Mistranslating the genetic code with leucine in yeast and mammalian cells.

Translation fidelity relies on accurate aminoacylation of transfer RNAs (tRNAs) by aminoacyl-tRNA synthetases (AARSs). AARSs specific for alanine (Ala), leucine (Leu), serine, and pyrrolysine do not recognize the anticodon bases. Single nucleotide anticodon variants in their cognate tRNAs can lead to mistranslation. Human genomes include both rare and more common mistranslating tRNA variants. We investigated three rare human tRNALeu variants that mis-incorporate Leu at phenylalanine or tryptophan codons. Expression of each tRNALeu anticodon variant in neuroblastoma cells caused defects in fluorescent protein production without significantly increased cytotoxicity under normal conditions or in the context of proteasome inhibition. Using tRNA sequencing and mass spectrometry we confirmed that each tRNALeu variant was expressed and generated mistranslation with Leu. To probe the flexibility of the entire genetic code towards Leu mis-incorporation, we created 64 yeast strains to express all possible tRNALeu anticodon variants in a doxycycline-inducible system. While some variants showed mild or no growth defects, many anticodon variants, enriched with G/C at positions 35 and 36, including those replacing Leu for proline, arginine, alanine, or glycine, caused dramatic reductions in growth. Differential phenotypic defects were observed for tRNALeu mutants with synonymous anticodons and for different tRNALeu isoacceptors with the same anticodon. A comparison to tRNAAla anticodon variants demonstrates that Ala mis-incorporation is more tolerable than Leu at nearly every codon. The data show that the nature of the amino acid substitution, the tRNA gene, and the anticodon are each important factors that influence the ability of cells to tolerate mistranslating tRNAs.

Trade-offs between overall survival and side effects in the treatment of metastatic breast cancer: eliciting preferences of patients with primary and metastatic breast cancer using a discrete choice experiment.

OBJECTIVES: There has been a recent proliferation in treatment options for patients with metastatic breast cancer. Such treatments often involve trade-offs between overall survival and side effects. Our study aims to estimate the trade-offs that could be used to inform decision-making at the individual and policy level. DESIGN: We designed a discrete choice experiment (DCE) to look at preferences for avoiding severity levels of side effects when choosing treatment for metastatic breast cancer. Treatment attributes were: fatigue, nausea, diarrhoea, other side effects (peripheral neuropathy, hand-foot syndrome and mucositis) and urgent hospital admission and overall survival. Responses were analysed using an error component logit model. We estimated the relative importance of attributes and minimum acceptable survival for improvements in side effects. SETTING: The DCE was completed online by UK residents with self-reported diagnoses of breast cancer. PARTICIPANTS: 105 respondents participated, of which 72 patients had metastatic breast cancer and 33 patients had primary breast cancer. RESULTS: Overall survival had the largest relative importance, followed by other side effects, diarrhoea, nausea and fatigue. The risk of urgent hospital admission was not significant. While overall survival was the most important attribute, respondents were willing to forgo some absolute probability of overall survival for reductions in all Grade 2 side effects (12.02% for hand-foot syndrome, 11.01% for mucositis, 10.42% for peripheral neuropathy, 6.33% for diarrhoea and 3.62% for nausea). Grade 1 side effects were not significant, suggesting respondents have a general tolerance for them. CONCLUSIONS: Patients are willing to forgo overall survival to avoid particular severity levels of side effects. Our results have implications for data collected in research studies and can help inform person-centred care and shared decision-making.

Early prehabilitation reduces admissions and time in hospital in patients with newly diagnosed lung cancer.

OBJECTIVES: Lung cancer is the leading cause of cancer death in the UK. Prehabilitation aims to maximise patient fitness and minimise the negative impact of anticancer treatment. What constitutes prehabilitation before non-surgical anticancer treatment is not well established. We present data from a pilot project of Early prehabilitation In lung Cancer. METHODS: All new patients with likely advanced lung cancer were offered prehabilitation at respiratory clinic, if fit for further investigation. Prehabilitation included assessment and appropriate intervention from a consultant in palliative medicine, registered dietitian and rehabilitation physiotherapist. Four objective endpoints were identified, namely admissions to hospital, time spent in the hospital, treatment rates and overall survival. Outcomes were to be compared with 178 prehab eligible historical controls diagnosed from 2019 to 2021. RESULTS: From July 2021 to June 2023, 65 patients underwent prehabilitation and 72% of patients underwent all 3 interventions. 54 patients had a stage 3 or 4 lung cancer. In the prehab group, fewer patients attended Accident and Emergency (31.5 vs 37.4 attendances per 100 patients) and fewer were admitted (51.9 vs 67.9) when compared with historical controls. Those receiving prehab spent a lot less time in the hospital (129.7 vs 543.5 days per 100 patients) with shorter admissions (2.5 vs 8 days). Systemic anticancer treatment rates increased in the short term but were broadly similar overall. Median survival was higher in the prehabilitation group (0.73 vs 0.41 years, p=0.046). CONCLUSIONS: Early prehabilitation appears to reduce time spent in the hospital. It may improve survival. Further work is required to understand its full effect on treatment rates.

Variation in colorectal cancer treatment and outcomes in Scotland: real world evidence from national linked administrative health data.

Background: Colorectal cancer (CRC) is the fourth most common type of cancer in the United Kingdom and the second leading cause of cancer death. Despite improvements in CRC survival over time, Scotland lags behind its UK and European counterparts. In this study, we carry out an exploratory analysis which aims to provide contemporary, population level evidence on CRC treatment and survival in Scotland. Methods: We conducted a retrospective population-based analysis of adults with incident CRC registered on the Scottish Cancer Registry (Scottish Morbidity Record 06 (SMR06)) between January 2006 and December 2018. The CRC cohort was linked to hospital inpatient (SMR01) and National Records of Scotland (NRS) deaths records allowing a description of their demographic, diagnostic and treatment characteristics. Cox proportional hazards regression models were used to explore the demographic and clinical factors associated with all-cause mortality and CRC specific mortality after adjusting for patient and tumour characteristics among people identified as early-stage and treated with surgery. Results: Overall, 32,691 (73%) and 12,184 (27%) patients had a diagnosis of colon and rectal cancer respectively, of whom 55% and 53% were early-stage and treated with surgery. Five year overall survival (CRC specific survival) within this cohort was 72% (82%) and 76% (84%) for patients with colon and rectal cancer respectively. Cox proportional hazards models revealed significant variation in mortality by sex, area-based deprivation and geographic location. Conclusions: In a Scottish population of patients with early-stage CRC treated with surgery, there was significant variation in risk of death, even after accounting for clinical factors and patient characteristics.

New quality outcome indicators for bone metastases: expert consensus analysis of patients, their families and specialist healthcare professionals.

OBJECTIVES: As workload increases, surgical care for patients with bone metastases is increasingly decentralised, with a shift in management away from primary bone tumour units to local centres. We must ensure that patients have similar outcomes regardless of where they receive their treatment. The aim was to develop and validate a set of quality outcome indicators (QOIs) to evaluate treatment success for patients undergoing surgery for bone metastases. METHODS: Outcome recommendations were adapted from the literature and field tested in a retrospective patient cohort to determine feasibility. The provisional outcome indicators were assessed during a modified RAND/Delphi consensus process by a group of patients, relatives and healthcare professionals with validated targets added. RESULTS: 1534 articles were reviewed. 38 quality objectives were extracted and assessed for feasibility using clinical records for 117 patients. 28 provisional outcome indicators proceeded to expert consensus and were reviewed by a group of 22 panellists including 10 patients and 4 relatives/carers. After two rounds, 15 QOIs were generated, with validated targets based on expert consensus. These included specific statements such as 'surgery improves pain and reduces the need for morphine, target: at follow-up, pain is documented in 80% of individuals and 50% of these have reduced need for morphine'. CONCLUSIONS: The published evidence and guidelines were adapted into a set of outcome indicators validated by patients, their family/carers and healthcare professionals. These can be used to compare care between centres and identify units of excellence in maximising good outcome after surgery for bone metastases.

Automated radiosynthesis of [18F]DPA-714 on a commercially available IBA Synthera®.

The goal of this work was to develop a reliable method to produce the well-validated microglial activation PET tracer, [18F]DPA-714, routinely for clinical and preclinical research using an IBA Synthera®. Optimization of literature methods included reduced precursor mass and use of TBA HCO3 as the phase transfer agent in place of Kryptofix® 222 in a 65-min synthesis with an average activity yield of 24.6 ± 3.8% (n = 5). Successful quality control testing and process validation results are reported.

rTMS for post-covid-19 condition: A sham-controlled case series involving iTBS-300 and iTBS-600.

Post-Covid-19 Condition (PCC) is a syndrome comprised of symptoms persisting 3 months or more beyond SARS-CoV-2 primary infection. It is typically characterized by fatigue, cognitive problems and psychiatric symptoms, as well as cardiac symptoms that contribute to exercise intolerance in many. Despite the high prevalence of PCC among those with a prior SARS-CoV-2 infection, there is currently no widely accepted rehabilitation strategy, and many conventional modalities are movement-based. Non-invasive brain stimulation methods such as repetitive transcranial magnetic stimulation (rTMS) may have some potential to alleviate the cognitive and affective symptoms of PCC without reliance on exercise. The purpose of the present study was to explore the feasibility and tolerability of using rTMS to treat symptoms of "brain fog" and affective disturbance among those living with PCC, using a case series design. We enrolled four individuals with PCC following a confirmed SARS-CoV-2 infection, at least 3 months after the resolution of the primary infection. Participants were randomized to 4 sessions of active and 2 sessions of sham intermittent theta-burst stimulation (iTBS); two intensities of iTBS were evaluated: iTBS-300 and iTBS-600. No adverse events occurred in active or sham stimulation; 2 participants reported tingling sensation on the scalp but no other tolerability issues. Trends in symptoms suggested improvements in cognitive interference, quality of life, and anxiety in the majority of participants. In summary, in this case series iTBS was well tolerated among 4 individuals with PCC; active stimulation was associated with positive trends in some primary symptom clusters as compared with sham stimulation. Future studies should examine the effects of iTBS on PCC symptoms in the context of experimental studies and randomized controlled trials.

Cross-sectional and longitudinal neural predictors of physical activity and sedentary behaviour from a 6-month randomized controlled trial.

A sedentary lifestyle offers immediate gratification, but at the expense of long-term health. It is thus critical to understand how the brain evaluates immediate rewards and long-term health effects in the context of deciding whether to engage in moderate-to-vigorous physical activity (MVPA) or sedentary behaviour (SB). In this secondary analysis of a 6-month randomized controlled trial to increase MVPA and reduce SB among community-dwelling adults, we explored how neural activity during an executive control task was associated with MVPA and SB levels. At baseline, a subset of participants (n = 26/61) underwent task-based functional magnetic resonance imaging (fMRI) to examine neural activity underlying executive control using the Now/Later task. MVPA and SB were measured objectively using the Sensewear Mini at baseline, and 2, 4, and 6 months follow-up. We then examined the associations of baseline neural activation underlying executive control with: (1) baseline MVPA or SB; and (2) changes in MVPA and SB over 6 months. Our results determined that there is a complex neurocognitive system associated with MVPA levels, while SB appears to lack any neurocognitive control. In other words, MVPA appears to require neurocognitive effort, while SB may be the default behavioural pattern in adults.

Comparison of Circulating Tumor DNA Assays for Molecular Residual Disease Detection in Early-Stage Triple-Negative Breast Cancer.

PURPOSE: Detection of circulating tumor DNA (ctDNA) in patients who have completed treatment for early-stage breast cancer is associated with a high risk of relapse, yet the optimal assay for ctDNA detection is unknown. EXPERIMENTAL DESIGN: The cTRAK-TN clinical trial prospectively used tumor-informed digital PCR (dPCR) assays for ctDNA molecular residual disease (MRD) detection in early-stage triple-negative breast cancer. We compared tumor-informed dPCR assays with tumor-informed personalized multimutation sequencing assays in 141 patients from cTRAK-TN. RESULTS: MRD was first detected by personalized sequencing in 47.9% of patients, 0% first detected by dPCR, and 52.1% with both assays simultaneously (P < 0.001; Fisher exact test). The median lead time from ctDNA detection to relapse was 6.1 months with personalized sequencing and 3.9 months with dPCR (P = 0.004, mixed-effects Cox model). Detection of MRD at the first time point was associated with a shorter time to relapse compared with detection at subsequent time points (median lead time 4.2 vs. 7.1 months; P = 0.02). CONCLUSIONS: Personalized multimutation sequencing assays have potential clinically important improvements in clinical outcome in the early detection of MRD.

Cancer pain assessment and management: does an institutional approach individualise and reduce cost of care?

OBJECTIVES: To understand individual prescribing and associated costs in patients managed with the Edinburgh Pain Assessment and management Tool (EPAT). METHODS: The EPAT study was a two-arm parallel group cluster randomised (1:1) trial, including 19 UK cancer centres. Study outcome assessments, including pain levels, analgesia and non-pharmacological and anaesthetic interventions, collected at baseline, 3-5 days and, if applicable, 7-10 days after admission. Costs calculated for inpatient length of stay (LoS), medications and complex pain interventions. Analysis accounted for the clustered nature of the trial design. In this post-hoc analysis, healthcare utilisation and costs are presented descriptively. PARTICIPANTS: 10 centres randomised to EPAT (487 patients) and 9 (449 patients) to usual care (UC). MAIN OUTCOME MEASURES: Pharmacological and non-pharmacological management, complex pain interventions, length of hospital stay and costs related to these outcomes. RESULTS: The mean per patient hospital cost was £3866 with EPAT and £4194 with UC, reflecting a mean LoS of 2.9 days and 3.1 days, respectively. Costs were lower for non-opioids, Non-steroidal anti-inflammatories (NSAIDs) and opioids but slightly higher for adjuvants with EPAT than with UC. The mean per-patient opioid costs were £17.90 (EPAT) and £25.80 (UC). Mean per patient costs of all medication were £36 (EPAT) and £40 (UC).Complex pain intervention costs were £117 with EPAT per patient and £90 with UC. Overall mean cost per patient was £4018.3 (95% CI 3698.9 to 4337.8) with EPAT and £4323.8 (95% CI 4060.0 to 4587.7) with UC. CONCLUSIONS: EPAT facilitated personalised medicine and may result in less opioids, more specific treatments, improved pain outcomes and cost savings.

Early prehabilitation in suspected locally advanced and metastatic lung cancer.

OBJECTIVES: The most common treatment for locally advanced and metastatic lung cancer is best supportive care. Patients with lung cancer are often comorbid with a high symptom burden. We wanted to assess whether early prehabilitation was feasible in patients with likely lung cancer. METHODS: Patients were offered prehabilitation if they were attending the new patient respiratory clinic, had a CT scan suggesting stage III or IV lung cancer and undergoing further investigations. Patients receiving palliative care were ineligible. All prehabilitation patients were referred to a palliative medicine physician, registered dietitian and rehabilitation physiotherapist. RESULTS: 50 patients underwent prehabilitation between June 2021 and August 2022. The median age was 72 years (range 54-89 years). 48 patients had lung cancer. 84% of patients attended all three interventions.Half of the palliative care consultations focused on pain. Half of the patients seen had a change in medication. 25% of patients' weights were stable, 32% required a food-first strategy and 33% required oral nutritional supplements. 57% of patients discussed managing breathlessness with the physiotherapist. CONCLUSIONS: Early prehabilitation is feasible alongside the investigation of locally advanced and metastatic lung cancer. Further work will aim to assess its impact on admission to the hospital, survival and treatment rates.

Diabetes status and cognitive function in middle-aged and older adults in the Canadian longitudinal study on aging.

Objectives: Diabetes is recognized as a significant risk factor for cognitive impairment. However, this association has not been thoroughly examined using large-scale population-based datasets in the Canadian context. The objective of this study was to investigate the potential association between cognitive function and diabetes in a large population-based sample of middle-aged and older Canadians. Methods: We utilized baseline data from the Canadian Longitudinal Study on Aging (N=30,097) to test our hypotheses, using five indicators of cognitive function (animal fluency, Stroop interference, reaction time, immediate and delayed memory recall). We conducted multivariate multivariable linear regression and subsequently performed tests for moderation analysis with lifestyle factors and health status. Results: The analysis revealed that type 2 diabetes (T2DM) was associated with lower performance on most cognitive tasks, including those assessing executive function (b=0.60, 95% CI 0.31 to 0.90), reaction time (b=16.94, 95% CI 9.18 to 24.70), immediate memory recall (b=-0.10, 95% CI -0.18 to -0.02), and delayed memory recall (b=-0.12, 95% CI -0.21 to -0.02). However, no significant association was observed between other types of diabetes and cognitive performance. Moderation effects were largely null for T2DM, with the exception of alcohol intake for reaction time, and physical activity for animal fluency. Conclusions: The study showed that individuals with T2DM exhibit poor performance on tasks that assess executive function, reaction time, and memory. Therefore, optimizing cognitive health among individuals with T2DM should be a priority in primary care. Additionally, further studies should examine this association using longitudinal data.

Painterly Style Transfer With Learned Brush Strokes.

Real-world paintings are made, by artists, using brush strokes as the rendering primitive to depict semantic content. The bulk of the Neural Style Transfer (NST) is known transferring style using texture patches, not strokes. The output looks like the content image, but some are traced over using the style texture: it does not look painterly. We adopt a very different approach that uses strokes. Our contribution is to analyse paintings to learn stroke families-that is, distributions of strokes based on their shape (a dot, straight lines, curved arcs, etc.). When synthesising a new output, these distributions are sampled to ensure the output is painted with the correct style of stroke. Consequently, our output looks more "painterly" than NST output based on texture. Furthermore, where strokes are placed is an important contributing factor in determining output quality, and we have also addressed this aspect. Humans place strokes to emphasize salient semantically meaningful image content. Conventional NST uses a content loss premised on filter responses that is agnostic to salience. We show that replacing that loss with one based on the language-image model benefits the output through greater emphasis of salient content.

Economic Evaluation of Exercise or Cognitive and Social Enrichment Activities for Improved Cognition After Stroke.

Importance: Cognitive impairment is prevalent in survivors of stroke, affecting approximately 30% of individuals. Physical exercise and cognitive and social enrichment activities can enhance cognitive function in patients with chronic stroke, but their cost-effectiveness compared with a balance and tone program is uncertain. Objective: To conduct a cost-effectiveness and cost-utility analysis of multicomponent exercise or cognitive and social enrichment activities compared with a balance and tone program. Design, Setting, and Participants: This economic evaluation used a Canadian health care systems perspective and the Vitality study, a randomized clinical trial aimed at improving cognition after stroke with a 6-month intervention and a subsequent 6-month follow-up (ie, 12 months). The economic evaluation covered the duration of the Vitality trial, between June 6, 2014, and February 26, 2019. Participants were community-dwelling adults aged 55 years and older who experienced a stroke at least 12 months prior to study enrollment in the Vancouver metropolitan area, British Columbia, Canada. Data were analyzed from June 1, 2022, to March 31, 2023. Interventions: Participants were randomly assigned to twice-weekly classes for 1 of the 3 groups: multicomponent exercise program, cognitive and social enrichment activities program, or a balance and tone program (control). Main Outcomes and Measures: The primary measures for the economic evaluation included cost-effectiveness (incremental costs per mean change in cognitive function, evaluated using the Alzheimer Disease Assessment Scale-Cognitive-Plus), cost-utility (incremental cost per quality-adjusted life-year gained), intervention costs, and health care costs. Since cognitive benefits 6 months after intervention cessation were not observed in the primary randomized clinical trial, an economic evaluation at 12 months was not performed. Results: Among 120 participants (mean [SD] age, 71 [9] years; 74 [62%] male), 34 were randomized to the multicomponent exercise program, 34 were randomized to the social and cognitive enrichment activities program, and 52 were randomized to the balance and tone control program. At the end of the 6-month intervention, the cost per mean change in Alzheimer Disease Assessment Scale-Cognitive-Plus score demonstrated that exercise was more effective and costlier compared with the control group in terms of cognitive improvement with an incremental cost-effectiveness ratio of CAD -$8823. The cost per quality-adjusted life-year gained for both interventions was negligible, with exercise less costly (mean [SD] incremental cost, CAD -$32 [$258]) and cognitive and social enrichment more costly than the control group (mean [SD] incremental cost, CAD $1018 [$378]). The balance and tone program had the lowest delivery cost (CAD $777), and the exercise group had the lowest health care resource utilization (mean [SD] $1261 [$1188]) per person. Conclusions and Relevance: The findings of this economic evaluation suggest that exercise demonstrated potential for cost-effectiveness to improve cognitive function in older adults with chronic stroke during a 6-month intervention.

Randomised, placebo-controlled, phase 3 trial of the effect of the omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) on colorectal cancer recurrence and survival after surgery for resectable liver metastases: EPA for Metastasis Trial 2 (EMT2) study protocol.

INTRODUCTION: There remains an unmet need for safe and cost-effective adjunctive treatment of advanced colorectal cancer (CRC). The omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) is safe, well-tolerated and has anti-inflammatory as well as antineoplastic properties. A phase 2 randomised trial of preoperative EPA free fatty acid 2 g daily in patients undergoing surgery for CRC liver metastasis showed no difference in the primary endpoint (histological tumour proliferation index) compared with placebo. However, the trial demonstrated possible benefit for the prespecified exploratory endpoint of postoperative disease-free survival. Therefore, we tested the hypothesis that EPA treatment, started before liver resection surgery (and continued postoperatively), improves CRC outcomes in patients with CRC liver metastasis. METHODS AND ANALYSIS: The EPA for Metastasis Trial 2 trial is a randomised, double-blind, placebo-controlled, phase 3 trial of 4 g EPA ethyl ester (icosapent ethyl (IPE; Vascepa)) daily in patients undergoing liver resection surgery for CRC liver metastasis with curative intent. Trial treatment continues for a minimum of 2 years and maximum of 4 years, with 6 monthly assessments, including quality of life outcomes, as well as annual clinical record review after the trial intervention. The primary endpoint is CRC progression-free survival. Key secondary endpoints are overall survival, as well as the safety and tolerability of IPE. A minimum 388 participants are estimated to provide 247 CRC progression events during minimum 2-year follow-up, allowing detection of an HR of 0.7 in favour of IPE, with a power of 80% at the 5% (two sided) level of significance, assuming drop-out of 15%. ETHICS AND DISSEMINATION: Ethical and health research authority approval was obtained in January 2018. All data will be collected by 2025. Full trial results will be published in 2026. Secondary analyses of health economic data, biomarker studies and other translational work will be published subsequently. TRIAL REGISTRATION NUMBER: NCT03428477.

Evaluation of the association of area-level socioeconomic deprivation and breast cancer recurrence by oestrogen receptor subtypes in Scotland.

BACKGROUND: Women from socioeconomically deprived areas have lower breast cancer (BC) incidence rates for screen-detected oestrogen receptor (ER) + tumours and higher mortality for select tumour subtypes. We aimed to determine if ipsilateral breast cancer recurrence (IBR) differs by Scottish Index of Multiple Deprivation (SIMD) quintile and tumour subtype in Scotland. METHODS: Patient data for primary invasive BC diagnosed in 2007-2008 in Scotland was analysed. Manual case-note review for 3495 patients from 10 years post-diagnosis was used. To determine the probability of IBR while accounting for the competing risk of death from any cause, cumulative incidence functions stratified by ER subtype and surgery were plotted. Multivariable Cox Proportional Hazards models were used to estimate the association of SIMD accounting for other predictors of IBR. RESULTS: Among 2819 ER + tumours, 423 patients had a recurrence and 438 died. SIMD was related to death (p = 0.018) with the most deprived more likely to have died in the 10-year period (17.7% vs. 12.9%). We found no significant differences by SIMD in prognostic tumour characteristics (grade, TNM stage, treatment, screen-detection) or risk of IBR. Among 676 patients diagnosed with ER- tumours, 105 died and 185 had a recurrence. We found no significant differences in prognostic tumour characteristics by SIMD except screen detection with the most deprived more likely than the least to have their tumours detected from screening (46.9% vs. 28%, p = 0.03). Among patients with ER- tumours, 50% had mastectomy and the most deprived had increased 5-year IBR risk compared to the least deprived (HR 3.03 [1.41-6.53]). CONCLUSIONS: IBR is not a major contributor to mortality differences by SIMD for the majority of BC patients in our study. The lack of inequities in IBR are likely due to standardised treatment protocols and access to healthcare. The association with socioeconomic deprivation and recurrence for ER- tumours requires further study.

Next-generation cognitive assessment: Combining functional brain imaging, system perturbations and novel equipment interfaces.

Conventional cognitive assessment is widely used in clinical and research settings, in educational institutions, and in the corporate world for personnel selection. Such approaches involve having a client, a patient, or a research participant complete a series of standardized cognitive tasks in order to challenge specific and global cognitive abilities, and then quantify performance for the desired end purpose. The latter may include a diagnostic confirmation of a disease, description of a state or ability, or matching cognitive characteristics to a particular occupational role requirement. Metrics derived from cognitive assessments are putatively informative about important features of the brain and its function. For this reason, the research sector also makes use of cognitive assessments, most frequently as a stimulus for cognitive activity from which to extract functional neuroimaging data. Such "task-related activations" form the core of the most widely used neuroimaging technologies, such as fMRI. Much of what we know about the brain has been drawn from the interleaving of cognitive assessments of various types with functional brain imaging technologies. Despite innovation in neuroimaging (i.e., quantifying the neural response), relatively little innovation has occurred on task presentation and volitional response measurement; yet these together comprise the core of cognitive performance. Moreover, even when cognitive assessment is interleaved with functional neuroimaging, this is most often undertaken in the research domain, rather than the primary applications of cognitive assessment in diagnosis and monitoring, education and personnel selection. There are new ways in which brain imaging-and even more importantly, brain modulation-technologies can be combined with automation and artificial intelligence to deliver next-generation cognitive assessment methods. In this review paper, we describe some prototypes for how this can be done and identify important areas for progress (technological and otherwise) to enable it to happen. We will argue that the future of cognitive assessment will include semi- and fully-automated assessments involving neuroimaging, standardized perturbations via neuromodulation technologies, and artificial intelligence. Furthermore, the fact that cognitive assessments take place in a social/interpersonal context-normally between the patient and clinician-makes the human-machine interface consequential, and this will also be discussed.

Multicenter, Prospective, Randomized Controlled Trial of High-Sensitivity Cardiac Troponin I-Guided Combination Angiotensin Receptor Blockade and Beta-Blocker Therapy to Prevent Anthracycline Cardiotoxicity: The Cardiac CARE Trial.

BACKGROUND: Anthracycline-induced cardiotoxicity has a variable incidence, and the development of left ventricular dysfunction is preceded by elevations in cardiac troponin concentrations. Beta-adrenergic receptor blocker and renin-angiotensin system inhibitor therapies have been associated with modest cardioprotective effects in unselected patients receiving anthracycline chemotherapy. METHODS: In a multicenter, prospective, randomized, open-label, blinded end-point trial, patients with breast cancer and non-Hodgkin lymphoma receiving anthracycline chemotherapy underwent serial high-sensitivity cardiac troponin testing and cardiac magnetic resonance imaging before and 6 months after anthracycline treatment. Patients at high risk of cardiotoxicity (cardiac troponin I concentrations in the upper tertile during chemotherapy) were randomized to standard care plus cardioprotection (combination carvedilol and candesartan therapy) or standard care alone. The primary outcome was adjusted change in left ventricular ejection fraction at 6 months. In low-risk nonrandomized patients with cardiac troponin I concentrations in the lower 2 tertiles, we hypothesized the absence of a 6-month change in left ventricular ejection fraction and tested for equivalence of ±2%. RESULTS: Between October 2017 and June 2021, 175 patients (mean age, 53 years; 87% female; 71% with breast cancer) were recruited. Patients randomized to cardioprotection (n=29) or standard care (n=28) had left ventricular ejection fractions of 69.4±7.4% and 69.1±6.1% at baseline and 65.7±6.6% and 64.9±5.9% 6 months after completion of chemotherapy, respectively. After adjustment for age, pretreatment left ventricular ejection fraction, and planned anthracycline dose, the estimated mean difference in 6-month left ventricular ejection fraction between the cardioprotection and standard care groups was -0.37% (95% CI, -3.59% to 2.85%; P=0.82). In low-risk nonrandomized patients, baseline and 6-month left ventricular ejection fractions were 69.3±5.7% and 66.4±6.3%, respectively: estimated mean difference, 2.87% (95% CI, 1.63%-4.10%; P=0.92, not equivalent). CONCLUSIONS: Combination candesartan and carvedilol therapy had no demonstrable cardioprotective effect in patients receiving anthracycline-based chemotherapy with high-risk on-treatment cardiac troponin I concentrations. Low-risk nonrandomized patients had similar declines in left ventricular ejection fraction, bringing into question the utility of routine cardiac troponin monitoring. Furthermore, the modest declines in left ventricular ejection fraction suggest that the value and clinical impact of early cardioprotection therapy need to be better defined in patients receiving high-dose anthracycline. REGISTRATION: URL: https://doi.org; Unique identifier: 10.1186/ISRCTN24439460. URL: https://www.clinicaltrialsregister.eu/ctr-search/search; Unique identifier: 2017-000896-99.

The relationship between energy and non-energy factors and CO2 emissions in New Zealand.

The use of renewable energy as a fuel source and expansion of forest areas are the best ways for reducing CO2 emissions. This study aims to examine the effects of forest plantation area, renewable energies, real gross domestic product (GDP), and technological innovation on CO2 emissions in 9 regions of New Zealand between 2006 and 2019. For this purpose, it employs a pooled mean group methodology. Investigating the regional impacts of various variables, especially the forest area, on CO2 emissions is the main contribution of this study. The results suggest that planted forest areas can reduce CO2 emissions in the long run, but its impact in the short run is not significant. Non-renewable energy consumption is the major contributor to CO2 emissions in both the short and long run. While technological innovation and renewable energy consumption appear effective in reducing carbon emissions in the short term, they still contribute to increased CO2 emissions in the long term. At the regional level, we found that the forest plantation areas in Manawatu-Whanganui and Gisborne are important regions for reducing CO2 emissions. By taking account of these results, New Zealand should take swift action to properly manage and increase the current level of forest areas and if applicable expand them. It also needs to improve the current level of use of renewable energy to achieve its abatement goals.