bluuebunny/crossref_metadata_2025 huggingface dataset:
Timing of Surgery for Thoracolumbar Spine Trauma
Authors: Ruddell Jack H. , DePasse J. Mason , Tang Oliver Y. , Daniels Alan H.
Published: October 2020

Study Design:

Large multicenter retrospective cohort study.

Objective:

The objective of this study was to analyze the effect of fusion timing on inpatient outcomes in a nationally representative population with thoracolumbar fracture and concurrent neurological injury.

Summary of Background Data:

Among thoracolumbar trauma admissions, concurrent neurological injury is associated with greater long-term morbidity. There is little consensus on optimal surgical timing for these patients; previous investigations fail to differentiate thoracolumbar fracture with and without neurological injury.

Materials and Methods:

We analyzed 19,136 nonelective National Inpatient Sample cases (2004–2014) containing International Classifications of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes for closed thoracic/lumbar fracture with neurological injury and procedure codes for primary thoracolumbar/lumbosacral fusion, excluding open/cervical fracture. Timing classification from admission to fusion was same-day, 1–2-, 3–6-, and ≥7-day delay. Primary outcomes included in-hospital mortality, complications, and infection; secondary outcomes included total and postoperative length of stay and charges. Logistic regressions and generalized linear models with gamma distribution and log-link evaluated the effect of surgical timing on primary and secondary outcomes, respectively, controlling for age, sex, fracture location, fusion approach, multiorgan system injury severity score, and medical comorbidities.

Results:

Patients undergoing surgery ≤72 hours (n=12,845) had the lowest odds of in-hospital cardiac [odds ratio (OR)=0.595; 95% confidence interval (CI), 0.357–0.991] and respiratory complications (OR=0.495; 95% CI, 0.313–0.784) and infection (OR=0.615; 95% CI, 0.390–0.969). No differences were observed between same-day (n=4724) and 1–2-day delay (n=8121) (P>0.05). Lowest odds of hemorrhage or hematoma was observed following 3–6-day delay (OR=0.467; 95% CI, 0.236–0.922). A ≥7-day delay to fusion (n=2,002) was associated with greatest odds of hemorrhage/hematoma (OR=2.019; 1.107–3.683), respiratory complications (OR=1.850; 95% CI, 1.076–3.180), and infection (OR=3.155; 95% CI, 1.891–5.263) and greatest increases in mean postoperative length of stay (4.26% or 35.3% additional days) and charges (163,562 or 71.7% additional US dollars) (P<0.001).

Conclusions:

Patients with thoracolumbar fracture and associated neurological injury who underwent surgery within 3 days of admission experienced fewer in-hospital complications. These benefits may be due to secondary injury mechanism avoidance and earlier mobilization.

Level of Evidence:

Level III.
Socioeconomic Factors Account for Variability in Language Skills in Preschoolers with Autism Spectrum Disorders
Authors: Olson Lindsay , Kinnear Mikaela , Chen Bosi , Reynolds Sarah , Ibarra Cynthia , Wang Tiffany , Linke Annika , Fishman Inna
Published: October 2020

Objective:

Although no longer required for a diagnosis, language delays are extremely common in children diagnosed with autism spectrum disorders (ASD). Factors associated with socioeconomic status (SES) have broad-reaching impact on language development in early childhood. Despite recent advances in characterizing autism in early childhood, the relationship between SES and language development in ASD has not received much attention.

The objective of this study was

to examine whether toddlers and preschoolers with ASD from low-resource families are more likely to experience language delays above and beyond those associated with autism itself.

Methods:

Developmental and diagnostic assessments including the Mullen Scales of Early Learning, the Autism Diagnostic Observation Schedule, Second Edition, and the Vineland Adaptive Behavior Scales were obtained from 62 young children with ASD and 45 typically developing children aged 15 to 64 months. Sociodemographic information including household income, maternal education, and racial/ethnic identity was obtained from caregivers. Multiple regression models were used to test for associations between socioeconomic indices and language scores.

Results:

Maternal education accounted for variability in expressive language (EL) and receptive language (RL), with lower SES indices associated with lower language skills, and more so in children with ASD.

Conclusion:

These results demonstrate that variability in EL and RL skills in young children with autism can be accounted for by socioeconomic variables. These findings highlight the necessity for targeted intervention and effective implementation strategies for children with ASD from low-resource households and communities and for policies designed to improve learning opportunities and access to services for these young children and their families.
Understanding the Relationship Between Nursing Home Experience With Human Immunodeficiency Virus and Patient Outcomes
Authors: Meyers David J. , Wilson Ira B. , Lee Yoojin , Rahman Momotazur
Published: October 2020

Background:

As the population with human immunodeficiency virus (HIV) continues to age, the need for nursing home (NH) care is increasing.

Objectives:

To assess whether NH’s experience in treating HIV is related to outcomes.

Research Design:

We used claims and assessment data to identify individuals with and without HIV who were admitted to NHs in 9 high HIV prevalent states. We classified NHs into HIV experience categories and estimate the effects of NH HIV experience on patient’s outcomes. We applied an instrumental variable using distances between each individual’s residence and NHs with different HIV experience.

Subjects:

In all, 5,929,376 admissions for those without HIV and 53,476 admissions for residents with HIV.

Measures:

Our primary outcomes were 30-day hospital readmissions, likelihood of becoming a long stay resident, and 180-day mortality posthospital discharge.

Results:

Residents with HIV tended to have poorer outcomes than residents without HIV, regardless of the NH they were admitted to. Residents with HIV admitted to high HIV experience NHs were more likely to be readmitted to the hospital than those admitted to NHs with lower HIV experience (19.6% in 0% HIV NHs, 18.7% in 05% HIV NHs and 22.9% in 5%–50% HIV NHs).

Conclusions:

Residents with HIV experience worse outcomes in NHs than residents without HIV. Increased HIV experience was not related to improved outcomes.
Prospective Evaluation of the Safety and Efficacy of THRIVE for Children Undergoing Airway Evaluation
Authors: Okland Tyler S. , Liu George S. , Caruso Thomas J. , Sidell Douglas R.
Published: October 2020

Background:

Transnasal Humidified Rapid-Insufflation Ventilatory Exchange (THRIVE) is a humidified high-flow nasal cannula capable of extending apneic time. Although THRIVE is assumed to stent upper airway soft tissues, this has not been objectively evaluated. Also, there are no prior studies providing safety and efficacy data for those patients undergoing upper airway evaluation using THRIVE.

Methods:

This report is a prospective study of the safety and efficacy of THRIVE in pediatric patients younger than 18 years old undergoing drug-induced sleep endoscopy. We positioned a flexible laryngoscope to view the larynx, and photographs were taken with no THRIVE flow (control) and with THRIVE flow at 10 and 20 liters per minute (LPM). Upper airway patency was measured using epiglottis to posterior pharynx distance, laryngeal inlet area, and modified Cormack–Lehane score at the trialed parameters. Vomiting and aspiration were our primary safety endpoints.

Results:

Eleven patients (6 women) with a mean age of 5.3 ± 2.1 years (2–8 years; SD, 2.05) were enrolled. Measurements of upper airway patency showed a significant THRIVE flow–associated increase in epiglottis to posterior pharynx distance (105 ± 54 at 10 L/min and 199 ± 67 at 20 L/min; P = 0.007) and nonsignificant increase of laryngeal inlet area (206 ± 148 at 10 L/min and 361 ± 190 at 20 L/min; P = 0.07). Cormack–Lehane score improved significantly at higher THRIVE volumes (P = 0.006).

Conclusions:

THRIVE appears to safely improve upper airway patency during sleep endoscopy in the pediatric patient. In this study, we objectively document the flow-dependent increase in laryngeal patency associated with THRIVE.
Perioperative Temperature Management in Children: What Matters?
Authors: Lee Shu Ying , Wan Sharon Yuan Kwan , Tay Chin Lin , Tan Zi Hui , Wong Irene , Chua Maureen , Allen John C.
Published: October 2020

Introduction:

Inadvertent perioperative hypothermia is common and associated with increased risk of perioperative complications. Adult data drives most guidelines for pediatric perioperative temperature management and does not consistently demonstrate effectiveness in children. This study aims to identify risk factors for hypothermia and determine the effectiveness of current interventions in the pediatric population.

Methods:

We carried out a prospective observational study in children undergoing anesthesia in our tertiary pediatric unit. We included 869 patients (<16 y) undergoing emergency/elective surgeries over 2 months. Our team recorded the incidence of hypothermia (tympanic core temperature < 36°C) within 15 minutes of arrival to the postanesthetic care unit. We collected data such as patient demographic, surgical, anesthetic (including monitoring and warming measures used), and operating theater (OT) temperature. We performed statistical analysis to identify risk factors associated with hypothermia.

Results:

Postoperative hypothermia incidence was 12.3% (107/869). The mean core temperature on arrival to the postanesthetic care unit was 36.6°C (+SD 0.45) in normothermic patients versus 35.6°C (+SD 0.34) in hypothermic patients. Multivariable analysis identified starting ambient OT temperature [odds ratio (OR) = 0.83, confidence interval (CI): 0.71–0.96; P = 0.010], intraoperative temperature monitoring (OR = 0.49, CI: 0.28–085; P = 0.011), use of occlusive dressing (OR = 0.35, CI: 0.15–0.85; P = 0.020), and active forced-air warming (OR = 0.42, CI: 0.25–0.70; P = 0.001) as factors independently protective of postoperative hypothermia. Hypothermia occurred less frequently with emergency vs. elective procedures (OR 0.43, CI: 0.21–0.91; P = 0.026).

Conclusions:

Routine core temperature monitoring and active forced-air warming are useful measures to prevent hypothermia. Additionally, occlusive covers and controlling ambient OT temperature are cost-effective and safe methods to reduce inadvertent hypothermia.
Behavioral Interventions can Mitigate Adverse Pregnancy Outcomes Among Women Conceiving on ART and Those Initiated on ART During Pregnancy: Findings From the MOTIVATE Trial in Southwestern Kenya
Authors: Onono Maricianah , Odwar Tobias , Wahome Samuel , Helova Anna , Bukusi Elizabeth Anne , Hampanda Karen , Turan Janet , Abuogi Lisa
Published: October 2020

Background:

Antiretroviral therapy (ART) is essential for the elimination of mother-to-child transmission and improved health outcomes for women living with HIV (WLWH). However, adverse pregnancy outcomes (APOs) among pregnant women on ART are a growing concern.

Methods:

We investigated the associations between timing of ART initiation and APOs among pregnant WLWH receiving behavioral interventions (community mentor mothers and text messaging) in the Mother-Infant Visit Adherence and Treatment Engagement (MOTIVATE) study in southwestern Kenya. Log binomial models were used for estimation of relative risks (RRs) (adjusted for the clustered nature of data) evaluating APOs with 3 exposure comparisons: (1) preconception ART initiation vs. postconception initiation; (2) among postconception ART initiating women, comparisons across gestational ages at cART initiation (first versus second and third trimester exposure), and (3) intervention allocation.

Results:

Of the 1275 women included in this analysis, 388 (30%) had an APO: 306 preterm births, 38 low birth weight infants, 33 stillbirths, and 11 miscarriages. In multivariable analysis, viral load ≥1000 copies/mL, moderate and severe anemia at baseline increased risk of APOs. Among women initiating ART before and after conception, no difference was observed in the composite APO. Women who received community mentor mother visits alone (aRR 0.74: 95% CI: 0.71 to 0.76) or text messages alone (aRR 0.79: 95% CI: 0.70 to 0.89) had lower risks of experiencing any APOs.

Conclusions:

Receiving supportive behavioral interventions may mitigate the risk of experiencing an APO among WLWH on ART. Further studies are needed to investigate the underlying mechanisms and optimize the benefits of these interventions.
Epicanthoplasty With Rotated-advanced-back Cut Flap
Authors: Yang Liya , Huang Yuanliang , Li HaiDong
Published: October 2020

Background:

Epicanthoplasty is one of the most popular cosmetic surgeries in Asia. The aim of this study was to present a rotated, advanced, back cut flap (R-A-B flap) that leads to correct the congenital epicanthus effectively with satisfactory results.

Methods:

From January of 2017 to December of 2018, we performed the modified cut back flap epicanthoplasty to correct epicanthus. The esthetic results were evaluated with patients’ feedback: perfect, good, dissatisfied, or failed.

Results:

A total of 118 patients were involved. Postoperative evaluation using a grading scale indicated “perfect" results for 86 patients (73%) and “good" results for 32 patients (27%). No patients rated the results as “dissatisfied" or “failed." There were no significant postoperative complications.

Conclusion:

The R-A-B flap for epicanthoplasty is a reliable and simple method, resulting in good cosmetic outcome with minimal scar formation.
A comparison of metrics for quantifying cranial suture complexity
Authors: White Heather E. , Clavel Julien , Tucker Abigail S. , Goswami Anjali
Published: October 2020

Cranial sutures play critical roles in facilitating postnatal skull development and function. The diversity of function is reflected in the highly variable suture morphology and complexity. Suture complexity has seldom been studied, resulting in little consensus on the most appropriate approach for comparative, quantitative analyses. Here, we provide the first comprehensive comparison of current approaches for quantifying suture morphology, using a wide range of two-dimensional suture outlines across extinct and extant mammals (n= 79). Five complexity metrics (sinuosity index (SI), suture complexity index (SCI), fractal dimension (FD) box counting, FD madogram and a windowed short-time Fourier transform with power spectrum density (PSD) calculation) were compared with each other and with the shape variation in the dataset. Analyses of suture shape demonstrate that the primary axis of variation captured attributes other than complexity, supporting the use of a complexity metric over raw shape data for sutural complexity analyses. Each approach captured different aspects of complexity. PSD successfully discriminates different sutural features, such as looping patterns and interdigitation amplitude and number, while SCI best-captured variation in interdigitation number alone. Therefore, future studies should consider the relevant attributes for their question when selecting a metric for comparative analysis of suture variation, function and evolution.
Frozen verses: Antarctic minke whales (Balaenoptera bonaerensis) call predominantly during austral winter
Authors: Filun Diego , Thomisch Karolin , Boebel Olaf , Brey Thomas , Širović Ana , Spiesecke Stefanie , Van Opzeeland Ilse
Published: October 2020

The recent identification of the bio-duck call as Antarctic minke whale (AMW) vocalization allows the use of passive acoustic monitoring to retrospectively investigate year-round spatial-temporal patterns in minke whale occurrence in ice-covered areas. Here, we present an analysis of AMW occurrence patterns based on a 9-year passive acoustic dataset (2008–2016) from 21 locations throughout the Atlantic sector of the Southern Ocean (Weddell Sea). AMWs were detected acoustically at all mooring locations from May to December, with the highest presence between August and November (bio-duck calls present at more than 80% of days). At the southernmost recording locations, the bio-duck call was present up to 10 months of the year. Substantial inter-annual variation in the seasonality of vocal activity correlated to variation in local ice concentration. Our analysis indicates that part of the AMW population stays in the Weddell Sea during austral winter. The period with the highest acoustic presence in the Weddell Sea (September–October) coincides with the timing of the breeding season of AMW in lower latitudes. The bio-duck call could therefore play a role in mating, although other behavioural functions of the call cannot be excluded to date.
Effects of annealing atmosphere on the performance of Cu(InGa)Se2films sputtered from quaternary targets
Authors: Zhang Leng , Yu Yongyi , Yu Jing , Wei Yaowei
Published: October 2020

Quaternary sputtering without additional selenization is a low-cost alternative method for the preparation of Cu(InGa)Se2(CIGS) thin film for photovoltaics. However, without selenization, the device efficiency is much lower than that with selenization. To comprehensively examine this problem, we compared the morphologies, depth profiles, compositions, electrical properties and recombination mechanism of the absorbers fabricated with and without additional selenization. The results revealed that the amount of surface Se on CIGS films annealed in a Se-free atmosphere is less than that on CIGS films annealed in a Se-containing atmosphere. Additionally, the lower amount of surface Se reduced the carrier concentration, enhanced the resistivity of the CIGS film and allowed CIGS/CdS interface recombination to be the dominant recombination mechanism of CIGS device. The increase of interface recombination reduced the efficiency of the device annealed in a Se-free atmosphere.
Theoretical analysis of superadiabatic combustion for non-stationary filtration combustion by excess enthalpy function
Authors: Shi Junrui , Mao Mingming , Liu Yongqi , Lv Jinsheng
Published: October 2020

The superadiabatic combustion for non-stationary filtration combustion is analytically studied. The non-dimensional excess enthalpy function (
H
) equation is theoretically derived based on a one-dimensional, two-temperature model. In contrast to the
H
equation for the stationary filtration combustion, a new term, which takes into account the effect of non-dimensional combustion wave speed, is included in the
H
equation for transient filtration combustion. The governing equations with boundary conditions are solved by commercial software Fluent. The predictions show that the maximum non-dimensional gas and solid temperatures in the flame zone are greater than 3 for equivalence ratio of 0.15. An examination of the four source terms in the
H
equation indicates that the thermal conductivity ratio

(

Γ

s

)

between the solid and gas phases is the dominant one among the four terms and basically determines
H
distribution. For lean premixed combustion in porous media, the superadiabatic combustion effect is more pronounced for the lower

Γ

s

.
An investigation on the effect of high energy storage anchor on surrounding rock conditions
Authors: Wu Bowen , Wang Xiangyu , Bai Jianbiao , Wu Wenda , Meng Ningkang , Lin Huasheng
Published: October 2020

High pre-tension bolt is an effective strata control technique and is the key to ensure the stability of anchorage and roadway. Based on the performances of high energy storage tension rock bolts in different rock properties, this study proposed a constitutive model to describe the energy balance of anchor under uniaxial compression. UDEC was used to simulate the behaviour of anchor in coal under uniaxial compression and the results were analysed to study the rock mechanical properties, degree of damage and energy evolution. Simulation results showed that tension rock bolts can improve the mechanical properties and energy storage capacities of the anchor. The energy evolution was divided into three stages: (i) the external work was stored in the form of elastic strain energy (

U
e

) in the anchor prior to the yielding strength; (ii) the elastic strain energy reached its maximum near the peak strength; (iii) energy was dissipated from fracture friction (

W
f)

, plastic deformation (

W
p

) and acoustic emission (

U
r

) during post-peak stage. The installation of tension rock bolts was more suitable for medium hard rock (e.g. sandy mudstone), whereas it was not effective for hard rock (e.g. sandstone).
Monitoring and traceability of genetically modified soya bean event GTS 40-3-2 during soya bean protein concentrate and isolate preparation
Authors: Du Yan , Chen Fusheng , Chen Chen , Liu Kunlun
Published: October 2020

To evaluate DNA fragmentation and GMO quantification during soya bean protein concentrate and isolate preparation, genetically modified soya bean event GTS 40-3-2 (Roundup Ready
TM
soya bean, RRS) was blended with conventional soya beans at mass percentages of 0.9%, 2%, 3%, 5% and 10%. Qualitative PCR and real-time PCR were used to monitor the taxon-specific
lectin
and exogenous
cp4 epsps
target levels in all of the main products and by-products, which has practical significance for RRS labelling threshold and traceability. Along the preparation chain, the majority of DNA was distributed in main products, and the DNA degradation was noticed. From a holistic perspective, the
lectin
target degraded more than
cp4 epsps
target during both of the two soya bean proteins preparations. Therefore, the transgenic contents in the final protein products were higher than the actual mass percentages of RRS in raw materials. Our results are beneficial to the improvement of GMO labelling legislation and the protection of consumer rights.
Novel statistical emulator construction for volcanic ash transport model Ash3d with physically motivated measures
Authors: Yang Qingyuan , Pitman E. Bruce , Spiller Elaine , Bursik Marcus , Bevilacqua Andrea
Published: October 2020

Statistical emulators are a key tool for rapidly producing probabilistic hazard analysis of geophysical processes. Given output data computed for a relatively small number of parameter inputs, an emulator interpolates the data, providing the expected value of the output at untried inputs and an estimate of error at that point. In this work, we propose to fit Gaussian Process emulators to the output from a volcanic ash transport model, Ash3d. Our goal is to predict the simulated volcanic ash thickness from Ash3d at a location of interest using the emulator. Our approach is motivated by two challenges to fitting emulators—characterizing the input wind field and interactions between that wind field and variable grain sizes. We resolve these challenges by using physical knowledge on tephra dispersal. We propose new physically motivated variables as inputs and use normalized output as the response for fitting the emulator. Subsetting based on the initial conditions is also critical in our emulator construction. Simulation studies characterize the accuracy and efficiency of our emulator construction and also reveal its current limitations. Our work represents the first emulator construction for volcanic ash transport models with considerations of the simulated physical process.
Deterministic normal contact of rough surfaces with adhesion using a surface integral method
Authors: Ghanbarzadeh Ali , Faraji Mostafa , Neville Anne
Published: October 2020

The fundamental problem of adhesion in the presence of surface roughness and its effect on the prediction of friction has been a hot topic for decades in numerous areas of science and engineering, attracting even more attention in recent years in areas such as geotechnics and tectonics, nanotechnology, high-value manufacturing and biomechanics. In this paper a new model for deterministic calculation of the contact mechanics for rough surfaces in the presence of adhesion is presented. The contact solver is an in-house boundary element method that incorporates fast Fourier transform for numerical efficiency. The adhesive contact model considers full Lennard-Jones potentials and surface integration at the asperity level and is validated against models in the literature. Finally, the effect of surface roughness on the adhesion between surfaces was studied, and it was shown that the root mean square gradient of surface roughness can change the adhesive pressures irrespective of the root mean square surface roughness. We have tested two adhesion parameters based on Johnson's modified criteria and Ciavarella's model. We showed that Civarella's model introduces the most reasonable criteria suggesting that the RMS roughness and large wavelength of surfaces roughness are the important parameters of adhesion between rough surfaces.
Temperature change is an important departure cue in nocturnal migrants: controlled experiments with wild-caught birds in a proof-of-concept study
Authors: Klinner Thomas , Schmaljohann Heiko
Published: October 2020

The decision-making process of migrating birds at stopover sites is a complex interplay of the innate migration program and both intrinsic and extrinsic factors. While it is well studied how variation in precipitation, wind and air pressure influence this process, there is less evidence of the effects of temperature changes on the departure decision. Thus, we lack knowledge on how the predicted changes due to global climate change in temperature alone may affect the decision-making process during migration. Aiming to fill parts of this gap, we conducted a proof-of-concept study by manipulating the ambient temperature of temporarily confined wild-caught migrant songbirds under constant feeding conditions. In spring, departure probability increased with a 20°C rise in temperature for both a medium-distance migrant (European robin,Erithacus rubecula) and a long-distance migrant (northern wheatear,Oenanthe oenanthe), and in autumn, departure probabilities of the long-distance migrant both decreased with a 20°C rise and increased with a 20°C drop. Consequently, the temperature is an important departure cue influencing the decision-making process of migrating songbirds. Incorporating causal relationships between changes in temperature and departure probability in migration models could substantially improve our ability to predict the effects of climate change on the phenology of migratory birds.
Vaccination reshapes the virus-specific T cell repertoire in unexposed adults
Authors: Pan Yi-Gen , Aiamkitsumrit Benjamas , Bartolo Laurent , Wang Yifeng , Lavery Criswell , Marc Adam , Holec Patrick V. , Rappazzo C. Garrett , Eilola Theresa , Gimotty Phyllis A. , Hensley Scott E. , Antia Rustom , Zarnitsyna Veronika I. , Birnbaum Michael E. , Su Laura F.
Published: October 2020

How baseline T cell characteristics impact human T cell responses to novel pathogens remains unknown. Here, we address this question by studying the CD4+ T cell response in unexposed individuals to live attenuated yellow fever virus (YFV) vaccine. We quantified virus-specific population dynamics over time using class II peptide-MHC tetramers. Our data revealed that, even in the absence of known viral exposure, memory phenotype T cells were found in the majority of virus-specific precursors in healthy adults. Pre-existing memory T cells can be divided into two groups; abundant pre-vaccine populations that underwent limited overall expansion and rare cells that generated naive-like responses and preferentially contributed to the memory repertoire after vaccination. Single cell T cell receptor (TCR) sequencing was used to track the evolution of immune responses to different epitopes and showed an association between preservation of unexpanded TCRs before exposure and the robustness of post-vaccine responses. Instead of a further increase in pre-established TCR clones, vaccination boosted the representation of rare TCRs. Thus, vaccine restructures the abundance and clonal hierarchy of virus-specific T cells. Our results link T cell precursor states to post-exposure responses, identifying peripheral education of virus-specific repertoire as a key component of effective vaccination.
Persistence with oral bisphosphonates and denosumab among older adults in primary care in Ireland
Authors: Walsh Mary E. , Fahey Tom , Moriarty Frank
Published: October 2020

Purpose

Gaps in pharmacological treatment for osteoporosis can reduce effectiveness. This study aimed to estimate persistence rates for oral bisphosphonates and denosumab in older primary care patients and identify factors associated with discontinuation.

Methods

Older patients newly prescribed oral bisphosphonates or denosumab between 2012 and 2017 were identified from 44 general practices (GP) in Ireland. Persistence without a coverage gap of >90 days was calculated for both medications from therapy initiation. Factors associated with time to discontinuation were explored using Cox regression analysis. Exposures included age-group, osteoporosis diagnosis, fracture history, calcium/vitamin D prescription, number of other medications, health cover, dosing frequency (bisphosphonates) and previous bone-health medication (denosumab).

Results

Of 41,901 patients, n=1,569 newly initiated on oral bisphosphonates and n=1,615 on denosumab. Two-year persistence was 49.4% for oral bisphosphonates and 53.8% for denosumab and <10% were switched to other medication. Having state-funded health cover was associated with a lower hazard of discontinuation for both oral bisphosphonates (HR=0.49, 95%CI=0.36-0.66, p<0.01) and denosumab (HR=0.71, 95%CI=0.57-0.89, p<0.01). Older age-group, number of medications and calcium/vitamin D prescription were also associated with better bisphosphonate persistence while having osteoporosis diagnosed was associated with better denosumab persistence.

Conclusion

Persistence for osteoporosis medications is sub-optimal. Of concern, few patients are switched to other bone-health treatments when denosumab is stopped which could increase fracture risk. Free access to GP services and medications may have resulted in better medication persistence in this cohort. Future research should explore prescribing choices in primary-care osteoporosis management and evaluate cost-effectiveness of interventions for improving persistence.

Gaps in pharmacological treatment for osteoporosis can reduce its effectiveness. This study found approximately half of older adults in primary care newly initiated on bisphosphonates or denosumab were still taking these after 2 years. Abrupt discontinuation of denosumab without switching to an alternative is concerning due to increased fracture risk.
Spatial distribution of neuropathology and neuroinflammation elucidate the biomechanics of fluid percussion injury
Authors: Beitchman Joshua A. , Lifshitz Jonathan , Harris Neil G. , Thomas Theresa C. , Lafrenaye Audrey D. , Hånell Anders , Dixon C. Edward , Povlishock John T. , Rowe Rachel K.
Published: October 2020

Diffuse brain injury is better described as multi-focal, where pathology can be found adjacent to seemingly uninjured neural tissue. In experimental diffuse brain injury, pathology and pathophysiology have been reported far more lateral than predicted by the impact site. Finite element biomechanical models of diffuse brain injury predict regions of maximum stress and strain. However, the application of a skull with uniform thickness may mask the pathophysiology due to varying thickness of human and animal skulls. Force applied to the intact skull would diffuse the forces, whereas forces applied through an open skull are distributed along paths of least resistance within and then exiting the skull. We hypothesized that the local thickening of the rodent skull at the temporal ridges serves to focus the intracranial mechanical forces experienced during brain injury and generate predictable pathology in underlying cortical tissue. We demonstrated local thickening of the skull at the temporal ridges using contour analysis of coronal skull sections and oblique sectioning on MRI. After diffuse brain injury induced by midline fluid percussion injury (mFPI), pathological foci along the anterior-posterior length of cortex under the temporal ridges were evident acutely (1, 2, 7 days) and chronically (28 days) post-injury by deposition of argyophilic reaction product. Area CA3 of the hippocampus and lateral nuclei of the thalamus showed pathological change, suggesting that mechanical forces to or from the temporal ridges shear subcortical regions. A proposed model of mFPI biomechanics suggests that injury force vectors reflect off the skull base and radiate toward the temporal ridge due to the material properties of the skull based on thickness, thereby injuring ventral thalamus, dorsolateral hippocampus, and sensorimotor cortex. Surgically thinning the temporal ridge prior to injury reduced the injury-induced inflammation in sensorimotor cortex. These data build evidence for the temporal ridges of the rodent skull to contribute to the observed pathology, whether by focusing extracranial forces to enter the cranium or intracranial forces to escape the cranium. Pre-clinical investigations can take advantage of the predicted pathology to explore injury mechanisms and treatment efficacy.

Highlights

The temporal ridge is 75% thicker than the adjacent skull of the rodent

Experimental diffuse TBI neuropathology occurs beneath the length of the temporal ridge

Neuropathology encompasses sensorimotor cortex, somatosensory thalamus, and dorsolateral hippocampus

Proposed mechanism of biomechanical injury forces include the temporal ridge
Waves out of the Korean Peninsula and inter- and intra-species replacements in freshwater fishes in Japan
Authors: Taniguchi Shoji , Bertl Johanna , Futschik Andreas , Kishino Hirohisa , Okazaki Toshio
Published: October 2020

The Japanese archipelago is located at the periphery of the continent of Asia. Rivers in the Japanese archipelago, separated from the continent of Asia about 17 Ma, have experienced an intermittent exchange of freshwater fish taxa through a narrow land bridge generated by lowered sea level. As the Korean Peninsula and Japanese archipelago were not covered by an ice sheet during glacial periods, phylogeographical analyses in this region can trace the history of biota for a long time beyond the last glacial maximum. In this study, we analyzed the phylogeography of four freshwater fish taxa,Hemibarbus longirostris, dark chubNipponocypris temminckii, Tanakiassp. andCarassiusssp., whose distributions include both the Korean Peninsula and western Japan. We found for each taxon that a small component of diverse Korean clades of freshwater fishes migrated in waves into the Japanese archipelago to form the current phylogeographic structure of biota. Indigenous populations were replaced by succeeding migrants. We refer to this phenomenon as “waves out of the Korean Peninsula,” with parallels to “out of Africa” in humans.
Tyramine receptor drives olfactory response to (E)-2-decenal in the stink bugHalyomorpha halys
Authors: Finetti Luca , Pezzi Marco , Civolani Stefano , Calò Girolamo , Scapoli Chiara , Bernacchia Giovanni
Published: October 2020

In insects, the tyramine receptor 1 (TAR1) has been shown to control several physiological functions, including olfaction. We investigated the molecular and functional profile of theHalyomorpha halystype 1 tyramine receptor gene (HhTAR1) and its role in olfactory functions of this pest. Molecular and pharmacological analyses confirmed that theHhTAR1gene codes for a true TAR1. The RT-qPCR analysis revealed thatHhTAR1is expressed mostly in adult brain and antennae as well as in early development stages (eggs, 1stand 2ndinstar nymphs). In particular, among the antennomeres that compose a typicalH. halysantenna,HhTAR1was more expressed in flagellomeres. Scanning electron microscopy (SEM) investigation revealed the type and distribution of sensilla on adultH. halysantennae: both flagellomeres appear rich in trichoid and grooved sensilla, known to be associated with olfactory functions. Through a RNAi approach, topically deliveredHhTAR1dsRNA induced a 50 % gene downregulation after 24 h inH. halys2ndinstar nymphs. An innovative behavioral assay revealed thatHhTAR1RNAi-silenced 2ndinstar nymphs were less susceptible to the alarm pheromone component (E)-2 decenal as compared to control. These results provide critical information concerning the TAR1 role in olfaction regulation, especially alarm pheromone reception, inH. halys. Furthermore, considering the emerging role of TAR1 as target of biopesticides, this work paves the way for further investigation on innovative methods for controllingH. halys.
“A novel female-specific circadian clock mechanism regulating metabolism”
Authors: Mekbib Tsedey , Suen Ting-Chung , Rollins-Hairston Aisha , Smith Kiandra , Armstrong Ariel , Gray Cloe , Owino Sharon , Baba Kenkichi , Baggs Julie E. , Ehlen J. Christopher , Tosini Gianluca , DeBruyne Jason P.
Published: October 2020

Circadian clocks enable organisms to predict and align their behaviors and physiologies to constant daily day-night environmental cycle. Because the ubiquitin ligase Siah2 has been identified as a potential regulator of circadian clock function in cultured cells, we have used Siah2-deficient mice to examine its functionin vivo. Our experiments demonstrate a striking and unexpected sexually dimorphic effect ofSiah2deficiency on the regulation of rhythmically expressed genes. The absence of Siah2 in females, but not in males, altered the expression of core circadian clock genes and drastically remodeled the rhythmic hepatic transcriptome. Siah2 loss, only in females, increased the expression of 100’s of genes selectively at mid-day, resulting in a >50% increase in the number of rhythmically expressed genes, and shifted the expression of 100’s of other genes from a mid-night peak, to a mid-day peak. The combined result is a near inversion of overall rhythmicity in gene expression selectively in Siah2-deficient females. This dramatic reorganization created a substantial misalignment between rhythmic liver functions and feeding/behavioral rhythms, and consequently disrupted daily patterns of lipid/lipoprotein metabolism and metabolic responses to high-fat diet. Collectively, our results suggest that Siah2 is part of a female-specific circadian mechanism important for maintaining metabolic homeostasis and may play a key role in establishing sexual dimorphisms in metabolism, and broadly reveal that circadian clocks may drive rhythms using novel sex-specific transcriptional pathways.
SunRISE: long-term imaging of individual mRNA molecules in living cells
Authors: Guo Yue , Lee Robin E. C.
Published: October 2020

Single-cell imaging of individual mRNAs has revealed core mechanisms of the central dogma. However, most approaches require cell fixation or have limited sensitivity for live-cell applications. Here, we describe SunRISE (SunTag-based Reporter for Imaging Signal Enriched mRNA), a computationally and experimentally optimized approach for unambiguous single-mRNA detection in living cells. We demonstrate SunRISE with long-term epifluorescence imaging, using translational stress to track mRNA phase separation and recovery from cytosolic droplets.
A genetic variant protective against severe COVID-19 is inherited from Neandertals
Authors: Zeberg Hugo , Pääbo Svante
Published: October 2020

It was recently shown that the major genetic risk factor associated with becoming severely ill with COVID-19 when infected by SARS-CoV-2 is inherited from Neandertals. Thanks to new genetic association studies additional risk factors are now being discovered. Using data from a recent genome-wide associations from the Genetics of Mortality in Critical Care (GenOMICC) consortium, we show that a haplotype at a region associated with requiring intensive care is inherited from Neandertals. It encodes proteins that activate enzymes that are important during infections with RNA viruses. As compared to the previously described Neandertal risk haplotype, this Neandertal haplotype is protective against severe COVID-19, is of more moderate effect, and is found at substantial frequencies in all regions of the world outside Africa.
Membrane transporter dimerization driven by differential lipid solvation energetics of dissociated and associated states
Authors: Chadda Rahul , Bernhardt Nathan , Kelley Elizabeth G. , Teixeira Susana C. M. , Griffith Kacie , Gil-Ley Alejandro , Öztürk Tuğba N. , Hughes Lauren E. , Forsythe Ana , Krishnamani Venkatramanan , Faraldo-Gómez José D. , Robertson Janice L.
Published: October 2020

Over two-thirds of integral membrane proteins of known structure assemble into oligomers. Yet, the forces that drive the association of these proteins remain to be delineated, as the lipid bilayer is a solvent environment that is both structurally and chemically complex. In this study we reveal how the lipid solvent defines the dimerization equilibrium of the CLC-ec1 Cl-/H+antiporter. Integrating experimental and computational approaches, we show that monomers associate to avoid a thinned-membrane defect caused by their exposed dimerization interfaces. In this defect, lipids are strongly tilted and less densely packed than in the bulk, with a larger degree of entanglement between opposing leaflets and greater water penetration into the bilayer interior. Dimerization restores the membrane to a near-native state and therefore, appears to be driven by the larger free-energy cost of lipid solvation of the dissociated protomers. Supporting this theory, we demonstrate that addition of short-chain lipids strongly shifts the dimerization equilibrium towards the monomeric state, and show that the cause of this effect is that these lipids preferentially solvate the defect. Importantly, we show that this shift requires only minimal quantities of short-chain lipids, with no measurable impact on either the macroscopic physical state of the membrane or the protein’s biological function. Based on these observations, we posit that free-energy differentials for local lipid solvation define membrane-protein association equilibria. With this, we argue that preferential lipid solvation is a plausible cellular mechanism for lipid regulation of oligomerization processes, as it can occur at low concentrations and does not require global changes in membrane properties.

IMPACT STATEMENT

Differences in the lipid solvation energetics of associated and dissociated states is a primary driving force for membrane protein oligomerization, presenting a molecular mechanism for lipid regulation in biology.
Ready-to-use nanopore platform for the detection of any DNA/RNA oligo at attomole range using an Osmium tagged complementary probe
Authors: Kang Albert S. W. , Bernasconi Janette G. , Jack William , Kanavarioti Anastassia
Published: October 2020

Nanopores can serve as single molecule sensors. We exploited the MinION, a portable nanopore device from Oxford Nanopore Technologies (ONT), and repurposed it to detect any DNA/RNA oligo (target) in a complex mixture by conducting voltage-driven ion-channel measurements. The detection and quantitation of the target is enabled by the use of a unique complementary probe. Using a validated labeling technology, probes are tagged with a bulky Osmium tag (Osmium tetroxide 2,2’-bipyridine), in a way that preserves strong hybridization between probe and target. Intact oligos traverse the MinION’s nanopore relatively quickly compared to the device’s acquisition rate, and exhibit count of events comparable to the baseline. Counts are reported by a publicly available software,OsBp_detect. Due to the presence of the bulky Osmium tag, probes traverse more slowly, produce multiple counts over the baseline, and are even detected at single digit attomole (amole) range. In the presence of the target the probe is “silenced”. Silencing is attributed to a 1:1 double stranded (ds) complex that doesn’t fit and can’t traverse this nanopore. This ready-to-use platform can be tailored as a diagnostic test to meet the requirements for point-of-care cell-free tumor DNA (ctDNA) and microRNA (miRNA) detection and quantitation in body fluids.
Sub-second heat inactivation of coronavirus
Authors: Jiang Yuqian , Zhang Han , Wippold Jose A. , Gupta Jyotsana , Dai Jing , de Figueiredo Paul , Leibowitz Julian L. , Han Arum
Published: October 2020

Heat treatment denatures viral proteins that comprise the virion, making virus incapable of infecting a host. Coronavirus (CoV) virions contain single-stranded RNA genomes with a lipid envelope and 4 proteins, 3 of which are associated with the lipid envelope and thus are thought to be easily denatured by heat or surfactant-type chemicals. Prior studies have shown that a temperature of as low as 75 °C and treatment duration of 15 min can effectively inactivate CoV. The applicability of a CoV heat inactivation method greatly depends on the length of time of a heat treatment and the temperature needed to inactivate the virus. With the goal of finding conditions where sub-second heat exposure of CoV can sufficiently inactivate CoV, we designed and developed a simple system that can measure sub-second heat inactivation of CoV. The system is composed of capillary stainless-steel tubing immersed in a temperature-controlled oil bath followed by an ice bath, through which virus solution can be flowed at various speeds. Flowing virus solution at different speeds, along with a real-time temperature monitoring system, allows the virus to be accurately exposed to a desired temperature for various durations of time. Using mouse hepatitis virus (MHV), a beta-coronavirus, as a model system, we identified that 85.2 °C for 0.48 s exposure is sufficient to obtain > 5 Log10reduction in viral titer (starting titer: 5 × 107PFU/mL), and that when exposed to 83.4 °C for 0.95 s, the virus was completely inactivated (zero titer, > 6 Log10reduction).

IMPORTANCE

Three coronaviruses (CoVs) have now caused global outbreaks within the past 20 years, with the COVID19 pandemic caused by SARS-CoV-2 still ongoing. Methods that can rapidly inactivate viruses, especially CoVs, can play critical roles in ensuring public safety and safeguarding personal health. Heat treatment of viruses to inactive them can be an efficient and inexpensive method, with the potential to be incorporated into various human-occupied spaces. In this work, a simple system that can heat-treat viruses for extremely short period was developed and utilized to show that sub-second exposure of CoV to heat is sufficient to inactivate CoV. This opens up the possibility of developing instruments and methods of disinfecting CoV in diverse settings, including rapid liquid disinfection and airborne virus disinfection. The developed method can also be broadly utilized to assess heat sensitivity of viruses other viral pathogens of interest and develop sub-second rapid heat inactivation approaches.
Can measurements of inflammatory biomarkers be used to spot viral infections?
Authors: Sinha Anirban , Lutter René , Dekker Tamara , Dierdorp Barbara , Sterk Peter J. , Frey Urs , Delgado-Eckert Edgar
Published: October 2020

Accurate detection of human respiratory viral infections is highly topical. We investigated how strongly inflammatory biomarkers (FeNO, eosinophils, neutrophils, and cytokines in nasal lavage fluid) and lung function parameters change upon rhinovirus-16 infection, in order to explore their potential use for infection detection. To this end, within a longitudinal cohort study, healthy and mildly asthmatic volunteers were experimentally inoculated with rhinovirus-16 and time series of these parameters/biomarkers were systematically recorded and compared between the pre- and post-infection phases of the study, which lasted 2 and 1 month/s, respectively. We found that the parameters’/biomarkers’ ability to discriminate between the infected and the uninfected state varied over the observation time period. Consistently over time, the concentration of cytokines in nasal lavage fluid showed moderate to very good discrimination performance, thereby qualifying for disease progression monitoring. On the other hand, lung function and FeNO, while quickly and non-invasively measurable using cheap portable devices (e.g., at airports), performed poorly.