Programmable RNA-Guided RNA Effector Proteins Built from Human Parts.

Epitranscriptomic regulation controls information flow through the central dogma and provides unique opportunities for manipulating cells at the RNA level. However, both fundamental studies and potential translational applications are impeded by a lack of methods to target specific RNAs with effector proteins. Here, we present CRISPR-Cas-inspired RNA targeting system (CIRTS), a protein engineering strategy for constructing programmable RNA control elements. We show that CIRTS is a simple and generalizable approach to deliver a range of effector proteins, including nucleases, degradation machinery, translational activators, and base editors to target transcripts. We further demonstrate that CIRTS is not only smaller than naturally occurring CRISPR-Cas programmable RNA binding systems but can also be built entirely from human protein parts. CIRTS provides a platform to probe fundamental RNA regulatory processes, and the human-derived nature of CIRTS provides a potential strategy to avoid immune issues when applied to epitranscriptome-modulating therapies.

Lupus nephritis and socioeconomic status: Findings from the Southern California lupus registry.

OBJECTIVE: Lupus nephritis (LN) is a major cause of morbidity and mortality in systemic lupus erythematosus (SLE). Despite multiple studies addressing healthcare disparities, disparate outcomes in LN persist. We investigate herein the association between socioeconomic status (SES) and LN as well as the association between SES, SLE disease activity index (SLEDAI), and treatment response. METHODS: Patients were selected from the Southern California Lupus Registry (SCOLR), a registry enrolling all-comers with SLE. Analysis was completed on individuals with public vs. private insurance. Insurance and ethnicity were used as surrogate variables for SES, and we tested differences in means. RESULTS: After adjusting for age and sex, public insurance was independently associated with the prevalence of LN. Analysis of 35 patients revealed greater proteinuria and mean SLEDAI in patients with public insurance at baseline and 6 months. Baseline, 6-, and 12-month SLEDAI means were significantly lower in Asian/Pacific Islanders (PI) compared to others. While non-Hispanic Whites demonstrated mean SLEDAI improvement over 6 months, Asians/PI, Blacks, and Hispanics demonstrated worsened disease activity on average. CONCLUSION: Low SES, when defined by insurance, is associated with greater adverse outcomes in SLE. This is the first regional study that compares differences in treatment response in LN patients with low SES as well as association of SES with long-term outcomes in SLE and LN in southern California.

Colon and rectal cancer treatment patterns and their associations with clinical, sociodemographic and lifestyle characteristics: analysis of the Australian 45 and Up Study cohort.

BACKGROUND: Colorectal cancer is the third most diagnosed cancer globally and the second leading cause of cancer death. We examined colon and rectal cancer treatment patterns in Australia. METHODS: From cancer registry records, we identified 1,236 and 542 people with incident colon and rectal cancer, respectively, diagnosed during 2006-2013 in the 45 and Up Study cohort (267,357 participants). Cancer treatment and deaths were determined via linkage to routinely collected data, including hospital and medical services records. For colon cancer, we examined treatment categories of "surgery only", "surgery plus chemotherapy", "other treatment" (i.e. other combinations of surgery/chemotherapy/radiotherapy), "no record of cancer-related treatment, died"; and, for rectal cancer, "surgery only", "surgery plus chemotherapy and/or radiotherapy", "other treatment", and "no record of cancer-related treatment, died". We analysed survival, time to first treatment, and characteristics associated with treatment receipt using competing risks regression. RESULTS: 86.4% and 86.5% of people with colon and rectal cancer, respectively, had a record of receiving any treatment ≤2 years post-diagnosis. Of those treated, 93.2% and 90.8% started treatment ≤2 months post-diagnosis, respectively. Characteristics significantly associated with treatment receipt were similar for colon and rectal cancer, with strongest associations for spread of disease and age at diagnosis (p<0.003). For colon cancer, the rate of "no record of cancer-related treatment, died" was higher for people with distant spread of disease (versus localised, subdistribution hazard ratio (SHR)=13.6, 95% confidence interval (CI):5.5-33.9), age ≥75 years (versus age 45-74, SHR=3.6, 95%CI:1.8-7.1), and visiting an emergency department ≤1 month pre-diagnosis (SHR=2.9, 95%CI:1.6-5.2). For rectal cancer, the rate of "surgery plus chemotherapy and/or radiotherapy" was higher for people with regional spread of disease (versus localised, SHR=5.2, 95%CI:3.6-7.7) and lower for people with poorer physical functioning (SHR=0.5, 95%CI:0.3-0.8) or no private health insurance (SHR=0.7, 95%CI:0.5-0.9). CONCLUSION: Before the COVID-19 pandemic, most people with colon or rectal cancer received treatment ≤2 months post-diagnosis, however, treatment patterns varied by spread of disease and age. This work can be used to inform future healthcare requirements, to estimate the impact of cancer control interventions to improve prevention and early diagnosis, and serve as a benchmark to assess treatment delays/disruptions during the pandemic. Future work should examine associations with clinical factors (e.g. performance status at diagnosis) and interdependencies between characteristics such as age, comorbidities, and emergency department visits.

The 'hot zone policy' for colorectal cancer screening presents unique risks and opportunities for rural Australia.

OBJECTIVE: Colorectal cancer has geographic inequities in Australia, with higher mortality rates and lower participation in the National Bowel Cancer Screening Program (NBCSP) in remote and rural areas. The at-home kit is temperature-sensitive, necessitating a 'hot zone policy' (HZP); kits are not sent when an area's average monthly temperature is above 30°C. Australians in HZP areas are susceptible to potential screening disruptions but may benefit from well-timed interventions to improve participation. This study describes the demographics of HZP areas and estimates the impacts of potential screening changes. METHODS: The number of individuals in HZP areas was estimated, as well as correlations with remoteness, socio-economic and Indigenous status. The potential impacts of screening changes were estimated. RESULTS: Over a million eligible Australians live in HZP areas, which are more likely to be remote/rural, have lower socio-economic status and higher Indigenous populations. Predictive modelling estimates that any 3-month screening disruption would increase CRC mortality rates up to 4.1 times more in HZP areas vs unaffected areas, while targeted intervention could decrease mortality rates 3.4 times more in HZP areas. CONCLUSION: People living in affected areas would be negatively impacted by any NBCSP disruption, compounding existing inequities. However, well-timed health promotion could have a stronger impact.

Noncontrast MRI for Hepatocellular Carcinoma Detection: A Systematic Review and Meta-analysis - A Potential Surveillance Tool?

BACKGROUND AND AIMS: This meta-analysis investigates the diagnostic performance of non-contrast magnetic resonance imaging (MRI) for the detection of hepatocellular carcinoma (HCC). METHODS: A systematic review was performed to May 2020 for studies which examined the diagnostic performance of non-contrast MRI (multi-sequence or diffusion-weighted imaging (DWI)- alone) for HCC detection in high risk patients. The primary outcome was accuracy for the detection of HCC. Random effects models were used to pool outcomes for sensitivity, specificity, positive likelihood ratio (LR) and negative LR. Subgroup analyses for cirrhosis and size of the lesion were performed. RESULTS: Twenty-two studies were included involving 1685 patients for per-patient analysis and 2128 lesions for per-lesion analysis. Multi-sequence non-contrast MRI (NC-MRI) using T2+DWI±T1 sequences had a pooled per-patient sensitivity of 86.8% (95%CI:83.9-89.4%), specificity of 90.3% (95%CI:87.3-92.7%), and negative LR of 0.17 (95%CI:0.14-0.20). DWI-only MRI (DW-MRI) had a pooled sensitivity of 79.2% (95%CI:71.8-85.4%), specificity of 96.5% (95%CI:94.3-98.1%) and negative LR of 0.24 (95%CI:1.62-0.34). In patients with cirrhosis, NC-MRI had a pooled per-patient sensitivity of 87.3% (95%CI:82.7-91.0%) and specificity of 81.6% (95%CI:75.3-86.8%), whilst DWI-MRI had a pooled sensitivity of 71.4% (95%CI:60.5-80.8%) and specificity of 97.1% (95%CI:91.9-99.4%). For lesions <2 cm, the pooled per-lesion sensitivity was 77.1% (95%CI:73.8-80.2%). For lesions >2 cm, pooled per-lesion sensitivity was 88.5% (95%CI:85.0-91.5%). CONCLUSION: Non-contrast MRI has a moderate negative LR and high specificity with acceptable sensitivity for the detection of HCC, even in patients with cirrhosis and with lesions <2 cm. Prospective trials to validate if non-contrast MRI can be used for HCC surveillance is warranted.

Lynch syndrome testing of colorectal cancer patients in a high-income country with universal healthcare: a retrospective study of current practice and gaps in seven australian hospitals.

BACKGROUND: To inform effective genomic medicine strategies, it is important to examine current approaches and gaps in well-established applications. Lynch syndrome (LS) causes 3-5% of colorectal cancers (CRCs). While guidelines commonly recommend LS tumour testing of all CRC patients, implementation in health systems is known to be highly variable. To provide insights on the heterogeneity in practice and current bottlenecks in a high-income country with universal healthcare, we characterise the approaches and gaps in LS testing and referral in seven Australian hospitals across three states. METHODS: We obtained surgery, pathology, and genetics services data for 1,624 patients who underwent CRC resections from 01/01/2017 to 31/12/2018 in the included hospitals. RESULTS: Tumour testing approaches differed between hospitals, with 0-19% of patients missing mismatch repair deficiency test results (total 211/1,624 patients). Tumour tests to exclude somatic MLH1 loss were incomplete at five hospitals (42/187 patients). Of 74 patients with tumour tests completed appropriately and indicating high risk of LS, 36 (49%) were missing a record of referral to genetics services for diagnostic testing, with higher missingness for older patients (0% of patients aged ≤ 40 years, 76% of patients aged > 70 years). Of 38 patients with high-risk tumour test results and genetics services referral, diagnostic testing was carried out for 25 (89%) and identified a LS pathogenic/likely pathogenic variant for 11 patients (44% of 25; 0.7% of 1,624 patients). CONCLUSIONS: Given the LS testing and referral gaps, further work is needed to identify strategies for successful integration of LS testing into clinical care, and provide a model for hereditary cancers and broader genomic medicine. Standardised reporting may help clinicians interpret tumour test results and initiate further actions.

Quantifying face mask comfort.

Face mask usage is one of the most effective ways to limit SARS-CoV-2 transmission, but a mask is only useful if user compliance is high. Through anonymous surveys (n = 679), it was shown that mask discomfort is the primary source of noncompliance in mask wearing. Further, through these surveys, three critical predicting variables that dictate mask comfort were identified: air resistance, water vapor permeability, and face temperature change. To validate these predicting variables in a physiological context, experiments (n = 9) were performed to measure the respiratory rate and change in face temperature while wearing different types of three commonly used masks. Finally, using values of these predicting variables from experiments and the literature, and surveys asking users to rate the comfort of various masks, three machine learning algorithms were trained and tested to generate overall comfort scores for those masks. Although all three models performed with an accuracy of approximately 70%, the multiple linear regression model provides a simple analytical expression to predict the comfort scores for common face masks provided the input predicting variables. As face mask usage is crucial during the COVID-19 pandemic, the goal of this quantitative framework to predict mask comfort is hoped to improve user experience and prevent discomfort-induced noncompliance.

Risk quantification for SARS-CoV-2 infection through airborne transmission in university settings.

The COVID-19 pandemic has significantly impacted learning as many institutions switched to remote or hybrid instruction. An in-depth assessment of the risk of infection that considers environmental setting and mitigation strategies is needed to make safe and informed decisions regarding reopening university spaces. A quantitative model of infection probability that accounts for space-specific parameters is presented to enable assessment of the risk in reopening university spaces at given densities. The model uses the fraction of the campus population that are viral shedders, room capacity, face covering filtration efficiency, air exchange rate, room volume, and time spent in the space as parameters to calculate infection probabilities in teaching spaces, dining halls, dorms, and shared bathrooms. The model readily calculates infection probabilities in various university spaces, with face covering filtration efficiency and air exchange rate being among the dominant variables. When applied to university spaces, this model demonstrated that, under specific conditions that are feasible to implement, in-person classes could be held in large lecture halls with an infection risk over the semester <1%. Meal pick-ups from dining halls and usage of shared bathrooms in residential dormitories among small groups of students could also be accomplished with low risk. The results of applying this model to spaces at Harvard University (Cambridge and Allston campuses) and Stanford University are reported. Finally, a user-friendly web application was developed using this model to calculate infection probability following input of space-specific variables. The successful development of a quantitative model and its implementation through a web application may facilitate accurate assessments of infection risk in university spaces. However, since this model is thus far unvalidated, validation using infection rate and contact tracing data from university campuses will be crucial as such data becomes available at larger scales. In light of the impact of the COVID-19 pandemic on universities, this tool could provide crucial insight to students, faculty, and university officials in making informed decisions.

Screen-detected and interval colorectal cancers in England: Associations with lifestyle and other factors in women in a large UK prospective cohort.

Faecal occult blood (FOB) - based screening programmes for colorectal cancer detect about half of all cancers. Little is known about individual health behavioural characteristics which may be associated with screen-detected and interval cancers. Electronic linkage between the UK National Health Service Bowel Cancer Screening Programme (BCSP) in England, cancer registration and other national health records, and a large on-going UK cohort, the Million Women Study, provided data on 628,976 women screened using a guaiac-FOB test (gFOBt) between 2006 and 2012. Relative risks (RRs) and 95% confidence intervals (CIs) were estimated by logistic and Cox regression for associations between individual lifestyle factors and risk of colorectal tumours. Among screened women, 766 were diagnosed with screen-detected colorectal cancer registered within 2 years after a positive gFOBt result, and 749 with interval colorectal cancers registered within 2 years after a negative gFOBt result. Current smoking was significantly associated with risk of interval cancer (RR 1.64, 95%CI 1.35-1.99) but not with risk of screen-detected cancer (RR 1.03, 0.84-1.28), and was the only factor of eight examined to show a significant difference in risk between interval and screen-detected cancers (p for difference, 0.003). Compared to screen-detected cancers, interval cancers tended to be sited in the proximal colon or rectum, to be of non-adenocarcinoma morphology, and to be of higher stage.

Evaluation of the benefits, harms and cost-effectiveness of potential alternatives to iFOBT testing for colorectal cancer screening in Australia.

The Australian National Bowel Cancer Screening Program (NBCSP) will fully roll-out 2-yearly screening using the immunochemical Faecal Occult Blood Testing (iFOBT) in people aged 50 to 74 years by 2020. In this study, we aimed to estimate the comparative health benefits, harms, and cost-effectiveness of screening with iFOBT, versus other potential alternative or adjunctive technologies. A comprehensive validated microsimulation model, Policy1-Bowel, was used to simulate a total of 13 screening approaches involving use of iFOBT, colonoscopy, sigmoidoscopy, computed tomographic colonography (CTC), faecal DNA (fDNA) and plasma DNA (pDNA), in people aged 50 to 74 years. All strategies were evaluated in three scenarios: (i) perfect adherence, (ii) high (but imperfect) adherence, and (iii) low adherence. When assuming perfect adherence, the most effective strategies involved using iFOBT (annually, or biennially with/without adjunct sigmoidoscopy either at 50, or at 54, 64 and 74 years for individuals with negative iFOBT), or colonoscopy (10-yearly, or once-off at 50 years combined with biennial iFOBT). Colorectal cancer incidence (mortality) reductions for these strategies were 51-67(74-80)% in comparison with no screening; 2-yearly iFOBT screening (i.e. the NBCSP) would be associated with reductions of 51(74)%. Only 2-yearly iFOBT screening was found to be cost-effective in all scenarios in context of an indicative willingness-to-pay threshold of A$50,000/life-year saved (LYS); this strategy was associated with an incremental cost-effectiveness ratio of A$2,984/LYS-A$5,981/LYS (depending on adherence). The fully rolled-out NBCSP is highly cost-effective, and is also one of the most effective approaches for bowel cancer screening in Australia.

Factors associated with participation in colorectal cancer screening in Australia: Results from the 45 and Up Study cohort.

The Australian Government's National Bowel Cancer Screening Program (NBCSP) was introduced in 2006 to provide free home-based immunochemical faecal occult blood test (iFOBT) to eligible Australians turning 55 and 65years in that year. With the gradual inclusion of additional age cohorts, the rollout of the NBCSP is being implemented in the context of a degree of opportunistic or de facto screening. This study investigated factors associated with self-reported ever-uptake of the NBCSP and of any CRC screening using follow-up questionnaire data from 105,897 Australians aged ≥45years enrolled in the 45 and Up Study in New South Wales, Australia. Of the 91,968 study participants with information on CRC screening behaviour, 70,444 (76.6%) reported ever-uptake of any CRC screening. 63,777 study participants were eligible for a NBCSP invitation, of these 33,148 (52.0%) reported ever-uptake of screening through the NBCSP. Current smoking (RR=0.86, 0.83-0.90), non-participation in breast cancer screening (female) or PSA testing (male) (RR=0.84, 0.81-0.86), poor self-reported health (RR=0.89, 0.86-0.91), lower levels of education (RR=0.91, 0.90-0.93), and not speaking English at home (RR=0.88, 0.85-0.91) were associated with reduced ever-uptake of screening within the NBCSP and of any CRC screening. Individuals with a family history of CRC were less likely to screen through the NBCSP (RR=0.71, 0.69-0.73), but more likely to participate in any CRC screening (RR=1.18, 1.17-1.19). Smokers, disadvantaged groups and those with non-English speaking backgrounds are less likely to have ever-participated in organised screening through the NBCSP or in any form of CRC screening, supporting efforts to improve participation in these groups.

The Impact of Mismatch Repair Status in Colorectal Cancer on the Decision to Treat With Adjuvant Chemotherapy: An Australian Population-Based Multicenter Study.

BACKGROUND: Testing for mismatch repair (MMR) status in colorectal cancer (CRC) may provide useful prognostic and predictive information. We evaluated the impact of such testing on real-world practice regarding adjuvant chemotherapy for patients with resected CRC. PATIENTS AND METHODS: A total of 175 patients with stage II and III mismatch repair-deficient (MMRD) CRC were identified from an Australian population-based study of incident CRCs. Their treatment decisions were compared with those for a cohort of 773 stage-matched patients with mismatch repair-proficient (MMRP) CRCs. The effect of MMR status, age, and pathologic characteristics on treatment decisions was determined using multiple regression analysis. RESULTS: Overall, 32% of patients in stage II and 71% of patients in stage III received adjuvant chemotherapy. Among the stage II patients, those with MMRD cancer were less likely to receive chemotherapy than were MMRP cases (15% vs. 38%; p < .0001). In this group, the treatment decision was influenced by age, tumor location, and T stage. MMR status influenced the treatment decision such that its impact diminished with increasing patient age. Among patients with stage III tumors, no difference was found in the chemotherapy rates between the MMRD and MMRP cases. In this group, age was the only significant predictor of the treatment decision. CONCLUSION: The findings of this study suggest that knowledge of the MMR status of sporadic CRC influences treatment decisions for stage II patients, in an era when clear recommendations as to how these findings should influence practice are lacking. IMPLICATIONS FOR PRACTICE: Microsatellite instability (MSI) is a molecular marker of defective DNA mismatch repair found in 15% of sporadic colorectal cancers. Until recently, expert guidelines on the role of MSI as a valid biomarker in the selection of stage II patients for adjuvant chemotherapy were lacking. Conducted at a time when the clinical utility of routine MSI testing was unclear, this study found that clinicians were influenced by MSI status in selecting stage II patients for chemotherapy. Furthermore, the impact of MSI on treatment decisions was greatest in younger patients and declined progressively until age 80 years, when no effect was found.

α,ß-Unsaturated aldehyde pollutant acrolein suppresses cardiomyocyte contractile function: Role of TRPV1 and oxidative stress.

Air pollution is associated with an increased prevalence of heart disease and is known to trigger a proinflammatory response via stimulation of transient receptor potential vanilloid cation channels (TRPV1, also known as the capsaicin receptor). This study was designed to examine the effect of acrolein, an essential α,ß-unsaturated aldehyde pollutant, on myocardial contractile function and the underlying mechanism involved with a focus on TRPV1 and oxidative stress. Cardiomyocyte mechanical and intracellular Ca(2+) properties were evaluated using an IonOptix MyoCam® system including peak shortening (PS), maximal velocity of shortening/relengthening (± dL/dt), time-to-PS (TPS), time-to-90% relengthening (TR90 ), fura-2 fluorescence intensity (FFI) and intracellular Ca(2+) decay. Changes in apoptosis and TRPV1 were evaluated using Western blot analysis. The degree of oxidative stress was assessed using the ratio between reduced and oxidized glutathione. Results obtained revealed that exposure of cardiomyocytes to acrolein acutely compromised contractile and intracellular Ca(2+) properties including depressed PS, ± dL/dt and ΔFFI, as well as prolonged TR90 and intracellular Ca(2+) decay. In addition, acrolein exposure upregulated TRPV1 associated with an increase in both apoptosis and oxidative stress. However, the acrolein-induced cardiomyocyte contractile and intracellular Ca(2+) anomalies, as well as apoptosis (as evidenced by Bcl-2, Bax, FasL, Caspase-3 and -8), were negated by the reactive oxygen species (ROS) scavenger glutathione or the TRPV1 antagonist capsazepine. Collectively these data suggest that the α,ß-unsaturated aldehyde pollutant acrolein may play a role in the pathogenesis and sequelae of air pollution-induced heart disease via a TRPV1- and oxidative stress-dependent mechanism.

α,ß-Unsaturated aldehyde crotonaldehyde triggers cardiomyocyte contractile dysfunction: role of TRPV1 and mitochondrial function.

Recent evidence has suggested that cigarette smoking is associated with an increased prevalence of heart diseases. Given that cigarette smoking triggers proinflammatory response via stimulation of the capsaicin-sensitive transient receptor potential cation channel TRPV1, this study was designed to evaluate the effect of an essential α,ß-unsaturated aldehyde from cigarette smoke crotonaldehyde on myocardial function and the underlying mechanism with a focus on TRPV1 and mitochondria. Cardiomyocyte mechanical and intracellular Ca2+ properties were evaluated including peak shortening (PS), maximal velocity of shortening/relengthening (±dL/dt), time-to-PS (TPS), time-to-90% relengthening (TR90), fura-2 fluorescence intensity (FFI), intracellular Ca2+ decay and SERCA activity. Apoptosis and TRPV1 were evaluated using Western blot analysis. Production of reactive oxygen species (ROS) and DNA damage were measured using the intracellular fluoroprobe 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate and 8-hydroxy-2'-deoxyguanosine (8-OHdG), respectively. Our data revealed that crotonaldehyde interrupted cardiomyocyte contractile and intracellular Ca2+ property including depressed PS, ±dL/dt, ΔFFI and SERCA activity, as well as prolonged TR90 and intracellular Ca2+ decay. Crotonaldehyde exposure increased TRPV1 and NADPH oxidase levels, promoted apoptosis, mitochondrial injury (decreased aconitase activity, PGC-1α and UCP-2) as well as production of ROS and 8-OHdG. Interestingly, crotonaldehyde-induced cardiac defect was obliterated by the ROS scavenger glutathione and the TRPV1 inhibitor capsazepine. Capsazepine (not glutathione) ablated crotonaldehyde-induced mitochondrial damage. Capsazepine, glutathione and the NADPH inhibitor apocynin negated crotonaldehyde-induced ROS accumulation. Our data suggest a role of crotonaldehyde compromises cardiomyocyte mechanical function possibly through a TRPV1- and mitochondria-dependent oxidative stress mechanism.

Acculturation and depressive symptoms in latino caregivers of cognitively impaired older adults.

ABSTRACT Background: Caregiving for older adults is a growing public health concern because of the negative psychological effects it has on caregivers. Despite the growing Latino caregiver population, little is known regarding how the effects of acculturation on caregiver depressive symptoms might vary by caregiver age. This study aimed to examine the relationship between language acculturation and depressive symptoms in Latino caregivers, and to test whether this relationship was moderated by age. Methods: Ninety-four Latino caregivers of cognitively impaired older adults with and without dementia were identified through an ongoing epidemiological cohort study. Caregivers were interviewed in their homes, in either Spanish or English. A Poisson regression was used to analyze the caregiver characteristics associated with caregiver depressive symptoms. Results: Language acculturation was positively associated with caregiver depressive symptoms, as was age, female gender, and being married or living with someone. Those with excellent or good health and who had spent more than one year caregiving had lower depressive symptoms. Finally, the positive relationship between language acculturation and depressive symptoms was increased in older caregivers. Conclusions: Language acculturation appears to be a risk factor for depressive symptoms in Latino caregivers of cognitively impaired older adults. The relationship between language acculturation and depressive symptoms is complex such that caregiver age and health status further nuance this relationship. Future research should explore the independent and interactive effects of these variables on depressive symptoms.

Augmented Reality Improves Pediatric Mask Induction: A Prospective, Matched Case-Control Study.

Introduction: Pediatric perioperative anxiety is a significant problem during mask induction for general anesthesia. Immersive technologies, such as extended reality headsets, are a promising strategy for alleviating anxiety. Our primary aim was to investigate mask acceptance during inhalational induction utilizing augmented reality (AR). Methods: This was a prospective, matched case-control study at a quaternary academic hospital. Fifty pediatric patients using AR for mask induction were matched to 150 standard-of-care (SOC) controls. The primary outcome was measured with the Mask Acceptance Scale (MAS). Secondary outcomes of cooperation and emergent delirium (ED) were assessed. Results: MAS scores ≥2 occurred at 4% (95% CI [0, 9.4%]) with AR versus 19.3%, (95% CI [13%, 25.7%]) with SOC (RR 0.21, 95% CI [0.05, 0.84], P = .027). Ninety-eight percent of AR patients were cooperative versus 91.3% with SOC (P = .457). Zero percent had ED with AR versus 0.7% with SOC (P = 1.000). Conclusions: AR during mask induction improved mask acceptance compared to SOC. No relationship was observed between AR and cooperation or ED. Future research will investigate the integration of AR into clinical practice as a nonpharmacologic intervention.

Improving colonoscopy prioritisation and promoting the National Bowel Cancer Screening Program: keys to reducing bowel cancer burden.

Australia's National Bowel Cancer Screening Program (NBCSP) has the potential to prevent almost 84 000 bowel cancer deaths if 60% program participation rates could be reached and maintained over the next two decades. Immunochemical faecal occult blood test (iFOBT) is used as an initial screening tool. Participants who test positive are referred for colonoscopy for diagnostic assessment. Concerns about colonoscopy capacity and lengthy wait times between positive iFOBT and colonoscopy have hampered efforts to promote the program. However, a separate research paper published in this issue of PHRP shows that only an estimated 10-14% of Medicare-funded colonoscopies (almost 75% of all colonoscopies) in Australia are generated by the NBCSP. Inappropriate use of colonoscopy as a primary screening tool and failure to prioritise NBCSP participants may be the main reasons for long colonoscopy wait times associated with the program. Promoting clinical practice guidelines, and the Direct Access Colonoscopy initiative for priority patients, are key to reducing colonoscopy wait times and proactive promotion of the NBCSP.

Multiplexed inhibition of immunosuppressive genes with Cas13d for on-demand combinatorial cancer immunotherapy.

Checkpoint blockade immunotherapy is a potent class of cancer treatment, however, the complex immunosuppressive tumor microenvironment (TME) often requires multi-agent combinations to be effective. Current cancer immunotherapy combination approaches are cumbersome, usually involving one-drug-at-a-time scheme. Here, we devise Multiplex Universal Combinatorial Immunotherapy via Gene-silencing (MUCIG), as a versatile approach for combinatorial cancer immunotherapy. We harness CRISPR-Cas13d to efficiently target multiple endogenous immunosuppressive genes on demand, allowing us to silence various combinations of multiple immunosuppressive factors in the TME. Intratumoral AAV-mediated administration of MUCIG (AAV-MUCIG) elicits significant anti-tumor activity with several Cas13d gRNA compositions. TME target expression analysis driven optimization led to a simplified off-the-shelf MUCIG targeting a four gene combination (PGGC: Pdl1, Galectin9, Galectin3 and Cd47 ). AAV-PGGC shows significant in vivo efficacy in syngeneic tumor models. Single cell and flow profiling revealed that AAV-PGGC remodeled the TME by increasing CD8 + T cell infiltration and reducing myeloid-derived immunosuppressive cells (MDSCs). MUCIG thus serves as a universal method to silence multiple immune genes in vivo, and can be delivered via AAV as a therapeutic approach.

Determining efficacy of dynamic multimedia bowel preparation instructions versus standard instructions on adenoma detection and patient reported measures (DIGICLEAN trial): a study protocol for a multicentre, colonoscopist-blinded, randomised controlled trial.

INTRODUCTION: Colonoscopy plays important roles in bowel cancer screening and treatment. Poor bowel preparation occurs in 20-25% of colonoscopies. This negatively impacts adenoma and sessile serrated lesion detection rates, procedural time, requirement for repeat colonoscopies, healthcare costs and likelihood of patient withdrawal from screening programmes. It is unclear whether a combination of multimedia modalities can improve bowel preparation quality, adenoma detection rates and patient-reported measures in those undergoing colonoscopy assessment. METHODS: The DIGICLEAN trial is a prospective, parallel, multicentre, colonoscopist-blinded, randomised controlled trial. The trial will enrol 1294 participants aged 45 years and older who are indicated for a colonoscopy as an outpatient with a positive faecal occult blood test, iron deficiency anaemia or rectal bleeding. Participants will be randomised into the interventional arm, where bowel preparation instructions are delivered via a web-based application which uses scheduled short messaging service, regular patient survey assessment, email and videos; or the control arm, where routine standard written, verbal or emailed instructions are administered. The web-based application will assess patient-reported bloating, constipation and dietary adherence leading up to the colonoscopy. Depending on patient responses, additional aperients may be encouraged digitally in the interventional arm with same instructions made available in written format for the control arm. Patient-reported measures will be collected in both arms the day after the procedure using the validated Newcastle ENDOPREM questionnaire. In some sites, participants will undergo digital pre-anaesthetic screening as well. The co-primary endpoints are the adenoma detection rates and patient-reported measures taken after the colonoscopy. ETHICS AND DISSEMINATION: Ethics approval for this study was obtained from the Western Sydney Local Health District Human Research Ethics Committee (2022/ETH00059). Findings will be reported at national and international gastroenterology meetings and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12622000747729.

Colonoscopies in Australia - how much does the National Bowel Cancer Screening Program contribute to colonoscopy use?

Objectives and importance of study: Colorectal cancer (CRC) is Australia's fourth most commonly diagnosed cancer. CRC screening is an effective intervention to reduce this burden. The National Bowel Cancer Screening Program (NBCSP) provides 2-yearly immunochemical faecal occult blood tests (iFOBTs) to Australians aged 50-74 years; a diagnostic colonoscopy is conducted after a positive iFOBT. Clinical guidelines inform colonoscopy usage, and appropriate use of these guidelines is vital to investigate gastrointestinal symptoms, detect bowel abnormalities and CRC, and remove precancerous polyps. Colonoscopy services are under strain, with limited formal strategies to prioritise patients. There are concerns among practitioners and patient advocates that the NBCSP generates additional colonoscopy requests and increases wait times, worsening patient outcomes and prolonging distress. In this research study, we estimate and project colonoscopy use in Australia from 2001 to 2030 and determine the impact of the NBCSP by examining model-estimated NBCSP colonoscopy demand. METHODS: Colonoscopy use in Australia was compiled using Medicare Benefits Schedule (MBS) claims for colonoscopies from 2001 to 2019. From these data, projections were made from 2020 to 2030. Policy1-Bowel, a microsimulation model, was used to estimate NBCSP-related colonoscopy demand from screening follow-up and colonoscopic surveillance from 2006 to 2030. RESULTS: MBS-funded colonoscopy use increased from 284 676 in 2001 to 663 213 in 2019. Annual use is projected to be more than 780 000 by 2030. Of these, 10-14% are projected to be generated by the NBCSP. Per-capita MBS-funded colonoscopy utilisation increased 0.2% annually over 2015-2019, a slowing of growth compared to previous trends. CONCLUSION: The NBCSP accounts for a modest fraction of colonoscopy use in Australia, and a better understanding of colonoscopy use not associated with the NBCSP is needed. Promoting adherence to guideline-recommended iFOBT and colonoscopy use could ease pressure on services and improve outcomes.