bluuebunny/crossref_metadata_2025 huggingface dataset:
Reducing Surgical Site Infections in Spine Tumor Surgery
Authors: Mesfin Addisu , Baldwin Avionna , Bernstein David N. , Emanski Eric , Molinari Robert , Menga Emmanuel , Rubery Paul T.
Published: July 2019

Study Design.

Case control series.

Objective.

The aim of this study was to evaluate and compare the effectiveness of methods to decrease surgical site infections (SSIs) following spine tumor surgery.

Summary of Background Data.

With the aging population of the United States, the prevalence of cancer and associated metastatic spine disease is increasing. The most common complication of spine tumor surgery is SSI.

Methods.

This a single-institution case-control series of patients undergoing spine tumor surgery from June 2003 to October 2018. Patients were grouped into the following groups: Betadine irrigation and intrawound vancomycin powder (BIVP), intrawound vancomycin powder only (IVP), and patients receiving neither (NONE). The primary outcome was SSIs/wound complications.

Results.

One hundred fifty-one spine tumor patients undergoing 174 procedures meeting our inclusion criteria were identified. The BIVP group had 60 patients (73 procedures); the IVP group had 46 patients (47 procedures); and the NONE group had 45 patients (54 procedures). The overall infection rate was 8.6% of all procedures (15/174) and 9.9% (15/151) of all patients. Bivariate analysis comparing patients with and without infections noted the patients with SSIs had significantly higher rates of preoperative radiation treatment (53.3% in infection group vs. 25.5% in noninfection group), P = 0.02. Patients undergoing procedures in the BIVP group had a significantly lower rate of infections (2.7%) than the patients in the IVP (12.8%) and NONE (13%) groups, P = 0.04. Stepwise regression analysis was used to evaluate further factors associated with SSIs. Elevated BMI was significantly associated with SSIs in the model [P = 0.02, odds ratio (OR) 1.14]. BIVP was also protective against infections as compared to the IVP and NONE groups, P = 0.02, OR 0.02.

Conclusion.

BIVP led to a significant decrease in SSI rates following spine tumor surgery. Administration of BIVP is not time consuming and decreased SSI rates.

Level of Evidence: 3
Indirect Decompression on MRI Chronologically Progresses After Immediate Postlateral Lumbar Interbody Fusion
Authors: Nakashima Hiroaki , Kanemura Tokumi , Satake Kotaro , Ishikawa Yoshimoto , Ouchida Jun , Segi Naoki , Yamaguchi Hidetoshi , Imagama Shiro
Published: July 2019

Mini

On magnetic resonance imaging, indirect decompression using lateral lumbar interbody fusion and posterior fixation was confirmed immediately after surgery and also continuously progressed after surgery, particularly during the first 6 months. Thecal sac enlargement was also confirmed, and is suspected to be caused by the atrophy of the ligamentum flavum and the disc.

Study Design.

A prospective cohort study.

Objective.

The aim of this study was to investigate radiographical changes related to indirect decompression using lateral lumbar interbody fusion (LLIF) with posterior fixation.

Summary of Background Data.

Indirect lumbar decompression via LLIF is used to treat degenerative lumbar diseases requiring neural decompression. Although evidence suggests that thecal sac enlargement follows shortly after surgery, few studies have described the postoperative changes on MRIs.

Methods.

This study involved 102 patients who underwent indirect decompression at 136 levels, with LLIF and posterior fixation. Magnetic resonance imaging (MRIs) were collected preoperatively and several times postoperatively (over a 2-year period starting immediately after surgery). We then quantified the cross-sectional areas of the thecal sac and ligamentum flavum, as well as the anteroposterior diameter of disc bulging, and qualitatively assessed lumbar spinal stenosis according to a modified version of Schizas’ classification [Grades A (mild) to C (severe)]. The Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) was used for the assessment of the clinical symptoms.

Results.

All changes were observable immediately after surgery, progressed over time, and were significantly different statistically at 2 years after surgery. The thecal sac was significantly larger (189% of preoperative; P < 0.0001), while the ligamentum flavum and disc bulge were significantly smaller [58.9% and 67.3% of preoperative (P < 0.001), respectively]. The number of patients with grade C (severe) lumbar stenosis also dropped significantly (preoperative, 17.6%; 2 years postoperative, 0%). There were no significant differences in JOABPEQ results at 6 months, 1 year, and 2 years postsurgery.

Conclusion.

Indirect decompression produces immediate positive results that continue to improve over time. The cross-sectional area of the thecal sac doubled by 2 years after surgery, and the ligamentum flavum cross-sectional area and disc bulging both shrank significantly. At the same time, however, postoperative radiographical improvements do not appear to correlate with clinical symptoms.

Level of Evidence: 3
Surgical Management and Adjuvant Therapy for Patients With Neurological Deficits From Vertebral Hemangiomas
Authors: Piper Keaton , Zou Liling , Li Dongmei , Underberg Daniel , Towner James , Chowdhry Amit K. , Li Yan Michael
Published: July 2019

Study Design.

Meta-analysis.

Objective.

To understand the benefits and limitations of surgical management and adjuvant therapies for patients presenting with neurological deficits from vertebral hemangiomas (VH).

Summary of Background Data.

VH is the most common benign spine tumor but rarely causes symptoms. Patients with back pain alone are treated with conservative management (kyphoplasty and radiation therapy), while those with neurological deficits require complex multi-modal treatment plans.

Methods.

A PubMed literature search for “symptomatic vertebral hemangioma with spinal cord compression” identified 47 articles. From these articles and their references, 19 observational studies on patients who underwent surgery for VH met inclusion criteria. Meta-analyses were performed comparing outcomes of the surgical and adjuvant therapies using Stata13 software. For those with insufficient data for meta-analyses, descriptive analyses of variables were completed.

Results.

One hundred ninety seven surgical cases of VH with neurologic deficits were identified. Surgery provided a complete remission of symptoms in 84% of patients, however 18% of patients had recurrence of hemangioma. Adjuvant interventions included radiation, embolization, and kyphoplasty. Radiation therapy (XRT) was associated with a lower recurrence rate and an increase in minor transient adverse effects. Preoperative embolization performed in 98 patients was associated with improved symptoms, reduced complications, lower recurrence rate, less blood loss, and higher incidence of pathologic vertebral fractures. Meta-analyses did not yield statistically significant results, likely due to the heterogeneity amongst the studies and small sample sizes, but the results compiled together provide insight on potential benefits of preoperative embolization for symptomatic relief and reduced risk of recurrence with XRT that deserves further study.

Conclusion.

For patients with neurologic deficits from spinal cord or nerve root compression, surgery provides improvement in symptoms. Recurrence of VH and symptoms refractory to surgery can be further reduced by adjuvant therapies such as embolization, kyphoplasty, and radiation with some unique risks to each therapy.

Level of Evidence: 2
Medication use and climacteric syndrome: a cross-sectional population-based study
Authors: de Moraes Anna Valéria Gueldini , Costa-Paiva Lúcia , Lui-Filho Jeffrey Frederico , Pedro Adriana Orcesi
Published: July 2019

Objective:

The aim of this study was to evaluate medication use during the climacteric period and assess its association with sociodemographic factors, morbidities, and climacteric symptoms.

Methods:

Secondary analysis of data from a previous exploratory cross-sectional population-based study, conducted with 749 women (45-60 y), with the help of home interviews. Associations between medication use and climacteric symptoms were analyzed, and their correlations with other variables were made. Univariate analysis was made using the χ2 test, followed by Bonferroni correction (multiple comparison method). Values were adjusted for age using the polytomic logistic multivariate regression analysis. Using Poisson regression analysis, simple and multiple, we identified the main factors for medication use, with forward stepwise variable selection criteria (95% CI).

Results:

The mean age was 52.5 years and menopause occurred at 46.5 years (mean). The overall prevalence of medication use was 68.8%. The use of exclusive medications for relieving climacteric symptoms was associated with the absence of diseases (prevalence ratio [PR] = 8.2; 95% CI = 3.5-18.9; P<0.001) and menopause onset between 40 and 44 years (PR = 4.9; 95% CI = 2.0-11.9; P<0.001). Polypharmacy was associated with the highest number of diseases (PR = 10.6; 95% CI = 4.6-24.2; P<0.001) and somatic Menopause Rating Scale (MRS) score >3 (PR = 1.4; 95% CI = 1.01-1.96; P = 0.044).

Conclusions:

The prevalence of medication use among middle-aged women was high and was associated with the age of menopause onset, chronic diseases, and obesity/overweight status.
Efficacy and Safety of OTX-101, a Novel Nanomicellar Formulation of Cyclosporine A, for the Treatment of Keratoconjunctivitis Sicca: Pooled Analysis of a Phase 2b/3 and Phase 3 Study
Authors: Sheppard John , Kannarr Shane , Luchs Jodi , Malhotra Ranjan , Justice Angela , Ogundele Abayomi , Darby Charles , Bacharach Jason
Published: July 2019

Background:

OTX-101 (CEQUA™) is approved in the United States for treatment of keratoconjunctivitis sicca (KCS). This pooled analysis of 2 studies (phase 2b/3 and phase 3) evaluates the efficacy and safety of OTX-101 0.09% in the intent-to-treat (ITT) population and the subgroup of patients with a baseline Schirmer score less than 10 mm.

Methods:

In these randomized, multicenter, double-masked, vehicle-controlled studies, patients received 1 drop of either OTX-101 or vehicle in both eyes twice daily. A Schirmer's test was performed at baseline and day 84/early discontinuation. Symptom Assessment iN Dry Eye (SANDE) scores and adverse events were monitored at each visit.

Results:

The pooled analysis included 523 and 525 patients randomized to OTX-101 0.09% and vehicle, respectively. In the ITT population, 16.6% of eyes receiving OTX-101 and 9.0% of eyes receiving vehicle showed a day 84 increase in Schirmer score ≥10 mm from baseline (P<0.0001). In the subgroup with Schirmer score less than 10 mm at baseline, 18.7% and 10.2% of eyes receiving OTX-101 and vehicle, respectively, exhibited this outcome (P=0.0001). The mean (SD) percent change from baseline in global SANDE scores on day 84 in the ITT population was −29.0% (39.0%) and −30.4% (39.5%) for OTX-101 and vehicle groups, respectively. In the subgroup, the mean (SD) percent change was −27.3% (39.7%) and −31.4% (38.3%) for OTX-101 and vehicle groups, respectively. Adverse events were mostly mild to moderate.

Conclusions:

OTX-101 improved tear production compared with vehicle. Both OTX-101 and vehicle showed improved SANDE scores over baseline. OTX-101 was well tolerated in patients with KCS.
Long-term Clinical Outcomes of Ahmed and Baerveldt Drainage Device Surgery for Pediatric Glaucoma Following Cataract Surgery
Authors: Esfandiari Hamed , Kurup Sudhi P. , Torkian Pooya , Mets Marilyn B. , Rahmani Bahram , Tanna Angelo P.
Published: July 2019

Precis:

In this retrospective case series, both Baerveldt and Ahmed glaucoma drainage devices resulted in good long-term outcomes in eyes with pediatric glaucoma following cataract surgery (GFCS).

Background:

The aim of this study was to describe the long-term safety and efficacy of primary glaucoma drainage device surgery in patients with pediatric GFCS.

Methods:

We retrospectively identified 28 eyes of 28 patients with GFCS that underwent tube shunt surgery with the Ahmed Glaucoma Valve or Baerveldt Glaucoma Implant. The primary outcome measure was a surgical failure, defined as intraocular pressure (IOP) >21 mm Hg or not reduced by 20% below baseline on 2 consecutive follow-up visits after 3 months, IOP <5 mm Hg on 2 consecutive follow-up visits after 3 months, and reoperation for glaucoma.

Results:

The mean duration between cataract removal and the diagnosis of glaucoma was 3.6±1.5 years. Kaplan-Meier survival curves indicated a mean time to failure of 41.9±2.1 months after drainage device surgery. The cumulative probability of failure at 1, 2, 3, and 4 years was 3.6%, 19%, 28%, and 28%. IOP was significantly decreased from 29.3±4.1 mm Hg preoperatively to 17.6±1.6 mm Hg at the final follow-up visit (P<0.001). The number of glaucoma medications at baseline was 3.1±0.6, which decreased to 2.1±0.7 at the final visit (P=0.001).

Conclusions:

Glaucoma drainage device surgery results in good long-term outcomes in patients with GFCS.
Childhood Glaucoma: Long-Term Outcomes of Glaucoma Drainage Device Implantation Within the First 2 Years of Life
Authors: Daniel Moritz C. , Mohamed-Noriega Jibran , Petchyim Sakaorat , Brookes John
Published: July 2019

Précis:

Glaucoma drainage device (GDD) implantation within the first 2 years of life yields an overall success rate of 59.0% at 5 years. It is safe and requires a relatively low number of postoperative interventions.

Purpose:

The purpose of this study was to evaluate the long-term outcomes of the treatment of childhood glaucoma with GDDs within the first 2 years of life.

Methods:

A total of 43 children (60 eyes) having undergone GDD implantation within the first 2 years of life at Moorfields Eye Hospital between July 2005 and November 2014 were included in this retrospective case series. Kaplan-Meier survival curves were created for the evaluation of surgical success. Log-rank analysis was performed for the detection of risk factors for failure. Main outcome measures: Overall success rates at 1, 5, and 7 years after surgery. Surgical success: intraocular pressure ≥5/≤21 mm Hg, no further glaucoma surgery required, nonoccurrence of loss of perception of light or devastating complications.

Results:

The results are listed as follows: Median duration of follow-up was 48.0 months. Median age at surgery was 11.5 months. Seventy-three percentage of children were white. Most common types of glaucoma were primary congenital glaucoma [(PCG); 67%], glaucoma following cataract surgery (18%), and anterior segment dysgenesis (10%). Overall success rates were 93%, 59%, and 59%, respectively. There were no differences in the survival rates as a function of PCG/non-PCG, sex, and removal of intraluminal stent suture. Mean number of general anesthesia administrations during the first postoperative year was 1.8.

Conclusions:

GDD implantation within the first 2 years of life is effective and safe. The low number of general anesthesia administrations required during the first postoperative year could help to reduce the burden placed on children and carers. Further research is required to directly compare the efficiency of GDD implantation with other surgical options.
The Resilient Athlete: Lessons Learned in the Military
Authors: Barcia Anthony M. , Shaha James S. , Tokish John M.
Published: July 2019

Resilience, the capacity to recover from a setback or adversity, is a concept that has received considerable recent attention. An individual’s resilience predicts their life trajectory following stressful events and this has increasingly been shown in a wide variety of applications. Our understanding of the degree to which we can modify our resilience, and the optimal means to do so, remains in its infancy. The US military has embraced extensive efforts to quantify and build resilience in service members in an effort to preserve the fighting force. We specifically look at the understanding of resilience as it relates to the athletes in terms of competition and return from injury. This article explores the concept of resilience, the efforts to build resilience, lessons learned from the military and applications of the resilience concept to surgical and trauma patients.
Blood Flow Restriction Therapy: From Development to Applications
Authors: Anderson Ashley B. , Owens Johnny G. , Patterson Stephen D. , Dickens Jonathan F. , LeClere Lance E.
Published: July 2019

Blood flow restriction (BFR) has been shown to produce beneficial adaptations to skeletal muscle. These adaptations have been documented in the civilian and military populations. BFR therapy may provide patients a safe method to begin strength training at earlier stages of rehabilitation to allow for earlier and more effective return to activity and improved military readiness. The purpose was to review BFR therapy physiology, complications, side effects, standardized treatment algorithms, and long-term patient outcomes.
The Warrior Model for Human Performance Optimization
Authors: Sell Timothy C. , Lutz Robert H. , Faherty Mallory S.
Published: July 2019

Special Operations Combat Personnel (SOCP) face significant challenges and occupational demands that put them at significant risk for musculoskeletal injury. Musculoskeletal injury leads to lost-duty days, medical disqualification, and compromises operational readiness and mission success. Optimizing human performance and developing injury prevention strategies can position SOCP for success, but human performance optimization is a complex process that demands the integration of multiple disciplines to address a broad range of capabilities necessary for this success. The Warrior Model for Human Performance Optimization outlines a step-by-step approach to human performance optimization embedded within a scientific, evidenced-based approach to injury prevention and performance optimization that includes a step to ensure specificity of training and interventions. This evidence-based approach can insure that SOCP capabilities match the demands of occupation enabling them to successfully execute their occupation tasks without risk of injury. While the focus of this review is on military personnel, the same principles have application to nonmilitary high-performance athletes.
Providers’ Perspectives on Treating Patients With Thalassemia
Authors: Radke Taylor , Paulukonis Susan , Hulihan Mary M. , Feuchtbaum Lisa
Published: July 2019

In recent years, California has experienced a steady rise in Asian immigration which has led to a corresponding increased prevalence of clinically significant thalassemia in this state. As part of the Public Health Research, Education and Surveillance for Hemoglobinopathies emoglobinopathies project, a survey was developed to collect information from California providers who care for thalassemia patients in an effort to better understand their practice patterns, barriers to providing care, and educational needs. When asked about educational needs, providers most frequently expressed a desire for care and management guidelines (65.3%), health educational materials for patients (47.2%), and information on complications and clinical outcomes (32.1%). Only one quarter of providers (24.0%) reported that all of their thalassemia patients have a coordinated care plan. The increase in California thalassemia cases highlights the importance of provider knowledge to effectively serve the patients in their communities. Provider education and dissemination of treatment standards can not only improve knowledge about the disease but also increase awareness about the importance of coordinating care among a multidisciplinary team of specialists. Improvement in these areas will help achieve the overarching goal of better outcomes and quality of life for patients with thalassemia.
Examining the Relationship Between Patient Fatigue-Related Symptom Clusters and Carer Depressive Symptoms in Advanced Cancer Dyads
Authors: Buck Harleah G. , Benitez Bryan , Fradley Michael G. , Donovan Kristine A. , McMillan Susan C. , Reich Richard R. , Wang Hsiao-Lan
Published: July 2019

Background

Most symptom management takes place in the community, conducted by patient and/or informal carer dyads with guidance from clinicians. Given the prevalence of cancer, there is a critical need for examination of the impact of managing multiple symptoms, particularly those that cluster with fatigue, on informal carers.

Objectives

To (1) examine clustering of patient fatigue-related symptom severity and distress in individuals with cancer and (2) test the hypothesis that patient fatigue-related symptom clusters (severity, distress) will be positively associated with carer depressive symptoms.

Methods

Secondary analysis of 689 hospice patient/informal carer dyads using exploratory factor analysis and structural equation modeling. Patient symptoms were measured by the Memorial Symptom Assessment Scale, and carer depressive symptoms were measured by the Center for Epidemiological Study–Depression Scale.

Results

Patients were 73 (SD, 12) years old, and 43% were female. Carers were 65 years (SD, 14) years old, and 74% were female. For symptom severity, dyspnea, dry mouth, lack of appetite, drowsiness, cough, dizziness, and difficulty swallowing clustered with fatigue. For symptom distress, dyspnea, cough, and dry mouth clustered with fatigue. Structural equation modeling results indicated that the patient fatigue severity cluster was positively related to carer depressive symptoms (b = 0.12, P < .05), but distress was not.

Conclusion

Managing multiple symptoms that cluster with fatigue negatively impacts informal carers.

Implications for Practice

When patients complain of severe fatigue, clinicians need to explore all causes and ask about other symptoms while exploring whether the informal carer is feeling burdened or depressed.
“I Am Sure That They Use My PROM Data for Something Important.” A Qualitative Study About Patients’ Experiences From a Hematologic Outpatient Clinic
Authors: Thestrup Hansen Stine , Kjerholt Mette , Friis Christensen Sarah , Brodersen John , Hølge-Hazelton Bibi
Published: July 2019

Background

Patient-reported outcome measures (PROMs) in clinical practice have the potential to contribute to and support shared decision-making processes by giving voice to patient concerns during consultations. However, the perspectives of patients diagnosed with chronic hematologic cancer on the use of PROMs are unknown.

Objective

To describe how patients diagnosed with hematologic cancer experience participating in a randomized PROM intervention study, including initial invitation, completion of questionnaires, and outpatient clinic visits.

Methods

A qualitative conceptual framework guided the study, using Interpretive Description with a focused ethnographic approach to explore patient experiences with PROMs in applied practice. Analysis was inspired by Habermas’ social theory of communicative action.

Results

The analysis revealed 3 predominant themes of patient experiences: that PROMs were “In the service of a good cause,” “The questions are not really spot on,” and “PROMs are sometimes used for something,” that is, unknown to the patient.

Conclusions

The patients’ experiences were dominated by the perspective of the healthcare system and by gratitude and imbalanced power relations. During completion of questionnaires, patients struggled to identify with items, and the questionnaires were associated with low content validity. When visiting the outpatient clinic, patients reported that doctors and nurses rarely discussed patients’ PROMs.

Implications for Practice

This study contributes knowledge of patient experiences of the integration of PROMs in hematologic outpatient clinical practice. Findings can guide further research and improve future implementation of PROMs.
Melorheostosis
Authors: Fick Cameron N. , Fratzl-Zelman Nadja , Roschger Paul , Klaushofer Klaus , Jha Smita , Marini Joan C. , Bhattacharyya Timothy
Published: July 2019

Melorheostosis is a rare sclerosing bone disease characterized by excessive cortical bone deposition that is frequently on the differential diagnosis for bone biopsies. Although the radiologic pattern of “dripping candle wax” is well known, the pathologic findings have been poorly defined. Here, we comprehensively describe the histology of melorheostosis in 15 patients who underwent bone biopsies. Common histologic findings included: dense cortical bone (73.3%), woven bone (60%), and hypervascular features and increased porosity (66.7%). One third of the patients (5/15) also had prominent cement lines. Multiple patients had >1 histologic pattern (ie, dense cortical bone and hypervascularity). Overall, this study suggests that melorheostosis exists with several histologically distinct patterns. When confronted with a case of suspected melorheostosis, the clinical pathologist should use the histologic features common to melorheostotic lesions presented here in conjunction with the patient’s clinical presentation and radiographic findings to arrive at a diagnosis. An illustrative case is presented.
Urothelial Carcinoma In Situ With Plasmacytoid Features
Authors: Sangoi Ankur R. , Falzarano Sara M. , Nicolas Marlo , McKenney Jesse K.
Published: July 2019

Although there are 5 well-described morphologic patterns of (nonglandular) urothelial carcinoma in situ (CIS), we have encountered a novel pattern of flat urothelial carcinoma with plasmacytoid features characterized by a triad of morphologic findings including abnormal architecture with cellular rounding, enlarged nuclei with eccentric nuclear localization, and dense globular eosinophilic cytoplasm. A total of 23 cases of plasmacytoid CIS (mean age: 74.1 y, range: 58 to 91 y) were collected and reviewed. We excluded cases in which the diagnostic biopsy had any of the following findings admixed in the same tissue biopsy sample as the plasmacytoid CIS: traditional patterns of CIS, noninvasive glandular CIS, papillary urothelial carcinoma, or invasive carcinoma. Immunostains for CK20, CD44, p53, and e-cadherin were performed on available blocks. History of prior urothelial neoplasia, prior treatment, and clinical follow-up were obtained from medical records and pathology re-review. Immunohistochemical analysis of plasmacytoid CIS showed diffuse/strong CK20 reactivity in 96% of cases (23/24), an abnormal p53 reactivity pattern (either overexpression or “null phenotype”) in 37% of cases (7/19), absence of CD44 reactivity in the neoplastic cells in 63% of cases (15/24), and retained membranous e-cadherin expression in 100% of cases (18/18). Clinical follow-up (average follow-up time: 37.7 mo, range: 7 to 115 mo) showed recurrence/new occurrence in 52% of cases (12/23), including all 4 of the 23 patients who initially presented with de novo plasmacytoid CIS (ie, no prior or concomitant urothelial neoplasia). The histologic features, the immunophenotype, the association with other forms of urothelial neoplasia, and the risk of recurrence and progression in de novo lesions support that plasmacytoid CIS represents a novel pattern of flat urothelial carcinoma. These histologic features may be more subtle than in other more typical patterns of CIS and should be carefully distinguished from therapy-related/reactive changes.
Stromal p16 Expression Helps Distinguish Atypical Polypoid Adenomyoma From Myoinvasive Endometrioid Carcinoma of the Uterus
Authors: Kihara Atsushi , Amano Yusuke , Yoshimoto Taichiro , Matsubara Daisuke , Fukushima Noriyoshi , Fujiwara Hiroyuki , Niki Toshiro
Published: July 2019

Atypical polypoid adenomyoma (APA) is a polypoid lesion that is comprised of atypical endometrial glands and fibromuscular stroma, which pathologists often confuse with myoinvasive endometrioid carcinoma. Here, we characterized the immunohistochemical and molecular features of the stromal components of APA to find distinct markers between APA and myoinvasive endometrioid carcinoma. First, we examined the immunohistochemical expression and gene mutations that were previously investigated in uterine and breast fibroepithelial lesions using 12 cases of APA. α-smooth muscle actin was diffusely positive in the stromal component in all cases, whereas desmin and h-caldesmon were focally expressed in 8 cases. Positive expression was also observed in 9 cases for CD10, 12 cases for estrogen receptor, 3 cases for HMGA2, and 3 cases for MDM2. All cases showed normal p53 expression and negative staining of HMGA1 and nuclear β-catenin. No mutations in MED12 exon 2 and the TERT promoter were found in any cases. p16 was positive in all cases and showed diffuse expression in 10 cases. We assessed stromal p16 expression in 84 cases of myoinvasive endometrioid carcinoma. The stromal p16 status was negative in all myoinvasive carcinomas, but there was 1 case with focal staining. There was a significant difference in stromal p16 expression between APA and myoinvasive endometrioid carcinoma (P<0.001). Stromal p16 expression was more suggestive of APA than myoinvasive endometrioid carcinoma among endometrial fibroepithelial lesions.
4-Phenylbutyrate Prevents Endoplasmic Reticulum Stress-Mediated Apoptosis Induced by Heatstroke in the Intestines of Mice
Authors: Cao Yan , Liu Zhifeng , Xiao Weiwei , Gu Zhengtao , Xiao Guizhen , Yuan Fangfang , Chen Fang , Pei Yanfang , Li Hui , Su Lei
Published: July 2019

Objective:

Heatstroke can induce serious physiological dysfunction in the intestine. However, the underlying mechanisms of this condition are unknown, and therapeutic strategies are not available. In this study, we explored the role of endoplasmic reticulum (ER) stress signaling in this process and assessed whether pretreating mice with an inhibitor of ER stress could alleviate intestinal damage.

Methods:

A heatstroke model was established in male mice. Mice were pretreated with 4-phenylbutyrate (4-PBA) before exposure to heat stress. Intestinal morphological changes were observed by hematoxylin and eosin (H&E) staining and transmission electron microscopy. The TUNEL assay was used to detect intestinal apoptosis. The expression of the ER stress-related proteins and apoptosis-related proteins was investigated by the Western blot assay.

Results:

Compared with control group, mice with heatstroke exhibited evidence of intestinal injury and epithelial apoptosis, accompanied by significantly increased expression of ER stress-related proteins in the intestines. The intestinal injury score and level of intestinal epithelial apoptosis were significantly reduced after administration of 4-PBA. Furthermore, the levels of the intestinal ER stress-related proteins GRP78, PERK, p-eIF2α, ATF4, and CHOP were decreased after 4-PBA treatment.

Conclusions:

Our results indicate that the ER stress-mediated apoptosis pathway is activated during heat stress-induced intestinal injury. 4-PBA can inhibit heatstroke-induced intestinal ER stress and attenuate intestinal injury. We provide evidence that the beneficial effect of 4-PBA is closely related to the inhibition of ER stress-mediated apoptosis. These findings suggest that ER stress may be a novel therapeutic target in patients with heatstroke.
Epidemiology of amyotrophic lateral sclerosis: an update of recent literature
Authors: Longinetti Elisa , Fang Fang
Published: July 2019

Purpose of review

The cause of amyotrophic lateral sclerosis (ALS) remains unknown for most of the patients with the disease. Epidemiologic studies can help describe disease burden and examine its potential risk factors, providing thereby evidence base for future mechanistic studies. With this review, we aimed to provide a summary of epidemiologic studies published during the past 18 months, which studied the incidence and risk factors for ALS.

Recent findings

An increasing incidence and prevalence of ALS continue to be reported from different parts of the world. Several previously studied risk factors are confirmed as causally related to ALS by Mendelian randomization analysis. The previously known prognostic indicators for ALS appear to be the same across populations.

Provided with the increasing number of patients diagnosed with ALS and the improved societal awareness of the disease, more resources should be allocated to the research and care of ALS. Population-based studies, especially population-based disease registers, should be the priorities in ALS research, and more data from outside Europe are needed in gaining a better global perspective of the disease.
The congenital myasthenic syndromes: expanding genetic and phenotypic spectrums and refining treatment strategies
Authors: Vanhaesebrouck An E. , Beeson David
Published: July 2019

Purpose of review

Congenital myasthenic syndromes (CMS) are a group of heterogeneous inherited disorders caused by mutations in genes encoding proteins whose function is essential for the integrity of neuromuscular transmission. This review updates the reader on the expanding phenotypic spectrum and suggested improved treatment strategies.

Recent findings

As next-generation sequencing is taken into the clinic, its use is both continuing to unearth new causative genes in which mutations underlie CMS and also broadening the phenotypic spectrum for known CMS genes. The number of genes in which mutations may cause neuromuscular transmission defects has now passed 30. The defective transmission may be part of an overall more complex phenotype in which there may be muscle, central nervous system or other involvement. Notably, mutations in series of genes encoding proteins located in the presynatic motor bouton have been identified. Rare cases of mutations in basal laminar proteins of the synaptic cleft are coming to light and additional mutations/phenotypic features have been located in some of the larger neuromuscular junction proteins such as AGRN and MUSK, where previously mutation screening by sanger sequencing was time consuming and costly. Finally, there are more reports of the beneficial effects of treatment with β2-adrenergic receptor agonists in patients, and the study of their action in disease models.

Recent studies of the CMS illustrate the increasing complexity of the genetics and pathophysiological mechanisms involved. With therapy tailored for the underlying disease mechanism treatment, although incomplete, is usually life-transforming. However, treatment for newly identified conditions in which myasthenia is only one component within complex multisystem disorder will prove challenging.
Anti-consensus: detecting trees that have an evolutionary signal that is lost in consensus
Authors: Huson Daniel H. , Albrecht Benjamin , Patz Sascha , Steel Mike
Published: July 2019

Abstract

In phylogenetics, a set of gene trees is often summarized by a consensus tree, such as the majority consensus, which is based on the set of all splits that are present in more than 50% of the input trees. A “consensus network” is obtained by lowering the threshold and considering all splits that are contained in 10% of the trees, say, and then computing the corresponding splits network. By construction and in practice, a consensus network usually shows the majority tree, extended by a number of rectangles that represent local rearrangements around internal nodes of the consensus tree. This may lead to the false conclusion that the input trees do not differ in a significant way because “even a phylogenetic network” does not display any large discrepancies. To harness the full potential of a phylogenetic network, we introduce the new concept of an anti-consensus network that aims at representing the largest interesting discrepancies found in a set of gene trees. We provide an efficient algorithm for computing an anti-consensus and illustrate its application using a set of gene trees from species and strains in the genus Kosakonia.
A dynamic role for dopamine receptors in the control of mammalian spinal networks
Authors: Sharples Simon A. , Burma Nicole E. , Borowska-Fielding Joanna , Kwok Charlie H.T. , Eaton Shane E.A. , Baker Glen B. , Jean-Xavier Celine , Zhang Ying , Trang Tuan , Whelan Patrick J.
Published: July 2019

Dopamine is well known to regulate movement through the differential control of direct and indirect pathways in the striatum that express D1 and D2 receptors respectively. The spinal cord also expresses all dopamine receptors however; how the specific receptors regulate spinal network output in mammals is poorly understood. We explore the receptor-specific mechanisms that underlie dopaminergic control of spinal network output of neonatal mice during changes in spinal network excitability. During spontaneous activity, which is a characteristic of developing spinal networks operating in a low excitability state, we found that dopamine is primarily inhibitory. We uncover an excitatory D1-mediated effect of dopamine on motoneurons and network output that also involves co-activation with D2 receptors. Critically, these excitatory actions require higher concentrations of dopamine; however, analysis of dopamine concentrations of neonates indicates that endogenous levels of spinal dopamine are low. Because endogenous levels of spinal dopamine are low, this excitatory dopaminergic pathway is likely physiologically-silent at this stage in development. In contrast, the inhibitory effect of dopamine, at low physiological concentrations is mediated by parallel activation of D2, D3, D4 and α2 receptors which is reproduced when endogenous dopamine levels are increased by blocking dopamine reuptake and metabolism. We provide evidence in support of dedicated spinal network components that are controlled by excitatory D1 and inhibitory D2 receptors that is reminiscent of the classic dopaminergic indirect and direct pathway within the striatum. These results indicate that network state is an important factor that dictates receptor-specific and therefore dose-dependent control of neuromodulators on spinal network output and advances our understanding of how neuromodulators regulate neural networks under dynamically changing excitability.

Significance statement

Monoaminergic neuromodulation of neural networks is dependent not only on target receptors but also on network state. We studied the concentration-dependent control of spinal networks of the neonatal mouse, in vitro, during a low excitability state characterized by spontaneous network activity. Spontaneous activity is an essential element for the development of networks. Under these conditions, we defined converging receptor and cellular mechanisms that contribute to the diverse, concentration-dependent control of spinal motor networks by dopamine, in vitro. These experiments advance understanding of how monoamines modulate neuronal networks under dynamically changing excitability conditions and provide evidence of dedicated D1 and D2 regulated network components in the spinal cord that are consistent with those reported in the striatum.
Characterization of a Y-specific duplication/insertion of the anti-Mullerian hormone type II receptor gene based on a chromosome-scale genome assembly of yellow perch, Perca flavescens
Authors: Feron Romain , Zahm Margot , Cabau Cédric , Klopp Christophe , Roques Céline , Bouchez Olivier , Eché Camille , Valière Sophie , Donnadieu Cécile , Haffray Pierrick , Bestin Anastasia , Morvezen Romain , Acloque Hervé , Euclide Peter T. , Wen Ming , Jouano Elodie , Schartl Manfred , Postlethwait John H. , Schraidt Claire , Christie Mark R. , Larson Wes , Herpin Amaury , Guiguen Yann
Published: July 2019

Background

Yellow perch, Perca flavescens, is an ecologically and commercially important species native to a large portion of the northern United States and southern Canada. It is also a promising candidate species for aquaculture. No yellow perch reference genome, however, has been available to facilitate improvements in both fisheries and aquaculture management practices.

Findings

By combining Oxford Nanopore Technologies long-reads, 10X genomics Illumina short linked reads and a chromosome contact map produced with Hi-C, we generated a high-continuity chromosome scale yellow perch genome assembly of 877.4 Mb. It contains, in agreement with the known diploid chromosome yellow perch count, 24 chromosome-size scaffolds covering 98.8% of the complete assembly (N50 = 37.4 Mb, L50 = 11). Genome annotation identified 41.7% (366 Mb) of repeated elements and 24,486 genes including 16,579 genes (76.3%) significantly matching with proteins in public databases. We also provide a first characterization of the yellow perch sex determination locus that contains a male-specific duplicate of the anti-Mullerian hormone type II receptor gene (amhr2by) inserted at the proximal end of the Y chromosome (chromosome 9). Using this sex-specific information, we developed a simple PCR genotyping test which accurately differentiates XY genetic males (amhr2by+) from XX genetic females (amhr2by−).

Conclusions

Our high-quality genome assembly is an important genomic resource for future studies on yellow perch ecology, toxicology, fisheries, and aquaculture research. In addition, the characterization of the amhr2by gene as a candidate sex determining gene in yellow perch provides a new example of the recurrent implication of the transforming growth factor beta pathway in fish sex determination, and highlights gene duplication as an important genomic mechanism for the emergence of new master sex determination genes.
Genetic overlap between psychotic experiences in the community across age and with psychiatric disorders
Authors: Barkhuizen Wikus , Pain Oliver , Dudbridge Frank , Ronald Angelica
Published: July 2019

Background

This study explores the degree to which genetic influences on psychotic experiences are stable across adolescence and adulthood, and their overlap with psychiatric disorders.

Methods

Genome-wide association results were obtained for adolescent psychotic experiences and negative symptom traits (N = 6,297-10,098), schizotypy (N = 3,967-4,057) and positive psychotic experiences in adulthood (N = 116,787-117,794), schizophrenia (N = 150,064), bipolar disorder (N = 41,653) and depression (N = 173,005). Linkage disequilibrium score regression was used to estimate genetic correlations. Implicated genes from functional and gene-based analyses were compared. Mendelian Randomization was performed on trait pairs with significant genetic correlations.

Results

Subclinical auditory and visual hallucinations and believing in conspiracies during adulthood were significantly genetically correlated with schizophrenia (rg = .27-.67) and major depression (rg = .41-.96) after correction for multiple testing. Auditory and visual subclinical hallucinations were highly genetically correlated (rg = .95). Cross-age genetic correlations for psychotic experiences were not significant. Gene mapping and gene association analyses revealed 14 possible genes associated with psychotic experiences that overlapped across age for psychotic experiences or between psychotic experiences and psychiatric disorders. Mendelian Randomization indicated bidirectional associations between auditory and visual hallucinations in adults but did not support causal relationships between psychotic experiences and psychiatric disorders.

Conclusions

Psychotic experiences in adulthood may be more linked genetically to schizophrenia and major depression than psychotic experiences in adolescence. Our study implicated specific genes that are associated with psychotic experiences across development as well as genes shared between psychotic experiences and psychiatric disorders.
The glycine locating at random coil of picornaviruses VP3 enhances viral pathogenicity by targeting p53 to promote apoptosis and autophagy
Authors: Mao Ruoqing , Yang Fan , Sun Dehui , Zhou Xiaoli , Zhu Zixiang , Guo Xuan , Liu Huanan , Tian Hong , Zhang Keshan , Dang Wen , Wu Qingfeng , Ma Xinwen , Liu Xiangtao , Zheng Haixue
Published: July 2019

Picornaviruses, comprising important and widespread pathogens of humans and animals, have evolved to control apoptosis and autophagy for their replication and spread. However, the underlying mechanism of the association between apoptosis/autophage and viral pathogenicity remains unclear. In the present study, VP3 of picornaviruses was demonstrated to induce apoptosis and autophagy. Foot-and-mouth disease virus (FMDV), which served as a research model here, can strongly induce both apoptosis and autophagy in the skin lesions. By directly interacting with p53, FMDV-VP3 facilitates its phosphorylation and translocation, resulting in Bcl-2 family-mediated apoptosis and LC3-dependent autophagy. The single residue Gly129 of FMDV-VP3 plays a crucial role in apoptosis and autophagy induction and the interaction with p53. Consistently, the comparison of rescued FMDV with mutated Gly129 and parental virus showed that the Gly129 is indispensable for viral replication and pathogenicity. More importantly, the Gly129 locates at a bend region of random coil structure, the mutation of Gly to Ala remarkably shrunk the volume of viral cavity. Coincidentally, the Gly is conserved in the similarly location of other picornaviruses, including poliovirus (PV), enterovirus 71 (EV71), coxsackievirus (CV) and seneca valley virus (SVA). This study demonstrates that picornaviruses induce apoptosis and autophagy to facilitate its pathogenicity and the Gly is functional site, providing novel insights into picornavirus biology.
Spontaneous polyploids and antimutators compete during the evolution of mutator cells
Authors: Tracy Maxwell A. , Lee Mitchell B. , Hearn Brady L. , Dowsett Ian T. , Thurber Luke C. , Loo Jason , Loeb Anisha M. , Preston Kent , Tuncel Miles I. , Ghodsian Niloufar , Bode Anna , Tang Thao T. , Chia Andy R. , Herr Alan J.
Published: July 2019

Heterozygous mutations affecting DNA polymerase (Pol) exonuclease domains and homozygous inactivation of mismatch repair (MMR) each generate “mutator” phenotypes capable of driving tumorigenesis. Cancers with both defects exhibit an explosive increase in mutation burden that appears to reach a threshold, consistent with selection acting against further mutation accumulation. In haploid yeast, simultaneous defects in polymerase proofreading and MMR select for “antimutator” mutants that suppress the mutator phenotype. We report here that spontaneous polyploids also escape this “error-induced extinction” and routinely out-compete antimutators in evolved haploid cultures. We performed similar experiments to explore how diploid yeast adapt to the mutator phenotype. We first evolved cells with homozygous mutations affecting proofreading and MMR, which we anticipated would favor tetraploid emergence. While tetraploids arose with a low frequency, in most cultures, a single antimutator clone rose to prominence carrying biallelic mutations affecting the polymerase mutator alleles. Variation in mutation rate between subclones from the same culture suggests there exists continued selection pressure for additional antimutator alleles. We then evolved diploid yeast modeling MMR-deficient cancers with the most common heterozygous exonuclease domain mutation (POLE-P286R). Although these cells grew robustly, within 120 generations, all subclones carried truncating or nonsynonymous mutations in thePOLE-P286Rhomologous allele (pol2-P301R) that suppressed the mutator phenotype as much as 100-fold. Independent adaptive events in the same culture were common. Our findings suggest that analogous tumor cell populations may adapt to the threat of extinction by polyclonal mutations that neutralize thePOLEmutator allele and preserve intra-tumoral genetic diversity for future adaptation.