bluuebunny/crossref_metadata_2025 huggingface dataset:
Ritual Law in Rabbinic Judaism
Authors: Marx Dalia , Levine David
Published: November 2019

The influence of the Jerusalem Temple and its rituals persisted in Jewish religious expression even after its destruction. Reactions to this religious rift incorporated the Temple experience as an ongoing resource. The complex and multifaceted transition from Temple to synagogue, and from priests to rabbis, regarded the Temple and its cult as a validating component. The Temple and its attendant practices were present in the assorted domains of rabbinic ritual law. Whether dealing with issues of purity, tithing, prayer, holidays, or home rituals, different strategies were employed when appealing to Temple practice: maintaining continuity, modifying and adapting to changed circumstances, acknowledging break and rupture, and suggesting new modes of religious expression. As in other areas, rabbinic ritual law is marked by its progression toward comprehensiveness, systemization, and abstraction, and it is a foundational stage in the trajectory of Jewish law and practice regarding ritual.
Novel associations between cytokines and pulmonary involvement in juvenile dermatomyositis – a cross-sectional study of long-term disease
Authors: Marstein Henriette , Schwartz Thomas , Aaløkken Trond Mogens , Lund May Britt , Flatø Berit , Sjaastad Ivar , Sanner Helga
Published: November 2019

Objectives

To examine associations between cytokines and pulmonary involvement in patients with medium- to long-term JDM.

Methods

In a cross-sectional study, 58 patients examined median (range) 16.8 (6.6–27.0) years after symptom onset were stratified in inactive (JDM-inactive) and active (JDM-active) disease (updated PRINTO criteria); 56 age/sex matched controls were included. Twenty-nine cytokines (in serum) were analysed (Luminex technology/ELISA). Pulmonary function test included forced vital capacity, total lung capacity (TLC) and diffusing capacity for carbon monoxide reported as % of predicted and low forced vital capacity/TLC/diffusing capacity for carbon monoxide. In patients, the presence of clinical pulmonary damage was assessed and high resolution computed tomography scans were scored for interstitial lung disease, chest wall calcinosis and airways disease.

Results

Median age of patients was 21 (7–55) years, 59% were female and 36% inactive. In JDM-active and all patients, higher MCP-1, IP-10 and eotaxin correlated with high-resolution computed tomography findings (rs 0.34–0.61; P < 0.05). MCP-1 and eotaxin correlated with pulmonary damage in JDM-active and all patients (rs 0.41–0.49; P < 0.01). Higher TGF-β1 and PDGF (growth factors) were associated with lower lung volumes (forced vital capacity/TLC measures) in all patients; PDGF in JDM-active and TGF-β1 in JDM-inactive patients. IP-10 correlated with TLC% in JDM-active patients. No associations between cytokines and pulmonary function test were found in controls.

Conclusions

In JDM, we found a novel association (not previously described in myositis) between eotaxin and pulmonary involvement; we have previously shown an association between eotaxin and cardiac dysfunction. The associations between IP-10/growth factors/MCP-1 and pulmonary involvement are novel in JDM and were mostly seen in JDM-active patients.
Spending on Children across Four Countries: Variation in the Role of Income and Women’s Labor Force Participation
Authors: Kornrich Sabino , Ruppanner Leah , Lappegård Trude
Published: November 2019

Scholars have recently documented inequalities in parents’ spending on children in the United States. This article situates these trends cross-nationally by using expenditure data from the United States, Australia, Spain, and Norway. The article investigates differences across countries in the links between household income, female labor force participation, and spending on children. The links between income, female labor force participation, and spending are largest in the United States and smallest in Norway, while Spain and Australia are intermediate cases, suggesting that public provision lessens inequalities in parental spending on children.
KCa3.1 channel mediates inflammatory signaling of pancreatic β cells and progression of type 2 diabetes mellitus
Authors: Pang Zheng‐Da , Wang Yan , Wang Xiao‐Jing , She Gang , Ma Xiao‐Zhen , Song Zheng , Zhao Li‐Mei , Wang Hui‐Fang , Lai Bao‐Chang , Gou Wei , Du Xiao‐Jun , Deng Xiu‐Ling
Published: November 2019

Chronic islet inflammation is associated with development of type 2 diabetes mellitus (T2DM). Intermediate‐conductance calcium‐activated K+ (KCa3.1) channel plays an important role in inflammatory diseases. However, the role and regulation of KCa3.1 in pancreatic β cells in progression of T2DM remain unclarified. In the present study, we evaluated the effect of the specific KCa3.1 channel blocker 1‐[(2‐chlorophenyl)diphenylmethyl]‐1H‐pyrazole (TRAM‐34) on diabetic phenotype in the db/db model. In diabetic mice, blockade of KCa3.1 significantly improved glucose tolerance, enhanced secretion of postprandial insulin level, and reduced loss of β‐cell mass through attenuating the expression and secretion of inflammatory mediators. Furthermore, in cultured pancreatic β cells, exposure to high levels of glucose or palmitic acid significantly increased expression and current density of the KCa3.1 channel as well as secretion of proinflammatory chemokines, and the effects were similarly reversed by preincubation with TRAM‐34 or a NF‐κB inhibitor pyrrolidinedithiocarbamate. Additionally, expression of KCa3.1 in pancreas islet cells was up‐regulated by activation of NF‐κBwithIL‐1β stimulation. In summary, up‐regulated KCa3.1 due to activation of NF‐κB pathway leads to pancreatic inflammation via expression and secretion of chemokines and cytokines by pancreatic β cells, thereby facilitating progression of T2DM.—Pang, Z.‐D., Wang, Y., Wang, X.‐J., She, G., Ma, X.‐Z., Song, Z., Zhao, L.‐M., Wang, H.‐F., Lai, B.‐C., Gou, W., Du, X.‐J., Deng, X.‐L. KCa3.1 channel mediates inflammatory signaling of pancreatic β cells and progression of type 2 diabetes mellitus. FASEB J. 33, 14760‐14771 (2019). www.fasebj.org
Intravitreal injection of mesenchymal stem cells evokes retinal vascular damage in rats
Authors: Huang Hongpeng , Kolibabka Matthias , Eshwaran Rachana , Chatterjee Anupriya , Schlotterer Andrea , Willer Hélène , Bieback Karen , Hammes Hans‐Peter , Feng Yuxi
Published: November 2019

The aim of this study is to investigate the vascular outcome after intravitreal mesenchymal stem cell (MSC) administration in rats without or with damage to the neurovascular unit [transgenic (TGR) rats]. Male Sprague‐Dawley (SD) and TGR rats received an intravitreal injection of 2 × 104 rat bone marrow‐derived MSCs (BMSCs) or human adipose‐derived stem cells (ASCs) at postnatal d 30. After 4 wk, vasculature, neuronal function, and gene expression in the retinas were evaluated using retinal morphometry, electroretinography, immunofluorescence, Western blot, and quantitative PCR. Intravitreal administration of rat BMSCs and human ASCs in both SD and TGR eyes induced cataract, loss of pericytes, and increased formation of acellular capillaries. BMSCs remained in the vitreous cavity and did not migrate into the retinas. Intravitreal administration of BMSCs impacted retinal neuronal function in neither SD nor TGR rats. Retinal glial activation, elevation of IL‐1β, C3, arginase 1, and heat shock protein 90 were detected in BMSC‐injected SD rats. Intravitreal administration of MSCs induces cataract, retinal vasoregression, activation of retinal glial cells, and inflammatory response in rat eyes.—Huang, H., Kolibabka, M., Eshwaran, R., Chatterjee, A., Schlotterer, A., Willer, H., Bieback, K., Hammes, H.‐P., Feng, Y. Intravitreal injection of mesenchymal stem cells evokes retinal vascular damage in rats. FASEB J. 33, 14668‐14679 (2019). www.fasebj.org
Molecular model of the ferroportin intracellular gate and implications for the human iron transport cycle and hemochromatosis type 4A
Authors: Guellec Julie , Elbahnsi Ahmad , Tertre Marlene Le , Uguen Kevin , Gourlaouen Isabelle , Férec Claude , Ka Chandran , Callebaut Isabelle , Gac Gerald Le
Published: November 2019

Ferroportin 1 (FPN1) is a major facilitator superfamily transporter that is essential for proper maintenance of human iron homeostasis at the systemic and cellular level. FPN1 dysfunction leads to the progressive accumulation of iron in reticuloendothelial cells, causing hemochromatosis type 4A (or ferroportin disease), an autosomal dominant disorder that displays large phenotypic heterogeneity. Although crystal structures have unveiled the outward‐ and inward‐facing conformations of the bacterial homolog Bdellovibrio bacteriovorus Fpn (or Bd2019) and calcium has recently been identified as an essential cofactor, our molecular understanding of the iron transport mechanism remains incomplete. Here, we used a combination of molecular modeling, molecular dynamics simulations, and Ala site‐directed mutagenesis, followed by complementary in vitro functional analyses, to explore the structural architecture of the human FPN1 intracellular gate. We reveal an interdomain network that involves 5 key amino acids and is likely very important for stability of the iron exporter facing the extracellular milieu. We also identify inter‐ and intradomain interactions that rely on the 2 Asp84 and Asn174 critical residues and do not exist in the bacterial homolog. These interactions are thought to play an important role in the modulation of conformational changes during the transport cycle. We interpret these results in the context of hemochromatosis type 4A, reinforcing the idea that different categories of loss‐of‐function mutations exist. Our findings provide an unprecedented view of the human FPN1 outward‐facing structure and the particular function of the so‐called “gating residues” in the mechanism of iron export.—Guellec, J., Elbahnsi, A., Le Tertre, M., Uguen, K., Gourlaouen, I., Férec, C., Ka, C., Callebaut, I., Le Gac, G. Molecular model of the ferroportin intracellular gate and implications for the human iron transport cycle and hemochromatosis type 4A. FASEB J. 33, 14625‐14635 (2019). www.fasebj.org
Accreditation of Canadian Undergraduate Medical Education Programs: A Study of Measures of Effectiveness
Authors: Blouin Danielle
Published: November 2019

Purpose

Undergraduate medical education (UME) programs participate in accreditation with the belief that it contributes to improving UME quality and, ultimately, patient care. Linkages between accreditation and UME quality are incomplete. Previous studies focused on student performance on national examinations, medical school processes, medical school’s organizational culture types, and degree of implementation of quality improvement activities as markers of the effectiveness of accreditation. The current study sought to identify new indicators of accreditation effectiveness, to better understand the value and impact of accreditation.

Method

This qualitative study used an expert-oriented evaluation approach to identify novel markers of accreditation effectiveness. From March 2015 to March 2016, leaders and teachers at 16 of the 17 Canadian UME programs were invited to participate in interviews and focus group discussions aimed at identifying measures of accreditation effectiveness. Themes were extracted using the method of constant comparative analysis.

Results

Sixty-three individuals from 13 (81%) medical schools participated. Eight themes were formulated: Student/graduate performance, UME program processes, quality assurance and continuous quality improvement, stakeholder satisfaction, stakeholder expectations, engagement, research, and UME program quality. The latter 5 themes have not been previously studied as measures of accreditation effectiveness. All themes appear applicable to accreditation of graduate medical education as well. A framework is proposed to guide future research on the impact of accreditation.

Conclusions

Eight themes were generated, representing direct and indirect indicators of the impact of accreditation. The themes are integrated into a framework proposed to guide future research on the value of accreditation along the continuum of medical education.
Reporting Quality Analysis of Randomized Controlled Trials in Journal of Neurosurgical Anesthesiology: A Methodological Assessment
Authors: Kim Soo Yeon , Kim Kyu Nam , Kim Dong Won , Kang Mi Sun
Published: November 2019

Background:

Randomized controlled trials (RCTs) are considered to provide high levels of evidence to optimize decision-making for patient care, although there can be a risk bias in their design, conduct, and analysis. Quality assessment of RCTs is necessary to assess whether they provide reliable results with little bias.

Materials and Methods:

We assessed the reporting quality of RCTs published in the Journal of Neurosurgical Anesthesiology (JNA) between January 1, 2000 and December 31, 2017 using the Jadad scale, van Tulder scale, and Cochrane Collaboration Risk of Bias Tool (CCRBT).

Results:

We identified 130 RCTs and 570 original articles. Among the 130 RCTs, 92 (70.8%) presented an appropriate blinding method, and 70 (53.8%) described an appropriate allocation method. For the entire period, the percentages of high-quality reporting articles were 71.5%, 73.1%, and 13.8% in the Jadad scale, van Tulder scale, and CCRBT assessments, respectively. There was an improvement in the van Tulder scale over time (coefficients [95% confidence interval {CI}]=0.08 [0.01-0.15]; P=0.02). Appropriate reporting of allocation in the Jadad scale (coefficients [95% CI]=1.68 [1.28-2.07]; P<0.001) and van Tulder scale (coefficients [95% CI]=2.34 [1.97-2.70]; P<0.001), and reporting of blinding in the Jadad (coefficients [95% CI]=1.09 [0.66-1.52]; P<0.001) and van Tulder scores (coefficients [95% CI]=1.85 [1.45-2.25]; P<0.001), were associated with high-quality reporting.

Conclusions:

The ratio of high-quality reporting RCTs in JNA was consistently high compared with other journals. Thorough consideration of allocation concealment during the peer review process can further improve the reporting quality of RCTs in JNA.
Stillbirth Associated With Infection in a Diverse U.S. Cohort
Authors: Page Jessica M. , Bardsley Tyler , Thorsten Vanessa , Allshouse Amanda A. , Varner Michael W. , Debbink Michelle P. , Dudley Donald J. , Saade George R. , Goldenberg Robert L. , Stoll Barbara , Hogue Carol J. , Bukowski Radek , Conway Deborah , Reddy Uma M. , Silver Robert M.
Published: November 2019

OBJECTIVE:

To better characterize infection-related stillbirth in terms of pathogenesis and microbiology.

METHODS:

We conducted a secondary analysis of 512 stillbirths in a prospective, multisite, geographically, racially and ethnically diverse, population-based study of stillbirth in the United States. Cases underwent evaluation that included maternal interview, chart abstraction, biospecimen collection, fetal autopsy, and placental pathology. Recommended evaluations included syphilis and parvovirus serology. Each case was assigned probable and possible causes of death using the INCODE Stillbirth Classification System. Cases where infection was assigned as a probable or possible cause of death were reviewed. For these cases, clinical scenario, autopsy, maternal serology, culture results, and placental pathology were evaluated.

RESULTS:

For 66 (12.9%) cases of stillbirth, infection was identified as a probable or possible cause of death. Of these, 36% (95% CI 35–38%) were categorized as a probable and 64% (95% CI 62–65%) as a possible cause of death. Infection-related stillbirth occurred earlier than non–infection-related stillbirth (median gestational age 22 vs 28 weeks,P=.001). Fetal bacterial culture results were available in 47 cases (71%), of which 35 (53%) grew identifiable organisms. The predominant species wereEscherichia coli(19, 29%), group B streptococcus (GBS) (8, 12%), and enterococcus species (8, 12%). Placental pathology revealed chorioamnionitis in 50 (76%), funisitis in 27 (41%), villitis in 11 (17%), deciduitis in 35 (53%), necrosis in 27 (41%), and viral staining in seven (11%) cases. Placental pathology found inflammation or evidence of infection in 65 (99%) cases and fetal autopsy in 26 (39%) cases. In infection-related stillbirth cases, the likely causative nonbacterial organisms identified were parvovirus in two (3%) cases, syphilis in one (2%) case, cytomegalovirus (CMV) in five (8%) cases, and herpes in one (2%) case.

CONCLUSION:

Of infection-related stillbirth cases in a large U.S. cohort,E coli, GBS, and enterococcus species were the most common bacterial pathogens and CMV the most common viral pathogen.
Trends in Use and Effect on Survival of Simple Hysterectomy for Early-Stage Cervical Cancer
Authors: Sia Tiffany Y. , Chen Ling , Melamed Alexander , Tergas Ana I. , Khoury-Collado Fady , Hou June Y. , St. Clair Caryn M. , Ananth Cande V. , Neugut Alfred I. , Hershman Dawn L. , Wright Jason D.
Published: November 2019

OBJECTIVE:

To identify use and outcomes of simple hysterectomy compared with radical hysterectomy for women with early-stage cervical cancer.

METHODS:

The National Cancer Database was used to review the cases of women with stage IA2 and IB1 (2 cm or less) cervical cancer from 2004 to 2015. Patients were classified based on whether they underwent simple or radical hysterectomy. Survival was examined after propensity score weighting.

RESULTS:

Simple hysterectomy was performed in 44.6% of women with stage IA2 (n=1,530) and 35.3% of those with stage IB1 (n=3,931) tumors. Rates of simple hysterectomy increased from 37.8% to 52.7% from 2004 to 2014 for stage IA2 cancers and from 29.7% to 43.8% between 2004 and 2013 for stage IB1 cancers. For stage IA2 cancers, younger women and those treated at an academic medical center were less likely to undergo simple hysterectomy. For stage IB1 cancers, black women were more likely to undergo simple hysterectomy, and those treated at an academic medical center were less likely to undergo simple hysterectomy. After propensity score weighting, there was no association between route of hysterectomy and survival for stage IA2 cancers (hazard ratio [HR] 0.70, 95% CI 0.41–1.20, 5-year survival 95.1% for radical hysterectomy vs 97.6% for simple hysterectomy). For stage IB1 cancers, patients who underwent simple hysterectomy were at 55% increased risk of death (HR 1.55, 95% CI 1.18–2.03, and 5-year survival was 95.3% for radical hysterectomy vs 92.4% for simple hysterectomy).

CONCLUSION:

Although there was no association between surgical radicality and survival for women with stage IA2 tumors, there was a 55% increase in mortality for women with stage IB1 neoplasms who underwent simple compared with radical hysterectomy. Radical hysterectomy is the treatment of choice for women with stage IB1 cervical cancer.
All Disclosure is Good Disclosure
Authors: Iyer Sravisht , Yoo Joon S. , Jenkins Nathaniel W. , Parrish James M. , Khechen Benjamin , Haws Brittany E. , Nolte Michael T. , Brundage Thomas S. , Hrynewycz Nadia M. , Phillips Frank M. , Singh Kern
Published: November 2019

Study Design:

This was a prospective study.

Objective:

To determine patient awareness of surgeon-industry relationships, how these relationships affect patient perceptions of surgeons, and which relationships cause the greatest concern to patients.

Summary of Background Data:

The prevalence of orthopedic surgeon-industry relationships led to the establishment of a national database of physician-industry interaction [Open Payments Database (OPD)] as part of the Physician Payments Sunshine Act (PPSA).

Materials and Methods:

A 10-item questionnaire was administered to patients before their first evaluation. Two questions asked about awareness of the surgeon’s industry relationships and of the OPD. One question evaluated the importance of surgeon-industry relationships of patients when choosing a provider. Six questions assessed patient perception of specific types of surgeon-industry relationships. Lastly, each patient ranked specific types of surgeon-industry relationships (1—most concerning to 6—least/not concerning). The distribution of patient-perceptions was compared using a Friedman 2-way analysis of variance by Ranks test. Distributions across awareness were compared using a Kruskal-Wallis test.

Results:

A total of 205 patients completed the survey. A majority of patients were unaware of their surgeons’ relationships with industry and the existence of the OPD. However, most patients considered surgeon-industry relationships an important, very important or most important part of choosing their physician. There were significant differences in how industry relationships affected patient perceptions. Research funding had the most positive impact on perception. Financial ownership was reported to be the most concerning relationship followed by royalty payments and consulting.

Conclusions:

Our results suggest that despite a lack of awareness, most patients consider surgeon-industry relationships an important factor in choosing their doctor. Patients generally report a more positive view of surgeons that have active relationships with industry. These results emphasize the value of disclosure for surgeons; it provides transparency and improves their standing amongst a majority of their patients.
Prognostic Significance of Nuclear Factor Kappa B Expression in Locally Advanced Cervical Cancer Patients Treated Definitively With Concurrent Chemoradiation
Authors: Altoos Basel , Small Christina , Dalal Prarthana , Attieh Darlene , El Achy Samar , Parimi Vamsi , Wei Jian-Jun , Helenowski Irene , Donnelly Eric D. , Strauss Jonathan , Small William , Refaat Tamer
Published: November 2019

Objectives:

Nuclear factor kappa B (NFkB) is a transcription factor shown to confer treatment resistance in tumors. A previous report suggested an association between pretreatment NFkB and poorer outcomes for cervical cancer patients treated with chemoradiation therapy (CRT). We aimed to validate their findings in a larger patient cohort.

Materials and Methods:

This Institutional Review Board approved study included patients with locally advanced cervical cancer patients treated with CRT. Evaluation of both nuclear and cytoplasmic immunoreactivity for NFkB was scored semiquantitatively by 3 pathologists. Cytoplasmic positivity incorporated both the intensity and percentage of immunoreactivity in invasive carcinoma (H-score), whereas nuclear positivity was assessed by percentage of positive cells. Outcomes were stratified by NFkB overexpression and tumor characteristics. Overall survival (OS), progression-free survival (PFS), distant metastases-free survival (DMFS), and local regional control (LC) were obtained using Kaplan-Meier and differences between groups were evaluated by the log-rank test. Hazard ratios were obtained using Cox regression for both univariate and multivariate analyses.

Results:

The mean age was 51 years old and most (78.57%) had locally advanced disease. Five-year OS, PFS, LC, and DMFS in the entire cohort were 57.18% (confidence interval [CI], 34.06%-74.82%), 48.07% (CI, 25.50%-67.52%), 72.11% (CI, 49.96%-85.73%), and 62.85% (CI, 36.33%-80.82%), respectively. There was no significant association between NFkB expression (H-index ≥180) and 3-year and 5-year OS (P-value=0.34), PFS (P-value=0.21), LC (P-value=0.86), or DMFS (P-value=0.18).

Conclusions:

Our study demonstrated that cytoplasmic NFkB-p65 expression (H-index ≥180) was associated with a nonstatistically significant trend toward poor clinical outcomes in locally advanced cervical cancer patients treated definitively with CRT.
Alterations in pronociceptive and antinociceptive mechanisms in patients with low back pain: a systematic review with meta-analysis
Authors: McPhee Megan E. , Vaegter Henrik Bjarke , Graven-Nielsen Thomas
Published: November 2019

Altered pronociceptive and antinociceptive mechanisms are often implicated in painful conditions and have been increasingly studied over the past decade. For some painful conditions, alterations are well-established, but in populations with low back pain (LBP), there remains considerable debate whether these mechanisms are altered. The present systematic review aimed to address this issue by identifying studies assessing conditioned pain modulation (CPM) and/or temporal summation of pain (TSP) in patients with LBP, comparing with either a healthy control group or using a method with reference data available. Qualitative synthesis and quantitative meta-analysis of group differences were performed. For CPM and TSP, 20 and 29 original articles were eligible, with data for meta-analysis obtainable from 18 (1500 patients and 505 controls) and 27 (1507 patients and 1127 controls) studies, respectively. Most studies were of poor-to-fair quality with significant heterogeneity in study size, population, assessment methodology, and outcome. Nonetheless, CPM was impaired in patients with LBP compared with controls (standardized mean difference = −0.44 [−0.64 to −0.23], P < 0.001), and the magnitude of this impairment was related to pain chronicity (acute/recurrent vs chronic, P = 0.003), duration (R
S = −0.62, P = 0.006), and severity (R
S = −0.54, P = 0.02). Temporal summation of pain was facilitated in patients with LBP compared with controls (standardized mean difference = 0.50 [0.29-0.72], P < 0.001), and the magnitude of this facilitation was weakly related to pain severity (R
S= 0.41, P = 0.04) and appeared to be influenced by test modality (P < 0.001). Impaired CPM and facilitated TSP were present in patients with LBP compared with controls, although the magnitude of differences was small which may direct future research on the clinical utility.
Biomarkers for predicting central neuropathic pain occurrence and severity after spinal cord injury: results of a long-term longitudinal study
Authors: Gruener Hila , Zeilig Gabi , Gaidukov Evgeni , Rachamim-Katz Orna , Ringler Erez , Blumen Nava , Engel-Haber Einat , Defrin Ruth
Published: November 2019

Central neuropathic pain (CNP) after spinal cord injury (SCI) is debilitating and immensely impacts the individual. Central neuropathic pain is relatively resistant to treatment administered after it develops, perhaps owing to irreversible pathological processes. Although preemptive treatment may overcome this shortcoming, its administration necessitates screening patients with clinically relevant biomarkers that could predict CNP early post-SCI. The aim was to search for such biomarkers by measuring pronociceptive and for the first time, antinociceptive indices early post-SCI. Participants were 47 patients with acute SCI and 20 healthy controls. Pain adaptation, conditioned pain modulation (CPM), pain temporal summation, wind-up pain, and allodynia were measured above, at, and below the injury level, at 1.5 months after SCI. Healthy control were tested at corresponding regions. Spinal cord injury patients were monitored for CNP emergence and characteristics at 3 to 4, 6 to 7, and 24 months post-SCI. Central neuropathic pain prevalence was 57.4%. Central neuropathic pain severity, quality, and aggravating factors but not location somewhat changed over 24 months. Spinal cord injury patients who eventually developed CNP exhibited early, reduced at-level pain adaptation and CPM magnitudes than those who did not. The best predictor for CNP emergence at 3 to 4 and 7 to 8 months was at-level pain adaptation with odds ratios of 3.17 and 2.83, respectively (∼77% probability) and a cutoff value with 90% sensitivity. Allodynia and at-level CPM predicted CNP severity at 3 to 4 and 24 months, respectively. Reduced pain inhibition capacity precedes, and may lead to CNP. At-level pain adaptation is an early CNP biomarker with which individuals at risk can be identified to initiate preemptive treatment.
Implementation of an educational program to improve precepting skills
Authors: Fincham Sarah J. , Smith Todd , Purath Janet
Published: November 2019

Background:

Educating health care providers is dependent on developing high-quality clinical preceptors, yet preceptors face widespread challenges to precepting, such as time constraints and lack of formal preceptor training.

Local problem:

Our college of nursing conducted a needs assessment survey of our preceptors to better understand the barriers to and incentives for precepting. Formal preceptor training was identified as an intervention to support preceptors.

Methods:

Based on survey responses and a literature review of best practices, a preceptor training program was developed and delivered to local health care partners. Posttraining surveys were used to measure the effectiveness of the training.

Intervention:

We developed a one-hour formal preceptor training program. The main components included 1) orienting a student, 2) applying the Recorder/Reporter-Interpreter-Manager-Educator (RIME) framework for clinical evaluation, 3) One-Minute Preceptor (OMP) methodology for clinical teaching, 4) strategies for giving students feedback, and 5) communicating with the university.

Results:

Preceptor training was delivered to health care providers (N = 58) at eight clinics and one nurse practitioner (NP) professional group. Most participants (86%) had never received training in the RIME framework or OMP method (80%). The participants rated the following aspects of training as very useful or moderately useful: Orientation checklist (100%), RIME framework (96%), and OMP (100%).

Conclusions:

We found that training preceptors on evidence-based, time-efficient strategies for precepting is feasible and valuable. If continued and expanded, this training may positively affect retention and recruitment of preceptors for our university's NP students. This training may be transferable to other geographical settings.
The preoperative platelet to albumin ratio predicts the prognosis of hepatocellular carcinoma patients without portal hypertension after liver resection
Authors: Li Chuan , Peng Wei , Zhang Xiao-Yun , Wen Tian-Fu , Chen Li-Ping
Published: November 2019

There is little information concerning the predictive ability of the preoperative platelet to albumin ratio (PAR) in hepatocellular carcinoma (HCC) patients after liver resection. In the current study, we aimed to assess the prognostic power of the PAR in HCC patients without portal hypertension (PH) following liver resection.

Approximately 628 patients were included in this study. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive value of the PAR for both recurrence-free survival (RFS) and overall survival (OS). Univariate and multivariate analyses were used to identify the independent risk factors for both RFS and OS.

During the follow-up period, 361 patients experienced recurrence, and 217 patients died. ROC curve analysis suggested that the best cut-off value of the PAR for RFS was greater than 4.8. The multivariate analysis revealed that microvascular invasion (MVI), tumor size >5 cm, high aspartate aminotransferase-to-platelet count ratio index (APRI) and high PAR were four independent risk factors for both RFS and OS. Patients with a low PAR had significantly better RFS and OS than those with a high PAR.

The PAR may be a useful marker to predict the prognosis of HCC patients after liver resection. HCC patients with a high preoperative PAR had a higher recurrent risk and lower long-term survival rate than those with a low preoperative PAR.
Successful Use of Hematopoietic Stem Cell Transplantation for 2 Pediatric Cases of Glanzmann Thrombasthenia and Review of the Literature
Authors: Friend Brian D. , Roach Gavin D. , Kempert Pamela H. , Moore Theodore B.
Published: November 2019

Glanzmann thrombasthenia is a rare platelet disorder characterized by an abnormal integrin receptor on the surface of platelets that results in the failure of platelets to aggregate. Currently, curative therapy is allogeneic hematopoietic stem cell transplantation (HSCT). The authors report 2 patients with Glanzmann thrombasthenia who successfully underwent allogeneic HSCT from unrelated donors, including one using umbilical cord blood stem cells. Although both patients had evidence of engraftment, hematopoietic recovery, and normalization of platelet aggregation, they also experienced several post-transplant complications. Allogeneic HSCT carries a significant risk of morbidity and mortality that should be considered before proceeding with the transplant.
A Study of Tolerability, Satisfaction, and Cost Reduction Using a 10% Immunoglobulin Product at Higher Administration Rates
Authors: Bauer Susan , Fadeyi Michael , Chan Sheryl
Published: November 2019

Gammaplex 10% (immune globulin intravenous [human], Bio Products Laboratory, Ltd) can be administered with a 15-minute rate-escalation protocol. This analysis examined safety, patient satisfaction, and cost savings in 49 patients administered Gammaplex 10% via rapid infusion over 11 months. Fourteen patients reported 38 adverse reactions, 37 of which were deemed minor/moderate. Patient satisfaction was very good/outstanding. Infusions were estimated to be 2.4 hours shorter than previously administered intravenous immunoglobulin infusions, saving $151.61 per visit in nursing costs. Rapid infusion of Gammaplex 10% was found to be a safe option to reduce the costs of intravenous immunoglobulin treatment while maintaining patient satisfaction.
Consensus Definition of Muscle Tightness From Multidisciplinary Perspectives
Authors: Bhimani Rozina , Gaugler Joseph E. , Felts Jill
Published: November 2019

Background

Muscle tightness is a complex ailment that affects quality of life in people who experience it. Muscle tightness is not clearly defined by the National Library of Medicine, which creates confusion in clinical practice.

Objectives

The purpose of this study was to identify the attributes of muscle tightness from expert clinicians’ perception and develop a consensus definition from multidisciplinary perspectives.

Methods

This nonintervention study employed semistructured interviews using qualitative design. Twelve multidisciplinary expert clinicians participated in the study.

Results

The results indicate that limited range of motion is a key feature of muscle tightness; however, there are six other attributes: loss of function, changes in muscle texture, change in sensation, asymmetry, pain, and contracted muscle state. These attributes are largely subjective and are interrelated.

Discussion

The new definition captures the multiple domains of muscle tightness. Lack of a standardized tool is a challenge, particularly when subjective assessments require patients’ input. Development of such a tool to measure muscle tightness is advocated.
The Monocle Sign in FDG-PET
Authors: Orita Erika , Meerwein Christian M. , Pizzuto Daniele A. , Stolzmann Paul , Huellner Martin W.
Published: November 2019

We report three cases of unilateral 18F-FDG uptake in the orbicularis oculi muscle in subjects with contralateral peripheral facial nerve palsy. We argue that this asymmetric uptake pattern in fact reflects lack of metabolism on the side affected by facial nerve palsy, owing to denervation. Since the unilateral periorbital uptake resembles a monocle, we chose to call this finding the monocle sign. The monocle sign should not be confused with inflammation or tumor, but should prompt a neurological assessment for facial nerve palsy and a potential underlying disease.
Ahmed Hassan Zewail. 26 February 1946—2 August 2016
Authors: Thomas John Meurig
Published: November 2019

Ahmed Zewail will forever be remembered for three main reasons: first, he was the individual who first demonstrated that the structure and dynamics of atoms in the transition state of chemical reactions could be determined through the judicious use of ultrafast lasers, in a field that he pioneered, for which he coined, called femtochemistry; second, he transformed both gas phase electron diffraction and transmission electron microscopy by improving their temporal resolution some 10 orders of magnitude, while simultaneously retaining the spatial resolution of electron microscopy at the atomic level; and third, he was the first US Science Envoy to the Middle East (appointed by President Obama). To all who knew him, he was a warm-hearted, life-enhancing person endowed with exceptional technical virtuosity as an experimentalist and a profound thinker, whose prodigality of output was also exceptional. He exhibited remarkable skills as an enterprising fundraiser in his determination to establish the Zewail City of Science and Technology on the outskirts of his beloved Cairo. He also influenced greatly the L'Oréal–UNESCO scheme for awarding prizes to women in science.
A perceptual bias for man-made objects in humans
Authors: Hussain Ismail Ahamed Miflah , Solomon Joshua A. , Hansard Miles , Mareschal Isabelle
Published: November 2019

Ambiguous images are widely recognized as a valuable tool for probing human perception. Perceptual biases that arise when people make judgements about ambiguous images reveal their expectations about the environment. While perceptual biases in early visual processing have been well established, their existence in higher-level vision has been explored only for faces, which may be processed differently from other objects. Here we developed a new, highly versatile method of creating ambiguous hybrid images comprising two component objects belonging to distinct categories. We used these hybrids to measure perceptual biases in object classification and found that images of man-made (manufactured) objects dominated those of naturally occurring (non-man-made) ones in hybrids. This dominance generalized to a broad range of object categories, persisted when the horizontal and vertical elements that dominate man-made objects were removed and increased with the real-world size of the manufactured object. Our findings show for the first time that people have perceptual biases to see man-made objects and suggest that extended exposure to manufactured environments in our urban-living participants has changed the way that they see the world.
Aedes
vector–host olfactory interactions in sylvatic and domestic dengue transmission environments
Authors: Tchouassi David P. , Jacob Juliah W. , Ogola Edwin O. , Sang Rosemary , Torto Baldwyn
Published: November 2019

Interactions between
Aedes
(
Stegomyia
) species and non-human primate (NHP) and human hosts govern the transmission of the pathogens, dengue, zika, yellow fever and chikungunya viruses. Little is known about
Aedes
mosquito olfactory interactions with these hosts in the domestic and sylvatic cycles where these viruses circulate. Here, we explore how the different host-derived skin odours influence
Aedes
mosquito responses in these two environments. In field assays, we show that the cyclic ketone cyclohexanone is a signature cue for
Aedes
mosquitoes to detect the NHP baboon, sykes and vervet, whereas for humans, it is the unsaturated aliphatic keto-analogue 6-methyl-5-hepten-2-one (sulcatone). We find that in the sylvatic environment, CO
2
-baited traps combined with either cyclohexanone or sulcatone increased trap catches of
Aedes
mosquitoes compared to traps either baited with CO
2
alone or CO
2
combined with NHP- or human-derived crude skin odours. In the domestic environment, each of these odourants and crude human skin odours increased
Aedes aegypti
catches in CO
2
-baited traps. These results expand our knowledge on the role of host odours in the ecologies of
Aedes
mosquitoes, and the likelihood of associated spread of pathogens between primates and humans. Both cyclohexanone and sulcatone have potential practical applications as lures for monitoring
Aedes
disease vectors.
Prospective Evaluation of a Breast Cancer Risk Model Integrating Classical Risk Factors and Polygenic Risk in 15 Cohorts from Six Countries
Authors: Wilcox Amber N , Choudhury Parichoy Pal , Gao Chi , Hüsing Anika , Eriksson Mikael , Shi Min , Scott Christopher , Carter Brian D , Martin Kara , Harkness Elaine , Brook Mark N , Ahearn Thomas U , Mavaddat Nasim , Antoniou Antonis C , Chang-Claude Jenny , Simard Jacques , Jones Michael E , Orr Nick , Schoemaker Minouk J , Swerdlow Anthony J , Sampson Sarah , Newman William G , van Veen Elke M , Evans D. Gareth R , MacInnis Robert J , Giles Graham G , Southey Melissa , Milne Roger L , Gapstur Susan M , Gaudet Mia M , Winham Stacey J , Brandt Kathy , Norman Aaron , Vachon Celine M , Sandler Dale P , Weinberg Clarice R , Czene Kamila , Gabrielson Marike , Hall Per , van Gils Carla H , Khaw Kay-Tee , Barrdahl Myrto , Kaaks Rudolf , Ridker Paul M , Buring Julie E , Chasman Dan I , Easton Douglas F , Schmidt Marjanka K , Kraft Peter , Garcia-Closas Montserrat , Chatterjee Nilanjan
Published: November 2019

PURPOSE

Risk-stratified breast cancer prevention requires accurate identification of women at sufficiently different levels of risk. We conducted a comprehensive evaluation of a model integrating classical risk factors and a recently developed 313-variant polygenic risk score (PRS) to predict breast cancer risk.

METHODS

Fifteen prospective cohorts from six countries with 237,632 women (7,529 incident breast cancer patients) of European ancestry aged 19-75 years at baseline were included. Calibration of five-year risk was assessed by comparing predicted and observed proportions of cases overall and within risk categories. Risk stratification for women of European ancestry aged 50-70 years in those countries was evaluated by the proportion of women and future breast cancer cases crossing clinically-relevant risk thresholds.

RESULTS

The model integrating classical risk factors and PRS accurately predicted five-year risk. For women younger than 50 years, median (range) expected-to-observed ratio across the cohorts was 0.94 (0.72 to 1.01) overall and 0.9 (0.7 to 1.4) at the highest risk decile. For women 50 years or older, these ratios were 1.04 (0.73 to 1.31) and 1.2 (0.7 to 1.6), respectively. The proportion of women in the general population identified above the 3% five-year risk threshold (used for recommending risk-reducing medications in the US) ranged from 7.0% in Germany (∼841,000 of 12 million) to 17.7% in the US (∼5.3 of 30 million). At this threshold, 14.7% of US women were re-classified by the addition of PRS to classical risk factors, identifying 12.2% additional future breast cancer cases.

CONCLUSION

Evaluation across multiple prospective cohorts demonstrates that integrating a 313-SNP PRS into a risk model substantially improves its ability to stratify women of European ancestry for applying current breast cancer prevention guidelines.
Human regulatory T cells at the maternal-fetal interface show functional site-specific adaptation with tumor-infiltrating-like features
Authors: Wienke Judith , Brouwers Laura , van der Burg Leone , Mokry Michal , Scholman Rianne C. , Nikkels Peter G.J. , van Rijn Bas , van Wijk Femke
Published: November 2019

Objectives

Regulatory T cells (Tregs) are crucial for maintaining immune tolerance against the semi-allogeneic fetus during pregnancy. Since their functional profile at the human maternal-fetal interface is still elusive, we investigated the transcriptional profile and functional adaptation of human uterine Tregs (uTregs) during pregnancy.

Methods

Blood and uterine biopsies from the placental bed (=maternal-fetal interface) and incision site (=control), were obtained from women with uneventful pregnancies undergoing primary Caesarean section. Tregs and CD4+non-Tregs (Tconv) were isolated for transcriptomic profiling by Cel-Seq2. Results were validated on protein and single cell level by flow cytometry.

Results

Placental bed uterine Tregs (uTregs) showed elevated expression of Treg signature markers compared to blood Tregs, including FOXP3, CTLA4 and TIGIT. The uTreg transcriptional profile was indicative of late-stage effector Treg differentiation and chronic activation with high expression of immune checkpoints GITR, TNFR2, OX-40, 4-1BB, genes associated with suppressive capacity (CTLA4, HAVCR2, IL10, IL2RA, LAYN, PDCD1), activation (HLA-DR, LRRC32), and transcription factors MAF, PRDM1, BATF, and VDR. uTregs mirrored uTconv Th1 polarization, and characteristics indicating tissue-residency, including high CD69, CCR1, and CXCR6. The particular transcriptional signature of placental bed uTregs overlapped strongly with the specialized profile of human tumor-infiltrating Tregs, and, remarkably, was more pronounced at the placental bed than uterine control site.

Conclusion

uTregs at the maternal-fetal interface acquire a highly differentiated effector Treg profile similar to tumor-infiltrating Tregs, which is locally enriched compared to a distant uterine site. This introduces the novel concept of site-specific transcriptional adaptation of human Tregs within one organ.
Escape from nonsense mediated decay associates with anti-tumor immunogenicity
Authors: Litchfield Kevin , Reading James , Lim Emilia , Xu Hang , Liu Po , AL-Bakir Maise , Wong Sophia , Rowan Andrew , Funt Sam , Merghoub Taha , Lauss Martin , Svane Inge Marie , Jönsson Göran , Herrero Javier , Larkin James , Quezada Sergio A. , Hellmann Matthew D. , Turajlic Samra , Swanton Charles
Published: November 2019

Frameshift insertion/deletions (fs-indels) are an infrequent but potentially highly immunogenic mutation subtype. Although fs-indel transcripts are susceptible to degradation through the non-sense mediated decay (NMD) pathway, we hypothesise that some fs-indels escape degradation and lead to an increased abundance of tumor specific neoantigens, that are highly distinct from self. We analysed matched DNA and RNA sequencing data from TCGA, and five separate melanoma cohorts treated with immunotherapy. Using allele-specific expression analysis we show that expressed fs-indels were enriched in genomic positions predicted to escape NMD, and associated with higher protein expression, consistent with degradation escape (“NMD-escape”). Across four independent cohorts, fs-indel NMD-escape mutations were found to be significantly associated with clinical benefit to checkpoint inhibitor (CPI) therapy (Pmeta=0.0039), a stronger association than either nsSNV (Pmeta=0.073) or fs-indel (Pmeta=0.064) count. NMD-escape mutations were additionally shown to have independent predictive power in the “low-TMB” setting, and may serve as a biomarker to rescue patients judged ineligible for CPI based on overall TMB, but still with a high chance of response (low-TMB cohort: NMD-escape-positive % clinical benefit=53%, NMD-escape-negative % clinical benefit=16%, P=0.0098). Furthermore, in an adoptive cell therapy (ACT) treated cohort, NMD-escape mutation count was the most significant biomarker associated with clinical benefit (P=0.021). Analysis of functional T-cell reactivity screens from recent personalized vaccine and CPI studies shows direct evidence of fs-indel derived neoantigens eliciting patient anti-tumor immune response (n=15). We additionally observe a subset of fs-indel mutations, with highly elongated neo open reading frames, which are found to be significantly enriched for immunogenic reactivity in these patient studies (P=0.0032). Finally, consistent with the potency of NMD-escape derived neo-antigens and ongoing immune-editing, NMD-escape fs-indels appear to be under negative selective pressure in untreated TCGA cases. Given the strongly immunogenic potential, and relatively rare nature of NMD-escape fs-indels, these alterations may be attractive candidates in immunotherapy biomarker optimisation and neoantigen ACT or vaccine strategies.