Chronic Liver Enzyme Elevation and Use of Contemporary ARVs Among People With HIV.

Background: While use of some older antiretroviral drugs (ARVs) is associated with chronic liver enzyme elevation (cLEE), the impact of newer ARVs remains unknown. Methods: People with HIV enrolled in the RESPOND cohort who started an ARV after January 1, 2012 were included (baseline). The primary outcome was first cLEE individuals were censored at first of cLEE, last visit, death, or December 31, 2021. Incidence rates (IRs; events/1000 person-years) were calculated for each ARV overall and by ARV exposure (6-12 months, 1-2 years, and 2+ years). Poisson regression was used to estimate the incidence rate ratio (IRR) of cLEE and its association with individual ARVs and ARV class. Results: Of 17 106 individuals included contributing 87 924 person-years of follow-up, 1932 (11.3%) experienced cLEE (incidence rate [IR], 22.0; 95% CI, 21.0-23.0). There was no evidence of a cumulative ARV effect on cLEE incidence, (6-12 months: IR, 45.8; 95% CI, 41.4-50.19; 1-2 years: IR, 34.3; 95% CI, 31.5-37.4; and 2+ years: IR, 18.5; 95% CI, 17.4-19.7). Any use (vs no prior use) of non-nucleoside reverse transcriptase inhibitors (NNRTIs) as a class and tenofovir disoproxil fumarate (TDF) was independently associated with an increased IRR of cLEE, and any use of darunavir (DRV) was associated with a decreased risk of cLEE. Conclusions: cLEE is common and more frequent during the first year after initiating new ARVs. With a >5-year median follow-up, we found no short-term liver safety concerns with the use of INSTIs. Use of NNRTIs and TDF was associated with an increased cLEE risk, while DRV was associated with lower risk.

MRI for Differentiation between HPV-Positive and HPV-Negative Oropharyngeal Squamous Cell Carcinoma: A Systematic Review.

Human papillomavirus (HPV) is an important risk factor for oropharyngeal squamous cell carcinoma (OPSCC). HPV-positive (HPV+) cases are associated with a different pathophysiology, microstructure, and prognosis compared to HPV-negative (HPV-) cases. This review aimed to investigate the potential of magnetic resonance imaging (MRI) to discriminate between HPV+ and HPV- tumours and predict HPV status in OPSCC patients. A systematic literature search was performed on 15 December 2022 on EMBASE, MEDLINE ALL, Web of Science, and Cochrane according to PRISMA guidelines. Twenty-eight studies (n = 2634 patients) were included. Five, nineteen, and seven studies investigated structural MRI (e.g., T1, T2-weighted), diffusion-weighted MRI, and other sequences, respectively. Three out of four studies found that HPV+ tumours were significantly smaller in size, and their lymph node metastases were more cystic in structure than HPV- ones. Eleven out of thirteen studies found that the mean apparent diffusion coefficient was significantly higher in HPV- than HPV+ primary tumours. Other sequences need further investigation. Fourteen studies used MRI to predict HPV status using clinical, radiological, and radiomics features. The reported areas under the curve (AUC) values ranged between 0.697 and 0.944. MRI can potentially be used to find differences between HPV+ and HPV- OPSCC patients and predict HPV status with reasonable accuracy. Larger studies with external model validation using independent datasets are needed before clinical implementation.

Real-world evidence of survival benefit of remdesivir: study of 419 propensity score-matched patients hospitalized over the alpha and delta waves of COVID-19 in New Orleans, LA.

Background: The direct acting antiviral remdesivir (RDV) has shown promising results in randomized clinical trials. This study is a unique report of real clinical practice RDV administration for COVID-19 from alpha through delta variant circulation in New Orleans, Louisiana (NOLA). Patients in NOLA have among US worst pre-COVID health outcomes, and the region was an early epicenter for severe COVID. Methods: Data were directly extracted from electronic medical records through REACHnet. Of 9,106 adults with COVID, 1,928 were admitted to inpatient care within 7 days of diagnosis. The propensity score is based upon 22 selected covariates, related to both RDV assignment and outcome of interest. RDV and non-RDV patients were matched 1:1 with replacement, by location and calendar period of admission. Primary and secondary endpoints were, death from any cause and inpatient discharge, within 28 and 14 days after inpatient admission. Results: Of 448 patients treated with RDV, 419 (94%) were successfully matched to a non-RDV patient. 145 (35%) patients received RDV for < 5 days, 235 (56%) for 5 days, and 39 (9%) for > 5 days. 96% of those on RDV received it within 2 days of admission. RDV was more frequently prescribed in patients with pneumonia (standardized difference: 0.75), respiratory failure, hypoxemia, or dependence on supplemental oxygen (0.69), and obesity (0.35) within 5 days prior to RDV initiation or corresponding day in non-RDV patients (index day). RDV patients were numerically more likely to be on steroids within 5 days prior to index day (86 vs. 82%) and within 7 days after inpatient admission (96 vs. 87%). RDV was significantly associated with lower risk of death within 14 days after admission (hazard ratio [HR]: 0.37, 95% CI: 0.19 to 0.69, p = 0.002) but not within 28 days (HR: 0.62, 95% CI: 0.36 to 1.07, p = 0.08). Discharge within 14 days of admission was significantly more likely for RDV patients (p < 0.001) and numerically more likely within 28 days after admission (p = 0.06). Conclusion: Overall, our findings support recommendation of RDV administration for COVID-19 in a highly comorbid, highly impoverished population representative of both Black and White subjects in the US Gulf South.

Real-World Use of Hypofractionated Radiotherapy for Primary CNS Tumors in the Elderly, and Implications on Medicare Spending.

BACKGROUND: For elderly patients with high-grade gliomas, 3-week hypofractionated radiotherapy (HFRT) is noninferior to standard long-course radiotherapy (LCRT). We analyzed real-world utilization of HFRT with and without systemic therapy in Medicare beneficiaries treated with RT for primary central nervous system (CNS) tumors using Centers for Medicare & Medicaid Services data. METHODS: Radiation modality, year, age (65-74, 75-84, or ≥85 years), and site of care (freestanding vs hospital-affiliated) were evaluated. Utilization of HFRT (11-20 fractions) versus LCRT (21-30 or 31-40 fractions) and systemic therapy was evaluated by multivariable logistic regression. Medicare spending over the 90-day episode after RT planning initiation was analyzed using multivariable linear regression. RESULTS: From 2015 to 2019, a total of 10,702 RT courses (ie, episodes) were included (28% HFRT; 65% of patients aged 65-74 years). A considerable minority died within 90 days of RT planning initiation (n=1,251; 12%), and 765 (61%) of those received HFRT. HFRT utilization increased (24% in 2015 to 31% in 2019; odds ratio [OR], 1.2 per year; 95% CI, 1.1-1.2) and was associated with older age (≥85 vs 65-74 years; OR, 6.8; 95% CI, 5.5-8.4), death within 90 days of RT planning initiation (OR, 5.0; 95% CI, 4.4-5.8), hospital-affiliated sites (OR, 1.4; 95% CI, 1.3-1.6), conventional external-beam RT (vs intensity-modulated RT; OR, 2.7; 95% CI, 2.3-3.1), and no systemic therapy (OR, 1.2; 95% CI, 1.1-1.3; P<.001 for all). Increasing use of HFRT was concentrated in hospital-affiliated sites (P=.002 for interaction). Most patients (69%) received systemic therapy with no differences by site of care (P=.12). Systemic therapy utilization increased (67% in 2015 to 71% in 2019; OR, 1.1 per year; 95% CI, 1.0-1.1) and was less likely for older patients, patients who died within 90 days of RT planning initiation, those who received conventional external-beam RT, and those who received HFRT. HFRT significantly reduced spending compared with LCRT (adjusted ß for LCRT = +$8,649; 95% CI, $8,544-$8,755), whereas spending modestly increased with systemic therapy (adjusted ß for systemic therapy = +$270; 95% CI, $176-$365). CONCLUSIONS: Although most Medicare beneficiaries received LCRT for primary brain tumors, HFRT utilization increased in hospital-affiliated centers. Despite high-level evidence for elderly patients, discrepancy in HFRT implementation by site of care persists. Further investigation is needed to understand why patients with short survival may still receive LCRT, because this has major quality-of-life and Medicare spending implications.

An Analysis of Positron Emission Tomography Maximum Standard Uptake Value Among Patients With Head and Neck Cancer Receiving Photon and Proton Radiation.

PURPOSE: One main advantage of proton therapy versus photon therapy is its precise radiation delivery to targets without exit dose, resulting in lower dose to surrounding healthy tissues. This is critical, given the proximity of head and neck tumors to normal structures. However, proton planning requires careful consideration of factors, including air-tissue interface, anatomic uncertainties, surgical artifacts, weight fluctuations, rapid tumor response, and daily variations in setup and anatomy, as these heterogeneities can lead to inaccuracies in targeting and creating unwarranted hotspots to a greater extent than photon radiation. In addition, the elevated relative biological effectiveness at the Bragg peak's distal end can also increase hot spots within and outside the target area. METHODS AND MATERIALS: The purpose of this study was to evaluate for a difference in positron emission tomography (PET) standard uptake value (SUV) after definitive treatment, between intensity modulated proton therapy (IMPT) and intensity modulated photon therapy (IMRT). In addition, we compared the biologic dose between PET areas of high and low uptake within the clinical target volume-primary of patients treated with IMPT. This work is assuming that the greater SUV may potentially result in greater toxicities. For the purposes of this short communication, we are strictly focusing on the SUV and do not have correlation with toxicity outcomes. To accomplish this, we compared the 3- and 6-month posttreatment fluorodeoxyglucose PET scans for 100 matched patients with oropharyngeal cancer treated definitively without surgery using either IMPT (n = 50) or IMRT (n = 50). RESULTS: Our study found a significant difference in biologic dose between the high- and low-uptake regions on 3-month posttreatment scans of IMPT. However, this difference did not translate to a significant difference in PET uptake in the clinical target volume-primary at 3 and 6 months' follow-up between patients who received IMPT versus IMRT. CONCLUSIONS: Studies have proposed that proton's greater relative biological effectiveness at the Bragg peak could lead to tissue inflammation. Our study did not corroborate these findings. This study's conclusion underscores the need for further investigations with ultimate correlation with clinical toxicity outcomes.

Clinical Experience With an Offline Adaptive Radiation Therapy Head and Neck Program: Dosimetric Benefits and Opportunities for Patient Selection.

PURPOSE: The objective of this study was to develop a linear accelerator (LINAC)-based adaptive radiation therapy (ART) workflow for the head and neck that is informed by automated image tracking to identify major anatomic changes warranting adaptation. In this study, we report our initial clinical experience with the program and an investigation into potential trigger signals for ART. METHODS AND MATERIALS: Offline ART was systematically performed on patients receiving radiation therapy for head and neck cancer on C-arm LINACs. Adaptations were performed at a single time point during treatment with resimulation approximately 3 weeks into treatment. Throughout treatment, all patients were tracked using an automated image tracking system called the Automated Watchdog for Adaptive Radiotherapy Environment (AWARE). AWARE measures volumetric changes in gross tumor volumes (GTVs) and selected normal tissues via cone beam computed tomography scans and deformable registration. The benefit of ART was determined by comparing adaptive plan dosimetry and normal tissue complication probabilities against the initial plans recalculated on resimulation computed tomography scans. Dosimetric differences were then correlated with AWARE-measured volume changes to identify patient-specific triggers for ART. Candidate trigger variables were evaluated using receiver operator characteristic analysis. RESULTS: In total, 46 patients received ART in this study. Among these patients, we observed a significant decrease in dose to the submandibular glands (mean ± standard deviation: -219.2 ± 291.2 cGy, P < 10-5), parotids (-68.2 ± 197.7 cGy, P = .001), and oral cavity (-238.7 ± 206.7 cGy, P < 10-5) with the adaptive plan. Normal tissue complication probabilities for xerostomia computed from mean parotid doses also decreased significantly with the adaptive plans (P = .008). We also observed systematic intratreatment volume reductions (ΔV) for GTVs and normal tissues. Candidate triggers were identified that predicted significant improvement with ART, including parotid ΔV = 7%, neck ΔV = 2%, and nodal GTV ΔV = 29%. CONCLUSIONS: Systematic offline head and neck ART was successfully deployed on conventional LINACs and reduced doses to critical salivary structures and the oral cavity. Automated cone beam computed tomography tracking provided information regarding anatomic changes that may aid patient-specific triggering for ART.

The molecular machinery of meiotic recombination.

Meiotic recombination, a cornerstone of eukaryotic diversity and individual genetic identity, is essential for the creation of physical linkages between homologous chromosomes, facilitating their faithful segregation during meiosis I. This process requires that germ cells generate controlled DNA lesions within their own genome that are subsequently repaired in a specialised manner. Repair of these DNA breaks involves the modulation of existing homologous recombination repair pathways to generate crossovers between homologous chromosomes. Decades of genetic and cytological studies have identified a multitude of factors that are involved in meiotic recombination. Recent work has started to provide additional mechanistic insights into how these factors interact with one another, with DNA, and provide the molecular outcomes required for a successful meiosis. Here, we provide a review of the recent developments with a focus on protein structures and protein-protein interactions.

Feasibility of Prospective Assignment of Initial Method of Detection of Breast Cancer: A Multicenter Pilot Study.

OBJECTIVE: To determine the feasibility of standardized, prospective assignment of initial method of detection (MOD) of breast cancer by radiologists in diverse practice settings. METHODS: This multicenter, retrospective study analyzed the rate of assignment of MOD in four geographically varied health systems. A universal protocol for basic MOD assignment was agreed upon by the authors before start of the pilot study. Radiologists at each site were instructed how to assign MOD. Charts were then reviewed to determine the frequency and accuracy of MOD assignment for all cases subsequently diagnosed with breast cancer. When available, data regarding frequency of tumor registry abstraction were also reviewed for frequency and accuracy. RESULTS: A total of 2,328 patients with a new diagnosis of breast cancer were evaluated across the sites over the study period. Of these patients, initial MOD was prospectively assigned by the radiologist in 94% of cases. Of the cases in which MOD was assigned, retrospective review confirmed accurate assignment in 96% of cases. CONCLUSIONS: Prospective, standardized assignment of initial MOD of breast cancer is feasible across different practice sites and can be accurately captured in tumor registries. Standard collection of MOD would provide critical data about the impact of screening mammography in the United States.

Hypoxia-Directed Treatment of Human Papillomavirus-Related Oropharyngeal Carcinoma.

PURPOSE: Standard curative-intent chemoradiotherapy for human papillomavirus (HPV)-related oropharyngeal carcinoma results in significant toxicity. Since hypoxic tumors are radioresistant, we posited that the aerobic state of a tumor could identify patients eligible for de-escalation of chemoradiotherapy while maintaining treatment efficacy. METHODS: We enrolled patients with HPV-related oropharyngeal carcinoma to receive de-escalated definitive chemoradiotherapy in a phase II study (ClinicalTrials.gov identifier: NCT03323463). Patients first underwent surgical removal of disease at their primary site, but not of gross disease in the neck. A baseline 18F-fluoromisonidazole positron emission tomography scan was used to measure tumor hypoxia and was repeated 1-2 weeks intratreatment. Patients with nonhypoxic tumors received 30 Gy (3 weeks) with chemotherapy, whereas those with hypoxic tumors received standard chemoradiotherapy to 70 Gy (7 weeks). The primary objective was achieving a 2-year locoregional control (LRC) of 95% with a 7% noninferiority margin. RESULTS: One hundred fifty-eight patients with T0-2/N1-N2c were enrolled, of which 152 patients were eligible for analyses. Of these, 128 patients met criteria for 30 Gy and 24 patients received 70 Gy. The 2-year LRC was 94.7% (95% CI, 89.8 to 97.7), meeting our primary objective. With a median follow-up time of 38.3 (range, 22.1-58.4) months, the 2-year progression-free survival (PFS) and overall survival (OS) rates were 94% and 100%, respectively, for the 30-Gy cohort. The 70-Gy cohort had similar 2-year PFS and OS rates at 96% and 96%, respectively. Acute grade 3-4 adverse events were more common in 70 Gy versus 30 Gy (58.3% v 32%; P = .02). Late grade 3-4 adverse events only occurred in the 70-Gy cohort, in which 4.5% complained of late dysphagia. CONCLUSION: Tumor hypoxia is a promising approach to direct dosing of curative-intent chemoradiotherapy for HPV-related carcinomas with preserved efficacy and substantially reduced toxicity that requires further investigation.

Validation of a deep-learning segmentation model for adult and pediatric head and neck radiotherapy in different patient positions.

Background and purpose: Autocontouring for radiotherapy has the potential to significantly save time and reduce interobserver variability. We aimed to assess the performance of a commercial autocontouring model for head and neck (H&N) patients in eight orientations relevant to particle therapy with fixed beam lines, focusing on validation and implementation for routine clinical use. Materials and methods: Autocontouring was performed on sixteen organs at risk (OARs) for 98 adult and pediatric patients with 137 H&N CT scans in eight orientations. A geometric comparison of the autocontours and manual segmentations was performed using the Hausdorff Distance 95th percentile, Dice Similarity Coefficient (DSC) and surface DSC and compared to interobserver variability where available. Additional qualitative scoring and dose-volume-histogram (DVH) parameters analyses were performed for twenty patients in two positions, consisting of scoring on a 0-3 scale based on clinical usability and comparing the mean (Dmean) and near-maximum (D2%) dose, respectively. Results: For the geometric analysis, the model performance in head-first-supine straight and hyperextended orientations was in the same range as the interobserver variability. HD95, DSC and surface DSC was heterogeneous in other orientations. No significant geometric differences were found between pediatric and adult autocontours. The qualitative scoring yielded a median score of ≥ 2 for 13/16 OARs while 7/32 DVH parameters were significantly different. Conclusions: For head-first-supine straight and hyperextended scans, we found that 13/16 OAR autocontours were suited for use in daily clinical practice and subsequently implemented. Further development is needed for other patient orientations before implementation.

An ESCRT grommet cooperates with a diffusion barrier to maintain nuclear integrity.

The molecular mechanisms by which the endosomal sorting complexes required for transport (ESCRT) proteins contribute to the integrity of the nuclear envelope (NE) barrier are not fully defined. We leveraged the single NE hole generated by mitotic extrusion of the Schizosaccharomyces pombe spindle pole body to reveal two modes of ESCRT function executed by distinct complements of ESCRT-III proteins, both dependent on CHMP7/Cmp7. A grommet-like function is required to restrict the NE hole in anaphase B, whereas replacement of Cmp7 by a sealing module ultimately closes the NE in interphase. Without Cmp7, nucleocytoplasmic compartmentalization remains intact despite NE discontinuities of up to 540 nm, suggesting mechanisms to limit diffusion through these holes. We implicate spindle pole body proteins as key components of a diffusion barrier acting with Cmp7 in anaphase B. Thus, NE remodelling mechanisms cooperate with proteinaceous diffusion barriers beyond nuclear pore complexes to maintain the nuclear compartment.

Stem cell-like T cell depletion in the recurrent head and neck cancer immune microenvironment.

Human papilloma virus (HPV)-related oncogenesis in head and neck cancer establishes a local microenvironment rich with immune cells, however the composition of the microenvironment in recurrent disease following definitive treatment is poorly understood. Here, we investigate the composition and spatial relationships between tumor and immune cells in recurrent head and neck cancer following curative intent chemoradiotherapy. Multiplexed immunofluorescence with 12 unique markers, through two multiplex immunofluorescent panels, was performed to evaluate 27 tumor samples including 18 pre-treatment primary and 9 paired recurrent tumors. Tumor and immune cell populations were phenotyped and quantified using a previously validated semi-automated digital pathology platform for cell segmentation. Spatial analysis was conducted by evaluating immune cells within the tumor, peri-tumoral stroma, and distant stroma. Initial tumors in patients with subsequent recurrence were found to be enriched in tumor associated macrophages and displayed an immune excluded spatial distribution. Recurrent tumors after chemoradiation were hypo-inflamed, with a statistically significant reduction in the recently identified stem-like TCF1+ CD8 T-cells, which normally function to maintain HPV-specific immune responses in the setting of chronic antigen exposure. Our findings indicate that the tumor microenvironment of recurrent HPV-related head and neck cancers displays a reduction in stem-like T cells, consistent with an immune microenvironment with a reduced ability to mount T-cell-driven anti-tumor immune responses.

SARS-CoV-2 post-acute sequelae in previously hospitalised patients: systematic literature review and meta-analysis.

BACKGROUND: Many individuals hospitalised with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection experience post-acute sequelae of SARS-CoV-2 infection (PASC), sometimes referred to as "long COVID". Our objective was to conduct a systematic literature review and meta-analysis to identify PASC-associated symptoms in previously hospitalised patients and determine the frequency and temporal nature of PASC. METHODS: Searches of MEDLINE, Embase, Cochrane Library (2019-2021), World Health Organization International Clinical Trials Registry Platform and reference lists were performed from November to December 2021. Articles were assessed by two reviewers against eligibility criteria and a risk of bias tool. Symptom data were synthesised by random effects meta-analyses. RESULTS: Of 6942 records, 52 studies with at least 100 patients were analysed; ∼70% were Europe-based studies. Most data were from the first wave of the pandemic. PASC symptoms were analysed from 28 days after hospital discharge. At 1-4 months post-acute SARS-CoV-2 infection, the most frequent individual symptoms were fatigue (29.3% (95% CI 20.1-40.6%)) and dyspnoea (19.6% (95% CI 12.8-28.7%)). Many patients experienced at least one symptom at 4-8 months (73.1% (95% CI 44.2-90.3%)) and 8-12 months (75.0% (95% CI 56.4-87.4%)). CONCLUSIONS: A wide spectrum of persistent PASC-associated symptoms were reported over the 1-year follow-up period in a significant proportion of participants. Further research is needed to better define PASC duration and determine whether factors such as disease severity, vaccination and treatments have an impact on PASC.

Concurrent carboplatin and paclitaxel definitive radiation therapy for locally advanced head and neck cancer.

BACKGROUND: We report the outcomes of cisplatin-ineligible HNSCC patients treated with definitive chemoradiation and concurrent carboplatin and paclitaxel. MATERIALS AND METHODS: We included consecutive HNSCC patients treated from 2013 to 2021 that received definitive chemoradiation with carboplatin and paclitaxel. Locoregional recurrences (LRR) and distant metastases (DM) were estimated using cumulative incidence functions. Progression free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier methods. RESULTS: Sixty-five patients were identified with median age of 71 years (range 44-85). Median radiation dose was 70 Gy and the median doses of carboplatin and paclitaxel were AUC 1 and 40 mg/m2 , respectively. At a median follow-up of 29 (range 5-91) months, the 2-year rates of LRR, DM, PFS, and OS were 8.8%, 9.4%, 72.2%, and 88.7%, respectively. In total, there were 5 LRR, 7 DM, and 12 deaths. CONCLUSIONS: Chemoradiation with carboplatin and paclitaxel is an excellent option for cisplatin-ineligible HNSCC patients.

Use of eye-tracking to evaluate human factors in accessing neonatal resuscitation equipment and medications for advanced resuscitation: A simulation study.

Introduction: Emergency neonatal resuscitation equipment is often organized into "code carts". Simulation studies previously examined human factors of neonatal code carts and equipment; however, visual attention analysis with eye-tracking might further inform equipment design. Objectives: To evaluate human factors of neonatal resuscitation equipment by: (1) comparing epinephrine preparation speed from adult pre-filled syringe vs. medication vial, (2) comparing equipment retrieval times from two carts and (3) utilizing eye-tracking to study visual attention and user experience. Methods: We conducted a 2-site randomized cross-over simulation study. Site 1 is a perinatal NICU with carts focused on airway management. Site 2 is a surgical NICU with carts improved with compartments and task-based kits. Participants were fitted with eye-tracking glasses then randomized to prepare two epinephrine doses using two methods, starting with an adult epinephrine prefilled syringe or a multiple access vial. Participants then obtained items for 7 tasks from their local cart. Post-simulation, participants completed surveys and semi-structured interviews while viewing eye-tracked video of their performance. Epinephrine preparation times were compared between the two methods. Equipment retrieval times and survey responses were compared between sites. Eye-tracking was analyzed for areas of interest (AOIs) and gaze shifts between AOIs. Interviews were subject to thematic analysis. Results: Forty HCPs participated (20/site). It was faster to draw the first epinephrine dose using the medication vial (29.9s vs. 47.6s, p < 0.001). Time to draw the second dose was similar (21.2s vs. 19s, p = 0.563). It was faster to obtain equipment from the Perinatal cart (164.4s v 228.9s, p < 0.027). Participants at both sites found their carts easy to use. Participants looked at many AOIs (54 for Perinatal vs. 76 for Surgical carts, p < 0.001) with 1 gaze shifts/second for both.Themes for epinephrine preparation include: Facilitators and Threats to Performance, and Discrepancies due to Stimulation Conditions. Themes for code carts include: Facilitators and Threats to Performance, Orienting with Prescan, and Suggestions for Improvement. Suggested cart improvements include: adding prompts, task-based grouping, and positioning small equipment more visibly. Task-based kits were welcomed, but more orientation is needed. Conclusions: Eye-tracked simulations provided human factors assessment of emergency neonatal code carts and epinephrine preparation.

Post-operative PET/CT improves the detection of early recurrence of squamous cell carcinomas of the oral cavity.

BACKGROUND: We evaluate the impact of post-operative 18-fluorodeoxyglucose positron emission tomography with computed tomography (PET/CT) for radiation planning on the detection of early recurrence (ER) and treatment outcomes in oral squamous cell carcinoma (OSCC). METHODS: We retrospectively reviewed the records of patients treated with post-operative radiation between 2005 and 2019 for OSCC at our institution. Extracapsular extension and positive surgical margins were classified as high risk features; pT3-4, node positivity, lymphovascular invasion, perineural invasion, tumor thickness >5 mm, and close surgical margins were considered intermediate risk features. Patients with ER were identified. Inverse probability of treatment weighting (IPTW) was used to adjust for imbalances between baseline characteristics. RESULTS: 391 patients with OSCC were treated with post-operative radiation. 237 (60.6%) patients underwent post-operative PET/CT planning vs. 154 (39.4%) who were planned with CT only. Patients screened with post-operative PET/CT were more likely to be diagnosed with ER than those planned with CT only (16.5 vs. 3.3%, p < 0.0001). Among patients with ER, those with intermediate features were more likely than those high risk features to undergo major treatment intensification, including re-operation, the addition of chemotherapy, or intensification of radiation by ≥ 10 Gy (91% vs. 9%, p < 0.0001). Post-operative PET/CT was associated with improved disease-free and overall survival for patients with intermediate risk features (IPTW log-rank p = 0.026 and p = 0.047, respectively) but not high risk features (IPTW log-rank p = 0.44 and p = 0.96). CONCLUSIONS: Use of post-operative PET/CT is associated with increased detection of early recurrence. Among patients with intermediate risk features, this may translate to improved disease-free survival.

Investigating the potential added value of [ 18 F]FDG-PET/CT in long COVID patients with persistent symptoms: a proof of concept study.

OBJECTIVE: Since the end of 2019, the coronavirus disease 2019 (COVID-19) virus has infected millions of people, of whom a significant group suffers from sequelae from COVID-19, termed long COVID. As more and more patients emerge with long COVID who have symptoms of fatigue, myalgia and joint pain, we must examine potential biomarkers to find quantifiable parameters to define the underlying mechanisms and enable response monitoring. The aim of this study is to investigate the potential added value of [ 18 F]FDG-PET/computed tomography (CT) for this group of long COVID patients. METHODS: For this proof of concept study, we evaluated [ 18 F]FDG-PET/CT scans of long COVID patients and controls. Two analyses were performed: semi-quantitative analysis using target-to-background ratios (TBRs) in 24 targets and total vascular score (TVS) assessed by two independent nuclear medicine physicians. Mann-Whitney U -test was performed to find significant differences between the two groups. RESULTS: Thirteen patients were included in the long COVID group and 25 patients were included in the control group. No significant differences ( P  < 0.05) were found between the long COVID group and the control group in the TBR or TVS assessment. CONCLUSION: As we found no quantitative difference in the TBR or TVS between long COVID patients and controls, we are unable to prove that [ 18 F]FDG is of added value for long COVID patients with symptoms of myalgia or joint pain. Prospective cohort studies are necessary to understand the underlying mechanisms of long COVID.

Evaluation of Proton Therapy Reirradiation for Patients With Recurrent Head and Neck Squamous Cell Carcinoma.

Importance: Use of proton therapy reirradiation (PT-ReRT) for head and neck cancer is increasing; however, reports are heterogenous and outcomes can be difficult to interpret. Objective: To evaluate outcomes and toxic effects following PT-ReRT in a uniform and consecutive cohort of patients with head and neck squamous cell carcinoma. Design, Setting, and Participants: This retrospective cohort study included patients with recurrent primary head and neck squamous cell carcinoma who were treated with PT-ReRT from January 1, 2013, to December 31, 2020, at a single institution. Patient, clinical, and treatment characteristics were obtained, and multidisciplinary review was performed to record and grade early and late toxic effects. Exposures: Proton therapy reirradiation. Main Outcomes and Measures: Follow-up was defined from the start of PT-ReRT. The Kaplan-Meier method was used for outcomes of interest, including local control (LC), locoregional control, distant metastatic control, progression-free survival, and overall survival (OS). Cox proportional hazards regression modeling was used to assess associations of covariates with OS. Results: A total of 242 patients (median [range] age, 63 [21-96] years; 183 [75.6%] male) were included. Of these patients, 231 (95.9%) had a Karnofsky performance status score of 70 or higher, and 145 (59.9%) had at least a 10-pack-year smoking history. Median (range) follow-up was 12.0 (5.8-26.0) months for all patients and 24.5 (13.8-37.8) months for living patients. A total of 206 patients (85.1%) had recurrent disease vs second primary or residual disease. The median (range) interval between radiation courses was 22 (1-669) months. Median PT-ReRT dose was 70 cobalt gray equivalents (CGE) for the fractionated cohort and 44.4 CGE for the quad shot cohort. For the fractionated cohort, the 1-year LC was 71.8% (95% CI, 62.8%-79.0%) and the 1-year OS was 66.6% (95% CI, 58.1%-73.8%). For the quad shot cohort, the 1-year LC was 61.6% (95% CI, 46.4%-73.6%) and the 1-year OS was 28.5% (95% CI, 19.4%-38.3%). Higher Karnofsky performance status scores (hazard ratio [HR], 0.50; 95% CI, 0.25-0.99; P = .046) and receipt of salvage surgery prior to PT-ReRT (HR, 0.57; 95% CI, 0.39-0.84; P = .005) were associated with improved OS, whereas receipt of quad shot (HR, 1.97; 95% CI, 1.36-2.86; P < .001) was associated with worse OS. There were a total of 73 grade 3 and 6 grade 4 early toxic effects. There were 79 potential grade 3, 4 grade 4, and 5 grade 5 late toxic effects. Conclusions and Relevance: The findings of this cohort study suggest that, compared with previous reports with photon-based reirradiation, patients are living longer with aggressive PT-ReRT; however, surviving patients remain at risk of early and late complications.

Benefit of B7-1 staining and abatacept for treatment-resistant post-transplant focal segmental glomerulosclerosis in a predominantly pediatric cohort: time for a reappraisal.

BACKGROUND: Primary FSGS manifests with nephrotic syndrome and may recur following KT. Failure to respond to conventional therapy after recurrence results in poor outcomes. Evaluation of podocyte B7-1 expression and treatment with abatacept (a B7-1 antagonist) has shown promise but remains controversial. METHODS: From 2012 to 2020, twelve patients developed post-KT FSGS with nephrotic range proteinuria, failed conventional therapy, and were treated with abatacept. Nine/twelve (< 21 years old) experienced recurrent FSGS; three adults developed de novo FSGS, occurring from immediately, up to 8 years after KT. KT biopsies were stained for B7-1. RESULTS: Nine KTRs (75%) responded to abatacept. Seven of nine KTRs were B7-1 positive and responded with improvement/resolution of proteinuria. Two patients with rFSGS without biopsies resolved proteinuria after abatacept. Pre-treatment UPCR was 27.0 ± 20.4 (median 13, range 8-56); follow-up UPCR was 0.8 ± 1.3 (median 0.2, range 0.07-3.9, p < 0.004). Two patients who were B7-1 negative on multiple KT biopsies did not respond to abatacept and lost graft function. One patient developed proteinuria while receiving belatacept, stained B7-1 positive, but did not respond to abatacept. CONCLUSIONS: Podocyte B7-1 staining in biopsies of KTRs with post-transplant FSGS identifies a subset of patients who may benefit from abatacept. A higher resolution version of the Graphical abstract is available as Supplementary information.