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.

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.

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.

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.

Modalities to Treat Venous Ulcers: Compression, Surgery, and Bioengineered Tissue.

BACKGROUND: Venous leg ulcers (VLUs) represent the most common ulcers of the lower extremity. VLUs are notorious for delayed and prolonged healing with high rates of recurrence. Most patients with VLUs also have significant comorbidities that interfere with primary wound healing. Thus, caring for patients with VLUs requires an interdisciplinary approach that addresses the abnormal venous anatomy and the downstream effects that lead to inflammation, ulceration, and a hostile wound microenvironment. METHODS: The current literature regarding venous ulcer treatment with an emphasis on compression, surgical options, and use of bioengineered tissue was reviewed. A combination of society guidelines, Cochrane reviews, and over 80 primary articles with high-level evidence were utilized to develop this summary and algorithm for an integrated approach to treating patients with venous ulcers. Details regarding compression modalities and venous diagnostic imaging are presented to help the clinician understand the rationale for using these technologies. RESULTS: The comprehensive approach to the patient with chronic venous insufficiency (CVI) includes advances in compression, diagnostics, minimally invasive surgical treatment of venous disease, wound bed preparation, and bioengineered skin and soft tissue substitutes. An algorithm that incorporates early treatment of the ulcer and the venous disease leading to healing with prevention of recurrence is presented. CONCLUSIONS: Utilizing guidelines that incorporate evidence-based modalities will lead to the highest quality outcomes with the most appropriate resource utilization. A proactive approach to treating venous disease will alleviate suffering and prevent the long-term sequelae of CVI.

Grafix®, a Cryopreserved Placental Membrane, for the Treatment of Chronic/Stalled Wounds.

Objective: To discuss the use of Grafix®, a commercially available, cryopreserved placental membrane, for the treatment of chronic/stalled wounds of different etiologies. Approach: To describe the unique composition of Grafix, to provide an overview of the existing clinical evidence supporting the benefits of Grafix for wound treatment, and to share the experience of the South Shore Hospital Center for Wound Healing (Weymouth, MA) with Grafix for the treatment of nonhealing wounds. Results: Clinical evidence supports the safety and efficacy of Grafix for the treatment of chronic/stalled wounds, including those that have failed other advanced treatment modalities. Innovation: Grafix is a cryopreserved placental membrane manufactured utilizing a novel technology that enables the preservation of all placental membrane components in their native state. Placental membranes have a unique composition of extracellular matrix, growth factors, and cells (including mesenchymal stem cells), which makes this tissue unique among other advanced biological wound treatment modalities. Conclusion: Clinical evidences support the benefits of Grafix for head-to-toe wound treatment.

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.

A prospective, randomized, controlled trial comparing the effects of noncontact, low-frequency ultrasound to standard care in healing venous leg ulcers.

Current scientific evidence suggests venous leg ulcers (VLUs) that do not respond to guideline-defined care may have a wound microenvironment that is out of physiological balance. A prospective, randomized, controlled, multicenter trial was conducted to compare percent wound size reduction, proportions healed, pain, and quality-of-life (QOL) outcomes in patients randomized to standard care (SC) alone or SC and 40 kHz noncontact, low-frequency ultrasound (NLFU) treatments 3 times per week for 4 weeks. One hundred, twelve (112) eligible participants with documented venous stasis, a VLU >30 days' duration, measuring 4 cm2 to 50 cm2, and demonstrated arterial flow were enrolled. Of these, 81 reduced <30% in size during the 2-week run-in study phase and were randomized (SC, n = 40; NLFU+SC, n = 41). Median age of participants was 59 years; 83% had multiple complex comorbidities. Index ulcers were 56% recurrent, with a median duration of 10.3 months (range 1 month to 204.5 months) and median ulcer area of 11.0 cm2 (range 3.7 cm2-41.3 cm2). All participants received protocol-defined SC compression (30-40 mm Hg), dressings to promote a moist wound environment, and sharp debridement at the bedside for a minimum of 1 time per week. Ulcer measurements were obtained weekly using digital planimetry. Pain and QOL scores were assessed at baseline and after 4 weeks of treatment using the Visual Analog Scale and the Short Form-36 Health Survey. After 4 weeks of treatment, average wound size reduction was 61.6% ± 28.9 in the NLFU+SC compared to 45% ± 32.5 in the SC group (P = 0.02). Reductions in median (65.7% versus 44.4%, P = 0.02) and absolute wound area (9.0 cm2 versus 4.1 cm2, P = 0.003) as well as pain scores (from 3.0 to 0.6 versus 3.0 to 2.4, P = 0.01) were also significant. NLFU therapy with guideline-defined standard VLU care should be considered for healing VLUs not responding to SC alone. The results of this study warrant further research on barriers to healing and the changes occurring in the tissue of the wound to explore theories that the microenvironment impacts wounds that do not heal despite provision of guideline-defined care.

Diabetic vascular disease: characteristics of vascular disease unique to the diabetic patient.

Diabetes is a cardiovascular disease affecting almost every arterial vascular bed with significant consequences. Vascular disease is one part of a triopathy of complications that singularly but most commonly in combination makes the diabetic patient uniquely susceptible to lower extremity complications. The other two conditions are neuropathy and an altered response to infection. Diabetic peripheral arterial disease has a predilection for the smaller below knee tibial/peroneal arteries and there is no microvascular occlusive arterial disease affecting the diabetic foot. Microvascular dysfunction is not an occlusive phenomenon and supports an aggressive approach to treating existing macrovascular atherogenic occlusive disease complicating diabetic wounds of all extremities. Individualized, patient-centered treatment utilizing all available endovascular and open revascularization options best ensures the highest quality outcomes at a cost our healthcare system can afford.

Black holes in an expanding universe.

An exact solution representing black holes in an expanding universe is found. The black holes are maximally charged and the universe is expanding with arbitrary equation of state (P = w rho with -1 < or = for all w < or = 1). It is an exact solution of the Einstein-scalar-Maxwell system, in which we have two Maxwell-type U(1) fields coupled to the scalar field. The potential of the scalar field is an exponential. We find a regular horizon, which depends on one parameter [the ratio of the energy density of U(1) fields to that of the scalar field]. The horizon is static because of the balance on the horizon between gravitational attractive force and U(1) repulsive force acting on the scalar field. We also calculate the black hole temperature.

Naturalness of CP violation in the standard model.

We construct a natural measure on the space of Cabibbo-Kobayashi-Maskawa matrices in the standard model, assuming the fermion mass matrices are randomly selected from a distribution which incorporates the observed quark mass hierarchy. This measure allows us to assess the likelihood of Jarlskog's CP violation parameter J taking its observed value J approximately 3 x 10(-5). We find that the observed value, while well below the mathematically allowed maximum, is in fact typical once the observed quark masses are assumed.

Open M5-branes.

We show how, in heterotic M theory, an M5-brane in the 11-dimensional bulk may end on an "M9-brane" boundary, the M5-brane boundary being a Yang-monopole 4-brane. This possibility suggests various novel 5-brane configurations of heterotic M theory, in particular, a static M5-brane suspended between the two M9-brane boundaries, for which we find the asymptotic heterotic supergravity solution.

Lower extremity bypass in patients with diabetic foot ulcers.

The assessment and management of ischemia for the diabetic patient must be a part of an evidence-based treatment algorithm for wound healing. In 1999, the American Diabetes Association published a consensus position to provide guidance to health care professionals who manage foot wounds in patients with diabetes. The consensus panel recognized six approaches that are supported by clinical trials or well-established principles of wound healing: off-loading, debridement, dressings, antibiotics, vascular reconstruction, and amputation or reconstructive foot surgery when necessary. Adjunctive medical therapies include normalization of blood glucose, treatment of comorbid conditions, control of edema, nutritional repletion, and physical and emotional therapy. Education and prevention of recurrence are essential in any treatment algorithm. Box 1 and Box 2 are algorithms developed by the author and used in clinical management of diabetic lower extremity wounds. The author's multidisciplinary team approach is evidenced based with documented healing and a reduction in amputation at every level. For the patient, it best allows a return to function and well-being. Focusing on quality maximizes the cost/benefit ratio.

Uniqueness and nonuniqueness of static black holes in higher dimensions.

We prove a uniqueness theorem for asymptotically flat static charged dilaton black-hole solutions in higher-dimensional space-times. We also construct infinitely many nonasymptotically flat regular static black holes on the same space-time manifold with the same spherical topology. An application to the uniqueness of a class of flat p-branes is also given.

Factors that predict site of outflow target artery anastomosis in infrainguinal revascularization.

INTRODUCTION: Lower extremity revascularization is indicated for limb salvage and incapacitating leg claudication. Many risk factors (age, hypertension, diabetes, tobacco use, dyslipidemia, etc) have been associated with atherosclerosis and the development of peripheral arterial occlusive disease. However, whether these risk factors or the surgical indication (claudication or limb salvage) influences the extent and location of infrainguinal disease and hence the target artery (distal anastomosis) is unclear. This study examines the risk factors and indication for infrainguinal revascularization with respect to the type of bypass performed. METHODS: Three hundred fifty-two infrainguinal revascularizations in 282 patients were retrospectively reviewed. Patient data, including demographics, cardiovascular risk factors, indications, types of revascularization, and perioperative complications and mortality, were collected. Data were analyzed with t test, chi(2) test, Fisher exact test, and multiple logistic regression. RESULTS: The indication for surgical revascularization was claudication in 70 patients and limb salvage in 282. The likelihood of a popliteal anastomosis (above or below knee) versus a tibial or pedal anastomosis was decreased with increasing age (P =.002) and diabetes (P =.0001), and smoking increased the likelihood (P =.056). However, popliteal bypass also was strongly associated with claudication as the surgical indication (odds ratio [OR], 8.7; P =.0001), and 90% of the claudicant group had undergone popliteal anastomosis. Claudication and popliteal anastomosis were both linked to smoking; 97% of subjects who underwent operation for claudication were smokers compared with 75% of subjects who underwent tibial or pedal anastomosis for limb salvage (P =.001). After adjustment for indication, the likelihood of popliteal anastomosis was still decreased with diabetes (OR, 0.46; P =.002), and age had a borderline significant effect (P =.077). When the analysis was stratified by indication for surgery, the likelihood of popliteal bypass among patients who underwent operation for claudication was not influenced by age, diabetes, or smoking. However, within the subset of patients who underwent operation for limb salvage, the likelihood of any popliteal anastomosis was diminished by diabetes (OR, 0.50; P =.007), age (OR, 0.968 per year; P =.01), and chronic renal insufficiency (OR, 0.476; P =.04). CONCLUSION: Infrainguinal peripheral arterial occlusive disease is not a homogenous disease entity. Claudication and limb salvage are associated with two distinct patterns of vascular disease with different risk factors. Patients who undergo operation for claudication are seen at an earlier age, have a high prevalence of smoking, and have proximal disease and a greater likelihood of a popliteal anastomosis. In contrast, patients for limb salvage are less likely to have a popliteal bypass, favoring a more distal target outflow anastomosis that is strongly influenced by advanced age, diabetes, and chronic renal insufficiency.