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Kret et al. (2020) thoroughly reviewed expressions of basic emotions in humans and great apes and concluded that, although there are some species variations, many features of emotional expressions are conserved across humans and non-human great apes (hereafter, great apes). Here, we argue that the comparison between emotional expressions of humans and great apes is incomplete unless the whole range of emotions, including more complex self-conscious emotions is taken into account. Previously, such emotions were thought to be restricted to humans because of the advanced socio-cognitive skills they require (e.g., Parr et al., 2005). However, recent studies suggest that great apes might have these necessary socio-cognitive skills (e.g., Krupenye and Call, 2019; Krachun et al., 2019). To that end, we suggest that comparative studies on emotions should incorporate self-conscious emotions. Here, we discuss the human and great apes literature on self-conscious emotional expressions, namely embarrassment, shyness, shame, guilt, and jealousy 1 .

ObjectivesPaediatric cancer is a leading cause of death for children. Children in low-income and middle-income countries (LMICs) were four times more likely to die than children in high-income countries (HICs). This study aimed to test the hypothesis that the COVID-19 pandemic had affected the delivery of healthcare services worldwide, and exacerbated the disparity in paediatric cancer outcomes between LMICs and HICs.DesignA multicentre, international, collaborative cohort study.Setting91 hospitals and cancer centres in 39 countries providing cancer treatment to paediatric patients between March and December 2020.ParticipantsPatients were included if they were under the age of 18 years, and newly diagnosed with or undergoing active cancer treatment for Acute lymphoblastic leukaemia, non-Hodgkin’s lymphoma, Hodgkin lymphoma, Wilms’ tumour, sarcoma, retinoblastoma, gliomas, medulloblastomas or neuroblastomas, in keeping with the WHO Global Initiative for Childhood Cancer.Main outcome measureAll-cause mortality at 30 days and 90 days.Results1660 patients were recruited. 219 children had changes to their treatment due to the pandemic. Patients in LMICs were primarily affected (n=182/219, 83.1%). Relative to patients with paediatric cancer in HICs, patients with paediatric cancer in LMICs had 12.1 (95% CI 2.93 to 50.3) and 7.9 (95% CI 3.2 to 19.7) times the odds of death at 30 days and 90 days, respectively, after presentation during the COVID-19 pandemic (pConclusionsThe COVID-19 pandemic has affected paediatric oncology service provision. It has disproportionately affected patients in LMICs, highlighting and compounding existing disparities in healthcare systems globally that need addressing urgently. However, many patients with paediatric cancer continued to receive their normal standard of care. This speaks to the adaptability and resilience of healthcare systems and healthcare workers globally.

BACKGROUND Liver cancer is the fifth most common cancer and the second cause of cancer-related deaths worldwide. Transarterial chemoembolization (TACE) is the best treatment of intermediate hepatocellular carcinoma (HCC). Doxorubicin is the most commonly used drug despite a low level of evidence. AIM To compare the objective response rate of idarubicin-based TACE (Ida-TACE) against doxorubicin-based TACE (Dox-TACE) in intermediate stage HCC. METHODS Between January 2012 and December 2014, all patients treated with TACE at our academic hospital were screened. Inclusion criteria were patients with Child-Pugh score A or B, a performance status below or equal to 1, and no prior TACE. Either lipiodol TACE or drug-eluting beads TACE could be performed with 10 mg of idarubicin or 50 mg of doxorubicin. Each patient treated with idarubicin was matched with two doxorubicin-treated patients. The TACE response was assessed by independent radiologists according to the mRECIST criteria. RESULTS Sixty patients were treated with doxorubicin and thirty with idarubicin. There were 93% and 87% of cirrhotic patients and 87% and 70% of Child-Pugh A in the doxorubicin and idarubicin groups, respectively. The median number of HCC per patient was two in both groups with 31% and 26% of single nodules in doxorubicin and idarubicin groups, respectively. Objective response rate after first TACE was 76.7% and 73.3% (P = 0.797) with 41.7% and 40.0% complete response in doxorubicin and idarubicin groups, respectively. Progression-free survival was 7.7 mo in both groups, and liver transplant-free survival was 24.9 mo and 21.9 mo in doxorubicin and idarubicin groups, respectively. Safety profiles were similar in both groups, with grade 3-4 adverse events in 35% of Dox-TACE and 43% of Ida-TACEs. CONCLUSION Ida-TACE and Dox-TACE showed comparable results in terms of efficacy and safety. Ida-TACE may represent an interesting alternative to Dox-TACE in the management of patients with intermediate stage HCC.

The technique of 3D printing offers a high potential for further optimization of spinal surgery. This new technology has been published for different areas in the field of spinal surgery, e.g. in preoperative planning, intraoperative use as well as to create patient-specific implants. For example, it has been demonstrated that preoperative 3‑dimensional visualization of spinal deformities is helpful in planning procedures. Moreover, insertion of pedicle screws seems to be more accurate when using individualized templates to guide the drill compared to freehand techniques. This review summarizes the current literature dealing with 3D printing in spinal surgery with special consideration of the current applications, the limitations and the future potential.Die Technik des 3D-Drucks bietet viel Potenzial in der Wirbelsäulenchirurgie. Diese neue Technologie fand bereits in unterschiedlichen Bereichen der spinalen Chirurgie Anwendung; hierzu zählen die präoperative Planung sowie die intraoperative Insertion und Herstellung von patientenspezifischen Implantaten. Zum Beispiel konnte gezeigt werden, dass die präoperative dreidimensionale Visualisierung spinaler Deformitäten in der Operationsplanung hilfreich ist und die Platzierung von Pedikelschrauben durch individuelle Templates präziser ist als in der Freihandtechnik. Das vorliegende Review fasst die aktuelle Literatur über den 3D-Druck in der Wirbelsäulenchirurgie systematisch unter Berücksichtigung des aktuellen Stands der Anwendungen, der Limitierungen und des Potenzials zusammen.

Imaging studies with PET tracers acting as fibroblast activation protein inhibitors (FAPIs) show promising results that could usefully complement [

IntroductionChildhood cancer is a leading cause of death. It is unclear whether the COVID-19 pandemic has impacted childhood cancer mortality. In this study, we aimed to establish all-cause mortality rates for childhood cancers during the COVID-19 pandemic and determine the factors associated with mortality.MethodsProspective cohort study in 109 institutions in 41 countries. Inclusion criteria: children ResultsAll-cause mortality was 3.4% (n=71/2084) at 30-day follow-up, 5.7% (n=113/1969) at 90-day follow-up and 13.0% (n=206/1581) at 12-month follow-up. The median time from diagnosis to multidisciplinary team (MDT) plan was longest in low-income countries (7 days, IQR 3–11). Multivariable analysis revealed several factors associated with 12-month mortality, including low-income (OR 6.99 (95% CI 2.49 to 19.68); pConclusionsChildren with cancer are more likely to die within 30 days if infected with SARS-CoV-2. However, timely treatment reduced odds of death. This report provides crucial information to balance the benefits of providing anticancer therapy against the risks of SARS-CoV-2 infection in children with cancer.

Small cell lung cancer (SCLC) is the most fatal form of lung cancer, with dismal survival, limited therapeutic options, and rapid development of chemoresistance. We identified the lysine methyltransferase SMYD3 as a major regulator of SCLC sensitivity to alkylation-based chemotherapy. RNF113A methylation by SMYD3 impairs its interaction with the phosphatase PP4, controlling its phosphorylation levels. This cross-talk between posttranslational modifications acts as a key switch in promoting and maintaining RNF113A E3 ligase activity, essential for its role in alkylation damage response. In turn, SMYD3 inhibition restores SCLC vulnerability to alkylating chemotherapy. Our study sheds light on a novel role of SMYD3 in cancer, uncovering this enzyme as a mediator of alkylation damage sensitivity and providing a rationale for small-molecule SMYD3 inhibition to improve responses to established chemotherapy. Significance: SCLC rapidly becomes resistant to conventional chemotherapy, leaving patients with no alternative treatment options. Our data demonstrate that SMYD3 upregulation and RNF113A methylation in SCLC are key mechanisms that control the alkylation damage response. Notably, SMYD3 inhibition sensitizes cells to alkylating agents and promotes sustained SCLC response to chemotherapy. This article is highlighted in the In This Issue feature, p. 2007

Given its similarities with mammalian systems, the zebrafish has emerged as a potential model to study the blood-brain barrier (BBB). Capillary endothelial cells at the human BBB express high levels of P-glycoprotein (P-gp, encoded by the ABCB1 gene) and ABCG2 (encoded by the ABCG2 gene). However, little information has been available about ATP-binding cassette transporters expressed at the zebrafish BBB. In this study, we focus on the characterization and tissue localization of two genes that are similar to human ABCB1, zebrafish abcb4 and abcb5. Cytotoxicity assays with stably-transfected cell lines revealed that zebrafish Abcb5 cannot efficiently transport the substrates doxorubicin and mitoxantrone compared to human P-gp and zebrafish Abcb4. Additionally, zebrafish Abcb5 did not transport the fluorescent probes BODIPY-ethylenediamine or LDS 751, while they were readily transported by Abcb4 and P-gp. A high-throughput screen conducted with 90 human P-gp substrates confirmed that zebrafish Abcb4 has overlapping substrate specificity with P-gp. Basal ATPase activity of zebrafish Abcb4 and Abcb5 was comparable to that of human P-gp. In the brain vasculature, RNAscope probes to detect abcb4 colocalized with staining by the P-gp antibody C219, while abcb5 was not detected. Zebrafish abcb4 also colocalized with claudin-5 expression in brain endothelial cells. Abcb4 and Abcb5 had different tissue localizations in multiple zebrafish tissues, consistent with different functions. The data suggest that zebrafish Abcb4 most closely phenocopies P-gp and that the zebrafish may be a viable model to study the role of the multidrug transporter P-gp at the BBB.

A consistent finding in the literature is that men overperceive sexual interest in women (i.e., sexual overperception bias). Several potential mechanisms have been proposed for this bias, including projecting one’s own interest onto a given partner, sexual desire, and self-rated attractiveness. Here, we examined the influence of these factors in attraction detection accuracy during speed-dates. Sixty-seven participants (34 women) split in four groups went on a total of 10 speed-dates with all opposite-sex members of their group, resulting in 277 dates. The results showed that attraction detection accuracy was reliably predicted by projection of own interest in combination with participant sex. Specifically, men were more accurate than women in detecting attraction when they were not interested in their partner compared to when they were interested. These results are discussed in the wider context of arousal influencing detection of partner attraction. Supplementary Information The online version contains supplementary material available at 10.1007/s10508-021-02017-5.

Protein arginine methyltransferases (PRMTs) are required for the regulation of RNA processing factors. Type I PRMT enzymes catalyze mono- and asymmetric dimethylation; Type II enzymes catalyze mono- and symmetric dimethylation. To understand the specific mechanisms of PRMT activity in splicing regulation, we inhibited Type I and II PRMTs and probed their transcriptomic consequences. Using the newly developed Splicing Kinetics and Transcript Elongation Rates by Sequencing (SKaTER-seq) method, analysis of co-transcriptional splicing demonstrated that PRMT inhibition resulted in altered splicing rates. Surprisingly, co-transcriptional splicing kinetics did not correlate with final changes in splicing of polyadenylated RNA. This was particularly true for retained introns (RI). By using actinomycin D to inhibit ongoing transcription, we determined that PRMTs post-transcriptionally regulate RI. Subsequent proteomic analysis of both PRMT-inhibited chromatin and chromatin-associated polyadenylated RNA identified altered binding of many proteins, including the Type I substrate, CHTOP, and the Type II substrate, SmB. Targeted mutagenesis of all methylarginine sites in SmD3, SmB, and SmD1 recapitulated splicing changes seen with Type II PRMT inhibition, without disrupting snRNP assembly. Similarly, mutagenesis of all methylarginine sites in CHTOP recapitulated the splicing changes seen with Type I PRMT inhibition. Examination of subcellular fractions further revealed that RI were enriched in the nucleoplasm and chromatin. Taken together, these data demonstrate that, through Sm and CHTOP arginine methylation, PRMTs regulate the post-transcriptional processing of nuclear, detained introns.

International audience; Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related deaths worldwide, and its incidence is rising. HCC develops almost exclusively on the background of chronic liver inflammation, which can be caused by chronic alcohol consumption, viral hepatitis, or an unhealthy diet. The key role of chronic inflammation in the process of hepatocarcinogenesis, including in the deregulation of innate and adaptive immune responses, has been demonstrated. The inhibition of Akt (also known as Protein Kinase B) directly affects cancer cells, but this therapeutic strategy also exhibits indirect anti-tumor activity mediated by the modulation of the tumor microenvironment, as demonstrated by using Akt inhibitors AZD5363, MK-2206, or ARQ 092. Moreover, the isoforms of Akt converge and diverge in their designated roles, but the currently available Akt inhibitors fail to display an isoform specificity. Thus, selective Akt inhibition needs to be better explored in the context of HCC and its possible combination with immunotherapy. This review presents a compact overview of the current knowledge concerning the role of Akt in HCC and the effect of Akt inhibition on the HCC and liver tumor microenvironment.

Mutations in epigenetic regulators are common in relapsed pediatric acute lymphoblastic leukemia (ALL). Here, we uncovered the mechanism underlying the relapse of ALL driven by an activating mutation of the

BACKGROUND: Frequent migraine headaches are disabling and aeromedically disqualifying. Four new monoclonal antibody medications, targeting calcitonin gene-related peptide (CGRP), have been approved by the U.S. Food and Drug Administration (FDA) since 2018, with more expected in the coming years. These medications present new alternatives for the treatment of migraine unresponsive to other therapeutic and prophylactic agents.CASE REPORT: We present a case of a 45-yr-old commercial pilot who presented with migraine headaches increasing in frequency to 1315 per month in spite of the use of propranolol for prophylaxis and sumatriptan for abortive treatment of the headaches. Upon presentation, he was not flying due to his frequent headaches and he was started on monthly subcutaneous injections of fremanezumab. Following his second injection, his headaches stopped entirely, and he has continued on the medication and not experienced another migraine headache. He underwent an aeromedical neurology evaluation and consideration for Authorization of Special Issuance of Medical Certificate, which was granted by the Federal Aviation Administration (FAA).DISCUSSION: This is the first case to our knowledge of the successful use of an anti-CGRP monoclonal antibody medication in an active pilot. The pilot appears to be a super responder to the medication, having achieved complete remission of a nearly life-long condition. Though only a small portion of treated individuals will see this sort of response, these medications represent an effective additional option for migraine prophylaxis in the pilot population.Garber MA, Sirven JI, Roth RS, Hemphill JM. Migraine prophylaxis using novel monoclonal antibody injections in a commercial pilot. Aerosp Med Hum Perform. 2020; 91(10):824825.

Protein lysine methylation is a functionally diverse post-translational modification involved in various major cellular processes. Lysine methylation can modulate proteins activity, stability, localization, and/or interaction, resulting in specific downstream signaling and biological outcomes. Lysine methylation is a dynamic and fine-tuned process, deregulation of which often leads to human pathologies. In particular, the lysine methylome and its associated signaling network can be linked to carcinogenesis and cancer progression. Histone modifications and chromatin regulation is a major aspect of lysine methylation importance, but increasing evidence suggests that a high relevance and impact of non-histone lysine methylation signaling has emerged in recent years. In this review, we draw an updated picture of the current scientific knowledge regarding non-histone lysine methylation signaling and its implication in physiological and pathological processes. We aim to demonstrate the significance of lysine methylation as a major and yet underestimated posttranslational modification, and to raise the importance of this modification in both epigenetic and cellular signaling by focusing on the observed activities of SET- and 7β-strandcontaining human lysine methyltransferases. Recent evidence suggests that what has been observed so far regarding lysine methylation’s implication in human pathologies is only the tip of the iceberg. Therefore, the exploration of the “methylome network” raises the possibility to use these enzymes and their substrates as promising new therapeutic targets for the development of future epigenetic and methyllysine signaling cancer treatments.

With rising health care costs in the United States, trainees will be increasingly challenged in discussing testing stewardship with patients. We piloted a high-value care (HVC) communication skills curriculum utilizing the Four Habits Model for communication. We hoped residents would 1) learn to apply the Four Habits communication model to HVC discussions with standardized patients (SP) and 2) improve value-based communication skills through training in a high-intensity curriculum with feedback from trained faculty facilitators and peers. Thirty interns at the University of Minnesota were randomized to a standard HVC communication SP encounter (n = 15) or a high-intensity HVC communication skills curriculum (n = 15). The high-intensity curriculum included video and audio-recorded SP encounters followed by facilitated small group discussions/feedback. Experiences were reported in a post-intervention survey; communication skills were assessed with the CARE empathy scale. 70% (21/30) of interns (57% high intensity, 43% standard) responded to the survey. In total, 88% of high intensity v. 44% of standard interns agreed/strongly agreed that the curriculum was valuable for their communication skills. High-intensity interns were more likely to report that feedback was valuable with subsequent incorporation of feedback into future patient encounters. High-intensity participants also reported higher levels of interest in future HVC curricula (55% vs 22%). There was no difference in overall performance on the CARE empathy scale. Our HVC high-intensity skills curriculum was well received by interns and provided opportunities to practice structured conversations and debrief around testing stewardship.

The implantation of an internal biliary stent (IBS) during liver transplantation has recently been shown to reduce biliary complications. To avoid a potentially morbid ablation procedure, we developed a resorbable and radiopaque internal biliary stent (RIBS). We studied the mechanical and radiological properties of RIBS upon in vivo implantation in rats and we evaluated RIBS implantability in human anatomical specimens. For this purpose, a blend of PLA50-PEG-PLA50 triblock copolymer, used as a polymer matrix, and of X-ray-visible triiodobenzoate-poly(e-caprolactone) copolymer (PCL-TIB), as a radiopaque additive, was used to design X-ray-visible RIBS. Samples were implanted in the peritoneal cavity of rats. The radiological, chemical, and biomechanical properties were evaluated during degradation. Further histological studies were carried out to evaluate the degradation and compatibility of the RIBS. A human cadaver implantability study was also performed. The in vivo results revealed a decline in the RIBS mechanical properties within 3 months, whereas clear and stable X-ray visualization of the RIBS was possible for up to 6 months. Histological analyses confirmed compatibility and resorption of the RIBS, with a limited inflammatory response. The RIBS could be successfully implanted in human anatomic specimens. The results reported in this study will allow the development of trackable and degradable IBS to reduce biliary complications after liver transplantation. STATEMENT OF SIGNIFICANCE: Biliary reconstruction during liver transplantation is an important source of postoperative morbidity and mortality although it is generally considered as an easy step of a difficult surgery. In this frame, internal biliary stent (IBS) implantation is beneficial to reduce biliary anastomosis complications (leakage, stricture). However, current IBS are made of non-degradable silicone elastomeric materials, which leads to an additional ablation procedure involving potential complications and additional costs. The present study provides in vitro and human postmortem implantation data related to the development and evaluation of a resorbable and radiopaque internal biliary stent (RIBS) that could tackle these drawbacks.

Aim of the present study is to compare magnetic resonance imaging (MRI) and positron emission tomography (PET) parameters in the follow up of chronic periaortitis (CP), with a focus on changes in the apparent diffusion coefficient (ADC) and standardized uptake values (SUV). 127 patients with CP were treated in our urology between 2007 and 2017. We identified 14 patients with parallel abdominal MRI and PET-CT examinations before therapy and in the follow up resulting in a total of 56 examinations. Relative contrast uptake and diffusion-weighted MRI parameters were compared to SUV in the corresponding PET-CT examinationsand laboratory infection markers. All examined MRI and PET-CT parameters showed significant changes between basis and follow-up examinations. Median ADC values increased significantly (p

Background and purpose In 2011, fingolimod was approved in Switzerland for the treatment of relapsing-remitting multiple sclerosis (RRMS). The aim of the present study was to assess the effectiveness and retention of fingolimod in a real-life Swiss setting, in which patients can receive fingolimod as both first- and second-line treatment for RRMS. Methods This cross-sectional, observational study with retrospective data collection was performed at 19 sites that comprised both hospitals and office-based physicians across Switzerland. Sites were asked to document eligible patients in consecutive chronological order to avoid selection bias. Demographic and clinical data from 274 consenting adult patients with RRMS who had received treatment with fingolimod were analyzed. Results Mean treatment duration with fingolimod was 32 months. Under fingolimod, 77.7% of patients remained free from relapses and 90.3% did not experience disability progression. The proportion of patients who were free from any clinical disease activity, i.e. without relapses and disability progression, was 72.1%. A total of 28.5% of patients had been RRMS treatment-naive prior to fingolimod therapy. High long-term treatment retention rates ranging between 95.7% at 24 months and 87.8% at 36 months were observed. Conclusion In this Swiss cohort of naive and pre-treated subjects with RRMS, the majority of patients under fingolimod treatment showed freedom from relapses and disability progression. In addition, treatment retention rate over 2 and 3 years was high, irrespective of previous treatment.

In line with other major surgeries including breast cancer surgery (BCS), recent studies suggest a striking rate of chronic postsurgical pain (CPSP) following breast reconstruction. This commentary will critically examine evidence for the degree to which the prevalence of CPSP following breast reconstruction is directly attributable to reconstructive surgery. The discussion will trace similarities and distinctions between breast reconstruction and BCS in considering the risk for CPSP, and describe recent advances in the definition of CPSP, highlighting methodological limitations in the general investigation of CPSP, which also characterize the study of CPSP more specifically for breast reconstruction outcome. A convenience sample of relevant studies examining CPSP following breast reconstruction reveals inadequate evidence to support a serious concern for reconstruction-induced CPSP and further that these studies fail to adhere to recommended methodological standards to effectively isolate surgery as the etiology of persistent pain reported by women following reconstructive surgery. Suggestions for future exploration of problematic chronic pain after breast reconstruction are considered.

At the moment of the diagnosis of hepatocellular carcinoma (HCC), 70% of patients have only access to palliative treatments, with very few therapeutic options. Liver immunology is very specific, and liver immunotolerance is particularly developed because of the constant and massive influx of antigens. Deregulation of hepatic immunotolerance is implicated in chronic liver diseases development and particularly in liver carcinogenesis. For these reasons, HCC may be an excellent candidate for anticancer immunotherapies such as immune checkpoint inhibitors targeting CTLA-4 and PD-L1/PD-1. Nonetheless, because of the specific immune environment of the liver and the frequent association of HCC with hepatocellular insufficiency, the safety and the efficacy of these new treatments have to be properly studied in this situation. Thus, multiple phase II and III studies are in progress studying immune checkpoint inhibitor monotherapies, combination of different immunotherapies or local strategies such as transarterial chemoembolization combined with immune checkpoint inhibitors. Currently, only the final results of the tremelimumab phase II and the Nivolumab phase I/II study (CheckMate-040) are available. The latter is promising but need to be confirmed by the ongoing phase III studies to confirm the place of immunotherapy in the treatment of HCC. With many new molecular targets and therapeutic combination, immunotherapy represents a new hope in treating HCC patients although serious evaluation is still needed to confirm its interest.

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related mortality worldwide. The AKT pathway has been found activated in 50% of HCC cases, making it a promising target. Therefore, we assess efficacy of the allosteric AKT inhibitor ARQ 092 compared with untreated control and standard treatment, sorafenib, in vitro and in vivo. ARQ 092 blocked phosphorylation of AKT in vitro and strongly inhibited cell growth with significantly higher potency than sorafenib. Similarly, apoptosis and cell migration were strongly reduced by ARQ 092 in vitro. To mimic human advanced HCC, we used a diethylnitrosamine-induced cirrhotic rat model with fully developed HCC. MRI analyses showed that ARQ 092 significantly reduced overall tumor size. Furthermore, number of tumors was decreased by ARQ 092, which was associated with increased apoptosis and decreased proliferation. Tumor contrast enhancement was significantly decreased in the ARQ 092 group. Moreover, on tumor tissue sections, we observed a vascular normalization and a significant decrease in fibrosis in the surrounding liver of animals treated with ARQ 092. Finally, pAKT/AKT levels in ARQ 092–treated tumors were reduced, followed by downregulation of actors of AKT downstream signaling pathway: pmTOR, pPRAS40, pPLCγ1, and pS6K1. In conclusion, we demonstrated that ARQ 092 blocks AKT phosphorylation in vitro and in vivo. In the HCC-rat model, ARQ 092 was well tolerated, showed antifibrotic effect, and had stronger antitumor effect than sorafenib. Our results confirm the importance of targeting AKT in HCC. Mol Cancer Ther; 16(10); 2157–65. ©2017 AACR.

Quality control monitoring of cell lines utilized in biomedical research is of utmost importance and is critical for the reproducibility of data. Two key pitfalls in tissue culture are 1) cell line authenticity and 2) Mycoplasma contamination. As a collaborative research institute, the National Center for Advancing Translational Sciences (NCATS) receives cell lines from a range of commercial and academic sources, which are adapted for high-throughput screening. Here, we describe the implementation of routine NCATS-wide Mycoplasma testing and short tandem repeat (STR) testing for cell lines. Initial testing identified a >10% Mycoplasma contamination rate. While the implementation of systematic testing has not fully suppressed Mycoplasma contamination rates, clearly defined protocols that include the immediate destruction of contaminated cell lines wherever possible has enabled rapid intervention and removal of compromised cell lines. Data for >2000 cell line samples tested over 3 years, and case studies are provided. STR testing of 186 cell lines with established STR profiles revealed only five misidentified cell lines, all of which were received from external labs. The data collected over the 3 years since implementation of this systematic testing demonstrate the importance of continual vigilance for rapid identification of "problem" cell lines, for ensuring reproducible data in translational science research.

Background Fecal incontinence frequently occurs after total mesorectal excision for rectal cancer. This prospective study analyzed predictive factors and the impact of pelvic intraoperative neuromonitoring at different follow-up intervals. Methods Fifty-two patients were included undergoing total mesorectal excision for rectal cancer, and 29 under control of pelvic intraoperative neuromonitoring. Fecal incontinence was assessed using the Wexner Score at 3 and 6 months after stoma closure (follow-ups 1 and 2) as well as 1 and 2 years after surgery (follow-ups 3 and 4). Risk factors were identified by means of logistic regression. Results New onset of fecal incontinence was significantly lower in the neuromonitoring group at each follow-up (follow-up 1: 2 of 29 patients (7%) vs. 8 of 23 (35%), (p = 0.014); follow-up 2: 3 of 29 (10%) vs. 9 of 23 (39%), (p = 0.017); follow-up 3: 5 of 29 (17%) vs. 11 of 23 (48%), p = 0.019; follow-up 4: 6 of 28 (21%) vs. 11 of 22 (50%), p = 0.035). Non-performance of neuromonitoring was found to be an independent predictor for fecal incontinence throughout the survey. Neoadjuvant chemoradiotherapy was an independent predictor in the further course 1 and 2 years after surgery. Conclusions Performance of pelvic intraoperative neuromonitoring is associated with significantly lower rates of fecal incontinence. Neoadjuvant chemoradiotherapy was found to have negative late effects. This became evident 1 year after surgery.

BACKGROUND: Elevated Metrorail systems differ from conventional trains by their slower speeds and collisions with pedestrians predominantly occurring at accessible stations or platforms. Here, the orthopedic implications of pedestrians struck by a Metrorail are evaluated, as were the correlations of substance abuse and psychiatric history on injury and death. METHODS: Retrospective cohort study at a single Level-1 trauma center of patients requiring admission with orthopedic injuries following Metrorail impact from 1/2004-2/2017. Demographics, substance abuse, psychiatric history, intentionality, LOS, follow-up, fracture characteristics, and management were studied. RESULTS: 33 patients sustained 104 total orthopedic injuries requiring admission; nine sustained 15 traumatic amputations. There were at least 37 open fractures, with some incomplete data in deceased (5) and amputation (9) patients. Suicide attempts were completed at 35.7% and were associated with a documented psychiatric illness and prior psychiatric evaluation. Spine injuries were associated with increased traumatic brain injuries, rib fractures, and open pelvic ring injuries, yet fewer humerus fractures. Open fractures were significantly predictive of death. 14 patients (42.4%) required ICU admission, and 26 (78.8%) patients required orthopaedic surgery (mean 1.3 ± 1.4 operations). CONCLUSIONS: Metrorail systems are unique sources of orthopaedic injuries requiring high rates of critical care and surgical intervention. Patients sustain multiple injuries, many with amputations. With this mechanism, there is a high rate of open fractures and suicide. Trauma centers should emphasize an extensive evaluation of orthopaedic injuries in this patient setting. Level of Evidence: II

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related deaths worldwide and its incidence is rising. Percutaneous locoregional therapies, such as radiofrequency ablation and microwave ablation, are widely used as curative treatment options for patients with small HCC, but their effectiveness remains restricted because of the associated high rate of recurrence, occurring in about 70% of patients at five years. These thermal ablation techniques have the particularity to induce immunomodulation by destroying tumours, although this is not sufficient to raise an effective antitumour immune response. Ablative therapies combined with immunotherapies could act synergistically to enhance antitumour immunity. This review aims to understand the different immune changes triggered by radiofrequency ablation and microwave ablation as well as the interest in using immunotherapies in combination with thermal ablation techniques as a tool for complementary immunomodulation.

As one of the most popular sports in the world, soccer injury rates involving the knee continue to rise. An alarming trend of knee injuries, including increased anterior cruciate ligament ruptures, underscores the need to review our current understanding of these injuries in soccer players. This article includes a critical review of the epidemiology of knee injuries in soccer, anterior cruciate ligament and other ligamentous injuries, cartilage and meniscal injury, post-traumatic osteoarthritis, as well as current prevention initiatives.

Rationale: The Scleroderma Lung Study II (SLS II) demonstrated significant improvements in pulmonary function and dyspnea at 24 months compared with baseline when patients with symptomatic scleroderma–related interstitial lung disease (SSc-ILD) were treated with either cyclophosphamide for 1 year (followed for another year on placebo) or mycophenolate mofetil for 2 years in a randomized, double-blind clinical trial. Physiologic and clinical outcomes of SLS II have been published previously. Objectives: The aim of the study was to assess changes from baseline in the extent of SSc-ILD on high-resolution computed tomography (HRCT) measured in the SLS II participants using quantitative image analysis after 2 years and to determine whether these HRCT changes were correlated with the changes in physiologic and clinical measures over the same time interval. Methods: Ninety-seven of the 142 randomized subjects (cyclophosphamide group, 47 subjects; mycophenolate mofetil group, 50 subjects) participating in SLS II underwent thoracic volumetric thin-section HRCT at both baseline and 24 months. Quantitative computer-aided diagnosis scores using volumetric HRCT scans were obtained using a previously developed computer-aided system. The scores were quantitative lung fibrosis, quantitative ground glass, quantitative honeycomb, and quantitative interstitial lung disease (QILD), the latter representing the sum of quantitative lung fibrosis, quantitative ground glass, and quantitative honeycomb. These scores were obtained both for the whole lung and for individual lobes. Paired t tests were used for the combined (pooled) cyclophosphamide and mycophenolate mofetil groups to compare 24-month changes from baseline in both the whole lung and the lobe of maximal involvement as determined at baseline (worst lobe). Results: At the end of the 24-month trial, QILD in the whole lung was significantly reduced by a mean of 2.51% in the pooled groups (adjusted 95% confidence interval, −4.00 to −1.03%; P = 0.001). There was no significant difference in the QILD score improvement between the cyclophosphamide (−2.66%) and mycophenolate (−2.38%) groups when assessed separately (P = 0.88). For the pooled group, the 24-month changes in QILD scores in the whole lung correlated significantly with other outcomes, including 24-month changes in forced vital capacity (ρ = −0.37), single-breath diffusing capacity of the lung for carbon monoxide (ρ = −0.22), and breathlessness as measured by the Transition Dyspnea Index (ρ = −0.26). Conclusions: Treatment of SSc-ILD with either cyclophosphamide for 1 year, followed by placebo for a second year, or mycophenolate for 2 years was associated with a significant reduction (improvement) in the extent of HRCT SSc-ILD assessed by computer-aided diagnosis scores, which correlated well with one or more other measures of treatment response. These findings demonstrate that actual changes in lung structure accompany improvements in physiologic and/or symptomatic measures in SSc-ILD.

Recent estimates suggest an annual incidence of greater than 125,000 femoral neck fractures. Surgical treatment is indicated for the majority of these fractures, which are estimated to double by the year 2050. Most displaced femoral neck fractures in elderly patients are treated with arthroplasty secondary to high complication rates associated with internal fixation. Traditional implants used for internal fixation, typically in elderly patients with stable fracture morphology and younger patients regardless of morphology, include the sliding hip screw (SHS), with or without a supplemental anti-rotation screw, and multiple cancellous lag screws. Complications have been reported with both of these fixation techniques, especially as they apply to treating displaced femoral neck fractures in the elderly. Yet, complications of nonunion, loss of fixation and osteonecrosis, among others, still frequently occur in stable patterns of femoral neck fracture treated with internal fixation. Accordingly, additional implants have been designed recently to improve outcomes and avoid such complications in this population. The Targon Femoral Neck Plate (Aesculap, Tuttlinger, Germany) has been used in Europe for the treatment of both displaced and nondisplaced femoral neck fractures by combining a side plate and multiple cancellous lag screws. Multiple studies have shown superior rates of both nonunion and osteonecrosis when compared to the SHS and multiple cancellous screws in both displaced and nondisplaced femoral neck fractures. This article details the design rationale, surgical technique and early postoperative results of a new hybrid implant used for the treatment of both displaced and nondisplaced femoral neck fractures.

Observational study.To evaluate how online patient comments will affect website ratings for spine surgeons.With the ever-growing utilization of physician review websites, healthcare consumers are assuming more control over whom they choose for care. We evaluated patient feedback and satisfaction scores of spine surgeons using comments from three leading physician rating websites: Healthgrades.com, Vitals.com, Google.com. This is the largest review of online comments and the largest review of spine surgeon comments.From the North American Spine Society (NASS) membership directory, 210 spine surgeons practicing in Florida (133 orthopedic trained; 77 neurosurgery trained) with online comments available for review were identified, yielding 4701 patient comments. These were categorized according to subject: (1) surgeon competence, (2) surgeon likeability/character, (3) office staff, ease of scheduling, office environment. Type 1 and 2 comments were surgeon-dependent factors whereas type 3 comments were surgeon-independent factors. Patient comments also reported a score (1-5), 5 being the most favorable and 1 being the least favorable.There were 1214 (25.8%) comments from Healthgrades, 2839 (60.4%) from Vitals, and 648 (13.8%) from Google. 89.9% (4225) of comments pertained to surgeon outcomes and likeability (comment type 1 and 2), compared with 10.1% (476) surgeon-independent comments (comment type 3) (P 0.0001). There was a significantly higher number of favorable ratings associated with surgeon-dependent comments (types 1 and 2) compared with surgeon-independent comments (type 3). Surgeon-independent comments were associated with significantly lower scores compared with comments regarding surgeon-dependent factors on all review sites.Spine surgeons are more likely to receive favorable reviews for factors pertaining to outcomes, likeability/character, and negative reviews based on ancillary staff interactions, billing, and office environment. Surgeons should continue to take an active role in modifying factors patients perceive as negative, even if not directly related to the physician.3.

Summary Given the immense antigenic load present in the microbiome, we hypothesized that microbiota mimotopes can be a persistent trigger in human autoimmunity via cross-reactivity. Using antiphospholipid syndrome (APS) as a model, we demonstrate cross-reactivity between non-orthologous mimotopes expressed by a common human gut commensal, Roseburia intestinalis (R. int), and T and B cell autoepitopes in the APS autoantigen β2-glycoprotein I (β2GPI). Autoantigen-reactive CD4+ memory T cell clones and an APS-derived, pathogenic monoclonal antibody cross-reacted with R. int mimotopes. Core-sequence-dependent anti-R. int mimotope IgG titers were significantly elevated in APS patients and correlated with anti-β2GPI IgG autoantibodies. R. int immunization of mice induced β2GPI-specific lymphocytes and autoantibodies. Oral gavage of susceptible mice with R. int induced anti-human β2GPI autoantibodies and autoimmune pathologies. Together, these data support a role for non-orthologous commensal-host cross-reactivity in the development and persistence of autoimmunity in APS, which may apply more broadly to human autoimmune disease.

Assessment of the interactions between a drug and its protein target in a physiologically relevant cellular environment constitutes a major challenge in the pre-clinical drug discovery space. The Cellular Thermal Shift Assay (CETSA) enables such an assessment by quantifying the changes in the thermal stability of proteins upon ligand binding in intact cells. Here, we present the development and validation of a homogeneous, standardized, target-independent, and high-throughput (384- and 1536-well formats) CETSA platform that uses a split Nano Luciferase approach (SplitLuc CETSA). The broad applicability of the assay was demonstrated for diverse targets, and its performance was compared with independent biochemical and cell-based readouts using a set of well-characterized inhibitors. Moreover, we investigated the utility of the platform as a primary assay for high-throughput screening. The SplitLuc CETSA presented here enables target engagement studies for medium and high-throughput applications. Additionally, it provides a rapid assay development and screening platform for targets where phenotypic or other cell-based assays are not readily available.

STUDY DESIGN Retrospective cohort study. OBJECTIVE To identify patient characteristics and associated injuries in those sustaining a spine fracture from personal watercraft (PWC) usage. SUMMARY OF BACKGROUND DATA There are few studies regarding PWC use and injuries, and even more scarce are studies evaluating PWC usage and spine injuries. Identifying high-risk actions and individuals can help to effectively treat them, reduce mortality, and possibly avoid certain spine fractures. METHODS Retrospective analysis of 142 patients admitted from the emergency department with PWC-related injuries at a single-level I trauma center from January 1, 2004 to May 1, 2017. Twenty-six (18.3%) sustained a spine fracture, totaling 71 fractures. Statistical analysis was used to investigate the patient characteristics, specific mechanisms of injury, injury severity score (ISS), and associated injuries. Patients expiring (12) had incomplete evaluations and were excluded from most reported results. RESULTS Spine fractures were not associated with age, race, or sex, but were associated with a higher ISS, intensive care unit length, in-patient length of stay, cerebral injury, and abdominal/genitourinary (GU) injury. There were 8 cervical fractures, 22 thoracic fractures, 33 lumbar, and 8 sacral fractures. Axial load injuries were associated with vertebral body fractures and specifically burst fractures. Being a driver or passenger did not influence likelihood of a spine fracture, but did correlate with abdominal/GU injury. Five (19.2%) of patients with spine fractures required eight spine surgeries during admission. Mortality was associated with females, severe systemic injuries (ISS ≥ 15), direct collision mechanism of injury, and the spring season. CONCLUSION PWC usage may result in spine fractures with a moderate percentage requiring orthopedic surgery. Additional studies should examine how hull or seat modifications can lessen the risk of axial loads leading to spine fractures. PWC patients with spine fractures should also be evaluated for abdominal/GU and cerebral injuries at presentation. LEVEL OF EVIDENCE 4.

Despite better knowledge of its genetic basis, pancreatic cancer is still highly lethal with very few therapeutic options. In this review, we discuss the potential impact of epigenetic therapies, focusing on lysine methylation signaling and its implication in pancreatic cancer.Protein lysine methylation, a key mechanism of posttranslational modifications of histone proteins, has emerged as a major cell signaling mechanism regulating physiologic and pathologic processes including cancer. This finely tuned and dynamic signaling mechanism is regulated by lysine methyltransferases (KMT), lysine demethylases (KDM) and signal transducers harboring methyl-binding domains. Recent evidence demonstrates that overexpression of cytoplasmic KMT and resulting enhanced lysine methylation is a reversible event that enhances oncogenic signaling through the Ras and Mitogen-Activated Protein Kinases pathway in pancreatic cancer, opening perspectives for new anticancer chemotherapeutics aimed at controlling these activities.The development of potent and specific inhibitors of lysine methylation signaling may represent a hitherto largely unexplored avenue for new forms of targeted therapy in cancer, with great potential for yet hard-to-treat cancers such as pancreatic cancer.

Retroperitoneal fibrosis (RPF) is an uncommon chronic inflammatory disease of the rear abdomen and it is commonly associated with the complication of uni- or bilateral hydronephrosis. Despite the rarity of this disease, multiple publications concerning etiology, diagnosis, therapy monitoring and both medical and surgical therapy have been published in recent years. Recent research has focused on asbestos exposure as a possible risk factor, the meaning of IgG4-associated RPF, measuring disease activity using different radiological and nuclear medicine procedures, and new approaches to medical therapy. Goals of treatment were characterized as the correct diagnosis, preservation of renal function and freedom from stents, steroids and pain. On the basis of these goals, the most important insights and developments of the last 5 years regarding RPF are presented.

When soft tissue sarcomas are treated with neoadjuvant chemotherapy, the number of cycles of chemotherapy is usually dependent on the tumor's initial response. Popular methods to assess tumor response include Response Evaluation Criteria in Solid Tumors (RECIST) criteria, which rely solely on tumor size, and maximum standardized uptake value (SUVmax) reduction in positron emission tomography (PET), which requires an expensive and high radiation test. We hypothesized that contrast-enhanced magnetic resonance imaging (MRI) may offer a good alternative by providing additional information beyond tumor size.Following IRB approval, a retrospective review identified patients with soft tissue sarcomas who underwent both PET and MRI before and after two cycles of neoadjuvant chemotherapy. Five readers independently examined the MRI exams for: changes in size, T2 or T1 signal, necrosis and degree of enhancement. Readers then made a subjective binary assessment of tumor response to therapy. Each reader repeated the anonymized randomized reading at least 2 weeks apart. 18 F-FDG PET exams were interpreted by a nuclear medicine specialist. The maximum standardized uptake values (SUVmax) for pre and post-chemotherapy exams were compared. Intra- and inter-reader agreement was assessed using Cohen's kappa and Light's kappa, respectively. .Twenty cases were selected for this multireader study, of which 9 (45%) were responders and 11 were nonresponders by SUVmax. Using all MRI criteria, 43% were classified as responders based on MRI and 1.5% were classified as responders by RECIST criteria. Using PET as the reference, the sensitivity and the specificity of the MRI diagnosis for response using all findings were 50% and 63%, respectively. There was fair to moderate intrareader (kappa = 0.37) and inter-reader (kappa = 0.48) agreement for the MRI diagnosis of response. None of the individual MRI signal characteristics were significantly different between the PET responders and nonresponders. Additionally, no MRI findings were significantly different between those with and without good clinical responses.By our assessment, there is a poor correlation between tumor response by RECIST criteria and PET SUVmax. In addition, varying MR features did not help in diagnosing tumor response. Imaging of tumor response remains a challenging area that requires further research.

Purpose The ideal approach to complex ventral hernia repair is frequently debated. Differences in processing techniques among biologic materials may impact hernia repair outcomes. This study evaluates the outcomes of hernia repair with a terminally sterilized human acellular dermal matrix (TS-HADM) (AlloMax® Surgical Graft, by C. R. Bard/Davol, Inc., Warwick, RI, USA) treated with low-dose gamma irradiation. Methods A single-arm multi-center retrospective observational study of patients undergoing hernia repair with TS-HADM was performed. Data analyses were exploratory only; no formal hypothesis testing was pre-specified. Results Seventy-eight patients (43F, 35M) underwent incisional hernia repair with a TS-HADM. Mean follow-up was 20.5 months. Preoperative characteristics include age of 56.6 ± 11.1 years, BMI 36.7 ± 9.9 kg/m2, and mean hernia defect size 187 cm2. Sixty-five patients underwent component separation technique (CST) with a reinforcing graft. Overall, 21.8 % developed recurrences. Recurrences occurred in 15 % of patients repaired with CST. Major wound complications occurred in 31 % of patients overall. Based upon CDC surgical wound classification, major wound complications were seen in 26, 40, 56, and 50 % of Class 1, 2, 3, and 4 wounds, respectively. No grafts required removal. Conclusions Hernia recurrences are not uncommon following complex abdominal wall reconstruction. Improved outcomes are seen when a TS-HADM is utilized as reinforcement to primary fascial closure.

Unplanned hospital readmissions are common early post-kidney transplantation. We investigated the relationship between early hospital readmissions and clinical outcomes in a single-center retrospective study that included all adult kidney transplant patients between 2004 and 2008 with follow-up to December 2012. The early hospital readmissions within the first 30 d were numbered and the diagnosis ascertained. Patients were grouped as none, once, and twice or more readmissions. Predictors of early readmissions were assessed, and clinical outcomes and patient and death-censored kidney survival were compared. Among 1064 patients, 203 (19.1%) patients had once and 83 (7.8%) patients had twice or more readmissions within 30 d. Surgical complications, infections, and acute kidney injuries/acute rejection were three most common diagnoses. The length of initial hospital stay and African American race were among the variables associated significantly with readmissions. Patients with early readmissions had lower baseline renal function (p

BACKGROUND Transanal endoscopic microsurgery is used in the surgical management of advanced rectal polyps and early rectal cancers. There are case reports of transanal endoscopic microsurgery colorectal anastomoses being performed with laparoscopic assistance in humans. METHODS The concept of a transanal endoscopic microsurgery colorectal anastomosis without laparoscopic assistance has been discussed and trialed on animal and cadaveric specimens; however, to date, there have been no technical reports of this particular procedure in the literature. RESULTS We present a technical note describing a transanal endoscopic microsurgery intraperitoneal colorectal anastomosis in a live human without laparoscopic assistance.

Ureteral strictures are uncommon complications of radiotherapy which are often recognized late. Their consequences range from harmless dilatation of the ureter to loss of renal function and potential life-threatening urosepsis.Therapy of radiogenic ureteral stricture is a challenging task for every urologist. Several surgical strategies including minimally invasive procedures, reconstruction and partial or complete replacement of the ureter are available.This article provides an overview of the various options in the treatment of radiogenic stricture of the ureter, focusing on the use of ileum and colon segments for ureteral substitution.

The potential of bispecific T cell-engaging antibodies is hindered by manufacturing challenges and short serum half-life. We circumvented these limitations by treating mice with in vitro-transcribed pharmacologically optimized, nucleoside-modified mRNA encoding the antibody. We achieved sustained endogenous synthesis of the antibody, which eliminated advanced tumors as effectively as the corresponding purified bispecific antibody. Because manufacturing of pharmaceutical mRNA is fast, this approach could accelerate the clinical development of novel bispecific antibodies.

Chronic opioid usage (COU) for analgesia is common among patients with end-stage renal disease. In order to test whether a prior history of COU negatively affects post-kidney transplant outcomes, we retrospectively examined clinical outcomes in adult kidney transplant patients. Among 1064 adult kidney transplant patients, 452 (42.5%) reported the presence of various body pains and 108 (10.2%) reported a prior history of COU. While the overall death or kidney graft loss was not statistically different between patients with and without a history of COU, the cumulative mortality rate at 1, 3, and 5 years after transplantation, and during the entire study period, appeared significantly higher for patients with than without a history of COU (6.5, 18.5, and 20.4 vs. 3.2, 7.5, and 12.7%, respectively). Multivariate Cox regression analysis adjusted for potential confounding factors in entire cohorts and Cox regression analysis in 1:3 propensity-score matched cohorts suggest that a positive history of COU was significantly associated with nearly a 1.6- to 2-fold increase in the risk of death (hazard ratio 1.65, 95% confidence interval 1.04-2.60, and hazard ratio 1.92, 95% confidence interval 1.08-3.42, respectively). Thus, a history of chronic opioid usage prior to transplantation appears to be associated with increased mortality risk. Additional studies are warranted to confirm the observed association and to understand the mechanisms.