Predictors of women’s positive childbirth pain experience: Findings from an Icelandic national study

Publication date: Available online 22 September 2017
Source:Women and Birth
Author(s): Sigfridur Inga Karlsdottir, Herdis Sveinsdottir, Hildur Kristjansdottir, Thor Aspelund, Olof Asta Olafsdottir
BackgroundPain in childbirth has been identified as one of the major components in the childbirth experience and an important topic that needs to be addressed during pregnancy, birth and the after-birth period.AimThe aim of the study was to describe women's childbirth pain experience and to identify predictors of women's positive childbirth pain experience.MethodA population-based cross-sectional cohort study design was implemented, with convenient consecutive sampling, stratified according to residency. Pregnant women were recruited through 26 health care centers. Participants were sent a questionnaire by mail during early pregnancy and another one five to six months after childbirth. A multiple regression analysis was done, with women's childbirth pain experiences as the dependent variable.FindingsAltogether 726 women participated in the study, with a response rate of 68%. The strongest predictors for women's positive childbirth pain experience were positive attitude to childbirth during pregnancy; support from midwife during childbirth; use of epidural analgesia and low intensity of pain in childbirth.DiscussionThe majority of the women in the study experienced childbirth pain as a positive experience, which is in line with studies that have demonstrated that pain in childbirth is different from other kinds of pain. In addition to epidural use as a predictor for positive childbirth pain experience, many other strong predictors exist and must be acknowledged.ConclusionWhen planning pregnancy and childbirth services, predictors of positive experience of childbirth pain should be considered and investigated further.



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Are we practicing anesthesia in a 'current' manner?.

No abstract available

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Safety and efficacy of epidural analgesia.

Purpose of review: Epidural analgesia remains a widely used analgesic technique. This article aims to assess the safety of epidural analgesia by balancing efficacy and complications, of epidural analgesia for acute, labor and chronic pain. Recent findings: Main indications for epidural analgesia include major open abdominal surgery, thoracotomy and labor analgesia. Past and current literature show that epidural analgesia leads to statistically significant, but possibly clinically less meaningful, reductions in pain scores compared with intravenous analgesia. The debate continues whether epidural analgesia leads to decreased complications and improved outcome. Noninferiority of alternative regional analgesic approaches, that is continuous-wound-infiltration, peripheral nerve blocks or surgical site infiltration, appears to be present and is promising for the future. Serious adverse events after epidural analgesia seem to occur more often than was previously thought and clinicians must realize that incidence rates differ in specific perioperative patient populations. Summary: Epidural analgesia for obstetric analgesic purposes is considered to be well tolerated in young, healthy women, since efficacy has been proven and complications leading to permanent neurological damage seldomly occur. Safety of epidural analgesia for perioperative and chronic pain treatment is more difficult to balance; careful selection of appropriate patients cannot be over-emphasized. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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New advancements in spinal cord stimulation for chronic pain management.

Purpose of review: To update the recent development of spinal cord stimulation (SCS) technology in the management of chronic pain. Recent Findings: Efficacy of SCS therapy has been significantly improved by the recent development of high frequency (HF-10 kHz) stimulation, burst stimulation, and dorsal root ganglion (DRG) stimulation. A few latest SCS modalities are in clinical trial. New approaches to guide lead placement and advances in surgical lead are introduced. Summary: HF-10 SCS is free of paresthesia and associated with significantly better coverage of axial lower back pain. Burst stimulation invokes minimal paresthesia and provides better coverage of low back pain. DRG stimulation results in better outcomes in patients with complex regional pain syndrome. It requires less energy and delivers consistent stimulation regardless of postural variations. Clinical trials with new SCS modalities, such as Stimwaves, are under way to make SCS wireless. Intraoperative neuromonitoring and paresthesia atlas may be used to guide lead placement. Multicolumn surgical paddle leads enable a combination of independent current control with up to 32 contacts for better programming and better coverage. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Nonoperating room anesthesia for endoscopic procedures.

Purpose of review: The purpose of this review is to take a look on some practical aspects of anesthetic care in the endoscopy suite, concerning the general approach, safety, and monitoring issues. Recent findings: Concerning propofol popularity for sedation during endoscopic procedures new studies create doubt in the safety of higher doses of propofol used for sedation. Careful titration of propofol, addition of synergistic supplements like ketamine and dexmedetomidine, and monitoring of anesthetic depth may limit the dose of propofol given to the patients. Capnography has the potential to detect airway compromise earlier than pulse-oximetry and by this enhancing patient safety. Summary: Sedation or anesthesia in the endoscopy suite is not without risk. For complex and longer lasting procedures and in patients with significant comorbidities and risk factors, good clinical judgment, built on experience, is essential and to foster this, it seems prudent to build up a group of anesthesiologists dedicated to a special sedation service. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Enhancing the quality and safety of the perioperative patient.

Purpose of review: Many possible hazards bedevil the perioperative patient. This review focuses on a number of aspects of perioperative management where the patient's quality and safety can be enhanced. Recent findings: Our understanding of the relationship between preoperative preparation and postoperative outcomes has improved. There have also been recent developments in our understanding of how to construct useful cognitive aids and make the best use of checklists by understanding the cultural environment supporting their use. Postoperatively, the concept of 'failure to rescue' in the surgical patients has been explored. Summary: A clear vision of what postoperative recovery should mean for practitioner and patients; careful risk stratification and prophylactic measures to avoid postoperative complications; the judicious use of checklists and other cognitive aids to complement clinical expertise in promoting safety within each local context; and the prompt recognition and rescue of postoperative problems when they occur are all important aspects of a safe perioperative care. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Optimizing education in difficult airway management: meeting the challenge.

Purpose of review: The last 2 decades have seen a vast change in the science and technology of airway management. As a result, there is an increasing need to equip anesthesiologists with the new knowledge and skills for the safe management of a difficult airway. Recent findings: In addition to knowledge and expertise, human factors and nontechnical skills (NTS), including situational awareness, communication and team work, play an important role during difficult airway management and contribute to the outcome. Didactic sessions are useful to impart knowledge. Self-learning, interactive discussions, simulation and debriefing are important tools for teaching and training in difficult airway management. Manikin training and simulation enable development of technical as well as NTS without subjecting patients to risk and allow multiple training sessions of relatively uncommon scenarios. Guidelines are useful teaching tools, whereas cognitive tools such as the Vortex approach may be useful during a difficult airway. Summary: There is need for research on difficult airway management and optimized training methods. Research is also required to determine the barriers to adoption of guidelines and strategies to ensure widespread dissemination and implementation of guidelines and best practices for difficult airway management. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Are we fully utilizing the functionalities of modern operating room ventilators?.

Purpose of review: The modern operating room ventilators have become very sophisticated and many of their features are comparable with those of an ICU ventilator. To fully utilize the functionality of modern operating room ventilators, it is important for clinicians to understand in depth the working principle of these ventilators and their functionalities. Recent findings: Piston ventilators have the advantages of delivering accurate tidal volume and certain flow compensation functions. Turbine ventilators have great ability of flow compensation. Ventilation modes are mainly volume-based or pressure-based. Pressure-based ventilation modes provide better leak compensation than volume-based. The integration of advanced flow generation systems and ventilation modes of the modern operating room ventilators enables clinicians to provide both invasive and noninvasive ventilation in perioperative settings. Ventilator waveforms can be used for intraoperative neuromonitoring during cervical spine surgery. Summary: The increase in number of new features of modern operating room ventilators clearly creates the opportunity for clinicians to optimize ventilatory care. However, improving the quality of ventilator care relies on a complete understanding and correct use of these new features. Video abstract: http://ift.tt/2hpXORl. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Anesthesia information management: clinical decision support.

Purpose of review: Perioperative informatics tools continue to be developed at a rapid pace and offer clinicians the potential to greatly enhance clinical decision making. The goal of this review is to bring the reader updates on perioperative information management and discuss future research directions in the field. Recent findings: Clinical decision support tools become more timely, accurate, and, in some instances, have been shown to improve patient outcomes. When correctly implemented, they are critical tools for optimization of perioperative care. Summary: Perioperative informaticians continue to test new and innovative ways to enhance the delivery of anesthesia care, improving the safety and efficacy of perioperative management. Future work will continue to refine tools to ensure that perioperative informatics provides clinicians timely and accurate feedback, with demonstrable evidence that a decision support system improves patient outcomes. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Emotional Impact of End-of-Life Decisions on Professional Relationships in the ICU: An Obstacle to Collegiality?.

Objectives: End-of-life decisions are not only common in the ICU but also frequently elicit strong feelings among health professionals. Even though we seek to develop more collegial interprofessional approaches to care and health decision-making, there are many barriers to successfully managing complex decisions. The aim of this study is to better understand how emotions influence the end-of-life decision-making process among professionals working in ICU. Design: Qualitative study with clinical interviews. All interviews were transcribed verbatim and analyzed thematically using interpretative phenomenological analysis. Setting: Two independent ICUs at the "Centre Hospitalier de l'Universite de Montreal." Subjects: Ten physicians and 10 nurses. Interventions: None. Measurements and Main Results: During the end-of-life decision-making process, families and patients restructure the decision-making frame by introducing a strong emotional dimension. This results in the emergence of new challenges quite different from the immediacy often associated with intensive care. In response to changes in decision frames, physicians rely on their relationship with the patient's family to assist with advanced care decisions. Nurses, however, draw on their relationship and proximity to the patient to denounce therapeutic obstinacy. Conclusions: Our study suggests that during the end-of-life decision-making process, nurses' feelings toward their patients and physicians' feelings toward their patients' families influence the decisions they make. Although these emotional dimensions allow nurses and physicians to act in a manner that is consistent with their professional ethics, the professionals themselves seem to have a poor understanding of these dimensions and often overlook them, thus hindering collegial decisions. Copyright (C) by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Guidelines for the Diagnosis and Management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in Critically Ill Patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017.

Objective: To update the 2008 consensus statements for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in adult and pediatric patients. Participants: A multispecialty task force of 16 international experts in critical care medicine, endocrinology, and guideline methods, all of them members of the Society of Critical Care Medicine and/or the European Society of Intensive Care Medicine. Design/Methods: The recommendations were based on the summarized evidence from the 2008 document in addition to more recent findings from an updated systematic review of relevant studies from 2008 to 2017 and were formulated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The strength of each recommendation was classified as strong or conditional, and the quality of evidence was rated from high to very low based on factors including the individual study design, the risk of bias, the consistency of the results, and the directness and precision of the evidence. Recommendation approval required the agreement of at least 80% of the task force members. Results: The task force was unable to reach agreement on a single test that can reliably diagnose CIRCI, although delta cortisol (change in baseline cortisol at 60 min of = 3 days at full dose in patients with septic shock that is not responsive to fluid and moderate- to high-dose vasopressor therapy (conditional, low quality of evidence). We suggest not using corticosteroids in adult patients with sepsis without shock (conditional recommendation, moderate quality of evidence). We suggest the use of IV methylprednisolone 1 mg/kg/day in patients with early moderate to severe acute respiratory distress syndrome (PaO2/FiO2

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Critical Illness-Related Corticosteroid Insufficiency (CIRCI): A Narrative Review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM).

Objective: To provide a narrative review of the latest concepts and understanding of the pathophysiology of critical illness-related corticosteroid insufficiency (CIRCI). Participants: A multi-specialty task force of international experts in critical care medicine and endocrinology and members of the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Data Sources: Medline, Database of Abstracts of Reviews of Effects (DARE), Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Database of Systematic Reviews. Results: Three major pathophysiologic events were considered to constitute CIRCI: dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, altered cortisol metabolism, and tissue resistance to glucocorticoids. The dysregulation of the HPA axis is complex, involving multidirectional crosstalk between the CRH/ACTH pathways, autonomic nervous system, vasopressinergic system, and immune system. Recent studies have demonstrated that plasma clearance of cortisol is markedly reduced during critical illness, explained by suppressed expression and activity of the primary cortisol-metabolizing enzymes in the liver and kidney. Despite the elevated cortisol levels during critical illness, tissue resistance to glucocorticoids is believed to occur due to insufficient glucocorticoid alpha-mediated anti-inflammatory activity. Conclusions: Novel insights into the pathophysiology of CIRCI add to the limitations of the current diagnostic tools to identify at-risk patients and may also impact how corticosteroids are used in patients with CIRCI. Copyright (C) by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Measuring Emergency Department Patient Population Acuity

Abstract

Background

Emergency department (ED) acuity is the general level of patient illness, urgency for clinical intervention, and intensity of resource use in an ED environment. The relative strength of commonly used measures of ED acuity is not well understood.

Methods

We performed a retrospective cross-sectional analysis of ED-level data to evaluate the relative strength of association between commonly used proxy measures with a full spectrum measure of ED acuity. Common measures included the percentage of patients with Emergency Severity Index (ESI) scores of 1 or 2, case mix index (CMI), academic status, annual ED volume, inpatient admission rate, percentage of Medicare patients, and patients-seen-per-attending-hour. Our reference standard for acuity is the percentage of high acuity charts (PHAC) coded and billed according to the Centers for Medicare and Medicaid Service's Ambulatory Payment Classification (APC) system. High acuity charts included those APC 4, 5 or critical care. PHAC was represented as a fractional response variable. We examined the strength of associations between common acuity measures and PHAC using Spearman's rank correlation coefficients (r_s) and regression models including a quasi-binomial generalized linear model and linear regression.

Results

In our univariate analysis, the percentage of patients ESI 1or 2, CMI, academic status and annual ED volume had statistically significant associations with PHAC. None explained more than 16% of PHAC variation. For regression models including all common acuity measures, academic status was the only variable significantly associated with PHAC.

Conclusion

ESI had the strongest association with PHAC followed by CMI and annual ED volume. Academic status captures variability outside of that explained by ESI, CMI, annual ED volume, percentage Medicare patients, or patients-per-attending-per-hour. All measures combined only explained only 42.6% of PHAC variation.

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Decision Making in Orthopaedic Trauma

Abstract

The first edition of Decision Making in Orthopaedic Trauma, is a uniquely formatted textbook intended to guide medical students, resident physicians-in-training, and practicing clinicians in the acute management of a comprehensive range of orthopedic emergencies. The authors of the individual algorithms are members of the faculty at the University of California, San Francisco (UCSF) / Zuckerberg San Francisco General (ZSFG) Orthopaedic Trauma Institute. Relying on their extensive professional experience and relevant evidence based publications, they created an easy to access format that provides a quick, simple to use reference for the critical decision points for a variety of traumatic orthopedic conditions. Using an algorithm-based approach, clinicians are guided through critical decision trees to assist decision making in the evaluation and treatment of a wide variety of orthopedic emergencies, from simple fractures through complex life and limb threatening conditions. The text includes 80 chapters, each composed of a 1-page, beautifully styled and easy to follow flow diagram for decision making, followed by a page listing relevant evidence-based references.

This article is protected by copyright. All rights reserved.

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Mutations in DNM1L , as in OPA1 , result indominant optic atrophy despite opposite effectson mitochondrial fusion and fission

Abstract

Dominant optic atrophy is a blinding disease due to the degeneration of the retinal ganglion cells, the axons of which form the optic nerves. In most cases, the disease is caused by mutations in OPA1, a gene encoding a mitochondrial large GTPase involved in cristae structure and mitochondrial network fusion. Using exome sequencing, we identified dominant mutations in DNM1L on chromosome 12p11.21 in three large families with isolated optic atrophy, including the two families that defined the OPA5 locus on chromosome 19q12.1-13.1, the existence of which is denied by the present study. Analyses of patient fibroblasts revealed physiological abundance and homo-polymerization of DNM1L, forming aggregates in the cytoplasm and on highly tubulated mitochondrial network, whereas neither structural difference of the peroxisome network, nor alteration of the respiratory machinery was noticed. Fluorescence microscopy of wild-type mouse retina disclosed a strong DNM1L expression in the ganglion cell layer and axons, and comparison between 3-month-old wild-type and Dnm1l^+/− mice revealed increased mitochondrial length in retinal ganglion cell soma and axon, but no degeneration. Thus, our results disclose that in addition to OPA1, OPA3, MFN2, AFG3L2 and SPG7, dominant mutations in DNM1L jeopardize the integrity of the optic nerve, suggesting that alterations of the opposing forces governing mitochondrial fusion and fission, similarly affect retinal ganglion cell survival.

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Long Cold Ischemia Times in Same Hospital Deceased Donor Transplants.

Background: Recent changes in deceased donor organ allocation for livers (Share-35) and kidneys (KAS) have resulted in broader sharing of organs and increased cold ischemia time (CIT). Broader organ sharing however is not the only cause of increased CIT. Methods: This was a retrospective registry study of CIT in same-hospital liver transplants (SHLT, n=4,347) and kidney transplants (SHKT, n=9,707) between 2004 and 2014. Results: In SHLT, median (IQR) CIT was 5.0 (3.5-6.5) hours versus 6.6 (5.1-8.4) hours in other-hospital LT. DCD donors, donor biopsy, male recipient, recipient obesity, and previous transplant were associated with increased CIT. MELD at transplant of 29+ or status 1a was associated with decreased CIT. SHLT CIT varied by OPO and transplant-center (p

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Feasibility of Monotherapy by Rituximab Without Additional Desensitization in ABO-incompatible Living Donor Liver Transplantation.

Background: Rituximab is a cornerstone in the regimens of desensitization for ABO-incompatible living donor liver transplantation (ABO-i LT) that makes this modality an acceptable option for liver transplantation. Plasmapheresis (PP) to reduce anti-ABO antibody titer and local infusion therapy (LI) were practiced as the strategies for desensitization before the application of rituximab and were reported as additional treatments. The aim of this study was to clarify the feasibility of monotherapy by rituximab without any additional desensitization treatments in ABO-i LT. Methods: Forty patients receiving ABO-i LDLT with Rituximab were enrolled in this retrospective study. The patients were divided into 2 groups: the rituximab with pretransplant PP and posttransplant LI (RPL) group (n=20) and the rituximab monotherapy without any additional treatment (RM) group (n=20). The groups were then compared in terms of the rates of patient survival, antibody-mediated rejection (AMR), and infection. Results: The 1-, 3-, and 5-year patient survival rates were 85%, 85%, and 85% in the RPL group and 89%, 80%, and 80% in the RM group, respectively. There was no significant difference in patient survival between the 2 groups. There were no episodes of AMR in either group. The RM group had a lower rate of fungal and viral infections than the RPL group. Conclusions: Pretransplant rituximab without additional treatments yielded satisfactory outcomes comparable to that with additional treatments such as PP and LI. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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The St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2017: the point of view of an International Panel of Experts in Radiation Oncology

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Overall survival analysis of EXAM, a phase 3 trial of cabozantinib in patients with radiographically progressive medullary thyroid carcinoma

Abstract

Background

Primary analysis of the double-blind, phase 3 EXAM trial demonstrated significant improvement in progression-free survival (PFS) with cabozantinib versus placebo in patients with progressive medullary thyroid cancer (MTC). Final analysis of overall survival (OS), a key secondary endpoint, was performed after long-term follow-up.

Patients and Methods

EXAM compared cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomized (2:1) to cabozantinib (140 mg/day) or placebo. Final OS and updated safety data are reported.

Results

Minimum follow-up was 42 months. Kaplan-Meier analysis showed a 5.5-month increase in median OS with cabozantinib versus placebo (26.6 v 21.1 months), although the difference did not reach statistical significance (stratified hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.64 to 1.12; P = 0.24). In an exploratory assessment of OS, PFS, and objective response rate, cabozantinib appeared to have a larger treatment effect in patients with RET M918T mutation–positive tumors compared with patients not harboring this mutation. For patients with RET M918T-positive disease, median OS was 44.3 months for cabozantinib versus 18.9 months for placebo (HR, 0.60; 95% CI, 0.38 to 0.94; P = 0.03 [not adjusted for multiple subgroup analyses]), with correspoding values of 20.2 versus 21.5 months (HR, 1.12; 95% CI, 0.70–1.82; P = 0.63) in the RET M918T-negative subgroup. Median treatment duration was 10.8 months with cabozantinib and 3.4 months with placebo. The safety profile for cabozantinib remained consistent with that of the primary analysis.

Conclusion

The secondary endpoint was not met in this final OS analysis from the trial of cabozantinib in patients with metastatic, radiographically progressive MTC. A statistically non-significant increase in OS was observed for cabozantinib compared with placebo. Exploratory analyses suggest patients with RET M918T–positive tumors may experience a greater treatment benefit with cabozantinib.

Trial Registration Number

NCT00704730

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Role of adjuvant chemotherapy in early stage endometrioid and clear cell ovarian cancer

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Toxicity Adjustment in the ESMO-MCBS: A Gestalt Approach?

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Checkpoint blockade for metastatic melanoma and Merkel cell carcinoma in HIV-positive patients

nivolumabpembrolizumabipilimumabmelanomaHIVAIDS

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A prospective evaluation of plasma phospholipid fatty acids and breast cancer risk in the EPIC study

Abstract

Background Intakes of specific fatty acids have been postulated to impact breast cancer risk but epidemiological data based on dietary questionnaires remain conflicting.Material and methods We assessed the association between plasma phospholipid fatty acids and breast cancer risk in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Sixty fatty acids were measured by gas chromatography in pre-diagnostic plasma phospholipids from 2,982 incident breast cancer cases matched to 2,982 controls. Conditional logistic regression models were used to estimate relative risk of breast cancer by fatty acid level. The false discovery rate (q-values) was computed to control for multiple comparisons. Subgroup analyses were performed by estrogen receptor (ER) and progesterone receptor (PR) expression in the tumours.Results A high level of palmitoleic acid (odds ratio, OR for the highest quartile compared with the lowest OR[Q4-Q1]=1.37; 95%CI=1.14-1.64; p for trend=0.0001, q-value=0.004) as well as a high desaturation index (DI₁₆) (16:1n-7/16:0) (OR[Q4-Q1]=1.28; 95%CI=1.07-1.54; p for trend=0.002, q-value=0.037), as biomarkers of de novo lipogenesis, were significantly associated with increased risk of breast cancer. Levels of industrial trans-fatty acids were positively associated with ER-negative tumors (OR for the highest tertile compared with the lowest [T3-T1]=2.01; 95% CI = 1.03-3.90; p for trend=0.047), while no association was found for ER-positive tumors (P-heterogeneity =0.01). No significant association was found between n-3 polyunsaturated fatty acids and breast cancer risk, overall or by hormonal receptor.Conclusion These findings suggest that increased de novo lipogenesis, acting through increased synthesis of palmitoleic acid, could be a relevant metabolic pathway for breast tumorigenesis. Dietary trans fatty acids derived from industrial processes may specifically increase ER-negative breast cancer risk.

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Evaluation of lytic bacteriophages for control of multidrug-resistant Salmonella Typhimurium

The emergence of antibiotic-resistant bacteria can cause serious clinical and public health problems. This study describes the possibility of using bacteriophages as an alternative agent to control multidrug-r...

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Assessment of the effect of larval source management and house improvement on malaria transmission when added to standard malaria control strategies in southern Malawi: study protocol for a cluster-randomised controlled trial

Due to outdoor and residual transmission and insecticide resistance, long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) will be insufficient as stand-alone malaria vector control interve...

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Predictive implications of albumin and C-reactive protein for progression to pneumonia and poor prognosis in Stenotrophomonas maltophilia bacteremia following allogeneic hematopoietic stem cell transplantation

Stenotrophomonas maltophilia (S. maltophilia) bacteremia causes significant morbidity and mortality in immunocompromised hosts. However, incidence and risk factors for mortality in S. ...

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Rifampicin resistance in mycobacterium tuberculosis patients using GeneXpert at Livingstone Central Hospital for the year 2015: a cross sectional explorative study

Since the recent introduction of GeneXepert for the detection of Tuberculosis (TB) drug resistance mutations in both primary resistance and acquired resistance in Zambia, little has been documented in literatu...

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415 Discrepancy Between Gestalt and Subjective Wells in Workup of Pulmonary Embolism

Clinicians frequently use either their experience (or gestalt) to determine the pretest probability of pulmonary embolism (PE), or use a scoring system such as the Wells score. Research suggests that gestalt approach is equally safe as the Wells score algorithm in diagnosing PE. It also shows that that the subjective component of the Wells score drives most of its predictive accuracy. How well the subjective component of the Wells score corresponds to the provider's pretest gestalt for PE is not clear.

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414 Correlation Between Procalcitonin and Severity Scoring Systems in Hospitalized Patients With Diagnosis of Community Acquired Pneumonia

Know the result of disease severity and clinical results in community-acquired pneumonia (CAP) are preconditions for treatment options and management for health care resources. Various scoring systems as CURB-65 and SMART-COP have been developed to facilitate these awareness. However, the scoring systems have strengths and weaknesses against each other. In this study, we aimed to investigate the relationship between these two scoring systems with procalcitonin level which is highly sensitive in the diagnosis of community-acquired pneumonia.

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363 Patient Perceptions of Shared Decisionmaking in the Emergency Department: A Multi-Center Survey Study

Shared decisionmaking (SDM) in the emergency department (ED) has recently received increased attention. We sought to elicit ED patients' perceptions regarding desired level of involvement in their medical decisions as well as potential barriers and facilitators to SDM in the ED.

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362 Withdrawn

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76 Characteristics Associated With Hospital Admission from An Emergency Department Observation Unit

To determine patient characteristics associated with requiring hospital admission from an emergency department observation unit (OU).

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77 Patterns of Emergency Department High Utilizers at Grady Memorial Hospital

High utilizers of emergency care represent an area of unmet need and can be a financial burden on the health care system. We aimed to identify emergency department (ED) high utilizers at Grady and determine the relationship between high utilizer patients and total visits. Previous studies have identified predictive factors associated with ED high utilizers at a specific setting. The demographics and clinical features of Grady high utilizers are also described.

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78 Decreasing Emergency Department Utilization by Patients Followed by Pediatric Specialists

Specialist physicians have an important role in addressing ED utilization, especially at tertiary medical centers that treat highly specialized patients. We analyzed if reporting of ED utilization to pediatric specialist physicians can decrease ED visits.

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79 Reduced Emergency Department Visits, Hospital Days, and Costs After Implementation of Individualized Care Plans for “Frequent Flyers”

"Frequent flyers" - also known as health system high utilizers - pose special challenges for emergency departments (ED) and Inpatient units. By definition, these patients have a high number of potentially avoidable ED visits and hospitalizations. Increased visits are associated with increased cost, increased morbidity and mortality, and pose significant quality and safety concerns (ex: hospital acquired infections, increased ionizing radiation secondary to recurrent imaging, etc.). We sought to reduce variation in the care of this patient population across multiple EDs in our health system.

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80 Grady Memorial Hospital Emergent Dialysis Program

The literature is scant on the existence of emergent dialysis programs that operate within the capacity of an emergency department. Notwithstanding, it is unclear what the demographics of these patients are who utilize these services and how to optimize their care.

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Infiltrating Lobular Breast Cancer Presenting as Isolated Gastric Metastasis: a Case Report

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CD90 expression controls migration and predicts dasatinib response in glioblastoma.

Purpose: CD90 (Thy-1) is a glycophosphatidylinositol-anchored glycoprotein considered as a surrogate marker for a variety of stem cells including glioblastoma (GBM) stem cells (GSCs). However, the molecular and cellular functions of CD90 remain unclear. Experimental design: The function of CD90 in GBM was addressed using cellular models from immortalized and primary GBM lines, in vivo orthotopic mouse models, GBM specimens' transcriptome associated with MRI features from GBM patients. CD90 expression was silenced in U251 and GBM primary cells; and complemented in CD90 negative U87 cells. Results: We showed that CD90 is not only expressed on GSCs but also on more differentiated GBM cancer cells. In GBM patients, CD90 expression was associated with an adhesion/migration gene signature and with invasive tumor features. Modulation of CD90 expression in GBM cells dramatically impacted on their adhesion and migration properties. Moreover, orthotopic xenografts revealed that CD90 expression induced invasive phenotypes in vivo. Indeed, CD90 expression led to enhanced SRC and FAK signaling in our GBM cellular models and GBM patients' specimens. Pharmacologic inhibition of these signaling nodes blunted adhesion and migration in CD90 positive cells. Remarkably, dasatinib blunted CD90 dependent GBM cell invasion in vivo and killed CD90high primary GSC lines. Conclusion: Our data demonstrate that CD90 is an actor of GBM invasiveness through SRC dependent mechanisms and could be used as a predictive factor for dasatinib response in CD90high GBM patients.

http://ift.tt/2jStWBq

A novel Breast Cancer Index for prediction of distant recurrence in HR+ early stage breast cancer with 1 to 3 positive nodes

Purpose: Study objective was to characterize the prognostic performance of a novel Breast Cancer Index model (BCIN+), an integration of BCI gene expression, tumor size, and grade, specifically developed for assessment of distant recurrence (DR) risk in HR+ breast cancer patients with 1-3 positive lymph nodes (pN1). <br><br> Experimental Design: Analysis was conducted in a well-annotated retrospective series of pN1 patients (N=402) treated with adjuvant endocrine therapy with or without chemotherapy using a pre-specified model. The primary endpoint was time-to-DR. Results were determined blinded to clinical outcome. Kaplan-Meier estimates of overall (0-15y) and late (≥5y) DR, hazard ratios and 95% CIs were estimated. Likelihood ratio statistics assessed relative contributions of prognostic information. <br><br> Results: BCIN+ classified 81 patients (20%) as low risk with a 15-year DR rate of 1.3% (95%CI: 0.0-3.7%) vs 321 patients as high risk with a DR rate of 29.0% (23.2-34.4%). In patients DR-free for ≥5y (n=349), the late DR rate was 1.3% (95%CI: 0.0-3.7%) and 16.1% (10.6-21.3%) in low- and high-risk groups, respectively. BCI gene expression alone was significantly prognostic (LR-2=20.12, P<0.0001). Addition of tumor size (LR-2=13.29, P=0.0003) and grade (LR-2=12.72, P=0.0004) significantly improved prognostic performance. BCI added significant prognostic information to tumor size (LR-2=17.55, P<0.0001); addition to tumor grade was incremental (LR-2=2.38, P=0.1) with considerable overlap between prognostic values (LR-2=17.74). <br><br> Conclusions: The integrated BCIN+ identified 20% of pN1 patients with limited risk of recurrence over 15y, in whom extended endocrine treatment may be spared. Ongoing studies will characterize combined clinical-genomic risk assessment in node-positive patients.

http://ift.tt/2xYBOHS

Phase III clinical trial (RERISE study) results of Efficacy and safety of radotinib compared with imatinib in newly diagnosed chronic phase chronic myeloid leukemia

Purpose: Radotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) approved in Korea for CML-CP in patients newly diagnosed or with insufficient response to other TKIs. This study was conducted to evaluate the efficacy and safety of radotinib as first-line therapy for CML-CP. Methods: This multinational, open-label study assigned patients (1:1:1) to one of two twice-daily (bid) radotinib doses, or imatinib daily (qd). The primary endpoint was major molecular response (MMR) by 12 months. Results: Two hundred forty-one patients were randomized to receive radotinib 300 mg (n = 79) or 400 mg bid (n = 81), or imatinib 400 mg qd (n = 81). MMR rates by 12 months were higher in patients receiving radotinib 300 mg (52%) or radotinib 400 mg bid (46%) versus imatinib (30%; P = 0.0044 and P = 0.0342, respectively). Complete cytogenetic response (CCyR) rates by 12 months were higher for radotinib 300 mg (91%) versus imatinib (77%; P = 0.0120). Early molecular response at 3 months occurred in 86% and 87% of patients receiving radotinib 300 mg and radotinib 400 mg, respectively, and 71% of those receiving imatinib. By 12 months, no patients had progression to accelerated phase or blast crisis. Most adverse events were manageable with dose reduction. Conclusion: Radotinib demonstrated superiority over imatinib in CCyR and MMR in patients newly diagnosed with Philadelphia chromosome-positive CML-CP. This trial was registered at http://ift.tt/PmpYKN as NCT01511289.

http://ift.tt/2jTmeqz

In-depth genetic analysis of sclerosing epithelioid fibrosarcoma reveals recurrent genomic alterations and potential treatment targets

Purpose: Sclerosing epithelioid fibrosarcoma (SEF) is a highly aggressive soft tissue sarcoma closely related to low-grade fibromyxoid sarcoma (LGFMS). Some tumors display morphological characteristics of both SEF and LGFMS, so called hybrid SEF/LGFMS. Despite the overlap of gene fusion variants between these two tumor types, SEF is much more aggressive. The present study aimed to further characterize SEF and hybrid SEF/LGFMS genetically in order to better understand the role of the characteristic fusion genes and possible additional genetic alterations in tumorigenesis. Experimental Design: We performed whole exome sequencing, single nucleotide polymorphism (SNP) array analysis, RNA-sequencing (RNA-seq), global gene expression analyses and/or IHC on a series of 13 SEFs and 6 hybrid SEF/LGFMS. We also expressed the FUS-CREB3L2 and EWSR1-CREB3L1 fusion genes conditionally in a fibroblast cell line; these cells were subsequently analyzed by RNA-seq and expression of the CD24 protein was assessed by FACS analysis. Results: The SNP array analysis detected a large number of structural aberrations in SEF and SEF/LGFMS, many of which were recurrent, notably DMD microdeletions. RNA-seq identified FUS-CREM and PAX5-CREB3L1 as alternative fusion genes in one SEF each. CD24 was strongly upregulated, presumably a direct target of the fusion proteins. This was further confirmed by the gene expression analysis and FACS analysis on Tet-On 3G cells expressing EWSR1-CREB3L1. Conclusions: While gene fusions are the primary tumorigenic events in both SEF and LGFMS, additional genomic changes explain the differences in aggressiveness and clinical outcome between the two types. CD24 and DMD constitute potential therapeutic targets.

http://ift.tt/2jS4bkN

Radiomics Analysis for Evaluation of Pathological Complete Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer

Purpose: To develop and validate a radiomics model for evaluating pathological complete response (pCR) to neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer (LARC). Experimental Design: We enrolled 222 patients (152 in the primary cohort and 70 in the validation cohort) with clinicopathologically confirmed LARC who received chemoradiotherapy before surgery. All patients underwent T2-weighted and diffusion-weighted imaging before and after chemoradiotherapy; 2252 radiomic features were extracted from each patient pre- and post-treatment imaging. The 2-sample t-test and the least absolute shrinkage and selection operator regression were used for feature selection, whereupon a radiomics signature was built with support vector machines. Multivariable logistic regression analysis was then used to develop a radiomics model incorporating the radiomics signature and independent clinicopathological risk factors. The performance of the radiomics model was assessed by its calibration, discrimination, and clinical usefulness with independent validation. Results: The radiomics signature comprised 30 selected features and showed good discrimination performance in both the primary and validation cohorts. The individualized radiomics model, which incorporated the radiomics signature and tumor length, also showed good discrimination, with an area under the receiver operating characteristic curve of 0.9756 (95% confidence interval: 0.9185-0.9711) in the validation cohort, and good calibration. Decision curve analysis confirmed the clinical utility of the radiomics model. Conclusion: Using pre- and post-treatment MRI data, we developed a radiomics model with excellent performance for individualized, non-invasive prediction of pCR. This model may be used to identify LARC patients who can omit surgery after chemoradiotherapy.

http://ift.tt/2xYBGIo

Phospholipase D1 inhibition linked to upregulation of ICAT blocks colorectal cancer growth hyperactivated by Wnt/{beta}-catenin and PI3K/Akt Signaling

Purpose: Dysregulated expression of PLD1 has emerged as a hallmark feature of colorectal cancer (CRC), which remains a major cause of mortality worldwide. Aberrant activation of Wnt/β-catenin signaling is a critical event in the development of CRC. Here, we investigated molecular crosstalk between the Wnt/β-catenin and PI3K/Akt pathways via ICAT, a negative regulator of Wnt/β-catenin signaling. We also explored the effect of PLD1 inhibition on growth of CRC hyperactivated by Wnt/β-catenin and PI3K/Akt signaling. Experimental design: Expression of ICAT via targeting of PLD1 was assessed in vivo in ApcMin/+ mice, an AOM/DSS model, and in vitro using various CRC cells. The relationship between ICAT/PLD1 expression and prognostic survival value of 153 CRC patients was examined. The therapeutic efficacy of PLD1 inhibitor was determined using a patient-derived xenograft model carrying APC and PI3K mutations. Results: PLD1 promoted the Wnt/β-catenin signaling pathway by selectively down-regulating ICAT via the PI3K/Akt-TopBP1-E2F1 signaling pathways. Low PLD1 expression and high ICAT expression were significantly associated with increased survival in CRC patients and vice versa. Furthermore, PLD1 inhibition suppressed growth of CRC activated by the Wnt/β-catenin and PI3K signaling pathways. Conclusion: These results suggest that PLD1 linked to ICAT mediates molecular crosstalk between the Wnt/β-catenin and PI3K/Akt pathways and thus could be proposed as a novel CRC prognostic biomarker. These results may assist in the clinical development of a PLD1 inhibitor for treatment of CRC patients carrying APC and PI3KCA mutations.

http://ift.tt/2jS46xv

A pilot trial of humanized anti-GD2 monoclonal antibody (hu14.18K322A) with chemotherapy and natural killer cells in children with recurrent/refractory neuroblastoma

Purpose: Anti-GD2 monoclonal antibodies (mAb), acting via antibody-dependent cell-mediated cytotoxicity, may enhance the effects of chemotherapy. This pilot trial investigated a fixed dose of a unique anti-GD2 mAb, hu14.18K322A, combined with chemotherapy, cytokines and haploidentical natural killer (NK) cells. Experimental Design: Children with recurrent/refractory neuroblastoma received up to six courses of hu14.18K322A (40mg/m2/dose, days 2-5), GMCSF and IL-2 with chemotherapy: cyclophosphamide/topotecan (courses 1,2), irinotecan/temozolomide (courses 3,4) and ifosfamide/carboplatin/etoposide (courses 5,6). Parentally-derived NK cells were administered with courses 2, 4 and 6. Serum for pharmacokinetic studies of hu14.18K322A, soluble IL-2 receptor alpha (sIL-2Ra) levels and human anti-human antibodies (HAHA) were obtained. Results: Thirteen heavily pretreated patients (9 with prior anti-GD2 therapy) completed 65 courses. One patient developed an unacceptable toxicity (grade 4 thrombocytopenia >35 days). Four patients discontinued treatment for adverse events (hu14.18K322A allergic reaction, viral infection, surgical death, second malignancy). Common toxicities included grade 3/4 myelosuppression (13/13 patients) and grade 1/2 pain (13/13 patients). Eleven patients received 29 NK cell infusions. The response rate was 61.5% (4 CR, 1 VGPR, 3 PR) and 5 had stable disease. The median time to progression was 274 days (range, 239-568 days); 10 of 13 patients (77%) survived one year. Hu14.18K322A pharmacokinetics were not affected by chemotherapy or HAHA. All patients had increased sIL-2Ra levels, indicating immune activation. Conclusions: Chemotherapy plus hu14.18K322A, cytokines and NK cells is feasible and resulted in clinically meaningful responses in patients with refractory/recurrent neuroblastoma. Further studies of this approach are warranted in patients with relapsed and newly-diagnosed neuroblastoma.

http://ift.tt/2xYCe0U

Integrated analysis reveals tubal and ovarian originated serous ovarian cancer and predicts differential therapeutic responses

Purpose: The relative importance of fallopian tube (FT) compared to ovarian surface epithelium (OSE) in the genesis of serous type of ovarian cancer (SOC) is still unsettled. Here, we followed an integrated approach to study the tissue origin of SOC, as well as its association with clinical outcome and response to therapeutic drugs. Experimental Design: A collection of transcriptome data of 80 FTs, 89 OSEs and 2,668 SOCs was systematically analyzed to determine the characteristic of FT-like and OSE-like tumors. A molecular signature was developed for identifying tissue origin of SOC and then was used to re-evaluate the prognostic genes and therapeutic biomarkers of SOC of different tissue origins. IHC staining of tissue array and functional experiments on a panel of ovarian cancer cell lines were used to further validate the key findings. Results: The expression patterns of tissue specific genes, prognostic genes and molecular markers all support a dualistic tissue origin of SOC, from either FT or OSE. A molecular signature was established to identify the tissue identity of SOCs. Surprisingly, the signature showed a strong association with overall survival [OSE-like versus FT-like, HR = 4.16, 95%CI, 2.67-6.48, p<10-9]. The phamacogenomic approach revealed AXL to be a therapeutic target of the aggressive OSE-derived SOC. Conclusions: SOC has two subtypes originated from either FT or OSE, which show different clinical and pathological features.

http://ift.tt/2jS3ZSB

Immunomodulation by entinostat in renal cell carcinoma patients receiving high dose interleukin 2: a multicenter, single-arm, phase 1/2 trial (NCI-CTEP#7870)

Purpose: Based on preclinical data suggesting that the class I selective HDAC inhibitor entinostat exerts a synergistic antitumor effect in combination with high dose interleukin 2 (IL-2) in a renal cell carcinoma model by down-regulating Foxp3 expression and function of regulatory T cells (Treg), we conducted a phase I/II clinical study with entinostat and high dose IL-2 in patients with metastatic clear cell renal cell carcinoma (ccRCC). Experimental Design: Clear cell histology, no prior treatments, and being sufficiently fit to receive high dose IL-2 were the main eligibility criteria. The phase I portion consisted of two dose levels of entinostat (3 and 5 mg, PO every14 days) and a fixed standard dose of IL-2 (600,000 units/kg IV). Each course was 85 days. The primary end point was objective response rate and toxicity. Secondary end points included progression-free survival and overall survival. Results: 47 patients were enrolled. At a median follow-up of 21.9 months, the objective response rate was 37% (95% CI 22%-53%), the median progression-free survival was 13.8 months (95% CI 6.0-18.8), and the median overall survival was 65.3 months (95% CI 52.6.-65.3). The most common grade 3/4 toxicities were hypophosphatemia (16%), lymphopenia (15%), and hypocalcemia (7%), and all were transient. Decreased Treg were observed following treatment with entinostat, and lower numbers were associated with response (p=0.03). Conclusions: This trial suggests a promising clinical activity for entinostat in combination with high dose Il-2 in ccRCC patients, and provides the first example of an epigenetic agent being rationally combined with immunotherapy.

http://ift.tt/2xZfcad

Amplification of 1q32.1 refines the molecular classification of endometrial carcinoma

Purpose: Molecular classification of endometrial cancer (EC) identified distinct molecular subgroups. However, the largest subset of ECs remains poorly characterized and is referred to as the 'non-specific molecular profile' (NSMP) subgroup. Here, we aimed at refining the classification of this subgroup by profiling somatic copy number aberrations (SCNAs). Experimental Design: SCNAs were analyzed in 141 ECs using whole-genome SNP arrays and pooled with 361 ECs from The Cancer Genome Atlas. Genomic Identification of Significant Targets In Cancer (GISTIC) identified statistically-enriched SCNAs and penalized Cox regression assessed survival effects. The prognostic significance of relevant SCNAs was validated using multiplex ligation-dependent probe amplification in 840 ECs from the PORTEC-1/2 trials. Copy number status of genes was correlated with gene expression to identify potential cancer drivers. One plausible oncogene was validated in vitro using antisense oligonucleotide-based strategy. Results: SCNAs affecting chromosome 1q32.1 significantly correlated with worse relapse-free survival (RFS) in the NSMP subgroup (HR=2.12; 95%CI, 1.26-3.59; P=0.005). This effect was replicated in NSMP ECs from PORTEC-1/2 (HR=2.34; 95%CI, 1.17-4.70; P=0.017). A new molecular classification including the 1q32.1 amplification improved risk prediction of recurrence. MDM4 gene expression strongly correlated with 1q32.1 amplification. Silencing MDM4 inhibited cell growth in cell lines carrying 1q32.1 amplification, but not in non-amplified cell lines. Vice versa, increasing MDM4 expression in non-amplified cell lines stimulated cell proliferation. Conclusions: 1q32.1 amplification was identified as a prognostic marker for poorly-characterized NSMP ECs, refining the molecular classification of this subgroup. We functionally validated MDM4 as a potential oncogenic driver in the 1q32.1 region.

http://ift.tt/2jT8Nqz

Tumor heterogeneity predicts metastatic potential in colorectal cancer

Purpose: Tumors continuously evolve to maintain growth; secondary mutations facilitate this process, resulting in high tumor heterogeneity. In this study, we compared mutations in paired primary and metastatic colorectal cancer (CRC) tumor samples to determine whether tumor heterogeneity can predict tumor metastasis. Experimental design: Somatic variations in 46 pairs of matched primary-liver metastatic tumors and 42 primary tumors without metastasis were analyzed by whole exome sequencing. Tumor clonality was estimated from single nucleotide and copy number variations. The correlation between clinical parameters of patients and clonal heterogeneity in liver metastasis was evaluated. Results: Tumor heterogeneity across CRC samples was highly variable; however, a high degree of tumor heterogeneity was associated with a worse disease free survival. Highly heterogeneous primary CRC was correlated with a higher rate of liver metastasis. Recurrent somatic mutations in APC, TP53, and KRAS were frequently detected in highly heterogeneous CRC. The variant allele frequency of these mutations was high, while somatic mutations in other genes such as PIK3CA and NOTCH1 were low. The number and distribution of primary CRC sub-clones were preserved in metastatic tumors. Conclusions: Heterogeneity of primary CRC tumors can predict the potential for liver metastasis and thus, clinical outcome of patients.

http://ift.tt/2xZeY2R

The Graham–Cassidy Plan — The Most Harmful ACA-Repeal Bill Yet

Senate Republicans are making one last attempt to pass legislation repealing major provisions of the Affordable Care Act (ACA) before September 30, when their ability to use the "budget reconciliation" procedure to prevent a Democratic filibuster expires. This effort centers on a new proposal…

http://ift.tt/2hmQTfa

Cic loss promotes gliomagenesis via aberrant neural stem cell proliferation and differentiation

Inactivating mutations in the transcriptional repression factor Capicua (CIC) occur in ~50% of human oligodendrogliomas (OD), but mechanistic links to pathogenesis are unclear. To address this question, we generated Cic-deficient mice and human OD cell models. Genetic deficiency in mice resulted in a partially penetrant embryonic or perinatal lethal phenotype, with the production of an aberrant proliferative neural population in surviving animals. In vitro cultured neural stem cells derived from Cic conditional knockout mice bypassed an EGF requirement for proliferation and displayed a defect in their potential for oligodendrocyte differentiation. Cic is known to participate in gene suppression that can be relieved by EGFR signal, but we found that cic also activated expression of a broad range of EGFR-independent genes. In an orthotopic mouse model of glioma, we found that Cic loss potentiated the formation and reduced the latency in tumor development. Collectively, our results define an important role for CiC in regulating neural cell proliferation and lineage specification, and suggest mechanistic explanations for how CIC mutations may impact the pathogenesis and therapeutic targeting of oligodendroglioma.

http://ift.tt/2xljSqg

Mobilizing transit-amplifying cell-derived ectopic progenitors prevents hair loss from chemotherapy or radiation therapy

Genotoxicity-induced hair loss from chemotherapy and radiotherapy is often encountered in cancer treatment, and there is a lack of effective treatment. In growing hair follicles (HF), quiescent stem cells (SC) are maintained in the bulge region and hair bulbs at the base contain rapidly dividing, yet genotoxicity-sensitive transit-amplifying cells (TAC) that maintain hair growth. How genotoxicity-induced HF injury is repaired remains unclear. We report here that HF mobilize ectopic progenitors from distinct TAC compartments for regeneration in adaptation to the severity of dystrophy induced by ionizing radiation (IR). Specifically, after low-dose IR, keratin5+ basal hair bulb progenitors, rather than bulge SC, were quickly activated to replenish matrix cells and regenerated all concentric layers of HF, demonstrating their plasticity. After high-dose IR, when both matrix and hair bulb cells were depleted, the surviving outer root sheath cells rapidly acquired a SC-like state and fueled HF regeneration. Their progeny then homed back to SC niche and supported new cycles of HF growth. We also revealed that IR induced HF dystrophy and hair loss and suppressed WNT signaling in a p53- and dose-dependent manner. Augmenting WNT signaling attenuated the suppressive effect of p53 and enhanced ectopic progenitor proliferation after genotoxic injury, thereby preventing both IR- and cyclophosphamide-induced alopecia. Hence, targeted activation of TAC-derived progenitor cells, rather than quiescent bulge SC, for anagen HF repair can be a potential approach to prevent hair loss from chemotherapy and radiotherapy.

http://ift.tt/2fGAZZf

Next-generation sequencing in the clinical setting clarifies patient characteristics and potential actionability

Enhancements in clinical-grade next-generation sequencing (NGS) have fueled the advancement of precision medicine in the clinical oncology field. Here we survey the molecular profiles of 1,113 patients with diverse malignancies who successfully underwent clinical-grade NGS (236 to 404 genes) in an academic tertiary cancer center. Among the individual tumors examined, the majority showed at least one detectable alteration (97.2%). Amongst 2,045 molecular aberrations was involvement of 302 distinct genes. The most commonly altered genes were TP53 (47.0%), CDKN2A (18.0%), TERT (17.0%), and KRAS (16.0%), and the majority of patients had tumors that harbored multiple alterations. Tumors displayed a median of four alterations (range, 0-29). Most individuals had at least one potentially actionable alteration (94.7%), with the median number of potentially actionable alterations per patient being 2 (range, 0-13). A total of 94.2% patients exhibited a unique molecular profile, with either genes altered or loci within the gene(s) altered being distinct. Approximately 13% of patients displayed a genomic profile identical to at least one other patient; although genes altered were the same, the affected loci may have differed. Overall, our results underscore the complex heterogeneity of malignancies and argue that customized combination therapies will be essential to optimize cancer treatment regimens.

http://ift.tt/2xlYXDp

R-Spondin1/LGR5 Activates TGF{beta} Signaling and Suppresses Colon Cancer Metastasis

Leucine rich repeat containing G protein-coupled receptor 5 (LGR5), an intestinal stem cell marker is known to exhibit tumor suppressor activity in colon cancer, the mechanism of which is not understood. Here we show that R-spondin 1 (RSPO1)/LGR5 directly activates TGFβ signaling cooperatively with TGFβ type II receptor in colon cancer cells, enhancing TGFβ-mediated growth inhibition and stress-induced apoptosis. Knockdown of LGR5 attenuated downstream TGFβ signaling and increased cell proliferation, survival, and metastasis in an orthotopic model of colon cancer in vivo. Upon RSPO1 stimulation, LGR5 formed complexes with TGFβ receptors. Studies of patient specimens indicate that LGR5 expression was reduced in advanced stages and positively correlated with markers of TGFβ activation in colon cancer. Our study uncovers a novel crosstalk between LGR5 and TGFβ signaling in colon cancer and identifies LGR5 as a new modulator of TGFβ signaling able to suppress colon cancer metastasis.

http://ift.tt/2fHpDEA

First-Line Dabrafenib plus Trametinib Has Activity in BRAFV600E NSCLC [Research Watch]

Dabrafenib plus trametinib achieves responses in 64% of patients with metastatic BRAF^V600E NSCLC.

http://ift.tt/2wJkndU

GPC2 May Be an Immunotherapeutic Target in High-Risk Neuroblastoma [Research Watch]

A GPC2-targeting antibody–drug conjugate promotes tumor regression in a high-risk neuroblastoma PDX.

http://ift.tt/2ywjuD0

First-Line Abemaciclib Effective in ER+ Breast Cancer [News in Brief]

Up-front combination of CDK4/6 inhibitor with letrozole improves progression-free survival.

http://ift.tt/2wJklmi

Talimogene Laherparepvec Enhances the Efficacy of PD-1 Blockade [Research Watch]

Talimogene laherparepvec plus pembrolizumab achieved response in 62% of patients with melanoma.

http://ift.tt/2ywjlPY

Gammaproteobacteria Metabolize Gemcitabine to Promote Chemoresistance [Research Watch]

Most human PDACs harbor intratumor Gammaproteobacteria that may promote gemcitabine resistance.

http://ift.tt/2wJkkie

WNT and SHH Drive the Tumorigenesis of a Rare Embryonal Brain Tumor [Research Watch]

Coexpression of Wnt and Shh in Sox2⁺/Pax6⁺ apical radial glia in the VZ drives ETMR formation in vivo.

http://ift.tt/2ywjqTM

Molecular modeling studies of pseudouridine isoxazolidinyl nucleoside analogues as potential inhibitors of the pseudouridine 5ʹ-monophosphate glycosidase

Abstract

In this paper, we investigated the hypothesis that pseudouridine isoxazolidinyl nucleoside analogues could act as potential inhibitors of the pseudouridine 5ʹ-monophosphate glycosidase. This purpose was pursued using molecular modeling and in silico ADME-Tox profiling. From these studies emerged that the isoxazolidinyl derivative 1 5ʹ-monophosphate can be effectively accommodated within the active site of the enzyme with a ligand efficiency higher than that of the natural substrate. In this context, the poor nucleofugality of the N-protonated isoxazolidine prevents or slows down, the first mechanistic step proposed for the degradation of the pseudouridine 5ʹ-monophosphate glycosidase, leading to the enzyme inhibition. Finally, the results of the physicochemical and ADME-Tox informative analysis pointed out that compound 1 is weakly bounded to plasma protein, only moderately permeate the blood-brain barrier, and is non-carcinogen in rat and mouse. To the best of our knowledge, this is the first paper that introduces the possibility of inhibition of pseudouridine 5ʹ-monophosphate glycosidase by a molecule that competing with the natural substrate hinders the glycosidic C–C bond cleavage.

This article is protected by copyright. All rights reserved.

A series of pseudouridine isoxazolidinyl nucleoside analogues were in silico screened for their capacity to compete with pseudouridine 5ʹ-monophosphate in the occupancy of the active site of the pseudouridine 5ʹ-monophosphate glycosidase. Based on the computationally obtained results, derivative 1 5ʹ-monophosphate resulted as an ideal candidate to potential inhibit the enzyme activity also showing a weak capacity to binding to the plasma protein, only a moderate capacity to permeate the blood-brain barrier, and a non-carcinogenicity in rat and mouse.

http://ift.tt/2fnaaN6

Multi-locus sequence typing and virulence genotyping of Streptococcus suis serotype 9 isolates revealed high genetic and virulence diversity

Abstract

Streptococcus suis (S. suis) is an important swine pathogen that can cause a variety of diseases. S. suis serotype 9 (SS9) is a prevalent serotype, but limited information is available. Here, we studied and compared 30 SS9 isolates, including 24 isolates from China between year 2004 and 2013, 5 isolates from Vietnam and a serotype reference isolate from Denmark. A MLST analysis was performed to exploit the genetic relationships between those isolates. The phylogenetic tree based on the MLST data divides those isolates into two clades (I and II), revealing different evolutionary paths of collected strains. A virulence genotyping analysis was performed by detecting 23 virulence related genes; the clustering result also revealed two clusters (I and II), highly in accordance with MLST analysis result, showing that phylogenetic relatedness led to the presence of similar virulence genotypes. Murine model infection experiment was performed to assess the virulence of those strains in Cluster I and Cluster II, which displayed high virulence diversity even within a same cluster/ST. Notably, ST 243 could be regarded as a ST with high virulence potential in SS9. In conclusion, this study has revealed high genetic and virulence diversity in SS9 isolates.

http://ift.tt/2wMWtt6

Ammonia oxidisers in a non-nitrifying Brazilian savanna soil

Abstract

Low nitrification rates in Brazilian savanna (Cerrado) soils have puzzled researchers for decades. Potential mechanisms include biological inhibitors, low pH, low microbial abundance and low soil moisture content, which hinders microbial activity, including ammonia oxidation. Two approaches were used to evaluate these potential mechanisms, (i) manipulation of soil moisture and pH in microcosms containing Cerrado soil and (ii) assessment of nitrification inhibition in slurries containing mixtures of Cerrado soil and an actively nitrifying agricultural soil. Despite high ammonium concentration in Cerrado soil microcosms, little NO₃⁻ accumulation was observed with increasing moisture or pH, but in some Cerrado soil slurries, AOA amoA transcripts were detected after 14 days. In mixed soil slurries, the final NO₃⁻ concentration reflected the initial proportions of agricultural and Cerrado soils in the mixture, providing no evidence of nitrification inhibitors in Cerrado soil. AOA community denaturing gradient gel electrophoresis profiles were similar in the mixed and nitrifying soils. These results suggest that nitrification in Cerrado soils is not constrained by water availability, ammonium availability, low pH, or biological inhibitors and alternative potential explanations for low nitrification levels are discussed. Keywords: ammonia oxidisers, low nitrification, Brazilian savanna, inhibition, pH, soil moisture

http://ift.tt/2wNhmo7

Effect of Nucleos(t)ide Analogue Therapy on Risk of Intra-hepatic Cholangioarcinoma in Patients With Chronic Hepatitis B

Chronic infection with hepatitis B virus (HBV) increases risk of intrahepatic cholangiocarcinoma (ICC), but it is not clear whether antiviral therapy reduces risk. We investigated the association between nucleos(t)ide analogue therapy and ICC risk.

http://ift.tt/2ywWR17

Efficacy of Glecaprevir/Pibrentasvir for 8 or 12 Weeks in Patients with HCV Genotype 2, 4, 5, or 6 Infection Without Cirrhosis

Hepatitis C virus (HCV) has high genotypic diversity and global distribution. Agents that are effective against all major HCV genotypes, with shorter treatment duration, are needed to reduce disease burden. Glecaprevir (an NS3/4A protease inhibitor) and pibrentasvir (an NS5A inhibitor) have a high barrier to resistance and synergistic antiviral activity. We evaluated the safety and efficacy of 8 and 12 weeks' treatment with glecaprevir/pibrentasvir in patients with HCV genotype 2, 4, 5, or 6 infection without cirrhosis in 3 separate phase 3 trials.

http://ift.tt/2wGJK01

How well do current measures assess the impact of advance care planning on concordance between patient preferences for end of life care and the care received: A methodological review

Advance care planning is increasingly considered to be an essential element of quality End of Life (EOL) care. However, the implementation of Advance care planning (ACP) is not backed by a solid foundation of established evidence of clinical effectiveness (1). Syntheses of the ACP literature have concluded that while ACP interventions are likely to have benefits for patients, family, and healthcare staff, there is a lack of high quality research, particularly well-conducted RCTs, that evaluate ACP interventions (2, 3).

http://ift.tt/2yj7ILf

Psychometric Analysis of the Parenting Concerns Questionnaire in Women with Metastatic Cancer

Parenting concerns are a major source of distress for patients with advanced cancer. However, validated tools to measure this construct in advanced cancer patients are lacking.

http://ift.tt/2xpfdRo

Cytokine Gene Polymorphisms Associated With Various Domains Of Quality Of Life In Women With Breast Cancer

Little is known about the phenotypic and molecular characteristics associated with various domains of quality of life (QOL) in women following breast cancer surgery.

http://ift.tt/2yjoZDR

Effect of CD4 count on treatment toxicity and tumor recurrence in HIV positive patients with anal cancer

In this retrospective cohort study of 142 HIV-positive US veterans with anal cancer, pre-treatment immunosuppression resulted in greater acute hematologic toxicity and post-treatment immunosuppression resulted in a higher risk of tumor recurrence. This suggests that the immune system may play an important role in post-treatment cancer control.

http://ift.tt/2xnUL3B

Incidence of high-risk radiological features in patients without local recurrence following SABR for early stage non-small cell lung cancer

Local control rates are high using stereotactic ablative radiotherapy (SABR) for early stage non-small cell lung cancer. However, subsequent lung fibrosis can be difficult to distinguish from tumor recurrence. We investigated the incidence, and patterns of change in high-risk radiological features (HRF's) in patients known to have no local recurrence.

http://ift.tt/2xuCPWz

Analysis of chromatin opening in heterochromatic non-small cell lung cancer tumour initiating cells in relation to DNA damaging anti-tumour treatment

We investigated the involvement of chromatin structure in the context of non-small cell lung cancer tumour initiating cells, an aspect few studies have addressed. We have explored the efficacy of histone deacetylase inhibitors in targeting this cell population, alone or in combination with radiation/cisplatin. Heterochromatin structure seem to play a role in therapy resistance of these tumour initiating cells, which is especially interesting since these inhibitors are clinically available and heterochromatin marker selection is possible.

http://ift.tt/2xuDzew

P 20 fMRI-associations with performance increase by mental imagery training of finger sequence

Motor imagery (MI) is the mental simulation of action frequently used by professionals in different fields. The knowledge about changes in functional representation of motor patterns trained with mental imagery is sparse. In addition, we do not know how changes in functional representation during imagery training are associated with preciseness of imagined performance. We therefore intended to investigate changes in functional representation going along with performance changes (error, velocity) during a highly controlled (for intensity and temporal accuracy) mental imagery training (finger sequence performance) in 51 healthy young volunteers.

http://ift.tt/2xzVK2J

P 22 Defining the role of imaging methods in diagnostics symptomatic epilepsy in children

Defining the role of MRI and CT in the comprehensive assessment of the state of the central nervous system in children with symptomatic epilepsy.

http://ift.tt/2fpKOxT

P 21 Specific indicators of diffusion weighted magnetic resonance imaging in child cerebral palsy with symptomatic epilepsy

was to determine the characteristics of diffusion weighted Magnetic Resonance imaging indicators in children with symptomatic epilepsy with cerebral palsy.

http://ift.tt/2xzE3jL

Role of capsule endoscopy and fecal biomarkers in small-bowel Crohn's disease to assess remission and predict relapse

Capsule endoscopy (CE) is the most sensitive test to diagnose small-bowel Crohn's disease (CD). Conventional parameters poorly assess CD remission and although fecal biomarkers assess colonic activity, their role in assessing remission is uncertain. We report CE findings in small-bowel CD patients in clinical remission compared with fecal biomarkers and standard clinical tools to determine mucosal remission and predict relapses.

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P 19 Left posterior inferior frontal gyrus is causally involved in complex sentence comprehension

Storage and reordering of words are two core processes required for successful sentence comprehension. Storage is necessary whenever the verb and its arguments (i.e., subject and object) are separated over a long distance, while reordering is necessary whenever the argument order is atypical (e.g., object-first order in German, where subject-first order is typical). Previous neuroimaging work (Meyer et al., 2012) has associated storage with the left planum temporale (PT), and reordering with the left posterior inferior frontal gyrus (pIFG).

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In Situ MHC-tetramer Staining and Quantitative Analysis to Determine the Location, Abundance, and Phenotype of Antigen-specific CD8 T Cells in Tissues

Here, we describe a method that combines in situ MHC-tetramer staining with immunohistochemistry to determine localization, phenotype, and quantity of antigen-specific T cells in tissues. This protocol is used to determine the spatial and phenotypic characteristics of antigen-specific CD8 T cells relative to other cell type and structures in tissues.

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Cardiopulmonary Bypass in a Mouse Model: A Novel Approach

This paper describes how to perform cardiopulmonary bypass in mice. This novel model will facilitate the investigation of the molecular mechanisms involved in organ damage.

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Optical Coherence Tomography: Imaging Mouse Retinal Ganglion Cells In Vivo

This manuscript describes a protocol for the in vivo imaging of the mouse retina with high-resolution spectral domain optical coherence tomography (SD-OCT). It focuses on retinal ganglion cells (RGC) in the peripapillary region, with several scanning and quantifying approaches described.

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Genome-wide association studies identified loci contribute to phenotypic variance of gastric cancer

We read with great interest the article by Mocellin et al,1 who conducted a comprehensive meta-analysis that nominated 11 germline variants at nine loci significantly associated with gastric cancer (GC) with high level of summary evidence. Moreover, they also identified 38 single nucleotide polymorphisms (SNPs) with intermediate quality significant associations. Most of these loci were resulted from hypothesis-driven studies based on biological relevance, but most of these studies were small sample size and might lead to publication bias. In order to further evaluate their relevance with GC in individual large studies, we analysed these variants directly or their strong linkage disequilibrium SNPs using existing genome-wide association study (GWAS) datasets (including 2631 cases and 4373 controls) in Chinese populations, including those from Nanjing and Beijing populations conducted by our group2 and from Henan and Shanxi populations conducted by the USA National Cancer Institute.3

After exclusion of the...

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Hepatoma-intrinsic CCRK inhibition diminishes myeloid-derived suppressor cell immunosuppression and enhances immune-checkpoint blockade efficacy

Objective

Myeloid-derived suppressor cells (MDSCs) contribute to tumour immunosuppressive microenvironment and immune-checkpoint blockade resistance. Emerging evidence highlights the pivotal functions of cyclin-dependent kinases (CDKs) in tumour immunity. Here we elucidated the role of tumour-intrinsic CDK20, or cell cycle-related kinase (CCRK) on immunosuppression in hepatocellular carcinoma (HCC).

Design

Immunosuppression of MDSCs derived from patients with HCC and relationship with CCRK were determined by flow cytometry, expression analyses and co-culture systems. Mechanistic studies were also conducted in liver-specific CCRK-inducible transgenic (TG) mice and Hepa1–6 orthotopic HCC models using CRISPR/Cas9-mediated Ccrk depletion and liver-targeted nanoparticles for interleukin (IL) 6 trapping. Tumorigenicity and immunophenotype were assessed on single or combined antiprogrammed death-1-ligand 1 (PD-L1) therapy.

Results

Tumour-infiltrating CD11b⁺CD33⁺HLA-DR^– MDSCs from patients with HCC potently inhibited autologous CD8⁺T cell proliferation. Concordant overexpression of CCRK and MDSC markers (CD11b/CD33) positively correlated with poorer survival rates. Hepatocellular CCRK stimulated immunosuppressive CD11b⁺CD33⁺HLA-DR^– MDSC expansion from human peripheral blood mononuclear cells through upregulating IL-6. Mechanistically, CCRK activated nuclear factor-B (NF-B) via enhancer of zeste homolog 2 (EZH2) and facilitated NF-B-EZH2 co-binding to IL-6 promoter. Hepatic CCRK induction in TG mice activated the EZH2/NF-B/IL-6 cascade, leading to accumulation of polymorphonuclear (PMN) MDSCs with potent T cell suppressive activity. In contrast, inhibiting tumorous Ccrk or hepatic IL-6 increased interferon ⁺tumour necrosis factor-α⁺CD8⁺ T cell infiltration and impaired tumorigenicity, which was rescued by restoring PMN-MDSCs. Notably, tumorous Ccrk depletion upregulated PD-L1 expression and increased intratumorous CD8⁺ T cells, thus enhancing PD-L1 blockade efficacy to eradicate HCC.

Conclusion

Our results delineate an immunosuppressive mechanism of the hepatoma-intrinsic CCRK signalling and highlight an overexpressed kinase target whose inhibition might empower HCC immunotherapy.

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Improving future studies in chronic pancreatitis: a paradigm shift in our understanding?

We read with interest the study by de la Iglesia-García et al1 The authors present a detailed, well-conducted meta-analysis of the efficacy of pancreatic enzyme replacement therapy (PERT) in patients with chronic pancreatitis (CP) who also have evidence of exocrine pancreatic insufficiency (EPI). Using level 1 evidence studies, the primary endpoint of fat absorption is shown to increase with PERT, with additional improvements shown in GI symptoms and quality of life. The authors should be commended for their work clarifying the beneficial use of PERT in this group of patients, but they and the preceding commentary by Windsor2 highlight the heterogenicity of the criteria used to diagnose CP and the greater need for a clear consensus to help target and guide dosing of PERT. Although a recent consensus to produce a mechanistic definition for CP has been undertaken,3 it is acknowledged that there is heterogeneity in...

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Issue Information - Masthead

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Issue Information - TOC

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Annals of Neurology: Volume 82, Number 3, September 2017

ON THE COVER: A nerve fascicle of a human thoracodorsal nerve stained by using immunofluorescence against choline acetyltransferase (green) to visualize cholinergic (motor) axons and neurofilament (red), which stains all myelinated and unmyelinated axons irrespective of their axon quality (motor or sensory). Doubly labeled motor axons appear yellow due to the overlap of green and red. Note the uneven distribution of motor axons, which constitute only about 10% of axons in spinal nerves that innervate the human upper limbs. See Gesslbauer et al, pp. 396–408 in this issue for further details. Ann Neurol 2017;82:1–1

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Polygenic hazard scores in preclinical Alzheimer disease

Identifying asymptomatic older individuals at elevated risk for developing Alzheimer disease (AD) is of clinical importance. Among 1,081 asymptomatic older adults, a recently validated polygenic hazard score (PHS) significantly predicted time to AD dementia and steeper longitudinal cognitive decline, even after controlling for APOE ɛ4 carrier status. Older individuals in the highest PHS percentiles showed the highest AD incidence rates. PHS predicted longitudinal clinical decline among older individuals with moderate to high Consortium to Establish a Registry for Alzheimer's Disease (amyloid) and Braak (tau) scores at autopsy, even among APOE ɛ4 noncarriers. Beyond APOE, PHS may help identify asymptomatic individuals at highest risk for developing Alzheimer neurodegeneration. Ann Neurol 2017;82:484–488

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Issue Information - Copyright

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FDA Expands Approval of Fulvestrant for Advanced Breast Cancer

FDA has expanded its approval of fulvestrant (Faslodex®) as a standalone treatment for postmenopausal women with advanced HR-positive, HER2-negative breast cancer who have not previously undergone endocrine therapy.

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Personalized peptide vaccination as second-line treatment for metastatic upper tract urothelial carcinoma

Summary

This study investigated on the applicability of personalized peptide vaccination (PPV) for patients with metastatic upper tract urothelial cancer (mUTUC) after failure of platinum-based chemotherapy. In this single arm, open-label, phase II clinical trial, patients with mUTUC received PPV at a single institution. PPV treatment used a maximum of four peptides chosen from 27 candidate peptides according to human leukocyte antigen types and peptide-reactive immunoglobulin G titers, for 6 subcutaneous injections weekly as one cycle. The safety of PPV, as well as its influence on host immunity and effect on OS were assessed. Forty-eight patients were enrolled in this study. PPV were well tolerated without severe adverse events. Median survival time (MST) was 7.3 months (95% CI, 5.3 to 13.1) with 13.0 months for patients receiving combined salvage chemotherapy (95% CI, 5.7 to 17.5) and 4.5 months for patients receiving PPV alone (95% CI, 1.7 to 10.1) (p=0.080). Patients with positive cytotoxic T lymphocyte (CTL) responses demonstrated a significantly longer survival than patients with negative CTL responses (HR, 0.37; 95%CI, 0.16 to 0.85; p = 0.019). Multivariate Cox regression analysis showed that lower numbers of Bellmunt risk factors and lower levels of B cell activating factor (BAFF) were significantly associated with favorable OS for patients under PPV treatment. This study demonstrated that PPV for patients with mUTUC after failure of platinum-based chemotherapy induced substantial peptide-specific CTL responses without severe adverse events and has the potential to prolong survival when combined with salvage chemotherapy.

This article is protected by copyright. All rights reserved.

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High-speed Continuous-wave Stimulated Brillouin Scattering Spectrometer for Material Analysis

We describe the construction of a rapid continuous-wave-stimulated-Brillouin-scattering (CW-SBS) spectrometer. The spectrometer employs single-frequency diode-lasers and an atomic vapor notch-filter to acquire transmission spectra of turbid/non-turbid samples with high spectral-resolution at speeds up to 100-fold faster than those of existing CW-SBS spectrometers. This improvement enables high-speed Brillouin material analysis.

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Detection of copy number variations in epilepsy using exome data

Epilepsies are common neurological disorders and genetic factors contribute to their pathogenesis. Copy number variations (CNVs) are increasingly recognized as an important etiology of many human diseases including epilepsy. Whole exome sequencing (WES) is becoming a standard tool for detecting pathogenic mutations and has recently been applied to detecting CNVs. Here, we analyzed 294 families with epilepsy using WES, and focused on 168 families with no causative single nucleotide variants (SNVs) in known epilepsy-associated genes to further validate CNVs using two different CNV detection tools using WES data. We confirmed 18 pathogenic CNVs, and two deletions and two duplications at chr15q11.2 of clinically unknown significance. Of note, we were able to identify small CNVs less than 10 kb in size, which might be difficult to detect by conventional microarray. We revealed two cases with pathogenic CNVs that one of the two CNV detection tools failed to find, suggesting that using different CNV tools is recommended to increase diagnostic yield. Considering a relatively high discovery rate of CNVs (18 out of 168 families, 10.7%) and successful detection of CNV with <10 kb in size, CNV detection by WES may be able to surrogate, or at least complement, conventional microarray analysis.

WES was performed in a total of 294 families with epilepsy. Then, WES-based CNV detection in 168 families were conducted after excluding 126 families with causative SNVs, and 18 families with pathogenic CNVs were identified. CNVs were detected in two ways: 1) two-step detection: XHMM and subsequent Nord's method (left in a dotted box), and 2) Nord's method targeting 303 epilepsy genes (right in a dotted box). Seventeen and one pathogenic CNVs were detected by methods 1) and 2), respectively. [WES: whole exome sequencing, CNV: copy number variation, SNV: single nucleotide variant, XHMM: eXome Hidden Markov Model]

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INPP5K variant causes autosomal recessive congenital cataract in a Pakistani family

Congenital cataract (CC) is clinically and genetically highly heterogeneous. Here, we enrolled a consanguineous kindred (LUCC15) from Pakistan, with three affected individuals suffering with CC. Exome sequencing revealed a transition mutation [c.149T>C; p.(Ile50Thr)] in INPP5K. Inositol polyphosphate-5-phosphatase K, encoded by INPP5K, is involved in dephosphorylation of phosphatidylinositol (PtdIns) 4,5-bisphosphate, and PtdIns 3,4,5-trisphosphate. Recently, pathogenic variants in INPP5K have been reported in families with congenital muscular dystrophies, intellectual disability, and cataract. In our family LUCC15, mild to moderate intellectual disability along with speech impairment was observed in two affected individuals. Magnetic resonance imaging of brain and muscles tissues did not reveal any cerebellar or muscular atrophy. However, electromyography of both upper and lower limbs revealed irritable myopathy. Comparison of clinical phenotype of all the known affected individuals, including LUCC15 family, homozygous for INPP5K alleles revealed reduced penetrance of muscular dystrophy and intellectual disability. Similarly, skeletal muscle abnormalities were highly variable among inpp5ka zebrafish mutants analyzed in this study. These phenotypic variabilities may be due to epigenetic factors and/or genetic modifiers.

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Expanding the genetic heterogeneity of intellectual disability

Abstract

Intellectual disability (ID) is a common morbid condition with a wide range of etiologies. The list of monogenic forms of ID has increased rapidly in recent years thanks to the implementation of genomic sequencing techniques. In this study, we describe the phenotypic and genetic findings of 68 families (105 patients) all with novel ID-related variants. In addition to established ID genes, including ones for which we describe unusual mutational mechanism, some of these variants represent the first confirmatory disease–gene links following previous reports (TRAK1, GTF3C3, SPTBN4 and NKX6-2), some of which were based on single families. Furthermore, we describe novel variants in 14 genes that we propose as novel candidates (ANKHD1, ASTN2, ATP13A1, FMO4, MADD, MFSD11, NCKAP1, NFASC, PCDHGA10, PPP1R21, SLC12A2, SLK, STK32C and ZFAT). We highlight MADD and PCDHGA10 as particularly compelling candidates in which we identified biallelic likely deleterious variants in two independent ID families each. We also highlight NCKAP1 as another compelling candidate in a large family with autosomal dominant mild intellectual disability that fully segregates with a heterozygous truncating variant. The candidacy of NCKAP1 is further supported by its biological function, and our demonstration of relevant expression in human brain. Our study expands the locus and allelic heterogeneity of ID and demonstrates the power of positional mapping to reveal unusual mutational mechanisms.

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Digital Pathology for the Primary Diagnosis of Breast Histopathological Specimens: An Innovative Validation and Concordance Study

Abstract

Aim

To train and individually validate a group of breast pathologists in specialty specific digital primary diagnosis using a novel protocol endorsed by the Royal College of Pathologists' new guideline for digital pathology. The protocol allows early exposure to live digital reporting, in a risk mitigated environment, and focusses on patient safety and professional development.

Methods and Results

3 specialty breast pathologist completed training in use of a digital microscopy system, and were exposed to a training set of 20 challenging cases, designed to help them identify personal digital diagnostic pitfalls. Following this, the 3 pathologists viewed a total of 694 live, entire breast cases. All primary diagnoses were made on digital slides, with immediate glass review and reconciliation before final case sign out. There was complete clinical concordance between the glass and digital impression of the case in 98.8% of cases. Only 1.2% of cases had a clinically significant difference in diagnosis/prognosis on glass and digital slide reads. All pathologists elected to continue using the digital microscope as standard for breast histopathology specimens, with deferral to glass for a limited number of clinical/histological scenarios as a safety net.

Conclusion

Individual training and validation for digital primary diagnosis allows pathologists to develop competence and confidence in their digital diagnostic skills, and aids safe and responsible transition from the light microscope to the digital microscope.

This article is protected by copyright. All rights reserved.

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Physical activity and the risk of hip fracture in the elderly: a prospective cohort study

Abstract

Physical activity has been inversely associated with the risk of hip fracture, however, few studies have been conducted on the contributions from different domains of physical activity. This study was performed to investigate the association between daily household activities, leisure time physical activity, work-related physical activity and total physical activity during a 24-h period, and the risk of hip fracture. In the Swedish National March Cohort we followed 23,881 men and women aged of 50 and over from 1997 until 2010. Information on domain-specific physical activity was collected at baseline using a questionnaire. We fitted separate multivariable adjusted Cox proportional hazard models to each domain to obtain hazard ratios (HRs) with 95% confidence intervals (CIs). Each model was mutually adjusted for the other domains of physical activity. During a mean follow-up period of 12.2 years we identified 824 incidents of hip fracture. Subjects who spent less than 1 h per week engaged in daily household activities had an 85% higher risk of hip fracture than subjects spending ≥6 h per week carrying out daily household activities (HR 1.85; 95% CI 1.01–3.38). Subjects engaged in leisure time physical activities for >3.1 MET-h/day had a 24% lower risk of hip fracture (HR 0.76; 95% CI 0.59–0.98) than subjects spending <1.1 MET-h/day performing such activities. No association was found between hip fracture and work-related or total physical activity. We conclude that daily household activities and leisure time physical activity may independently decrease the risk of hip fracture in those aged 50 and over.

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The Patient Protection and Affordable Care Act dependent coverage expansion: Disparities in impact among young adult oncology patients

BACKGROUND

Private health insurance is associated with improved outcomes in patients with cancer. However, to the authors' knowledge, little is known regarding the impact of the Patient Protection and Affordable Care Act Dependent Coverage Expansion (ACA-DCE), which extended private insurance to young adults (to age 26 years) beginning in 2010, on the insurance status of young adults with cancer.

METHODS

The current study was a retrospective, population-based analysis of hospitalized young adult oncology patients (aged 22-30 years) in California during 2006 through 2014 (11,062 patients). Multivariable regression analyses examined factors associated with having private insurance. Results were presented as adjusted odds ratios and 95% confidence intervals. A difference-in-difference analysis examined the influence of the ACA-DCE on insurance coverage by race/ethnicity and federal poverty level.

RESULTS

Multivariable regression demonstrated that patients of black and Hispanic race/ethnicity were less likely to have private insurance before and after the ACA-DCE, compared with white patients. Younger age (22-25 years) was associated with having private insurance after implementation of the ACA-DCE (odds ratio, 1.20; 95% confidence interval, 1.06-1.35). In the difference-in-difference analysis, private insurance increased among white patients aged 22 to 25 years who were living in medium-income (2006-2009: 64.6% vs 2011-2014: 69.1%; P = .003) and high-income (80.4% vs 82%; P = .043) zip codes and among Asians aged 22 to 25 years living in high-income zip codes (73.2 vs 85.7%; P = .022). Private insurance decreased for all Hispanic patients aged 22 to 25 years between the 2 time periods.

CONCLUSIONS

The ACA-DCE provision increased insurance coverage, but not among all patients. Private insurance increased for white and Asian patients in higher income neighborhoods, potentially widening social disparities in private insurance coverage among young adults with cancer. Cancer 2017. © 2017 American Cancer Society.

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Epirubicin suppresses proliferative and metastatic potential by down-regulating TGFBI expression in urothelial carcinoma

Abstract

Transforming growth factor-β-induced (TGFΒI) is considered to be a vital gene in several carcinomas. In this study we determined the effect of TGFBI on the proliferative and metastatic potential of human urothelial carcinoma (UC) cells as well as its mRNA and protein expression, which were detected by RT-PCR and Western blot, respectively. UC cell proliferation was analyzed by WST-1 assay and Hoechst 33258 staining. The effect of TGFBI on UC cell metastasis was analyzed using adhesion, migration, and invasion assays. We found that TGFBI increased the proliferation of UC cells. Moreover, TGFBI enhanced the adhesion, migration, and invasion of UC cells by up-regulating MMP-2, MMP-9 and calpain-2 expression. We evaluated the effect of Epirubicin (EPI) on the regulation of TGFBI expression and found that TGFBI acts as a downstream target of EPI and is suppressed by EPI in UC cells. EPI is more effective in inhibiting the proliferation and metastasis of UC cells with high TGFBI expression. This study demonstrates that TGFBI might lead to tumorigenesis and progression of UC and those cells with high TGFBI expression may be vulnerable to relapse. EPI could prove to be a therapeutic option in patients with high TGFBI expressing UC cells.

This article is protected by copyright. All rights reserved.

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Case-matched study of short-term effects of 3D vs 2D laparoscopic radical resection of rectal cancer

Abstract

Background

The purpose of this study is to compare and evaluate the security and efficacy of 3D vs 2D laparoscopy in rectal cancer treatment.

Methods

Forty-six patients who suffered from rectal cancer and went on laparoscopic radical resection of rectal carcinoma in Peking University Shougang Hospital from Feb. 2015 to Mar. 2016 were included in the study. They were randomly divided into two groups. The 23 patients operated with the 3D system were compared with 23 patients operated with the 2D system by perioperative data.

Results

There were no significant differences in age, sex, pathological type, tumor differentiation, TNM staging, and surgical procedures (P > 0.05). The average operating time of 3D laparoscopic surgery group (172.2 ± 27.5 min) was shorter than that of 2D group (192.6 ± 22.3) (P < 0.05); the rate of transfer to laparotomy is lower in 2D group (72.7%) than in 3D group (86.4%), but they have no significant difference; and the intraoperative blood loss (247.0 ± 173.6 ml vs 282.6 ± 195.6 ml), postoperative passage of flatus (2.8 ± 0.8 days vs 3.1 ± 1.0 days), and indwelling catheter time (5.6 ± 1.9 days vs 6.3 ± 2.0 days) in 3D group and 2D group (P > 0.05) were not significantly different. There were no differences in other complications between the two groups. No significantly different recrudescence and death rates were found between the two groups (P > 0.05).

Conclusion

The 3D laparoscopy shortens the operation time of rectum cancer. 3D laparoscopic surgery is more efficient in treatment of rectal cancer than 2D laparoscopy and is worth of being generalized.

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Mouth breathing: Symptoms, complications, and treatment

What causes mouth breathing? When should a healthcare professional be consulted and what might the diagnosis be? How is mouth breathing treated?

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New Research From Psychological Science

Read about the latest research published in Psychological Science:

Topological Relations Between Objects Are Categorically Coded

Andrew Lovett and Steven L. Franconeri

How do people compare images? The authors hypothesized that people use categorical relations between objects rather than metric changes of objects when comparing images. The researchers examined three topographical categories (overlapping, touching, and containing) in four studies in which participants were shown pairs of filled or unfilled circles that were briefly masked before reappearing. Participants were instructed to indicate whether the circles had changed or stayed the same. On half the trials, the circles stayed the same; on a quarter of the trials, the circles changed in a way that was purely metric; and on a quarter of the trials, the circles changed in a way that was categorical (e.g., the circles changed from overlapping to merely touching one another). The researchers found that participants were more accurate at detecting changes that crossed categorical boundaries. The authors suggest that this experiment can serve as a template for future investigations of the categories people perceive when observing between-object relations.

Thinking More or Feeling Less? Explaining the Foreign-Language Effect on Moral Judgment

Sayuri Hayakawa, David Tannenbaum, Albert Costa, Joanna D. Corey, and Boaz Keysar

Recent studies have shown that responses to moral dilemmas depend on whether the decision is made in a native or foreign language, creating a moral foreign-language effect (MFLE). The effects of foreign language on moral decision making may be explained by the blunted-deontology account (i.e., foreign language stunts emotional processing) and the heightened-utilitarianism account (i.e., foreign language encourages deliberative thinking). The present study used six experiments to investigate the effect of foreign languages on moral dilemmas. Participants read scenarios designed to separately measure deontological and utilitarian responses to moral dilemmas. For each scenario, participants indicated either the appropriateness of an action or whether they would perform the action themselves. Participants completed the task in either their native language or a foreign language (English, German, or Spanish). Researchers found that use of a foreign language blunted deontological responding but did not heighten utilitarian responses. Foreign language seems to blunt emotional responses rather than encourage deliberative thinking.

More Is Meaningful: The Magnitude Effect in Intertemporal Choice Depends on Self-Control

Ian C. Ballard, Bokyung Kim, Anthony Liatsis, Gökhan Aydogan, Jonathan D. Cohen, and Samuel M. McClure

The magnitude effect is a phenomenon in which larger rewards or outcomes are discounted over time at a lower rate than are smaller rewards. The researchers suggest that such a lower rate of discounting for larger rewards is driven in part by differential exertion of self-control. Specifically, they hypothesize that people exert more self-control in high-reward situations than in low-reward situations. The researchers examined the influence of self-control on the magnitude effect in three studies in which participants chose between receiving smaller rewards after a short delay or larger rewards after a longer delay. Participants chose between two low-magnitude rewards or two high-magnitude rewards. In a first study, the researchers found that frontal-executive-control areas of the brain were more engaged when making difficult decisions — an effect that was enhanced for high-magnitude reward decisions. A second study showed that hunger — a factor thought to reduce self-control — reduced the magnitude effect. Finally, a third study showed that a self-control-boosting exercise also reduced the magnitude effect. The influence of self-control on the magnitude effect provides support for an underlying role in this phenomenon.

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