perform tenodesis. In patients older than 40 years, type 2 and type 4 SLAP tears are predominantly treated with biceps tenodesis with debridement of the SLAP tear, if indicated. SLAP repair is rarely indicated in patients older than 40 years because the tissue is usually degenerative and frayed.

Editorial Commentary: Interposition Graft Bridging Reconstruction: Good Mid-Term Outcomes for Massive Irreparable Rotator Cuff Tears.

Massive irreparable rotator cuff tears without glenohumeral arthritis are a common cause of shoulder pain and disability. Many surgical treatment options have been proposed, including debridement, partial repair, tendon transfer, superior capsule reconstruction, balloon spacer placement, bursal acromial reconstruction, and reverse shoulder arthroplasty. Interposition graft bridging reconstruction, as evidenced by the mid-term results of the current study, may also be considered, at least for now. However, let's see if this procedure will truly stand the test of time because all orthopaedic surgeons know that the one thing that ruins good results is long-term follow-up!