Extraislet expression of islet antigen boosts T cell exhaustion to partially prevent autoimmune diabetes.

Persistent antigen exposure results in the differentiation of functionally impaired, also termed exhausted, T cells which are maintained by a distinct population of precursors of exhausted T (TPEX) cells. T cell exhaustion is well studied in the context of chronic viral infections and cancer, but it is unclear whether and how antigen-driven T cell exhaustion controls progression of autoimmune diabetes and whether this process can be harnessed to prevent diabetes. Using nonobese diabetic (NOD) mice, we show that some CD8+ T cells specific for the islet antigen, islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) displayed terminal exhaustion characteristics within pancreatic islets but were maintained in the TPEX cell state in peripheral lymphoid organs (PLO). More IGRP-specific T cells resided in the PLO than in islets. To examine the impact of extraislet antigen exposure on T cell exhaustion in diabetes, we generated transgenic NOD mice with inducible IGRP expression in peripheral antigen-presenting cells. Antigen exposure in the extraislet environment induced severely exhausted IGRP-specific T cells with reduced ability to produce interferon (IFN)γ, which protected these mice from diabetes. Our data demonstrate that T cell exhaustion induced by delivery of antigen can be harnessed to prevent autoimmune diabetes.

Altering ß Cell Antigen Exposure to Exhausted CD8+ T Cells Prevents Autoimmune Diabetes in Mice.

Chronic destruction of insulin-producing pancreatic ß cells by T cells results in autoimmune diabetes. Similar to other chronic T cell-mediated pathologies, a role for T cell exhaustion has been identified in diabetes in humans and NOD mice. The development and differentiation of exhausted T cells depends on exposure to Ag. In this study, we manipulated ß cell Ag presentation to target exhausted autoreactive T cells by inhibiting IFN-γ-mediated MHC class I upregulation or by ectopically expressing the ß cell Ag IGRP under the MHC class II promotor in the NOD8.3 model. Islet PD-1+TIM3+CD8+ (terminally exhausted [TEX]) cells were primary producers of islet granzyme B and CD107a, suggestive of cells that have entered the exhaustion program yet maintained cytotoxic capacity. Loss of IFN-γ-mediated ß cell MHC class I upregulation correlated with a significant reduction in islet TEX cells and diabetes protection in NOD8.3 mice. In NOD.TII/8.3 mice with IGRP expression induced in APCs, IGRP-reactive T cells remained exposed to high levels of IGRP in the islets and periphery. Consequently, functionally exhausted TEX cells, with reduced granzyme B expression, were significantly increased in these mice and this correlated with diabetes protection. These results indicate that intermediate Ag exposure in wild-type NOD8.3 islets allows T cells to enter the exhaustion program without becoming functionally exhausted. Moreover, Ag exposure can be manipulated to target this key cytotoxic population either by limiting the generation of cytotoxic TIM3+ cells or by driving their functional exhaustion, with both resulting in diabetes protection.

Synthesis of rearranged indole diterpenes of the paxilline type.

Covering: up to 2021Rearranged indole diterpenes of the paxilline type comprise a large group of fungal metabolites that possess diverse structural features and potentially useful biological effects. The unique indoloterpenoid motif, which is common to all congeners, was first confirmed by crystallographic studies of paxilline. This family of natural products has fascinated organic chemists for the past four decades and has inspired numerous syntheses and synthetic approaches. The present review highlights efforts that have laid the foundation and introduced new directions to this field of natural product synthesis. The introduction includes a summary of biosynthetic considerations and biological activities, the main body of the manuscript provides a detailed discussion of selected syntheses, and the review concludes with a brief outlook on the future of the field.

Clinically actionable genotypes for anticancer prescribing among >1500 patients with pharmacogenomic testing.

BACKGROUND: In recent years, there has been increasing evidence supporting the role of germline pharmacogenomic factors predicting toxicity for anticancer therapies. Although somatic genomic data are used frequently in oncology care planning, germline pharmacogenomic testing is not. This study hypothesizes that comprehensive germline pharmacogenomic profiling could have high relevance for cancer care. METHODS: Between January 2011 and August 2020, patients at the University of Chicago Medical Center were genotyped across custom germline pharmacogenomic panels for reasons unrelated to cancer care. Actionable anticancer pharmacogenomic gene/drug interactions identified by the FDA were defined including: CYP2C9 (erdafitinib), CYP2D6 (gefitinib), DPYD (5-fluorouracil and capecitabine), TPMT (thioguanine and mercaptopurine), and UGT1A1 (belinostat, irinotecan, nilotinib, pazopanib, and sacituzumab-govitecan hziy). The primary objective was to determine the frequency of individuals with actionable or high-risk genotypes across these 5 key pharmacogenes, thus potentially impacting prescribing for at least 1 of these 11 commonly prescribed anticancer therapies. RESULTS: Data from a total of 1586 genotyped individuals were analyzed. The oncology pharmacogene with the highest prevalence of high-risk, actionable genotypes was UGT1A1, impacting 17% of genotyped individuals. Actionable TPMT and DPYD genotypes were found in 9% and 4% of patients, respectively. Overall, nearly one-third of patients genotyped across all 5 genes (161/525, 31%) had at least one actionable genotype. CONCLUSIONS: These data suggest that germline pharmacogenomic testing for 5 key pharmacogenes could identify a substantial proportion of patients at risk with standard dosing, an estimated impact similar to that of somatic genomic profiling. LAY SUMMARY: Differences in our genes may explain why some drugs work safely in certain individuals but can cause side effects in others. Pharmacogenomics is the study of how genetic variations affect an individual's response to medications. In this study, an evaluation was done for important genetic variations that can affect the tolerability of anticancer therapy. By analyzing the genetic results of >1500 patients, it was found that nearly one-third have genetic variations that could alter recommendations of what drug, or how much of, an anticancer therapy they should be given. Performing pharmacogenomic testing before prescribing could help to guide personalized oncology care.

Domestic dogs (Canis lupus familiaris) are sensitive to the correlation between pitch and timbre in human speech.

The perceived pitch of human voices is highly correlated with the fundamental frequency (f0) of the laryngeal source, which is determined largely by the length and mass of the vocal folds. The vocal folds are larger in adult males than in adult females, and men's voices consequently have a lower pitch than women's. The length of the supralaryngeal vocal tract (vocal-tract length; VTL) affects the resonant frequencies (formants) of speech which characterize the timbre of the voice. Men's longer vocal tracts produce lower frequency, and less dispersed, formants than women's shorter vocal tracts. Pitch and timbre combine to influence the perception of speaker characteristics such as size and age. Together, they can be used to categorize speaker sex with almost perfect accuracy. While it is known that domestic dogs can match a voice to a person of the same sex, there has been no investigation into whether dogs are sensitive to the correlation between pitch and timbre. We recorded a female voice giving three commands ('Sit', 'Lay down', 'Come here'), and manipulated the recordings to lower the fundamental frequency (thus lowering pitch), increase simulated VTL (hence affecting timbre), or both (synthesized adult male voice). Dogs responded to the original adult female and synthesized adult male voices equivalently. Their tendency to obey the commands was, however, reduced when either pitch or timbre was manipulated alone. These results suggest that dogs are sensitive to both the pitch and timbre of human voices, and that they learn about the natural covariation of these perceptual attributes.

Pilot Findings of Pharmacogenomics in Perioperative Care: Initial Results From the First Phase of the ImPreSS Trial.

BACKGROUND: Pharmacogenomics, which offers a potential means by which to inform prescribing and avoid adverse drug reactions, has gained increasing consideration in other medical settings but has not been broadly evaluated during perioperative care. METHODS: The Implementation of Pharmacogenomic Decision Support in Surgery (ImPreSS) Trial is a prospective, single-center study consisting of a prerandomization pilot and a subsequent randomized phase. We describe findings from the pilot period. Patients planning elective surgeries were genotyped with pharmacogenomic results, and decision support was made available to anesthesia providers in advance of surgery. Pharmacogenomic result access and prescribing records were analyzed. Surveys (Likert-scale) were administered to providers to understand utilization barriers. RESULTS: Of eligible anesthesiology providers, 166 of 211 (79%) enrolled. A total of 71 patients underwent genotyping and surgery (median, 62 years; 55% female; average American Society of Anesthesiologists (ASA) score, 2.6; 58 inpatients and 13 ambulatories). No patients required postoperative intensive care or pain consultations. At least 1 provider accessed pharmacogenomic results before or during 41 of 71 surgeries (58%). Faculty were more likely to access results (78%) compared to house staff (41%; P = .003) and midlevel practitioners (15%) ( P < .0001). Notably, all administered intraoperative medications had favorable genomic results with the exception of succinylcholine administration to 1 patient with genomically increased risk for prolonged apnea (without adverse outcome). Considering composite prescribing in preoperative, recovery, throughout hospitalization, and at discharge, each patient was prescribed a median of 35 (range 15-83) total medications, 7 (range 1-22) of which had annotated pharmacogenomic results. Of 2371 prescribing events, 5 genomically high-risk medications were administered (all tramadol or omeprazole; with 2 of 5 pharmacogenomic results accessed), and 100 genomically cautionary mediations were administered (hydralazine, oxycodone, and pantoprazole; 61% rate of accessing results). Providers reported that although results were generally easy to access and understand, the most common reason for not considering results was because remembering to access pharmacogenomic information was not yet a part of their normal clinical workflow. CONCLUSIONS: Our pilot data for result access rates suggest interest in pharmacogenomics by anesthesia providers, even if opportunities to alter prescribing in response to high-risk genotypes were infrequent. This pilot phase has also uncovered unique considerations for implementing pharmacogenomic information in the perioperative care setting, and new strategies including adding the involvement of surgery teams, targeting patients likely to need intensive care and dedicated pain care, and embedding pharmacists within rounding models will be incorporated in the follow-on randomized phase to increase engagement and likelihood of affecting prescribing decisions and clinical outcomes.

Acute Itch Induces Attentional Avoidance of Itch-related Information.

Attention is known to modulate itch intensity. In contrast, the reverse relationship, i.e. the degree to which the presence of an acute itch affects attention, is currently not well understood. The aims of this study were to investigate whether acute itch induces an attentional bias towards or away from visual itch-related stimuli, and if so, whether it occurs in the early or later stages of processing. A volunteer sample of 60 healthy individuals were subjected to a skin prick (either histamine or placebo), followed by completion of a spatial cueing paradigm using itch-related and neutral words as cues, in order to obtain reaction time estimates of attentional bias. The results suggest that experience of acute itch induces attentional avoidance of visual itch threats. This attentional avoidance occurs at a later processing stage in the form of facilitated disengagement of attention from itch and/or delayed disengagement from neutral information.

Co-Infection with 4 Species of Mycobacteria Identified by Using Next-Generation Sequencing.

We identified co-infection with 4 species of mycobacteria in a woman in New York, New York, USA, by using next-generation sequencing. This procedure is useful for identifying co-infections with multiple mycobacteria, tracing the geographic origin of strains, investigating transmission dynamics in susceptible populations, and gaining insight into prevention and control.

Pre-pandemic cognitive function and COVID-19 mortality: prospective cohort study.

Poorer performance on standard tests of pre-morbid cognitive function is related to an elevated risk of death from lower respiratory tract infections but the link with coronavirus (COVID­19) mortality is untested. Participants in UK Biobank, aged 40 to 69 years at study induction (2006-10), were administered a reaction time test, an indicator of information processing speed, and also had their verbal-numeric reasoning assessed. Between April 1st and September 23rd 2020 there were 388 registry-confirmed deaths (138 women) ascribed to COVID-19 in 494,932 individuals (269,602 women) with a reaction time test result, and 125 such deaths (38 women) in the subgroup of 180,198 people (97,794 women) with data on verbal-numeric reasoning. In analyses adjusted for age, sex, and ethnicity, a one standard deviation slower reaction time was related to a higher rate of death from COVID-19 (hazard ratio; 95% confidence interval: 1.18; 1.09, 1.28), as was a one standard deviation disadvantage on the verbal-numeric reasoning test (1.32; 1.09, 1.59). While there was some attenuation in these relationships after adjustment for additional covariates which included socio-economic status and lifestyle factors, the two pre-pandemic indicators of cognitive function continued to be related to COVID-19 mortality.

Acute and cumulative benefits of Photobiomodulation for xerostomia: A systematic review and meta-analysis.

The objective was to explore the effectiveness of photobiomodulation therapy for treating patients who suffer xerostomia and/or hyposalivation due to the most prevalent clinical diagnoses. We searched PubMed, Scopus, Web of Science, CINAHL and Cochrane Library for randomized or clinical controlled trials published until 31 October 2019. Risk of bias assessment and meta-analysis were conducted using the Cochrane tools. A total of 274 records were retrieved, and 11 met the inclusion criteria. Interventions whose parameters ranged between wavelengths of 790-830 nm (infrared), 30-120 mW of power and an energy density below 30 J/cm-2 were associated with improvements in xerostomia/hyposalivation. As for the assessment of methodological quality, 10 of the 11 articles included had a high risk of overall bias. Only 3 articles provided sufficient information to conduct a meta-analysis for quality of life, compared with placebo in patients with burning mouth syndrome, showing a standardized mean difference between groups from baseline of -0.90 (-1.48; -0.32). The present review and meta-analysis suggest that photobiomodulation therapy is an effective, non-invasive and safe approach in patients with xerostomia. However, despite the potential, it is not possible to reach a reliable consensus on the parameters to be used, and future studies should be conducted by standardizing intervention protocols.

Ultrasound-Guided Percutaneous Iliotibial Band Release for External Coxa Saltans: A Cadaveric Study.

The surgical treatment of external coxa saltans is not standardized. Many techniques for iliotibial release have been described, both open and arthroscopic. No technique describes ultrasound release. In this cadaveric study, we describe a minimally invasive technique for percutaneous iliotibial release with ultrasound guidance, designed to be performed under local anesthesia. The future objective would be to perform an active intraoperative test of the snapping hip to confirm adequate release, thus reducing the risk of recurrence.

Patient Satisfaction with Outpatient Cervical Ripening in Parous Women.

OBJECTIVE: This study aimed to assess whether patient satisfaction differs between women beginning cervical ripening in the outpatient versus inpatient setting. STUDY DESIGN: We performed a planned secondary analysis evaluating patient satisfaction randomized to outpatient versus inpatient cervical ripening. In the original randomized controlled trial, low-risk parous women ≥39 weeks who required cervical ripening for induction and had reassuring fetal heart rate monitoring were included and randomized to inpatient versus outpatient ripening with a transcervical Foley's catheter. All women were then admitted to the labor ward on the following day. Patient satisfaction was evaluated using three separate surveys. The first two surveys, Six Simple Questions and Lady-X, were previously validated. The third survey used visual analog scales to assess overall pain experienced during Foley's placement, overall pain experienced during labor, how likely they would be to choose the same type of care for their next pregnancy, and how likely they would be to recommend their method of cervical ripening to friends/family. RESULTS: From May 2016 to October 2017, 129 women were randomized (outpatient, 65; inpatient, 64). Based on survey results, there was no difference in satisfaction between outpatient and inpatient cervical ripening with transcervical Foley's catheterization, with high satisfaction in both groups. Patients in both the outpatient and inpatient groups would choose the same type of care for their next pregnancy (on a scale of 1-7, median (25th-75th percentile): 7 [7-7] vs. 7 [6-7], respectively, p = 0.75) and would be very likely to recommend their method of induction to a friend or family member (on a scale of 0-100, 99 [80-100] vs. 99 [65-100], respectively, p = 0.60). CONCLUSION: Parous women's satisfaction does not differ between inpatient and outpatient cervical ripening with transcervical Foley's catheterization. KEY POINTS: · Outpatient cervical ripening may allow providers to incorporate the benefits of electively inducing women as well as decrease the time spent in the labor and delivery unit.. · Parous women's satisfaction does not differ between inpatient and outpatient cervical ripening with transcervical Foley.. · Additional prospective evaluation is warranted to further characterize patient preferences in relation to the location of cervical ripening..

Volatile Organic Compounds as Insect Repellents and Plant Elicitors: an Integrated Pest Management (IPM) Strategy for Glasshouse Whitefly (Trialeurodes vaporariorum).

The glasshouse whitefly (Trialeurodes vaporariorum Westwood) is a polyphagous arthropod pest that is of particular detriment to glasshouse grown tomato (Solanum lycopersicum) across temperate regions of the world. Control of whiteflies with synthetic pesticides has resulted in the evolution of resistant genotypes and a reduction in natural enemies, thus highlighting the need for environmentally sound control strategies. Volatile organic compounds (VOCs) offer an environmentally benign alternative to synthetic chemical sprays and this study explored the use of VOCs as insect repellents and plant defence elicitors to control whiteflies on tomato in a commercial glasshouse setting. Limonene in the form of a volatile dispenser system was found to successfully repel whitefly from the target crop and increased fruit yield by 32% during a heavy whitefly infestation. Analysis of tomato herbivore induced plant volatiles (HIPVs) led us to select methyl salicylate (MeSA) as the plant elicitor and application of MeSA to un-infested tomato plants was found to successfully reduce whitefly population development and increase yield by 11%, although this difference was marginally statistically significant. Combination of these two methods was also effective but whitefly abundance in combined plots was similar to the standalone limonene treatment across the course of the experiment. All of the VOC based control methods we used had a negative impact on whitefly performance, with more pronounced effects during the first few weeks of infestation. In subsequent laboratory experiments, we found elevated peroxidase (POD) activity and a significant increase in TPX1 and PR1 transcripts in MeSA treated plants. This led us to deduce that MeSA immediately induced plant defences, rather than priming them. We did however see evidence for residual priming, as plants treated with MeSA and infested with whiteflies produced significantly higher levels of POD activity than whitefly infestation alone. Despite the fact that our treatments failed to synergise, our methods can be optimised further, and the effectiveness of the standalone treatments is promising for future studies. In particular, our repellent limonene dispensers were extremely effective at deterring whiteflies and offer a low economic cost and easy to implement whitefly control option. The methods we have used here could be incorporated into current integrated pest management (IPM) systems, a sustainable approach to pest control which will be central to our efforts to manage whitefly populations under glass in the future.

Out-of-home care in childhood and biomedical risk factors in middle-age: National birth cohort study.

OBJECTIVE: With there being an apparent impact of experience of out-of-home care in childhood on chronic disease and mortality, we examined how such adversity might be embodied such that it has a measurable impact on human biology, so mediating this relationship. METHODS: We used data from the UK National Child Development Study in which exposure to public care was prospectively gathered on three occasions up to age 16. Study members also participated in a social survey at age 42 and a clinical examination at age 44/45 when cardiovascular, inflammatory, neuroendocrine, and respiratory risk markers for mortality were collected, 19 of which were included as endpoints in the present analyses. RESULTS: Of the 8012 participants in the biomedical survey, 4% (n = 322) had been in care at some point in childhood and/or adolescence. We found the expected marked differences in the early life characteristics of poverty, health, and disability in children with experience of public care relative to their unexposed counterparts. After controlling for these confounding factors, however, care in childhood was essentially unrelated to biomarkers in middle-age. We also found no consistent links between these biomarkers and the duration, timing, or type of care. CONCLUSIONS: Our results suggest that the biomarkers captured in the present study are unlikely to mediate the link between public care in childhood and later chronic disease or mortality. Processes involving mental health, socioeconomic position, and health behaviors would seem to be a potential alternative pathway warranting investigation.

A Radical-Polar Crossover Annulation To Access Terpenoid Motifs.

A new catalytic radical-polar crossover annulation between two unsaturated carbonyl compounds is described. The annulation proceeds under exceptionally mild conditions and provides direct and expedient access to complex terpenoid motifs. Application of this chemistry allows for synthesis of forskolin, a densely functionalized terpenoid, in 14 steps from commercially available material.

Effects of Short-term Temperature Change in the Innocuous Range on Histaminergic and Non-histaminergic Acute Itch.

While temperatures in the noxious range are well-known to inhibit acute itch, the impact of temperature in the innocuous temperature range is less well understood. We investigated the effect of alternating short-term temperature changes in the innocuous range on histamine and cowhage-induced acute itch, taking into account individual differences in baseline skin temperature and sensory thresholds. Results indicate that cooling the skin to the cold threshold causes a temporary increase in the intensity of histamine-induced itch, in line with previous findings. Skin warming increased cowhage-induced itch intensity. Potential mecha-nisms of this interaction between thermosensation and pruritoception could involve cold-sensitive channels such as TRPM8, TREK-1 or TRPC5 in the case of histamine. The rapid modulation of cowhage induced itch - but not histamine-induced itch - by transient skin warming could be related to the lower temperature threshold of pruriceptive polymodal C-fibres (cowhage) as compared to the higher temperature threshold of the mechanoinsensitive C-fibres conveying histaminergic itch.

WITHDRAWN: Ozone therapy for the treatment of dental caries.

BACKGROUND: Dental caries is a bacterially mediated disease characterised by demineralisation of the tooth surface, which may lead to cavitation, discomfort, pain and eventual tooth loss. Ozone is toxic to certain bacteria in vitro and it has been suggested that delivering ozone into a carious lesion might reduce the number of cariogenic bacteria. This possibly could arrest the progress of the lesion and may, in the presence of fluoride, perhaps allow remineralisation to occur. This may in turn delay or prevent the need for traditional dental conservation by 'drilling and filling'. OBJECTIVES: To assess whether ozone is effective in arresting or reversing the progression of dental caries. SEARCH METHODS: We searched the Cochrane Oral Health Group's Trials Register (to 7 November 2003); Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2003, Issue 3); MEDLINE and PREMEDLINE (OVID) (1966 to November 2003); EMBASE (OVID) (1980 to November 2003); CINAHL (OVID) (1982 to November 2003); AMED (OVID) (1985 to November 2003). Quintessence was handsearched through 2002 and KaVo were contacted as manufacturers of the HealOzone apparatus for any additional published or unpublished trials. SELECTION CRITERIA: Inclusion was assessed independently by at least two reviewers. Trials were only included if they met the following criteria: randomisation in a controlled trial; single surface in vivo carious lesion accessible to ozone application; clear allocation concealment; ozone application to the lesions in the intervention group; no such application of ozone in the control group; outcomes measured after at least 6 months. DATA COLLECTION AND ANALYSIS: Reviewers independently extracted information in duplicate. A paucity of comparable data did not allow meta-analytic pooling of the included studies. MAIN RESULTS: Three trials were included, with a combined total of 432 randomised lesions (137 participants). Forty-two conference papers, abstracts and posters were excluded (from an unknown number of studies). The risk of bias in all studies appeared high. The analyses of all three studies were conducted at the level of the lesion, which is not independent of the person, for this reason pooling of data was not appropriate or attempted. Individual studies showed inconsistent effects of ozone on caries, across different measures of caries progression or regression. Few secondary outcomes were reported, but one trial reported an absence of adverse events. AUTHORS' CONCLUSIONS: Given the high risk of bias in the available studies and lack of consistency between different outcome measures, there is no reliable evidence that application of ozone gas to the surface of decayed teeth stops or reverses the decay process. There is a fundamental need for more evidence of appropriate rigour and quality before the use of ozone can be accepted into mainstream primary dental care or can be considered a viable alternative to current methods for the management and treatment of dental caries.

Characteristics of Social Networks and Mortality Risk: Evidence From 2 Prospective Cohort Studies.

The size of a person's social network is linked to health and longevity, but it is unclear whether the number of strong social ties or the number of weak social ties is most influential for health. We examined social network characteristics as predictors of mortality in the Finnish Public Sector Study (n = 7,617) and the Health and Social Support Study (n = 20,816). Social network characteristics were surveyed at baseline in 1998. Information about mortality was obtained from the Finnish National Death Registry. During a mean follow-up period of 16 years, participants with a small social network (≤10 members) were more likely to die than those with a large social network (≥21 members) (adjusted hazard ratio (HR) = 1.23, 95% confidence interval (CI): 1.04, 1.46). Mortality risk was increased among participants with both a small number of strong ties (≤2 members) and a small number of weak ties (≤5 members) (HR = 1.55, 95% CI: 1.26, 1.79) and among participants with both a large number of strong ties and a small number of weak ties (HR = 1.28, 95% CI: 1.08, 1.52), but not among those with a small number of strong ties and a large number of weak ties (HR = 1.04, 95% CI: 0.87, 1.25). These findings suggest that in terms of mortality risk, the number of weak ties may be an important component of social networks.

The classification of pediatric and young adult renal cell carcinomas registered on the children's oncology group (COG) protocol AREN03B2 after focused genetic testing.

BACKGROUND: Renal cell carcinomas (RCCs) are rare in young patients. Knowledge of their pathologic and molecular spectrum remains limited, and no prospective studies have been performed to date in this population. This study analyzes patients diagnosed with RCC who were prospectively enrolled in the AREN03B2 Children's Oncology Group (COG). The objective was to classify these tumors with the aid of focused genetic testing and to characterize their features. METHODS: All tumors registered as RCC by central review were retrospectively re-reviewed and underwent additional ancillary studies. Tumors were classified according to the 2016 World Health Organization classification system when possible. RESULTS: In total, 212 tumors were identified, and these were classified as microphthalmia transcription factor (MiT) translocation RCC (MiT-RCC) (41.5%), papillary RCC (16.5%), renal medullary carcinoma (12.3%), chromophobe RCC (6.6%), clear cell RCC (3.3%), fumarate hydratase-deficient RCC (1.4%), and succinate dehydrogenase-deficient RCC (0.5%). Other subtypes included tuberous sclerosis-associated RCC (4.2%), anaplastic lymphoma kinase (ALK)-rearranged RCC (3.8%), thyroid-like RCC (1.4%), myoepithelial carcinoma (0.9%), and unclassified (7.5%). MiT-RCCs were classified as either transcription factor E3 (TFE3) (93.2%) or EB (TFEB) (6.8%) translocations, and characterization of fusion partners was possible in most tumors. CONCLUSIONS: The current study delineates the frequency of distinct RCC subtypes in a large prospective series of young patients and contributes knowledge to the diagnostic, clinical, and genetic features of MiT-RCC, the most common subtype among this age group. The identification of rare subtypes expands the spectrum of RCC in young patients, supporting the need for a thorough diagnostic workup. These studies may aid in the introduction of specific therapies for different RCC subtypes in the future. Cancer 2018. © 2018 American Cancer Society.

Cost-benefit analysis of antibiofilm microbiological techniques for peri-prosthetic joint infection diagnosis.

BACKGROUND: Implant-related infections, including those of peri-prosthetic joint (PJIs), osteosynthesis and other biomaterials, are biofilm-related. Pathogen identification is considered the diagnostic benchmark; however, the presence of bacterial biofilms makes pathogen detection with traditional microbiological techniques only partially effective. To improve microbiological diagnostic accuracy, some biofilm debonding techniques have been recently proposed. Aim of this health economics assessment study was to evaluate their economic impact on hospital costs. METHODS: Direct and indirect hospital costs connected with the routine introduction of sonication and dithiothreitol treatment applied to hip and knee PJIs and of tissue cultures were examined. In particular the consequences of diagnostic inaccuracy, the opportunities, costs, and risks of each technique were calculated. RESULTS: Considering an average of five samples per patient, processed separately with traditional tissue culture with or without sonication of prosthetic components, or pooled together using the MicroDTTect device (a close system for sample collection, transport and treatment with Dithiothreitol for microbial release from biofilm), the overall mean direct cost per patient was € 397 and € 393 for sonication or MicroDTTect, respectively, compared to € 308 for traditional tissue cultures. In terms of opportunity costs, MicroDTTect was the most effective technique, allowing for a 35% or 55% reduction in time required for sample treatment, compared to tissue cultures combined or not with sonication, respectively. Pooling together direct and indirect costs associated with false positive and negative results of the different diagnostic techniques, unnecessary medical treatments and possible medical claims, MicroDTTect or sonication become increasingly cost-effective when the extra-costs, generated by diagnostic inaccuracy of traditional tissue culture, took place, respectively, in 2% or 20% or more of the patients. CONCLUSIONS: This is the first study specifically focused on the economic impact of the routine clinical use of microbiological antibiofilm sampling and processing techniques in orthopaedics. Although our results may suffer from a potential country and hospital bias, as the data collection process for direct and indirect costs is specific to each institution and country, this analysis highlights the potential economic advantage to hospitals associated with the routine introduction of antibiofilm techniques for microbiological diagnosis of PJI.