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Se determinó los niveles de hormona tiroidea en niños normales con marasmo y con Kwashiorkor. La tiroxina sérica (T4 ) es más alta por debajo del año de edad que al nacimiento o después del año. La tiroxina libre (T4 L) es más alta a los 2-3 meses que posteriormente. La globulina de enlace (TBG) disminuye ligera pero no significativamente con la edad. La hormona tirotropa (TSH), elevada en el suero del cordón umbilical, disminuye a valores normales del adulto, a los 2-3 meses de edad. A pesar de tener globulina de enlace de tiroxina (TBG) normal, la tiroxina sérica (T4 ) puede estar disminuida en el marasmo y durante su recuperación; la tiroxina libre (T4 -L) puede estar alta o baja inicialmente, normal o baja durante la recuperación; la hormona tirotropa (TSH) en el suero estuvo baja o normal en ambas oportunidades. En el Kwashiorkor la globulina de enlace de tiroxina (TBG) inicialmente baja, explicó los niveles bajos de tiroxina (T4 ) pero la tiroxina libre {T4 -L) fue normal o elevada; la hormona tirotropa (TSH) fue normal. Durante la recuperación, la globulina de enlace de tiroxina (TBG) retornó a lo normal, pero la tiroxina (T4 ) sólo lo hizo parcialmente y la tiroxina libre (T4 -L) disminuyó lo mismo que la hormona tirotropa (TSH). La pre-albúmina de enlace de tiroxina (TBPA) no varió significativamente con la edad ni el estado nutricional.

The integration of Quality Management System (QMS) principles into the life cycle of development, deployment, and utilization of machine learning (ML) and artificial intelligence (AI) technologies within healthcare settings holds the potential to close the AI translation gap by establishing a robust framework that accelerates the safe, ethical, and effective delivery of AI/ML in day-to-day patient care. Healthcare organizations (HCOs) can implement these principles effectively by embracing an enterprise QMS analogous to those in regulated industries. By establishing a QMS explicitly tailored to health AI technologies, HCOs can comply with evolving regulations and minimize redundancy and rework while aligning their internal governance practices with their steadfast commitment to scientific rigor and medical excellence.

In magnetic fusion devices, error field (EF) sources, spurious magnetic field perturbations, need to be identified and corrected for safe and stable (disruption-free) tokamak operation. Within Work Package Tokamak Exploitation RT04, a series of studies have been carried out to test the portability of the novel non-disruptive method, designed and tested in DIII-D (Paz-Soldan et al 2022 Nucl. Fusion 62 126007), and to perform an assessment of model-based EF control strategies towards their applicability in ITER. In this paper, the lessons learned, the physical mechanism behind the magnetic island healing, which relies on enhanced viscous torque that acts against the static electro-magnetic torque, and the main control achievements are reported, together with the first design of the asynchronous EF correction current/density controller for ITER.

JET, the world’s largest operating tokamak with unique Be/W wall and tritium handling capability, completed a Deuterium-Tritium (D-T) campaign in 2021 (Maggi et al 29th Fusion Energy Conf. ) following a decade of preparatory experiments, dedicated enhancements, technical rehearsals and training (Horton et al 2016 Fusion Eng. Des. 109–111 925). Operation with tritium raises significant technical, safety and scientific challenges not encountered in standard protium or deuterium operation. This contribution describes the tritium operational requirements, pulses and technical preparations, new operating procedures, lessons learned and details on the achieved operational availability and performance. The preparation and execution of the recent JET tritium experiments benefitted from the previous experience in 1991 (Preliminary Tritium Experiment), 1997 (DTE1 campaign) and 2003 (Trace Tritium Campaigns) and consisted of the following five phases: technical rehearsals and scenario preparation, tritium commissioning, 100% tritium campaign, D-T campaign (DTE2), tritium clean-up. Following the clean-up JET resumed normal operation and is currently undertaking a further D-T campaign (DTE3).

Endoscopy is the gold standard for the diagnosis of cancers and cancer precursors in the oesophagus and stomach. Early detection of upper GI cancers requires high-quality endoscopy and awareness of the subtle features these lesions carry. Endoscopists performing surveillance of high-risk patients including those with Barrett’s oesophagus, previous squamous neoplasia or chronic atrophic gastritis should be familiar with endoscopic features, classification systems and sampling techniques to maximise the detection of early cancer. In this article, we review the current approach to diagnosis of these conditions and the latest advanced imaging and diagnostic techniques.

BackgroundThe Surviving Sepsis Campaign suggested preferential resuscitation with balanced crystalloids, such as Lactated Ringer’s (LR), although the level of recommendation was weak, and the quality of evidence was low. Past studies reported an association of unbalanced solutions, such as normal saline (NS), with increased AKI risks, metabolic acidosis, and prolonged ICU stay, although some of the findings are conflicting. We have compared the outcomes with the preferential use of normal saline vs. ringer’s lactate in a cohort of sepsis patients.MethodWe performed a retrospective cohort analysis of patients visiting the ED of 19 different Mayo Clinic sites between August 2018 to November 2020 with sepsis and receiving at least 30 mL/kg fluid in the first 6 h. Patients were divided into two cohorts based on the type of resuscitation fluid (LR vs. NS) and propensity-matching was done based on clinical characteristics as well as fluid amount (with 5 ml/kg). Single variable logistic regression (categorical outcomes) and Cox proportional hazards regression models were used to compare the primary and secondary outcomes between the 2 groups.ResultsOut of 2022 patients meeting our inclusion criteria; 1,428 (70.6%) received NS, and 594 (29.4%) received LR as the predominant fluid (>30 mL/kg). Patients receiving predominantly NS were more likely to be male and older in age. The LR cohort had a higher BMI, lactate level and incidence of septic shock. Propensity-matched analysis did not show a difference in 30-day and in-hospital mortality rate, mechanical ventilation, oxygen therapy, or CRRT requirement. We did observe longer hospital LOS in the LR group (median 5 vs. 4 days, p = 0.047 and higher requirement for ICU post-admission (OR: 0.70; 95% CI: 0.51–0.96; p = 0.026) in the NS group. However, these did not remain statistically significant after adjustment for multiple testing.ConclusionIn our matched cohort, we did not show any statistically significant difference in mortality rates, hospital LOS, ICU admission after diagnosis, mechanical ventilation, oxygen therapy and RRT between sepsis patients receiving lactated ringers and normal saline as predominant resuscitation fluid. Further large-scale prospective studies are needed to solidify the current guidelines on the use of balanced crystalloids.

Plankton form the base of the marine food web and are sensitive indicators of environmental change. Plankton time series are therefore an essential part of monitoring progress towards global biodiversity goals, such as the Convention on Biological Diversity Aichi Targets, and for informing ecosystem-based policy, such as the EU Marine Strategy Framework Directive. Multiple plankton monitoring programmes exist in Europe, but differences in sampling and analysis methods prevent the integration of their data, constraining their utility over large spatio-temporal scales. The Plankton Lifeform Extraction Tool brings together disparate European plankton datasets into a central database from which it extracts abundance time series of plankton functional groups, called “lifeforms”, according to shared biological traits. This tool has been designed to make complex plankton datasets accessible and meaningful for policy, public interest, and scientific discovery. It allows examination of large-scale shifts in lifeform abundance or distribution (for example, holoplankton being partially replaced by meroplankton), providing clues to how the marine environment is changing. The lifeform method enables datasets with different plankton sampling and taxonomic analysis methodologies to be used together to provide insights into the response to multiple stressors and robust policy evidence for decision making. Lifeform time series generated with the Plankton Lifeform Extraction Tool currently inform plankton and food web indicators for the UK's Marine Strategy, the EU's Marine Strategy Framework Directive, and for the Convention for the Protection of the Marine Environment of the North-East Atlantic (OSPAR) biodiversity assessments. The Plankton Lifeform Extraction Tool currently integrates 155 000 samples, containing over 44 million plankton records, from nine different plankton datasets within UK and European seas, collected between 1924 and 2017. Additional datasets can be added, and time series can be updated. The Plankton Lifeform Extraction Tool is hosted by The Archive for Marine Species and Habitats Data (DASSH) at https://www.dassh.ac.uk/lifeforms/ (last access: 22 November 2021, Ostle et al., 2021). The lifeform outputs are linked to specific, DOI-ed, versions of the Plankton Lifeform Traits Master List and each underlying dataset.

The presence of antibiotic residues in water is linked to the emergence of antibiotic resistance globally and necessitates novel decontamination strategies to minimize antibiotic residue exposure in both the environment and food. A holistic assessment of cold atmospheric pressure plasma technology (CAPP) for β-lactam antibiotic residue removal is described in this study. CAPP operating parameters including plasma jet voltage, gas composition and treatment time were optimized, with highest β-lactam degradation efficiencies obtained for a helium jet operated at 6 kV. Main by-products detected indicate pH-driven peroxidation as a main mechanism of CAPP-induced decomposition of β-lactams. No in vitro hepatocytotoxicity was observed in HepG2 cells following exposure to treated samples, and E. coli exposed to CAPP-degraded β-lactams did not exhibit resistance development. In surface water, over 50% decrease in antibiotic levels was achieved after only 5 min of treatment. However, high dependence of treatment efficiency on residue concentration, pH and presence of polar macromolecules was observed.

Due to its remote location and extreme weather conditions, atmospheric in situ measurements are rare in the Southern Ocean. As a result, aerosol–cloud interactions in this region are poorly understood and remain a major source of uncertainty in climate models. This, in turn, contributes substantially to persistent biases in climate model simulations such as the well-known positive shortwave radiation bias at the surface, as well as biases in numerical weather prediction models and reanalyses. It has been shown in previous studies that in situ and ground-based remote sensing measurements across the Southern Ocean are critical for complementing satellite data sets due to the importance of boundary layer and low-level cloud processes. These processes are poorly sampled by satellite-based measurements and are often obscured by multiple overlying cloud layers. Satellite measurements also do not constrain the aerosol–cloud processes very well with imprecise estimation of cloud condensation nuclei. In this work, we present a comprehensive set of ship-based aerosol and meteorological observations collected on the 6-week Southern Ocean Ross Sea Marine Ecosystem and Environment voyage (TAN1802) voyage of RV Tangaroa across the Southern Ocean, from Wellington, New Zealand, to the Ross Sea, Antarctica. The voyage was carried out from 8 February to 21 March 2018. Many distinct, but contemporaneous, data sets were collected throughout the voyage. The compiled data sets include measurements from a range of instruments, such as (i) meteorological conditions at the sea surface and profile measurements; (ii) the size and concentration of particles; (iii) trace gases dissolved in the ocean surface such as dimethyl sulfide and carbonyl sulfide; (iv) and remotely sensed observations of low clouds. Here, we describe the voyage, the instruments, and data processing, and provide a brief overview of some of the data products available. We encourage the scientific community to use these measurements for further analysis and model evaluation studies, in particular, for studies of Southern Ocean clouds, aerosol, and their interaction. The data sets presented in this study are publicly available at https://doi.org/10.5281/zenodo.4060237 (Kremser et al., 2020).

Many proteins display conformational changes resulting from allosteric regulation. Often only a few residues are crucial in conveying these structural and functional allosteric changes. These regions that undergo a significant change in structure upon receiving an input signal, such as molecular recognition, are defined as switch-like regions. Identifying these key residues within switch-like regions can help elucidate the mechanism of allosteric regulation and provide guidance for synthetic regulation. In this study, we combine a novel computational workflow with biochemical methods to identify a switch-like region in the N-terminal domain of human SIRT1 (hSIRT1), a lysine deacetylase that plays important roles in regulating cellular pathways. Based on primary sequence, computational methods predicted a region between residues 186–193 in hSIRT1 to exhibit switch-like behavior. Mutations were then introduced in this region and the resulting mutants were tested for allosteric reactions to resveratrol, a known hSIRT1 allosteric regulator. After fine-tuning the mutations based on comparison of known secondary structures, we were able to pinpoint M193 as the residue essential for allosteric regulation, likely by communicating the allosteric signal. Mutation of this residue maintained enzyme activity but abolished allosteric regulation by resveratrol. Our findings suggest a method to predict switch-like regions in allosterically regulated enzymes based on the primary sequence. If further validated, this could be an efficient way to identify key residues in enzymes for therapeutic drug targeting and other applications.

Contemporary bioinformatic and chemoinformatic capabilities hold promise to reshape knowledge management, analysis and interpretation of data in natural products research. Currently, reliance on a disparate set of non-standardized, insular, and specialized databases presents a series of challenges for data access, both within the discipline and for integration and interoperability between related fields. The fundamental elements of exchange are referenced structure-organism pairs that establish relationships between distinct molecular structures and the living organisms from which they were identified. Consolidating and sharing such information via an open platform has strong transformative potential for natural products research and beyond. This is the ultimate goal of the newly established LOTUS initiative, which has now completed the first steps toward the harmonization, curation, validation and open dissemination of 750,000+ referenced structure-organism pairs. LOTUS data is hosted on Wikidata and regularly mirrored on https://lotus.naturalproducts.net. Data sharing within the Wikidata framework broadens data access and interoperability, opening new possibilities for community curation and evolving publication models. Furthermore, embedding LOTUS data into the vast Wikidata knowledge graph will facilitate new biological and chemical insights. The LOTUS initiative represents an important advancement in the design and deployment of a comprehensive and collaborative natural products knowledge base.

Abstract A high CO2 carbonate gas field offshore Sarawak, Malaysia, is scheduled for development. Fines migration has been identified as a potential risk for a sustained and stable production for this field, triggering this investigation. The reservoir investigated (subdivided in S3, S2, S1 formation) has an average 8% clays, of which over 50% are migratory illites and 15% migratory kaolinite. This paper discusses the laboratory findings and factors contributing to fines migration for this reservoir. We conducted core flood tests to determine critical flow rates for the onset of fines migration of high CO2 hydrocarbon gas and CO2-saturated brine within the production gas zone. In addition, we measured total suspended solids during each incremental rate stage and performed scanning electron microscopy–energy-dispersive X-ray (SEM–EDX) analysis on the effluents collected. We also performed mineralogical analysis of formation rocks to determine clay types, amount, and morphology. Core floods performed with CO2-saturated brine on S3 and S2 cores showed damage at a critical flow rate of 10 ml/min with permeability recovery of 65–75%. This shows that CO2-saturated brine tends to mobilize the fines such as illite and kaolinite. Core floods performed with high CO2 hydrocarbon gas showed permeability recovery of 93–96% at rates up to 10 ml/min. SEM analysis on effluents collected showed presence of silicate and carbonate particles with size of 5–50 μm. A combined salt dropout and fines mobilization core flood showed a higher degree of formation damage due to fines mobilization with 74% permeability recovery compared to baseline permeability compared to core floods with high CO2 hydrocarbon gas. However, the formation damage due to fines mobilization for this experiment was reversible. Overall, the results indicate that a high potential for fines migration in this type of carbonate system exists for CO2-saturated brine flow with significant less potential for dry CO2 flow.

Purpose: Thumb basal joint arthritis is a common degenerative condition of the hand that is often managed with thumb basal joint arthroplasty (BJA). This procedure generally results in a high level of patient satisfaction; however, the rate and cause of early unplanned reoperation after thumb BJA are not well-understood. Therefore, we performed a review to better understand the rate and cause of early reoperation. Methods: A retrospective review of all thumb BJA cases performed at a single private academic center between 2014 and 2016 yielded 637 patients and 686 primary thumb BJAs with a minimum 1-year follow-up (mean, 2.4 years). Data collection included patient demographics, surgical technique and type of thumb BJA performed, time to reoperation, reason for early reoperation (within 2 years), and type of reoperation. Results: Of 686 patients undergoing thumb BJAs, 10 had unplanned early reoperation (1.5%). Mean duration between the index procedure and reoperation was 5.2 months (range, 0.5–14.3 months). Of the 10 unplanned early reoperations, 4 thumbs in 4 patients required revision arthroplasties owing to persistent pain. Time to reoperation for revision arthroplasty was 9.6 months (range, 3.9–14.3 months). Three of 10 reoperations resulted from early infection, 2 from unplanned early removal of symptomatic K-wires, and one from radial sensory neuritis. Conclusions: In this series of nearly 700 consecutive cases, we identified an unexpected early reoperation rate of 1.5%, with only a 0.6% reoperation rate specifically for painful subsidence requiring a revision arthroplasty. Mean time to revision was 9.6 months. These rates are lower than those published previously and should be considered by patients and surgeons when planning thumb BJA. Type of study/level of evidence: Prognostic IV. Key words: Basal joint arthroplasty, Reoperation, Revision, Thumb, Trapeziometacarpal arthritis

Flavonoids are a vast group of metabolites that are essential for vascular plant physiology and, thus, occur ubiquitously in plant-based/-derived foods. The solitary designation of thousands of known flavonoids hides the fact that their metabolomes are structurally highly diverse, consist of disparate subgroups, yet undergo a certain degree of metabolic interconversion. Unsurprisingly, flavonoids have been an important theme in nutrition research. Already in the 1930s, it was discovered that the ability of synthetic Vitamin C to treat scurvy was inferior to that of plant extracts containing Vitamin C. Subsequent experimental evidence led to the proposal of Vitamin P (permeability) as an essential phytochemical nutrient. However, attempts to isolate and characterize Vitamin P gave confusing and sometimes irreproducible results, which today can be interpreted as rooted in the unrecognized (residual) complexity of the intervention materials. Over the years, primarily flavonoids (and some coumarins) were known as having Vitamin P-like activity. More recently, in a NAPRALERT meta-analysis, essentially all of these Vitamin P candidates were identified as IMPs (Invalid/Improbable/Interfering Metabolic Panaceas). While the historic inability to define a single compound and specific mode of action led to general skepticism about the Vitamin P proposition for “bioflavonoids,” the more logical conclusion is that several abundant and metabolically labile plant constituents fill this essential role in human nutrition at the interface of vitamins, cofactors, and micronutrients. Reviewing 100+ years of the multilingual Vitamin P and C literature provides the rationales for this conclusion and new perspectives for future research.

Saliva represents an ideal matrix for diagnostic biomarker development as it is readily available and requires no invasive collection procedures. However, salivary RNA is labile and rapidly degrades. Previous attempts to isolate RNA from saliva have yielded poor quality and low concentrations. Here we compare collection and processing methods and propose an approach for future studies. The effects of RNA stabilisers, storage temperatures, length of storage and fasting windows were investigated on pooled saliva samples from healthy volunteers. Isolated RNA was assessed for concentration and quality. Bacterial growth was investigated through RT-PCR using bacterial and human primers. Optimal conditions were implemented and quality controlled in a clinical setting. The addition of RNAlater increased mean RNA yield from 4912 ng/μl to 15,473 ng and RNA Integrity Number (RIN) from 4.5 to 7.0. No significant changes to RNA yield were observed for storage at room temperature beyond 1 day or at -80 °C. Bacterial growth did not occur in samples stored at ambient temperature for up to a week. There was a trend towards higher RNA concentration when saliva was collected after overnight fasting but no effect on RIN. In the clinic, RNA yields of 6307 ng and RINs of 3.9 were achieved, improving on previous reports. The method we describe here is a robust, clinically feasible saliva collection method using preservative that gives high concentrations and improved RINs compared to saliva collected without preservative.

Summary: Background: Screening for Barrett's oesophagus relies on endoscopy, which is invasive and few who undergo the procedure are found to have the condition. We aimed to use machine learning techniques to develop and externally validate a simple risk prediction panel to screen individuals for Barrett's oesophagus. Methods: In this prospective study, machine learning risk prediction in Barrett's oesophagus (MARK-BE), we used data from two case-control studies, BEST2 and BOOST, to compile training and validation datasets. From the BEST2 study, we analysed questionnaires from 1299 patients, of whom 880 (67·7%) had Barrett's oesophagus, including 40 with invasive oesophageal adenocarcinoma, and 419 (32·3%) were controls. We randomly split (6:4) the cohort using a computer algorithm into a training dataset of 776 patients and a testing dataset of 523 patients. We compiled an external validation cohort from the BOOST study, which included 398 patients, comprising 198 patients with Barrett's oesophagus (23 with oesophageal adenocarcinoma) and 200 controls. We identified independently important diagnostic features of Barrett's oesophagus using the machine learning techniques information gain and correlation-based feature selection. We assessed multiple classification tools to create a multivariable risk prediction model. Internal validation of the model using the BEST2 testing dataset was followed by external validation using the BOOST external validation dataset. From these data we created a prediction panel to identify at-risk individuals. Findings: The BEST2 study included 40 diagnostic features. Of these, 19 added information gain but after correlation-based feature selection only eight showed independent diagnostic value including age, sex, cigarette smoking, waist circumference, frequency of stomach pain, duration of heartburn and acidic taste, and taking antireflux medication, of which all were associated with increased risk of Barrett's oesophagus, except frequency of stomach pain, with was inversely associated in a case-control population. Logistic regression offered the highest prediction quality with an area under the receiver-operator curve (AUC) of 0·87 (95% CI 0·84–0·90; sensitivity set at 90%; specificity of 68%). In the testing dataset, AUC was 0·86 (0·83–0·89; sensitivity set at 90%; specificity of 65%). In the external validation dataset, the AUC was 0·81 (0·74–0·84; sensitivity set at 90%; specificity of 58%). Interpretation: Our diagnostic model offers valid predictions of diagnosis of Barrett's oesophagus in patients with symptomatic gastro-oesophageal reflux disease, assisting in identifying who should go forward to invasive confirmatory testing. Our predictive panel suggests that overweight men who have been taking antireflux medication for a long time might merit particular consideration for further testing. Our risk prediction panel is quick and simple to administer but will need further calibration and validation in a prospective study in primary care. Funding: Charles Wolfson Charitable Trust and Guts UK.

Poultry manure is the primary cause of nitrate (NO3−) exceedances in the transboundary Abbotsford–Sumas aquifer (ASA; Canada–USA) based on synoptic surveys two decades apart, but questions remained about seasonal and spatial aspects of agricultural nitrate fluxes to the aquifer to help better focus remediation efforts. We conducted over 700 monthly δ15N and δ18O of nitrate assays, focusing on shallow groundwater (3− concentrations in these wells ranged from 1.3 to 99 mg N L−1 (n = 1041) with a mean of 16.2±0.4 mg N L−1. The high-frequency 15N and 18O isotope data allowed us to identify three distinctive NO3− source patterns: (i) primarily from synthetic fertilizer, (ii) dynamic changes in nitrate due to changes in land use, and (iii) from a mix of poultry manure and fertilizer. A key finding was that the source(s) of nitrate in recharge could be quickly influenced by short-term near-field management practices and stochastic precipitation events, which ultimately impact long-term nitrate contamination trends. Overall, the isotope data affirmed a subtle decadal-scale shift in agricultural practices from manure increasingly towards fertilizer nitrate sources; nevertheless, poultry-derived N remains a predominant source of nitrate contamination. Because the aquifer does not generally support denitrification, remediation of the Abbotsford–Sumas aquifer is possible only if agricultural N sources are seriously curtailed, a difficult proposition due to longstanding high-value intensive poultry and raspberry and blueberry operations over the aquifer.

Phospholipase A2 (PLA2) enzymes were first recognized as an enzyme activity class in 1961. The secreted (sPLA2) enzymes were the first of the five major classes of human PLA2s to be identified and now number nine catalytically-active structurally homologous proteins. The best-studied of these, group IIA sPLA2, has a clear role in the physiological response to infection and minor injury and acts as an amplifier of pathological inflammation. The enzyme has been a target for anti-inflammatory drug development in multiple disorders where chronic inflammation is a driver of pathology since its cloning in 1989. Despite intensive effort, no clinically approved medicines targeting the enzyme activity have yet been developed. This review catalogues the major discoveries in the human group IIA sPLA2 field, focusing on features of enzyme function that may explain this lack of success and discusses future research that may assist in realizing the potential benefit of targeting this enzyme. Functionally-selective inhibitors together with isoform-selective inhibitors are necessary to limit the apparent toxicity of previous drugs. There is also a need to define the relevance of the catalytic function of hGIIA to human inflammatory pathology relative to its recently-discovered catalysis-independent function.

Brunfelsia cabiesesiana J. G. Graham, sp. nov. (Solanaceae), a new species from montane cloud forests of Ucayali and Pasco Departments, Peru, is described and illustrated. The new species differs from all other members of the genus Brunfelsia by its cauline inflorescences. A key to the Peruvian species of Brunfelsia is presented.

Intentional drug overdoses with antidepressant and antipsychotic medications are an increasingly common problem. Currently, there is little guidance with regard to reintroduction of these medications after intentional overdoses. We have used published toxicological and pharmacokinetic data to obtain factors which control the recovery from overdoses. From such data, we have proposed guidance regarding their reintroduction, provided there are no adverse effects or contraindications. Tentatively, we suggest that when adverse effects from the overdose are lost, treatment could recommence after a further mean half-life of elimination. Most antidepressant and antipsychotic drugs are metabolized by cytochrome P450 enzymes and, where cytochrome P450 inhibitors are co-ingested, serial plasma concentrations should optimally be obtained in order to assess a suitable time for reintroduction of the psychoactive drugs. We hope the proposals presented will stimulate research and discussion that lead to better guidance for clinicians concerning reintroduction of psychoactive medication after intentional overdose.

Introduction. Barrett’s oesophagus (BE) is a precursor to oesophageal adenocarcinoma (OAC). Endoscopic surveillance is performed to detect dysplasia arising in BE as it is likely to be amenable to curative treatment. At present, there are no guidelines on who should perform surveillance endoscopy in BE. Machine learning (ML) is a branch of artificial intelligence (AI) that generates simple rules, known as decision trees (DTs). We hypothesised that a DT generated from recognised expert endoscopists could be used to improve dysplasia detection in non-expert endoscopists. To our knowledge, ML has never been applied in this manner. Methods. Video recordings were collected from patients with non-dysplastic (ND-BE) and dysplastic Barrett’s oesophagus (D-BE) undergoing high-definition endoscopy with i-Scan enhancement (PENTAX®). A strict protocol was used to record areas of interest after which a corresponding biopsy was taken to confirm the histological diagnosis. In a blinded manner, videos were shown to 3 experts who were asked to interpret them based on their mucosal and microvasculature patterns and presence of nodularity and ulceration as well as overall suspected diagnosis. Data generated were entered into the WEKA package to construct a DT for dysplasia prediction. Non-expert endoscopists (gastroenterology specialist registrars in training with variable experience and undergraduate medical students with no experience) were asked to score these same videos both before and after web-based training using the DT constructed from the expert opinion. Accuracy, sensitivity, and specificity values were calculated before and after training where p

Coxiella burnetii is the causative agent of Q fever and an obligate intracellular pathogen in nature that survives and grows in a parasitophorous vacuole (PV) within eukaryotic host cells. C. burnetii promotes intracellular survival by subverting apoptotic and pro-inflammatory signaling pathways that are typically regulated by nuclear transcription factor-B (NF-B). We and others have demonstrated that C. burnetii NMII proteins inhibit expression of pro-inflammatory cytokines and induce expression of anti-apoptotic genes during infection. Here, we demonstrate that C. burnetii promotes intracellular survival by modulating NF-B subunit p65 (RelA) phosphorylation, and thus activation, in a Type Four B Secretion System (T4BSS)-dependent manner. Immunoblot analysis of RelA phosphorylated at serine-536 demonstrated that C. burnetii increases NF-κB activation via the canonical pathway. However, RelA phosphorylation levels were even higher in infected cells where bacterial protein or mRNA synthesis was inhibited. Importantly, we demonstrate that inhibition of RelA phosphorylation impairs PV formation and C. burnetii growth. We found that a T4BSS-defective mutant (CbΔdotA) elicited phosphorylated RelA levels similar to those of wild type C. burnetii infection treated with Chloramphenicol. Moreover, cells infected with CbΔdotA or wild type C. burnetii treated with Chloramphenicol showed similar levels of GFP-RelA nuclear localization, and significantly increased localization compared to wild type C. burnetii infection. These data indicate that without de novo protein synthesis and a functional T4BSS, C. burnetii is unable to modulate NF-kB activation, which is crucial for optimal intracellular growth.