Variants in ZFX are associated with an X-linked neurodevelopmental disorder with recurrent facial gestalt.

Pathogenic variants in multiple genes on the X chromosome have been implicated in syndromic and non-syndromic intellectual disability disorders. ZFX on Xp22.11 encodes a transcription factor that has been linked to diverse processes including oncogenesis and development, but germline variants have not been characterized in association with disease. Here, we present clinical and molecular characterization of 18 individuals with germline ZFX variants. Exome or genome sequencing revealed 11 variants in 18 subjects (14 males and 4 females) from 16 unrelated families. Four missense variants were identified in 11 subjects, with seven truncation variants in the remaining individuals. Clinical findings included developmental delay/intellectual disability, behavioral abnormalities, hypotonia, and congenital anomalies. Overlapping and recurrent facial features were identified in all subjects, including thickening and medial broadening of eyebrows, variations in the shape of the face, external eye abnormalities, smooth and/or long philtrum, and ear abnormalities. Hyperparathyroidism was found in four families with missense variants, and enrichment of different tumor types was observed. In molecular studies, DNA-binding domain variants elicited differential expression of a small set of target genes relative to wild-type ZFX in cultured cells, suggesting a gain or loss of transcriptional activity. Additionally, a zebrafish model of ZFX loss displayed an altered behavioral phenotype, providing additional evidence for the functional significance of ZFX. Our clinical and experimental data support that variants in ZFX are associated with an X-linked intellectual disability syndrome characterized by a recurrent facial gestalt, neurocognitive and behavioral abnormalities, and an increased risk for congenital anomalies and hyperparathyroidism.

Safety and Efficiency Analysis of Operational Decision-Making During Cone Beam Computed Tomography-Based Online Adaptive Radiation Therapy.

PURPOSE: Cone beam computed tomography (CBCT)-based online adaptive radiation therapy (ART) is especially beneficial for patients with large interfractional anatomic changes. However, treatment planning and review decisions need to be made at the treatment console in real-time and may be delegated to clinical staff whose conventional scope of practice does not include making such decisions. Therefore, implementation can create new safety risks and inefficiencies. The objective of this work is to systematically analyze the safety and efficiency implications of human decision-making during the treatment session for CBCT-based online ART. METHODS AND MATERIALS: The analysis was performed by applying the Systems-Theoretical Process Analysis technique and its extension for human decision-making. Four centers of different CBCT-based online ART practice models comprised the analysis team. RESULTS: The general radiation therapy control structure was refined to model the interactions between routine treatment delivery staff and in-person or remote support staff. The treatment delivery staff perform 6 key control actions. Eighteen undesirable states of those control actions were identified as affecting safety and/or efficiency. In turn, 97 hazardous clinical scenarios were identified, with the control action "prepare and position patient" having the least number of scenarios and "delineate/edit influencer and target structures" having the most. Five of these are specific to either in-person or remote support during the treatment session, and 12 arise from staff support in general. CONCLUSIONS: An optimally safe and efficient online ART program should require little to no support staff at the treatment console to reduce staff coordination. Uptraining of the staff already at the treatment console is needed to achieve this goal. Beyond the essential knowledge and skills such as contour editing and the selection of an optimal plan, uptraining should also target the specific cognitive biases identified in this work and the cognitive strategies to overcome these biases. Additionally, technological and organizational changes are necessary.

Hemodynamic significance of intracranial atherosclerotic disease and ipsilateral imaging markers of cerebral small vessel disease.

INTRODUCTION: Cerebral small vessel disease (CSVD) commonly exists in patients with symptomatic intracranial atherosclerotic disease (sICAD). We aimed to investigate the associations of hemodynamic features of sICAD lesions with imaging markers and overall burden of CSVD. PATIENTS AND METHODS: Patients with anterior-circulation sICAD (50%-99% stenosis) were analyzed in this cross-sectional study. Hemodynamic features of a sICAD lesion were quantified by translesional pressure ratio (PR = Pressurepost-stenotic/Pressurepre-stenotic) and wall shear stress ratio (WSSR = WSSstenotic-throat/WSSpre-stenotic) via CT angiography-based computational fluid dynamics modeling. PR ⩽median was defined as low ("abnormal") PR, and WSSR ⩾ fourth quartile as high ("abnormal") WSSR. For primary analyses, white matter hyperintensities (WMHs), lacunes, and cortical microinfarcts (CMIs) were assessed in MRI and summed up as overall CSVD burden, respectively in ipsilateral and contralateral hemispheres to sICAD. Enlarged perivascular spaces (EPVSs) and cerebral microbleeds (CMBs) were assessed for secondary analyses. RESULTS: Among 112 sICAD patients, there were more severe WMHs, more lacunes and CMIs, and more severe overall CSVD burden ipsilaterally than contralaterally (all p < 0.05). Abnormal PR and WSSR (vs normal PR and WSSR) was significantly associated with moderate-to-severe WMHs (adjusted odds ratio = 10.12, p = 0.018), CMI presence (5.25, p = 0.003), and moderate-to-severe CSVD burden (12.55; p = 0.033), ipsilaterally, respectively independent of contralateral WMHs, CMI(s), and CSVD burden. EPVSs and CMBs were comparable between the two hemispheres, with no association found with the hemodynamic metrics. DISCUSSION AND CONCLUSION: There are more severe WMHs and CMI(s) in the hemisphere ipsilateral than contralateral to sICAD. The hemodynamic significance of sICAD lesions was independently associated with severities of WMHs and CMI(s) ipsilaterally.

Underlying Causes of TIA and Minor Ischemic Stroke and Risk of Major Vascular Events.

Importance: The coexistence of underlying causes in patients with transient ischemic attack (TIA) or minor ischemic stroke as well as their associated 5-year risks are not well known. Objective: To apply the ASCOD (atherosclerosis, small vessel disease, cardiac pathology, other cause, or dissection) grading system to assess coexistence of underlying causes of TIA and minor ischemic stroke and the 5-year risk for major vascular events. Design, Setting, and Participants: This international registry cohort (TIAregistry.org) study enrolled 4789 patients from June 1, 2009, to December 31, 2011, with 1- to 5-year follow-up at 61 sites in 21 countries. Eligible patients had a TIA or minor stroke (with modified Rankin Scale score of 0 or 1) within the last 7 days. Among these, 3847 patients completed the 5-year follow-up by December 31, 2016. Data were analyzed from October 1, 2022, to June 15, 2023. Exposure: Five-year follow-up. Main Outcomes and Measures: Estimated 5-year risk of the composite outcome of stroke, acute coronary syndrome, or cardiovascular death. Results: A total of 3847 patients (mean [SD] age, 66.4 [13.2] years; 2295 men [59.7%]) in 42 sites were enrolled and participated in the 5-year follow-up cohort (median percentage of 5-year follow-up per center was 92.3% [IQR, 83.4%-97.8%]). In 998 patients with probable or possible causal atherosclerotic disease, 489 (49.0%) had some form of small vessel disease (SVD), including 110 (11.0%) in whom a lacunar stroke was also probably or possibly causal, and 504 (50.5%) had no SVD; 275 (27.6%) had some cardiac findings, including 225 (22.6%) in whom cardiac pathology was also probably or possibly causal, and 702 (70.3%) had no cardiac findings. Compared with patients with none of the 5 ASCOD categories of disease (n = 484), the 5-year rate of major vascular events was almost 5 times higher (hazard ratio [HR], 4.86 [95% CI, 3.07-7.72]; P < .001) in patients with causal atherosclerosis, 2.5 times higher (HR, 2.57 [95% CI, 1.58-4.20]; P < .001) in patients with causal lacunar stroke or lacunar syndrome, and 4 times higher (HR, 4.01 [95% CI, 2.50-6.44]; P < .001) in patients with causal cardiac pathology. Conclusion and Relevance: The findings of this cohort study suggest that in patients with TIA and minor ischemic stroke, the coexistence of atherosclerosis, SVD, cardiac pathology, dissection, or other causes is substantial, and the 5-year risk of a major vascular event varies considerably across the 5 categories of underlying diseases. These findings further suggest the need for secondary prevention strategies based on pathophysiology rather than a one-size-fits-all approach.

Phenylalanine hydroxylase deficiency treatment and management: A systematic evidence review of the American College of Medical Genetics and Genomics (ACMG).

PURPOSE: Elevated serum phenylalanine (Phe) levels due to biallelic pathogenic variants in phenylalanine hydroxylase (PAH) may cause neurodevelopmental disorders or birth defects from maternal phenylketonuria. New Phe reduction treatments have been approved in the last decade, but uncertainty on the optimal lifespan goal Phe levels for patients with PAH deficiency remains. METHODS: We searched Medline and Embase for evidence of treatment concerning PAH deficiency up to September 28, 2021. Risk of bias was evaluated based on study design. Random-effects meta-analyses were performed to compare IQ, gestational outcomes, and offspring outcomes based on Phe ≤ 360 µmol/L vs > 360 µmol/L and reported as odds ratio and 95% CI. Remaining results were narratively synthesized. RESULTS: A total of 350 studies were included. Risk of bias was moderate. Lower Phe was consistently associated with better outcomes. Achieving Phe ≤ 360 µmol/L before conception substantially lowered the risk of negative effect to offspring in pregnant individuals (odds ratio = 0.07, 95% CI = 0.04-0.14; P < .0001). Adverse events due to pharmacologic treatment were common, but medication reduced Phe levels, enabling dietary liberalization. CONCLUSIONS: Reduction of Phe levels to ≤360 µmol/L through diet or medication represents effective interventions to treat PAH deficiency.

The correlation between intracranial arterial calcification and the outcome of reperfusion therapy.

OBJECTIVE: Intracranial arterial calcification (IAC) is a risk factor of ischemic stroke. However, the relationship between IAC patterns and clinical outcome of ischemic stroke remains controversial. We aimed to investigate the correlation between IAC patterns and the effects of reperfusion therapy among acute stroke patients. METHODS: Consecutive acute ischemic stroke patients who underwent reperfusion therapy were included. IAC was categorized as intimal or medial. Based on its involvement, IAC was further classified as diffuse or focal. Neurologic dysfunction was assessed by the National Institute of Health stroke scale (NIHSS). Clinical outcome including favorable neurologic outcome (FNO) and early neurologic deterioration (END) were assessed. RESULTS: Of 130 patients, 117 had IAC. Intimal IAC was identified in 74.6% of patients and medial IAC was present in 64.6% of patients. Diffuse IAC was present in 31.5% of patients. All diffuse IACs were medial pattern. Diffuse IAC was associated with higher baseline NIHSS (p = 0.011) and less FNO (p = 0.047). Compared with patients with focal or single diffuse IAC, patients with multiple diffuse IAC had higher baseline NIHSS (p = 0.002) and less FNO (p = 0.024). Multivariable linear regression (p < 0.001) and logistic regression (p = 0.027) suggested that multiple diffuse IAC was associated with higher baseline NIHSS and less FNO. No significant association was found between END and different IAC patterns. INTERPRETATION: Multiple diffuse medial IAC may predict severer neurologic dysfunction and less favorable neurologic outcome after reperfusion therapy in acute stroke patients.

Facilitating the application of systems-theoretic process analysis in healthcare: Creating control structures using process maps.

Systems-theoretic process analysis (STPA) is a prospective safety assessment tool increasingly applied in healthcare. A problem hampering STPA proliferation is the difficulty of modeling systems for analysis by creating control structures. In this work, a method is proposed to use existing process maps-commonly available in healthcare-when creating a control structure. The proposed method entails (1) extract information from the process map, (2) determine the modeling boundary of the control structure, (3) transfer the extracted information to the control structure, (4) add additional information to complete the control structure. Two case studies were conducted: (1) ambulance patient offloading in the emergency department and (2) ischemic stroke care with intravenous thrombolysis. The amount of process map-derived information in the control structures was quantified. On average, 68% of the information in the final control structures was derived from the process map. Additional control actions and feedback were added from nonprocess map sources for management and frontline controllers. Despite the differences between process maps and control structures, much of the information in a process map can be used when creating a control structure. The method enables the creation of a control structure from a process map to be done in a structured fashion.

Effect of atherosclerosis on 5-year risk of major vascular events in patients with transient ischaemic attack or minor ischaemic stroke: an international prospective cohort study.

BACKGROUND: The prevalence of atherosclerosis and the long-term risk of major vascular events in people who have had a transient ischaemic attack or minor ischaemic stroke, regardless of the causal relationship between the index event and atherosclerosis, are not well known. In this analysis, we applied the ASCOD (atherosclerosis, small vessel disease, cardiac pathology, other causes, and dissection) grading system to estimate the 5-year risk of major vascular events according to whether there was a causal relationship between atherosclerosis and the index event (ASCOD grade A1 and A2), no causal relationship (A3), and with or without a causal relationship (A1, A2, and A3). We also aimed to estimate the prevalence of different grades of atherosclerosis and identify associated risk factors. METHODS: We analysed patient data from TIAregistry.org, which is an international, prospective, observational registry of patients with a recent (within the previous 7 days) transient ischaemic attack or minor ischaemic stroke (modified Rankin Scale score of 0-1) from 61 specialised centres in 21 countries in Europe, Asia, the Middle East, and Latin America. Using data from case report forms, we applied the ASCOD grading system to categorise the degree of atherosclerosis in our population (A0: no atherosclerosis; A1 or A2: atherosclerosis with stenosis ipsilateral to the cerebral ischaemic area; A3: atherosclerosis in vascular beds not related to the ischaemic area or ipsilateral plaques without stenosis; and A9: atherosclerosis not assessed). The primary outcome was a composite of non-fatal stroke, non-fatal acute coronary syndrome, or cardiovascular death within 5 years. FINDINGS: Between June 1, 2009, and Dec 29, 2011, 4789 patients were enrolled to TIAregistry.org, of whom 3847 people from 42 centres participated in the 5-year follow-up; 3383 (87·9%) patients had a 5-year follow-up visit (median 92·3% [IQR 83·4-97·8] per centre). 1406 (36·5%) of 3847 patients had no atherosclerosis (ASCOD grade A0), 998 (25·9%) had causal atherosclerosis (grade A1 or A2), and 1108 (28·8%) had atherosclerosis that was unlikely to be causal (grade A3); in 335 (8·7%) patients, atherosclerosis was not assessed (grade A9). The 5-year event rate of the primary composite outcome was 7·7% (95% CI 6·3-9·2; 101 events) in patients categorised with grade A0 atherosclerosis, 19·8% (17·4-22·4; 189 events) in those with grade A1 or A2, and 13·8% (11·8-16·0; 144 events) in patients with grade A3. Compared with patients with grade A0 atherosclerosis, patients categorised as grade A1 or A2 had an increased risk of the primary composite outcome (hazard ratio 2·77, 95% CI 2·18-3·53; p<0·0001), as did patients with grade A3 (1·87, 1·45-2·42; p<0·0001). Except for age, male sex, and multiple infarctions on neuroimaging, most of the risk factors that were identified as being associated with grade A1 or A2 atherosclerosis were modifiable risk factors (ie, hypertension, dyslipidaemia, overweight, smoking cigarettes, and low physical activity; all p values <0·025). INTERPRETATION: In patients with transient ischaemic attack or minor ischaemic stroke, those with atherosclerosis have a much higher risk of major vascular events within 5 years than do those without atherosclerosis. Preventive strategies addressing complications of atherosclerosis should focus on individuals with atherosclerosis rather than grouping together all people who have had a transient ischaemic attack or minor ischaemic stroke (including those without atherosclerosis). FUNDING: AstraZeneca, Sanofi, Bristol Myers Squibb, SOS Attaque Cérébrale Association.

Family- and neighborhood-level environmental associations with physical health conditions in 9- and 10-year-olds.

OBJECTIVE: To determine how environmental factors are associated with physical health conditions in 9- to 10-year-old participants in the Adolescent Brain Cognitive Development (ABCD) Study, and how they are moderated by family-level socioeconomic status (SES). METHOD: We performed cross-sectional analyses of 8,429 youth participants in the ABCD Study, in which nine physical health conditions (having underweight or overweight/obesity, not participating in sports activities, short sleep duration, high sleep disturbances, lack of vigorous and strengthening-related physical activity, miscellaneous medical problems, and traumatic brain injury) were regressed on three environmental factors [neighborhood disadvantage (area deprivation index [ADI]), risk of lead exposure, and concentrations of particulate matter 2.5 (PM2.5)] and their interaction with family-level SES (i.e., parent-reported annual household income). Environmental data were geocoded to participants' primary residential addresses at 9- to 10-year-olds. RESULTS: Risk of lead exposure and ADI were positively associated with the odds of having overweight/obesity, not participating in sports activity, and short sleep durations. ADI was also positively associated with high sleep disturbances. PM2.5 was positively associated with the odds of having overweight/obesity and reduced vigorous physical activity. Family-level SES moderated relationships between ADI and both underweight and overweight/obesity, with high SES being associated with more pronounced changes given increased ADI. CONCLUSIONS: Policymakers and public health officials must implement policies and remediation strategies to ensure children are free from exposure to neurotoxicant and environmental factors. Physical health conditions may be less of a product of an individual's choices and more related to environmental influences. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Immune checkpoint inhibitors and tyrosine kinase inhibitors in patients with advanced hepatocellular carcinoma: Does the sequence matter?

INTRODUCTION: Combination therapy with immune checkpoint inhibitor (ICI) and antivascular endothelial growth factor (anti-VEGF) is currently the first line treatment for advanced hepatocellular carcinoma (aHCC). However, there are many patients who may not be able to receive combination therapy due to underlying comorbidities or resource limitations. For these patients, systemic treatment options include single agent tyrosine kinase inhibitors (TKIs) or ICI monotherapy. However, whether an optimal sequence of systemic therapy exists remains unknown. We aim to explore the impact of sequencing of TKI and ICI therapy in terms of response rates and to examine the safety of their use in sequential order. METHODS: Patients with aHCC treated with both ICI and TKI between December 30, 2013 and June 13, 2018 were retrospectively identified. Patients were classified into two groups: those who received TKI in the first-line (TKI1), followed by ICI (ICI2) and those who received ICI (ICI1) in the first-line followed by TKI (TKI2). The primary objective of the study was to identify differences in objective response rate (ORR) and disease control rate (DCR), as evaluated based on response evaluation criteria in solid tumor v1.1 for TKI1, TKI2, ICI1, and ICI2. Secondary objectives included comparison of progression free survival (PFS) for each line of therapy, overall survival (OS) and adverse events (AEs). RESULTS: Twenty-seven and 23 patients were classified into group 1 and 2, respectively. Objective response rates of TKI1 and TKI2 were 3.8% and 17.6%, respectively (p = .28); DCR to TKI1 versus TKI2 was 23.1% versus 35.3% (p = .49). ORRs of ICI1 and ICI2 were 8.7% and 14.3%, respectively (p = .66); DCR to ICI2 versus ICI1 was 56.5% versus 42.9% (p = .37). Median PFS was not significant between TKI1 and TKI2 (PFS 3.06 versus 1.61 months, p = .097) as well as between ICI2 and ICI1 (PFS 1.84 versus 2.37 month, p = .32). Median OS was also not significantly different between both groups (OS 20.63 versus 13.93 months, p = .20) on univariable and multivariable analysis (OS adjusted hazard ratio [HR] 2.07, 95% CI .83-5.18, p = .118). The proportion of patients who experienced adverse events of any grade was similar in both groups (TKI1 59.3% versus TKI2 52.2%; ICI1 78.3% versus ICI2 70.4%). CONCLUSION: Our study suggests that the sequence of TKI versus ICI therapy in patients with aHCC may not matter, given similar efficacy and toxicity profile when either agent is received in the first or second-line setting. This finding is of value in the real-world setting, where patients may be frail or have comorbidities that render them unable to tolerate combination therapy (ICI and TKI/anti-VEGF). For these patients, sequential exposure to both classes of drugs (ICI and TKI) may be a suitable option.

Loss-of-function variants in MYCBP2 cause neurobehavioural phenotypes and corpus callosum defects.

The corpus callosum is a bundle of axon fibres that connects the two hemispheres of the brain. Neurodevelopmental disorders that feature dysgenesis of the corpus callosum as a core phenotype offer a valuable window into pathology derived from abnormal axon development. Here, we describe a cohort of eight patients with a neurodevelopmental disorder characterized by a range of deficits including corpus callosum abnormalities, developmental delay, intellectual disability, epilepsy and autistic features. Each patient harboured a distinct de novo variant in MYCBP2, a gene encoding an atypical really interesting new gene (RING) ubiquitin ligase and signalling hub with evolutionarily conserved functions in axon development. We used CRISPR/Cas9 gene editing to introduce disease-associated variants into conserved residues in the Caenorhabditis elegans MYCBP2 orthologue, RPM-1, and evaluated functional outcomes in vivo. Consistent with variable phenotypes in patients with MYCBP2 variants, C. elegans carrying the corresponding human mutations in rpm-1 displayed axonal and behavioural abnormalities including altered habituation. Furthermore, abnormal axonal accumulation of the autophagy marker LGG-1/LC3 occurred in variants that affect RPM-1 ubiquitin ligase activity. Functional genetic outcomes from anatomical, cell biological and behavioural readouts indicate that MYCBP2 variants are likely to result in loss of function. Collectively, our results from multiple human patients and CRISPR gene editing with an in vivo animal model support a direct link between MYCBP2 and a human neurodevelopmental spectrum disorder that we term, MYCBP2-related developmental delay with corpus callosum defects (MDCD).

PNC-27, a Chimeric p53-Penetratin Peptide Binds to HDM-2 in a p53 Peptide-like Structure, Induces Selective Membrane-Pore Formation and Leads to Cancer Cell Lysis.

PNC-27, a 32-residue peptide that contains an HDM-2 binding domain and a cell-penetrating peptide (CPP) leader sequence kills cancer, but not normal, cells by binding to HDM-2 associated with the plasma membrane and induces the formation of pores causing tumor cell lysis and necrosis. Conformational energy calculations on the structure of PNC-27 bound to HDM-2 suggest that 1:1 complexes form between PNC-27 and HDM-2 with the leader sequence pointing away from the complex. Immuno-scanning electron microscopy was carried out with cancer cells treated with PNC-27 and decorated with an anti-PNC-27 antibody coupled to 6 nm gold particles and an anti-HDM-2 antibody linked to 15 nm gold particles. We found multiple 6 nm- and 15 nm-labeled gold particles in approximately 1:1 ratios in layered ring-shaped structures in the pores near the cell surface suggesting that these complexes are important to the pore structure. No pores formed in the control, PNC-27-treated untransformed fibroblasts. Based on the theoretical and immuno-EM studies, we propose that the pores are lined by PNC-27 bound to HDM-2 at the membrane surface with the PNC-27 leader sequence lining the pores or by PNC-27 bound to HDM-2.

Cerebral Augmentation Effect Induced by External Counterpulsation Is Not Related to Impaired Dynamic Cerebral Autoregulation in Ischemic Stroke.

Background and Purpose: Dynamic cerebral autoregulation is impaired after ischemic stroke. External counterpulsation (ECP) augments the cerebral blood flow of patients with ischemic stroke by elevation of blood pressure (BP). We aimed to investigate if cerebral augmentation effects during ECP were associated with impaired dynamic cerebral autoregulation in patients after acute ischemic stroke. Methods: Forty patients with unilateral ischemic stroke and large artery atherosclerosis in the anterior circulation territory within 7 days from symptom onset and eighteen healthy controls were recruited. We monitored changes in mean flow velocity over both middle cerebral arteries (MCA) by transcranial Doppler (TCD) before, during, and immediately after ECP. Cerebral augmentation index was MCA mean flow velocity increase in percentage during ECP compared with baseline to evaluate the augmentation effects of ECP. Spontaneous arterial BP and cerebral blood flow velocity in both bilateral MCAs were recorded using a servo-controlled plethysmograph and TCD, respectively. Transfer function analysis was used to derive the autoregulatory parameters, including phase difference (PD), and gain. Results: The cerebral augmentation index in patients with stroke was significantly higher on both the ipsilateral and contralateral sides than that in controls, while the PD in patients with stroke was significantly lower on both sides than those in controls (all P < 0.05). The cerebral augmentation index did not correlate with PD and gain on either the ipsilateral or contralateral side of patients with stroke or in controls (all P > 0.05). The cerebral augmentation index of patients with stroke was significantly related to mean BP change on the ipsilateral side (R 2 = 0.108, P = 0.038). Conclusion: The degree of ECP-induced cerebral augmentation effects as measured by the cerebral augmentation index did not correlate with the magnitude of impaired dynamic cerebral autoregulation.

A system-based operational assessment of external beam radiotherapy.

PURPOSE: Advanced technologies have led to improvements in modern radiotherapy over the years. However, adoption of advanced technologies can present challenges to existing clinical operations and negatively impact safety. The purpose of this work is to perform an assessment of modern radiotherapy for the operational objectives of safety, efficiency, and financial viability. METHODS: This work focuses on external beam radiotherapy (EBRT). The operational assessment included department management, treatment planning, treatment delivery, and associated workflows for three equipment configurations of Ethos, Halcyon, and TrueBeam with the ARIA information system, Eclipse treatment planning, and IDENTIFY surface guidance. Systems-theoretic process analysis (STPA) was used to analyze the related workflows. Control actions, unsafe contexts of those control actions, and associated causal scenarios that can lead to unsafe radiation and non-radiation physical injury (safety objective), reduced treatment capacity (efficiency objective), and costs that exceed budget (financial viability objective) were identified. RESULTS: The number of control actions (and causal scenarios) were 18 (254), 18 (267), and 20 (267) for the equipment configurations of Halcyon, TrueBeam, and Ethos, respectively. The extent that safety, efficiency, and financial viability were impacted is similar across the different equipment configurations, but there were some noteworthy differences related to information transfer and workflow bottlenecks potentially impacting access to care. Seventy-five percent of the scenarios across all three configurations were related to safety. Overall, 29% of the scenarios impacted more than one operational objective and 48% were related to human decisions during the process of care. Planned or unplanned process changes were responsible for 8% of the causal scenarios. CONCLUSIONS: Broad-based clinical improvements may be realized by addressing causal scenarios that impact multiple objectives. Redesigning the roles and responsibilities of the clinical team and some aspects of the radiotherapy workflow may be helpful to fully realize the benefits of advanced technologies. Radiotherapy may benefit from additional tools to improve the consistency between decisions and actions when system or process changes occur.

Intracranial Arterial Calcification and Intracranial Atherosclerosis: Close but Different.

BACKGROUND AND PURPOSE: Intracranial arterial calcification (IAC) may be present in the intimal or medial arterial layer. This study aimed to elucidate the link between the calcification and atherosclerotic disease in the intracranial vasculature. METHODS: Consecutive patients with acute ischemic stroke were included. Bilateral intracranial segment of the internal carotid artery, M1 segment of the middle cerebral artery, intracranial segment of the vertebral artery, and the basilar artery were visualized by the multi-detector computed tomography (CT) and vessel-wall magnetic resonance imaging (vwMRI) within 14 days after stroke onset. IAC was into the intimal or medial pattern. Subsequently, on the vwMRI, we assessed the luminal stenosis, eccentricity, plaque burden, and intraplaque hemorrhage (IPH) as markers of atherosclerosis at each IAC site. RESULTS: Among 69 patients with stroke, IAC was identified in 35% of (161/483) artery segments, of which 61.5% were predominantly intimal calcification and 38.5% were predominantly medial calcification. About 79.8% of intimal calcifications and 64.5% of medial calcifications co-existed with atherosclerotic plaques. Intimal calcification was associated with luminal stenosis (p = 0.003) caused by atherosclerotic lesions. Compared with the medial IAC, intimal IAC was more often accompanied by eccentric plaques (p = 0.02), larger plaque burden (p = 0.001), and IPH (p = 0.001). CONCLUSION: Our multimodal imaging-based comparison study on intracranial arteriosclerosis demonstrated that intimal IAC, compared with medial IAC, was more often accompanied by the luminal stenosis, larger plaque burden, eccentricity, and IPH, providing strong evidence for clinical evaluation on the mechanism, risk, and prognosis of ischemic stroke.

Impact of Immune-Related Adverse Events on Efficacy of Immune Checkpoint Inhibitors in Patients with Advanced Hepatocellular Carcinoma.

INTRODUCTION: Development of immune-related adverse events (irAEs) has been associated with enhanced efficacy with the use of immune checkpoint inhibitors (ICIs). It remains unknown whether such an association exists in advanced hepatocellular carcinoma (aHCC). This study aims to evaluate the association between irAEs and ICI efficacy in patients with aHCC. METHODS: We performed a retrospective cohort study on patients with aHCC who received at least one dose of an ICI between May 2015 and November 2019 at the National Cancer Centre Singapore. The primary study objectives were to compare the overall survival (OS) and progression-free survival (PFS) between patients with and without irAEs. Complementary multivariable landmark analyses were performed at the 6-week and 12-week landmarks. Data cutoff was December 31, 2020. RESULTS: One hundred and sixty-eight patients were included. Median age was 69 years, 85.7% were male, 57.7% had hepatitis B infection, 60.7% had ECOG 0, and 78.0% had Child-Pugh A liver cirrhosis. 82.7% received ICI monotherapy, while 17.3% received ICI in combination. Development and severity of irAE were correlated with survival. The median PFS for grade ≥3 irAE versus grades 1-2 irAE versus no irAE was 8.5 versus 3.6 versus 1.3 mths (p < 0.001). The median OS for grade ≥3 irAE versus grades 1-2 irAE versus no irAE was 26.9 versus 14.0 versus 4.6 mths (p < 0.001). Patients with ≥2 irAEs had a significantly longer OS on multivariable analysis (adjusted hazard ratio [aHR]0.35, p < 0.001). The presence of grade ≥3 irAEs was associated with a significantly longer OS on the multivariable analysis at the 6-week landmark (aHR0.34, p = 0.030) and 12-week landmark (aHR0.28, p = 0.011). The use of systemic corticosteroids in patients with irAE was associated with a trend toward a longer OS (20.7 vs. 14.3 mths, p = 0.064). CONCLUSION: Our study suggests that the presence of all-grade irAEs may be a potential prognostic biomarker in patients with aHCC treated with ICI. Patients with more severe irAEs and multisystem involvement have better prognosis. The prompt use of systemic corticosteroids to treat patients with irAEs is key to ensure the best long-term outcomes for these patients.

Investigating career-related teacher support for Chinese secondary school students in Hong Kong.

Teachers play a critical role in facilitating the career and life planning of secondary school students. This paper describes the development of the Career-Related Teacher Support Scale (Hong Kong Secondary Students Form). Based on data obtained from 493 students in Hong Kong, five types of career-related teacher support were identified with the most important form of support being teachers' knowledge about the world of work and study path requirements. A correlation model yielded the best fit to the data. No variance in response pattern appeared across genders, and the new scale was found to have good validity and reliability.

Enquête sur le soutien des enseignant·e·s lié à la carrière pour les étudiant·e·s chinois du secondaire à Hong Kong Les enseignant·e·s jouent un rôle essentiel en facilitant la planification de la carrière et de la vie des élèves du secondaire. Cet article décrit le développement de l'échelle Career-Related Teacher Support Scale (Hong Kong Secondary Students Form). Sur la base des données obtenues auprès de 493 étudiantes à Hong Kong, cinq types de soutien des enseignantes liés à la carrière ont été identifiés, la forme de soutien la plus importante étant les connaissances des enseignantes sur le monde du travail et les exigences des filières d'études. Un modèle de corrélation s'est avéré le mieux adapté aux données. Aucune variance dans le modèle de réponse n'est apparue entre les sexes, et la nouvelle échelle s'est avérée avoir une bonne validité et fiabilité.

Investigando el Apoyo Docente al Desarrollo de la Carrera para estudiantes chinos de secundaria en Hong Kong Los profesores desempeñan un papel fundamental a la hora de facilitar la planificación de la carrera y la vida de los estudiantes de secundaria. Este artículo describe el desarrollo de la Escala de Apoyo Docente al Desarrollo de la Carrera (Cuestionario para Estudiantes de Secundaria de Hong Kong). Sobre la base de los datos obtenidos de 493 estudiantes en Hong Kong, se identificaron cinco tipos de apoyo de los docentes relacionados con la carrera, siendo la forma más importante de apoyo el conocimiento de los docentes sobre el mundo del trabajo y los requisitos de las trayectorias educativas. El mejor ajuste para los datos fue aportado por un modelo de correlación. No apareció ninguna variabilidad en el patrón de respuesta relacionada con el género, y se encontró que la nueva escala tiene buena validez y fiabilidad.

Evolving ischemic stroke subtypes in 15 years: A hospital-based observational study.

BACKGROUND: Depicting the time trends of ischemic stroke subtypes may inform healthcare resource allocation on etiology-based stroke prevention and treatment. AIM: To reveal the evolving ischemic stroke subtypes from 2004 to 2018. METHODS: We determined the stroke etiologies of consecutive first-ever transient ischemic attack or ischemic stroke patients admitted to a regional hospital in Hong Kong from 2004 to 2018. We analyzed the age-standardized incidences and the two-year recurrence rate of major ischemic stroke subtypes. RESULTS: Among 6940 patients admitted from 2004 to 2018, age-standardized incidence of ischemic stroke declined from 187.0 to 127.4 per 100,000 population (p < 0.001), driven by the decrease in large artery disease (43.0-9.67 per 100,000 population (p < 0.001)), and small vessel disease (71.9-45.7 per 100,000 population (p < 0.001)). Age-standardized incidence of cardioembolic stroke did not change significantly (p = 0.2). Proportion of cardioembolic stroke increased from 20.4% in 2004-2006 to 29.3% in 2016-2018 (p < 0.001). Two-year recurrence rate of intracranial atherothrombotic stroke reduced from 19.3% to 5.1% (p < 0.001) with increased prescriptions of statin (p < 0.001) and dual antiplatelet therapy (p < 0.001). In parallel with increased anticoagulation use across the study period (p < 0.001), the two-year recurrence of AF-related stroke reduced from 18.9% to 6% (p < 0.001). CONCLUSION: Etiology-based risk factor control might have led to the diminishing stroke incidences related to atherosclerosis. To tackle the surge of AF-related strokes, arrhythmia screening, anticoagulation usage, and mechanical thrombectomy service should be reinforced. Comparable preventive strategies might alleviate the enormous stroke burden in mainland China.

Understanding the Clinical Implications of Intracranial Arterial Calcification Using Brain CT and Vessel Wall Imaging.

Background and Purpose: Intracranial arterial calcification (IAC) has been the focus of much attention by clinicians and researchers as an indicator of intracranial atherosclerosis, but correlations of IAC patterns (intimal or medial) with the presence of atherosclerotic plaques and plaque stability are still a matter of debate. Our study aimed to assess the associations of IAC patterns identified on computed tomography (CT) with the presence of plaque detected on vessel wall magnetic resonance imaging and plaque stability. Materials and Methods: Patients with stroke or transient ischemic attack and intracranial artery stenosis were recruited. IAC was detected and localized (intima or media) on non-contrast CT images. Intracranial atherosclerotic plaques were identified using vessel wall magnetic resonance imaging and matched to corresponding CT images. Associations between IAC patterns and culprit atherosclerotic plaques were assessed by using multivariate regression. Results: Seventy-five patients (mean age, 63.4 ± 11.6 years; males, 46) were included. Two hundred and twenty-one segments with IAC were identified on CT in 66 patients, including 86 (38.9%) predominantly intimal calcifications and 135 (61.1%) predominantly medial calcifications. A total of 72.0% of intimal calcifications coexisted with atherosclerotic plaques, whereas only 10.2% of medial calcifications coexisted with plaques. Intimal calcification was more commonly shown in non-culprit plaques than culprit plaques (25.9 vs. 9.4%, P = 0.008). The multivariate mixed logistic regression adjusted for the degree of stenosis showed that intimal calcification was significantly associated with non-culprit plaques (OR, 2.971; 95% CI, 1.036-8.517; P = 0.043). Conclusion: Our findings suggest that intimal calcification may indicate the existence of a stable form of atherosclerotic plaque, but plaques can exist in the absence of intimal calcification especially in the middle cerebral artery.