Within-diver variability in venous gas emboli (VGE) following repeated dives.

Introduction: Venous gas emboli (VGE) are widely used as a surrogate endpoint instead of decompression sickness (DCS) in studies of decompression procedures. Peak post-dive VGE grades vary widely following repeated identical dives but little is known about how much of the variability in VGE grades is proportioned between-diver and within-diver. Methods: A retrospective analysis of 834 man-dives on six dive profiles with post-dive VGE measurements was conducted under controlled laboratory conditions. Among these data, 151 divers did repeated dives on the same profile on two to nine occasions separated by at least one week (total of 693 man-dives). Data were analysed for between- and within-diver variability in peak post-dive VGE grades using mixed-effect models with diver as the random variable and associated intraclass correlation coefficients. Results: Most divers produced a wide range of VGE grades after repeated dives on the same profile. The intraclass correlation coefficient (repeatability) was 0.33 indicating that 33% of the variability in VGE grades is between-diver variability; correspondingly, 67% of variability in VGE grades is within-diver variability. DCS cases were associated with an individual diver's highest VGE grades and not with their lower VGE grades. Conclusions: These data demonstrate large within-diver variability in VGE grades following repeated dives on the same dive profile and suggest there is substantial within-diver variability in susceptibility to DCS. Post-dive VGE grades are not useful for evaluating decompression practice for individual divers.

Developing Integrated Approaches for Testing and Assessment (IATAs) in order to support nanomaterial safety.

Due to the unique characteristics of nanomaterials (NM) there has been an increase in their use in nanomedicines and innovative medical devices (MD). Although large numbers of NMs have now been developed, comprehensive safety investigations are still lacking. Current gaps in understanding the potential mechanisms of NM-induced toxicity can make it challenging to determine the safety testing necessary to support inclusion of NMs in MD applications. This article provides guidance for implementation of pre-clinical tailored safety assessment strategies with the aim to increase the translation of NMs from bench development to clinical use. Integrated Approaches to Testing and Assessment (IATAs) are a key tool in developing these strategies. IATAs follow an iterative approach to answer a defined question in a specific regulatory context to guide the gathering of relevant information for safety assessment, including existing experimental data, integrated with in silico model predictions where available and appropriate, and/or experimental procedures and protocols for generating new data to fill gaps. This allows NM developers to work toward current guidelines and regulations, while taking NM specific considerations into account. Here, an example IATA for NMs with potential for direct blood contact was developed for the assessment of haemocompatibility. This example IATA brings together the current guidelines for NM safety assessment within a framework that can be used to guide information and data gathering for the safety assessment of intravenously injected NMs. Additionally, the decision framework underpinning this IATA has the potential to be adapted to other testing needs and regulatory contexts.

Disease activity and treatment efficacy using patient-level Psoriasis Area and Severity Index scores from tildrakizumab phase 3 clinical trials.

BACKGROUND: It is unclear whether primary efficacy outcomes in plaque psoriasis clinical trials represent residual disease during treatment. OBJECTIVES: To evaluate supplementing dichotomous efficacy with residual disease activity. METHODS: This post hoc analysis used pooled, patient-level data after tildrakizumab 100 mg (N = 616) or placebo (N = 309) treatment from reSURFACE 1/2 (NCT01722331/NCT01729754) phase 3 clinical trials of patients with moderate to severe plaque psoriasis. RESULTS: Median baseline Psoriasis Area and Severity Index (PASI) was 17.9 for patients receiving tildrakizumab 100 mg. At Week 12, median PASI was 2.9, whereas dichotomous PASI 90 response rate was 36.9%, and absolute PASI <5.0, <3.0, and <1.0 were 64.0%, 50.8%, and 23.3%, respectively. At Week 28, median PASI was 1.7, whereas PASI 90 response rate was 51.9%, and absolute PASI <5.0, <3.0, and <1.0 were 75.3%, 62.8%, and 38.0%, respectively. Dermatology Life Quality Index and PASI scores were correlated through Week 28 (r = 0.51, p ≤ .0001). CONCLUSIONS: Disease activity was more reliably estimated by PASI scores than percentage PASI improvement; this may partially explain efficacy disparities between clinical trials and practice. These results suggest supplementing dichotomous PASI improvement with PASI scores and consideration of patient treatment goals could facilitate clinical decisions.

Asylum seekers and refugees in Northern Ireland: the impact of post-migration stressors on mental health.

OBJECTIVES: In recent years, Northern Ireland has seen an increase in the numbers of asylum seekers and refugees. Given its status as a post-conflict region, this is a relatively new phenomenon for the area. Northern Ireland is also the only part of the United Kingdom (UK) without a refugee integration strategy. In 2016, we conducted an extensive study for the racial equality unit of the Office of the First and Deputy First Minister in Stormont on the everyday life experience of asylum seekers and refugees in Northern Ireland with view to understanding how service delivery and notions of integration/inclusion impact. METHODS: This was a mixed methods study using quantitative survey methods and in-depth semi-structured interviews with service providers, asylum seekers, refugees and new UK citizens. We examined a range of service provision such as education, labour, legal provision, housing and health. RESULTS: This article examines the issue of mental health with respect to asylum seekers and refugees in Northern Ireland. The results delineate how asylum seekers and refugee's mental health is dramatically impacted by the asylum system in Northern Ireland (and hence, the UK) and the dearth thereof, of particular and necessary supports and access issues in the space of health and mental health in Northern Ireland. We describe how post-migration stressors experienced through the UK asylum system further compound mental health issues. The findings provide a focus on the asylum system, housing and employment. CONCLUSIONS: Our research found a dearth of mental health supports in Northern Ireland and concluded that the asylum system in the UK (as a form of post-migration stressor) further exacerbates and contributes to poor mental health and well-being for many asylum seekers and refugees.

Hemodialysis catheter integrity during mechanical power injection of iodinated contrast medium for computed tomography angiography.

PURPOSE: CT angiography (CTA) requires vascular access with flow rates of 5-7 mL/s. Hemodialysis (HD) is performed at 6-10 mL/s. The purpose of our study is to evaluate the structural integrity of HD catheters in the administration of contrast media via a mechanical power injector under varying conditions. METHODS: Four HD catheters were evaluated in an in vitro study. Tested were contrast media type (iopamidol 300 and 370 mgI/mL), temperature (25 and 37 °C), catheter diameter (14 Fr to 16 Fr all with double-lumen capacity), catheter length (19-32 cm), and simultaneous double-lumen or single-lumen injection within each of the catheters. Peak plateau pressures (psi) were recorded with flow rates from 5 to 20 mL/s in 5 mL/s increments. In total, 864 unique injections were performed. RESULTS: No catheter failure (bulging/rupture) was observed in 864 injections. Maximum pressure for single-lumen injection was 51.7 psi (double-lumen: 26.3 psi). Peak pressures were significantly lower in simultaneous double-lumen vs. single-lumen injections (p < 0.001) and low vs. high viscosity contrast media (p < 0.001). Neither larger vs. smaller diameter lumens (p = 0.221) nor single-lumen injection in arterial vs. venous (p = 0.834) were significantly different. CONCLUSION: HD catheters can be used to safely administer iodinated contrast media via mechanical power injection in in vitro operating conditions. Maximum peak pressure is below the manufacturer's 30 psi limit at flow rates up to 20 mL/s in double-lumen injections and up to 10 mL/s in single-lumen injections, which is higher than the usual maximum of 8 mL/s for CT angiography in clinical settings.

The impact of teaching experimental research on-line: Research-informed teaching and COVID-19.

INTRODUCTION: As part of the BSc (Hons) Diagnostic Radiography programme students learn and undertake research relevant to their development as first post radiographers (dose optimisation and image quality) within the Research-Informed Teaching experience (RiTe). Due to the COVID-19 pandemic, the delivery of RiTe to our year 2 students was moved to an online format using Microsoft Teams and Blackboard Collaborate and focused on a key area of current practice - COVID-19 and chest X-ray imaging. Within RiTe students are placed into collaborative enquiry-based learning (CEBL) groups to share tasks, but to also support and learn from one another. METHODS: An online survey was used to explore the year 2 student cohort task value and self-efficacy of this online version of RiTe. RESULTS: A 73% (32/44) response rate was achieved. Students found the online version of RiTe to be a positive learning and development experience. There was strong agreement that they not only found it relevant to their area of practice (task-value), but also strongly agreed that they understood and could master the skills taught (self-efficacy). CONCLUSION: This online version of RiTe was effectively structured to help scaffold student learning and development of research data analysis skills despite the lack of face-to-face teaching. The students also valued the topic area (COVID-19 and chest X-ray imaging). A blended learning approach with RiTe will be used next year with a combination of collaborative online teaching and physical data collection and analysis in the university-based X-ray imaging laboratory. Further evaluation and data collection will also be undertaken. IMPLICATIONS FOR PRACTICE: University-based empirical work in groups to learn about research can be replaced by an online mechanism whilst still maintaining task-value and acceptable self-efficacy.

Problem based learning in radiography education: A narrative review.

OBJECTIVES: Radiography practice is fast developing with new imaging updates and challenging scenarios to deal with on a frequent basis. There is a need to equip students with the skill to be independent learners and develop critical thinking skills, so they can change their practice as the profession evolves. Problem Based Learning (PBL) has widely been adopted in medical and nursing training worldwide as a result of its desirable benefits. In order to ascertain the efficacy of the technique, this paper presents a review of the essential aspects of PBL, such as the theories, process, key roles and implication for radiography education and practice. KEY FINDINGS: The use of a defined model provides a useful structure to the PBL exercise with the addition of reflection, which is a pertinent inclusion within the process. The role of the facilitator in PBL is significant to students' learning as they help guide the students to the learning outcomes and provide support to the group; however, their skills development is an important factor to consider in PBL. CONCLUSION: This teaching approach has key benefits in radiography education and training in particular, its impact on preparing students for autonomous clinical practice. IMPLICATIONS FOR PRACTICE: The application of PBL in developing students' critical thinking and decision-making abilities support the narrowing of the spoon-feeding expectation of students and render it a useful pedagogical implementation within radiography programmes.

Esophageal atresia and tracheoesophageal fistula associated with tetralogy of Fallot: a review of mortality.

INTRODUCTION: Oesophageal atresia ± tracheoesophageal fistula (EA/TEF) associated with congenital heart disease (CHD) carries a worse prognosis than EA/TEF alone. Though the Spitz classification takes major CHD into account, there are no data regarding survival with the specific combination of EA/TEF and Tetralogy of Fallot (TOF). With advances in postnatal care, we hypothesised that, survival is improving in these complex patients. This study reports morbidity and mortality outcomes of newborns with oesophageal atresia and TOF cardiac malformations METHODS: All patients with EA/TEF and TOF treated at Alder Hey Children's Hospital between the years 2000-2020, were identified. Data sets regarding gestation, birth weight, associated anomalies, operative intervention, morbidity, and mortality were analysed. RESULTS: Of a total of 350, EA/TEF patients 9 (2.6%) cases had EA/TEF associated with TOF (M:F 4:5). The median gestational age was 35/40 (range 28-41 weeks) with a median birth weight of 1790 g (range 1060-3350 g). Overall survival was 56% (5/9 cases) and all survivors remain under follow up (range 37-4458 days). Surgical strategies for managing EA/TEF with Fallot's tetralogy included 6/9 primary repairs and 3/9 cases with TEF ligation only (+ gastrostomy ± oesophagostomy). CONCLUSIONS: This study reports outcome data from one of the largest series of EA TEF patients with Fallot's tetralogy. Whilst outcomes may be challenging for this unique patient cohort, survival metrics provide important prognostic information that can be widely shared with health care teams and parents.

Iso-risk air no decompression limits after scoring marginal decompression sickness cases as non-events.

Decompression sickness (DCS) in humans is associated with reductions in ambient pressure that occur during diving, aviation, or certain manned spaceflight operations. Its signs and symptoms can include, but are not limited to, joint pain, radiating abdominal pain, paresthesia, dyspnea, general malaise, cognitive dysfunction, cardiopulmonary dysfunction, and death. Probabilistic models of DCS allow the probability of DCS incidence and time of occurrence during or after a given hyperbaric or hypobaric exposure to be predicted based on how the gas contents or gas bubble volumes vary in hypothetical tissue compartments during the exposure. These models are calibrated using data containing the pressure and respired gas histories of actual exposures, some of which resulted in DCS, some of which did not, and others in which the diagnosis of DCS was not clear. The latter are referred to as marginal DCS cases. In earlier works, a marginal DCS event was typically weighted as 0.1, with a full DCS event being weighted as 1.0, and a non-event being weighted as 0.0. Recent work has shown that marginal DCS events should be weighted as 0.0 when calibrating gas content models. We confirm this indication in the present work by showing that such models have improved performance when calibrated to data with marginal DCS events coded as non-events. Further, we investigate the ramifications of derating marginal events on model-prescribed air diving no-stop limits.

Probabilistic pharmacokinetic models of decompression sickness in humans: Part 2, coupled perfusion-diffusion models.

Decompression sickness (DCS) can be experienced following a reduction in ambient pressure; such as that associated with diving or ascent to high altitudes. DCS is believed to result when supersaturated inert gas dissolved in biological tissues exits solution and forms bubbles. Models to predict the probability of DCS are typically based on nitrogen and/or helium gas uptake and washout in several theoretical tissues, each represented by a single perfusion-limited compartment. It has been previously shown that coupled perfusion-diffusion compartments are better descriptors than solely perfusion-based models of nitrogen and helium uptake and elimination kinetics observed in the brain and skeletal muscle of sheep. In this work, we examine the application of these coupled pharmacokinetic structures with at least one diffusion compartment to the prediction of the incidence of decompression sickness in humans. We compare these models to LEM-NMRI98, a well-described U.S. Navy gas content model, consisting of three uncoupled perfusion-limited compartments incorporating oxygen and linear-exponential kinetics. Pharmacokinetic gas content models with a diffusion component describe the probability of DCS in human bounce dives made with air, single non-air bounce dives, and oxygen decompression dives better than LEM-NMRI98. However, for the full data set, LEM-NMRI98 remains the best descriptor of the data.

Bimodal decompression sickness onset times are not related to dive type or event severity.

Human decompression sickness (DCS) is a condition associated with depressurization during underwater diving. Human research dive trial data containing dive outcome (DCS, no-DCS) and symptom information are used to calibrate probabilistic DCS models. DCS symptom onset time information is visualized using occurrence density functions (ODF) which plot the DCS onset rate per unit time. For the BIG292 human dive trial data set, a primary U.S. Navy model calibration set, the ODFs are bimodal, however probabilistic models do not produce bimodal ODFs. We investigate the source of bimodality by partitioning the BIG292 data based on dive type, DCS event severity, DCS symptom type, institution, and chronology of dive trial. All but one variant of data partitioning resulted in a bimodal or ambiguously shaped ODF, indicating that ODF bimodality is not related to the dive type or the DCS event severity. Rather, we find that the dive trial medical surveillance protocol used to determine DCS symptom onset time may have biased the reported event window. Thus, attempts to develop probabilistic DCS models that reproduce BIG292 bimodality are unlikely to result in an improvement in model performance for data outside of the calibration set.

Probabilistic pharmacokinetic models of decompression sickness in humans, part 1: Coupled perfusion-limited compartments.

Decompression sickness (DCS) is a disease caused by gas bubbles forming in body tissues following a reduction in ambient pressure, such as occurs in scuba diving. Probabilistic models for quantifying the risk of DCS are typically composed of a collection of independent, perfusion-limited theoretical tissue compartments which describe gas content or bubble volume within these compartments. It has been previously shown that 'pharmacokinetic' gas content models, with compartments coupled in series, show promise as predictors of the incidence of DCS. The mechanism of coupling can be through perfusion or diffusion. This work examines the application of five novel pharmacokinetic structures with compartments coupled by perfusion to the prediction of the probability and time of onset of DCS in humans. We optimize these models against a training set of human dive trial data consisting of 4335 exposures with 223 DCS cases. Further, we examine the extrapolation quality of the models on an additional set of human dive trial data consisting of 3140 exposures with 147 DCS cases. We find that pharmacokinetic models describe the incidence of DCS for single air bounce dives better than a single-compartment, perfusion-limited model. We further find the U.S. Navy LEM-NMRI98 is a better predictor of DCS risk for the entire training set than any of our pharmacokinetic models. However, one of the pharmacokinetic models we consider, the CS2T3 model, is a better predictor of DCS risk for single air bounce dives and oxygen decompression dives. Additionally, we find that LEM-NMRI98 outperforms CS2T3 on the extrapolation data.

Hypoxia determines survival outcomes of bacterial infection through HIF-1alpha dependent re-programming of leukocyte metabolism.

Hypoxia and bacterial infection frequently co-exist, in both acute and chronic clinical settings, and typically result in adverse clinical outcomes. To ameliorate this morbidity, we investigated the interaction between hypoxia and the host response. In the context of acute hypoxia, both S. aureus and S. pneumoniae infections rapidly induced progressive neutrophil mediated morbidity and mortality, with associated hypothermia and cardiovascular compromise. Preconditioning animals through longer exposures to hypoxia, prior to infection, prevented these pathophysiological responses and profoundly dampened the transcriptome of circulating leukocytes. Specifically, perturbation of HIF pathway and glycolysis genes by hypoxic preconditioning was associated with reduced leukocyte glucose utilisation, resulting in systemic rescue from a global negative energy state and myocardial protection. Thus we demonstrate that hypoxia preconditions the innate immune response and determines survival outcomes following bacterial infection through suppression of HIF-1α and neutrophil metabolism. The therapeutic implications of this work are that in the context of systemic or tissue hypoxia therapies that target the host response could improve infection associated morbidity and mortality.

A qualitative analysis of staff-client interactions within a breast cancer assessment clinic.

OBJECTIVES: Breast screening clients recalled to an assessment clinic experience high levels of anxiety. The culture of the assessment clinic may impact upon client experience, which may influence their future re-engagement in screening. This study aimed to explore the culture of staff-client interactions within a breast cancer assessment clinic. MATERIALS AND METHODS: Following an ethnographic approach, twenty-three client journeys were observed, followed by semi-structured interviews with the clients. The observation and interview data were analysed to produce research themes, which were then explored within two focus groups to add a practitioner perspective. RESULTS: Multiple staff-client interaction events were observed over a period of several weeks. Client interview feedback was overwhelmingly positive. Three recurrent and sequential themes emerged: breaking down barriers, preparing the ground and sign-posting. These themes outline the changing focus of staff-client interactions during the client's clinic journey, encompassing how anxieties were expressed by clients, and responded to by practitioners. CONCLUSION: This study was the first to explore in depth the staff-client interaction culture within a breast assessment clinic using an ethnographic approach. A new perspective on professional values and behaviours has been demonstrated via a model of staff-client interaction. The model documents the process of guiding the client from initial confusion and distress to an enhanced clarity of understanding. A recommendation most likely to have a positive impact on the client experience is the introduction of a client navigator role to guide the clients through what is often a lengthy, stressful and confusing process.

Diagnostic accuracy of midtrimester antenatal ultrasound for multicystic dysplastic kidneys.

OBJECTIVES: To establish the diagnostic accuracy of obstetric ultrasound at a tertiary fetal medicine center in the prenatal detection of unilateral and bilateral multicystic dysplastic kidney (MCDK) in fetuses in which this condition was suspected, and to undertake a systematic review of the relevant literature. METHODS: This was a retrospective observational study of all cases referred to a regional tertiary fetal medicine unit due to suspicion of either unilateral or bilateral MCDK between 1997 and 2015. Diagnosis was confirmed by postnatal ultrasound reports or postmortem examination. The accuracy of prenatal ultrasound in the diagnosis of MCDK was calculated. Using a systematic search strategy we also performed a review of the literature regarding the prenatal diagnosis and diagnostic accuracy of MCDK. RESULTS: We included 144 women in our analysis; 37 (25.7%) opted for pregnancy termination (TOP) (due to unilateral MCDK with additional abnormalities, suspected bilateral MCDK or severe obstructive uropathy). Complete pre- and postnatal data were available in 126 pregnancies, including 104 livebirths, 19 TOPs with postmortem findings available and three intrauterine fetal deaths. Two infants died shortly after birth (due to known bilateral MCDK or known cranial vault defect). The overall number of cases of MCDK confirmed postnatally was 100; of these, 98 were diagnosed prenatally (true positive), while two were thought to be hydronephrosis prenatally (false negative) and the diagnosis of MCDK was made after birth. In nine cases, the initial antenatal diagnosis of suspected MCDK was revised, either later in pregnancy (n = 2) or postnatally (n = 7) (false positive). Overall, the diagnostic accuracy in our population for the use of antenatal ultrasound to detect MCDK was 91.3%, while that reported in the existing literature was found to range from 53.3% to 100%. MCDK was isolated in the majority (71%) of cases, while in 29% of cases it was found to be associated with other renal and extrarenal fetal abnormalities. CONCLUSIONS: Antenatal ultrasound had a diagnostic accuracy of about 91% in the prediction of postnatal MCDK and can therefore be used to guide antenatal counseling. However, prenatal or postnatal revision of the diagnosis occurred in about 7% of cases and parents should be counseled appropriately. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Thirty-days readmissions in pediatric surgery: The first U.K. experience.

INTRODUCTION: The aim of this study was to investigate readmissions within 30days of operation (ReAd) in the setting of a tertiary pediatric surgical practice in the UK. METHODS: Using Hospital Episode Statistics, cases that were readmitted within 30days of primary operation were identified retrospectively. Demographics including age, gender, preexisting comorbidities, diagnosis on primary admission and the treatment, length of stay, and diagnosis on readmission with treatment, including further surgical intervention, were collected from discharge summaries and hospital notes. Neonates were excluded from this study. Comorbidities, involving one or more systems, were also identified for each case of readmission. ReAds were classified into emergency and elective cohort depending on the nature of the primary operation. Outcomes were compared between these two groups. Data were quoted as median (range) unless indicated otherwise. Data were analyzed using SPSS software Desktop 22.0, using Mann-Whitney U and Chi-Squared tests, with a consideration that a P≤0.05 was significant. RESULTS: A total of 2378 procedures were performed during the study period. Elective cases, including day cases, accounted for 77% (n=1837) of all cases. The remaining 23% (n=541) were emergency cases. Total unplanned readmission rate within 30days (ReAd) was 2%. Further surgical procedures were required in 38%. Having excluded neonates, the most common primary procedure leading to readmission within 30days was appendicectomy (26%). Overall, the most common cause for readmission within 30days was postoperative infection (30%). The ReAd in emergency cohort was 3.5% in comparison to 1.5% in elective, which was significantly different (P value=0.007). CONCLUSION: Readmission within thirty days of primary procedure in pediatric surgery has little published data. An efficient discharge planning may play a vital role in preventing unwanted readmission. Elective operations had a significantly lower readmission rate than emergency operations. Having excluded neonates, appendicectomy was found to be the most common operation associated with readmission in the pediatric surgical practice. Although widely used as quality care indicator in adults, more studies are required to validate readmission rate as a quality of care indicator in pediatric surgery practice.

Historical Perspective: What Constitutes Discovery (of a New Virus)?

A historic review of the discovery of new viruses leads to reminders of traditions that have evolved over 118 years. One such tradition gives credit for the discovery of a virus to the investigator(s) who not only carried out the seminal experiments but also correctly interpreted the findings (within the technological context of the day). Early on, ultrafiltration played a unique role in "proving" that an infectious agent was a virus, as did a failure to find any microscopically visible agent, failure to show replication of the agent in the absence of viable cells, thermolability of the agent, and demonstration of a specific immune response to the agent so as to rule out duplicates and close variants. More difficult was "proving" that the new virus was the etiologic agent of the disease ("proof of causation")-for good reasons this matter has been revisited several times over the years as technologies and perspectives have changed. One tradition is that the discoverers get to name their discovery, their new virus (unless some grievous convention has been broken)-the stability of these virus names has been a way to honor the discoverer(s) over the long term. Several vignettes have been chosen to illustrate several difficulties in holding to the traditions (vignettes chosen include vaccinia and variola viruses, yellow fever virus, and influenza viruses. Crimean-Congo hemorrhagic fever virus, Murray Valley encephalitis virus, human immunodeficiency virus 1, Sin Nombre virus, and Ebola virus). Each suggests lessons for the future. One way to assure that discoveries are forever linked with discoverers would be a permanent archive in one of the universal virus databases that have been constructed for other purposes. However, no current database seems ideal-perhaps members of the global community of virologists will have an ideal solution.

Molecular profiling reveals primary mesothelioma cell lines recapitulate human disease.

Malignant mesothelioma (MM) is an aggressive, fatal tumor strongly associated with asbestos exposure. There is an urgent need to improve MM patient outcomes and this requires functionally validated pre-clinical models. Mesothelioma-derived cell lines provide an essential and relatively robust tool and remain among the most widely used systems for candidate drug evaluation. Although a number of cell lines are commercially available, a detailed comparison of these commercial lines with freshly derived primary tumor cells to validate their suitability as pre-clinical models is lacking. To address this, patient-derived primary mesothelioma cell lines were established and characterized using complementary multidisciplinary approaches and bioinformatic analysis. Clinical markers of mesothelioma, transcriptional and metabolic profiles, as well as the status of p53 and the tumor suppressor genes CDKN2A and NF2, were examined in primary cell lines and in two widely used commercial lines. Expression of MM-associated markers, as well as the status of CDKN2A, NF2, the 'gatekeeper' in MM development, and their products demonstrated that primary cell lines are more representative of the tumor close to its native state and show a degree of molecular diversity, thus capturing the disease heterogeneity in a patient cohort. Molecular profiling revealed a significantly different transcriptome and marked metabolic shift towards a greater glycolytic phenotype in commercial compared with primary cell lines. Our results highlight that multiple, appropriately characterised, patient-derived tumor cell lines are required to enable concurrent evaluation of molecular profiles versus drug response. Furthermore, application of this approach to other difficult-to-treat tumors would generate improved cellular models for pre-clinical evaluation of novel targeted therapies.

Is routine excision of testicular remnants in testicular regression syndrome indicated?

BACKGROUND: Undescended testicles are a common finding in full-term male infants. In the majority of these infants, the testicle spontaneously descends in the first year of life. However, in others, it remains impalpable in an abnormal position or there may only be a small abnormal testicular remnant present. For these infants there is still controversy surrounding inguinal exploration and/or excision of these testicular remnants at the time of operative intervention. The controversy centres on their potential future malignant potential. AIM: The aim of the study was to ascertain the incidence of the presence of either germ cells (GCs) or seminiferous tubules (SNTS) in the excised testicular remnants. This was performed at a paediatric surgical tertiary centre and contributes to the evidence base for this condition. METHOD: A retrospective data analysis occurring over a 15-year period of all excised testicular remnants. The testicular remnants were analysed for age, laterality, histological analysis and clinical diagnosis. Subset analysis included subdivision into both intra-abdominal or inguinal positions, and age ranges. Statistical analysis was using Fisher's exact test and a P-value of <0.05 was considered to be significant. RESULTS: A total of 140 paediatric male patients were identified as having had a testicular remnant excised during the study period. Their demographics and also the main results are summarised in the overall summary Table. The mean age at intervention was 3.5 years (range: 3 months to 17 years). A total of 132/140 of the boys underwent excision of an inguinal testicular regression syndrome (TRS) remnant and 8/140 an intra-abdominal remnant. Comparison of these two groups revealed no significant difference for the presence of GCs (12 (9%) vs 2 (25%), P = 0.18). However, intra-abdominal TRS remnants were much more likely to contain SNTs (27 (21%) vs 7 (88%), P = 0.0002). There was no decreased incidence of either GCs or SNTs with increased patient age. DISCUSSION: The main reason for the debate over the management of boys with TRS is the variable incidence of viable germ cells reported in different studies: it has been reported between 0 and 16%. The incidence of GCs (10%) and also SNT (24%) in the present series therefore contributes to this evidence base and is in the middle of this range. It is still unclear as to whether these remnants have a future malignancy risk, as there is only one case of intratubular germ cell neoplasia (ITGCN) in a testicular remnant reported in the literature and this was not immunohistochemically supported. The presence of ITGCN, although considered as a precursor to the development of a testicular germ cell tumour in adult patients, has also not been established in paediatric patients. The natural history of the GCs in TRS specimens is also unknown. In the present series, however, there was no decreased incidence demonstrated with increased patient age, although older patient numbers limited this subset analysis. Despite this controversy, as these patients were already under general anaesthetic, an inguinal exploration and excision of any TRS remnant that was present did not significantly increase the operative procedure or time, and removed any potential malignancy risk. CONCLUSION: This evidence supports the exploration and excision of inguinal testicular remnants, as one in ten boys have GCs present and one in four have SNTs, which may have a potential future malignant transformation risk.