Scenarios for modeling solar radiation modification.

Making informed future decisions about solar radiation modification (SRM; also known as solar geoengineering)-approaches such as stratospheric aerosol injection (SAI) that would cool the climate by reflecting sunlight-requires projections of the climate response and associated human and ecosystem impacts. These projections, in turn, will rely on simulations with global climate models. As with climate-change projections, these simulations need to adequately span a range of possible futures, describing different choices, such as start date and temperature target, as well as risks, such as termination or interruptions. SRM modeling simulations to date typically consider only a single scenario, often with some unrealistic or arbitrarily chosen elements (such as starting deployment in 2020), and have often been chosen based on scientific rather than policy-relevant considerations (e.g., choosing quite substantial cooling specifically to achieve a bigger response). This limits the ability to compare risks both between SRM and non-SRM scenarios and between different SRM scenarios. To address this gap, we begin by outlining some general considerations on scenario design for SRM. We then describe a specific set of scenarios to capture a range of possible policy choices and uncertainties and present corresponding SAI simulations intended for broad community use.

Factors affecting salvage rate of infected prosthetic mesh.

BACKGROUND: Prosthetic mesh infection (PMI) is a challenging complication of ventral hernia repair (VHR). The sparsity of data leaves only experience and judgment to guide surgical decision-making. METHODS: Retrospective review of patients diagnosed with PMI. Subsequent abdominal operation (SAO) constitutes any intraabdominal operation occurring after the index hernia repair prior to PMI presentation. Any mesh removal was considered salvage failure. Analysis was performed using Chi-square test, Fishers Exact, or Mann-Whitney U test. Analyses completed using R Version 3.0.2. RESULTS: We identified 213 instances of PMI. Most cases (58.7%) involved intraperitoneal mesh. Thirty-seven percent of patients had an SAO, only 25.3% of which were clean cases. Enteroprosthetic fistula occurred in 38 patients (17.8%). Mean time to presentation was 19.9 mos after index hernia repair or SAO for infection alone, and 48.1 mos when a fistula was present (p < 0.001). Percutaneous drainage was used to treat 29 cases, successfully in 10 (34.5%), 8 of which were macroporous polypropylene and 2 biologic mesh. Negative pressure wound therapy (NPWT) was used in 46 patients, but successful in only 16 (34.8%), all of which were macroporous polypropylene. Local wound care alone successfully salvaged only 16 of 85 meshes (18.8%), 13 of which were macroporous polypropylene. Macroporous polypropylene mesh was salvaged in 65% of cases overall, and 72.2% when in an extraperitoneal position. Mesh salvage was not possible in any case involving composite or PTFE mesh, and rarely for microporous polypropylene (7.7%) multifilament polyester (4.2%), or intraperitoneal mesh (2.4%). Closure of the defect after mesh removal significantly lowers recurrence rate (p < 0.001). CONCLUSION: PMI involving composite, PTFE, multifilament polyester, or microporous polypropylene mesh requires explantation in nearly all cases. Infected macroporous polypropylene mesh in an extraperitoneal position is salvageable in most cases. Furthermore, the risk of secondary mesh infection after SAO, particularly with intraperitoneal mesh, should be considered during index VHR.

MR1-restricted mucosal-associated invariant T (MAIT) cells respond to mycobacterial vaccination and infection in nonhuman primates.

Studies on mucosal-associated invariant T cells (MAITs) in nonhuman primates (NHP), a physiologically relevant model of human immunity, are handicapped due to a lack of macaque MAIT-specific reagents. Here we show that while MR1 ligand-contact residues are conserved between human and multiple NHP species, three T-cell receptor contact-residue mutations in NHP MR1 diminish binding of human MR1 tetramers to macaque MAITs. Construction of naturally loaded macaque MR1 tetramers facilitated identification and characterization of macaque MR1-binding ligands and MAITs, both of which mirrored their human counterparts. Using the macaque MR1 tetramer we show that NHP MAITs activated in vivo in response to both Bacillus Calmette-Guerin vaccination and Mycobacterium tuberculosis infection. These results demonstrate that NHP and human MR1 and MAITs function analogously, and establish a preclinical animal model to test MAIT-targeted vaccines and therapeutics for human infectious and autoimmune disease.

Endovascular Repair of Ruptured Popliteal Artery Aneurysms: A Case Report and Review of the Literature.

OBJECTIVE/BACKGROUND: The objectives were to report the management and outcomes of a 96-year-old man who presented with an acutely swollen right leg due to a ruptured popliteal aneurysm, and to review the relevant literature. METHODS: A ruptured popliteal artery aneurysm is a rare diagnosis and is one that is often missed at time of presentation. Previous case reports have documented successful outcomes following surgical repair, and a smaller number following endovascular repair. This is a case report of a 96-year-old man who eventually underwent endovascular repair of a ruptured popliteal artery aneurysm after a delay in diagnosis. A literature review was performed to analyse published data in this field. RESULTS: The patient underwent an uncomplicated endovascular repair with a GORE® VIABAHN® stent. A 15-week follow-up ultrasound demonstrated biphasic flow in a patent stent-graft with an unchanged aneurysm sac size and no evidence of an endoleak. A review of the literature demonstrated nine cases of ruptured non-mycotic popliteal artery aneurysms treated endovascularly. Seven cases survived the postoperative period, three had no follow-up recorded, and four cases had patent stent-grafts at time of follow-up. CONCLUSION: Safe and effective endovascular repair of a ruptured popliteal artery aneurysm with endograft patency seen at the 15-week follow-up is reported. Review of the literature suggests that open repair remains the first-line management choice; however, endovascular repair is a valuable alternative. There is a further need for longer-term monitoring of endograft patency following endovascular repair.

PAR-1 antagonist vorapaxar favorably improves global thrombotic status in patients with coronary disease.

To assess the effect of vorapaxar on global thrombotic and thrombolytic status. The propensity for thrombus formation is determined by the balance between prothrombotic factors and endogenous thrombolysis. Impaired thrombolytic status increases cardiovascular risk. Vorapaxar is a novel, oral, protease-activated receptor-1 antagonist that inhibits thrombin-induced platelet activation. In the TRACER and TRA 2°P-TIMI 50 studies, patients with acute coronary syndromes and established atherosclerosis were randomized to vorapaxar 2.5 mg daily or placebo, in addition to standard care. In 57 patients enrolled in a single center, blood was tested with the point-of-care global thrombosis test, on and off treatment. This automated test employs non-anticoagulated blood to assess thrombotic and thrombolytic status, measuring the time required to form a shear-induced thrombus under physiological conditions (occlusion time, OT), and subsequently, the time to achieve endogenous lysis of the thrombus (lysis time, LT). Patients on vorapaxar exhibited longer OT on vs. off treatment [median 561 s (interquartile range 422-654) vs. 372 s(338-454), P = 0.003] and shorter LT on treatment than off [1,158 s(746-1,492) vs. 1,733 s(1,388-2,230), P = 0.016]. Patients on placebo showed no difference in OT [419 s(343-514) vs. 411 s(346-535), P = 0.658] or LT [1,236 s(985-1,594) vs. 1,400 s(1,092-1,686), P = 0.524] on and off treatment. During treatment, OT was longer in patients taking vorapaxar [561 s(422-654) vs. 419 s(343-514), P = 0.009], but LT was similar in vorapaxar and placebo arms [1,158 s(746-1,492) vs. 1,236 s(985-1,594), P = 0.277]. Vorapaxar prolongs OT and shortens LT, with favorable effects on thrombotic and thrombolytic status. In addition to its antiplatelet effect, vorapaxar may enhance endogenous thrombolysis, which is frequently impaired in coronary disease.

An antibiotic formulary for a tertiary care foot clinic: admission avoidance using intramuscular antibiotics for borderline foot infections in people with diabetes.

AIMS: To develop an antibiotic foot formulary for the empirical treatment of diabetes-related foot infections presenting to our service. Subsequently, to asses costs associated with the introduction of our protocol, in particular to assess the effect on admissions avoidance and any cost savings achieved. METHODS: We reviewed several existing antibiotic protocols. We analysed data on costs related to treatment and admission rates prior to and after the introduction of the protocol. RESULTS: We rationalized our antibiotic protocol and adapted the Infectious Disease Society of America guideline by introducing a category of 'moderate infection-borderline admission' to our classification. This enabled the administration of outpatient intramuscular antibiotics. After introducing the rationalized protocol, our average antibiotic prescribing costs for a 3-week course of treatment fell from £17.12 to £16.42. Over 22 months of follow-up, 26 episodes were eligible for treatment with intramuscular antibiotics. Over the same time period, 121 people were admitted directly from the foot clinic. The costs saved as a result of avoided or delayed admission for those 26 episodes was over £76 000. For 12 people who required subsequent admission, their length of hospital stay was significantly shorter than those admitted directly [9.25 days (range 2-25) vs. 16.11 (2-64), P = 0.045]. CONCLUSIONS: By modifying the Infectious Disease Society of America classification and adopting a protocol to administer outpatient oral and intramuscular antibiotics, we have led to substantial cost savings, shorter hospital admissions and also have developed a successful admissions avoidance strategy.

Use of a Poroelastic Model to Predict Intramuscular Pressure.

Measurement of individual muscle tension in a clinical setting has yet to be achieved. Previous investigators have suggested that the tension in skeletal muscle, comprised of approximately 70% fluid, could be determined using interstitial muscle fluid pressure (IMP). A computational model is needed to aid in understanding IMP distribution in muscles of varying geometry and contractile states without exhaustive testing. The first aim of this study was to determine a set of transversely isotropic material properties (i.e., permeability, relaxed modulus, and drained Poisson's ratio) for excised skeletal muscle using inverse finite element analysis with a poroelastic constitutive formulation on tension data from either longitudinal or transverse uniaxial load-relaxation tests of skeletal muscle tissue. The second aim was to compare pore pressure estimated from a model to experimental pressure measurements to assess its ability to accurately predict IMP. Results of this study indicated that skeletal muscle was transversely isotropic under load-relaxation as demonstrated by significant differences in the drained Poisson's ratio. It was also noted that the drained Poisson's ratios under both longitudinal and transverse loading were negative in these tests of excised muscle tissue. Pore pressure calculated with this model provided a good prediction of the development of IMP. These results point to the benefit of using a poroelastic model of skeletal muscle to predict IMP.

Clinical experience of a new NPWT system in diabetic foot ulcers and post-amputation wounds.

OBJECTIVE: The primary aim of this pilot observational study was to assess the reduction in wound depth and area achieved with a new negative pressure wound therapy (NPWT) system in diabetic patients with foot ulcers and post-amputation wounds. Secondary aims were to assess pain levels, extent of exudate removal, and ease of use of the system for both the patient and care giver. METHOD: Patients in both acute and home care settings were enrolled into this 4-week study. Dressings were changed three times per week. Wound area and depth, exudate removal and pain severity were evaluated at each dressing change. At the final visit, the investigators and patients were surveyed with respect to equipment and dressings used in the study. RESULTS: Sixteen patients were enrolled into the study. Data relating to 14 patients with a variety of post-amputation wounds were included in the intention-to-treat (ITT) analysis. The post-amputation wounds showed a general trend for a reduction in the median wound surface area between baseline (22.9cm2; range 0.5-55) and the final visit (15.3cm2; range 2.4-63.5). This equates to a median change (calculated from the percentage change in wound area for each patient individually) of -41% (range -82% to +15%). There was also a general trend in reduction in the median depth between baseline (17mm; range 0-35) to final visit (5mm; range 0-35). One patient presented with a foot ulcer that demonstrated a 50% reduction in depth from baseline to the final assessment. The device effectively managed wound exudate and most patients reported low pain levels during therapy. Ease of use of the system was rated very highly by investigators and patients. CONCLUSION: This pilot study indicates that the use of the new NPWT system can be expected to have a positive effect on the healing of post-amputation wounds and foot ulcers in patients with diabetes. The findings demonstrate that the system is easy to use, effectively controls exudate and minimises pain and inconvenience for patients being treated with NPWT. DECLARATION OF INTEREST: This study was sponsored by Mölnlycke Heath Care (Gothenburg, Sweden) and Medela AG (Baar, Switzerland). The authors have no other conflicts of interest that are directly relevant to the content of this manuscript.

Dual modulation of urinary bladder activity and urine flow by prostanoid EP3 receptors in the conscious rat.

BACKGROUND AND PURPOSE: Cyclooxygenase inhibitors function to reduce levels of prostaglandin E(2) (PGE(2)) and are broadly efficacious in models of bladder overactivity. We therefore investigated a regulation of urinary bladder function in conscious rats by modulation of the EP(3) receptor for PGE(2). EXPERIMENTAL APPROACH: The activity of the EP(3) receptor agonist GR63799X, and EP(3) receptor antagonists, CM9 and DG041, at recombinant EP(3) receptors was evaluated in vitro. In vivo, intraduodenal dosing during conscious, continuous-filling cystometry of spontaneously hypertensive rats was utilized to determine the urodynamic effect of EP(3) receptor modulation. KEY RESULTS: GR63799X dose-dependently (0.001-1 mg x kg(-1)) reduced bladder capacity, as indicated by a reduction in both the micturition interval and volume of urine per void. In contrast, CM9 (10 and 30 mg x kg(-1)) and DG041 (30 mg x kg(-1)) enhanced bladder capacity, as indicated by significantly longer micturition intervals and larger void volumes. CM9 and DG041 inhibited the responses to GR63799X supporting the in vivo activity of these pharmacological agents at the EP(3) receptor. In addition to its effect on bladder capacity, GR63799X increased endogenous urine production. Intra-arterial infusion of saline mimicked the enhancement of urine flow observed with GR63799X, and the response was inhibited by CM9. CONCLUSIONS AND IMPLICATIONS: These data support the EP(3) receptor as a modulator of urinary bladder activity in the conscious rat, and in addition, indicate a role for EP(3) receptor activity in regulating urine flow.

Factors associated with exacerbation of heart failure include treatment adherence and health literacy skills.

We determined the factors associated with exacerbation of heart failure, using a cohort (n = 192) nested within a randomized trial at a university-affiliated ambulatory practice. Factors associated with emergency or hospital care included left ventricular ejection fraction, hematocrit and serum sodium levels, refill adherence, and the ability to read a prescription label. Refill adherence of <40% was associated with a threefold higher incidence of hospitalization for heart failure than a refill adherence of >or=80% (P = 0.002). In multivariable analysis, prescription label reading skills were associated with a lower incidence of heart failure-specific emergency care (incidence rate ratio, 0.76; 95% confidence interval (CI), 0.19-0.69), and participants with adequate health literacy had a lower risk of hospitalization for heart failure (incidence rate ratio, 0.34; 95% CI, 0.15-0.76). We conclude that inadequate treatment adherence and health literacy skills are key factors in the exacerbation of heart failure. These findings emphasize the need for careful instruction of patients about their medications.

Constitutive modeling of skeletal muscle tissue with an explicit strain-energy function.

While much work has previously been done in the modeling of skeletal muscle, no model has, to date, been developed that describes the mechanical behavior with an explicit strain-energy function associated with the active response of skeletal muscle tissue. A model is presented herein that has been developed to accommodate this design consideration using a robust dynamical approach. The model shows excellent agreement with a previously published model of both the active and passive length-tension properties of skeletal muscle.

Paralogues of porcine aromatase cytochrome P450: a novel hydroxylase activity is associated with the survival of a duplicated gene.

The gonadal and placental paralogues of porcine aromatase cytochrome P450 (P450arom) were examined for novel catalytic properties to shed light on the evolutionary survival of duplicated copies of an enzyme critical to reproduction. Recombinant gonadal P450arom catalyzed the formation of a novel metabolite from testosterone, identified by gas chromatography/mass spectrometry and biochemical analyses as 1 beta-hydroxytestosterone (1 beta OH-T), in almost equal proportion to 17beta-estradiol (E(2)). This activity was absent in reactions with the porcine placental paralogue (or other orthologues) of P450arom and was minimal with androstenedione. Incubations with both porcine enzymes and with bovine and human P450arom demonstrated that 1 beta OH-T was not aromatizable, and 1 beta OH-T activated the androgen receptor of prostate cancer cells in vitro. Porcine testicular and follicular granulosa tissues synthesized 1 beta OH-T, which was also detected in testicular venous plasma. These results constitute the first of identification of a novel, perhaps potent, nonaromatizable metabolite of testosterone, whose synthesis (paradoxically) can be definitively ascribed to the activity of the gonadal paralogue of porcine P450arom. It probably represents an evolutionary gain of function associated with fixation and the survival of the genes after CYP19 duplication. Novel activities and adaptive functions may exist among other duplicated vertebrate aromatases.

A 2-D model of wheelchair propulsion.

PURPOSE: To illustrate the potential benefits of kinetic and kinematic models in the exploration of biomechanical studies as illustrated using a simple 2-D static optimization model of wheelchair propulsion. METHOD: A four-bar linkage analysis was used to determine sagittal plane motion through the range of wheelchair propulsion. Using anthropometric measures of wheelchair users, this analysis determined the angles of shoulder and elbow flexion/extension at a given point in the propulsion cycle. Maximal strength inputs for the model were collected from isokinetic measurements of shoulder and elbow moments. The torque inputs were given as functions of sagittal plane joint angles. Through selection of appropriate model performance criteria, optimization techniques determined shoulder and elbow torque contributions throughout the propulsion cycle. Variations in the model parameters of anterior-posterior (AP) seat position and handrim size went used to show potential of model to evaluate wheelchair configuration using the performance criteria of propulsive moment (Mo) and efficiency as defined by fractional effective force (FEF). RESULTS: The model was able to predict the magnitude and direction of force applied to the handrim from shoulder and elbow moments. These joint moments may be examined along with the generated wheelchair axle propulsion moment. While the model showed no significant changes in either Mo or FEF for AP seat changes, an increase in handrim size was shown to increase FEF. CONCLUSIONS: This model was able to simulate wheelchair propulsion and allow for performance analyses. The open nature of the model allowed for tweaking of the kinematic inputs to examine the sensitivity of such factors as seat position and handrim size in wheelchair propulsion. Strength inputs to the model may also be altered to study the potential effects of strength training or muscle weakness.

An integrated clinical approach to predicting the benefit of tirofiban in non-ST elevation acute coronary syndromes. Application of the TIMI Risk Score for UA/NSTEMI in PRISM-PLUS.

AIMS: We evaluated the TIMI Risk Score for Unstable Angina and Non-ST Elevation Myocardial Infarction for predicting clinical outcomes and the efficacy of tirofiban in non-ST elevation acute coronary syndromes. METHODS AND RESULTS: Developed in TIMI 11B, the risk score is calculated as the sum of seven presenting characteristics (age > or =65 years, > or =3 cardiac risk factors, documented coronary disease, recent severe angina, ST deviation > or =0.5 mm, elevated cardiac markers, prior aspirin use). The risk score was validated in the PRISM-PLUS database (n=1915) and tested for interaction with the efficacy of tirofiban+heparin vs heparin alone. The risk score revealed an increasing gradient of risk for death, myocardial infarction or recurrent ischaemia at 14 days ranging from 7.7-30.5% (P<0.001). Dichotomized at the median, patients with a score > or =4 derived a greater relative risk reduction with tirofiban (P((Interaction))=0.025). Among patients with normal creatine kinase myocardial bands, the risk score showed a 3.5-fold gradient of risk (P<0.001) and identified a population that derived significant benefit from tirofiban (RR 0.73, P=0.027). CONCLUSION: The TIMI Risk Score is a simple clinical tool for risk assessment that may aid in the early identification of patients who should be considered for treatment with potent antiplatelet therapy.