128 research outputs found
The occurrence of dental caries is associated with atherosclerosis
OBJECTIVE: Previous studies have suggested that marginal periodontitis is a risk factor for developing atherosclerosis. The objective of this study was to determine whether caries may also be associated with atherosclerosis. METHODS: The computed tomography data sets of 292 consecutive patients, 137 women and 155 men with a mean age of 54.1±17.3 years, were analyzed. Caries were quantified based on the number of decayed surfaces of all the teeth, and periodontitis was quantified on the basis of the horizontal bone loss in the jaw. The presence of chronic apical periodontitis (CAP) was assessed, and the aortic atherosclerotic burden was quantified using a calcium scoring method. RESULTS: The patients wit
Building Bridges Between Community Based Organizations and Technology: Exploring Tools for Community Participation and Economic Development for the Dudley Street Neighborhood Initiative
Technology plays a vital role in public and private businesses, governments, and organizations, and can be especially useful to organizations that may know the least about it. Unfortunately, many Community Based Organizations (CBOs) have traditionally been unable to embrace contemporary tools due to lack of capacity, time or money. This paper begins to identify issues related to the technology gap faced by CBOs in a case study that examines community economic empowerment for the Dudley Street Neighborhood Initiative® (DSNI). The problem was approached through a community-university partnership between the Cornell University CRP 607 GIS Workshop Class (Sibley Consulting) and DSNI. One of the main technological tools used in bridging this gap was the use of geographic information systems (GIS). With an increase in GIS capability, DSNI can collect, manage, analyze and visualize neighborhood data, thus providing simple but powerful knowledge to the community. A geodatabase should be created where new and existing data can be stored, updated, and utilized repetitively. The geodatabase will allow DSNI to manipulate the data for a wide range of uses such as evaluating neighborhood trends for economic development. This classroom experiment provided students with an opportunity to provide professional technology services as a ‘mock’ consulting team. However, all of the data, maps and geospatial and other web-based technology evaluations will be utilized by DSNI and will have an immediate impact on the future of the Dudley neighborhood. This report is an educational tool for DSNI in order to evaluate the future database design and community GIS application. This report can also be seen as a model by which other community-university teams can measure their successful implementation to create a resident led community database information management system. A series of base maps which depict existing conditions along with secondary data resources have been used to evaluate the Dudley Neighborhood in Roxbury and North Dorchester, Massachusetts
Patient Centeredness in Electronic Communication: Evaluation of Patient-to-Health Care Team Secure Messaging
BACKGROUND: As information and communication technology is becoming more widely implemented across health care organizations, patient-provider email or asynchronous electronic secure messaging has the potential to support patient-centered communication. Within the medical home model of the Veterans Health Administration (VA), secure messaging is envisioned as a means to enhance access and strengthen the relationships between veterans and their health care team members. However, despite previous studies that have examined the content of electronic messages exchanged between patients and health care providers, less research has focused on the socioemotional aspects of the communication enacted through those messages.
OBJECTIVE: Recognizing the potential of secure messaging to facilitate the goals of patient-centered care, the objectives of this analysis were to not only understand why patients and health care team members exchange secure messages but also to examine the socioemotional tone engendered in these messages.
METHODS: We conducted a cross-sectional coding evaluation of a corpus of secure messages exchanged between patients and health care team members over 6 months at 8 VA facilities. We identified patients whose medical records showed secure messaging threads containing at least 2 messages and compiled a random sample of these threads. Drawing on previous literature regarding the analysis of asynchronous, patient-provider electronic communication, we developed a coding scheme comprising a series of a priori patient and health care team member codes. Three team members tested the scheme on a subset of the messages and then independently coded the sample of messaging threads.
RESULTS: Of the 711 messages coded from the 384 messaging threads, 52.5% (373/711) were sent by patients and 47.5% (338/711) by health care team members. Patient and health care team member messages included logistical content (82.6%, 308/373 vs 89.1%, 301/338), were neutral in tone (70.2%, 262/373 vs 82.0%, 277/338), and respectful in nature (25.7%, 96/373 vs 33.4%, 113/338). Secure messages from health care team members sometimes appeared hurried (25.4%, 86/338) but also displayed friendliness or warmth (18.9%, 64/338) and reassurance or encouragement (18.6%, 63/338). Most patient messages involved either providing or seeking information; however, the majority of health care team member messages involved information provision in response to patient questions.
CONCLUSIONS: This evaluation is an important step toward understanding the content and socioemotional tone that is part of the secure messaging exchanges between patients and health care team members. Our findings were encouraging; however, there are opportunities for improvement. As health care organizations seek to supplement traditional encounters with virtual care, they must reexamine their use of secure messaging, including the patient centeredness of the communication, and the potential for more proactive use by health care team members
Molecular matched targeted therapies for primary brain tumors—a single center retrospective analysis
PURPOSE: Molecular diagnostics including next generation gene sequencing are increasingly used to determine options for individualized therapies in brain tumor patients. We aimed to evaluate the decision-making process of molecular targeted therapies and analyze data on tolerability as well as signals for efficacy. METHODS: Via retrospective analysis, we identified primary brain tumor patients who were treated off-label with a targeted therapy at the University Hospital Frankfurt, Goethe University. We analyzed which types of molecular alterations were utilized to guide molecular off-label therapies and the diagnostic procedures for their assessment during the period from 2008 to 2021. Data on tolerability and outcomes were collected. RESULTS: 413 off-label therapies were identified with an increasing annual number for the interval after 2016. 37 interventions (9%) were targeted therapies based on molecular markers. Glioma and meningioma were the most frequent entities treated with molecular matched targeted therapies. Rare entities comprised e.g. medulloblastoma and papillary craniopharyngeoma. Molecular targeted approaches included checkpoint inhibitors, inhibitors of mTOR, FGFR, ALK, MET, ROS1, PIK3CA, CDK4/6, BRAF/MEK and PARP. Responses in the first follow-up MRI were partial response (13.5%), stable disease (29.7%) and progressive disease (46.0%). There were no new safety signals. Adverse events with fatal outcome (CTCAE grade 5) were not observed. Only, two patients discontinued treatment due to side effects. Median progression-free and overall survival were 9.1/18 months in patients with at least stable disease, and 1.8/3.6 months in those with progressive disease at the first follow-up MRI. CONCLUSION: A broad range of actionable alterations was targeted with available molecular therapeutics. However, efficacy was largely observed in entities with paradigmatic oncogenic drivers, in particular with BRAF mutations. Further research on biomarker-informed molecular matched therapies is urgently necessary. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11060-022-04049-w
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The elongation factor Spn1 is a multi-functional chromatin binding protein.
The process of transcriptional elongation by RNA polymerase II (RNAPII) in a chromatin context involves a large number of crucial factors. Spn1 is a highly conserved protein encoded by an essential gene and is known to interact with RNAPII and the histone chaperone Spt6. Spn1 negatively regulates the ability of Spt6 to interact with nucleosomes, but the chromatin binding properties of Spn1 are largely unknown. Here, we demonstrate that full length Spn1 (amino acids 1-410) binds DNA, histones H3-H4, mononucleosomes and nucleosomal arrays, and has weak nucleosome assembly activity. The core domain of Spn1 (amino acids 141-305), which is necessary and sufficient in Saccharomyces cerevisiae for growth under ideal growth conditions, is unable to optimally interact with histones, nucleosomes and/or DNA and fails to assemble nucleosomes in vitro. Although competent for binding with Spt6 and RNAPII, the core domain derivative is not stably recruited to the CYC1 promoter, indicating chromatin interactions are an important aspect of normal Spn1 functions in vivo. Moreover, strong synthetic genetic interactions are observed with Spn1 mutants and deletions of histone chaperone genes. Taken together, these results indicate that Spn1 is a histone binding factor with histone chaperone functions
Genetic Identification of a Network of Factors that Functionally Interact with the Nucleosome Remodeling ATPase ISWI
Nucleosome remodeling and covalent modifications of histones play fundamental roles in chromatin structure and function. However, much remains to be learned about how the action of ATP-dependent chromatin remodeling factors and histone-modifying enzymes is coordinated to modulate chromatin organization and transcription. The evolutionarily conserved ATP-dependent chromatin-remodeling factor ISWI plays essential roles in chromosome organization, DNA replication, and transcription regulation. To gain insight into regulation and mechanism of action of ISWI, we conducted an unbiased genetic screen to identify factors with which it interacts in vivo. We found that ISWI interacts with a network of factors that escaped detection in previous biochemical analyses, including the Sin3A gene. The Sin3A protein and the histone deacetylase Rpd3 are part of a conserved histone deacetylase complex involved in transcriptional repression. ISWI and the Sin3A/Rpd3 complex co-localize at specific chromosome domains. Loss of ISWI activity causes a reduction in the binding of the Sin3A/Rpd3 complex to chromatin. Biochemical analysis showed that the ISWI physically interacts with the histone deacetylase activity of the Sin3A/Rpd3 complex. Consistent with these findings, the acetylation of histone H4 is altered when ISWI activity is perturbed in vivo. These findings suggest that ISWI associates with the Sin3A/Rpd3 complex to support its function in vivo
Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic non-inferiority randomised controlled trial
Background: Bullous pemphigoid (BP) is a blistering skin disorder with increased mortality. We tested whether a strategy of starting treatment with doxycycline conveys acceptable short-term blister control whilst conferring long-term safety advantages over starting treatment with oral corticosteroids.
Methods: Pragmatic multi-centre parallel-group randomised controlled trial of adults with BP (≥3 blisters ≥2 sites and linear basement membrane IgG/C3) plus economic evaluation. Participants were randomised to doxycycline (200 mg/day) or prednisolone (0·5 mg/kg/day). Localised adjuvant potent topical corticosteroids (<30 g/week) was permitted weeks 1-3. The non-inferiority primary effectiveness outcome was the proportion of participants with ≤3 blisters at 6 weeks. We assumed that doxycycline would be 25% less effective than corticosteroids with a 37% acceptable margin of noninferiority. The primary safety outcome was the proportion with severe, life-threatening or fatal treatment-related adverse events by 52 weeks. Analysis used a regression model adjusting for baseline disease severity, age and Karnofsky score, with missing data imputed.
Results: 132 patients were randomised to doxycycline and 121 to prednisolone from 54 UK and 7 German dermatology centres. Mean age was 77·7 years and 68.4% had moderate to severe baseline disease. For those starting doxycycline, 83/112 (74·1%) had ≤3 blisters at 6 weeks compared with 92/101 (91·1%) for prednisolone, a difference of 18·6% favouring prednisolone (upper limit of 90% CI, 26·1%, within the predefined 37% margin). Related severe, life-threatening and fatal events at 52 weeks were 18·5% for those starting doxycycline and 36·6% for prednisolone (mITT analysis), an adjusted difference of 19·0% (95% CI, 7·9%, 30·1%, p=0·001).
Conclusions: A strategy of starting BP patients on doxycycline is non-inferior to standard treatment with oral prednisolone for short-term blister control and significantly safer long-term
A multilaboratory comparison of calibration accuracy and the performance of external references in analytical ultracentrifugation.
Analytical ultracentrifugation (AUC) is a first principles based method to determine absolute sedimentation coefficients and buoyant molar masses of macromolecules and their complexes, reporting on their size and shape in free solution. The purpose of this multi-laboratory study was to establish the precision and accuracy of basic data dimensions in AUC and validate previously proposed calibration techniques. Three kits of AUC cell assemblies containing radial and temperature calibration tools and a bovine serum albumin (BSA) reference sample were shared among 67 laboratories, generating 129 comprehensive data sets. These allowed for an assessment of many parameters of instrument performance, including accuracy of the reported scan time after the start of centrifugation, the accuracy of the temperature calibration, and the accuracy of the radial magnification. The range of sedimentation coefficients obtained for BSA monomer in different instruments and using different optical systems was from 3.655 S to 4.949 S, with a mean and standard deviation of (4.304 ± 0.188) S (4.4%). After the combined application of correction factors derived from the external calibration references for elapsed time, scan velocity, temperature, and radial magnification, the range of s-values was reduced 7-fold with a mean of 4.325 S and a 6-fold reduced standard deviation of ± 0.030 S (0.7%). In addition, the large data set provided an opportunity to determine the instrument-to-instrument variation of the absolute radial positions reported in the scan files, the precision of photometric or refractometric signal magnitudes, and the precision of the calculated apparent molar mass of BSA monomer and the fraction of BSA dimers. These results highlight the necessity and effectiveness of independent calibration of basic AUC data dimensions for reliable quantitative studies
Acute mountain sickness.
Acute mountain sickness (AMS) is a clinical syndrome occurring in otherwise healthy normal individuals who ascend rapidly to high altitude. Symptoms develop over a period ofa few hours or days. The usual symptoms include headache, anorexia, nausea, vomiting, lethargy, unsteadiness of gait, undue dyspnoea on moderate exertion and interrupted sleep. AMS is unrelated to physical fitness, sex or age except that young children over two years of age are unduly susceptible. One of the striking features ofAMS is the wide variation in individual susceptibility which is to some extent consistent. Some subjects never experience symptoms at any altitude while others have repeated attacks on ascending to quite modest altitudes. Rapid ascent to altitudes of 2500 to 3000m will produce symptoms in some subjects while after ascent over 23 days to 5000m most subjects will be affected, some to a marked degree. In general, the more rapid the ascent, the higher the altitude reached and the greater the physical exertion involved, the more severe AMS will be. Ifthe subjects stay at the altitude reached there is a tendency for acclimatization to occur and symptoms to remit over 1-7 days
Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis
BACKGROUND Two phase 3 trials (UNCOVER-2 and UNCOVER-3) showed that at 12 weeks of treatment, ixekizumab, a monoclonal antibody against interleukin-17A, was superior to placebo and etanercept in the treatment of moderate-to-severe psoriasis. We report the 60-week data from the UNCOVER-2 and UNCOVER-3 trials, as well as 12-week and 60-week data from a third phase 3 trial, UNCOVER-1. METHODS We randomly assigned 1296 patients in the UNCOVER-1 trial, 1224 patients in the UNCOVER-2 trial, and 1346 patients in the UNCOVER-3 trial to receive subcutaneous injections of placebo (placebo group), 80 mg of ixekizumab every 2 weeks after a starting dose of 160 mg (2-wk dosing group), or 80 mg of ixekizumab every 4 weeks after a starting dose of 160 mg (4-wk dosing group). Additional cohorts in the UNCOVER-2 and UNCOVER-3 trials were randomly assigned to receive 50 mg of etanercept twice weekly. At week 12 in the UNCOVER-3 trial, the patients entered a long-term extension period during which they received 80 mg of ixekizumab every 4 weeks through week 60; at week 12 in the UNCOVER-1 and UNCOVER-2 trials, the patients who had a response to ixekizumab (defined as a static Physicians Global Assessment [sPGA] score of 0 [clear] or 1 [minimal psoriasis]) were randomly reassigned to receive placebo, 80 mg of ixekizumab every 4 weeks, or 80 mg of ixekizumab every 12 weeks through week 60. Coprimary end points were the percentage of patients who had a score on the sPGA of 0 or 1 and a 75% or greater reduction from baseline in Psoriasis Area and Severity Index (PASI 75) at week 12. RESULTS In the UNCOVER-1 trial, at week 12, the patients had better responses to ixekizumab than to placebo; in the 2-wk dosing group, 81.8% had an sPGA score of 0 or 1 and 89.1% had a PASI 75 response; in the 4-wk dosing group, the respective rates were 76.4% and 82.6%; and in the placebo group, the rates were 3.2% and 3.9% (P<0.001 for all comparisons of ixekizumab with placebo). In the UNCOVER-1 and UNCOVER-2 trials, among the patients who were randomly reassigned at week 12 to receive 80 mg of ixekizumab every 4 weeks, 80 mg of ixekizumab every 12 weeks, or placebo, an sPGA score of 0 or 1 was maintained by 73.8%, 39.0%, and 7.0% of the patients, respectively. Patients in the UNCOVER-3 trial received continuous treatment of ixekizumab from weeks 0 through 60, and at week 60, at least 73% had an sPGA score of 0 or 1 and at least 80% had a PASI 75 response. Adverse events reported during ixekizumab use included neutropenia, candidal infections, and inflammatory bowel disease. CONCLUSIONS In three phase 3 trials involving patients with psoriasis, ixekizumab was effective through 60 weeks of treatment. As with any treatment, the benefits need to be weighed against the risks of adverse events. The efficacy and safety of ixekizumab beyond 60 weeks of treatment are not yet known
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