EfficientQ: An efficient and accurate post-training neural network quantization method for medical image segmentation.

Model quantization is a promising technique that can simultaneously compress and accelerate a deep neural network by limiting its computation bit-width, which plays a crucial role in the fast-growing AI industry. Despite model quantization's success in producing well-performing low-bit models, the quantization process itself can still be expensive, which may involve a long fine-tuning stage on a large, well-annotated training set. To make the quantization process more efficient in terms of both time and data requirements, this paper proposes a fast and accurate post-training quantization method, namely EfficientQ. We develop this new method with a layer-wise optimization strategy and leverage the powerful alternating direction method of multipliers (ADMM) algorithm to ensure fast convergence. Furthermore, a weight regularization scheme is incorporated to provide more guidance for the optimization of the discrete weights, and a self-adaptive attention mechanism is proposed to combat the class imbalance problem. Extensive comparison and ablation experiments are conducted on two publicly available medical image segmentation datasets, i.e., LiTS and BraTS2020, and the results demonstrate the superiority of the proposed method over various existing post-training quantization methods in terms of both accuracy and optimization speed. Remarkably, with EfficientQ, the quantization of a practical 3D UNet only requires less than 5 min on a single GPU and one data sample. The source code is available at https://github.com/rongzhao-zhang/EfficientQ.

Addition of Metastasis-Directed Therapy to Systemic Therapy for Oligometastatic Pancreatic Ductal Adenocarcinoma (EXTEND): A Multicenter, Randomized Phase II Trial.

PURPOSE: The EXTEND trial tested the hypothesis that adding comprehensive metastasis-directed therapy (MDT) to chemotherapy would improve progression-free survival (PFS) over chemotherapy alone among patients with oligometastatic pancreatic ductal adenocarcinoma (PDAC). METHODS: EXTEND (ClinicalTrials.gov identifier: NCT03599765) is a multicenter, phase II basket trial randomly assigning patients with ≤five metastases 1:1 to MDT plus systemic therapy versus systemic therapy. Disease progression was defined by radiologic criteria (RECIST v1.1), clinical progression, or death. The primary end point was PFS in the per-protocol population, evaluated after all patients achieved at least 6 months of follow-up. Exploratory end points included systemic immune response measures. RESULTS: Between March 19, 2019, and February 13, 2023, 41 patients were randomly assigned and 40 were eligible for the primary analysis of PFS (19 patients in the MDT arm; 21 patients in the control arm). At a median follow-up time of 17 months, the median PFS time was 10.3 months (95% CI, 4.6 to 14.0) in the MDT arm versus 2.5 months (95% CI, 1.7 to 5.1) in the control arm. PFS was significantly improved by the addition of MDT to systemic therapy (P = .030 for stratified log-rank test) with a hazard ratio of 0.43 (95% CI, 0.20 to 0.94). No grade ≥3 or greater adverse events related to MDT were observed. Systemic immune activation events were associated with MDT and correlated with improved PFS. CONCLUSION: This study supports the addition of MDT to systemic therapy for patients with oligometastatic PDAC. Induction of systemic immunity is a possible mechanism of benefit. These results warrant confirmatory trials to refine treatment strategy and provide external validation.

The human CD47 checkpoint is targeted by an immunosuppressive Aedes aegypti salivary factor to enhance arboviral skin infectivity.

The Aedes aegypti mosquito is a vector of many infectious agents, including flaviviruses such as Zika virus. Components of mosquito saliva have pleomorphic effects on the vertebrate host to enhance blood feeding, and these changes also create a favorable niche for pathogen replication and dissemination. Here, we demonstrate that human CD47, which is known to be involved in various immune processes, interacts with a 34-kilodalton mosquito salivary protein named Nest1. Nest1 is up-regulated in blood-fed female A. aegypti and facilitates Zika virus dissemination in human skin explants. Nest1 has a stronger affinity for CD47 than its natural ligand, signal regulatory protein α, competing for binding at the same interface. The interaction between Nest1 with CD47 suppresses phagocytosis by human macrophages and inhibits proinflammatory responses by white blood cells, thereby suppressing antiviral responses in the skin. This interaction elucidates how an arthropod protein alters the human response to promote arbovirus infectivity.

Plasma collagen neoepitopes are associated with multiorgan disease in the ACCESS and GRADS sarcoidosis cohorts.

INTRODUCTION: The pathogenesis of sarcoidosis involves tissue remodelling mediated by the accumulation of abnormal extracellular matrix, which is partly the result of an imbalance in collagen synthesis, cross-linking and degradation. During this process, collagen fragments or neoepitopes, are released into the circulation. The significance of these circulating collagen neoepitopes in sarcoidosis remains unknown. METHODS: We employed plasma samples from patients with sarcoidosis enrolled in A Case Control Etiologic Study of Sarcoidosis (ACCESS) and Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS), and healthy control patients recruited from the Yale community. Plasma concentrations of type III and VI collagen degradation (C3M and C6M) and formation (PRO-C3 and PRO-C6) were quantified via neoepitope-specific competitive ELISA, and statistical associations were sought with clinical phenotypes. RESULTS: Relative to healthy controls, the plasma of both sarcoidosis cohorts was enriched for C3M and C6M, irrespective of corticosteroid use and disease duration. While circulating collagen neoepitopes were independent of Scadding stage, there was a significant association between multiorgan disease and PRO-C3, PRO-C6 and C3M in the ACCESS cohort; PRO-C3 and C6M displayed this property in GRADS. These findings were unrelated to plasma levels of interleukin-4 (IL-4), IL-5, IL-6, IL-9, IL-10 and IL-13. Moreover, PRO-C3 was associated with dermatological disease in both cohorts. DISCUSSION: In two well-characterised sarcoidosis cohorts, we discovered that the plasma is enriched for neoepitopes of collagen degradation (C3M and C6M). In multiorgan disease, there was an association with circulating neoepitopes of type III formation (PRO-C3), perhaps mediated by dermatological sarcoidosis. Further investigation in this arena has the potential to foster new insights into the pathogenic mechanisms of this complex disease.

Shallow conductance decay along the heme array of a single tetraheme protein wire.

Multiheme cytochromes (MHCs) are the building blocks of highly conductive micrometre-long supramolecular wires found in so-called electrical bacteria. Recent studies have revealed that these proteins possess a long supramolecular array of closely packed heme cofactors along the main molecular axis alternating between perpendicular and stacking configurations (TST = T-shaped, stacked, T-shaped). While TST arrays have been identified as the likely electron conduit, the mechanisms of outstanding long-range charge transport observed in these structures remain unknown. Here we study charge transport on individual small tetraheme cytochromes (STCs) containing a single TST heme array. Individual STCs are trapped in a controllable nanoscale tunnelling gap. By modulating the tunnelling gap separation, we are able to selectively probe four different electron pathways involving 1, 2, 3 and 4 heme cofactors, respectively, leading to the determination of the electron tunnelling decay constant along the TST heme motif. Conductance calculations of selected single-STC junctions are in excellent agreement with experiments and suggest a mechanism of electron tunnelling with shallow length decay constant through an individual STC. These results demonstrate that an individual TST motif supporting electron tunnelling might contribute to a tunnelling-assisted charge transport diffusion mechanism in larger TST associations.

Survival Outcomes in Older Adult Acute Lymphoblastic Leukemia Patients Analyzed by Facility Volume and Type: A National Cancer Database Analysis.

BAKGROUND: It is important to understand the outcomes of adult acute lymphoblastic leukemia (ALL) patients at different facilities as treatment paradigms change. AIMS: Our primary objective was to determine adult ALL overall survival (OS) by facility volume and type. Secondary objectives included identifying sociodemographic factors that may have impacted outcomes and analyzing treatment patterns by facility volume and type. METHODS: This was a retrospective analysis of the National Cancer Database (NCDB) that included patients ≥40 years diagnosed with ALL between 2004 and 2016. RESULTS: A total of 14 593 patients were included in this study. Univariate OS was greatest at low volume (LV) and community programs (CPs) and the least at high volume (HV) and academic programs (AP). This difference was lost after multivariable Cox proportional hazards model analysis, which found no difference in survival by facility volume or type, however, survival was significantly influenced by age, race, Hispanic ethnicity, insurance, and residence location (p < 0.05). Patients treated at HV and APs compared to LV and CP received more anti-neoplastic directed therapy. CONCLUSION: Our results suggest treatment facility volume and type do not impact older adult ALL patient (≥40 years) survival, however confounding sociodemographic differences do impact survival outcomes, despite more aggressive and novel treatment approaches provided at HV and APs.

Clinical spreading of muscle weakness in amyotrophic lateral sclerosis (ALS): a study in 910 patients.

BACKGROUND: Neuroanatomical staging of sporadic amyotrophic lateral sclerosis (ALS) indicates that neurodegeneration may spread corticofugally. METHODS: We conducted an observational study to define the initial sites of disease onset and the clinical progression ('spreading patterns') of motor deficits in a cohort of 910 ALS patients in Germany. RESULTS: Mean age of ALS onset was 59.0 ± 12.6 years for males and 61.2 ± 10.5 years for females, the mean ALSFRS-R was 35.1 ± 9.2, and 7.7% of the cohort reported a family history. Onset of motor symptoms was bulbar/upper limb in 26.8%/35.9%, the right arm initially being slightly more often affected than the left (18.5% vs.16.3%). Testing on concordance of handedness and onset in the dominant arm did not reach significance. Lower limb onset was observed in 37.3%. Unilateral limb onset patients reported horizontal spreading about three times more often than vertical spreading. 71/244 bulbar onset patients reported spreading pattern to the legs, and 17/339 lumbar onset patients reported spreading secondarily to the bulbar region. DISCUSSION: Our results indicate that, although the phenotype of so-called 'spinal' or 'intraspinal' spreading predominated, we also observed an additional clinical spreading pattern: 29.1% of patients with bulbar onset experienced spreading clinically to the legs (vice versa in 5.0% of lumbar onset patients). For obvious neuroanatomical reasons, this pattern hardly can be explained solely by a 'spinal' or an 'intraspinal' pattern of spreading. Instead, these findings complement insights from previous clinical and clinicopathological studies supporting a cortical initiation of ALS.

Establishment of regression-based isometric strength reference values for the upper limb in persons with multiple sclerosis.

BACKGROUND: Muscle weakness is common and significantly affects persons with multiple sclerosis (PwMS), with dysfunction in upper limb (UL) muscle groups occurring in approximately 60% of PwMS. OBJECTIVE: To develop gender-specific regression-based prediction equations, with 95% confidence intervals for maximal bilateral UL isometric strength (shoulder abduction and adduction, wrist flexion and extension) and hand grip strength in PwMS. DESIGN: Cross-sectional study. SETTING: Comprehensive MS center. PARTICIPANTS: 256 PwMS. INTERVENTIONS: Not Applicable. MAIN OUTCOME MEASURES: Shoulder abduction and adduction and wrist flexion and extension isometric strength (Biodex System 4 Pro Dynamometer) and hand grip strength (Jamar handheld dynamometer) were measured. Disease characteristics (disability and disease duration) and demographics (age, height, and weight) were collected. Regression-based predictive equations were generated for the UL muscle groups for each gender and limb, using age, height, weight, disability, and disease duration as covariates. Variables were compared between genders using the Mann-Whitney U test. Maximal voluntary contraction (MVC) reference values (mean ± SD) were reported based on age (<30, 30-39, 40-49, 50-59, 60-69 years) and disability (mild, moderate, severe ambulant, and severe nonambulant) for each gender and limb. RESULTS: Regression-based equations were developed for both genders' strongest and weakest limb, accounting for age, height, weight, disability, and disease duration. MVC was higher in men than women (p < .001) in all muscle groups. Overall, MVC was significantly related to age in 14, height in 5, weight in 6, disability in 14, and disease duration in none of the 20 models. CONCLUSION: This is the first study to provide regression-based prediction equations for strongest and weakest MVC of UL muscle groups and demonstrated an inverse relationship between MVC with disability and age. Regression-based reference strength values can help clinicians understand muscular strength along a spectrum of PwMS and can aid in goal setting and education for realistic outcomes.

Clinical and paraclinical features of first unprovoked seizures in the elderly.

PURPOSE: The prevalence of unprovoked seizures and epilepsy rises significantly in later life stages. This study examines various factors in elderly patients (over 65 years) with their first unprovoked seizures, comparing findings with younger patients. METHODS: We analyzed electronic medical records of individuals with first unprovoked seizures retrospectively. Diagnosis was based on patient history and witness accounts, and exclusion of other potential causes. Data included demographics, physical examination, seizure characteristics, neuroimaging, EEG findings, laboratory markers, potential causes, prescribed anti-seizure medications (ASMs) at diagnosis and follow-up, seizure-related injuries and hospital stay length. RESULTS: We enrolled 391 patients (mean age 73.02 ± 16.5, 219 females). Most had late-onset (≥65 years) seizures (n = 295, 75.5 %). Status epilepticus was diagnosed in 10.2 %, more in the late-onset group. Elderly patients most often had focal seizures with impaired consciousness, while younger patients had focal to bilateral tonic-clonic seizures. (55.9 % vs 36.5 %). Late-onset seizures were linked to cerebrovascular diseases, small vessel disease, and cerebral atrophy, while early-onset cases were associated with brain tumors or unknown causes. Brain imaging revealed potentially epileptogenic abnormalities in 59.1 %. Positive paraneoplastic or autoimmune antibodies were found in 0.8 %. Abnormal EEGs were present in 25.9 %, more in the late-onset group. Most patients were discharged with levetiracetam (LEV) or lamotrigine (LTG) monotherapy. Nine patients with late-onset seizures died during in-hospital follow-up. CONCLUSION: Our findings can contribute to the improved identification and characterization of patients with late-onset seizures, facilitating targeted diagnostics and appropriate treatment in this challenging patient population.

Association between high-density mapping of atypical atrial flutter, clinical outcomes and healthcare utilization.

BACKGROUND: Success of atypical atrial flutter (AAFL) ablation has historically been limited by difficulty mapping the complex re-entrant circuits involved. While high-density (HD) mapping has become commonplace in clinical practice, there are limited data on outcomes of HD versus non-HD mapping for AAFL ablation. OBJECTIVE: To compare clinical outcomes and healthcare utilization using HD mapping versus non-HD mapping for AAFL ablation. METHODS: Retrospective analysis of all AAFL procedures between 2005 and 2022 at an academic medical center was conducted. Procedures utilizing a 16-electrode HD Grid catheter and Precision mapping system were compared to procedures using prior generation 10-20 electrode spiral catheters and the Velocity system (Abbott, IL). Cox regression models and Poisson regression models were utilized to examine procedural and healthcare utilization outcomes. Models were adjusted for left ventricular ejection fraction, CHA2DS2-VASc, and history of prior ablation. RESULTS: There were 108 patients (62% HD mapping) included in the analysis. Baseline clinical characteristics were similar between groups. Use of HD mapping was associated with a higher rate of AAFL circuit delineation (92.5% vs. 76%; p = .014) and a greater adjusted procedure success rate, defined as non-inducibility at procedure end, (aRR (95% CI) 1.26 (1.02-1.55) p = .035) than non-HD mapping. HD mapping was also associated with a lower rate of ED visits (aIRR (95% CI) 0.32 (0.14-0.71); p = .007) and hospitalizations (aIRR (95% CI) 0.32 (0.14-0.68); p = .004) for AF/AFL/HF through 1 year. While there was a lower rate of recurrent AFL through 1 year among HD mapping cases (aHR (95% CI) 0.60 (0.31-1.16) p = .13), statistical significance was not met likely due to the low sample size and higher rate of ambulatory rhythm monitoring in the HD group (61% vs. 39%, p = .025). CONCLUSION: Compared to non-HD mapping, AAFL ablation with HD mapping is associated with improvements in the ability to define the AAFL circuit, greater procedural success, and a reduction in the number of ED visits and hospitalization for AF/AFL/HF.

Trends of liver transplantation in Asia.

Liver transplantation (LT) in Asia started comparatively early in 1964, just 1 year after Starzl's trail-blazing first attempt. Despite the quick start, LT was slow to develop in this region. Limited access to universal healthcare, lack of public understanding and support as well as the absence of strong legislation, on a backdrop of a wide range of diverse social, religious, economic and cultural background are all contributory factors. Through strong administrative efforts, the number of DDLTs in selected Asian countries has been slowly rising in recent years. However, Asians are generally still less likely to donate organs than Caucasians after death. The strong demand for LT with limited access to deceased organs has, therefore, led to constant need for innovation in LT this region, with the pioneering of various LDLT techniques and safe expansion of donor pool being driven primarily by Asian centers. Familiarity and the development of technical expertise in donor surgery have also resulted in Asian centers repeatedly pushing the boundaries on minimally invasive donor and recipient surgery. In this article, we focus on the past and present states of LT in Asia and explore the future trends of LT in this region.

scMicrobe PTA: near complete genomes from single bacterial cells.

Microbial genomes produced by standard single-cell amplification methods are largely incomplete. Here, we show that primary template-directed amplification (PTA), a novel single-cell amplification technique, generated nearly complete genomes from three bacterial isolate species. Furthermore, taxonomically diverse genomes recovered from aquatic and soil microbiomes using PTA had a median completeness of 81%, whereas genomes from standard multiple displacement amplification-based approaches were usually <30% complete. PTA-derived genomes also included more associated viruses and biosynthetic gene clusters.

A Diffusion-Based Approach for Simulating Forward-in-Time State-Dependent Speciation and Extinction Dynamics.

We establish a general framework using a diffusion approximation to simulate forward-in-time state counts or frequencies for cladogenetic state-dependent speciation-extinction (ClaSSE) models. We apply the framework to various two- and three-region geographic-state speciation-extinction (GeoSSE) models. We show that the species range state dynamics simulated under tree-based and diffusion-based processes are comparable. We derive a method to infer rate parameters that are compatible with given observed stationary state frequencies and obtain an analytical result to compute stationary state frequencies for a given set of rate parameters. We also describe a procedure to find the time to reach the stationary frequencies of a ClaSSE model using our diffusion-based approach, which we demonstrate using a worked example for a two-region GeoSSE model. Finally, we discuss how the diffusion framework can be applied to formalize relationships between evolutionary patterns and processes under state-dependent diversification scenarios.

Sonothrombolysis in Patients With ST-Elevation Myocardial Infarction With Electrocardiographic No-Reflow After Percutaneous Coronary Intervention: A Randomized Controlled Trial.

BACKGROUND AND AIMS: Approximately 50% of patients with ST elevation myocardial infarction (STEMI) treated with percutaneous coronary intervention (PCI) experience microvascular no-reflow. Pre- and post-PCI sonothrombolysis has been shown to decrease infarct size and improve left ventricular (LV) systolic function in STEMI patients receiving urgent PCI. The aim of this study was to investigate whether post-PCI sonothrombolysis alone in STEMI patients with persistent ST elevation could reduce no-reflow and infarct size. METHODS: Patients with STEMI with symptoms <12 hours who had persistent ST elevation (≤70% ST resolution) after primary PCI were randomized to sonothrombolysis or control. The primary end point was summed (Σ) ST elevation 60 minutes after study intervention. Secondary end points included infarct size, myocardial perfusion score, LV ejection fraction on cardiovascular magnetic resonance imaging at 2 months follow-up, and clinical outcome at 6-month follow-up. RESULTS: Sixty-seven STEMI patients with persistent ST elevation after PCI were randomized (49 left anterior descending, 18 right coronary/left circumflex artery). No difference was observed in Σ ST elevation 60 minutes after study intervention (mean difference, 0.6 mm; 95% CI, -1.1 to 2.2, P = .50). Complete ST resolution occurred in 14 (40%) of patients treated with sonothrombolysis compared to 6 (19%) of controls (P = .16). Myocardial perfusion score index (1.5 ± 0.3 vs 1.5 ± 0.3, P = .93), infarct size (18.0% ± 10% vs 16.8% ± 11%; P = .29) and LV ejection fraction on cardiovascular magnetic resonance (46% ± 8% vs 47% ± 11% in the control group; P = .86) were comparable. Incidence of all-cause death, acute coronary syndrome, and hospital admission for heart failure at 6-month follow-up was similar between the groups (sonothrombolysis, 2; control, 5). CONCLUSIONS: In STEMI patients with persistent ST elevation after PCI, post-PCI sonothrombolysis did not result in more ST resolution or smaller infarct size compared to control subjects. The incidence of the combined clinical end points was remarkably low in this high-risk patient population.

Fungal Head and Neck Dermatitis: Current Understanding and Management.

Head and neck dermatitis (HND) is a form of atopic dermatitis (AD) that affects the seborrheic areas of the body and causes greater quality of life detriments than other types of AD. HND can be challenging to treat since first-line topical therapies may be ineffective or intolerable for long-term use on areas affected by HND while dupilumab may cause dupilumab-associated HND (DAHND). Current evidence implicates fungi, particularly Malassezia spp., in the pathogenesis of HND. Penetration of fungal antigens through the defective AD skin barrier activates the innate and adaptive immune systems to cause cutaneous inflammation via the T helper (Th)17 and/or Th2 axes. Malassezia sensitization may distinguish HND from other forms of AD. Multiple double-blind, placebo-controlled trials have shown antifungals to benefit HND, yet the persistence of symptom relief with sustained use remains unclear. Oral antifungals appear more effective than topical antifungals but may be harmful with long-term use. DAHND may also be fungal-mediated given improvement with antifungals and evidence of an overactive immune response against Malassezia in these patients. Janus kinase inhibitors are effective for HND, including DAHND, but may cause significant side effects when administered systemically. OX40/OX40L inhibitors and tralokinumab may be promising options for HND on the horizon. Demographic and environmental factors influence the host mycobiome and should be considered in future precision-medicine approaches as microbiome composition and diversity are linked to severity of HND.

Clinical and patient-reported outcomes and neurofilament response during tofersen treatment in SOD1-related ALS-A multicenter observational study over 18 months.

INTRODUCTION/AIMS: In amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (SOD1-ALS), tofersen received accelerated approval in the United States and is available via expanded access programs (EAP) outside the United States. This multicenter study investigates clinical and patient-reported outcomes (PRO) and serum neurofilament light chain (sNfL) during tofersen treatment in an EAP in Germany. METHODS: Sixteen SOD1-ALS patients receiving tofersen for at least 6 months were analyzed. The ALS progression rate (ALS-PR), as measured by the monthly change of the ALS functional rating scale-revised (ALSFRS-R), slow vital capacity (SVC), and sNfL were investigated. PRO included the Measure Yourself Medical Outcome Profile (MYMOP2), Treatment Satisfaction Questionnaire for Medication (TSQM-9), and Net Promoter Score (NPS). RESULTS: Mean tofersen treatment was 11 months (6-18 months). ALS-PR showed a mean change of -0.2 (range 0 to -1.1) and relative reduction by 25%. Seven patients demonstrated increased ALSFRS-R. SVC was stable (mean 88%, range -15% to +28%). sNfL decreased in all patients except one heterozygous D91A-SOD1 mutation carrier (mean change of sNfL -58%, range -91 to +27%, p < .01). MYMOP2 indicated improved symptom severity (n = 10) or yet perception of partial response (n = 6). TSQM-9 showed high global treatment satisfaction (mean 83, SD 16) although the convenience of drug administration was modest (mean 50, SD 27). NPS revealed a very high recommendation rate for tofersen (NPS +80). DISCUSSION: Data from this EAP supported the clinical and sNfL response to tofersen in SOD1-ALS. PRO suggested a favorable patient perception of tofersen treatment in clinical practice.

The Assistant Clinical Research Coordinator Program: A Pathway for Recruitment in Radiation Oncology.

Purpose: Recruiting prospective physicians to radiation oncology can be challenging, because of limited familiarity with the field. The Assistant Clinical Research Coordinator (ACRC) program can help provide trainees early exposure to radiation oncology. Methods and Materials: The ACRC program involves hiring a college graduate to provide administrative and research support for faculty members. The program was developed with our institution's clinical trials office, which provided guidance on regulatory compliance and training. A structured selection process identifies top candidates, and a rigorous onboarding process ensures smooth transitions between ACRCs. We report characteristics and outcomes of ACRC employees and surveyed them to assess their program experience using a Likert scale. Results: From 2005 to 2023, the ACRC program paired 73 ACRCs with faculty. Most faculty (68%) are currently supported by ACRCs. In 2023, 113 applications were received for 4 positions. ACRCs have contributed to research publications (293 as coauthors and 43 as first authors) and taken on leadership roles in the department. Most program alumni have attended medical school (34 of 64 program graduates; 53%). Eight have chosen to specialize in radiation oncology (13%; 2 applying into radiation oncology, 1 in residency, and 5 attendings). Of the 25% of alumni who responded to our survey, 77% responded that the mentorship provided by the ACRC program was very or extremely effective in guiding their academic development. All respondents rated the research opportunities as good or excellent, and 77% rated the clinical experience opportunities as good or excellent. Most (77%) reported that the ACRC program had substantial or significant influence on their choice of career path. Conclusions: The ACRC program provides an opportunity to address recruitment challenges in radiation oncology by offering early exposure to the field, clinical research skills, and mentorship. With the strong interest in our job posting this year, there is potential to expand this program to other institutions.

Single-fraction radiation retreatment for bone metastases: role of a rapid access clinic.

OBJECTIVES: This study investigates retreatment rates in single-fraction radiation therapy (SFRT) for painful bone metastasis in patients with limited life expectancy. We compared retreatment-free survival (RFS) in patients from a rapid access bone metastases clinic (RABC) and non-RABC patients, identifying factors associated with retreatment. METHODS: In this observational study, we analysed RABC patients who received SFRT between April 2018 and November 2019, using non-RABC SFRT patients as a comparison group. Patients with prior or perioperative radiation therapy (RT) were excluded. The primary endpoint was same-site and any-site retreatment with RT or surgery. Patient characteristics were compared using χ2 and Student's t-tests, with RFS estimates based on a multistate model considering death as a competing risk using Aalen-Johansen estimates. RESULTS: We identified 151 patients (79 RABC, 72 non-RABC) with 225 treatments (102 RABC, 123 non-RABC) meeting eligibility criteria. Of the 22 (10.8%) same-site retreatments, 5 (22.7%) received surgery, 14 (63.6%) received RT and 3 (13.6%) received both RT and surgery. We found no significant differences in any-site RFS (p=0.97) or same-site RFS (p=0.11). CONCLUSIONS: RFS is high and similar comparable in the RABC and non-RABC cohorts. Retreatment rates are low, even in patients with low Eastern Cooperative Oncology Group scores.

Dynamics of synaptic damage in severe traumatic brain injury revealed by cerebrospinal fluid SNAP-25 and VILIP-1.

BACKGROUND: Biomarkers of neuronal, glial cells and inflammation in traumatic brain injury (TBI) are available but they do not specifically reflect the damage to synapses, which represent the bulk volume of the brain. Experimental models have demonstrated extensive involvement of synapses in acute TBI, but biomarkers of synaptic damage in human patients have not been explored. METHODS: Single-molecule array assays were used to measure synaptosomal-associated protein-25 (SNAP-25) and visinin-like protein 1 (VILIP-1) (along with neurofilament light chain (NFL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), glial fibrillar acidic protein (GFAP), interleukin-6 (IL-6) and interleukin-8 (IL-8)) in ventricular cerebrospinal fluid (CSF) samples longitudinally acquired during the intensive care unit (ICU) stay of 42 patients with severe TBI or 22 uninjured controls. RESULTS: CSF levels of SNAP-25 and VILIP-1 are strongly elevated early after severe TBI and decline in the first few days. SNAP-25 and VILIP-1 correlate with inflammatory markers at two distinct timepoints (around D1 and then again at D5) in follow-up. SNAP-25 and VILIP-1 on the day-of-injury have better sensitivity and specificity for unfavourable outcome at 6 months than NFL, UCH-L1 or GFAP. Later elevation of SNAP-25 was associated with poorer outcome. CONCLUSION: Synaptic damage markers are acutely elevated in severe TBI and predict long-term outcomes, as well as, or better than, markers of neuroaxonal injury. Synaptic damage correlates with initial injury and with a later phase of secondary inflammatory injury.

Calcineurin inhibition rescues alloantigen-specific central memory T cell subsets that promote chronic GVHD.

Calcineurin inhibitors (CNIs) constitute the backbone of modern acute graft-versus-host disease (aGVHD) prophylaxis regimens but have limited efficacy in the prevention and treatment of chronic GVHD (cGVHD). We investigated the effect of CNIs on immune tolerance after stem cell transplantation with discovery-based single-cell gene expression and T cell receptor (TCR) assays of clonal immunity in tandem with traditional protein-based approaches and preclinical modeling. While cyclosporin and tacrolimus suppressed the clonal expansion of CD8+ T cells during GVHD, alloreactive CD4+ T cell clusters were preferentially expanded. Moreover, CNIs mediated reversible dose-dependent suppression of T cell activation and all stages of donor T cell exhaustion. Critically, CNIs promoted the expansion of both polyclonal and TCR-specific alloreactive central memory CD4+ T cells (TCM) with high self-renewal capacity that mediated cGVHD following drug withdrawal. In contrast to posttransplant cyclophosphamide (PT-Cy), CSA was ineffective in eliminating IL-17A-secreting alloreactive T cell clones that play an important role in the pathogenesis of cGVHD. Collectively, we have shown that, although CNIs attenuate aGVHD, they paradoxically rescue alloantigen-specific TCM, especially within the CD4+ compartment in lymphoid and GVHD target tissues, thus predisposing patients to cGVHD. These data provide further evidence to caution against CNI-based immune suppression without concurrent approaches that eliminate alloreactive T cell clones.