Contrast Enhanced-Magnetic Resonance Imaging as a Surrogate to Map Verteporfin Delivery in Photodynamic Therapy

The use of in vivo contrast-enhanced magnetic resonance (MR) imaging as a surrogate for photosensitizer (verteporfin) dosimetry in photodynamic therapy of pancreas cancer is demonstrated by correlating MR contrast uptake to ex vivo fluorescence images on excised tissue. An orthotopic pancreatic xenograft mouse model was used for the study. A strong correlation ([i]r=0.57 ) was found for bulk intensity measurements of T1-weighted gadolinium enhancement and verteporfin fluorescence in the tumor region of interest. The use of contrast-enhanced MR imaging shows promise as a method for treatment planning and photosensitizer dosimetry in human photodynamic therapy (PDT) of pancreas cancer

Encouraging eyewitnesses to falsely corroborate allegations: effects of rapport-building and incriminating evidence

Building rapport involves developing a harmonious relationship with another person and conveying understanding and acceptance towards that person. Law enforcement officers use rapport-building to help gather information from witnesses. But could rapport-building, in some situations, work to contaminate eyewitness testimony? Research shows that compelling incriminating evidence can lead people to corroborate false accusations made against another person. We investigated whether rapport-building – when combined with either Verbal or Verbal+Visual false evidence – might boost these corroboration rates. Subjects took part in a pseudo-gambling task, in which their counterpart was falsely accused of cheating. Using a 2 (Rapport: Rapport vs. No-rapport) × 2 (Incriminating Evidence: Verbal vs. Verbal+Visual) between-subjects design, we persuaded subjects to corroborate the accusation. We found that both rapport and verbal+visual incriminating evidence increased the compliance rate. Even when the incriminating evidence was only presented verbally, rapport-building subjects were almost three times as likely to corroborate a false accusation compared to subjects who did not undergo rapport-building. Our results suggest that although there is widespread and strong support for using rapport-building in interviews, doing so also has the potential to aggravate the contaminating power of suggestive interview techniques

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Use of Multiprognostic Index Domain Scores, Clinical Data, and Machine Learning to Improve 12-Month Mortality Risk Prediction in Older Hospitalized Patients: Prospective Cohort Study

BackgroundThe Multidimensional Prognostic Index (MPI) is an aggregate, comprehensive, geriatric assessment scoring system derived from eight domains that predict adverse outcomes, including 12-month mortality. However, the prediction accuracy of using the three MPI categories (mild, moderate, and severe risk) was relatively poor in a study of older hospitalized Australian patients. Prediction modeling using the component domains of the MPI together with additional clinical features and machine learning (ML) algorithms might improve prediction accuracy. ObjectiveThis study aims to assess whether the accuracy of prediction for 12-month mortality using logistic regression with maximum likelihood estimation (LR-MLE) with the 3-category MPI together with age and gender (feature set 1) can be improved with the addition of 10 clinical features (sodium, hemoglobin, albumin, creatinine, urea, urea-to-creatinine ratio, estimated glomerular filtration rate, C-reactive protein, BMI, and anticholinergic risk score; feature set 2) and the replacement of the 3-category MPI in feature sets 1 and 2 with the eight separate MPI domains (feature sets 3 and 4, respectively), and to assess the prediction accuracy of the ML algorithms using the same feature sets. MethodsMPI and clinical features were collected from patients aged 65 years and above who were admitted to either the general medical or acute care of the elderly wards of a South Australian hospital between September 2015 and February 2017. The diagnostic accuracy of LR-MLE was assessed together with nine ML algorithms: decision trees, random forests, extreme gradient boosting (XGBoost), support-vector machines, naïve Bayes, K-nearest neighbors, ridge regression, logistic regression without regularization, and neural networks. A 70:30 training set:test set split of the data and a grid search of hyper-parameters with 10-fold cross-validation—was used during model training. The area under the curve was used as the primary measure of accuracy. ResultsA total of 737 patients (female: 370/737, 50.2%; male: 367/737, 49.8%) with a median age of 80 (IQR 72-86) years had complete MPI data recorded on admission and had completed the 12-month follow-up. The area under the receiver operating curve for LR-MLE was 0.632, 0.688, 0.738, and 0.757 for feature sets 1 to 4, respectively. The best overall accuracy for the nine ML algorithms was obtained using the XGBoost algorithm (0.635, 0.706, 0.756, and 0.757 for feature sets 1 to 4, respectively). ConclusionsThe use of MPI domains with LR-MLE considerably improved the prediction accuracy compared with that obtained using the traditional 3-category MPI. The XGBoost ML algorithm slightly improved accuracy compared with LR-MLE, and adding clinical data improved accuracy. These results build on previous work on the MPI and suggest that implementing risk scores based on MPI domains and clinical data by using ML prediction models can support clinical decision-making with respect to risk stratification for the follow-up care of older hospitalized patients

in cancer care: a systematic review

Examining and addressing evidence-practice gap