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Abstract Traditional approaches to the human cochlear nerve have been impeded by its bony encasement deep inside the skull base. We present an innovative, minimally invasive, therapeutic pathway for direct access to the nerve to deliver novel regenerative therapies. Neuroanatomical studies on 10 cadaveric human temporal bones were undertaken to identify a potentially safe therapeutic pathway to the cochlear nerve. Simulations based on three-dimensional delineation of anatomical structures obtained from synchrotron phase-contrast imaging were analyzed. This enabled the identification of an approach to the nerve in the fundus of the internal auditory meatus by trephining the medial modiolar wall of the cochlea via the round window for a median depth of 1.48 mm (range 1.21–1.91 mm). The anatomical access was validated on 9 additional human temporal bones using radio-opaque markers and contrast injection with micro-computed tomography surveillance. We thus created an effective conduit for the delivery of therapeutic agents to the cochlear nerve.

Abstract The HOVON 104 studied bortezomib‐dexamethasone induction therapy and autologous stem cell transplantation in 50 patients, of whom 35 received an autologous stem cell transplantation (ASCT). We demonstrate a 5‐year overall survival (OS) of 73% and progression‐free survival (PFS) of 52% for all 50 patients with a median follow‐up of 61.3 months. For the 35 transplanted patients, calculated from the date of ASCT, the 5‐year OS and PFS were 91% and 68%, respectively. After ASCT, the rate of organ response improved over time but stabilized around 3 years. A complete cardiac response was seen in around 60% of patients and remained stable from 2 years onward. Reaching complete renal response was slower over time and achieved by 61% of the renal‐affected patients at 5 years. We confirm the excellent outcomes after ASCT and demonstrate a 60% complete organ response with longer follow‐up.

Abstract Background Patient experiences with COVID-19 aftercare remain largely unknown. We evaluated COVID-19 aftercare from a patient perspective one year after hospitalization, assessing satisfaction and its associated factors, and unmet needs. Methods The Satisfaction with COVID-19 Aftercare Questionnaire (SCAQ) was developed as part of a multicenter prospective cohort study and administered one year after hospital discharge. The SCAQ assesses (1) patient satisfaction, comprising information provision, rehabilitation, follow-up by hospitals and general practitioners (GPs), the most important aftercare topics, and overall satisfaction, and (2) unmet needs. Results 487/561 (87%) COVID-19 patients completed the SCAQ, all had been discharged from the hospital between March 2020 and May 2021. Among responders, the median age of patients was 60 (IQR 54–67) years, 338 (69%) were male, and the median length of stay in the hospital was 13 (6–27) days. Patients were least satisfied with information on who could be contacted with questions when health problems arise (59% satisfied or very satisfied). Many patients (75%) received rehabilitation, most frequently community-based (70%). Across the different community-based therapies, ≥ 60% of patients were satisfied with shared-decision making and ≥ 70% with the received therapy; a majority (≥ 79%) indicated a preference for receiving the same therapy again if needed. Regarding follow-up by hospitals, 86% of patients received this follow-up, most frequently visiting a pulmonologist (96%), being generally satisfied with the received aftercare. Aftercare from GPs was received by 39% of patients, with 88% being satisfied with the GP’s availability and 79% with referral to appropriate aftercare providers. Patients (> 50%) considered information-related items most important in aftercare. Overall, patients rated their satisfaction with aftercare 8/10 (7–9) points. Those who received medical rehabilitation (versus no rehabilitation, adjusted beta 0.61 [95%CI 0.11 to 1.11], p = 0.02) or aftercare by a hospital medical specialist (1.1 [0.46 to 1.64], p

Background: Diabetes mellitus (DM) is increasing drastically and affecting the individuals globally, especially in the low- and middle-income countries like India. The poor glycaemic control results in micro-vascular and macro-vascular complications, leading to dysfunction of multiple organs. This study aimed to evaluate the association between the risk factors and microalbuminuria levels among patients with type 2 DM on oral hypoglycaemic agents. Materials and Methods: Hundred type 2 DM patients fulfilling the inclusion and exclusion criteria were selected by convenient random sampling. Demographic details, biochemical markers, and anti-diabetic medication details were collected. The findings were analyzed statistically using Chi-square test and one-way analysis of variance (ANOVA) with SPSS software 21.0. Results: Among the different combination therapies, 59% were commonly using metformin and teneligliptin. There was a significant association noted between microalbuminuria and risk factors like age, duration of disease, body mass index (BMI) (25.5 ± 2.9), fasting blood sugar (151 ± 53.2 mg/dL), post prandial blood sugar (227.01 ± 70.9 mg/dL), blood urea (24.42 ± 9.3 mg/dL), and serum creatinine (1.5 ± 0.2 mg/dL) (P < 0.001). One-way ANOVA showed statistical significance between microalbuminuria and the different treatment groups (P < 0.0001). Conclusion: Microalbuminuria was associated with age, duration of diabetes, glycaemic control, and BMI. In contrast, there was no significant difference noted between the genders and microalbuminuria. Microalbuminuria is an early indication of nephropathy in diabetes patients. The early identification of the risk factors is important, and it is always recommended to screen for microalbuminuria in all the diabetic patients for early detection and prevention of diabetic nephropathy and their associated complications.

Objectives: Various mechanisms, such as immune dysregulation, viral reservoir, and auto-immunity, are hypothesized to underlie the pathogenesis of long-term health problems after hospitalization for COVID-19. We aimed to assess the effect of in-hospital COVID-19 treatments on prominent long-term health problems. Methods: In this prospective multicenter cohort study, we enrolled patients (age ≥18 years) who had been hospitalized for COVID-19 in the Netherlands between July 2020 and October 2021. We retrospectively collected data on in-hospital COVID-19 treatments, including steroid, anti-inflammatory, and antiviral treatments. Patients completed questionnaires on self-reported recovery, dyspnea, fatigue, cognitive failures, and health-related quality of life and performed the 6-minute walk test at the 2-year follow-up visit. Results: Five hundred two patients with COVID-19 were included, all were discharged from the hospital between March 2020 and June 2021. The median age at admission was 60.0 (IQR 53.0-68.0) years and 350 (69.7%) patients were male. At hospital admission, 5/405 (1.2%) of the patients had been vaccinated against SARS-CoV-2. Among all 502 patients, the majority (248 [49.4%]) received steroids only, 57 (11.4%) anti-inflammatory treatment, 78 (15.5%) antiviral treatment, and 119 (23.7%) none during hospitalization. Long-term health problems were common in all groups. We found that in-hospital treatments were not significantly associated with health problems at 2 years after hospital discharge, nor after adjusting for confounders. Conclusion: Many patients with COVID-19 suffer from long-term health problems 2 years after hospital discharge. Acute treatment for COVID-19 is not associated with long-term health problems.

In stroke rehabilitation, simple robotic devices hold the potential to increase the training dosage in group therapies and to enable continued therapy at home after hospital discharge. However, we identified a lack of portable and cost-effective devices that not only focus on improving motor functions but also address sensory deficits. Thus, we designed a minimally-actuated hand training device that incorporates active grasping movements and passive pronosupination, complemented by a rehabilitative game with meaningful haptic feedback. Following a human-centered design approach, we conducted a usability study with 13 healthy participants, including three therapists. In a simulated unsupervised environment, the naive participants had to set up and use the device based on written instructions. Our mixed-methods approach included quantitative data from performance metrics, standardized questionnaires, and eye tracking, alongside qualitative feedback from semi-structured interviews. The study results highlighted the device's overall ease of setup and use, as well as its realistic haptic feedback. The eye-tracking analysis further suggested that participants felt safe during usage. Moreover, the study provided crucial insights for future improvements such as a more intuitive and comfortable wrist fixation, more natural pronosupination movements, and easier-to-follow instructions. Our research underscores the importance of continuous testing in the development process and offers significant contributions to the design of user-friendly, unsupervised neurorehabilitation technologies to improve sensorimotor stroke rehabilitation.

Abstract Background Fatigue is one of the most commonly reported symptoms after subarachnoid hemorrhage (SAH) and is indirectly associated with physical activity (PA). Associations between fatigue and PA are primarily examined based on conventional measures (i.e. a single fatigue score or average PA levels), thereby assuming that fatigue and PA do not fluctuate over time. However, levels of fatigue and PA may not be stable and may interrelate dynamically in daily life. Insight in direct relationships between fatigue and PA in daily life, could add to the development of personalized rehabilitation strategies. Therefore we aimed to examine bidirectional relationships between momentary fatigue and PA in people with SAH. Methods People (n = 38) with SAH who suffer from chronic fatigue were included in an observational study using Ecological Momentary Assessment (EMA) and accelerometry. Momentary fatigue was assessed on a scale from 1 to 7 (no to extreme fatigue), assessed with 10–11 prompts per day for 7 consecutive days using EMA with a mobile phone. PA was continuously measured during this 7-day period with a thigh-worn Activ8 accelerometer and expressed as total minutes of standing, walking, running and cycling in a period of 45 min before and after a momentary fatigue prompt. Multilevel mixed model analyses including random effects were conducted. Results Mean age was 53.2 years (SD = 13.4), 58% female, and mean time post SAH onset was 9.5 months (SD = 2.1). Multilevel analyses with only time effects to predict fatigue and PA revealed that fatigue significantly (p

Purpose: To systematically review the risk of permanent disability related to road traffic injuries (RTIs) and to determine the implications for future research regarding permanent impairment following road traffic crashes. Methods: We conducted this systematic review according to the preferred reporting items for systematic reviews and meta-analysis statement. An extended search of the literature was carried out in 4 major electronic databases for scientific research papers published from January 1980 to February 2020. Two teams include 2 reviewers each, screened independently the titles/abstracts, and after that, reviewed the full text of the included studies. The quality of the studies was assessed using the strengthening the reporting of observational studies in epidemiology (STROBE) checklist. A third reviewer was assessed any discrepancy and all data of included studies were extracted. Finally, the data were systematically analyzed, and the related data were interpreted. Results: Five out of 16 studies were evaluated as high-quality according to the STROBE checklist. Fifteen studies ranked the initial injuries according to the abbreviated injury scale 2005. Five studies reported the total risk of permanent medical impairment following RTIs which varied from 2% to 23% for car occupants and 2.8% to 46% for cyclists. Seven studies reported the risk of permanent medical impairment of the different body regions. Eleven studies stated the most common body region to develop permanent impairment, of which 6 studies demonstrated that injuries of the cervical spine and neck were at the highest risk of becoming permanent injured. Conclusion: The finding of this review revealed the necessity of providing a globally validated method to evaluate permanent medical impairment following RTIs across the world. This would facilitate decision-making about traffic injuries and efficient management to reduce the financial and psychological burdens for individuals and communities.

Abstract Introduction The International Consortium for Health Outcomes Measurement (ICHOM) developed a standard set of patient-centered outcome measures for use in stroke patients. In addition to the Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health, it is comprised of 25 questions that are not part of a specific questionnaire. This study aimed to translate these 25 single questions into Dutch. Methods Two native Dutch-speaking translators independently translated the original ICHOM questions into Dutch. A consensus translation was made by these translators and a third person. This translation was subsequently translated back to English independently by two native English-speaking translators. Afterwards a pre-final version was made by consensus of a committee. After field-testing among 30 stroke patients, a final version was made. Results The forward and backward translations led to eight cross-cultural adaptations. Based on the interviews with stroke patients, 12 questions were changed to enhance comprehensibility leading to a final Dutch translation of the 25 single questions. Conclusions A Dutch translation of the 25 single questions of the ICHOM Standard Set for Stroke was developed. Now a complete ICHOM Standard Set for Stroke can be used in Dutch populations allowing comparison and improvement of stroke care.

Abstract Traumatic events that affect physiology and behavior in the current generation may also impact future generations. We demonstrate that an ecologically realistic degree of predation risk prior to conception causes lasting changes in the first filial (F1) and second filial (F2) generations. We exposed male and female mice to a live rat (predator stress) or control (non-predator) condition for 5 min. Ten days later, stressed males and females were bred together as were control males and females. Adult F1 offspring from preconception-stressed parents responded to a mild stressor with more anxiety-like behavior and hyperarousal than offspring from control parents. Exposing these F1 offspring to the mild stressor increased neuronal activity (cFOS) in the hippocampus and altered glucocorticoid system function peripherally (plasma corticosterone levels). Even without the mild stressor, F1 offspring from preconception-stressed parents still exhibited more anxiety-like behaviors than controls. Cross-fostering studies confirmed that preconception stress, not maternal social environment, determined offspring behavioral phenotype. The effects of preconception parental stress were also unexpectedly persistent and produced similar behavioral phenotypes in the F2 offspring. Our data illustrate that a surprisingly small amount of preconception predator stress alters the brain, physiology, and behavior of future generations. A better understanding of the ‘long shadow’ cast by fearful events is critical for understanding the adaptive costs and benefits of transgenerational plasticity. It also suggests the intriguing possibility that similar risk-induced changes are the rule rather than the exception in free-living organisms, and that such multigenerational impacts are as ubiquitous as they are cryptic.

Abstract Background Upper limb impairments in a hemiparetic arm are clinically quantified by well-established clinical scales, known to suffer poor validity, reliability, and sensitivity. Alternatively, robotics can assess motor impairments by characterizing joint dynamics through system identification. In this study, we establish the merits of quantifying abnormal synergy, spasticity, and changes in joint viscoelasticity using system identification, evaluating (1) feasibility and quality of parametric estimates, (2) test–retest reliability, (3) differences between healthy controls and patients with upper limb impairments, and (4) construct validity. Methods Forty-five healthy controls, twenty-nine stroke patients, and twenty cerebral palsy patients participated. Participants were seated with the affected arm immobilized in the Shoulder-Elbow-Perturbator (SEP). The SEP is a one-degree-of-freedom perturbator that enables applying torque perturbations to the elbow while providing varying amounts of weight support to the human arm. Participants performed either a ‘do not intervene’ or a resist task. Elbow joint admittance was quantified and used to extract elbow viscosity and stiffness. Fifty-four of the participants performed two sessions to establish the test–retest reliability of the parameters. Construct validity was assessed by correlating system identification parameters to parameters extracted using a SEP protocol that objectifies current clinical scales (Re-Arm protocol). Results Feasibility was confirmed by all participants successfully completing the study protocol within ~ 25 min without reporting pain or burden. The parametric estimates were good with a variance-accounted-for of ~ 80%. A fair to excellent test–retest reliability was found ( $$ICC = 0.46-0.98$$ I C C = 0.46 - 0.98 ) for patients, except for elbow stiffness with full weight support ( $$ICC = 0.35$$ I C C = 0.35 ). Compared to healthy controls, patients had a higher elbow viscosity and stiffness during the ‘do not intervene’ task and lower viscosity and stiffness during the resist task. Construct validity was confirmed by a significant (all $$p

Abstract Monotherapy with Menin inhibitor (MI), e.g., SNDX-5613, induces clinical remissions in patients with relapsed/refractory AML harboring MLL1-r or mtNPM1, but most patients either fail to respond or eventually relapse. Utilizing single-cell RNA-Seq, ChiP-Seq, ATAC-Seq, RNA-Seq, RPPA, and mass cytometry (CyTOF) analyses, present pre-clinical studies elucidate gene-expression correlates of MI efficacy in AML cells harboring MLL1-r or mtNPM1. Notably, MI-mediated genome-wide, concordant, log2 fold-perturbations in ATAC-Seq and RNA-Seq peaks were observed at the loci of MLL-FP target genes, with upregulation of mRNAs associated with AML differentiation. MI treatment also reduced the number of AML cells expressing the stem/progenitor cell signature. A protein domain-focused CRISPR-Cas9 screen in MLL1-r AML cells identified targetable co-dependencies with MI treatment, including BRD4, EP300, MOZ and KDM1A. Consistent with this, in vitro co-treatment with MI and BET, MOZ, LSD1 or CBP/p300 inhibitor induced synergistic loss of viability of AML cells with MLL1-r or mtNPM1. Co-treatment with MI and BET or CBP/p300 inhibitor also exerted significantly superior in vivo efficacy in xenograft models of AML with MLL1-r. These findings highlight novel, MI-based combinations that could prevent escape of AML stem/progenitor cells following MI monotherapy, which is responsible for therapy-refractory AML relapse.

Objective: To examine the daily course of, and factors associated with, momentary fatigue after subarachnoid haemorrhage, and to explore subgroups of patients with distinct diurnal patterns of fatigue. Design: Observational study using ecological momentary assessment. Subjects: A total of 41 participants with subarachnoid haemorrhage. Methods: Patients with fatigue were included within one year post-onset. Momentary fatigue (scale 1–7) was assessed with repeated measurements (10–11 times/day) during 7 consecutive days. Multilevel-mixed-model analyses and latent-class trajectory modelling were conducted. Results: Mean (standard deviation; SD) age of the group was 53.9 (13.0) years, 56% female, and mean (SD) time post-subarachnoid haemorrhage onset was 9.3 (3.2) months. Mean (SD) momentary fatigue over all days was 3.22 (1.47). Fatigue increased significantly (p

BackgroundMany patients with SARS-CoV-2 infection develop long COVID with fatigue as one of the most disabling symptoms. We performed clinical and immune profiling of fatigued and non-fatigued long COVID patients and age- and sex-matched healthy controls (HCs).MethodsLong COVID symptoms were assessed using patient-reported outcome measures, including the fatigue assessment scale (FAS, scores ≥22 denote fatigue), and followed up to one year after hospital discharge. We assessed inflammation-related genes in circulating monocytes, serum levels of inflammation-regulating cytokines, and leukocyte and lymphocyte subsets, including major monocyte subsets and senescent T-lymphocytes, at 3-6 months post-discharge.ResultsWe included 37 fatigued and 36 non-fatigued long COVID patients and 42 HCs. Fatigued long COVID patients represented a more severe clinical profile than non-fatigued patients, with many concurrent symptoms (median 9 [IQR 5.0-10.0] vs 3 [1.0-5.0] symptoms, p24%). Immune abnormalities that were found in the entire group of long COVID patients were low grade inflammation (increased inflammatory gene expression in monocytes, increased serum pro-inflammatory cytokines) and signs of T-lymphocyte senescence (increased exhausted CD8+ TEMRA-lymphocytes). Immune profiles did not significantly differ between fatigued and non-fatigued long COVID groups. However, the severity of fatigue (total FAS score) significantly correlated with increases of intermediate and non-classical monocytes, upregulated gene levels of CCL2, CCL7, and SERPINB2 in monocytes, increases in serum Galectin-9, and higher CD8+ T-lymphocyte counts.ConclusionLong COVID with fatigue is associated with many concurrent and persistent symptoms lasting up to one year after hospitalization. Increased fatigue severity associated with stronger signs of monocyte activation in long COVID patients and potentially point in the direction of monocyte-endothelial interaction. These abnormalities were present against a background of immune abnormalities common to the entire group of long COVID patients.

Arterial dysfunction is major risk factor for cardiovascular complications, and arterial stiffness is an independent risk factor in end-stage renal disease patients. As the distance from the heart increases, arterial stiffness (pulse wave velocity) becomes progressively more marked. This generates a centrifugal stiffness gradient, which leads to partial, continuous local wave reflections, which in turn attenuate the transmission of pulsatile pressure into the microcirculation, thus limiting the potentially deleterious outcomes both upstream (on the heart: left-ventricular hypertrophy and coronary perfusion) and downstream (on the renal and cerebral microcirculation: reduced glomerular filtration and impaired cognitive functions). The impact of arterial aging is greater on the aorta and central capacitive arteries, and it is characterized by a loss or reversal of the physiological stiffness gradient between central and peripheral arteries. Recently, however, in contrast to observations on the aorta, several studies have shown less pronounced, absent, or even negative associations between muscular peripheral arteries and age–stiffness relationships, which may be associated with a decrease in or reversal of the stiffness gradient. These findings point to a potential benefit of assessing the muscular peripheral arteries to predict the risk of cardiovascular disease and suggest that reversal of the stiffness gradient may be an independent risk factor for all-cause mortality.

Abstract Background Systemic inflammation is associated with skeletal muscle atrophy and metabolic dysfunction. Although the nucleotide‐binding oligomerization domain‐like receptor family pyrin domain containing 3 (NLRP3) inflammasome contributes to cytokine production in immune cells, its role in skeletal muscle is poorly understood. Here, we studied the link between inflammation, NLRP3, muscle morphology, and metabolism in in vitro cultured C2C12 myotubes, independent of immune cell involvement. Methods Differentiated C2C12 myotubes were treated with lipopolysaccharide (LPS; 0, 10, and 100–200 ng/mL) to induce activation of the NLRP3 inflammasome with and without MCC950, a pharmacological inhibitor of NLRP3‐induced IL‐1β production. We assessed markers of the NLRP3 inflammasome, cell diameter, reactive oxygen species, and mitochondrial function. Results NLRP3 gene expression and protein concentrations increased in a time‐dependent and dose‐dependent manner. Intracellular IL‐1β concentration significantly increased (P

Abstract The human inner ear contains minute three-dimensional neurosensory structures that are deeply embedded within the skull base, rendering them relatively inaccessible to regenerative therapies for hearing loss. Here we provide a detailed characterisation of the functional architecture of the space that hosts the cell bodies of the auditory nerve to make them safely accessible for the first time for therapeutic intervention. We used synchrotron phase-contrast imaging which offers the required microscopic soft-tissue contrast definition while simultaneously displaying precise bony anatomic detail. Using volume-rendering software we constructed highly accurate 3-dimensional representations of the inner ear. The cell bodies are arranged in a bony helical canal that spirals from the base of the cochlea to its apex; the canal volume is 1.6 μL but with a diffusion potential of 15 μL. Modelling data from 10 temporal bones enabled definition of a safe trajectory for therapeutic access while preserving the cochlea’s internal architecture. We validated the approach through surgical simulation, anatomical dissection and micro-radiographic analysis. These findings will facilitate future clinical trials of novel therapeutic interventions to restore hearing.

Summary: Background: Limited evidence existed on the comparative effectiveness of decompressive craniectomy (DC) versus craniotomy for evacuation of traumatic acute subdural hematoma (ASDH) until the recently published randomised clinical trial RESCUE-ASDH. In this study, that ran concurrently, we aimed to determine current practice patterns and compare outcomes of primary DC versus craniotomy. Methods: We conducted an analysis of centre treatment preference within the prospective, multicentre, observational Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (known as CENTER-TBI) and NeuroTraumatology Quality Registry (known as Net-QuRe) studies, which enrolled patients throughout Europe and Israel (2014–2020). We included patients with an ASDH who underwent acute neurosurgical evacuation. Patients with severe pre-existing neurological disorders were excluded. In an instrumental variable analysis, we compared outcomes between centres according to treatment preference, measured by the case-mix adjusted proportion DC per centre. The primary outcome was functional outcome rated by the 6-months Glasgow Outcome Scale Extended, estimated with ordinal regression as a common odds ratio (OR), adjusted for prespecified confounders. Variation in centre preference was quantified with the median odds ratio (MOR). CENTER-TBI is registered with ClinicalTrials.gov, number NCT02210221, and the Resource Identification Portal (Research Resource Identifier SCR_015582). Findings: Between December 19, 2014 and December 17, 2017, 4559 patients with traumatic brain injury were enrolled in CENTER-TBI of whom 336 (7%) underwent acute surgery for ASDH evacuation; 91 (27%) underwent DC and 245 (63%) craniotomy. The proportion primary DC within total acute surgery cases ranged from 6 to 67% with an interquartile range (IQR) of 12–26% among 46 centres; the odds of receiving a DC for prognostically similar patients in one centre versus another randomly selected centre were trebled (adjusted median odds ratio 2.7, p

IntroductionPancreatic cancer is associated with poor prognosis, and limited treatment options are available for the majority of patients. Natural killer (NK) cells in combination with antibodies inducing antibody-dependent cell-mediated cytotoxicity (ADCC) could be a highly effective new therapeutic option in pancreatic cancer. Accurate predictive preclinical models are needed to develop successful NK cell immunotherapy. Tumor organoids, in vitro 3D organ-like structures that retain important pathophysiological characteristics of the in vivo tumor, may provide such a model. In the current study, we assessed the cytotoxic potential of adoptive NK cells against human pancreatic cancer organoids. We hypothesized that NK cell anti-tumor responses could be enhanced by including ADCC-triggering antibodies.MethodsWe performed cytotoxicity assays with healthy donor-derived IL-2-activated NK cells and pancreatic cancer organoids from four patients. A 3D cytotoxicity assay using live-cell-imaging was developed and enabled real-time assessment of the response.ResultsWe show that NK cells migrate to and target pancreatic cancer organoids, resulting in an increased organoid death, compared to the no NK cell controls (reaching an average fold change from baseline of 2.1±0.8 vs 1.4±0.6). After 24-hours of co-culture, organoid 2D growth increased. Organoids from 2 out of 4 patients were sensitive to NK cells, while organoids from the other two patients were relatively resistant, indicating patient-specific heterogeneity among organoid cultures. The ADCC-inducing antibodies avelumab (anti-PD-L1) and trastuzumab (anti-HER2) increased NK cell-induced organoid cell death (reaching an average fold change from baseline of 3.5±1.0 and 4.5±1.8, respectively). Moreover, combination therapy with avelumab or trastuzumab resulted in complete disintegration of organoids. Finally, inclusion of ADCC-inducing antibodies was able to overcome resistance in NK-organoid combinations with low or no kill.DiscussionThese results support the use of organoids as a relevant and personalized model to study the anti-tumor response of NK cells in vitro and the potential of ADCC-inducing antibodies to enhance NK cell effector function.

Background: Emerging data suggest that dose-sparing several key cardiac regions is prognostically beneficial in lung cancer radiotherapy. The cardiac substructures are challenging to contour due to their complex geometry, poor soft tissue definition on computed tomography (CT) and cardiorespiratory motion artefact. A neural network was previously trained to generate the cardiac substructures using three-dimensional radiotherapy planning CT scans (3D-CT). In this study, the performance of that tool on the average intensity projection from four-dimensional (4D) CT scans (4D-AVE), now commonly used in lung radiotherapy, was evaluated. Materials and Methods: The 4D-AVE of n=20 patients completing radiotherapy for lung cancer 2015–2020 underwent manual and automated cardiac substructure segmentation. Manual and automated substructures were compared geometrically and dosimetrically. Two senior clinicians also qualitatively assessed the auto-segmentation tool’s output. Results: Geometric comparison of the automated and manual segmentations exhibited high levels of similarity across parameters, including volume difference (11.8% overall) and Dice similarity coefficient (0.85 overall), and were consistent with 3D-CT performance. Differences in mean (median 0.2 Gy, range −1.6–0.3 Gy) and maximum (median 0.4 Gy, range −2.2–0.9 Gy) doses to substructures were generally small. Nearly all structures (99.5 %) were deemed to be appropriate for clinical use without further editing. Conclusions: Cardiac substructure auto-segmentation using a deep learning-based tool trained on a 3D-CT dataset was feasible on the 4D-AVE scan, meaning this tool is suitable for use on 4D-CT radiotherapy planning scans. Application of this tool would increase the practicality of routine clinical cardiac substructure delineation, and enable further cardiac radiation effects research.

Background and purpose: Radiomics features derived from medical images have the potential to act as imaging biomarkers to improve diagnosis and predict treatment response in oncology. However, the complex relationships between radiomics features and the biological characteristics of tumours are yet to be fully determined. In this study, we developed a preclinical cone beam computed tomography (CBCT) radiomics workflow with the aim to use in vivo models to further develop radiomics signatures. Materials and methods: CBCT scans of a mouse phantom were acquired using onboard imaging from a small animal radiotherapy research platform (SARRP, Xstrahl). The repeatability and reproducibility of radiomics outputs were compared across different imaging protocols, segmentation sizes, pre-processing parameters and materials. Robust features were identified and used to compare scans of two xenograft mouse tumour models (A549 and H460). Results: Changes to the radiomics workflow significantly impact feature robustness. Preclinical CBCT radiomics analysis is feasible with 119 stable features identified from scans imaged at 60 kV, 25 bin width and 0.26 mm slice thickness. Large variation in segmentation volumes reduced the number of reliable radiomics features for analysis. Standardization in imaging and analysis parameters is essential in preclinical radiomics analysis to improve accuracy of outputs, leading to more consistent and reproducible findings. Conclusions: We present the first optimised workflow for preclinical CBCT radiomics to identify imaging biomarkers. Preclinical radiomics has the potential to maximise the quantity of data captured in in vivo experiments and could provide key information supporting the wider application of radiomics.

Abstract Background Angiography and embolization (AE) is a lifesaving, high radiation dose procedure for treatment of abdominal arterial hemorrhage (AAH). Interventional radiologists have utilized pre-procedure CT angiography (CTA) and newer fluoroscopic systems in an attempt to reduce radiation dose and procedure time. Purpose To study the factors contributing to the radiation dose of AE for AAH and to compare to the reference standard. Materials and methods This retrospective single-centre observational cohort study identified 154 consecutive AE procedures in 138 patients (median age 65 years; interquartile range 54–77; 103 men) performed with a C-arm fluoroscopic system (Axiom Artis DTA or Axiom Artis Q (Siemens Healthineers)), between January 2010 and December 2017. Parameters analysed included: demographics, fluoroscopy system, bleeding location, body mass index (BMI), preprocedural CT, air kerma-area product (PKA), reference air kerma (Ka,r), fluoroscopy time (FT) and the number of digital subtraction angiography (DSA) runs. Factors affecting dose were assessed using Mann–Whitney U, Kruskal–Wallis one-way ANOVA and linear regression. Results Patients treated with the new angiographic system (NS) had a median PKA, median Ka,r, Q3 PKA and Q3 Ka,r that were 74% (p

Abstract Treatment with Menin inhibitor (MI) disrupts the interaction between Menin and MLL1 or MLL1-fusion protein (FP), inhibits HOXA9/MEIS1, induces differentiation and loss of survival of AML harboring MLL1 re-arrangement (r) and FP, or expressing mutant (mt)-NPM1. Following MI treatment, although clinical responses are common, the majority of patients with AML with MLL1-r or mt-NPM1 succumb to their disease. Pre-clinical studies presented here demonstrate that genetic knockout or degradation of Menin or treatment with the MI SNDX-50469 reduces MLL1/MLL1-FP targets, associated with MI-induced differentiation and loss of viability. MI treatment also attenuates BCL2 and CDK6 levels. Co-treatment with SNDX-50469 and BCL2 inhibitor (venetoclax), or CDK6 inhibitor (abemaciclib) induces synergistic lethality in cell lines and patient-derived AML cells harboring MLL1-r or mtNPM1. Combined therapy with SNDX-5613 and venetoclax exerts superior in vivo efficacy in a cell line or PD AML cell xenografts harboring MLL1-r or mt-NPM1. Synergy with the MI-based combinations is preserved against MLL1-r AML cells expressing FLT3 mutation, also CRISPR-edited to introduce mtTP53. These findings highlight the promise of clinically testing these MI-based combinations against AML harboring MLL1-r or mtNPM1.

Abstract Background Stroke survivors show deteriorated physical functioning and physical activity levels. Physical activity levels of stroke survivors are generally low. It is increasingly recognized that physical activity is a multidimensional construct that cannot be captured in a single outcome. In-depth insight into multidimensional physical activity patterns may guide the development and timing of targeted rehabilitation interventions. This longitudinal cohort study explored how multidimensional physical activity outcomes develop during recovery in the subacute phase after stroke and if changes in physical activity were correlated to recovery of lower limb motor function. Methods Patients were recruited during inpatient rehabilitation. At 3, 12, and 26 weeks post-onset, motor function was measured by the Fugl-Meyer Lower Extremity Assessment (FMA-LE). Physical activity was measured with the Activ8 accelerometer in multiple outcomes: counts per minute during walking (CPMwalking; a measure of Intensity), number of active bouts (Frequency), mean length of active bouts (Distribution) and % of waking time in upright positions (Duration). Generalized estimating equations (GEE) were used to study changes in physical activity over time and the relation with the change in lower limb motor recovery. Results Thirty-nine patients (age 56 ± 9, 77% male, 89% ischemic stroke) were included. GEE models showed a significant main effect of time for PA Intensity (+ 13%, p = 0.007) and Duration (+ 64%, p = 0.012) between 3 and 12 weeks. Motor function did not show a significant effect in all PA models across the 3 timepoints (p > 0.020). A significant interaction effect of time × motor function was observed (p

The unique shape and size dependant properties of nanoparticles (NPs) are responsible for their emerging, extensive applications in everyday industry. The application of NP inks for printed flexible electronics requires an additional post processing step since the presence of additives and stabilizers in the NP based inks often results in inferior electrical properties of the printed patterns. Laser sintering is a well-established technique for past number of years and is extensively used with continuous wave (CW), long, and short pulsed lasers. The literature is enriched with conventional sintering methods however the field of ultrashort laser sintering is relatively under-reported compared to CW laser and nanosecond laser-based techniques. This study concisely focuses on the potential use of ultrashort laser pulse processing of NPs and NP based thin films. The review provides the recent advances on ultrashort lasers sintering with a key focus on femtosecond laser pulses.

Aging has a significant impact on physiology with implications for central nervous system function coincident with increased vulnerability to stress exposures. A number of stress-sensitive molecular mechanisms are hypothesized to underpin age-related changes in brain function. Recent cumulative evidence also suggests that aging impacts gut microbiota composition. However, the impact of such effects on the ability of mammals to respond to stress in aging is still relatively unexplored. Therefore, in this study we assessed the ability of a microbiota-targeted intervention (the prebiotic FOS-Inulin) to alleviate age-related responses to stress. Exposure of aged C57BL/6 mice to social defeat led to an altered social interaction phenotype in the social interaction test, which was reversed by FOS-Inulin supplementation. Interestingly, this occured independent of affecting social defeat-induced elevations in the stress hormone corticosterone. Additionally, the behavioral modifications following FOS-Inulin supplementation were also not coincident with improvement of pro-inflammatory markers. Metabolomics analysis was performed and intriguingly, age associated metabolites were shown to be reduced in the prefrontal cortex of stressed aged mice and this deficit was recovered by FOS-Inulin supplementation. Taken together these results suggest that prebiotic dietary intervention rescued the behavioral response to stress in aged mice, not through amelioration of the inflammatory response, but by restoring the levels of key metabolites in the prefrontal cortex of aged animals. Therefore, dietary interventions could be a compelling avenue to improve the molecular and behavioral manifestations of chronic stress exposures in aging via targeting the microbiota-gut brain axis.

Introduction A large proportion of patients experience a wide range of sequelae after acute COVID-19, especially after severe illness. The long-term health sequelae need to be assessed. Our objective was to longitudinally assess persistence of symptoms and clusters of symptoms up to 12 months after hospitalisation for COVID-19 and to assess determinants of the main persistent symptoms. Methods In this multicenter prospective cohort study patients with COVID-19 are followed up for 2 years with measurements at 3, 6, 12 and 24 months after hospital discharge. Here, we present interim results regarding persistent symptoms up to 12 months. Results We included 492 patients; mean±sd age was 60.2±10.7 years, 335 (68.1%) were males, median length of hospital stay was 11 (6.0–27.0) days. At 3 months after discharge 97.0% of the patients had at least one persisting symptom, this declined to 95.5% and 92.0% at 6 and 12 months, respectively (p=0.010). Muscle weakness, exertional dyspnoea, fatigue, and memory and concentration problems were the most prevalent symptoms with rates over 50% during follow-up. Over time, muscle weakness, hair loss and exertional dyspnoea decreased significantly (p

Abstract Background First studies indicate that up to 6 months after hospital discharge, coronavirus disease 2019 (COVID-19) causes severe physical, cognitive, and psychological impairments, which may affect participation and health-related quality of life (HRQoL). After hospitalization for COVID-19, a number of patients are referred to medical rehabilitation centers or skilled nursing facilities for further treatment, while others go home with or without aftercare. The aftercare paths include 1] community-based rehabilitation; 2] in- and outpatient medical rehabilitation; 3] inpatient rehabilitation in skilled nursing facilities; and 4] sheltered care (inpatient). These aftercare paths and the trajectories of recovery after COVID-19 urgently need long-term in-depth evaluation to optimize and personalize treatment. CO-FLOW aims, by following the outcomes and aftercare paths of all COVID-19 patients after hospital discharge, to systematically study over a 2-year period: 1] trajectories of physical, cognitive, and psychological recovery; 2] patient flows, healthcare utilization, patient satisfaction with aftercare, and barriers/facilitators regarding aftercare as experienced by healthcare professionals; 3] effects of physical, cognitive, and psychological outcomes on participation and HRQoL; and 4] predictors for long-term recovery, health care utilization, and patient satisfaction with aftercare. Methods CO-FLOW is a multicenter prospective cohort study in the mid-west of the Netherlands with a 2-year follow-up period. Measurements comprise non-invasive clinical tests and patient reported outcome measures from a combined rehabilitation, pulmonary, and intensive care perspective. Measurements are performed at 3, 6, 12, and 24 months after hospital discharge and, if applicable, at rehabilitation discharge. CO-FLOW aims to include at least 500 patients who survived hospitalization for COVID-19, aged ≥18 years. Discussion CO-FLOW will provide in-depth knowledge on the long-term sequelae of COVID-19 and the quality of current aftercare paths for patients who survived hospitalization. This knowledge is a prerequisite to facilitate the right care in the right place for COVID-19 and comparable future infectious diseases. Trial registration The Netherlands Trial Register (NTR), https://www.trialregister.nl . Registered: 12-06-2020, CO-FLOW trialregister no. NL8710.

Abstract Due to their efficient recognition and lysis of malignant cells, natural killer (NK) cells are considered as specialized immune cells that can be genetically modified to obtain capable effector cells for adoptive cellular treatment of cancer patients. However, biological and technical hurdles related to gene delivery into NK cells have dramatically restrained progress. Recent technological advancements, including improved cell expansion techniques, chimeric antigen receptors (CAR), CRISPR/Cas9 gene editing and enhanced viral transduction and electroporation, have endowed comprehensive generation and characterization of genetically modified NK cells. These promising developments assist scientists and physicians to design better applications of NK cells in clinical therapy. Notably, redirecting NK cells using CARs holds important promise for cancer immunotherapy. Various preclinical and a limited number of clinical studies using CAR-NK cells show promising results: efficient elimination of target cells without side effects, such as cytokine release syndrome and neurotoxicity which are seen in CAR-T therapies. In this review, we focus on the details of CAR-NK technology, including the design of efficient and safe CAR constructs and associated NK cell engineering techniques: the vehicles to deliver the CAR-containing transgene, detection methods for CARs, as well as NK cell sources and NK cell expansion. We summarize the current CAR-NK cell literature and include valuable lessons learned from the CAR-T cell field. This review also provides an outlook on how these approaches may transform current clinical products and protocols for cancer treatment.

Purpose: Injuries are one of the leading causes of death and lead to a high social and financial burden. Injury patterns can vary significantly among different age groups and body regions. This study aimed to evaluate the relationship between mechanism of injury, patient comorbidities and severity of injuries. Methods: The study included trauma patients from July 2016 to June 2018, who were admitted to Sina Hospital, Tehran, Iran. The inclusion criteria were all injured patients who had at least one of the following: hospital length of stay more than 24 h, death in hospital, and transfer from the intensive care unit of another hospital. Data collection was performed using the National Trauma Registry of Iran minimum dataset. Results: The most common injury mechanism was road traffic injuries (49.0%), followed by falls (25.5%). The mean age of those who fell was significantly higher in comparison with other mechanisms (p

This study aims to evaluate the feasibility and explore the efficacy of the Arm Activity Tracker (AAT). The AAT is a device based on wrist-worn accelerometers that provides visual and tactile feedback to stimulate daily life upper extremity (UE) activity in stroke patients. Methods: A randomised, crossover within-subject study was conducted in sub-acute stroke patients admitted to a rehabilitation centre. Feasibility encompassed (1) adherence: the dropout rate and the number of participants with insufficient AAT data collection; (2) acceptance: the technology acceptance model (range: 7–112) and (3) usability: the system usability scale (range: 0–100). A two-way ANOVA was used to estimate the difference between the baseline, intervention and control conditions for (1) paretic UE activity and (2) UE activity ratio. Results: Seventeen stroke patients were included. A 29% dropout rate was observed, and two participants had insufficient data collection. Participants who adhered to the study reported good acceptance (median (IQR): 94 (77–111)) and usability (median (IQR): 77.5 (75–78.5)-). We found small to medium effect sizes favouring the intervention condition for paretic UE activity (η2G = 0.07, p = 0.04) and ratio (η2G = 0.11, p = 0.22). Conclusion: Participants who adhered to the study showed good acceptance and usability of the AAT and increased paretic UE activity. Dropouts should be further evaluated, and a sufficiently powered trial should be performed to analyse efficacy.

Abstract Background It is unclear how arm use in daily life changes after stroke since studies investigating the change in arm use poststroke are scarce. The aim of this study was to investigate the change in arm use during the first six months poststroke. Secondary aim was to compare arm use changes between arm recovery clusters. Methods Arm use was measured during week 3, 12, and 26 poststroke with accelerometers on the wrists and the nonaffected leg. Outcomes were the amount of affected and nonaffected arm use during sitting and standing per day and per sit/stand hour, and the daily ratio between arms. Arm function was measured with the Fugl-Meyer Upper Extremity Scale to identify recovery clusters (poor/moderate/excellent). Generalized estimating equations compared arm use outcomes between time points and between recovery clusters. Results Thirty-three stroke patients participated. Affected arm use per day increased between week 3 and 12 (30 %; p = 0.04) and it increased per sit/stand hour between week 3–12 (31 %; p

Abstract Background Prolonged disorders of consciousness (PDOC) may occur after severe brain injury. Two diagnostic entities are distinguished within PDOC: unresponsive wakefulness syndrome (UWS, previously known as vegetative state) and minimally conscious state (MCS). Patients with PDOC may benefit from early intensive neurorehabilitation (EIN). In the Netherlands, the EIN programme is provided by one designated expert rehabilitation centre and forms the starting point of a dedicated chain of specialised rehabilitation and care for this group. This study project, called DOCTOR: Disorders of Consciousness; Treatment and Outcomes Registry, sets up a registry and systematically investigates multiple short- and long-term outcomes of patients with PDOC who receive EIN. Methods Single-centre prospective cohort study with a 2-year follow-up period. Patients with PDOC due to acute brain injury who receive EIN, aged 16 years and older are included. Measurements will take place at start EIN, in week 5, 10, and at discharge from the EIN programme (duration = max 14 weeks) and at week 28, 40, 52, and 104 after admission to the EIN programme, following patients through the health-care chain. Outcome measures are the changes over time in level of consciousness, using the Coma Recovery Scale-Revised; the frequency and type of medical complications; the mortality rate; level of disability, including the level of motor, cognitive, behavioural and emotional functioning; participation; and quality of life. Secondary outcomes include self-efficacy of caregivers, caregivers’ strain and cost-effectiveness of the programme. Discussion The DOCTOR study will provide insight in the recovery patterns and predictors of recovery for multiple outcomes in PDOC patients after following EIN. The results of the study will enable us to benchmark and improve EIN and the organisation of the health-care chain, both for patients with PDOC and for their families. Trial registration Netherlands Trial Register, NL 8138 . Retrospectively registered 6 November 2019.

Background: Transcranial direct current stimulation (tDCS) has emerged as a non-invasive brain stimulation technique. Most studies show that anodal tDCS increases cortical excitability. However, this effect has been found to be highly variable. Objective: To test the effect of anodal tDCS on cortical excitability and the interaction effect of two participant-specific factors that may explain individual differences in sensitivity to anodal tDCS: the Brain Derived Neurotrophic Factor Val66Met polymorphism (BDNF genotype) and the latency difference between anterior-posterior and lateromedial TMS pulses (APLM latency). Methods: In 62 healthy participants, cortical excitability over the left motor cortex was measured before and after anodal tDCS at 2 mA for 20 min in a pre-registered, double-blind, randomized, placebo-controlled trial with repeated measures. Results: We did not find a main effect of anodal tDCS, nor an interaction effect of the participant-specific predictors. Moreover, further analyses did not provide evidence for the existence of responders and non-responders. Conclusion: This study indicates that anodal tDCS at 2 mA for 20 min may not reliably affect cortical excitability.

Glioblastoma (GBM) accounts for over 50% of gliomas and carries the worst prognosis of all solid tumors. Owing to the limited local control afforded by surgery alone, efficacious adjuvant treatments such as radiotherapy (RT) and chemotherapy are fundamental in achieving durable disease control. The best clinical outcomes are achieved with tri-modality treatment consisting of surgery, RT and systemic therapy. While RT-chemotherapy combination regimens are well established in oncology, this approach was largely unsuccessful in GBM until the introduction of temozolomide. The success of this combination has stimulated the search for other candidate drugs for concomitant use with RT in GBM. This review seeks to collate the current evidence for these agents and synthesize possible future directions for the field.

Transcranial direct current stimulation (tDCS) over the contralateral primary motor cortex of the target muscle (conventional tDCS) has been described to enhance corticospinal excitability, as measured with transcranial magnetic stimulation. Recently, tDCS targeting the brain regions functionally connected to the contralateral primary motor cortex (motor network tDCS) was reported to enhance corticospinal excitability more than conventional tDCS. We compared the effects of motor network tDCS, 2 mA conventional tDCS, and sham tDCS on corticospinal excitability in 21 healthy participants in a randomized, single-blind within-subject study design. We applied tDCS for 12 min and measured corticospinal excitability with TMS before tDCS and at 0, 15, 30, 45, and 60 min after tDCS. Statistical analysis showed that neither motor network tDCS nor conventional tDCS significantly increased corticospinal excitability relative to sham stimulation. Furthermore, the results did not provide evidence for superiority of motor network tDCS over conventional tDCS. Motor network tDCS seems equally susceptible to the sources of intersubject and intrasubject variability previously observed in response to conventional tDCS.

Objective: To determine whether fatigue is associated with participation and health-related quality of life 5 years after perimesencephalic subarachnoid haemorrhage. Design: Multicentre cross-sectional study. Subjects: Forty-six patients with perimesencephalic subarachnoid haemorrhage. Methods: Fatigue was assessed with the Fatigue Severity Scale, participation (frequency, restrictions, satisfaction) with the Utrecht Scale for Evaluation of Rehabilitation-Participation, healthrelated quality of life with the Stroke-Specific Quality of Life Scale-12, symptoms of depression and anxiety with the Hospital Anxiety and Depression Scale, and coping with the Coping Inventory for Stressful Situations. Results: A total of 46 patients were included (63% men, mean age 50.4 ± 9.4 years), with a mean time of 4.7 ± 1.6 years after perimesencephalic subarachnoid haemorrhage onset. Fatigued patients (33%) had worse participation (p < 0.01) and health-related quality of life (p < 0.001) than non-fatigued patients, and more often had hypertension, depression, anxiety and emotion-oriented coping (p < 0.05). Fatigue severity was inversely and independently (p < 0.005) associated with participation frequency (B = –3.62), satisfaction (B = –4.54), having restrictions (odds ratio = 2.48, 95% confidence interval 1.079–5.685), and health-related quality of life (B = –0.19), adjusted for depression, anxiety, and/or hypertension. Conclusion: Five years after perimesencephalic subarachnoid haemorrhage, one-third of patients still reported fatigue, which was associated with worse participation and health-related quality of life. Future studies should examine whether these patients may benefit from rehabilitation aimed at fatigue. LAY ABSTRACT A subarachnoid haemorrhage (SAH) is a subtype of stroke. Of all patients with SAH, approximately 10% are diagnosed with non-aneurysmal perimesencephalic subarachnoid haemorrhage (PM-SAH). PM-SAH is generally considered a benign form of SAH; however we have previously found that one-third of patients with PM-SAH are still fatigued 5 years after PM-SAH. Fatigue may be related to reduced participation and health-related quality of life, both of which are considered important rehabilitation outcomes. Therefore, this study examined whether fatigue is associated with participation and health-related quality of life after PM-SAH. The results showed that, 5 years after PM-SAH, fatigued patients had worse participation and quality of life than non-fatigued patients. In addition, more severe fatigue was associated with worse participation, regarding frequency, satisfaction and restrictions, and with worse health-related quality of life. Further studies are necessary to determine whether patients with PM-SAH may benefit from rehabilitation aimed at fatigue.

Abstract Introduction There has been a recent explosion of research into the field of artificial intelligence as applied to clinical radiology with the advent of highly accurate computer vision technology. These studies, however, vary significantly in design and quality. While recent guidelines have been established to advise on ethics, data management and the potential directions of future research, systematic reviews of the entire field are lacking. We aim to investigate the use of artificial intelligence as applied to radiology, to identify the clinical questions being asked, which methodological approaches are applied to these questions and trends in use over time. Methods and analysis We will follow the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines and by the Cochrane Collaboration Handbook. We will perform a literature search through MEDLINE (Pubmed), and EMBASE, a detailed data extraction of trial characteristics and a narrative synthesis of the data. There will be no language restrictions. We will take a task-centred approach rather than focusing on modality or clinical subspecialty. Sub-group analysis will be performed by segmentation tasks, identification tasks, classification tasks, pegression/prediction tasks as well as a sub-analysis for paediatric patients. Ethics and dissemination Ethical approval will not be required for this study, as data will be obtained from publicly available clinical trials. We will disseminate our results in a peer-reviewed publication. Registration number PROSPERO: CRD42020154790

Lung cancer is the leading cause of cancer mortality worldwide and most patients are unsuitable for ‘gold standard’ treatment, which is concurrent chemoradiotherapy. CONCORDE is a platform study seeking to establish the toxicity profiles of multiple novel radiosensitisers targeting DNA repair proteins in patients treated with sequential chemoradiotherapy. Time-to-event continual reassessment will facilitate efficient dose-finding.

Abstract Background Differentiating combined pulmonary fibrosis with emphysema (CPFE) from pure emphysema can be challenging on high-resolution computed tomography (HRCT). This has antifibrotic therapy implications. Methods Twenty patients with suspected CPFE underwent late gadolinium-enhanced (LGE) thoracic magnetic resonance imaging (LGE-MRI) and HRCT. Data from twelve healthy control subjects from a previous study who underwent thoracic LGE-MRI were included for comparison. Quantitative LGE signal intensity (SI) was retrospectively compared in regions of fibrosis and emphysema in CPFE patients to similar lung regions in controls. Qualitative comparisons for the presence/extent of reticulation, honeycombing, and traction bronchiectasis between LGE-MRI and HRCT were assessed by two readers in consensus. Results There were significant quantitative differences in fibrosis SI compared to emphysema SI in CPFE patients (25.8, IQR 18.4–31.0 versus 5.3, IQR 5.0–8.1, p < 0.001). Significant differences were found between LGE-MRI and HRCT in the extent of reticulation (12.5, IQR 5.0–20.0 versus 25.0, IQR 15.0–26.3, p = 0.038) and honeycombing (5.0, IQR 0.0–10.0 versus 20.0, IQR 10.6–20.0, p = 0.001) but not traction bronchiectasis (10.0, IQR 5–15 versus 15.0, IQR 5–15, p = 0.878). Receiver operator curve analysis of fibrosis SI compared to similarly located regions in control subjects showed an area under the curve of 0.82 (p = 0.002). A SI cutoff of 19 yielded a sensitivity of 75% and specificity of 86% in differentiating fibrosis from similarly located regions in control subjects. Conclusion LGE-MRI can differentiate CPFE from pure emphysema and may be a useful adjunct test to HRCT in patients with suspected CPFE.

Abstract Background ALK-rearrangement is observed in

Abstract Background The last two decades have seen revolutionary developments in both radiotherapy technology and postgraduate medical training. Trainees are expected to attain competencies using a mix of experiential learning, formal postgraduate teaching, self-directed learning and peer education. Radiation (Clinical) Oncology is a recognised ‘craft specialty’ where the apprenticeship model of training is applicable. This scoping review examines the evidence in relation to how medical trainees learn radiotherapy. Methods A systematic search of MEDINE and EMBASE was undertaken to identify studies of trainee and/or trainer experience of radiotherapy learning published 1999–2018. Results pertaining to Medical Oncology, workforce trends, undergraduate radiotherapy exposure, academic training, global health, non-medical staff, health service infrastructure and recruitment to training programmes were not included. Results A total of 146 publications were included in the synthesis. Five themes were apparent through careful iterative analysis representing broadly inter-related issues. Most articles studied radiotherapy training from the perspective of the trainee doctor. Most literature reports results of observational, local or national surveys with a tightly defined scope. Considerable variation exists within hospitals, within countries, over time and between different curricular areas. Conclusions Medical education has not kept pace with changes in the field of radiotherapy and large differences are demonstrated in experience between trainees in different hospitals, countries and training stages. Interpersonal relationships, departmental organisation, and national curricula impact on training quality. Qualitative and quantitative research examining modern radiotherapy learning has been uncommon and uncoordinated, until recently. To date no single study has been designed to comprehensively assess a department’s training scheme.

Abstract Background CT bleeding study (CTA) is regularly requested in acute abdominal haemorrhage (AAH) with haemodynamic instability by clinical teams and interventional radiologists because CTA can; detect arterial bleeding at low rates of hemorrhage, accurately localize the bleeding point and characterize the etiology. How best to manage an unstable patient who has an AAH with a haematoma and no acute vascular findings on CTA represents a difficult clinical scenario for treating physicians and Interventional Radiologists. Purpose To review the conventional angiography (CA) findings and clinical outcome of hemodynamically unstable patients with AAH who had a preceding negative CTA. Materials and methods All patients who were hemodynamically unstable and underwent CTA and CA for acute arterial abdominal hemorrhage at our institution between 01/01/2010 and 31/12/2017 were identified. Patients with obstetric, penetrating trauma, abdominal aortic or venous sources of hemorrhage were excluded. Patients who had a negative CTA before CA were included. Patient medical records were reviewed for clinical outcome. Results In the study period 160 hemodynamically unstable patients underwent 178 CA procedures. 155 CA procedures were preceded by CTA. 141 CTAs demonstrated active bleeding or an abnormal artery. 14 CTAs in 13 patients demonstrated hematoma but no acute bleeding (mean age = 56-years; M:F, 12:1). Eight of the 14 CA studies demonstrated: active bleeding (n = 4), pseudoaneurysm (n = 1) or a truncated artery (n = 3). Cases of renal hemorrhage demonstrated a significantly higher proportion of false negative CTA studies (36%). Selective (n = 8) or empiric (n = 4) embolization was performed in twelve cases. All patients stopped bleeding and there were no mortalities. Conclusion In a cohort of hemodynamically unstable patients, 57% (8/14) of cases with no acute vascular findings on CTA demonstrated a source of hemorrhage on CA. The false negative rate of CTA was significantly higher for renal tract hemorrhage compared to other sites of bleeding.