External validation of a convolutional neural network artificial intelligence tool to predict malignancy in pulmonary nodules.

BACKGROUND: Estimation of the risk of malignancy in pulmonary nodules detected by CT is central in clinical management. The use of artificial intelligence (AI) offers an opportunity to improve risk prediction. Here we compare the performance of an AI algorithm, the lung cancer prediction convolutional neural network (LCP-CNN), with that of the Brock University model, recommended in UK guidelines. METHODS: A dataset of incidentally detected pulmonary nodules measuring 5-15 mm was collected retrospectively from three UK hospitals for use in a validation study. Ground truth diagnosis for each nodule was based on histology (required for any cancer), resolution, stability or (for pulmonary lymph nodes only) expert opinion. There were 1397 nodules in 1187 patients, of which 234 nodules in 229 (19.3%) patients were cancer. Model discrimination and performance statistics at predefined score thresholds were compared between the Brock model and the LCP-CNN. RESULTS: The area under the curve for LCP-CNN was 89.6% (95% CI 87.6 to 91.5), compared with 86.8% (95% CI 84.3 to 89.1) for the Brock model (p≤0.005). Using the LCP-CNN, we found that 24.5% of nodules scored below the lowest cancer nodule score, compared with 10.9% using the Brock score. Using the predefined thresholds, we found that the LCP-CNN gave one false negative (0.4% of cancers), whereas the Brock model gave six (2.5%), while specificity statistics were similar between the two models. CONCLUSION: The LCP-CNN score has better discrimination and allows a larger proportion of benign nodules to be identified without missing cancers than the Brock model. This has the potential to substantially reduce the proportion of surveillance CT scans required and thus save significant resources.

Structural reorganization of the interleukin-7 signaling complex.

We report here an unliganded receptor structure in the common gamma-chain (γ(c)) family of receptors and cytokines. The crystal structure of the unliganded form of the interleukin-7 alpha receptor (IL-7Rα) extracellular domain (ECD) at 2.15 Å resolution reveals a homodimer forming an "X" geometry looking down onto the cell surface with the C termini of the two chains separated by 110 Å and the dimer interface comprising residues critical for IL-7 binding. Further biophysical studies indicate a weak association of the IL-7Rα ECDs but a stronger association between the γ(c)/IL-7Rα ECDs, similar to previous studies of the full-length receptors on CD4(+) T cells. Based on these and previous results, we propose a molecular mechanism detailing the progression from the inactive IL-7Rα homodimer and IL-7Rα-γ(c) heterodimer to the active IL-7-IL-7Rα-γ(c) ternary complex whereby the two receptors undergo at least a 90° rotation away from the cell surface, moving the C termini of IL-7Rα and γ(c) from a distance of 110 Å to less than 30 Å at the cell surface. This molecular mechanism can be used to explain recently discovered IL-7- and γ(c)-independent gain-of-function mutations in IL-7Rα from B- and T-cell acute lymphoblastic leukemia patients. The mechanism may also be applicable to other γ(c) receptors that form inactive homodimers and heterodimers independent of their cytokines.

Ice shelf basal channel shape determines channelized ice-ocean interactions.

Growing evidence has confirmed the critical role played by basal channels beneath Antarctic ice shelves in both ice shelf stability and freshwater input to the surrounding ocean. Here we show, using a 3D ice shelf-ocean boundary current model, that deeper basal channels can lead to a significant amplification in channelized basal melting, meltwater channeling, and warming and salinization of the channel flow. All of these channelized quantities are also modulated by channel width, with the level of modulation determined by channel height. The explicit quantification of channelized basal melting and the meltwater transport in terms of channel cross-sectional shape is potentially beneficial for the evaluation of ice shelf mass balance and meltwater contribution to the nearshore oceanography. Complicated topographically controlled circulations are revealed to be responsible for the unique thermohaline structure inside deep channels. Our study emphasizes the need for improvement in observations of evolving basal channels and the hydrography inside them, as well as adjacent to the ice front where channelized meltwater emerges.

Drivers of Antarctic sea ice advance.

Antarctic sea ice is mostly seasonal. While changes in sea ice seasonality have been observed in recent decades, the lack of process understanding remains a key challenge to interpret these changes. To address this knowledge gap, we investigate the processes driving the ice season onset, known as sea ice advance, using remote sensing and in situ observations. Here, we find that seawater freezing predominantly drives advance in the inner seasonal ice zone. By contrast, in an outer band a few degrees wide, advance is due to the import of drifting ice into warmer waters. We show that advance dates are strongly related to the heat stored in the summer ocean mixed layer. This heat is controlled by the timing of sea ice retreat, explaining the tight link between retreat and advance dates. Such a thermodynamic linkage strongly constrains the climatology and interannual variations, albeit with less influence on the latter.

Sea level rise from West Antarctic mass loss significantly modified by large snowfall anomalies.

Mass loss from the West Antarctic Ice Sheet is dominated by glaciers draining into the Amundsen Sea Embayment (ASE), yet the impact of anomalous precipitation on the mass balance of the ASE is poorly known. Here we present a 25-year (1996-2021) record of ASE input-output mass balance and evaluate how two periods of anomalous precipitation affected its sea level contribution. Since 1996, the ASE has lost 3331 ± 424 Gt ice, contributing 9.2 ± 1.2 mm to global sea level. Overall, surface mass balance anomalies contributed little (7.7%) to total mass loss; however, two anomalous precipitation events had larger, albeit short-lived, impacts on rates of mass change. During 2009-2013, persistently low snowfall led to an additional 51 ± 4 Gt yr-1 mass loss in those years (contributing positively to the total loss of 195 ± 4 Gt yr-1). Contrastingly, extreme precipitation in the winters of 2019 and 2020 decreased mass loss by 60 ± 16 Gt yr-1 during those years (contributing negatively to the total loss of 107 ± 15 Gt yr-1). These results emphasise the important impact of extreme snowfall variability on the short-term sea level contribution from West Antarctica.

Aicardi-Goutieres syndrome gene and HIV-1 restriction factor SAMHD1 is a dGTP-regulated deoxynucleotide triphosphohydrolase.

The SAMHD1 protein is an HIV-1 restriction factor that is targeted by the HIV-2 accessory protein Vpx in myeloid lineage cells. Mutations in the SAMHD1 gene cause Aicardi-Goutières syndrome, a genetic disease that mimics congenital viral infection. To determine the physiological function of the SAMHD1 protein, the SAMHD1 gene was cloned, recombinant protein was produced, and the catalytic activity of the purified enzyme was identified. We show that SAMHD1 contains a dGTP-regulated deoxynucleotide triphosphohydrolase. We propose that Vpx targets SAMHD1 for degradation in a viral strategy to control cellular deoxynucleotide levels for efficient replication.

Collaboration between an NHS University Teaching Hospital and independent hospital to maintain CT colonography service provision during the 2020 COVID-19 pandemic.

Our trust performed CTCs at 93% of the capacity of the previous year, scanning 1265 patients in 2020, compared with 1348 in 2019. We describe the changes made to our service to achieve this, which included collaboration with the colorectal surgical team to prioritise existing CTC patients according to faecal-immunochemical tests and full blood count results, and the associated challenges which included image transfer delays and patient attendance for scans. Furthermore, the endoscopy and radiology services used the opportunity created by co-location at the same hospital site to provide a same day incomplete colonoscopy and staging service for optically confirmed cancers. Collaboration between the NHS and independent sector allowed us to achieve continuity of service provision during the height of the COVID-19 pandemic without substituting unprepared CT abdomen and pelvis instead of the more sensitive CTC.

Two-timescale response of a large Antarctic ice shelf to climate change.

A potentially irreversible threshold in Antarctic ice shelf melting would be crossed if the ocean cavity beneath the large Filchner-Ronne Ice Shelf were to become flooded with warm water from the deep ocean. Previous studies have identified this possibility, but there is great uncertainty as to how easily it could occur. Here, we show, using a coupled ice sheet-ocean model forced by climate change scenarios, that any increase in ice shelf melting is likely to be preceded by an extended period of reduced melting. Climate change weakens the circulation beneath the ice shelf, leading to colder water and reduced melting. Warm water begins to intrude into the cavity when global mean surface temperatures rise by approximately 7 °C above pre-industrial, which is unlikely to occur this century. However, this result should not be considered evidence that the region is unconditionally stable. Unless global temperatures plateau, increased melting will eventually prevail.

Modulation of coxsackie and adenovirus receptor expression for gene transfer to normal and dystrophic skeletal muscle.

BACKGROUND: Efficient adenovirus (AdV)-mediated gene transfer is possible only in immature muscle or regenerating muscle, suggesting that a developmentally regulated event plays a major role in limiting AdV uptake in mature skeletal muscle. Previously, we showed that the expression of the primary coxsackie and adenovirus receptor (CAR) is severely down-regulated during muscle maturation and that, in muscle-specific CAR transgenic mice, there is significant enhancement of AdV-mediated gene transfer to mature skeletal muscle. METHODS: To evaluate whether increasing CAR expression can also augment gene transfer to dystrophic muscle that has many regenerating fibers, we crossed CAR transgenics with dystrophin-deficient mice (mdx/CAR). We also tested a two-step protocol in which CAR levels were increased in the target muscle, prior to administration of AdV, through the use of recombinant adeno-associated virus (AAV2) expressing CAR. Lastly, we assessed the effect of histone deacetylase inhibitors on CAR and AdV transduction efficiency in myoblasts and mdx muscle. RESULTS: Although somewhat higher rates of transduction can be achieved in adult mdx mice than in normal mice as a result of ongoing muscle regeneration in these animals, CAR expression in the mdx background (mdx/CAR transgenics) still markedly improved the susceptibility of mature muscle to AdV-mediated gene transfer of dystrophin. Prior administration of AAV2-CAR to normal muscle led to significantly increased transduction by subsequent injection of AdV. The histone deacetylase inhibitor valproate increased CAR transcript and protein levels in myoblasts and mdx muscle, and also increased AdV-mediated gene transfer. CONCLUSIONS: We have developed a method of increasing CAR levels in both normal and regenerating muscle.

A comparison of statistical selection strategies for univariate and bivariate log-linear models.

In this study, eight statistical selection strategies were evaluated for selecting the parameterizations of log-linear models used to model the distributions of psychometric tests. The selection strategies included significance tests based on four chi-squared statistics (likelihood ratio, Pearson, Freeman-Tukey, and Cressie-Read) and four additional strategies (Akaike information criterion (AIC), Bayesian information criterion (BIC), consistent Akaike information criterion (CAIC), and a measure attributed to Goodman). The strategies were evaluated in simulations for different log-linear models of univariate and bivariate test-score distributions and two sample sizes. Results showed that all eight selection strategies were most accurate for the largest sample size considered. For univariate distributions, the AIC selection strategy was especially accurate for selecting the correct parameterization of a complex log-linear model and the likelihood ratio chi-squared selection strategy was the most accurate strategy for selecting the correct parameterization of a relatively simple log-linear model. For bivariate distributions, the likelihood ratio chi-squared, Freeman-Tukey chi-squared, BIC, and CAIC selection strategies had similarly high selection accuracies.

Reporting radiographers and their role in thoracic CT service improvement: managing the pulmonary nodule.

OBJECTIVES: The use of cross-sectional imaging in clinical medicine has been a major step forward in the management of many conditions but with that comes the increasing demand on resources and the detection of other potentially significant findings. This, in the context of a shortage of skilled radiologists, means that new ways of working are important. In thoracic CT, pulmonary nodules are a significant challenge because they are so common. Poor and inconsistent management can both cause harm to patients and waste resources so it is important that the latest guidelines are followed. The latter mandate the use of semi-automated volumetry that allows more precise management but is time-consuming. METHODS: Reporting radiographers were iteratively trained in the use of semi-automated volumetry for pulmonary nodules by experienced thoracic radiologists. Once trained in this specific aspect, radiographers completed reporting of pulmonary nodules, checked by radiologists. RESULTS: Radiographer reporting reduced radiologist time in reporting nodules and measuring their volume. Most of the volumetry was completed prior to the multidisciplinary meeting. This facilitated an increase in the number of patients discussed in 60 min from 15 to 22. Radiographers failed to detect few nodules, although a second read by radiologists is required in any case for other aspects of the reporting. CONCLUSION: Reporting radiographers, working with radiologists in a supportive setting, can deliver the radiology in a lung nodule pathway, reducing the time commitment from radiologists and the pulmonary nodule multidisciplinary team members, whilst using this as an opportunity to conduct research.

Zoonotic causes of febrile illness in malaria endemic countries: a systematic review.

Fever is one of the most common reasons for seeking health care globally and most human pathogens are zoonotic. We conducted a systematic review to describe the occurrence and distribution of zoonotic causes of human febrile illness reported in malaria endemic countries. We included data from 53 (48·2%) of 110 malaria endemic countries and 244 articles that described diagnosis of 30 zoonoses in febrile people. The majority (17) of zoonoses were bacterial, with nine viruses, three protozoa, and one helminth also identified. Leptospira species and non-typhoidal salmonella serovars were the most frequently reported pathogens. Despite evidence of profound data gaps, this Review reveals widespread distribution of multiple zoonoses that cause febrile illness. Greater understanding of the epidemiology of zoonoses in different settings is needed to improve awareness about these pathogens and the management of febrile illness.

Seawater softening of suture zones inhibits fracture propagation in Antarctic ice shelves.

Suture zones are abundant on Antarctic ice shelves and widely observed to impede fracture propagation, greatly enhancing ice-shelf stability. Using seismic and radar observations on the Larsen C Ice Shelf of the Antarctic Peninsula, we confirm that such zones are highly heterogeneous, consisting of multiple meteoric and marine ice bodies of diverse provenance fused together. Here we demonstrate that fracture detainment is predominantly controlled by enhanced seawater content in suture zones, rather than by enhanced temperature as previously thought. We show that interstitial seawater can reduce fracture-driving stress by orders of magnitude, promoting both viscous relaxation and the development of micro cracks, the incidence of which scales inversely with stress intensity. We show how simple analysis of viscous buckles in ice-penetrating radar data can quantify the seawater content of suture zones and their modification of the ice-shelf's stress regime. By limiting fracture, enhancing stability and restraining continental ice discharge into the ocean, suture zones act as vital regulators of Antarctic mass balance.

Downregulation of CD46 during muscle differentiation: implications for gene transfer to human skeletal muscle using group B adenoviruses.

Adenoviral vectors that use the coxsackievirus and adenovirus receptor do not transduce mature muscle efficiently. Group B adenoviruses use CD46 as their cell attachment receptor. To evaluate the utility of vectors based on group B adenoviruses for gene transfer to human skeletal muscle, we assessed the expression of CD46 in biopsied normal skeletal muscle samples and in muscles from patients with Duchenne muscular dystrophy. Transcript levels of CD46 were extremely low in mature muscle and CD46 immunoreactivity was detected only on blood vessels in the muscle sections. Although myoblasts cultured from biopsied samples had robust cell surface CD46 expression by flow cytometry, CD46 transcript levels were barely detectable after differentiation of the myoblasts into myotubes. The myotubes were also much less susceptible to infection with an adenoviral vector carrying the fiber of serotype 35 adenovirus (AdF35). These results suggest that for skeletal muscle, vectors derived from group B adenoviruses may not be a suitable alternative to the commonly used Ad5 vectors.

Clinical outcomes of ABO-incompatible RBC transfusions.

Factors that predict outcome after ABO-incompatible RBC transfusions are not well defined. We studied whether the volume of incompatible blood transfused would determine the signs and symptoms and survival outcome for ABO-incompatible RBC transfusions. We reviewed ABO-incompatible RBC transfusions from our institutions and our consultations for 35 years and from a survey of America's Blood Centers' members regarding causes, volume, signs, symptoms, and outcomes of ABO-incompatible RBC transfusions in their service areas from 1995 through 2005. All ABO-incompatible transfusions were due to error; 26 (62%) of 42 occurred at the patient's bedside. Of 36 patients who received more than 50 mL of incompatible blood, 23 (64%) manifested signs or symptoms related to the incompatible transfusion, and 6 (17)% died. Only 3 (25%) of 12 patients who received 50 mL or less of incompatible blood had associated signs or symptoms, and none died. Hypotension, hemoglobinuria, and/or hemoglobinemia were the most frequent findings in survivors and patients who died.ABO-incompatible RBC transfusion does not inevitably mean death or even occurrence of symptoms. Prompt recognition and discontinuation of the transfusion are critical because transfusing less ABO-incompatible blood may minimize signs and symptoms and may prevent death.

Interaction of the Coxsackie and adenovirus receptor (CAR) with the cytoskeleton: binding to actin.

The Coxsackie and adenovirus receptor (CAR) is a cell adhesion molecule that is highly expressed in the developing brain. CAR is enriched in growth cone particles (GCP) after subcellular fractionation. In GCP, we identified actin as an interaction partner of the cytoplasmic domain of CAR. In vivo, actin and CAR co-immunoprecipitate and co-localize. In vitro, the binding is direct, with a K(d) of approximately 2.6 microM, and leads to actin bundling. We previously demonstrated that CAR interacts with microtubules. These data suggest a role for CAR in processes requiring dynamic reorganization of the cytoskeleton such as neurite outgrowth and cell migration.

Submental midline dermoid cyst in a 25-year-old man.

A 25-year-old man presented with a painless, nontender, nonerythematous sublingual mass that had gradually increased in size over the preceding 2 years. Fine-needle aspiration biopsy was nondiagnostic. During the week following our evaluation, the mass became increasingly painful and swollen, and it severely impaired his speech and swallowing. Magnetic resonance imaging demonstrated a sharply demarcated, fluid-filled, sublingual cyst that measured approximately 7.1 x 4.5 x 2.9 cm. During surgical excision, the mass was found to contain a large amount of sebaceous material, which was removed along with the entire capsule of the cyst. Histologic examination of the cystic contents identified epidermis, sebaceous glands, and hair follicles along with copious sebaceous material. These findings are consistent with a dermoid cyst.

Miniaturized system of a gas chromatograph coupled with a Paul ion trap mass spectrometer.

Miniature gas chromatography (GC) and miniature mass spectrometry (MS) instrumentation has been developed to identify and quantify the chemical compounds present in complex mixtures of gases. The design approach utilizes micro-GC components coupled with a Paul quadrupole ion trap (QIT) mass spectrometer. Inherent to the system are high sensitivity, good dynamic range, good QIT resolution, low GC flow-rates to minimize vacuum requirements and the need for consumables; and the use of a modular approach to adapt to volatile organic compounds dissolved in water or present in sediment. Measurements are reported on system response to gaseous species at concentrations varying over four orders of magnitude. The ability of the system to deal with complicated mixtures is demonstrated, and future improvements are discussed. The GC/QIT system described herein has a mass, volume and power that are, conservatively, one-twentieth of those of commercial off-the-shelf systems. Potential applications are to spacecraft cabin-air monitoring, robotic planetary exploration and trace-species detection for residual gas analysis and environmental monitoring.

A Note on Statistical Hypothesis Testing Based on Log Transformation of the Mantel-Haenszel Common Odds Ratio for Differential Item Functioning Classification.

When differential item functioning (DIF) is investigated, DIF classification is made using statistical test results and estimated DIF sizes in practice. One of the well-known DIF classifications is that of the Educational Testing Service (ETS) A (negligible DIF), B (medium DIF), and C (large DIF) rules. This article provides a clarifying note on (a) a sketch of the proof of the asymptotic normality of what is known as the Mantel-Haenszel (MH) delta, which provides the basis of a point and an interval null hypothesis test based on the MH delta, and (b) how to conduct an interval null hypothesis test using the MH delta, which is necessary for the C DIF classification.