Peripheral Sites Research Articles

Ultrasonic backscatter measurements of cancellous bone in the near field of a planar transducer

Ultrasonic backscatter techniques may be used to detect changes in bone caused by osteoporosis and other diseases. Typical measurement locations include peripheral skeletal sites such as the heel, which may place the interrogated region of bone tissue in the acoustic near field of the transducer. The purpose of this study is to investigate how measurements in the near field of a planar transducer affect backscatter parameters used for ultrasonic bone assessment. Ultrasonic measurements were performed in a water tank using a planar 2.25 MHz transducer. Signals were acquired for five transducer-specimen distances: N/4, N/2, 3N/4, N, and 5N/4 where N is the near-field distance, a location that represents the transition from the near field to far field. Three backscatter parameters previously identified as potentially useful for ultrasonic bone assessment purposes were investigated: AIB, FSAB, and FIAB. All three parameters depended on transducer-specimen distance to varying degrees with FSAB exhibiting the greatest dependence on distance. These results suggest that laboratory studies of bone should evaluate the performance of backscatter parameters using clinically relevant transducer-specimen distances including distances where the ultrasonically interrogated region is in the near field of the transducer.

Functional outcomes between headache surgery and targeted botox injections: A prospective multicenter pilot study

IntroductionChronic migraine headaches (MH) are a principal cause of disability worldwide. This study evaluated and compared functional outcomes after peripheral trigger point deactivation surgery or botulinum neurotoxin A (BTA) treatment in patients with MH. MethodsA long-term, multicenter, and prospective study was performed. Patients with chronic migraine were recruited at the Ohio State University and Massachusetts General Hospital and included in each treatment group according to their preference (BTA or surgery). Assessment tools including the Migraine Headache Index (MHI), Migraine Disability Assessment Questionnaire (MIDAS) total, MIDAS A, MIDAS B, Migraine Work and Productivity Loss Questionnaire-question 7 (MWPLQ7), and Migraine-Specific Quality of Life Questionnaire (MSQ) version 2.1 were used to evaluate functional outcomes. Patients were evaluated prior to treatment and at 1, 2, and 2.5 years after treatment. ResultsA total of 44 patients were included in the study (surgery=33, BTA=11). Patients treated surgically showed statistically significant improvement in headache intensity as measured on MIDAS B (p = 0.0464) and reduced disability as measured on MWPLQ7 (p = 0.0120) compared to those treated with BTA injection. No statistical difference between groups was found for the remaining functional outcomes. Mean scores significantly improved over time independently of treatment for MHI, MIDAS total, MIDAS A, MIDAS B, and MWPLQ 7 (p<0.05). However, no difference in mean scores over time was observed for MSQ. ConclusionsHeadache surgery and targeted BTA injections are both effective means of addressing peripheral trigger sites causing headache pain. However, lower pain intensity and work-related disabilities were found in the surgical group.

Towards Development of High-Performance Perovskite Solar Cells Based on Pyrrole Materials for Hole Transport Layer by Using Computational Approach

Perovskite solar cells (PSCs) have emerged as innovative materials in advanced photovoltaic technology due to their enhanced efficiency and good stability. While considering role of dopant materials in HTMs especially Spiro-OMeTAD through previous studies, a bi-functional dopant named PFPPY has been brought into special attention. Based on framework of experimentally synthesized PFPPY, five dopant molecules (P1–P5) have been designed through structural alterations at peripheral sites. These newly developed molecules, sharing a common core i.e. 1,4-dihydropyrrolo[3,2-b]pyrrole (PPY), were then theoretically studied and related to reference via computational approach. Distribution of frontier molecular orbitals (FMOs) along with density of states, spectral properties, reorganizational energies, binding energy, and transition density matrix analysis was practiced at [Formula: see text]B97XD functional using DFT and TD–DFT methodology. Bathochromic shift of absorption (in dichloromethane) was clearly observed for all designed dopants (P1–P5) than reference PFPPY which sets the ways for reduced optical band gaps ([Formula: see text]. The energy gaps ([Formula: see text] of these five novel designed materials were found to be lesser comparaed to PFPPY which leads to excellent ICT properties. Of all dopant molecules, highest dipole moment (6.511401 D) possessed by P4 is credited to its maximum absorption peak (1008 nm) in infrared region. However, greater hole transfer rate was disclosed by P1 relative to other designed dopants because of its lowest reorganization energy values. According to above computed results, we expect that molecular engineering of pyrrole-based dopant molecules (P1–P5) will allow them to act as promising HTMs. Conclusively, these molecules have potential to substitute PFPPY and are highly recommend in photovoltaic field for future work.

Life on the edge-a changing genetic landscape within an iconic American pika metapopulation over the last half century.

Declines and extirpations of American pika (Ochotona princeps) populations at historically occupied sites started being documented in the literature during the early 2000s. Commensurate with global climate change, many of these losses at peripheral and lower elevation sites have been associated with changes in ambient air temperature and precipitation regimes. Here, we report on a decline in available genetic resources for an iconic American pika metapopulation, located at the southwestern edge of the species distribution in the Bodie Hills of eastern California, USA. Composed of highly fragmented habitat created by hard rock mining, the ore dumps at this site were likely colonized by pikas around the end of the 19th century from nearby natural talus outcrops. Genetic data extracted from both contemporary samples and archived natural history collections allowed us to track population and patch-level genetic diversity for Bodie pikas across three distinct sampling points during the last half- century (1948-1949, 1988-1991, 2013-2015). Reductions in within-population allelic diversity and expected heterozygosity were observed across the full time period. More extensive sampling of extant patches during the 1988-1991 and 2013-2015 periods revealed an increase in population structure and a reduction in effective population size. Furthermore, census records from the last 51 years as well as archived museum samples collected in 1947 from a nearby pika population in the Wassuk range (Nevada, USA) provide further support of the increasing isolation and genetic coalescence occurring in this region. This study highlights the importance of museum samples and long-term monitoring in contextualizing our understanding of population viability.

Impacts of Skin Color and Hypoxemia on Noninvasive Assessment of Peripheral Blood Oxygen Saturation: A Scoping Review.

Standard pulse oximeters estimate arterial blood saturation (SaO2) non-invasively by emitting and detecting light of a specific wavelength through a cutaneous vascular bed, such as a digit or the ear lobe. The quantity measured at these peripheral sites is designated as oxygen saturation (SpO2). Most reliable pulse oximeters are calibrated from measurements of healthy volunteers using some form of oxygen desaturation method. As the degree of inducible hypoxemia is limited, the calibration below achievable desaturation levels is usually extrapolated, leading to potential measurement error at low SaO2 values, especially in highly pigmented skin. Such skin color-related errors (SCRE) are the topic of this scoping review. Specifically, this study aimed to identify the combined impact of skin color and reduced SaO2 on the non-invasive assessment of SpO2 and report the consequences of potential inaccuracies. Three databases were searched (Cumulated Index to Nursing and Allied Health Literature (CINAHL), PubMed, and Web of Science) for peer-reviewed prospective and retrospective studies published in English between 2000 and 2022 involving human patients with hypoxemia that included a measure of skin color (Fitzpatrick scale or race/ethnicity). Ten studies met the criteria and were included in the final review. Eight of these studies reported statistically significant higher pulse oximeter readingsin darker-skinned patients with hypoxia compared to their arterial blood gas measurements. Occult hypoxia was more prevalent in Black and Hispanic patients than in White patients. Minority patients overall (Black, Asian, and American Indian) were more likely to have a SaO2 < 88% that was not detected by pulse oximetry (occult hypoxemia) during hospitalization. With greater levels of hypoxemia, the differences between SpO2 and SaO2 were greater. If SaO2 was < 90%, then SpO2 was overestimated in all ethnicities but worse in minorities. In conclusion, the bias found in pulse oximeter readings in the skin of color broadly impacts patients with hypoxemia. The failure of SpO2 measuring devices to detect occult hypoxemia can delay the delivery of life-saving treatment to critically ill patients requiring respiratory rehabilitation and supplemental oxygen therapy. This may lead to adverse health outcomes, increased in-hospital mortality, and complications such as organ dysfunction. An improvement in pulse oximeter detection mechanisms that would include all skin pigmentations is therefore much desired to optimize individual healthcare status and minimize disparities in treatment.

Inhibition mechanism of fisetin on acetylcholinesterase and its synergistic effect with galantamine

The search for acetylcholinesterase (AChE) inhibitors produced by natural sources is of great significance for the prevention and therapy of Alzheimer's disease and has been widely concerned. In this study, fisetin, a flavonoid compound of plant origin, displayed a mixed inhibition mode on AChE (IC50 = 8.88 ± 0.14 μM). Fluorescence spectra analysis revealed that fisetin statically quenched AChE fluorescence, and the ground state complex was formed by hydrogen bonds and hydrophobic interactions. Circular dichroism assays showed that fisetin induced AChE structure loosened with a decrease in α-helix structure (from 20.6 % to 19.5 %). Computer simulation exhibited that fisetin bound to both the peripheral anionic site (PAS) and the catalytic active site (CAS) and increased the stability of the AChE. Interestingly, the combination of fisetin and galantamine enhanced the binding affinity between AChE and galantamine and induced AChE structure further loosened, while the inhibition mode was still the mixed type. The heatmap analysis indicated that galantamine (0.2 μM) combined with fisetin (2.25 μM) had a significant synergy on AChE inhibition, probably because fisetin binding at the PAS-AChE induced conformation changes of the gorge and CAS, which enhanced galantamine binding affinity with CAS, and a further loose structure of AChE was induced by the mixture, so finally the interaction between the substrate and AChE was strongly affected. This work may offer a theoretical reference for the functional research of fisetin as a potential AChE inhibitor and an enhanced supplement for galantamine.

Study on the active ingredients of Shenghui decoction inhibiting acetylcholinesterase based on molecular docking and molecular dynamics simulation.

We aim to investigate the mechanism and effective components of Shenghui decoction (SHD), which has been shown to inhibit acetylcholinesterase (AChE) through molecular docking (MD) and molecular dynamics simulation (MDS). The effective ingredients in SHD were collected through the TCMSP database and literature review. All components were docked with AChE using CDOCKER. Receptor ligand interaction analysis was performed for the optimal ligand. Two simulation models (model I and II) containing AChE and acetylcholine (ACh) were constructed, in which model II contained the best-docked ligand. Perform 90ns MDS on 2 models. After the simulation, the distance between ACh and AChE peripheral active sites were calculated in both models. The root mean square deviation (RMSD) curve of ligand and receptor, the radius of gyration (Rog) of the receptor, the distance between ligand center and binding site center, and the binding energy of ligand and receptor were calculated in model II. 98 ingredients of SHD were collected, and the best ligand was Tumulosic acid. The residues that form conventional hydrogen bonds between AChE and Tumulosic acid include Tyr132 and Glu201. MDS revealed that ACh could bind to AChE active site in model I. In model II, ACh cannot bind to the binding cavity because the ligand occupies the active site. The RMSD of AChE and Tumulosic acid tends to be stable, the Rog curve of AChE is relatively stable, and the distance between ligand and binding cavity does not fluctuate greatly, indicating that the structure of receptor and ligand is relatively stable. The binding energy of AChE and Tumulosic acid was -24.14 ± 2.46 kcal/mol. SHD contains many effective ingredients that may inhibit AChE activity. Tumulosic acid can occupy the binding site to prevent ACh from entering the chemical domain, thus exerting AChE inhibitory effect.

Calcium binding and permeation in TRPV channels: Insights from molecular dynamics simulations.

Some calcium channels selectively permeate Ca2+, despite the high concentration of monovalent ions in the surrounding environment, which is essential for many physiological processes. Without atomistic and dynamical ion permeation details, the underlying mechanism of Ca2+ selectivity has long been an intensively studied, yet controversial, topic. This study takes advantage of the homologous Ca2+-selective TRPV6 and non-selective TRPV1 and utilizes the recently solved open-state structures and a newly developed multisite calcium model to investigate the ion binding and permeation features in TRPV channels by molecular dynamics simulations. Our results revealed that the open-state TRPV6 and TRPV1 show distinct ion binding patterns in the selectivity filter, which lead to different ion permeation features. Two Ca2+ ions simultaneously bind to the selectivity filter of TRPV6 compared with only one Ca2+ in the case of TRPV1. Multiple Ca2+ binding at the selectivity filter of TRPV6 permeated in a concerted manner, which could efficiently block the permeation of Na+. Cations of various valences differentiate between the binding sites at the entrance of the selectivity filter in TRPV6. Ca2+ preferentially binds to the central site with a higher probability of permeation, repelling Na+ to a peripheral site. Therefore, we believe that ion binding competition at the selectivity filter of calcium channels, including the binding strength and number of binding sites, determines Ca2+ selectivity under physiological conditions.

Anti-acetylcholinesterase mechanism of kaempferol and its synergistic effect with galanthamine hydrobromide

Kaempferol, a natural flavonoid compound, was found to suppress the activity of AChE in a reversible mixed-inhibition with an IC50 value of 12.43 ± 0.19 μM. Fluorescence spectra showed that the fluorescence burst mechanism of kaempferol on AChE was of static burst type, and it was coupled with AChE to form a complex with a moderate binding affinity driven mainly by hydrogen bonding and hydrophobic interactions. The analysis of circular dichroism spectra found that kaempferol induced structural relaxation of AChE with a decrease in α-helix content (from 19.64% to 18.02%). Computer simulation showed that kaempferol was a two-site inhibitor that bound to both the catalytic active site (Trp86, Glu202, Tyr337) and peripheral anionic site (Tyr72, Asp74, Tyr124 and Tyr341) of AChE, inducing the enzyme structure to become more stable, then the substrate was prevented from binding to the active site of AChE, and the catalytic activity of AChE was inhibited. Moreover, kaempferol binding at the PAS-AChE site induced a conformational change of AChE that may increase the binding affinity of galanthamine to the enzyme, and thus kaempferol and galanthamine synergistically inhibited the activity of AChE. This work may offer novel insights into the development of kaempferol as a food functional factor for the cure of AD.

Bilateral Femoral Cannulation Is Associated With Reduced Severe Limb Ischemia-Related Complications Compared With Unilateral Femoral Cannulation in Adult Peripheral Venoarterial Extracorporeal Membrane Oxygenation: Results From the Extracorporeal Life Support Registry.

Peripheral venoarterial extracorporeal membrane oxygenation (ECMO) with femoral access is obtained through unilateral or bilateral groin cannulation. Whether one cannulation strategy is associated with a lower risk for limb ischemia remains unknown. We aim to assess if one strategy is preferable. A retrospective cohort study based on the Extracorporeal Life Support Organization registry. ECMO centers worldwide included in the Extracorporeal Life Support Organization registry. All adult patients (≥ 18 yr) who received peripheral venoarterial ECMO with femoral access and were included from 2014 to 2020. Unilateral or bilateral femoral cannulation. The primary outcome was the occurrence of limb ischemia defined as a composite endpoint including the need for a distal perfusion cannula (DPC) after 6 hours from implantation, compartment syndrome/fasciotomy, amputation, revascularization, and thrombectomy. Secondary endpoints included bleeding at the peripheral cannulation site, need for vessel repair, vessel repair after decannulation, and in-hospital death. Propensity score matching was performed to account for confounders. Overall, 19,093 patients underwent peripheral venoarterial ECMO through unilateral ( n = 11,965) or bilateral ( n = 7,128) femoral cannulation. Limb ischemia requiring any intervention was not different between both groups (bilateral vs unilateral: odds ratio [OR], 0.92; 95% CI, 0.82-1.02). However, there was a lower rate of compartment syndrome/fasciotomy in the bilateral group (bilateral vs unilateral: OR, 0.80; 95% CI, 0.66-0.97). Bilateral cannulation was also associated with lower odds of cannulation site bleeding (bilateral vs unilateral: OR, 0.87; 95% CI, 0.76-0.99), vessel repair (bilateral vs unilateral: OR, 0.55; 95% CI, 0.38-0.79), and in-hospital mortality (bilateral vs unilateral: OR, 0.85; 95% CI, 0.81-0.91) compared with unilateral cannulation. These findings were unchanged after propensity matching. This study showed no risk reduction for overall limb ischemia-related events requiring DPC after 6 hours when comparing bilateral to unilateral femoral cannulation in peripheral venoarterial ECMO. However, bilateral cannulation was associated with a reduced risk for compartment syndrome/fasciotomy, lower rates of bleeding and vessel repair during ECMO, and lower in-hospital mortality.

Novel 2-Amino-pyrano[3,2-c]quinoline-3-carbonitrile Derivatives Bearing Benzyloxy Phenyl Moiety as Butyrylcholinesterase Inhibitors: Design, Synthesis, In Vitro Evaluation, and Molecular Docking Studies

Background: Alzheimer’s disease (AD), the main form of dementia, is a multifactorial neurodegenerative disease, and several hypotheses have been proposed for its pathogenesis. Among them, cholinergic hypofunction is the main reason and plays a significant role in cognitive impairment. According to this theory, ChE inhibitors improve the performance of the cholinergic system and increase memory function. Thus, this study investigated a novel series of 2-amino-pyrano[3,2-c]quinoline-3-carbonitrile derivatives bearing benzyloxy phenyl moiety as ChE enzyme inhibitors. Methods: The synthesized compounds 6a-o are divided into three series based on benzyloxy phenyl moiety. The structure of all compounds was identified by the NMR (1 H and 13C) and IR spectra. Then, their inhibitory activities against ChE enzymes were evaluated by Ellman’s spectrophotometrical method. The kinetic and molecular docking studies were performed for compound 6l as the most potent butyrylcholinesterase (BChE) inhibitor. Results: The 2-amino-4-(4-((4-fluorobenzyl)oxy)-3-methoxyphenyl)-5-oxo-5,6-dihydro-4H-pyrano[3,2-c] quinoline-3-carbonitrile (6l) demonstrated the best anti-BChE activity with a half maximal inhibitory concentration value of 1.00±0.07. The kinetic and molecular docking studies confirmed that 6l is a mixed inhibitor and binds to both the anionic catalytic site and peripheral anionic site (PAS) of BChE. In silico study approved that the methoxy group on the middle phenyl ring has a significant role in interacting with the PAS of the enzyme. Conclusion: These findings indicated that 2-amino-pyrano[3,2-c]quinoline-3-carbonitrile derivatives bearing benzyloxy phenyl moiety have therapeutic potential as BChE inhibitors in the last stages of AD.

Novel Lawsone-Quinoxaline Hybrids as New Dual Binding Site Acetylcholinesterase Inhibitors.

A new family of lawsone-quinoxaline hybrids was designed, synthesized, and evaluated as dual binding site cholinesterase inhibitors (ChEIs). In vitro tests revealed that compound 6d was the most potent AChEI (IC50 = 20 nM) and BChEI (IC50 = 220 nM). The compound 6d did not show cytotoxicity against the SH-SY5Y neuronal cells (GI50 > 100 μM). In silico and enzyme kinetic experiments demonstrated that compound 6d bound to both the catalytic anionic site and the peripheral anionic site of HuAChE. The lawsone-quinoxaline hybrids exhibited potential for further development of potent acetylcholinesterase inhibitors for the treatment of Alzheimer's disease.

N-methylpiperazinyl and piperdinylalkyl-O-chalcone derivatives as potential polyfunctional agents against Alzheimer's disease: Design, synthesis and biological evaluation.

The series of N-methylpiperazinyl and piperdinylalkyl-O-chalcone derivatives as potential polyfuctional agents against Alzheimer's disease that have been designed, synthesized and then evaluated biologically using in vitro assays for the inhibition of acetylcholinesterase (AChE) activity, AGEs, and free radical formation. The majority of synthesized compounds inhibited AChE & AGEs with additional free radical scavenging activities at nanomolar concentrations. Among these, compound 5k was found to have potent AChE inhibitory activity (IC50 = 11.6 nM), superior than the reference compound donepezil (15.68 nM) along with the good anti-AGEs and free radical formation effect. Its potency was justified by docking studies that revealed its dual binding characteristic with both catalytic active site and peripheral anionic site of AChE, simultaneously. Furthermore, the in vivo evaluation of 5k against streptozotocin (STZ)-induced dementia in rats also showed improvement of memory functions (Morris water maze test) in animals. Also, 5k inhibited STZ-inudced brain AChE activity and oxidative stress which further strengthen the observed in vitro effects. The stability of the ligand-protein complex was then analyzed using a simulation-based interaction protocol. The results revealed that these N-methylpiperazinyl and piperdinylalkyl-O-chalcone derivatives could be considered for potential polyfunctional anti-Alzheimer's molecules.

Comparison of radial, dorsalis pedis, and posterior tibial arteries for ultrasound-guided arterial catheterisation with dynamic needle tip positioning in paediatric patients: a randomised controlled trial

BackgroundArterial catheterisation in children can be challenging and time-consuming. We aimed to compare the success rates of ultrasound-guided arterial catheterisation utilising the short-axis out-of-plane approach with dynamic needle tip positioning in the radial, dorsalis pedis, and posterior tibial arteries in paediatric patients. We also examined the factors influencing the catheterisation success using dynamic needle tip positioning. MethodsPaediatric patients (aged <3 yr) undergoing cardiac surgery were randomly assigned to three groups based on puncture sites: radial artery (Group R), dorsalis pedis artery (Group D), and posterior tibial artery (Group P). The first-attempt and overall success rates of arterial catheterisation were compared, followed by multiple logistic regression analysis (dependent variable: first-attempt success; independent variables: body weight, diameter and depth of the artery, targeted artery, and trisomy 21). ResultsThe study included 270 subjects (n=90 per group). There was no significant difference in the first-attempt (Group R: 82%, Group D: 76%, and Group P: 81%) and overall success rates (Group R: 94%, Group D: 93%, and Group P: 91%) among the three groups. The diameter of the artery (per 0.1 mm) (odds ratio: 1.32, 95% confidence interval: 1.09–1.60) and trisomy 21 (odds ratio: 0.43, 95% confidence interval: 0.20–0.92) were independent predictors of first-attempt success or failure. ConclusionThe first-attempt and overall success rates of arterial catheterisation of the dorsalis pedis and posterior tibial arteries were not inferior to those in the radial artery when using dynamic needle tip positioning. These two lower extremity peripheral arteries present viable alternative catheterisation sites in paediatric patients. Clinical trial registrationUMIN000042847.

Immune cells as messengers from the CNS to the periphery: the role of the meningeal lymphatic system in immune cell migration from the CNS.

In recent decades there has been a large focus on understanding the mechanisms of peripheral immune cell infiltration into the central nervous system (CNS) in neuroinflammatory diseases. This intense research led to several immunomodulatory therapies to attempt to regulate immune cell infiltration at the blood brain barrier (BBB), the choroid plexus (ChP) epithelium, and the glial barrier. The fate of these infiltrating immune cells depends on both the neuroinflammatory environment and their type-specific interactions with innate cells of the CNS. Although the fate of the majority of tissue infiltrating immune cells is death, a percentage of these cells could become tissue resident immune cells. Additionally, key populations of immune cells can possess the ability to "drain" out of the CNS and act as messengers reporting signals from the CNS toward peripheral lymphatics. Recent data supports that the meningeal lymphatic system is involved not just in fluid homeostatic functions in the CNS but also in facilitating immune cell migration, most notably dendritic cell migration from the CNS to the meningeal borders and to the draining cervical lymph nodes. Similar to the peripheral sites, draining immune cells from the CNS during neuroinflammation have the potential to coordinate immunity in the lymph nodes and thus influence disease. Here in this review, we will evaluate evidence of immune cell drainage from the brain via the meningeal lymphatics and establish the importance of this in animal models and humans. We will discuss how targeting immune cells at sites like the meningeal lymphatics could provide a new mechanism to better provide treatment for a variety of neurological conditions.

Surgical videos used for face-to-face and virtual oral assessment: experiences of examiners and trainees.

Background&#x0D; Varied assessment strategies are required in the process of deciding whether a surgeon is competent to graduate. Despite doubts about the reliability of the oral examination and the challenges of standardising examiner practices, it remains an important assessment method in surgical exit examinations. Structured orals may facilitate the measurement of course outcomes.&#x0D; Objectives &#x0D; This study explored the experiences of surgical trainees and examiners using a video-assisted, mock structured oral examination (SOE) as an assessment tool.&#x0D; Methods&#x0D; This descriptive study incorporated procedural videos in a case-based SOE format. One group of trainees had face-to-face contact with the examiner, and the other was assessed on an online platform, e.g., Microsoft Teams™, with a remote examiner. After the SOE, a focus group interview was conducted with surgical trainees and individual interviews with examiners.&#x0D; Results &#x0D; Themes were developed from the interview transcripts. These centred around the utility of videos in this examination format and technical issues during the SOE. Further themes highlighted the standardization of questions and preparation of examiners.&#x0D; Conclusion &#x0D; Overall, procedural videos as part of the mock SOE were experienced as valuable. Adding video recordings to the online platform posed administrative and technical challenges. However, the trainees and the examiners could log in from peripheral clinical training sites, which was experienced as an advantage. This study provides a glimpse into the application of procedural videos during SOEs as an assessment tool, from the perspective of surgical trainees and examiners. Efforts should focus on standardization of the examination format, optimizing technical issues, and improving examiner preparation.

Bone erosions associated with systemic bone loss on HR-pQCT in women with longstanding polyarticular juvenile idiopathic arthritis

ObjectivesTo analyze longstanding polyarticular juvenile idiopathic arthritis (pJIA) for possible associations between localized bone damage (erosions), and systemic bone loss. Besides, to compare the systemic bone mass of pJIA with healthy controls. MethodsThirty-four pJIA women and 99 healthy controls (HC) were included. Radius and tibia of all subjects were scanned by HR-pQCT. Volumetric bone mineral density (vBMD), bone microarchitecture, and -finite element parameters were analyzed. Patients underwent HR-pQCT of 2nd and 3rd metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of the dominant hand, for bone erosions quantification. ResultsThe mean age of patients was 31.5 ± 7.4yrs with a mean disease duration of 21.7 ± 9.2yrs. Bone erosions were detectable in 79% of patients. The number of bone erosions was positively correlated with cortical porosity (Ct.Po) at tibia (r = 0.575, p = 0.001), and radius (r = 0.423, p = 0.018); and negatively correlated with cortical vBMD at tibia (r=-0.420, p = 0.015). In a logistic regression analysis, adjusted for anti-CCP, the presence of bone erosions was independently associated with Ct.Po at radius (p = 0.018) and cortical vBMD at tibia (p = 0.020). Moreover, cortical and trabecular vBMD, trabecular number, and μ-finite element parameters were decreased in patients compared to HC (p < 0.05). ConclusionBone erosions in longstanding pJIA women were associated with decreased cortical bone parameters, and these patients showed systemic bone impairment at peripheral sites compared with healthy controls.

Targeted cell delivery of mesenchymal stem cell therapy for cardiovascular disease applications: a review of preclinical advancements.

Cardiovascular diseases (CVD) continue to be the leading cause of morbidity and mortality globally and claim the lives of over 17 million people annually. Current management of CVD includes risk factor modification and preventative strategies including dietary and lifestyle changes, smoking cessation, medical management of hypertension and cholesterol lipid levels, and even surgical revascularization procedures if needed. Although these strategies have shown therapeutic efficacy in reducing major adverse cardiovascular events such as heart attack, stroke, symptoms of chronic limb-threatening ischemia (CLTI), and major limb amputation significant compliance by patients and caregivers is required and off-target effects from systemic medications can still result in organ dysfunction. Stem cell therapy holds major potential for CVD applications but is limited by the low quantities of cells that are able to traffic to and engraft at diseased tissue sites. New preclinical investigations have been undertaken to modify mesenchymal stem cells (MSCs) to achieve targeted cell delivery after systemic administration. Although previous reviews have focused broadly on the modification of MSCs for numerous local or intracoronary administration strategies, here we review recent preclinical advances related to overcoming challenges imposed by the high velocity and dynamic flow of the circulatory system to specifically deliver MSCs to ischemic cardiac and peripheral tissue sites. Many of these technologies can also be applied for the targeted delivery of other types of therapeutic cells for treating various diseases.

Revealing protonation states and tracking substrate in serine hydroxymethyltransferase with room-temperature X-ray and neutron crystallography

Pyridoxal 5’-phosphate (PLP)-dependent enzymes utilize a vitamin B6-derived cofactor to perform a myriad of chemical transformations on amino acids and other small molecules. Some PLP-dependent enzymes, such as serine hydroxymethyltransferase (SHMT), are promising drug targets for the design of small-molecule antimicrobials and anticancer therapeutics, while others have been used to synthesize pharmaceutical building blocks. Understanding PLP-dependent catalysis and the reaction specificity is crucial to advance structure-assisted drug design and enzyme engineering. Here we report the direct determination of the protonation states in the active site of Thermus thermophilus SHMT (TthSHMT) in the internal aldimine state using room-temperature joint X-ray/neutron crystallography. Conserved active site architecture of the model enzyme TthSHMT and of human mitochondrial SHMT (hSHMT2) were compared by obtaining a room-temperature X-ray structure of hSHMT2, suggesting identical protonation states in the human enzyme. The amino acid substrate serine pathway through the TthSHMT active site cavity was tracked, revealing the peripheral and cationic binding sites that correspond to the pre-Michaelis and pseudo-Michaelis complexes, respectively. At the peripheral binding site, the substrate is bound in the zwitterionic form. By analyzing the observed protonation states, Glu53, but not His residues, is proposed as the general base catalyst, orchestrating the retro-aldol transformation of L-serine into glycine.

Peripheral cord insertion is associated with adverse pregnancy outcome only when accompanied by clinically significant placental pathology.

To examine the relationship between umbilical cord insertion site, placental pathology and adverse pregnancy outcome in a cohort of normal and complicated pregnancies. Sonographic measurement of the cord insertion and detailed placental pathology were performed in 309 participants. Associations between cord insertion site, placental pathology and adverse pregnancy outcome (pre-eclampsia, preterm birth, small-for-gestational age) were examined. A total of 93 (30%) participants were identified by pathological examination to have a peripheral cord insertion site. Only 41 of the 93 (44%) peripheral cords were detected by prenatal ultrasound. Peripherally inserted cords were associated significantly (P < 0.0001) with diagnostic placental pathology (most commonly with maternal vascular malperfusion (MVM)); of which 85% had an adverse pregnancy outcome. In cases of isolated peripheral cords, without placental pathology, the incidence of adverse outcome was not statistically different when compared to those with central cord insertion and no placental pathology (31% vs 18%; P = 0.3). A peripheral cord with an abnormal umbilical artery (UA) pulsatility index (PI) corresponded to an adverse outcome in 96% of cases compared to 29% when the UA-PI was normal. This study demonstrates that peripheral cord insertion is often part of the spectrum of findings of MVM disease and is associated with adverse pregnancy outcome. However, adverse outcome was uncommon when there was an isolated peripheral cord insertion and no placental pathology. Therefore, additional sonographic and biochemical features of MVM should be sought when a peripheral cord is observed. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.