bluuebunny/crossref_metadata_2025 huggingface dataset:
BATF2 prevents T-cell-mediated intestinal inflammation through regulation of the IL-23/IL-17 pathway
Authors: Kayama Hisako , Tani Haruka , Kitada Shoko , Opasawatchai Anunya , Okumura Ryu , Motooka Daisuke , Nakamura Shota , Takeda Kiyoshi
Published: February 2019

Inappropriate activation of the IL-23 signaling pathway causes chronic inflammation through the induction of immunopathological Th17 cells in several tissues including the intestine, whereas adequate Th17 responses are essential for host defense against harmful organisms. In the intestinal lamina propria, IL-23 is primarily produced by innate myeloid cells including dendritic cells (DCs) and macrophages (Mϕs). However, the molecular mechanisms underlying the regulation of IL-23 production by these cells remains poorly understood. In this study, we demonstrated that BATF2 regulates intestinal homeostasis by inhibiting IL-23-driven T-cell responses. Batf2 was highly expressed in intestinal innate myeloid subsets, such as monocytes, CD11b+ CD64+ Mϕs and CD103+ DCs. Batf2−/− mice spontaneously developed colitis and ileitis with altered microbiota composition. In this context, IL-23, but not TNF-α and IL-10, was produced in high quantities by intestinal CD11b+ CD64+ Mϕs from Batf2−/− mice compared with wild-type mice. Moreover, increased numbers of IFN-γ+, IL-17+ and IFN-γ+ IL-17+ CD4+ T cells, but not IL-10+ CD4+ T cells, accumulated in the colons and small intestines of Batf2−/− mice. In addition, RORγt-expressing innate lymphoid cells were increased in Batf2−/− mice. Batf2−/−Rag2−/− mice showed a reduction in intestinal inflammation present in Batf2−/− mice. Furthermore, the high numbers of intestinal IL-17+ and IFN-γ+ IL-17+ CD4+ T cells were markedly reduced in Batf2−/− mice when introducing Il23a deficiency, which was associated with the abrogation of intestinal inflammation. These results indicated that BATF2 in innate myeloid cells is a key molecule for the suppression of IL-23/IL-17 pathway-mediated adaptive intestinal pathology.
The Experience With Flow Diverters in the Treatment of Posterior Inferior Cerebellar Artery Aneurysms
Authors: Atallah Elias , Saad Hassan , Li Jonathan , Kumar Ayan , Tjoumakaris Stavropoula , Chalouhi Nohra , Hasan David , Zarzour Hekmat , Herial Nabeel , Gooch Michael Reid , Rosenwasser Robert H , Jabbour Pascal
Published: February 2019

BACKGROUND

The use of the pipeline embolization device (PED; Medtronic, Dublin, Ireland) in the posterior circulation has been limited and infrequently reported compared to other off-label utilizations. Posterior inferior cerebellar artery aneurysms (PICAA) constitute 1 of the least reported posterior circulation aneurysms treated with PED. No clinical studies have addressed the treatment of these aneurysms with flow diversion exclusively.

OBJECTIVE

To appraise the feasibility and the safety of PED in the treatment of PICAAs.

METHODS

Data on 12 consecutive patients, treated between 2011-2017 with PED for their PICAA, was retrospectively reviewed. To control confounding, we used multivariable logistic regression and propensity score conditioning.

RESULTS

Of 534 patients, 12 (9/12, 75% males) were identified and constituted our study population. The average aneurysm size was 8.47 mm (SD = 2.6, 3.7-14). Patients were followed-up for an average of 10.3 months (SD = 11 mo). Two of 12 (16.7%) had a prior history of subarachnoid hemorrhage. Eight of 12 (67%) of the aneurysms were saccular, 3/12 (25%) were dolichoectatic, and 1/12 (8%) was a small blister aneurysm. Eleven of 12 (92%) aneurysms were treated with 1 PED; 2/12 (16.7%) patients received combined pipeline assisted coiling. All patients had a complete occlusion, regression, and resolution of their aneurysm(s). PED deployment was neither complicated with any hemorrhagic or clinically significant thromboembolic events nor with device migration in any of our patients. Three of 12 (25%) patients had a benign intrastent stenosis. No mortality, among our 12 patients, was noted throughout the follow-up period.

CONCLUSION

PED, deployed by specialized experts, should be safe in treating PICAA. It can be contemplated as a novel alternative treatment of aneurysms located at the PICA-VA bifurcation or within the PICA.
Support, information, and integration of genetics for children with congenital lower limb deficiencies in British Columbia, Canada
Authors: Campbell Teresa , Chen Ching-Yi (Jenny) , Chhina Harpreet , Chahal Rajpreet , Cooper Anthony , Elliott Alison M
Published: February 2019

Objectives

Children and families affected by congenital limb deficiencies (CLD) require a unique level of emotional support from diagnosis through to adolescence. The following study aims to collect data on Canadian paediatric patients affected by a CLD followed at BC Children’s Hospital (BCCH), Department of Orthopaedics.

Methods

Parents of children with a CLD were asked to complete a written questionnaire examining their experiences. Qualitative and quantitative data were collected concerning parent satisfaction with patient referrals, emotional support, and knowledge of their child’s diagnosis.

Results

Twenty-five completed questionnaires were returned. Fifty per cent of the parents reported they were either very satisfied, or satisfied, with the emotional support provided by health care providers (HCPs). Twenty-five per cent of the parents were unsatisfied with the emotional support received by HCPs. Forty-eight per cent of the parents could not recall the specific name of their child’s diagnosis; 20% of the parents reported their child did not have diagnosis. All the patients in our study had received a clinical diagnosis. Twenty-eight per cent of the parents in this study were also seen in medical genetics.

Conclusions

Families require additional resources for emotional support, peer support, and referrals to support organizations. Gaps in parent knowledge regarding their child’s CLD suggest the need for formalized communication strategies for HCPs. Furthermore, patients with CLDs and their families may benefit from improved communication between orthopaedic and medical genetic services at the time of diagnosis. Integration of genetic counsellors may improve emotional supports and education for families with regards to testing and reproductive planning.
Tree Response to Herbivory Is Affected by Endogenous Rhythmic Growth and Attenuated by Cotreatment With a Mycorrhizal Fungus
Authors: Bacht Michael , Tarkka Mika T. , López Iván Fernández , Bönn Markus , Brandl Roland , Buscot François , Feldhahn Lasse , Grams Thorsten E. E. , Herrmann Sylvie , Schädler Martin
Published: February 2019

Herbivores and mycorrhizal fungi interactively influence growth, resource utilization, and plant defense responses. We studied these interactions in a tritrophic system comprising Quercus robur, the herbivore Lymantria dispar, and the ectomycorrhizal fungus Piloderma croceum under controlled laboratory conditions at the levels of gene expression and carbon and nitrogen (C/N) allocation. Taking advantage of the endogenous rhythmic growth displayed by oak, we thereby compared gene transcript abundances and resource shifts during shoot growth with those during the alternating root growth flushes. During root flush, herbivore feeding on oak leaves led to an increased expression of genes related to plant growth and enriched gene ontology terms related to cell wall, DNA replication, and defense. C/N-allocation analyses indicated an increased export of resources from aboveground plant parts to belowground. Accordingly, the expression of genes related to the transport of carbohydrates increased upon herbivore attack in leaves during the root flush stage. Inoculation with an ectomycorrhizal fungus attenuated these effects but, instead, caused an increased expression of genes related to the production of volatile organic compounds. We conclude that oak defense response against herbivory is strong in root flush at the transcriptomic level but this response is strongly inhibited by inoculation with ectomycorrhizal fungi and it is extremely weak at shoot flush.
Evaluating the Effectiveness of Survival Guides Among Student and New Nurse Practitioners
Authors: Hoffman Jenni L.
Published: February 2019

The transition between student and new nurse practitioner (NP) can be challenging. Survival guides given to student NPs may help ease the transition and make it a successful one. This study evaluates the effectiveness of survival guides in two student NP cohorts in the fall 2015 and fall 2016 semesters. Students completed a brief online survey at graduation, and three and six months after graduation. Results support the inclusion of survival guides in NP curricula as a creative way to positively support the transition from student to new NP and improve preparation for NP practice.
Evaluation of the Brief Alcohol Withdrawal Scale Protocol at an Academic Medical Center
Authors: Lindner Brian K. , Gilmore Vi T. , Kruer Rachel M. , Alvanzo Anika AH. , Chen Edward S. , Murray Paula , Niessen Timothy , Perrin Keisha , Rastegar Darius A. , Young Samantha , Jarrell Andrew S.
Published: February 2019

Objectives:

The standard of care for treatment of alcohol withdrawal is symptom-triggered dosing of benzodiazepines using a withdrawal scale. Abbreviated scales are desired for clinician efficiency. The objective of this study was to evaluate the use of the 5-item Brief Alcohol Withdrawal Scale (BAWS) protocol.

Methods:

This single-center, retrospective, observational, cohort study assessed patients ordered the BAWS protocol between August 1, 2016 and July 31, 2017. Data were collected on benzodiazepine exposure, duration of treatment, withdrawal severity, agitation, over-sedation, and delirium while being treated for alcohol withdrawal. Comparisons were made to analyze predetermined patient subgroups.

Results:

Seven hundred ninety-nine patients were initiated on the BAWS protocol. Patients received a median (IQR) of 0 (0–4) lorazepam equivalents (LEs) and were on the BAWS protocol for a median (IQR) of 44.9 (22.4–77.2) hours. Of the patients that received benzodiazepines while on the BAWS protocol, a median (IQR) of 4 (2–11) LEs were given. Seventeen (2.1%) patients had severe withdrawal. Days of agitation, over-sedation, and delirium were minimal, with the median (IQR) of 0 (0–0). Few patients received adjunctive medications for symptom management. Intensive care unit (ICU) patients had more severe withdrawal than non-ICU patients, but received the same cumulative benzodiazepine dose.

Conclusions:

Most patients on the BAWS protocol received little-to-no benzodiazepines; severe withdrawal, agitation, delirium, or over-sedation were uncommon. This is the first evaluation of the BAWS protocol on a diverse population of hospitalized patients.
Toward Understanding Cerebral Blood Flow during Cardiopulmonary Bypass
Authors: Reves J. G.
Published: February 2019

Factors and Their Influence on Regional Cerebral Blood Flow during Nonpulsatile Cardiopulmonary Bypass. By Govier AV, Reves JG, McKay RD, Karp RB, Zorn GL, Morawetz RB, Smith LR, Adams M, and Freeman AM. Ann Thorac Surg. 1984; 38:609–13. Reprinted with permission.

In this study, we examined the relationship of regional cerebral blood flow (CBF) to mean arterial pressure, systemic blood flow, partial pressure of arterial carbon dioxide (PaCO2), nasopharyngeal temperature, and hemoglobin during hypothermic nonpulsatile cardiopulmonary bypass (CPB). Regional CBF was determined by clearance of xenon 133 in 67 patients undergoing coronary bypass grafting procedures. There was a significant decrease in regional CBF (55% decrease) during CPB, with nasopharyngeal temperature and PaCO2 being the only two significant factors (p < 0.05). In a subgroup of 10 patients, variation of pump flow between 1.0 and 2.0 L/min/m2 did not significantly affect regional CBF. We conclude that cerebral autoregulation is retained during hypothermic CPB. Under the usual conditions of CPB, variations in flow and pressure are not associated with important physiologic or detrimental clinical effects.
Effects of Prophylactic Oxytocin on Bleeding Outcomes in Women Undergoing Dilation and Evacuation
Authors: Whitehouse Katherine , Tschann Mary , Soon Reni , Davis James , Micks Elizabeth , Salcedo Jennifer , Savala Michael , Kaneshiro Bliss
Published: February 2019

OBJECTIVE:

To estimate whether routine use of intravenous oxytocin decreases the frequency of interventions to control excess blood loss during dilation and evacuation (D&E).

METHODS:

In this multisite, randomized, double-blind, placebo-controlled trial, women undergoing D&E at 18–24 weeks of gestation received 30 units of oxytocin in 500 mL of intravenous fluid or 500 mL of intravenous fluid alone initiated on speculum placement. The primary outcome was the frequency of interventions to control excess bleeding. A sample size of 75 patients per group was needed to detect a 15% decrease in intervention from 20% to 5% with 80% power and two-sided alpha 0.05. Secondary outcomes included measured blood loss, complications, procedure duration, postoperative pain, and patient satisfaction.

RESULTS:

From November 2014 to February 2018, we screened 337 women and randomized 160 to receive prophylactic oxytocin (n=82) or placebo (n=78). Demographic characteristics were similar between groups. The frequency of interventions for bleeding, our primary outcome, was 7.3% in the oxytocin group vs 16.7% in the placebo group, difference of 9.4% (95% CI −21.0% to 1.9%). Interventions primarily included uterine massage and uterotonic administration. Among our secondary outcomes, median measured blood loss was lower in the oxytocin group at 152 (interquartile range 98–235) mL vs 317 (interquartile range 168–464) mL (95% CI 71.6–181.5). Frequency of hemorrhage, defined as blood loss of 500 mL or more and 1,000 mL or more, was lower in the oxytocin group at 3.7% vs 21.8%, difference of 18% (95% CI −29 to −6.9%) and 1.2% vs 10.3%, difference of 9.0% (95% CI −17 to −0.7%), respectively. Procedures were shorter in the oxytocin group at a median of 11.0 (interquartile range 8.0–14.0) vs 13.5 (interquartile range 10.0–19.0) minutes in the placebo group (95% CI 1.0–4.0). We found no differences in the frequency of nonhemorrhage complications, pain scores, or satisfaction scores between groups.

CONCLUSION:

Prophylactic use of oxytocin during D&E at 18–24 weeks of gestation did not decrease the frequency of interventions to control bleeding. However, oxytocin did decrease blood loss and frequency of hemorrhage.

CLINICAL TRIAL REGISTRATION:

ClinicalTrials.gov, www.clinicaltrials.gov, NCT02083809.
Medical Assessment and Triage of Pediatric Patients with Anorexia Nervosa in Primary Care
Authors: Homan Kendra J. , Sim Leslie A. , Crowley Susan L. , Lebow Jocelyn R. , Kransdorf Lisa N.
Published: February 2019

Objective:

To examine the medical assessment and triage of pediatric patients with anorexia nervosa (AN) initially seen in primary care.

Methods:

A retrospective cohort study was conducted for all pediatric patients with AN who had eating/weight concerns and initially identified symptoms in primary care in a single health care system between January 1, 2010, and December 31, 2016. Information on presenting concern, medical assessment/laboratory tests, clinical diagnoses, treatment recommendations, and referrals were abstracted from the medical record.

Results:

Forty-one (mean age = 13.7 years; SD = 2.2) pediatric patients with AN had eating/weight concerns and initially identified symptoms in a primary care. Overall, only 5% (n = 2/41) of patients received an AN diagnosis during the index visit; a minority were assessed for electrolyte disturbance (n = 20), electrocardiogram abnormality (n = 18), hypothermia (n = 13), binge/purge behaviors (n = 13), orthostatic hypotension (n = 2), or dehydration (n = 1), and only 56% (n = 23) received triage consistent with practice recommendations. Although 61% (n = 25) met criteria for inpatient admission, inpatient hospitalization was recommended for only 2 patients. Patients who received triage consistent with practice recommendations received AN diagnosis and treatment significantly earlier than those who did not (p < 0.01 and p = 0.001, respectively).

Conclusion:

Findings suggest that pediatric patients with AN may not be receiving medical assessment and triage per practice recommendations in the primary care setting. Understanding barriers to evidence-based care for pediatric eating disorders may inform provider education and system-wide changes to enhance outcomes in these patients.
Detection of Pathogenic Germline Variants Among Patients With Advanced Colorectal Cancer Undergoing Tumor Genomic Profiling for Precision Medicine
Authors: You Y. Nancy , Borras Ester , Chang Kyle , Price Brandee A. , Mork Maureen , Chang George J. , Rodriguez-Bigas Miguel A. , Bednarski Brian K. , Meric-Bernstam Funda , Vilar Eduardo
Published: February 2019

BACKGROUND:

Genomic profiling of colorectal cancer aims to identify actionable somatic mutations but can also discover incidental germline findings.

OBJECTIVE:

The purpose of this study was to report the detection of pathogenic germline variants that confer heritable cancer predisposition.

DESIGN:

This was a retrospective study.

SETTINGS:

The study was conducted at a tertiary-referral institution.

PATIENTS:

Between 2012 and 2015, 1000 patients with advanced cancer underwent targeted exome sequencing of a 202-gene panel. The subgroup of 151 patients with advanced colorectal cancer who underwent matched tumor-normal (blood) sequencing formed our study cohort.

INTERVENTIONS:

Germline variants in 46 genes associated with hereditary cancer predisposition were classified according to a defined algorithm based on in silico predictions of pathogenicity. Patients with presumed pathogenic variants were examined for type of mutation, as well as clinical, pedigree, and clinical genetic testing data.

MAIN OUTCOME MEASURES:

We measured detection of pathogenic germline variants.

RESULTS:

A total of 1910 distinct germline variants were observed in 151 patients. After filtering, 15 pathogenic germline variants (9.9%) were found in 15 patients, arising from 9 genes of varying penetrance for colorectal cancer (APC (n = 2; 13%), ATM (n = 1; 6%), BRCA1 (n = 2; 13%), CDH1 (n = 2; 13%), CHEK2 (n = 4; 27%), MSH2 (n = 1; 7%), MSH6 (n = 1; 7%), NF2 (n = 1; 7%), and TP53 (n = 1; 7%)). Patients with pathogenic variants were diagnosed at a younger age than those without (median, 45 vs 52 y; p = 0.03). Of the 15 patients, 7 patients (46.7%) with variants in low/moderate- penetrant genes for colorectal cancer would likely have not been tested based on clinical and pedigree criteria, where 2 harbored clinically actionable variants (CDH1 and NF2, 28.5% of 7).

LIMITATIONS:

This study was limited by its small sample size and advanced-stage patients.

CONCLUSIONS:

Tumor-normal sequencing can incidentally discover clinically unsuspected germline variants that confer cancer predisposition in 9.9% of patients with advanced colorectal cancer. Precision medicine should integrate clinical cancer genetics to inform and interpret the actionability of germline variants and to provide follow-up care to mutation carriers. See Video Abstract at http://links.lww.com/DCR/A906.
Recent Advances in Fertility Preservation and Counseling for Reproductive-Aged Women with Colorectal Cancer: A Systematic Review
Authors: Shandley Lisa M. , McKenzie Laurie J.
Published: February 2019

BACKGROUND:

The incidence of colorectal cancer among reproductive-aged women is increasing. Concerns regarding future fertility are secondary only to concerns regarding survival and may significantly impact quality of life among reproductive-aged female cancer survivors. Fertility preservation counseling reduces long-term regret and dissatisfaction among cancer survivors. Health care providers counseling patients with colorectal cancer must understand the impact of cancer treatment on future reproductive potential.

OBJECTIVE:

This review aims to examine the effects that colorectal cancer treatments have on female fertility and summarize existing and emerging options for fertility preservation.

DATA SOURCES:

EMBASE, National Library of Medicine (MEDLINE)/PubMed, Cochrane Review Library were the data sources for this review.

STUDY SELECTION:

A systematic literature review was performed using exploded MeSH terms to identify articles examining the effect of surgery, chemotherapy, and radiation, as well as fertility preservation options for colorectal cancer on female fertility. Relevant studies were included.

MAIN OUTCOME MEASURES:

The primary outcome was the effect of colorectal cancer treatment on fertility.

RESULTS:

There are limited data regarding the impact of colorectal surgery on fertility. The gonadotoxic effects of chemotherapy on reproductive capacity depend on age at the time of chemotherapy administration, cumulative chemotherapy, radiation dose, type of agent, and baseline fertility status. Chemotherapy-induced risks for colorectal cancers are considered low to moderate, whereas pelvic radiation with a dose of 45 to 50 Gray induces premature menopause in greater than 90% of patients. Ovarian transposition may reduce but not eliminate the damaging effect of radiation on the ovaries. Embryo and oocyte cryopreservation are considered standard of care for women desiring fertility preservation, with oocyte cryopreservation no longer being considered experimental. Ovarian tissue cryopreservation remains experimental but may be an option for select patients. The use of gonadotropin-releasing hormone agonists remains controversial and has not been definitively shown to preserve fertility.

LIMITATIONS:

The limitations of this review are the lack of randomized controlled trials and high-quality studies, as well as the small sample sizes and the use of surrogate fertility markers.

CONCLUSION:

Reproductive-aged women with colorectal cancer benefit from fertility preservation counseling before the initiation of cancer treatment.
Intravenous Drug Use–Related Complications of the Hand and Upper Extremity
Authors: Pong Taylor M. , Oflazoglu Kamilcan , Helliwell Lydia A. , Chen Neal C. , Eberlin Kyle R.
Published: February 2019

Background:

In the last decade, there has been an increase in intravenous drug use (IVDU) and associated medical problems. Users commonly inject into their upper extremities, which can result in infection and other sequelae in this area. The goal of this study was to compare demographics and treatment for upper extremity infections between intravenous drug users and non-intravenous drug users over the past 10 years at 1 level I emergency department (ED).

Methods:

This was a retrospective case–control study. All patients presenting to the ED with an upper extremity infection in 2005, 2010, and 2015 were identified using the ninth revision of the International Statistical Classification of Diseases and Related Health Problems and Current Procedural Terminology codes. Patients with an IVDU-related infection were identified by manually reviewing the medical record and matched with patients with non-IVDU–related infection on demographics. Patient-related factors, infection specifics, and treatment parameters were compared in both groups.

Results:

The number of IVDU-related upper extremity infection cases presenting to the ED increased 126% over the 10-year period (65 cases in 2005, 109 cases in 2010, and 147 cases in 2015). The location of infection in the IVDU group was more likely to be in a typical injection site (forearm, P < 0.001; wrist, P = 0.002), and IVDU patients had 33% more hospital admissions and stayed in the hospital longer (3 days versus 0.59; P < 0.001). These patients also were more likely to have a computed tomography scan (P < 0.001) and have Methicillin-resistant Staphylococcus aureus (MRSA) or Methicillin-sensitive Staphylococcus aureus (MSSA) (P = 0.009).

Conclusions:

Over a 10-year period, the number of IVDU-related upper extremity infections more than doubled, with more severe infections that underwent advanced imaging and intensive treatment.
Low-Fidelity Spectral Analysis Utilizing a Binomial Discriminator for Weak-Source Detection Decisions
Authors: Lindsay J. , Meengs M. , Fischer J. C. , Brogan J. , Brandl A.
Published: February 2019

The identification of radiological sources by analysis of a gamma spectrum usually relies on the location of the set of radionuclide-specific electron energies corresponding to the incident photons interacting by photoelectric absorption in the detection medium. The challenge in low-level detection applications is the identification of these “photopeaks” above the background counts registered in the detector from the natural radiation environment and system noise. For source detection decisions, regions of the gamma spectrum other than at the photopeak energies may provide additional information about the presence of a source and allow for a higher rate of correct identification of a weak source. A statistical algorithm utilizing low-fidelity spectral data partitioned into three distinct regions and employing a binomial discriminator was tested in a laboratory setting against the traditional approach of source identification by exceeding a decision threshold within the photopeak region of interest. For an unshielded 137Cs source with no significant scatter between the source and the detector, the traditional peak identification method performs as well or better than most algorithm settings for various source strengths. However, an algorithm which also includes information in the energy range of Compton scattered photons provides improved detection capabilities for shielded weak sources. Such algorithms, including higher-fidelity developments, could be deployed to improve current tools for the search for orphan radiological sources and in the characterization of low-level environmental contamination.
One-Hour High Sensitivity Troponin Testing: A Safe and Effective Triage Tool for the Emergency Department
Authors: Shabbir Asad , Fan Lampson , Fraser Gregory , Cassar Mark Philip , Swinburn Jon
Published: February 2019

The latest European Society of Cardiology guideline on the management of acute coronary syndromes without persistent ST-elevation stipulates several acceptable pathways through which patients presenting with chest pain can be assessed for unstable coronary disease. This article reviews the data behind the “rule-in and rule-out algorithm,” which can exclude acute myocardial infarction within 1 hour of presentation through the use of fifth generation high-sensitivity troponin assays.
Double-Line Reflection Pattern as a Simple Method to Determine Graft Orientation of Descemet Membrane Endothelial Keratoplasty
Authors: Berrospi Rubén D. , Galvis Virgilio , Bhogal Maninder , Tello Alejandro
Published: February 2019

Purpose:

To describe a simple finding, consisting of a double-line reflection from the graft inside the anterior chamber, that can be used to determine the correct donor tissue orientation in Descemet membrane endothelial keratoplasty: which we would like to call Berrospi's sign.

Methods:

Evaluation of the presence of linear reflection from the donor tissue when implanted in the anterior chamber.

Results:

A distinctive double-line reflection pattern was identified when careful observation of the curls of the scroll was performed under the surgical microscope, which was a confirmatory sign that the graft was in the correct position.

Conclusions:

This method of confirming correct graft orientation requires no additional procedures, equipment, or manipulation of the donor tissue and can be used in conjunction with other marking methods already described.
Rapid Influenza Testing in Infants and Children Younger than 6 Years in Primary Care
Authors: van Esso Diego L. , Valente Ana Marta , Vilà Monica , Casanovas Josep M. , de Quixano Marta , Rodrigo Carlos , Anton Andres , Pumarola Tomas
Published: February 2019

Influenza is often misdiagnosed in children because of the low sensitivity of clinical diagnosis because of nonspecific signs and symptoms. This can be overcome by using digital immunoassays or rapid molecular diagnostic tests with adequate sensitivity and specificity. When using these tests at the patient care site, antibiotic consumption and number of healthcare consultations were reduced.
Assessing Toddlers and Preschool Children Using the Checklist for Autism Spectrum Disorder
Authors: Mayes Susan D.
Published: February 2019

Brief, clinically feasible instruments are needed to assess autism spectrum disorder (ASD) in toddlers and preschoolers so that children can access early evidence-based intervention. Study purposes were to (1) compare scores on the 30-item Checklist for Autism Spectrum Disorder (CASD) and 6-item CASD-Short Form (CASD-SF) for toddlers and preschoolers and older children with ASD to determine whether scores differed by age and (2) establish sensitivity and specificity for the CASD and CASD-SF for toddlers and preschoolers. Samples were 1,266 children with ASD 1–17 years of age, 97 toddlers and preschoolers with diagnoses other than ASD, and 65 typical toddlers and preschoolers. CASD and CASD-SF scores were somewhat higher for toddlers and preschoolers than for older children with ASD, indicating that young children were not at increased risk for being missed. All toddlers and preschoolers with ASD had CASD scores in the autism range, and 99.7% had CASD-SF scores in the autism range. CASD and CASD-SF scores correctly identified 100% and 96.9% of typical toddlers and preschoolers and 100% and 96.2% of toddlers and preschoolers with disorders other than ASD, respectively, as not having ASD. Results demonstrate high CASD and CASD-SF sensitivity and specificity for toddlers and preschoolers.
Towards a neurobiological understanding of pain in neurofibromatosis type 1: mechanisms and implications for treatment
Authors: Bellampalli Shreya S. , Khanna Rajesh
Published: February 2019

Neurofibromatosis type 1 (NF1) is the most common of a group of rare diseases known by the term, “Neurofibromatosis,” affecting 1 in 3000 to 4000 people. NF1 patients present with, among other disease complications, café au lait patches, skin fold freckling, Lisch nodules, orthopedic complications, cutaneous neurofibromas, malignant peripheral nerve sheath tumors, cognitive impairment, and chronic pain. Although NF1 patients inevitably express pain as a debilitating symptom of the disease, not much is known about its manifestation in the NF1 disease, with most current information coming from sporadic case reports. Although these reports indicate the existence of pain, the molecular signaling underlying this symptom remains underexplored, and thus, we include a synopsis of the literature surrounding NF1 pain studies in 3 animal models: mouse, rat, and miniswine. We also highlight unexplored areas of NF1 pain research. As therapy for NF1 pain remains in various clinical and preclinical stages, we present current treatments available for patients and highlight the importance of future therapeutic development. Equally important, NF1 pain is accompanied by psychological complications in comorbidities with sleep, gastrointestinal complications, and overall quality of life, lending to the importance of investigation into this understudied phenomenon of NF1. In this review, we dissect the presence of pain in NF1 in terms of psychological implication, anatomical presence, and discuss mechanisms underlying the onset and potentiation of NF1 pain to evaluate current therapies and propose implications for treatment of this severely understudied, but prevalent symptom of this rare disease.
Insight into the genetic architecture of back pain and its risk factors from a study of 509,000 individuals
Authors: Freidin Maxim B. , Tsepilov Yakov A. , Palmer Melody , Karssen Lennart C. ,   CHARGE Musculoskeletal Working Group, Suri Pradeep , Aulchenko Yurii S. , Williams Frances M.K.
Published: February 2019

Back pain (BP) is a common condition of major social importance and poorly understood pathogenesis. Combining data from the UK Biobank and CHARGE consortium cohorts allowed us to perform a very large genome-wide association study (total N = 509,070) and examine the genetic correlation and pleiotropy between BP and its clinical and psychosocial risk factors. We identified and replicated 3 BP-associated loci, including one novel region implicating SPOCK2/CHST3 genes. We provide evidence for pleiotropic effects of genetic factors underlying BP, height, and intervertebral disk problems. We also identified independent genetic correlations between BP and depression symptoms, neuroticism, sleep disturbance, overweight, and smoking. A significant enrichment for genes involved in the central nervous system and skeletal tissue development was observed. The study of pleiotropy and genetic correlations, supported by the pathway analysis, suggests at least 2 strong molecular axes of BP genesis, one related to structural/anatomical factors such as intervertebral disk problems and anthropometrics, and another related to the psychological component of pain perception and pain processing. These findings corroborate with the current biopsychosocial model as a paradigm for BP. Overall, the results demonstrate BP to have an extremely complex genetic architecture that overlaps with the genetic predisposition to its biopsychosocial risk factors. The work sheds light on pathways of relevance in the prevention and management of low BP.
Effects of Cytochrome P450 2C19 Genetic Polymorphisms on Responses to Escitalopram and Levels of Brain-Derived Neurotrophic Factor in Patients With Panic Disorder
Authors: He Qianqian , Mei Yan , Liu Yuanyuan , Yuan Zhuo , Zhang Jian , Yan Hong , Shen Li , Zhang Yong
Published: February 2019

Purpose/Background

The purpose of this study was to examine the relationships between ytochrome P450 family 2 subfamily C member 19 (CYP2C19) polymorphisms, brain-derived neurotrophic factor (BDNF) plasma levels, and treatment responses to escitalopram in Chinese patients with panic disorder (PD).

Methods/Procedures

Ninety patients with PD were administered the Panic Disorder Severity Scale–Chinese Version (PDSS-CV) and Hamilton Anxiety Scale (HAMA-14) from baseline to 8 weeks. Escitalopram treatment (10 mg/d) was administered for 8 consecutive weeks. Three CYP2C19 metabolizers, including extensive metabolizers, intermediate metabolizers, and poor metabolizers (PMs), and 5 CYP2C19 genotypes were detected by polymerase chain reaction–genotyping microarray analysis. Baseline plasma BDNF levels were tested using human BDNF enzyme-linked immunosorbent assay kits.

Findings/Results

Our findings showed no significant differences in demographic data, baseline PDSS-CV scores, or HAMA-14 scores between the 3 CYP2C19 metabolizer groups (P's > 0.05). Repeated-measures analysis showed a significant reduction in PDSS-CV (F = 221.49, df = 3, P < 0.001) and HAMA-14 (F = 260.47, df = 3, P < 0.001) scores over 8 weeks in PD patients. In addition, patients with PMs had a greater reduction in HAMA-14 scores (F = 2.14, P = 0.049) than did those with extensive metabolizers and intermediate metabolizers. Moreover, our findings showed that patients with *2/*2 genotypes had a greater reduction in PDSS-CV scores than did those with other genotypes (F = 2.14, df = 12, P = 0.015).

Implications/Conclusions

Our study provides preliminary evidence of the effects of CYP2C19 PMs on treatment responses to escitalopram in Chinese PD patients, but no significant correlation between treatment responses and BDNF levels was found.
Demonstrating advanced practice provider value: Implementing a new advanced practice provider billing algorithm
Authors: Brooks Paula B. , Fulton Megan E.
Published: February 2019

Background:

Rapid changes in health care are driving the adjustment of work flow by which providers serve patients in team-based care. Specifically, there is a need to develop more effective and efficient utilization with accurate attribution of advanced practice providers' (APPs) productivity.

Local Problem:

The Directors of the APP-Best Practice Center conducted assessments of each clinical area at MUSC Health, a large academic medical center. A knowledge gap was identified, not only regarding billing practices of the APPs (nurse practitioners/physician assistants) but also in the utilization of APPs to practice to the fullest extent of their license, education, and experience.

Methods:

By substantiating APPs' contribution margin through the process of implementing a new standardized APP billing algorithm, a change in practice was accepted by senior leadership and a new APP billing algorithm was built while following updated practice laws, compliance/legal standards, and hospital bylaws/regulations.

Interventions:

A new billing algorithm was implemented on July 1, 2017, and outcomes were evaluated 12 months after implementation.

Results:

This project uncovered the work already performed by APPs while increasing relative value units, collections, and overall patient encounters by the APP/physician team. Findings suggest improved utilization and appropriate attribution of productivity.

Conclusions:

With the APP work force growing, the implementation of electronic medical record systems, and today's health care financial constraints, it is imperative that health care systems standardize their billing practices. The APP billing algorithm is a critical tool that will help to meet this demand.
Direct Interactions With Cancer-Associated Fibroblasts Lead to Enhanced Pancreatic Cancer Stem Cell Function
Authors: Begum Asma , McMillan Ross H. , Chang Yu-Tai , Penchev Vesselin R. , Rajeshkumar N.V. , Maitra Anirban , Goggins Michael G. , Eshelman James R. , Wolfgang Christopher L. , Rasheed Zeshaan A. , Matsui William
Published: February 2019

Objective

Cancer-associated fibroblasts (CAFs) play an important role in the progression of pancreatic ductal adenocarcinoma (PDAC) by promoting tumor cell migration and drug resistance. We determined the impact of CAFs on PDAC cancer stem cells (CSCs).

Methods

Fibroblast cell lines from patients' tumors were cocultured with PDAC cells and examined for clonogenic growth and self-renewal using colony-forming assays and migration in vitro. Changes in the frequency of CSCs was determined by flow cytometry. The effect of integrin–focal adhesion kinase (FAK) signaling on CAF-mediated clonogenic growth was evaluated using short hairpin RNAs against β1 integrin and FAK as well as a small-molecule FAK inhibitor.

Results

Cancer-associated fibroblasts enhanced PDAC clonogenic growth, self-renewal, and migration that was associated with an increase in the frequency of CSCs. These fibroblast cells were activated by PDAC cells and increased collagen synthesis resulting in FAK activation in PDAC cells. Knockdown of β1-integrin and FAK or the inhibition of FAK kinase activity in PDAC cells abrogated the impact of CAFs on clonogenic growth.

Conclusion

Therefore, CAFs enhance PDAC clonogenic growth, self-renewal, and the frequency of CSCs through type I collagen production that enhances integrin-FAK signaling in PDAC cells.
Association of Pancreatic Steatosis With Chronic Pancreatitis, Obesity, and Type 2 Diabetes Mellitus
Authors: Tirkes Temel , Jeon Christie Y. , Li Liang , Joon Aron Y. , Seltman Ted A. , Sankar Meghana , Persohn Scott A. , Territo Paul R.
Published: February 2019

Objective

The aim of this study was to determine the association of the pancreatic steatosis with obesity, chronic pancreatitis (CP), and type 2 diabetes mellitus.

Methods

Patients (n = 118) were retrospectively identified and categorized into no CP (n = 60), mild (n = 21), moderate (n = 27), and severe CP (n = 10) groups based on clinical history and magnetic resonance cholangiopancreatography using the Cambridge classification as the diagnostic standard. Visceral and subcutaneous compartments were manually segmented, and fat tissue was quantitatively measured on axial magnetic resonance imaging.

Results

Pancreatic fat fraction showed a direct correlation with fat within the visceral compartment (r = 0.54). Patients with CP showed higher visceral fat (P = 0.01) and pancreatic fat fraction (P < 0.001): mild, 24%; moderate, 23%; severe CP, 21%; no CP group, 15%. Patients with type 2 diabetes mellitus showed higher pancreatic steatosis (P = 0.03) and higher visceral (P = 0.007) and subcutaneous fat (P = 0.004). Interobserver variability of measuring fat by magnetic resonance imaging was excellent (r ≥ 0.90–0.99).

Conclusions

Increased visceral adipose tissue has a moderate direct correlation with pancreatic fat fraction. Chronic pancreatitis is associated with higher pancreatic fat fraction and visceral fat. Type 2 diabetes mellitus is associated with higher pancreatic fat fraction and visceral and subcutaneous adiposity.
Prediction of Recurrence With KRAS Mutational Burden Using Ultrasensitive Digital Polymerase Chain Reaction of Radial Resection Margin of Resected Pancreatic Ductal Adenocarcinoma
Authors: Kim Sung Joo , Kim Mi-Ju , Han Ji-Soo , Sung You-Na , An Soyeon , Lee Jae Hoon , Song Ki Byung , Hwang Dae Wook , Lee Sang Soo , Cho HyungJun , Kim Song Cheol , Eshleman James R. , Hong Seung-Mo
Published: February 2019

Objective

Although complete surgical resection is the only curative method for pancreatic cancer, the radial resection margins of pylorus-preserving pancreaticoduodenectomy specimens might be underevaluated.

Methods

KRAS mutation was assessed with droplet digital polymerase chain reaction on cells collected from the radial resection margins of 81 patients, and the results were compared with those of conventional pathologic resection margin (pRM) evaluation.

Results

KRAS mutation was detected in 76 patients (94%), and molecular resection margin (mRM) positivity defined by a KRAS mutation rate of 4.19% or greater was observed in 18 patients (22%). Patients with mRM-positive had significantly worse recurrence-free survival (RFS) than those with mRM-negative in entire groups (P = 0.008) and in subgroups without chemotherapy or radiation therapy (all, P < 0.001). When combined pRMs-mRMs were evaluated, patients with combined pRM-mRM–positive (either pRM- or mRM-positive) had significantly worse RFS than those with combined resection margin–negative (both pRM and mRM negative) by univariate (P = 0.002) and multivariate (P = 0.03) analyses.

Conclusions

KRAS mutational analysis with ultrasensitive droplet digital polymerase chain reaction of the radial resection margin in pancreatic cancer patients who underwent pylorus-preserving pancreaticoduodenectomy can provide more accurate information on RFS by using alone or in combination with conventional pRM evaluation, especially in patients without chemotherapy or radiation therapy.
Performance of DAXX Immunohistochemistry as a Screen for DAXX Mutations in Pancreatic Neuroendocrine Tumors
Authors: Hechtman Jaclyn F. , Klimstra David S. , Nanjangud Gouri , Frosina Denise , Shia Jinru , Jungbluth Achim A.
Published: February 2019

Objectives

DAXX immunohistochemistry (IHC) is often used as a surrogate for sequencing. We aimed to elucidate the sensitivity of IHC for DAXX mutation.

Methods

All pancreatic neuroendocrine tumors (PanNETs) with DAXX mutations detected by sequencing and a subset of DAXX wild-type PanNETs were analyzed for DAXX expression by IHC.

Results

Of 154 PanNETs with MSK-IMPACT testing, 36 (30%) harbored DAXX mutations. DAXX mutations were associated with TSC2 mutations (46% vs 10%, P < 0.0001), tended to co-occur with MEN1 mutations (63% vs 49%, P = 0.11), and tended to be mutually exclusive with ATRX mutations (11% vs 25%, P = 0.053). Of 27 available DAXX mutant PanNETs, 23 lost DAXX expression (85.2%). All 4 DAXX mutants with retained expression harbored DAXX mutations within the SUMO-interacting motif of the last exon. Telomere-specific fluorescence in situ hybridization demonstrated alternative lengthening of telomeres in all 4 cases. Of 20 PanNETs with wild-type DAXX, 19 retained DAXX IHC expression (95%).

Conclusions

The sensitivity and specificity of IHC for DAXX mutation are 85% and 95%, respectively. Last exon DAXX mutant PanNETs often show alternative lengthening of telomeres despite retained DAXX expression, likely due to escape of nonmediated decay.
Serum Serine Peptidase Inhibitor Kazal-Type 1, Trypsinogens 1 to 3, and Complex of Trypsin 2 and α1-Antitrypsin in the Diagnosis of Severe Acute Pancreatitis
Authors: Rainio Mia , Lindström Outi , Penttilä Anne , Itkonen Outi , Kemppainen Esko , Stenman Ulf-Håkan , Kylänpää Leena
Published: February 2019

Objectives

We explored prediction of severe acute pancreatitis (AP) and development of organ dysfunction (OD).

Methods

Serum concentrations of serine peptidase inhibitor Kazal type 1 (SPINK1), trypsinogen 1, trypsinogen 2, and trypsinogen 3, complex between trypsin 2 and α1-antitrypsin, serum C-reactive protein, creatinine, and pancreatic amylase were measured in 239 AP patients with disease onset within 72 hours.

Results

SPINK1 distinguished most accurately patients who later developed severe AP. The area under the receiver operating characteristic curve for SPINK1 was 0.742, followed by trypsinogen 2 (0.726), complex between trypsin 2 and α1-antitrypsin (0.657), creatinine (0.656), trypsinogen 1 (0.652), trypsinogen 3 (0.557), and C-reactive protein (0.499). With a cutoff of 166 μg/L, SPINK1 had a specificity of 93%, a sensitivity of 48%, and diagnostic odds ratio of 11.52. In multivariate logistic regression analysis, only SPINK1 was an independent predictor of severe AP among patients presenting without OD on admission (P < 0.001).

Conclusions

Plasma levels of the biomarkers and creatinine correlated with the severity of AP and development of OD. In patients presenting without OD at admission, SPINK1 was an independent marker for later development of severe AP.
Mean Corpuscular Volume to White Blood Cell Ratio for Thiopurine Monitoring in Pediatric Inflammatory Bowel Disease
Authors: Kandavel Prashanthi , Eder Sally J. , Newman Noah E. , Waljee Akbar K. , Whitfield Emily P. , Adler Jeremy
Published: February 2019

Objectives:

Thiopurines, commonly used to treat inflammatory bowel disease, cause lymphopenia and red blood cell macrocytosis, requiring therapeutic monitoring. Mean corpuscular volume/white blood cell (MCV/WBC) ratio has been proposed as a surrogate for therapeutic monitoring. Our aim was to investigate MCV/WBC ratio for assessing clinical response to thiopurines among pediatric patients with inflammatory bowel disease.

Methods:

We performed a retrospective cross‐sectional study at a tertiary care center using laboratory results and standardized physician global assessments (PGA) among pediatric patients taking thiopurines. Erythrocyte sedimentation rate (ESR), C‐reactive protein (CRP), fecal calprotectin, and 6‐thioguanine nucleotides were assessed when available. The primary outcome was association between MCV/WBC ratio and clinical remission assessed by ESR, CRP, calprotectin, or PGA. We also used a composite outcome requiring all available data to be normal. Analyses were limited to 1 occurrence per patient, >60 days after starting thiopurine, and comparators were required to be within 14 days of one another.

Results:

A total of 471 patients met inclusion criteria. MCV/WBC ratio poorly predicted quiescent disease as defined by PGA (area under receiver operating characteristic curve [AuROC] 0.55, 95% confidence interval [CI] 0.43–0.66). MCV/WBC ratio better predicted quiescent disease defined as normal CRP (AuROC 0.64, 95% CI 0.58–0.70) or normal ESR (AuROC 0.59, 95% CI 0.52–0.66). When the composite outcome measure was used, MCV/WBC ratio had an AuROC of 0.65 (95% CI 0.59–0.70), indicating it is reasonably accurate in discriminating between clinical remission and active disease.

Conclusions:

MCV/WBC ratio is a noninferior, easy, and low‐cost alternative to thiopurine metabolite monitoring.