iVOMS: Instrumented Vestibular / Ocular motor screen in healthy controls and mild traumatic brain injury.

Objective Vestibular/ocular deficits occur with mild traumatic brain injury (mTBI). The vestibular/ocular motor screening (VOMS) tool is used to assess individuals post-mTBI, which primarily relies upon subjective self-reported symptoms. Instrumenting the VOMS (iVOMS) with technology may allow for more objective assessment post-mTBI, which reflects actual task performance. This study aimed to validate the iVOMS analytically and clinically in mTBI and controls. Methods Seventy-nine people with sub-acute mTBI (<12 weeks post-injury) and forty-four healthy control participants performed the VOMS whilst wearing a mobile eye-tracking on a one-off visit. People with mTBI were included if they were within 12 weeks of a physician diagnosis. Participants were excluded if they had any musculoskeletal, neurological or sensory deficits which could explain dysfunction. A series of custom-made eye tracking algorithms were used to assess recorded eye-movements. Results The iVOMS was analytically valid compared to the reference (ICC2,1 0.85-0.99) in mTBI and controls. The iVOMS outcomes were clinically valid as there were significant differences between groups for convergence, vertical saccades, smooth pursuit, vestibular ocular reflex and visual motion sensitivity outcomes. However, there was no significant relationship between iVOMS outcomes and self-reported symptoms. Conclusion The iVOMS is analytically and clinically valid in mTBI and controls, but further work is required to examine the sensitivity of iVOMS outcomes across the mTBI spectrum. Findings also highlighted that symptom and physiological issue resolution post-mTBI may not coincide and relationships need further examination.

Faith-based leaders' perceptions on the implementation of programs to promote healthy lifestyles in churches in Barbados-a mixed-methods analysis.

Background: There is a high burden of chronic diseases such as hypertension and diabetes in small island developing states (SIDS). SIDS governments have committed to a range of public health, healthcare, and fiscal measures to reduce this burden including community-based health education in collaboration with civil society organizations. We sought to explore perceived acceptability, appropriateness, and feasibility of implementing self-management health programs in 20 faith-based organizations in the small island developing state of Barbados. Methods: This was a concurrent mixed methods study - a quantitative online survey and a qualitative inquiry using semi-structured interviews. Acceptability, appropriateness and feasibility of the intervention were assessed using the following quantitative assessment tools: Acceptability of Intervention Measure (AIM), Intervention Appropriateness Measure (IAM) and Feasibility of Intervention Measure (FIM). Thirteen in-depth interviews were conducted virtually, recorded and transcribed verbatim. Transcripts were analyzed using thematic analysis based on deductive codes from Proctor's implementation outcomes definitions. Results: From the 52 respondents of the survey, the median and interquartile ranges for the AIM, IAM and FIM scales were 16 (15-20), 16 (16-20) and 16 (15-17) (out of 20), respectively. We found high levels of acceptability, 82% (95% CI (69%, 95%)) of leaders indicating that health programs in churches met with their approval; and high levels of appropriateness-90% (95% CI (80%, 100%)) indicating health programs in churches were "fitting" and "a good match". Feasibility scores were lower, with 60% (95% CI (44%, 76%)) indicating that health programs in churches would be easy to use. In interviews, leaders expressed acceptance of healthy lifestyle programs in churches and described their appropriateness through alignment with church doctrines stating, "the body is the temple of God". They felt that economic impacts from COVID-19 were likely to be a barrier to the success of programs. Leaders expressed the need for support from healthcare providers who are sensitive and respectful of church culture. Conclusion: We found that health-based programs in churches align well with church doctrines, but the success of these programs will depend on establishing trust through the engagement of church-based champions, tailoring programming to include a biblical perspective and engaging entire households.

Visual Exploration While Walking With and Without Visual Cues in Parkinson's Disease: Freezer Versus Non-Freezer.

BACKGROUND: Visual cues can improve gait in Parkinson's disease (PD), including those experiencing freezing of gait (FOG). However, responses are variable and underpinning mechanisms remain unclear. Visuo-cognitive processing (measured through visual exploration) has been implicated in cue response, but this has not been comprehensively examined. OBJECTIVE: To examine visual exploration and gait with and without visual cues in PD who do and do not self-report FOG, and healthy controls (HC). METHODS: 17 HC, 21 PD without FOG, and 22 PD with FOG walked with and without visual cues, under single and dual-task conditions. Visual exploration (ie, saccade frequency, duration, peak velocity, amplitude, and fixation duration) was measured via mobile eye-tracking and gait (ie, gait speed, stride length, foot strike angle, stride time, and stride time variability) with inertial sensors. RESULTS: PD had impaired gait compared to HC, and dual-tasking made gait variables worse across groups (all P < .01). Visual cues improved stride length, foot strike angle, and stride time in all groups (P < .01). Visual cueing also increased saccade frequency, but reduced saccade peak velocity and amplitude in all groups (P < .01). Gait improvement related to changes in visual exploration with visual cues in PD but not HC, with relationships dependent on group (FOG vs non-FOG) and task (single vs dual). CONCLUSION: Visual cues improved visual exploration and gait outcomes in HC and PD, with similar responses in freezers and non-freezers. Freezer and non-freezer specific associations between cue-related changes in visual exploration and gait indicate different underlying visuo-cognitive processing within these subgroups for cue response.

Ocular microtremor: a structured review.

Ocular microtremor (OMT) is the smallest of three involuntary fixational micro eye movements, which has led to it being under researched in comparison. The link between OMT and brain function generates a strong rationale for further study as there is potential for its use as a biomarker in populations with neurological injury and disease. This structured review focused on populations previously studied, instrumentation used for measurement, commonly reported OMT outcomes, and recommendations concerning protocol design and future studies. Current methods of quantifying OMT will be reviewed to analyze their efficacy and efficiency and guide potential development and understanding of novel techniques. Electronic databases were systematically searched and compared with predetermined inclusion criteria. 216 articles were identified in the search and screened by two reviewers. 16 articles were included for review. Findings showed that piezoelectric probe is the most common method of measuring OMT, with fewer studies involving non-invasive approaches, such as contact lenses and laser imaging. OMT frequency was seen to be reduced during general anesthesia at loss of consciousness and in neurologically impaired participants when compared to healthy adults. We identified the need for a non-invasive technique for measuring OMT and highlight its potential in clinical applications as an objective biomarker for neurological assessments. We highlight the need for further research on the clinical validation of OMT to establish its potential to identify or predict a meaningful clinical or functional state, specifically, regarding accuracy, precision, and reliability of OMT.

BRCA-deficient metastatic prostate cancer has an adverse prognosis and distinct genomic phenotype.

BACKGROUND: Genomic alterations in DNA damage response (DDR) genes are common in metastatic castration-resistant prostate cancer (mCRPC). Understanding how these genomic events impact prognosis and/or treatment response is vital for optimising clinical outcomes. METHODS: Targeted sequencing was performed on 407 plasma samples from 375 men with mCRPC. Using the CLIA-certified PredicineCARE™ cell-free DNA (cfDNA) assay, pathogenic alterations in 152 key genes (including 27 DDR-related genes) were assessed, as was the presence and mechanisms of biallelic loss in BRCA2. FINDINGS: At least one DDR alteration was present in 34.5% (129/375) of patients (including monoallelic alterations). The most frequently altered DDR genes were BRCA2 (19%), ATM (13%), FANCA (5%), CHEK2 (5%) and BRCA1 (3%). Patients with BRCA alterations, especially BRCA2, had significantly worse progression-free survival (PFS) (Hazard ratio (HR) 3.3 [95% CI 1.9-6.0]; Cox regression p < 0.001), overall survival (HR 2.2 [95% CI 1.1-4.5]; Cox regression p = 0.02) and PSA response rates to androgen receptor (AR) pathway inhibitors (32% vs 60%, chi-square p = 0.02). BRCA-deficient tumours were also enriched for alterations within multiple genes including in the AR and PI3K pathways. Zygosity of BRCA2 alterations had no discernible impact on clinical outcomes, with similarly poor PFS for monoallelic vs biallelic loss (median 3.9 months vs 3.4 months vs copy neutral 9.8 months). INTERPRETATION: These data emphasise that the BRCA genes, in particular BRCA2, are key prognostic biomarkers in mCRPC. The clinical utility of BRCA2 as a marker of poor outcomes may, at least in cfDNA assays, be independent of the zygosity state detected. Enrichment of actionable genomic alterations in cfDNA from BRCA-deficient mCRPC may support rational co-targeting strategies in future clinical trials. FUNDING: Several funding sources have supported this study. A full list is provided in the Acknowledgments. No funding was received from Predicine, Inc. during the conduct of the study.

Combination of Clinical and Gait Measures to Classify Fallers and Non-Fallers in Parkinson's Disease.

Although the multifactorial nature of falls in Parkinson's disease (PD) is well described, optimal assessment for the identification of fallers remains unclear. Thus, we aimed to identify clinical and objective gait measures that best discriminate fallers from non-fallers in PD, with suggestions of optimal cutoff scores. METHODS: Individuals with mild-to-moderate PD were classified as fallers (n = 31) or non-fallers (n = 96) based on the previous 12 months' falls. Clinical measures (demographic, motor, cognitive and patient-reported outcomes) were assessed with standard scales/tests, and gait parameters were derived from wearable inertial sensors (Mobility Lab v2); participants walked overground, at a self-selected speed, for 2 min under single and dual-task walking conditions (maximum forward digit span). Receiver operating characteristic curve analysis identified measures (separately and in combination) that best discriminate fallers from non-fallers; we calculated the area under the curve (AUC) and identified optimal cutoff scores (i.e., point closest-to-(0,1) corner). RESULTS: Single gait and clinical measures that best classified fallers were foot strike angle (AUC = 0.728; cutoff = 14.07°) and the Falls Efficacy Scale International (FES-I; AUC = 0.716, cutoff = 25.5), respectively. Combinations of clinical + gait measures had higher AUCs than combinations of clinical-only or gait-only measures. The best performing combination included the FES-I score, New Freezing of Gait Questionnaire score, foot strike angle and trunk transverse range of motion (AUC = 0.85). CONCLUSION: Multiple clinical and gait aspects must be considered for the classification of fallers and non-fallers in PD.

Sonification for Personalised Gait Intervention.

Mobility challenges threaten physical independence and good quality of life. Often, mobility can be improved through gait rehabilitation and specifically the use of cueing through prescribed auditory, visual, and/or tactile cues. Each has shown use to rectify abnormal gait patterns, improving mobility. Yet, a limitation remains, i.e., long-term engagement with cueing modalities. A paradigm shift towards personalised cueing approaches, considering an individual's unique physiological condition, may bring a contemporary approach to ensure longitudinal and continuous engagement. Sonification could be a useful auditory cueing technique when integrated within personalised approaches to gait rehabilitation systems. Previously, sonification demonstrated encouraging results, notably in reducing freezing-of-gait, mitigating spatial variability, and bolstering gait consistency in people with Parkinson's disease (PD). Specifically, sonification through the manipulation of acoustic features paired with the application of advanced audio processing techniques (e.g., time-stretching) enable auditory cueing interventions to be tailored and enhanced. These methods used in conjunction optimize gait characteristics and subsequently improve mobility, enhancing the effectiveness of the intervention. The aim of this narrative review is to further understand and unlock the potential of sonification as a pivotal tool in auditory cueing for gait rehabilitation, while highlighting that continued clinical research is needed to ensure comfort and desirability of use.

Visual Cues for Turning in Parkinson's Disease.

Turning is a common impairment of mobility in people with Parkinson's disease (PD), which increases freezing of gait (FoG) episodes and has implications for falls risk. Visual cues have been shown to improve general gait characteristics in PD. However, the effects of visual cues on turning deficits in PD remains unclear. We aimed to (i) compare the response of turning performance while walking (180° and 360° turns) to visual cues in people with PD with and without FoG; and (ii) examine the relationship between FoG severity and response to visual cues during turning. This exploratory interventional study measured turning while walking in 43 participants with PD (22 with self-reported FoG) and 20 controls using an inertial sensor placed at the fifth lumbar vertebrae region. Participants walked straight and performed 180° and 360° turns midway through a 10 m walk, which was done with and without visual cues (starred pattern). The turn duration and velocity response to visual cues were assessed using linear mixed effects models. People with FoG turned slower and longer than people with PD without FoG and controls (group effect: p < 0.001). Visual cues reduced the velocity of turning 180° across all groups and reduced the velocity of turning 360° in people with PD without FoG and controls. FoG severity was not significantly associated with response to visual cues during turning. Findings suggest that visual cueing can modify turning during walking in PD, with response influenced by FoG status and turn amplitude. Slower turning in response to visual cueing may indicate a more cautious and/or attention-driven turning pattern. This study contributes to our understanding of the influence that cues can have on turning performance in PD, particularly in freezers, and will aid in their therapeutic application.

Gait Impairment in Traumatic Brain Injury: A Systematic Review.

INTRODUCTION: Gait impairment occurs across the spectrum of traumatic brain injury (TBI); from mild (mTBI) to moderate (modTBI), to severe (sevTBI). Recent evidence suggests that objective gait assessment may be a surrogate marker for neurological impairment such as TBI. However, the most optimal method of objective gait assessment is still not well understood due to previous reliance on subjective assessment approaches. The purpose of this review was to examine objective assessment of gait impairments across the spectrum of TBI. METHODS: PubMed, AMED, OVID and CINAHL databases were searched with a search strategy containing key search terms for TBI and gait. Original research articles reporting gait outcomes in adults with TBI (mTBI, modTBI, sevTBI) were included. RESULTS: 156 citations were identified from the search, of these, 13 studies met the initial criteria and were included into the review. The findings from the reviewed studies suggest that gait is impaired in mTBI, modTBI and sevTBI (in acute and chronic stages), but methodological limitations were evident within all studies. Inertial measurement units were most used to assess gait, with single-task, dual-task and obstacle crossing conditions used. No studies examined gait across the full spectrum of TBI and all studies differed in their gait assessment protocols. Recommendations for future studies are provided. CONCLUSION: Gait was found to be impaired in TBI within the reviewed studies regardless of severity level (mTBI, modTBI, sevTBI), but methodological limitations of studies (transparency and reproducibility) limit clinical application. Further research is required to establish a standardised gait assessment procedure to fully determine gait impairment across the spectrum of TBI with comprehensive outcomes and consistent protocols.

The Relationship between the Oral Microbiota and Metabolic Syndrome.

The oral microbiota plays a crucial role in both systemic inflammation and metabolic syndrome (MetS), which is characterised by low-grade inflammation. Studies have analysed the gut microbiota using stool specimens from subjects with MetS; however, the etiological role of the oral microbiota in the development of MetS is still uncertain. We investigated the oral microbiota of 128 subgingival plaque samples from a South African cohort with and without MetS. After a comprehensive analysis of the oral microbiota, we observed a significant increase in Gram-positive aerobic and anaerobic microbiota in those with MetS. We observed an abundance of Actinomyces, Corynebacterium, and Fusobacterium genera in the MetS group, which differed significantly from previous studies, which found Granulicatella to be enriched in MetS. To further assess the impact of the metabolic parameters (FBG, Waist C, HDL, TGs, and BP) on the oral microbiota, we calculated the odds ratio (ORs) for significant oral microbiota identified between the MetS groups. We found that different species were associated with at least four MetS risk factors. This study has shown that the oral microbiota is disrupted in MetS and may promote inflammation providing a gateway to other systemic diseases, including diabetes and cardiovascular diseases.

Assessing the effectiveness and implementation of a chronic disease self-management programme in faith-based organisations in Barbados: protocol for a cluster randomised parallel trial.

INTRODUCTION: In the COVID-19 environment of reduced patient interaction with the healthcare system, evidenced-based self-care of chronic disease is vital. We will evaluate the effect of an online chronic disease self-management programme (CDSMP) plus medication adherence tools on systolic blood pressure (SBP) (primary aim) and, seek to understand the barriers and facilitators to implementation of this modified CDSMP in faith-based organisations (FBOs) (secondary aim). METHODS: We will conduct an unblinded cluster randomised trial in FBOs throughout Barbados. Eligibility: Persons ages 35-70 years; a previous diagnosis of hypertension or currently on antihypertensive therapy and the occurrence of two or more blood pressure readings above 130 mm Hg (systolic) or 80 mm Hg (diastolic) on the day of recruitment. Persons not known to have hypertension but who have two or more blood pressure readings at or above 130 mm Hg (systolic) or 80 mm Hg (diastolic) on two recruitment days at least 1 week apart will also be eligible. The unit of randomisation is a church cluster which consists of 7-9 churches. We will perform block randomisation to assign 24 clusters to intervention or control. The intervention has three components: modified CDSMP workshops, distribution of medication pill boxes and use of social media (WhatsApp V.2.0) to encourage medication adherence. Controls will receive one didactic lecture only. We will determine the mean changes in SBP levels for the intervention group versus controls and compare differences in outcomes 6 months' post intervention using mixed effects regression models. ETHICS AND DISSEMINATION: This project has received ethical approval from the Institutional Review Board of the University of the West Indies in Barbados. Dissemination will use peer-reviewed publications, policy briefs to government and guidelines to leaders of FBOs. We aim to increase the proportion of patients with controlled hypertension and inform implementation of self-management programmes in small populations. TRAIL REGISTRATION NUMBER: NCT04437966.

Plasma Cell-Free DNA Profiling of PTEN-PI3K-AKT Pathway Aberrations in Metastatic Castration-Resistant Prostate Cancer.

Tumor tissue from metastatic castration-resistant prostate cancer (mCRPC) harbors frequent copy number variations (CNVs) in the PTEN-PI3K-AKT pathway. However, identifying CNVs in plasma cell-free DNA (cfDNA) has proven to be challenging. With emerging data supporting Akt inhibition in PTEN-deficient mCRPC, we profiled PTEN-PI3K-AKT pathway aberrations in patients with mCRPC using a novel cfDNA assay optimized for CNV detection. METHODS: A next-generation sequencing-based cfDNA assay was used to profile 231 patients with mCRPC from two independent cohorts (Australian, n = 78; United States, n = 153). PTEN-PI3K-AKT pathway genomic aberrations were correlated with clinical outcomes, including progression-free survival and overall survival (OS). RESULTS: PTEN loss and PIK3CA gain were detected in 37% (85 of 231) and 17% (39 of 231) of patients, respectively. Poorer outcomes were observed in patients with PTEN-PI3K-AKT pathway aberrations, including those with dual PTEN loss and PIK3CA gain (hazard ratio 2.3, 95% CI 1.2 to 4.4). Cumulative CNV burden in the PTEN-PI3K-AKT and androgen receptor (AR) pathways was associated with significantly worse clinical outcomes (0 v 1 v ≥ 2 CNVs in Australian cohort: median OS 33.5 v 17.2 v 9.7 months, P < .001; 0 v 1 v ≥ 2 CNVs in US cohort: median OS 35.5 v 14.3 v 9.2 months, P < .001). Notably, 21% (31 of 146) of PTEN-neutral patients harbored alternative PTEN-PI3K-AKT pathway aberrations. CONCLUSION: PTEN-PI3K-AKT pathway CNVs were readily detected using our cfDNA assay, with the prevalence of PTEN loss comparable with tissue-based studies. Additional PTEN-PI3K-AKT pathway aberrations were found in one fifth of PTEN-neutral cases. Concurrent CNVs in the PTEN-PI3K-AKT and AR pathways portended poor survival, and identifying this high-risk patient subset for dual AR/Akt inhibition may optimize precision treatment with Akt inhibitors in mCRPC.

Whole blood GRHL2 expression as a prognostic biomarker in metastatic hormone-sensitive and castration-resistant prostate cancer.

BACKGROUND: As potent systemic therapies transition earlier in the prostate cancer disease course, molecular biomarkers are needed to guide optimal treatment selection for metastatic hormone-sensitive prostate cancer (mHSPC). The value of whole blood RNA to detect candidate biomarkers in mHSPC remains largely undefined. METHODS: In this cohort study, we used a previously optimised whole blood reverse transcription polymerase chain reaction assay to assess the prognostic utility [measured by seven-month undetectable prostate-specific antigen (PSA) and time to castration-resistance (TTCR)] of eight prostate cancer-associated gene transcripts in 43 mHSPC patients. Transcripts with statistically significant associations (P<0.05) were further investigated in a metastatic castration-resistant prostate cancer (mCRPC) cohort (n=119) receiving contemporary systemic therapy, exploring associations with PSA >50% response (PSA50), progression-free survival (PFS) and overall survival (OS). Clinical outcomes were prospectively collected in a protected digital database. Kaplan-Meier estimates and multivariable Cox proportional-hazards models assessed associations between gene transcripts and clinical outcomes (mHSPC covariates: disease volume, docetaxel use and haemoglobin level; mCRPC covariates: prior exposure to chemotherapy or ARPIs, haemoglobin, performance status and presence of visceral disease). Follow-up was performed monthly during ARPI treatment, three-weekly during taxane chemotherapy, and three-monthly during androgen deprivation therapy (ADT) monotherapy. Serial PSA measurements were performed before each follow-up visit and repeat imaging was at the discretion of the investigator. RESULTS: Detection of circulating Grainyhead-like 2 (GRHL2) transcript was associated with poor outcomes in mHSPC and mCRPC patients. Detectable GRHL2 expression in mHSPC was associated with a lower rate of seven-month undetectable PSA levels (25% vs. 65%, P=0.059), and independently associated with shorter TTCR (HR 7.3, 95% CI: 1.5-36, P=0.01). In the mCRPC cohort, GRHL2 expression predicted significantly lower PSA50 response rates (46% vs. 69%, P=0.01), and was independently associated with shorter PFS (HR 3.1, 95% CI: 1.8-5.2, P<0.001) and OS (HR 2.9, 95% CI: 1.6-5.1, P<0.001). Associations were most apparent in patients receiving ARPIs. CONCLUSIONS: Detectable circulating GRHL2 was a negative prognostic biomarker in our mHSPC and mCRPC cohorts. These data support further investigation of GRHL2 as a candidate prognostic biomarker in metastatic prostate cancer, in addition to expanding efforts to better understand a putative role in therapeutic resistance to AR targeted therapies.

Dynamics of hepatic steatosis resolution and changes in gut microbiome with weight loss in nonalcoholic fatty liver disease.

BACKGROUND: Weight loss is recommended as the primary treatment for nonalcoholic fatty liver disease (NAFLD). However, the magnitude and velocity of hepatic steatosis resolution with weight loss is unclear, making it difficult to counsel patients seeking weight loss for treatment of NAFLD. The aim of this study was to determine the rate of hepatic steatosis improvement and stool microbiome changes associated with rapid diet-induced weight loss in NAFLD. METHODS: Fourteen NAFLD patients (mean ± standard deviation, body mass index [BMI] 36.4 ± 4 kg/m2) enrolled in a 12-week meal replacement program underwent frequent measurement of Fibroscan-controlled attenuation parameter (CAP). Magnetic resonance imaging (MRI-Dixon method) for hepatic fat quantitation and stool microbiome analysis (16S rRNA gene sequencing) were completed in 11 subjects at baseline and Week 12. RESULTS: At Week 12, mean (95% confidence interval) weight loss was -13.4 (-15.2, -11.5)% and CAP score -26.6 (-35.6, -17.6)% (both Ps < 0.001). CAP scores changed at a rate of -4.9 dB/m/kg (-30.1 dB/m per unit BMI) in Weeks 1-4 and -0.6 dB/m/kg (-2.4 dB/m per unit BMI) in Weeks 8-12. MRI-determined hepatic fat fraction decreased by -74.1% (p < 0.001) at a rate of -0.51%/kg (-3.19% per unit BMI), with complete steatosis resolution in 90% patients. BMI change was associated with decreased stool microbial diversity (coefficient = 0.17; Shannon Index), increased abundance of Prevotella_9 (Bacteroidetes; coefficient = 0.96) and decreased abundance of Phascolarctobacterium (Firmicutes; coefficient = -0.42) (both Ps < 0.05). CONCLUSIONS: Diet-induced intensive weight loss is associated with rapid improvement and complete resolution of hepatic steatosis and decreased stool microbial diversity. These findings highlight the dynamic nature of hepatic fat and may help clinicians to develop evidence-based treatment goals for patients with NAFLD and obesity who undertake weight loss interventions. Further research is warranted to understand the effects of intensive weight loss and gut microbiome changes on long-term NAFLD resolution.

Children's Pain During IV Induction: A Randomized-Controlled Trial With the MEDi® Robot.

OBJECTIVE: This study examined the impact of a humanoid robot (MEDi®) programmed to teach deep breathing as a coping strategy, on children's pain and fear as primary and secondary outcomes, respectively, during intravenous (IV) line placement. The completion of IV induction was also examined as an exploratory outcome. METHODS: In this randomized controlled, two-armed trial, 137 children (4-12 years) were recruited in Short Stay Surgery at a tertiary pediatric hospital. Patients were randomly assigned to standard care (SC) with Ametop© only (N = 60) or SC and robot-facilitated intervention (N = 59) before induction. Pain and fear before, during, and after IV insertion were rated by patients and observers. RESULTS: No significant differences were found between groups and there were no changes over time for pain or fear (ps > .05). Exploratory analyses show that patients in the MEDi® group were 5.04 times more likely to complete IV induction, compared to SC, Fisher's exact test: X2 (1) = 4.85, p = .04, φc = 0.22, odds ratio = 5.04, 95% CI [1.06, 24.00]. CONCLUSION: This study was the first to examine children's IV induction experience when provided MEDi® support. Reasons for nonsignificance, limitations, and research suggestions were made.

Prognostic Utility of a Whole-blood Androgen Receptor-based Gene Signature in Metastatic Castration-resistant Prostate Cancer.

BACKGROUND: The treatment paradigm for metastatic castration-resistant prostate cancer (mCRPC) has evolved significantly in recent years. Identifying predictive and/or prognostic biomarkers in the context of this rapidly expanding therapeutic armamentarium remains a pressing and unmet clinical need. OBJECTIVE: To develop a prognostic whole-blood gene signature for mCRPC patients. DESIGN, SETTING, AND PARTICIPANTS: As part of an ongoing prospective, multicentre biomarker research study (Australian Prostate Biomarker Alliance), we enrolled 115 mCRPC patients commencing chemotherapy (n = 34) or androgen receptor (AR) pathway inhibitors therapy (n = 81) and obtained pretreatment whole-blood samples in PAXgene RNA tubes. Gene expression was assessed using reverse transcription-polymerase chain reaction. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Gene transcripts correlating with overall survival (OS) at p < 0.10 in univariate Cox regression models were incorporated into a multigene signature. Kaplan-Meier survival estimates and multivariate analyses were used to assess association with clinical outcomes. Prognostic strength of the signature was estimated using a concordance probability estimate (CPE). RESULTS AND LIMITATIONS: Based on univariate analysis for OS, the following genes were incorporated into a multigene signature: AR splice variant 7 (AR-V7), and three androgen-regulated genes: GRHL2, HOXB13, and FOXA1. The number of positive transcripts clearly stratified survival outcomes (median OS: not reached vs 24.8 mo vs 16.2 mo for 0, 1, and ≥2 transcripts, respectively; p = 0.0052). Notably, this multigene signature retained prognostic significance on multivariable analysis (hazard ratio, 2.1; 95% confidence interval, 1.1-4.0; p = 0.019). Moreover, CPE for this model was 0.78, indicating strong discriminative capacity. Limitations include short follow-up time. CONCLUSIONS: Our data demonstrate the prognostic utility of a novel whole-blood AR-based signature in mCRPC patients commencing contemporary systemic therapies. Our pragmatic assay requires minimal processing, can be performed in most hospital laboratories, and could represent a key prognostic tool for risk stratification in mCRPC. PATIENT SUMMARY: We found that expression of certain genes associated with the androgen receptor could help determine how long men with advanced prostate cancer survive after starting modern drug therapies.

The Garlic Compound Z-Ajoene, S-Thiolates COX2 and STAT3 and Dampens the Inflammatory Response in RAW264.7 Macrophages.

SCOPE: Garlic (Allium sativum) has been used for centuries as a prophylactic and therapeutic medicinal agent to control inflammation-associated pathologies. To investigate the underlying mechanisms, an in vitro inflammatory model is established using RAW264.7 murine macrophages exposed to low-doses of lipopolysaccharide (LPS) in the presence of garlic compounds allicin and Z-ajoene (ZA), mimicking regular garlic consumption. METHODS AND RESULTS: Both allicin and Z-ajoene dampen both transcript and protein expression of the pro-inflammatory cytokines IL1ß, IL6, and IL12ß, and upregulate the expression of the anti-inflammatory cytokine IL10. Protein arrays of selected secreted inflammatory mediators confirm that Z-ajoene has a pronounced down-regulatory effect on LPS-induced inflammatory cytokines and chemokines. Many of these proteins are known targets of the transcription factor signal transducer and activator of transcription 3 (STAT3); and indeed, Z-ajoene or its analogue dansyl-ajoene is found to decrease phosphorylation and nuclear translocation of STAT3, and to covalently modify the protein by S-thiolation at Cys108, Cys367, and Cys687. Z-Ajoene dose-dependently and non-competitively inhibit the activity of cyclooxygenase 2 (COX2), possibly attributed to S-thiolation at Cys9 and Cys299. CONCLUSION: The characterization of Z-ajoene's activity of targeting and covalently modifying STAT3 and COX2, both important regulators of inflammation, may contribute to the health benefits of regular dietary garlic consumption.

Evaluating and Enhancing the Preparation of Patients and Families before Pediatric Surgery.

Surgery can be a difficult and unfamiliar experience for children and their families. We examined the ability of existing information to help families feel better prepared for surgery at the Alberta Children's Hospital (ACH) and evaluated the best way to enhance its content and accessibility. We developed an online survey for families who have had surgery at ACH. Participants were recruited through pre-existing patient networks and from the ACH Short Stay Unit (SSU) between October 2018 and October 2019. The survey asked participants to evaluate the information available to prepare them for surgery and requested suggestions for improvement. Our survey results show that those who completed the in-person Surgery 101 program felt significantly more prepared for surgery. Of those who did not attend; 40% would have been interested in participating but were unaware that the program existed; and 17% planned to attend but were unable to; due to work or travel distance. Participants felt additional resources via online content or paper handouts would be most valuable. We used this information to prepare an online accessible summary of the Surgery 101 program and tour in the form of a video to reach more Albertan families preparing for surgery for their children.

Combined Cell-free DNA and RNA Profiling of the Androgen Receptor: Clinical Utility of a Novel Multianalyte Liquid Biopsy Assay for Metastatic Prostate Cancer.

BACKGROUND: The androgen receptor (AR) remains a critical driver in metastatic castration-resistant prostate cancer (mCRPC). Profiling AR aberrations in both circulating DNA and RNA may identify key predictive and/or prognostic biomarkers in the context of contemporary systemic therapy. OBJECTIVE: To profile AR aberrations in circulating nucleic acids and correlate with clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS: We prospectively enrolled 67 mCRPC patients commencing AR pathway inhibitors (ARPIs; n = 41) or taxane chemotherapy (n = 26). Using a first-in-class next-generation sequencing-based assay, we performed integrated cell-free DNA (cfDNA) and cell-free RNA (cfRNA) profiling from a single 10 ml blood tube. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Kaplan-Meier survival estimates and multivariable Cox regression analyses were used to assess associations between clinical outcomes and the following AR aberrations: copy number variation, splice variants (AR-V7 and AR-V9) and somatic mutations. RESULTS AND LIMITATIONS: Cell-free DNA and cfRNA were successfully sequenced in 67 (100%) and 59 (88%) patients, respectively. Thirty-six (54%) patients had one or more AR aberrations. AR gain and cumulative number of AR aberrations were independently associated with clinical/radiographic progression-free survival (PFS; hazard ratio [HR] 3.2, p = 0.01 and HR 3.0 for 0 vs ≥2, p = 0.04) and overall survival (HR 2.8, p = 0.04 and HR 2.9 for 0 vs ≥2, p = 0.03). Notably, concurrent AR gain and AR splice variant expression (AR gain/AR-V+) was associated with shorter prostate-specific antigen PFS on both ARPIs (HR 6.7, p = 0.009) and chemotherapy (HR 3.9, p = 0.04). Importantly, key findings were validated in an independent cohort of mCRPC patients (n = 40), including shorter OS in AR gain/AR-V+ disease (HR 3.3, p = 0.02). Limitations include sample size and follow-up period. CONCLUSIONS: We demonstrate the utility of a novel, multianalyte liquid biopsy assay capable of simultaneously detecting AR alterations in cfDNA and cfRNA. Concurrent profiling of cfDNA and cfRNA may provide vital insights into disease biology and resistance mechanisms in mCRPC. PATIENT SUMMARY: In this study of men with advanced prostate cancer, DNA and RNA abnormalities in the androgen receptor detected in blood were associated with poor outcomes on available drug treatments. This information could be used to better guide treatment of advanced prostate cancer.