Commissioning an ultra-high-dose-rate electron linac with end-to-end tests.

OBJECTIVE: The FLASH effect can potentially be used to improve the therapeutic ratio of radiotherapy (RT) through delivery of Ultra-high-dose-rate (UHDR) irradiation. Research is actively being conducted to translate UHDR-RT and for this purpose the Mobetron is capable of producing electron beams at both UHDR and conventional dose rates for FLASH research and translation. This work presents commissioning of an UHDR Mobetron with end-to-end tests developed for preclinical research. Approach. UHDR electron beams were commissioned with an efficient approach utilizing a 3D-printed water tank and film to fully characterize beam characteristics and dependences on field size, pulse width (PW) and pulse repetition frequency (PRF). This commissioning data was used to implement a beam model using the GAMOS Monte Carlo toolkit for the preclinical research. Then, the workflow for preclinical FLASH irradiation was validated with end-to-end tests delivered to a 3D-printed mouse phantom with internal inhomogeneities. Main results. PDDs, profiles and output factors acquired with radiochromic films were precisely measured, with a PRF that showed little effect on the UHDR beam energy and spatial characteristics. Increasing PW reduced the Dmax and R50 by 2.08 mm/µs and 1.28 mm/µs respectively. An end-to-end test of the preclinical research workflow showed that both profiles in head-foot and lateral directions were in good agreement with the MC calculations for the heterogeneous 3D printed mouse phantom with Gamma index above 93% for 2mm/2% criteria, and 99% for 3mm/3%. Significance. The UHDR Mobetron is a versatile tool for FLASH preclinical research and this comprehensive beam model and workflow was validated to meet the requirements for conducting translational FLASH research.

Quantitative, real-time scintillation imaging for experimental comparison of different dose and dose rate estimations in UHDR proton pencil beams.

BACKGROUND: Ultra-high dose rate radiotherapy (UHDR-RT) has demonstrated normal tissue sparing capabilities, termed the FLASH effect; however, available dosimetry tools make it challenging to characterize the UHDR beams with sufficiently high concurrent spatial and temporal resolution. Novel dosimeters are needed for safe clinical implementation and improved understanding of the effect of UHDR-RT. PURPOSE: Ultra-fast scintillation imaging has been shown to provide a unique tool for spatio-temporal dosimetry of conventional cyclotron pencil beam scanning (PBS) deliveries, indicating the potential use for characterization of UHDR PBS proton beams. The goal of this work is to introduce this novel concept and demonstrate its capabilities in recording high-resolution dose rate maps at FLASH-capable proton beam currents, as compared to log-based dose rate calculation, internally developed UHDR beam simulation, and a fast point detector (EDGE diode). METHODS: The light response of a scintillator sheet located at isocenter and irradiated by PBS proton fields (40-210 nA, 250 MeV) was imaged by an ultra-fast iCMOS camera at 4.5-12 kHz sampling frequency. Camera sensor and image intensifier gain were optimized to maximize the dynamic range; the camera acquisition rate was also varied to evaluate the optimal sampling frequency. Large field delivery enabled flat field acquisition for evaluation of system response homogeneity. Image intensity was calibrated to dose with film and the recorded spatio-temporal data was compared to a PPC05 ion chamber, log-based reconstruction, and EDGE diode. Dose and dose rate linearity studies were performed to evaluate agreement under various beam conditions. Calculation of full-field mean and PBS dose rate maps were calculated to highlight the importance of high resolution, full-field information in UHDR studies. RESULTS: Camera response was linear with dose (R2 = 0.997) and current (R22 = 0.98) in the range from 2-22 Gy and 40-210 nA, respectively, when compared to ion chamber readings. The deviation of total irradiation time calculated with the imaging system from the log file recordings decreased from 0.07% to 0.03% when imaging at 12 kfps versus 4.5 kfps. Planned and delivered spot positions agreed within 0.2 ± $\pm$ 0.1 mm and total irradiation time agreed within 0.2 ± $\pm$ 0.2 ms when compared with the log files, indicating the high concurrent spatial and temporal resolution. For all deliveries, the PBS dose rate measured at the diode location agreed between the imaging and the diode within 3% ± $\pm$ 2% and with the simulation within 5% ± $\pm$ 3% CONCLUSIONS: Full-field mapping of dose and dose rate is imperative for complete understanding of UHDR PBS proton dose delivery. The high linearity and various spatiotemporal metric reporting capabilities confirm the continued use of this camera system for UHDR beam characterization, especially for spatially resolved dose rate information.

Child and caregiver predictors of primary caregiver participation in families of school-aged Autistic children.

Engaging in meaningful activities (e.g., leisure, spiritual, fitness) significantly affects caregivers' quality of life (QoL), yet the determinants of participation in caregivers of Autistic children remain largely unknown. The current study examined child and caregiver correlates of primary caregiver participation in meaningful activities. One hundred and six primary caregivers of Autistic children (7-12 years) were recruited from three unique cohorts of Autistic children in this cross-sectional study. Primary caregivers completed online questionnaires measuring occupational gaps (i.e., desired activities caregivers are not participating in), QoL, parenting stress, perceived family outcomes, and social support. In addition to undertaking direct assessments of children's cognition and language, primary caregivers also reported on their child's adaptive behavior, social-emotional skills, and participation. Caregivers reporting fewer occupational gaps (i.e., ≤2 desired activities) were more likely to have Autistic children with no co-occurring conditions, who were older, and with better adaptive behaviors, social-emotional skills, and more frequent home and school participation, compared to caregivers reporting many gaps (i.e., ≥3 desired activities). Caregivers with fewer occupational gaps also reported improved QoL, parenting stress, social support, perceived community inclusiveness, and family outcomes. Logistic regression analysis identified child age, child adaptive behavior, social-emotional skills, home participation, and the caregivers' perceived family outcomes and QoL as important predictors of their occupational gaps. The findings demonstrate that caregiver participation in desired activities was associated with increased functional ability and independence of the child, as well as their perceived capacity to meet their child's needs. Supporting parents' sense of efficacy in meeting their children's needs and building their skills and knowledge will serve to improve both caregiver and child outcomes.

Electron beam response corrections for an ultra-high-dose-rate capable diode dosimeter.

BACKGROUND: Ultra-high-dose-rate (UHDR) electron beams have been commonly utilized in FLASH studies and the translation of FLASH Radiotherapy (RT) to the clinic. The EDGE diode detector has potential use for UHDR dosimetry albeit with a beam energy dependency observed. PURPOSE: The purpose is to present the electron beam response for an EDGE detector in dependence on beam energy, to characterize the EDGE detector's response under UHDR conditions, and to validate correction factors derived from the first detailed Monte Carlo model of the EDGE diode against measurements, particularly under UHDR conditions. METHODS: Percentage depth doses (PDDs) for the UHDR Mobetron were measured with both EDGE detectors and films. A detailed Monte Carlo (MC) model of the EDGE detector has been configured according to the blueprint provided by the manufacturer under an NDA agreement. Water/silicon dose ratios of EDGE detector for a series of mono-energetic electron beams have been calculated. The dependence of the water/silicon dose ratio on depth for a FLASH relevant electron beam was also studied. An analytical approach for the correction of PDD measured with EDGE detectors was established. RESULTS: Water/silicon dose ratio decreased with decreasing electron beam energy. For the Mobetron 9 MeV UHDR electron beam, the ratio decreased from 1.09 to 1.03 in the build-up region, maintained in range of 0.98-1.02 at the fall-off region and raised to a plateau in value of 1.08 at the tail. By applying the corrections, good agreement between the PDDs measured by the EDGE detector and those measured with film was achieved. CONCLUSIONS: Electron beam response of an UHDR capable EDGE detector was derived from first principles utilizing a sophisticated MC model. An analytical approach was validated for the PDDs of UHDR electron beams. The results demonstrated the capability of EDGE detector in measuring PDDs of UHDR electron beams.

Intracellular Oxygen Transient Quantification in Vivo During Ultra-High Dose Rate FLASH Radiation Therapy.

PURPOSE: Large, rapid extracellular oxygen transients (ΔpO2) have been measured in vivo during ultra-high dose rate radiation therapy; however, it has been unclear if they match intracellular oxygen levels. Here, the endogenously produced protoporphyrin IX (PpIX) delayed fluorescence signal was measured as an intracellular in-vivo oxygen sensor to quantify these transients, with direct comparison to extracellular pO2. Intracellular ΔpO2 is closer to the cellular DNA, the site of major radiobiological damage, and therefore should help elucidate radiochemical mechanisms of the FLASH effect and potentially be translated to human tissue measurement. METHODS AND MATERIALS: PpIX was induced in mouse skin through intraperitoneal injection of 250 mg/kg of aminolevulinic acid. The animals were also administered a 50 µL intradermal injection of 10 µM oxyphor G4 (PdG4) for phosphorescence lifetime pO2 measurement. Paired oxygen transients were quantified in leg or flank tissues while delivering 10 MeV electrons in 3 µs pulses at 360 Hz for a total dose of 10 to 28 Gy. RESULTS: Transient reductions in pO2 were quantifiable in both PpIX delayed fluorescence and oxyphor phosphorescence, corresponding to intracellular and extracellular pO2 values, respectively. Reponses were quantified for 10, 22, and 28 Gy doses, with ΔpO2 found to be proportional to the dose on average. The ΔpO2 values were dependent on initial pO2 in a logistic function. The average and standard deviations in ΔpO2 per dose were 0.56 ± 0.18 mm Hg/Gy and 0.43 ± 0.06 mm Hg/Gy for PpIX and oxyphor, respectively, for initial pO2 > 20 mm Hg. Although there was large variability in the individual animal measurements of ΔpO2, the average values demonstrated a direct and proportional correlation between intracellular and extracellular pO2 changes, following a linear 1:1 relationship. CONCLUSIONS: A fundamentally new approach to measuring intracellular oxygen depletion in living tissue showed that ΔpO2 transients seen during ultra-high dose rate radiation therapy matched those quantified using extracellular oxygen measurement. This approach could be translated to humans to quantify intracellular ΔpO2. The measurement of these transients could potentially allow the estimation of intracellular reactive oxygen species production.

Anesthetic Oxygen Use and Sex Are Critical Factors in the FLASH Sparing Effect.

Purpose: Ultra High Dose-Rate (UHDR) radiation has been reported to spare normal tissue, compared with Conventional Dose-Rate (CDR) radiation. However, important work remains to be done to improve the reproducibility of the FLASH effect. A better understanding of the biologic factors that modulate the FLASH effect may shed light on the mechanism of FLASH sparing. Here, we evaluated whether sex and/or the use of 100% oxygen as a carrier gas during irradiation contribute to the variability of the FLASH effect. Methods and Materials: C57BL/6 mice (24 male, 24 female) were anesthetized using isoflurane mixed with either room air or 100% oxygen. Subsequently, the mice received 27 Gy of either 9 MeV electron UHDR or CDR to a 1.6 cm2 diameter area of the right leg skin using the Mobetron linear accelerator. The primary postradiation endpoint was time to full thickness skin ulceration. In a separate cohort of mice (4 male, 4 female), skin oxygenation was measured using PdG4 Oxyphor under identical anesthesia conditions. Results: Neither supplemental oxygen nor sex affected time to ulceration in CDR irradiated mice. In the UHDR group, skin damage occured earlier in male and female mice that received 100% oxygen compared room air and female mice ulcerated sooner than male mice. However, there was no significant difference in time to ulceration between male and female UHDR mice that received room air. Oxygen measurements showed that tissue oxygenation was significantly higher when using 100% oxygen as the anesthesia carrier gas than when using room air, and female mice showed higher levels of tissue oxygenation than male mice under 100% oxygen. Conclusions: The skin FLASH sparing effect is significantly reduced when using oxygen during anesthesia rather than room air. FLASH sparing was also reduced in female mice compared to male mice. Both tissue oxygenation and sex are likely sources of variability in UHDR studies. These results suggest an oxygen-based mechanism for FLASH, as well as a key role for sex in the FLASH skin sparing effect.

First Monte Carlo beam model for ultra-high dose rate radiotherapy with a compact electron LINAC.

BACKGROUND: FLASH radiotherapy based on ultra-high dose rate (UHDR) is actively being studied by the radiotherapy community. Dedicated UHDR electron devices are currently a mainstay for FLASH studies. PURPOSE: To present the first Monte Carlo (MC) electron beam model for the UHDR capable Mobetron (FLASH-IQ) as a dose calculation and treatment planning platform for preclinical research and FLASH-radiotherapy (RT) clinical trials. METHODS: The initial beamline geometry of the Mobetron was provided by the manufacturer, with the first-principal implementation realized in the Geant4-based GAMOS MC toolkit. The geometry and electron source characteristics, such as energy spectrum and beamline parameters, were tuned to match the central-axis percentage depth dose (PDD) and lateral profiles for the pristine beam measured during machine commissioning. The thickness of the small foil in secondary scatter affected the beam model dominantly and was fine tuned to achieve the best agreement with commissioning data. Validation of the MC beam modeling was performed by comparing the calculated PDDs and profiles with EBT-XD radiochromic film measurements for various combinations of applicators and inserts. RESULTS: The nominal 9 MeV electron FLASH beams were best represented by a Gaussian energy spectrum with mean energy of 9.9 MeV and variance (σ) of 0.2 MeV. Good agreement between the MC beam model and commissioning data were demonstrated with maximal discrepancy < 3% for PDDs and profiles. Hundred percent gamma pass rate was achieved for all PDDs and profiles with the criteria of 2 mm/3%. With the criteria of 2 mm/2%, maximum, minimum and mean gamma pass rates were (100.0%, 93.8%, 98.7%) for PDDs and (100.0%, 96.7%, 99.4%) for profiles, respectively. CONCLUSIONS: A validated MC beam model for the UHDR capable Mobetron is presented for the first time. The MC model can be utilized for direct dose calculation or to generate beam modeling input required for treatment planning systems for FLASH-RT planning. The beam model presented in this work should facilitate translational and clinical FLASH-RT for trials conducted on the Mobetron FLASH-IQ platform.

Using focus groups to inform a peer health navigator service for people who are transgender and gender diverse in Saskatchewan, Canada.

BACKGROUND: This study investigated healthcare access and quality for people who are transgender and gender-diverse (PTGD) in Saskatchewan (SK), Canada, to inform a larger project that was piloting two peer health navigators for PTGD. METHODS: Two online focus groups were held. Nineteen participants were recruited to represent a broad range in age, gender and location in SK. Transcripts of the focus groups were analyzed using a thematic approach. RESULTS: The core theme that was identified was participants' desire for culturally safe healthcare. This core theme had two component themes: (1) systemic healthcare factors and (2) individual healthcare provider (HCP) factors. The healthcare system primarily acted as a barrier to culturally safe healthcare. HCPs could be either barriers or facilitators of culturally safe care; however, negative experiences outweighed positive ones. CONCLUSIONS: PTGD in SK face discrimination, with delays and barriers to care at all levels of the healthcare system. Peer health navigators can address some of these discrepancies; however, greater support is required for PTGD to be able to access culturally safe healthcare. PATIENT OR PUBLIC CONTRIBUTION: People with lived experience/PTGD were involved in all stages of this project. They were included on the team as community researchers and co-developed the research project, conducted the focus groups, participated in the analyses and are co-authors. As well, both navigators and all the participants in the focus groups were also PTGD.

Leisure, community, workforce participation and quality of life in primary and secondary caregivers of autistic children.

Parents of Autistic children often modify their participation in leisure, social, and employment activities to meet the caregiving needs of their child. However, few studies have examined the impact this has on caregiver quality of life (QoL). The aim in the current study was to examine the role of participation in a range of activities on QoL amongst primary and secondary caregivers of school-aged Autistic children. Eighty-eight primary (93% mothers) and 63 secondary (91% fathers) caregivers of Autistic children (aged 7- to 12-years) participated in this cross-sectional study, with time pressure, participation, social support, parenting stress, and QoL measured via an online questionnaire. Compared to secondary caregivers, primary caregivers reported fewer employment hours, increased time pressure, less participation in desired activities, and higher perceived responsibility of domestic and child-rearing tasks. Similar levels of leisure frequency, parenting stress, and QoL were identified by both caregivers. Hierarchical regression revealed caregiver participation as important for QoL in both primary and secondary caregivers. However, when measures of caregiver well-being were added to the model, the unique contribution of participation to QoL was reduced, particularly for secondary caregivers. Overall, the findings demonstrate that despite differences in caregiver roles and responsibilities, participation in meaningful activities was important for QoL in all caregivers.

Imaging and characterization of optical emission fromex vivotissue during conventional and UHDR PBS proton therapy.

Objective. Imaging of optical photons emitted from tissue during radiotherapy is a promising technique for real-time visualization of treatment delivery, offering applications in dose verification, treatment monitoring, and retrospective treatment plan comparison. This research aims to explore the feasibility of intensified imaging of tissue luminescence during proton therapy (PT), under both conventional and ultra-high dose rate (UHDR) conditions.Approach. Conventional and UHDR pencil beam scanning (PBS) PT irradiation of freshex vivoporcine tissue and tissue-mimicking plastic phantom was imaged using intensified complementary metal-oxide-semiconductor(CMOS) cameras. The optical emission from tissue was characterized during conventional irradiation using both blue and red-sensitive intensifiers to ensure adequate spectral coverage. Spectral characterization was performed using bandpass filters between the lens and sensor. Imaging of conventional proton fields (240 MeV, 10 nA) was performed at 100 Hz frame rate, while UHDR PBS proton delivery (250 MeV, 99 nA) was recorded at 1 kHz frame rate. Dependence of optical emission yield on proton energy was studied using an optical tissue-mimicking plastic phantom and a range shifter. Finally, we demonstrated fast beam tracking capability of fast camera towardsin vivomonitoring of FLASH PT.Main results. Under conventional treatment dose rates optical emission was imaged with single spot resolution. Spot profiles were found to agree with the treatment planning system calculation within >90% for all spectral bands and spot intensity was found to vary with spectral filtration. The resultant polychromatic emission presented a maximum intensity at 650 nm and decreasing signal at lower wavelengths, which is consistent with expected attenuation patterns of high fat and muscle tissue. For UHDR beam imaging, optical yield increased with higher proton energy. Imaging at 1 kHz allowed continuous monitoring of delivery during porcine tissue irradiation, with clear identification of individual dwell positions. The number of dwell positions matched the treatment plan in total and per row showing adequate temporal capability of iCMOS imaging.Significance. For the first time, this study characterizes optical emission from tissue during PT and demonstrates our capability of fast optical tracking of pencil proton beam on the tissue anatomy in both conventional and UHDR setting. Similar to the Cherenkov imaging in radiotherapy, this imaging modality could enable a seamless, independent validation of PT treatments.

Identifying a Cohort of People Who Are Transgender and Gender-Diverse Within Saskatchewan's Administrative Health Databases.

This was a retrospective cohort study. Algorithms were developed to identify a cohort of people who were trans and gender diverse (PTGD) among provincial-level administrative health databases (physician, hospital, emergency department, and pharmacy) from April 1, 2012 to September 30, 2020. Then, healthcare usage was compared between the identified cohort and the general population. There were 6466 unique individuals identified in the cohort, out of a total population of 1.2 million Saskatchewan residents (~0.5%). They had a mean age of 42.5 (SD 17.7) years. 1946 (30.1%) had a female sex marker and 4560 (69.9%) had a male sex marker, which may not indicate their lived gender. The cohort had increased healthcare usage 2 years prior to their index date, compared to the general population, which continued to rise to 1 year past their index date across physician, emergency department visits, and hospitalizations. The results for drugs were mixed. The percentage of PTGD identified in Saskatchewan was comparable to other studies. Healthcare utilization among the cohort was higher than the general population. Further research could use external data sources to validate and improve the cohort identification methods. The large majority of individuals with a male sex marker deserves further investigation.

Anesthetic oxygen use and sex are critical factors in the FLASH sparing effect.

Introduction: Ultra-high dose-rate (UHDR) radiation has been reported to spare normal tissue compared to conventional dose-rate (CDR) radiation. However, reproducibility of the FLASH effect remains challenging due to varying dose ranges, radiation beam structure, and in-vivo endpoints. A better understanding of these inconsistencies may shed light on the mechanism of FLASH sparing. Here, we evaluate whether sex and/or use of 100% oxygen as carrier gas during irradiation contribute to the variability of the FLASH effect. Methods: C57BL/6 mice (24 male, 24 female) were anesthetized using isoflurane mixed with either room air or 100% oxygen. Subsequently, the mice received 27 Gy of either 9 MeV electron UHDR or CDR to a 1.6 cm2 diameter area of the right leg skin using the Mobetron linear accelerator. The primary post-radiation endpoint was time to full thickness skin ulceration. In a separate cohort of mice (4 male, 4 female) skin oxygenation was measured using PdG4 Oxyphor under identical anesthesia conditions. Results: In the UHDR group, time to ulceration was significantly shorter in mice that received 100% oxygen compared to room air, and amongst them female mice ulcerated sooner compared to males. However, no significant difference was observed between male and female UHDR mice that received room air. Oxygen measurements showed significantly higher tissue oxygenation using 100% oxygen as the anesthesia carrier gas compared to room air, and female mice showed higher levels of tissue oxygenation compared to males under 100% oxygen. Conclusion: The FLASH sparing effect is significantly reduced using oxygen during anesthesia compared to room air. The FLASH sparing was significantly lower in female mice compared to males. Both tissue oxygenation and sex are likely sources of variability in UHDR studies. These results suggest an oxygen-based mechanism for FLASH, as well as a key role for sex in the FLASH skin sparing effect.

A systematic review of physical function tests as predictors of key clinical outcomes for adults with blood cancers.

PURPOSE: To determine which standardized physical performance tests are being used specifically in the assessment of adult patients before, during, or after undergoing treatment for hematologic malignancy and which of these functional tests have been demonstrated to have a correlation with key objective clinical outcome measures including mortality, progression-free survival, complete remission, hospital readmissions, emergency department visits, and hospital length of stay. METHODS: PubMed/MEDLINE electronic databases were searched up to June 2021. Searches were restricted to English language. All resulting studies from the electronic database search were assessed by two reviewers for original research with physical performance data exclusive to patients with hematological malignancy. Studies with confounding intervention or the inclusion of pediatric patients were excluded. The quality of the remaining studies was assessed using PRISMA guidelines and Tooth Criteria by two reviewers, using a third reviewer to resolve any discrepancies. The main characteristics of each article, including sample size, population characteristics, physical performance testing methods, and significant and non-significant findings were extracted and compared. Additionally, one reviewer performed a literature review of the safety of physical performance testing. RESULTS: One thousand two hundred fifty-six screened database results resulted in 14 studies included in the systematic review. All studies scored ≥ 0.59 on the Tooth Criteria, indicating moderate to high quality of reporting. Our review found six recurring measures of objective physical function assessed for correlation with clinical outcomes, primarily morbidity and mortality. The heterogeneity of each study precluded aggregate data analysis. CONCLUSIONS: This review was a first step in evaluating which objective physical performance tests are best suited for identifying functional impairment before, during, and after oncologic treatment for adults with blood cancers. Additional studies are needed to determine the optimal objective functional measures to use as a guide in clinical decision-making in the hematologic patient population.

In vitro modeling of CD8+ T cell exhaustion enables CRISPR screening to reveal a role for BHLHE40.

Identifying molecular mechanisms of exhausted CD8 T cells (Tex) is a key goal of improving immunotherapy of cancer and other diseases. However, high-throughput interrogation of in vivo Tex can be costly and inefficient. In vitro models of Tex are easily customizable and quickly generate high cellular yield, enabling CRISPR screening and other high-throughput assays. We established an in vitro model of chronic stimulation and benchmarked key phenotypic, functional, transcriptional, and epigenetic features against bona fide in vivo Tex. We leveraged this model of in vitro chronic stimulation in combination with CRISPR screening to identify transcriptional regulators of T cell exhaustion. This approach identified several transcription factors, including BHLHE40. In vitro and in vivo validation defined a role for BHLHE40 in regulating a key differentiation checkpoint between progenitor and intermediate Tex subsets. By developing and benchmarking an in vitro model of Tex, then applying high-throughput CRISPR screening, we demonstrate the utility of mechanistically annotated in vitro models of Tex.

Wellness Wheel Clinics: A First Nation community-partnered care model improving healthcare access, from healthcare providers' perspectives.

First Nation people residing in rural and remote communities have limited primary healthcare access, which often affects chronic disease management leading to poor health outcomes. Individuals with lived experiences of chronic disease and substance use, along with health directors, advocated for improved services. Subsequently, an urban healthcare team in partnership with four First Nation communities developed an Outreach clinic to address healthcare access barriers. Established in 2016, this community-led clinic improves primary care access and chronic disease management in First Nation communities. Employing a qualitative research design, interviews were conducted with 15 clinic providers and 9 community members to explore the clinic's 1-year post-implementation impacts. Thematic data analysis indicated that engagement and approval by community leadership, support from Elders and community members and collaboration with existing community healthcare staff were crucial for establishing the Outreach clinic. Initial logistical challenges with space allocation, equipment, medical supplies, funding, staffing, medical records and appointment scheduling were resolved through community consultation and creative solutions. A nurse coordinator ensured continuity of care and was integral to ensuring clients receive seamless care. The commitment of the outreach team and the collective goal of providing client-centered care were instrumental in the clinic's success. In partnership with communities, access to healthcare in First Nation communities can be enhanced by coordinating Outreach clinics through existing community healthcare facilities.

In Vitro Modeling of CD8 T Cell Exhaustion Enables CRISPR Screening to Reveal a Role for BHLHE40.

Identifying novel molecular mechanisms of exhausted CD8 T cells (T ex ) is a key goal of improving immunotherapy of cancer and other diseases. However, high-throughput interrogation of in vivo T ex can be costly and inefficient. In vitro models of T ex are easily customizable and quickly generate high cellular yield, offering an opportunity to perform CRISPR screening and other high-throughput assays. We established an in vitro model of chronic stimulation and benchmarked key phenotypic, functional, transcriptional, and epigenetic features against bona fide in vivo T ex . We leveraged this model of in vitro chronic stimulation in combination with pooled CRISPR screening to uncover transcriptional regulators of T cell exhaustion. This approach identified several transcription factors, including BHLHE40. In vitro and in vivo validation defined a role for BHLHE40 in regulating a key differentiation checkpoint between progenitor and intermediate subsets of T ex . By developing and benchmarking an in vitro model of T ex , we demonstrate the utility of mechanistically annotated in vitro models of T ex , in combination with high-throughput approaches, as a discovery pipeline to uncover novel T ex biology.

When tissue is not the only issue: Poorly differentiated lung squamous-cell carcinoma with adrenal, costochondral, and cardiac metastases - case report.

Nonmelanoma skin cancer is the most common cancer in the world, and lung cancer is the leading cause of death from cancer. Histologically, squamous cell carcinoma (SCC) is the second most prevalent type of both skin and lung cancers. We report the case of a 38-year-old female with metastatic, poorly differentiated lung SCC detected on chest X-ray after she presented to the hospital with cough and dyspnea. She had had a 7.5 cm moderately differentiated well-circumscribed posterior scalp SCC completely excised eight years earlier. CT scan showed a large right lung mass, nodular filling defect in the left atrium (LA), and metastases to the adrenal glands and the first rib. Her pulmonary tumor extends to the LA via the right superior pulmonary vein, which is rarely reported in the literature. Ultrasound-guided biopsy of the rib mass showed poorly differentiated SCC. The patient received urgent radiotherapy, given superior vena cava and mainstem bronchus compression. Head CT showed no brain metastasis. A biopsy of the left adrenal initially reported an undifferentiated pleomorphic sarcoma; however, a second pathologist reported it as a poorly differentiated carcinoma of lung origin. At least three pathologists verified the specimen, and it had a PD-L1 test with a 1-49% score. An initial echocardiogram confirmed the LA mass. The patient received a Paclitaxel-Carboplatin-Pembrolizumab regimen as the first-line treatment for metastatic SCC. A repeat echocardiogram after cycle 1 showed a decrease in the size of the tumor in the LA. Almost five months after her initial visit, this young woman's symptoms and performance status have improved post-palliative radiotherapy and chemo-immunotherapy. Follow-up CT showed smaller lung, nodal, adrenal, and costochondral masses, and evidence of necrosis. This case is clinically relevant because it represents a common problem presenting uncommonly. Moreover, it highlights that ultrasound-guided interventions and medical imaging are essential in directing metastatic cancer diagnosis, treatment, and follow-up, especially when pathology cannot confirm but only presume a specific diagnosis.

Ultra-fast, high spatial resolution single-pulse scintillation imaging of synchrocyclotron pencil beam scanning proton delivery.

Objective.To demonstrates the ability of an ultra-fast imaging system to measure high resolution spatial and temporal beam characteristics of a synchrocyclotron proton pencil beam scanning (PBS) system.Approach.An ultra-fast (1 kHz frame rate), intensified CMOS camera was triggered by a scintillation sheet coupled to a remote trigger unit for beam on detection. The camera was calibrated using the linear (R2> 0.9922) dose response of a single spot beam to varying currents. Film taken for the single spot beam was used to produce a scintillation intensity to absolute dose calibration.Main results. Spatial alignment was confirmed with the film, where thexandy-profiles of the single spot cumulative image agreed within 1 mm. A sample brain patient plan was analyzed to demonstrate dose and temporal accuracy for a clinically-relevant plan, through agreement within 1 mm to the planned and delivered spot locations. The cumulative dose agreed with the planned dose with a gamma passing rate of 97.5% (2 mm/3%, 10% dose threshold).Significance. This is the first system able to capture single-pulse spatial and temporal information for the unique pulse structure of a synchrocyclotron PBS systems at conventional dose rates, enabled by the ultra-fast sampling frame rate of this camera. This study indicates that, with continued camera development and testing, target applications in clinical and FLASH proton beam characterization and validation are possible.

Social and Behavioural Outcomes of School Aged Autistic Children Who Received Community-Based Early Interventions.

The school-age outcomes of autistic children who received early interventions (EI) remains limited. Adaptive functioning, social, peer play skills, problem behaviours, and attitudes towards school of 31 autistic children who received community-based group early start Denver model (G-ESDM) were compared to 28 age matched autistic children who received other community interventions. Similar adaptive behaviours, social skills, problem behaviours and attitudes towards school were found. Play disruption was the only dimension of play to differ; children that received community interventions demonstrated higher levels of play disruption compared to the G-ESDM group. Children had pervasive challenges in adaptive behaviour, social and play behaviour at school, irrespective of EI type. Thus, ongoing provisions are needed to support development into the school years.

Multiscale 3D genome organization underlies ILC2 ontogenesis and allergic airway inflammation.

Innate lymphoid cells (ILCs) are well-characterized immune cells that play key roles in host defense and tissue homeostasis. Yet, how the three-dimensional (3D) genome organization underlies the development and functions of ILCs is unknown. Herein, we carried out an integrative analysis of the 3D genome structure, chromatin accessibility and gene expression in mature ILCs. Our results revealed that the local 3D configuration of the genome is rewired specifically at loci associated with ILC biology to promote their development and functional differentiation. Importantly, we demonstrated that the ontogenesis of ILC2s and the progression of allergic airway inflammation are determined by a unique local 3D configuration of the region containing the ILC-lineage-defining factor Id2, which is characterized by multiple interactions between the Id2 promoter and distal regulatory elements bound by the transcription factors GATA-3 and RORα, unveiling the mechanism whereby the Id2 expression is specifically controlled in group 2 ILCs.