Graft Copolymers with Complex Polyether Structures: Poly(ethylene oxide)‐graft‐Poly(isobutyl vinyl ether) by Combination of Living Anionic and Photoinduced Cationic Graft Polymerization

A novel polymerization mechanism transformation strategy, involving anionic ring‐opening polymerization and photoinduced cationic polymerization, is successfully applied for the synthesis of poly(ethylene oxide)‐graft‐poly(isobutyl vinyl ether) (PEO‐g‐PIBVE). First, poly(ethylene oxide‐co‐ethoxyl vinyl glycidyl ether) [P(EO‐co‐EVGE)] is synthesized by living anionic polymerization. The vinyl moieties of the functional PEO‐based polymer are converted to the hydrogen iodide adduct by photolysis of diphenyliodonium iodide, monitored using NMR spectroscopy. A modified mode of Lewis acid‐catalyzed living cationic polymerization is performed as a “grafting from” method to generate PIBVE segments grafted onto the PEO main chain. Both the intermediates and the final graft copolymers are characterized by gel‐permeation chromato­graphy (GPC) and ¹H NMR analysis.

     

Classification of Lower Extremity Movement Patterns Based on Visual Assessment: Reliability and Correlation With 2-Dimensional Video Analysis

Context:

Abnormal movement patterns have been implicated in lower extremity injury. Reliable, valid, and easily implemented assessment methods are needed to examine existing musculoskeletal disorders and investigate predictive factors for lower extremity injury.

Objective:

To determine the reliability of experienced and novice testers in making visual assessments of lower extremity movement patterns and to characterize the construct validity of the visual assessments.

Design:

Cross-sectional study.

Setting:

University athletic department and research laboratory.

Patients or Other Participants:

Convenience sample of 30 undergraduate and graduate students who regularly participate in athletics (age = 19.3 ± 4.5 years). Testers were 2 experienced physical therapists and 1 novice postdoctoral fellow (nonclinician).

Main Outcome Measure(s):

We took videos of 30 athletes performing the single-legged squat. Three testers observed the videos on 2 occasions and classified the lower extremity movement as dynamic valgus, no change, or dynamic varus. The classification was based on the estimated change in frontal-plane projection angle (FPPA) of the knee from single-legged stance to maximum single-legged squat depth. The actual FPPA change was measured quantitatively. We used percentage agreement and weighted κ to examine tester reliability and to determine construct validity of the visual assessment.

Results:

The κ values for intratester and intertester reliability ranged from 0.75 to 0.90, indicating substantial to excellent reliability. Percentage agreement between the visual assessment and the quantitative FPPA change category was 90%, with a κ value of 0.85.

Conclusions:

Visual assessments were made reliably by experienced and novice testers. Additionally, movement-pattern categories based on visual assessments were in excellent agreement with objective methods to measure FPPA change. Therefore, visual assessments can be used in the clinic to assess movement patterns associated with musculoskeletal disorders and in large epidemiologic studies to assess the association between lower extremity movement patterns and musculoskeletal injury.Key Words: movement analysis, screening, athletic injuries, knee valgus

Key Points

• With training and the use of standardized techniques, both experienced and novice testers reliably classified lower extremity movement patterns based on visual assessment.
• Movement-pattern category-based visual assessments were in excellent agreement with objective methods to measure changes in frontal-plane projection angle.
• Visual assessment based on the methods described in this study may be used in the clinical setting, as well as in large epidemiologic studies and screening assessments for sport participation, to identify distinct categories of lower extremity movement patterns.

Abnormal movement patterns of the lower extremity have been implicated in noncontact anterior cruciate ligament (ACL) injuries¹ and other musculoskeletal problems, such as patellofemoral pain^2–4 and acetabular labral tears.⁵ In addition, correcting these abnormal movement patterns has been shown to prevent ACL injury⁶ and is proposed to reduce symptoms in people with preexisting pain conditions.^5,7,8 Thus, assessment of lower extremity movement patterns may be a way to guide treatment of existing musculoskeletal pain problems and to identify people at risk for future injury or musculoskeletal pain. To facilitate the examination of existing musculoskeletal disorders and the investigation of predictive factors of lower extremity injury, reliable, valid, and feasible methods to assess lower extremity movement patterns are needed.One method to assess lower extremity movement patterns is the Landing Error Scoring System (LESS).^9–11 The LESS uses a standard technique to make visual assessments of movement patterns during a drop vertical jump. The LESS is reliable and valid^9–11; however, the drop vertical jump is a relatively high-level activity and may not be the best way to assess movement patterns in patients with existing injury or in athletes whose sports do not involve landing from a jump. In addition, the drop vertical jump is a bilateral activity that may allow the participant to use 1 limb to compensate for the other. Visual assessment of the single-legged squat (SLSquat), a unilateral limb task, may provide an alternative to the LESS.We have developed standardized methods using a visual assessment of the frontal-plane projection angle (FPPA) to classify the lower extremity movement pattern during an SLSquat. The FPPA is a 2-dimensional (2-D) representation of the lower extremity position¹² and has been used to identify differences between men and women¹² and between women with patellofemoral pain and control participants^4,13 and to detect change in movement patterns after specific training.¹⁴ We established specific criteria to define the categories of lower extremity movement pattern based on the change in FPPA (FPPA change) during motion. The tester observes the angle formed between a line that bisects the thigh and a line that bisects the lower leg. During movement tests, the tester compares the FPPA at the start position with the FPPA at the end position. For example, to assess an SLSquat, the examiner compares the FPPA during the start position of single-legged stance with the end position of maximum squat depth. The difference observed in FPPA from the start to the end position can then be classified as dynamic valgus (change in the valgus direction), no change, or dynamic varus (change in the varus direction). We have used this assessment extensively in the clinical setting, but we have not assessed the rater reliability or the construct validity of our visual assessments.The purpose of this study was to assess the intratester and intertester reliability of 3 testers (2 experienced, 1 novice) categorizing the lower extremity movement pattern demonstrated during an SLSquat. A standardized protocol was used to assess videos of healthy participants performing the SLSquat. We hypothesized that the testers, both experienced and novice, would demonstrate good to excellent reliability using the standardized methods. In addition, we used the objective measure of quantifying FPPA as described by Willson and Davis¹² to determine the construct validity of our visual assessments. We hypothesized that we would see good to excellent agreement between our visual assessments and the quantitative FPPA change.     

Benefits of implementing a rapid access clinic in a high-volume inflammatory bowel disease center:Access,resource utilization and outcomes

BACKGROUND Emergency situations in inflammatory bowel diseases(IBD)put significant burden on both the patient and the healthcare system.AIM To prospectively measure Quality-of-Care indicators and resource utilization after the implementation of the new rapid access clinic service(RAC)at a tertiary IBD center.METHODS Patient access,resource utilization and outcome parameters were collected from consecutive patients contacting the RAC between July 2017 and March 2019 in this observational study.For comparing resource utilization and healthcare costs,emergency department(ED)visits of IBD patients with no access to RAC services were evaluated between January 2018 and January 2019.Time to appointment,diagnostic methods,change in medical therapy,unplanned ED visits,hospitalizations and surgical admissions were calculated and compared.RESULTS 488 patients(Crohn’s disease:68.4%/ulcerative colitis:31.6%)contacted the RAC with a valid medical reason.Median time to visit with an IBD specialist following the index contact was 2 d.Patients had objective clinical and laboratory assessment(C-reactive protein and fecal calprotectin in 91%and 73%).Fast-track colonoscopy/sigmoidoscopy was performed in 24.6%of the patients,while computed tomography/magnetic resonance imaging in only 8.1%.Medical therapy was changed in 54.4%.ED visits within 30 d following the RAC visit occurred in 8.8%(unplanned ED visit rate:5.9%).Diagnostic procedures and resource utilization at the ED(n=135 patients)were substantially different compared to RAC users:Abdominal computed tomography was more frequent(65.7%,P<0.001),coupled with multiple specialist consults,more frequent hospital admission(P<0.001),higher steroid initiation(P<0.001).Average medical cost estimates of diagnostic procedures and services per patient was$403 CAD vs$1885 CAD comparing all RAC and ED visits.CONCLUSION Implementation of a RAC improved patient care by facilitating easier access to IBD specific medical care,optimized resource utilization and helped avoiding ED visits and subsequent hospitalizations.     

Identification of Streptococcal M-Protein Cardiopathogenic Epitopes in Experimental Autoimmune Valvulitis

The M protein of rheumatogenic group A streptococci induces carditis and valvulitis in Lewis rats and may play a role in pathogenesis of rheumatic heart disease. To identify the epitopes of M5 protein that produce valvulitis, synthetic peptides spanning A, B, and C repeat regions contained within the extracellular domain of the streptococcal M5 protein were investigated. A repeat region peptides NT4, NT5/6, and NT7 induced valvulitis similar to the intact pepsin fragment of M5 protein. T cell lines from rats with valvulitis recognized M5 peptides NT5/6 and NT6. Passive transfer of an NT5/6-specific T cell line into naïve rats produced valvulitis characterized by infiltration of CD4+ cells and upregulation of VCAM-1, while an NT6-specific T cell line did not target the valve. Our new data suggests that M protein-specific T cells may be important mediators of valvulitis in the Lewis rat model of rheumatic carditis.     

Image-guided bronchoscopy for histopathologic diagnosis of pure ground glass opacity: a case report

Guided bronchoscopy has been found to be useful for the diagnosis of solid peripheral pulmonary lesions (PPLs) but more evidence on ground glass opacities (GGOs), especially those without a solid component, are lacking. A 69-year-old male, asymptomatic, heavy smoker was referred to our department for non-surgical diagnosis of a focal pure GGO in the right upper lobe that was found incidentally on computed tomography (CT). Transbronchial biopsy (TBB) with the aide of endobronchial ultrasound with a guide sheath (EBUS-GS), virtual bronchoscopic navigation (VBN), and fluoroscopy was performed for sampling. There were no complications after the procedure. The diagnosis of adenocarcinoma with lepidic growth pattern was established from the fourth and fifth TBB specimens and was confirmed on subsequent surgical resection. Image-guided bronchoscopy with TBB was successful for the diagnosis of a pure GGO. Use of a larger biopsy device may be helpful for the histopathologic diagnosis of lung adenocarcinoma with lepidic growth.     

Craniofacial bone atrophy in Parry Romberg syndrome demonstrated using a Bayesian hierarchical model

PurposeParry Romberg syndrome (PRS) is a condition characterized by progressive hemifacial atrophy, predominantly affecting the soft tissues. Associated bone retraction is a common clinical feature of PRS but has never been assessed. Here we used 3D imaging and Bayesian statistics in order to demonstrate and quantify bone atrophy in PRS.Materials and methodsTen non-operated patients with PRS (4/10 males) and 12 age-matched controls (7/12 males) were included into the study. The average age at CT-scan was 9.67 ± 4.13 years for PRS patients and 12.5 ± 4.37 years for controls. Soft and hard tissue atrophy levels were quantified using computed tomography scans, based on the distances between surfaces of the affected side and the non-affected contralateral side, both for the skin and the bone. We used a hierarchical Bayesian model with clinical priors in order to assess the relationship between hard and soft tissue atrophies.ResultsPRS patients had significant hard tissue atrophy, and atrophy extents were similar for soft and hard tissues. There was a trend for a correlation between the extent of hard tissue retraction and the extent of soft tissue retraction, and we could not demonstrate that the relationship between hard and soft tissue retractions was different in PRS and controls.ConclusionOur results indicated that bone atrophy was most probably a primary process rather than a phenomenon secondary to soft tissue retraction. We have provided the first assessment of bone atrophy in PRS patients using Bayesian statistics.     

Modeling local and cross-species neuron number variations in the cerebral cortex as arising from a common mechanism

A massive increase in the number of neurons in the cerebral cortex, driving its size to increase by five orders of magnitude, is a key feature of mammalian evolution. Not only are there systematic variations in cerebral cortical architecture across species, but also across spatial axes within a given cortex. In this article we present a computational model that accounts for both types of variation as arising from the same developmental mechanism. The model employs empirically measured parameters from over a dozen species to demonstrate that changes to the kinetics of neurogenesis (the cell-cycle rate, the progenitor death rate, and the “quit rate,” i.e., the ratio of terminal cell divisions) are sufficient to explain the great diversity in the number of cortical neurons across mammals. Moreover, spatiotemporal gradients in those same parameters in the embryonic cortex can account for cortex-wide, graded variations in the mature neural architecture. Consistent with emerging anatomical data in several species, the model predicts (i) a greater complement of neurons per cortical column in the later-developing, posterior regions of intermediate and large cortices, (ii) that the extent of variation across a cortex increases with cortex size, reaching fivefold or greater in primates, and (iii) that when the number of neurons per cortical column increases, whether across species or within a given cortex, it is the later-developing superficial layers of the cortex which accommodate those additional neurons. We posit that these graded features of the cortex have computational and functional significance, and so must be subject to evolutionary selection.Changes in brain structure follow a remarkably stable pattern over ∼450 My in the vertebrate lineage: it is always the same brain parts that become enlarged when overall brain size increases (1). Moreover, in studies of individual variation in humans and other mammals, when overall brain size is larger, those same divisions as would be predicted by looking at brain enlargement across taxa are also found to be preferentially enlarged (2, 3). Such regularities in brain scaling from the individual to the taxon level suggest that the developmental mechanisms which generate central nervous systems are strongly conserved across species (4).To tease apart the features of the isocortex contributed by the scaling of conserved developmental mechanisms from those features which might be specially selected for in a given niche or species, we have created an empirically informed, mathematical model of cortical neurogenesis. The model elucidates how the dials and levers made available by conserved developmental mechanisms allow selection to shape the basic landscape of the embryonic cortex. The extent to which any particular cortical area (e.g., a visual or language area) has been a special subject of selection can be better evaluated given the baselines provided by this evolutionary developmental or “evo-devo” model.The modeling approach presented here provides an explicit structure to assimilate known data and predict unknowns, both for developmental kinetic parameters and for the resultant time courses of neuronal and progenitor cell populations, for the entire range of mammalian brain sizes and across a spatial axis within the respective cortices. Our model incorporates important insights from several previously published mathematical models of cortical neurogenesis which focus on more limited sets of species or which consider spatial variations in a single species (5–10).     

A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome

Wolfram syndrome is a genetic disorder characterized by diabetes and neurodegeneration and considered as an endoplasmic reticulum (ER) disease. Despite the underlying importance of ER dysfunction in Wolfram syndrome and the identification of two causative genes, Wolfram syndrome 1 (WFS1) and Wolfram syndrome 2 (WFS2), a molecular mechanism linking the ER to death of neurons and β cells has not been elucidated. Here we implicate calpain 2 in the mechanism of cell death in Wolfram syndrome. Calpain 2 is negatively regulated by WFS2, and elevated activation of calpain 2 by WFS2-knockdown correlates with cell death. Calpain activation is also induced by high cytosolic calcium mediated by the loss of function of WFS1. Calpain hyperactivation is observed in the WFS1 knockout mouse as well as in neural progenitor cells derived from induced pluripotent stem (iPS) cells of Wolfram syndrome patients. A small-scale small-molecule screen targeting ER calcium homeostasis reveals that dantrolene can prevent cell death in neural progenitor cells derived from Wolfram syndrome iPS cells. Our results demonstrate that calpain and the pathway leading its activation provides potential therapeutic targets for Wolfram syndrome and other ER diseases.The endoplasmic reticulum (ER) takes center stage for protein production, redox regulation, calcium homeostasis, and cell death (1, 2). It follows that genetic or acquired ER dysfunction can trigger a variety of common diseases, including neurodegenerative diseases, metabolic disorders, and inflammatory bowel disease (3, 4). Breakdown in ER function is also associated with genetic disorders such as Wolfram syndrome (5–8). It is challenging to determine the exact effects of ER dysfunction on the fate of affected cells in common diseases with polygenic and multifactorial etiologies. In contrast, we reasoned that it should be possible to define the role of ER dysfunction in mechanistically homogenous patient populations, especially in rare diseases with a monogenic basis, such as Wolfram syndrome (9).Wolfram syndrome (OMIM 222300) is a rare autosomal recessive disorder characterized by juvenile-onset diabetes mellitus and bilateral optic atrophy (7). Insulin-dependent diabetes usually occurs as the initial manifestation during the first decade of life, whereas the diagnosis of Wolfram syndrome is invariably later, with onset of symptoms in the second and ensuing decades (7, 10, 11). Two causative genes for this genetic disorder have been identified and named Wolfram syndrome 1 (WFS1) and Wolfram syndrome 2 (WFS2) (12, 13). It has been shown that multiple mutations in the WFS1 gene, as well as a specific mutation in the WFS2 gene, lead to β cell death and neurodegeneration through ER and mitochondrial dysfunction (5, 6, 14–16). WFS1 gene variants are also associated with a risk of type 2 diabetes (17). Moreover, a specific WFS1 variant can cause autosomal dominant diabetes (18), raising the possibility that this rare disorder is relevant to common molecular mechanisms altered in diabetes and other human chronic diseases in which ER dysfunction is involved.Despite the underlying importance of ER malfunction in Wolfram syndrome, and the identification of WFS1 and WFS2 genes, a molecular mechanism linking the ER to death of neurons and β cells has not been elucidated. Here we show that the calpain protease provides a mechanistic link between the ER and death of neurons and β cells in Wolfram syndrome.