Ultrasound Assessment of Postprocedural Arterial Pseudoaneurysms: Techniques, Clinical Implications, and Emergency Department Integration.

This narrative aims to evaluate the efficacy of point-of-care ultrasound (POCUS) in the early diagnosis and management of postprocedural arterial pseudoaneurysms in the emergency department (ED). We hypothesize that POCUS can be used as the first line of imaging to distinguish vascular from non-vascular causes and diagnose a pseudoaneurysm if present. A comprehensive review of cases involving postprocedural pseudoaneurysms was conducted. We focus on patients who underwent endovascular procedures, including transfemoral and transradial arterial access for cardiac interventions, or received laceration repair after blunt head trauma. We analyzed each case's clinical symptoms, POCUS findings, and subsequent management. POCUS demonstrated high efficacy in early diagnosis by detecting pseudoaneurysm sacs with characteristic bi-directional flows (yin-yang sign) and, in some cases, partial thrombosis. The early identification of potential arterial complications allowed for efficient planning of further imaging and expedited surgical consultation, leading to timely and definitive management. Our study emphasizes the significance of using POCUS as the primary imaging modality for early detection and diagnosis of postprocedural arterial pseudoaneurysms. Incorporating POCUS into the initial assessment of patients presenting with pain and swelling at the site of arterial access or laceration repair can streamline consultation and potentially reduce the need for additional imaging, optimizing patient care in the ED setting.

Cost drivers for benign hysterectomy within a health care system: Influence of patient, perioperative, and hospital factors.

OBJECTIVE: To identify patient, perioperative, and hospital factors that drive total hospital charges for benign hysterectomy. METHODS: The authors conducted a retrospective cohort study between July 2014 and February 2019 at five academic and community hospitals within an integrated healthcare system in the state of Maryland with a Global Budget Revenue methodology for hospital charges. Predictor variables included patient, perioperative and hospital characteristics. One-way analysis of variance was used to compare charges among approaches. A multiple linear regression model was built to account for the interaction between covariates. RESULTS: A total of 2592 patients underwent hysterectomy via laparoscopic (61%), abdominal (16%), robotic (14%), or vaginal (9%) approaches. Before adjusting for covariates, laparoscopic and vaginal approaches had similar charges ($11 637 and $12 229, respectively), while robotic and open approaches had higher charges ($17 535 and $19 099, respectively). After adjusting, charges for open, laparoscopic, and robotic approaches were higher than the vaginal approach ($692, $712, and $1279, respectively). Each operating room minute resulted in an increased cost of $46. Length of stay >23 h was associated with an increase of $865. Year, uterine size, body mass index, additional procedures, and transfusion influenced charges. CONCLUSION: Perioperative and hospital characteristics significantly influence hospital charges for benign hysterectomy, more so than nonmodifiable patient characteristics. This provides opportunities to reduce healthcare expenditures, such as improving operating room efficiency and reducing length of stay.

The Use of Cerebral NIRS Monitoring to Identify Acute Brain Injury in Patients With VA-ECMO.

Acute brain injury (ABI) increases morbidity and mortality in patients with veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Optimal neurologic monitoring methods have not been well-explicated. We studied the use of Near-infrared Spectroscopy (NIRS) to monitor cerebral regional oxygenation tissue saturation (rSO2) and its relation to ABI in VA-ECMO. In this prospective, observational cohort study of 39 consecutive patients, we analyzed the ability of rSO2 values from continuous bedside NIRS monitoring to predict ABI during VA-ECMO support. ABI occurred in 24 (61.5%) patients. Those with ABI had a lower pre-ECMO Glasgow Coma Scale, more blood product transfusions of pRBCs and FFP, and higher APACHEII score. Baseline rSO2 values were not significantly different between cohorts (54.25 vs 58.50, p = 0.260), while the minimum rSO2 value was lower for patients who experienced an ABI than those who did not (39.75 vs 44.50, p = 0.039). In patients with ABI, 21 (87.5%) had a drop in rSO2 of 25% from baseline, compared to only 7 (46.7%) patients without ABI (p = 0.017). By ROC analysis, we found that desaturations with >25% drop from the baseline rSO2 on VA-ECMO exhibited 86% sensitivity and 55% specificity to predict ABI, with an area under the curve of 0.68. Patients with ABI were more likely to have withdrawal of life sustaining therapy (17 vs 5, p = 0.049), while neurologic outcome and mortality were not statistically different between patients with or without ABI. Our results support that cerebral NIRS is a useful, real-time bedside neuromonitoring tool to detect ABI in VA-ECMO patients. A >25% drop from the baseline was sensitive in predicting ABI occurrence. Further research is needed to assess how to implement this knowledge to utilize NIRS in developing appropriate intervention strategy in VA-ECMO patients.

Therapeutic drug monitoring of valproic acid in extracorporeal membrane oxygenation.

INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) is a life-saving therapy for those in cardiopulmonary failure, including post-cardiac arrest. Despite a high volume of ECMO patients using anti-seizure medication, there is a paucity of data concerning the dosing, levels, and clinical scenarios for their use. CASE REPORT: We present three cases of ECMO patients post-PEA arrest who were on valproic acid (VPA) for treatment of seizure and/or myoclonus. The total and free levels of VPA are reported. DISCUSSION: The trough levels are consistent throughout therapy, suggesting VPA is not significantly removed by the ECMO circuitry. Although the total serum levels remained below the toxic range, the free level was elevated in two patients. These patients did not develop signs of toxicity. CONCLUSION: VPA may be an effective anti-seizure medication in ECMO patients. Free VPA levels should be more readily available to better quantify efficacy or toxicity, especially in ECMO patients.

SARS-CoV-2 safer infection sites: moral entitlement, pragmatic harm reduction strategy or ethical outrage?

The pandemic of SARS-CoV-2 has led to unprecedented changes to society, causing unique problems that call for extraordinary solutions. We consider one such extraordinary proposal: 'safer infection sites' that would offer individuals the opportunity to be intentionally infected with SARS-CoV-2, isolate, and receive medical care until they are no longer infectious. Safer infection could have value for various groups of workers and students. Health professionals place themselves at risk of infection daily and extend this risk to their family members and community. Similarly, other essential workers who face workplace exposure must continue their work, even if have high-risk household members and live in fear of infecting. When schools are kept closed because of the fear that they will be sites of significant transmission, children and their families are harmed in multiple ways and college students who are living on campus, whether or not they are attending classes in person, are contributing to high rates of transmission and experiencing high rates of exposure. We consider whether offering safer infection sites to these groups could be ethically defensible and identify the empirical unknowns that would need to resolve before reaching definitive conclusions. This article is not an endorsement of intentional infection with the coronavirus, but rather is meant to spark conversation on the ethics of out-of-the-box proposals. Perhaps most meaningfully, our paper explores the value of control and peace of mind for those among us most impacted by the pandemic: those essential workers risking the most to keep us safe.

A first-in-human proof-of-concept trial of intravaginal artesunate to treat cervical intraepithelial neoplasia 2/3 (CIN2/3).

OBJECTIVE: Most treatment options for cervical intraepithelial neoplasia 2/3 (CIN2/3) are either excisional or ablative, and require sequential visits to health care providers. Artesunate, a compound that is WHO-approved for treatment of acute malaria, also has cytotoxic effect on squamous cells transformed by HPV. We conducted a first-in-human Phase I dose-escalation study to assess the safety and efficacy of self-administered artesunate vaginal inserts in biopsy-confirmed CIN2/3. METHODS: Safety analyses were based on patients who received at least one dose, and were assessed by the severity, frequency, and duration of reported adverse events. Tolerability was assessed as the percentage of subjects able to complete their designated dosing regimen. Modified intention-to-treat analyses for efficacy and viral clearance were based on patients who received at least one dose for whom endpoint data were available. Efficacy was defined as histologic regression to CIN1 or less. Viral clearance was defined as absence of HPV genotoype (s) detected at baseline. RESULTS: A total of 28 patients received 1, 2, or 3 five-day treatment cycles at study weeks 0, 2, and 4, respectively, prior to a planned, standard-of-care resection at study week 15. Reported adverse events were mild, and self-limited. In the modified intention-to-treat analysis, histologic regression was observed in 19/28 (67.9%) subjects. Clearance of HPV genotypes detected at baseline occurred in 9 of the 19 (47.4%) subjects whose lesions underwent histologic regression. CONCLUSIONS: Self-administered vaginal artesunate inserts were safe and well-tolerated, at clinically effective doses to treat CIN2/3. These findings support proceeding with Phase II clinical studies.

Current status of therapeutic HPV vaccines.

The accumulating successes of immune-based treatments for solid tumors have prompted an explosion of cancer clinical trials testing strategies to elicit tumor-specific immune effector responses, either alone, in combination with immune checkpoint blockade, or with conventional cancer treatment modalities. However, across the board, clinical responses have been achieved in only a limited subset of cancer patients, underscoring a critical need to identify mechanisms and biomarkers of response, as well as mechanisms of resistance to therapy. Cancers caused by human papillomavirus (HPV) are driven by two viral oncoproteins, E6 and E7, both of which are functionally required for cellular transformation, thereby providing non-'self', tumor-specific antigenic targets. Immune responses that are specific for either or both of these oncoproteins can be used to follow the magnitude and kinetics of immune responses to therapeutic interventions. Moreover, identifying neoantigens is not a concern in early-stage disease - since HPV cancers are driven by HPV oncoproteins, the somatic mutational load in early disease is low, particularly in comparison to non-HPV-related squamous cancers arising in the same organ site [1,2]. Cancers caused by HPV are a model clinical setting in which to test principles of immunotherapies, and to discover mechanisms of interactions between tumors and their attendant immune milieu. In this review, we will use examples of insights gained from studies of HPV disease to illustrate major themes of immune-based therapeutic strategies.

Structure-Function Implications of the Ability of Monoclonal Antibodies Against α-Galactosylceramide-CD1d Complex to Recognize ß-Mannosylceramide Presentation by CD1d.

iNKT cells are CD1d-restricted T cells recognizing lipid antigens. The prototypic iNKT cell-agonist α-galactosylceramide (α-GalCer) alongside compounds with similar structures induces robust proliferation and cytokine production of iNKT cells and protects against cancer in vivo. Monoclonal antibodies (mAbs) that detect CD1d-α-GalCer complexes have provided critical information for understanding of antigen presentation of iNKT cell agonists. Although most iNKT cell agonists with antitumor properties are α-linked glycosphingolipids that can be detected by anti-CD1d-α-GalCer mAbs, ß-ManCer, a glycolipid with a ß-linkage, induces strong antitumor immunity via mechanisms distinct from those of α-GalCer. In this study, we unexpectedly discovered that anti-CD1d-α-GalCer mAbs directly recognized ß-ManCer-CD1d complexes and could inhibit ß-ManCer stimulation of iNKT cells. The binding of anti-CD1d-α-GalCer mAb with ß-ManCer-CD1d complexes was also confirmed by plasmon resonance and could not be explained by α-anomer contamination. The binding of anti-CD1d-α-GalCer mAb was also observed with CD1d loaded with another ß-linked glycosylceramide, ß-GalCer (C26:0). Detection with anti-CD1d-α-GalCer mAbs indicates that the interface of the ß-ManCer-CD1d complex exposed to the iNKT cell TCR can assume a structure like that of CD1d-α-GalCer, despite its disparate carbohydrate structure. These results suggest that certain ß-linked monoglycosylceramides can assume a structural display similar to that of CD1d-α-GalCer and that the data based on anti-CD1d-α-GalCer binding should be interpreted with caution.

Intratumorally delivered formulation, INT230-6, containing potent anticancer agents induces protective T cell immunity and memory.

The benefits of anti-cancer agents extend beyond direct tumor killing. One aspect of cell death is the potential to release antigens that initiate adaptive immune responses. Here, a diffusion enhanced formulation, INT230-6, containing potent anti-cancer cytotoxic agents, was administered intratumorally into large (approx. 300mm3) subcutaneous murine Colon26 tumors. Treatment resulted in regression from baseline in 100% of the tumors and complete response in up to 90%. CD8+ or CD8+/CD4+ T cell double-depletion at treatment onset prevented complete responses, indicating a critical role of T cells in promoting complete tumor regression. Mice with complete response were protected from subcutaneous and intravenous re-challenge of Colon26 cells in a CD4+/CD8+ dependent manner. Thus, immunological T cell memory was induced by INT230-6. Colon26 tumors express the endogenous retroviral protein gp70 containing the CD8+ T-cell AH-1 epitope. AH-1-specific CD8+ T cells were detected in peripheral blood of tumor-bearing mice and their frequency increased 14 days after treatment onset. AH-1-specific CD8+ T cells were also significantly enriched in tumors of untreated mice. These cells had an activated phenotype and highly expressed Programmed cell-death protein-1 (PD-1) but did not lead to tumor regression. CD8+ T cell tumor infiltrate also increased 11 days after treatment. INT230-6 synergized with checkpoint blockade, inducing a complete remission of the primary tumors and shrinking of untreated contralateral tumors, which demonstrates not only a local but also systemic immunological effect of the combined therapy. Similar T-cell dependent inhibition of tumor growth was also found in an orthotopic 4T1 breast cancer model.

Blockade of only TGF-ß 1 and 2 is sufficient to enhance the efficacy of vaccine and PD-1 checkpoint blockade immunotherapy.

Checkpoint inhibition has established immunotherapy as a major modality of cancer treatment. However, the success of cancer immunotherapy is still limited as immune regulation of tumor immunity is very complicated and mechanisms involved may also differ among cancer types. Beside checkpoints, other good candidates for immunotherapy are immunosuppressive cytokines. TGF-ß is a very potent immunosuppressive cytokine involved in suppression of tumor immunity and also necessary for the function of some regulatory cells. TGF-ß has three isoforms, TGF-ß 1, 2 and 3. It has been demonstrated in multiple mouse tumor models that inhibition of all three isoforms of TGF-ß facilitates natural tumor immunosurveillance and tumor vaccine efficacy. However, individual isoforms of TGF-ß are not well studied yet. Here, by using monoclonal antibodies (mAbs) specific for TGF-ß isoforms, we asked whether it is necessary to inhibit TGF-ß3 to enhance tumor immunity. We found that blockade of TGF-ß1 and 2 and of all isoforms provided similar effects on tumor natural immunosurveillance and therapeutic vaccine-induced tumor immunity. The protection was CD8+ T cell-dependent. Blockade of TGF-ß increased vaccine-induced Th1-type response measured by IFNγ production or T-bet expression in both tumor draining lymph nodes and tumors, although it did not increase tumor antigen-specific CD8+ T cell numbers. Therefore, protection correlated with qualitative rather than quantitative changes in T cells. Furthermore, when combined with PD-1 blockade, blockade of TGF-ß1 and 2 further increased vaccine efficacy. In conclusion, blocking TGF-ß1 and 2 is sufficient to enhance tumor immunity, and it can be further enhanced with PD-1 blockade.