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Crohn's disease is an inflammatory condition of the intestine characterized by largely unknown etiology and a relapse remission cycle of disease control. While possible triggers have been identified, research is inconsistent on the precise cause of these relapses, especially in the under-researched pediatric population. We hypothesized that patients in remission would have persistent microbial and inflammatory changes in small intestinal tissue that might trigger relapse. To this end, we analyzed intestinal biopsy samples from six patients with pediatric Crohn's disease in remission and a control group of 16 pediatric patients with no evident pathogenic abnormality. We identified compositional microbiota differences, including decreases in the genera Streptococcus and Actinobacillus as well as increases in Oribacterium and Prevotella in patients with controlled Crohn's disease compared to controls. Further, a histologic analysis found that patients with controlled Crohn's disease had increased epithelial integrity, and decreased intraepithelial lymphocytes compared with controls. Additionally, we observed increased peripheral CD4 + T cells in patients with pediatric Crohn's disease. These results indicate that markers of intestinal inflammation are responsive to Crohn's disease treatment, however the interventions may not resolve the underlying dysbiosis. These findings suggest that persistent dysbiosis may increase vulnerability to relapse of pediatric Crohn's disease. This study used a nested cohort of patients from the Bangladesh Environmental Enteric Dysfunction (BEED) study (ClinicalTrials.gov ID: NCT02812615 Date of first registration: 24/06/2016)., (© 2024. The Author(s).)

Small intestine bacterial overgrowth (SIBO) has been associated with enteric inflammation, linear growth stunting, and neurodevelopmental delays in children from low-income countries. Little is known about the histologic changes or epithelial adherent microbiota associated with SIBO. We sought to describe these relationships in a cohort of impoverished Bangladeshi children. Undernourished 12-18-month-old children underwent both glucose hydrogen breath testing for SIBO and duodenoscopy with biopsy. Biopsy samples were subject to both histological scoring and 16s rRNA sequencing. 118 children were enrolled with 16s sequencing data available on 53. Of 11 histological features, we found that SIBO was associated with one, enterocyte injury in the second part of the duodenum (R = 0.21, p = 0.02). SIBO was also associated with a significant increase in Campylobacter by 16s rRNA analysis (Log 2-fold change of 4.43; adjusted p = 1.9 x 10-6). These findings support the growing body of literature showing an association between SIBO and enteric inflammation and enterocyte injury and further delineate the subgroup of children with environmental enteric dysfunction who have SIBO. Further, they show a novel association between SIBO and Campylobacter. Mechanistic work is needed to understand the relationship between SIBO, enterocyte injury, and Campylobacter., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Fahim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

WHO works, on a daily basis, with countries globally to detect, prepare for and respond to acute public health events. A vital component of a health response is the dissemination of accurate, reliable and authoritative information. The Disease Outbreak News (DON) reports are a key mechanism through which WHO communicates on acute public health events to the public. The decision to produce a DON report is taken on a case-by-case basis after evaluating key criteria, and the subsequent process of producing a DON report is highly standardised to ensure the robustness of information. DON reports have been published since 1996, and up to 2022 over 3000 reports have been published. Between 2018 and 2022, the most frequently published DON reports relate to Ebola virus disease, Middle East respiratory syndrome, yellow fever, polio and cholera. The DON web page is highly visited with a readership of over 2.6 million visits per year, on average. The DON report structure has evolved over time, from a single paragraph in 1996 to a detailed report with seven sections currently. WHO regularly reviews the DON report process and structure for improvements. In the last 25 years, DON reports have played a unique role in rapidly disseminating information on acute public health events to health actors and the public globally. They have become a key information source for the global public health response to the benefit of individuals and communities., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Purpose: Rotational malalignment (≥ 10°) is a frequent pitfall of intramedullary-nailing of tibial shaft fractures. This study aimed to develop an intraoperative fluoroscopy protocol, coined 'C-Arm Rotational View (CARV)', to significantly reduce the risk for rotational malalignment and to test its clinical feasibility., Methods: A cadaver and clinical feasibility study was conducted to develop the CARV-technique, that included a standardized intraoperative fluoroscopy sequence of predefined landmarks on the uninjured and injured leg in which the rotation of the C-arm was used to verify for rotational alignment. A mid-shaft tibia fracture was simulated in a cadaver and an unlocked intramedullary-nail was inserted. Random degrees of rotational malalignment were applied using a hand-held goniometer via reference wires at the fracture site. Ten surgeons, blinded for the applied rotation, performed rotational corrections according to (1) current clinical practice after single-leg and dual-leg draping, and (2) according to the CARV-protocol. The primary outcome measure was the accuracy of the corrections relative to neutral tibial alignment. The CARV-protocol was tested in a small clinical cohort., Results: In total, 180 rotational corrections were performed by 10 surgeons. Correction according to clinical practice using single-leg and dual-leg draping resulted in a median difference of, respectively, 10.0° (IQR 5.0°) and 10.0° (IQR 5.0°) relative to neutral alignment. Single-leg and dual-leg draping resulted in malalignment (≥10°) in, respectively, 67% and 58% of the corrections. Standardized correction using the CARV resulted in a median difference of 5.0° (IQR 5.0°) relative to neutral alignment, with only 12% categorized as malalignment (≥10°). The incidence of rotational malalignment after application of the CARV decreased from 67% and 58% to 12% (p =  <0.001). Both consultants and residents successfully applied the CARV-protocol. Finally, three clinical patients with a tibial shaft fracture were treated according to the CARV-protocol, resulting all in acceptable alignment (<10°) based on postoperative CT-measurements., Conclusion: This study introduces an easy-to-use and clinically feasible standardized intraoperative fluoroscopy protocol coined 'C-arm rotational view (CARV)' to minimize the risk for rotational malalignment following intramedullary-nailing of tibial shaft fractures., (© 2022. The Author(s).)

Introduction: Rotational malalignment occurs in up to 30% of cases after intramedullary nailing of tibial shaft fractures. The aim of this study is to assess the clinical feasibility of a newly introduced standardised intraoperative fluoroscopy protocol coined 'C-arm rotational view (CARV)' in order to reduce the risk of rotational malalignment during intramedullary nailing of tibial shaft fractures. The CARV includes predefined fluoroscopy landmark views of the uninjured side to obtain correct alignment of the injured side with use of the rotation of the C-arm., Methods and Analysis: This randomised controlled trial will be conducted in a level 1 trauma centre. Adult patients with an open or closed tibial fracture, eligible for intramedullary nailing, will be enrolled in the study. The interventional group will undergo intramedullary nailing guided by the CARV protocol to obtain accurate alignment. The control group is treated according to current clinical practice, in which alignment control of the tibia is based on clinical estimation of the treating surgeon. The primary endpoint is defined as the degree of rotation measured on low-dose postoperative CT scans., Ethics and Dissemination: The study protocol will be performed in line with local ethical guidelines and the Declaration of Helsinki. The results of this trial will be disseminated in a peer-reviewed manuscript. Future patients are likely to benefit from this trial as it aims to provide a clinically feasible and easy-to-use standardised fluoroscopy protocol to reduce the risk for rotational malalignment during intramedullary nailing of tibial shaft fractures., Trial Registration Number: NCT05459038., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Stretch-induced collagen uncrimping underlies the nonlinear mechanical behavior of the sclera according to what is often called the process of recruitment. We recently reported experimental measurements of sclera collagen crimp and pressure-induced uncrimping. Our studies, however, were cross-sectional, providing statistical descriptions of crimp with no information on the effects of stretch on specific collagen bundles. Data on bundle-specific uncrimping is necessary to better understand the effects of macroscale input on the collagen microscale and tissue failure. Our goal in this project was to measure bundle-specific stretch-induced collagen uncrimping of sclera. Three goat eyes were cryosectioned sagittally (30 μm). Samples of equatorial sclera were isolated, mounted to a custom uni-axial stretcher and imaged with polarized light microscopy at various levels of clamp-to-clamp stretch until failure. At each stretch level, local strain was measured using image tracking techniques. The level of collagen crimping was determined from the bundle waviness, defined as the circular standard deviation of fiber orientation along a bundle. Eye-specific recruitment curves were then computed using eye-specific waviness at maximum stretch before sample failure to define fibers as recruited. Nonlinear mixed effect models were used to determine the associations of waviness to local strain and recruitment to clamp-to-clamp stretch. Waviness decreased exponentially with local strain (p < 0.001), whereas bundle recruitment followed a sigmoidal curve with clamp-to-clamp stretch (p < 0.001). Individual bundle responses to stretch varied substantially, but recruitment curves were similar across sections and eyes. In conclusion, uni-axial stretch caused measurable bundle-specific uncrimping, with the sigmoidal recruitment pattern characteristic of fiber-reinforced soft tissues., (Copyright © 2023 by ASME.)

Introduction: Definitive treatment of distal extra-articular fractures of the tibia is challenging and both minimal invasive plate osteosynthesis (MIPO) and intramedullary nailing (IMN) are considered to be feasible surgical modalities with their own implant-specific merits and demerits. This retrospective study was designed to compare MIPO versus IMN in terms of fracture healing, complications, functional and radiological outcomes and to assess the efficacy of intra-operative alignment control to reduce the rate of malalignment after definitive fixation of distal extra-articular fractures of the tibia., Materials and Methods: All consecutive adult patients with extra-articular distal meta- or diaphyseal tibia fractures that were treated between January 2012 and September 2019 either with MIPO or IMN were included. Outcome measures included fracture healing, complications (infection, malalignment, subsequent surgeries), functional and radiological outcomes. Intra-operative alignment control encompassed bilateral draping of the lower extremities., Results: A total of 135 patients were included out of which 72 patients (53%) were treated with MIPO and 63 patients (47%) underwent IMN. There was a significantly higher incidence of non-union for fractures treated with IMN (13 (22%) vs. 4 (6%), p = 0.04). There was no significant difference between both groups in terms of rotational malalignment (3% vs. 10%) and angular malalignment (4% vs. 5%). A significantly higher rate of infection was found after MIPO after correction of significant differences in baseline characteristics. No differences were found in subsequent surgeries or functional outcomes., Conclusion: Both MIPO and IMN are reliable surgical techniques. IMN is associated with higher rates of non-union, whereas MIPO results in a higher risk for infection. The incidence of malalignment was surprisingly low endorsing the utility of the intra-operative alignment control., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Solvents such as butanol are important platform chemicals and are often produced from petrochemical sources. Production of butanol and other compounds from renewable and sustainable resources can be achieved by solventogenic bacteria, such as the hyper-butanol producer Clostridium saccharoperbutylacetonicum . Its sol operon consists of the genes encoding butyraldehyde dehydrogenase, CoA transferase, and acetoacetate decarboxylase ( bld , ctfA , ctfB , adc ) and the gene products are involved in butanol and acetone formation. It is important to understand its regulation to further optimize the solvent production. In this study, a new long non-coding antisense transcript complementary to the complete sol operon, now called Assolrna, was identified by transcriptomic analysis and the regulatory mechanism of Assolrna was investigated. For this purpose, the promoter-exchange strain C. saccharoperbutylacetonicum ΔP asr :: P asr ** was constructed. Additionally, Assolrna was expressed plasmid-based under control of the native P asr promoter and the lactose-inducible P bgaL promoter in both the wild type and the promoter-exchange strain. Solvent formation was strongly decreased for all strains based on C. saccharoperbutylacetonicum ΔP asr :: P asr ** and growth could not be restored by plasmid-based complementation of the exchanged promoter. Interestingly, very little sol mRNA expression was detected in the strain C. saccharoperbutylacetonicum ΔP asr :: P asr ** lacking Assolrna expression. Butanol titers were further increased for the overexpression strain C. saccharoperbutylacetonicum [pMTL83151&#95; asr &#95;P bgaL ] compared to the wild type. These results suggest that Assolrna has a positive effect on sol operon expression. Therefore, a possible stabilization mechanism of the sol mRNA by Assolrna under physiological concentrations is proposed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Baur, Poehlein, Renz, Hollitzer, Montoya Solano, Schiel-Bengelsdorf, Daniel and Dürre.)

Purpose: There is currently no consensus regarding the need for fixation of concomitant fibula fractures in patients with surgically treated distal tibia fracture. Although studies have shown it to be beneficial for fractures involving the syndesmosis, it remains unclear for suprasyndesmotic fractures. This study evaluates what effect the fixation of such suprasyndesmotic fibula fractures had on patients who underwent fixation of distal tibia fractures., Methods: This retrospective cohort study included all consecutive adult patients who received surgical treatment for an extra-articular or simple intraarticular distal tibia fracture between 2012 and 2020 and had a concomitant fibula fracture proximal to the syndesmosis. Two groups were formed depending on whether the fibula was stabilized. The need for revision surgery, the occurrence of complications, fracture healing, rotational and angular malalignment were evaluated for both groups., Results: This study included 120 patients, of which 40 (33.3%) had operative treatment of the fibula fracture. Of those with stabilized fibula fractures, 28 (70%) were treated with a plate and 12 (30%) with a titanium elastic nail. The group of patients with surgically treated fibula fractures had significantly more angular malalignments (10% vs 1.2%, p = 0.042), while there was no difference regarding rotational malalignment or fracture healing. Further, infections of the fibular surgical site occurred in 15% of surgically treated patients leading to significantly more revision surgeries in this group (40% vs 20%, p = 0.03). All infections occurred when a plate was used., Conclusion: This study was unable to show any benefit from stabilizing concomitant, suprasyndesmotic fibula fractures in surgically treated distal tibia fractures. On the contrary, infection, revision surgery and angular malalignment were more frequent when the fibula was fixed. Therefore, such concomitant fibula fractures should not routinely be fixed and if stabilization is deemed necessary, the implant should be chosen carefully., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Diarrhea is responsible for the deaths of more than 500,000 children each year, many of whom reside in low-to-middle-income countries (LMICs). Additionally, children with multiple diarrheal infections early in life have increased growth stunting and malnutrition and decreased vaccine efficacy. Two bacteria that contribute to the burden of diarrhea are Campylobacter jejuni and Campylobacter coli, both are endemic in Bangladesh. However, not all children that are exposed to these pathogens, including Campylobacter, will experience diarrhea. We hypothesized that host genetics may influence susceptibility to Campylobacter infections and performed a genome-wide association study in 534 children from two independent birth cohorts in Dhaka, Bangladesh. Infants were monitored for diarrhea for the first 2 years of life and only defined as controls if all diarrheal samples in the first year were negative for Campylobacter jejuni / C. coli. Each cohort was analyzed separately under an additive model and adjusted for length-for-age z-scores at birth and 12 months, sex, water treatment, and ancestry. In a fixed effect inverse-variance weighted meta-analysis of these two cohorts, we identified a genome-wide significant region on chromosome 8 in intron 4 of the rho guanine nucleotide exchange factor 10 gene ( ARHGEF10 ). Individuals with the G allele (rs13281104) had a 2-fold lower risk of having a Campylobacter-associated diarrheal episode than individuals with the A allele (OR 0.41, 95% CI 0.29 to 0.58, P = 3.6 × 10 -7 ). This SNP is associated with decreased expression of the neighboring gene, CLN8 , which may be involved in the transport of the cytolethal distending toxin produced by Campylobacter. IMPORTANCE Children in low-to-middle-income countries often suffer from multiple enteric infections in their first few years of life, many of which have the potential for long-lasting effects. These children are already likely to be malnourished and underweight, and chronic intestinal disturbances exacerbate these conditions. Despite public health interventions aimed at improving water, sanitation, and hygiene, enteric infections are still a leading cause of death for children under five. Previous work has included transmission dynamics, pathogen characteristics, and evaluation of interventions. Here, we examined the role of host genetic variation in susceptibility to diarrhea-associated Campylobacter infection. In our meta-analysis of two independent birth cohorts from Dhaka, Bangladesh, we found that children carrying a specific genetic variant (rs13281104, in an intron of ARHGEF10 ) were half as likely to have a diarrhea-associated Campylobacter infection in their first year of life. This protective effect may be achieved by decreasing gene expression and thereby impacting host-pathogen interactions and host immune response.

Purpose: This study aimed to investigate the association between serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and incident metabolic disease in a cohort of community-based older Chinese people., Patients and Methods: Five thousand healthy Gaohang residents who attended community health checks at the Shanghai East Hospital in 2013 were recruited. Biological, biochemical, and lifestyle variables were collected. The cohort was followed for new-onset metabolic disease in 2014 and 2017, with a final study population of 3,123 (63%) after follow-up. The study outcome included type-2 diabetes mellitus and metabolic syndrome., Results: Baseline AST and ALT were associated with incident type-2 diabetes mellitus (HR 1.019, 95% CI 1.006-1.032, p = 0.003 and HR 1.016, 95% CI 1.008-1.025, p < 0.001 respectively). These associations persisted after adjusting for traditional risk factors including age, sex, income, waist circumference, systolic blood pressure, diastolic blood pressure, HbA1c, triglyceride, cholesterol, HDL and eGFR. Baseline AST and ALT were associated with incident metabolic syndrome in the crude analysis (HR 0.980, 95% CI 0.965-0.996, p = 0.012 and HR 0.992, 95% CI 0.988-0.997, p = 0.001, respectively). However, the association between AST and ALT with metabolic syndrome was non-significant after adjusting for biochemical parameters such as the lipid profile., Conclusion: This study demonstrated that serum AST and ALT are associated with new-onset type-2 diabetes mellitus, independent of traditional risk factors, in a cohort of older Chinese people. These findings may contribute to disease risk stratification and management in type-2 diabetes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lan, Zhang, Lin, Meng, Buys, Fan and Sun.)

To mitigate the unprecedented health, social, and economic damage of COVID-19, the Philippines is undertaking a nationwide vaccination program to mitigate the effects of the global pandemic. In this study, we interrogated COVID-19 vaccine intent in the country by deploying a nationwide open-access online survey, two months before the rollout of the national vaccination program. The Health Belief Model (HBM) posits that people are likely to adopt disease prevention behaviors and to accept medical interventions like vaccines if there is sufficient motivation and cues to action. A majority of our 7,193 respondents (62.5%) indicated that they were willing to be vaccinated against COVID-19. Moreover, multivariable analysis revealed that HBM constructs were associated with vaccination intention in the Philippines. Perceptions of high susceptibility, high severity, and significant benefits were all good predictors for vaccination intent. We also found that external cues to action were important. Large majorities of our respondents would only receive the COVID-19 vaccines after many others had received it (72.8%) or after politicians had received it (68.2%). Finally, our study revealed that most (21%) were willing to pay an amount of PHP 1,000 (USD20) for the COVID-19 vaccines with an average willing-to-pay amount of PHP1,892 (USD38)., Competing Interests: The authors declare there are no competing interests., (©2022 Caple et al.)

Geographic information science (GIS) has emerged as a unique tool that is extremely valuable in various research which involves spatial-temporal aspects. The geographical distribution of the epidemic is considered a significant characteristic that can be analyzed using GIS and spatial statistics. Proper knowledge can assist in controlling, mitigating, and mapping factors for detecting the transmission as well as the disease dynamics, and it provides geographical information of the outbreak and it can also give a glimpse of the disease trend and hotspots as well as provide ways to further evaluate the associated risk. This study analyzed the countries' total confirmed cases, total death cases, and the total recovered cases using an (IDW) geospatial technique which is an inherent tool used in ArcMap for spatial analysis. In order to identify the hotspots for COVID-19 cases, the Getis-Ord Gi* statistic method was applied with a confidence level of 95% in Herat and 90% for Kabul, Kapisa, and Logar provinces. The data considered in this research ranged from the period of 23rd July 2020 to 24th February 2021. All the COVID-19 confirmed, recovered, and death cases were correlated with provincial population density using the Pearson Correlation coefficient. Among the total cases 54,487, 32% cases were reported in the capital of the country (Kabul), and the mortality rate was 31% followed by Herat (18% deaths), Balkh (7% deaths), and Nangarhar (6% deaths). Most of the recoveries were observed in Kabul with (30%) followed by Herat (16%), Bamyan (10%), Balkh (5%), and Kandahar (5%). The results for Global Moran's I showed that the incidence rate of the total COVID-19 cases was in the random pattern, with the Moran Index of - 0.14. Given the z-score of - 1.62, the pattern does not appear to be significantly different than random. There was a strong correlation between the COVID-19 variables and population density [with r (33) = 0.827], [ r (33) = 0.819] and [ r (33) = 0.817] for the total cases, death cases, and recovered cases, respectively. Even though GIS has limited applicability in detecting the type and its spatial pattern of the epidemic, there is a high potential to use these tools in managing and controlling the pandemic. Moreover, GIS helps us better in comprehending the epidemic and assists us in addressing those fractions of the population and communities which are underserved during the disease outbreak., Competing Interests: Conflict of interestAuthors declare no conflict of interest., (© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2022.)

Disagreement is essential to scientific progress but the extent of disagreement in science, its evolution over time, and the fields in which it happens remain poorly understood. Here we report the development of an approach based on cue phrases that can identify instances of disagreement in scientific articles. These instances are sentences in an article that cite other articles. Applying this approach to a collection of more than four million English-language articles published between 2000 and 2015 period, we determine the level of disagreement in five broad fields within the scientific literature (biomedical and health sciences; life and earth sciences; mathematics and computer science; physical sciences and engineering; and social sciences and humanities) and 817 meso-level fields. Overall, the level of disagreement is highest in the social sciences and humanities, and lowest in mathematics and computer science. However, there is considerable heterogeneity across the meso-level fields, revealing the importance of local disciplinary cultures and the epistemic characteristics of disagreement. Analysis at the level of individual articles reveals notable episodes of disagreement in science, and illustrates how methodological artifacts can confound analyses of scientific texts., Competing Interests: WL, KB, VL, CS, Nv, LW, DM No competing interests declared, (© 2021, Lamers et al.)

Objectives: To assess the effectiveness of suprapatellar (SP)-nailing versus infrapatellar (IP)-nailing of tibia fractures in anterior knee pain, complications (retropatellar chondropathy, infection, and malalignment) and physical functioning and quality of life. A clinical question-driven and thorough systematic review of current literature is provided., Data Source: PubMed and Embase databases were searched for studies published between 2010 and 2020 relating to SP and IP-nailing of tibia fractures. The study is performed in concordance with PRISMA-guidelines., Study Selection: Studies eligible for inclusion were randomized controlled trials, prospective and retrospective observational studies reporting on outcomes of interest., Data Extraction: Data extraction was performed independently by 2 assessors. Methodological quality and risk of bias was assessed according to the guidelines of the McMaster Critical Appraisal., Data Synthesis: Continuous variables are presented as means with SD and dichotomous variables as frequency and percentages. The weighted mean, standardized weighted mean differences, and 95% confidence interval were calculated. A pooled analysis could not be performed because of differences in outcome measures, time-points, and heterogeneity., Results: Fourteen studies with 1447 patients were analyzed. The weighted incidence of anterior knee pain was 29% after SP-nailing and 39% after IP-nailing, without reported significance. There was a significant lower rate of malalignment after the SP-approach (4% vs. 26%) with small absolute differences in all planes. No substantial differences were observed in retropatellar chondropathy, infection, physical functioning, and quality of life., Conclusions: This systematic review does not reveal superiority of either technique in any of the respective outcomes of interest. Definitive choice should depend on the surgeon's experience and available resources., Level of Evidence: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: The authors report no conflict of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

As the COVID-19 pandemic unfolds, researchers from all disciplines are coming together and contributing their expertise. CORD-19, a dataset of COVID-19 and coronavirus publications, has been made available alongside calls to help mine the information it contains and to create tools to search it more effectively. We analyse the delineation of the publications included in CORD-19 from a scientometric perspective. Based on a comparison to the Web of Science database, we find that CORD-19 provides an almost complete coverage of research on COVID-19 and coronaviruses. CORD-19 contains not only research that deals directly with COVID-19 and coronaviruses, but also research on viruses in general. Publications from CORD-19 focus mostly on a few well-defined research areas, in particular: coronaviruses (primarily SARS-CoV, MERS-CoV and SARS-CoV-2); public health and viral epidemics; molecular biology of viruses; influenza and other families of viruses; immunology and antivirals; clinical medicine. CORD-19 publications that appeared in 2020, especially editorials and letters, are disproportionately popular on social media. While we fully endorse the CORD-19 initiative, it is important to be aware that CORD-19 extends beyond research on COVID-19 and coronaviruses., Competing Interests: The authors have declared that no competing interests exist.

Collagen fibers organized circumferentially around the canal in the peripapillary sclera are thought to provide biomechanical support to the sensitive tissues within the optic nerve head (ONH). Recent studies have demonstrated the existence of a family of fibers in the innermost sclera organized radially from the scleral canal. Our goal was to determine the role of these radial fibers in the sensitivity of scleral canal biomechanics to acute increases in intraocular pressure (IOP). Following the same general approach of previous parametric sensitivity studies, we created nonlinear generic finite element models of a posterior pole with various combinations of radial and circumferential fibers at an IOP of 0 mmHg. We then simulated the effects of normal and elevated IOP levels (15 and 30 mmHg). We monitored four IOP-induced geometric changes: peripapillary sclera stretch, scleral canal displacement, lamina cribrosa displacement, and scleral canal expansion. In addition, we examined the radial (maximum tension) and through-thickness (maximum compression) strains within the ONH tissues. Our models predicted that: 1) radial fibers reduced the posterior displacement of the lamina, especially at elevated IOP; 2) radial fibers reduced IOP-induced radial strain within the peripapillary sclera and retinal tissue; and 3) a combination of radial and circumferential fibers maintained strains within the ONH at a level similar to those conferred by circumferential fibers alone. In conclusion, radial fibers provide support for the posterior globe, additional to that provided by circumferential fibers. Most importantly, a combination of both fiber families can better protect ONH tissues from excessive IOP-induced deformation than either alone., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Intramedullary (IM) nailing is the treatment of choice for most tibial shaft fractures. However, an iatrogenic pitfall may be rotational malalignment. The aims of this retrospective analysis were to determine (1) the prevalence of rotational malalignment using postoperative computed tomography (CT) as the reference standard; (2) the average baseline tibial torsion of uninjured limbs; and (3) based on that normal torsion, whether the contralateral, uninjured limb can be reliably used as the reference standard., Methods: The study included 154 patients (71% male and 29% female) with a median age of 37 years. All patients were treated for a unilateral tibial shaft fracture with an IM nail and underwent low-dose bilateral postoperative CT to assess rotational malalignment., Results: More than one-third of the patients (n = 55; 36%) had postoperative rotational malalignment of ≥10°. Right-sided tibial shaft fractures were significantly more likely to display external rotational malalignment whereas left-sided fractures were predisposed to internal rotational malalignment. The uninjured right tibiae were an average of 4° more externally rotated than the left (mean rotation and standard deviation, 41.1° ± 8.0° [right] versus 37.0° ± 8.2° [left]; p < 0.01). Applying this 4° correction to our cohort not only reduced the prevalence of rotational malalignment (n = 45; 29%), it also equalized the distribution of internal and external rotational malalignment between the left and right tibiae., Conclusions: This study confirms a high prevalence of rotational malalignment following IM nailing of tibial shaft fractures (36%). There was a preexisting 4° left-right difference in tibial torsion, which sheds a different light on previous studies and current clinical practice and could have important implications for the diagnosis and management of tibial rotational malalignment., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Citation networks of scientific publications offer fundamental insights into the structure and development of scientific knowledge. We propose a new measure, called intermediacy, for tracing the historical development of scientific knowledge. Given two publications, an older and a more recent one, intermediacy identifies publications that seem to play a major role in the historical development from the older to the more recent publication. The identified publications are important in connecting the older and the more recent publication in the citation network. After providing a formal definition of intermediacy, we study its mathematical properties. We then present two empirical case studies, one tracing historical developments at the interface between the community detection literature and the scientometric literature and one examining the development of the literature on peer review. We show both conceptually and empirically how intermediacy differs from main path analysis, which is the most popular approach for tracing historical developments in citation networks. Main path analysis tends to favour longer paths over shorter ones, whereas intermediacy has the opposite tendency. Compared to the main path analysis, we conclude that intermediacy offers a more principled approach for tracing the historical development of scientific knowledge., Competing Interests: The authors have no conflicting interests to declare., (© 2020 The Authors.)

Background: Research in depression has progressed rapidly over the past four decades. Yet depression rates are not subsiding and treatment success is not improving. We examine the extent to which the gap between science and practice is associated with the level of integration in how depression is considered in research and stakeholder-relevant documents., Methods: We used a network-science perspective to analyze similar uses of depression relevant terms in the Google News corpus (approximately 1 billion words) and the Web of Science database (120 000 documents)., Results: These analyses yielded consistent pictures of insular modules associated with: (1) patient/providers, (2) academics, and (3) industry. Within academia insular modules associated with psychology, general medical, and psychiatry/neuroscience/biology were also detected., Conclusions: These analyses suggest that the domain of depression is fragmented, and that advancements of relevance to one stakeholder group (academics, industry, or patients) may not translate to the others. We consider potential causes and associated responses to this fragmentation that could help to unify and advance translation from research on depression to the clinic, largely involving harmonizing employed language, bridging conceptual domains, and increasing communication across stakeholder groups.

This study investigated the structure of psychological literature as represented by a corpus of 676,393 articles in the period from 1950 to 1999. The corpus was extracted from 1,269 journals indexed by PsycINFO. The data in our analysis consisted of the relevant terms mined from the titles and abstracts of all of the articles in the corpus. Based on the co-occurrences of these terms, we developed a series of chronological visualizations using a bibliometric software tool called VOSviewer. These visualizations produced a stable structure through the 5 decades under analysis, and this structure was analyzed as a data-mined proxy for the disciplinary formation of scientific psychology in the second part of the 20th century. Considering the stable structure uncovered by our term co-occurrence analysis and its visualization, we discuss it in the context of Lee Cronbach's "Two Disciplines of Scientific Psychology" (1957) and conventional history of 20th-century psychology's disciplinary formation and history of methods. Our aim was to provide a comprehensive digital humanities perspective on the large-scale structural development of research in English-language psychology from 1950 to 1999. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Collagen is a major constituent of the eye and understanding its architecture and biomechanics is critical to preserve and restore vision. We, recently, demonstrated polarized light microscopy (PLM) as a powerful technique for measuring properties of the collagen fibers of the eye, such as spatial distribution and orientation. Our implementation of PLM, however, required sectioning the tissues for imaging using transmitted light. This is problematic because it limits analysis to thin sections. This is not only slow, but precludes study of dynamic events such as pressure-induced deformations, which are central to the role of collagen. We introduce structured polarized light microscopy (SPLM), an imaging technique that combines structured light illumination with PLM to allow imaging and measurement of collagen fiber properties in thick ocular tissues. Using pig and sheep eyes, we show that SPLM rejects diffuse background light effectively in thick tissues, significantly enhancing visualization of optic nerve head (ONH) structures, such as the lamina cribrosa, and improving the accuracy of the collagen fiber orientation measurements. Further, we demonstrate the integration of SPLM with an inflation device to enable direct visualization, deformation tracking, and quantification of collagen fibers in ONHs while under controlled pressure., ((2018) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE).)

Introduction: The purpose of this study is to evaluate the intra- and inter-observer reliability of low-dose protocolled bilateral postoperative Computed Tomography (CT)-assessment of rotational malalignment after intramedullary nailing (IMN) of tibial shaft fractures., Materials and Methods: 156 patients were prospectively included with tibial shaft fractures that were treated with IMN in a Level-I Trauma Centre. All patients underwent post-operative bilateral low-dose CT-assessment (effective dose of 0.03784 - 0.05768 mGy) as per hospital protocol. Four observers performed the validated reproducible measurements of tibial torsion in degrees, based on standardized techniques. The Intra-Class Coefficient (ICC) was calculated to evaluate intra- and inter-observer reliability. The intra- and inter-observer reliability was categorized according to Landis and Koch., Results: Intra-observer reliability for quantification of rotational malalignment on post-operative CT after IMN of tibial shaft fractures was excellent with 0.95 (95% CI = 0.92-0.97). The overall inter-observer reliability was 0.90 (95% CI = 0.87-0.92), also excellent according Landis and Koch., Conclusion: Firstly, bilateral post-operative low-dose -similar radiation exposure as plain chest radiographs- CT assessment of tibial rotational alignment is a reliable diagnostic imaging modality to assess rotational malalignment in patients following IMN of tibial shaft fractures and it allows for early revision surgery. Secondly, it may contribute to our understanding of the incidence-, predictors- and clinical relevance of post-operative tibial rotational malalignment in patients treated with IMN for a tibial shaft fracture, and facilitates future studies on this topic., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The collagen fiber architecture of the peripapillary sclera (PPS), which surrounds the scleral canal, is a critical factor in determining the mechanical response of the optic nerve head (ONH) to variations in intraocular pressure (IOP). Experimental and clinical evidence point to IOP-induced deformations within the scleral canal as important contributing factors of glaucomatous neural tissue damage and consequent vision loss. Hence, it is imperative to understand PPS architecture and biomechanics. Current consensus is that the fibers of the PPS form a closed ring around the canal to support the delicate neural tissues within. We propose an alternative fiber architecture for the PPS, in which the scleral canal is supported primarily by long-running fibers oriented tangentially to the canal. We present evidence that this tangential model is consistent with histological observations in multiple species, and with quantitative measurements of fiber orientation obtained from small angle light scattering and wide-angle X-ray scattering. Using finite element models, we investigated the biomechanical implications of a tangential fiber PPS architecture. We found that the tangential arrangement of fibers afforded better mechanical support to the tissues within the scleral canal as compared to a simple circumferential ring of fibers or a combination of fibers oriented radially and circumferentially. We also found that subtle variations from a tangential orientation could reproduce clinically observed ONH behavior which has yet to be explained using current theories of PPS architecture and simulation, namely, the contraction of the scleral canal under elevated IOP., Statement of Significance: It is hypothesized that vision loss in glaucoma is due to excessive mechanical deformation within the neural tissue inside the scleral canal. This study proposes a new model for how the collagen of the peripapillary sclera surrounding the canal is organized to support the delicate neural tissue inside. Previous low-resolution studies of the peripapillary sclera suggested that the collagen fibers are arranged in a ring around the canal. Instead, we provide microscopic evidence suggesting that the canal is also supported by long-running interwoven fibers oriented tangentially to the canal. We demonstrate that this arrangement has multiple biomechanical advantages over a circular collagen arrangement and can explain previously unexplained experimental findings including contraction of the scleral canal under elevated intraocular pressure., (Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Purpose: To test the hypothesis that human, monkey, pig, sheep, cow, and goat eyes exhibit circumferential, radial, and interweaving collagen architecture in the posterior sclera., Methods: We analyzed 1,327 cryosections from the posterior poles of 4 human, 4 monkey, 5 pig, 8 sheep, 1 goat, and 2 cow eyes. Images were acquired using polarized light microscopy and processed to obtain polar fiber orientations relative to the center of the canal. Circumferential, radial, and interweaving regions were identified and analyzed for mean fiber orientation and anisotropy and region width and thickness., Results: Every eye exhibited circumferential, radial, and interweaving fibers in consistent locations. Radial fibers extended out from near the canal into the peripapillary and peripheral sclera in the innermost sclera. Circumferential fibers were directly adjacent to the canal and most prevalent in the outermost, posterior sclera. Interweaving fibers were found throughout the sclera thickness. Across all species, median anisotropy in the radial, circumferential, and interweaving regions were 0.95, 0.96, and 0.28, respectively., Conclusions: Regions of radial, circumferential, and interweaving fibers occur in the posterior pole sclera of human, monkey, pig, sheep, cow, and goat eyes. The consistency across species in scleral architecture suggests that they are primary organizational components whose functions should be better understood.

Purpose: To compare the collagen microstructural crimp characteristics between thin and thick lamina cribrosa (LC) beams., Methods: Seven eyes from four sheep were fixed at 5 mm Hg IOP in 10% formalin. For each eye, one to three coronal cryosections through the LC were imaged with polarized light microscopy and analyzed to visualize the LC and determine collagen fiber microstructure. For every beam, we measured its width and three characteristics of the crimp of its collagen fibers: waviness, tortuosity, and amplitude. Linear mixed effects models were used to test whether crimp characteristics were associated with the LC beam width., Results: For each eye and over all the eyes, LC beam width was positively associated with crimp waviness and tortuosity, and negatively associated with crimp amplitude (P's < 0.0001). Thin beams, average width 13.11 μm, had average (SD) waviness, tortuosity, and amplitude of 0.27 (0.17) radians, 1.017 (0.028) and 1.88 (1.41) μm, respectively. For thick beams, average width 26.10 μm, these characteristics were 0.33 (0.18) radians, 1.025 (0.037) and 1.58 (1.36) μm, respectively., Conclusions: Our results suggest heterogeneity in LC beam mechanical properties. Thin beams were less wavy than their thicker counterparts, suggesting that thin beams may stiffen at lower IOP than thick beams. This difference may allow thin beams to support similar amounts of IOP-induced force as thicker beams, thus providing a similar level of structural support to the axons at physiologic IOP, despite the differences in width. Measurements of beam-level mechanical properties are needed to confirm these predictions.

Collagen fibers play a central role in normal eye mechanics and pathology. In ocular tissues, collagen fibers exhibit a complex 3-dimensional (3D) fiber orientation, with both in-plane (IP) and out-of-plane (OP) orientations. Imaging techniques traditionally applied to the study of ocular tissues only quantify IP fiber orientation, providing little information on OP fiber orientation. Accurate description of the complex 3D fiber microstructures of the eye requires quantifying full 3D fiber orientation. Herein, we present 3dPLM, a technique based on polarized light microscopy developed to quantify both IP and OP collagen fiber orientations of ocular tissues. The performance of 3dPLM was examined by simulation and experimental verification and validation. The experiments demonstrated an excellent agreement between extracted and true 3D fiber orientation. Both IP and OP fiber orientations can be extracted from the sclera and the cornea, providing previously unavailable quantitative 3D measures and insight into the tissue microarchitecture. Together, the results demonstrate that 3dPLM is a powerful imaging technique for the analysis of ocular tissues., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Our goal was to systematically quantify the collagen crimp morphology around the corneoscleral shell, and test the hypothesis that collagen crimp is not uniform over the globe. Axial longitudinal cryosections (30 μm) of three sheep eyes, fixed at 0 mmHg IOP, were imaged using polarized light microscopy to quantify the local collagen in 8 regions: two corneal (central and peripheral) and six scleral (limbus, anterior-equatorial, equatorial, posterior-equatorial, posterior and peripapillary). Collagen crimp period (length of one wave), tortuosity (path length divided by end-to-end length), waviness (SD of orientation), amplitude (half the peak to trough distance), and conformity (width of contiguous similarly oriented bundles) were measured in each region. Measurements were obtained on 8216 collagen fiber bundles. When pooling measurements across the whole eye globe, the median crimp values were: 23.9 μm period, 13.2 μm conformity, 0.63 μm amplitude, 1.006 tortuosity, and 12.7° waviness. However, all parameters varied significantly across the globe. Median bundle periods in the central cornea, limbus, and peripapillary sclera (PPS) were 14.1 μm, 29.5 μm, and 22.9 μm, respectively. Median conformities were 20.8 μm, 14.5 μm, and 15.1 μm, respectively. Median tortuosities were 1.005, 1.007, and 1.007, respectively. Median waviness' were 11.4°, 13.2°, and 13.2°, respectively. Median amplitudes were 0.35 μm, 0.87 μm, and 0.65 μm, respectively. All parameters varied significantly across the globe. All regions differed significantly from one another on at least one parameter. Regions with small periods had large conformities, and bundles with high tortuosity had high waviness and amplitude. Waviness, tortuosity, and amplitude, associated with nonlinear biomechanical behavior, exhibited "double hump" distributions, whereas period and conformity, representing tissue organization, were substantially different between sclera and cornea. Though the biomechanical implications and origin of the patterns observed remain unclear, our findings of well-defined patterns of collagen crimp across the corneoscleral shell, consistent between eyes, support the existence of mechanisms that regulate collagen characteristics at the regional or smaller levels. These results are experimental data necessary for more realistic models of ocular biomechanics and remodeling., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: Collagen is the main load-bearing component of the eye, and collagen crimp is a critical determinant of tissue mechanical behavior. We test the hypothesis that collagen crimp morphology varies over the human cornea and sclera and with age., Methods: We analyzed 42 axial whole-globe sections from 20 normal eyes of 20 human donors, ranging in age from 0.08 (1 month) to 97 years. The sections were imaged using polarized light microscopy to obtain μm-scale fiber bundle/lamellae orientation from two corneal and six scleral regions. Crimp morphology was quantified through waviness, tortuosity, and amplitude., Results: Whole-globe median waviness, tortuosity, and amplitude were 0.127 radians, 1.002, and 0.273 μm, respectively. These parameters, however, were not uniform over the globe, instead exhibiting distinct, consistent patterns. All crimp parameters decreased significantly with age, with significantly different age-related decreases between regions. The crimp morphology of the limbus changed the most drastically with age, such that it had the largest crimp in neonates, and among the smallest in the elderly., Conclusions: Age-related decreases in crimp parameters are likely one of the mechanisms underlying age-related stiffening of the sclera and cornea, potentially influencing sensitivity to IOP. Further work is needed to determine the biomechanical implications of the crimp patterns observed. The comparatively large changes in the crimp morphology of the limbus, especially in the early years of life, suggest that crimp in this region may play a role in eye development, although the exact nature of this is unclear.

Our goal was to quantify and characterize how the collagen fiber crimp waviness of the lamina cribrosa (LC) and peripapillary sclera (PPS) changes with intraocular pressure (IOP). Thirteen sheep (ovine) eyes were immersion and perfusion fixed while maintaining IOP at 0, 10, 15, 20, or 50 mmHg. Coronal optic nerve head (ONH) sections (30 µm) were imaged with polarized light microscopy (PLM) and analyzed for collagen fiber orientation and waviness (SD of fiber orientation). In the LC, the waviness of every LC beam was measured. In the PPS, at least 900 collagen bundles were measured per eye. Using the waviness at 50 mmHg IOP, we defined tissue-specific thresholds to determine the fraction of loaded or recruited fibers. We found that fiber waviness decreased with IOP (P < 0.001). At every IOP, the waviness of the collagen fibers, and the fraction of fibers recruited in the LC were smaller or equal than those of the PPS (P < 0.001). At 15 mmHg IOP, both LC and PPS had ¾ recruited fibers and ¼ left in reserve. The decreased waviness with IOP and associated fiber recruitment is experimental evidence of fiber-based nonlinear biomechanical behavior of the ONH. At all IOPs the PPS had an equal or larger fraction of fibers recruited than the LC. That both LC and PPS had the same fraction of recruited and reserve fibers at normal IOP suggests that this may be an optimal fraction of recruitment for healthy eyes. Whether this extends to human eyes remains unknown., Statement of Significance: Collagen fibers exhibit a natural waviness or crimp that largely determine the nonlinear biomechanics of soft tissue. Experimental measurements of crimp morphology in the sheep eye, and how it changes with intraocular pressure (IOP), however, are exceedingly sparse. We quantified how posterior eye crimp changes with increasing IOP. We found that the lamina cribrosa and peripapillary sclera have fundamentally different crimp, and with increasing IOP, have different proportions of fibers that straighten, or get recruited, versus remaining wavy, or in reserve. Interestingly, at physiologic IOP of 15 mmHg, both tissues had about ¾ fibers recruited and ¼ fibers in reserve, indicating there may be an optimal fraction of fibers., (Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

We have explored the collaborative network of the current American Society for Mass Spectrometry (ASMS) membership using bibliometric methods. The analysis shows that 4249 members are connected in a single, large, co-authorship graph, including the majority of the most published authors in the field of mass spectrometry. The map reveals topographical differences between university groups and national laboratories, and that the co-authors with the strongest links have long worked together at the same location. We have collected and summarized information on the geographical distribution of members, showing a high coverage of active researchers in North America and Western Europe. Looking at research fields, we could also identify a number of new or 'hot' topics among ASMS members. Interactive versions of the maps are available on-line at https://goo.gl/UBNFMQ (collaborative network) and https://goo.gl/WV25vm (research topics). Graphical Abstract ᅟ.

There is increasing clinical evidence that the eye is not only affected by intraocular pressure (IOP), but also by intracranial pressure (ICP). Both pressures meet at the optic nerve head of the eye, specifically the lamina cribrosa (LC). The LC is a collagenous meshwork through which all retinal ganglion cell axons pass on their way to the brain. Distortion of the LC causes a biological cascade leading to neuropathy and impaired vision in situations such as glaucoma and idiopathic intracranial hypertension. While the effect of IOP on the LC has been studied extensively, the coupled effects of IOP and ICP on the LC remain poorly understood. We investigated in-vivo the effects of IOP and ICP, controlled via cannulation of the eye and lateral ventricle in the brain, on the LC microstructure of anesthetized rhesus monkeys eyes using the Bioptigen spectral-domain optical coherence tomography (OCT) device (Research Triangle, NC). The animals were imaged with their head upright and the rest of their body lying prone on a surgical table. The LC was imaged at a variety of IOP/ICP combinations, and microstructural parameters, such as the thickness of the LC collagenous beams and diameter of the pores were analyzed. LC microstructure was confirmed by histology. We determined that LC microstructure deformed in response to both IOP and ICP changes, with significant interaction between the two. These findings emphasize the importance of considering both IOP and ICP when assessing optic nerve health.

Purpose: The purpose of this study was to determine how the architecture of the lamina cribrosa (LC) microstructure, including the shape and size of the lamina pores, influences the IOP-induced deformation of the neural tissues within the LC pores using computational modeling., Methods: We built seven specimen-specific finite element models of LC microstructure with distinct nonlinear anisotropic properties for LC beams and neural tissues based on histological sections from three sheep eyes. Changes in shape (aspect ratio and convexity) and size (area and perimeter length) due to IOP-induced hoop stress were calculated for 128 LC pores. Multivariate linear regression was used to determine if pore shape and size were correlated with the strain in the pores. We also compared the microstructure models to a homogenized model built following previous approaches., Results: The LC microstructure resulted in focal tensile, compressive, and shear strains in the neural tissues of the LC that were not predicted by homogenized models. IOP-induced hoop stress caused pores to become larger and more convex; however, pore aspect ratio did not change consistently. Peak tensile strains within the pores were well predicted by a linear regression model considering the initial convexity (negative correlation, P < 0.001), aspect ratio (positive correlation, P < 0.01), and area (negative correlation, P < 0.01). Significant correlations were also found when considering the deformed shape and size of the LC pores., Conclusions: The deformation of the LC neural tissues was largely dependent on the collagenous LC beams. Simple measures of LC pore shape and area provided good estimates of neural tissue biomechanical insult.

Advances in imaging have made it increasingly common to study soft tissues without first embedding them in plastic or paraffin and without using labels or stains. The process, however, usually still involves fixation and cryosectioning, which could deform the tissues. Our goal was to quantify the morphological changes of ocular tissues caused by formalin fixation and cryosectioning. From each of 6 porcine eyes, 4 regions were obtained: cornea, equatorial and posterior sclera, and posterior pole containing the optic nerve head. Samples were imaged using visible light microscopy fresh, 1-minute and 24-hours post-fixation, and post-cryosectioning. Effects were assessed by 14 parameters representing sample size and shape. Overall, formalin fixation and sectioning caused only minimal changes to the ocular tissues, with average percentage parameter differences of 0.1%, 1%, and 1.2% between fresh and post-fixing by 1 minute, 24 hours, and post-cryosectioning, respectively. Parameter changes were not directional, and were only weakly dependent on the duration of fixation and the region of the eye. These results demonstrate that formalin fixation and cryosectioning are good choices for studying ocular tissue morphology and structure, as they do not cause the large tissue shrinkage or distortions typically associated with other, more complicated, techniques.

It is widely considered that intraocular pressure (IOP)-induced deformation within the neural tissue pores of the lamina cribrosa (LC) contributes to neurodegeneration and glaucoma. Our goal was to study how the LC microstructure and mechanical properties determine the mechanical insult to the neural tissues within the pores of the LC. Polarized light microscopy was used to measure the collagen density and orientation in histology sections of three sheep optic nerve heads (ONH) at both mesoscale (4.4μm) and microscale (0.73μm) resolutions. Mesoscale fiber-aware FE models were first used to calculate ONH deformations at an IOP of 30mmHg. The results were then used as boundary conditions for microscale models of LC regions. Models predicted large insult to the LC neural tissues, with 95th percentile 1st principal strains ranging from 7 to 12%. Pores near the scleral boundary suffered significantly higher stretch compared to pores in more central regions (10.0±1.4% vs. 7.2±0.4%; p=0.014; mean±SD). Variations in material properties altered the minimum, median, and maximum levels of neural tissue insult but largely did not alter the patterns of pore-to-pore variation, suggesting these patterns are determined by the underlying structure and geometry of the LC beams and pores. To the best of our knowledge, this is the first computational model that reproduces the highly heterogeneous neural tissue strain fields observed experimentally., Statement of Significance: The loss of visual function associated with glaucoma has been attributed to sustained mechanical insult to the neural tissues of the lamina cribrosa due to elevated intraocular pressure. Our study is the first computational model built from specimen-specific tissue microstructure to consider the mechanics of the neural tissues of the lamina separately from the connective tissue. We found that the deformation of the neural tissue was much larger than that predicted by any recent microstructure-aware models of the lamina. These results are consistent with recent experimental data and the highest deformations were found in the region of the lamina where glaucomatous damage first occurs. This study provides new insight into the complex biomechanical environment within the lamina., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Purpose: Although collagen microstructural crimp is a major determinant of ocular biomechanics, no direct measurements of optic nerve head (ONH) crimp have been reported. Our goal was to characterize the crimp period of the lamina cribrosa (LC) and peripapillary sclera (PPS) at low and normal IOPs., Methods: ONHs from 11 sheep eyes were fixed at 10-, 5-, or 0-mm Hg IOP and crimp periods measured manually from coronal cryosections imaged with polarized light microscopy (PLM). Using linear mixed-effect models, we characterized the LC and PPS periods, and how they varied with distance from the scleral canal edge., Results: A total of 17,374 manual collagen crimp period measurements were obtained with high repeatability (1.9 μm) and reproducibility (4.7 μm). The periods were smaller (P < 0.001) and less variable in the LC than in the PPS: average (SD) of 13.8 (3.1) μm in the LC, and 31.0 (10.4) μm in the PPS. LC crimp period did not vary with distance from the scleral canal wall (P > 0.1). PPS period increased with the square root of the distance to the canal (P < 0.0001)., Conclusions: Small, uniform crimp periods within the sheep LC and immediately adjacent PPS may indicate that these tissues are setup to prevent large or heterogeneous deformations that insult the neural tissues within the canal. An increasing more variable period with distance from the canal provides a smooth transition of mechanical properties that minimizes stress and strain concentrations.

The eye is a complex structure composed of several interconnected tissues acting together, across the whole globe, to resist deformation due to intraocular pressure (IOP). However, most work in the ocular biomechanics field only examines the response to IOP over smaller regions of the eye. We used high-field MRI to measure IOP induced ocular displacements and deformations over the whole globe. Seven sheep eyes were obtained from a local abattoir and imaged within 48 h using MRI at multiple levels of IOP. IOP was controlled with a gravity perfusion system and a cannula inserted into the anterior chamber. T2-weighted imaging was performed to the eyes serially at 0 mmHg, 10 mmHg, 20 mmHg and 40 mmHg of IOP using a 9.4 T MRI scanner. Manual morphometry was conducted using 3D visualization software to quantify IOP-induced effects at the globe scale (e.g. axial length and equatorial diameters) or optic nerve head scale (e.g. canal diameter, peripapillary sclera bowing). Measurement sensitivity analysis was conducted to determine measurement precision. High-field MRI revealed an outward bowing of the posterior sclera and anterior bulging of the cornea due to IOP elevation. Increments in IOP from 10 to 40 mmHg caused measurable increases in axial length in 6 of 7 eyes of 7.9 ± 5.7% (mean ± SD). Changes in equatorial diameter were minimal, 0.4 ± 1.2% between 10 and 40 mmHg, and in all cases less than the measurement sensitivity. The effects were nonlinear, with larger deformations at normal IOPs (10-20 mmHg) than at elevated IOPs (20-40 mmHg). IOP also caused measurable increases in the nasal-temporal scleral canal diameter of 13.4 ± 9.7% between 0 and 20 mmHg, but not in the superior-inferior diameter. This study demonstrates that high-field MRI can be used to visualize and measure simultaneously the effects of IOP over the whole globe, including the effects on axial length and equatorial diameter, posterior sclera displacement and bowing, and even changes in scleral canal diameter. The fact that the equatorial diameter did not change with IOP, in agreement with previous studies, indicates that a fixed boundary condition is a reasonable assumption for half globe inflation tests and computational models. Our results demonstrate the potential of high-field MRI to contribute to understanding ocular biomechanics, and specifically of the effects of IOP in large animal models., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: The purpose of this study was to leverage polarized light microscopy (PLM) to visualize the collagen fiber architecture of posterior pole and optic nerve head with micrometer-scale resolution and to identify and quantify major organizational components., Methods: Eight sheep posterior poles were cryosectioned and imaged using PLM. Collagen fiber orientation was determined by using custom scripts, and the resulting orientation maps were inspected and quantified to identify major structural elements and tested for differences in mean fiber orientation and anisotropy, using linear mixed effect models., Results: Images revealed an intricate organization of collagen fibers in the posterior pole. In the lamina cribrosa, interweaving fibers formed large knots and wrapped around nerve fiber pores, with beam insertions into the scleral canal wall that were either narrow and straight or wide. In the peripapillary sclera, three significantly different (P < 0.0001) components were identified: fibers oriented circumferentially proximal to the canal, radially in the innermost sclera, and unaligned with interweaving fibers. The radial fibers were between 60 and 180 μm thick, extending at least 3 mm from the canal., Conclusions: PLM revealed structural aspects of the lamina cribrosa and sclera that may have important biomechanical roles but that were previously unreported or not characterized quantitatively. In the lamina cribrosa, these roles included wide and narrow beam insertions and details of collagen fibers interweaving and wrapping around the pores. In the sclera, we described regions of circumferential, radial, and unaligned "random" fibers. Although there is consensus that circumferential fibers protect neural tissues by resisting canal expansion, the role of the radial fibers remains unclear.

Clustering scientific publications in an important problem in bibliometric research. We demonstrate how two software tools, CitNetExplorer and VOSviewer, can be used to cluster publications and to analyze the resulting clustering solutions. CitNetExplorer is used to cluster a large set of publications in the field of astronomy and astrophysics. The publications are clustered based on direct citation relations. CitNetExplorer and VOSviewer are used together to analyze the resulting clustering solutions. Both tools use visualizations to support the analysis of the clustering solutions, with CitNetExplorer focusing on the analysis at the level of individual publications and VOSviewer focusing on the analysis at an aggregate level. The demonstration provided in this paper shows how a clustering of publications can be created and analyzed using freely available software tools. Using the approach presented in this paper, bibliometricians are able to carry out sophisticated cluster analyses without the need to have a deep knowledge of clustering techniques and without requiring advanced computer skills.

Objective: To compare the safety and efficacy of hyaluronan (HA) injections with standard extracorporeal shock wave therapy (ESWT) in the treatment of painful midportion Achilles' tendinopathy., Design: Multinational, prospective, randomized controlled, blinded-observer trial., Setting: Ambulatory care., Participants: Adults (N=62) with Achilles' midportion tendinopathy for ≥6 weeks and a pain score of at least 40mm (Huskisson visual analog scale [VAS], 100mm) were randomized, and 59 were analyzed in the intention-to-treat data set. There were no withdrawals because of adverse effects., Interventions: Two peritendinous HA injections versus 3 ESWT applications at weekly intervals., Main Outcome Measures: Primary efficacy criterion was changed from the Victorian Institute of Sports Assessment-Achilles' questionnaire (VISA-A) score to the percent change in pain (VAS) at 3 months posttreatment, compared with baseline values. Main secondary parameters were VISA-A, Clinical Global Impression (CGI), and clinical parameters., Results: HA treatment provided a clinically relevant improvement in Achilles' midportion tendinopathy. A large superiority of the HA group, compared with ESWT application, was observed for percent change in pain (VAS), and this superiority was proven to be statistically significant (Mann-Whitney statistic [MW]=.7507 with P=.0030 lower than required α=.025 significance level 1-sided; Mann-Whitney U test) at 3 months posttreatment. Similar findings for HA were also observed at 4 weeks (MW=.6425, P=.0304) and 6 months (MW=.7172, P=.0018). Advantage of HA treatment was confirmed by VISA-A questionnaire, CGI, and clinical parameters. Ten adverse events, 4 in the HA group and 6 in the ESWT group, were reported, but none were classified as serious., Conclusions: Two peritendinous HA injections showed greater treatment success in Achilles' midportion tendinopathy compared with standard ESWT., (Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

The microstructural organization and composition of the corneoscleral shell (CSS) determine the biomechanical behavior of the eye, and are important in diseases such as glaucoma and myopia. However, limited techniques can assess these properties globally, non-invasively and quantitatively. In this study, we hypothesized that multi-modal magnetic resonance imaging (MRI) can reveal the effects of biomechanical or biochemical modulation on CSS. Upon intraocular pressure (IOP) elevation, CSS appeared hyperintense in both freshly prepared ovine eyes and living rat eyes using T2-weighted MRI. Quantitatively, transverse relaxation time (T2) of CSS increased non-linearly with IOP at 0-40 mmHg and remained longer than unloaded tissues after being unpressurized. IOP loading also increased fractional anisotropy of CSS in diffusion tensor MRI without apparent change in magnetization transfer MRI, suggestive of straightening of microstructural fibers without modification of macromolecular contents. Lastly, treatments with increasing glyceraldehyde (mimicking crosslinking conditions) and chondroitinase-ABC concentrations (mimicking glycosaminoglycan depletion) decreased diffusivities and increased magnetization transfer in cornea, whereas glyceraldehyde also increased magnetization transfer in sclera. In summary, we demonstrated the changing profiles of MRI contrast mechanisms resulting from biomechanical or biochemical modulation of the eye non-invasively. Multi-modal MRI may help evaluate the pathophysiological mechanisms in CSS and the efficacy of corneoscleral treatments., Competing Interests: The author(s) have made the following disclosure(s): J.S.S.: Royalties e Zeiss, Dublin, CA (for intellectual property licensed by the Massachusetts Institute of Technology and Massachusetts Eye and Ear Infirmary).

Clustering methods are applied regularly in the bibliometric literature to identify research areas or scientific fields. These methods are for instance used to group publications into clusters based on their relations in a citation network. In the network science literature, many clustering methods, often referred to as graph partitioning or community detection techniques, have been developed. Focusing on the problem of clustering the publications in a citation network, we present a systematic comparison of the performance of a large number of these clustering methods. Using a number of different citation networks, some of them relatively small and others very large, we extensively study the statistical properties of the results provided by different methods. In addition, we also carry out an expert-based assessment of the results produced by different methods. The expert-based assessment focuses on publications in the field of scientometrics. Our findings seem to indicate that there is a trade-off between different properties that may be considered desirable for a good clustering of publications. Overall, map equation methods appear to perform best in our analysis, suggesting that these methods deserve more attention from the bibliometric community.

The "magic angle" MRI effect can enhance signal intensity in aligned collagenous structures oriented at approximately 55° with respect to the main magnetic field. The difficulty of positioning tissue inside closed-bore scanners has hampered magic angle use in research and clinics. An MRI-conditional mechatronic system has been developed to control sample orientation inside a 9.4T small bore MRI scanner. The system orients samples to within 0.5° and enables a 600% increase in tendon signal intensity.

Purpose: Laplace's Law, with its compactness and simplicity, has long been employed in ophthalmology for describing the mechanics of the corneoscleral shell. We questioned the appropriateness of Laplace's Law for computing wall stress in the eye considering the advances in knowledge of ocular biomechanics., Methods: In this manuscript we recapitulate the formulation of Laplace's Law, as well as common interpretations and uses in ophthalmology. Using numerical modeling, we study how Laplace's Law cannot account for important characteristics of the eye, such as variations in globe shape and size or tissue thickness, anisotropy, viscoelasticity, or that the eye is a living, dynamic organ., Results: We show that accounting for various geometrical and material factors, excluded from Laplace's Law, can alter estimates of corneoscleral wall stress as much as 456% and, therefore, that Laplace's Law is unreliable., Conclusions: We conclude by illustrating how computational techniques, such as finite element modeling, can account for the factors mentioned above, and are thus more suitable tools to provide quantitative characterization of corneoscleral biomechanics.

Characterizing the collagen fiber orientation and organization in the eye is necessary for a complete understanding of ocular biomechanics. In this study, we assess the performance of polarized light microscopy to determine collagen fiber orientation of ocular tissues. Our results demonstrate that the method provides objective, accurate, repeatable and robust data on fiber orientation with µm-scale resolution over a broad, cm-scale, field of view, unaffected by formalin fixation, without requiring tissue dehydration, labeling or staining. Together, this shows that polarized light microscopy is a powerful method for studying collagen architecture in the eye, with applications ranging from normal physiology and aging, to pathology and transplantation.

Purpose: The structure and biomechanics of the sclera and cornea are central to several eye diseases such as glaucoma and myopia. However, their roles remain unclear, partly because of limited noninvasive techniques to assess their fibrous microstructures globally, longitudinally, and quantitatively. We hypothesized that magic angle-enhanced magnetic resonance imaging (MRI) can reveal the structural details of the corneoscleral shell and their changes upon intraocular pressure (IOP) elevation., Methods: Seven ovine eyes were extracted and fixed at IOP = 50 mm Hg to mimic ocular hypertension, and another 11 eyes were unpressurized. The sclera and cornea were scanned at different angular orientations relative to the main magnetic field inside a 9.4-Tesla MRI scanner. Relative MRI signal intensities and intrinsic transverse relaxation times (T2 and T2*) were determined to quantify the magic angle effect on the corneoscleral shells. Three loaded and eight unloaded tendon samples were scanned as controls., Results: At magic angle, high-resolution MRI revealed distinct scleral and corneal lamellar fibers, and light/dark bands indicative of collagen fiber crimps in the sclera and tendon. Magic angle enhancement effect was the strongest in tendon and the least strong in cornea. Loaded sclera, cornea, and tendon possessed significantly higher T2 and T2* than unloaded tissues at magic angle., Conclusions: Magic angle-enhanced MRI can detect ocular fibrous microstructures without contrast agents or coatings and can reveal their MR tissue property changes with IOP loading. This technique may open up new avenues for assessment of the biomechanical and biochemical properties of ocular tissues in aging and in diseases involving the corneoscleral shell., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

Purpose: To compare three methods of Schlemm's canal (SC) cross-sectional area (CSA) measurement., Methods: Ten eyes (10 healthy volunteers) were imaged three times using spectral-domain optical coherence tomography (Cirrus HD-OCT, Zeiss, Dublin, California, USA). Aqueous outflow vascular structures and SC collector channel ostia were used as landmarks to identify a reference location within the limbus. SC CSA was assessed within a 1 mm segment (±15 frames of the reference, 31 frames in all) by three techniques. (1) Using a random number table, SC CSA in five random frames from the set of 31 surrounding the reference were measured and averaged. (2) The most easily visualised SC location (subjective) was measured, and (3) SC CSA was measured in all 31 consecutive B-scans, and averaged. (comprehensive average, gold standard). Subjective and random CSAs were compared with the comprehensive by general estimating equation modelling, and structural equation modelling quantified agreement., Results: The average from five random locations (4175±1045 µm(2)) was not significantly different than that obtained from the gold standard comprehensive assessment (4064±1308 µm(2), p=0.6537). Subjectively located SC CSA (7614±2162 µm(2)) was significantly larger than the comprehensive gold standard SC CSA (p<0.0001). The average of five random frames produced significantly less bias than did subjective location, yielding a calibration line crossing the 'no-bias' line., Discussion: Subjectively located SC CSA measurements produce high estimates of SC CSA. SC assessed by measuring five random locations estimate CSA was similar to the gold standard estimate., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background and Purpose: The alpha angle is the most used measurement to classify concavity of the femoral head-neck junction. It is not only used for treatment decisions for hip impingement, but also in cohort studies relating hip morphology and osteoarthritis. Alpha angle measurement requires identification of the femoral neck axis, the definition of which may vary between studies. The original "3-point method" uses 1 single point to construct the femoral neck axis, whereas the "anatomic method" uses multiple points and attempts to define the true anatomic neck axis. Depending on the method used, the alpha angle may or may not account for other morphological characteristics such as head-neck offset., Methods: We compared 2 methods of alpha angle measurement (termed "anatomic" and "3-point") in 59 cadaver femora and 83 cross-table lateral radiographs of asymptomatic subjects. Results were compared using Bland-Altman plots., Results: Discrepancies of up to 13 degrees were seen between the methods. The 3-point method had an "equalizing effect" by disregarding femoral head position relative to the neck: in femora with high alpha angle, it resulted in lower values than anatomic measurement, and vice versa in femora with low alpha angles. Using the anatomic method, we derived a reference interval for the alpha angle in normal hips in the general population of 30-66 degrees., Interpretation: We recommend the anatomic method because it also reflects the position of the femoral head on the neck. Consensus and standardization of technique of alpha angle measurement is warranted, not only for planar measurements but also for CT or MRI-based measurements.