Diamorphine pharmacokinetics and conversion factor estimates for intranasal diamorphine in paediatric breakthrough pain:systematic review

BACKGROUND: Intranasal diamorphine is a potential treatment for breakthrough pain but few paediatric data are available to assist dose estimation. AIM: To determine an intranasal diamorphine dose in children through an understanding of pharmacokinetics. DESIGN: A systematic review of the literature was undertaken to seek diamorphine pharmacokinetic parameters in neonates, children and adults. Parenteral and enteral diamorphine bioavailability were reviewed with respect to formation of the major metabolite, morphine. Clinical data quantifying equianalgesic effects of diamorphine and morphine were reviewed. REVIEW SOURCES: PubMed (1960-2020); EMBASE (1980-2020); IPA (1973-2020) and original human research studies that reported diacetylmorphine and metabolite after any dose or route of administration. RESULTS: The systematic review identified 19 studies: 16 in adults and 1 in children and 2 neonatal reports. Details of study participants were extracted. Age ranged from premature neonates to 67 years and weight 1.4-88 kg. Intranasal diamorphine bioavailability was predicted as 50%. The equianalgesic intravenous conversion ratio of morphine:diamorphine was 2:1. There was heterogeneity between pharmacokinetic parameter estimates attributed to routes of administration, lack of size standardisation, methodology and pharmacokinetic analysis. Estimates of the pharmacokinetic parameters clearance and volume of distribution were reduced in neonates. There were insufficient paediatric data to characterise clearance or volume maturation of either diamorphine or its metabolites. CONCLUSIONS: We estimate equianalgesic ratios of intravenous morphine:diamorphine 2:1, intravenous morphine:intranasal diamorphine 1:1 and oral morphine:intranasal diamorphine of 1:3. These ratios are based on adult literature, but are reasonable for deciding on an initial dose of 0.1 mg/kg in children 4-13 years

Inhibition of Chondrosarcoma Growth by mTOR Inhibitor in an In Vivo Syngeneic Rat Model

BACKGROUND: Chondrosarcomas are the second most frequent primary malignant type of bone tumor. No effective systemic treatment has been identified in advanced or adjuvant phases for chondrosarcoma. The aim of the present study was to determine the antitumor effects of doxorubicin and everolimus, an mTOR inhibitor on chondrosarcoma progression. METHODS AND FINDINGS: Doxorubin and/or everolimus were tested in vivo as single agent or in combination in the rat orthotopic Schwarm chondrosarcoma model, in macroscopic phase, as well as with microscopic residual disease. Response to everolimus and/or doxorubicin was evaluated using chondrosarcoma volume evolution (MRI). Histological response was evaluated with % of tumor necrosis, tumor proliferation index, metabolism quantification analysis between the treated and control groups. Statistical analyses were performed using chi square, Fishers exact test. Doxorubicin single agent has no effect of tumor growth as compared to no treatment; conversely, everolimus single agent significantly inhibited tumor progression in macroscopic tumors with no synergistic additive effect with doxorubicin. Everolimus inhibited chondrosarcoma proliferation as evaluated by Ki67 expression did not induce the apoptosis of tumor cells; everolimus reduced Glut1 and 4EBP1 expression. Importantly when given in rats with microscopic residual diseases, in a pseudo neoadjuvant setting, following R1 resection of the implanted tumor, everolimus significantly delayed or prevented tumor recurrence. CONCLUSIONS: MTOR inhibitor everolimus blocks cell proliferation, Glut1 expression and HIF1a expression, and prevents in vivo chondrosarcoma tumor progression in both macroscopic and in adjuvant phase post R1 resection. Taken together, our preclinical data indicate that mTOR inhibitor may be effective as a single agent in treating chondrosarcoma patients. A clinical trial evaluating mTOr inhibitor as neo-adjuvant and adjuvant therapy in chondrosarcoma patients is being constructed

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Primary central nervous system lymphoma in an Asian population : a 15-year experience

The aim of this study was to characterize primary central nervous system lymphoma (PCNSL) among Asian patients and to determine their outcomes with different therapeutic modalities. Patients and Methods: Between 1990 and 2005, 37 patients with PCNSL were analyzed within 5 different treatment groups: radiotherapy alone (arm A), combined chemoradiation (arm B), chemotherapy alone with methotrexate (MTX) &#8805; 1 g/m2 (arm C), miscellaneous therapy (arm D), and best supportive care (arm E). Results: The median age at presentation was 59 years, and the majority of patients were male (68). All patients had aggressive diffuse large B-cell lymphoma. The number of patients in arms A to E were 6, 16, 3, 8 and 4, respectively. The overall median survival was 7.4 months, 54.1 months, not reached, 8.9 months and 0.9 months, respectively. Use of MTX 1-2.5 g/m2 per cycle and an ECOG performance status of 0-2 were each associated with improved survival on univariate analysis (p = 0.022 and p = 0.049, respectively). Compared to radiotherapy alone, use of combined chemo-radiation was associated with a trend towards improved overall median survival (7.4 vs. 54.1 months, p = 0.058). Conclusion: The clinical characteristics and treatment outcomes in our Asian patients were comparable to those reported in Western series. Use of MTX 1-2.5 g/m2 per cycle and an ECOG performance status of 0-2 were associated with improved survival

High SUV uptake on FDG-PET/CT predicts for an aggressive B-cell lymphoma in a prospective study of primary FDG-PET/CT staging in lymphoma

Background: Data assessing the role of positron emission tomography (PET)/computed tomography (CT) imaging in lymphoma staging is still being accumulated and current staging is based primarily on CT. This study aims to compare the value of PET/CT over conventional CT and bone marrow biopsy (BMB) in the initial evaluation of patients with lymphoma. Methods: Data on 122 patients with PET/CT scans as part of their initial staging were prospectively collected and reviewed. All patients had complete staging, including BMB. Results: Among the 122 patients, 101 had non-Hodgkin's lymphoma (NHL) and 21 had Hodgkin's lymphoma (HL). Compared with conventional CT, PET/CT upstaged 21 (17%) cases [B-cell non-Hodgkin's lymphoma (B-NHL), 12; T-cell non-Hodgkin's lymphoma (T-NHL), 3; HL, 6]. Of significance, in 13 patients with 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG)-avid splenic lesions, four had normal CT findings. A maximum FDG uptake of >10 standardized uptake value (SUV) seems to significantly correlate with an aggressive B-cell lineage (odds ratio 2.47, 95% confidence interval 2.23–2.70). Overall, PET scan was concordant with BMB results in 108 (89%) and discordant in 14 (11%) cases. In HL, our data show that PET scan and marrow results agreed in 19 of the cases (90%), being concordantly negative in 18 cases and concordantly positive in one, giving a negative predictive value (NPV) of 100%, sensitivity of 100% and specificity of 90%. Of note, all 13 with early-stage HL had negative PET/CT scan and BMB. In NHL, all 17 cases of T-NHL had concordant PET and BMB results. In patients with aggressive B-NHL, BMB and PET/CT agreed in 58 patients (92%) and disagreed in five (8%), while the corresponding rates in indolent B-cell lymphoma were 14 (67%) and seven patients (33%), respectively. All seven were falsely negative. Conclusions: PET/CT upstages 17% of cases and detects occult splenic involvement. This may have potential therapeutic and prognostic implications. SUV >10 may predict for an aggressive histology. Except for indolent B-NHL, our data show that PET scans have a good overall NPV in excluding lymphomatous bone marrow involvement. This is particularly true of early-stage HL, suggesting that BMB may be safely omitted in this group

The conundrum in smart city governance: Interoperability and compatibility in an ever-growing ecosystem of digital twins

Today, technological developments are ever-growing yet fragmented. Alongside inconsistent digital approaches and attitudes across city administrations, such developments have made it difficult to reap the benefits of city digital twins. Bringing together experiences from five research projects, this paper discusses these digital twins based on two digital integration methodologies - systems and semantic integration. We revisit the nature of the underlying technologies, and their implications for interoperability and compatibility in the context of planning processes and smart urbanism. Semantic approaches present a new opportunity for bidirectional data flows that can inform both governance processes and technological systems to co-create, cross-pollinate, and support optimal outcomes. Building on this opportunity, we suggest that considering the technological dimension as a new addition to the trifecta of economic, environmental, and social sustainability goals that guide planning processes, can aid governments to address this conundrum of fragmentation, interoperability, and compatibility

Mental Health of the General Population during the 2019 Coronavirus Disease (COVID-19) Pandemic: A Tale of Two Developing Countries

Background: This study aimed to compare the severity of psychological impact, anxiety and depression between people from two developing countries, Iran and China, and to correlate mental health parameters with variables relating to the COVID-19 pandemic. Although China and Iran are developing countries based on the World Bank’s criteria, these two countries are different in access to resources and health care systems. We hypothesized that Iranians would show higher levels of depression, anxiety and stress as compared to Chinese. Methods: This study collected information related to the COVID-19 pandemic including physical health, precautionary measures and knowledge about the pandemic. We also used validated questionnaires such as the Impact of Event Scale-Revised (IES-R) and the Depression, Anxiety and Stress Scale (DASS-21) to assess the mental health status. Results: There were a total of 1411 respondents (550 from Iran; 861 from China). The mean IES-R scores of respondents from both countries were above the cut-off for post-traumatic stress disorder (PTSD) symptoms. Iranians had significantly higher levels of anxiety and depression (p &lt; 0.01). Significantly more Iranians believed COVID-19 was transmitted via contact, practised hand hygiene, were unsatisfied with health information and expressed less confidence in their doctors, but were less likely to wear a facemask (p &lt; 0.001). Significantly more Iranians received health information related to COVID-19 via television while Chinese preferred the Internet (p &lt; 0.001). Conclusions: This cross-country study found that Iranians had significantly higher levels of anxiety and depression as compared to Chinese. The difference in reported measures between respondents from Iran and China were due to differences in access to healthcare services and governments’ responses to the pandemic

Prognostic factors in patients with diffuse large B cell lymphoma : before and after the introduction of rituximab

This study attempted to evaluate the usefulness of the International Prognostic Index (IPI) as a prognostic model in patients treated with R-CHOP (rituximab, cyclophosphamide, vincristine, adriamycin and prednisolone) chemotherapy. We compared 279 patients with DLBCL. Among them, 183 received CHOP while 96 received R-CHOP. Results showed that there were no statistically significant differences between the two groups of patients in terms of both the patient and the lymphoma characteristics. The estimated 2-year survival was significantly higher among patients treated with R-CHOP compared to CHOP alone (85.6% vs. 64.7%, P = 0.004). Both the IPI and age-adjusted IPI were less useful as prognostic models in patients receiving R-CHOP compared to CHOP. In the multivariate analysis, age ≥ 60, elevated serum LDH, low serum albumin and advanced stages of disease were each independently associated with decreased survival in patients treated with CHOP. In contrast, among those treated with R-CHOP, only male sex and advanced stage of disease were each independently associated with decreased survival. Using these two factors, patients treated with R-CHOP could be separated into three prognostic groups with 5-year estimated survival ranging from 47% to 100% (P < 0.0001). In summary, we can conclude that with the significant improvement in survival following the use of rituximab, the relevance of previously recognized prognostic factors has to be reassessed and re-evaluated