Citations

AbstractThis report reviews the image acquisition and reconstruction characteristics of C‐arm Cone Beam Computed Tomography (C‐arm CBCT) systems and provides guidance on quality control of C‐arm systems with this volumetric imaging capability. The concepts of 3D image reconstruction, geometric calibration, image quality, and dosimetry covered in this report are also pertinent to CBCT for Image‐Guided Radiation Therapy (IGRT). However, IGRT systems introduce a number of additional considerations, such as geometric alignment of the imaging at treatment isocenter, which are beyond the scope of the charge to the task group and the report.Section 1 provides an introduction to C‐arm CBCT systems and reviews a variety of clinical applications. Section 2 briefly presents nomenclature specific or unique to these systems. A short review of C‐arm fluoroscopy quality control (QC) in relation to 3D C‐arm imaging is given in Section 3. Section 4 discusses system calibration, including geometric calibration and uniformity calibration. A review of the unique approaches and challenges to 3D reconstruction of data sets acquired by C‐arm CBCT systems is give in Section 5. Sections 6 and 7 go in greater depth to address the performance assessment of C‐arm CBCT units. First, Section 6 describes testing approaches and phantoms that may be used to evaluate image quality (spatial resolution and image noise and artifacts) and identifies several factors that affect image quality. Section 7 describes both free‐in‐air and in‐phantom approaches to evaluating radiation dose indices.The methodologies described for assessing image quality and radiation dose may be used for annual constancy assessment and comparisons among different systems to help medical physicists determine when a system is not operating as expected. Baseline measurements taken either at installation or after a full preventative maintenance service call can also provide valuable data to help determine whether the performance of the system is acceptable. Collecting image quality and radiation dose data on existing phantoms used for CT image quality and radiation dose assessment, or on newly developed phantoms, will inform the development of performance criteria and standards. Phantom images are also useful for identifying and evaluating artifacts. In particular, comparing baseline data with those from current phantom images can reveal the need for system calibration before image artifacts are detected in clinical practice. Examples of artifacts are provided in Sections 4, 5, and 6.

Background The formation of dissecting pseudoaneurysms (dPSAs) is a common sequela of cervical artery dissection, which has been suggested to increase thrombotic risk in previous studies. This study reported clinical features and long‐term outcomes of cervical internal carotid (cICA) and vertebral artery (cVA) dPSAs. Methods We performed a retrospective chart review over a 10‐year period (January 2012–December 2021). Baseline demographics and clinical characteristics, medical and endovascular treatments, and long‐term outcomes were reported for cICA and cVA dPSA groups separately. Nonparametric tests were used to compare group differences. Results In our cohort, 120 (12%) of 999 cervical artery dissection patients had dPSA, with 85% occurring in the cICA and 15% in the cVA. Most dPSAs occurred spontaneously or in association with minor trauma. Compared with cICA dPSA, patients with cVA dPSA were younger (median age [range]=34.5 [24–70] versus 52 [30–77]; P <0.01), had a smaller dPSA size (median size [range]=4.5 mm [2–17] versus 8 mm [1.2–32]; P <0.01), and were more likely to reduce in size at follow‐up (median size change [range]=−2.8 mm [−17;0] versus 0 [−24;10.8]). Antithrombotic therapy was predominately aspirin monotherapy. No patients with cVA dPSA experienced recurrent strokes and only 3% of patients with cICA dPSA developed new/recurrent stroke in the territory of dPSA while on an antithrombotic regimen requiring endovascular intervention, and none of the dPSAs ruptured. A total of 98% of the patients had an excellent outcome (modified Rankin scale 0–2 at final follow‐up). Conclusion Most cICA and cVA dPSAs have a benign prognosis with medical therapy alone. Further prospective randomized clinical trials are needed to provide high quality evidence on the necessity of additional endovascular therapy at diagnosis in addition to medical therapy alone.

Phosphoglucomutase-1-congenital disorder of glycosylation (PGM1-CDG) (OMIM: 614921) is a rare autosomal recessive inherited metabolic disease caused by the deficiency of the PGM1 enzyme. Like other CDGs, PGM1-CDG has a multisystemic presentation. The most common clinical findings include liver involvement, rhabdomyolysis, hypoglycemia, and cardiac involvement. Phenotypic severity can vary, though cardiac presentation is usually part of the most severe phenotype, often resulting in early death. Unlike the majority of CDGs, PGM1-CDG has a treatment: oral D-galactose (D-gal) supplementation, which significantly improves many aspects of the disorder. Here, we describe five PGM1-CDG patients treated with D-gal and report both on novel clinical symptoms in PGM1-CDG as well as the effects of the D-gal treatment. D-gal resulted in notable clinical improvement in four patients, though the efficacy of treatment varied between the patients. Furthermore, there was a significant improvement or normalization in transferrin glycosylation, liver transaminases and coagulation factors in three patients, creatine kinase (CK) levels in two, while hypoglycemia resolved in two patients. One patient discontinued the treatment due to urinary frequency and lack of clinical improvement. Furthermore, one patient experienced recurrent episodes of rhabdomyolysis and tachycardia even on higher doses of therapy. D-gal also failed to improve the cardiac function, which was initially abnormal in three patients, and remains the biggest challenge in treating PGM1-CDG. Together, our findings expand the phenotype of PGM1-CDG and underline the importance of developing novel therapies that would specifically treat the cardiac phenotype in PGM1-CDG.

Abstract Background Fanconi anemia (FA) is an inherited disorder characterized by congenital malformations, bone marrow failure and malignancies. Hematopoietic cell transplant (HCT) is the only proven cure for the hematological complications. FA patients have increased chromosomal instability and aberrant DNA repair and thus can only tolerate low doses of chemotherapy or radiation as part of conditioning prior to HCT. Yet, they are still prone to severe regimen related toxicities (RRT) including hemorrhagic cystitis (HC) from cyclophosphamide (CY). Objective As CYP2B6 is a primary enzyme responsible for the catalyzation of the prodrug form of CY, understanding the association between CYP2B6 genetic variants and HC in FA patients may predict which patients will be more susceptible to developing HC. Study Design: A descriptive genetic association study was performed to identify genetic variants associated with HC in patients with FA who underwent HCT between 1999 and 2017. All patients received a CY-based preparative regimen and had pretransplant recipient DNA available for genomic analysis. Results Forty FA pediatric patients were eligible for this analysis. They had received HCT from matched sibling donors (n = 6) or alternative donors (n = 34) for marrow failure (n = 38) or myelodysplastic syndrome (n = 2). The incidence of HC was 32.5% which occurred at a median of 32 days (range 20–180) after HCT. Nine patients had a concomitant viral infection (BK virus, n = 8 both adenovirus and BK virus, n = 1). No genetic variants were significantly associated with HC. The top variants were rs2279343 (g.23060A > G), and rs2279344 (g.23280G > A) in the CYP2B6 gene. The incidence of HC among FA patients with the rs2279343 variant was 42% (CI 22–62%) compared to 20% (CI 0–40%) among those without the variant (p = 0.19). The incidence of HC among patients with the variant in rs2279344 was 40% (CI 22–58%) compared to 10% (CI 0–28%) among those without (p = 0.11). Conclusion No variants in our analysis were statistically associated with HC. The data suggest that CYP2B6 variants may increase the risk for HC in FA patients who received a CY based preparative therapy but these risk variants must be further evaluated in a larger population.

Background: COVID-19 is associated with higher morbidity and mortality in patients with chronic liver diseases (CLDs). However, our understanding of the long-term outcomes of COVID-19 in patients with CLD is limited. Methods: We conducted a multicenter, observational cohort study of adult patients with CLD who were diagnosed with COVID-19 before May 30, 2020, to determine long-term clinical outcomes. We used a control group of patients with CLD confirmed negative for COVID-19. Results: We followed 666 patients with CLD (median age 58 years, 52.8% male) for a median of 384 (interquartile range: 31–462) days. The long-term mortality was 8.1%; with 3.6% experiencing delayed COVID-19-related mortality. Compared to a propensity-matched control group of patients with CLD without COVID-19 (n=1332), patients with CLD with COVID-19 had worse long-term survival [p<0.001; hazards ratio (HR): 1.69; 95% CI: 1.19–2.41] and higher rate of hospitalization (p<0.001, HR: 2.00, 1.62–2.48) over a 1-year follow-up period. Overall, 29.9% of patients reported symptoms of long-COVID-19. On multivariable analysis, female sex (p=0.05, HR: 2.45, 1.01–2.11), Hispanic ethnicity (p=0.003, HR: 1.94, 1.26–2.99), and severe COVID-19 requiring mechanical ventilation (p=0.028, HR: 1.74, 1.06–2.86) predicted long-COVID-19. In survivors, liver-related laboratory parameters showed significant improvement after COVID-19 resolution. COVID-19 vaccine status was available for 72% (n=470) of patients with CLD and history of COVID-19, of whom, 70% (n=326) had received the COVID-19 vaccine. Conclusions: Our large, longitudinal, multicenter study demonstrates a high burden of long-term mortality and morbidity in patients with CLD and COVID-19. Symptoms consistent with long-COVID-19 were present in 30% of patients with CLD. These results illustrate the prolonged implications of COVID-19 both for recovering patients and for health care systems.

Lithium has been a cornerstone treatment for bipolar disorder (BD). Despite descriptions in the literature regarding associations between long-term lithium therapy (LTLT) and development of a thyroid disorder (overt/subclinical hypo/hyperthyroidism, thyroid nodule, and goiter) in BD, factors such as time to onset of thyroid abnormalities and impact on clinical outcomes in the course of illness have not been fully characterized. In this study we aimed to compare clinical characteristics of adult BD patients with and without thyroid disorders who were on LTLT. We aimed to identify the incidence of thyroid disorders in patients with BD on LTLT and response to lithium between patients with and without thyroid disorders in BD. The Cox proportional model was used to find the median time to the development of a thyroid disorder. Our results showed that up to 32% of patients with BD on LTLT developed a thyroid disorder, of which 79% developed hypothyroidism, which was corrected with thyroid hormone replacement. We did not find significant differences in lithium response between patients with or without thyroid disorders in BD. Findings from this study suggest that patients with BD and comorbid thyroid disorders when adequately treated have a response to lithium similar to patients with BD and no thyroid disorders.

AbstractPurposeProton pump inhibitors (PPIs) are widely prescribed medications. Various adverse clinical effects of PPIs have been reported in the literature, particularly over the past decade. The purpose of this article is to review published data primarily describing adverse effects associated with PPI use and to help clinicians determine which patients may still benefit from therapy despite safety concerns.SummaryAssociations between PPIs and the following have been described: bone fracture, acute and chronic kidney disease, gastrointestinal infections, deficiencies in vitamin B12 and magnesium, and coronavirus disease 2019 and respiratory infections. For inclusion in this review, studies must have evaluated potential adverse events associated with PPIs as a primary or secondary objective. Increased risks of bone fracture, acute and chronic kidney disease, gastrointestinal infections, and magnesium deficiency were consistently reported, albeit mostly in studies involving low-quality data (case-control and/or observational studies) and subject to bias. In the only pertinent randomized controlled trial to date, chronic pantoprazole use was associated with a greater risk of enteric infections relative to placebo use; there was no significant between-group difference in any other adverse event evaluated. PPIs continue to be recommended by the American College of Gastroenterology as a first-line treatment for management of gastroesophageal reflux disease and in the acute period following upper gastrointestinal and ulcer bleeding.ConclusionHigher-quality data is needed to better understand PPI-associated risks of the adverse effects listed above. Until then, clinicians may consider greater vigilance with PPI use; however, the data does not demonstrate a need for wide adoption of de-escalation strategies solely out of safety concerns.

Abstract Myeloid cells comprising up to 50% of total tumor mass in glioblastoma (GBM) contribute to tumor progression and immunosuppression. Restraining glioma-induced myeloid cell infiltration increases functional T cells within the tumors, improves the efficacy of checkpoint blockade, and significantly extends mouse survival. Here, we focus on an ion channel, voltage-gated proton channel Hv1, which is mainly expressed in myeloid cells and shapes the physiological functions of myeloid cells. Our bioinformatics analysis demonstrated that elevated Hv1 expression in the tumor mass correlates with poor disease prognosis in patients. Using the leading immunocompetent model of GBM in mice, we showed that Hv1 knockout mice (Hv1−/−) exhibit slower glioma progression and prolonged survival. Using in vivo two-photon imaging, we found that myeloid cells infiltrate into tumor mass since early time points and have intimate interaction with tumor cells. Notably, by full-spectrum flow cytometry, we found that Hv1−/− mice have reduced monocyte/macrophage infiltration, and increased PD-1+ CD4+ T cells in the tumor-burdened hemisphere. As a result, we combined anti-PD-1 treatment with Hv1 knockout in the middle stage of glioma, and found that approximately 30% of Hv1−/− mice were cured. Together, our results demonstrated that Hv1 controls myeloid infiltration and could be a novel therapeutic target for the treatment of GBM. Supported by R01NS110825, R01NS088627

Abstract Immune-mediated blood brain barrier (BBB) disruption is a prominent feature of various neurological conditions for which an emerging role of CD8 T cells is being realized. Our laboratory has developed a unique model of CD8 T cell-mediated BBB disruption which employs a variation of the Theiler’s murine encephalomyelitis virus infection (TMEV) infection. Upon intravenous administration of VP2121–130 viral peptide during peak anti-viral adaptive response, Db:VP2121–130 epitope specific CD8 T cells induce BBB disruption in a perforin dependent manner. In this model, we addressed the role of microglia in tandem with CD8+ T cells. Using real time two-photon in vivo imaging, we demonstrate that microglia adopt distinct morphological features including enlarged cell body and fewer ramified processes as early as 6 hours post administration of VP2 peptide. Notably, perforin-deficient mice failed to display BBB disruption and had significantly diminished microglial expression of MHC-II and CD68 in this model. This study demonstrates CD8 T cell promote microglia activation through a perforin-dependent process during BBB disruption. Importantly, microglia are activated concurrently with the onset of vascular permeability and could serve as a critical cell type in this process.