Choroid plexus volumes and auditory verbal learning scores are associated with conversion from mild cognitive impairment to Alzheimer's disease.

PURPOSE: Mild cognitive impairment (MCI) can be the prodromal phase of Alzheimer's disease (AD) where appropriate intervention might prevent or delay conversion to AD. Given this, there has been increasing interest in using magnetic resonance imaging (MRI) and neuropsychological testing to predict conversion from MCI to AD. Recent evidence suggests that the choroid plexus (ChP), neural substrates implicated in brain clearance, undergo volumetric changes in MCI and AD. Whether the ChP is involved in memory changes observed in MCI and can be used to predict conversion from MCI to AD has not been explored. METHOD: The current study used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database to investigate whether later progression from MCI to AD (progressive MCI [pMCI], n = 115) or stable MCI (sMCI, n = 338) was associated with memory scores using the Rey Auditory Verbal Learning Test (RAVLT) and ChP volumes as calculated from MRI. Classification analyses identifying pMCI or sMCI group membership were performed to compare the predictive ability of the RAVLT and ChP volumes. FINDING: The results indicated a significant difference between pMCI and sMCI groups for right ChP volume, with the pMCI group showing significantly larger right ChP volume (p = .01, 95% confidence interval [-.116, -.015]). A significant linear relationship between the RAVLT scores and right ChP volume was found across all participants, but not for the two groups separately. Classification analyses showed that a combination of left ChP volume and auditory verbal learning scores resulted in the most accurate classification performance, with group membership accurately predicted for 72% of the testing data. CONCLUSION: These results suggest that volumetric ChP changes appear to occur before the onset of AD and might provide value in predicting conversion from MCI to AD.

First-Strike Rapid Predictive Dosimetry and Dose Response for 177Lu-PSMA Therapy in Metastatic Castration-Resistant Prostate Cancer.

We devised and clinically validated a schema of rapid personalized predictive dosimetry for 177Lu-PSMA-I&T in metastatic castration-resistant prostate cancer. It supersedes traditional empiric prescription by providing clinically meaningful predicted absorbed doses for first-strike optimization. Methods: Prostate-specific membrane antigen PET was conceptualized as a simulation study that captures the complex dosimetric interplay between tumor, marrow, and kidneys at a single time point. Radiation principles of fractionation, heterogeneity, normal-organ constraints (marrow, kidney), absorbed dose, and dose rate were introduced. We created a predictive calculator in the form of a free, open-source, and user-friendly spreadsheet that can be completed within minutes. Our schema achieves speed and accuracy by sampling tissue radioconcentrations (kBq/cm3) to be analyzed in conjunction with clinical input from the user that reflect dosimetric preconditions. The marrow-absorbed dose constraint was 0.217 Gy (dose rate, ≤0.0147 Gy/h) per fraction with an interfraction interval of at least 6 wk. Results: Our first 10 patients were analyzed. The first-strike mean tumor-absorbed dose threshold for any prostate-specific antigen (PSA) response was more than 10 Gy (dose rate, >0.1 Gy/h). The metastasis with the lowest first-strike tumor-absorbed dose correlated the best with the percentage decrease of PSA; its threshold to achieve hypothetical zero PSA was 20 Gy or more. Each patient's PSA doubling time can be used to personalize their unique absorbed dose-response threshold. The predicted mean first-strike prescription constrained by marrow-absorbed dose rate per fraction was 11.0 ± 4.0 GBq. Highly favorable conditions (tumor sink effect) were dosimetrically expressed as the combination of tumor-to-normal-organ ratios of more than 150 for marrow and more than 4 for kidney. Our schema obviates the traditional role of the SUV as a predictive parameter. Conclusion: Our rapid schema is feasible to implement in any busy real-world theranostics unit and exceeds today's best practice standards. Our dosimetric thresholds and predictive parameters can radiobiologically rationalize each patient's first-strike prescription down to a single becquerel. Favorable tumor-to-normal-organ ratios can be prospectively exploited by predictive dosimetry to optimize the first-strike prescription. The scientific framework of our schema may be applied to other systemic radionuclide therapies.

Ancient mitogenomes from Pre-Pottery Neolithic Central Anatolia and the effects of a Late Neolithic bottleneck in sheep (Ovis aries).

Occupied between ~10,300 and 9300 years ago, the Pre-Pottery Neolithic site of Asikli Höyük in Central Anatolia went through early phases of sheep domestication. Analysis of 629 mitochondrial genomes from this and numerous sites in Anatolia, southwest Asia, Europe, and Africa produced a phylogenetic tree with excessive coalescences (nodes) around the Neolithic, a potential signature of a domestication bottleneck. This is consistent with archeological evidence of sheep management at Asikli Höyük which transitioned from residential stabling to open pasturing over a millennium of site occupation. However, unexpectedly, we detected high genetic diversity throughout Asikli Höyük's occupation rather than a bottleneck. Instead, we detected a tenfold demographic bottleneck later in the Neolithic, which caused the fixation of mitochondrial haplogroup B in southwestern Anatolia. The mitochondrial genetic makeup that emerged was carried from the core region of early Neolithic sheep management into Europe and dominates the matrilineal diversity of both its ancient and the billion-strong modern sheep populations.

IPEM topical report: results of a 2022 UK survey on the use of linac manufacturer integrated quality control (MIQC).

In recent years Radiotherapy linear accelerator (linac) vendors have developed their own integrated quality control (QC) systems. Such manufacturer-integrated-quality-control (MIQC) has the potential to improve both the quality and efficiency of linac QC but is currently being developed and utilised in the absence of specific best-practice guidance. An Institute of Physics and Engineering in Medicine working party was commissioned with a view to develop guidance for the commissioning and implementation of MIQC. This study is based upon a survey of United Kingdom (UK) radiotherapy departments performed by the working party. The survey was distributed to all heads of radiotherapy physics in the UK and investigated availability and uptake, community beliefs and opinions, utilisation, user experience and associated procedures. The survey achieved a 95% response rate and demonstrated strong support (>95%) for its use and further development. MIQC systems are available in 79% of respondents' centres, and are in clinical use in 66%. The most common MIQC system was Varian MPC, in clinical use in 58% of responding centres, with CyberKnife AQA\E2E in 11%, TomoTherapy TQA in 8% and no users of Elekta Machine QA. A majority of users found their MIQC to be easy to use, reliable, and had five or more years of experience. Most users reported occasions of discrepancy in results between MIQC and conventional testing, but the majority considered this acceptable, indicating a false reporting frequency of quarterly or less. MIQC has shown value in preventative maintenance and early detection of machine deviations. There were inconsistent approaches in the utilisation and commissioning tests performed. Fewer than half of users perform QC of MIQC. 45% of responders have modified their QC processes with the introduction of MIQC, via replacement of conventional tests or reduction in their frequency. Future guidance is recommended to assist in the implementation of MIQC.

Trustworthy Data and AI Environments for Clinical Prediction: Application to Crisis-Risk in People With Depression.

Depression is a common mental health condition that often occurs in association with other chronic illnesses, and varies considerably in severity. Electronic Health Records (EHRs) contain rich information about a patient's medical history and can be used to train, test and maintain predictive models to support and improve patient care. This work evaluated the feasibility of implementing an environment for predicting mental health crisis among people living with depression based on both structured and unstructured EHRs. A large EHR from a mental health provider, Mersey Care, was pseudonymised and ingested into the Natural Language Processing (NLP) platform CogStack, allowing text content in binary clinical notes to be extracted. All unstructured clinical notes and summaries were semantically annotated by MedCAT and BioYODIE NLP services. Cases of crisis in patients with depression were then identified. Random forest models, gradient boosting trees, and Long Short-Term Memory (LSTM) networks, with varying feature arrangement, were trained to predict the occurrence of crisis. The results showed that all the prediction models can use a combination of structured and unstructured EHR information to predict crisis in patients with depression with good and useful accuracy. The LSTM network that was trained on a modified dataset with only 1000 most-important features from the random forest model with temporality showed the best performance with a mean AUC of 0.901 and a standard deviation of 0.006 using a training dataset and a mean AUC of 0.810 and 0.01 using a hold-out test dataset. Comparing the results from the technical evaluation with the views of psychiatrists shows that there are now opportunities to refine and integrate such prediction models into pragmatic point-of-care clinical decision support tools for supporting mental healthcare delivery.

The Bcvic1 and Bcvic2 vegetative incompatibility genes in Botrytis cinerea encode proteins with domain architectures involved in allorecognition in other filamentous fungi.

Vegetative incompatibility is a fungal allorecognition system characterised by the inability of genetically distinct conspecific fungal strains to form a viable heterokaryon and is controlled by multiple polymorphic loci termed vic (vegetative incompatibility) or het (heterokaryon incompatibility). We have genetically identified and characterised the first vic locus in the economically important, plant-pathogenic, necrotrophic fungus Botrytis cinerea. A bulked segregant approach coupled with whole genome Illumina sequencing of near-isogenic lines of B. cinerea was used to map a vic locus to a 60-kb region of the genome. Within that locus, we identified two adjacent, highly polymorphic open reading frames, Bcvic1 and Bcvic2, which encode predicted proteins that contain domain architectures implicated in vegetative incompatibility in other filamentous fungi. Bcvic1 encodes a predicted protein containing a putative serine esterase domain, a NACHT family of NTPases domain, and several Ankyrin repeats. Bcvic2 encodes a putative syntaxin protein containing a SNARE domain; such proteins typically function in vesicular transport. Deletion of Bcvic1 and Bcvic2 individually had no effect on vegetative incompatibility. However, deletion of the region containing both Bcvic1 and Bcvic2 resulted in mutant lines that were severely restricted in growth and showed loss of vegetative incompatibility. Complementation of these mutants by ectopic expression restored the growth and vegetative incompatibility phenotype, indicating that Bcvic1 and Bcvic2 are controlling vegetative incompatibility at this vic locus.

Multi-vessel giant coronary artery aneurysms: An unusual cause of chest pain.

We describe an unusual case of multi-vessel giant coronary artery aneurysms complicated by acute coronary syndrome despite escalation of therapy. A 65-year-old man with hypertension and hypercholesterolemia presented to clinic with atypical chest pain over 4 months. Outpatient computed tomography coronary angiography (CTCA) demonstrated giant coronary aneurysms involving all 3 major coronary arteries. Outpatient coronary angiogram findings were in concordance with the CTCA with no definite obstructive coronary disease. Myocardial perfusion imaging was normal. He was commenced on dual antiplatelet therapy (DAPT). At 6 months, he presented with chest pain and non-ST-elevation myocardial infarction. Repeat coronary angiogram demonstrated occluded first septal LAD branch which previously had aneurysmal dilatation. DAPT was changed to long-term oral anticoagulation. He remains well at 18 months. This case highlights the importance of multi-modality imaging in the diagnosis and workup of coronary artery aneurysms and challenges in management; an individualized approach is required.

Application of failure mode and effects analysis to validate a novel hybrid Linac QC program that integrates automated and conventional QC testing.

A hybrid quality control (QC) program was developed that integrates automated and conventional Linac QC, realizing the benefits of both automated and conventional QC, increasing efficiency and maintaining independent measurement methods. Failure mode and effects analysis (FMEA) was then applied in order to validate the program prior to clinical implementation. The hybrid QC program consists of automated QC with machine performance check and DailyQA3 array on the TrueBeam Linac, and Delta4 volumetric modulated arc therapy (VMAT) standard plan measurements, alongside conventional monthly QC at a reduced frequency. The FMEA followed the method outlined in TG-100. Process maps were created for each treatment type at our center: VMAT, stereotactic body radiotherapy (SBRT), conformal, and palliative. Possible failure modes were established by evaluating each stage in the process map. The FMEA followed semiquantitative methods, using data from our QC records from eight Linacs over 3 years for the occurrence estimates, and simulation of failure modes in the treatment planning system, with scoring surveys for severity and detectability. The risk priority number (RPN) was calculated from the product of the occurrence, severity, and detectability scores and then normalized to the maximum and ranked to determine the most critical failure modes. The highest normalized RPN values (100, 90) were found to be for MLC position dynamic for both VMAT and SBRT treatments. The next highest score was 35 for beam position for SBRT, and the majority of scores were less than 20. Overall, these RPN scores for the hybrid Linac QC program indicated that it would be acceptable, but the high RPN score associated with the dynamic MLC failure mode indicates that it would be valuable to perform more rigorous testing of the MLC. The FMEA proved to be a useful tool in validating hybrid QC.

Implementation of a comprehensive set of optimised CBCT protocols and validation through imaging quality and dose audit.

OBJECTIVES: Cone-beam computed tomography (CBCT) for radiotherapy treatment verification has increased in frequency; therefore, it is crucial to optimise image quality and radiation dose to patients. The aim of this study was to implement optimised CBCT protocols for the Varian TrueBeams for most tumour sites in adult patients. METHODS: A combination of patient size-specific CBCT protocols from the literature and developed in-house was used. Scans taken before and after optimisation were compared by senior radiographers and physicists to evaluate how changes affected image quality and clinical usability for online image registration. The change in dose for each new CBCT protocol was compared to the Varian default. A clinical audit was performed following implementation to evaluate the changes in imaging dose for all patients receiving a CBCT during that period. RESULTS: Ten CBCT protocols were introduced including head and neck and patient-size-specific thorax and pelvis/abdomen protocols. Scans from 102 patients with images before and after optimisation were assessed, none of the scans showed image quality changes compromising clinical usability and for some image quality was improved. Between November 2020 and June 2021, 1185 patients had CBCTs using the new protocols. The imaging dose was reduced for 52% of patients, remained the same for 37% and increased for 12%. CONCLUSIONS: This study showed that substantial dose reductions and image quality improvements can be achieved with simple changes in the default settings of the Varian TrueBeam CBCT without affecting the radiographers' confidence in online image registration. ADVANCES IN KNOWLEDGE: This study represents a comprehensive assessment and optimisation of CBCT protocols for most sites, validated on a large cohort of patients.

The Potential of Molecular Indicators of Plant Virus Infection: Are Plants Able to Tell Us They Are Infected?

To our knowledge, there are no reports that demonstrate the use of host molecular markers for the purpose of detecting generic plant virus infection. Two approaches involving molecular indicators of virus infection in the model plant Arabidopsis thaliana were examined: the accumulation of small RNAs (sRNAs) using a microfluidics-based method (Bioanalyzer); and the transcript accumulation of virus-response related host plant genes, suppressor of gene silencing 3 (AtSGS3) and calcium-dependent protein kinase 3 (AtCPK3) by reverse transcriptase-quantitative PCR (RT-qPCR). The microfluidics approach using sRNA chips has previously demonstrated good linearity and good reproducibility, both within and between chips. Good limits of detection have been demonstrated from two-fold 10-point serial dilution regression to 0.1 ng of RNA. The ratio of small RNA (sRNA) to ribosomal RNA (rRNA), as a proportion of averaged mock-inoculation, correlated with known virus infection to a high degree of certainty. AtSGS3 transcript decreased between 14- and 28-days post inoculation (dpi) for all viruses investigated, while AtCPK3 transcript increased between 14 and 28 dpi for all viruses. A combination of these two molecular approaches may be useful for assessment of virus-infection of samples without the need for diagnosis of specific virus infection.

Care After Presenting with Seizures (CAPS): An analysis of the impact of a seizure referral pathway and nurse support on neurology referral rates for patients admitted with a seizure.

INTRODUCTION: The National Audit of Seizure Management in Hospitals (NASH) identified low referral rates to neurology and epilepsy services after an emergency department attendance or admission with a seizure. METHODS: National Health Service Secondary Users Service (SUS) data were used to assess the impact of a seizure pathway at seven hospitals in Cheshire & Merseyside, which was implemented in 2014. Three of these hospitals also had a nurse employed part-time to support the pathway. Patients admitted with a seizure between 2011 and 2018 inclusive were identified using an algorithm based on ICD-10 codes, and the primary outcome was a neurology referral within 3 months of admission. Regression models were used to assess the impact of age, deprivation and comorbidity on post admission clinic referral rates. RESULTS: 13,285 admissions with seizure were included in the analysis. 5,677 had not attended a neurology clinic appointment in the 12 months before the admission. The percentage of whom that were offered an appointment following the admission was: 16.0% before the pathway and 35.9% with the nurse-supported pathway, which was significant in the regression model. 4,700 admissions had attended a neurology clinic appointment in the 12 months before the admission. Of this group, the percentage of whom that were offered an appointment following the admission was: 55.2% before the pathway and 62.4% with the nurse-supported pathway, an increase that was not significant in the regression model. The regression models identified significant health inequalities whereby older patients, those with comorbidities and those living in deprived areas were significantly less likely to be referred. CONCLUSION: Neurology out-patient appointment rates following an admission with seizures are low, worryingly so for those with no neurology appointment in the previous 12 months. A nurse-supported pathway can improve appointment rates, but the effect is modest. Further service redesign is required; the impact of which should be rigorously evaluated.

Long-term experience of MPC across multiple TrueBeam linacs: MPC concordance with conventional QC and sensitivity to real-world faults.

Machine Performance Check (MPC) is an automated Quality Control (QC) tool that is integrated into the TrueBeam and Halcyon linear accelerators (Linacs), utilizing the imaging systems to verify the Linac beam and geometry. This work compares the concordance of daily MPC results with conventional QC tests over a 3-year period for eight Linacs in order to assess the sensitivity of MPC in detecting faults. The MPC output measurements were compared with the monthly ionization chamber measurements for 6 and 10 MV photon beams and 6, 9, 12, 16, and 18 MeV electron beams. All 6 MV Beam and Geometry (6MVBG) MPC test failures were analyzed to determine the failure rate and the number of true and false negative results, using the conventional QC record as the reference. The concordance between conventional QC test failures and MPC test failures was investigated. The mean agreement across 1933 MPC output and monthly comparison chamber measurements for all beam energies was 0.2%, with 97.8% within 1.5%, and a maximum difference of 2.9%. Of the 5000-6000 MPC individual test parameter results for the 6MVBG test, the highest failure rate was BeamOutputChange (0.5%), then BeamCenterShift (0.3%), and was ≤ 0.1% for the remaining parameters. There were 50 true negative and 27 false negative out of tolerance MPC results, with false negatives resolved by repeating MPC or by independent measurement. The analysis of conventional QC failures demonstrated that MPC detected all failures, except occasions when MPC reported output within tolerance, a result of the MPC-chamber response variation. The variation in MPC output versus chamber measurement indicates MPC is appropriate for daily output constancy but not for the measurement of absolute output. The comparison of the 6MVBG results and conventional records provides evidence that MPC is a sensitive method of performing beam and mechanical checks in a clinical setting.

Fast and accurate quantification of insertion-site specific transgene levels from raw seed samples using solid-state nanopore technology.

Many modern crop varieties contain patented biotechnology traits, and an increasing number of these crops have multiple (stacked) traits. Fast and accurate determination of transgene levels is advantageous for a variety of use cases across the food, feed and fuel value chain. With the growing number of new transgenic crops, any technology used to quantify them should have robust assays that are simple to design and optimize, thereby facilitating the addition of new traits to an assay. Here we describe a PCR-based method that is simple to design, starts from whole seeds, and can be run to end-point in less than 5 minutes. Subsequent relative quantification (trait vs. non-trait) using capillary electrophoresis performed in 5% increments across the 0-100% range showed a mean absolute error of 1.9% (s.d. = 1.1%). We also show that the PCR assay can be coupled to non-optical solid-state nanopore sensors to give seed-to-trait quantification results with a mean absolute error of 2.3% (s.d. = 1.6%). In concert, the fast PCR and nanopore sensing stages demonstrated here can be fully integrated to produce seed-to-trait quantification results in less than 10 minutes, with high accuracy across the full dynamic range.

Broad range of missense error frequencies in cellular proteins.

Assessment of the fidelity of gene expression is crucial to understand cell homeostasis. Here we present a highly sensitive method for the systematic Quantification of Rare Amino acid Substitutions (QRAS) using absolute quantification by targeted mass spectrometry after chromatographic enrichment of peptides with missense amino acid substitutions. By analyzing incorporation of near- and non-cognate amino acids in a model protein EF-Tu, we show that most of missense errors are too rare to detect by conventional methods, such as DDA, and are estimated to be between <10-7-10-5 by QRAS. We also observe error hotspots of up to 10-3 for some types of mismatches, including the G-U mismatch. The error frequency depends on the expression level of EF-Tu and, surprisingly, the amino acid position in the protein. QRAS is not restricted to any particular miscoding event, organism, strain or model protein and is a reliable tool to analyze very rare proteogenomic events.

A novel chrysovirus from a clinical isolate of Aspergillus thermomutatus affects sporulation.

A clinical isolate of Aspergillus thermomutatus (Teleomorph: Neosartorya pseudofischeri) was found to contain ~35 nm isometric virus-like particles associated with four double-stranded (ds) RNA segments, each of which coded for a single open reading frame. The longest dsRNA element (3589 nt) encodes a putative RNA-dependent RNA polymerase (1114 aa), the second longest dsRNA element (2772 nt) encodes a coat protein (825 aa), and the other two dsRNAs (2676 nt, 2514 nt) encode hypothetical proteins of 768 aa and 711 aa, respectively. Phylogenetic analysis of the amino acid sequences showed 41-60% similarity to the proteins coded by the dsRNAs of the most closely related virus, Penicillium janczewskii chrysovirus 2, indicating that it is a new species based on the International Committee on Taxonomy of Viruses criteria for the genus Chrysovirus. This is the first virus reported from A. thermomutatus and was tentatively named Aspergillus thermomutatus chrysovirus 1. A virus free line of the fungal isolate, cured by cycloheximide treatment, produced large numbers of conidia but no ascospores at both 20°C and 37°C, whereas the virus infected line produced ten-fold fewer conidia at 20°C and a large number of ascospores at both temperatures. The effects of the virus on fungal sporulation have interesting implications for the spread of the fungus and possible use of the virus as a biological control agent.

The Effect of Aspergillus Thermomutatus Chrysovirus 1 on the Biology of Three Aspergillus Species.

This study determined the effects of Aspergillus thermomutatus chrysovirus 1 (AthCV1), isolated from Aspergillus thermomutatus, on A. fumigatus, A. nidulans and A. niger. Protoplasts of virus-free isolates of A. fumigatus, A. nidulans and A. niger were transfected with purified AthCV1 particles and the phenotype, growth and sporulation of the isogenic AthCV1-free and AthCV1-infected lines assessed at 20 °C and 37 °C and gene expression data collected at 37 °C. AthCV1-free and AthCV1-infected A. fumigatus produced only conidia at both temperatures but more than ten-fold reduced compared to the AthCV1-infected line. Conidiation was also significantly reduced in infected lines of A. nidulans and A. niger at 37 °C. AthCV1-infected lines of A. thermomutatus and A. nidulans produced large numbers of ascospores at both temperatures, whereas the AthCV1-free line of the former did not produce ascospores. AthCV1-infected lines of all species developed sectoring phenotypes with sclerotia produced in aconidial sectors of A. niger at 37 °C. AthCV1 was detected in 18% of sclerotia produced by AthCV1-infected A. niger and 31% of ascospores from AthCV1-infected A. nidulans. Transcriptome analysis of the naturally AthCV1-infected A. thermomutatus and the three AthCV1-transfected Aspergillus species showed altered gene expression as a result of AthCV1-infection. The results demonstrate that AthCV1 can infect a range of Aspergillus species resulting in reduced sporulation, a potentially useful attribute for a biological control agent.

ICTV Virus Taxonomy Profile: Hypoviridae.

The Hypoviridae, comprising one genus, Hypovirus, is a family of capsidless viruses with positive-sense, ssRNA genomes of 9.1-12.7 kb that possess either a single large ORF or two ORFs. The ORFs appear to be translated from genomic RNA by non-canonical mechanisms, i.e. internal ribosome entry site-mediated and stop/restart translation. Hypoviruses have been detected in ascomycetous or basidiomycetous filamentous fungi, and are considered to be replicated in host Golgi-derived, lipid vesicles that contain their dsRNA as a replicative form. Some hypoviruses induce hypovirulence to host fungi, while others do not. This is a summary of the current ICTV report on the taxonomy of the Hypoviridae, which is available at www.ictv.global/report/hypoviridae.

Scalable and accurate deep learning with electronic health records.

Predictive modeling with electronic health record (EHR) data is anticipated to drive personalized medicine and improve healthcare quality. Constructing predictive statistical models typically requires extraction of curated predictor variables from normalized EHR data, a labor-intensive process that discards the vast majority of information in each patient's record. We propose a representation of patients' entire raw EHR records based on the Fast Healthcare Interoperability Resources (FHIR) format. We demonstrate that deep learning methods using this representation are capable of accurately predicting multiple medical events from multiple centers without site-specific data harmonization. We validated our approach using de-identified EHR data from two US academic medical centers with 216,221 adult patients hospitalized for at least 24 h. In the sequential format we propose, this volume of EHR data unrolled into a total of 46,864,534,945 data points, including clinical notes. Deep learning models achieved high accuracy for tasks such as predicting: in-hospital mortality (area under the receiver operator curve [AUROC] across sites 0.93-0.94), 30-day unplanned readmission (AUROC 0.75-0.76), prolonged length of stay (AUROC 0.85-0.86), and all of a patient's final discharge diagnoses (frequency-weighted AUROC 0.90). These models outperformed traditional, clinically-used predictive models in all cases. We believe that this approach can be used to create accurate and scalable predictions for a variety of clinical scenarios. In a case study of a particular prediction, we demonstrate that neural networks can be used to identify relevant information from the patient's chart.

Conditional Switch between Frameshifting Regimes upon Translation of dnaX mRNA.

Ribosome frameshifting during translation of bacterial dnaX can proceed via different routes, generating a variety of distinct polypeptides. Using kinetic experiments, we show that -1 frameshifting predominantly occurs during translocation of two tRNAs bound to the slippery sequence codons. This pathway depends on a stem-loop mRNA structure downstream of the slippery sequence and operates when aminoacyl-tRNAs are abundant. However, when aminoacyl-tRNAs are in short supply, the ribosome switches to an alternative frameshifting pathway that is independent of a stem-loop. Ribosome stalling at a vacant 0-frame A-site codon results in slippage of the P-site peptidyl-tRNA, allowing for -1-frame decoding. When the -1-frame aminoacyl-tRNA is lacking, the ribosomes switch into -2 frame. Quantitative mass spectrometry shows that the -2-frame product is synthesized in vivo. We suggest that switching between frameshifting routes may enrich gene expression at conditions of aminoacyl-tRNA limitation.