bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mks6 mutations reveal tissue‐ and cell type‐specific roles for the cilia transition zone
Authors: Lewis Wesley R. , Bales Katie L. , Revell Dustin Z. , Croyle Mandy J. , Engle Staci E. , Song Cheng Jack , Malarkey Erik B. , Uytingco Cedric R. , Shan Dan , Antonellis Patrick J. , Nagy Tim R. , Kesterson Robert A. , Mrug Michal M. , Martens Jeffrey R. , Berbari Nicolas F. , Gross Alecia K. , Yoder Bradley K. 
Published: August 2018

ABSTRACTThe transition zone (TZ) is a domain at the base of the cilium that is involved in maintaining ciliary compartment‐specific sensory and signaling activity by regulating cilia protein composition. Mutations in TZ proteins result in cilia dysfunction, often causing pleiotropic effects observed in a group of human diseases classified as ciliopathies. The purpose of this study is to describe the importance of the TZ component Meckel‐Grüber syndrome 6 (Mks6) in several organ systems and tissues regarding ciliogenesis and cilia maintenance using congenital and conditional mutant mouse models. Similar to MKS, congenital loss of Mks6 is embryonic lethal, displaying cilia loss and altered cytoskeletal microtubule modifications but only in specific cell types. Conditional Mks6 mutants have a variable cystic kidney phenotype along with severe retinal degeneration with mislocalization of phototransduction cascade proteins. However, other phenotypes, such as anosmia and obesity, which are typically associated with cilia and TZ dysfunction, were not evident. These data indicate that despite Mks6 being a core TZ component, it has tissue‐ or cell type‐specific functions important for cilia formation and cilia sensory and signaling activities.—Lewis, W. R., Bales, K. L., Revell, D. Z., Croyle, M. J., Engle, S. E., Song, C. J., Malarkey, E. B., Uytingco, C. R., Shan, D., Antonellis, P. J., Nagy, T. R., Kesterson, R. A., Mrug, M. M., Martens, J. R., Berbari, N. F., Gross, A. K., Yoder, B. K. Mks6 mutations reveal tissue‐ and cell type‐specific roles for the cilia transition zone. FASEB J. 33, 1440–1455 (2019). www.fasebj.org
Supporting Resident Research Learning in the Workplace: A Rapid Realist Review
Authors: Noble Christy , Billett Stephen R. , Phang Dana T.Y. , Sharma Siddharth , Hashem Fahid , Rogers Gary D. 
Published: August 2018

Purpose
Residents are increasingly expected to engage in practice-based research; however, engagement in research whilst also fulfilling clinical duties is often challenging. Evidence suggests that residents require specific developmental experiences, along with clinical practice, to become effective researchers. The authors therefore conducted a rapid realist review to explore strategies and key mechanisms supporting effective resident research activities in clinical settings. They examined relationships amongst different clinical contexts, learning mechanisms, and research engagement outcomes to provide evidence-based, theory-informed recommendations for improving resident research engagement and extending understandings of workplace learning in health care settings.

Method
In 2015–2016, the authors used a rapid realist methodology informed by workplace learning theory to review international literature published between January 2005 and December 2015. The review drew upon sources from OVID Medline, ERIC, Embase, and AustHealth. The authors screened articles for eligibility using inclusion criteria and appraised articles using realist review quality criteria.

Results
The authors included 51 articles in the review. The review process identified three key mechanisms for effective integration and support of resident research engagement, as informed by workplace learning theory: (1) opportunities to engage in practice-informed research supported by longitudinal curricula, (2) guidance by clinician–researchers, and (3) assessing residents’ research readiness and promoting their intentionality for engagement.

Conclusions
This review extends existing literature and informs workplace-based research engagement strategies for residents whilst demonstrating the applicability of workplace learning theory to improving residents’ research engagement. The authors propose a learning model to support effective resident research engagement through clinical practice.
Narrative Intersectionality in Caring for Marginalized or Disadvantaged Patients: Thinking Beyond Categories in Medical Education and Care
Authors: Blackie Michael , Wear Delese , Zarconi Joseph 
Published: August 2018

Categories are essential to doctors’ thinking and reasoning about their patients. Much of the clinical categorization learned in medical school serves useful purposes, but an extensive literature exists on students’ reliance on broad systems of social categorization. In this article, the authors challenge some of the orthodoxies of categorization by combining narrative approaches to medical practice with the theoretical term “intersectionality” to draw students’ attention to the important intersecting, but often overlooked, identities of their patients. Although intersectionality applies for all patients, the focus here is on its importance in understanding and caring for marginalized or disadvantaged persons.
Intersectionality posits that understanding individual lives requires looking beyond categories of identity in isolation and instead considering them at their intersection, where interrelated systems of power and oppression, advantage and discrimination are at play and determine access to social and material necessities of life. Combined with narrative approaches that emphasize the singularity of a person’s story, narrative intersectionality can enable a more robust understanding of how injustice and inequality interrelate multidimensionally to produce social disadvantage.
The authors apply this framework to two films that present characters whose lives are made up of numerous and often-contradictory identities to highlight what physicians may be overlooking in the care of patients. If the education of physicians encourages synthesis and categorization aimed at the critically useful process of making clinical “assessments” and “plans,” then there must also be emphasis in their education on what might be missing from that process.
Changes in Physicians’ Intrapersonal Empathy After a Communication Skills Training in Japan
Authors: Yamada Yu , Fujimori Maiko , Shirai Yuki , Ninomiya Hitomi , Oka Takakazu , Uchitomi Yosuke 
Published: August 2018

Purpose
To investigate whether physicians’ intrapersonal empathy increased after a communication skills training (CST) workshop.

Method
Participants were oncologists from across Japan with three or more years of clinical experience in oncology. They were recruited through the Internet and via direct contact by the workshop organizers. Participants attended 1 of 132 two-day CST workshops, held between November 2007 and March 2011. Prior to the workshop (baseline/T1), participants completed a survey with demographic questions, the Jefferson Scale of Physician Empathy (JSPE), and the Interpersonal Reactivity Index (IRI). The JSPE was administered again immediately after completion of the workshop (follow-up/T2). Then the JSPE and IRI were administered as part of a three-month follow-up (T3) survey. Changes in participants’ mean total JSPE scores, JSPE subscale scores, and IRI subscale scores were compared using multivariate analysis of variance.

Results
Of the 507 workshop participants who received the three-month follow-up survey, 383 responded (response rate: 75.5%). Total JSPE scores and JSPE subscale scores at T2 and T3 were significantly higher than those at T1 (P < .01). IRI-Perspective Taking and IRI-Empathic Concern subscale scores increased significantly from T1 to T3 (P < .01), whereas IRI-Fantasy and IRI-Personal Distress subscale scores showed no significant changes. The JSPE scores of palliative care physician participants were significantly higher than those of medical oncologist participants at T1 and T3. No signifi cant differences were found by specialty at T2.

Conclusions
The intrapersonal empathy of oncologists in Japan increased after a two-day CST workshop.
Alpha 2-Macroglobulin as Dual Regulator for Both Anabolism and Catabolism in the Cartilaginous Endplate of Intervertebral Disc
Authors: Huang Bao , Chen Jian , Zhang Xuyang , Wang Jiasheng , Zheng Zeyu , Shan Zhi , Liu Junhui , Zhu Zhihai , Zhao Fengdong 
Published: August 2018

Study Design.
Basic science study.

Objective.
To illustrate supplemental alpha-2 macroglobulin (α2 M) has beneficial effects on cartilaginous endplates (CEPs) that may slow the progression of intervertebral disc (IVD) degeneration.

Summary of Background Data.
CEPs play a vital role in progression of intervertebral disc degenerative diseases. However, the ideal and economic therapies for CEPs degeneration are still urgently required.

Methods.
Firstly, we confirmed degenerative CEP characters by H&E and Safranin O fast green staining and detected increasing level of α2 M and matrix metalloproteinase 13(MMP-13) in degenerative CEP by immunohistochemistry. Then, effects of exogenous α2 M on tumor necrosis factor alpha (TNF-α)-induced CEP catabolic enzyme and anabolic molecules were evaluated by qRT-PCR, Western blotting and ELISA in cultured CEP cells obtained from rats. Furthermore, suppression of α2 M on TNF-α-induced activation of NF-кB signaling pathway was measured by Western blotting and immunofluorescence. In addition, function of α2 M on TNF-α-treated ex vivo IVDs from rats lumbar IVDs was estimated by measuring the expression of MMP-13, Sox9, aggrecan, and type II collagen in CEP area.

Results.
Compared with normal CEP, level of α2 M was slightly increased in CEP from degenerative patients, whereas MMP-13 was sharply elevated. In vitro, α2 M inhibited expression and activity of MMP-3 or MMP-13 in a dose-dependent manner in rat CEP cells stimulated by TNF-α. The α2 M refrained phosphorylation of IκBα and inhibited nuclear translocation of p65. Finally, supplemental α2 M reduced expression of MMP-13, and promoted expression of Sox9, aggrecan, and type II collagen in CEP area of ex vivo IVDs cultured with TNF-α.

Conclusion.
α2 M is not sufficiently produced to inactivate higher concentrations of catabolic factor MMP-13 found in the degenerated CEP. Supplemental α2 M protects against the progression of IVD degeneration by inhibiting effects of proinflammatory cytokines.

Level of Evidence: N/A
Ultrasound Assessment of the Change in Carotid Corrected Flow Time in Fluid Responsiveness in Undifferentiated Shock
Authors: Barjaktarevic Igor , Toppen William E. , Hu Scott , Aquije Montoya Elizabeth , Ong Stephanie , Buhr Russell , David Ian J. , Wang Tisha , Rezayat Talayeh , Chang Steven Y. , Elashoff David , Markovic Daniela , Berlin David , Cannesson Maxime 
Published: August 2018

Objectives:
Adequate assessment of fluid responsiveness in shock necessitates correct interpretation of hemodynamic changes induced by preload challenge. This study evaluates the accuracy of point-of-care Doppler ultrasound assessment of the change in carotid corrected flow time induced by a passive leg raise maneuver as a predictor of fluid responsiveness. Noninvasive cardiac output monitoring (NICOM, Cheetah Medical, Newton Center, MA) system based on a bioreactance method was used.

Design:
Prospective, noninterventional study.

Setting:
ICU at a large academic center.

Patients:
Patients with new, undifferentiated shock, and vasopressor requirements despite fluid resuscitation were included. Patients with significant cardiac disease and conditions that precluded adequate passive leg raising were excluded.

Interventions:
Carotid corrected flow time was measured via ultrasound before and after a passive leg raise maneuver. Predicted fluid responsiveness was defined as greater than 10% increase in stroke volume on noninvasive cardiac output monitoring following passive leg raise. Images and measurements were reanalyzed by a second, blinded physician. The accuracy of change in carotid corrected flow time to predict fluid responsiveness was evaluated using receiver operating characteristic analysis.

Measurements and Main Results:
Seventy-seven subjects were enrolled with 54 (70.1%) classified as fluid responders by noninvasive cardiac output monitoring. The average change in carotid corrected flow time after passive leg raise for fluid responders was 14.1 ± 18.7 ms versus –4.0 ± 8 ms for nonresponders (p < 0.001). Receiver operating characteristic analysis demonstrated that change in carotid corrected flow time is an accurate predictor of fluid responsiveness status (area under the curve, 0.88; 95% CI, 0.80–0.96) and a 7 ms increase in carotid corrected flow time post passive leg raise was shown to have a 97% positive predictive value and 82% accuracy in detecting fluid responsiveness using noninvasive cardiac output monitoring as a reference standard. Mechanical ventilation, respiratory rate, and high positive end-expiratory pressure had no significant impact on test performance. Post hoc blinded evaluation of bedside acquired measurements demonstrated agreement between evaluators.

Conclusions:
Change in carotid corrected flow time can predict fluid responsiveness status after a passive leg raise maneuver. Using point-of-care ultrasound to assess change in carotid corrected flow time is an acceptable and reproducible method for noninvasive identification of fluid responsiveness in critically ill patients with undifferentiated shock.
PHENOTYPIC VARIABILITY OF RECESSIVE RDH12-ASSOCIATED RETINAL DYSTROPHY
Authors: Zou Xuan , Fu Qing , Fang Sha , Li Hui , Ge Zhongqi , Yang Lizhu , Xu Mingchu , Sun Zixi , Li Huajin , Li Yumei , Dong Fangtian , Chen Rui , Sui Ruifang 
Published: August 2018

Purpose:
To characterize the phenotypic variability and report the genetic defects in a cohort of Chinese patients with biallelic variants of the retinol dehydrogenase 12 (RDH12) gene.

Methods:
The study included 38 patients from 38 unrelated families with biallelic pathogenic RDH12 variants. Systematic next-generation sequencing data analysis, Sanger sequencing validation, and segregation analysis were used to identify the pathogenic mutations. Detailed ophthalmic examinations, including electroretinogram, fundus photography, fundus autofluorescence and optical coherence tomography, and statistical analysis were performed to evaluate phenotype variability.

Results:
Twenty-five different mutations of RDH12 were identified in the 38 families. Six of these variants were novel. Val146Asp was observed at the highest frequency (23.7%), and it was followed by Arg62Ter (14.5%) and Thr49Met (9.2%). Twenty-three probands were diagnosed with early-onset severe retinal dystrophy, 6 with Leber congenital amaurosis, 7 with autosomal recessive retinitis pigmentosa, and 2 with cone-rod dystrophy. Self-reported nyctalopia occurred in about a half of patients (55.3%) and was significantly more common among older patients (P < 0.01). Nyctalopia was not significantly associated with best-corrected visual acuity (P = 0.72), but older patients had significantly greater best-corrected visual acuity loss (P < 0.01). Only 15.8% of the patients had nystagmus, which was significantly more likely to occur among 36.8% of the patients with hyperopia >3D (P < 0.01) and/or in cases of reduced best-corrected visual acuity (P = 0.01), but was not associated with age (P = 0.87).

Conclusion:
Several high-frequency RDH12 variants were identified in patients with inherited retinal dystrophies, most of which were missense mutations. Variable but characteristic phenotypes of a progressive nature was observed. Overall, the findings indicated that biallelic RDH12 mutations are a common cause of early-onset retinal dystrophy and a rare cause of cone-rod dystrophy.
Clinical and Magnetic Resonance Imaging Characteristics of Postfenestration Optic Nerve Sheath Pseudomeningoceles
Authors: Rafailov Leon , Rubinstein Daniel , Wladis Edward J. , Mirani Neena , Frohman Larry P. , Langer Paul D. , Turbin Roger E. 
Published: August 2018

Purpose:
The clinical significance of postoperative pseudomeningocele formation following optic nerve sheath fenestration (ONSF) has not been fully characterized. A literature review identifies 9 previously published cases the authors believe demonstrate pseudomeningocele formation and approximately 19 other similar findings that were either transient or less defined blebs. This study was undertaken to more clearly define the clinical, radiographic, and histopathologic features associated with this entity.

Methods:
Sixteen-year, single-center, retrospective chart review of all ONSF cases performed by 2 surgeons. Clinical data, intracranial pressure, radiographic imaging, and histopathology of clinically detected pseudomeningoceles after ONSF were reviewed.

Results:
Eighty-six eyes in 57 patients underwent ONSF (28 unilateral, 12 bilateral sequential, 17 bilateral simultaneous). Forty-nine of 57 patients had elevated intracranial pressure preoperatively (41 idiopathic intracranial hypertension, 4 venous thrombosis, 2 meningitis, 1 arteriovenous malformation, and 1 sarcoid). In 32 patients undergoing postoperative imaging, 4 eyes (4.7%) in 4 patients developed well-defined pseudomeningoceles, of which 3 were symptomatic and 2 required surgical revision. Each pseudomeningocele developed in the setting of elevated preoperative intracranial pressure (350, 360, 430, 500 mm H20). Magnetic resonance imaging and/or computed tomography revealed sharply demarcated fluid-filled sacs adjacent to the optic nerve. The contents of these sacs were hypointense on T1-weighted imaging, hyperintense on T2-weighting, variably enhanced with contrast, and hypointense on fluid attenuated inversion recovery, and were thus consistent with cerebrospinal fluid. Histopathologic analysis of one of these outpouchings demonstrated an acellular, fibrocollagenized lining consistent with pseudomeningocele. Three eyes in 3 additional patients had less well-defined findings on imaging interpreted as bleb-like or cyst-like change.

Conclusions:
Pseudomeningoceles following ONSF may be asymptomatic or may cause symptomatic orbital mass effect and rarely visual loss, amendable to surgical excision. Post-ONSF pseudomeningoceles are identified on computed tomography or magnetic resonance imaging to occur at the locations of fenestration sites and contain cerebrospinal fluid communicating with the subdural space that may act as a “filtration” bleb in some cases. Imaging findings may represent a spectrum spanning intraorbital cerebrospinal fluid leakage, partial walling off of bleb, or fully developed cysts. Resection of optic nerve pseudomeningoceles is considered in symptomatic cysts or eyes with papilledema that fails to improve.
Phase I Trial Evaluating the Safety of Preoperative Gemcitabine/nab-Paclitaxel With Concurrent Radiation Therapy for Borderline Resectable Pancreatic Cancer
Authors: Takahashi Hidenori , Akita Hirofumi , Ioka Tatsuya , Wada Hiroshi , Tomokoni Akira , Asukai Kei , Ohue Masayuki , Yano Masahiko , Ishikawa Osamu 
Published: August 2018

Objectives
The objectives of this study were to assess the feasibility of preoperative gemcitabine/nab-paclitaxel–based chemoradiation therapy (CRT) for patients with borderline resectable pancreatic cancer (BRPC), which consists of induction chemotherapy and subsequent CRT, and to determine the recommended dose (RD) of gemcitabine/nab-paclitaxel with concurrent radiation therapy in a phase I trial.

Methods
Patients with BRPC received gemcitabine (1000 mg/m2)/nab-paclitaxel (125 mg/m2) on days 1, 8, and 15 during each 4-week cycle, which was repeated for 2 cycles as induction chemotherapy. After induction chemotherapy, the patients received gemcitabine/nab-paclitaxel with concurrent radiation therapy. During CRT, the patients were scheduled to receive gemcitabine/nab-paclitaxel at 7 dose levels using a standard 3 + 3 dose escalation scheme. Radiation therapy was concurrently delivered at a total dose of 60 Gy.

Results
Thirty-eight patients initiated induction gemcitabine/nab-paclitaxel. Among these patients, 30 received subsequent gemcitabine/nab-paclitaxel–based CRT. The RD was determined to be level 5 (gemcitabine, 800 mg/m2; nab-paclitaxel, 100 mg/m2). The dose-limiting toxicities included hematologic toxicity, infection, febrile neutropenia, and peripheral neuropathy. Twenty-four of 30 patients underwent pancreatectomy, and the R0 resection rate was 96%.

Conclusions
The RD of gemcitabine/nab-paclitaxel–based CRT after induction gemcitabine/nab-paclitaxel for patients with BRPC was 800 and 100 mg/m2, respectively.
Pancreatitis-Associated Genes and Pancreatic Cancer Risk
Authors: Cazacu Irina Mihaela , Farkas Nelli , Garami András , Balaskó Márta , Mosdósi Bernadett , Alizadeh Hussain , Gyöngyi Zoltán , Rakonczay Zoltán , Vigh Éva , Habon Tamás , Czopf László , Lazarescu Marilena Alina , Erőss Bálint , Sahin-Tóth Miklós , Hegyi Péter 
Published: August 2018

ObjectiveThe aim of this study was to evaluate the connection between pancreatic cancer (PC) and genetic variants associated with chronic pancreatitis via systematic review and meta-analysis.MethodsThe data search was performed in 3 major databases (PubMed, Embase, and Cochrane Library). The selected studies have looked into the presence of the pancreatitis-associated genes in patients with PC and in control subjects, the outcome being the frequency of the mutations in the 2 groups. For the binary outcomes, pooled odds ratio (OR) and 95% confidence interval (CI) were calculated.ResultsTen articles proved to be eligible for the qualitative synthesis, and 8 articles were suitable for statistical analysis. Six case-control studies, comprising 929 PC cases and 1890 control subjects for serine protease inhibitor Kazal type 1 (SPINK1) mutations, and 5 case-control studies, comprising 1674 PC cases and 19,036 control subjects forCFTRmutations, were enrolled in our analysis.SPINK1mutations showed no association with PC (OR, 1.52; 95% CI, 0.67–3.45;P= 0.315), whereas mutations inCFTRmodestly increased the risk of PC (OR, 1.41; 95% CI, 1.07–1.84;P= 0.013).ConclusionOur meta-analysis showed that mutations inCFTRmodestly increase the risk of PC, whereas no association was found betweenSPINK1and PC.