Contextualizing the Role of Volumetric Analysis in Pulmonary Nodule Assessment: AJR Expert Panel Narrative Review.

Pulmonary nodules are managed on the basis of their size and morphologic characteristics. Radiologists are familiar with assessing nodule size by measuring diameter using manually deployed electronic calipers. Size may also be assessed with 3D volumetric measurements (referred to as volumetry) obtained with software. Nodule size and growth are more accurately assessed with volumetry than on the basis of diameter, and the evidence supporting clinical use of volumetry has expanded, driven by its use in lung cancer screening nodule management algorithms in Europe. The application of volumetry has the potential to reduce recommendations for imaging follow-up of indeterminate solid nodules without impacting cancer detection. Although changes in scanning conditions and volumetry software packages can lead to variation in volumetry results, ongoing technical advances have improved the reliability of calculated volumes. Volumetry is now the primary method for determining size of solid nodules in the European lung cancer screening position statement and British Thoracic Society recommendations. The purposes of this article are to review technical aspects, advantages, and limitations of volumetry and, by considering specific scenarios, to contextualize the use of volumetry with respect to its importance in morphologic evaluation, its role in predicting malignancy in risk models, and its practical impact on nodule management. Implementation challenges and areas requiring further evidence are also highlighted.

Uncovered versus covered stent in management of large bowel obstruction due to colorectal malignancy: a systematic review and meta-analysis.

PURPOSE: To compare outcomes of uncovered stent and covered stent in management of large bowel obstruction secondary to colorectal malignancy. METHODS: We conducted a search of electronic databases identifying studies comparing outcomes of uncovered and covered stents in management of large bowel obstruction secondary to colorectal malignancy. The Cochrane risk-of-bias tool and the Newcastle-Ottawa scale were used to assess the included studies. Random or fixed effects modelling were applied as appropriate to calculate pooled outcome data. RESULTS: One randomised controlled trial (RCT) and nine observational studies, enrolling 753 patients, were identified. Uncovered stent was associated with lower risks of complications (RR 0.57 95% CI 0.44-0.74, P < 0.0001), tumour overgrowth (RR 0.29 95% CI 0.09-0.93, P = 0.04), and stent migration (RR 0.29 95% CI 0.17-0.48, P < 0.00001); longer duration of patency (MD 18.47 95% CI 10.46-26.48, P < 0.00001); lower need for stent reinsertion (RR 0.38 95% CI 0.17-0.86, P = 0.02); and higher risk of tumour ingrowth (RR 4.53 95% CI 1.92-10.69, P = 0.0008). Rates of technical success (RR 1.02 95% CI 0.99-1.04, P = 0.21), clinical success (RR 1.03 95% CI 0.98-1.08, P = 0.32), perforation (RD 0.01 95% CI - 0.03-0.02, P = 0.65), bleeding (RD 0.00 95% CI - 0.03-0.03, P = 0.98), stool impaction (RR 0.56 95% CI 0.12-2.04, P = 0.38) and stent obstruction (RR 2.23 95% CI 0.94-5.34, P = 0.97) were similar. CONCLUSIONS: Our results suggest that uncovered stents are superior as indicated by fewer complications, lower rates of stent migration, longer duration of patency and a reduced need for stent reinsertion. The best available evidence is mainly derived from non-randomised studies; there is a need for more RCTs.

Cells with Treg-specific FOXP3 demethylation but low CD25 are prevalent in autoimmunity.

Identification of alterations in the cellular composition of the human immune system is key to understanding the autoimmune process. Recently, a subset of FOXP3+ cells with low CD25 expression was found to be increased in peripheral blood from systemic lupus erythematosus (SLE) patients, although its functional significance remains controversial. Here we find in comparisons with healthy donors that the frequency of FOXP3+ cells within CD127lowCD25low CD4+ T cells (here defined as CD25lowFOXP3+ T cells) is increased in patients affected by autoimmune disease of varying severity, from combined immunodeficiency with active autoimmunity, SLE to type 1 diabetes. We show that CD25lowFOXP3+ T cells share phenotypic features resembling conventional CD127lowCD25highFOXP3+ Tregs, including demethylation of the Treg-specific epigenetic control region in FOXP3, HELIOS expression, and lack of IL-2 production. As compared to conventional Tregs, more CD25lowFOXP3+HELIOS+ T cells are in cell cycle (33.0% vs 20.7% Ki-67+; P = 1.3 × 10-9) and express the late-stage inhibitory receptor PD-1 (67.2% vs 35.5%; P = 4.0 × 10-18), while having reduced expression of the early-stage inhibitory receptor CTLA-4, as well as other Treg markers, such as FOXP3 and CD15s. The number of CD25lowFOXP3+ T cells is correlated (P = 3.1 × 10-7) with the proportion of CD25highFOXP3+ T cells in cell cycle (Ki-67+). These findings suggest that CD25lowFOXP3+ T cells represent a subset of Tregs that are derived from CD25highFOXP3+ T cells, and are a peripheral marker of recent Treg expansion in response to an autoimmune reaction in tissues.

IL-21 production by CD4+ effector T cells and frequency of circulating follicular helper T cells are increased in type 1 diabetes patients.

AIMS/HYPOTHESIS: Type 1 diabetes results from the autoimmune destruction of insulin-secreting pancreatic beta cells by T cells. Despite the established role of T cells in the pathogenesis of the disease, to date, with the exception of the identification of islet-specific T effector (Teff) cells, studies have mostly failed to identify reproducible alterations in the frequency or function of T cell subsets in peripheral blood from patients with type 1 diabetes. METHODS: We assessed the production of the proinflammatory cytokines IL-21, IFN-γ and IL-17 in peripheral blood mononuclear cells from 69 patients with type 1 diabetes and 61 healthy donors. In an additional cohort of 30 patients with type 1 diabetes and 32 healthy donors, we assessed the frequency of circulating T follicular helper (Tfh) cells in whole blood. IL-21 and IL-17 production was also measured in peripheral blood mononuclear cells (PBMCs) from a subset of 46 of the 62 donors immunophenotyped for Tfh. RESULTS: We found a 21.9% (95% CI 5.8, 40.2; p = 3.9 × 10(-3)) higher frequency of IL-21(+) CD45RA(-) memory CD4(+) Teffs in patients with type 1 diabetes (geometric mean 5.92% [95% CI 5.44, 6.44]) compared with healthy donors (geometric mean 4.88% [95% CI 4.33, 5.50]). Consistent with this finding, we found a 14.9% increase in circulating Tfh cells in the patients (95% CI 2.9, 26.9; p = 0.016). CONCLUSIONS/INTERPRETATION: These results indicate that increased IL-21 production is likely to be an aetiological factor in the pathogenesis of type 1 diabetes that could be considered as a potential therapeutic target.

Incidentally detected pancreatic duct dilatation on ultrasound and role of MRI.

OBJECTIVE: The clinical significance of incidentally detected pancreatic duct (PD) dilatation at ultrasound (US) without a visualized underlying cause is unclear. We aimed to assess the role of subsequent MRI (including MRCP) and to identify US imaging and laboratory findings predictive of underlying pancreaticobiliary malignancy at the time of initial US. MATERIALS AND METHODS: Patients with incidentally detected PD dilatation at ultrasound from 2011 to 2019 that had an ensuing MRI were included. Based on MRI results patients were divided into three groups: malignant pancreaticobiliary causes, benign causes and idiopathic PD dilatation. Subsequently the diagnostic ability of MRI was assessed. Initial ultrasound findings and laboratory results were compared between groups to identify predictors of underlying pancreaticobiliary pathology. A p-value < .05 was considered statistically significant. RESULTS: In 37/59 (63%) patients PD dilatation was confirmed on MRI. MRI demonstrated malignant 7/59 (12%) and benign 10/59 (17%) causes of PD dilatation detected at initial ultrasound. Sensitivity, specificity, negative predictive value, positive predictive value and accuracy of MRI to ascertain the cause of PD dilatation was 89%, 100%, 95%, 100% and 97% respectively. Patients with a larger magnitude of PD dilatation, concomitant CBD dilatation and elevated lipase values were more likely to have underlying pancreaticobiliary malignancy (p < 0.05). No patient with initial negative MRI had pancreaticobiliary malignancy on subsequent work-up. CONCLUSION: Incidentally detected PD dilatation on ultrasound is an important finding and should prompt referral to MRI. MRI is an accurate, noninvasive method for identifying the underlying cause of PD dilatation in these patients and in excluding pancreaticobiliary malignancy.

Artificial Intelligence Algorithms in Health Care: Is the Current Food and Drug Administration Regulation Sufficient?

Given the growing use of machine learning (ML) technologies in health care, regulatory bodies face unique challenges in governing their clinical use. Under the regulatory framework of the Food and Drug Administration, approved ML algorithms are practically locked, preventing their adaptation in the ever-changing clinical environment, defeating the unique adaptive trait of ML technology in learning from real-world feedback. At the same time, regulations must enforce a strict level of patient safety to mitigate risk at a systemic level. Given that ML algorithms often support, or at times replace, the role of medical professionals, we have proposed a novel regulatory pathway analogous to the regulation of medical professionals, encompassing the life cycle of an algorithm from inception, development to clinical implementation, and continual clinical adaptation. We then discuss in-depth technical and nontechnical challenges to its implementation and offer potential solutions to unleash the full potential of ML technology in health care while ensuring quality, equity, and safety. References for this article were identified through searches of PubMed with the search terms "Artificial intelligence," "Machine learning," and "regulation" from June 25, 2017, until June 25, 2022. Articles were also identified through searches of the reference list of the articles. Only papers published in English were reviewed. The final reference list was generated based on originality and relevance to the broad scope of this paper.

Postgraduate radiology education: what has Covid-19 changed?

Radiology training in the UK follows a standardised pathway with formative and summative assessments throughout. The Covid-19 pandemic has affected multiple existing educational methods commonly used during radiology training including small group teaching, multidisciplinary team meetings, online e-learning modules, radiology courses, exam provision and more. As such, significant adaptations have been implemented in order to maintain the standard of radiology training which come with their respective advantages and disadvantages. However, the question still remains as to the effectiveness of these methods, their acceptability and longevity. In this review, we discuss these educational adaptations and future directions for training in the ongoing pandemic.

Addressing Equity in Global Medical Education During the COVID-19 Pandemic: The Global Medical Education Collaborative.

PROBLEM: The COVID-19 pandemic has presented a unique set of challenges to medical education globally. Low- and middle-income countries (LMICs) have faced unique barriers in transitioning to virtual modalities, and many medical students in LMICs experienced dramatically reduced educational time. The authors created the Global Medical Education Collaborative (GMEC) to address this problem by providing free, online, case-based tutorials to medical students in LMICs during the pandemic. APPROACH: The authors developed a needs assessment to gauge students' educational requirements, which informed GMEC's 2 primary goals: to provide free access to interactive online tutorials for students in LMICs and to bridge the physical distance between educators and learners via an online platform. A pilot program in Nigeria (April 26-May 26, 2020) helped inform the current strategy and logistics. Tutors and students were recruited via social media and medical education networks at the authors' home institutions. OUTCOMES: Within the first 2 months (April 26-June 26, 2020), 324 students representing 12 countries and 20+ medical schools joined GMEC. Additionally, 95 physicians and trainees joined as tutors and, collectively, delivered 52 tutorials. Students responded to a needs assessment querying confidence in various clinical domains, interest in covering clinical topics, barriers to virtual learning, and the effect of the pandemic on their education. Tutors held 1-hour, interactive tutorials over Zoom covering a variety of clinical topics. According to surveys, 91% of students (71 of 78) felt more confident in the material related to the tutorial's topic after participating. NEXT STEPS: GMEC will continue to engage students, tutors, and collaborators to facilitate the delivery of innovative, high-quality tutorials to students affected by COVID-19 in LMICs. To ensure that the platform is sustainable and aligned with GMEC's mission to promote equity in global medical education, the collaborative will need to be agile and responsive.

The utility of a convolutional neural network (CNN) model score for cancer risk in indeterminate small solid pulmonary nodules, compared to clinical practice according to British Thoracic Society guidelines.

PURPOSE: To determine how implementation of an artificial intelligence nodule algorithm, the Lung Cancer Prediction Convolutional Neural Network (LCP-CNN), at the point of incidental nodule detection would have influenced further investigation and management using a series of threshold scores at both the benign and malignant end of the spectrum. METHOD: An observational retrospective study was performed in the assessment of nodules between 5-15 mm (158 benign, 32 malignant) detected on CT scans, which were performed as part of routine practice. The LCP-CNN was applied to the baseline CT scan producing a percentage score, and subsequent imaging and management determined for each threshold group. We hypothesized that the 5% low risk threshold group requires only one follow-up, the 0.56% very low risk threshold group requires no follow-up and the 80% high risk threshold group warrants expedited intervention. RESULTS: The 158 benign nodules had an LCP-CNN score between 0.1 and 70.8%, median 5.5% (IQR 1.4-18.0), whilst the 32 cancer nodules had an LCP-CNN score between 10.1 and 98.7%, median 59.0% (IQR 37.1-83.9). 24/61 CT scans in the 0.56-5% group (n = 37) and 21/21 CT scans <0.56% group (n = 13) could be obviated resulting in an overall reduction of 18.6% (45/242) CT scans in the benign cohort. In the 80% group (n = 10), expedited intervention of malignant nodules could result in a 3.6-month reduction in time delay in 5 cancer patients. CONCLUSION: We show the potential of artificial intelligence to reduce the need for follow-up scans and intervention in low-scoring benign nodules, whilst potentially accelerating the investigation and treatment of high-scoring cancer nodules.

Academic medicine: the continuing challenges.

BACKGROUND: Numbers of academic medicine trainees have been declining internationally. Many countries have taken differing approaches to improving recruitment, with some having established pathways. In the UK, the academic foundation programme (AFP) is one such pathway aimed towards those interested in an academic medical career. Variation exists amongst universities with respect to application and success rates. As a group of AFP doctors, we aimed to explore these issues. Numbers of academic medicine trainees have been declining internationally METHODS: We created and implemented a 1-day national course, comprising lectures and small group workshops, geared towards informing applicants about the AFP. It was evaluated via pre- and post-course questionnaires using a Likert scale, ranging from 1 to 5. We created and implemented a 1-day national course, comprising lectures and small group workshops, geared towards informing applicants about the AFP RESULTS: A total of 150 attendees were present from 16 different medical schools; 95% (143/150) of the attendees filled in both questionnaires. Attendees appeared unaware of the stages involved in the application process and felt underprepared. Following the course, learners reported median scores (with interquartile limits) that demonstrated increased overall knowledge, from 2 (1) to 4 (1) (p < 0.01), and increased preparedness, from 2 (1) to 3 (1) (p < 0.01). DISCUSSION: Our findings indicate that recruitment remains challenging, even in countries with established pathways. In the UK, the awareness of these pathways appears to be poor and courses such as ours may remedy that. Further exploration into the most effective methods to increase recruitment is necessary. The effect of institutional disparities in research culture and impact on application success needs investigation. Perhaps medical schools should introduce students to the prospect of academic careers earlier in training. Globally, efforts still need to be concentrated largely towards establishing integrated pathways.

Interventional radiology training: where will technology take us?

Interventional radiology is a relatively young specialty, and it is undergoing a period of considerable growth. The benefits of a minimally invasive approach are clear, with smaller incisions, less pain, and faster recovery times being the principal benefits compared to surgical alternatives. Trainees need to acquire the technical skills and the clinical acumen to accurately deliver targeted treatment and safely follow up patients after the procedure. The need to maintain an efficient interventional radiology service whilst also giving sufficient time for trainee education is a challenge. In order to compensate for this, novel technologies like virtual reality (VR), augmented reality (AR), cadaveric simulation, and three-dimensional (3D) printing have been postulated as a means of supplementing training. In this article, we outline the main features of these innovative strategies and discuss the evidence base behind them. Benefits of these techniques beyond pure clinical training include the standardization of educational cases, access to training at any time, and less risk to patients. The main disadvantage is the large financial outlay required. Therefore, before widespread uptake can be recommended, further research is needed to confirm the educational benefit of these novel techniques, both in and of themselves and in comparison to existing clinical-based education.

Tumor- and cytokine-primed human natural killer cells exhibit distinct phenotypic and transcriptional signatures.

An emerging cellular immunotherapy for cancer is based on the cytolytic activity of natural killer (NK) cells against a wide range of tumors. Although in vitro activation, or "priming," of NK cells by exposure to pro-inflammatory cytokines, such as interleukin (IL)-2, has been extensively studied, the biological consequences of NK cell activation in response to target cell interactions have not been thoroughly characterized. We investigated the consequences of co-incubation with K562, CTV-1, Daudi RPMI-8226, and MCF-7 tumor cell lines on the phenotype, cytokine expression profile, and transcriptome of human NK cells. We observe the downregulation of several activation receptors including CD16, CD62L, C-X-C chemokine receptor (CXCR)-4, natural killer group 2 member D (NKG2D), DNAX accessory molecule (DNAM)-1, and NKp46 following tumor-priming. Although this NK cell phenotype is typically associated with NK cell dysfunction in cancer, we reveal the upregulation of NK cell activation markers, such as CD69 and CD25; secretion of pro-inflammatory cytokines, including macrophage inflammatory proteins (MIP-1) α /ß and IL-1ß/6/8; and overexpression of numerous genes associated with enhanced NK cell cytotoxicity and immunomodulatory functions, such as FAS, TNFSF10, MAPK11, TNF, and IFNG. Thus, it appears that tumor-mediated ligation of receptors on NK cells may induce a primed state which may or may not lead to full triggering of the lytic or cytokine secreting machinery. Key signaling molecules exclusively affected by tumor-priming include MAP2K3, MARCKSL1, STAT5A, and TNFAIP3, which are specifically associated with NK cell cytotoxicity against tumor targets. Collectively, these findings help define the phenotypic and transcriptional signature of NK cells following their encounters with tumor cells, independent of cytokine stimulation, and provide insight into tumor-specific NK cell responses to inform the transition toward harnessing the therapeutic potential of NK cells in cancer.

Neonatal and adult recent thymic emigrants produce IL-8 and express complement receptors CR1 and CR2.

The maintenance of peripheral naive T lymphocytes in humans is dependent on their homeostatic division, not continuing emigration from the thymus, which undergoes involution with age. However, postthymic maintenance of naive T cells is still poorly understood. Previously we reported that recent thymic emigrants (RTEs) are contained in CD31+CD25- naive T cells as defined by their levels of signal joint T cell receptor rearrangement excision circles (sjTRECs). Here, by differential gene expression analysis followed by protein expression and functional studies, we define that the naive T cells having divided the least since thymic emigration express complement receptors (CR1 and CR2) known to bind complement C3b- and C3d-decorated microbial products and, following activation, produce IL-8 (CXCL8), a major chemoattractant for neutrophils in bacterial defense. We also observed an IL-8-producing memory T cell subpopulation coexpressing CR1 and CR2 and with a gene expression signature resembling that of RTEs. The functions of CR1 and CR2 on T cells remain to be determined, but we note that CR2 is the receptor for Epstein-Barr virus, which is a cause of T cell lymphomas and a candidate environmental factor in autoimmune disease.

The Brugada syndrome revisited.

The Brugada syndrome is a rare but well-defined cause of sudden cardiac death. The key underlying abnormality is a decrease in net depolarising current due to a genetic defect, though recent evidence also implicates structural abnormalities in some patients. Diagnosis requires a Brugada-type ECG as well as typical clinical features: such clinical considerations are currently key in guiding risk stratification and hence management. Whilst pharmacological therapies are under investigation, the only intervention with a robust evidence base remains insertion of an implantable cardioverter defibrillator. Further research will be required to allow more effective risk stratification and hence more rational therapy.

DPP-IV inhibitors: Beyond glycaemic control?

Dipeptidyl-peptidase-IV (DPP-IV) inhibitors are a new class of oral hypoglycaemic agents recently approved for the management of type 2 diabetes mellitus. Early data suggested that they had a positive impact on the cardiovascular system: treatment appeared to result in improvements in cardiac performance, blood pressure and lipid levels. However, recent clinical findings bring this into question. Our understanding of the physiological actions of these agents is complicated by the fact that DPP-IV has a wide range of substrates in addition to glucagon-like peptide 1. Indeed, DPP-IV inhibition alters concentrations of a wide variety of cytokines and neuropeptides. A deeper understanding of the physiological effects of these drugs as well as their true impact on cardiovascular risk is needed before consideration can be given to extending their use beyond the treatment of diabetes.