Type I interferon protects neurons from prions in in vivo models

Abstract

Infectious prions comprising abnormal prion protein, which is produced by structural conversion of normal prion protein, are responsible for transmissible spongiform encephalopathies including Creutzfeldt-Jakob disease in humans. Prions are infectious agents that do not possess a genome and the pathogenic protein was not thought to evoke any immune response. Although we previously reported that interferon regulatory factor 3 (IRF3) was likely to be involved in the pathogenesis of prion diseases, suggesting the protective role of host innate immune responses mediated by IRF3 signalling, this remained to be clarified. Here, we investigated the reciprocal interactions of type I interferon evoked by IRF3 activation and prion infection and found that infecting prions cause the suppression of endogenous interferon expression. Conversely, treatment with recombinant interferons in an ex vivo model was able to inhibit prion infection. In addition, cells and mice deficient in type I interferon receptor (subunit interferon alpha/beta receptor 1), exhibited higher susceptibility to 22L-prion infection. Moreover, in in vivo and ex vivo prion-infected models, treatment with RO8191, a selective type I interferon receptor agonist, inhibited prion invasion and prolonged the survival period of infected mice. Taken together, these data indicated that the interferon signalling interferes with prion propagation and some interferon-stimulated genes might play protective roles in the brain. These findings may allow for the development of new strategies to combat fatal diseases.

http://bit.ly/2DZeqf6

A probabilistic map of negative motor areas of the upper limb and face: a brain stimulation study

Abstract

Negative motor responses (NMRs) are defined as movement arrests induced by direct electrical stimulation of the brain. The NMRs manifest themselves after the disruption of a corticosubcortical network involved in motor control, referred to as the 'negative motor network'. At present, the spatial topography of the negative motor areas (NMAs) is poorly known. Hence, the objectives of the present study were to establish the first probabilistic map of the NMAs of the upper limbs and face, identify potential subareas, and investigate the NMAs' relationships with the primary motor cortex. A total of 117 patients with low grade glioma underwent awake surgery with direct electrostimulation. The Montreal Neurological Institute coordinates of sites eliciting NMRs (face and upper limbs) were registered. A probabilistic map was created, and subareas were identified in a cluster analysis. Each cluster was then plotted on the Glasser atlas and the 1200 Subjects Group Average Data from the Human Connectome Project, in order to study connectivity and compare the results with recent parcellation data. We elicited 386 NMRs (mean ± standard deviation current intensity: 2.26 ± 0.5 mA) distributed throughout the precentral gyrus in both hemispheres. In each hemisphere, we found two clusters for facial NMRs. For upper limb NMRs, we found two clusters in the right hemisphere; and three in the left. Each cluster overlapped with parcellations from the Glasser atlas. For the face, the NMAs were associated with areas 55b and 6v. For the upper limbs, the NMAs were linked to areas 6v, 6d, and 55b. Each NMA cluster showed a specific pattern of functionally connected areas, such as the inferior frontal gyrus, supplementary motor area, parietal areas, and posterior superior temporal gyrus. The white matter pathways projecting to these subareas involved the frontal aslant tract and the frontostriatal tract—both of which are well known to be associated with NMRs. This study constitutes the largest series to date of NMRs mapped to the lateral surface of both hemispheres. Rather than being randomly distributed, the NMAs appeared to be well structured and corresponded to parcellations identified by functional neuroimaging. Moreover, the white matter pathways known to drive NMRs are also connected to regions encompassing NMAs. Taken as a whole, our results suggest that NMAs belong to a large-scale modulatory motor network. Our new probabilistic map might constitute a valuable tool for use in further clinical and fundamental studies of motor control.

http://bit.ly/2GvX0Z9

Checkpoint inhibition of PD-L1 and CTLA-4 in a child with refractory acute leukemia

International Journal of Hematologic Oncology, Ahead of Print.


http://bit.ly/2Gy5ZJh

Surgical Resection of the Primary Tumor in Women With De Novo Stage IV Breast Cancer: Contemporary Practice Patterns and Survival Analysis

Objective: We evaluated patterns of surgical care and their association with overall survival among a contemporary cohort of women with stage IV breast cancer. Background: Surgical resection of the primary tumor remains controversial among women with stage IV breast cancer. Methods: Women diagnosed with clinical stage IV breast cancer from 2003 to 2012 were identified from the American College of Surgeons National Cancer Database. Those with intact primary tumors who were alive 12 months after diagnosis were categorized by treatment sequence: (1) surgery before systemic therapy, (2) systemic therapy before surgery, and (3) systemic therapy alone. Multivariate logistic regression was used to estimate the association of treatment sequence with surgery type. Overall survival was estimated using multivariate Cox proportional hazards models. Results: Among 24,015 women, 56.2% (13,505) underwent systemic therapy alone and 43.8% (10,510) underwent surgical resection. Rates of surgery decreased slightly over time (43.1% in 2003 to 41.9% in 2011). Treatment with systemic therapy before surgery was associated with larger tumor size (median 4.5 vs 3.1 cm, P

http://bit.ly/2RJp6lG

Changing Autonomy in Operative Experience Through UK General Surgery Training: A National Cohort Study

Objectives: To determine the operative experience of UK general surgery trainees and assess the changing procedural supervision and acquisition of competency assessments through the course of training. Background: Competency assessment is changing with concepts of trainee autonomy decisions (termed entrustment decisions) being introduced to surgical training. Methods: Data from the Intercollegiate Surgical Curriculum Programme and the eLogbook databases for all UK General Surgery trainees registered from August 1, 2007 who had completed training were used. Total and index procedures (IP) were counted and variation by year of training assessed. Recorded supervision codes and competency assessment outcomes for IPs were assessed by year of training. Results: We identified 311 trainees with complete data. Appendicectomy was the most frequently undertaken IP during first year of training [mean procedures (mp) = 26] and emergency laparotomy during final year of training (mp = 27). The proportion of all IPs recorded as unsupervised increased through training (P

http://bit.ly/2WRnj1x

Comment on “Medial Open Transversus Abdominis Plane (MOTAP) Catheters Reduce Opioid Requirements and Improve Pain Control Following Open Liver Resection: a Multicenter, Blinded, Randomized Controlled Trial”

No abstract available

http://bit.ly/2DoRR1I

Entrustable Professional Activities: The Future of Competency-based Education in Surgery May Already Be Here

No abstract available

http://bit.ly/2RK2yRH

Modeling Surgical Technical Skill Using Expert Assessment for Automated Computer Rating

Objective: Computer vision was used to predict expert performance ratings from surgeon hand motions for tying and suturing tasks. Summary Background Data: Existing methods, including the objective structured assessment of technical skills (OSATS), have proven reliable, but do not readily discriminate at the task level. Computer vision may be used for evaluating distinct task performance throughout an operation. Methods: Open surgeries was videoed and surgeon hands were tracked without using sensors or markers. An expert panel of 3 attending surgeons rated tying and suturing video clips on continuous scales from 0 to 10 along 3 task measures adapted from the broader OSATS: motion economy, fluidity of motion, and tissue handling. Empirical models were developed to predict the expert consensus ratings based on the hand kinematic data records. Results: The predicted versus panel ratings for suturing had slopes from 0.73 to 1, and intercepts from 0.36 to 1.54 (Average R2 = 0.81). Predicted versus panel ratings for tying had slopes from 0.39 to 0.88, and intercepts from 0.79 to 4.36 (Average R2 = 0.57). The mean square error among predicted and expert ratings was consistently less than the mean squared difference among individual expert ratings and the eventual consensus ratings. Conclusions: The computer algorithm consistently predicted the panel ratings of individual tasks, and were more objective and reliable than individual assessment by surgical experts.

http://bit.ly/2RPrabG

Comment on “Prediction of Hepatocellular Carcinoma Recurrence Beyond Milan Criteria After Resection: Validation of a Clinical Risk Score in Aninternational Cohort”

No abstract available

http://bit.ly/2GiGhJm

The Impact of Corporate Payments on Robotic Surgery Research: A Systematic Review

Objective: To quantify the influence of financial conflict of interest (COI) payments on the reporting of clinical results for robotic surgery. Data Sources and Study Selection: A systematic search (Ovid MEDLINE databases) was conducted (May 2017) to identify randomized controlled trials (RCTs) and observational studies comparing the efficacy of the da Vinci robot on clinical outcomes. Financial COI data for authors (per study) were determined using open payments database. Main Outcomes and Measures: Primary outcomes assessed were receipt of financial COI payments and overall conclusion reported between robotic versus comparative approach. Quality/risk of bias was assessed using Newcastle-Ottawa Scale (NOS)/Cochrane risk of bias tool. Disclosure discrepancies were also analyzed. Data Extraction and Synthesis: Study characteristics, surgical subspecialty, methodological assessment, reporting of disclosure statements, and study findings dual abstracted. The association of the amount of financial support received as a predictor of reporting positive findings associated robotic surgery was assessed at various cut-offs of dollar amount received by receiver operating curve (ROC). Results: Thirty-three studies were included, 9 RCTs and 24 observational studies. There was a median, 111 patients (range 10 to 6420) across studies. A little more than half (17/33) had a conclusion statement reporting positive results in support of robotic surgery, with 48% (16/33) reporting results not in favor [equivocal: 12/33 (36%), negative: 4/33 (12%)]. Nearly all (91%) studies had authors who received financial COI payments, with a median of $3364.46 per study (range $9 to $1,775,378.03). ROC curve demonstrated that studies receiving greater than $9557.31 (cutpoint) were more likely to report positive robotic surgery results (sensitivity: 0.65, specificity: 0.81, area under the curve: 0.73). Studies with financial COI payment greater than this amount were more likely to report beneficial outcomes with robotic surgery [(78.57% vs 31.58%, P = 0.013) with an odds ratio of 2.07 (confidence interval: 0.47–3.67; P = 0.011)]. Overall, studies were high quality/low risk of bias [median NOS: 8 (range 5 to 9)]; Cochrane risk: "low risk" (9/9, 100%)]. Conclusion and Relevance: Financial COI sponsorship appears to be associated with a higher likelihood of studies reporting a benefit of robotic surgery. Our findings suggest a dollar amount where financial payments influence reported clinical results, a concept that challenges the current guidelines, which do not account for the amount of COI funding received.

http://bit.ly/2WRnjyz

A Randomized Controlled Trial Comparing Epidural Analgesia Versus Continuous Local Anesthetic Infiltration Via Abdominal Wound Catheter in Open Liver Resection

Aim: To compare outcomes following open liver resection (OLR) between patients receiving thoracic epidural (EP) versus abdominal wound catheters plus patient-controlled analgesia (AWC-PCA). Method: Patients were randomized 1:1 to either EP or AWC-PCA within an enhanced recovery protocol. Primary outcome was length of stay (LOS), other variables included functional recovery, pain scores, peak flow, vasopressor and fluid requirements, and postoperative complications. Results: Between April 2015 and November 2017, 83 patients were randomized to EP (n = 41) or AWC-PCA (n = 42). Baseline demographics were comparable. No difference was noted in LOS (EP 6 d (3–27) vs AWC-PCA 6 d (3–66), P = 0.886). Treatment failure was 20% in the EP group versus 7% in the AWC-PCA (P = 0.09). Preoperative anesthetic time was shorter in the AWC-PCA group, 49 minutes versus 62 minutes (P = 0.003). EP patients required more vasopressor support immediately postoperatively on day 0 (14% vs 54%, P = 

http://bit.ly/2WRnhXt

Alternatively Activated Macrophages Drive Browning of White Adipose Tissue in Burns

Objective: The aim of this study was to uncover the mediators and mechanistic events that facilitate the browning of white adipose tissue (WAT) in response to burns. Background: In hypermetabolic patients (eg, burns, cancer), the browning of WAT has presented substantial clinical challenges related to cachexia, atherosclerosis, and poor clinical outcomes. Browning of the adipose tissue has recently been found to induce and sustain hypermetabolism. Although browning appears central in trauma-, burn-, or cancer-induced hypermetabolic catabolism, the mediators are essentially unknown. Methods: WAT and blood samples were collected from patients admitted to the Ross Tilley Burn Centre at Sunnybrook Hospital. Wild type, CCR2 KO, and interleukin (IL)-6 KO male mice were purchased from Jax laboratories and subjected to a 30% total body surface area burn injury. WAT and serum collected were analyzed for browning markers, macrophages, and metabolic state via histology, gene expression, and mitochondrial respiration. Results: In the present study, we show that burn-induced browning is associated with an increased macrophage infiltration, with a greater type 2 macrophage profile in the fat of burn patients. Similar to our clinical findings in burn patients, both an increase in macrophage recruitment and a type 2 macrophage profile were also observed in post burn mice. Genetic loss of the chemokine CCR2 responsible for macrophage migration to the adipose impairs burn-induced browning. Mechanistically, we show that macrophages recruited to burn-stressed subcutaneous WAT (sWAT) undergo alternative activation to induce tyrosine hydroxylase expression and catecholamine production mediated by IL-6, factors required for browning of sWAT. Conclusion: Together, our findings uncover macrophages as the key instigators and missing link in trauma-induced browning.

http://bit.ly/2RK2od3

Efficacy of Preoperative Oral Antibiotic Prophylaxis for the Prevention of Surgical Site Infections in Patients With Crohn Disease: A Randomized Controlled Trial

Objectives: We investigated the efficacy of oral antimicrobial prophylaxis in patients undergoing surgery for Crohn disease. Background: Although oral antibiotic prophylaxis with mechanical bowel preparation has been recommended for colorectal surgery, the use of this approach remains somewhat controversial. Moreover, the efficacy of this approach for inflammatory bowel disease also remains unclear. Methods: This study was conducted as a randomized controlled trial at the Hyogo College of Medicine. The study protocols were registered with the University Hospital Medical Information Network Clinical Trials Registry (000013369). In this study, 335 patients with Crohn disease who were scheduled to undergo intestinal resection with an open approach were randomly assigned to either group A or group B. The patients in group A received both preoperative oral antibiotics and intravenous antimicrobial prophylaxis, and intravenous antimicrobial prophylaxis alone was given to the patients in group B. All patients underwent preoperative mechanical bowel preparation with sodium picosulfate hydrate. The primary endpoint of this study was the incidence of surgical site infection (SSI) according to an intention-to-treat analysis. Results: Although the incidences of overall and organ/space SSI were not significantly different, the incidence of incisional SSI was significantly lower in group A (12/163; 7.4%) than in group B (27/162; 16.6%) (P = 0.01). In the multivariate analysis, the absence of oral antibiotic prophylaxis was an independent risk factor for incisional SSI (odds ratio: 3.3; 95% confidence interval: 1.3–8.3; P = 0.01). Conclusions: Combined oral and intravenous antimicrobial prophylaxis in patients with Crohn disease contributed to the prevention of SSI.

http://bit.ly/2ROB0uq

Compliance of Randomized Controlled Trials Published in General Surgical Journals With the CONSORT 2010 Statement

No abstract available

http://bit.ly/2RNeWAi

Comment on “ALPPS Improves Resectability Compared With Conventional Two-stage Hepatectomy in Patients With Advanced Colorectal Liver Metastasis”

No abstract available

http://bit.ly/2Dkjn0x

Diagnostic Accuracy of Different Surgical Procedures for Axillary Staging After Neoadjuvant Systemic Therapy in Node-positive Breast Cancer: A Systematic Review and Meta-analysis

Objective: The aim of this study was to perform a systematic review and meta-analysis to assess the accuracy of different surgical axillary staging procedures compared with ALND. Summary of Background Data: Optimal axillary staging after neoadjuvant systemic therapy (NST) in node-positive breast cancer is an area of controversy. Several less invasive procedures, such as sentinel lymph node biopsy (SLNB), marking axillary lymph node with radioactive iodine seed (MARI), and targeted axillary dissection (a combination of SLNB and a MARI-like procedure), have been proposed to replace the conventional axillary lymph node dissection (ALND) with its concomitant morbidity. Methods: PubMed and Embase were searched for studies comparing less invasive surgical axillary staging procedures to ALND to identify axillary burden after NST in patients with pathologically confirmed node-positive breast cancer (cN+). A meta-analysis was performed to compare identification rate (IFR), false-negative rate (FNR), and negative predictive value (NPV). Results: Of 1132 records, 20 unique studies with 2217 patients were included in quantitative analysis: 17 studies on SLNB, 1 study on MARI, and 2 studies on a combination procedure. Overall axillary pathologic complete response rate was 37%. For SLNB, pooled rates of IFR and FNR were 89% and 17%. NPV ranged from 57% to 86%. For MARI, IFR was 97%, FNR 7%, and NPV 83%. For the combination procedure, IFR was 100%, FNR ranged from 2% to 4%, and NPV from 92% to 97%. Conclusion: Axillary staging by a combination procedure consisting of SLNB with excision of a pre-NST marked positive lymph node appears to be most accurate for axillary staging after NST. More evidence from prospective multicenter trials is needed to confirm this.

http://bit.ly/2RK2voZ

Comment on “Does a Combination of Laparoscopic Approach and Full Fast Track Multimodal Management Decrease Postoperative Morbidity?”

No abstract available

http://bit.ly/2GgYoQ7

Cross-circulation and the Early Days of Cardiac Surgery

No abstract available

http://bit.ly/2WRnhqr

Selective citation in the literature on the hygiene hypothesis: a citation analysis on the association between infections and rhinitis

Objective

Our objective was to assess the occurrence and determinants of selective citation in scientific publications on Strachan's original hygiene hypothesis. His hypothesis states that lack of exposure to infections in early childhood increases the risk of rhinitis.

Setting

Web of Science Core Collection.

Participants

We identified 110 publications in this network, consisting of 5551 potential citations.

Primary and secondary outcome measures

Whether a citation occurs or not, measured and analysed according to the preregistered protocol.

Results

We found evidence for citation bias in this field: publications supportive of the hypothesis were cited more often than non-supportive publications (OR adjusted for study design [adjOR] 2.2, 95% CI 1.6 to 3.1), and the same was the case for publications with mixed findings (adjOR 3.1, 95% CI 2.2 to 4.5). Other relevant determinants for citation were type of exposure, specificity, journal impact factor, authority and self-citation. Surprisingly, prospective cohort studies were cited less often than other empirical studies.

Conclusions

There is clear evidence for selective citation in this research field, and particularly for citation bias.

http://bit.ly/2WNG3z8

Effects of maternal B12 supplementation on neurophysiological outcomes in children: a study protocol for an extended follow-up from a placebo randomised control trial in Bangalore, India

Introduction

Vitamin B12 deficiency is highly prevalent in pregnant Indian women. Neuropsychological tests have shown an association between low maternal vitamin B12 status and poorer cognitive performances in the offspring, although findings from these studies have been inconsistent. Vitamin B12 has an important role in the formation of myelin which is important for the transmission speed of neural impulses and myelination in the central nervous system has been linked to cognition. Assessing neurophysiological measures using event-related potentials (ERPs) in children may provide additional information on the effect of maternal vitamin B12 supplementation on offspring brain function. The study examines the effects of oral vitamin B12 daily supplements (50 µg) to pregnant Indian women on child neurophysiological function at 72 months.

Methods and analysis

We previously conducted a double-blind, placebo-controlled study to examine the effects of maternal vitamin B12 supplementation on cognitive outcomes in their offspring using the Bayley scales of infant development, third edition. In this extended follow-up of the same cohort of mother-child dyad, we propose to use ERP to study the long-term impact of maternal B12 supplementation on brain function in children at 72 months of age. We intend to use P300 and mismatch negativity (MMN) as measures of neurophysiological outcomes. The primary outcome of this study will be child neurophysiological measures (as measured by amplitude and latency of P300 and MMN) assessed at 72 months of age in children whose mothers received vitamin B12 compared with neurophysiological status of children whose mothers received placebo.

Ethics and dissemination

The study was approved by the Institutional Ethical Board of St. John's Medical College and the Harvard School of Public Health Human Subjects Committee. Results obtained will be presented at national and international research meetings and published in peer-reviewed scientific journals.

Trial registration number

NCT00641862.

http://bit.ly/2RNO1of

Healthcare professionals perceptions of learning communication in the healthcare workplace: an Australian interview study

Objectives

The literature focuses on teaching communication skills in the 'classroom', with less focus on how such skills are informally learnt in the healthcare workplace. We grouped healthcare work based on the cure:care continuum to explore communication approaches based on work activities. This study asks: 1) How do healthcare professionals believe they learn communication in the workplace? 2) What are the differences (if any) across the 'type of work' as represented by the cure:care continuum?

Design

This qualitative study used semi-structured individual interviews.

Setting

Community care and acute hospitals in Australia (Victoria and New South Wales).

Participants

Twenty qualified healthcare professionals (medicine n=4, nursing n=3, allied health n=13) from various clinical specialties (eg, acute, rehabilitation, surgery, palliative care) participated.

Methods

Data were analysed using framework analysis, which involved the development of a thematic coding framework. Findings were mapped to participants' descriptions of work using the cure:care continuum.

Results

Three themes were identified that varied across the cure:care continuum: professional discourse—tying communication approaches to work activities; personal identities—the influence of personal identities on healthcare communication and role modelling—the influence of others in the socially bound context of healthcare work.

Conclusions

This study highlights the influence of professional, personal and social factors on the learning of healthcare communication in the workplace. Our study illuminates differences in communication practice related to work activities, as conceptualised by the cure:care continuum. The results call for further examination of the 'nature' of work activities and the concomitant influence on developing healthcare communication.

http://bit.ly/2WOUF1i

Correction: Revealed versus concealed criteria for placental insufficiency in an unselected obstetric population in late pregnancy (RATIO37): randomised controlled trial study protocol

Figueras F, Gratacos E, Rial M, et al. Revealed versus concealed criteria for placental insufficiency in an unselected obstetric population in late pregnancy (RATIO37): randomised controlled trial study protocol. BMJ Open 2017;7:e014835. doi: 10.1136/bmjopen-2016-014835.

This article was previously published with an error in the author list.

Two co-authors were missed off the original author list, Eran Ashwal and Kacerovsky, Marian.

Eran Ashwal's affiliation is Lis Hospital for Women, Tel Aviv University, Tel Aviv, Israel.

Marian Kacerovsky's affiliation is Department of Obstetrics and Gynecology, Charles University in Prague, Faculty of Medicine Hradec Kralove, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic.

The author order is also incorrect.

The updated author list should be as follows:

Figueras, Francesc

Gratacos, Eduard

Rial, Marta

Gull, Ilan

Eran, Ashwal

Kacerovsky, Marian

Lubusky, Marek

Krofta, Ladislav

Cruz, Rogelio

Cruz, Monica

Martinez, Miguel

Parra, Mauro

Socias, Pamela

Aleuanlli, Maria Cristina

http://bit.ly/2RM6fGL

Post-traumatic stress disorder in UK civilians with traumatic brain injury: an observational study of TBI clinic attendees to estimate PTSD prevalence and its relationship with radiological markers of brain injury severity

Objectives

To estimate the prevalence of post-traumatic stress disorder (PTSD) in a large civilian population with traumatic brain injury (TBI), and to assess whether brain injury severity is correlated with PTSD symptoms.

Design

Observational, cross-sectional study.

Setting and participants

Outpatient clinic in a major UK trauma centre and secondary care hospital. Estimates of PTSD prevalence are based on 171 sampled individuals attending TBI clinic within an 18-month period. Analysis of the relationship between TBI severity and PTSD was performed on the subset of 127 patients for whom injury severity data were also available.

Methods

Civilian TBI clinic attendees completed validated self-report questionnaires assessing PTSD (PTSD Checklist Civilian Version (PCL-C)) and other psychiatric symptoms. From this, the prevalence of PTSD was estimated in our cohort. Postresuscitation Glasgow Coma Score and Marshall grade on CT brain scan were recorded as indicators of brain injury severity. A hierarchical regression explored whether TBI severity may predict PTSD scores.

Results

A high prevalence of PTSD was estimated (21% with PCL-C score >50). Higher Marshall grading displayed a slight negative correlation with PTSD symptoms. This statistically significant relationship persisted after confounding factors such as depression and postconcussion symptoms were controlled for.

Conclusions

PTSD and TBI frequently coexist, share antecedents and overlap in their resultant symptoms. This complexity has given rise to conflicting hypotheses about relationships between the two. This research reveals that PTSD is common in civilians with TBI (adding to evidence drawn from military populations). The analysis indicated that more severe brain injury may exert a slight protective influence against the development of PTSD—potentially by disrupting implicit access to traumatic memories, or via overlapping neuropsychiatric symptoms that impede diagnosis. The association suggests that further research is warranted to explore the reuse of routine clinical and neuroimaging data—investigating its potential to predict risk of psychiatric morbidity.

http://bit.ly/2WOUBi4

Elevated Expressions of Survivin and Endoglin in Patients with Hepatic Carcinoma

Cancer Biotherapy and Radiopharmaceuticals, Volume 34, Issue 1, Page 7-12, February 2019.


http://bit.ly/2GuhXDL

Paraduodenal inflammatory pseudotumor masquerading as malignancy

A 30-year-old woman presented with severe abdominal pain and abdominal distension. CT demonstrated two intra-abdominal masses, one involving the left lateral segment of the liver and the other adjacent to the duodenum. Initial biopsies were consistent with focal nodular hyperplasia of the liver and non-specific lymphocytic infiltrate in the paraduodenal mass. Due to persistent symptoms, the patient underwent laparoscopic resection of the paraduodenal mass. Final pathology was consistent with an inflammatory pseudotumour and the patient's symptoms subsequently resolved.

http://bit.ly/2MTUSLU

Prolonged neonatal hyperbilirubinaemia in a case of congenital hypopituitarism

http://bit.ly/2MZ4dCk

One month of nitrous oxide abuse causing acute vitamin B 12 deficiency with severe neuropsychiatric symptoms

A 21-year-old university student studying abroad in the USA presented to the emergency department with double vision, lower extremity weakness with difficulty ambulating and other neuropsychiatric symptoms. MRI of the brain and spinal cord were normal. Vitamin B₁₂ was 78 pg/mL (58 pmol/L, reference 211–911 pg/mL). The patient had been using nitrous oxide capsules used for whipped cream recharging, which she obtained from other students, a few times daily for a month for the purpose of anxiety relief. The patient was not a vegan or vegetarian. The patient was treated with intramuscular vitamin B₁₂ repletion with partial resolution of neurologic symptoms and discharged on vitamin B₁₂ supplementation.

http://bit.ly/2SyZ9tv

Lipoma arborescens: a rare cause of clicking in the knee

Lipoma arborescens (LA) is a rare condition with synovial membrane lipomatous proliferation. It most commonly affects the knee joint, in the suprapatellar pouch. It can present as a painful knee with an effusion. Diagnosis is via MRI demonstrating a synovial mass with frond-like appearance, and histology showing mature adipose cells, with an overlying synovial membrane. Treatment options include non-operative measures with analgesia, or operative intervention to resect the lesion. We describe a unique case of LA present in the anterolateral knee joint, presenting with persistent painful clicking in the knee. The patient underwent an open total resection of the lesion, with resolution of symptoms.

http://bit.ly/2MVLKGz

Endocarditis following IUD insertion in a patient with tetralogy of Fallot

The role of antibiotic prophylaxis for prevention of infective endocarditis is unknown. Endocarditis prophylaxis is recommended for certain high-risk individuals prior to dental procedures. To our knowledge, this is the first case reported in the literature of a patient with complex congenital heart disease developing endocarditis in the period immediately following otherwise uncomplicated intrauterine device insertion.

http://bit.ly/2SyZ6hj

Orbital floor fracture with periorbital haematoma

http://bit.ly/2MTMVX6

Review and Classification Update: Unilateral condylar hyperplasia

Unilateral condylar hyperplasia is characterised by slow progressive growth of the different parts of mandible, the aetiology of which is still unclear. It is a self-limiting condition mostly seen between the age of 11–30 years causing facial asymmetry and its progression ceases after a certain time. In literature until now very few cases have been reported and every case that is being reported adds to its features or the aetiology. Previously, it has been classified into two types that is, hemimandibular hyperplasia and hemimandibular elongation. Here, we report a similar case with a few features distinct from those reported earlier.

http://bit.ly/2SED5gU

More than meets the eye

We report an extremely rare case of a hybrid tumour of the maxillary sinus. A 51-year-old man presented with a 6-week history of nasal congestion and epiphora. Radiological imaging demonstrated a maxillary sinus tumour, with extensive local invasion. Surgical excision included maxillectomy, left eye exenteration and free flap closure. Histology of the excised specimen showed a rare hybrid tumour containing adenoid cystic carcinoma, salivary duct carcinoma, epithelial-myoepithelial carcinoma and basal cell adenoma. Hybrid tumours are very rare tumour entities which are composed of at least two distinct tumour types. Each tumour entity conforms with a defined tumour type. The tumour entities of a hybrid tumour are not separated but have an identical origin within a definite topographical area. Diagnosis and appropriate management requires high index of suspicion, pathological endeavour to look for a more aggressive accompanying tumour and adequate oncological treatment according to the highest grade of tumour.

http://bit.ly/2MZ4dlO

Spontaneous intracranial hypotension associated with pachymeningeal enhancement in a patient with systemic lupus erythematosus (SLE): an extremely rare presenting feature

A 16-years-old girl presented to our institution with history of severe bilateral headache for 5 days associated with vomiting. She also had fever for 2 months without any localising symptoms and skin lesions for 1 month. Examination revealed erythematous rash over bridge of nose and ear lobes, ulcer over hard palate and tenderness of small joints of both hands. Systemic examination was unremarkable except for bilateral papilloedema. Investigations revealed anaemia, leucopenia and elevated erythrocyte sedimentation rate. Cranial imaging revealed diffuse pachymeningeal enhancement with subdural effusion. Lumbar puncture revealed no abnormal findings in cerebrospinal fluid except low opening pressure. Antinuclear antibody was 4+ with anti-Sm antibody positive. She was diagnosed to have spontaneous intracranial hypotension associated with pachymeningeal enhancement secondary to systemic lupus erythematosus. She showed dramatic improvement with steroid and azathioprine therapy. She continues to be asymptomatic after 2 years of follow-up.

http://bit.ly/2SyYZ5n

Complete recovery in Wernickes encephalopathy complicating hyperemesis gravidarum

Wernicke's encephalopathy (WE) is an uncommon neurological complication in pregnancies complicated with hyperemesis due to thiamine deficiency. In women with hyperemesis, inadvertent glucose administration prior to thiamine supplementation triggers the development of neurological manifestations. Delay in the diagnosis can lead to maternal morbidity, and in one-third of cases may lead to persistence of some neurological deficit. With early recognition and thiamine supplementation, complete recovery is reported. We report a case of WE complicating a case of triplet pregnancy with hyperemesis gravidarum, which highlights the importance of early recognition and treatment, resulting in complete recovery as in the index case.

http://bit.ly/2MZ4chK

Identification and Functional Testing of Novel Interacting Protein Partners for the Stress Sensors Wsc1p and Mid2p of Saccharomyces cerevisiae

Wsc1p and Mid2p are transmembrane signaling proteins of cell wall stress in the budding yeast Saccharomyces cerevisiae. When an environmental stress compromises cell wall integrity, they activate a cell response through the Cell Wall Integrity (CWI) pathway. Studies have shown that the cytoplasmic domain of Wsc1p initiates the CWI signaling cascade by interacting with Rom2p, a Rho1-GDP-GTP exchange factor. Binding of Rom2p to the cytoplasmic tail of Wsc1p requires dephosphorylation of specific serine residues but the mechanism by which the sensor is dephosphorylated and how it subsequently interacts with Rom2p remains unclear. We hypothesize that Wsc1p and Mid2p must be physically associated with interacting proteins other than Rom2p that facilitate its interaction and regulate the activation of CWI pathway. To address this, a cDNA plasmid library of yeast proteins was expressed in bait strains bearing membrane yeast two-hybrid (MYTH) reporter modules of Wsc1p and Mid2p, and their interacting preys were recovered and sequenced. 14 previously unreported interactors were confirmed for Wsc1p and 29 for Mid2p. The interactors' functionality were assessed by cell growth assays and CWI pathway activation by western blot analysis of Slt2p/Mpk1p phosphorylation in null mutants of each interactor under defined stress conditions. The susceptibility of these strains to different stresses were tested against antifungal agents and chemicals. This study reports important novel protein interactions of Wsc1p and Mid2p that are associated with the cellular response to oxidative stress induced by Hydrogen Peroxide and cell wall stress induced by Caspofungin.

http://bit.ly/2SfT1XV

RNAi Screen in Tribolium Reveals Involvement of F-BAR Proteins in Myoblast Fusion and Visceral Muscle Morphogenesis in Insects

In a large-scale RNAi screen in Tribolium castaneum for genes with knock-down phenotypes in the larval somatic musculature, one recurring phenotype was the appearance of larval muscle fibers that were significantly thinner than those in control animals. Several of the genes producing this knock-down phenotype corresponded to orthologs of Drosophila genes that are known to participate in myoblast fusion, particularly via their effects on actin polymerization. A new gene previously not implicated in myoblast fusion but displaying a similar thin-muscle knock-down phenotype was the Tribolium ortholog of Nostrin, which encodes an F-BAR and SH3 domain protein. Our genetic studies of Nostrin and Cip4, a gene encoding a structurally related protein, in Drosophila show that the encoded F-BAR proteins jointly contribute to efficient myoblast fusion during larval muscle development. Together with the F-Bar protein Syndapin they are also required for normal embryonic midgut morphogenesis. In addition, Cip4 is required together with Nostrin during the profound remodeling of the midgut visceral musculature during metamorphosis. We propose that these F-Bar proteins help govern proper morphogenesis particularly of the longitudinal midgut muscles during metamorphosis.

http://bit.ly/2DgpW45

A Large Scale Systemic RNAi Screen in the Red Flour Beetle Tribolium castaneum Identifies Novel Genes Involved in Insect Muscle Development

Although muscle development has been widely studied in Drosophila melanogaster there are still many gaps in our knowledge, and it is not known to which extent this knowledge can be transferred to other insects. To help in closing these gaps we participated in a large-scale RNAi screen that used the red flour beetle, Tribolium castaneum, as a screening platform. The effects of systemic RNAi were screened upon double-stranded RNA injections into appropriate muscle-EGFP tester strains. Injections into pupae were followed by the analysis of the late embryonic/early larval muscle patterns, and injections into larvae by the analysis of the adult thoracic muscle patterns. Herein we describe the results of the first-pass screens with pupal and larval injections, which covered ~8,500 and ~5,000 genes, respectively, of a total of ~16,500 genes of the Tribolium genome. Apart from many genes known from Drosophila as regulators of muscle development, a collection of genes previously unconnected to muscle development yielded phenotypes in larval body wall and leg muscles as well as in indirect flight muscles. We then present the main candidates from the pupal injection screen that remained after being processed through a series of verification and selection steps. Further, we discuss why distinct though overlapping sets of genes are revealed by the Drosophila and Tribolium screening approaches.

http://bit.ly/2ShofxG

Ion Channel Contributions to Wing Development in Drosophila melanogaster

During morphogenesis, cells communicate with each other to shape tissues and organs. Several lines of recent evidence indicate that ion channels play a key role in cellular signaling and tissue morphogenesis. However, little is known about the scope of specific ion-channel types that impinge upon developmental pathways. The Drosophila melanogaster wing is an excellent model in which to address this problem as wing vein patterning is acutely sensitive to changes in developmental pathways. We conducted a screen of 180 ion channels expressed in the wing using loss-of-function mutant and RNAi lines. Here we identify 44 candidates that significantly impacted development of the Drosophila melanogaster wing. Calcium, sodium, potassium, chloride, and ligand-gated cation channels were all identified in our screen, suggesting that a wide variety of ion channel types are important for development. Ion channels belonging to the pickpocket family, the ionotropic receptor family, and the bestrophin family were highly represented among the candidates of our screen. Seven new ion channels with human orthologs that have been implicated in human channelopathies were also identified. Many of the human orthologs of the channels identified in our screen are targets of common general anesthetics, anti-seizure and anti-hypertension drugs, as well as alcohol and nicotine. Our results confirm the importance of ion channels in morphogenesis and identify a number of ion channels that will provide the basis for future studies to understand the role of ion channels in development.

http://bit.ly/2DoauTM

GSK, Merck KGaA Partner to Develop M7824 [News in Brief]

Deal for anti–PD-L1/TGFβ bifunctional fusion protein could top $4.2 billion.

http://bit.ly/2Dj8agA

Ligand binding domain activating mutations of ESR1 rewire cellular metabolism of breast cancer cells

Purpose: Mutations in the ligand binding domain (LBD) of estrogen receptor α (ER) confer constitutive transcriptional activity and resistance to endocrine therapies in breast cancer patients. Accumulating clinical data suggest adverse outcome for patients harboring tumors expressing these mutations. We aimed to elucidate mechanisms conferring this aggressive phenotype. Experimental Design: Cells constitutively expressing physiologic levels of ER harboring activating LBD mutations were generated and characterized for viability, invasiveness and tumor formation in vivo. Gene expression profile was studied using microarray and RNAseq technologies. Metabolic properties of the cells were assessed using global metabolite screen and direct measurement of metabolic activity. Results: Cells expressing mutated ER showed increased proliferation, migration and in vivo tumorogenicity compared to cells expressing the WT-ER, even in the presence of estrogen. Expression of the mutated ER was associated with upregulation of genes involved in invasion and metastases, as well as elevation of genes associated with tumor cell metabolism. Indeed, a metabolic examination revealed four distinct metabolic profiles: WT-ER expressing cells either untreated or estrogen-treated and Mutated-ER expressing cells either untreated or estrogen-treated. Pathway analyses indicated elevated TCA cycle activity of 537S-ER expressing cells. Thus, while WT-ER cells were mostly glucose-dependent, 537S-ER were not addicted to glucose and were able to utilize glutamine as an alternative carbon source. Conclusions:Taken together, these data indicate estrogen-independent rewiring of breast cancer cell metabolism by LBD-activating mutations. These unique metabolic activities may serve as a potential vulnerability and aid in the development of novel treatment strategies to overcome endocrine resistance.

http://bit.ly/2BoRX9F

Alpha particle Radium 223 dichloride in high-risk osteosarcoma: a phase I dose escalation trial

Purpose: The prognosis of metastatic osteosarcoma continues to be poor. We hypothesized that alpha-emitting, bone-targeting radium 223 dichloride (²²³RaCl₂) can be safely administered to patients with osteosarcoma and that early signals of response or resistance can be assessed by quantitative and qualitative correlative imaging studies and biomarkers. Experimental Design: A 3+3 phase I, dose-escalation trial of ²²³RaCl₂ (50, 75, and 100 kBq/kg) was designed in recurrent/metastatic osteosarcoma patients aged ≥15 years. Objective measurements included changes in SUV of PET (18FDG and/or NaF-18) and single-photon-emission-computed-tomography-computed tomography (99mTc-MDP) as well as alkaline phosphatase and bone turnover markers at baseline, mid-study, and the end of the study. Results: Among 18 patients enrolled (including 15 males) aged 15-71 years, tumor locations included spine (n=12, 67%), pelvis (n=10, 56%), ribs (n=9, 50%), extremity (n=7, 39%), and skull (n=2, 11%). Patients received 1-6 cycles of ²²³RaCl₂; cumulative doses were 6.84-57.81 MBq. NaF PET revealed more sites of metastases than did FDG PET. One patient showed a metabolic response on FDG PET and NaF PET. Four patients had mixed responses, and one patient had a response in a brain metastasis. Bronchopulmonary hemorrhage from Grade 3 thrombocytopenia (N=1) was a DLT. The median overall survival time was 25 weeks. Conclusions: The first evaluation of the safety and efficacy of an alpha particle in high-risk osteosarcoma shows that the recommended phase II dose for ²²³RaCl₂ in osteosarcoma is 100 kBq/kg monthly (twice the dose approved for prostate cancer), with minimal hematologic toxicity, setting the stage for combination therapies.

http://bit.ly/2TEOivw

C8orf76 promotes gastric tumorigenicity and metastasis by directly inducing lncRNA DUSP5P1 and associates with patient outcomes

Purpose: We identified for the first time that C8orf76 (chromosome 8 open reading frame 76) is preferentially amplified in gastric cancer (GC). We elucidated its role and clinical significance in gastric carcinogenesis. Experimental Design:The clinical impact of C8orf76 was assessed in 592 GCs. The biological function of C8orf76 was studied in vitro, in vivo and in GC patient-derived organoid models. C8orf76 downstream effector and pathways were identified by RNA-sequencing, ChIP-sequencing, luciferase reporter and electrophoretic mobility shift assay. Results:C8orf76 was upregulated in 69.74% and 65.71% of two independent cohorts of GCs and was positively associated with C8orf76 amplification. Multivariate analysis showed that GC patients with C8orf76 amplification (cohort I n=129; cohort II, n=107) or overexpression (n=356) had a significantly shortened survival. C8orf76 significantly promoted GC cell proliferation, cell cycle transformation, migration/invasion, but suppressed cell apoptosis. Silencing C8orf76 expression exerted opposite effects in vitro, and significantly inhibited xenograft tumor growth, lung metastasis and liver metastasis in nude mice. Silencing C8orf76 also significantly suppressed the growth of patient-derived organoids. Mechanically, C8orf76 activated MAPK/ERK signaling cascade. C8orf76 directly bound to the promoter region of lncRNA DUSP5P1 with a binding motif of AGGCTG and activated DUSP5P1 transcription. DUSP5P1 induced MAPK/ERK signaling and promoted gastric tumorigenesis. Knockdown DUSP5P1 abrogated the effect of C8orf76 in activating MAPK/ERK cascade and the tumor-promoting function. Conclusions:C8orf76 directly binds to oncogenic lncRNA DUSP5P1 to induce its expression and activates MAPK signaling. C8orf76 plays pivotal oncogenic role in gastric carcinogenesis and is an independent prognostic factor for GC patients.

http://bit.ly/2Bm7Ltt

Inhibitory Effect of ( 2R )-1-(1-Benzofuran-2-yl)-N-propylpentan-2-amine on Lung Adenocarcinoma

Abstract

BPAP is a potent enhancer substance with catecholaminergic and serotoninergic activity in the brain. It was discovered that it is also effective against certain types of experimental cancers, showing the most promising results in case of lung cancer. That is why we tested its efficacy in two different doses in a newly developed EGFR wild type mouse lung adenocarcinoma xenograft model. Experiments were conducted on FVB/N and SCID mouse strains treated with low and high dose of BPAP. Body weight, survival, and tumor volumes were recorded. Furthermore, the activity of major signaling pathways of NSCLC such as MAPK and Akt/mTOR as well as cell cycle regulation were determined. Significant inhibition of tumor growth was exerted by both doses, but the mechanism of action was different. High dose directly inhibited, whereas low dose activated the main signaling pathways. Exposure to low dose BPAP resulted in elevated activity of the mTOR pathway together with p16^INK-induced cell cycle arrest, a typical feature of geroconversion, a senescent state characterized by loss of cell proliferation. Finally the events culminated in cell cycle inhibition point in case of both doses mirrored by the decrease of cyclin D1, CDK4 and PCNA. In addition, BPAP treatment had a beneficial effect on bodyweight suggesting that the compound at least in part is able to compensate the cancer-related wasting. In view of the low toxicity and confirmed antitumor effect of BPAP against experimental lung adenocarcinoma, this novel compound deserves further attention.

http://bit.ly/2MYWYKE

Loss of Foxp3 and Tsc1 Accelerate Prostate Cancer Progression through a Synergistic Transcriptional and Post-translational Regulation of c-MYC

Although c-MYC and mTOR are frequently activated proteins in prostate cancer, any interaction between the two is largely untested. Here we characterize the functional crosstalk between FOXP3-c-MYC and TSC1-mTOR signaling during tumor progression. Deletion of Tsc1 in mouse embryonic fibroblasts (MEF) decreased phosphorylation of c-MYC at threonine 58 (pT58) and increased phosphorylation at serine 62 (pS62), an observation validated in prostate cancer cells. Conversely, inhibition of mTOR increased pT58 but decreased pS62. Loss of both Foxp3 and Tsc1 in prostate cancer cells synergistically enhanced c-MYC expression via regulation of c-Myc transcription and protein phosphorylation. This crosstalk between FOXP3 and TSC1 appeared to be mediated by both the mTOR-4EBP1-c-MYC and FOXP3-c-MYC pathways. In mice, Tsc1 and Foxp3 double-deletions in the prostate led to prostate carcinomas at an early age; this did not occur in these mice with an added c-Myc deletion. In addition, we observed synergistic anti-tumor effects of co-treating mice with inhibitors of mTOR and c-MYC in prostate cancer cells as well as in Foxp3 and Tsc1 double-mutant mice. In human prostate cancer, loss of nuclear FOXP3 is often accompanied by low expression of TSC1. Since loss of Foxp3 transcriptionally induces c-Myc expression and loss of Tsc1 activates mTOR signaling, these data suggest crosstalk between FOXP3-c-MYC and TSC1-mTOR signaling that converges on c-MYC to regulate tumor progression. Co-administration of c-Myc and mTOR inhibitors may overcome the resistance to mTOR inhibition so commonly observed prostate cancer cells.

http://bit.ly/2HYMGLB

Spleen tyrosine kinase-mediated autophagy is required for epithelial-mesenchymal plasticity and metastasis in breast cancer

The ability of breast cancer cells to transiently transition between epithelial and mesenchymal states contributes to their metastatic potential. Therefore, driving tumor cells into a stable mesenchymal state, as opposed to complete tumor cell eradication, presents an opportunity to pharmacologically limit disease progression by promoting an asymptomatic state of dormancy. Here we compare a reversible model of epithelial-mesenchymal transition (EMT) induced by TGF-β to a stable mesenchymal phenotype induced by chronic exposure to the ErbB kinase inhibitor lapatinib. Only cells capable of returning to an epithelial phenotype resulted in skeletal metastasis. Gene expression analyses of the two mesenchymal states indicated similar transition expression profiles. A potently downregulated gene in both datasets was spleen tyrosine kinase (SYK). In contrast to this similar diminution in mRNA, kinome analyses using a peptide array and DNA-conjugated peptide substrates showed a robust increase in SYK activity upon TGF-β-induced EMT only. SYK was present in cytoplasmic RNA processing depots known as P-bodies formed during the onset of EMT, and SYK activity was required for autophagy-mediated clearance of P-bodies during mesenchymal-epithelial transition (MET). Genetic knockout of autophagy related 7 (ATG7) or pharmacological inhibition of SYK activity with fostamatib, a clinically approved inhibitor of SYK, prevented P-body clearance and MET, inhibiting metastatic tumor outgrowth. Overall, the current study suggests assessment of SYK activity as a biomarker for metastatic disease and the use of fostamatinib as a means to stabilize the latency of disseminated tumor cells.

http://bit.ly/2Gd7uNT

Phosphatase 1 nuclear targeting subunit mediates recruitment and function of poly (ADP-ribose) polymerase 1 in DNA repair

Poly (ADP-ribose) polymerases (PARP), particularly PARP1, play an essential role in the detection and repair of DNA single strand breaks (SSB) and double strand breaks (DSB). PARP1 accumulates at DNA damage sites within seconds after DNA damage to catalyze the massive induction of substrate protein poly ADP-ribosylation (PARylation). However, the molecular mechanisms underlying the recruitment and activation of PARP1 in DNA repair are not fully understood. Here we show that PNUTS is a robust binding partner of PARP1. Inhibition of PNUTS led to strong accumulation of endogenous DNA damage and sensitized the cellular response to a wide range of DNA-damaging agents, implicating PNUTS as an essential and multifaceted regulator of DNA repair. Recruitment of PNUTS to laser-induced DNA damage was similar to that of PARP1, and depletion or inhibition of PARP1 abrogated recruitment of PNUTS to sites of DNA damage. Conversely, PNUTS was required for efficient induction of substrate PARylation after DNA damage. PNUTS bound the BRCA1 C-terminal (BRCT) domain of PARP1 and was required for the recruitment of PARP1 to sites of DNA damage. Finally, depletion of PNUTS rendered cancer cells hypersensitive to PARP inhibition. Taken together, our study characterizes PNUTS as an essential partner of PARP1 in DNA repair and a potential drug target in cancer therapy.

http://bit.ly/2HYMDiT

Effect of increased body mass index on risk of diagnosis or death from cancer

Effect of increased body mass index on risk of diagnosis or death from cancer

Effect of increased body mass index on risk of diagnosis or death from cancer, Published online: 08 February 2019; doi:10.1038/s41416-019-0386-9

Effect of increased body mass index on risk of diagnosis or death from cancer

https://go.nature.com/2GAfXtw

Parents Conflicted About Opioid Use in Children

THURSDAY, Feb. 7, 2019 -- Parents are conflicted about the use of prescribed opioids in children, with most concerned about side effects and risks but believing opioids are the most effective option for managing pain, according to a survey...

http://bit.ly/2WRIcJU

FDA: Number of U.S. Women With Breast Implant-Caused Cancer Has Increased

THURSDAY, Feb. 7, 2019 -- There has been an increase in the number of U.S. women diagnosed with a cancer caused by breast implants, the U.S. Food and Drug Administration said Wednesday. The number of women with breast implant-associated anaplastic...

http://bit.ly/2ROs1tc

Dialysis Staff-Initiated CPR Ups Outcomes in Cardiac Arrest

THURSDAY, Feb. 7, 2019 -- For patients with out-of-hospital cardiac arrest (OHCA) occurring in outpatient dialysis clinics, dialysis staff-initiated cardiopulmonary resuscitation (CPR) is associated with improved outcomes, according to a study...

http://bit.ly/2WRa6Gj

Chronic Rhinosinusitis Linked to Depression, Anxiety

THURSDAY, Feb. 7, 2019 -- Chronic rhinosinusitis (CRS) is associated with incidence of depression and anxiety, according to a study published online Feb. 7 in JAMA Otolaryngology-Head & Neck Surgery. Jong-Yeup Kim, M.D., Ph.D., from Konyang...

http://bit.ly/2RKwoFS

Many Children Not Following Toothbrushing Recommendations

THURSDAY, Feb. 7, 2019 -- Most children are not brushing their teeth early enough, and many are not using the proper amount of toothpaste, according to research published in the Feb. 1 issue of the U.S. Centers for Disease Control and Prevention...

http://bit.ly/2WHB6aW

Meeting abstracts from the Annual Conference Clinical Genetics of Cancer 2018

http://bit.ly/2ShEwTs

Effect of increased body mass index on risk of diagnosis or death from cancer

https://go.nature.com/2SGnAp7

Setting minimum standards for training in EUS and ERCP: results from a prospective multicenter study evaluating learning curves and competence among advanced endoscopy trainees

Minimum EUS and ERCP volumes that should be offered per trainee in "high quality" advanced endoscopy training programs (AETPs) are not established. We aimed to define the number of procedures required by an "average" advanced endoscopy trainee (AET) to achieve competence in technical and cognitive EUS and ERCP tasks to help structure AETPs.

http://bit.ly/2RMRiUG

Expression of E cadherin and Ki 67: Emerging Prognostic Markers in Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subgroup of breast cancer which lacks effective target therapy. Expression of biomarkers is one of the important deciding factors for treatment strategies. The aim of this study was to evaluate expression of E cadherin and Ki 67 in relation to clinicopathological features. This prospective observational study included 141 cases of TNBC. Immunohistochemical staining was employed to analyze two biomarkers: E cadherin and Ki 67 on formalin-fixed paraffin-embedded tumor samples obtained from patients defined as TNBC. The age of the patients ranged from 26 to 84 years. Positive lymph nodes were found in 82 (58.1%). The tumor was grade 3 in 105 (74.4%). The E cadherin receptor was positive in 83 (58.8%). The Ki Index was > 10% in 89 (63.12%). The Ki 67 expression was significantly associated with a high nuclear grade (p = 0.000). The significant association noted between loss of E cadherin expression and positive lymph node (p = 0.0296). According to the results, TNBCs are frequently associated with the younger age groups, and the majority is poorly differentiated. The majorities of these have high expression of the Ki 67 and significantly associated with the higher nuclear grade. Loss of E cadherin was significantly associated with positive lymph nodes. Hence, evaluating the expression of E cadherin and Ki 67 routinely would be helpful for evaluating prognostic implications.

http://bit.ly/2WNAgtj

Correlation Between Pelvic Peritoneal Disease and Nodal Metastasis in Advanced Ovarian Cancer: Can Intraoperative Findings Define the Need for Systematic Nodal Dissection?

Abstract

To explore the relationship of peritoneal, and rectal involvement with lymph nodal metastases to identify clinical parameters to guide systematic nodal dissection in advanced ovarian cancer (stage 3c). It is a retrospective study of stage III C epithelial ovarian cancers undergoing cytoreductive surgery with systematic nodal dissection, from January 2011 to December 2016. LS3 score is a cumulative score given for the presence of size 3 lesion (peritoneal disease measuring more than 5 cm) in regions 5, 6, and 7. The depth of rectal involvement was assigned progressive numerical values from 1 (for serosa) to maximum 4 (for mucosa) to generate rectal involvement score. There were 91 patients. 48.35% patients had LS3 lesions in regions 5, 6, 7. Of these, 36% (27/44) had positive nodes. Of the 41 node-positive cases, 43.9% had single and 34.14% had two station involvements. Rectum was involved in 47 patients (51.64%), serosal involvement being the most common type (50.57%). Twenty patients had positive mesorectal nodes (42.55%). The presence of rectal involvement was influenced by the Peritoneal Carcinomatosis Index (PCI) score, the presence of LS3 in lower quadrants (p = 0.008), and LSE score of lower quadrants (p = 0.003). With the increasing depth of rectal infiltration, mesorectal positivity increased significantly (p = 0.000). In multivariate analysis, lower quadrant (regions 5, 6, 7) PCI, LS3 in lower quadrants, LS3 score, rectal involvement score, and the total number of lines of chemotherapy significantly affected different nodal disease parameters. In advanced ovarian cancer, LS3 disease in regions 5, 6, and 7 and rectal involvement directly impact the nodal metastasis and hence mandates a systematic nodal dissection. Mesorectal nodal involvement significantly increases with the increasing depth of rectal involvement necessitating systematic mesorectal nodal clearance for all rectal resections.

http://bit.ly/2RPbXYt

Outcomes after Proton Therapy for Treatment of Pediatric High-Risk Neuroblastoma

Primary site irradiation for patients with high-risk neuroblastoma is necessary, but is associated with exposure of uninvolved kidneys, liver, and bowel. Proton therapy may spare normal tissues. We present the largest ever population of patients with neuroblastoma treated with proton therapy, demonstrating minimal toxicity and 97% local disease free survival. This treatment is safe and allows minimization of dose to normal tissues in young patients with neuroblastoma, who require intensive multimodality therapy.

http://bit.ly/2WRtGSq

Erratum Regarding “A Randomized Trial of a Multicomponent Intervention to Promote Medication Adherence: The Teen Adherence in Kidney Transplant Effectiveness of Intervention Trial (TAKE-IT)” (Am J Kidney Dis. 2018;72[1]:30-41)

In the Original Investigation entitled "A Randomized Trial of a Multicomponent Intervention to Promote Medication Adherence: The Teen Adherence in Kidney Transplant Effectiveness of Intervention Trial (TAKE-IT)" that appeared in the July 2018 issue of AJKD (Foster et al, volume 72, issue 1, pages 30-41), there was an error in the timing adherence analyses. This error was uncovered in the course of secondary analyses of the TAKE-IT data performed by the authors. In particular, the "Outcomes Measures" subsection of Methods on page 32, states that "timing adherence" was calculated as the "proportion of prescribed doses taken within 1 hour before to 2 hours after the prescribed dosing time." In fact, the results presented in the article were calculated using timing adherence defined as doses taken within 3 hours before or after the prescribed dosing time.

http://bit.ly/2DkkugI

Remembering the Power of Stories in Pediatric Research

Pediatric research is detailed, exacting, and scientific. It provides a clear picture, a freeze frame of the study of a particular issue related to children in their infancy, toddlerhood, childhood, and adolescence. Within studies, the clinical statistics automatically mask faces, remove stories, and keep the focus on sterile data in hopes of educating colleagues on important health topics such as the quality of life for infants with bronchopulmonary dysplasia, as reported by Brady et al1 in this volume of The Journal.

http://bit.ly/2DYzqCu

Prostate cancer and subsequent nutritional outcomes: the role of diagnosis and treatment

Abstract

Purpose

To comprehensively explore the role of a prostate cancer diagnosis and its treatment to several outcomes including diet, Hemoglobin A1c, and weight status, in a large, nationally representative, cross-sectional study.

Methods

This analysis used five cross sections from the publicly available National Health and Nutrition Evaluation Survey (NHANES) from 2001 to 2010. A sample of 289 men with a history of prostate cancer was matched to a comparison group of 655 men with elevated prostate-specific antigen (> 4 ng/mL) but no reported diagnosis of prostate cancer. Analyses were stratified by diabetic or pre-diabetes status and treatment including surgery, radiotherapy, or both. Outcomes of interest included several broad macronutrient categories, HbA1c, body mass index, and obesity status. Multivariate regression analyses were conducted to clarify the associations of a prostate cancer diagnosis with these outcomes. Demographic and socioeconomic factors, including age, education, race, income, and marital status, were controlled for in all models.

Results

The clinical and demographic characteristics were relatively well balanced between the "at risk" comparison group and the group of men diagnosed with prostate cancer. Diabetic or pre-diabetic men diagnosed with prostate cancer were more likely to be obese (p < 0.05) and have a higher BMI (p < 0.10). On multivariate analysis, compared to controls, men with prostate cancer treated with surgery and radiation therapy were predicted to have a higher BMI (p < 0.01) and were more likely to be obese (p < 0.05). These findings were largely driven by the diabetic and pre-diabetic sample. Further diabetics and pre-diabetics with prostate cancer treated with both radiation and surgery were predicted to consume an average of 72 and 59 more daily grams of carbohydrates and sugar, respectively, compared to controls (p < 0.05).

Conclusion

Men with prostate cancer report fewer behaviors and outcomes consistent with optimal glycemic management including a higher BMI, and in diabetics and pre-diabetics, increased carbohydrate sugar consumption. Men with more intense treatment including surgery and radiotherapy appeared to be more likely to be obese and make poorer dietary carbohydrate and sugar choices compared to men without prostate cancer.

Implications for Cancer Survivors

Men treated for prostate cancer have, on average, very long survivorship periods and are susceptible to diabetes and its complications. Interventions designed to improve diabetes awareness and self-management, especially weight and dietary sugar control, may be useful in this population.

http://bit.ly/2tb3wMU

Efficient Construction of Drug-like Bispirocyclic Scaffolds Via Organocatalytic Cycloadditions of α-Imino γ-Lactones and Alkylidene Pyrazolones

Enantiomerically enriched bispiro[γ-butyrolactone-pyrrolidin-4,4'-pyrazolone] skeletons are asymmetrically synthesized through a simple organocatalytic 1,3-dipolar cycloaddition reaction.

http://bit.ly/2RHOvw5

Extraction of Extracellular Vesicles from Whole Tissue

Here, we provide a detailed protocol to isolate small extracellular vesicles (EVs) from whole tissues, including brain and tumor specimens. This method offers a reproducible technique to extract EVs from solid tissue for further downstream analyses.

http://bit.ly/2SA02lw

Most Americans Concerned About Weight, Link to Heart Health

THURSDAY, Feb. 7, 2019 -- Most Americans are concerned about their weight and understand the connection between weight and cardiovascular health, but a substantial proportion of them are not doing much to lose excess weight, according to a Cleveland...

http://bit.ly/2I0aPRS

Discord Found in Clinician-, Criteria-Based Fibromyalgia Diagnosis

THURSDAY, Feb. 7, 2019 -- There is disagreement between clinical diagnosis and criteria-based diagnosis of fibromyalgia, according to a study published online Feb. 6 in Arthritis Care & Research. Frederick Wolfe, M.D., from the National Data...

http://bit.ly/2Sx1ghA

Drug Combo Tolerated in Younger Children With Cystic Fibrosis

THURSDAY, Feb. 7, 2019 -- Lumacaftor/ivacaftor treatment is generally safe and well tolerated for children aged 2 to 5 years with cystic fibrosis (CF) homozygous for the F508del-CFTR mutation, according to a study published online Jan. 24 in The...

http://bit.ly/2HZ9Tgz

Conservative Management Feasible for Adnexal Masses

THURSDAY, Feb. 7, 2019 -- The risk for malignancy and acute complications is low for patients with an adnexal mass with benign ultrasound morphology who are managed conservatively, according to a study published online Feb. 5 in the The Lancet...

http://bit.ly/2SxyDAK

Shoulder Decompression Surgery Not Recommended

THURSDAY, Feb. 7, 2019 -- For adults with atraumatic shoulder pain for more than three months diagnosed as subacromial pain syndrome (SAPS), subacromial decompression surgery is not recommended, according to a clinical practice guideline published...

http://bit.ly/2SylJlT

T2DM Initially Remits in Majority Who Undergo Gastric Bypass

THURSDAY, Feb. 7, 2019 -- Roux-en-Y gastric bypass (RYGB) is associated with high levels of type 2 diabetes remission at one year, although 27 percent relapse after five years, according to a study published online Feb. 6 in Diabetologia. Lene R....

http://bit.ly/2SxYk49

Trazodone Not Associated With Reduced Risk for Dementia

THURSDAY, Feb. 7, 2019 -- Trazodone is not associated with a reduced risk for dementia compared with other antidepressants at the prodromal stage of disease, according to a study published online Feb. 5 in PLOS Medicine. Ruth Brauer, Ph.D., from the...

http://bit.ly/2SDHhxq

Chemical Isolation, Quantification, and Separation of Skin Lipids from Reptiles

In reptiles, skin lipids from conspecifics are crucial for sexual signaling, with potential use in invasive species management. Here, we describe protocols for extracting skin lipids from shed skin or whole animals, determining and analyzing the total lipid mass, and separating the lipids using fractionation via column chromatography.

http://bit.ly/2DmXuOe

Benefits and Barriers to and Desired Outcomes with Exercise in Patients with ESKD

Background and objectives

Patients with ESKD are sedentary. When patient-identified barriers to exercise are addressed, recruitment and retention in exercise trials remain low, suggesting that the trial design may not resonate with them. Therefore, we conducted a survey of patients on dialysis to assess perceived benefits and barriers to exercise and discover preferred outcomes and exercise type by dialysis modality and age in anticipation of designing future randomized, controlled trials.

Design, setting, participants, & measurements

English- and French-speaking patients with ESKD treated with hemodialysis or peritoneal dialysis were recruited from two tertiary care hospitals in Ottawa and Montreal, Canada. Summary descriptive statistics were used to describe patient responses; then, they were separated by dialysis modality and age category.

Results

The survey was completed by 423 participants. Current activity levels were similar across modalities (P=0.35); 78% of younger patients walked at least 10 minutes at a time on 3 or more days compared with only 58% of older patients (P=0.001). The two most desired benefits of exercise were improved energy (18%) and strength (14%). The third priority differed, such that improved sleep, maintenance of independence, and longevity were selected by patients on peritoneal dialysis, patients on in-center hemodialysis, and patients on home hemodialysis, respectively. Older patients were most interested in improvements in energy, strength, and maintenance of independence, whereas younger patients were interested in improving energy, longevity, and transplant candidacy. Only 25% of patients were able to exercise without difficulty; the major barriers for the remaining patients were feeling patients were feeling too tired (55%), short of breath (50%), and too weak (49%). If patients were to exercise, they wanted to exercise at home (73%) using a combination of aerobic and resistance training (41%), regardless of modality or age category.

Conclusions

The majority of patients undergoing maintenance dialysis in two tertiary hospitals in Ottawa and Montreal report similar desired outcomes and barriers, with greater differences by age category than modality.

http://bit.ly/2GtM2Dv

Increasing Awareness of Early Risk of AKI in Neonates

http://bit.ly/2DZeYl4

A Patients View on Exercise and ESKD

http://bit.ly/2GtRrdD

The Case for a Bariatric-Centered Approach to CKD Care

http://bit.ly/2GsCit0

Medication Prescription Patterns for Secondary Hyperparathyroidism: More Questions than Answers

http://bit.ly/2DYpqZY

Fruit and Vegetable Intake and Mortality in Adults undergoing Maintenance Hemodialysis

Background and objectives

Higher fruit and vegetable intake is associated with lower cardiovascular and all-cause mortality in the general population. It is unclear whether this association occurs in patients on hemodialysis, in whom high fruit and vegetable intake is generally discouraged because of a potential risk of hyperkalemia. We aimed to evaluate the association between fruit and vegetable intake and mortality in hemodialysis.

Design, setting, participants, & measurements

Fruit and vegetable intake was ascertained by the Global Allergy and Asthma European Network food frequency questionnaire within the Dietary Intake, Death and Hospitalization in Adults with ESKD Treated with Hemodialysis study, a multinational cohort study of 9757 adults on hemodialysis, of whom 8078 (83%) had analyzable dietary data. Adjusted Cox regression analyses clustered by country were conducted to evaluate the association between tertiles of fruit and vegetable intake with all-cause, cardiovascular, and noncardiovascular mortality. Estimates were calculated as hazard ratios with 95% confidence intervals (95% CIs).

Results

During a median follow up of 2.7 years (18,586 person-years), there were 2082 deaths (954 cardiovascular). The median (interquartile range) number of servings of fruit and vegetables was 8 (4–14) per week; only 4% of the study population consumed at least four servings per day as recommended in the general population. Compared with the lowest tertile of servings per week (0–5.5, median 2), the adjusted hazard ratios for the middle (5.6–10, median 8) and highest (>10, median 17) tertiles were 0.90 (95% CI, 0.81 to 1.00) and 0.80 (95% CI, 0.71 to 0.91) for all-cause mortality, 0.88 (95% CI, 0.76 to 1.02) and 0.77 (95% CI, 0.66 to 0.91) for noncardiovascular mortality and 0.95 (95% CI, 0.81 to 1.11) and 0.84 (95% CI, 0.70 to 1.00) for cardiovascular mortality, respectively.

Conclusions

Fruit and vegetable intake in the hemodialysis population is low and a higher consumption is associated with lower all-cause and noncardiovascular death.

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Does an Apple (or Many) Each Day, Keep Mortality Away?

http://bit.ly/2DYWD7W

Clinical Pharmacology of Oral Anticoagulants in Patients with Kidney Disease

Oral anticoagulants are commonly used drugs in patients with CKD and patients with ESKD to treat atrial fibrillation to reduce stroke and systemic embolism. Some of these drugs are used to treat or prevent deep venous thrombosis and pulmonary embolism in patients with CKD who undergo knee and hip replacement surgeries. Warfarin is the only anticoagulant that is approved for use by the Food and Drug Administration in individuals with mechanical heart valves. Each oral anticoagulant affects the coagulation profile in the laboratory uniquely. Warfarin and apixaban are the only anticoagulants that are Food and Drug Administration approved for use in patients with CKD and patients with ESKD. However, other oral anticoagulants are commonly used off label in this patient population. Given the acquired risk of bleeding from uremia, these drugs are known to cause increased bleeding events, hospitalization, and overall morbidity. Each anticoagulant has unique pharmacologic properties of which nephrologists need to be aware to optimally manage patients. In addition, nephrologists are increasingly asked to aid in the management of adverse bleeding events related to oral anticoagulant use in patients with CKD and patients with ESKD. This article summarizes the clinical pharmacology of these drugs and identifies knowledge gaps in the literature related to their use.

http://bit.ly/2GsC5Ge

Assessing Clinical Relevance of Uremic Toxins

http://bit.ly/2DYCeQk

Assessment and Management of Hypertension among Patients on Peritoneal Dialysis

Approximately 7%–10% of patients with ESKD worldwide undergo peritoneal dialysis (PD) as kidney replacement therapy. The continuous nature of this dialytic modality and the absence of acute shifts in pressure and volume parameters is an important differentiation between PD and in-center hemodialysis. However, the burden of hypertension and prognostic association of BP with mortality follow comparable patterns in both modalities. Although management of hypertension uses similar therapeutic principles, long-term preservation of residual diuresis and longevity of peritoneal membrane function require particular attention in the prescription of the appropriate dialysis regimen among those on PD. Dietary sodium restriction, appropriate use of icodextrin, and limited exposure of peritoneal membrane to bioincompatible solutions, as well as adaptation of the PD regimen to the peritoneal transport characteristics, are first-line therapeutic strategies to achieve adequate volume control with a potential long-term benefit on technique survival. Antihypertensive drug therapy is a second-line therapeutic approach, used when BP remains unresponsive to the above volume management strategies. In this article, we review the available evidence on epidemiology, diagnosis, and treatment of hypertension among patients on PD and discuss similarities and differences between PD and in-center hemodialysis. We conclude with a call for randomized trials aiming to elucidate several areas of uncertainty in management of hypertension in the PD population.

http://bit.ly/2GziHHX

Incidence and Risk Factors of Early Onset Neonatal AKI

Background and objectives

Neonatal AKI is associated with poor short- and long-term outcomes. The objective of this study was to describe the risk factors and outcomes of neonatal AKI in the first postnatal week.

Design, setting, participants, & measurements

The international retrospective observational cohort study, Assessment of Worldwide AKI Epidemiology in Neonates (AWAKEN), included neonates admitted to a neonatal intensive care unit who received at least 48 hours of intravenous fluids. Early AKI was defined by an increase in serum creatinine >0.3 mg/dl or urine output <1 ml/kg per hour on postnatal days 2–7, the neonatal modification of Kidney Disease: Improving Global Outcomes criteria. We assessed risk factors for AKI and associations of AKI with death and duration of hospitalization.

Results

Twenty-one percent (449 of 2110) experienced early AKI. Early AKI was associated with higher risk of death (adjusted odds ratio, 2.8; 95% confidence interval, 1.7 to 4.7) and longer duration of hospitalization (parameter estimate: 7.3 days 95% confidence interval, 4.7 to 10.0), adjusting for neonatal and maternal factors along with medication exposures. Factors associated with a higher risk of AKI included: outborn delivery; resuscitation with epinephrine; admission diagnosis of hyperbilirubinemia, inborn errors of metabolism, or surgical need; frequent kidney function surveillance; and admission to a children's hospital. Those factors that were associated with a lower risk included multiple gestations, cesarean section, and exposures to antimicrobials, methylxanthines, diuretics, and vasopressors. Risk factors varied by gestational age strata.

Conclusions

AKI in the first postnatal week is common and associated with death and longer duration of hospitalization. The AWAKEN study demonstrates a number of specific risk factors that should serve as "red flags" for clinicians at the initiation of the neonatal intensive care unit course.

http://bit.ly/2DYctzB

Variability in Cinacalcet Prescription across US Hemodialysis Facilities

Background and objectives

Calcimimetic drugs used to treat secondary hyperparathyroidism are being considered for inclusion in the Medicare ESRD Prospective Payment System bundle after an evaluation period. Understanding of utilization patterns of calcimimetics across dialysis facilities may help align financial incentives with clinical objectives. Our study's purpose was to describe the distribution of cinacalcet prescription across United States hemodialysis facilities and to explore factors that may influence cinacalcet utilization.

Design, setting, participants, & measurements

We used monthly cross-sectional data from the Dialysis Outcomes and Practice Patterns Study in 2014 to characterize the distribution of cinacalcet prescription across 203 United States hemodialysis facilities (10,521 patients). On the basis of associations with parathyroid hormone levels from patient-level analyses, we used linear mixed-effects regressions to estimate the associations between three facility-level exposures (black race, <65 years old, and having ≥3 years on dialysis [vintage]) and the prevalence of cinacalcet prescription, adjusting for facility- and patient-level potential confounders.

Results

The mean percentage of patients in each facility with cinacalcet prescription was 23% in June 2014 (median, 22%; interquartile range, 13%–30%). Adjusted for facility-level and nonexposure patient-level variables, the difference in prevalence of cinacalcet prescription between facilities with the highest and lowest quartiles of percentage of black patients was 7.8% (95% confidence interval [95% CI], 0.8% to 14.8%; P for trend =0.03). The adjusted prevalence difference was 7.3% for the percentage of patients aged <65 years (95% CI, –0.1% to 14.7%; P for trend =0.06) and 11.9% for the percentage of patients with ≥3 years of dialysis (95% CI, 2.4% to 21.4%; P for trend =0.02). These associations changed appreciably, becoming much weaker or even reversing, after further adjusting for the patient-level exposure variables.

Conclusions

Facilities treating more patients who are black, under age 65 years, and having dialysis vintage ≥3 years have higher average levels of cinacalcet prescription. However, these differences were strongly attenuated after accounting for the unbalanced distributions of these patient case-mix variables.

http://bit.ly/2GvOgSO

Clinical Outcomes of Failing to Dose-Reduce Cephalosporin Antibiotics in Older Adults with CKD

Background and objectives

Current dosing recommendations for cephalosporin antibiotics are on the basis of pharmacokinetic studies and are frequently ignored in practice. This study was undertaken to investigate the clinical outcomes of failing to dose-reduce cephalosporin antibiotics in CKD.

Design, setting, participants, & measurements

Retrospective cohort study conducted in Ontario, Canada using linked population-based health care databases. Nine thousand three hundred forty-seven outpatients (median age 83; interquartile range, 77–88 years; 57% women) with an eGFR<30 ml/min per 1.73 m² and no prior history of dialysis were dispensed oral cephalexin, cefuroxime, or cefprozil between April of 2007 and March of 2016. Two thirds of the patients (6253 of 9347) received a higher than recommended daily dose of cephalexin (>1000 mg), cefuroxime (>500 mg), or cefprozil (>500 mg). The primary outcome was a hospital encounter (emergency room visit or hospital admission) with a condition listed as a possible side-effect of cephalosporins. Secondary outcomes were antibiotic treatment failure and all-cause mortality. All measures were assessed in the 30 days after cephalosporin initiation.

Results

Patients who received a higher than recommended dose of a cephalosporin antibiotic were similar in multiple indicators of baseline health to patients who received a reduced dose. Overall, 6% of patients presented to hospital with a possible cephalosporin side-effect, 13% failed antibiotic treatment, and 3% died. Compared with a reduced dose, receiving a higher dose of antibiotic was not associated with a different rate of side-effects (adjusted odds ratio, 1.00; 95% confidence interval, 0.84 to 1.20), treatment failure (1.01; 0.88 to 1.15), or death (0.99; 0.76 to 1.29).

Conclusions

In this study we failed to demonstrate any association between the dose of cephalosporin antibiotic administered to elderly patients with CKD and the risk of side-effects leading to hospitalization, treatment failure, or mortality.

http://bit.ly/2DZRZGB

Trimethylamine N-Oxide and Cardiovascular Outcomes in Patients with ESKD Receiving Maintenance Hemodialysis

Background and objectives

Trimethylamine N-oxide (TMAO), a compound derived from byproducts of intestinal bacteria, has been shown to accelerate atherosclerosis in rodents. To date, there are conflicting data regarding the association of serum TMAO with cardiovascular outcomes in patients with ESKD, a population exhibiting both high serum TMAO and excessive atherosclerosis.

Design, setting, participants, & measurements

We measured baseline serum TMAO concentrations in a subset of participants (n=1243) from the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial and conducted post hoc analyses evaluating the association between baseline serum TMAO and cardiovascular outcomes.

Results

We observed a wide distribution of serum TMAO in our cohort, with approximately 80% of participants exhibiting TMAO concentrations ≥56 µM and a maximum TMAO concentration of 1103.1 µM. We found no association between TMAO and our primary outcome, a composite of cardiovascular mortality, myocardial infarction, peripheral vascular event, stroke, and hospitalization for unstable angina. Moreover, in unadjusted and adjusted analyses, we observed no relation between TMAO and all-cause mortality, the independent components of our composite outcome, or the original EVOLVE primary outcome. Although we did observe higher TMAO concentrations in white participants, further subgroup analyses did not confirm the previously identified interaction between TMAO and race observed in a prior study in patients receiving dialysis.

Conclusions

We found no evidence linking TMAO to adverse clinical outcomes in patients receiving maintenance hemodialysis with moderate to severe secondary hyperparathyroidism.

http://bit.ly/2GzI6Rs

Correction

http://bit.ly/2GzHlYC

Integration of Genetic Testing and Pathology for the Diagnosis of Adults with FSGS

Background and objectives

FSGS and nephrotic syndrome studies have shown that single gene causes are more likely to be found in pediatric cases than adults. Consequently, many studies have examined limited gene panels in largely pediatric cohorts.

Design, setting, participants, & measurements

Whole-exome sequencing was performed in adults with FSGS diagnosed between 1976 and 2017 in the Toronto GN Registry. An expanded panel of 109 genes linked to FSGS, glomerular basement membrane abnormalities, as well as causes of pediatric ESKD including congenital abnormalities of the kidney and urinary tract (CAKUT) and nephronophthisis, were examined.

Results

The cohort was composed of 193 individuals from 179 families. Nearly half (49%) developed ESKD at a mean age of 47±17 years. The genetic diagnostic rate was 11%. Of definitely pathogenic variants, 55% were in COL4A (A3/A4/A5), 40% were in podocyte genes, and 5% were in CAKUT genes. Many, but not all individuals with COL4A definitely pathogenic variants had some evidence of glomerular basement membrane abnormalities. The estimated mean survival/age of kidney failure for individuals with COL4A definitely pathogenic variants was 58 years (95% confidence interval, 49 to 69), far later than what has been reported in the literature. Likely pathogenic variants were identified in an additional 9% of the cohort, with most in COL4A. Correlation with glomerular basement membrane morphology suggested a causal role for at least some of these likely pathogenic variants.

Conclusions

Even with an expanded gene panel, we find that COL4A disorders are the leading monogenic cause in adults diagnosed with FSGS.

Podcast

This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_01_15_CJASNPodcast_19_02_.mp3

http://bit.ly/2E0mwnP

Patient Entrepreneurs to Drive Health Care Innovation for Kidney Disease

http://bit.ly/2GzHJ9w

Freiburg Neuropathology Case Conference

http://bit.ly/2HZm39o

High Sensitivity Measurement of Transcription Factor-DNA Binding Affinities by Competitive Titration Using Fluorescence Microscopy

Here we present a novel method for determining binding affinities at equilibrium and in solution with high sensitivity on a large scale. This improves the quantitative analysis of transcription factor-DNA binding. The method is based on automated fluorescence anisotropy measurements in a controlled delivery system.

http://bit.ly/2tazRnd

Cancers, Vol. 11, Pages 194: CircSMARCA5 Regulates VEGFA mRNA Splicing and Angiogenesis in Glioblastoma Multiforme Through the Binding of SRSF1

Cancers, Vol. 11, Pages 194: CircSMARCA5 Regulates VEGFA mRNA Splicing and Angiogenesis in Glioblastoma Multiforme Through the Binding of SRSF1

Cancers doi: 10.3390/cancers11020194

Authors: Barbagallo Caponnetto Brex Mirabella Barbagallo Lauretta Morrone Certo Broggi Caltabiano Barbagallo Spina-Purrello Ragusa Di Pietro Hansen Purrello

Circular RNAs are a large group of RNAs whose cellular functions are still being investigated. We recently proposed that circSMARCA5 acts as sponge for the splicing factor Serine and Arginine Rich Splicing Factor 1 (SRSF1) in glioblastoma multiforme (GBM). After demonstrating by RNA immunoprecipitation a physical interaction between SRFS1 and circSMARCA5, we assayed by real-time PCR in a cohort of 31 GBM biopsies and 20 unaffected brain parenchyma controls (UC) the expression of total, pro-angiogenic (Iso8a) and anti-angiogenic (Iso8b) mRNA isoforms of Vascular Endothelial Growth Factor A (VEGFA), a known splicing target of SRSF1. The Iso8a to Iso8b ratio: (i) increased in GBM biopsies with respect to UC (p-value &lt; 0.00001); (ii) negatively correlated with the expression of circSMARCA5 (r-value = &minus;0.46, p-value = 0.006); (iii) decreased in U87-MG overexpressing circSMARCA5 with respect to negative control (p-value = 0.0055). Blood vascular microvessel density, estimated within the same biopsies, negatively correlated with the expression of circSMARCA5 (r-value = &minus;0.59, p-value = 0.00001), while positively correlated with that of SRSF1 (r-value = 0.38, p-value = 0.00663) and the Iso8a to Iso8b ratio (r-value = 0.41, p-value = 0.0259). Kaplan-Meier survival analysis showed that GBM patients with low circSMARCA5 expression had lower overall and progression free survival rates than those with higher circSMARCA5 expression (p-values = 0.033, 0.012, respectively). Our data convincingly suggest that circSMARCA5 is an upstream regulator of pro- to anti-angiogenic VEGFA isoforms ratio within GBM cells and a highly promising GBM prognostic and prospective anti-angiogenic molecule.

http://bit.ly/2SDyj3e

Cancers, Vol. 11, Pages 195: Efficacy and Safety of Ablative Therapy in the Treatment of Patients with Metastatic Pheochromocytoma and Paraganglioma

Cancers, Vol. 11, Pages 195: Efficacy and Safety of Ablative Therapy in the Treatment of Patients with Metastatic Pheochromocytoma and Paraganglioma

Cancers doi: 10.3390/cancers11020195

Authors: Kohlenberg Welch Hamidi Callstrom Morris Sprung Bancos Young

Metastatic pheochromocytoma and paraganglioma (PPGL) are incurable neuroendocrine tumors. The goals of treatment include palliating symptoms and reducing tumor burden. Little is known about the use of radiofrequency ablation (RFA), cryoablation (CRYO), and percutaneous ethanol injection (PEI) to treat metastatic PPGL. We performed a retrospective study of patients age 17 years and older with metastatic PPGL who were treated with ablative therapy at Mayo Clinic, USA, between June 14, 1999 and November 14, 2017. Our outcomes measures were radiographic response, procedure-related complications, and symptomatic improvement. Thirty-one patients with metastatic PPGL had 123 lesions treated during 42 RFA, 23 CRYO, and 4 PEI procedures. The median duration of follow-up was 60 months (range, 0&ndash;163 months) for non-deceased patients. Radiographic local control was achieved in 69/80 (86%) lesions. Improvement in metastasis-related pain or symptoms of catecholamine excess was achieved in 12/13 (92%) procedures. Thirty-three (67%) procedures had no known complications. Clavien-Dindo Grade I, II, IV, and V complications occurred after 7 (14%), 7 (14%), 1 (2%), and 1 (2%) of the procedures, respectively. In patients with metastatic PPGL, ablative therapy can effectively achieve local control and palliate symptoms.

http://bit.ly/2MUGpPU

Cancers, Vol. 11, Pages 196: Emerging Molecular Technologies in Renal Cell Carcinoma: Liquid Biopsy

Cancers, Vol. 11, Pages 196: Emerging Molecular Technologies in Renal Cell Carcinoma: Liquid Biopsy

Cancers doi: 10.3390/cancers11020196

Authors: Cimadamore Gasparrini Massari Santoni Cheng Lopez-Beltran Scarpelli Montironi

: Liquid biopsy, based on the circulating tumor cells (CTCs) and cell-free nucleic acids has potential applications at multiple points throughout the natural course of cancer, from diagnosis to follow-up. The advantages of doing ctDNA assessment vs. tissue-based genomic profile are the minimal procedural risk, the possibility to serial testing in order to monitor disease-relapse and response to therapy over time and to reduce hospitalization costs during the entire process. However, some critical issues related to ctDNA assays should be taken into consideration. The sensitivity of ctDNA assays depends on the assessment technique and genetic platforms used, on tumor-organ, stage, tumor heterogeneity, tumor clonality. The specificity is usually very high, whereas the concordance with tumor-based biopsy is generally low. In patients with renal cell carcinoma (RCC), qualitative analyses of ctDNA have been performed with interesting results regarding selective pressure from therapy, therapeutic resistance, exceptional treatment response to everolimus and mutations associated with aggressive behavior. Quantitative analyses showed variations of ccfDNA levels at different tumor stage. Compared to CTC assay, ctDNA is more stable than cells and easier to isolate. Splice variants, information at single-cell level and functional assays along with proteomics, transcriptomics and metabolomics studies can be performed only in CTCs.

http://bit.ly/2SDxQhu

The path of an esophageal carcinoma patient from curative to palliative treatment

Summary

We hereby report the course and management of a patient with human epidermal growth factor receptor 2 negative esophageal cancer who received neoadjuvant chemoradiation, surgical resection and subsequently palliative therapy for recurrent disease. The critical role of the staging procedure is discussed. Additionally the options of systemic palliative therapies are presented and the rationale for immuno-oncologic treatment is highlighted. The patient received pembrolizumab as second-line therapy, which unfortunately did not result in a response and caused minor autoimmune side effects.

http://bit.ly/2Syn4sT

Pseudotyping retrovirus like particles vaccine candidates with Hepatitis C virus envelope protein E2 requires the cellular expression of CD81

Hepatitis C virus (HCV) infects 3% of world population being responsible for nearly half a million deaths annually urging the need for a prophylactic vaccine. Retrovirus like particles are commonly used scaffo...

http://bit.ly/2GgaUz7

Characterization of the protein fraction of the extracellular polymeric substances of three anaerobic granular sludges

Extracellular polymeric substances (EPS) play major roles in the efficacy of biofilms such as anaerobic granules, ranging from structural stability to more specific functions. The EPS of three granular anaerob...

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High Genetic Diversity of Vibrio parahaemolyticus Isolated from Tidal Water and Mud of Southern Coast of South Korea

ABSTRACT

A horizontal, fluorophore-enhanced, repetitive extragenic palindromic-PCR (rep-PCR) DNA fingerprinting technique (HFERP) was adapted to examine the genotypic richness and source differentiation of Vibrio parahaemolyticus (n = 1,749) isolated from tidal water and mud of southern coast of South Korea. The number of unique genotypes observed from June (163, 51.9%), September (307, 63.9%), December (205, 73.8%), and February (136, 74.7%), indicating a high degree of genetic diversity. Contrary, lower genetic diversity was detected in April (99, 46.8%), including predominant genotypes comprised >30 V. parahaemolyticus isolates. Jackknife analysis indicated that 65.1% tidal water isolates and 87.1% mud isolates were correctly assigned to their source groups. Sixty-nine isolates of pathogenic V. parahaemolyticus were clustered into two groups, separated by sampling month, source of isolation, and serogroups. Serotypes O1, O4, O5, O10/O12, and O11 were the dominant serovariants, while serotypes O3/O13 was highly detected in April where there were no pathogenic V. parahaemolyticus. Most of the V. parahaemolyticus isolates were resistant to ampicillin, ceftazidime, and sulfamethoxazole. Interestingly, four V. parahaemolyticus isolates resistant to carbepenem did not contain the known carbapenemase-encoding gene, but possess an extended-spectrum β-lactamase bla_TEM.

http://bit.ly/2SFu8nW

4DMRI-based investigation on the interplay effect for pencil beam scanning proton therapy of pancreatic cancer patients

Abstract

Background

Time-resolved volumetric magnetic resonance imaging (4DMRI) offers the potential to analyze 3D motion with high soft-tissue contrast without additional imaging dose. We use 4DMRI to investigate the interplay effect for pencil beam scanning (PBS) proton therapy of pancreatic cancer and to quantify the dependency of residual interplay effects on the number of treatment fractions.

Methods

Based on repeated 4DMRI datasets for nine pancreatic cancer patients, synthetic 4DCTs were generated by warping static 3DCTs with 4DMRI deformation vector fields. 4D dose calculations for scanned proton therapy were performed to quantify the interplay effect by CTV coverage (v95) and dose homogeneity (d5/d95) for incrementally up to 28 fractions. The interplay effect was further correlated to CTV motion characteristics. For quality assurance, volume and mass conservation were evaluated by Jacobian determinants and volume-density comparisons.

Results

For the underlying patient cohort with CTV motion amplitudes < 15 mm, we observed significant correlations between CTV motion amplitudes and both the length of breathing cycles and the interplay effect. For individual fractions, tumor underdosage down to v95 = 70% was observed with pronounced dose heterogeneity (d5/d95 = 1.3). For full × 28 fractionated treatments, we observed a mitigation of the interplay effect with increasing fraction numbers. On average, after seven fractions, a CTV coverage with 95–107% of the prescribed dose was reached with sufficient dose homogeneity. For organs at risk, no significant differences were found between the static and accumulated dose plans for 28 fractions.

Conclusion

Intrafractional organ motion exhibits a large interplay effect for PBS proton therapy of pancreatic cancer. The interplay effect correlates with CTV motion, but can be mitigated efficiently by fractionation, mainly due to different breathing starting phases in fractionated treatments. For hypofractionated treatments, a further restriction of motion may be required. Repeated 4DMRI measurements are a viable tool for pre- and post-treatment evaluations of the interplay effect.

http://bit.ly/2GzpKQy

Frontal cortex and striatal cellular and molecular pathobiology in individuals with Down syndrome with and without dementia

Abstract

Although, by age 40, individuals with Down syndrome (DS) develop amyloid-β (Aβ) plaques and tau-containing neurofibrillary tangles (NFTs) linked to cognitive impairment in Alzheimer's disease (AD), not all people with DS develop dementia. Whether Aβ plaques and NFTs are associated with individuals with DS with (DSD +) and without dementia (DSD −) is under-investigated. Here, we applied quantitative immunocytochemistry and fluorescent procedures to characterize NFT pathology using antibodies specific for tau phosphorylation (pS422, AT8), truncation (TauC3, MN423), and conformational (Alz50, MC1) epitopes, as well as Aβ and its precursor protein (APP) to frontal cortex (FC) and striatal tissue from DSD + to DSD − cases. Expression profiling of single pS422 labeled FC layer V and VI neurons was also determined using laser capture microdissection and custom-designed microarray analysis. Analysis revealed that cortical and striatal Aβ plaque burdens were similar in DSD + and DSD − cases. In both groups, most FC plaques were neuritic, while striatal plaques were diffuse. By contrast, FC AT8-positive NFTs and neuropil thread densities were significantly greater in DSD + compared to DSD −, while striatal NFT densities were similar between groups. FC pS422-positive and TauC3 NFT densities were significantly greater than Alz50-labeled NFTs in DSD + , but not DSD − cases. Putaminal, but not caudate pS422-positive NFT density, was significantly greater than TauC3-positive NFTs. In the FC, AT8 + pS422 + Alz50, TauC3 + pS422 + Alz50, pS422 + Alz50, and TauC3 + pS422 positive NFTs were more frequent in DSD + compared to DSD- cases. Single gene-array profiling of FC pS422 positive neurons revealed downregulation of 63 of a total of 864 transcripts related to Aβ/tau biology, glutamatergic, cholinergic, and monoaminergic metabolism, intracellular signaling, cell homeostasis, and cell death in DSD + compared DSD − cases. These observations suggest that abnormal tau aggregation plays a critical role in the development of dementia in DS.

http://bit.ly/2MUxQEK