bluuebunny/crossref_metadata_2025 huggingface dataset:
The surgical treatment of spinal deformity in children with non-ambulatory myelomeningocele
Authors: Tsirikos Athanasios I. , Wordie Sarah J.
Published: June 2021

Aims

To report the outcome of spinal deformity correction through anterior spinal fusion in wheelchair-bound patients with myelomeningocele.

Methods

We reviewed 12 consecutive patients (7M:5F; mean age 12.4 years (9.2 to 16.8)) including demographic details, spinopelvic parameters, surgical correction, and perioperative data. We assessed the impact of surgery on patient outcomes using the Spina Bifida Spine Questionnaire and a qualitative questionnaire.

Results

The mean follow-up was 5.4 years (2 to 14.9). Nine patients had kyphoscoliosis, two lordoscoliosis, and one kyphosis. All patients had a thoracolumbar deformity. Mean scoliosis corrected from 89.6° (47° to 151°) to 46.5° (17° to 85°; p < 0.001). Mean kyphosis corrected from 79.5° (40° to 135°) to 49° (36° to 65°; p < 0.001). Mean pelvic obliquity corrected from 19.5° (8° to 46°) to 9.8° (0° to 20°; p < 0.001). Coronal and sagittal balance restored to normal. Complication rate was 58.3% (seven patients) with no neurological deficits, implant failure, or revision surgery. The degree of preoperative spinal deformity, especially kyphosis and lordosis, correlated with increased blood loss and prolonged hospital/intensive care unit stay. The patients reported improvement in function, physical appearance, and pain after surgery. The parents reported decrease in need for everyday care.

Conclusion

Anterior spinal fusion achieved satisfactory deformity correction with high perioperative complication rates, but no long-term sequelae among children with high level myelomeningocele. This resulted in physical and functional improvement and high reported satisfaction. Cite this article: Bone Joint J 2021;103-B(6):1133–1141.
Intraoperative Femoral Condyle Fracture during Bone Preparation in a Cruciate-retaining Primary Total Knee Arthroplasty
Authors: Thorat Babaji , Singh Avtar , Vohra Rajeev , Patel Dharmesh , Nisar Sheikh Khalid
Published: June 2021

Introduction: Intraoperative fracture in revision knee arthroplasty is commonly described. Intraoperative fracture during primary total knee arthroplasty (TKA) is a significant yet infrequently reported complication. The literature about intraoperative fractures during primary TKA is limited. It is usually seen in posterior-stabilized prosthesis during primary TKA, however, its occurrence in cruciate-retaining (CR) primary TKA is rarely reported.
Case Report: The authors describe a unique case of intraoperative medial femoral condyle fracture in primary CR TKA during bone preparation. The fracture was managed successfully by fixation with a 3.5 mm screw followed by cemented primary CRTKA. Bony union was achieved with a good clinical outcome as shown by the Knee Society Knee Score of 86 and a Function Score of 90 without any signs of prosthesis failure/loosening at 2 years’ follow-up.
Discussion: Careful pre-operative evaluation and planning are necessary for patients with risk factors to avoid poor outcome. A stable internal fixation abiding the standard principles of fracture fixation and arthroplasty is needed to achieve a satisfactory functional and radiographic outcome, thus avoids early prosthetic failure
Keywords: Intraoperative fracture, complication, distal femur, medial condyle, primary total knee arthroplasty, cruciate retaining.
A Rare Case of Contiguous Three-level Lumbar Burst Fractures-treated with Combined Posterior Stabilization and Anterior Fusion
Authors: Dhillon Charanjit Singh , Nanakkal Ahamed Shafeek , Chhasatia Nilay Prafulsinh , Medagam Narendra Reddy , Khatavi Anandkumar
Published: June 2021

Introduction: Burst fractures occur frequently in high energy trauma and are commonly associated with falls from height and road traffic accidents. While multiple burst fractures are not uncommon in thoracic spine, three or more contiguous level burst fractures are a relative rarity especially, in lumbar spine. The treatment of multilevel burst fractures must be individualized, and each fracture should be treated according to its inherent stability. To the best of our knowledge, this is the only case of such injury reported in English literature.
Case Report: A 17-year-old girl who sustained contiguous three-level lumbar burst fractures with neurological compromise following alleged history of fall from height. Radiographs/computed tomography scan revealed burst fractures of L2, L3, and L4 vertebrae with retropulsion of bony fragments at all the levels. Patient underwent minimally invasive posterior stabilization and anterior Hemi-corpectomy of L2, L4, and fusion. The patient recovered completely from neurological deficits by the end of 6 months.
Conclusion: Multiple contiguous burst fractures in the lumbar spine are a rare entity. To the best of our knowledge, this is the only case of such injury reported in English literature. The treatment requires a thorough assessment of the fracture pattern and often requires a combination of surgical approaches. Each fracture merits treatment based on individual characteristics of fracture patterns and the amount of canal compromise at each level.
Keywords: Lumbar, burst fracture, multiple, contiguous.
Genetic Association and Role of Surgery for the Treatment of Lower Limb Deformities in Diastrophic Dysplasia: A Case Report
Authors: Tripathi Anchal Kumar , Choudhary Sunny , Singh Vivek , Verma Prashant Kumar
Published: June 2021

Introduction: Diastrophic dysplasia (DTD) results from SCN26A2 gene mutation, with autosomal recessive inheritance and widely variable phenotype. The gene has been mapped to chromosome 5q32-q33.1.
Case Report: We present a case of a 4-year-old female with short stature, bilateral feet and knee deformity, and dysplastic facies. SCN26A2 mutations were seen in patient as well as parents. She underwent multiple orthopedic procedures involving metatarsals, gastrosoleus, and distal femur. Based on typical clinical features, DTD was suspected. Genetic studies of patient and parents provided the exact diagnosis in this case.
Conclusion: Genetic diagnosis and family counseling are important caveat of management. Key features like ear abnormalities help to suspect diagnosis which requires a high index of suspicion. Associated bony and soft-tissue abnormalities of lower limb may require surgical intervention for improvement of gait, functions, and cosmesis.
Keywords: Diastrophic dysplasia, Skeletal dysplasia, Ear abnormalities, SCN26A2, Osteotomy.
Pelvic Fracture Associated with Intrapelvic Dislocation of Testis
Authors: Chouhan Varun , ladhania Manish , Chouhan Kiran
Published: June 2021

Introduction: Intrapelvic testicular dislocation is rare injury with the possibility of missed or delayed diagnosis. Timely diagnosis of intrapelvic testicular dislocation can prevent iatrogenic testicular injury during surgery and its long-term sequel.
Case Report: A 30-year-old male after motorbike accident presented with a pelvic injury with intrapelvic dislocation of testis. Timely and appropriate diagnosis of injuries, specially intrapelvic dislocation of testis, required early orchidopexy and open reduction and internal fixation of the anterior column, leading to excellent outcome.
Conclusion: In cases of polytrauma and pelvic injuries specially motorbike accidents, testicular dislocation should be ruled out before definitive surgery. Adequate communication and co-ordination between orthopedic surgeon, radiologist, and urologist can lead to excellent outcomes.
Keywords: Testicular dislocation, ectopic testicular dislocation, intrapelvic dislocation of testis.
Tunable properties of one-dimensional GaAs/AlAs-based photonic crystal containing two defect layers
Authors: Biswal Amita , Kumar R. , Nayak Chittaranjan , Dhanalakshmi Samiappan , Behera Harekrushna
Published: June 2021

The characteristics of an optical tunable filter are elicited theoretically in this study. Here, the characteristic matrix method is used to investigate the behavior of the defect modes in GaAs/AlAs-based one-dimensional defective multilayered photonic crystals consisting of two externally magnetized GaAs defect layers. The external magnetic field is applied to GaAs for the consideration of the defect mode in the middle of the structure. The effects on the defect modes for distinct values of the external magnetic field, electron density, and angle of incidence for both the TE and TM waves are analyzed. The numerical results convey that the frequency of the defect mode can be tuned effectively by changing the values of the physical parameters. Besides, the modes of propagation play a major role in the shifting trend of occurrence of the defect modes in the higher frequency region. The contour plots for electron density and incident angle show two clear defect peaks for both TE and TM waves. Moreover, the Brewster angle verifies the complete transmission through the defective symmetric optical media. The proposed structure can be used to design the narrowband and multichannel tunable transmission filters at the terahertz region.
Untrained networks for compressive lensless photography
Authors: Monakhova Kristina , Tran Vi , Kuo Grace , Waller Laura
Published: June 2021

Compressive lensless imagers enable novel applications in an extremely compact device, requiring only a phase or amplitude mask placed close to the sensor. They have been demonstrated for 2D and 3D microscopy, single-shot video, and single-shot hyperspectral imaging; in each case, a compressive-sensing-based inverse problem is solved in order to recover a 3D data-cube from a 2D measurement. Typically, this is accomplished using convex optimization and hand-picked priors. Alternatively, deep learning-based reconstruction methods offer the promise of better priors, but require many thousands of ground truth training pairs, which can be difficult or impossible to acquire. In this work, we propose an unsupervised approach based on untrained networks for compressive image recovery. Our approach does not require any labeled training data, but instead uses the measurement itself to update the network weights. We demonstrate our untrained approach on lensless compressive 2D imaging, single-shot high-speed video recovery using the camera’s rolling shutter, and single-shot hyperspectral imaging. We provide simulation and experimental verification, showing that our method results in improved image quality over existing methods.
Multi-functional high-efficiency reflective polarization converter based on an ultra-thin graphene metasurface in the THz band
Authors: Barkabian Mahsa , Sharifi Nahid , Granpayeh Nosrat
Published: June 2021

In this study, an ultra-thin reflective metasurface is proposed for polarization conversion in the terahertz band. Each unit cell of metasurface is composed of graphene ribbons lying diagonally on silicon substrate. A reflective metal is also placed at the bottom of the structure. Our polarization converter works as a linear polarization converter (LPC) and linear to circular polarization converter (LTC-PC) by variation of the chemical potential of graphene, which can actively be changed by chemical doping or electrical bias of the graphene. The working bandwidth of LPC changes by adjusting the chemical potential of the graphene. The LPC structure has more than 99% polarization conversion ratio in the frequency range of 0.83-0.92 THz, even by changing the angle of incident wave up to 45°, the results are still acceptable. The LTC-PC has less than 3dB axial ratio (AR) in the frequency range of 0.6-0.67 THz for left-handed circularly polarized (LHCP) waves and 0.72-0.97 THz for right-handed circularly polarized (RHCP) waves. To verify the simulation results, an equivalent circuit model based on the structure performance is proposed. Equivalent circuit model results agree very well with the simulation results. Due to the fabrication feasibility, ultra-thin thickness, incident angle insensitive, and high efficiency, our structure has great potential in state-of-the-art technologies such as imaging, sensing, communication, and other optical applications.
Metamaterial perfect absorber with morphology-engineered meta-atoms using deep learning
Authors: Han Cheng , Zhang Baifu , Wang Hao , Ding Jianping
Published: June 2021

Metamaterial perfect absorbers (MPAs) typically have regularly-shaped unit structures owing to constraints on conventional analysis methods, limiting their absorption properties. We propose an MPA structure with a general polygon-shaped meta-atom. Its irregular unit structure provides multiple degrees-of-freedom, enabling flexible properties, such as dual-band absorption. We constructed a deep neural network to predict the parameters of the corresponding MPA structure with a given absorptivity as input, and vice versa. The mean-square error was as low as 0.0017 on the validation set. This study provides a basis for the design of complicated artificial electromagnetic structures for application in metamaterials and metasurfaces.
Mode division multiplexing for multiple particles noncontact simultaneous trap
Authors: Zhang Yaxun , Zhou Yu , Tang Xiaoyun , Wang Zhen , Zhang Yu , Liu Zhihai , Zhang JianZhong , Yang Jun , Yuan Libo
Published: June 2021

We propose and demonstrate an optical trap on the basis of a normal single-mode fiber (SMF), which is used to trap two particles in the axial direction at the same time without contact based on mode division multiplexing technology. We design and manufacture a tapered fiber probe. The

L
P

11

mode beam is excited by docking a normal SMF to a 980 nm SMF with a 2 µm offset. Then the beams of

L
P

01

and

L
P

11

are both transmitted in the fiber. To converge the

L
P

11

mode beam, a SMF with a tapered end is used to produce a cage for trapping the first microparticle. This particle acts as a lens to converge the

L
P

01

mode beam to trap the second microparticle. We verify the feasibility of trapping two particles simultaneously through simulation. With this function, the proposed optical trap is easier to manipulate different individual particles for comparison and testing, which can promote the development of the biological, biophysical, colloidal, and soft matter fields.
Low random duty-cycle errors in periodically poled KTP revealed by sum-frequency generation
Authors: Mann Felix , Chrzanowski Helen M. , Ramelow Sven
Published: June 2021

Low-noise quantum frequency conversion in periodically poled nonlinear crystals has proved challenging when the pump wavelength is shorter than the target wavelength. This is—at least in large part—a consequence of the parasitic spontaneous parametric downconversion of pump photons, whose efficiency is increased by fabrication errors in the periodic poling. Here we characterize the poling quality of commercial periodically poled bulk potassium titanyl phosphate (ppKTP) by measuring the sum-frequency generation (SFG) efficiency over a large phase mismatch range from 0 to more than

400
π

. Over the probed range, the SFG efficiency behaves nearly ideally and drops to a normalized efficiency of

10

−
6

. Our results demonstrate that any background pedestal that would be formed by random duty-cycle errors in ppKTP is substantially reduced when compared to periodically poled lithium niobate. The standard deviation of the random duty-cycle errors can be estimated to be smaller than 2% of the domain length. From this, we expect a noise spectral density that is at least 1 order of magnitude smaller than that of current state-of-the-art single-step frequency converters.
Resonant optical effects in composite Co/opal-based magnetoplasmonic structures
Authors: Kolmychek I. A. , Mamonov E. A. , Gusev N. S. , Sapozhnikov M. V. , Golubev V. G. , Murzina T. V.
Published: June 2021

Plasmonic structures are extremely attractive for the light flow manipulation. In turn, the spectrum of the plasmon excitations can be controlled by external magnetic field, thus giving rise to magnetoplasmonics. However, in the case of traditional magnetoplasmonic structures, the enhancement of magneto-optical (MO) effects is often accompanied by the transmission damp, which constricts the area of their applications. This paper examines resonant optical effects in composite structures based on artificial opal films covered by a thin cobalt layer, which forms a 2D hexagonal lattice of nanoholes in the metal film. Such periodic structure exhibits surface plasmon polariton-assisted extraordinary transmission along with the increase of odd in magnetization intensity magnetooptical effect in the Voigt geometry. Local field enhancement accompanying the surface plasmon polaritons excitation in composite Co/opal structure provides a distinct enhancement of the magnetization-induced second harmonic generation (SHG) and relevant MO effects at the SHG wavelength that appear as Fano-type resonances. High transmission along with resonantly-high MO effects make Co/opal films promising in plasmonic applications.
An in vitro model of tumor heterogeneity resolves genetic, epigenetic, and stochastic sources of cell state variability
Authors: Hayford Corey E. , Tyson Darren R. , Robbins C. Jack , Frick Peter L. , Quaranta Vito , Harris Leonard A.
Published: June 2021

Tumor heterogeneity is a primary cause of treatment failure and acquired resistance in cancer patients. Even in cancers driven by a single mutated oncogene, variability in response to targeted therapies is well known. The existence of additional genomic alterations among tumor cells can only partially explain this variability. As such, nongenetic factors are increasingly seen as critical contributors to tumor relapse and acquired resistance in cancer. Here, we show that both genetic and nongenetic factors contribute to targeted drug response variability in an experimental model of tumor heterogeneity. We observe significant variability to epidermal growth factor receptor (EGFR) inhibition among and within multiple versions and clonal sublines of PC9, a commonly used EGFR mutant nonsmall cell lung cancer (NSCLC) cell line. We resolve genetic, epigenetic, and stochastic components of this variability using a theoretical framework in which distinct genetic states give rise to multiple epigenetic “basins of attraction,” across which cells can transition driven by stochastic noise. Using mutational impact analysis, single-cell differential gene expression, and correlations among Gene Ontology (GO) terms to connect genomics to transcriptomics, we establish a baseline for genetic differences driving drug response variability among PC9 cell line versions. Applying the same approach to clonal sublines, we conclude that drug response variability in all but one of the sublines is due to epigenetic differences; in the other, it is due to genetic alterations. Finally, using a clonal drug response assay together with stochastic simulations, we attribute subclonal drug response variability within sublines to stochastic cell fate decisions and confirm that one subline likely contains genetic resistance mutations that emerged in the absence of drug treatment.
A return-on-investment approach for prioritization of rigorous taxonomic research needed to inform responses to the biodiversity crisis
Authors: Melville Jane , Chapple David G. , Keogh J. Scott , Sumner Joanna , Amey Andrew , Bowles Phil , Brennan Ian G. , Couper Patrick , Donnellan Stephen C. , Doughty Paul , Edwards Danielle L. , Ellis Ryan J. , Esquerré Damien , Fenker Jéssica , Gardner Michael G. , Georges Arthur , Haines Margaret L. , Hoskin Conrad J. , Hutchinson Mark , Moritz Craig , Nankivell James , Oliver Paul , Pavón-Vázquez Carlos J. , Pepper Mitzy , Rabosky Daniel L. , Sanders Kate , Shea Glenn , Singhal Sonal , Worthington Wilmer Jessica , Tingley Reid
Published: June 2021

Global biodiversity loss is a profound consequence of human activity. Disturbingly, biodiversity loss is greater than realized because of the unknown number of undocumented species. Conservation fundamentally relies on taxonomic recognition of species, but only a fraction of biodiversity is described. Here, we provide a new quantitative approach for prioritizing rigorous taxonomic research for conservation. We implement this approach in a highly diverse vertebrate group—Australian lizards and snakes. Of 870 species assessed, we identified 282 (32.4%) with taxonomic uncertainty, of which 17.6% likely comprise undescribed species of conservation concern. We identify 24 species in need of immediate taxonomic attention to facilitate conservation. Using a broadly applicable return-on-investment framework, we demonstrate the importance of prioritizing the fundamental work of identifying species before they are lost.
Fungal and host protein persulfidation are functionally correlated and modulate both virulence and antifungal response
Authors: Sueiro-Olivares Monica , Scott Jennifer , Gago Sara , Petrovic Dunja , Kouroussis Emilia , Zivanovic Jasmina , Yu Yidong , Strobel Marlene , Cunha Cristina , Thomson Darren , Fortune-Grant Rachael , Thusek Sina , Bowyer Paul , Beilhack Andreas , Carvalho Agostinho , Bignell Elaine , Filipovic Milos R. , Amich Jorge
Published: June 2021

Aspergillus fumigatusis a human fungal pathogen that can cause devastating pulmonary infections, termed “aspergilloses,” in individuals suffering immune imbalances or underlying lung conditions. As rapid adaptation to stress is crucial for the outcome of the host–pathogen interplay, here we investigated the role of the versatile posttranslational modification (PTM) persulfidation for both fungal virulence and antifungal host defense. We show that anA.fumigatusmutant with low persulfidation levels is more susceptible to host-mediated killing and displays reduced virulence in murine models of infection. Additionally, we found that a single nucleotide polymorphism (SNP) in the human gene encoding cystathionine γ-lyase (CTH) causes a reduction in cellular persulfidation and correlates with a predisposition of hematopoietic stem cell transplant recipients to invasive pulmonary aspergillosis (IPA), as correct levels of persulfidation are required for optimal antifungal activity of recipients’ lung resident host cells. Importantly, the levels of host persulfidation determine the levels of fungal persulfidation, ultimately reflecting a host–pathogen functional correlation and highlighting a potential new therapeutic target for the treatment of aspergillosis.
Implications of diffusion and time-varying morphogen gradients for the dynamic positioning and precision of bistable gene expression boundaries
Authors: Perkins Melinda Liu
Published: June 2021

The earliest models for how morphogen gradients guide embryonic patterning failed to account for experimental observations of temporal refinement in gene expression domains. Following theoretical and experimental work in this area, dynamic positional information has emerged as a conceptual framework to discuss how cells process spatiotemporal inputs into downstream patterns. Here, we show that diffusion determines the mathematical means by which bistable gene expression boundaries shift over time, and therefore how cells interpret positional information conferred from morphogen concentration. First, we introduce a metric for assessing reproducibility in boundary placement or precision in systems where gene products do not diffuse, but where morphogen concentrations are permitted to change in time. We show that the dynamics of the gradient affect the sensitivity of the final pattern to variation in initial conditions, with slower gradients reducing the sensitivity. Second, we allow gene products to diffuse and consider gene expression boundaries as propagating wavefronts with velocity modulated by local morphogen concentration. We harness this perspective to approximate a PDE model as an ODE that captures the position of the boundary in time, and demonstrate the approach with a preexisting model for Hunchback patterning in fruit fly embryos. We then propose a design that employs antiparallel morphogen gradients to achieve accurate boundary placement that is robust to scaling. Throughout our work we draw attention to tradeoffs among initial conditions, boundary positioning, and the relative timescales of network and gradient evolution. We conclude by suggesting that mathematical theory should serve to clarify not just our quantitative, but also our intuitive understanding of patterning processes.
Categorical judgments do not modify sensory representations in working memory
Authors: Luu Long , Stocker Alan A.
Published: June 2021

Categorical judgments can systematically bias the perceptual interpretation of stimulus features. However, it remained unclear whether categorical judgments directly modify working memory representations or, alternatively, generate these biases via an inference process down-stream from working memory. To address this question we ran two novel psychophysical experiments in which human subjects had to reverse their categorical judgments about a stimulus feature, if incorrect, before providing an estimate of the feature. If categorical judgments indeed directly altered sensory representations in working memory, subjects’ estimates should reflect some aspects of their initial (incorrect) categorical judgment in those trials. We found no traces of the initial categorical judgment. Rather, subjects seemed to be able to flexibly switch their categorical judgment if needed and use the correct corresponding categorical prior to properly perform feature inference. A cross-validated model comparison also revealed that feedback may lead to selective memory recall such that only memory samples that are consistent with the categorical judgment are accepted for the inference process. Our results suggest that categorical judgments do not modify sensory information in working memory but rather act as top-down expectations in the subsequent sensory recall and inference process.
Quantifying cell transitions in C. elegans with data-fitted landscape models
Authors: Camacho-Aguilar Elena , Warmflash Aryeh , Rand David A.
Published: June 2021

Increasing interest has emerged in new mathematical approaches that simplify the study of complex differentiation processes by formalizing Waddington’s landscape metaphor. However, a rational method to build these landscape models remains an open problem. Here we study vulval development in C. elegans by developing a framework based on Catastrophe Theory (CT) and approximate Bayesian computation (ABC) to build data-fitted landscape models. We first identify the candidate qualitative landscapes, and then use CT to build the simplest model consistent with the data, which we quantitatively fit using ABC. The resulting model suggests that the underlying mechanism is a quantifiable two-step decision controlled by EGF and Notch-Delta signals, where a non-vulval/vulval decision is followed by a bistable transition to the two vulval states. This new model fits a broad set of data and makes several novel predictions.
TSCCA: A tensor sparse CCA method for detecting microRNA-gene patterns from multiple cancers
Authors: Min Wenwen , Chang Tsung-Hui , Zhang Shihua , Wan Xiang
Published: June 2021

Existing studies have demonstrated that dysregulation of microRNAs (miRNAs or miRs) is involved in the initiation and progression of cancer. Many efforts have been devoted to identify microRNAs as potential biomarkers for cancer diagnosis, prognosis and therapeutic targets. With the rapid development of miRNA sequencing technology, a vast amount of miRNA expression data for multiple cancers has been collected. These invaluable data repositories provide new paradigms to explore the relationship between miRNAs and cancer. Thus, there is an urgent need to explore the complex cancer-related miRNA-gene patterns by integrating multi-omics data in a pan-cancer paradigm. In this study, we present a tensor sparse canonical correlation analysis (TSCCA) method for identifying cancer-related miRNA-gene modules across multiple cancers. TSCCA is able to overcome the drawbacks of existing solutions and capture both the cancer-shared and specific miRNA-gene co-expressed modules with better biological interpretations. We comprehensively evaluate the performance of TSCCA using a set of simulated data and matched miRNA/gene expression data across 33 cancer types from the TCGA database. We uncover several dysfunctional miRNA-gene modules with important biological functions and statistical significance. These modules can advance our understanding of miRNA regulatory mechanisms of cancer and provide insights into miRNA-based treatments for cancer.
Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics Initiative: A Mendelian randomization study
Authors: Butler-Laporte Guillaume , Nakanishi Tomoko , Mooser Vincent , Morrison David R. , Abdullah Tala , Adeleye Olumide , Mamlouk Noor , Kimchi Nofar , Afrasiabi Zaman , Rezk Nardin , Giliberti Annarita , Renieri Alessandra , Chen Yiheng , Zhou Sirui , Forgetta Vincenzo , Richards J. Brent
Published: June 2021

Background

Increased vitamin D levels, as reflected by 25-hydroxy vitamin D (25OHD) measurements, have been proposed to protect against COVID-19 based on in vitro, observational, and ecological studies. However, vitamin D levels are associated with many confounding variables, and thus associations described to date may not be causal. Vitamin D Mendelian randomization (MR) studies have provided results that are concordant with large-scale vitamin D randomized trials. Here, we used 2-sample MR to assess evidence supporting a causal effect of circulating 25OHD levels on COVID-19 susceptibility and severity.

Methods and findings

Genetic variants strongly associated with 25OHD levels in a genome-wide association study (GWAS) of 443,734 participants of European ancestry (including 401,460 from the UK Biobank) were used as instrumental variables. GWASs of COVID-19 susceptibility, hospitalization, and severe disease from the COVID-19 Host Genetics Initiative were used as outcome GWASs. These included up to 14,134 individuals with COVID-19, and up to 1,284,876 without COVID-19, from up to 11 countries. SARS-CoV-2 positivity was determined by laboratory testing or medical chart review. Population controls without COVID-19 were also included in the control groups for all outcomes, including hospitalization and severe disease. Analyses were restricted to individuals of European descent when possible. Using inverse-weighted MR, genetically increased 25OHD levels by 1 standard deviation on the logarithmic scale had no significant association with COVID-19 susceptibility (odds ratio [OR] = 0.95; 95% CI 0.84, 1.08; p = 0.44), hospitalization (OR = 1.09; 95% CI: 0.89, 1.33; p = 0.41), and severe disease (OR = 0.97; 95% CI: 0.77, 1.22; p = 0.77). We used an additional 6 meta-analytic methods, as well as conducting sensitivity analyses after removal of variants at risk of horizontal pleiotropy, and obtained similar results. These results may be limited by weak instrument bias in some analyses. Further, our results do not apply to individuals with vitamin D deficiency.

Conclusions

In this 2-sample MR study, we did not observe evidence to support an association between 25OHD levels and COVID-19 susceptibility, severity, or hospitalization. Hence, vitamin D supplementation as a means of protecting against worsened COVID-19 outcomes is not supported by genetic evidence. Other therapeutic or preventative avenues should be given higher priority for COVID-19 randomized controlled trials.
Risk of prostate cancer in relatives of prostate cancer patients in Sweden: A nationwide cohort study
Authors: Xu Xing , Kharazmi Elham , Tian Yu , Mukama Trasias , Sundquist Kristina , Sundquist Jan , Brenner Hermann , Fallah Mahdi
Published: June 2021

Background

Evidence-based guidance for starting ages of screening for first-degree relatives (FDRs) of patients with prostate cancer (PCa) to prevent stage III/IV or fatal PCa is lacking in current PCa screening guidelines. We aimed to provide evidence for risk-adapted starting age of screening for relatives of patients with PCa.

Methods and findings

In this register-based nationwide cohort study, all men (aged 0 to 96 years at baseline) residing in Sweden who were born after 1931 along with their fathers were included. During the follow-up (1958 to 2015) of 6,343,727 men, 88,999 were diagnosed with stage III/IV PCa or died of PCa. The outcomes were defined as the diagnosis of stage III/IV PCa or death due to PCa, stratified by age at diagnosis. Using 10-year cumulative risk curves, we calculated risk-adapted starting ages of screening for men with different constellations of family history of PCa. The 10-year cumulative risk of stage III/IV or fatal PCa in men at age 50 in the general population (a common recommended starting age of screening) was 0.2%. Men with≥2 FDRs diagnosed with PCa reached this screening level at age 41 (95% confidence interval (CI): 39 to 44), i.e., 9 years earlier, when the youngest one was diagnosed before age 60; at age 43 (41 to 47), i.e., 7 years earlier, when≥2 FDRs were diagnosed after age 59, which was similar to that of men with 1 FDR diagnosed before age 60 (41 to 45); and at age 45 (44 to 46), when 1 FDR was diagnosed at age 60 to 69 and 47 (46 to 47), when 1 FDR was diagnosed after age 69. We also calculated risk-adapted starting ages for other benchmark screening ages, such as 45, 55, and 60 years, and compared our findings with those in the guidelines. Study limitations include the lack of genetic data, information on lifestyle, and external validation.

Conclusions

Our study provides practical information for risk-tailored starting ages of PCa screening based on nationwide cancer data with valid genealogical information. Our clinically relevant findings could be used for evidence-based personalized PCa screening guidance and supplement current PCa screening guidelines for relatives of patients with PCa.
Association between industry payments and prescriptions of long-acting insulin: An observational study with propensity score matching
Authors: Inoue Kosuke , Tsugawa Yusuke , Mangione Carol M. , Duru O. Kenrik
Published: June 2021

Background

The rapidly increased spending on insulin is a major public health issue in the United States. Industry marketing might be one of the upstream determinants of physicians’ prescription of long-acting insulin—the most commonly used and costly type of insulin, but the evidence is lacking. We therefore aimed to investigate the association between industry payments to physicians and subsequent prescriptions of long-acting insulin.

Methods and findings

Using the databases of Open Payments and Medicare Part D, we examined the association between the receipt of industry payments for long-acting insulin in 2016 and (1) the number of claims; (2) the costs paid for all claims; and (3) the costs per claim of long-acting insulin in 2017. We also examined the association between the receipt of payments and the change in these outcomes from 2016 to 2017. We employed propensity score matching to adjust for the physician-level characteristics (sex, years in practice, specialty, and medical school attended). Among 145,587 eligible physicians treating Medicare beneficiaries, 51,851 physicians received industry payments for long-acting insulin worth $22.3 million. In the propensity score–matched analysis including 102,590 physicians, we found that physicians who received the payments prescribed a higher number of claims (adjusted difference, 57.8; 95% CI, 55.8 to 59.7), higher costs for total claims (adjusted difference, +$22,111; 95% CI, $21,387 to $22,836), and higher costs per claim (adjusted difference, +$71.1; 95% CI, $69.0 to $73.2) of long-acting insulin, compared with physicians who did not receive the payments. The association was also found for changes in these outcomes from 2016 to 2017. Limitations to our study include limited generalizability, confounding, and possible reverse causation.

Conclusions

Industry marketing payments to physicians for long-acting insulin were associated with the physicians’ prescriptions and costs of long-acting insulin in the subsequent year. Future research is needed to assess whether policy interventions on physician–industry financial relationships will help to ensure appropriate prescriptions and limit overall costs of this essential drug for diabetes care.
Integrated treatment of hepatitis C virus infection among people who inject drugs: A multicenter randomized controlled trial (INTRO-HCV)
Authors: Fadnes Lars T. , Aas Christer Frode , Vold Jørn Henrik , Leiva Rafael Alexander , Ohldieck Christian , Chalabianloo Fatemeh , Skurtveit Svetlana , Lygren Ole Jørgen , Dalgård Olav , Vickerman Peter , Midgard Håvard , Løberg Else-Marie , Johansson Kjell Arne ,   for the INTRO-HCV Study Group
Published: June 2021

Background

The standard pathways of testing and treatment for hepatitis C virus (HCV) infection in tertiary healthcare are not easily accessed by people who inject drugs (PWID). The aim of this study was to evaluate the efficacy of integrated treatment of chronic HCV infection among PWID.

Methods and findings

INTRO-HCV is a multicenter, randomized controlled clinical trial. Participants recruited from opioid agonist therapy (OAT) and community care clinics in Norway over 2017 to 2019 were randomly 1:1 assigned to the 2 treatment approaches. Integrated treatment was delivered by multidisciplinary teams at opioid agonist treatment clinics or community care centers (CCCs) for people with substance use disorders. This included on-site testing for HCV, liver fibrosis assessment, counseling, treatment, and posttreatment follow-up. Standard treatment was delivered in hospital outpatient clinics. Oral direct-acting antiviral (DAA) medications were administered in both arms. The study was not completely blinded. The primary outcomes were time-to-treatment initiation and sustained virologic response (SVR), defined as undetectable HCV RNA 12 weeks after treatment completion, analyzed with intention to treat, and presented as hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals.

Among 298 included participants, 150 were randomized to standard treatment, of which 116/150 (77%) initiated treatment, with 108/150 (72%) initiating within 1 year of referral. Among those 148 randomized to integrated care, 145/148 (98%) initiated treatment, with 141/148 (95%) initiating within 1 year of referral. The HR for the time to initiating treatment in the integrated arm was 2.2 (1.7 to 2.9) compared to standard treatment. SVR was confirmed in 123 (85% of initiated/83% of all) for integrated treatment compared to 96 (83% of initiated/64% of all) for the standard treatment (OR among treated: 1.5 [0.8 to 2.9], among all: 2.8 [1.6 to 4.8]). No severe adverse events were linked to the treatment.

Conclusions

Integrated treatment for HCV in PWID was superior to standard treatment in terms of time-to-treatment initiation, and subsequently, more people achieved SVR. Among those who initiated treatment, the SVR rates were comparable. Scaling up of integrated treatment models could be an important tool for elimination of HCV.

Trial registration

ClinicalTrials.gov.no NCT03155906
Species composition and risk of transmission of some Aedes-borne arboviruses in some sites in Northern Ghana
Authors: Joannides Joannitta , Dzodzomenyo Mawuli , Azerigyik Faustus , Agbosu Eudocia Esinam , Pratt Deborah , Nyarko Osei Joseph Harold , Pwalia Rebecca , Amlalo Godwin Kwame , Appawu Maxwell , Takashi Hayashi , Iwanaga Shiroh , Buchwald Andrea , Rochford Rosemary , Boakye Daniel , Koram Kwadwo , Bonney Kofi , Dadzie Samuel
Published: June 2021

Aedes-borne viral diseases mainly Yellow Fever (YF), Dengue (DEN), Zika (ZIK) and Chikungunya (CHK) have contributed to many deaths’ in the world especially in Africa. There have been major outbreaks of these diseases in West Africa. Although, YF outbreaks have occurred in Ghana over the years, no outbreak of DEN, ZIK and CHK has been recorded. However, the risk of outbreak is high due to its proximity to West African countries where outbreaks have been recently been recorded. This study surveyed the mosquito fauna to assess the risk of transmission of Yellow fever (YFV), Dengue (DENV), Chikungunya (CHKV) and Zika (ZIKV) viruses in Larabanga and Mole Game Reserve areas in Northern Ghana. The immature and adult stages ofAedesmosquitoes were collected from Larabanga and Mole Game Reserve area. There was a significant (P>0.001) number of mosquitoes collected during the rainy season than the dry season. A total of 1,930Aedesmosquitoes were collected during the rainy season and morphologically identified. Of these, 1,915 (99.22%) wereAedes aegyptiand 15 (0.22%) wereAedes vittatus. During the dry season, 27Ae.aegyptimosquitoes were collected. A total of 415Ae.aegyptimosquitoes were molecularly identified to subspecies level of whichAe.(Ae) aegypti aegyptiwas the predominant subspecies. BothAe.aegypti aegypti and Ae aegypti formosusexist in sympatry in the area. AllAedespools (75) were negative for DENV, ZIKV and CHKV when examined by RT- PCR. Three Larval indices namely House Index, HI (percentage of houses positive forAedeslarvae or pupae), Container Index, CI (the percentage of containers positive forAedeslarvae or pupae) and Breteau Index, BI (number of positive containers per 100 houses inspected) were assessed as a measure for risk of transmission in the study area. The HI, CI and BI for both sites were as follows; Mole Game Reserve (HI, 42.1%, CI, 23.5% and BI, 100 for rainy season and 0 for all indices for dry season) and Larabanga (39%, 15.5% and 61 for rainy season and 2.3%, 1.3% and 2.3 for dry season). The spatial distribution ofAedesbreeding sites in both areas indicated thatAedeslarvae were breeding in areas with close proximity to humans. Lorry tires were the main source ofAedeslarvae in all the study areas. Information about the species composition and the potential role ofAedesmosquitoes in future outbreaks of the diseases that they transmit is needed to design efficient surveillance and vector control tools.
IHR-PVS National Bridging Workshops, a tool to operationalize the collaboration between human and animal health while advancing sector-specific goals in countries
Authors: Belot Guillaume , Caya François , Errecaborde Kaylee Myhre , Traore Tieble , Lafia Brice , Skrypnyk Artem , Montabord Djhane , Carron Maud , Corning Susan , Sreedharan Rajesh , Isla Nicolas , Schmidt Tanja , Gongal Gyanendra , Samhouri Dalia , Perez-Gutierrez Enrique , Riviere-Cinnamond Ana , Xing Jun , Chungong Stella , de la Rocque Stephane
Published: June 2021

Collaborative, One Health approaches support governments to effectively prevent, detect and respond to emerging health challenges, such as zoonotic diseases, that arise at the human-animal-environmental interfaces. To overcome these challenges, operational and outcome-oriented tools that enable animal health and human health services to work specifically on their collaboration are required. While international capacity and assessment frameworks such as the IHR-MEF (International Health Regulations—Monitoring and Evaluation Framework) and the OIE PVS (Performance of Veterinary Services) Pathway exist, a tool and process that could assess and strengthen the interactions between human and animal health sectors was needed. Through a series of six phased pilots, the IHR-PVS National Bridging Workshop (NBW) method was developed and refined. The NBW process gathers human and animal health stakeholders and follows seven sessions, scheduled across three days. The outputs from each session build towards the next one, following a structured process that goes from gap identification to joint planning of corrective measures. The NBW process allows human and animal health sector representatives to jointly identify actions that support collaboration while advancing evaluation goals identified through the IHR-MEF and the OIE PVS Pathway. By integrating sector-specific and collaborative goals, the NBWs help countries in creating a realistic, concrete and practical joint road map for enhanced compliance to international standards as well as strengthened preparedness and response for health security at the human-animal interface.
The effect of prior long-term recellularization with keratocytes of decellularized porcine corneas implanted in a rabbit anterior lamellar keratoplasty model
Authors: Fernández-Pérez Julia , Madden Peter W. , Brady Robert Thomas , Nowlan Peter F. , Ahearne Mark
Published: June 2021

Decellularized porcine corneal scaffolds are a potential alternative to human cornea for keratoplasty. Although clinical trials have reported promising results, there can be corneal haze or scar tissue. Here, we examined if recellularizing the scaffolds with human keratocytes would result in a better outcome. Scaffolds were prepared that retained little DNA (14.89 ± 5.56 ng/mg) and demonstrated a lack of cytotoxicity by in vitro. The scaffolds were recellularized using human corneal stromal cells and cultured for between 14 in serum-supplemented media followed by a further 14 days in either serum free or serum-supplemented media. All groups showed full-depth cell penetration after 14 days. When serum was present, staining for ALDH3A1 remained weak but after serum-free culture, staining was brighter and the keratocytes adopted a native dendritic morphology with an increase (p < 0.05) of keratocan, decorin, lumican and CD34 gene expression. A rabbit anterior lamellar keratoplasty model was used to compare implanting a 250 μm thick decellularized lenticule against one that had been recellularized with human stromal cells after serum-free culture. In both groups, host rabbit epithelium covered the implants, but transparency was not restored after 3 months. Post-mortem histology showed under the epithelium, a less-compact collagen layer, which appeared to be a regenerating zone with some α-SMA staining, indicating fibrotic cells. In the posterior scaffold, ALDH1A1 staining was present in all the acellular scaffold, but in only one of the recellularized lenticules. Since there was little difference between acellular and cell-seeded scaffolds in our in vivo study, future scaffold development should use acellular controls to determine if cells are necessary.
Prevalence of elevated liver transaminases and their relationship with alcohol use in people living with HIV on anti-retroviral therapy in Uganda
Authors: Freiman J. Morgan , Fatch Robin , Cheng Debbie , Emenyonu Nneka , Ngabirano Christine , Geadas Carolina , Adong Julian , Muyindike Winnie R. , Linas Benjamin P. , Jacobson Karen R. , Hahn Judith A.
Published: June 2021

Background

Isoniazid preventive therapy (IPT) reduces tuberculosis reactivation and mortality among persons living with HIV (PLWH), yet hepatotoxicity concerns exclude “regular and heavy alcohol drinkers” from IPT. We aimed to determine the prevalence of elevated liver transaminases among PLWH on antiretroviral therapy (ART) who engage in alcohol use.

Setting

The Immune Suppression Syndrome Clinic of Mbarara, Uganda.

Methods

We defined elevated liver transaminases as ≥1.25 times (X) the upper limit of normal (ULN) for alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST). We evaluated the associations of current alcohol use and other variables of interest (sex, body mass index, and ART regimen) with elevated transaminases at study screening, using multivariable logistic regression to obtain adjusted odds ratios (aOR) and 95% confidence intervals (CI).

Results

Among 1301 participants (53% female, median age 39 years, 67.4% current alcohol use), 18.8% (95% CI: 16.8–21.1) had elevated transaminases pre-IPT, with few (1.1%) severe (≥5X the ULN). The proportion with any elevation among those currently using alcohol and those abstaining was 22.3% and 11.6%, respectively (p<0.01). In multivariable analyses, those currently using alcohol had higher odds of elevated transaminases compared to those abstaining (aOR 1.65, 95% CI 1.15–2.37) as did males compared to females (aOR 2.68, 95% CI 1.90–3.78).

Conclusions

Pre-IPT elevated transaminases among PLWH receiving ART were common, similar to prior estimates, but severe elevations were rare. Current drinking and male sex were independently associated with elevated transaminases. Further research is needed to determine the implications of such transaminase elevations and alcohol use on providing IPT.