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IntroductionInflammatory bowel disease (IBD), namely ulcerative colitis and Crohn’s disease, is a chronic relapsing immune-mediated condition that may cause an impairment of social functions due to stigmatisation. Resilience instead is associated with an improvement in coping with adversities and thus may counteract the detrimental effects of stigmatisation. We herein sought to determine the fluctuation of stigmatisation and resilience in a cohort of patients with IBD at 1-year follow-up.MethodsThis is a prospective, monocentric study conducted in a tertiary referral centre. All patients with IBD were assessed at enrolment and at oneyear follow-up. Several clinical and demographic variables were collected. Stigmatisation was assessed through a validated Italian version of the Perceived Stigma Scale for IBD (PSS-IBD), while resilience was assessed through the 25-item Connor Davidson Resilience Scale (CD-RISC25). Also, self-efficacy (SEF) and self-esteem (SES) scales were assessed.ResultsIn this study, 105 patients were included (46 Crohn’s disease, 59 ulcerative colitis; overall mean age 47 years ±11, M:F ratio 1:1.2). None of the 4 scales showed a statistically significant variation at one year compared to baseline (median CD-RISC25 64 at baseline vs 61 at follow-up; SEF 31 vs 30; SES 32.5 vs 32; PSS-IBD 0.45 vs 0.45). A statistically significant and inverse correlation was found between CD-RISC25 and PSS-IBD (rho -0.222, p=0.01), SEF and PSS-IBD (rho -0.219, p= 0.01), SES and PSS-IBD (-0.316, p=0.003). CD-RISC25 was found to be positively associated with inactive IBD (p=0.05).DiscussionIn this prospective study we have shown for the first time that stigmatisation, resilience, SEF and SEM did not change over a one-year time span, suggesting that, based on the information gathered, these characteristics may be independent from IBD severity or IBD flares. Furthermore, we found an inverse correlation of stigma with resilience, SEF and SES, suggesting an important role that these variables may have on preventing stigmatisation.

Glycans play a fundamental role in several biological processes, such as cell–cell adhesion, signaling, and recognition. Similarly, abnormal glycosylation is involved in many pathological processes, among which include tumor growth and progression. Several highly glycosylated proteins found in blood are currently used in clinical practice as cancer biomarkers (e.g., CA125, PSA, and CA19-9). The development of novel non-invasive diagnostic procedures would greatly simplify the screening and discovery of pathologies at an early stage, thus also allowing for simpler treatment and a higher success rate. In this observational study carried out on 68 subjects diagnosed with either breast or lung cancer and 34 healthy volunteers, we hydrolyzed the glycoproteins in saliva and quantified the obtained free sugars (fucose, mannose, galactose, glucosamine, and galactosamine) by using high-performance anion-exchange chromatography with pulsed-amperometric detection (HPAEC-PAD). The glycosidic profiles were compared by using multivariate statistical analysis, showing differential glycosylation patterns among the three categories. Furthermore, Receiver Operating Characteristics (ROC) analysis allowed obtaining a reliable and minimally invasive protocol able to discriminate between healthy and pathological subjects.

Background Inflammatory bowel disease (IBD), namely ulcerative colitis and Crohn’s disease, is a chronic relapsing immune-mediated condition that may cause an impairment of social functions due to stigmatisation. Resilience instead is associated with an improvement in coping with adversities and thus may counteract the detrimental effects of stigmatisation. We here sought to determine the fluctuation of stigmatisation and resilience in a cohort of patients with IBD at 1-year follow-up. Methods This is a prospective, monocentric study conducted in a tertiary referral centre. All patients with IBD were assessed at enrolment and at one-year follow-up. Several clinical and demographic variables were collected. Stigmatisation was assessed through a validated Italian version of the Perceived Stigma Scale for IBD (PSS-IBD), while resilience was assessed through the 25-item Connor Davidson Resilience Scale (CD-RISC25). Also, self-efficacy scale (SEF), and self-esteem scale (SES) were assessed. Results In this study, 105 patients were enrolled (46 Crohn’s disease, 59 ulcerative colitis; mean age 47 years ±11, M:F ratio 1:1.2). None of the 4 scales showed a significant variation at one year compared to baseline (median CD-RISC25 64 at baseline vs 61 at follow-up; SEF 31 vs 30; SES 32.5 vs 32; PSS-IBD 0.45 vs 0.45). A statistically significant and inverse correlation was found between CD-RISC25 and PSS-IBD (rho -0.222, p=0.01), SEF and PSS-IBD (rho -0.219, p= 0.01), SES and PSS-IBD (-0.316, p=0.003). CD-RISC25 was found to be positively associated with inactive IBD (p=0.05). Conclusion Patients with IBD may perceive stigmatisation due to their disease, and this variable is stable on a long term. Interventions aimed at improving resilience, self-esteem, and self-efficacy may potentially counteract stigmatisation.

Objectives: Aim of the study was to describe the use and pharmacoutilization profiles of recommended drugs for HF patients, hospital re-admission rates, mortality rates and determine healthcare res...

Introduction Inadequately controlled severe asthma patients require additional therapy accounting for significant clinical and economic burden. Our analysis aims to determine the cost-effectiveness of omalizumab in the management of severe allergic asthma in Italy based on observational data from the PROXIMA study. Methods Observational data on efficacy, healthcare resource utilization and changes in quality of life at 12 months after the initiation of omalizumab were examined to estimate the cost-effectiveness compared to pre-omalizumab period and results were expressed with Incremental Cost-Effectiveness Ratio (ICER). The cost-utility analysis estimated the cost per quality-adjusted life-year (QALY) gained. Direct health costs were assessed from the perspective of the Italian National Health Service (NHS). Results Omalizumab reduced the incidence of exacerbations, number of hospitalizations, physician visits, and improved quality of life after 12 months of treatment. Omalizumab had a greater effectiveness than pre-omalizumab treatment involving 0.132 QALYs gained and led to a €3729 per patient reduction in direct healthcare costs, excluding the add-on treatment cost. Nevertheless, the addition of omalizumab cost led to €7478 increase in total direct costs with respect to pre-omalizumab period. Based on difference in total direct cost and difference in QALY between post and pre-omalizumab period, the ICER was €56,847. According to sensitivity analysis, omalizumab provided a cost-effective use of NHS resources, already at 20% discounted price. Conclusion This study offers a real-world evidence of omalizumab effectiveness in Italy. Despite the high acquisition cost of the innovative drug, omalizumab is a sustainable treatment option for patients with uncontrolled severe allergic asthma.

COVID-19 patients typically present with lower airway disease, although involvement of other organ systems is usually the rule. Hematological manifestations such as thrombocytopenia and reduced lymphocyte and eosinophil numbers are highly prevalent in COVID-19 and have prognostic significance. Few data, however, are available about the prevalence and significance of anemia in COVID-19. In an observational study, we investigated the prevalence, pathogenesis and clinical significance of anemia among 206 patients with COVID-19 at the time of their hospitalization in an Internal Medicine unit. The prevalence of anemia was 61% in COVID-19, compared with 45% in a control group of 71 patients with clinical and laboratory findings suggestive of COVID-19, but nasopharyngeal swab tests negative for SARS-CoV-2 RNA (p = 0.022). Mortality was higher in SARS-CoV-2 positive patients. In COVID-19, females had lower hemoglobin concentration than males and a higher prevalence of moderate/severe anemia (25% versus 13%, p = 0.032). In most cases, anemia was mild and due to inflammation, sometimes associated with iron and/or vitamin deficiencies. Determinants of hemoglobin concentration included: erythrocyte sedimentation rate, serum cholinesterase, ferritin and protein concentrations and number of chronic diseases affecting each patient. Hemoglobin concentration was not related to overall survival that was, on the contrary, influenced by red blood cell distribution width, age, lactate dehydrogenase and the ratio of arterial partial oxygen pressure to inspired oxygen fraction. In conclusion, our results highlight anemia as a common manifestation in COVID-19. Although anemia does not directly influence mortality, it usually affects elderly, frail patients and can negatively influence their quality of life.

The management of traumatic hemorrhagic shock has evolved, with increasing emphasis on damage control resuscitation principles. Despite these advances, hemorrhage is still the leading preventable cause of death in trauma. This issue provides evidence-based recommendations for the assessment and treatment of traumatic hemorrhagic shock. Hemostatic techniques as well as correction of hemorrhagic hypovolemia and traumatic coagulopathy are presented. The safety and efficacy of practices such as resuscitative endovascular balloon occlusion of the aorta (REBOA), viscoelastic clot testing, and whole blood resuscitation are also reviewed.

To assess whether inhaled nitrous oxide is noninferior to intravenous (IV) sedation for pain control during outpatient surgical abortion between 12 and 16 weeks of gestation.We enrolled women undergoing surgical abortion at 12-16 weeks of gestation into a multisite, double-blind clinical trial. Participants were randomized to sedation with nitrous oxide (70% nitrous/30% oxygen) or IV fentanyl (100 micrograms) and midazolam (2 mg). Paracervical block was administered to both groups. The primary outcome measure was immediate postabortion recall of maximum pain on a 100-mm visual analog scale.Between August 2016 and March 2017, we assessed 170 women for eligibility and enrolled 39, 19 in the nitrous group and 20 in the IV sedation group. Seven participants in the nitrous group (36.8%) required conversion to IV sedation for inadequate pain control. No participants in the IV sedation group required additional medication. The proportion of women requiring additional pain control in the nitrous group exceeded our predefined stopping rule. Intention-to-treat analysis demonstrated that immediate postabortion visual analog scale pain scores were lower by 20.1 mm (95% CI 1.6-38.6) in women randomized to IV sedation than in women randomized to nitrous.Intravenous sedation is a better choice than inhaled nitrous oxide for pain control in second-trimester abortion.ClinicalTrials.gov, NCT02755090.

Protein biomarkers are important diagnostic tools for cancer and several other diseases. To be validated in a clinical context, a biomarker should satisfy some requirements including the ability to provide reliable information on a pathological state by measuring its expression levels. In parallel, the development of an approach capable of detecting biomarkers with high sensitivity and specificity would be ideally suited for clinical applications. Here, we performed an immune-based label free assay using Surface Plasmon Resonance (SPR)-based detection of the soluble form of E-cadherin, a cell-cell contact protein that is involved in the maintaining of tissue integrity. With this approach, we obtained a specific and quantitative detection of E-cadherin from a few hundred microliters of serum of breast cancer patients by obtaining a 10-fold enhancement in the detection limit over a traditional colorimetric ELISA.

Although many studies have been carried out in order to understand the implication of copper (Cu) in the pathogenesis of multiple sclerosis (MS), the exact role that this metal plays in the disease is not still clear. Because of the lack of information in this subject, the present study compared the serum and cerebrospinal (CSF) levels of copper in MS patients in respect to a control group, matched for age and sex, finding a significant increase of metal concentrations, in both biological fluids of MS subjects. To confirm the possible impairment of Cu metabolism, we analyzed ceruloplasmin (Cp) level and activity, seeing as this protein is an established peripheral marker in diseases associated with Cu imbalance. By comparing these two parameters between control and MS subjects, we found an increase of Cp levels, associated with a decrease in Cp activity, in the second group. By analysing these data, free copper levels were calculated, significantly increased in serum of MS subjects; the increase in free copper could be one of the predisposing factors responsible for the Cu altered levels in CSF of MS patients. At the same time, this alteration could be attributable to the inability to incorporate Cu by Cp, probably due to the high oxidative environment found in serum of MS patients. Overall, all these copper alterations may play a role in MS pathogenesis.

Preliminary evidence supports the notion that COVID-19 patients may have an increased susceptibility to develop venous thromboembolism (VTE). However, the magnitude of this association still needs to be defined. Furthermore, clinical predictors of thrombogenesis, and the relationship with the inflammatory status are currently unknown. On this basis, we conducted a retrospective, observational study on 259 consecutive COVID-19 patients admitted to an academic tertiary referral hospital in Northern Italy between March 19th and April 6th, 2020. Records of COVID-19 patients with a definite VTE event were reviewed for demographic information, co-morbidities, risk factors for VTE, laboratory tests, and anticoagulation treatment. Twenty-five cases among 259 COVID-19 patients developed VTE (9.6%), all of them having a Padua score 4, although being under standard anticoagulation prophylaxis since hospital admission. In the VTE subcohort, we found a significant positive correlation between platelet count (PLT) and either C reactive protein (CRP) (p 0.0001) or lactate dehydrogenase (LDH) (p = 0.0013), while a significant inverse correlation was observed between PLT and mean platelet volume (p 0.0001). Platelet-to-lymphocyte ratio significantly correlated with CRP (p 0.0001). The majority of VTE patients was male and younger compared to non-VTE patients (p = 0.002 and p = 0.005, respectively). No significant difference was found in D-dimer levels between VTE and non VTE patients, while significantly higher levels of LDH (p = 0.04) and IL-6 (p = 0.04) were observed in VTE patients in comparison to non-VTE patients. In conclusion, our findings showed a quite high prevalence of VTE in COVID-19 patients. Raised inflammatory indexes and increased serum levels of pro-inflammatory cytokines should raise the clinical suspicion of VTE.

Supplemental material, Supplementary_material__Search_strategy_PubMed for Omalizumab and long-term quality of life outcomes in patients with moderate-to-severe allergic asthma: a systematic review by Giorgio Lorenzo Colombo, Sergio Di Matteo, Chiara Martinotti, Martina Oselin, Maria Chiara Valentino, Giacomo Matteo Bruno, Claudia Pitotti and Francesco Menzella in Therapeutic Advances in Respiratory Disease

Supplemental material, Supplementary_material__Quality_assessment__before-after_studies_OMA-QoL for Omalizumab and long-term quality of life outcomes in patients with moderate-to-severe allergic asthma: a systematic review by Giorgio Lorenzo Colombo, Sergio Di Matteo, Chiara Martinotti, Martina Oselin, Maria Chiara Valentino, Giacomo Matteo Bruno, Claudia Pitotti and Francesco Menzella in Therapeutic Advances in Respiratory Disease

Rapid alkylations of thiols are performed in a packed-bed flow reactor where potassium carbonate acts as a heterogeneous base in anhydrous solvents at ambient temperature. The reaction also has a high efficiency as the removal of the solvent is the only work up required to isolate the product. The products can be used in a subsequent oxidation which was performed sequentially in semibatch mode. The alkylations of phenol and benzyl amine have been demonstrated on an array of bases, but higher temperatures and longer reaction times are required than with thiols.

Introduction: Poorly controlled allergic asthma is associated with increased medical resource utilisation (MRU). PROXIMA study demonstrated effects of omalizumab on asthma control in Italian patients with severe allergic asthma (SAA). Here, we report effect of omalizumab on MRU in SAA patients. Methods: PROXIMA was a 2-phase observational study: cross-sectional phase enrolled patients with SAA (GINA step 4) requiring step-up therapy; longitudinal prospective phase enrolled patients receiving omalizumab as per clinician’s judgement at baseline visit. During the longitudinal phase, effect of omalizumab on number of hospitalisations/emergency room (ER) visits, medical visits to general practitioners (GP9s)/specialists, and outpatients/ER examinations was assessed by a dedicated questionnaire. Results: Of 365 patients enrolled, 123 contributed to longitudinal population. A considerable decrease in total number of hospitalisations/ER visits from 6 months before baseline visit (n=58) to 6 month follow-up visit was observed (n=3), which was maintained at 12 months (n=3). A continual decrease in number of GP’s/specialist’s visits and outpatients/ER examinations was observed from 6 months before baseline visit to 6 and 12 months of treatment (Table). Conclusion: In an Italian real-life setting, a decrease in MRU was observed with omalizumab treatment demonstrating improved symptoms in SAA patients.

Study objective Intravenous subdissociative-dose ketamine has been shown to be effective for pain management, but has not been specifically studied for headaches in the emergency department (ED). For this reason, we designed a study to compare standard treatment (prochlorperazine) with ketamine in patients with benign headaches in the ED. Methods This study was a multicenter, double-blind, randomized, controlled trial with a convenience sample of patients presenting to the ED with benign headaches. Patients were randomized to receive either prochlorperazine and diphenhydramine or ketamine and ondansetron. Patients' headache severity was measured on a 100-mm visual analog scale (VAS) at 0, 15, 30, 45, and 60 minutes. Nausea, vomiting, anxiety, and the need for rescue medications were also tracked. Patients were contacted at 24 to 48 hours posttreatment to rate their satisfaction and to determine whether they were still experiencing a headache. Results There were a total of 54 subjects enrolled. Two patients in the ketamine group and one in the prochlorperazine group withdrew because of adverse effects of the medications. In regard to the primary outcome, at 60 minutes, the prochlorperazine group had a mean improvement in VAS pain scores of 63.5 mm compared with 43.5 mm in the ketamine group, corresponding to a between-groups difference of 20.0 mm (95% confidence interval [CI] 2.8 to 37.2 mm) and a P value of .026. At 45 minutes, the prochlorperazine group had a mean improvement in pain scores of 56.1 mm compared with 38.0 mm in the ketamine group, a difference of 18.1 mm (95% CI 1.0 to 35.2 mm). At 24- to 48-hour follow-up, the mean satisfaction score was 8.3 of 10 for prochlorperazine and 4.9 of 10 for ketamine, a difference of 3.4 (95% CI 1.2 to 5.6). There was not a statistically significant difference in the percentage of patients who had a headache at follow-up or in other secondary outcomes. Conclusion Prochlorperazine appears to be superior to ketamine for the treatment of benign headaches in the ED.

A primigravid immigrant woman presented for termination of a 16-week pregnancy. The cervix was obscured by a transverse vaginal septum and was only identifiable by ultrasound. We used mifepristone for cervical preparation before concurrent septoplasty and dilation and evacuation.

Derivative longevity risk solutions, such as bespoke and indexed longevity swaps, allow pension schemes, and annuity providers to swap out longevity risk, but introduce counterparty credit risk, which can be mitigated if not fully eliminated by collateralization. We examine the impact of bilateral default risk and collateral rules on the marking to market of longevity swaps, and show how longevity swap rates must be determined endogenously from the collateral flows associated with the marking-to-market procedure. For typical interest rate and mortality parameters, we find that the impact of collateralization is modest in the presence of symmetric default risk, but more pronounced when default risk and/or collateral rules are asymmetric. Our results suggest that the overall cost of collateralization is comparable with, and often much smaller than, that found in the interest rate swaps market, which may then provide the appropriate reference framework for the credit enhancement of both indemnity-based and indexed longevity risk solutions.

Ideally, the portfolio is at the highest level of an organization as it shows the organization's truest intent, direction, and priorities. But, portfolios can exist at various levels such as business units, departments, divisions, and even at the program level. At the program level, the program manager can be considered a mini portfolio manager. The objective is at any time to ensure the portfolio represents a view of its selected components and reflects the organizational strategy and objectives regardless if the programs or projects have interdependencies, as the portfolio represents all the work under way in the organization. This means portfolio management includes all the activities to identify and align organizational priorities, determine governance and performance frameworks, measure the value/benefit of what is being done, make investment decisions, foster communication, and manage resource allocation. This chapter illustrates the various interrelations between program and portfolio management to show how programs can support portfolio in delivering business value.

The objective of this study was to assess the cost effectiveness of the dual bronchodilator indacaterol/glycopyrronium (IND/GLY) compared with salmeterol/fluticasone combination (SFC) in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) who had a history of one or no exacerbations in the previous year, in Canada, France, Italy, and Portugal. A patient-level simulation was developed to compare the costs and outcomes of IND/GLY versus SFC based on data from the LANTERN trial (NCT01709903). Monte-Carlo simulation methods were employed to follow individual patients over various time horizons. Population and efficacy inputs were derived from the LANTERN trial. Considering the payers’ perspective, only direct costs were included. Costs and health outcomes were discounted annually at 3.0 % for all countries. Unit costs were taken from publically available sources with all costs converted to euros (€). The cost base year was 2015. Deterministic and probabilistic sensitivity analyses were undertaken to test the robustness of the model results. IND/GLY was found to be the dominant (more effective and less costly) treatment option compared with SFC in all four countries. The use of IND/GLY was associated with mean total cost savings per patient over a lifetime of €6202, €1974, €1611, and €220 in Canada, France, Italy, and Portugal, respectively. Sensitivity analysis showed that exacerbation rates had the largest impact on incremental costs and quality-adjusted life-years (QALYs). The probability of IND/GLY being cost effective was estimated to be >95 % for thresholds above €5000/QALY. In patients with moderate to severe COPD, IND/GLY is likely to be a cost-effective treatment alternative compared with SFC.

To determine whether hydroxocobalamin will improve survival compared with epinephrine and saline solution controls in a model of cyanide-induced cardiac arrest.Forty-five swine (38 to 42 kg) were tracheally intubated, anesthetized, and central venous and arterial continuous cardiovascular monitoring catheters were inserted. Potassium cyanide was infused until cardiac arrest developed, defined as mean arterial pressure less than 30 mm Hg. Animals were treated with standardized mechanical chest compressions and were randomly assigned to receive one of 3 intravenous bolus therapies: hydroxocobalamin, epinephrine, or saline solution (control). All animals were monitored for 60 minutes after cardiac arrest. Additional epinephrine infusions were used in all arms of the study after return of spontaneous circulation for systolic blood pressure less than 90 mm Hg. A sample size of 15 animals per group was determined according to a power of 80%, a survival difference of 0.5, and an α of 0.05. Repeated-measure ANOVA was used to determine statistically significant changes between groups over time.Baseline weight, time to arrest, and cyanide dose at cardiac arrest were similar in the 3 groups. Coronary perfusion pressures with chest compressions were greater than 15 mm Hg in both treatment groups indicating sufficient compression depth. Zero of 15 (95% confidence interval [CI] 0% to 25%) animals in the control group, 11 of 15 (73%; 95% CI 48% to 90%) in the hydroxocobalamin group, and 11 of 15 (73%; 95% CI 48% to 90%) in the epinephrine group survived to the conclusion of the study (P.001). The proportion of animals with return of spontaneous circulation at 5 minutes was 4 of 15 (27%; 95% CI 10% to 52%), and that of return of spontaneous circulation at 10 minutes was 11 of 15 (73%; 95% CI 48% to 90%) in the 2 treatment groups. Additional epinephrine infusion after return of spontaneous circulation was administered for hypotension in 2 of 11 (18%; 95% CI 4% to 48%) hydroxocobalamin animals and in 11 of 11 (100%; 95% CI 70% to 100%) of the epinephrine animals (P.001). At 60 minutes, serum lactate was significantly lower in the hydroxocobalamin group compared with the epinephrine group (4.9 [SD 2.2] versus 12.3 [SD 2.2] mmol/L), and the pH was significantly higher (7.34 [SD 0.03] versus 7.15 [SD 0.07]). Serial blood cyanide levels in the hydroxocobalamin group were also lower than that of the epinephrine group from cardiac arrest through the conclusion of the study.Intravenous hydroxocobalamin and epinephrine both independently improved survival compared with saline solution control in our swine model of cyanide-induced cardiac arrest. Hydroxocobalamin improved mean arterial pressure and pH, decreased blood lactate and cyanide levels, and decreased the use of rescue epinephrine therapy compared with that in the epinephrine group.

Study objective We compare the efficacy of hydroxocobalamin to sodium thiosulfate to reverse the depressive effects on mean arterial pressure in a swine model of acute cyanide toxicity and gain a better understanding of the mechanism of action of the hydroxocobalamin in reversal of the toxicity. Methods Swine were intubated, anesthetized, and instrumented with central arterial and venous lines and a pulmonary artery catheter. Animals (n=36) were randomly assigned to one of 3 groups: hydroxocobalamin alone (150 mg/kg), sodium thiosulfate alone (413 mg/kg), or hydroxocobalamin (150 mg/kg)+sodium thiosulfate (413 mg/kg) and monitored for 60 minutes after the start of antidotal infusion. Cyanide was infused until severe hypotension developed, defined as blood pressure 50% of baseline mean arterial pressure. Repeated-measures ANOVA was used to determine statistically significant changes between groups over time. Results Time to hypotension (25, 28, and 33 minutes), cyanide dose at hypotension (4.7, 5.0, and 5.6 mg/kg), and mean cyanide blood levels (3.2, 3.7, and 3.8 μg/mL) and lactate levels (7, 8.2, 8.3 and mmol/L) were similar. All 12 animals in the sodium thiosulfate group died compared with 2 of 12 in the hydroxocobalamin/sodium thiosulfate group and 1 of 12 in hydroxocobalamin group. No statistically significant differences were detected between the hydroxocobalamin and hydroxocobalamin/sodium thiosulfate groups for carbon monoxide, mean arterial pressure, cyanide levels, or mortality at 60 minutes. Lactate level (2.6 versus 2.1 mmol/L), pH (7.44 versus 7.42), and bicarbonate level (25 versus 26 mEq/L) at 60 minutes were also similar between groups. Conclusion Sodium thiosulfate failed to reverse cyanide-induced shock in our swine model of severe cyanide toxicity. Further, sodium thiosulfate was not found to be effective when added to hydroxocobalamin in the treatment of cyanide-induced shock. Hydroxocobalamin alone was again found to be effective for severe cyanide toxicity.

Cyanide causes severe cardiac toxicity resulting in tachycardia, hypotension, and cardiac arrest; however, the clinical diagnosis can be difficult to make. A clinical finding that may precede or predict cyanide-induced hypotension may be a trigger to provide treatment earlier and improve outcomes in cyanide toxicity. Our primary objective was to determine if there is a clinically significant change in ST segment deviation measured on ECG during intravenous cyanide infusion that may predict cyanide-induced hypotension. As part of a larger study comparing antidotes for cyanide-induced shock, 30 swine were anesthetized and monitored and then intoxicated with a continuous cyanide infusion until severe hypotension (50 % of baseline mean arterial pressure) occurred. ECGs were obtained at baseline, every 5 min during infusion, and at the development of hypotension. Repeated measures of analysis of variance were used to determine significance. The mean weight for the 30 swine at baseline was 48 kg (range 45–52), pulse rate 86 beats/min (range 55–121), and systolic blood pressure 109 mmHg (range 90–121). The mean time to hypotension was 31 min (range 16–39). The mean amount of cyanide infused was 5 mg/kg (range 2.5–6.3 mg/kg). All animals (30/30) had ECG changes in repolarization or depolarization during cyanide infusion. Significant rhythm, repolarization, and conduction changes from baseline were observed prior to severe hypotension (p

Study objective: Community-associated methicillin-resistant Staphylococcus aureus is now the leading cause of uncomplicated skin abscesses in the United States, and the role of antibiotics is controversial. We evaluate whether trimethoprim-sulfamethoxazole reduces the rate of treatment failures during the 7 days after incision and drainage and whether it reduces new lesion formation within 30 days. Methods: In this multicenter, double-blind, randomized, placebo-controlled trial, we randomized adults to oral trimethoprimsulfamethoxazole or placebo after uncomplicated abscess incision and drainage. Using emergency department rechecks at 2 and 7 days and telephone follow-up, we assessed treatment failure within 7 days, and using clinical follow-up, telephone follow-up, and medical record review, we recorded the development of new lesions within 30 days. Results: We randomized 212 patients, and 190 (90%) were available for 7-day follow-up. We observed a statistically similar incidence of treatment failure in patients receiving trimethoprim-sulfamethoxazole (15/88; 17%) versus placebo (27/102; 26%), difference 9%, 95% confidence interval ‐2% to 21%; P.12. On 30-day follow-up (successful in 69% of patients), we observed fewer new lesions in the antibiotic (4/46; 9%) versus placebo (14/50; 28%) groups, difference 19%, 95% confidence interval 4% to 34%, P.02. Conclusion: After the incision and drainage of uncomplicated abscesses in adults, treatment with trimethoprimsulfamethoxazole does not reduce treatment failure but may decrease the formation of subsequent lesions. [Ann Emerg Med. 2010;56:283-287.]

Purpose: We aimed to estimate the 3-year budget impact of replacing salmeterol/fluticasone with indacaterol/glycopyrronium for the treatment of chronic obstructive pulmonary disease patients in Italy. Methods: The budget impact model included patients with moderate, severe, and very severe chronic obstructive pulmonary disease and was developed using data from the FLAME study. The budget impact model considered direct medical costs from the National Healthcare System perspective over a 3-year time-horizon. Costs of drugs, adverse events, and exacerbations were estimated using public net prices for drugs and national (inpatient/outpatient) tariffs for patient management. Data on adverse events and exacerbations were derived from FLAME and other clinical trials. The model assumed an increasing uptake of indacaterol/glycopyrronium, substituting it for salmeterol/fluticasone. Two sensitivity analyses were conducted. In the first, every long-acting muscarinic antagonist/inhaled corticosteroid switch to indacaterol/glycopyrronium; in the second, drugs compliance varies from 20% to 60%. Results: The target population was estimated at 572,788 patients in the first year, increasing to 585,491 in the third year. The alternative treatment pattern, with a higher indacaterol/glycopyrronium uptake, was associated with a total cost of €1.69 billion over 3 years, while the total costs in the current treatment pattern amounted to €1.71 billion. Thus, increasing indacaterol/glycopyrronium use provided total savings of €17.3 million over 3 years. Sensitivity analysis confirmed robustness of the results. Conclusion: Increasing the uptake of indacaterol/glycopyrronium was estimated to be cost-saving for the Italian National Healthcare System, both when drug-related expenditures and total costs were considered. Savings increased with the number of patients switching to indacaterol/glycopyrronium.

Objectives Easily administrated cyanide antidotes are needed for first responders, military troops, and emergency department staff after cyanide exposure in mass casualty incidents or due to smoke inhalation during fires involving many victims. Hydroxocobalamin has proven to be an effective antidote, but cannot be given intramuscularly because the volume of diluent needed is too large. Thus, intraosseous (IO) infusion may be an alternative, as it is simple and has been recommended for the administration of other resuscitation drugs. The primary objective of this study was to compare the efficacy of IO delivery of hydroxocobalamin to intravenous (IV) injection for the management of acute cyanide toxicity in a well-described porcine model. Methods Twenty-four swine (45 to 55 kg) were anesthetized, intubated, and instrumented with continuous mean arterial pressure (MAP) and cardiac output monitoring. Cyanide was continuously infused until severe hypotension (50% of baseline MAP), followed by IO or IV hydroxocobalamin treatment. Animals were randomly assigned to receive IV (150 mg/kg) or IO (150 mg/kg) hydroxocobalamin and monitored for 60 minutes after start of antidotal infusion. The primary outcome measure was the change in MAP after antidotal treatment from onset of hypotension (time zero) to 60 minutes. A sample size of 12 animals per group was determined by group size analysis based on power of 80% to detect a one standard deviation of the mean MAP between the groups with an alpha of 0.05. Whole blood cyanide, lactate, pH, nitrotyrosine (nitric oxide marker) levels, cerebral and renal near infrared spectrometry (NIRS) oxygenation, and inflammatory markers were also measured. Repeated-measures analysis of variance was used to determine statistically significant changes between groups over time. Results At baseline and at the point of hypotension, physiologic parameters were similar between groups. At the conclusion of the study, 10 out of 12 animals in the IV group and 10 out of 12 in IO group survived (p = 1.0). Both groups demonstrated a similar return to baseline MAP (p = 0.997). Cardiac output, oxygen saturation, and systemic vascular resistance were also found to be similar between groups (p > 0.4), and no difference was detected between bicarbonate, pH, and lactate levels (p > 0.8). Cyanide levels were undetectable after the hydroxocobalamin infusion throughout the study in both groups (p = 1.0). Cerebral and renal NIRS oxygenation decreased in parallel to MAP during cyanide infusion and increased after antidote infusion in both groups. Serum nitrotyrosine increased during cyanide infusion in all animals and then decreased in both study arms after hydroxocobalamin infusion (p > 0.5). Serum cytokines increased starting at cyanide infusion and no difference was detected between groups (tumor necrosis factor-α, interleukin [IL]-1β, IL-6, and IL-10). Conclusions The authors found no difference in the efficacy of IV versus IO hydroxocobalamin in the treatment of severe cyanide toxicity in a validated porcine model. Resumen Objetivos se necesitan antidotos para el cianuro de facil administracion para los primeros respondedores, las tropas militares y el personal del servicio de urgencias tras una exposicion al mismo en grandes cantidades o debido a la inhalacion de humo durante fuegos que involucren a muchas victimas. La hidroxocobalamina ha demostrado ser un antidoto efectivo, pero no puede ser administrada por via intramuscular debido a que el volumen de disolvente necesario es demasiado grande. Por ello, la via intraosea (IO) puede ser una alternativa, por su sencillez, y ha sido recomendada para la administracion de otros farmacos durante la resucitacion. El objetivo principal del estudio fue comparar la eficacia de la administracion IO de hidroxocobalamina con la inyeccion IV para el manejo de la intoxicacion aguda por cianuro en un modelo porcino bien descrito. Metodologia Veinticuatro cerdos (45 a 55 kg) se anestesiaron, intubaron e instrumentalizaron con monitorizacion continua de la presion arterial media (PAM) y el gasto cardiaco. El cianuro se perfundio de forma continua hasta la hipotension grave (50% de la PAM basal) seguido por el tratamiento con hidroxocobalamina IO o IV. Los animales fueron asignados de forma aleatorizada a recibir hidroxocobalamina por via IV (150 mg/kg) o IO (150 mg/kg) y fueron monitorizados durante 60 minutos tras el inicio de la infusion del antidoto. La medida de resultado principal fue el cambio en la PAM tras el tratamiento con el antidoto desde el inicio de la hipotension (tiempo cero) hasta los 60 minutos. Se determino un tamano muestral de 12 animales por grupo basandose en un poder del 80% para detectar una desviacion estandar de la media de PAM entre los grupos con un error alfa de 0,05. Se midio tambien el cianuro en sangre, lactato, pH, niveles nitrotirosina (marcador de oxido nitrico), la oxigenacion cerebral y renal mediante un espectrometro de infrarrojo cercano (NIRS, near infrared spectrometry) y marcadores de inflamacion. Se utilizo el analisis de la varianza para medidas repetidas para determinar los cambios estadisticamente significativos entre los grupos con el paso del tiempo. Resultados Basalmente y en el momento de la hipotension, los parametros fisiologicos fueron similares entre los grupos. Al final del estudio, 10 de los 12 animales en el grupo IV y 10 de los 12 en el grupo IO sobrevivieron (p = 1.0). Ambos grupos demostraron un retorno similar a la PAM basal (p = 0,997). El gasto cardiaco, la saturacion de oxigeno y la resistencia vascular sistemica se encontraron tambien similares entre los grupos (p > 0,4); y no se detectaron diferencias entre los niveles de bicarbonato, pH y lactato (p > 0,8). Las concentraciones de cianuro fueron indetectables tras la infusion de hidroxocobalamina durante el estudio en ambos grupos (p = 1.0). La oxigenacion cerebral y renal mediante espectroscopia funcional cercana al infrarrojo disminuyo de forma paralela a la PAM durante la infusion de cianuro y se incremento tras la infusion del antidoto en ambos grupos. La nitrotirosina serica se incremento durante la infusion de cianuro en todos los animales y despues descendio en ambos brazos del estudio tras la infusion de hidroxicobalamina (p > 0,5). Las citoquinas sericas se incrementaron al iniciar la infusion de cianuro y no se detecto diferencia entre los grupos (TNF-α, IL-1β, IL-6, y IL-10). Conclusiones No se encontraron diferencias en la eficacia de la hidroxocobalimina intravenosa frente a la intraosea en el tratamiento de la intoxicacion grave por cianuro en un modelo porcino validado.

Few biochemical and molecular details are available on microspore growth and development. In this work, a nuclease was partially purified from diffusates of barley (Hordeum vulgare L.) microspores by using concanavalin-A as ligand. The chromatographic preparation contained a 34-kDa protein with nucleolytic activity; the enzyme (called BMN: barley microspore nuclease) was very stable at pH8.0 and temperatures below 50 degrees C. Activity was highest at pH 5.6 and increased almost exponentially with temperature until a breakpoint between activity and stability was reached at 70 degrees C. Although BMN was able to cleave RNA, the enzyme showed a remarkable preference for DNA, especially in the single-stranded form. The best homopolymeric substrates were poly(dA) and poly(A), whereas poly(dC), poly(G) and poly(I) were almost completely uncleaved. When incubated with intact nuclei, BMN caused a nucleosomal DNA ladder of approximately 200 bp. On the basis of DNA laddering, substrate specificity, Mg2+ -dependence and best performance at apoplastic pH, BMN can be referred to as a putative apoptotic nuclease involved in pollen development.

Partially delactosated and demineralized whey protein powders were purified from pooled milks of individual cows homozygous for the β -lactoglobulin ( β -Lg) genetic variants A and B ( whey A and whey B). The protein composition of the two samples was similar. The two whey protein powders were dissolved in water at different pH (2, 4.5, 6.8) and NaCl concentrations (150 and 400 mmol/dm 3 ), and emulsions were made utilizing grape-seed oil. Emulsion stability (ES), emulsion activity index (EAI) and emulsion capacity (EC) were examined. The results showed the influence of the two genetic variants of β -Lg on the functional behaviour of whey. Emulsion obtained from B powder solutions showed the higher stability at the different test conditions. The best results occurred at pH 6.8 with no significant differences between the two tested NaCl concentrations. At pH2 and 400 mmol/dm 3 NaCl, both samples did not demonstrate any stability. Data on emulsion capacity indicated that whey B is less affected by the different physicochemical conditions tested (pH, NaCl concentration, heat treatment at 90°Cl5 min), while whey A gave the highest and the lowest EC values depending on the experimental conditions.

Reaction of the sterically demanding ligand precursor [(CHBut)2(C5H2But2)2]K2 with SnCl2 in THF gave the air-stable ansa-stannocene complex rac[(CHBut)2(C5H2But2)2]Sn. A single-crystal X-ray structure of the ansa-stannocene revealed a C2-symmetric and slipped bent structure, with the Sn2+ displaced toward an η2 bonding mode between bridged, highly tilted, and staggered 2,4-di-tert-butylcyclopentadienyl rings.

[Abstract not given by author]

We sought to compare the flow rates of the proximal tibia, the distal femur, and the proximal humerus using high pressure (greater than 300 mmHg) through an intraosseous (IO) infusion needle in an adult swine model.We performed a prospective interventional study in 11 swine. After placement of central vein and arterial lines, blood was removed via the central line until the animal's mean arterial pressure decreased 25% from the recorded baseline. We inserted a 25-mm IO needle into the proximal tibia and 45-mm needles into the distal femur and proximal humerus. All extremities were utilized in each study animal. We infused normal saline at each site for 10 minutes with a pressure bag inflated to the highest achievable pressure (greater than 300 mmHg) as measured at the infusion site with a calibrated portable inline pressure gauge. We measured the volume of normal saline remaining and we calculated infusion rates for each site. We then compared infusion flow rates between the three locations. Statistical analysis and comparison of the infusion rates of all three study arms were as performed using analysis of variance (ANOVA).The average weight of the swine was 71 kg (range 64-84 kg). Successful placement of the IO needle was confirmed at all three sites. The mean infusion flow rate was 213 mL/min (standard deviation [SD] 53.2 mL/min) for the proximal humerus, 138 mL/min (SD 65.3 mL/min) for the distal femur, and 103 mL/min (SD 48.1 mL/min) for the proximal tibia (p0.001). The flow rate through the proximal humerus was statistically greater than that for the proximal tibia and the distal femur (p0.001). The flow rates through the proximal tibia and distal femur were similar.The humerus is a suitable alternative site for IO placement, with a potential for higher flow rates than the proximal tibia and distal femur when resuscitating a patient.

It was previously demonstrated that some plant inhibitors are able to inactivate the bacterial proteinase subtilisin ; since information concerning the effect of plant inhibitors on other microbial proteinases remains limited, we decided to determine the activity of the soybean Kunitz and Bowman-Birk inhibitors (KI and BBI, respectively) on 14 proteinases of fungal and bacterial origin. The results show that microbial proteinases are frequently inhibited by KI and BBI and that proteinases with the same EC number (eg subtilisin Carlsberg and subtilisin BPN') may equally give different responses to the inhibitors. In particular, all serine proteinases examined were affected by both KI and BBI while metalloproteinases were not. Inhibition was also achieved on a range of microbial proteinases for which the mechanistic class is yet to be established ; the data suggest that they belong to the serine type. In one instance, activation instead of inhibition was noted.

Objectives: Our objective was to assess patients understanding of emergency department (ED) wait times and why patients may leave the waiting room before seeing a provider. Methods: Survey of patients in the ED waiting room of an urban tertiary care military hospital where civilian and military patients are treated. Results: A total of 508/517 surveys (98%) were completed. Age ranges were 18 to 35 years (49%), 36 to 60 (31%), or older than 60 (20%). Education levels were high school (20%), some college (37%), or college graduate (39%). Of 503 respondents, 125 (25%) had left an ED waiting room before seeing a provider. The reasons included excessive wait times (91%) and family responsibilities (5%). Five hundred eight reported the factors that would motivate them to wait to see the physician (not leave without being seen [LWOBS]) were the severity of illness (64%), and if they received an update of wait times (26%); 82% (391/480) understood that severely ill patients were seen first. Patients attributed long wait times to doctors and nurses caring for other patients (292/583, 50%) and insufficient physician and nurse staffing (245, 42%). Of 802 responses for ideas to improve the wait, 34% said regular updates on estimated wait times, 21% said television shows or movies to view, 20% said books and magazines to read, and 11% said computers to access. Conclusions: Long wait times were the primary reason that patients left before seeing a provider, despite having ready access to care. Respondents attributed long wait times to patient volume and inadequate staffing. Regular updates on wait times and material for entertainment may improve the waiting experience and reduce LWOBS.