Integrating patients in time series clinical transcriptomics data.

MOTIVATION: Analysis of time series transcriptomics data from clinical trials is challenging. Such studies usually profile very few time points from several individuals with varying response patterns and dynamics. Current methods for these datasets are mainly based on linear, global orderings using visit times which do not account for the varying response rates and subgroups within a patient cohort. RESULTS: We developed a new method that utilizes multi-commodity flow algorithms for trajectory inference in large scale clinical studies. Recovered trajectories satisfy individual-based timing restrictions while integrating data from multiple patients. Testing the method on multiple drug datasets demonstrated an improved performance compared to prior approaches suggested for this task, while identifying novel disease subtypes that correspond to heterogeneous patient response patterns. AVAILABILITY AND IMPLEMENTATION: The source code and instructions to download the data have been deposited on GitHub at https://github.com/euxhenh/Truffle.

The impact of elective surgery postponement during COVID-19 on emergency bellwether procedures in a large tertiary centre in Singapore.

The coronavirus disease 2019 (COVID-19) pandemic drove many healthcare systems worldwide to postpone elective surgery to increase healthcare capacity, manpower, and reduce infection risk to staff. The aim of this study was to assess the impact of an elective surgery postponement policy in response to the COVID-19 pandemic on surgical volumes and patient outcomes for three emergency bellwether procedures. A retrospective cohort study of patients who underwent any of the three emergency procedures [Caesarean section (CS), emergency laparotomy (EL), and open fracture (OF) fixation] between 1 January 2018 and 31 December 2021 was conducted using clinical and surgical data from electronic medical records. The volumes and outcomes of each surgery were compared across four time periods: pre-COVID (January 2018-January 2020), elective postponement (February-May 2020), recovery (June-November 2020), and postrecovery (December 2020-December 2021) using Kruskal-Wallis test and segmented negative binomial regression. There was a total of 3886, 1396, and 299 EL, CS, and OF, respectively. There was no change in weekly volumes of CS and OF fixations across the four time periods. However, the volume of EL increased by 47% [95% confidence interval: 26-71%, P = 9.13 × 10-7) and 52% (95% confidence interval: 25-85%, P = 3.80 × 10-5) in the recovery and postrecovery period, respectively. Outcomes did not worsen throughout the four time periods for all three procedures and some actually improved for EL from elective postponement onwards. Elective surgery postponement in the early COVID-19 pandemic did not affect volumes of emergency CS and OF fixations but led to an increase in volume for EL after the postponement without any worsening of outcomes.

Cavernous sinus haemangioma: systematic review and pooled analysis relating to a rare skull base pathology.

Cavernous sinus haemangiomas (CSHs) are rare malformations of the microcirculation arising from the cavernous sinus. A systematic review and pooled data analysis of the associated clinical features, diagnostic modalities, management, and outcomes for CSHs was done. In total, 68 articles (338 cases) were eligible for analysis based on our selection criteria. The primary outcome measures were the occurrence of (i) and (ii) symptom resolution/improvement. Categorical outcome variables were assessed by binary logistic regression at 5% significance level. With headaches (39.9%) and diplopia (36.5%) as the most common presenting symptoms reported, dynamic contrast-enhanced MRI was the most commonly used diagnostic modality and was the most definitive pre-treatment imaging modality for diagnosing CSH with a sensitivity of 89.5%. The majority of CSHs were managed with radiosurgery (47.9% of cases), 37.9% by surgical resection alone, and 14.2% by a combination of both. Compared to patients that were treated with surgical resection only, those treated solely with radiosurgery had a 100% decrease in the odds of developing post-treatment complications (adjusted OR: 0.00, 95% CI: 0.00-0.002, p < 0.001), with a 5.03 times greater odds of symptom resolution/improvement (adjusted OR: 5.03, 95% CI: 1.89-13.4, p = 0.001). Patients that underwent combined therapy had a 79% reduction in risk of developing post-treatment complications (adjusted OR: 0.21, 95% CI: 0.06-0.68, p = 0.01), with no statistically significant difference in the odds of symptom resolution/improvement, compared to those that had surgery only. In conclusion, radiosurgery offered the best outcomes with regards to symptom resolution/improvement and post-treatment complications in patients with CSH.

QuickMIRSeq: a pipeline for quick and accurate quantification of both known miRNAs and isomiRs by jointly processing multiple samples from microRNA sequencing.

BACKGROUND: Genome-wide miRNA expression data can be used to study miRNA dysregulation comprehensively. Although many open-source tools for microRNA (miRNA)-seq data analyses are available, challenges remain in accurate miRNA quantification from large-scale miRNA-seq dataset. We implemented a pipeline called QuickMIRSeq for accurate quantification of known miRNAs and miRNA isoforms (isomiRs) from multiple samples simultaneously. RESULTS: QuickMIRSeq considers the unique nature of miRNAs and combines many important features into its implementation. First, it takes advantage of high redundancy of miRNA reads and introduces joint mapping of multiple samples to reduce computational time. Second, it incorporates the strand information in the alignment step for more accurate quantification. Third, reads potentially arising from background noise are filtered out to improve the reliability of miRNA detection. Fourth, sequences aligned to miRNAs with mismatches are remapped to a reference genome to further reduce false positives. Finally, QuickMIRSeq generates a rich set of QC metrics and publication-ready plots. CONCLUSIONS: The rich visualization features implemented allow end users to interactively explore the results and gain more insights into miRNA-seq data analyses. The high degree of automation and interactivity in QuickMIRSeq leads to a substantial reduction in the time and effort required for miRNA-seq data analysis.

The Rat microRNA body atlas; Evaluation of the microRNA content of rat organs through deep sequencing and characterization of pancreas enriched miRNAs as biomarkers of pancreatic toxicity in the rat and dog.

BACKGROUND: MicroRNAs (miRNA) are ~19-25 nucleotide long RNA molecules that fine tune gene expression through the inhibition of translation or degradation of the mRNA through incorporation into the RNA induced silencing complex (RISC). MicroRNAs are stable in the serum and plasma, are detectable in a wide variety of body fluids, are conserved across veterinary species and humans and are expressed in a tissue specific manner. They can be detected at low concentrations in circulation in animals and humans, generating interest in the utilization of miRNAs as serum and/or plasma based biomarkers of tissue injury. MicroRNA tissue profiling in rodents has been published, but sample an insufficient number of organs of toxicologic interest using microarray or qPCR technologies for miRNA detection. Here we impart an improved rat microRNA body atlas consisting of 21 and 23 tissues of toxicologic interest from male and female Sprague Dawley rats respectively, using Illumina miRNA sequencing. Several of the authors created a dog miRNA body atlas and we collaborated to test miRNAs conserved in rat and dog pancreas in caerulein toxicity studies utilizing both species. RESULTS: A rich data set is presented that more robustly defines the tissue specificity and enrichment profiles of previously published and undiscovered rat miRNAs. We generated 1,927 sequences that mapped to mature miRNAs in rat, mouse and human from miRBase and discovered an additional 1,162 rat miRNAs as compared to the current number of rat miRNAs in miRBase version 21. Tissue specific and enriched miRNAs were identified and a subset of these miRNAs were validated by qPCR for tissue specificity or enrichment. As an example of the power of this approach, we have conducted rat and dog pancreas toxicity studies and examined the levels of some tissue specific and enriched miRNAs conserved between rat and dog in the serum of each species. The studies demonstrate that conserved tissue specific/enriched miRs-216a-5p, 375-3p, 148a-3p, 216b-5p and 141-3p are candidate biomarkers of pancreatic injury in the rat and dog. CONCLUSIONS: A microRNA body atlas for rat and dog was useful in identifying new candidate miRNA biomarkers of organ toxicity in 2 toxicologically relevant species.

Perioperative immunonutrition in patients undergoing liver transplantation: a randomized double-blind trial.

UNLABELLED: Preliminary work suggested that perioperative immunonutrition (IMN) enriched in n-3 fatty acids, arginine, and nucleotides may improve preoperative nutritional status, enhance postoperative recovery, and reduce postoperative infectious complications in patients undergoing liver transplantation (LT). The current study examined these outcomes in a double-blind, randomized, controlled trial. Patients wait-listed for LT (n = 120) were randomized to either supplemental (0.6 L/d) oral IMN or an isocaloric control (CON). Enteral IMN or CON was resumed postoperatively and continued for at least 5 days. The change in total body protein (TBP) measured by neutron activation from study entry until immediately prior to LT was the primary endpoint and TBP measurements were repeated 10, 30, 90, 180, and 360 days after LT. Infectious complications were recorded for the first 30 postoperative days. Nineteen patients died or were delisted prior to LT. Fifty-two IMN and 49 CON patients received supplemental nutrition for a median (range) 56 (0-480) and 65 (0-348) days, respectively. Preoperative changes in TBP were not significant (IMN: 0.06 ± 0.15 [SEM]; CON: 0.12 ± 0.10 kg). Compared to baseline, a 0.7 ± 0.2 kg loss of TBP was seen in both groups at 30 days after LT (P < 0.0001) and, at 360 days, TBP had not increased significantly (IMN: 0.08 ± 0.19 kg; CON: 0.26 ± 0.23 kg). Infectious complications occurred in 31 (60%) IMN and 28 (57%) CON patients (P = 0.84). The median (range) postoperative hospital stay was 10 (5-105) days for IMN and 10 (6-27) days for CON patients (P = 0.68). CONCLUSION: In patients undergoing LT, perioperative IMN did not provide significant benefits in terms of preoperative nutritional status or postoperative outcome.

The learning curve for laparoscopic inguinal hernia repair: a newly qualified surgeon perspective.

BACKGROUND: The number of cases required to overcome the learning curve (LC) for laparoscopic extra-peritoneal inguinal hernia repair (TEP) varies widely in the literature. Less is known about the LC for inexperienced surgeons performing this procedure early in their career. The present study describes the technical challenges of TEP repair and the LC from the perspective of a recently qualified general surgeon. MATERIALS AND METHODS: Retrospective analysis of a single-surgeon experience of TEP repairs performed during the first 2 y of practice from 2011-2013. Patient demographics, hernia details, operative details, and postoperative outcome were all assessed. The CUSUM method was used to analyze the LC for operative time. RESULTS: There were 149 consecutive patients (mean age, 56 ± 17, 146 males, 24 bilateral, BMI 26 ± 4) followed for a median of 15 (4-26) mo. Direct herniae accounted for 61% of the cohort, and 16% were recurrent open presentations. The major complication and recurrence rate were <2%, and minor complications including urinary retention (15%) were reported. Re-admission rate was 6%. CUSUM analysis suggested an inflection point at 18 cases after which operative times were stabilized. CONCLUSIONS: For less experienced surgeons, standard surgical training provides for TEP hernia repair with satisfactory major complication, conversion, and recurrence rates. Minor complication rates can still be reduced further with further training and supervision from experienced peers.

Identification of tubular injury microRNA biomarkers in urine: comparison of next-generation sequencing and qPCR-based profiling platforms.

BACKGROUND: MicroRNAs (miRNAs) are small, non-coding RNAs that regulate protein levels post-transcriptionally. miRNAs play important regulatory roles in many cellular processes and have been implicated in several diseases. Recent studies have reported significant levels of miRNAs in a variety of body fluids, raising the possibility that miRNAs could serve as useful biomarkers. Next-generation sequencing (NGS) is increasingly employed in biomedical investigations. Although concordance between this platform and qRT-PCR based assays has been reported in high quality specimens, information is lacking on comparisons in biofluids especially urine. Here we describe the changes in miRNA expression patterns in a rodent model of renal tubular injury (gentamicin). Our aim is to compare RNA sequencing and qPCR based miRNA profiling in urine specimen from control and rats with confirmed tubular injury. RESULTS: Our preliminary examination of the concordance between miRNA-seq and qRT-PCR in urine specimen suggests minimal agreement between platforms probably due to the differences in sensitivity. Our results suggest that although miRNA-seq has superior specificity, it may not detect low abundant miRNAs in urine samples. Specifically, miRNA-seq did not detect some sequences which were identified by qRT-PCR. On the other hand, the qRT-PCR analysis was not able to detect the miRNA isoforms, which made up the majority of miRNA changes detected by NGS. CONCLUSIONS: To our knowledge, this is the first time that miRNA profiling platforms including NGS have been compared in urine specimen. miRNAs identified by both platforms, let-7d, miR-203, and miR-320, may potentially serve as promising novel urinary biomarkers for drug induced renal tubular epithelial injury.

Diagnostic criteria and core outcome set development for necrotising otitis externa: the COSNOE Delphi consensus study.

OBJECTIVE: Evidence for necrotising otitis externa (NOE) diagnosis and management is limited, and outcome reporting is heterogeneous. International best practice guidelines were used to develop consensus diagnostic criteria and a core outcome set (COS). METHODS: The study was pre-registered on the Core Outcome Measures in Effectiveness Trials (COMET) database. Systematic literature review identified candidate items. Patient-centred items were identified via a qualitative study. Items and their definitions were refined by multidisciplinary stakeholders in a two-round Delphi exercise and subsequent consensus meeting. RESULTS: The final COS incorporates 36 items within 12 themes: Signs and symptoms; Pain; Advanced Disease Indicators; Complications; Survival; Antibiotic regimes and side effects; Patient comorbidities; Non-antibiotic treatments; Patient compliance; Duration and cessation of treatment; Relapse and readmission; Multidisciplinary team management.Consensus diagnostic criteria include 12 items within 6 themes: Signs and symptoms (oedema, otorrhoea, granulation); Pain (otalgia, nocturnal otalgia); Investigations (microbiology [does not have to be positive], histology [malignancy excluded], positive CT and MRI); Persistent symptoms despite local and/or systemic treatment for at least two weeks; At least one risk factor for impaired immune response; Indicators of advanced disease (not obligatory but mut be reported when present at diagnosis). Stakeholders were unanimous that there is no role for secondary, graded, or optional diagnostic items. The consensus meeting identified themes for future research. CONCLUSION: The adoption of consensus-defined diagnostic criteria and COS facilitates standardised research reporting and robust data synthesis. Inclusion of patient and professional perspectives ensures best practice stakeholder engagement.

Pearls & Oy-sters: Sequential Bilateral Hearing and Vision Loss With Optic Disc Swelling Due to Sphenoid Bone Craniofacial Fibrous Dysplasia.

Bilateral optic disc swelling is a common finding but rarely associated with multiple cranial neuropathies. In this case, an 18-year-old man presented with subacute sequential hearing loss followed by subacute sequential visual loss. Clinical examination revealed bilateral optic disc swelling. Lumbar puncture revealed a normal opening pressure of 15 cmH2o. This case discusses a rare but important cause of bilateral optic disc swelling in the context of hearing loss, disequilibrium, and a normal CSF opening pressure. An overview of the literature is provided, and treatment options are discussed to guide further management of similar cases.

Estimating the pertussis burden in adolescents and adults in the United States between 2007 and 2019.

We developed a machine learning algorithm to identify undiagnosed pertussis episodes in adolescent and adult patients with reported acute respiratory disease (ARD) using clinician notes in an electronic healthcare record (EHR) database. Here, we utilized the algorithm to better estimate the overall pertussis incidence within the Optum Humedica clinical repository from 1 January 2007 through 31 December 2019. The incidence of diagnosed pertussis episodes was 1-5 per 100,000 annually, consistent with data registered by the US Centers for Disease Control and Prevention (CDC) over the same time period. Among 18,573,496 ARD episodes assessed, 1,053,946 were identified (i.e. algorithm-identified) as likely undiagnosed pertussis episodes. Accounting for these undiagnosed pertussis episodes increased the estimated pertussis incidence by 110-fold on average (34-474 per 100,000 annually). Risk factors for pertussis episodes (diagnosed and algorithm-identified) included asthma (Odds ratio [OR] 2.14; 2.12-2.16), immunodeficiency (OR 1.85; 1.78-1.91), chronic obstructive pulmonary disease (OR 1.63; 1.61-1.65), obesity (OR 1.44; 1.43-1.45), Crohn's disease (OR 1.39; 1.33-1.45), diabetes type 1 (OR 1.21; 1.17-1.24) and type 2 (OR 1.12; 1.1-1.13). Of note, all these risk factors, except Crohn's disease, increased the likelihood of severe pertussis. In conclusion, the incidence of pertussis in the adolescent and adult population in the USA is likely substantial, but considerably under-recognized, highlighting the need for improved clinical awareness of the disease and for improved control strategies in this population. These results will help better inform public health vaccination and booster programs, particularly in those with underlying comorbidities.

Development of an algorithm for finding pertussis episodes in a population-based electronic health record database.

While tetanus-diphtheria-acellular pertussis (Tdap) vaccines for adolescents and adults were licensed in 2005 and immunization strategies proposed, the burden of pertussis in this population remains under-recognized mainly due to atypical disease presentation, undermining efforts to optimize protection through vaccination. We developed a machine learning algorithm to identify undiagnosed/misdiagnosed pertussis episodes in patients diagnosed with acute respiratory disease (ARD) using signs, diseases and symptoms from clinician notes and demographic information within electronic health-care records (Optum Humedica repository [2007-2019]). We used two patient cohorts aged ≥11 years to develop the model: a positive pertussis cohort (4,515 episodes in 4,316 patients) and a negative pertussis (ARD) cohort (4,573,445 episodes and patients), defined using ICD 9/10 codes. To improve contrast between positive pertussis and negative pertussis (ARD) episodes, only episodes with ≥7 symptoms were selected. LightGBM was used as the machine learning model for pertussis episode identification. Model validity was determined using laboratory-confirmed pertussis positive and negative cohorts. Model explainability was obtained using the Shapley additive explanations method. The predictive performance was as follows: area under the precision-recall curve, 0.24 (SD, 7 × 10-3); recall, 0.72 (SD, 4 × 10-3); precision, 0.012 (SD, 1 × 10-3); and specificity, 0.94 (SD, 7 × 10-3). The model applied to laboratory-confirmed positive and negative pertussis episodes had a specificity of 0.846. Predictive probability for pertussis increased with presence of whooping cough, whoop, and post-tussive vomiting in clinician notes, but decreased with gastrointestinal bleeding, sepsis, pulmonary symptoms, and fever. In conclusion, machine learning can help identify pertussis episodes among those diagnosed with ARD.

Association of COVID-19 'circuit breaker' with higher rates of elderly trauma admissions.

Introduction: In December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) virus emerged and caused a worldwide pandemic, leading to measures being imposed by many countries to reduce its transmission. Singapore implemented the 'circuit breaker', which restricted all movements except for access to necessities and healthcare services. We aimed to investigate the impact of lockdown measures on the pattern of trauma and its effects. Methods: An observational, retrospective, single-centre descriptive study was conducted using the trauma registry in Singapore General Hospital. It included patients above 18 years old who presented to the emergency department with trauma and were subsequently admitted. Patients admitted from 1 February 2020 to 31 July 2020 and those admitted during the same timeframe in 2019 were studied. Subgroup analyses were performed for patients aged ≥65 years and those <65 years. Results: A total of 1,037 patients were included for analysis. A 17.6% increase in trauma presentations was seen from 2019 to 2020. Patients aged ≥65 years accounted for the rise in admissions. The predominant mechanism of injury was falls at home for older patients and vehicular accidents in patients <65 years. There were no significant differences in injury severity score, intensive care/high-dependency unit admission rates, length of stay, mortality rate, and subsequent need for inpatient rehabilitation. Conclusion: Our study provided information on differences in trauma presentations before and during the COVID-19 pandemic. Further studies are required to better inform on additional precautionary measures needed to reduce trauma and improve safety during future lockdowns and pandemics.

Finding disease similarity based on implicit semantic similarity.

Genomics has contributed to a growing collection of gene-function and gene-disease annotations that can be exploited by informatics to study similarity between diseases. This can yield insight into disease etiology, reveal common pathophysiology and/or suggest treatment that can be appropriated from one disease to another. Estimating disease similarity solely on the basis of shared genes can be misleading as variable combinations of genes may be associated with similar diseases, especially for complex diseases. This deficiency can be potentially overcome by looking for common biological processes rather than only explicit gene matches between diseases. The use of semantic similarity between biological processes to estimate disease similarity could enhance the identification and characterization of disease similarity. We present functions to measure similarity between terms in an ontology, and between entities annotated with terms drawn from the ontology, based on both co-occurrence and information content. The similarity measure is shown to outperform other measures used to detect similarity. A manually curated dataset with known disease similarities was used as a benchmark to compare the estimation of disease similarity based on gene-based and Gene Ontology (GO) process-based comparisons. The detection of disease similarity based on semantic similarity between GO Processes (Recall=55%, Precision=60%) performed better than using exact matches between GO Processes (Recall=29%, Precision=58%) or gene overlap (Recall=88% and Precision=16%). The GO-Process based disease similarity scores on an external test set show statistically significant Pearson correlation (0.73) with numeric scores provided by medical residents. GO-Processes associated with similar diseases were found to be significantly regulated in gene expression microarray datasets of related diseases.

Systematic review of the efficacy of a hybrid operating theatre in the management of severe trauma.

BACKGROUND: Hybrid operating theatres (OT) allow for simultaneous interventional radiology and operative procedures, serving as a one-stop facility for the treatment of severely injured patients. Several countries have adopted the use of the hybrid OT however their clinical impact in improving efficiency and quality of care remains unclear. This study systematically reviews the clinical impact of the hybrid OT for treatment of the severely injured. METHODS: A literature review of the PubMed, Embase and Cochrane databases was performed to identify all published articles in English, from 1st January 2000 to 31st December 2020, reporting on the impact of a hybrid OT for severe trauma. Articles were also reviewed for references of interest. RESULTS: Five studies reporting the clinical impact of the hybrid OT, in a total of 951 patients, were shortlisted. All were cohort studies that compared patient outcomes in the hybrid OT versus a conventional group. Out of 3 studies that assessed timeliness to intervention, one reported shorter time associated with the hybrid OT, while the other two reported no difference. Mortality outcomes were reported in 4 studies and showed no significant difference associated with treatment in the hybrid OT. Two studies revealed shorter total procedure times associated with the hybrid OT. Two out of 3 studies that evaluated blood transfusion requirements reported decreased transfusion rates in the hybrid OT group. Only 1 study examined complication rates and demonstrated morbidity benefits associated with the hybrid OT. CONCLUSION: Establishment of a hybrid OT requires a significant capital investment as well as a highly functioning multi-disciplinary team. The cost-benefit ratio remains unclear. Future studies, preferably in the form of clinical trials, are required to evaluate its usefulness in improving timeliness to definitive haemorrhage control and outcomes in severe trauma.

A clinical predictive model for risk stratification of patients with severe acute lower gastrointestinal bleeding.

BACKGROUND: Lower gastrointestinal bleeding (LGIB) is a common presentation of surgical admissions, imposing a significant burden on healthcare costs and resources. There is a paucity of standardised clinical predictive tools available for the initial assessment and risk stratification of patients with LGIB. We propose a simple clinical scoring model to prognosticate patients at risk of severe LGIB and an algorithm to guide management of such patients. METHODS: A retrospective cohort study was conducted, identifying consecutive patients admitted to our institution for LGIB over a 1-year period. Baseline demographics, clinical parameters at initial presentation and treatment interventions were recorded. Multivariate logistic regression was performed to identify factors predictive of severe LGIB. A clinical management algorithm was developed to discriminate between patients requiring admission, and to guide endoscopic, angiographic and/or surgical intervention. RESULTS: 226/649 (34.8%) patients had severe LGIB. Six variables were entered into a clinical predictive model for risk stratification of LGIB: Tachycardia (HR ≥ 100), hypotension (SBP < 90 mmHg), anaemia (Hb < 9 g/dL), metabolic acidosis, use of antiplatelet/anticoagulants, and active per-rectal bleeding. The optimum cut-off score of ≥ 1 had a sensitivity of 91.9%, specificity of 39.8%, and positive and negative predictive Values of 45% and 90.2%, respectively, for predicting severe LGIB. The area under curve (AUC) was 0.77. CONCLUSION: Early diagnosis and management of severe LGIB remains a challenge for the acute care surgeon. The predictive model described comprises objective clinical parameters routinely obtained at initial triage to guide risk stratification, disposition and inpatient management of patients.

Sex-dimorphic gene expression and ineffective dosage compensation of Z-linked genes in gastrulating chicken embryos.

BACKGROUND: Considerable progress has been made in our understanding of sex determination and dosage compensation mechanisms in model organisms such as C. elegans, Drosophila and M. musculus. Strikingly, the mechanism involved in sex determination and dosage compensation are very different among these three model organisms. Birds present yet another situation where the heterogametic sex is the female. Sex determination is still poorly understood in birds and few key determinants have so far been identified. In contrast to most other species, dosage compensation of bird sex chromosomal genes appears rather ineffective. RESULTS: By comparing microarrays from microdissected primitive streak from single chicken embryos, we identified a large number of genes differentially expressed between male and female embryos at a very early stage (Hamburger and Hamilton stage 4), long before any sexual differentiation occurs. Most of these genes are located on the Z chromosome, which indicates that dosage compensation is ineffective in early chicken embryos. Gene ontology analyses, using an enhanced annotation tool for Affymetrix probesets of the chicken genome developed in our laboratory (called Manteia), show that among these male-biased genes found on the Z chromosome, more than 20 genes play a role in sex differentiation. CONCLUSIONS: These results corroborate previous studies demonstrating the rather inefficient dosage compensation for Z chromosome in birds and show that this sexual dimorphism in gene regulation is observed long before the onset of sexual differentiation. These data also suggest a potential role of non-compensated Z-linked genes in somatic sex differentiation in birds.

Linguistic markers predict onset of Alzheimer's disease.

BACKGROUND: The aim of this study is to use classification methods to predict future onset of Alzheimer's disease in cognitively normal subjects through automated linguistic analysis. METHODS: To study linguistic performance as an early biomarker of AD, we performed predictive modeling of future diagnosis of AD from a cognitively normal baseline of Framingham Heart Study participants. The linguistic variables were derived from written responses to the cookie-theft picture-description task. We compared the predictive performance of linguistic variables with clinical and neuropsychological variables. The study included 703 samples from 270 participants out of which a dataset consisting of a single sample from 80 participants was held out for testing. Half of the participants in the test set developed AD symptoms before 85 years old, while the other half did not. All samples in the test set were collected during the cognitively normal period (before MCI). The mean time to diagnosis of mild AD was 7.59 years. FINDINGS: Significant predictive power was obtained, with AUC of 0.74 and accuracy of 0.70 when using linguistic variables. The linguistic variables most relevant for predicting onset of AD have been identified in the literature as associated with cognitive decline in dementia. INTERPRETATION: The results suggest that language performance in naturalistic probes expose subtle early signs of progression to AD in advance of clinical diagnosis of impairment. FUNDING: Pfizer, Inc. provided funding to obtain data from the Framingham Heart Study Consortium, and to support the involvement of IBM Research in the initial phase of the study. The data used in this study was supported by Framingham Heart Study's National Heart, Lung, and Blood Institute contract (N01-HC-25195), and by grants from the National Institute on Aging grants (R01-AG016495, R01-AG008122) and the National Institute of Neurological Disorders and Stroke (R01-NS017950).

Evolution of a Dedicated Emergency Surgery and Trauma (ESAT) unit over 3 years: sustained improved outcomes.

INTRODUCTION: The traditional 24-h call model faces pressure from competing needs between emergency and elective services. Recognizing this, a dedicated ESAT service was developed in Khoo Teck Puat Hospital in Singapore, with improved clinical outcomes. It was initially led by a single consultant (SC) in 2014, and subsequently evolved to a weekly consultant rotation (WC) roster in 2017 to achieve sustainability. METHODS: Each consultant led the ESAT WC service for a week and maintained ownership of their patients thereafter. All emergency surgical admissions between two distinct 6-month periods were reviewed, from May to October 2014 (pre-ESAT) and January to June 2017 (ESAT WC). Patient demographics, diagnoses, and operations were compared. Efficiency and clinical outcomes were evaluated. RESULTS: There were 1248 and 1284 patients in the pre-ESAT and ESAT WC group, respectively. Majority were males and in their 50s. Acute appendicitis, gallstone conditions, and soft-tissue infections made up half of the admissions. Trauma workload was comparable (7.8% pre-ESAT vs 9.5% ESAT WC). Cholecystectomies doubled during the ESAT period, 14.2% vs 7.2%, (p = 0.01). More consultants were involved in major cases (95.9% vs 86%), (p = 0.01) and more operations were performed during the day (52.1% vs 47.9%), (p = 0.01). Average time to OT was shorter and there were less major surgical complications (p = 0.02). Mortality (p = 0.08) and length of stay were reduced (4 vs 4.5 days), (p = 0.01). CONCLUSION: The ESAT WC service has sustained improved outcomes in our institution.