Static Black Binaries in de Sitter Space.

We construct the first four-dimensional multiple black hole solution of general relativity with a positive cosmological constant. The solution consists of two static black holes whose gravitational attraction is balanced by the cosmic expansion. These static binaries provide the first four-dimensional example of nonuniqueness in general relativity without matter.

The impact of the SARS-CoV-2 pandemic on the management of chronic limb-threatening ischemia and wound care.

In the wake of the coronavirus pandemic, the critical limb ischemia (CLI) Global Society aims to develop improved clinical guidance that will inform better care standards to reduce tissue loss and amputations during and following the new SARS-CoV-2 era. This will include developing standards of practice, improve gaps in care, and design improved research protocols to study new chronic limb-threatening ischemia treatment and diagnostic options. Following a round table discussion that identified hypotheses and suppositions the wound care community had during the SARS-CoV-2 pandemic, the CLI Global Society undertook a critical review of literature using PubMed to confirm or rebut these hypotheses, identify knowledge gaps, and analyse the findings in terms of what in wound care has changed due to the pandemic and what wound care providers need to do differently as a result of these changes. Evidence was graded using the Oxford Centre for Evidence-Based Medicine scheme. The majority of hypotheses and related suppositions were confirmed, but there is noticeable heterogeneity, so the experiences reported herein are not universal for wound care providers and centres. Moreover, the effects of the dynamic pandemic vary over time in geographic areas. Wound care will unlikely return to prepandemic practices. Importantly, Levels 2-5 evidence reveals a paradigm shift in wound care towards a hybrid telemedicine and home healthcare model to keep patients at home to minimize the number of in-person visits at clinics and hospitalizations, with the exception of severe cases such as chronic limb-threatening ischemia. The use of telemedicine and home care will likely continue and improve in the postpandemic era.

Chronic wounds: Treatment consensus.

The Wound Healing Foundation (WHF) recognised a need for an unbiased consensus on the best treatment of chronic wounds. A panel of 13 experts were invited to a virtual meeting which took place on 27 March 2021. The proceedings were organised in the sub-sections diagnosis, debridement, infection control, dressings, grafting, pain management, oxygen treatment, outcomes and future needs. Eighty percent or better concurrence among the panellists was considered a consensus. A large number of critical questions were discussed and agreed upon. Important takeaways included that wound care needs to be simplified to a point that it can be delivered by the patient or the patient's family. Another one was that telemonitoring, which has proved very useful during the COVID-19 pandemic, can help reduce the frequency of interventions by a visiting nurse or a wound care center. Defining patient expectations is critical to designing a successful treatment. Patient outcomes might include wound specific outcomes such as time to heal, wound size reduction, as well as improvement in quality of life. For those patients with expectations of healing, an aggressive approach to achieve that goal is recommended. When healing is not an expectation, such as in patients receiving palliative wound care, outcomes might include pain reduction, exudate management, odour management and/or other quality of life benefits to wound care.

Neighborhood social cohesion is associated with lower levels of interleukin-6 in African American women.

INTRODUCTION: Social cohesion is a positive neighborhood characteristic defined by feelings of connectedness and solidarity within a community. Studies have found significant associations between social cohesion and cardiovascular disease (CVD) risk factors and outcomes. Inflammation is one potential physiological pathway linking social cohesion to CVD development, but few studies have evaluated the relationship between social cohesion and inflammatory biomarkers. Prior research has also established that race and gender can modify the effects of neighborhood features, including social cohesion, on CVD risk factors and outcomes. This study aimed to examine the association between social cohesion and the inflammatory biomarkers interleukin-6 (IL-6) and C-reactive protein (CRP) in a cohort of African American and White women and men. MATERIALS AND METHODS: Data from the Morehouse and Emory Team Up to Eliminate Health Disparities (META-Health) Study were used to assess the association between social cohesion and inflammation among African American (n = 203) and White (n = 176) adults from the Atlanta metropolitan area. Social cohesion was measured using the social cohesion subscale from the Neighborhood Health Questionnaire. Inflammatory biomarkers were measured from plasma frozen at -70 °C. Multivariable linear regression analyses were conducted, controlling for demographic, clinical, behavioral, and psychosocial factors sequentially. Interaction by race and gender was also examined. RESULTS: In models adjusted for age, race, gender, and education, social cohesion was significantly associated with lower levels of IL-6 (ß = -0.06, p = 0.03). There was a significant race × social cohesion interaction (p = 0.04), and a marginally significant gender × race × social cohesion interaction (p = 0.09). In race-stratified models controlling for age, gender, and education, social cohesion was associated with lower IL-6 levels in African Americans (ß = -0.11, p = 0.01), but not Whites (ß = 0.01, p = 0.91). In fully adjusted race- and gender-stratified models, social cohesion was associated with lower levels of IL-6 in African American women only (ß = -0.15, p = 0.003). CRP was not associated with social cohesion in fully adjusted models. CONCLUSION: The association between social cohesion and lower levels of IL-6 is modified by gender and race, with the strongest association emerging for African American women. Although the pathways through which social cohesion impacts inflammation remain unclear, it is possible that for African American women social cohesion manifests through neighborhood networks.

Generating evidence to inform an update of asthma clinical practice guidelines: Perspectives from the National Heart, Lung, and Blood Institute.

Asthma is the most prevalent chronic respiratory disease worldwide. Its increasing prevalence and evidence of suboptimal control require renewed efforts in the development and widespread implementation of clinical practice guidelines for prevention, treatment, and control. Given the rapidly changing landscape and evolving best practices for guideline development, the National Heart, Lung, and Blood Institute made a commitment to support rigorous systematic evidence reviews that frontline health care providers and stakeholders could use to create new or update existing guidelines. This article describes the protocols, key questions, methodology, and analytic framework to support the update of the 2007 National Asthma Education and Prevention Program Expert Panel Report 3 (EPR-3) on the diagnosis and management of asthma in adults and children. It also describes the expert panel's practical experience in managing asthmatic patients across the age and severity spectrum. The article explains the process for ensuring that the expert panel's deliberations are conducted in accordance with the Institute of Medicine's standards and recommendations for guideline development. The outcome of this ambitious effort will be an update of the EPR-3 asthma guidelines and publication of the key recommendations in the Journal of Allergy and Clinical Immunology. Importantly, several novel approaches will be explored and incorporated as appropriate to accelerate adoption and sustained implementation of the guidelines.

Does noncontact low-frequency ultrasound therapy contribute to wound healing at the molecular level?

Noncontact low-frequency ultrasound (NLFU) is used to treat various types of chronic wounds including venous, diabetic, and pressure ulcers. The objective for this substudy of the IN BALANCE RCT VLU trial was to characterize and compare the NLFU treatment group and patients receiving standard of care (SOC) with respect to the effect of the assigned study treatment on content/quantity of inflammatory cytokines and fibrinogen as well as bacteria. Higher mean wound area reduction was observed in the NLFU treatment group (67.0%) compared to the SOC group (41.6%, p < 0.05). Hypertension, diabetes type II, coronary artery disease, and anemia were identified as the most common comorbidities of the Chronic venous leg ulcer (CVLU) patients included in the study. Pseudomonas, Corynebacterium, and unclassified Enterobacteriaceae were dominant in the highest number of samples. Anaerococcus, Peptoniphilus, and Finegoldia, had the highest median proportion in the samples overall. Peptoniphilus abundance decreased more in the NLFU treatment group relative to SOC; similar trends were observed for Anaerococcus and Finegoldia. Progression of mediators like TNF-alpha, IL-1beta, IL-6, IL-8, and IL-10 as well as PF4, TGF-beta, and fibrinogen was monitored and trends for several of the mediators were identified. Fibrinogen amounts were significantly reduced over time in the NLFU treatment group (p < 0.05). IL-8 levels declined in wound fluid from NLFU responders as well as SOC responders. Bacterial load (total bacterial abundance) determined local parameters of ulcer inflammation. If a bioburden of ≥ 10E5 was found compared to < 10E5 , levels of IL-1beta, IL-8, and TNF-alpha were significantly higher. In conclusion, NLFU treatment is an effective adjuvant tool for CVLU therapy. This study demonstrates that it improves wound healing by equally inhibiting abundant levels of pro-inflammatory cytokines as well as by reducing the overall bacterial burden.

Identification and content validation of wound therapy clinical endpoints relevant to clinical practice and patient values for FDA approval. Part 1. Survey of the wound care community.

Wounds that exhibit delayed healing add extraordinary clinical, economic, and personal burdens to patients, as well as to increasing financial costs to health systems. New interventions designed to ease such burdens for patients with cancer, renal, or ophthalmologic conditions are often cleared for approval by the U.S. Food and Drug Administration (FDA) using multiple endpoints but the requirement of complete healing as a primary endpoint for wound products impedes FDA clearance of interventions that can provide other clinical or patient-centered benefits for persons with wounds. A multidisciplinary group of wound experts undertook an initiative, in collaboration with the FDA, to identify and content validate supporting FDA criteria for qualifying wound endpoints relevant to clinical practice (CP) and patient-centered outcomes (PCO) as primary outcomes in clinical trials. As part of the initiative, a research study was conducted involving 628 multidisciplinary expert wound clinicians and researchers from 4 different groups: the interdisciplinary core advisory team; attendees of the Spring 2015 Symposium on Advanced Wound Care (SAWC); clinicians employed by a national network of specialty clinics focused on comprehensive wound care; and Association for the Advancement of Wound Care (AAWC) and Wound Healing Society (WHS) members who had not previously completed the survey. The online survey assessed 28 literature-based wound care endpoints for their relevance and importance to clinical practice and clinical research. Fifteen of the endpoints were evaluated for their relevance to improving quality of life. Twenty-two endpoints had content validity indexes (CVI) ≥ 0.75, and 15 were selected as meriting potential inclusion as additional endpoints for FDA approval of future wound care interventions. This study represents an important first step in identifying and validating new measurable wound care endpoints for clinical research and practice and for regulatory evaluation.

Obstructive sleep apnea risk and leukocyte telomere length in African Americans from the MH-GRID study.

PURPOSE: Shorter telomere length and obstructive sleep apnea are associated with increased oxidative stress and chronic inflammation, which are both considered leading causes of age-related diseases. Different forms of sleep disordered breathing have been linked to telomere length although their relationship remains uncertain. The purpose of this study was to explore the associations between the risk of obstructive sleep apnea and telomere length in African Americans. METHODS: The analysis included 184 women and 122 men aged 30-55 years from the Morehouse School of Medicine Study. Relative TL (T/S ratio) was measured from peripheral blood leukocytes using quantitative real-time polymerase chain reaction. The Berlin questionnaire was used for OSA risk assessments. Multivariable linear regression models were used to examine the associations between OSA risk and LTL. RESULTS: We observed that LTL varied by OSA risk in women (0.532 ± 0.006 vs. 0.569 ± 0.008) (p = 0.04). Multiple linear regression analysis confirmed that women at higher risk for OSA presented shorter LTL compared to those at lower risk, independent of age, income, education, obesity, smoking, alcohol consumption, and hypertension. These differences were not observed in men. CONCLUSIONS: Our findings suggest that OSA risk may contribute to the acceleration of cellular aging processes through telomere shortening.

A prospective, multicentre, open-label, single-arm clinical trial for treatment of chronic complex diabetic foot wounds with exposed tendon and/or bone: positive clinical outcomes of viable cryopreserved human placental membrane.

Complex diabetic foot ulcers (DFUs) with exposed tendon or bone remain a challenge. They are more susceptible to complications such as infection and amputation and require treatments that promote rapid development of granulation tissue and, ultimately, reepithelialisation. The clinical effectiveness of viable cryopreserved human placental membrane (vCHPM) for DFUs has been established in a level 1 trial. However, complex wounds with exposed deeper structures are typically excluded from randomised controlled clinical trials despite being common in clinical practice. We report the results of a prospective, multicentre, open-label, single-arm clinical trial to establish clinical outcomes when vCHPM is applied weekly to complex DFUs with exposed deep structures. Patients with type 1 or type 2 diabetes and a complex DFU extending through the dermis with evidence of exposed muscle, tendon, fascia, bone and/or joint capsule were eligible for inclusion. Of the 31 patients enrolled, 27 completed the study. The mean wound area was 14·6 cm2 , and mean duration was 7·5 months. For patients completing the protocol, the primary endpoint, 100% wound granulation by week 16, was met by 96·3% of patients in a mean of 6·8 weeks. Complete wound closure occurred in 59·3% (mean 9·1 weeks). The 4-week percent area reduction was 54·3%. There were no product-related adverse events. Four patients (13%) withdrew, two (6·5%) for non-compliance and two (6·5%) for surgical intervention.

Thermodynamics of Asymptotically Conical Geometries.

We study the thermodynamical properties of a class of asymptotically conical geometries known as "subtracted geometries." We derive the mass and angular momentum from the regulated Komar integral and the Hawking-Horowitz prescription and show that they are equivalent. By deriving the asymptotic charges, we show that the Smarr formula and the first law of thermodynamics hold. We also propose an analog of Christodulou-Ruffini inequality. The analysis can be generalized to other asymptotically conical geometries.

EB1 acetylation by P300/CBP-associated factor (PCAF) ensures accurate kinetochore-microtubule interactions in mitosis.

In eukaryotes, microtubules are essential for cellular plasticity and dynamics. Here we show that P300/CBP-associated factor (PCAF), a kinetochore-associated acetyltransferase, acts as a negative modulator of microtubule stability through acetylation of EB1, a protein that controls the plus ends of microtubules. PCAF acetylates EB1 on K220 and disrupts the stability of a hydrophobic cavity on the dimerized EB1 C terminus, which was previously reported to interact with plus-end tracking proteins (TIPs) containing the SxIP motif. As determined with an EB1 acetyl-K220-specific antibody, K220 acetylation is dramatically increased in mitosis and localized to the spindle microtubule plus ends. Surprisingly, persistent acetylation of EB1 delays metaphase alignment, resulting in impaired checkpoint silencing. Consequently, suppression of Mad2 overrides mitotic arrest induced by persistent EB1 acetylation. Thus, our findings identify dynamic acetylation of EB1 as a molecular mechanism to orchestrate accurate kinetochore-microtubule interactions in mitosis. These results establish a previously uncharacterized regulatory mechanism governing localization of microtubule plus-end tracking proteins and thereby the plasticity and dynamics of cells.

Social determinants of cardiovascular health among black and white women residing in Stroke Belt and Buckle regions of the South.

OBJECTIVE: To assess the associations of social determinants on cardiovascular health among White and Black residing in Stroke Belt (urban) and Stroke Buckle (rural) regions of the South. DESIGN: A cross-sectional observational analysis based on a random digit-dial telephone survey of a representative sample of White and Black adults residing in urban and rural Georgia conducted from 2004-2005. Separate logistic regression analyses examined the effects of social determinants on cardiovascular health within and between White and Black women and within and between urban and rural residential location. The main outcome measure was poor cardiovascular health defined as > or = 2 self-reported clinical cardiovascular disease risk factors (hypertension, diabetes, elevated cholesterol, overweight or obese). Social determinants were defined as socioeconomic status (SES), general daily stress, racial discrimination, and stress due to exposure to racial discrimination. Significance was established as a two-tailed P < .05. RESULTS: A total of 674 White and Black women aged 18-90 years were included in the sample. Results showed Black women with lower SES had worse cardiovascular health than White women in both rural and urban areas (rural odds ratio [OR] 2.68; confidence interval [CI] 1.44, 4.90; P = .001; urban OR = 2.92; CI = 1.62, 5.23; P = .0003). White women reporting high or very high exposure to general daily stress where more likely to have worse cardiovascular health than White women reporting very little to no daily stress (OR = 2.85; CI = 1.49, 5.44; P = .001). CONCLUSION: Our findings demonstrate the importance of social determinants associated with cardiovascular health. Tailored cardiovascular risk reduction intervention is needed among lower SES Black women in Stroke Belt and Buckle regions of the South, as well as stress-reduction intervention among White women in the South.