Citations

Abstract: Background: Allergic contact dermatitis is a common, pruritic, debilitating skin disease, affecting at least 20% of the population. Objective: To prospectively validate a computer vision algorithm across all Fitzpatrick skin types. Methods: Each participant was exposed to 10 allergens. The reference criterion was obtained 5 days after initial patch placement by a board-certified dermatologist. The algorithm processed photographs of the test site obtained on Day 5. Human performance in reading the photographs was also evaluated. Results: A total of 206 evaluable participants [mean age 39 years, 66% (136/206) female, and 47% with Fitzpatrick skin types IV–VI] completed testing. Forty-two percent (87/206) of participants experienced 1 or more allergic reaction resulting in a total of 132 allergic reactions. The model provided high discrimination (AUROC 0.86, 95% CI: 0.82–0.90) and specificity (93%, 95% CI: 92%–94%) but with lower sensitivity (58%, 95% CI: 49%–67%). Human performance interpreting the photographs ranged from providing similar performance to the algorithm to providing superior performance when combined across readers. There were no serious adverse events. Conclusions: The combination of a smartphone capture of patch testing sites with deep learning yielded high discrimination across a diverse sample.

Summary: Sacral reconstruction post tumor resection has historically been executed with the placement of hardware or free tissue transfer. Reconstruction using a vascularized bone graft is an alternative that avoids the complications associated with hardware placement or free tissue transfer. This article describes the first documented case of spinoplastic reconstruction using an iliac crest vascularized bone graft (IC-VBG) after the resection of a sacral ependymoma. This is a case of a 17-year-old boy with a history of a sacral myxopapillary ependymoma. He presented to a local emergency department complaining of 6 months of urinary incontinence and progressive paresthesias affecting the left lower extremity. Magnetic resonance imaging was significant for a lesion located in the extradural spinal canal. Biopsy confirmed a myxopapillary ependymoma, World Health Organization grade II. The initial intervention involved tumor resection with titanium hardware placement. He subsequently required replacement of the titanium hardware with carbon fiber, secondary to the need for surveillance imaging. He underwent harvesting and inset of the IC-VBG at the time of hardware replacement. IC-VBG is a safe and effective modality for spinoplastic reconstruction. It enhances the potential for solid bony union and offers a practical alternative to free bone transfer. This approach provides an asset to add to a reconstructive surgeon’s armamentarium, making it an essential tool for reconstructive surgeons working in conjunction with spinal surgery colleagues.

Background: For patients undergoing abdominal surgery, postoperative pulmonary complications (PPCs) are a major source of morbidity and mortality. The use of point-of-care ultrasonography (POCUS), and specifically POCUS of the lungs, has seen many advancements in recent years. Objectives: We hypothesize that perioperative lung ultrasonography can be used as a predictor for PPCs. Methods: In a Single, 1000 beds, trauma level I medical center, patients presenting for elective intra-abdominal surgery with no severe pulmonary or cardiac diseases were evaluated preoperatively with a standardized 12-point lung ultrasound exam. A second identical exam was performed after surgery in the post-anesthesia care unit. PPCs were also documented. All lung ultrasound exams were presented to a blinded researcher and a lung ultrasound score (LUS) was calculated. Statistical analysis comparing pre- and postoperative LUS and PPC scores were performed. Results: A total of 61 patients were evaluated. The pre-surgery median LUS was 0 (in the range of 0–6) and the post-surgery median LUS was 3 (in the range of 0–14). The pre- to postsurgical LUS delta was 3.4 (standard deviation of 3.3). A postoperative LUS of 6 or more was defined as “high.” A High LUS did not correlate with prolonged post-anesthesia care unit or hospital stay, prolonged oxygen support, or number of desaturation events. Conclusion: For elective abdominal surgery in relatively healthy patients, preoperative LUS usually begins at a normal level and becomes worse after general anesthesia. However, this difference in LUS is not significantly associated with clinically relevant postoperative pulmonary complications such as prolonged oxygen therapy, pneumonia, and noninvasive or invasive mechanical ventilation. Trial registration: Clinicaltrials.gov identifier: NCT05502926. Summary: This paper explores the use of point-of-care ultrasonography as a predictor for postoperative pulmonary complications. The findings suggest that while the lung ultrasound score worsens with general anesthesia, the differences are not significantly associated with postoperative pulmonary complications.

Abstract The A1 domain in Von Willebrand Factor (VWF) initiates coagulation through binding to platelet glycoprotein GPIbα receptors. Von Willebrand Disease (VWD)-Mutations in A1 that either impair (type 2M) or enhance (type 2B) platelet adhesion to VWF can locally destabilize and even misfold the domain. We leveraged misfolding in the gain-of-function type 2B VWD phenotype as a target, distinct from the normal conformation. Two nuclease-resistant 2′-fluoropyrimidine RNA aptamers were selected to discriminate normal A1 domains from a type 2B V1314D A1 variant in a glycosylated A1A2A3 tri-domain VWF-fragment. Two aptamers, W9 and V1, were isolated that selectively recognize, bind, and inhibit the A1–GPIbα interaction with WT A1A2A3 and V1314D A1A2A3, respectively. These aptamers were tested against their respective recombinant targets, plasma VWF, VWF concentrates, and patient plasma with the heterozygous type 2B VWD R1306W variant using clinical assays, surface plasmon resonance and inhibition assays of platelet adhesion to recombinant A1 and A1A2A3 domains under shear stress. The specificity of W9 and V1 aptamers confirms that pathological conformations of VWD Type 2B proteins are different from normal VWF. The availability of aptamers that distinguish normal plasma-derived VWF from VWD suggests potential applicability in clinical diagnosis of severe gain-of-function phenotypes.

Abstract Thromboembolic complication is common in severe coronavirus disease 2019 (COVID-19), leading to an investigation into the presence of prothrombotic antibodies akin to those found in heparin-induced thrombocytopenia (HIT). In a study of samples from 130 hospitalized patients, collected 3.6 days after COVID-19 diagnosis, 80% had immunoglobulin G (IgG) antibodies recognizing complexes of heparin and platelet factor 4 (PF4; PF4/H), and 41% had antibodies inducing PF4-dependent P-selectin expression in CpG oligodeoxynucleotide–treated normal platelets. Unlike HIT, both PF4/H-reactive and platelet-activating antibodies were found in patients with COVID-19 regardless of recent heparin exposure. Notably, PF4/H-reactive IgG antibodies correlated with those targeting the receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 spike protein. Moreover, introducing exogenous RBD to or removing RBD-reactive IgG from COVID-19 plasma or IgG purified from COVID-19 plasma significantly reduced their ability to activate platelets. RBD-specific antibodies capable of platelet activation were cloned from peripheral blood B cells of patients with COVID-19. These antibodies possessed sequence motifs in the heavy-chain complementarity-determining region 3 (HCDR3), resembling those identified in pathogenic HIT antibodies. Furthermore, IgG+ B cells having these HCDR3 signatures were markedly expanded in patients with severe COVID-19. Importantly, platelet-activating antibodies present in patients with COVID-19 were associated with a specific elevation of platelet α-granule proteins in the plasma and showed a positive correlation with markers for inflammation and tissue damage, suggesting a functionality of these antibodies in patients. The demonstration of functional and structural similarities between certain RBD-specific antibodies in patients with COVID-19 and pathogenic antibodies typical of HIT suggests a novel mechanism by which RBD-specific antibodies might contribute to thrombosis in COVID-19.

Abstract GBM AGILE(NCT03970447) is a phase 2/3 Bayesian adaptive registration platform trial testing multiple therapies against a common control. Paxalisib, a PI3K/mTOR inhibitor, is the 3rd arm in the trial to conclude evaluation. METHODS Paxalisib was open to patients with newly diagnosed unmethylated (NDU) and recurrent (RD) glioblastoma, with three possible signatures: NDU, RD, and All(NDU+RD). Arm enrollment occurred Dec2020 through May2022. Control patients were enrolled from study initiation (July2019) and were treated with temozolomide(NDU) or lomustine(RD). GBM AGILE investigational arms have 1 or 2 stages, with adaptive randomization in stage 1 and fixed randomization if arms continue to stage 2. Efficacy is based on OS hazard ratio(HR) of Arm/Control. Efficacy goal is final Bayesian probability ≥ 98% for HR<1.00 in combined Stages. An Arm continues to Stage 2 if Bayesian predictive power (PP) ≥ 0.8. An Arm stops accruing in Stage 1 if it reaches maximal sample size(N) or does not meet a minimum efficacy threshold (PP<0.25 for all signatures when N>50). Clinical cut-off is 12 months after accrual stops. The maximum N for paxalisib was approximately 150(Stage 1) and 50(Stage 2). RESULTS After paxalisib reached >150 patients in Stage 1, accrual stopped [Paxalisib/control N 54/75(NDU), 100/188(RD)]. Neither PP thresholds for moving to Stage 2 nor stopping for minimum efficacy were met. Following an unplanned public disclosure that the arm did not continue to stage 2, clinical cut-off for final analysis (planned May2023) was updated to public disclosure date (August2022). At final analysis mean HRs were 0.89(NDU), 1.25(RD), 1.05(All), probabilities of HR<1.00 of 0.72(NDU), 0.076(RD), 0.398(All). Model estimated median OS paxalisib/control (months) were 14.77/13.84(NDU) and 8.58/10.06(RD). CONCLUSION Paxalisib did not show survival benefit over cumulative control in final primary analysis; additional secondary analyses are being considered. GBM AGILE continues to rapidly and efficiently assess therapies in ND and RD glioblastoma.

Background: Traumatic carotid artery pseudoaneurysms (PSAs) represent a vascular anomaly with potential for serious complications, including stroke. Traditional treatments involve endovascular stenting, which may not be ideally suited to otherwise healthy vessels that have the potential to remodel. Given the limitations of smaller animal models in replicating human vasculature and the need for improved treatment modalities, this study introduces a novel swine model for the creation and evaluation of carotid PSAs. Methods: The PSAs were created from bovine dura and anastomosed in an end-to-side fashion to bilateral carotid arteries. The PSAs were radiologically followed up post-operatively and were harvested at 3 and 10 days for histological analysis. Results: Pseudoaneurysms were successfully created in both animals without intra-operative or immediate post-operative complications. Radiological analysis showed well-perfused PSAs with intra-aneurysmal turbulence, hemodynamically mimicking human carotid artery PSAs. There was no evidence of thrombus or arterial stenosis. Histological examinations revealed thrombus maturation and tight anastomosis of the PSA sac with the native artery. Conclusions: This PSA swine model offers a replicable, cost-effective, and easily implemented tool with the potential to advance carotid PSA management and educational efforts in vascular surgery. Clinical Impact The model presented in this methodology paper allows for a standardized PSA animal model allowing for the standardization of a clinical entity which is frequently heterogenenous in morphology. This can allow for the development of new therapies or provide a ground truth for computer modelling for further in silico study.

Abstract Background In BRAF-mutated high-risk melanoma, targeted therapy (BRAF/MEK inhibitors) and checkpoint inhibitor (CPI) immunotherapy have durable benefits as first-line (1L) adjuvant therapy. Based on differing action mechanisms of BRAF/MEK inhibitors and CPI immunotherapies, there is interest in evaluating the activity of 2L adjuvant targeted therapy in decreasing the risk of subsequent recurrence after repeat resection following relapse on/after 1L adjuvant CPI. Patients and methods This was a retrospective review of BRAF V600-mutated resected stage III/IV melanoma patients in the United States, Australia, and The Netherlands who received 1L adjuvant CPI immunotherapy, relapsed locoregionally/distantly, were again resected to no evidence of disease, and received dabrafenib/trametinib (dab/tram) as 2L adjuvant therapy. The primary endpoint was relapse-free survival (RFS) from initiation of 2L adjuvant dab/tram (RFS-2), analyzed via Kaplan-Meier methods. Results Thirty-eight patients were included (median age 50 years, 63% male, 87% stage III, median follow-up 19 months from 2L dab/tram initiation). Median dab/tram duration was 10.1 months (range: 1 day–22.7 months), with half discontinuing due to progression or adverse events. Median (95% CI) RFS-2 was 18.9 (14.9–28.1) months, with 91%, 81%, and 58% remaining relapse-free at 6, 12, and 18 months, respectively. Most patients remained distant metastasis-free at 6, 12, and 18 months (97%, 85%, and 71%, respectively). Two patients were deceased at the last follow-up, with 97% alive at 18 months. Conclusions Over 80% of patients remained relapse- and metastasis-free at 12 months after 2L dab/tram initiation, with only 2 deaths observed. Dab/tram appears to have activity in the 2L adjuvant setting, although more follow-up is required.

Lymphedema is a frequent complication of breast cancer treatment. As the survival rates of breast cancer continue to increase, the number of women with lymphedema will also increase. Surgical treatment of lymphedema has made significant advances during the past 20 years, and our understanding of these procedures continues to evolve. Vascularized lymph node transfer is an increasingly popular option for surgical treatment of lymphedema; however, the mechanism behind symptomatic relief is not fully understood. A proposed theory for improvement in lymphedema symptoms is lymphangiogenesis and spontaneous regeneration of lymphatic vessels, the timing and degree of which are not well defined. We present the case of a 40-year-old woman with a 10-year history of right upper extremity lymphedema secondary to bilateral mastectomy and right axillary lymph node dissection, who subsequently underwent vascularized omental lymph node transfer and lymphovenous bypass with radiographic evidence of spontaneous lymphatic reconnection within 9 months. To our knowledge, this is the earliest reported radiographic evidence of lymphatic regeneration in a human subject to date, adding to the growing body of evidence to support the therapeutic benefits of vascularized lymph node transfers.