Evidence for widespread changes in the structure, composition, and fire regimes of western North American forests.

Implementation of wildfire- and climate-adaptation strategies in seasonally dry forests of western North America is impeded by numerous constraints and uncertainties. After more than a century of resource and land use change, some question the need for proactive management, particularly given novel social, ecological, and climatic conditions. To address this question, we first provide a framework for assessing changes in landscape conditions and fire regimes. Using this framework, we then evaluate evidence of change in contemporary conditions relative to those maintained by active fire regimes, i.e., those uninterrupted by a century or more of human-induced fire exclusion. The cumulative results of more than a century of research document a persistent and substantial fire deficit and widespread alterations to ecological structures and functions. These changes are not necessarily apparent at all spatial scales or in all dimensions of fire regimes and forest and nonforest conditions. Nonetheless, loss of the once abundant influence of low- and moderate-severity fires suggests that even the least fire-prone ecosystems may be affected by alteration of the surrounding landscape and, consequently, ecosystem functions. Vegetation spatial patterns in fire-excluded forested landscapes no longer reflect the heterogeneity maintained by interacting fires of active fire regimes. Live and dead vegetation (surface and canopy fuels) is generally more abundant and continuous than before European colonization. As a result, current conditions are more vulnerable to the direct and indirect effects of seasonal and episodic increases in drought and fire, especially under a rapidly warming climate. Long-term fire exclusion and contemporaneous social-ecological influences continue to extensively modify seasonally dry forested landscapes. Management that realigns or adapts fire-excluded conditions to seasonal and episodic increases in drought and fire can moderate ecosystem transitions as forests and human communities adapt to changing climatic and disturbance regimes. As adaptation strategies are developed, evaluated, and implemented, objective scientific evaluation of ongoing research and monitoring can aid differentiation of warranted and unwarranted uncertainties.

The indications for and timing of haemodialysis in critically ill patients with acute kidney injury in Johannesburg, South Africa.

Background: Acute kidney injury (AKI) is common among patients admitted to the intensive care unit (ICU). It is an independent risk factor for morbidity and mortality. The optimal timing of renal replacement therapy (RRT) remains unknown, resulting in a wide variation in observed current practices. There is a paucity of data on current practices within ICUs in South Africa. Objectives: To describe current practices in the timing of RRT in patients with AKI admitted to the ICU. The secondary objectives were to describe the patient characteristics, severity of illness scores, staging at initiation of RRT, outcome at ICU discharge, and to estimate and describe delays in the initiation of RRT. Methods: A retrospective, descriptive study was conducted in an adult academic ICU in Soweto from 1 January 2014 to 31 December 2015. Results: There were 2 152 ICU admissions over the 2 years. Less than a tenth of the patients (3.5%; n=76) required RRT and the majority had sepsis (83%). The most common indication for RRT was oliguria/anuria (50%; n=38), followed by worsening urea/creatinine (29%; n=22), metabolic acidosis (11.8%; n=9), refractory hyperkalaemia (5.3%; n=4), fluid overload (2.6%; n=2) and other (1.3%; n=1). More than half of the patients (55%; n=42) had RRT instituted on admission day (D0 ), while 45% (n=34) had RRT initiated after D0 (D1-21). RRT was initiated at stage 3 AKI in 90% and 94% of D0 RRT group and D1-21 RRT group, respectively. The median (interquartile range (IQR)) time to starting RRT was 4 (4) hours once the decision to initiate RRT was made. The composite outcome of death, RRT dependence and diuretic dependence at ICU discharge was 21% and there was no difference between the two groups (p=0.22). The ICU mortality was 3%. Conclusion: The sampled population was young, predominantly male and had post emergency surgery with a high burden of sepsis and HIV. The observed current threshold for RRT was late (stage 3 AKI with classic/emergent indications) with outcomes comparable with the reviewed literature. Contributions of the study: The present study adds insight into the practice of initiating RRT in patients admitted to the ICU with AKI. These data have previously not been described in the South African context. The patient population differed from the literature in that they were young, predominantly male and had post-emergency surgery with a high burden of sepsis and HIV.

The promise and pitfalls of composite endpoints in sepsis and COVID-19 clinical trials.

Composite endpoints reveal the tendency for statistical convention to arise locally within subfields. Composites are familiar in cardiovascular trials, yet almost unknown in sepsis. However, the VITAMINS trial in patients with septic shock adopted a composite of mortality and vasopressor-free days, and an ordinal scale describing patient status rapidly became standard in COVID studies. Aware that recent use could incite interest in such endpoints, we are motivated to flag their potential value and pitfalls for sepsis research and COVID studies.

Spread of a model invasive alien species, the harlequin ladybird Harmonia axyridis in Britain and Ireland.

Invasive alien species are widely recognized as one of the main threats to global biodiversity. Rapid flow of information on the occurrence of invasive alien species is critical to underpin effective action. Citizen science, i.e. the involvement of volunteers in science, provides an opportunity to improve the information available on invasive alien species. Here we describe the dataset created via a citizen science approach to track the spread of a well-studied invasive alien species, the harlequin ladybird Harmonia axyridis (Coleoptera: Coccinellidae) in Britain and Ireland. This dataset comprises 48 510 verified and validated spatio-temporal records of the occurrence of H. axyridis in Britain and Ireland, from first arrival in 2003, to the end of 2016. A clear and rapid spread of the species within Britain and Ireland is evident. A major reuse value of the dataset is in modelling the spread of an invasive species and applying this to other potential invasive alien species in order to predict and prevent their further spread.

LOPP chemotherapy as a first-line treatment for dogs with T-cell lymphoma.

BACKGROUND: The aim of this study was to describe the use of a lomustine (CCNU), vincristine, procarbazine and prednisolone (LOPP) protocol used for treatment of chemotherapy naive T-cell lymphoma patients and to describe the response rate, toxicity and disease-free interval compared historically to CHOP chemotherapy. MATERIALS AND METHODS: Retrospective case study of 31 dogs with naïve T-cell lymphoma treated with a lomustine (CCNU), vincristine, procarbazine and prednisolone (LOPP) protocol. RESULTS: Thirty-one dogs with T cell lymphoma were treated. The overall response rate was 97%. Of the 30 dogs that had a response to LOPP chemotherapy, the median disease free interval was 176 days (range 0-1745 days). The median overall survival time for this study group was 323 days (range 51-1758 days). All deaths in this study were attributable to lymphoma. CONCLUSION: LOPP chemotherapy for T cell lymphoma is well tolerated with a low toxicity profile and an excellent overall response rate. This protocol showed minimal toxicity and comparable disease free interval and survival times for canine high grade T cell lymphoma treated with CHOP.

Negative pressure wound therapy using a portable single-use device for free skin grafts on the distal extremity in seven dogs.

OBJECTIVE: Retrospective study to describe clinical experience with a portable single-use negative pressure wound therapy device after application of full-thickness meshed skin grafts to wounds on the distal extremities of seven dogs. METHODS: Seven dogs were treated with portable NPWT after receiving skin grafts; six as the result of tumour resection and one for traumatic injury. Medical records were reviewed and data recorded on patient signalment, cause and location of wound, surgical technique, application and maintenance of portable NPWT, graft survival and outcome, and complications encountered with the system. CLINICAL OUTCOMES: NPWT was provided for between 4 and 7 days. Five patients were discharged from hospital during the treatment period. Application and maintenance of the portable device was technically easy and no major complications were encountered. Minor complications consisted of fluid accumulation in the evacuation tubing. All dogs achieved 100% graft survival. CONCLUSIONS: Application and maintenance of the portable device was technically straightforward. All dogs receiving portable NPWT after transfer of a free skin graft to the distal extremity had a successful outcome.

Oxyacetylene torch testing and microstructural characterization of tantalum carbide.

Tantalum carbide samples have been subjected to high-temperature testing at ∼2300°C using an oxyacetylene torch to evaluate their potential for ultra-high temperature applications. While large samples cracked during the rapid heating, indicating their inability to withstand thermal shock, small samples survived the severe test conditions. The oxidation products formed were characterized and found to comprise different phases of Ta2 O5 . The ultra-high temperature experienced by the samples resulted in the formation of many interesting microstructures, including the formation of submicron sized grains, which has not been reported previously in the literature, as well as the expected evidence of melting.

Effectiveness of etoposide chemomobilization in lymphoma patients undergoing auto-SCT.

The effectiveness of stem cell mobilization with G-CSF in lymphoma patients is suboptimal. We reviewed our institutional experience using chemomobilization with etoposide (VP-16; 375 mg/m(2) on days +1 and +2) and G-CSF (5 µg/kg twice daily from day +3 through the final day of collection) in 159 patients with lymphoma. This approach resulted in successful mobilization (>2 × 10(6) CD34+ cells collected) in 94% of patients (83% within 4 apheresis sessions). Fifty-seven percent of patients yielded at least 5 × 10(6) cells in 2 days and were defined as good mobilizers. The regimen was safe with a low rate of rehospitalization. Average costs were $14 923 for good mobilizers and $27 044 for poor mobilizers (P<0.05). Using our data, we performed a 'break-even' analysis that demonstrated that adding two doses of Plerixafor to predicted poor mobilizers at the time of first CD34+ cell count would achieve cost neutrality if the frequency of good mobilizers were to increase by 21%, while the frequency of good mobilizers would need to increase by 25% if three doses of Plerixafor were used. We conclude that chemomobilization with etoposide and G-CSF in patients with lymphoma is effective, with future opportunities for cost-neutral improvement using novel agents.

Further clinical validation of the walking impairment questionnaire for classification of walking performance in patients with peripheral artery disease.

The purpose of this study was to further validate the Walking Impairment Questionnaire (WIQ) as a self-report tool to aid in the clinical identification of walking ability of patients with peripheral artery disease (PAD). 132 patients with PAD and an ankle brachial index (ABI) ≤0.90 were enrolled; 123 provided complete data for the WIQ and standardized graded treadmill test. The WIQ scores were consistent with reported scores in other studies. The absolute claudication distance (ACD) ranged from 42.3 to 1589.2 meters; the peak walking time (PWT) ranged from 68 to 1800 seconds. Adjusted WIQ scores were positively and moderately associated with the log transformed ACD and PWT (r > .53, P < .001). Based on the area under the curve analysis, an overall WIQ score of 42.5 or less identified low performers (sensitivity 0.90, specificity 0.73); the combined subscale score of distance and stair of 75.5 or more identified high performers (sensitivity 0.41, specificity 0.90). We conclude that WIQ cut-offs appropriately classify walking performance in PAD patients, making this a potentially useful clinical tool. Consideration needs to be given to incorporating a standardized WIQ version into practice guidelines and the use of innovative strategies to facilitate clinical uptake.

LX4211, a dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a randomized, placebo-controlled trial.

Thirty-six patients with type 2 diabetes mellitus (T2DM) were randomized 1:1:1 to receive a once-daily oral dose of placebo or 150 or 300 mg of the dual SGLT1/SGLT2 inhibitor LX4211 for 28 days. Relative to placebo, LX4211 enhanced urinary glucose excretion by inhibiting SGLT2-mediated renal glucose reabsorption; markedly and significantly improved multiple measures of glycemic control, including fasting plasma glucose, oral glucose tolerance, and HbA(1c); and significantly lowered serum triglycerides. LX4211 also mediated trends for lower weight, lower blood pressure, and higher glucagon-like peptide-1 levels. In a follow-up single-dose study in 12 patients with T2DM, LX4211 (300 mg) significantly increased glucagon-like peptide-1 and peptide YY levels relative to pretreatment values, probably by delaying SGLT1-mediated intestinal glucose absorption. In both studies, LX4211 was well tolerated without evidence of increased gastrointestinal side effects. These data support further study of LX4211-mediated dual SGLT1/SGLT2 inhibition as a novel mechanism of action in the treatment of T2DM.

Cost-effectiveness analysis of levonorgestrel intrauterine system and thermal balloon ablation for heavy menstrual bleeding.

OBJECTIVE: To compare the cost-effectiveness of levonorgestrel intrauterine system (LNG-IUS) (Mirena; Schering Co., Turku, Finland) and thermal balloon ablation (Thermachoicetrade mark; Gynecare Inc., Menlo Park, CA, USA) for the treatment of heavy menstrual bleeding. DESIGN: An open, pragmatic, prospective randomised trial. SETTING: A menstrual disorders clinic at National Women's Hospital, Auckland, New Zealand. POPULATION: Seventy-nine women with self-defined heavy menstrual bleeding randomised to the LNG-IUS (40 women) or the thermal balloon ablation (39 women). METHODS: Decision tree modelling using primary source data was used to identify the incremental cost-effectiveness of the two treatments. MAIN OUTCOME MEASURES: Direct and indirect costs of medical treatment, including treatment costs, subsequent medical procedures, lost income and medical treatment for failed procedures. The change in quality of life as assessed by the Short Form-36 (SF-36) measured between time of treatment and 24 months was the primary outcome measure. Economic modelling examined the expected cost and outcome for a woman entering each treatment. Sensitivity analysis explored the robustness of the results. RESULTS: The expected cost of treatment was $NZ1241 ($US869) for the LNG-IUS and $NZ2418 ($US1693) for the thermal balloon ablation. The LNG-IUS was associated with an increase of 15 points on the SF-36 scale, compared with 12 points for the thermal balloon ablation. Sensitivity analysis indicates that the results are robust to a 25% decrease in the price of the primary cost drivers and to variations in the rates of failed treatment between the conditions. CONCLUSION: The LNG-IUS would appear to be cost-effective when compared with the thermal balloon ablation for treatment of heavy menstrual bleeding.

Are adjuvant therapies for tonsillectomy evidence based?

Our aim was to ascertain the current practice of adjuvant therapy for tonsillectomy and to determine whether it is evidence based. Anonymized postal questionnaires were sent to all UK otolaryngology consultants registered with the specialty association, and a literature search was performed using relevant search terms in all possible combinations. Among the responders there was little enthusiasm for routine intra-operative local anaesthesia, post-operative topical benzydamine hydrochloride (Difflam) spray or post-operative antibiotics. This is consistent with the lack of robust evidence to support any of these practices. Paracetamol (acetaminophen) is prescribed by almost 90 per cent for post-operative analgesia, and the current literature supports its efficacy and safety. Further, most practitioners combine paracetamol with opioids and/or non-steroidal anti-inflammatory drugs (NSAIDs). Evidence to support the additional use of these agents is, however, non-existent or limited. Some aspects of tonsillectomy care are uniform and evidence based. Others are heterogeneous and suffer from lack of adequate data in the literature.

Coronary heart disease risk assessment in diabetes mellitus: comparison of UKPDS risk engine with Framingham risk assessment function and its clinical implications.

AIMS: To assess differences between absolute coronary heart disease (CHD) risks calculated by Joint British Societies (JBS) risk calculator and UKPDS risk engine and its impact on CHD primary prevention management in diabetes mellitus (DM). METHODS: Seven hundred Type 2 DM patients without arterial complications were identified from nine general practices in the Scarborough area. Their absolute 10-year CHD risks were calculated. The differences in the proportion of patients identified for aspirin and statin under JBS and National Institute for Clinical Excellence (NICE) guidelines by these two methods were determined. The proportion of additional patients identified for statin in the Scarborough population as a consequence of CHD risk threshold reduction from 30 to 15% (as recommended by NICE) was also determined. RESULTS: UKPDS risk engine calculated significantly higher mean 10-year CHD risk (UKPDS vs. JBS, 21.5 vs. 18.3%, P < 0.0001). Both methods identified approximately 65% of patients to be eligible for aspirin and statin if NICE recommendations were followed. At a risk threshold of 30%, the UKPDS risk engine identified more patients for statin. Reducing the CHD risk threshold from 30 to 15% for statin initiation will identify an additional 0.5% of the total population for this treatment. CONCLUSIONS: Both methods are comparable in identifying at-risk patients under NICE recommendations. A high proportion has risk levels that merits primary CHD prevention. Lowering the risk threshold for statin treatment has a small numerical impact on the whole population.

Semiautomated data analysis of flow cytometric estimation of fetomaternal hemorrhage in D- women.

BACKGROUND: Accurate and reliable measurement of the volume of fetal D+ cells in D- women is required for adequate anti-D prophylaxis. A semiautomated flow cytometry assay based on a standardized calibration curve that was created with simulated fetomatemal hemorrhage (FMH) mixtures was developed. STUDY DESIGN AND METHODS: A calibration range of 0.083- to 2-percent D+ cells in the D-RBC mixtures (2-44 mL calculated FMH) was analyzed by use of a flow cytometer (XL-MCL, Coulter Electronics Ltd). Linear regression analysis of the calibration curve data with computer software (Excel, Microsoft) allowed semiautomated determination of the FMH volume. To optimize the assay, fresh versus frozen and thawed RBCs, RBCs from adults who are heterozygous for D or cord RBCs, and indirect- or direct-labeling techniques were evaluated by use of MoAbs. RESULTS: Fresh RBCs from adults heterozygous for D were chosen for routine use, although equivalent calibration curves were obtained with all cells tested (n = 12 calibration assays; r2 = 0.999; mean SD, 14%). A monoclonal anti-D reagent (Therad 10, Diagnostics Scotland) worked well in both indirect-(anti-IgG F(ab)-FITC) and direct-(anti-D-FITC) labeling methods compared to the use of BRAD-3 FITC. In routine practice, the FMH volumes obtained were mainly lower than those obtained in the Kleihauer Betke test when there was less than 4 mL of FMH. CONCLUSION: Semiautomated data acquisition and calibration curve analysis represents a further step toward standardization of flow cytometry for accurate FMH quantification and facilitates evaluation and control of day-to-day variations between laboratories, flow cytometers, and operators.

Extension of the therapeutic window for recombinant tissue plasminogen activator with argatroban in a rat model of embolic stroke.

BACKGROUND AND PURPOSE: Argatroban, a specific thrombin inhibitor, has been shown to reduce ischemic lesion size after focal cerebral ischemia in rats. In addition, recombinant tissue plasminogen activator (rtPA) has been shown to reduce ischemic lesion size in both rats and humans if given within 3 hours of symptom onset. We tested the hypothesis that the administration of argatroban with rtPA could extend the treatment window of stroke to 4 hours without increasing gross cerebral hemorrhage rates or reducing efficacy. METHODS: Male Wistar rats were subjected to middle cerebral artery (MCA) occlusion by a single fibrin-rich clot. After embolization, rats were administered argatroban at the following dose levels: 2.08, 6.25, and 18.75 microgram . kg(-1). min(-1). In a second experiment, rats received argatroban (6.25 microgram . kg(-1). min(-1)) or argatroban in combination with rtPA 4 hours after MCA occlusion. Tissue sections were then analyzed for lesion volume, gross hemorrhage and fibrin deposition. RESULTS: The 6.25 microgram. kg(-1). min(-1) dose demonstrated a significant reduction (P<0.05) in lesion volume after 48 hours (27.2+/-6.3%) compared with controls (35.3+/-3.7%). A significant reduction (P<0.05) in lesion volume was observed in the argatroban-plus-rtPA group (17.1+/-10.4%) compared with controls (35.3+/-3.7%). No increase in hemorrhagic transformation was observed. Fibrin deposition in the ipsilateral cortical microvasculature was significantly decreased in the 4-hour combination argatroban-plus-rtPA group compared with the controls (P<0.05). CONCLUSIONS: This study demonstrates that the combination of argatroban and rtPA extends the window of opportunity for treatment of stroke to 4 hours without increasing hemorrhagic transformation.

A carotid stenosis model in canines.

A carotid stenosis model was developed in canines in order to study the effects of systemic blood pressure and hemodilution on cerebrovascular perfusion and metabolism during cardiopulmonary bypass in the setting of significant coexistent inflow stenosis. Under general anesthesia, through a low midline neck incision, the carotid sheath was entered and the carotid artery was isolated and retracted medially. The vertebral artery could be identified posterolaterally. After ligating the vertebral artery with a 00 silk tie, carotid stenosis was created by tying bilateral carotid arteries over an 18-gauge needle using a 00 silk tie. The needle was then removed, leaving a tight stenosis. To determine the degree of stenosis, arteriograms were performed, revealing high-grade lesions of greater than 90% stenosis in the carotid arteries and absence of flow through the vertebral arteries. Cerebral blood flow studies during cardiopulmonary bypass (CPB) were performed, revealing a significant decline. Carotid arteries were harvested at the conclusion of the experiments, revealing tight lesions on direct inspection. The mean gradient measured across stenotic segments was >25 mm Hg. In conclusion, a carotid stenosis model can be created successfully in dogs by ligating the vertebral arteries bilaterally and simply using the shaft of a needle to standardize the lumen size of the carotid arteries. We found the diameter of an 18-gauge needle sufficient to produce stenoses of greater than 90% as evidenced by arteriograms.

Immunopathogenesis of hepatitis C viral infection: Th1/Th2 responses and the role of cytokines.

Hepatitis C virus is a common cause of hepatocellular injury that is associated with complex and vigorous immunologic mechanisms. Both humoral and cell-mediated immune responses participate in the host defense against hepatitis C viral infection, but there is increasing recognition of the roles played by the cell-mediated response, and in particular the cytokine system, in the immunopathogenesis of chronic hepatitis C. The cell-mediated response depends on cytotoxic and helper T-cell activity, and functions through the actions of cytokines to regulate macrophages, natural killer cells, and antiviral cellular proteins. Cytokines produced in the liver are essential in defending the host against hepatitis C invasion, but they have also been implicated in the hepatocellular injury seen in the majority of chronically infected patients. Cytokines are thought to be involved in the pathogenesis of hepatitis C under conditions where the virus can mutate effectively and evade T-cell immune defense mechanisms. Persistent infection upsets the balance between immunostimulatory and inhibitory cytokines which can prolong inflammation and lead to necrosis, fibrosis, and chronic liver disease.

CYP2E1-mediated modulation of valproic acid-induced hepatocytotoxicity.

OBJECTIVES: To determine the cytotoxicity of valproic acid (VPA) and its metabolite, 4-ene-valproic acid (4-ene-VPA) in human hepatoblastoma cells (Hep G2), and to study the modulatory effect of cytochrome P450 2E1 induction in this model. METHODS: Cells were exposed to VPA or 4-ene-VPA in the presence of either ethanol (EtOH), or EtOH combined with disulphiram (DS). Some cells were exposed to alpha-fluoro-VPA or to alpha-fluoro-4-ene-VPA in the absence of CYP2E1 inducers. Apoptosis and necrosis were measured by analyzing 6000 cells per sample using transmission electron microscopy, while cytokine release and apoptosis were quantitated by ELISA. RESULTS: VPA + EtOH increased VPA cytotoxicity. 4-ene-VPA + EtOH significantly increased toxicity, while DS + EtOH significantly reduced this toxicity. Alpha-fluorinated analogues reduced cytotoxicity compared to the corresponding VPA compounds. Neither VPA nor alpha-fluorinated VPA increased the release of IL-6 or TNF-alpha in media. A significant increase in the release of TNF-alpha was observed in cells exposed to 4-ene-VPA that further increased with EtOH exposure. CONCLUSIONS: Cells exposed to 4-ene-VPA experience greater cytotoxicity than those treated with VPA. Cytochrome P450 2E1 inducers enhance toxicity in VPA-exposed cells, while alpha-fluorination of VPA diminishes cytotoxicity by directly interfering with the beta-oxidation of the 4-ene-VPA metabolite.