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ImportanceSystematic data on the association between anticancer therapies and thromboembolic events (TEEs) in patients with COVID-19 are lacking.ObjectiveTo assess the association between anticancer therapy exposure within 3 months prior to COVID-19 and TEEs following COVID-19 diagnosis in patients with cancer.Design, Setting, and ParticipantsThis registry-based retrospective cohort study included patients who were hospitalized and had active cancer and laboratory-confirmed SARS-CoV-2 infection. Data were accrued from March 2020 to December 2021 and analyzed from December 2021 to October 2022.ExposureTreatments of interest (TOIs) (endocrine therapy, vascular endothelial growth factor inhibitors/tyrosine kinase inhibitors [VEGFis/TKIs], immunomodulators [IMiDs], immune checkpoint inhibitors [ICIs], chemotherapy) vs reference (no systemic therapy) in 3 months prior to COVID-19.Main Outcomes and MeasuresMain outcomes were (1) venous thromboembolism (VTE) and (2) arterial thromboembolism (ATE). Secondary outcome was severity of COVID-19 (rates of intensive care unit admission, mechanical ventilation, 30-day all-cause mortality following TEEs in TOI vs reference group) at 30-day follow-up.ResultsOf 4988 hospitalized patients with cancer (median [IQR] age, 69 [59-78] years; 2608 [52%] male), 1869 had received 1 or more TOIs. Incidence of VTE was higher in all TOI groups: endocrine therapy, 7%; VEGFis/TKIs, 10%; IMiDs, 8%; ICIs, 12%; and chemotherapy, 10%, compared with patients not receiving systemic therapies (6%). In multivariable log-binomial regression analyses, relative risk of VTE (adjusted risk ratio [aRR], 1.33; 95% CI, 1.04-1.69) but not ATE (aRR, 0.81; 95% CI, 0.56-1.16) was significantly higher in those exposed to all TOIs pooled together vs those with no exposure. Among individual drugs, ICIs were significantly associated with VTE (aRR, 1.45; 95% CI, 1.01-2.07). Also noted were significant associations between VTE and active and progressing cancer (aRR, 1.43; 95% CI, 1.01-2.03), history of VTE (aRR, 3.10; 95% CI, 2.38-4.04), and high-risk site of cancer (aRR, 1.42; 95% CI, 1.14-1.75). Black patients had a higher risk of TEEs (aRR, 1.24; 95% CI, 1.03-1.50) than White patients. Patients with TEEs had high intensive care unit admission (46%) and mechanical ventilation (31%) rates. Relative risk of death in patients with TEEs was higher in those exposed to TOIs vs not (aRR, 1.12; 95% CI, 0.91-1.38) and was significantly associated with poor performance status (aRR, 1.77; 95% CI, 1.30-2.40) and active/progressing cancer (aRR, 1.55; 95% CI, 1.13-2.13).Conclusions and RelevanceIn this cohort study, relative risk of developing VTE was high among patients receiving TOIs and varied by the type of therapy, underlying risk factors, and demographics, such as race and ethnicity. These findings highlight the need for close monitoring and perhaps personalized thromboprophylaxis to prevent morbidity and mortality associated with COVID-19–related thromboembolism in patients with cancer.

Pencil beam scanning delivered with continuous scanning has several advantages over conventional discrete spot scanning. Such advantages include improved beam delivery efficiency and reduced beam delivery time. However, a move dose is delivered between consecutive spots with continuous scanning, and current treatment planning systems do not take this into account. Therefore, continuous scanning and discrete spot plans have an inherent dose discrepancy. Using the operating parameters of the state-of-the-art particle therapy system, we conducted a proof-of-concept study in which we systematically generated 28 plans for cubic targets with different combinations of plan parameters and simulated the dose discrepancies between continuous scanning and a planned one. A nomograph to guide the selection of plan parameters was developed to reduce the dose discrepancy. The effectiveness of the nomograph was evaluated with two clinical cases (one prostate and one liver). Plans with parameters guided by the nomograph decreased dose discrepancy than those used standard plan parameters. Specifically, the 2%/2 mm gamma passing rate increased from 96.3% to 100% for the prostate case and from 97.8% to 99.7% for the liver case. The CTV DVH root mean square error decreased from 2.2% to 0.2% for the prostate case and from 1.8% to 0.9% for the liver case. The decreased dose discrepancy may allow the relaxing of the delivery constraint for some cases, leading to greater benefits in continuous scanning. Further investigation is warranted.

Abstract The Fontan procedure is the definitive treatment for patients with single-ventricle physiology. Surgical advances have led to a growing number of patients surviving into adulthood. Fontan-associated liver disease (FALD) encompasses a spectrum of pathologic liver changes that occur secondary to altered physiology including congestion, fibrosis, and the development of liver masses. Assessment of FALD is difficult and relies on using imaging alongside of clinical, laboratory, and pathology information. Ultrasound, computed tomography, and magnetic resonance imaging are capable of demonstrating physiologic and hepatic parenchymal abnormalities commonly seen in FALD. Several novel imaging techniques including magnetic resonance elastography are under study for use as biomarkers for FALD progression. Imaging has a central role in detection and characterization of liver masses as benign or malignant. Benign FNH-like masses are commonly encountered; however, these can display atypical features and be mistaken for hepatocellular carcinoma (HCC). Fontan patients are at elevated risk for HCC, which is a feared complication and has a poor prognosis in this population. While imaging screening for HCC is widely advocated, no consensus has been reached regarding an optimal surveillance regimen.

ImportanceParkinsonism and Parkinson disease (PD) are known to result from repetitive head impacts from boxing. Repetitive head impacts from American football may also be associated with increased risk of neurodegenerative pathologies that cause parkinsonism, yet in vivo research on the association between football play and PD is scarce and limited by small samples and equivocal findings.ObjectiveTo evaluate the association between football participation and self-reported parkinsonism or PD diagnosis.Design, Setting, and ParticipantsThis cross-sectional study leveraged data from the online Fox Insight study. Participants completed online questionnaires and self-reported whether they currently had a diagnosis of Parkinson disease or parkinsonism by a physician or other health care professional. In November 2020, the Boston University Head Impact Exposure Assessment was launched for data collection on repetitive head impacts. Data used for this manuscript were obtained from the Fox Insight database on June 9, 2022. A total of 1875 men who endorsed playing any organized sport were included. Former athletes were divided into those who participated in football (n = 729 [38.9%]) and those who participated in other sports (reference group).ExposuresSelf-reported participation in football, duration and level of football play, age at first exposure.Main Outcomes and MeasuresLogistic regression tested associations between PD status and history of football play, duration of football play, highest level played, and age at first exposure, controlling for age, education, history of diabetes or heart disease, body mass index, history of traumatic brain injury with loss of consciousness, and family history of PD.ResultsIn this sample of 1875 men (mean [SD] age, 67.69 [9.84] years) enriched for parkinsonism or PD (n = 1602 [85.4%]), 729 (38.9%) played football (mean [SD] duration, 4.35 [2.91] years). History of playing football was associated with higher odds of having a parkinsonism or PD diagnosis (odds ratio [OR], 1.61; 95% CI, 1.19-2.17). Among the entire sample, longer duration of play was associated with higher odds of having a parkinsonism or PD diagnosis (OR, 1.12; 95% CI, 1.06-1.19). Among football players, longer duration of football play (OR, 1.12; 95% CI, 1.02-1.23) and higher level of play (OR, 2.93; 95% CI, 1.28-6.73) were associated with higher odds of having parkinsonism or PD.Conclusions and RelevanceIn this cross-sectional study of participants enriched for PD, participation in football was associated with higher odds of having a reported parkinsonism or PD diagnosis.

AbstractIntroduction/PurposePercutaneous core‐needle biopsy of the testicle has been shown to be a safe and effective method of obtaining tissue for histological analysis and can be considered in specific clinical scenarios. While the use of spermatic cord block has been shown to be effective in pain relief in the emergent setting and as an anaesthetic option for inguinal surgery, its use in percutaneous core‐needle biopsy has not been well described. Through this case series, we present our experience and technique of ultrasound‐guided percutaneous core‐needle biopsy using spermatic cord block in the setting of indeterminant testicular masses.MethodsOur departmental biopsy database was reviewed to identify patients who underwent percutaneous core‐needle biopsy of the testicle from March 2010 to July 2022 and who also received spermatic cord block during the procedure.ResultsThree patients were identified who met the search criteria. All three patients presented for the evaluation of indeterminant testicular mass and had a known non‐testicular primary cancer diagnosis at the time of biopsy. All three biopsies were performed using a combination of spermatic cord block, moderate sedation, and local anaesthetic. Biopsies were obtained using an 18‐gauge spring‐loaded device with 4‐5 core samples obtained during each procedure. All biopsies were well tolerated without significant pain or post‐procedure complications.DiscussionUltrasound‐guided percutaneous core‐needle testicular biopsy using spermatic cord block is a safe and effective option in sampling indeterminate testicular masses while maintaining patient comfort.ConclusionThe inclusion of a spermatic cord block in combination with local anaesthetic and moderate sedation has become standard practice in our institution, as we believe this maximises patient comfort and safety resulting in a better patient experience.

AbstractObjectiveVisual assessment of magnetic resonance imaging (MRI) from the Human Epilepsy Project 1 (HEP1) found 18% of participants had atrophic brain changes relative to age without known etiology. Here, we identify the underlying factors related to brain volume differences in people with focal epilepsy enrolled in HEP1.MethodsEnrollment data for participants with complete records and brain MRIs were analyzed, including 391 participants aged 12–60 years. HEP1 excluded developmental or cognitive delay with intelligence quotient <70, and participants reported any formal learning disability diagnoses, repeated grades, and remediation. Prediagnostic seizures were quantified by semiology, frequency, and duration. T1‐weighted brain MRIs were analyzed using Sequence Adaptive Multimodal Segmentation (FreeSurfer v7.2), from which a brain tissue volume to intracranial volume ratio was derived and compared to clinically relevant participant characteristics.ResultsBrain tissue volume changes observable on visual analyses were quantified, and a brain tissue volume to intracranial volume ratio was derived to compare with clinically relevant variables. Learning difficulties were associated with decreased brain tissue volume to intracranial volume, with a ratio reduction of .005 for each learning difficulty reported (95% confidence interval [CI] = −.007 to −.002, p = .0003). Each 10‐year increase in age at MRI was associated with a ratio reduction of .006 (95% CI = −.007 to −.005, p < .0001). For male participants, the ratio was .011 less than for female participants (95% CI = −.014 to −.007, p < .0001). There were no effects from seizures, employment, education, seizure semiology, or temporal lobe electroencephalographic abnormalities.SignificanceThis study shows lower brain tissue volume to intracranial volume in people with newly treated focal epilepsy and learning difficulties, suggesting developmental factors are an important marker of brain pathology related to neuroanatomical changes in focal epilepsy. Like the general population, there were also independent associations between brain volume, age, and sex in the study population.

Abstract Objective . UNet-based deep-learning (DL) architectures are promising dose engines for traditional linear accelerator (Linac) models. Current UNet-based engines, however, were designed differently with various strategies, making it challenging to fairly compare the results from different studies. The objective of this study is to thoroughly evaluate the performance of UNet-based models on magnetic-resonance (MR)-Linac-based intensity-modulated radiation therapy (IMRT) dose calculations. Approach . The UNet-based models, including the standard-UNet, cascaded-UNet, dense-dilated-UNet, residual-UNet, HD-UNet, and attention-aware-UNet, were implemented. The model input is patient CT and IMRT field dose in water, and the output is patient dose calculated by DL model. The reference dose was calculated by the Monaco Monte Carlo module. Twenty training and ten test cases of prostate patients were included. The accuracy of the DL-calculated doses was measured using gamma analysis, and the calculation efficiency was evaluated by inference time. Results . All the studied models effectively corrected low-accuracy doses in water to high-accuracy patient doses in a magnetic field. The gamma passing rates between reference and DL-calculated doses were over 86% (1%/1 mm), 98% (2%/2 mm), and 99% (3%/3 mm) for all the models. The inference times ranged from 0.03 (graphics processing unit) to 7.5 (central processing unit) seconds. Each model demonstrated different strengths in calculation accuracy and efficiency; Res-UNet achieved the highest accuracy, HD-UNet offered high accuracy with the fewest parameters but the longest inference, dense-dilated-UNet was consistently accurate regardless of model levels, standard-UNet had the shortest inference but relatively lower accuracy, and the others showed average performance. Therefore, the best-performing model would depend on the specific clinical needs and available computational resources. Significance . The feasibility of using common UNet-based models for MR-Linac-based dose calculations has been explored in this study. By using the same model input type, patient training data, and computing environment, a fair assessment of the models’ performance was present.

Krabbe disease (KD) is a progressive and devasting neurological disorder that leads to the toxic accumulation of psychosine in the white matter of the central nervous system (CNS). The condition is inherited via biallelic, loss-of-function mutations in the galactosylceramidase (GALC) gene. To rescue GALC gene function in the CNS of the twitcher mouse model of KD, an adeno-associated virus serotype 1 vector expressing murine GALC under control of a chicken β-actin promoter (AAV1-GALC) was administered to newborn mice by unilateral intracerebroventricular injection. AAV1-GALC treatment significantly improved body weight gain and survival of the twitcher mice (n = 8) when compared with untreated controls (n = 5). The maximum weight gain after postnatal day 10 was significantly increased from 81% to 217%. The median lifespan was extended from 43 days to 78 days (range: 74–88 days) in the AAV1-GALC-treated group. Widespread expression of GALC protein and alleviation of KD neuropathology were detected in the CNS of the treated mice when examined at the moribund stage. Functionally, elevated levels of psychosine were completely normalized in the forebrain region of the treated mice. In the posterior region, which includes the mid- and the hindbrain, psychosine was reduced by an average of 77% (range: 53–93%) compared to the controls. Notably, psychosine levels in this region were inversely correlated with body weight and lifespan of AAV1-GALC-treated mice, suggesting that the degree of viral transduction of posterior brain regions following ventricular injection determined treatment efficacy on growth and survivability, respectively. Overall, our results suggest that viral vector delivery via the cerebroventricular system can partially correct psychosine accumulation in brain that leads to slower disease progression in KD.

Abstract Objectives We investigated coronavirus disease 2019 (COVID-19) vaccine safety in pregnant and breastfeeding women with autoimmune diseases (AID) in the COVID-19 Vaccination in Autoimmune Diseases (COVAD) study. Methods Delayed-onset (&gt;7 days) vaccine-related adverse events (AE), disease flares and AID-related treatment modifications were analysed upon diagnosis of AID vs healthy controls (HC) and the pregnancy/breastfeeding status at the time of at least one dose of vaccine. Results Among the 9201 participants to the self-administered online survey, 6787 (73.8%) were women. Forty pregnant and 52 breastfeeding patients with AID were identified, of whom the majority had received at least one dose of COVID-19 vaccine (100% and 96.2%, respectively). AE were reported significantly more frequently in pregnant than in non-pregnant patients (overall AE 45% vs 26%, P = 0.01; minor AE 40% vs 25.9%, P = 0.03; major AE 17.5% vs 4.6%, P &lt; 0.01), but no difference was found in comparison with pregnant HC. No difference was observed between breastfeeding patients and HC with respect to AE. Post-vaccination disease flares were reported by 17.5% of pregnant and 20% of breastfeeding patients, and by 18.3% of age- and disease-matched non-pregnant and non-breastfeeding patients (n = 262). All pregnant/breastfeeding patients who experienced a disease flare were managed with glucocorticoids; 28.6% and 20% of them required initiation or change in immunosuppressants, respectively. Conclusion This study provides reassuring insights into the safety of COVID-19 vaccines administered to women with AID during the gestational and post-partum periods, helping overcome hesitant attitudes, as the benefits for the mother and for the fetus by passive immunization appear to outweigh potential risks.