bluuebunny/crossref_metadata_2025 huggingface dataset:
Why People Feel Younger: Motivational and Social-Cognitive Mechanisms of the Subjective Age Bias and Its Implications for Work and Organizations
Authors: Weiss David , Weiss Mona
Published: August 2019

The term subjective age bias describes the phenomenon that from adolescence to old age most people feel significantly younger or older than their chronological age. Although recent advances in life-span development research demonstrate the fundamental role of subjective age bias for well-being, performance, and health, the underlying mechanisms are not well understood. By highlighting the motivational and social-cognitive mechanisms of the subjective age bias, we answer 3 crucial questions and discuss implications for work and organizations. We conclude with recommendations for future research.
Mycobacterium tuberculosis induces connective tissue growth factor expression through the TLR2‐JNK‐AP‐1 pathway in human lung fibroblasts
Authors: Lee Hong‐Sheng , Hua Hung‐Sheng , Wang Cheng‐Hui , Yu Ming‐Chih , Chen Bing‐Chang , Lin and Chien‐Huang
Published: August 2019

Mycobacterium tuberculosis (M.tb) infection in lung causes pulmonary fibrosis, which leads to the irreversible reduction of pulmonary function. Fibrotic protein connective tissue growth factor (CTGF) expression has been confirmed to play a crucial role in lung fibrosis. However, the underlying signal pathway and effect of M.tb on CTGF expression in human lung fibroblasts are unclear. Our results revaled that M.tb caused time‐ and concentration‐dependent increases in CTGF expression in human lung fibroblasts. A mechanistic investigation revealed that M.tb induced CTGF expression through TLR2 but not TLR4. The promoter activity assay indicated that M.tb‐induced CTGF activity was mainly controlled by the promoter region at —747 to —184 bp, which contained signal transducer and activator of transcription 3 and activator protein 1 (AP‐1) binding sites. Moreover, curcumin (AP‐1 inhibitor) restrained M.tb‐induced CTGF expression. M.tb also induced increases in AP‐1 luciferase activity and DNA binding activity of c‐Jun and c‐Fos on the CTGF promoter. Furthermore, the knockdown of c‐Jun by small interfering RNA attenuated M.tb‐induced CTGF expression and AP‐1 luciferase activity. A JNK inhibitor (SP600125) and a JNK dominant‐negative mutant suppressed M.tb‐induced CTGF expression. We also discovered that M.tb could induce the phosphorylation of JNK and c‐Jun. Furthermore, SP600125 inhibited M.tb‐induced c‐Jun phosphorylation and AP‐1‐luciferase activity. M.tb‐induced fibronectin expression was inhibited by anti‐CTGF antibody. These results demonstrate that M.tb is activated through TLR2 to induce JNK activation, further increasing the DNA binding activity of c‐Jun and c‐Fos and finally inducing CTGF expression and extracellular matrix production.—Lee, H.‐S., Hua, H.‐S., Wang, C.‐H., Yu, M.‐C., Chen, B.‐C., Lin, C.‐H. Mycobacterium tuberculosis induces connective tissue growth factor expression through the TLR2‐JNK‐AP‐1 pathway in human lung fibroblasts. FASEB J. 33, 12554–12564 (2019). www.fasebj.org
Behavior, body composition, and vascular phenotype of homocystinuric mice on methionine‐restricted diet or enzyme replacement therapy
Authors: Majtan Tomas , Park Insun , Cox Allaura , Branchford Brian R. , di Paola Jorge , Bublil Erez M. , Kraus Jan P.
Published: August 2019

Classic homocystinuria (HCU) is an inherited disorder characterized by elevated homocysteine (Hcy) in plasma and tissues resulting from cystathionine β‐synthase (CBS) deficiency. There is no cure, and patients are predominantly managed by methionine‐restricted diet (MRD) to limit the production of Hcy. In this study, we used the I278T mouse model of HCU to evaluate the long‐term impact of a novel enzyme replacement therapy [truncated human CBS C15S mutant modified with linear 20‐kDa N‐hydroxysuccinimide ester polyethylene glycol (OT‐58)] on clinical end points relevant to human patients with HCU. In addition, we compared its efficacy on a background of either MRD or normal methionine intake [regular diet (REG)] to that of MRD alone. We found that, compared with untreated I278T mice, OT‐58 treatment of I278T mice fed with the REG diet resulted in a 90% decrease in plasma Hcy concentrations and correction of learning/cognition, endothelial dysfunction, hemostasis, bone mineralization, and body composition. On background of the MRD, OT‐58 performed equally well with plasma Hcy entirely normalized. The MRD alone decreased plasma Hcy by 67% and corrected the HCU phenotype in I278T mice. However, the MRD increased anxiety and reduced bone mineral content in both I278T mice and wild‐type controls. This study shows that OT‐58 is a highly efficacious novel treatment for HCU on the background of either normal or restricted methionine intake.—Majtan, T., Park, I., Cox, A., Branchford, B. R., di Paola, J., Bublil, E. M., Kraus, J. P. Behavior, body composition, and vascular phenotype of homocystinuric mice on methionine‐restricted diet or enzyme replacement therapy. FASEB J. 33, 12477–12486 (2019). www.fasebj.org
Sin3a regulates the developmental progression through morula‐to‐blastocyst transition via Hdacl
Authors: Zhao Panpan , Li Shuang , Wang Huanan , Dang Yanna , Wang Lefeng , Liu Tong , Wang Shaohua , Li Xinhong , Zhang Kun
Published: August 2019

Suppressor interacting 3a (Sin3a) is a scaffold component of the chromatin repressive complex Sin3/histone deacetylase (Hdac). Sin3a has been shown as a hub gene driving preimplantation development in both mice and humans. However, its precise functions during preimplantation development remain unclear. Here, we show that the embryos arrested at morula stage upon specific depletion of Sin3a in mouse early embryos. Given the reduced cell number in Sin3a‐depleted embryos, blocked cell proliferation is observed, likely because of the increased level of Trp53 acetylation at lysine 379. Moreover, we found that Sin3a depletion reduces Cdx2 and Tir Na Nog (Nanog), suggesting a failure of the first cell fate decision. In addition, we noted a striking increase of genome‐wide DNA methylation, likely attributed to the increased nuclear DNA methyltransferase 1 observed in Sin3a‐depleted embryos. Notably, RNA sequencing analyses showed 717 genes are differentially expressed, and Gene Ontology analysis of down‐regulated genes (e.g., Hdac1) revealed top enriched terms involving protein deacetylation. Consistently, we confirmed a significant decrease of Hdac1 mRNA and protein abundance. Importantly, the development and Trp53 acetylation in Sin3a‐depleted embryos could be rescued by expression of Hdac1 but not Hdac2. In summary, our results indicate a vital role of Sin3a in safeguarding the developmental progression through the morula‐to‐blastocyst transition via Hdacl.—Zhao, P., Li, S., Wang, H., Dang, Y., Wang, L., Liu, T., Wang, S., Li, X., Zhang, K. Sin3a regulates the developmental progression through morula‐to‐blastocyst transition via Hdac1. FASEB J. 33, 12541–12553 (2019). www.fasebj.org
What is in the Myopathy Literature?
Authors: Lacomis David
Published: August 2019

In this issue, an article describing a newly defined entity, myoglobinopathy, is covered. This autosomal-dominant, adult-onset, proximal-predominant myopathy may be associated with cardiac involvement and is due to a mutation inMB. The presence of sarcoplasmic bodies is distinctive in muscle biopsy specimens. Next, variability in phenotypes and genotypes in patients withRYR1andTTNmutations is described. Several articles address respiratory dysfunction in myotonic dystrophy type 1, reporting that its severity is associated with the CTG-repeat size, age, and degree of muscle weakness. Several articles focus on muscle pain, including myalgias in mitochondrial disorders and the presence of inflammation in muscle biopsy specimens from patients with myalgias and abnormal electrodiagnostic testing. Finally, a form of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) myopathy mimicking limb-girdle muscular dystrophy is highlighted.
Peripheral Reconstructive Lamellar Keratoplasty for Late Ectasia After Penetrating Keratoplasty in Keratoconus Eyes
Authors: Malbran Enrique S. , Price Francis W. , Argañaraz Olivero Joaquín E. , Malbran Enrique , Malbran Jorge , Malbran Marcos , Rogel Leandro N. , Price Marianne O. , Gordillo Carlos H.
Published: August 2019

Purpose:

To describe outcomes of customized peripheral anterior lamellar keratoplasty (PALK) for late ectasia of the donor–recipient junction after penetrating keratoplasty (PK) for keratoconus.

Methods:

This was a single-center, retrospective review of 33 eyes (28 patients) that developed ectasia restricted to the graft–host junction; 17 eyes underwent PALK using lamellar resections of 8- to 11-mm width starting at the external margin of the previous PK and suturing a same-size donor graft (annular or segmental). Five eyes were excluded from analysis because of postoperative complications unrelated to the technique.

Results:

The average time between PK and diagnosis of secondary ectasia was 28 years (range 9–49 years). Slit-lamp examination showed localized thinning and elongation of the scar at the graft–host junction with well-defined biomicroscopic limits. Preoperatively, the mean keratometric measures were K1: 44.8 ± 4.8 D and K2: 54.1 ± 4.8 D and postoperatively K1: 47.5 ± 3.5 D and K2: 50.8 ± 2.6 D. The mean improvement in corrected visual acuity was 10 lines, and mean cylinder improved from 9.3 ± 2.1 D to 3.3 ± 1.4 D. All cases showed anatomical and refractive improvement.

Conclusions:

With long-term follow-up, late post-PK ectasia becomes an increasing problem. PALK can be a successful surgical option to reinforce the ectatic area while preserving a functional clear PK. By adding donor corneal tissue, PALK restores the ectatic area, improves visual acuity, keratometric values, and astigmatism, and preserves the functional graft while avoiding the higher risks of a larger diameter PK.
Effect of Foveal Location on Retinal Nerve Fiber Layer Thickness Profile in Superior Oblique Palsy Eyes
Authors: Akbari Mohammadreza , Nikdel Mojgan , Moghimi Sasan , Subramanian Prem S. , Fard Masoud Aghsaei
Published: August 2019

Précis:

Superior oblique palsy (SOP) eyes show thinner inferotemporal retinal nerve fiber layer (RNFL) without adjusting for foveal position. There was a strong correlation between the degree of torsion and the difference in the RNFL thickness before and after adjusting foveal location.

Purpose:

The impact of foveal position on RNFL thickness has been shown. In this study, we evaluate RNFL thickness profiles according to the disc-foveal angle in SOP and control eyes.

Materials and Methods:

In 44 eyes of 22 patients with unilateral congenital SOP and 42 eyes of 42 normal controls, the position of the fovea relative to the optic disc was calculated by optical coherence tomography using FoDi (fovea-to-disc) technology. After measuring RNFL thickness with FoDi alignment technology, each optical coherence tomography image was reevaluated with FoDi turned off, and the measurements were repeated to determine RNFL values according to the disc-foveal angle.

Results:

The average disc-foveal angle was −10.85±6.60 degrees and −10.71±6.63 degrees in the affected and fellow eyes of SOP patients; these values were significantly greater than control subjects (−5.88±4.09 degrees). There was no significant difference in RNFL sector values between SOP and control eyes with FoDi. From all RNFL sectors, the measured inferotemporal thickness was less in SOP eyes without FoDi than in SOP eyes with FoDi (129.7±20.5 µm vs. 144.6±17.8 µm, respectively, P=0.001). Differences of the RNFL thicknesses with and without FoDi in SOP eyes in the superotemporal and inferotemporal sectors were 5.40±13.42 and 14.84±15.00, respectively, which were significantly more than the same changes in control eyes with amount of 0.30±6.57 and 8.52±10.4 (P=0.02 for both sectors).

Conclusions:

In SOP eyes with large amounts of torsion, a correction for the disc-foveal angle is necessary for accurate determination of the RNFL thickness profile.
Optimizing impact through the Tiered Doctor of Nursing Practice Project Model
Authors: Melander Sheila , Howard Patricia B. , Williams Tracy E. , Tharp-Barrie Kim , El-Mallakh Peggy , MacCallum Tricia
Published: August 2019

Colleges of Nursing (CONs) and health care organizations (HCOs) are increasingly embracing academic-practice partnerships (AcaPP). An HCO's workforce development plan prompted an AcaPP agreement with a CON for the purpose of increasing the number of doctor of nursing practice (DNP) advanced practice nurses in the HCO. Over a period of 6 years, 4 consecutive cohorts of approximately 100 HCO baccalaureate prepared nurses were enrolled in the CON DNP program. The AcaPP environment facilitates large-scale DNP projects among successive cohorts of students. The purpose of this article is to describe the innovative Tiered DNP Project Model, defined as the process by which current students build on and expand select DNP projects implemented by students in initial cohorts. The tiered approach to the DNP project is facilitated by an advising model that occurs in the context of mutually agreed-upon goals and compatible with the HCO strategic plan and CON DNP program objectives. In the Tiered DNP Project Model, select studies are chosen for continuation by DNP students in subsequent cohorts based on nursing leadership guidance of alignment with HCO strategic goals. The model has resulted in driving improvements in HCO patient and systems outcomes, promoted practice scholarship, and contributed to the quality of the CON DNP program.
Heparin-Free Extracorporeal Life Support Using Tethered Liquid Perfluorocarbon: A Feasibility and Efficacy Study
Authors: Roberts Teryn R. , Harea George T. , Singha Priyadarshini , Sieck Kyle N. , Beely Brendan M. , Wendorff Daniel S. , Choi Jae Hyek , Ande Sreedevi , Handa Hitesh , Batchinsky Andriy I.
Published: August 2019

Coagulation management is the leading challenge during extracorporeal life support (ECLS) due to shear stress and foreign-surface–induced coagulation disturbance during circulation. A nonadhesive, liquid-infused coating called tethered liquid perfluorocarbon (TLP) was developed to prevent adhesion of blood on medical materials. We investigated the novel application of TLP to commercial ECLS circuits compared with standard heparin-coated circuits in vivo in anesthetized swine for 6 hours veno-venous ECLS (1 L/min blood flow) without systemic anticoagulation (n = 3/group). We hypothesized that TLP coating permits heparin-free circulation without untoward effects while reducing thrombus deposition compared with controls. Vital signs, respiration, gas transfer, coagulation, and histology were assessed. Scanning electron microscopy (SEM), elemental mapping, and digital imaging were used to assess thrombus deposition after circulation. There were no group differences in vitals, gas exchange, coagulation, and histology. In both groups, ECLS enabled a decrease in minute volume and end-tidal CO2, with concomitant increase in pH (p < 0.05). Scanning electron microscopy and digital imaging revealed significant thrombus on heparin-coated membranes, which was reduced or absent on TLP-coated materials. Tethered liquid perfluorocarbon permitted heparin-free ECLS without altering device performance and prevented thrombus deposition versus immobilized heparin. Pending multiday in vivo testing, TLP is a promising biomaterial solution to eliminate anticoagulation requirements during ECLS.
Trends in the Use of Skilled Nursing Facility and Home Health Care Under the Hospital Readmissions Reduction Program
Authors: Popescu Ioana , Sood Neeraj , Joshi Sushant , Huckfeldt Peter , Escarce José , Nuckols Teryl K.
Published: August 2019

Background:

Medicare’s Hospital Readmission Reduction Program (HRRP) penalizes hospitals with elevated 30-day readmission rates for acute myocardial infarction (AMI), heart failure (HF), or pneumonia. To reduce readmissions, hospitals may have increased referrals to skilled nursing facilities (SNFs) and home health care.

Research Design:

Outcomes included 30-day postdischarge utilization of SNF and home health care, including any use as well as days of use. Subjects included Medicare fee-for-service beneficiaries aged 65 years and older who were admitted with AMI, HF, or pneumonia to hospitals subject to the HRRP. Using an interrupted time-series analysis, we compared utilization rates observed after the announcement of the HRRP (April 2010 through September 2012) and after the imposition of penalties (October 2012 through September 2014) with projected utilization rates that accounted for pre-HRRP trends (January 2008 through March 2010). Models included patient characteristics and hospital fixed effects.

Results:

For AMI and HF, utilization of SNF and home health care remained stable overall. For pneumonia, observed utilization of any SNF care increased modestly (1.0%, P<0.001 during anticipation; 2.4%, P<0.001 after penalties) and observed utilization of any home health care services declined modestly (−0.5%, P=0.008 after announcement; −0.7%, P=0.045 after penalties) relative to projections. Beneficiaries with AMI and pneumonia treated at penalized hospitals had higher rates of being in the community 30 days postdischarge.

Conclusions:

Hospitals might be shifting to more intensive postacute care to avoid readmissions among seniors with pneumonia. At the same time, penalized hospitals’ efforts to prevent readmissions may be keeping higher proportions of their patients in the community.
Validating Reports of Chronic Conditions in the Medicare CAHPS Survey
Authors: Brault Matthew W. , Landon Bruce E. , Zaslavsky Alan M.
Published: August 2019

Background:

The Medicare Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey includes items about chronic conditions, health history, and self-rated health. Questions remain about the concordance between patient reports and administrative sources on questions related to health history.

Objective:

To validate CAHPS measures of chronic conditions against claims-based measures from the Medicare Chronic Conditions Warehouse (CCW).

Methods:

We linked CAHPS responses from 301,050 fee-for-service Medicare beneficiaries in 2010–2012 with summaries of their claims in the CCW and identified nearest equivalent measures of conditions across sources. We calculated sensitivities and specificities for conditions and estimated regression models to assess the effects of patient characteristics on the sensitivity.

Results:

The sensitivity of CAHPS measures differed across conditions, ranging from 0.513 for history of stroke to 0.773 for history of cancer. Sensitivity was generally lower for older beneficiaries, those reporting good self-rated health, and those with fair or poor mental health. Specificity was 0.904 or greater for all conditions, up to 0.961 for stroke.

Conclusions:

Despite difference in timeframes and definitions of conditions, the measured sensitivities demonstrated reasonable validity. Variation in sensitivity is consistent with covariates that either directly measure health severity within a diagnosis or can be construed as a proxy for severity of illness.
Transfusion support and alternatives for Jehovah's Witness patients
Authors: Crowe Elizabeth P. , DeSimone Robert A.
Published: August 2019

Purpose of review

Jehovah's Witness patients with critical anemia or undergoing major surgery are challenging for healthcare providers to manage, as most will decline transfusion of whole blood and its main components. Recent advances in our understanding of hemostatic agents, alternative hemoglobin-based oxygen carriers, and patient blood management have culminated in a complex array of options to manage critical anemia and bleeding in this patient population.

Recent findings

Refusal of blood products in the setting of critical anemia is associated with significant risk of morbidity and mortality. With implementation of patient blood management measures, targeted treatment of anemia and coagulopathy has reduced the need for transfusions. Likewise, increased clinical experience with hemoglobin-based oxygen carriers in Jehovah's Witnesses with critical anemia has provided new insights into their potential benefits and pitfalls.

Options and alternatives to manage the Jehovah's Witness patient in the perioperative setting or in the setting of critical anemia will be reviewed.
Agent-Based Modeling
Authors: McLean Allen , McDonald Wade , Goodridge Donna , Osgood Nathaniel
Published: August 2019

Background

For all our successes, many urgent health problems persist, and although some of these problems may be explored with established research methods, others remain uniquely challenging to investigate—maybe even impossible to study in the real world because of practical and pragmatic obstacles inherent to the nature of the research question.

Objectives

The purpose of this review article is to introduce agent-based modeling (ABM) and simulation and demonstrate its value and potential as a novel research method applied in nursing science.

Methods

An introduction to ABM and simulation is described. Examples of current research literature on the subject are provided. A case study example of community nursing and opioid dependence is presented.

Results

The use of ABM and simulation in human health research has increased dramatically over the past decade, and meaningful research is now commonly found published widely in respected, peer-reviewed journals. Absent from this list is innovative ABM and simulation research published by nurse researchers in nursing-specific journals.

Discussion

ABM and simulation is a powerful method with tremendous potential in nursing research. It is vital that nursing embrace and adopt innovative and advanced research methods if we are to remain a progressive voice in health research, practice, and policy.
Intraosseous Hibernoma: Five Cases and a Review of the Literature
Authors: Myslicki Francisco A. , Rosenberg Andrew E. , Chaitowitz Ivan , Subhawong Ty K.
Published: August 2019

We present 5 cases of intraosseous hibernoma, a rare benign tumor of brown fat. Our literature review reveals that the average age at presentation is 58.6 years, and 69.7% of patients are female. Lesions are most often located in the spine and pelvis. Computed tomography usually demonstrates sclerotic changes, although lesions can be lytic. Magnetic resonance imaging findings include heterogeneous T2 hyperintensity. Technetium 99m-methyl diphosphonate bone scan reveals variable radiotracer uptake, whereas 18F-labeled fluoro-2-deoxyglucose (FDG) PET-CT shows mild uptake. Intraosseous hibernoma should be considered when imaging demonstrates a fat-containing lesion in bone, especially one exhibiting FDG avidity.
The Role of Positron Emission Tomography/Magnetic Resonance Imaging in Gynecological Malignancies
Authors: Virarkar Mayur , Viswanathan Chitra , Iyer Revathy , de Castro Faria Silvana , Morani Ajaykumar , Carter Brett , Ganeshan Dhakshinamoorthy , Elsherif Sherif , Bhosale Priya R.
Published: August 2019

Accurate oncological staging for early detection is of utmost importance in patient care and increasing the overall patient survival outcome. Hybrid imaging in the form of positron emission tomography (PET)/computed tomography has been successfully implemented in oncological imaging and, where available, has been used consistently in patients with gynecologic malignancies. The implementation of PET/magnetic resonance imaging (MRI) enables high-quality assessment of gynecological malignancies by combining the diagnostic advantages of metabolic information of PET along with the high-resolution anatomical and functional information from the MRI to provide precise information about staging, recurrence, and metastases. This article will review the various applications of PET/MRI in gynecological cancer.
Identification of Antibiotic Administration as a Potentially Novel Factor Associated With Tacrolimus Trough Variability in Kidney Transplant Recipients: A Preliminary Study
Authors: Zheng YuanPu , Masand Anjali , Wagner Michael , Kapur Sandip , Dadhania Darshana , Lubetzky Michelle , Lee John Richard
Published: August 2019

Background.

Tacrolimus trough variability is an important risk factor for kidney allograft outcomes. Recent evidence suggests that the gut microbiota is associated with tacrolimus dosing requirements and direct metabolism of tacrolimus. We hypothesize that administration of antibiotics, which are known to alter the gut microbiota, is associated with tacrolimus trough variability.

Methods.

We conducted a retrospective chart review of subjects who received kidney transplants at our institution from 2012 to 2013 and evaluated subjects who received antibiotics during the first month of transplantation (Abx Group, N = 60) and subjects who did not (No Abx Group, N = 200). We evaluated whether antibiotic administration in the Abx Group had increased tacrolimus trough concentrations and concentration over tacrolimus dosage (C/D) after antibiotic administration. We also evaluated tacrolimus variability as measured by standard deviation (SD) and coefficient of variation between the Abx Group and No Abx Group.

Results.

In the Abx Group, tacrolimus trough concentration over tacrolimus dosage (C/D) increased 7 and 15 days after antibiotic administration (P = 0.001, P = 0.07, respectively, Wilcoxon signed-rank test). From postoperative day 31–45, the variability in tacrolimus trough levels in the Abx Group as measured by SD and coefficient of variation was significantly higher than the variability in the No Abx Group (P = 0.03, P = 0.02, Wilcoxon rank sum test, respectively).

Conclusions.

Our identification of antibiotic administration as a potentially new risk factor for tacrolimus trough variability suggests the need to carefully follow tacrolimus trough levels after antibiotic administration.
Outcomes After Transcervical Thymectomy for Ocular Myasthenia Gravis: A Retrospective Cohort Study With Inverse Probability Weighting
Authors: Hamedani Ali G. , Pistilli Maxwell , Singhal Sunil , Shindler Kenneth S. , Avery Robert A. , Tamhankar Madhura A. , Liu Grant T.
Published: August 2019

Background:

The benefit of thymectomy in reducing requirement for corticosteroids, symptom severity, need for immunosuppression, and hospitalization rates in patients with seropositive generalized myasthenia has recently been established. It is unclear whether this benefit applies to patients with myasthenia and purely ocular manifestations (ocular myasthenia gravis [OMG]).

Methods:

We conducted a retrospective single-center cohort study of patients with OMG. Patients were included if their diagnosis was confirmed by acetylcholine receptor or muscle-specific kinase antibodies, abnormal electrophysiology, or a positive edrophonium test and at least 1 year of clinical follow-up. At each visit, the presence and severity of ocular and generalized symptoms was ascertained using a 4-point scale. Prednisone dose, steroid-sparing agent use, and need for intravenous immunoglobulin or plasmapheresis were recorded. The effect of thymectomy on time-weighted prednisone dose and symptom severity score was assessed using linear regression models. To adjust for nonrandomization of thymectomy, we used inverse probability weighting using a propensity score model derived from the prethymectomy observation period for thymectomy patients and a 6-month lead-in period for nonthymectomy patients that incorporated age, sex, acetylcholine receptor antibody seropositivity, disease severity (as defined by both symptom severity and treatment requirement), and treating physician preferences.

Results:

Eighty-two patients (30 with thymectomy and 52 nonthymectomy) were included. In unadjusted analyses, time-weighted daily prednisone dose was 2.9 mg higher with thymectomy compared with nonthymectomy (95% CI: 0.2–5.7), but after inverse probability weighting, this was no longer statistically significant (difference = 1.7 mg, 95% CI: −0.8 to 4.2). There was no statistically significant difference in symptom severity score (adjusted difference = 0.35, 95% CI: −0.02 to 0.72) or risk of generalization (P = 0.22).

Conclusions:

In this retrospective study that used statistical techniques to account for nonrandomization, no significant differences in prednisone dose or symptom severity after thymectomy in ocular myasthenia were demonstrated.
Orbicularis Oculi Morphological Alterations in Affected and Nonaffected Sides in Hemifacial Spasm
Authors: Osaki Midori H. , Osaki Tammy H. , Osaki Teissy , Gameiro Gustavo R. , Belfort Rubens , Marie Suely K. N.
Published: August 2019

Background:

Although the nonaffected side appears to be clinically normal in hemifacial spasm (HFS), it is not known whether this side can be considered normal regarding histopathological findings. The purpose of this study was to objectively evaluate and compare orbicularis oculi samples of patients with HFS (not previously treated with botulinum toxin) and control patients undergoing cosmetic upper eyelid blepharoplasty.

Methods:

Orbicularis oculi samples from 22 eyelids were evaluated. There were 7 samples from the affected and 7 samples from the nonaffected sides of patients with HFS who had not been previously treated with botulinum toxin, and 8 samples from normal control patients. Muscle samples were prepared using hematoxylin and eosin staining, and a digital image analysis software was used for objective analyses.

Results:

When compared with normal controls, endomysial and perimysial connective tissue areas were significantly increased (P = 0.015) on the affected side in HFS, suggesting that this disorder is associated with chronic alterations that lead to muscle degeneration. Cell density was significantly reduced on the affected (P = 0.028) and also on the nonaffected sides in HFS (P = 0.003) compared with normal controls. This was observed, although, clinically, there were no signs or symptoms of increased muscular contraction on the nonaffected sides in any of the patients with HFS studied.

Conclusions:

Significant morphological differences in the orbicularis oculi muscle in patients with HFS were observed on both the affected and nonaffected sides. Our findings suggest a potential role for muscle homeostasis disturbances on both sides for patients with HFS. Affected sides in patients with HFS did, however, demonstrate muscle degeneration that was not present on the nonaffected sides.
Deep Learning and Transfer Learning for Optic Disc Laterality Detection: Implications for Machine Learning in Neuro-Ophthalmology
Authors: Liu T. Y. Alvin , Ting Daniel S. W. , Yi Paul H. , Wei Jinchi , Zhu Hongxi , Subramanian Prem S. , Li Taibo , Hui Ferdinand K. , Hager Gregory D. , Miller Neil R.
Published: August 2019

Background:

Deep learning (DL) has demonstrated human expert levels of performance for medical image classification in a wide array of medical fields, including ophthalmology. In this article, we present the results of our DL system designed to determine optic disc laterality, right eye vs left eye, in the presence of both normal and abnormal optic discs.

Methods:

Using transfer learning, we modified the ResNet-152 deep convolutional neural network (DCNN), pretrained on ImageNet, to determine the optic disc laterality. After a 5-fold cross-validation, we generated receiver operating characteristic curves and corresponding area under the curve (AUC) values to evaluate performance. The data set consisted of 576 color fundus photographs (51% right and 49% left). Both 30° photographs centered on the optic disc (63%) and photographs with varying degree of optic disc centration and/or wider field of view (37%) were included. Both normal (27%) and abnormal (73%) optic discs were included. Various neuro-ophthalmological diseases were represented, such as, but not limited to, atrophy, anterior ischemic optic neuropathy, hypoplasia, and papilledema.

Results:

Using 5-fold cross-validation (70% training; 10% validation; 20% testing), our DCNN for classifying right vs left optic disc achieved an average AUC of 0.999 (±0.002) with optimal threshold values, yielding an average accuracy of 98.78% (±1.52%), sensitivity of 98.60% (±1.72%), and specificity of 98.97% (±1.38%). When tested against a separate data set for external validation, our 5-fold cross-validation model achieved the following average performance: AUC 0.996 (±0.005), accuracy 97.2% (±2.0%), sensitivity 96.4% (±4.3%), and specificity 98.0% (±2.2%).

Conclusions:

Small data sets can be used to develop high-performing DL systems for semantic labeling of neuro-ophthalmology images, specifically in distinguishing between right and left optic discs, even in the presence of neuro-ophthalmological pathologies. Although this may seem like an elementary task, this study demonstrates the power of transfer learning and provides an example of a DCNN that can help curate large medical image databases for machine-learning purposes and facilitate ophthalmologist workflow by automatically labeling images according to laterality.
A Reliability and Comparative Analysis of the New Randomized King-Devick Test
Authors: Nguyen Minh Q. , King Doug , Pearce Alan J.
Published: August 2019

Objective:

The King-Devick (K-D) test is a rapid visual screening tool that can assess underlying brain trauma such as concussion via impairments in saccadic rhythm. A new tablet version of the K-D test using randomized numbers is now available, but reliability for this new version and comparison to the traditional K-D test has not yet been reported. Known for learning effects in the test, the aim of this study was to determine test–retest reliability and to compare performance of the new “randomized” version to the “traditional” K-D test version. We hypothesized that the “traditional” K-D test would show a greater rate of improvement with repeat application, compared with the “randomized” K-D test.

Methods:

Using a cross-sectional, repeated measures design in a healthy university student cohort (n = 96; age 21.6 ± 2.8 years; 49 women, 47 men), participants were required to complete the K-D test twice with a one-week break between testing sessions. Participants were randomly assigned into a “traditional” group, where they completed a test–retest of the established K-D protocol, using the same numbers; or the “randomized” group, where they completed test–retest protocol using 2 different sets of numbers.

Results:

Reliability testing showed a strong intraclass correlation coefficient for both the “traditional” test group (control group; 0.95 [CI: 0.91–0.97]) and the “randomized test group” (0.97 [CI: 0.95–0.98]). However, contrary to our hypothesis, no differences were found between “traditional” and “randomized” groups for baseline (control: 42.5 seconds [CI: 40.2–44.9 s] vs randomized: 41.5 [38.7–44.4], P = 0.23) and repeated testing between groups (control: 40.0 seconds [37.9–42.1 s] vs randomized: 39.5 [36.9–42.0], P = 0.55), with both groups showing improved times with repeated testing (control: 2.1 seconds [CI: 1.1–3.2 seconds] and randomized: 1.9 seconds CI: [0.9–2.9 seconds], P < 0.001).

Conclusions:

The “randomized” version of the K-D test, using different sets of numbers, demonstrates good reliability that is comparable to the traditional K-D testing protocol that uses the same number sets. However, similar to the “traditional” K-D test, learning effects were also observed in the “randomized” test, suggesting that learning effects are not because of content memorization, but rather familiarity of the test. As a result, although either test format is suitable for sideline concussion screening or return to play decisions, comparison of data should be made to the individual's baseline rather than to normative data sets.
Antipsychotic use in Northern Italian inter-episode bipolar disorder patients: considering both second- and first-generation agents
Authors: Cremaschi Laura , Ketter Terence Arthur , Arici Chiara , Miller Shefali , Hooshmand Farnaz , Dell’Osso Bernardo
Published: August 2019

Evidence supports increasing antipsychotic use in bipolar disorder, especially second-generation antipsychotics. However, data regarding first-generation antipsychotic contemporary use are limited. We studied 380 Northern Italian bipolar disorder inter-episode patients, grouped according to current antipsychotic use, stratified by bipolar subtype (BDI vs. BDII). Furthermore, we compared first-generation antipsychotic users vs. non-users. In our sample (n = 357), 81.8% were taking antipsychotics (74% second-generation antipsychotics, 24.1% first-generation antipsychotics), with antipsychotic use in BDI significantly more prevalent than in BDII (85.2% vs. 72.0%). Overall, antipsychotic users vs. non-users had higher rates of hypo/manic last episode, lifetime psychiatric hospitalization, psychosis, and current psychotropic use, but lower rates of anxiety disorder main comorbidity and current antidepressant use. First-generation antipsychotic use rates (30.3% in BDI vs. 6.5% in BDII) were associated with more frequently being unpartnered, having elevated first/last episodes, higher lifetime hospitalization, involuntary commitment, psychosis, and psychosocial rehabilitation rates, and more current psychotropic use, but lower Global Assessment Functioning scores and less current antidepressant use. Bipolar disorder patients had robust antipsychotic (second-generation antipsychotic > first-generation antipsychotic) use, consistently with previous reports. FGAs were still prescribed for a substantial group of patients, likely suffering from severe bipolar disorder. Prescriptions need to be monitored to assess their appropriateness and adherence to evidence-based recommendations.
Epigenome-wide association study of seizures in childhood and adolescence
Authors: Caramaschi Doretta , Hatcher Charlie , Mulder Rosa H. , Felix Janine F. , Cecil Charlotte A. M. , Relton Caroline L. , Walton Esther
Published: August 2019

The occurrence of seizures in childhood is often associated with neurodevelopmental impairments and school underachievement. Common genetic variants associated with epilepsy have been identified and epigenetic mechanisms have also been suggested to play a role. In this study we analysed the association of genome-wide blood DNA methylation with the occurrence of seizures in ∼800 children from the Avon Longitudinal Study of Parents and Children, UK, at birth (cord blood), during childhood and adolescence (peripheral blood). We also analysed the association between the lifetime occurrence of any seizures before age 13 with blood DNA methylation levels. We sought replication of the findings in the Generation R Study and explored causality using Mendelian randomization, i.e. using genetic variants as proxies. The results showed five CpG sites which were associated cross-sectionally with seizures either in childhood or adolescence (1-5% absolute methylation difference at pFDR<0.05), although the evidence of replication in an independent study was weak. One of these sites was located in the BDNF gene, which is highly expressed in the brain, and showed high correspondence with brain methylation levels. The Mendelian randomization analyses suggested that seizures might be causal for changes in methylation rather than vice-versa. In addition, seizure-associated methylation changes could affect other outcomes such as growth, cognitive skills and educational attainment. In conclusion, we present a link between seizures and DNA methylation which suggests that DNA methylation changes might mediate some of the effects of seizures on growth and neurodevelopment.
RasGRP1 (CalDAG-GEF-II) Mediates L-DOPA-induced Dyskinesia in a Mouse Model of Parkinson Disease
Authors: Ishragi Mehdi , Ramirez Jarquin Uri Nimrod , Shahani Neelam , Swarnkar Supriya , Galli Nicole , Rivera Oscar , Tsaprailis George , Scharager-Tapia Catherina , Crynen Gogce , Usiello Alessandro , Subramaniam Srinivasa
Published: August 2019

The therapeutic benefits of L–3,4–dihydroxyphenylalanine (L-DOPA) in Parkinson disease (PD) patients diminishes with the onset of abnormal involuntary movements (L-DOPA induced dyskinesia), a debilitating motor side effect. L-DOPA induced dyskinesia are due to altered dopaminergic signaling in the striatum, a brain region that controls motor and cognitive functions. However, the molecular mechanisms that promote L-DOPA-induced dyskinesia remain unclear. Here, we have reported that RasGRP1 (also known as CalDAG-GEF-II) physiologically mediated L-DOPA induced dyskinesia in a 6-hydroxy dopamine (6-OHDA) lesioned mouse model of PD. In this study, L-DOPA treatment rapidly upregulated RasGRP1 in the striatum. Our findings showed that RasGRP1 deleted mice (RasGRP1−/−) had drastically diminished L-DOPA-induced dyskinesia, andRasGRP1−/−mice did not interfere with the therapeutic benefits of L-DOPA. In terms of its mechanism, RasGRP1 mediates L-DOPA-induced extracellular regulated kinase (ERK), the mammalian target of rapamycin kinase (mTOR) and the cAMP/PKA pathway and binds directly with Ras-homolog-enriched in the brain (Rheb), which is a potent activator of mTOR, both in vitro and in the intact striatum. High-resolution tandem mass tag mass spectrometry analysis of striatal tissue revealed significant targets, such as phosphodiesterase (Pde1c), Pde2a, catechol-o-methyltransferase (comt), and glutamate decarboxylase 1 and 2 (Gad1 and Gad2), which are downstream regulators of RasGRP1 and are linked to L-DOPA-induced dyskinesia vulnerability. Collectively, the findings of this study demonstrated that RasGRP1 is a major regulator of L-DOPA-induced dyskinesia in the striatum. Drugs or gene-depletion strategies targeting RasGRP1 may offer novel therapeutic opportunities for preventing L-DOPA-induced dyskinesia in PD patients.
Oncogenic herpesvirus engages the endothelial transcription factors SOX18 and PROX1 to increase viral genome copies and virus production
Authors: Gramolelli Silvia , Elbasani Endrit , Nurminen Veijo , Tuohinto Krista , Günther Thomas , Kallinen Riikka E. , Kaijalainen Seppo P. , Diaz Raquel , Grundhoff Adam , Haglund Caj , Ziegelbauer Joseph M. , Bower Mark , Francois Mathias , Ojala Päivi M.
Published: August 2019

Kaposi sarcoma (KS) is a tumour of endothelial origin caused by KS herpesvirus (KSHV) infection and suggested to originate from lymphatic endothelial cells (LECs). While KSHV establishes latency in virtually all susceptible cell types, LECs support a spontaneous lytic gene expression program with high viral genome copies and release of infectious virus. Here, we investigated the role of PROX1, SOX18 and COUPTF2, drivers of lymphatic endothelial fate during embryogenesis, in this unique KSHV infection program. We found that these factors were co-expressed in KS tumours with the viral lytic marker K8.1, and that SOX18 and PROX1 regulate KSHV infection via two independent mechanisms. SOX18 binds to the viral origins of replication and its depletion or chemical inhibition significantly reduced the KSHV genome copies in LECs. PROX1 interacts with ORF50, the initiator of the lytic cascade, increases lytic gene expression and virus production and its depletion reduces KSHV spontaneous lytic reactivation. Upon lytic replication, PROX1 binds to the KSHV genome in the promoter region of ORF50 and enhances its transactivation activity. These results demonstrate the importance of two endothelial transcription factors in the regulation of the KSHV life cycle and introduce SOX18 inhibition as a potential, novel therapeutic modality for KS.
Cell-based Simulations of Biased Epithelial Lung Growth
Authors: Stopka Anna , Kokic Marco , Iber Dagmar
Published: August 2019

During morphogenesis, epithelial tubes elongate. In case of the mammalian lung, biased elongation has been linked to a bias in cell shape and cell division, but it has remained unclear whether a bias in cell shape along the axis of outgrowth is sufficient for biased outgrowth and how it arises. Here, we use our 2D cell-based tissue simulation softwareLBIBCellto investigate the conditions for biased epithelial outgrowth. We show that the observed bias in cell shape and cell division can result in the observed bias in outgrowth only in case of strong cortical tension, and comparison to biological data suggests that the cortical tension in epithelia is likely sufficient. We explore mechanisms that may result in the observed bias in cell division and cell shapes. To this end, we test the possibility that the surrounding tissue or extracellular matrix acts as a mechanical constraint that biases growth in longitudinal direction. While external compressive forces can result in the observed bias in outgrowth, we find that they do not result in the observed bias in cell shapes. We conclude that other mechanisms must exist that generate the bias in lung epithelial outgrowth.
Expansion of CRISPR loci with multiple memories of infection enables the survival of structured bacterial communities
Authors: Pyenson Nora C. , Marraffini Luciano A.
Published: August 2019

Type II CRISPR-Cas systems provide immunity against phages and plasmids that infect bacteria. Following infection, a short sequence of the phage genome known as the “spacer” is inserted into the CRISPR locus to capture a memory of the infection and immunize the host. Spacers are transcribed and processed into guide RNAs that direct the Cas9 nuclease to its target on the invader. Thousands of spacers are acquired to target the viral genome at multiple locations and neutralize phage mutants that evade the immunity specified by a single guide RNA. In liquid cultures, where phages and their hosts are constantly mixed, spacer diversity is generated at the population level, and a single immunization per cell is sufficient to confer robust immunity. Although rare, bacteria that acquire multiple spacers can also be found, demonstrating that type II CRISPR-Cas systems also have the capability of generating spacer diversity at the cellular level. However, conditions in which this feature is important for survival are poorly understood. Here we found that when phage infections occur on solid media, a high proportion of the surviving colonies display sectored morphologies that contain individual cells with multiple spacers. We show that this is the result of the bacteria-host co-evolution, in which the immunity provided by the initial acquired spacer is easily overcome by escaper phages that decimate all the progeny of the founder cell that do not acquire additional spacers. Our results reveal the versatility of type II CRISPR-Cas immunity, which can respond with both single or multiple spacer acquisition schemes to solve challenges presented by different environments.
Human ZKSCAN3 and Drosophila M1BP are functionally homologous transcription factors in autophagy regulation
Authors: Barthez Marine , Poplineau Mathilde , Elrefaey Marwa , Caruso Nathalie , Graba Yacine , Saurin Andrew J.
Published: August 2019

Autophagy is an essential cellular process that maintains homeostasis by recycling damaged organelles and nutrients during development and cellular stress. ZKSCAN3 is the sole identified master transcriptional repressor of autophagy in humans. How ZKSCAN3 achieves autophagy repression at the mechanistic or organismal level however still remains to be elucidated. Here, we demonstrate that vertebrate ZKSCAN3 and Drosophila M1BP are functionally homologous transcription factors in autophagy repression. Expression of ZKSCAN3 in Drosophila prevents premature autophagy onset due to loss of M1BP function and conversely, M1BP expression in human cells can prevent starvation-induced autophagy due to loss of nuclear ZKSCAN3 function. In Drosophila ZKSCAN3 binds genome-wide to sequences targeted by M1BP and transcriptionally regulates the majority of M1BP-controlled genes. These data allow the potential for transitioning the mechanisms, gene targets and plethora metabolic processes controlled by M1BP onto ZKSCAN3 and opens up Drosophila as a tool in studying the function of ZKSCAN3 in autophagy and tumourigenesis.