Pulmonary arterial hypertension (PAH) is a disease characterized by increased pulmonary pressures and chronic right heart failure. Therapies for moderate and severe PAH include subcutaneous (SQ) and ...intravenous (IV) prostanoids that improve symptoms and quality of life. However, treatment compliance can be limited by severe side effects and complications related to methods of drug administration. Inhaled prostanoids, which offer the advantage of direct delivery of the drug to the pulmonary circulation without need for invasive approaches, may serve as an alternative for patients unable to tolerate SQ/IV therapy. In this retrospective cohort study we collected clinical, hemodynamic, and functional data from 18 clinically stable patients with World Health Organization group I PAH seen in 6 large national PAH centers before and after transitioning to inhaled treprostinil from IV/SQ prostanoids. Before transition 15 patients had been receiving IV or SQ treprostinil (mean dose 73 ng/kg/min) and 3 patients had been on IV epoprostenol (mean dose 10 ng/kg/min) for an average duration of 113 ± 80 months. Although most patients who transitioned to inhaled treprostinil demonstrated no statistically significant worsening of hemodynamics or 6-minute walk distance, a minority demonstrated worsening of New York Heart Association functional class over a 7-month period. In conclusion, although transition of patients from IV/SQ prostanoids to inhaled treprostinil appears to be well tolerated in clinically stable patients, they should remain closely monitored for signs of clinical decompensation.
To perform a meta-analysis of randomized controlled trials (RCTs) of drug-eluting balloon (DEB) angioplasty and drug-eluting stents (DESs) for infrainguinal peripheral arterial disease.
Systematic ...searches were performed for all relevant RCTs.
Eight RCTs for DEB angioplasty and 12 RCTs for a DES in peripheral arterial disease were identified. Meta-analysis demonstrated statistically significant superiority of DEB over plain balloon angioplasty of femoral-popliteal disease for late lumen loss, restenosis, and target lesion revascularization, with no benefit in major amputation or mortality. Statistically significant superiority of DEB over percutaneous transluminal angioplasty (PTA) was demonstrated for infrapopliteal disease for restenosis and target lesion revascularization. Drug-eluting stents showed statistically significant superiority over bare metal stents (BMSs) of femoral-popliteal disease for late lumen loss and restenosis, with no benefit in mortality or amputation. Drug-eluting stents showed statistically significant superiority over BMSs of infrapopliteal disease restenosis and target lesion revascularization, with no benefit in amputation or mortality.
Drug-eluting balloon angioplasty and DESs demonstrated superior outcomes compared to PTA and BMS, with no difference in amputation or mortality.
To assess the efficacy of less than 3 cycles of intra-arterial chemotherapy (IAC) for retinoblastoma.
Retrospective, nonrandomized, interventional case series.
Eight patients.
Intra-arterial ...chemotherapy.
Tumor control and globe salvage.
Eight patients received fewer than 3 cycles of IAC for retinoblastoma because there was complete tumor control with no residual viable tumor (n = 7) or poor response (n = 1) with little hope that further therapy would benefit the patient. In 3 cases, additional vascular compromise precluded further IAC. The treatment was primary in 6 cases and secondary after failure of other treatment in 2 cases. The 8 eyes were classified (International Classification of Retinoblastoma) as group C (n = 2), group D (n = 3), group E (n = 1), and secondary treatment (n = 2). At initial examination, the main tumor showed a mean basal diameter of 16 mm, a thickness of 8.6 mm, vitreous seeds (n = 2), subretinal seeds (n = 6), and iris neovascularization (n = 1). Three patients were treated with a single cycle of IAC, and 5 patients were treated with 2 cycles of IAC. After IAC, complete tumor response was found in 7 eyes (88%) and partial response was found in 1 eye (13%). Over a mean of 13 months follow-up, there was intraretinal tumor recurrence (n = 1), subretinal seed recurrence (n = 1), and no case of vitreous seed recurrence. Globe salvage was achieved in 2 of 2 group C eyes (100%), 3 of 3 group D eyes (100%), 0 of 1 group E eye (0%), and 1 of 2 secondary treatment eyes (50%). Globe salvage was achieved in 6 of 8 eyes (75%), and 2 of 8 eyes (25%) required enucleation.
One or 2 cycles of IAC can be sufficient for selected eyes with group C or D retinoblastoma, with remarkable tumor control.
The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Abstract Study Aim Clinical guidelines recommend fibrinolysis or embolectomy for acute massive pulmonary embolism (PE) (MPE). However, actual therapy and outcomes of emergency department (ED) ...patients with MPE have not previously been reported. We characterize the current management of ED patients with MPE in a US registry. Methods A prospective, observational, multicenter registry of ED patients with confirmed PE was conducted from 2006 to 2008. Massive PE was defined as PE with an initial systolic blood pressure less than 90 mm Hg. We compared inpatient and 30-day mortality, bleeding complications, and recurrent venous thromboembolism. Results Of 1875 patients enrolled, 58 (3.1%) had MPE. There was no difference in frequency of parenteral anticoagulation (98.3% 95% confidence interval {CI}, 90.5-101.6 vs 98.5% 95% CI, 97.9-99.1, P = .902) between patients with and without MPE. Fibrinolytic therapy and embolectomy were infrequently used but were used more in patients with MPE than in patients without MPE (12.1% 95% CI, 3.7-20.5 vs 2.4% 95% CI, 1.7-3.1, P < .001, and 3.4% 95% CI, 0.0-8.1 vs 0.7% 95% CI, 0.3-1.1, P = .022, respectively). Comparison of outcomes revealed higher all-cause inpatient mortality (13.8% 95% CI, 4.9-22.7 vs 3.0% 95% CI, 2.2-3.8, P < .001), higher risk of inpatient bleeding complications (10.3% 95% CI, 2.5-18.1 vs 3.5% 95% CI, 2.7-4.3, P = .007), and a higher 30-day mortality (14.0% 95% CI, 4.4-23.6 vs 1.8% 95% CI, 1.2-2.4, P < .001) for patients with MPE. Conclusions In a contemporary registry of ED patients, MPE mortality was 4-fold higher than patients without MPE, yet only 12% of the MPE cohort received fibrinolytic therapy. Variability exists between the treatment of MPE and current recommendations.
Background Circulating proteins may serve as biomarkers for the early diagnosis and treatment of shock. We have recently demonstrated that treatment with suberoylanilide hydroxamic acid (SAHA), ...a histone deacetylase inhibitor, significantly improves survival in a rodent model of lipopolysaccharide (LPS)-induced septic shock. Preliminary proteomic data showed that LPS-induced shock altered a number of proteins in circulation, including histone H3 (H3) and citrullinated histone H3 (Cit H3). The present study was designed to confirm these findings and to test whether the pro-survival phenotype could be detected by an early alteration in serum biomarkers. Methods Three experiments were performed. In experiment I, Western blotting was performed on serum samples from male C57B1/6J mice ( n = 9, 3/group) that belonged to the following groups: (a) LPS (20 mg/kg)-induced septic shock, (b) SAHA-treated septic shock, and (c) sham (no LPS, no SAHA). In experiment II, HL-60 granulocytes were cultured and treated with LPS (100 ng/m1) in the absence or presence of SAHA (10 μmol/L). Sham (no LPS, no SAHA) granulocytes served as controls. The medium and cells were harvested at 3 hours, and proteins were measured with Western blots. In experiment III, a large dose (LD, 35 mg/kg) or small dose (SD, 10 mg/kg) of LPS was injected intraperitoneally into the C57B1/6J mice ( n = 10 per group). Blood was collected at 3 hours, and serum proteins were determined by Western blots or enzyme-linked immunosorbent assay (ELISA). All of the Western blots were performed with antibodies against H3, Cit H3, and acetylated H3 (Ac H3). ELISA was performed with antibody against tumor necrosis factor (TNF)-α. Survival rates were recorded over 7 days. Results In experiment I, intraperitoneal (IP) injection of LPS (20 mg/kg) significantly increased serum levels of H3, which was prevented by SAHA treatment. In experiment II, LPS (100 ng/mL) induced expression and secretion of Cit H3 and H3 proteins in neutrophilic HL-60 cells, which was decreased by SAHA treatment. In experiment III, administration of LPS (LD) caused a rise in serum H3 and Cit H3 but not Ac H3 at 3 hours, and all of these animals died within 23 hours (100% mortality). Decreasing the dose of LPS (SD) significantly reduced the mortality rate (10% mortality) as well as the circulating levels of Cit H3 (non detectable) and H3. An increase in serum TNF-α was found in both LPS (LD) and (SD) groups, but in a non–dose-dependent fashion. Conclusion Our results reveal for the first time that Cit H3 is released into circulation during the early stages of LPS-induced shock. Moreover, serum levels of Cit H3 are significantly associated with severity of LPS-induced shock. Therefore, Cit H3 could serve as a potential protein biomarker for early diagnosis of septic shock, and for predicting its lethality.
Background Peanut allergy is typically severe, lifelong, and prevalent. Objective To identify factors associated with peanut sensitization. Methods We evaluated 503 infants 3 to 15 months of age ...(mean, 9.4 months) with likely milk or egg allergy but no previous diagnosis of peanut allergy. A total of 308 had experienced an immediate allergic reaction to cow's milk and/or egg, and 204 had moderate to severe atopic dermatitis and a positive allergy test to milk and/or egg. A peanut IgE level ≥5 kUA /L was considered likely indicative of peanut allergy. Results A total of 140 (27.8%) infants had peanut IgE levels ≥5 kUA /L. Multivariate analysis including clinical, laboratory, and demographic variables showed frequent peanut consumption during pregnancy (odds ratio, 2.9; 95% CI, 1.7-4.9; P < .001), IgE levels to milk ( P = .001) and egg ( P < .001), male sex ( P = .02), and nonwhite race ( P = .02) to be the primary factors associated with peanut IgE ≥5 kUA/L. Frequency of peanut consumption during pregnancy and breast-feeding showed a dose-response association with peanut IgE ≥5 kUA /L, but only consumption during pregnancy was a significant predictor. Among 71 infants never breast-fed, frequent consumption of peanut during pregnancy was strongly associated with peanut IgE ≥5 kUA /L (odds ratio, 4.99, 95% CI, 1.69-14.74; P < .004). Conclusion In this cohort of infants with likely milk or egg allergy, maternal ingestion of peanut during pregnancy was strongly associated with a high level of peanut sensitization.
Pneumococcal conjugate vaccine (PCV) and Haemophilus influenzae type b (Hib) vaccine are now used in most countries. To monitor global and regional progress towards improving child health and to ...inform national policies for disease prevention and treatment, we prepared global, regional, and national disease burden estimates for these pathogens in children from 2000 to 2015.
Using WHO and Maternal and Child Epidemiology Estimation collaboration country-specific estimates of pneumonia and meningitis mortality and pneumonia morbidity from 2000 to 2015, we applied pneumococcal and Hib cause-specific proportions to estimate pathogen-specific deaths and cases. Summary estimates of the proportion of pneumonia deaths and cases attributable to these pathogens were derived from four Hib vaccine and six PCV efficacy and effectiveness study values. The proportion of meningitis deaths due to each pathogen was derived from bacterial meningitis aetiology and adjusted pathogen-specific meningitis case–fatality data. Pneumococcal and Hib meningitis cases were inferred from modelled pathogen-specific meningitis deaths and literature-derived case–fatality estimates. Cases of pneumococcal and Hib syndromes other than pneumonia and meningitis were estimated using the ratio of pathogen-specific non-pneumonia, non-meningitis cases to pathogen-specific meningitis cases from the literature. We accounted for annual HIV infection prevalence, access to care, and vaccine use.
We estimated that there were 294 000 pneumococcal deaths (uncertainty range UR 192 000–366 000) and 29 500 Hib deaths (18 400–40 700) in HIV-uninfected children aged 1–59 months in 2015. An additional 23 300 deaths (15 300–28 700) associated with pneumococcus and fewer than 1000 deaths associated Hib were estimated to have occurred in children infected with HIV. We estimate that pneumococcal deaths declined by 51% (7–74) and Hib deaths by 90% (78–96) from 2000 to 2015. Most children who died of pneumococcus (81%) and Hib (76%) presented with pneumonia. Less conservative assumptions result in pneumococcccal death estimates that could be as high as 515 000 deaths (302 000–609 000) in 2015. Approximately 50% of all pneumococcal deaths in 2015 occurred in four countries in Africa and Asia: India (68 700 deaths, UR 44 600–86 100), Nigeria (49 000 deaths, 32 400–59 000), the Democratic Republic of the Congo (14 500 deaths, 9300–18 700), and Pakistan (14 400 deaths, 9700–17 000). India (15 600 deaths, 9800–21 500), Nigeria (3600 deaths, 2200–5100), China (3400 deaths, 2300–4600), and South Sudan (1000 deaths, 600–1400) had the greatest number of Hib deaths in 2015. We estimated 3·7 million episodes (UR 2·7 million–4·3 million) of severe pneumococcus and 340 000 episodes (196 000–669 000) of severe Hib globally in children in 2015.
The widespread use of Hib vaccine and the recent introduction of PCV in countries with high child mortality is associated with reductions in Hib and pneumococcal cases and deaths. Uncertainties in the burden of pneumococcal disease are largely driven by the fraction of pneumonia deaths attributable to pneumococcus. Progress towards further reducing the global burden of Hib and pneumococcal disease burden will depend on the efforts of a few large countries in Africa and Asia.
Bill & Melinda Gates Foundation.
Locoregional recurrence is common after surgery for gastric cancer. Adjuvant therapy improves outcomes but with toxicity. This phase 1/2 study investigated infusional 5-fluorouracil (5-FU) in ...combination with biweekly cisplatin delivered concurrently with image guided high-precision radiation therapy.
Eligible patients had completely resected stage IB to IV (Union for International Cancer Control TNM 6th edition) nonmetastatic gastric adenocarcinoma. Treatment constituted 12 weeks of infusional 5-FU (200 mg/m
/day) with cisplatin added in a standard 3 + 3 dose escalation protocol (0, 20, 30, and 40 mg/m
) during weeks 1, 3, 5, and 7, and an additional week 9 dose in the final cohort. Radiation therapy (45 Gy in 25 fractions) was delivered during weeks 3 to 7. Maximum tolerated dose (MTD) was determined in phase 1 and confirmed in phase 2.
Among the 55 patients (median age, 54 years; range 28-77 years; 55% male), the median follow-up time was 3.0 years (range, 0.3-5.3 years). Five patients in phase 1 experienced dose-limiting toxicity, and MTD was determined as 4 cycles of 40 mg/m
cisplatin. Twenty-seven patients were treated at MTD. Acute grade 3 to 4 toxicity rate was 37.0% at MTD and 29.1% across all dose levels. No treatment-related deaths occurred. Fourteen patients experienced recurrent disease. The 2-year overall survival (OS) and relapse-free survival were 85% and 74%, respectively. Median OS has not been reached. Quality of life (QOL) was impaired during treatment, but most scores recovered by 4 weeks.
Cisplatin can be safely delivered with 5-FU-based chemoradiation therapy. Acute toxicity was acceptable, and patient-reported QOL showed the regimen was tolerable. Outcomes are encouraging and justify further study of this regimen.
Abstract Objective To review the effect of elective single embryo transfer (eSET) compared with double embryo transfer (DET) following in vitro fertilization (IVF), and to provide guidelines on the ...use of eSET in order to optimize live birth rates and minimize twin pregnancies. Options Rates of live birth, clinical pregnancy, and multiple pregnancy following eSET and DET are compared. Outcomes Live birth, clinical pregnancy, and multiple pregnancy rates, and cost-effectiveness. Evidence Published literature was retrieved through searches of PubMed, Medline, and The Cochrane Library in 2009, using appropriate controlled vocabulary (e.g., elective single embryo transfer) and key words (e.g., embryo transfer, in vitro fertilization, intracytoplasmic sperm injection, assisted reproductive technologies, blastocyst, and multiple pregnancy). Results were restricted to English language systematic reviews, randomized controlled trials/controlled clinical trials, and observational studies. There were no date restrictions. Searches were updated on a regular basis and incorporated in the guideline to November 2009. Additional references were identified through searches of bibliographies of identified articles and international medical specialty societies. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Values Available evidence was reviewed by the Joint Society of Obstetricians and Gynaecologist of Canada–Canadian Fertility and Andrology Society Clinical Practice Guidelines Committee and the Reproductive Endocrinology and Infertility Committee of the Society of Obstetricians and Gynaecologists of Canada, and was qualified using the evaluation of evidence criteria outlined in the report of the Canadian Task Force on Preventive Health Care. Benefits, Harms, and Costs This guideline is intended to minimize the occurrence of twin gestations while maintaining acceptable overall live birth rates following IVF-ET. Summary Statements 1. Indiscriminate application of eSET in populations with less than optimal prognosis for live birth will result in a significant reduction in effectiveness compared with DET. (I) 2. In women aged 38 years and over, eSET may result in a significant reduction in live birth rate compared with DET. (II-2) 3. Selective application of eSET in a small group of good-prognosis patients may be effective in reducing the overall multiple rate of an entire IVF population. (II-3) 4. Given the high costs of treatment, uptake of eSET would be enhanced by public funding of IVF treatment. (II-2) Recommendations 1. Patients should be informed of the reductions in both multiple pregnancy rate and overall live birth rate after a single fresh eSET when compared with DET in good-prognosis patients. (I-A) 2. Because the cumulative live birth rate after fresh eSET followed by transfer of a single frozen-thawed embryo is similar but not equivalent to the rate after fresh DET in good-prognosis patients, the eSET strategy should be used in order to avoid multiple pregnancy. (I-A) 3. Women aged 35 years or less, in their first or second IVF attempt, with at least 2 good quality embryos available for transfer should be considered good-prognosis patients. (I-A) 4. In order to maximize cumulative live birth rates following eSET, effective cryopreservation programs should be in place. (I-A) 5. In order to maintain the reduction in the rate of multiples achieved by fresh eSET, eSET should be performed in subsequent frozen-thawed embryo transfer cycles. (II-2A) 6. Because blastocyst stage embryo transfer generally increases the chance of implantation and live birth compared with cleavage stage embryo transfer, eSET should be performed in good-prognosis patients who have good quality blastocysts available. (I-A) 7. In women aged 36 to 37 years, eSET should be considered in good-prognosis patients with good quality embryos, particularly when blastocysts are available for transfer. (II-2A) 8. In oocyte donor–recipient cycles when the donor has good prognosis and when good quality embryos are available, eSET should be performed. (II-2B) 9. In women with medical or obstetrical contraindications to twin pregnancy, eSET should be performed. (III-B) 10. In order to achieve successful uptake of eSET, it is essential to provide patient and physician education regarding the risks of twin pregnancy and regarding the similar cumulative live birth rate following an eSET strategy and DET. (III-C) 11. When considering both direct health care and societal costs, it should be noted that live birth following eSET is significantly less expensive than DET in good-prognosis patients. (I-A) Therefore, from a cost-effectiveness perspective, eSET is indicated in good-prognosis patients. (III-A)
Objectives In vivo lung perfusion (IVLP) is an emergent strategy to treat lung metastases because it allows localized delivery of chemotherapy with minimal systemic exposure. Previously, short-term ...(±30 minutes) IVLP resulted in variable efficacy and significant lung toxicity. We hypothesize that a modified IVLP strategy derived from an ex vivo lung perfusion technique could minimize lung injury. Our objective was to demonstrate the feasibility and safety of a modified prolonged (4 hours) IVLP. Methods Six Yorkshire pigs were used for the experiments. A thoracotomy was performed, the left pulmonary artery and pulmonary veins were cannulated, and the left lung was isolated in situ. IVLP was performed at normothermia for 4 hours using Steen Solution (XVIVO Perfusion, Göteburg, Sweden) as perfusate. The flow rate was 16% of estimated cardiac output and left atrial pressure was maintained between 3 and 5 mm Hg. Perfusate was deoxygenated and supplied with CO2 to physiologic levels before entering the lungs. A protective mode of ventilation was used. After IVLP, the left lung was allowed to reperfuse for additional 4 hours. Airway dynamics, gas exchange, and pulmonary vascular resistance were used to assess left lung physiology. Histologic signs of lung injury were assessed before and after IVLP, and 4 hours after reperfusion. Results Lung function parameters were stable throughout the 4-hour IVLP and during reperfusion. No significant histologic evidence of acute lung injury was observed. Conclusions Four hours of IVLP is feasible without adding significant lung injury. Prolonged perfusion time and a protective protocol might provide safer and more efficacious treatment of pulmonary metastases.
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