bluuebunny/crossref_metadata_2025 huggingface dataset:
The Flow Structure in an Anatomically Realistic Cerebral Aneurysm Model With Small Aspect Ratio
Authors: Morino Taku , Takahashi Hikoichiro , Yamauchi Takatsugu , Tanishita Kazuo , Murayama Yuichi , Tateshima Satoshi , Vinuela Fernando
Published: November 2021

We measured the velocity profiles in an anatomically realistic model of a basilar tip aneurysm with small aspect ratio (depth / neck width) by LDV. We built an aneurysm model based on CT images. The maximum Reynolds number based on the diameter of basilar artery was 795 and the frequency parameter was 5.0. The inflow went into the aneurysm dome along the posterior wall. At the bleb, the flow separated from the wall and was decelerated. The outflow region was widely extended at the anterior side of the aneurysm with low velocity, because the dome shape developed asymmetrically to the anterior side. The shear stress at the bleb was intensified at the beginning of the deceleration phase, although the wall shear stress at intra-aneurysm points didn’t change drastically. We found out that aneurysms with small aspect ratio contains the peaked hemodynamic stress by using the realistic model. Therefore the diagnosis of aneurysm should be assessed by a realistic model.
Comparison of Experimental and Numerical Simulations of Flow Within an Arterio-Venous Graft
Authors: Fischer Paul F. , Lee Seung , Loth Francis , Bassiouny Hisham S. , Arslan Nurullah
Published: November 2021

This was a study to compare computational and experimental results of flow field inside the venous anastomosis of an arteriovenous (AV) graft. Laser Doppler anemometry (LDA) measurements were conducted inside an upscaled end-to-side graft model under steady flow conditions at Reynolds number 1820 which is representative of the in vivo flow conditions inside a human AV graft. The distribution of the velocity and turbulence intensity was measured at several locations in the plane of the bifurcation. This flow field was simulated using computation fluid dynamics (CFD) and shown to be in good agreement. Under steady flow conditions, the flow field demonstrated an unsteady character (transition to turbulence).
Langevin Dynamics of Hinge-Motion in Proteins
Authors: Bao Gang , Stott Shannon
Published: November 2021

Many proteins function in mechanically stressful environments. For example, shear flow in blood vessel may exert a force as high as hundreds of piconewtons on an individual selectin-ligand bond. With such a mechanical force, the receptor (selectin) may deform, thereby altering the conformational match between the receptor and the ligand. Although van der Waals forces, electrostatic and hydrophobic interactions are all important, it is often the 3D geometry local to the binding pocket that dictates the characteristics of the bond between the receptor and the ligand. Good conformational matches lead to strong and long-lasting bonds, whereas poor conformational matches do the converse. it is conceivable that conformational changes in proteins in response to various forces serve as a mechanism for transducing mechanical signals into biochemical responses.
A Cardio-Synchronized Injection System
Authors: Conti P. , Banetta L. , Ficola A. , Magnino F.
Published: November 2021

The main limit in today’s infusion systems is that they can yield high liquid volumes but at low velocity (gravity systems) or at some higher velocity, but with constant mass/velocity ratio (peristaltic systems). In any case, the blood injection is obtained without any synchronization with fast ventricular diastole nor any attempt is made to enhance blood circulation in the venous vessels (which can be drastically slowed down by the pressure drop in the circulatory system); this can induce non physiologic pressure rises in the central venous system. A prototypical cardio-synchronized injection system has been developed in order to avoid the negative effects of continuos high rate infusion, to allow a mass injection independent from the velocity, and to induce a pumping effect in the venous vessels. The system has been designed to reduce the impact on the central venous pressure and to allow lower mass injection at higher velocities.
Microstructural Characterization, Mechanical Properties and Wear Resistance of TiCP Reinforced Ni-Alloy Coatings by Laser Synthesis
Authors: Tu D. L. , Kar A. , Wu X. L.
Published: November 2021

Titanium carbide particle (TiCp)-reinforced Ni alloy composite coatings are synthesized by laser cladding using a cw 3 kW CO2 laser. Two kinds of coatings are possible in terms of the origin of TiCp: undissolved TiCp and in-situ generated TiCp. The former originates from the TiCp pre-coated on the sample whereas the latter from in-situ chemical reaction between titanium and graphite in the molten pool during laser irradiation. For the coating reinforced by TiCp formed in-situ, the sub-micron TiCp particles are formed and uniformly distributed because of the in-situ reaction and trapping effect during rapid solidification. Graded distribution of TiCp is obtained on a macro scale. The volume fraction increases from 1.86% at the coating-substrate interface to 38.4% at the coating surface. For the coating reinforced by undissolved TiCp, analytical transmission electron microscopy (ATEM) and high resolution transmission electron microscopy (HRTEM) observations show the existence of the epitaxial growth of TiC, the precipitation of CrB and M23C6, and the chemical reaction between Ti and B elements around phase interfaces of undissolved TiCp. In the matrix near the phase interface of undissolved TiCp, the loading curve obtained by nanoindenter exhibits pop-in phenomena due to the plastic deformation of cracks or debonding of TiCp from the matrix. For TiCp generated in-situ, no pop-in mark appears, indicating high fracture toughness. Coating with TiCp generated in-situ exhibits higher hardness and modulus than the coating with undissolved TiCp at regions near the phase interface. The coating reinforced by TiCp generated in-situ also displays higher impact wear resistance and abrasive wear resistance compared to the coatings with undissolved TiCp and without TiCp respectively.
Priorities and Expectations for Surface Engineering: A Personal View
Authors: Larsen-Basse Jorn
Published: November 2021

Surface engineering is currently attracting wide attention. The need to engineer surfaces for specific performance requirements has always been present but, until recently, the means available to accomplish this were few. The situation has changed dramatically during the past few decades when the rate, at which new surface modification processes appear, has escalated rapidly. The growth has been driven by synergistic advances in process control, modeling, materials and surface science, and in instrumentation which enables us to closely analyze and observe the surface and the near-surface material in great detail. At this point industrial adaptation of the new processes is lagging somewhat, awaiting maturation of the most promising processes so they can be reliably used in mass production.
Thermal Cycling Induced Bond-Coat Rumpling as a Precursor to TBC Failure
Authors: Clarke D. R. , Tolpygo V. K.
Published: November 2021

Microstructural observations of TBCs failed under thermal cycling conditions reveal that failure is associated with extensive local separations between either the thermally grown oxide and the TBC or within the TBC itself close to the thermally grown oxide. Based on extensive microstructural characterization and measurements of concentration profiles within the bond-coat, we present a new model for the cause of these separations based on local increases in the density of the bond coat associated with the beta-NiAl to gamma-prime Ni3Al phase transformation. The phase transformation, driven by aluminum depletion required to form the protective alumina thermally grown oxide, is constrained by the overlying TBC thereby generating tensile stresses across the TBC/TGO interface and its vicinity. The observations and evidence for the new model will be described together with the role of thermal cycling.
Synthesis and Characteristics of Interpenetrating Polymer Network Hydrogels Based on Silicone and Poly(vinyl alcohol)
Authors: Kim Seon Jeong , Shin Mi Seon
Published: November 2021

Hydrogels have become increasingly important for use in the biomedical field. They are used diagnostic, therapeutic and implantable devices(e.g. catheter, biosensor, artificial skin, controlled release drug delivery system and contact lenses). Also silicone derivatives are widely used owing to their favorable properties such as low-glass transition temperature, high gas permeability, high thermal stability and good biocompatibility. We have studied the interpenetrating polymer networks(IPN) by previous reports, and to report on the preparation and properties of poly(vinyl alcohol), (PVA) and vinyl terminated polydimethylsiloxane(PDMS) IPN hydrogel in this presentation. The IPN composed of PVA and PDMS was synthesized by the following method. PVA was dissolved in the water to make 10wt% aqueous solution. And PDMS was mixed with 0.5wt% 2,2-dimethyl-2-phenylacetophenone(DMPAP) and 0.5mol% methylenebis acrylicamide(MBAAm). This mixture was added to PVA aqueous solution and heated at 90oC for 3hrs. Various IP{Ns were prepared from different mol ratios of PVA/PDMS. Hydrogels obtained were characterized by using FT-IR, wide angle X-ray diffractometry(WAXD), differential scanning calorimetry(DSC), dielectric analysis(DEA), and equilibrium water content(EWC).
The Flow of UCM and Oldroyd-B Fluids Past a Cylinder
Authors: Alves Manuel A. , Pinho Fernando T. , Oliveira Paulo J.
Published: November 2021

Accurate solutions are obtained with the numerical method of Oliveira et al (1998) for the inertialess plane flow around a confined cylinder. This numerical procedure is based on the finite-volume method in non-orthogonal block-structured meshes with a collocated arrangement of the dependent variables, and makes use of a special interpolation practice to avoid stress-velocity decoupling. Two high-resolution schemes are implemented to represent the convective terms in the constitutive equations for the upper converted Maxwell and Oldroyd-B fluids, and the resulting predictions of the drag coefficient on the cylinder are shown to be as accurate as existing finite-element method predictions based on the very accurate h-p refinement technique.
A General Correlation for the Hydraulic Permeability of Arrays of Elliptical Fiber Bundles
Authors: Gravel E. M. , Papathanasiou T. D.
Published: November 2021

A computational analysis of viscous flow through arrays of fiber bundles is carried out using the Boundary Element Method. We consider fiber bundles of elliptical cross section, each made up of up to 350 individual filaments. Such arrays are dual-porosity systems, characterized by different inter- (ϕi) and intra-tow (ϕt) porosities as well as by varying number (Nf) of filaments within each bundle. Investigating the influence of these parameters on the hydraulic permeability of hexagonal arrays of such bundles is the subject of our simulations. The results are compared to earlier analytical models and a good agreement is found. A dimensionless correlation is proposed and the computed permeabilities for bundles of aspect ratio λ = 2 and λ = 3 are shown to fall on a single master curve. This offers a generalized model for the calculation of the permeability of such dual porosity systems from knowledge of ϕi, ϕt, λ and Nf.
Diffraction-grating beam splitter, interferometric-lithography nanopatterning with a multilongitudinal-mode diode laser
Authors: Sasidharan Vineeth , Neumann Alexander , Brueck S. R. J.
Published: November 2021

Large-area, oblique-incidence interferometric nanopatterning using a low-cost multilongitudinal-mode diode laser as the source and a spin-on-glass based diffraction-phase-mask grating beam splitter is demonstrated. The phase mask is engineered to have only two equal intensity orders (0th and −1st), dramatically simplifying the optical arrangement and decreasing the propagation distance between the beam splitter and the sample. The low-cost, high-power (150 mW) TEM00 405-nm diode laser operates with a large number of longitudinal modes, resulting in an impractical mask-to-sample-gap proximity requirement. A dual-grating-mask, achromatic interferometric scheme is introduced to extend this gap dimension to easily accessible scales. Uniform nanopatterns with a periodicity of 600 nm were fabricated over a 1 cm diameter area using this multimode diode laser. This technique is scalable and has the potential for large-area nanopatterning applications.
4D magnetic resonance imaging atlas construction using temporally aligned audio waveforms in speech
Authors: Xing Fangxu , Jin Riwei , Gilbert Imani R. , Perry Jamie L. , Sutton Bradley P. , Liu Xiaofeng , El Fakhri Georges , Shosted Ryan K. , Woo Jonghye
Published: November 2021

Magnetic resonance (MR) imaging is becoming an established tool in capturing articulatory and physiological motion of the structures and muscles throughout the vocal tract and enabling visual and quantitative assessment of real-time speech activities. Although motion capture speed has been regularly improved by the continual developments in high-speed MR technology, quantitative analysis of multi-subject group data remains challenging due to variations in speaking rate and imaging time among different subjects. In this paper, a workflow of post-processing methods that matches different MR image datasets within a study group is proposed. Each subject's recorded audio waveform during speech is used to extract temporal domain information and generate temporal alignment mappings from their matching pattern. The corresponding image data are resampled by deformable registration and interpolation of the deformation fields, achieving inter-subject temporal alignment between image sequences. A four-dimensional dynamic MR speech atlas is constructed using aligned volumes from four human subjects. Similarity tests between subject and target domains using the squared error, cross correlation, and mutual information measures all show an overall score increase after spatiotemporal alignment. The amount of image variability in atlas construction is reduced, indicating a quality increase in the multi-subject data for groupwise quantitative analysis.
Direct discrete complex image method for sound field evaluation above a non-locally reacting layer
Authors: Eser Martin , Gurbuz Caglar , Brandão Eric , Marburg Steffen
Published: November 2021

Thin layers of porous media are widely adopted in sound absorption and noise control applications due to their compact arrangement. Particularly, porous media with low flow resistivity exhibit complex, non-local reaction behavior. Therefore, sound field prediction above these media is computationally challenging. This is due to singularities and branch points in the expression for the reflection coefficient. This paper introduces a framework based on the direct discrete complex image method to analyze the sound field above a rigid-backed, non-locally reacting porous sample. In contrast to traditional complex image applications, the proposed framework avoids the extraction of the quasi-static term and the poles from the reflection coefficient. Instead, the reflection coefficient—including its singularities—is directly approximated in terms of a series of complex exponentials, whose coefficients are determined with the matrix pencil method. This study analyzes the sound field above two test samples made of melamine and rockwool. The sound field computation is efficient and accurate in the near- and in the far-field. Moreover, predicted specific impedances agree well with experimental in situ impedance measurements. The proposed framework serves for more applications including object detection in multilayered porous grounds or sound propagation prediction in layered atmosphere.
High Temperature Cycles Result in Maternal Transmission and Dengue Infection Differences Between
Wolbachia
Strains in Aedes aegypti
Authors: Mancini Maria Vittoria , Ant Thomas H. , Herd Christie S. , Martinez Julien , Murdochy Shivan M. , Gingell Daniel D. , Mararo Enock , Johnson Paul C. D. , Sinkins Steven P.
Published: November 2021

In the past decades, dengue incidence has dramatically increased all over the world. An emerging dengue control strategy utilizes
Aedes aegypti
mosquitoes artificially transinfected with the bacterial symbiont
Wolbachia
, with the ultimate aim of replacing wild mosquito populations.
Lineage Divergence and Vector-Specific Adaptation Have Driven Chikungunya Virus onto Multiple Adaptive Landscapes
Authors: Chen Rubing , Plante Jessica A. , Plante Kenneth S. , Yun Ruimei , Shinde Divya , Liu Jianying , Haller Sherry , Mukhopadhyay Suchetana , Weaver Scott C.
Published: November 2021

Since its introduction into the Caribbean in October 2013, CHIKV has rapidly spread to almost the entire neotropical region. However, its potential to further spread globally, including into more temperate climates, depends in part on its ability to be transmitted efficiently by
Aedes albopictus
, which can survive colder winters than
A. aegypti
.
Directional Gaussian Mixture Models of the Gut Microbiome Elucidate Microbial Spatial Structure
Authors: Pasarkar Amey P. , Joseph Tyler A. , Pe’er Itsik
Published: November 2021

The spatial arrangement of the microbes in the gut microbiome is a defining characteristic of its behavior. Various experimental studies have attempted to provide glimpses into the mechanisms that contribute to microbial arrangements.
Direct RNA Sequencing Unfolds the Complex Transcriptome of Vibrio parahaemolyticus
Authors: Al kadi Mohamad , Ishii Eiji , Truong Dang Tat , Motooka Daisuke , Matsuda Shigeaki , Iida Tetsuya , Kodama Toshio , Okuzaki Daisuke
Published: November 2021

Vibrio parahaemolyticus
is a halophilic bacterium found in the marine environment. Outbreaks of gastroenteritis resulting from seafood poisoning by these pathogens have risen over the past 2 decades.
Pyrrhotite–silicate melt partitioning of rhenium and the deep rhenium cycle in subduction zones
Authors: Xue Shuo , Li Yuan
Published: November 2021

The Re-Os isotopic system serves as an important tracer of recycled crust in Earth's deep mantle because of the large Re/Os ratios and time-integrated enrichment of radiogenic Os in Earth's crust. However, the Re distribution in Earth's known reservoirs is mass imbalanced, and the behavior of Re during subduction remains little understood. We performed laboratory experiments to determine the partition coefficients of Re between pyrrhotite and silicate melt () at 950–1080°C, 1–3 GPa, and oxygen fugacities (in log units relative to the fayalite-magnetite-quartz [FMQ] buffer) of FMQ–1.3 to FMQ +2. The obtained values are 200–25,000, which increase with decreasing oxygen fugacity and the total iron content (FeOtot) of silicate melt but decrease with increasing temperature or decreasing pressure. Applying to constrain the behavior of Re during slab melting demonstrates that slab melts contribute minimal Re to the sub-arc mantle, with most Re dissolved in sulfides subducted into Earth's deep mantle. Deep storage of recycled oceanic basalts and sediments can explain the mass imbalance of Re in Earth's primitive mantle, depleted mantle, and crust.
Late Pleistocene and early Holocene sea-level history and glacial retreat interpreted from shell-bearing marine deposits of southeastern Alaska, USA
Authors: Baichtal James F. , Lesnek Alia J. , Carlson Risa J. , Schmuck Nicholas S. , Smith Jane L. , Landwehr Dennis J. , Briner Jason P.
Published: November 2021

We leverage a data set of >720 shell-bearing marine deposits throughout southeastern Alaska (USA) to develop updated relative sea-level curves that span the past ∼14,000 yr. This data set includes site location, elevation, description when available, and 436 14C ages, 45 of which are published here for the first time. Our sea-level curves suggest a peripheral forebulge developed west of the retreating Cordilleran Ice Sheet (CIS) margin between ca. 17,000 and 10,800 calibrated yr B.P. By 14,870 ± 630 to 12,820 ± 340 cal. yr B.P., CIS margins had retreated from all of southeastern Alaska's fjords, channels, and passages. At this time, isolated or stranded ice caps existed on the islands, with alpine or tidewater glaciers in many valleys. Paleoshorelines up to 25 m above sea level mark the maximum elevation of transgression in the southern portion of the study region, which was achieved by 11,000 ± 390 to 10,500 ± 420 cal. yr B.P. The presence of Pacific sardine (Sardinops sagax) and the abundance of charcoal in sediments that date between 11,000 ± 390 and 7630 ± 90 cal. yr B.P. suggest that both ocean and air temperatures in southeastern Alaska were relatively warm in the early Holocene. The sea-level and paleoenvironmental reconstruction presented here can inform future investigations into the glacial, volcanic, and archaeological history of southeastern Alaska.
Systemic infection following intravesical therapy with BCG
Authors: Oliveira Ana Andrade , Morais Joana , Ribeiro Jorge , Gouveia Paulo Ferreira
Published: November 2021

Immunotherapy with BCG is an effective and widely used treatment for non-muscle-invasive bladder cancer. BCG sepsis is a rare but life-threatening and frequently not a straightforward complication of this treatment; in cases with a high index of suspicion, anti-bacillary treatment should not wait for laboratory confirmation and be instituted immediately. We report a severe case of BCG sepsis, in which timely diagnosis and initiation of antituberculosis agents enabled a full recovery.
Primary neuroendocrine tumour of the kidney in an asymptomatic patient involving a multidisciplinary approach
Authors: Navarro-Ballester Antonio , Rodenas-Hernández Jose Manuel , de Lázaro-de Molina Susana , Muñoz-Vicente Elia
Published: November 2021

Primary neuroendocrine tumours of the kidney are rare, and their pathophysiology is uncertain; since their discovery in 1966, they have been described only a few times in the literature. We present a case of a well-differentiated neuroendocrine tumour of the kidney in an asymptomatic patient, which required a multidisciplinary approach by the hospital’s team, including precise surgical treatment and an effective radiopathological diagnosis. The patient underwent right radical nephrectomy. During follow-up, he remained asymptomatic, and no metastases or complications were identified.
A de-escalated treatment strategy in the management of paediatric cervicofacial actinomycosis
Authors: Yeo Justin Jui Yuan , Hopkins Michael Edward , Isa Aidah
Published: November 2021

Actinomycosis is a rare invasive bacterial disease that is characterised by granulomatous inflammation often mistaken as malignancy. Traditionally, this has been managed with prolonged courses of antibiotics with durations up to 6–12 months. Surgical intervention as an adjuvant treatment has been shown to reduce the length of antibiotic treatment significantly to 4 weeks. We report a case of cervicofacial actinomycosis in a 12-year-old girl who was adequately treated with an 11-day course of antibiotics without surgical intervention and shows no signs of recurrence at 6 months post-treatment.
Enhancing primary care capacity in chronic kidney disease management: a quality improvement educational initiative
Authors: Smekal Michelle D , Bello Aminu K , Donald Maoliosa , Zaidi Deenaz , McBrien Kerry , Nicholson Katrina , Novak Ellen , Hemmelgarn Brenda
Published: November 2021

Background

Gaps in identification, medical management and appropriate referral for patients with chronic kidney disease (CKD) are evident.

Objective

We designed and implemented an interactive educational intervention (accredited workshop) to improve primary care providers’ awareness of tools to support guideline-concordant CKD management.

Design

We used the Kern method to design the educational intervention and targeted the accredited workshops to primary care team members (physicians, nurses and allied health) in Alberta, Canada. We conducted anonymous pre-workshop and post-workshop surveys to identify practice-specific barriers to care, identify potential solutions, and evaluate provider confidence pre-intervention and post-intervention. We used non-parametric statistics to analyse Likert-type survey data and descriptive content analysis to categorise responses to open-ended survey questions.

Results

We delivered 12 workshops to 114 providers from September 2017 through March 2019. Significant improvements (p<0.001) in confidence to appropriately identify, manage and refer patients with CKD were observed. Participants identified several patient-level, provider-level, and system-level barriers and potential solutions to care for patients with CKD; the majority of these barriers were addressed in the interactive workshop.

Conclusions

The Kern model was an effective methodology to design and implement an educational intervention to improve providers’ confidence in managing patients with CKD in primary care. Future research is needed to determine if these perceived knowledge and confidence improvements affect patient outcomes and whether improvements are sustained long term.
Health providers’ experiences with mental health specialist video consultations in primary care: a qualitative study nested within a randomised feasibility trial
Authors: Haun Markus W , Hoffmann Mariell , Wildenauer Alina , Tönnies Justus , Wensing Michel , Szecsenyi Joachim , Peters-Klimm Frank , Krisam Regina , Kronsteiner Dorothea , Hartmann Mechthild , Friederich Hans-Christoph
Published: November 2021

Objective

Despite available effective treatments for mental health disorders, few patients in need receive even the most basic care. Integrated telepsychiatry services may be a viable option to increase access to mental healthcare. The aim of this qualitative process evaluation embedded in a randomised controlled feasibility trial was to explore health providers’ experiences with a mental healthcare model integrating mental health specialist video consultations (MHSVC) and primary care.

Methods

A qualitative process evaluation focusing on MHSVC in primary care was conducted. In 13 semistructured interviews, we assessed the experience of all mental health specialists, primary care physicians and medical assistants who participated in the trial. A thematic analysis, focusing on the implementation, mechanisms of impact and context, was applied to investigate the data.

Results

Considering (1) the implementation, participants evaluated the consultations as feasible, easy to use and time saving. Concerning (2) the mechanisms of impact, the consultations were regarded as effective for patients. Providers attributed the patients’ improvements to two key aspects: the familiarity of the primary care practice and the fast access to specialist mental healthcare. Mental health specialists observed trustful therapeutic alliances emerging and described their experience as comparable to same-room care. However, compared with same-room care, specialists perceived the video consultations as more challenging and sometimes more exhausting due to the additional effort required for establishing therapeutic alliances. Regarding (3) the intervention’s context, shorter travel distances for patients positively affected the implementation, while technical failures, that is, poor Internet connectivity, emerged as the main barrier.

Conclusions

MHSVCs in primary care are feasible and successful in improving access to mental healthcare for patients. To optimise engagement and comfort of both patients and health providers, future work should focus on empirical determinants for establishing robust therapeutic alliances with patients receiving MHSVC (eg, leveraging non-verbal cues for therapeutic purposes).

Trial registration number

DRKS00015812; Results.
Effect of body mass index on vertebral and hip fractures in older people and differences according to sex: a retrospective Japanese cohort study
Authors: Shiomoto Kyohei , Babazono Akira , Harano Yumi , Fujita Takako , Jiang Peng , Kim Sung-A , Nakashima Yasuharu
Published: November 2021

Objectives

The purpose of this study was to investigate the incidence of vertebral and hip fractures in the older people and to clarify the relationship between these fractures and body mass index (BMI) along with the impact of sex differences.

Design

This was a retrospective cohort study.

Setting

We used administrative claims data between April 2010 and March 2018.

Participants

Older people aged ≥75 years who underwent health examinations in 2010 and were living in the Fukuoka Prefecture, Japan were included in the study. A total of 24 691 participants were included; the mean age was 79.4±4.3 years, 10 853 males and 13 838 females, and an the mean duration of observation was 6.9±1.6 years.

Primary and secondary outcome measures

We estimated the incidence of vertebral and hip fractures by BMI category (underweight: <18.5 kg/m2, normal weight: 18.5–24.9 kg/m2, overweight and obese: ≥25.0 kg/m2) using a Kaplan-Meier curve in males and females and determined fracture risk by sex using Cox proportional hazards regression analyses.

Results

The incidence of vertebral and hip fractures was 16.8% and 6.5%, respectively. The cumulative incidence of vertebral and hip fracture at the last observation (8 years) in each BMI groups (underweight/normal weight/overweight and obese) estimated using the Kaplan-Meier curve was 14.7%/10.4%/9.0% in males and 24.9%/23.0%/21.9% in females, and 6.3%/2.9%/2.4% in males and 14.1%/9.0%/8.1% in females, respectively, and both fractures were significantly higher in underweight groups regardless of sex. Multivariable Cox proportional hazards models showed that underweight was a significant risk factor only in males for vertebral fractures and in both males and females for hip fractures.

Conclusion

Underweight was associated with fractures in the ageing population, but there was a sex difference in the effect for vertebral fractures.
Using hierarchical clustering analysis to evaluate COVID-19 pandemic preparedness and performance in 180 countries in 2020
Authors: Sadeghi Banafsheh , Cheung Rex C Y , Hanbury Meagan
Published: November 2021

Objective

To rank and score 180 countries according to COVID-19 cases and fatality in 2020 and compare the results to existing pandemic vulnerability prediction models and results generated by standard epidemiological scoring techniques.

Setting

One hundred and eighty countries’ patients with COVID-19 and fatality data representing the healthcare system preparedness and performance in combating the pandemic in 2020.

Design

Using the retrospective daily COVID-19 data in 2020 broken into 24 half-month periods, we applied unsupervised machine learning techniques, in particular, hierarchical clustering analysis to cluster countries into five groups within each period according to their cumulative COVID-19 fatality per day over the year and cumulative COVID-19 cases per million population per day over the half-month period. We used the average of the period scores to assign countries’ final scores for each measure.

Primary outcome

The primary outcomes are the COVID-19 cases and fatality grades in 2020.

Results

The United Arab Emirates and the USA with F in COVID-19 cases, achieved A or B in the fatality scores. Belgium and Sweden ranked F in both scores. Although no African country ranked F for COVID-19 cases, several African countries such as Gambia and Liberia had F for fatality scores. More developing countries ranked D and F in fatality than in COVID-19 case rankings. The classic epidemiological measures such as averages and rates have a relatively good correlation with our methodology, but past predictions failed to forecast the COVID-19 countries’ preparedness.

Conclusion

COVID-19 fatality can be a good proxy for countries’ resources and system’s resilience in managing the pandemic. These findings suggest that countries’ economic and sociopolitical factors may behave in a more complex way as were believed. To explore these complex epidemiological associations, models can benefit enormously by taking advantage of methods developed in computer science and machine learning.
Minimal clinically important difference in means in vulnerable populations: challenges and solutions
Authors: Peacock Janet L , Lo Jessica , Rees Judith R , Sauzet Odile
Published: November 2021

Introduction and motivation

Many health studies measure a continuous outcome and compare means between groups. Since means for biological data are often difficult to interpret clinically, it is common to dichotomise using a cut-point and present the ‘percentage abnormal’ alongside or in place of means. Examples include birthweight where ‘abnormal’ is defined as <2500 g (low birthweight), systolic blood pressure with abnormal defined as >140 mm Hg (high blood pressure) and lung function with varying definitions of the ‘limit of normal’. In vulnerable populations with low means, for example, birthweight in a population of preterm babies, a given difference in means between two groups will represent a larger difference in the percentage with low birthweight than in a general population of babies where most will be full term. Thus, in general, the difference in percentage of patients with abnormal values for a given difference in means varies according to the reference population’s mean value. This phenomenon leads to challenges in interpreting differences in means in vulnerable populations and in defining an outcome-specific minimal clinically important difference (MCID) in means since the proportion abnormal, which is useful in interpreting means, is not constant—it varies with the population mean. This has relevance for study power calculations and data analyses in vulnerable populations where a small observed difference in means may be difficult to interpret clinically and may be disregarded, even if associated with a relatively large difference in percentage abnormal which is clinically relevant.

Methods

To address these issues, we suggest both difference in means and difference in percentage (proportion) abnormal are considered when choosing the MCID, and that both means and percentages abnormal are reported when analysing the data.

Conclusions

We describe a distributional approach to analyse proportions classified as abnormal that avoids the usual loss of precision and power associated with dichotomisation.
How do patients respond to safety problems in ambulatory care? Results of a retrospective cross-sectional telephone survey
Authors: Seufert Svenja , de Cruppé Werner , Assheuer Michaela , Leinert Johannes , Geraedts Max
Published: November 2021

Objectives

Patients in German ambulatory care frequently report patient safety problems (PSP). It is unclear whether patients report PSP back to their general practitioner (GP) or specialist in charge. This study reports on how patients respond to experienced PSP.

Design

Retrospective cross-sectional study.

Setting

Computer-assisted telephone interviews (CATI) with randomly recruited citizens aged ≥40 years in Germany.

Participants

10 037 citizens ≥40 years. About 52% of the interviewees were female, 38% were between 60 and 79 years old and about 47% reported that they were chronically ill. A total of 2589 PSPs was reported.

Primary and secondary measures/Results

According to the respondents (n=1422, 77%, 95% CI: 74.7 to 79.1), 72% (95% CI: 70.2 to 73.7) of PSP were reported back to the GP in charge or to another GP/specialist. Further reactions were taken by 65% (95% CI: 62.5 to 67.5) of the interviewees: around 63% (95% CI: 62.5 to 66.2) of the reported PSP led to a loss of faith in the physician or to complaints. χ2and binary logistic regression analyses show significant associations between the (a) reporting and (b) reaction behaviour and determinants like ‘medical treatment area’ ((a) χ2=17.13, p=0.009/(b) χ2=97.58, p=0.000), ‘PSP with/without harm’ ((a) χ2=111.84, p=0.000/(b) χ2=265.39, p=0.000) and sociodemographic characteristics when respondents are aged between 40 and 59 years ((a) OR 2.57/(b) OR 2.60) or have chronic illnesses ((a) OR 2.16/(b) OR 2.14).

Conclusion

The data suggest that PSPs are frequently reported back to the GP or specialist in charge and have a significant serious impact on the physician–patient relationship. Much could be learnt from the patient reporting and reacting behaviour to prevent PSPs in ambulatory care.
Promoting early diagnosis and recovering from the COVID-19 pandemic in lung cancer through public awareness campaigns: learning from patient and public insight work
Authors: Evison Matthew , Taylor Sarah , Grundy Seamus , Perkins Anna , Peake Michael
Published: November 2021

COVID-19 has had a devastating impact on outcomes in lung cancer leading to later stage presentation, less curative treatment and higher mortality. This has amplified the existing problem of late-stage presentation in lung cancer and is a call to arms for a multifaceted strategy to address this, including public awareness campaigns to promote healthcare review in patients with persistent chest symptoms. We report the learning from patient and public insight work from across the North of England exploring the barriers to seeking healthcare review with persistent chest symptoms. Members of the public described how a lack of importance is placed on the common symptoms of lung cancer and a feeling of being unworthy of review by healthcare professionals. They would feel motivated to seek review by dispelling the nihilism of lung cancer and would be able to take action more easily by removing the logistical hassle in the process. We propose a four-pillar framework (validation–endorsement–motivation–action) for developing the content of any public awareness campaigns promoting early diagnosis of lung cancer based on the findings of this comprehensive insight work. All providers and commissioners must work together to overcome the perceived and real barriers to patients with persistent chest symptoms.
52 Characterization of the tumor microenvironment in melanoma using Multiplexed Ion Beam Imaging (MIBI)
Authors: Ptacek Jason , Vesely Matthew , Rimm David , Hav Monirath , Aksoy Murat , Crow Ailey , Finn Jessica
Published: November 2021

Background

The complexity of the tumor microenvironment (TME) necessitates the application of high-dimensional methods that can spatially resolve the phenotypic heterogeneity that exists within tumors. MIBI, which combines time-of-flight secondary ion mass spectrometry (ToF-SIMS) with metal labeled antibodies to simultaneously image 40+ proteins at subcellular spatial resolution, was used to classify cell populations and their expression of immunoregulatory proteins within 54 melanoma samples.

Methods

A tissue microarray (TMA) comprised of 0.6 mm FFPE melanoma cores was stained with a panel of 30 metal labeled antibodies. The tissue was imaged using MIBI and multi-step processing was performed to create images of the samples. Single cell segmentation enabled enumeration of 32 cell populations and quantitative analyses were performed of both immune checkpoint expression and the spatial relationships between cells of different types.

Results

Tumor cells and immune cells represented 62% (1.4% - 92.2%) and 24% (2.0% - 92.1%), respectively, of the segmented cells from the melanoma samples. Fibroblasts, lymphatics, and blood vessels were also present at varying densities. Within the immune compartment, M2 macrophages, M2 monocytes, and monocyte-derived dendritic cells (mDCs) were most abundant, representing 36.3% (4.9% - 79.3%), 7.0% (0.0% - 30.6%), and 9.8% (0.0% - 34.6%), respectively, of the total immune cell infiltrate. Rare populations such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells were at greater than 100 cells/mm2 in six samples and four samples, respectively. The presence of immune checkpoint markers (IDO-1, LAG3, PD-1, PD-L1, TIM-3) varied between populations and between samples. A minority of the samples showed expression of IDO-1 and PD-L1 on myeloid populations. Interestingly, among the myeloid subsets, M2 macrophages and monocyte-derived dendritic cells showed the most abundant PD-L1 expression. Although many samples had few T cell infiltrates, those that did showed expression of PD-1, LAG-3, and TIM-3 on T cell populations.

Conclusions

MIBI offers high-parameter tissue imaging, at sensitivity and resolution suited to understanding the complex tumor immune landscape, including the spatial relationships of immune and tumor cells and the expression of immunoregulatory proteins. Datasets that quantify population densities and immune checkpoint expression levels across tumor samples, such as the present one, can be used to test for associations to clinical variables and further understand the TME at the cellular level.
62 Applying machine vision to empower preclinical development of cell engager and adoptive cell therapeutics in patient-derived organoid models of solid tumors
Authors: Khare Sonal , Ho Chi-Sing , Kannan Madhavi , Larsen Brian , Mapes Brandon , Shaxted Jenna , Venkataraman Jagadish , Salahudeen Ameen
Published: November 2021

Background

Cell engager and adoptive cell therapeutics have emerged as efficacious and durable treatments in patients with B-cell malignancies. Though many analogous strategies are under development in solid tumors, none have received approval. Preclinical development of these therapies requires cell labeling of immortalized cell lines and/or primary expanded T cells to distinguish target and effector cells. However, cell engager and adoptive cell therapies have had limited evidence of reproducibility in primary patient-derived models such as tumor organoid cultures thus far. Here, we build upon our tumor organoid platform1 to measure organoid specific responses to these therapies. Utilizing machine vision coupled with time-lapse-microscopy, we obtain multiparameter kinetic readouts of patient-derived tumor organoid cell killing and allogeneic MHC-matched primary peripheral blood mononuclear cells (PBMCs).

Methods

The patient-derived tumor organoids were co-cultured with PBMCs in the presence of engagers/activators and vital dyes and incubated for 96 hrs. Cell death was measured by quantifying the caspase 3/7 vital dye pixel intensities at different time points using high throughput imaging. As a first step, a fully convolutional neural network was trained to segment out organoids from brightfield images comprised of organoids, immune cells and potential background artifacts. This segmentation mask was then transferred over to registered caspase 3/7 images to quantify tumor cell specific phenotypes in a rapid and automated manner.

Results

The time-lapse imaging assay allowed for both the tracking of the organoid growth over time as well as the quantification of the kinetics of engagers/activators in comparison to controls resulting in accurate and precise technical reproducibility. Further, this assay allowed for the co-localization of the organoids and the immune cells over time, thus, enabling a spatiotemporal summary of dose dependent efficacy of candidate therapeutics.

Conclusions

We demonstrate the scalability and throughput of a machine vision tumor organoid immune co-culture platform across multiple unique patient-derived tumor organoid lines bearing a target of interest, enabling future discovery of biomarkers of therapeutic response and resistance.

Reference

Larsen B, Kannan M, Langer LF, Khan AA, Salahudeen AA, A pan-cancer organoid platform for precision medicine. Cell Reports 2021; 36:109429
72 Spatial whole transcriptome profiling of the tumor microenvironment in prostate carcinomas
Authors: Anaparthy Naishitha , Giangarra Valeria , Taylor Sarah , Turkekul Mesruh , Williams Stephen , Mielinis Paulius , Gallant Caroline
Published: November 2021

Background

Despite years of studies and effort, the best strategies for treating prostate cancer and minimizing the complications of treatment remain unanswered questions. This gap in knowledge is partially due to the inability to dissect the complex heterogeneous tumor microenvironment (TME) and immune compartment. Spatially resolved molecular profiling of tumor sections will enhance our understanding of these complexities; However, it has been particularly challenging to do spatial molecular profiling in formalin-fixed paraffin-embedded (FFPE) tissues due to RNA degradation associated with this tissue-embedding method, which is routinely used in oncology workflows. The 10x Genomics Visium Spatial Gene Expression Solution for FFPE tissue overcomes these limitations, enabling spatial gene expression analysis of FFPE tissues combined with classical histology staining techniques such as Hematoxylin & Eosin (H&E) staining and immunofluorescence.

Methods

We used the 10x Genomics Visium Spatial Gene Expression Solution for FFPE tissue to analyze and resolve tumorigenic profiles in sections of normal and adenocarcinoma prostate samples. This assay incorporates ~5,000 molecularly barcoded, spatially encoded capture probes in spots over which the tissue is placed, imaged, and permeabilized. Imaging and sequencing data are processed together, resulting in a spatially resolved transcriptional readout.

Results

We profiled the whole transcriptome in normal, invasive adenocarcinoma, and acinar cell carcinoma FFPE human prostate tissues. Unsupervised clustering of the whole transcriptome data from normal, invasive adenocarcinoma, and acinar cell prostate carcinoma FFPE sections enabled the identification of 2 different regions, which had a well defined spatial distribution within the tissues. Well known prostate gland and prostate-cancer markers were over-expressed in the corresponding healthy and cancerous portions of the tissue, validating the performance of this method. We found that, while in healthy tissues basal cells and luminal cells are spatially organized, this pattern is lost in tumor samples, where luminal cells are greatly expanded in the invasive carcinoma region and do not colocalize with basal cells. Moreover, T lymphocytes are dispersed throughout the whole tissue section in the adenocarcinoma, while plasma B cells are located in the peritumoral region which could impact prognosis.

Conclusions

Spatial whole transcriptome analysis opens new opportunities for better understanding the TME which can not only help discover novel predictive tumor biomarkers, but also enable identifying cell type and tumor region specific drug targets.