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STARDOM2 is a randomized, double-blind, phase 3 trial evaluating the efficacy and safety of co-crystal of tramadol-celecoxib (CTC)-a first-in-class analgesic co-crystal comprising racemic tramadol hydrochloride and celecoxib in a supramolecular network that modifies their pharmacokinetic properties-for the management of acute postoperative pain (NCT03062644; EudraCT:2016-000593-38).Patients with moderate-to-severe pain following abdominal hysterectomy were randomized 2:2:2:2:2:1 to oral CTC 100 mg (rac-tramadol hydrochloride 44 mg/celecoxib 56 mg) twice daily (BID); CTC 150 mg (66/84 mg) BID; CTC 200 mg (88/112 mg) BID; immediate-release tramadol 100 mg four times daily (QID); celecoxib 100 mg BID; or placebo, for 5 days. The primary endpoint was the sum of pain intensity differences over 0-4 h (SPIDsub0-4/sub). Key secondary endpoints were rescue medication use within 4 h, 50% response rate at 4 h, and safety/tolerability.Of 1355 patients enrolled, 1138 were randomized (full analysis set) and 1136 treated (safety analysis set). In the prespecified gatekeeping analysis of SPIDsub0-4/sub, CTC 200 mg was not superior to tramadol but showed non-inferior efficacy (p lt; 0.001) that was sustained throughout the 120-h period, despite a 5-day cumulative tramadol administration of 880 mg with CTC 200 mg BID versus 2000 mg with tramadol 100 mg QID. Treatment-emergent adverse events (TEAEs) and severe TEAEs were less common with CTC 200 mg versus tramadol. Treatment-related TEAEs were 14.4% with CTC 200 mg and 23.6% with tramadol.Although the study did not meet its primary endpoint, CTC 200 mg showed a clinically relevant improvement in overall benefit/risk profile versus tramadol alone, with considerably lower cumulative opioid exposure.In the randomized, double-blind, phase 3 STARDOM2 trial-in acute moderate-to-severe pain after abdominal hysterectomy-the novel co-crystal of tramadol-celecoxib (CTC) 200 mg BID was superior to placebo and non-inferior to tramadol 100 mg QID. Although superiority to tramadol was not reached, CTC 200 mg BID exposed patients to lower cumulative opioid (tramadol) doses than tramadol (100 mg QID) alone, with fewer treatment-emergent adverse events. CTC 200 mg thus has a clinically relevant improved benefit/risk profile compared with tramadol alone.

Due to safety concerns on estrogen-based treatments for genitourinary syndrome of menopause (GSM) in breast cancer survivors (BCS), new options are appearing, such as androgen-based treatments, which according to proprieties would not be transformed systemically to estrogens in patients receiving aromatase inhibitors (AIs).The aim of this pilot study is to assess the security and efficacy of vaginal prasterone (dehydroepiandrostenedione [DHEA]) in BCS treated with AIs.This open, prospective, pilot study included 10 BCS treated with AIs. All participants complained of severe GSM. DHEA was administrated as a vaginal ovule. Participants were instructed to use one ovule every night during the first month, and one ovule every two nights for the entire five remaining months. The patients were requested to attend seriated visits after the beginning of the prasterone treatment to evaluate symptoms, physical improvement and serum estradiol.Mean serum estradiol remained low from 3.4 pg/ml to 4.3 pg/ml (Symptoms and physical examination regarding sexuality and vaginal health improved significantly, while serum estradiol remained at low levels. Prasterone seems a safe and effective option to treat GSM in BCS receiving AIs.

The increasingly early diagnosis of breast disease and the more widespread use of primary systemic therapy leads to an increasing number of surgeries for non-palpable breast lesions (NPL) in clinical practice. Breast-conserving surgery often requires the use of an image-guided preoperative localization procedure, in which a device is placed within the lesion to be removed to guide the surgeon during surgery. These are patients with small, non-palpable tumors detected in the population screening mammogram, cases with significant reduction of the lesion after neoadjuvant chemotherapy and sometimes it is even necessary to mark axillary lymphadenopathies prior to systemic treatment. For decades, wire localization has been the standard for preoperative marking in breast cancer. Due to the external component of this device, extreme care must be taken not to alter its position before surgery, which is why it is placed hours before surgery and entails complex and limited flexibility in surgical programming. Intraoperative ultrasound improves this drawback but has the limitation that it can only be performed in those NPLs that have ultrasound translation. The Radioguided Occult Lesion Localization (ROLL) technique, although it is another alternative adopted by many institutions, is not without complications, among which the possibility of diffusion of the radiotracer into healthy tissue stands out. To overcome these problems, more recently

Preeclampsia is a multi-organ complication of pregnancy characterized by sudden hypertension and proteinuria that is among the leading causes of preterm delivery and maternal morbidity and mortality worldwide. The heterogeneity of preeclampsia poses a challenge for understanding its etiology and molecular basis. Intriguingly, risk for the condition increases in high-altitude regions such as the Peruvian Andes. To investigate the genetic basis of preeclampsia in a population living at high altitude, we characterized genome-wide variation in a cohort of preeclamptic and healthy Andean families (n = 883) from Puno, Peru, a city located above 3,800 meters of altitude. Our study collected genomic DNA and medical records from case-control trios and duos in local hospital settings. We generated genotype data for 439,314 SNPs, determined global ancestry patterns, and mapped associations between genetic variants and preeclampsia phenotypes. A transmission disequilibrium test (TDT) revealed variants near genes of biological importance for placental and blood vessel function. The top candidate region was found on chromosome 13 of the fetal genome and contains clotting factor genes PROZ, F7, and F10. These findings provide supporting evidence that common genetic variants within coagulation genes play an important role in preeclampsia. A selection scan revealed a potential adaptive signal around the ADAM12 locus on chromosome 10, implicated in pregnancy disorders. Our discovery of an association in a functional pathway relevant to pregnancy physiology in an understudied population of Native American origin demonstrates the increased power of family-based study design and underscores the importance of conducting genetic research in diverse populations.

Purpose Celecoxib-tramadol co-crystal (CTC) is a first-in-class co-crystal of celecoxib and racemic tramadol. This Phase 1 bioavailability study compared single-dose pharmacokinetic (PK) parameters of CTC with those of the individual reference products from the United States, immediate-release celecoxib and tramadol, taken alone and simultaneously to determine their systemic exposure. Methods This was a single-center, randomized, single-dose, open-label, 4-period, 4-sequence, crossover study conducted in healthy subjects between October and December 2016. Study treatments included 200-mg CTC (equivalent to 112-mg celecoxib and 88-mg tramadol; Treatment-1); 100-mg tramadol (Treatment-2); 100-mg celecoxib (Treatment-3); and 100-mg celecoxib plus 100-mg tramadol (Treatment-4). The PK parameters of interest were Cmax, AUC0–T, and AUC0–∞, which were also calculated normalized to the dose. Tmax was only considered as supportive. The statistical analysis was based on a parametric analysis of variance model of the PK parameters; the two-sided 90% CI of the ratio of geometric mean values for the Cmax, AUC0–T, and AUC0–∞ was based on ln-transformed data, and Tmax was rank-transformed. Findings Thirty-six subjects aged 18 to 55 years (21 male subjects, 15 female subjects; mean age, 35 years) participated in the study. Celecoxib from CTC presented a lower Cmax, reduced AUCs, and a faster Tmax. The interference in celecoxib absorption when celecoxib and tramadol are administered together was minimized with the CTC. For Treatment-1, -3, and -4, celecoxib PK parameters were 259, 318, and 165 ng/mL (Cmax), respectively; 1930, 2348, and 1929 ng • h/mL (AUC0–T); and 1.5, 3.0, and 2.5 hours (Tmax). Tramadol and its active metabolite O-desmethyl tramadol from CTC presented lower Cmax and AUCs as well as a longer Tmax. Tramadol/O-desmethyl tramadol PK parameters for Treatment-1, -2, and -4 were 214/55, 305/78, and 312/78 ng/mL for Cmax; 2507/846, 2709/965, and 2888/1010 ng • h/mL for AUC0–T; and 3.0/4.0, 2.0/2.5, and 1.9/2.5 hours for Tmax. Reported adverse events (none unexpected) occurred more frequently with Treatment-2 and Treatment-4. Implications The aim of this study was to compare the PK profile of the US-marketed tramadol and celecoxib products with CTC to determine their systemic exposure and to validate the dosing regimen for a subsequent pivotal factorial Phase 3study. PK parameters of each active component in CTC were favorably modified by co-crystallization and did not result in higher systemic exposure compared with US-marketed celecoxib, tramadol, and their concomitant administration. (Clin Ther. 2021;43:XXX–XXX) © 2021 Elsevier HS Journals, Inc.

To assess the impact of bloodstream infection (BSI) in patients with head and neck cancer (HNC) in the cetuximab era. We prospectively analysed the epidemiology, microbiology and outcomes of 51 BSI episodes occurring in 48 patients with HNC (2006–2017). We performed a retrospective matched-cohort study (1:2) to determine the risk factors for BSI. Finally, we compared patients who died with those who survived to identify risk factors for mortality. The most frequent HNC localization was the oropharynx (43%), and pneumonia was the most frequent source (25%). Gram-positive BSI occurred in 55% cases, mainly due to Streptococcus pneumoniae (21%), and among Gram-negatives, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae were the most frequent. Hypoalbuminemia (OR 8.4; 95% CI, 3.5–19.9), previous chemotherapy (OR, 3.2; 95% CI, 1.3–7.4) and cetuximab therapy (OR, 2.8; 95% CI, 1.6–6.7) were significant risk factors for BSI. Patients with BSI had a higher overall case-fatality rate than patients without BSI (OR, 4.4; 95% CI, 1.7–11.8). Hypoalbuminemia was an independent risk factor for the early (7 day) and overall (30 day) case-fatalities, with ORs of 0.8 (95% CI, 0.6–0.9) and 0.8 (95% CI, 0.7–0.97), respectively. The presence of comorbidities (OR, 7; 95% CI, 1.4–34) was also an independent risk factor for overall case-fatality. BSI causes high mortality in patients with HNC and is most often secondary to pneumonia. It occurs mainly among patients with hypoalbuminemia who receive treatment with cetuximab or chemotherapy. The development of BSI in patients with HNC impairs their outcome, especially in the presence of hypoalbuminemia and comorbidities.

β-Lactam/β-lactamase inhibitors (BLBLIs) were compared to carbapenems in two cohorts of hematological neutropenic patients with extended-spectrum-β-lactamase (ESBL) bloodstream infection (BSI): the empirical therapy cohort (174 patients) and the definitive therapy cohort (251 patients). The 30-day case fatality rates and other secondary outcomes were similar in the two therapy groups of the two cohorts and also in the propensity-matched cohorts. BLBLIs might be carbapenem-sparing alternatives for the treatment of BSI due to ESBLs in these patients., We thank the ESGBIS and the ESGICH study groups for supporting the study. This study was supported by Ministerio de Economía y Competitividad, Instituto de Salud Carlos III—cofinanced by European Development Regional Fund “A way to achieve Europe” EDRF, Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015).

Infection of long-term central venous catheters (CVCs) remains a challenge in the clinical management of cancer patients. We aimed to determine whether a lock solution with taurolidine-citrate-heparin would be more effective than placebo for preventing nontunneled CVC infection in high-risk neutropenic hematologic patients. We performed a prospective, multicenter, randomized (1:1), double-blind, parallel, superiority, placebo-controlled trial involving 150 hematological patients with neutropenia carrying nontunneled CVCs who were assigned to receive CVC lock solution with taurolidine-citrate-heparin or heparin alone. The primary endpoint was bacterial colonization of the CVC hubs. Secondary endpoints were the incidence of catheter-related bloodstream infection (CRBSI), CVC removal, adverse events related to the lock solution, and the 30-day case fatality rate. CVC lock solution with taurolidine-citrate-heparin was associated with less colonization of the CVC hubs than that with placebo, with no statistically significant differences: 4.1%, versus 10.1% (relative risk [RR] = 0.41, 95% confidence interval [CI] = 0.11 to 1.52), with a cumulative incidence of 4.17 (95% CI = 0.87 to 11.70) and 10.14 (95% CI = 4.18 to 19.79), respectively. There were no significant differences regarding the secondary endpoints. Only three episodes of CRBSI occurred during the study period. No adverse events related to the administration of the lock solution occurred. In this trial involving high-risk patients carrying nontunneled CVCs, the use of taurolidine-citrate-heparin did not show a benefit over the use of placebo. Nevertheless, the safety of this prevention strategy and the trend toward less hub colonization in the taurolidine-citrate-heparin group raise the interest in assessing its efficacy in centers with higher rates of CRBSI. (This study has been registered in ISRCTN under identifier ISRCTN47102251.), We thank the Bellvitge University Hospital Research Committee for the research grant awarded in 2012 and the nursing staff of the hematology departments. We thank CERCA Programme/Generalitat de Catalunya for institutional support. The TAURCAT study was a noncommercial, investigator-driven clinical trial funded by the Spanish Ministry of Science, Innovation and Universities, Instituto de Salud Carlos III (ISCIII) (grant PI13/01474), and the Spanish Network for Research in Infectious Diseases (REIPI; grant RD12/0015/0010), ISCIII, and by the Ministry of Economy, Industry and Competitiveness, cofinanced by European Development Regional Fund (A way to achieve Europe, Operational Program Intelligent Growth 2014-2020). The study also received an unrestricted grant from Bionet Medical S.L.

Summary Objectives To asses the clinical features, aetiology, antimicrobial resistance and outcomes of bacteraemic cholangitis in patients with solid tumours (ST). Methods All consecutive episodes of bacteraemia in hospitalized patients were prospectively analysed (2006–2015). Results Of 1852 episodes of bacteraemia, 750 involved patients with ST. Among them, 173 episodes (23%) were due to cholangitis. The most frequent neoplasms were hepato-biliary-pancreatic tumours (68.2%) and gastrointestinal cancer (18.5%); 57.2% of patients had a biliary stent in place. The most frequent causative agents were Escherichia coli (39.3%) followed by Klebsiella pneumoniae (15.1%) and Enterococcus faecium (7.8%). Forty-one episodes (18.7%) were caused by multidrug-resistant (MDR) microorganisms. Patients with a second episode of cholangitis were more likely to have an MDR isolate and to had received inadequate empirical antibiotic therapy. 7-day and 30-day case-fatality rates were 7.6% and 26%, respectively. The only risk factors independently associated with 30-day case-fatality rate were corticosteroids and malignancy-related complications. Conclusions Bacteraemic cholangitis is frequent in patients with ST, and is mainly caused by Enterobacteriaceae and E. faecium . The emergence of MDR is of special concern, particularly in patients with a second episode of bacteraemia. Case-fatality rates are high, especially among patients receiving corticosteroids and presenting malignancy-related complications.

To assess the etiology, clinical features and outcomes of bacteremia in older patients with solid tumors.All episodes of bacteremia in hospitalized patients with solid tumors were prospectively collected. Patients aged ≥70 years were compared to patients aged70 years. Risk factors for case-fatality rates in older patients were identified.We compared 217 episodes of bacteremia involving older patients and 525 occurring in younger patients. Older patients had more frequently other comorbidities, but were less commonly neutropenic and carried less frequently central venous catheters. Bacteremia from an abdominal source was more common in patients ≥70, whereas an endogenous source and catheter-related infection were less frequently observed. Streptococcus bovis group (3.7% vs. 0.8%, p = .01) and Listeria monocytogenes (4.6% vs. 1.9%, p = .04) were more common in older patients, whereas coagulase-negative staphylococci were less frequently found (1.4% vs. 5.3% p = .01). Infection due to multi-drug resistant (MDR) strains was significantly higher in older patients (17.1% vs. 10.9%, p = .02), who in addition, presented higher overall mortality (35.4% vs 27.7%, p = .04). In older patients, lung tumor, neutropenia, and low grade fever were associated with early mortality, whereas comorbidities, corticosteroids, septic shock and inadequate empirical antibiotic therapy were associated with overall mortality.We identified remarkable differences in the etiology and sources of bacteremia between older and younger cancer patients with bacteremia. Older patients had more frequent infection due to MDR organisms and presented a higher overall mortality. Corticosteroids and inadequate empirical antibiotic therapy are modifiable factors associated with mortality.

Summary Background Continuation of empirical antimicrobial therapy (EAT) for febrile neutropenia in patients with haematological malignancies until neutrophil recovery could prolong the therapy unnecessarily. We aimed to establish whether EAT discontinuation driven by a clinical approach regardless of neutrophil recovery would optimise the duration of therapy. Methods We did an investigator-driven, superiority, open-label, randomised, controlled phase 4 clinical trial in six academic hospitals in Spain. Eligible patients were adults with haematological malignancies or haemopoietic stem-cell transplantation recipients, with high-risk febrile neutropenia without aetiological diagnosis. An independent, computer-generated randomisation sequence was used to randomly enrol patients (1:1) to the experimental or control group. Investigators were masked to assignment only before randomisation. EAT based on an antipseudomonal β-lactam drug as monotherapy (ceftazidime or cefepime, meropenem or imipenem, or piperacillin-tazobactam) or as combination therapy (with an aminoglycoside, fluoroquinolone, or glycopeptide) was started according to local protocols and following international guidelines and recommendations. For the experimental group, EAT was withdrawn after 72 h or more of apyrexia plus clinical recovery; for the control group, treatment was withdrawn when the neutrophil count was also 0·5 × 10 9 cells per L or higher. The primary efficacy endpoint was the number of EAT-free days. Primary analyses were done in the intention-to-treat population. Efficacy and safety analyses were done in the intention-to-treat population and the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT01581333. Findings Between April 10, 2012, and May 31, 2016, 157 episodes among 709 patients assessed for eligibility were included in analyses. 78 patients were randomly assigned to the experimental group and 79 to the control group. The mean number of EAT-free days was significantly higher in the experimental group than in the control group (16·1 [SD 6·3] vs 13·6 [7·2], absolute difference −2·4 [95% CI −4·6 to −0·3]; p=0·026). 636 adverse events were reported (341 in the experimental group vs 295 in the control group; p=0·057) and most (580 [91%]; 323 in the experimental group vs 257 in the control group) were considered mild or moderate (grade 1–2). The most common adverse events in the experimental versus the control group were mucositis (28 [36%] of 78 patients vs 20 [25%] of 79 patients), diarrhoea (23 [29%] of 78 vs 24 [30%] of 79), and nausea and vomiting (20 [26%] of 78 vs 22 [28%] of 79). 56 severe adverse events were reported, 18 in the experimental group and 38 in the control group. One patient died in the experimental group (from hepatic veno-occlusive disease after an allogeneic haemopoietic stem-cell transplantation) and three died in the control group (one from multiorgan failure, one from invasive pulmonary aspergillosis, and one from a post-chemotherapy intestinal perforation). Interpretation In high-risk patients with haematological malignancies and febrile neutropenia, EAT can be discontinued after 72 h of apyrexia and clinical recovery irrespective of their neutrophil count. This clinical approach reduces unnecessary exposure to antimicrobials and it is safe. Funding Instituto de Salud Carlos III, Spanish Ministry of Economy (PI11/02674).

Objectives To assess the current incidence, clinical features, risk factors, aetiology, antimicrobial resistance and outcomes of polymicrobial bloodstream infection (PBSI) in patients with cancer. Methods All prospectively collected episodes of PBSI in hospitalised patients were compared with episodes of monomicrobial bloodstream infection (MBSI) between 2006 and 2015. Results We identified 194 (10.2%) episodes of PBSI and 1702 MBSI (89.8%). The presence of cholangitis, biliary stenting, neutropenia, corticosteroids, neutropenic enterocolitis and other abdominal infections were identified as risk factors for PBSI. Overall, Gram-negative organisms were the most frequent aetiology, but Enterococcus spp. were especially frequent causes of Gram-positive PBSI (30.8%). Multidrug-resistant (MDR) organisms were more commonly found in PBSI than in MBSI (20.6% vs 12.9%; p = 0.003). Compared to patients with MBSI, those with PBSI presented with higher early (15% vs 1.4%; p = 0.04) and overall (32% vs 20.9%; p

Information on the environmental variables that may affect the incidence of invasive aspergillosis (IA) is scarce. We sought to determine the relationship between airborne spore counts, climatic conditions and IA. We also examined whether circulating respiratory viruses predispose patients to IA in a multicentre cohort study of hospitalized adults with IA. Data on environmental mould spores, climatic conditions and circulating respiratory viruses were obtained from the Environmental Department of the Autonomous University of Barcelona, the Meteorological Service of Catalonia and the Acute Respiratory Infection Surveillance Project in Catalonia, respectively. Between 2008 and 2011, 165 patients with IA were identified. Diagnosis was based on one or more of the following: culture (125 cases), galactomannan antigen (98) and histology (34). One hundred and twenty-seven cases (77%) had criteria for probable IA and the remainder for proven IA. Environmental mould spore counts from the period 28–42 days preceding infection presented significant associations with admissions due to IA. None of the climatic conditions were associated with an increased risk of IA, but the presence of circulating respiratory viruses was associated with a higher risk of infection: the most strongly associated viruses were respiratory syncytial virus, influenza A(H1N1)pdm09 and adenovirus. In conclusion, the presence of high numbers of spores in the air increases the risk of admission due to IA. Circulating respiratory viruses appear to be associated with a higher risk of developing IA. Physicians should be aware of this association in order to optimize prevention and diagnosis strategies for IA during viral epidemic periods.

The aim of this study is to evaluate the relationship between the density of green spaces at different buffer sizes (300, 500, 1000 and 1500 m) and cardiovascular risk factors (obesity, hypertension, high cholesterol, and diabetes) as well as to study if the relationship is different for males and females. We conducted cross-sectional analyses using the baseline measures of the Heart Healthy Hoods study (N = 1625). We obtained data on the outcomes from clinical diagnoses, as well as anthropometric and blood sample measures. Exposure data on green spaces density at different buffer sizes were derived from the land cover distribution map of Madrid. Results showed an association between the density of green spaces within 300 and 500 m buffers with high cholesterol and diabetes, and an association between the density of green spaces within 1500 m buffer with hypertension. However, all of these associations were significant only in women. Study results, along with other evidence, may help policy-makers creating healthier environments that could reduce cardiovascular disease burden and reduce gender health inequities. Further research should investigate the specific mechanisms behind the differences by gender and buffer size of the relationship between green spaces and cardiovascular risk factors. This project was funded by the Instituto de Salud Carlos III, Subdirección General de Evaluación y Fomento de la Investigación, Government of Spain (PI18/00782) and by the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007–2013/ERC Starting Grant Heart Healthy Hoods Agreement no. 623 336893). P.G. was supported by the 2018 Alfonso Martín Escudero Research Grant.

Across Europe, excess body weight rates are particularly high among children and adolescents living in Southern European contexts. In Spain, current food policies appeal to voluntary self-regulation of the food industry and parents&rsquo, responsibility. However, there is no research (within Spain) assessing the food environment surrounding schools. We examined the association between neighborhood-level socioeconomic status (NSES) and the spatial access to an unhealthy food environment around schools using both counts and distance measures, across the city of Madrid. We conducted a cross-sectional study citywide (n = 2443 census tracts). In 2017, we identified all schools (n = 1321) and all food retailers offering unhealthy food and beverages surrounding them (n = 6530) using publicly available data. We examined both the counts of retailers (within 400 m) and the distance (in meters) from the schools to the closest retailer. We used multilevel regressions to model the association of neighborhood-level socioeconomic status (NSES) with both measures, adjusting both models for population density. Almost all schools (95%) were surrounded by unhealthy retailers within 400 m (median = 17 retailers, interquartile range = 8&ndash, 34). After adjusting for population density, NSES remained inversely associated with unhealthy food availability. Schools located in low-NSES areas (two lowest quintiles) showed, on average, 29% (IRR (Incidence Rate Ratio) = 1.29, 95% CI (Confidence Interval) = 1.12, 1.50) and 62% (IRR = 1.62, 95% CI = 1.35, 1.95) more counts of unhealthy retailers compared with schools in middle-NSES areas (ref.). Schools in high-NSES areas were farther from unhealthy food sources than those schools located in middle-NSES areas (&beta, = 0.35, 95% CI = 0.14, 0.47). Regulating the school food environment (within and beyond school boundaries) may be a promising direction to prevent and reduce childhood obesity.

ObjectivesTo describe the development and test–retest reliability of OHCITIES, an instrument characterising alcohol urban environment in terms of availability, promotion and signs of consumption.DesignThis study involved: (1) developing the conceptual framework for alcohol urban environment by means of literature reviewing and previous alcohol environment research experience; (2) pilot testing and redesigning the instrument; (3) instrument digitalisation; (4) instrument evaluation using test–retest reliability.SettingData for testing the reliability of the instrument were collected in seven census sections in Madrid in 2016 by two observers.Primary and secondary outcome measuresWe computed per cent agreement and Cohen’s kappa coefficients to estimate inter-rater and test–retest reliability for alcohol outlet environment measures. We calculated interclass coefficients and their 95% CIs to provide a measure of inter-rater reliability for signs of alcohol consumption measures.ResultsWe collected information on 92 on-premise and 24 off-premise alcohol outlets identified in the studied areas about availability, accessibility and promotion of alcohol. Most per cent-agreement values for alcohol measures in on-premise and off-premise alcohol outlets were greater than 80%, and inter-rater and test–retest reliability values were generally above 0.80. Observers identified 26 streets and 3 public squares with signs of alcohol consumption. Intraclass correlation coefficient between observers for any type of signs of alcohol consumption was 0.50 (95% CI −0.09 to 0.77). Few items promoting alcohol unrelated to alcohol outlets were found on public spaces.ConclusionsThe OHCITIES instrument is a reliable instrument to characterise alcohol urban environment. This instrument might be used to understand how alcohol environment associates with alcohol behaviours and its related health outcomes, and can help in the design and evaluation of policies to reduce the harm caused by alcohol.

[Introduction] Bloodstream infection (BSI) due to extended-spectrum β-lactamase-producing Gram-negative bacilli (ESBL-GNB) is increasing at an alarming pace worldwide. Although β-lactam/β-lactamase inhibitor (BLBLI) combinations have been suggested as an alternative to carbapenems for the treatment of BSI due to these resistant organisms in the general population, their usefulness for the treatment of BSI due to ESBL-GNB in haematological patients with neutropaenia is yet to be elucidated. The aim of the BICAR study is to compare the efficacy of BLBLI combinations with that of carbapenems for the treatment of BSI due to an ESBL-GNB in this population., [Methods and analysis] A multinational, multicentre, observational retrospective study. Episodes of BSI due to ESBL-GNB occurring in haematological patients and haematopoietic stem cell transplant recipients with neutropaenia from 1 January 2006 to 31 March 2015 will be analysed. The primary end point will be case-fatality rate within 30 days of onset of BSI. The secondary end points will be 7-day and 14-day case-fatality rates, microbiological failure, colonisation/infection by resistant bacteria, superinfection, intensive care unit admission and development of adverse events., [Sample size] The number of expected episodes of BSI due to ESBL-GNB in the participant centres will be 260 with a ratio of control to experimental participants of 2., [Ethics and dissemination] The protocol of the study was approved at the first site by the Research Ethics Committee (REC) of Hospital Universitari de Bellvitge. Approval will be also sought from all relevant RECs. Any formal presentation or publication of data from this study will be considered as a joint publication by the participating investigators and will follow the recommendations of the International Committee of Medical Journal Editors (ICMJE). The study has been endorsed by the European Study Group for Bloodstream Infection and Sepsis (ESGBIS) and the European Study Group for Infections in Compromised Hosts (ESGICH)., This study was supported by Ministerio de Economía y Competitividad, Instituto de Salud Carlos III—co-financed by European Development Regional Fund ‘A way to achieve Europe’ ERDF, Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015).

Background The axillary reverse mapping (ARM) technique has been proposed to prevent arm lymphedema. We conducted this study to assess the feasibility of the technique and the outcomes of patients with neoadjuvant chemotherapy (NAC). Methods From July 2009 to May 2010, a prospective study was performed in 36 patients with breast cancer undergoing an ALND. The ARM technique was performed injecting 3 cm3 of Patent Blue in the ipsilateral arm. Of the 36 patients, 29 patients received NAC previously to the ARM and 7 patients had an ALND and ARM performed as first treatment for positive axillary nodes. Results The identification rate of blue nodes was 83.3% (30 patients). Sentinel lymph node (SLN) was performed in 15 of 29 (42%) patients in the NAC group. Of these 15, two patients (13%) had a concordance between the blue and the hot node. Blue nodes were positive in 4 (13%) of the 30 patients. Conclusions The ARM technique is feasible in patients undergoing NAC. Patients with extensive nodal involvement have increased risk of having positive blue nodes. More studies are needed to assess the subgroup of patients with positive axilla that may have the blue node spared without compromising the oncological treatment. J. Surg. Oncol. 2012; 106:89–93. © 2012 Wiley Periodicals, Inc.

We aimed to assess the clinical features, aetiology and outcomes of bacteraemic pneumonia in neutropenic cancer patients (NCP) in the current era of increasing antimicrobial resistance.All episodes of bacteraemia occurring in hospitalized patients with cancer, including haematopoietic stem cell transplant recipients, from January 2006 to April 2015 were included.We identified 1723 episodes of bacteraemia, of which 795 occurred in neutropenic patients with cancer, and among them, 55 episodes were identified as bacteraemic pneumonia. The most frequent causative agents were Pseudomonas aeruginosa (39.6%), Streptococcus pneumoniae (20.6%) and Escherichia coli (8.6%). Among the Gram-negative organisms, 12.8% were multidrug resistant (MDR). Eleven patients (20%) required admission to intensive care, and eight (14.8%) underwent invasive mechanical ventilation. Nine patients (16.3%) received inadequate empirical antibiotic therapy, of whom six (66.6%) died; eight of these nine patients had pneumonia caused by resistant microorganisms. The early (48 h) case-fatality rate was 24% and the overall (30 day) case-fatality rate was 46.2%.Bacteraemic pneumonia is a frequent complication among NCP and is mainly caused by P. aeruginosa and S. pneumoniae. The emergence of MDR organisms is of special concern. Despite the improvement in the management of cancer patients, case-fatality rates of NCP with bacteraemic pneumonia remain high. Urgent assessment is needed to identify a better approach for the management and support of these patients.

Information regarding the processes leading to death in patients with invasive aspergillosis (IA) is lacking. We sought to determine the causes of death in these patients, the role that IA played in the cause, and the timing of death. The factors associated with IA-related mortality are also analyzed. We conducted a multicenter study (2008-2011) of cases of proven and probable IA. The causes of death and whether mortality was judged to be IA-related or IA-unrelated were determined by consensus using a six-member review panel. A multivariate analysis was performed to determine risk factors for IA-related death. Of 152 patients with IA, 92 (60.5%) died. Mortality was judged to be IA-related in 62 cases and IA-unrelated in 30. The most common cause of IA-related death was respiratory failure (50/62 patients), caused primarily by Aspergillus infection, although also by concomitant infections or severe comorbidities. Progression of underlying disease and bacteremic shock were the most frequent causes of IA-unrelated death. IA-related mortality accounted for 98% and 87% of deaths within the first 14 and 21 days, respectively. Liver disease (HR 4.54; 95% CI, 1.69-12.23) was independently associated with IA-related mortality, whereas voriconazole treatment was associated with reduced risk of death (HR 0.43; 95% CI, 0.20-0.93). In conclusion, better management of lung injury after IA diagnosis is the main challenge for physicians to improve IA outcomes. There are significant differences in causes and timing between IA-related and IA–unrelated mortality and these should be considered in future research to assess the quality of IA care.

This study was designed to compare the rate and extent of absorption of 2 oral formulations of ondansetron (CAS 99614-02-5) 8 mg orodispers- ible tablets in healthy volunteers. 22 subjects were administered ondansetron orodispersible tablets of test and reference formulation in a single-dose, 2-period, 2-sequence, fasting, open- label, crossover and randomised study. Plasma concentrations were determined by LC/MS/MS. Log-transformed AUCs and C max values were tested for bioequivalence based on the ratios of the geometric means (test/reference). T max was analysed nonparametrically. The 90 % confi dence intervals of the geometric mean values for the test/reference ratios for AUC 0-t and C max were within the bioequivalence acceptance range of 80-125 %. According to the European Guideline (1) it may be therefore concluded that test formula- tion of ondansetron 8 mg orodispersible tablet is bioequivalent to the reference formulation.

One bioequivalence study was carried out in healthy volunteers in order to compare the rate and extent of absorption of two oral formulations of quetiapine fumarate (CAS 111974-72-2) 25 mg film-coated tablet. Thirty subjects were administered quetiapine fumarate film-coated tablet of test and reference formulation in an open-label, randomised, fasting, two-period, two-sequence, crossover study. Blood samples were taken before and within 48 h after drug administration. Plasma concentrations were determined by LC/MS/MS. Log-transformed AUC and Cmax values were tested for bioequivalence based on the ratios of the geometric means (test/reference). Tmax was analysed nonparametrically. The 90% confidence intervals of the geometric mean values for the test/reference ratios for AUCo-t, and Cmax were within the bioequivalence acceptance range of 80-125%. It may be therefore concluded that the test formulation of quetiapine fumarate 25 mg film-coated tablet is bioequivalent to the reference product and can be prescribed interchangeably.

Two bioequivalence studies were carried out in healthy volunteers in order to compare the rate and extent of absorption of two dosage forms (film-coated tablet and orodispersible tablet) of oral olanzapine (CAS 132539-06-1) 10 mg test formulations and the respective brand formulations as reference. Twenty and twenty-six subjects were administered olanzapine film-coated tablet or orodispersible tablet of test and reference formulations in an open-label, randomised, fasting, two-period, two-sequence, crossover study. Blood samples were taken before and within 240 h after drug administration. Plasma concentrations were determined by LC/MS/MS. Log-transformed AUC and Cmax values were tested for bioequivalence based on the ratios of the geometric means (test/reference). tmax was analysed nonparametrically. The 90% confidence intervals of the geometric mean values for the test/reference ratios for AUC(0-t) and Cmax were within the bioequivalence acceptance range of 80-125%. It may be therefore concluded that the test formulations of olanzapine 10 mg film-coated tablet and orodispersible tablet are bioequivalent to the reference products and can be prescribed interchangeably.

To describe the prevalence of congenital varicella syndrome (CVS) within the population of presumably infected pregnant women.From 1993 to 2006, all women who presented vesicular rash or a suspicious contact were referred and evaluated in a special unit at our center. Those with residual immunity or were serologically negative were precluded from this study. Positive IgM cases underwent monthly ultrasound scans (US), fetal blood (FB) sampling (including IgM anti VZV and virus culture). Amniotic fluid sample for PCR was added to the diagnosis of positive IgM cases after 1997.A total of 276, of the 566 consulted women, tested positive for IgM anti VZV. Seventeen (6%) were excluded because of an unadvised termination of pregnancy and seven (2.55%) miscarried. Only seven (2.7%) were considered highly likely to have a VZV fetal infection. One case showed positive IgM in FB but developed normally. Another fetus showed positive PCR and infection was confirmed post TOP. Four cases that underwent TOP and histochemistry confirmed no more cases. Complete post-natal follow-up was carried out. The asymptomatic infected child grew healthy until the completion of screening tests when it reached 5 years old.The fetal infection rate in this cohort was 0.8%, but the best expected prevalence of CVS, according to our findings, should be 0.39% among infected women. This data should be considered and used during parental counselling.

Triflusal (CAS 322-79-2) is an antiplatelet agent that irreversibly acetylates cyclooxygenase isoform 1 (COX-1) and therefore inhibits thromboxane biosynthesis. The main metabolite of triflusal, 2-hydroxy-4-trifluoromethyl benzoic acid (HTB), possesses also antiaggregant activity. Recently a new oral 600 mg (10 ml) solution form of triflusal has been developed. The purpose of this clinical trial was to study the relative bioavailability of the new oral solution of triflusal versus the capsules formulation, both administered as a single dose. This was a randomized, two-way, cross-over, open-label, single-site phase I clinical trial, in 24 healthy volunteers who received triflusal as 600 mg oral solution and as two 300 mg capsules in a single administration separated by a washout period of at least 17 days. Blood samples were collected and plasma concentrations of HTB were measured. Pharmacokinetic parameters used for bioequivalence assessment included AUC(0-t), AUC(0-inf) and Cmax. The formulations were considered bioequivalent if the geometric mean ratios of AUC(0-t), AUC(0-inf) and Cmax were within the predetermined equivalence range (80% to 125%). Tolerability was based on the recording of adverse events (AEs), physical examination, electrocardiogram (ECG) and laboratory tests. The parameters for bioequivalence, mean [SD] values were as follows: AUC(0-t) (microg x h/ml): 3574.08 [628.17] for triflusal oral solution and 3901.78 [698.43] for triflusal capsules; AUC(0-infinity) (microg x h/ml): 4089.21 [842.54] for triflusal oral solution and 4471.33 [905.93] for triflusal capsules; Cmax, (microg/ml): 91.24 [12.88] for triflusal oral solution and 88.61 [13.46] for triflusal capsules; Cmax/AUC(0-infinity) (h(-1)): 0.03 (0.00) for triflusal oral solution and 0.02 (0.00) for triflusal capsules. The 90% confidence intervals for the ratio experimental/control by analysis of variance after log transformed AUC(0-infinity), AUC(0-t), and Cmax were within 80% to 125%. Similar results were found for the data without log transformation. All adverse events were of mild or moderate intensity and all subjects recovered. Nine and 12 subjects reported at least one adverse event during treatment with triflusal oral solution and with triflusal capsules, respectively. The most frequently reported adverse events were headache and dizziness. It was concluded that the 600-mg solution of triflusal appeared to be bioequivalent to the reference formulation capsules. Both formulations were well tolerated.

Background One of the benefits of neoadjuvant chemotherapy (NAC) is its ability to convert patients ineligible for breast conservative treatment (BCT) to be candidates for this treatment, although questions have been raised regarding the effectiveness of BCT in terms of loco-regional recurrence (LRR). The objective of this study is to evaluate LRR in this group and the influence of tumor characteristics in recurrence. Material and Methods Between 1996 and 2007, 137 patients were treated with BCT after NAC at our Service. After completion of NAC a multidisciplinary team evaluated the cases eligible for BCT. All patients treated with BCT had negative margins and received radiation therapy. Risk factors associated with local recurrence were analyzed using Kaplan–Meier survival curves and long-rang test. Results Information was obtained in 121 patients. Median age was 54 years old (SD: 12 years). At a median follow-up of 35 months (range, 18–87 months), 6 (4.95%) patients developed an LRR, with an accumulative incidence at 5 years of 7.3% (95% CI: 0.4–14.1%) and at 10 years of 11.5% (95% CI: 2.8–20.1%). Overall survival at 5 and 10 years was 94.8% (95% CI: 90.9–98.6%) and 82.3% (95% CI: 67.3–97.2%) respectively. Tumor size (T3) ( p p = 0.001) after surgery were strongly associated with LRR. Conclusions The results of this study confirm that BCT is an effective treatment in patients with NAC. Tumor size and pathological stage after systemic treatment influence loco-regional recurrence in patients with BCT.

To evaluate the stability of microalbuminuria figures in urine samples of diabetic patients, in terms of how the samples are kept, and the time between taking and reading.Descriptive, prospective and observational study.Primary care. Teaching health centre, Burgos.40 type-2 diabetics had their urinary excretion of albumin measured in 91 first-in-the-morning urine samples with Micral Test II reactive strips.Samples were analysed the day of their collection, then protected from light and kept at +4 degrees C, with further readings at 24, 48 and 72 hours and at 7, 14, 21 and 28 days after collection.49 (53.84%) of the 91 samples taken did not vary over the 28 days of the study. In the first three days, there were 64 with unvaried measurements (70.2%). Friedman's test showed p = 0.905.93% of samples positive at the beginning remained positive all the time;83% of samples negative at the beginning remained negative. Concordance observed was90%; kappa index80%.Collection of first urine samples in the morning, stored at +4 degrees C in a fridge and protected from light, did not significantly alter the result of the reading for 4 weeks. Such samples are useful in order to aid study of the albumin excretion rate using Micral Test II reactive strips.

Background Doxylamine succinate, an ethanolamine-based antihistamine, is used in the short-term management of insomnia because of its sedative effects. No data on the dose proportionality of the pharmacokinetics of doxylamine are available, although this drug has been marketed in European countries for more than 50 years. Objective The objective of this study was to evaluate and compare the dose proportionality between two marketed strengths (12.5 mg and 25 mg) of doxylamine hydrogen succinate after a single oral dose administration under fasting conditions in healthy human subjects. Study Design This was a single-center, randomized, single dose, laboratory-blinded, two-period, two-sequence, crossover study. Setting The study was conducted in a phase I clinical unit. Subjects and Methods A single oral dose of doxylamine hydrogen succinate of 12.5 mg (equivalent to 8.7 mg of doxylamine base) or 25 mg (equivalent to 17.4 mg of doxylamine base) was administered to healthy volunteers under fasting conditions in each study period. The drug administrations were separated by a wash-out period of 7 calendar days. Blood samples were collected for up to 60 h post-dose, and plasma doxylamine levels were determined by an ultra high-performance liquid chromatography method with tandem mass spectrometry detection. Pharmacokinetic parameters were calculated using non-compartmental analysis. Dose proportionality was assessed based on the parameter area under the concentration–time curve (AUCt normalized). Safety was evaluated through assessment of adverse events, standard laboratory evaluations, vital signs and 12-lead electrocardiogram (ECG). Results In total, 12 healthy volunteers (3 male; 9 female) were included in the study. Mean maximum observed plasma concentration (Cmax) and area under the concentration–time curve from time zero to time t (AUCt) of doxylamine hydrogen succinate 12.5 mg and 25 mg tablets increased linearly and dose-dependently [12.5 mg: mean Cmax 61.94 ng/mL, coefficient of variation (CV) 23.2 %; mean AUCt 817.33 ng·h/mL, CV 27.4 %; and 25 mg: mean Cmax 124.91 ng/mL, CV 18.7 %; mean AUCt 1630.85 ng·h/mL, CV 22.8 %]. Mean AUCt normalized was 815.43 ng·h/mL, CV 22.8 % for 25 mg. The dose-normalized geometric mean ratio (%, 12.5 mg/25 mg) of AUCt was 98.92 (90 % CI: 92.46, 105.83). The most common adverse event was somnolence. Conclusions Exposure to doxylamine was proportional over the therapeutic dose range of 12.5–25 mg in healthy volunteers. Based on the results, a predictable and linear increase in systemic exposure can be expected. Doxylamine hydrogen succinate was safe and well tolerated.

Introduction: Bloodstream infection (BSI) due to extended-spectrum β-lactamase-producing Gram-negative bacilli (ESBL-GNB) is increasing at an alarming pace worldwide. Although β-lactam/β-lactamase inhibitor (BLBLI) combinations have been suggested as an alternative to carbapenems for the treatment of BSI due to these resistant organisms in the general population, their usefulness for the treatment of BSI due to ESBL-GNB in haematological patients with neutropaenia is yet to be elucidated. The aim of the BICAR study is to compare the efficacy of BLBLI combinations with that of carbapenems for the treatment of BSI due to an ESBL-GNB in this population. Methods and analysis: A multinational, multicentre, observational retrospective study. Episodes of BSI due to ESBL-GNB occurring in haematological patients and haematopoietic stem cell transplant recipients with neutropaenia from 1 January 2006 to 31 March 2015 will be analysed. The primary end point will be case-fatality rate within 30 days of onset of BSI. The secondary end points will be 7-day and 14-day case-fatality rates, microbiological failure, colonisation/infection by resistant bacteria, superinfection, intensive care unit admission and development of adverse events. Sample size: The number of expected episodes of BSI due to ESBL-GNB in the participant centres will be 260 with a ratio of control to experimental participants of 2. Ethics and dissemination: The protocol of the study was approved at the first site by the Research Ethics Committee (REC) of Hospital Universitari de Bellvitge. Approval will be also sought from all relevant RECs. Any formal presentation or publication of data from this study will be considered as a joint publication by the participating investigators and will follow the recommendations of the International Committee of Medical Journal Editors (ICMJE). The study has been endorsed by the European Study Group for Bloodstream Infection and Sepsis (ESGBIS) and the European Study Group for Infections in Compromised Hosts (ESGICH).

Objective The objective of the study was to evaluate bioequivalence of two strengths (1 and 2 mg) of oral risperidone tablet formulations (test product manufactured by Vita-Invest, S.A., Barcelona, Spain, reference product manufactured by Janssen-Cilag Ltd., UK). Subjects and methods In each of the 2 studies, 30 healthy volunteers were administered 1 or 2 mg, respectively, of test or reference formulation under fasting conditions in an open, two-way crossover, controlled, randomized and single-site fashion. Blood withdrawal was performed prior to dosing as well as 15 min, 30 min, 1 h, 1.5 h, 2 h, 3 h, 5 h, 8 h, 12 h, 16 h, 24 h, 48 h, 72 h, and 96 h after drug administration. Plasma concentrations of risperidone and its metabolite 9-hydroxy-risperidone were analyzed using LC/MS/MS. Descriptive data of AUC0-t, AUC0- yen, Cmax, and Cmax/AUC0- yen were log-transformed to evaluate bioequivalence based on the ratios of the geometric means of test and reference formulations. tmax was analyzed using nonparametric methods. Results The results show that in both studies, 1 and 2 mg formulations, the 90% confidence intervals for the geometric means ratios of the test and reference products for both the parent compound risperidone and its metabolite 9-hydroxy-risperidone were all within the bioequivalence acceptance criteria of 0.80 - 1.25 of the European CPMP and the US FDA guidelines, with the exception of tmax for risperidone parent compound in the 2 mg formulation, which was slightly suprabioequivalent for test formulation. Conclusion This study demonstrated the bioequivalence between the test and the reference product of risperidone of both 1 and 2 mg formulations. Both formulations of each strength may, therefore, be prescribed interchangeably.