bluuebunny/crossref_metadata_2025 huggingface dataset:
The Impact of Temporal Artery Biopsy at a UK Tertiary Plastic Surgery Unit
Authors: Chew Bryan J. W. , Khajuria Ankur , Ibanez Javier
Published: December 2019

Background:

Guidelines recommend temporal artery biopsy (TAB) for patients suspected of having giant cell arteritis (GCA). We evaluated the impact of TAB on the diagnosis and management of patients with suspected GCA at a tertiary plastic surgery unit.

Methods:

A retrospective review of all TAB procedures performed at our centre over 7 years was performed. One hundred and one patients were included in the study. Patients were classified into 3 diagnostic groups: confirmed (positive TAB), presumed (negative TAB with high clinical suspicion) and unlikely (negative TAB with low clinical suspicion). The clinical presentation and management for each group were compared.

Results:

The average American College of Rheumatology (ACR) score was 3.07. The number of patients with an ACR score of ≥3 before TAB was 72 (71.3%) and remained the same after TAB. The number of patients who remained on steroid therapy was lower in the group with an unlikely diagnosis of GCA compared to the group with a confirmed diagnosis (p<0.05). Conversely, there was no significant difference in steroid therapy between those with a presumed and confirmed diagnosis (p>0.05).

Conclusions:

This study found a significant difference in steroid treatment between those with confirmed GCA and those where the diagnosis was unlikely showing that TAB may support decisions regarding steroid therapy. However, TAB was inappropriately requested for patients whose pre-TAB ACR score was ≥3 as this score is sufficient for the diagnosis of GCA. Therefore, the use of TAB should be limited to cases of diagnostic uncertainty.
EyeWatch Rescue of Refractory Hypotony After Baerveldt Drainage Device Implantation: Description of a New Technique
Authors: Elahi Sina , Bravetti Giorgio E. , Gillmann Kevin , Villamarin Adan , Meeus Léopold , Stergiopoulos Nikos , Mansouri Kaweh , Mermoud André
Published: December 2019

The most effective way to control glaucoma is by lowering intraocular pressure (IOP) in order to prevent the progression of the disease. Glaucoma drainage devices (GDDs) are surgical option reserved for refractory cases and have been designed to address known complications of conventional filtering surgery. They are, however, associated with a higher rate of complications related to early hypotony and late corneal decompensation. In the case of the commonly used Baerveldt Glaucoma Implant (BGI), techniques exist in an attempt to prevent early postoperative hypotony but can be highly variable and surgeon dependent. Moreover, the additional steps required can result in unstable IOP in the immediate postoperative period. In 2014, Villamarin and colleagues described for the first time an adjustable GDD, called the eyeWatch implant, designed to better control IOP fluctuations and avoid hypotony during the early postoperative period via magnetic control of the device tube lumen. This innovation provides the possibility to adjust the amount of aqueous humor outflow after device implantation in a noninvasive manner. We report the case of an 83-year-old patient with advanced pseudoexfoliative glaucoma, referred to our tertiary center because of disease progression despite topical therapy and having undergone deep sclerectomy. First, a BGI was implanted but was unfortunately complicated by a 3-month chronic refractory hypotony from day 8, and choroidal detachment despite medical management, choroidal drainage, and viscoelastic injections. After 3 months, the decision was made to rescue the situation with an eyeWatch adjunction to the BGI. Postoperatively, the IOP was successfully controlled through fine adjustments of the eyeWatch opening position, until the last visit 8 months after the rescue, with complete resolution of the choroidal detachment and without any medications. This demonstrates that the eyeWatch may offer an answer not only to the immediate postoperative hypotonic phase of the GDD surgery but also to the later cystic bleb hypertonic phase.
Neodymium Laser Treatment of IOP Rise Following Ex-Press Glaucoma Device Implantation: A Retrospective Review From 4 Institutions
Authors: Mustafa Majd , Shoham-Hazon Nir , Reiss George R. , Samuelson Thomas W. , Condon Gary , Ahmed Iqbal Ike K.
Published: December 2019

Précis:

Our retrospective study examined the use of neodymium laser in 53 eyes with high intraocular pressure (IOP) following Ex-Press filtration device implantation. We found a statistically significant immediate IOP-lowering effect in all eyes, with a mean IOP reduction of 13.34±8.99 mm Hg, and a posttreatment IOP of 14.30±8.57 mm Hg (P<0.0001). Of a subset of 43 eyes on which 6 months follow-up IOP data was available, 28 eyes achieved treatment success (IOP<18 without further surgical interventions) with a mean IOP of 11.39±4.03 mm Hg at 6 months.

Purpose:

The purpose of this study was to report on the use of neodymium laser for treatment of eyes with IOP rise following Ex-Press glaucoma filtration device implantation.

Methods:

We retrospectively examined the medical records of 73 patients who underwent Ex-Press device implantation at 4 medical institutions between 2007 and 2015 and subsequently developed an IOP rise. Enrollment criteria included patients with POAG on whom posttreatment IOP data is available. Indications for treatment with neodymium laser were an IOP above target and a flat bleb. To disrupt the presumed microblockage, the neodymium laser was aimed at the axial and relief ports of the Ex-Press device. Applanation tonometry measurements were followed up after neodymium treatment for variable time intervals. Success was defined as an IOP <18 mm Hg at 6 months without further surgical or laser-based glaucoma interventions.

Results:

A total of 73 charts were reviewed. Twenty patients were excluded due to insufficient data or a diagnosis other than POAG. Data from 53 eyes of the remaining 53 patients was analyzed. The mean duration between Ex-Press implantation and rise in IOP requiring neodymium intervention was 34.2 months (range, 1.1 to 67.2). We found a statistically significant immediate IOP-lowering effect in all eyes, with a mean IOP drop of 13.34±8.99 mm Hg, and a mean posttreatment IOP of 14.30±8.57 mm Hg (P<0.0001). Of a subset of 43 eyes on which 6 months follow-up IOP data was available, 11 eyes required further glaucoma intervention (surgery or laser-based); 4 eyes had an IOP of ≥18 at 6 months. In the remaining 28 successful eyes, a sustained IOP<18 mm Hg was observed at 6 months, with a mean pressure of 11.39±4.03 mm Hg (P<0.0001). Hypotony (IOP<5) occurred in 3 eyes immediately following treatment and self-resolved by 1 week.

Conclusion:

Our retrospective case series suggests that neodymium laser is a potential consideration in eyes with sustained IOP rise after Ex-Press device implantation.
The Physiologic Role of Corticosteroids in Menière's Disease: An Update on Glucocorticoid-mediated Pathophysiology and Corticosteroid Inner Ear Distribution
Authors: Froehlich Michael H. , Lambert Paul R.
Published: December 2019

There are multiple treatment options for Ménière's disease (MD), including dietary modifications, aminoglycoside therapy, and surgery. All have limitations, ranging from limited effectiveness to permanent hearing loss. Corticosteroids have long been used to manage MD due to their relative efficacy and tolerability, but the exact mechanism for disease alleviation is uncertain. Until recently, the precise distribution and role that glucocorticoid receptors play in inner ear diseases have remained largely uninvestigated. Several studies propose they influence mechanisms of fluid regulation through ion and water homeostasis. This review will provide an update on the basic science literature describing the activity of endogenous glucocorticoids and exogenous corticosteroids in the inner ear and the relevance to MD, as well as early clinical trial data pertaining to the application of novel technologies for more effective administration of corticosteroids for the treatment of MD.
The Distribution and Prevalence of Macrophages in the Cochlea Following Cochlear Implantation in the Human: An Immunohistochemical Study Using Anti-Iba1 Antibody
Authors: Okayasu Tadao , Quesnel Alicia M. , O’Malley Jennifer T. , Kamakura Takefumi , Nadol Joseph B.
Published: December 2019

Hypothesis:

Cochlear implantation may cause an increase in the number of macrophages in the human cochlea similar to previous findings in the vestibular endorgans.

Background:

Macrophages play a key role in both an inflammatory response and homeostatic maintenance. Recently, an increase in the prevalence of macrophages was demonstrated in the human vestibular endorgans after implantation. However, the prevalence of macrophages in the cochlea after implantation is unclear. The aim of this study was to compare the distribution and prevalence of macrophages in implanted human cochleae and the contralateral unimplanted ears.

Methods:

The prevalence of macrophages in the cochlea in 10 human subjects who had undergone unilateral cochlear implantation was studied by light microscopy using anti-Iba1 immunostaining. The densities of macrophages in the osseous spiral lamina (OSL) and Rosenthal's canal (RC) in implanted cochleae were compared with the contralateral unimplanted ears. The distribution of macrophage morphology (amoeboid, transitional, and ramified) was also compared.

Results:

There were activated and phagocytosing macrophages within the fibrotic sheath surrounding the electrode track and within fibrous tissue with lymphocytic infiltration in implanted ears. The densities of macrophages in OSL and RC in implanted ears were significantly greater than in unimplanted ears in some areas. There was also a difference in the prevalence of macrophage phenotype between the OSL and RC.

Conclusion:

An increase in the density of macrophages in the cochlea after cochlear implantation was demonstrated. Both phagocytosis and anti-inflammatory activity of macrophages were suggested by the distribution and prevalence of macrophages in the implanted cochlea.
Temporal Bone Anatomy in Superior Semicircular Canal Dehiscence: A Case Control Study on Bone Pneumatization and the Level of Middle Cranial Fossa
Authors: Tikka Theofano , Kontorinis Georgios
Published: December 2019

Objectives:

To assess for any association between the presence of superior semicircular canal dehiscence (SSCD) and temporal bone pneumatization and the height of middle fossa in symptomatic patients.

Study Design:

Retrospective case-control study.

Setting:

Tertiary, university referral center.

Patients:

Symptomatic patients with SSCD and a matched group of non-SSCD patients.

Intervention:

High-resolution computed tomography of the temporal bones.

Main Outcome Measures:

We graded the temporal bone pneumatization using the Virapongse classification and measured the distance between the middle fossa and the lateral semicircular canal on coronal plane at the most anterior aspect of the lateral and superior semicircular canals. We statistically compared all parameters (level of significance 0.05).

Results:

We enrolled 30 patients with SSCD, (males = 13, females = 17) with mean age of 47 years (SD: 26). The matched control group had similar baseline characteristics (p > 0.05). Grade 4 pneumatization was noted in 83.3% (n = 25) of SSCD patients with the remainder having grade 3. In the control group, 46.6% (n = 14) had a grade 4 pneumatization, 36.6% (n = 11) grade 3 and 16.6 5 (n = 5) grade 2. This difference was statistically significant (p = 0.003). The difference in the height of the middle cranial fossa between the two groups was also statistically significant (mean 3.80 [SD: 0.84] in SSCD group and 4.68 mm [SD: 0.85] in the control group; p < 0.0001).

Conclusions:

We found better-pneumatized mastoids in patients with SSCD, indicative of a direct association between temporal bone pneumatization and SSCD. Additionally, the middle fossa dura is lying significantly lower in patients with SSCD, factor of surgical importance.
Hyperventilation Syndrome: Investigating the Relationship Between Nijmegen Questionnaire, Vestibular Function Tests, and Patient Symptoms
Authors: Williams Christopher Y. K. , Williams Robert W. K. , Knight Richard , Hashmi Syed , Donnelly Neil , Bance Manohar
Published: December 2019

Objective:

To explore the Nijmegen Questionnaire (NQ) and its relationship to vestibular function tests and symptoms in patients with dizziness; to compare patient characteristics between those with a positive Nijmegen score and patients clinically diagnosed with hyperventilation syndrome (HVS).

Study Design:

Retrospective case series.

Setting:

Tertiary neurotology referral center.

Patients:

Patients seen at vestibular assessment were grouped according to positive (≥24) or negative (<24) Nijmegen scores; secondary analysis was performed on patients grouped by a clinical diagnosis of hyperventilation syndrome.

Intervention(s):

NQ, vestibular function tests, hospital anxiety and depression scale (HADS), vestibular rehabilitation benefit questionnaire (VRBQ).

Main Outcome Measure(s):

Medical records of patients presenting for vestibular assessment from January to December 2017 were retrospectively reviewed. Demographic data, self-reported questionnaire results, HVS diagnosis, vestibular test results, and reported symptoms were recorded.

Results:

In total, 359 patients presented for vestibular assessment with completed NQ. One hundred thirty nine patients (39%) had a positive (≥24) Nijmegen score. In 34 patients, a diagnosis of hyperventilation syndrome was recorded; 10 of these patients did not have a positive Nijmegen score.

There was no significant difference found in either vestibular lesion type or compensation status between patients with positive and negative Nijmegen scores (p > 0.05). Symptoms commonly described by patients with positive Nijmegen scores include “blurred vision,” “tingling,” “anxiety,” “shortness of breath,” “palpitations,” “panic,” “numbness,” “chest pain,” and “chest tightness.” In contrast, when grouped by HVS diagnosis, patients with HVS were significantly more likely to have No Lesion detected on vestibular function testing (p = 0.0366). “Panic,” “anxiety,” and “tingling” were the only significant symptoms reported more often in the HVS diagnosis group, while “nausea/vomiting” and “vertigo” were reported significantly less frequently compared with the non-HVS diagnosis group.

Conclusions:

Hyperventilation is a complex stimulus, with some effects manifesting in neurotology clinics. This study reveals discrepancies in both vestibular assessment findings and symptom profiles between patients with a positive screening score in the NQ and patients clinically diagnosed with hyperventilation syndrome. This data will inform clinicians’ interpretation of the NQ in the neurotologic setting.
Frequency and Predictors of Successful Transition of Care for Young Adults With Childhood Celiac Disease
Authors: Reilly Norelle R. , Hammer Marissa L. , Ludvigsson Jonas F. , Green Peter H.
Published: December 2019

Objectives:

Transition from pediatric to adult care for individuals with chronic conditions is important to prevent gaps in care, though this has not been well‐studied in celiac disease (CD). The aim of this study was to discern rates and predictors of successful transition of care for young adults with childhood‐diagnosed CD.

Methods:

An anonymous 21‐question online survey was sent to individuals on our center's email contact list seeking responses from those ages 18 to 25 years diagnosed with CD before age 18 years. Information collected included method of diagnosis, demographics, CD‐related care, reasons for not seeking care, and symptoms.

Results:

Respondents (n = 98), 70% women, had a median age of 21 years (IQR 19‐‐23 years). The majority were full or part‐time students (67%; 95% CI 59%–77%). Only 31% of respondents had successfully transitioned to an adult CD provider. Some 37% (95% CI 29%–48%) were not receiving any CD medical care. An older age at diagnosis was associated with successful transition to adult gastroenterology (P = 0.002) as well as with greater symptom scores (P = 0.002). Receiving a referral for ongoing adult CD care predicted successful transition to an adult provider (odds ratio [OR] 3.92, 95% CI 1.58–9.72).

Conclusions:

Transition of care for young adults with CD is inconsistent, particularly among asymptomatic patients. Receipt of a referral for an adult provider significantly improves follow‐up rates.
Psychometric Testing of a Patient Empowerment, Engagement, and Activation Survey
Authors: Stichler Jaynelle F. , Pelletier Luc R.
Published: December 2019

Background:

Patient or person-centered care has become a widely used philosophical framework and yet has varying definitions and characteristics. Person-centered care has recently been conceptualized as patient empowerment, engagement, and activation with studies citing positive outcomes.

Purpose:

This study reports the psychometric properties of the Patient Empowerment, Engagement, and Activation Survey.

Methods:

An instrument development and testing approach was used.

Results:

A 21-item survey was developed demonstrating respectable Cronbach α coefficients for the total scale (α = 0.88) and for each subscale: Empowerment (α = 0.71), Engagement (α = 0.81), and Activation (α = 0.76). A regression analysis with 1 item, “I am ready to be discharged” as the dependent variable and all other items as independent variables explained 65% of the variance in readiness for discharge (P < .001).

Discussion:

The Patient Empowerment, Engagement, and Activation Survey can be used to evaluate patients' perspectives of care quality (empowerment and engagement) and readiness for discharge (activation).
DSM-5 Personality Disorders and Traits in Patients With Severe Health Anxiety
Authors: Skjernov Mathias , Bach Bo , Fink Per , Fallon Brian , Soegaard Ulf , Simonsen Erik
Published: December 2019

Severe health anxiety (SHA)/hypochondriasis (HY) is often associated with personality pathology; however, studies report inconsistent results. In general populations, 12% have a personality disorder (PD). We assessed physician-referred psychiatric outpatients with SHA enrolled for a treatment study (n = 84) with the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) axis II (SCID-II), Personality Inventory for DSM-5 (PID-5), Whiteley Index 7, and Short Health Anxiety Inventory, and the healthy controls (n = 84) with PID-5 only. There were 71.4% of the patients who met criteria for PDs: avoidant (22.6%), obsessive-compulsive (16.7%), depressive (16.7%), dependent (7.1%), paranoid (3.6%), borderline (2.4%), and not otherwise specified (32.1%). Severity of personality pathology was associated with severity of health anxiety. In group comparisons, PID-5 trait domains of negative affectivity, detachment, low antagonism, and low disinhibition, and facets of anxiousness, separation insecurity, and low attention seeking emerged as unique predictors of SHA. Personality pathology is common among individuals with SHA/HY. Further research is needed to understand the nature of the relationship between health anxiety and personality pathology and to determine whether treatments that target both SHA/HY and personality pathology will improve short- and long-term outcomes.
Stress Ulcer Prophylaxis in Critically Ill Children: A Multicenter Observational Study
Authors: Duffett Mark , Chan Alice , Closs Jordan , McGloin Rumi , McKelvie Greg , Pong Sandra , Seto Winnie , Slaney Heather , Vaninetti Gina , Vanniyasingam Thuva
Published: December 2019

Objective:

To describe current stress ulcer prophylaxis practice in Canadian PICUs.

Design:

Multicenter cohort study. We defined stress ulcer prophylaxis as the use of a proton-pump inhibitor, histamine-2 receptor antagonist, or sucralfate within the first 2 PICU days among children who had not been on these medications at home and had no evidence of gastrointestinal bleeding.

Setting:

Seven PICUs in Canada.

Patients:

Three hundred seventy-eight children requiring mechanical ventilation.

Interventions:

None.

Measurements and Main Results:

Children were ventilated for a median (interquartile range) of 2 days (1–6 d) and stayed in the PICU for a median (interquartile range) of 4 days (2–10 d). The median (interquartile range) age was 1.3 years (0.3–6.7 yr). Seventy percent of all children received acid suppression during their PICU stay. One hundred sixty-seven (54%) of the 309 children eligible for stress ulcer prophylaxis received it. Histamine-2 receptor antagonists were the most frequently used class (66%), followed by proton-pump inhibitors (47%) and sucralfate (4%), and 20% received more than one class. Stress ulcer prophylaxis was continued on the PICU transfer orders for 34% of these children. Children who received prophylaxis were older and had a higher Pediatric Risk of Mortality III score, more often received nonsteroidal anti-inflammatory drugs and systemic corticosteroids and received less enteral nutrition. In multivariate analysis, age and invasive mechanical ventilation were independently associated with an increased likelihood of receiving stress ulcer prophylaxis and receiving feeds was independently associated with a decreased likelihood of receiving stress ulcer prophylaxis. Gastrointestinal bleeding was reported in 21 (6%) of 378 children; three (0.8%) were clinically important. Eighteen percent were treated for a new respiratory tract infection, and 1% developed Clostridium difficile–associated diarrhea.

Conclusions:

Stress ulcer prophylaxis is common in Canadian PICUs. Clinically important gastrointestinal bleeding and C. difficile–associated diarrhea are rare, and the utility of routine prophylaxis should be examined.
Viral suppression and factors associated with failure to achieve viral suppression among pregnant women in South Africa
Authors: Woldesenbet Selamawit A. , Kufa Tendesayi , Barron Peter , Chirombo Brian C. , Cheyip Mireille , Ayalew Kassahun , Lombard Carl , Manda Samuel , Diallo Karidia , Pillay Yogan , Puren Adrian J.
Published: December 2019

Objective:

To describe viral load levels among pregnant women and factors associated with failure to achieve viral suppression (viral load ≤50 copies/ml) during pregnancy.

Design:

Between 1 October and 15 November 2017, a cross-sectional survey was conducted among 15–49-year-old pregnant women attending antenatal care (ANC) at 1595 nationally representative public facilities.

Methods:

Blood specimens were taken from each pregnant woman and tested for HIV. Viral load testing was done on all HIV-positive specimens. Demographic and clinical data were extracted from medical records or self-reported. Survey logistic regression examined factors associated with failure to achieve viral suppression.

Result:

Of 10 052 HIV-positive participants with viral load data, 56.2% were virally suppressed. Participants initiating antiretroviral therapy (ART) prior to pregnancy had higher viral suppression (71.0%) by their third trimester compared with participants initiating ART during pregnancy (59.3%). Booking for ANC during the third trimester vs. earlier: [adjusted odds ratio (AOR) 1.8, 95% confidence interval (CI):1.4–2.3], low frequency of ANC visits (AOR for 2 ANC visits vs. ≥4 ANC visits: 2.0, 95% CI:1.7–2.4), delayed initiation of ART (AOR for ART initiated at the second trimester vs. before pregnancy:2.2, 95% CI:1.8–2.7), and younger age (AOR for 15–24 vs. 35–49 years: 1.4, 95% CI:1.2–1.8) were associated with failure to achieve viral suppression during the third trimester.

Conclusion:

Failure to achieve viral suppression was primarily associated with late ANC booking and late initiation of ART. Efforts to improve early ANC booking and early ART initiation in the general population would help improve viral suppression rates among pregnant women. In addition, the study found, despite initiating ART prior to pregnancy, more than one quarter of participants did not achieve viral suppression in their third trimester. This highlights the need to closely monitor viral load and strengthen counselling and support services for ART adherence.
Global Burden of Craniofacial Disorders: Where Should Volunteering Plastic Surgeons and Governments Focus Their Care?
Authors: Davé Dattesh R. , Nagarjan Neeraja , Canner Joseph K. , Kushner Adam L. , Wong Granger B.
Published: December 2019

Purpose:

Approximately 11% of the global burden of disease is surgically treatable. When located within the head, face, and neck region, plastic surgeons are particularly trained to treat these conditions. The purpose of this study was to describe the etiology, disability, and barriers to receiving care for diseases of the head, face, mouth, and neck region across 4 low-and-middle-income countries.

Methods:

The Surgeons OverSeas Assessment of Surgical Need (SOSAS) instrument is a cluster randomized, cross-sectional, national survey administered in Nepal, Rwanda, Sierra Leone, and Uganda from 2011 to 2014. The survey identifies demographic characteristics, etiology, disease timing, proportion seeking/receiving care, barriers to care, and disability.

Results:

Across the 4 countries, 1413 diseases of head, face, mouth, and neck region were identified. Masses (22.13%) and trauma (32.8%) were the most common etiology. Nepal reported the largest proportion of masses (40.22%) and Rwanda reported the largest amount of trauma (52.65%) (P < 0.001). Rwanda had the highest proportion of individuals seeking (89.6%) and receiving care (83.63%) while Sierra Leone reported the fewest (60% versus 47.77%, P < 0.001). In our multi-variate analysis literacy and chronic conditions were predictors for receiving care while diseases causing the greatest disability predicted not receiving care (ORa .58 and .48 versus 1.31 P < 0.001).

Conclusions:

The global volunteering plastic surgeon should be prepared to treat chronic craniofacial conditions. Furthermore, governments should address structural barriers, such as health illiteracy and lack of access to local plastic surgery care by supporting local training efforts.
Btk SH2-kinase interface is critical for allosteric kinase activation and its targeting inhibits B-cell neoplasms
Authors: Duarte Daniel P. , Lamontanara Allan J. , La Sala Giuseppina , Jeong Sukyo , Sohn Yoo-Kyoung , Panjkovich Alejandro , Georgeon Sandrine , Kükenshöner Tim , Marcaida Maria J. , Pojer Florence , De Vivo Marco , Svergun Dmitri , Kim Hak-Sung , Dal Peraro Matteo , Hantschel Oliver
Published: December 2019

Bruton’s tyrosine kinase (Btk) is a key component for B-cell maturation and activation. Btk loss-of-function mutations cause human X-linked agammaglobulinemia (XLA). In contrast, constitutive Btk signaling drives several B-cell neoplasms, which may be treated with tyrosine kinase inhibitors (TKIs). Here, we uncovered the molecular mechanism by which a subset of XLA mutations in the SH2 domain strongly perturbs Btk activation. Using a combination of molecular dynamics (MD) simulations and small-angle X-ray scattering (SAXS), we discovered an allosteric interface between the SH2 and kinase domain to which multiple XLA mutations map and which is required for Btk activation. As allosteric interactions provide unique targeting opportunities, we developed an engineered repebody protein binding to the Btk SH2 domain and able to disrupt the SH2-kinase interaction. The repebody prevented activation of wild-type and TKI-resistant Btk, inhibited Btk-dependent signaling and proliferation of malignant B-cells. Therefore, the SH2-kinase interface is critical for Btk activation and a targetable site for allosteric inhibition.
Thrombospondin-1 Promotes Circuit-Specific Synapse Formation via β1-Integrin
Authors: Koh Sehwon , Roy Suva , Eroglu Oznur , Strader Samuel , Chen William J. , Kay Jeremy N. , Field Greg D. , Eroglu Cagla
Published: December 2019

Glial cells regulate synaptic connectivity during development, but whether they selectively instruct the formation of specific synaptic circuits is not known. Here we show that the major perisynaptic glia of the retina, the Muller glia (MG), control the proper establishment of the direction-selective (DS) circuit by a synaptogenic protein, Thrombospondin 1 (TSP1). We found that TSP1 promotes excitatory synapse formation specifically in on-off Direction-Selective retinal Ganglion Cells (ooDSGCs). Lack of TSP1 leads to reduced synapse formation within the inner plexiform sublayers containing DS-circuit, resulting in deficits of ooDSGC function. Even though pan-TSP receptor, α2δ-1, interaction is required for TSP1-induced synapse formation, the ooDSGC-subtype specificity of TSP1 is conferred by a second neuronal TSP1 receptor, β1-Integrin. Furthermore, conditional deletion of β1-Integrin in ooDSGCs results in diminished excitatory synapse formation without disturbing laminar organization showing that MG-secreted TSP1 controls circuit-specific synapse formation via β1-Integrin.
Distinct architecture and composition of mouse axonemal radial spoke head revealed by cryo-EM
Authors: Zheng Wei , Li Fan , Ding Zhanyu , Liu Hao , Zhu Lei , Li Jiawei , Gao Qi , Fu Zhenglin , Peng Chao , Yan Xiumin , Zhu Xueliang , Cong Yao
Published: December 2019

The radial spoke (RS) transmits mechanochemical signals from the central pair apparatus (CP) to axonemal dynein arms to coordinate ciliary motility. The RS head, directly contacting with CP, differs dramatically in morphology between protozoan and mammal. Here we show the murine RS head is compositionally distinct from the Chlamydomonas one. Our reconstituted murine RS head core complex consists of Rsph1, Rsph3b, Rsph4a, and Rsph9, lacking Rsph6a whose orthologue exists in the Chlamydomonas RS head. We present the unprecedented cryo-EM structure of RS head core complex at 4.5-Å resolution and identified the subunit location and their interaction network. In this complex, Rsph3b, Rsph4a, and Rsph9 forms a compact body with Rsph4a serving possibly as an assembly scaffold and Rsph3b in a location that might link the head with stalk. Interestingly, two Rsph1 subunits constitute the two stretching-arms possibly for optimized RS-CP interaction. We also propose a sawtooth model for the RS-CP interaction. Our study suggests that the RS head experiences profound remodeling to probably comply with both structural and functional alterations of the axoneme during evolution.
Phage steering of antibiotic-resistance evolution in the bacterial pathogen Pseudomonas aeruginosa
Authors: Gurney James , Pradier Léa , Griffin Joanne S. , Gougat-Barbera Claire , Chan Benjamin K. , Turner Paul E. , Kaltz Oliver , Hochberg Michael E.
Published: December 2019

Antimicrobial resistance is a growing global concern and has spurred increasing efforts to find alternative therapeutics. Bacteriophage therapy has seen near constant use in eastern Europe since its discovery over a century ago. One promising approach is to use phages that not only reduce bacterial pathogen loads, but also select for phage resistance mechanisms that trade-off with antibiotic resistance – so called ‘phage steering’. Recent work has shown that phage OMKO1 can interact with efflux pumps and in so doing select for both phage resistance and antibiotic sensitivity. We tested the robustness of this approach to three different antibiotics in vitro and one in vivo. We show that in vitro OMKO1 can reduce antibiotic resistance either in the absence or the presence of antibiotics. Our in vivo experiment showed that phage increased the survival times of wax moth larvae and increased bacterial sensitivity to erythromycin, both in the absence and presence of the antibiotic. We discuss the implications of our findings for future research on this promising therapeutic approach using OMKO1.
Establishment Process of a Magic Trait Allele subject to Both Divergent Selection and Assortative Mating
Authors: Sakamoto T. , Innan H.
Published: December 2019

Sexual selection and divergent selection are among the major driving forces of reproductive isolation, which could eventually result in speciation. A magic trait is defined such that a single trait is subject to both divergent selection and sexual selection through phenotype-based assortative mating. We are here interested in the evolutionary behavior of alleles in a genetic locus responsible for a magic trait. We assume that, in a pair of homogeneous subpopulations, a mutant allele arises at the magic trait locus, and theoretically obtain the probability that the new allele establishes in the population. We also consider the trajectory of allele frequency along the establishment. Divergent selection simply favors the new allele to fix where it is beneficial, whereas assortative mating works against rare alleles. It is theoretically demonstrated that the fate of the new allele is determined by the relative contributions of the two selective forces, divergent selection and assortative mating, when the allele is rare so that the two selective forces counteract. We also show that random genetic drift also plays an important role. The theoretical results would contribute to improve our understanding of how natural selection initiates speciation.
Transcriptome analysis reveals salinity responses in four Tartary buckwheat cultivars
Authors: Song Jin-Nan , Liu Xue-Hua , Wang Ya-Qi , Yang Hong-Bing
Published: December 2019

Disclaimer Statement

The authors have withdrawn this manuscript (BIORXIV/2019/869263) entitled Transcriptome analysis reveals salinity responses in four Tartary buckwheat cultivars because it requires adding new data and further modifications. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Polyandry and paternity affect disease resistance in eusocial wasps: support for the parasite–pathogen hypothesis
Authors: Saga Tatsuya , Okuno Masaki , Loope Kevin J. , Tsuchida Koji , Ohbayashi Kako , Shimada Masakazu , Okada Yasukazu
Published: December 2019

Polyandry (multiple mating by females) is a central challenge for understanding the evolution of eusociality. Several hypotheses have been proposed to explain its observed benefits in eusocial Hymenoptera, and one, the parasite–pathogen hypothesis, proposes that high genotypic variance among workers for disease resistance prevents catastrophic colony collapse. We tested the parasite–pathogen hypothesis in the polyandrous waspVespula shidai. We infected isolated workers with the entomopathogenic fungusBeauveria bassianaand quantified their survival in the laboratory. Additionally, we conducted paternity analysis of the workers using nine microsatellite loci to investigate the relationship between survival and matriline/patriline of the workers. As predicted by the parasite–pathogen hypothesis, nestmate workers of different patrilines showed differential resistance toB. bassiana. We also demonstrated variations in virulence among strains ofB. bassiana. Our results are the first to directly support the parasite–pathogen hypothesis in eusocial wasps and suggest that similar evolutionary pressures drove the convergent origin and maintenance of polyandry in ants, bees, and wasps.
TBK1 regulates autophagic clearance of soluble mutant huntingtin and inhibits aggregation/toxicity in different models of Huntington’s disease
Authors: Hegde Ramanath Narayana , Chiki Anass , Petricca Lara , Martufi Paola , Arbez Nicolas , Mouchiroud Laurent , Auwerx Johan , Landles Christian , Bates Gillian P. , Singh-Bains Malvindar K. , Curtis Maurice A , Faull Richard L. M. , Ross Christopher A. , Caricasole Andrea , Lashuel Hilal A
Published: December 2019

Phosphorylation of the N-terminal domain of the Huntingtin (HTT) protein (at T3, S13, and S16) has emerged as a key regulator of HTT stability, clearance, localization, aggregation and toxicity. Herein, we report the discovery and validation of a kinase, TANK-binding kinase 1 (TBK1), that specifically and efficiently phosphorylates both wild-type and mutant full-length or N-terminal fragments of HTTin vitro(S13/S16) and in cell/ neuronal cultures (S13). We show that overexpression of TBK1 in mammalian cells, primary neurons and aCaenorhabditis elegansmodel of Huntington’s Disease (HD) increases mutant HTTex1 phosphorylation, lowers its levels, increases its nuclear localization and significantly reduces its aggregation and cytotoxicity. Our mechanistic studies demonstrate that the TBK1-mediated neuroprotective effects are due to phosphorylation-dependent inhibition of mutant HTTex1 aggregation and an increase in autophagic flux. These findings suggest that upregulation and/or activation of TBK1 represents a viable strategy for the treatment of HD.

Graphical abstract
Genomic prediction using low density marker panels in aquaculture: performance across species, traits, and genotyping platforms
Authors: Kriaridou Christina , Tsairidou Smaragda , Houston Ross D. , Robledo Diego
Published: December 2019

Genomic selection increases the rate of genetic gain in breeding programmes, which results in significant cumulative improvements in commercially important traits such as disease resistance. Genomic selection currently relies on collecting genome-wide genotype data accross a large number of individuals which requires substantial economic investment. However, global aquaculture production predominantly occurs in small and medium sized enterprises for whom this technology can be prohibitively expensive. For genomic selection to benefit these aquaculture sectors more cost-efficient genotyping is necessary. In this study the utility of low and medium density SNP panels (ranging from 100 to 9000 SNPs) to accurate predict breeding values was tested and compared in four aquaculture datasets with different characteristics (species, genome size, genotyping platform, family number and size, total population size, and target trait). A consistent pattern of genomic prediction accuracy was observed across species, with little or no reduction until SNP density was reduced below 1,000 SNPs. Below this SNP density, heritability estimates and genomic prediction accuracies tended to be lower and more variable (93 % of maximum accuracy achieved with 1,000 SNPs, 89 % with 500 SNPs, and 70% with 100 SNPs). Now that a multitude of studies have highlighted the benefits of genomic over pedigree-based prediction of breeding values in aquaculture species, the results of the current study highlight that these benefits can be achieved at lower SNP densities and at lower cost, raising the possibility of a broader application of genetic improvement in smaller and more fragmented aquaculture settings.
Long-Term In Vivo Biocompatibility of Single-Walled Carbon Nanotubes
Authors: Galassi Thomas V. , Antman-Passig Merav , Yaari Zvi , Jessurun Jose , Schwartz Robert E. , Heller Daniel A.
Published: December 2019

Over the past two decades, measurements of carbon nanotube toxicity and biodistribution have yielded a wide range of results. Properties such as nanotube type (single-walled vs. multi-walled), purity, length, aggregation state, and functionalization, as well as route of administration, greatly affect both the biocompatibility and biodistribution of carbon nanotubes. These differences suggest that generalizable conclusions may be elusive and that studies must be material- and application-specific. Here, we assess the short- and long-term biodistribution and biocompatibility of a single-chirality DNA-encapsulated single-walled carbon nanotube complex upon intravenous administration that was previously shown to function as an in-vivo reporter of endolysosomal lipid accumulation. Regarding biodistribution and fate, we found bulk specificity to the liver and >90% signal attenuation by 14 days in mice. Using near-infrared hyperspectral microscopy to measure single nanotubes, we found low-level, long-term persistence in organs such as the heart, liver, lung, kidney, and spleen. Measurements of histology, animal weight, complete blood count, and biomarkers of organ function all suggest short- and long-term biocompatibility. This work suggests that carbon nanotubes can be used as preclinical research tools in-vivo without affecting acute or long-term health.
Dimerization of human drebrin-like protein governs its biological activity
Authors: Ghosh Arindam , Enderlein Jörg , Butkevich Eugenia
Published: December 2019

Drebrin-like protein (DBNL) is a multidomain F-actin binding protein, which also interacts with other molecules within different intracellular pathways. Here, we present quantitative measurements on size and conformation of human DBNL. Using dual focus fluorescence correlation spectroscopy, we determined the hydrodynamic radius of DBNL monomer. Native gel electrophoresis and dual color fluorescence cross-correlation spectroscopy show that both endogenous and recombinant DBNL exist as dimer under physiological conditions. We demonstrate that C-terminal truncations of DBNL downstream of the coiled-coil domain result in its oligomerization at nanomolar concentration. In contrast, the ADF-H domain alone is a monomer, which displays a concentration-dependent self-assembly. In vivo FLIM-FRET imaging shows that the presence of only actin-binding domains is not sufficient for DBNL to localize properly at actin filament inside the cell. In summary, our work provides a detailed insight on structure-function relationship of human drebrin-like protein.
T-loops Refold after Telomerase Extension and Unfold Again at Late S/G2 for C-strand Fill-in
Authors: Mak Sabrina S.M. , Smiraldo Phillip G. , Chow Tracy T. , Wright Woodring E. , Shay Jerry W.
Published: December 2019

Telomeres are the structures that protect the ends of each chromosome and prevent them from being recognized as broken DNA in need of repair. During human fetal development telomere length is ~15 kb and is maintained by the ribonucleoprotein telomerase. In neonates telomerase becomes spliced into inactive forms in most tissues. Afterwards, lagging strand synthesis fails to copy the very end and telomeres become progressively shorter as cells divide. Part of the mechanism for avoiding the DNA damage machinery is by forming a t-loop structure that has no free end. The telomeric 3’ overhang is inserted into the duplex DNA where it displaces the G-rich strand, forming a D-loop. It is unknown whether this D-loop is the size of the overhang, or whether branch migration results in a larger D-loop. Telomere t-loops must unfold for replication and telomerase extension during S phase. It is also unknown whether t-loops remain unfolded after replication until C-strand fill-in at late S/G2, or if they refold after replication and then unfold again for fill-in at late S/G2. We have developed a biochemical t-loop assay to address these issues, and demonstrate that most t-loops persist throughout S phase both before and after their replication.

Highlights

T-loops unfold twice during each S-phase

Virtually all telomeres are packaged into t-loops

Large amounts of t-loops can easily be purified without specialized materials
Cytokines and schizophrenia revisited: a two-sample multi-marker Mendelian randomization approach
Authors: Ren Hongyan , Meng Yajing , Zhang Yamin , Wang Qiang , Deng Wei , Ma Xiaohong , Zhao Liansheng , Li Xiaojing , Wang Yingcheng , Sham Pak , Li Tao
Published: December 2019

Background

Schizophrenia is a complex mental disorder with recent evidence suggesting a critical immune component underpinning its pathophysiology. Two-sample Mendelian randomization (MR) provided an opportunity to probe the immune changes in schizophrenia by harnessing the increasing availability of summary-level data from large GWAS consortia.

Objective

To map the extensive immune response of schizophrenia in terms of cytokines/chemokines and to explore the effect of cytokines induced by schizophrenia (SCZ-induced cytokines) on the brain structure and function

Sources and methods

Using the summary-level data generated from GWAS of schizophrenia, cytokines in the peripheral blood and imaging-derived phenotypes (IDPs), we performed two rounds of two-sample MR analysis; the identified cytokines from first round of analysis (schizophrenia => cytokines) were modeled for its underlying structure and subsequent clustering analysis further grouped SCZ-induced cytokines based on their genetic similarities. The multi-phenotype summary statistics of each cytokine module were then used as instrumental variables (IVs) for the second round of MR analysis to detect their effect on brain structure and function.

Results

The first round of MR analysis identified nine cytokines, the highlight of which includes IL18 (OR = 1.292, P = 8.37 × 10−42) and TNFa (OR = 0.721, P = 7.33 × 10−6), to be causally associated with schizophrenia. These SCZ-induced cytokines could be clustered into three modules. The second round of MR analysis (cytokine module => IDPs) indicated that module B (SCGFb-IP10-CTACK-IL6) significantly increased the level of IDPs including IDP_T1_SIENAX_peripheral_grey_normalised_volume (β = 0.0453, P = 4.40×1010), IDP_dMRI_TBSS_MD_Posterior_corona_radiata_R (β= 0.0584, P = 8.89× 10−16) and IDP_dMRI_TBSS_MD_Cingulum_hippocampus_R (β = 0.0563, P = 9.88× 10−15), with module C (IL18-GROa-TNFa) increasing the level of IDP_dMRI_TBSS_L2_Posterior_thalamic_radiation_R (β= 0.0341, P = 2.67× 10−6).

Conclusion

Our study, for the first time, mapped the causal link from schizophrenia to the comprehensive immune responses, and the findings suggest immune networks play a role in pathophysiology of schizophrenia by mediating the deviations of total gray matter volume and white matter fibers possibly in the mesolimbic system.
Regulating lipid composition rationalizes acyl-tail saturation homeostasis in ectotherms
Authors: Girard M. , Bereau T.
Published: December 2019

Cell membranes mainly consist of lipid bilayers with an actively regulated composition. The underlying processes are still poorly understood, in particular how the hundreds of components are controlled. Surprisingly, in recent experiments on ectotherms, the cholesterol fraction, along with un- and mono-saturated acyl tail fractions and demixing temperatures, was shown to increase with body temperature. We establish a model based on chemical reaction networks to study regulation of membranes, resulting in multiple semi-grand canonical ensembles. By running computer simulations, we show that higher cholesterol fractions correlate with lower degrees of unsaturation, ultimately controlling the composition of lipid tails. Cholesterol also dictates membrane viscosity and regulation of the latter implies that cholesterol must increase with temperature. Overall, our model proposes a different picture of lipid regulation, where components can be passively, instead of actively, regulated.

SIGNIFICANCE

In this article, we propose a regulation model where only some of the components are actively regulated between membranes, while others are naturally balanced by chemical potentials. This model provides a rationale to recently measured puzzling trends in ectotherms, that is, increased plasma membrane cholesterol fraction with temperature. Here, we show that it is directly correlated with with acyl tail saturation and order parameter correlation length. Furthermore, we highlight the relation between cholesterol and membrane viscosity.