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Background HHT is an autosomal dominant disease with an estimated prevalence of at least 1/5000 which can frequently be complicated by the presence of clinically significant arteriovenous malformations in the brain, lung, gastrointestinal tract and liver. HHT is under-diagnosed and families may be unaware of the available screening and treatment, leading to unnecessary stroke and life-threatening hemorrhage in children and adults. Objective The goal of this international HHT guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT and the prevention of HHT-related complications and treatment of symptomatic disease. Methods The overall guidelines process was developed using the AGREE framework, using a systematic search strategy and literature retrieval with incorporation of expert evidence in a structured consensus process where published literature was lacking. The Guidelines Working Group included experts (clinical and genetic) from eleven countries, in all aspects of HHT, guidelines methodologists, health care workers, health care administrators, HHT clinic staff, medical trainees, patient advocacy representatives and patients with HHT. The Working Group determined clinically relevant questions during the pre-conference process. The literature search was conducted using the OVID MEDLINE database, from 1966 to October 2006. The Working Group subsequently convened at the Guidelines Conference to partake in a structured consensus process using the evidence tables generated from the systematic searches. Results The outcome of the conference was the generation of 33 recommendations for the diagnosis and management of HHT, with at least 80% agreement amongst the expert panel for 30 of the 33 recommendations.

Renal parenchymal cells produce cytokines, colony-stimulating factor-1 (CSF-1), granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNF-alpha), which recruit autoreactive T cells and, in turn, elicit renal injury in MRL-Fas(lpr) mice. To determine whether select T-cell populations regulate intrarenal nephritogenic cytokines (CSF-1, GM-CSF, and TNF-alpha) and renal disease, we compared MRL-Fas(lpr) mice that are genetically deficient in T-cell receptor (TCR) alpha beta T cells, CD4 T cells, and major histocompatibility complex class I (MHC class I), lacking CD8 and double negative (DN) T cells, with wild-type mice. To identify the T cells instrumental in downstream (effector) events, we delivered CSF-1 or GM-CSF into the kidney via gene transfer in these select T-cell-deficient and wild-type strains. Intrarenal CSF-1, GM-CSF, and TNF-alpha were absent or dramatically reduced in TCR alpha beta, CD4, and class I-deficient MRL-Fas(lpr) strains as compared with wild-type mice. In addition, the decrease in CSF-1, GM-CSF, and TNF-alpha was associated with a reduced kidney leukocytic infiltrates and spontaneous autoimmune nephritis. Intrarenal ex vivo retroviral gene transfer of CSF-1 and GM-CSF failed to elicit nephritis in these T-cell-deficient MRL strains (TCR alpha beta, CD4, CD8/DN) as compared with wild-type mice. Multiple T-cell populations initiate renal disease by increasing intrarenal nephritogenic cytokines, CSF-1, GM-CSF, and TNF-alpha. CSF-1 and GM-CSF recruit additional CD4 and CD8 and DN T cells, which augment downstream events, resulting in progressive autoimmune renal disease. We suggest that MRL-Fas(lpr) kidney disease is driven by a T-cell amplification feedback loop dependent on multiple T-cell populations.

Microvascular injury, inflammation, and coagulation play critical roles in the pathogenesis of acute lung injury (ALI). Plasma protein C levels are decreased in patients with acute lung injury and are associated with higher mortality and fewer ventilator-free days. To test the efficacy of activated protein C (APC) as a therapy for patients with ALI. Eligible subjects were critically ill patients who met the American/European consensus criteria for ALI. Patients with severe sepsis and an APACHE II score of 25 or more were excluded. Participants were randomized to receive APC (24 microg/kg/h for 96 h) or placebo in a double-blind fashion within 72 hours of the onset of ALI. The primary endpoint was ventilator-free days. APC increased plasma protein C levels (P = 0.002) and decreased pulmonary dead space fraction (P = 0.02). However, there was no statistically significant difference between patients receiving placebo (n = 38) or APC (n = 37) in the number of ventilator-free days (median [25-75% interquartile range]: 19 [0-24] vs. 19 [14-22], respectively; P = 0.78) or in 60-day mortality (5/38 vs. 5/37 patients, respectively; P = 1.0). There were no differences in the number of bleeding events between the two groups. APC did not improve outcomes from ALI. The results of this trial do not support a large clinical trial of APC for ALI in the absence of severe sepsis and high disease severity.

To measure the in vivorate of alveolar epithelial fluid clearance of the human lung inpatients with pulmonary alveolar phospholipoproteinosis (PAP). Prospective clinical study. The medical-surgical ICUs of a university teachinghospital. Four patients with idiopathic PAPrequiring therapeutic lung lavage. Large-volume lung lavage with isotonic saline solution using fiberopticbronchoscopy followed by serial sampling of alveolar fluid using awedged bronchial catheter. The rate of alveolar epithelial fluid clearance was calculated bymeasuring the concentration of protein in sequential samples. Alveolarepithelial fluid clearance over the first hour after lung lavage was53 ± 14% (mean ± SD). Sequential samples in two patientsindicated a sustained high rate of clearance over several hours. Plasmaand alveolar fluid epinephrine levels were in the normal range in twopatients. Alveolar fluidclearance is rapid after lung lavage in patients with PAP and appearsto be driven by catecholamine-independent mechanisms. The rapid rate ofalveolar epithelial fluid transport explains why patients with PAPtolerate large-volume lung lavage.

Degree of deacetylation (DDA) and molecular weight (MW) of chitosans are important to their physical and biological properties. In this study, two chitosans, HS (DDA = 73.3%) and AT (DDA = 76.8%), were deacetylated with 45% sodium hydroxide under nitrogen atmosphere at 80 °C or 90 °C for up to 120 min, to obtain two series of chitosans. The polymers produced were characterized for MW by gel permeation chromatography, DDA by titration and UV-vis methods, and crystallinity, hydrophilicity and thermal stability by X-ray diffraction, water contact angle and differential scanning calorimetry respectively. Films, made by solution casting in dilute acetic acid at ambient conditions, were evaluated for biological activity by albumin adsorption and the attachment and growth of a pre-osteoblast cell line. Chitosans with between 80–93% DDA’s (based on titration) were reproducibly obtained. Even though deacetylation under nitrogen was supposed to limit chain degradation during decetylation, MW decreased (by maximum of 37.4% of HS and 63.0% for AT) with increasing deacetylation reaction time and temperature. Crystallinity and decomposition temperature increased and water contact angles decreased with processing to increase DDA. Significantly less albumin was absorbed on films made with 93% DDA chitosans as compared with the original materials and the AT chitosans absorbed less than the HS chitosans. The cells on higher DDA chitosan films grew faster than those on lower DDA films. In conclusion, processing conditions increased DDA and influenced physicochemical and biological properties. However, additional studies are needed to unambiguously determine the influence of DDA or MW on in vitro and in vivo performance of chitosan materials for bone/implant applications.

There is a significant clinical need to develop alternatives to autografts and allografts for bone grafting procedures. Porous, biodegradable scaffolds based on the biopolymer chitosan have been investigated as bone graft substitutes, and the addition of calcium phosphate to these scaffolds has been shown to improve the mechanical properties of the scaffold and may increase osteoconductivity. In this study, in vitro mineralization was examined for osteoblasts seeded in a porous scaffold composed of fused chitosan/nano-hydroxyapatite microspheres. Human fetal osteoblasts were cultured on composite and chitosan scaffolds for 21 days. On days 1, 4, 7, 14, and 21, total dsDNA, alkaline phosphatase, type I collagen, and osteocalcin production were measured. Total cellularity (measured by dsDNA), alkaline phosphatase, and type I collagen production were similar between the two scaffold groups. However, osteocalcin production occurred significantly earlier (day 7 vs. day 21) and was more than three times greater (0.0022 vs. 0.0068 ng/mL/ng DNA) on day 21 when osteoblasts were cultured on composite scaffolds. Osteocalcin is a marker of late osteoblastic differentiation and mineralized bone matrix formation. Therefore, the increase in osteocalcin production seen when cells were cultured on composite scaffolds may indicate that these scaffolds were superior to chitosan-only scaffolds in facilitating osteoblast mineralization. Composite scaffolds were also shown to be biocompatible and osteoconductive in a preliminary critical size rat calvarial defect study. These results demonstrate the potential of composite chitosan/nano-hydroxyapatite scaffolds to be used in bone tissue engineering.

Virtual presence describes a users’ perception of a virtual reality (VR) environment (VRE), specifically, of their involvement (sense of control within a virtual environment with minimal distractions) and immersion (multi-input sensory engagement providing apparent realism of objects and interactions). In education, virtual presence is a significant construct as highly immersive VREs have been linked to users reporting memorable and exciting teaching experiences. Prior research has described that adults and children report different levels of presence when subjected to identical VREs, suggesting cognition may play some role in users’ perceptions of presence. According to Piaget, concrete operational development is a watershed moment when adolescents develop the ability to understand abstract concepts and make assessments what is and is not reality. This period in cognitive development may influence children’s and adolescents’ perceptions of presence. This is an exploratory study of seventy-five 6th-grade and seventy-six 9th-grade students who participated in an instructional module about cardiac anatomy and physiology using a 3-D, haptic-enabled, VR technology. When surveyed on their perceptions of virtual presence, there were no reported differences between grade levels. When assessed using a Piagetian inventory of cognitive development, the analyses indicated that the sixth-grade students’ understanding of spatial rotation and angular geometry was positively correlated with the reported perceived control and negatively correlated with distraction. This study suggests that the spatial acuity of younger learners plays an important role when using VR technologies for science learning. This research raises questions about the relevance of users’ cognitive development when using emergent VR technologies in the K–12 science classroom.

Contrary to many water customers’ beliefs, implementing efficient water rates, efficient plumbing, and conservation initiatives actually reduces the cost burden on water customers.

Rehabilitation of persistent imbalance in people with mild traumatic brain injury (mTBI) is challenging, and responsiveness to rehabilitation is often suboptimal. One reason for suboptimal outcomes may be patient heterogeneity within rehabilitation referrals. Specifically, people with greater vestibular and/or ocular-motor (V/O) symptoms may respond better to vestibular rehabilitation therapy (VRT) compared to those with greater mood or cognition symptoms. Poor performance of exercises may also explain suboptimal outcomes. This study aims to 1) assess if a wearable sensor-based multidimensional biofeedback system could enhance rehabilitation, 2) examine responsiveness to rehabilitation depending on the severity of V/O deficits, 3) characterize the impact of V/O deficits on gait and turning during seven days of unsupervised daily living and establish normative mobility data from active-duty service members. This study is a single-blinded randomized controlled trial involving 100 individuals experiencing persistent symptoms from subacute and chronic mTBI. Participants will be randomized into VRT with or without sensor-based biofeedback. Both groups will receive a 6-week VRT. All participants will be tested for balance, gait, turning, and V/O performance before and after VRT. We will compare the efficacy of VRT with or without biofeedback, stratified by the severity of V/O symptoms. Additionally, a subset of 50 participants with mTBI and 40 healthy active-duty service members will wear inertial sensors for seven days to quantify daily mobility. We will use the data to examine if the severity of V/O deficits following mTBI impacts daily mobility and to establish normative data for daily living mobility from military service members. This study will be the first clinical trial to investigate whether wearable technology can improve rehabilitation outcomes for those with V/O symptoms by providing real-time biofeedback during rehabilitation. This work will also help to identify individuals with sensorimotor deficits associated with V/O subtypes. These results will enhance the assessment and rehabilitative care following mTBI by integrating objective measures to identify and address V/O subtypes. Furthermore, establishing normative data for daily living mobility from service members will aid in return-to-duty decision making following mTBI. This protocol is registered on ClinicalTrials.gov under the number NCT06381674. Registered on April 04, 2024. Recruited period from June 2024 to September 2028. https://clinicaltrials.gov/study/NCT06381674. Trial Protocol v1 (Dated November 14, 2023).

This systematic review focused on the question, if and to what extent enamel matrix derivative (Emdogain ® [EMD]) promotes the regeneration of bone. The influence of combinations with other biomaterials was additionally evaluated. Twenty histomorphometric studies were included in this systematic review. Main results of the reviewed articles were (i) guide tissue regeneration (GTR) of infrabony defects seems to result in a higher degree of bone regeneration compared to treatment with EMD; (ii) combined therapy (GTR + EMD) of infrabony defects might not lead to better results than GTR therapy alone; (iii) there seems to be no additional benefit of combined therapy (GTR + EMD) in furcation defects over GTR therapy alone; (iv) EMD seems to lead to more bone regeneration of infrabony defects compared to open flap debridement; (v) however, EMD application might result in more bone formation when applied in supporting defects compared to nonsupporting defects; and (vi) EMD does not seem to promote external jaw/parietal bone formation in the titanium capsule model. The results of one study that suggest that EMD increases the initial growth of trabecular bone around endosseous implants by new bone induction need to be confirmed by additional research.