Long-term use of prescription opioids for non-cancer pain and mortality: a population-based, propensity-weighted cohort study.

OBJECTIVE: The objective of this study was to identify factors associated with long-term opioid use and to assess the association between long-term use and death. STUDY DESIGN: Retrospective cohort study combining several population-wide databases and covering a population of five million inhabitants, including all adults who were initiated on opioid treatment from 2014 to 2018 for non-cancer pain. METHODS: We used logistic regression models to identify factors associated with chronic opioid use and carried out survival analyses using multivariable Cox regression modelling for all-cause mortality during follow-up using inverse probability of treatment weighting (IPTW) and propensity scores based on the probability of using opioids chronically. RESULTS: Among 760,006 patients, 82,423 (10.85%) used opioids for 90 days or more after initiation. Initial therapy characteristics associated with higher risk for long-term use were initiating with long- and short-acting opioids (when compared to tramadol, odds ratio [OR]: 2.63, 95% confidence interval [CI]: 2.57, 2.69 and OR: 1.60, 95%CI: 1.46, 1.76, respectively), using higher daily doses (when compared to 50 morphine milligramme equivalent [MME] or less, prescribing 50 to 89 daily MME, OR: 1.76, 95%CI: 1.65, 1.87; 90 to 119 daily MME, OR: 2.44, 95%CI: 1.99, 3.01; and more than 120 daily MME, OR: 1.77, 95%CI: 1.64, 1.91), and overlapping with gabapentinoids (OR: 2.26, 95%CI: 2.20, 2.32), benzodiazepines (OR: 1.32, 95%CI: 1.30, 1.35), and antipsychotics (OR: 1.21, 95%CI: 1.16, 1.26). After IPTW, chronic opioid use was associated with higher risk of all-cause mortality when compared to short-term use (Hazard Ratio (HR): 1.37, 95%CI: 1.32, 1.42). Sensitivity analyses provided similar results. CONCLUSION: These findings may help healthcare managers to identify and address patients at higher risk of long-term use and riskier prescription patterns.

Antipsychotic use in a large community sample of patients with delusional disorder.

BACKGROUND: To examine clinical and sociodemographic differences between patients with delusional disorder; with and without diagnoses of an additional severe mental disorder (SMD) or cognitive impairment. METHODS: Population-based study including all individuals diagnosed with DD between 2005 and 2021 from a large catchment area in Madrid, Spain. Sociodemographic and clinical characteristics and the antipsychotic prescription patterns of the study population was described. Patients were divided into (i) patients with DD and no additional diagnosis of SMD or cognitive impairment (DD group), (ii) patients with DD and a diagnosis of an additional SMD (DD-SMD group), and (iii) patients with DD and cognitive impairment (DD-CI group). RESULTS: Of 1109 patients with a DD diagnosis (62.5 % female), 131 (11.8 %) patients were diagnosed with an additional SMD, and 69 (6.2 %) were diagnosed with cognitive impairment. DD-SMD patients were on average 10 years younger and had longer time between first mental healthcare contact and DD disorder than DD patients. DD-CI patients were on average 10 years older and had a higher proportion of females. Paliperidone (21.9 %) and aripiprazole (20.6 %) were the modal antipsychotic drugs chosen overall. DD-SMD patients were more likely to receive paliperidone and to be prescribed long-acting injectable medication; DD-CI were more likely to receive risperidone or quetiapine; and DD patients were more likely to receive olanzapine. CONCLUSIONS: Sociodemographic and clinical characteristics and choice of antipsychotic drug and delivery method for individuals with DD vary based on its comorbidity.

Parallel laser micromachining based on diffractive optical elements with dispersion compensated femtosecond pulses.

We experimentally demonstrate multi-beam high spatial resolution laser micromachining with femtosecond pulses. The effects of chromatic aberrations as well as pulse stretching on the material processed due to diffraction were significantly mitigated by using a suited dispersion compensated module (DCM). This permits to increase the area of processing in a factor 3 in comparison with a conventional setup. Specifically, 52 blind holes have been drilled simultaneously onto a stainless steel sample with a 30 fs laser pulse in a parallel processing configuration.

Prevalence of osteoporotic fracture risk factors and antiosteoporotic treatments in the Valencia region, Spain. The baseline characteristics of the ESOSVAL cohort.

UNLABELLED: This study provides information on the prevalence of the most important risk factors for osteoporosis and osteoporotic fracture in a large sample of women and men from the Valencia region and also provides the FRAX 10-year major and hip fracture risks for this population, as well as data about the use of diagnostic tests and antiosteoporotic treatments. INTRODUCTION: The purpose of this study was to describe demographic characteristics, osteoporosis risk factors, the 10-year risk of osteoporotic fracture, and the use of densitometry and antiosteoporotic treatments in the Valencia region, Spain. METHODS: A cross-sectional study using the ESOSVAL cohort baseline data was conducted. We analyze the data from 5,310 women and 5,725 men aged 50 and over who attended to 272 collaborating primary care centers in 2009-2010. We collected the demographic, anthropometric, clinical, and pharmacy data from the electronic medical record. RESULTS: The mean age of participants was 64.3 years old for women and 65.6 years old for men. The most frequent fracture risk factors were sedentary life (22.2 %) and previous fracture (15.8 %) in women and low calcium intake (21.4 %) and current smoker (20.9 %) in men. According to FRAX(®), the 10-year risk of presenting a major fracture was 5.5 % for the women and 2.8 % for the men. The 10-year risk for hip fracture was 1.9 and 1.1 % for the women and the men, respectively; 23.8 % of the women and 5.2 % of the men had a densitometry test, 27.7 % of the women and 3.5 % of the men were taking calcium and/or vitamin D supplements, and 28.2 % of the women (22.0 % in the 50-64 age group) and 2.3 % of the men were taking antiosteoporotic drugs. CONCLUSIONS: The prevalence of certain fracture risk factors not included in the FRAX tool (sedentary life, falls, low calcium intake) is high. In young women, their low risks estimated by FRAX contrast with the high figures for densitometry testing and treatment.

Improvement of the Pour Plate Method by Separate Sterilization of Agar and Other Medium Components and Reduction of the Agar Concentration.

Although the pour plate method is widely employed in microbiological quality control, it has certain drawbacks, including having to melt the culture medium before seeding. In this study, the preparation of the culture medium was modified by using a lower concentration of agar (10 g/L), which was separated from the nutrients during sterilization. The new protocol was assessed in media frequently used in microbiological quality control of food, cosmetics, and pharmaceutical products, with tryptic soy agar (TSA), Sabouraud 4% dextrose agar (SDA), and violet red bile glucose agar (VRBG). In comparison with the conventionally produced media, the modifications significantly improved the growth of Saccharomyces cerevisiae in SDA, Staphylococcus aureus, Salmonella enterica subsp. enterica serovar Typhimurium, and Candida albicans in TSA and Escherichia coli ATCC 8739 and ATCC 25922 and S. Typhimurium in VRBG. The modified VRBG was also more selective for Pseudomonas aeruginosa. Regarding physicochemical properties, a significantly lower pH was observed in TSA and VRBG and lower strength values in TSA. Sterilizing agar separately from the other components of the medium and reducing the agar concentration to 10 g/L can improve microorganism growth and enhance the selectivity of differential media in the pour plate method. These modifications could facilitate the automation of this culture technique. IMPORTANCE In the era of rapid microbiological methods, there is a need to improve long-established culture techniques. Drawbacks of the pour plate method include having to melt each medium separately before seeding. For this technique, we demonstrate that separating the agar from the other components of commonly used media during sterilization and reducing the agar concentration to 10 g/L can enhance microbial growth. The new protocol could have advantages in routine laboratory practice because less agar is required and the same molten agar suspension can be used to prepare different media. Moreover, these modifications could facilitate the automation of the pour plate method.

Agreement between semi-automatic radiographic morphometry and Genant semi-quantitative method in the assessment of vertebral fractures.

UNLABELLED: Semi-automatic morphometry is highly reproducible and not time intensive; however, no study has evaluated agreement between semi-automated morphometric methods and the Genant semi-quantitative method performed as a rule by radiologists. Our study shows substantial agreement between both methods; however, semi-automatic morphometry upgrades mild deformities and overestimates the prevalence of fractures. INTRODUCTION: The aim of this study was to evaluate the agreement between radiologists using the Genant semi-quantitative (SQ) method and semi-automated morphometry in the diagnosis of vertebral fractures in post-menopausal women. METHODS: Cross-sectional study was conducted in 2006-2007 in an age-stratified population-based sample of 824 post-menopausal women over the age of 50. From this population two sets of 95 and 50 X-ray were randomly extracted to test inter-rater agreement and agreement between SQ and semi-automated morphometry, and vertebral fractures were classified according to both methods. The Genant method was used to homogenise the diagnosis of fractures. Agreement was evaluated with weighted kappa. We evaluated each vertebral body independently and also the whole vertebral column (T4-L4) classifying women into the worst grade of fracture. For the qualitative interpretation of the agreement, we used the criteria described by Landis and Koch (Biometrics 33:159-174, 1977). RESULTS: The radiologists' agreement was 98.4% (Kappa, 0.75; 95% CI, 0.42-0.89). Agreement between semi-automated morphometry and SQ reached 97.6% and Kappa was 0.86 (95% CI, 0.66-0.94). In the whole evaluation of the spine semi-automated morphometry overestimates, the prevalence of fractures compared with the radiologists were 15.8% of women with fractures and 7.4% of women with moderate-severe fractures by semi-automated morphometry vs. 8.4% and 3.2% by the SQ method. The negative predictive value for MorphoXpress was 99% while the positive was 40%. CONCLUSIONS: Semi-automated morphometry shows high reliability and a substantial agreement with the SQ approach but overestimates the prevalence of fractures. Its role in routine clinical practice is limited because positive results should be reassessed by qualitative or semi-quantitative methods.

Improvement of Mueller-Kauffman Tetrathionate-Novobiocin (MKTTn) enrichment medium for the detection of Salmonella enterica by the addition of ex situ-generated tetrathionate.

The detection of Salmonella in food is based on the use of a selective enrichment broth such as Muller-Kauffman Tetrathionate-Novobiocin (MKTTn), in which tetrathionate plays a key role by providing Salmonella with a growth advantage. As sodium tetrathionate is unstable, it is generated in situ by the addition of iodine (Lugol's solution) before seeding. This step is cumbersome as the solution is easily spilled, compromising the performance of the medium and hindering the work of technicians. The aim of this study was to optimize MKTTn broth by generating tetrathionate ex situ through an external reaction between iodine and thiosulphate followed by lyophilization. Quality control procedures were performed to compare the modified and original media, testing pure productivity (enrichment with 50-120 CFU of Salmonella Thyphimurium ATCC 14028 and Salmonella Enteritidis ATCC 13076 and plating on Xylose Lysine Deoxycholate agar, XLD), mixed productivity (50-120 CFU of Salmonella strains and Pseudomonas aeruginosa and Escherichia coli at ≥104 CFU and XLD plating) and selectivity (≥104 CFU of P. aeruginosa and Enterococcus faecalis and plating on Tryptone Casein Soy agar, TSA). The modified MKTTn medium (S/L) performed comparably with the original medium in terms of growth of both Salmonella strains (>300 colonies in XLD), alone or with P. aeruginosa and E. coli. Quantitative assays showed no statistically significant differences in the number of colonies grown on XLD after 10-5 dilution (p = 0.7015 with S. Thyphimurium ATCC 14028 and p = 0.2387 with S. Enteritidis ATCC 13076; ANOVA test). MKTTn medium (S/L) was also selective against E. coli (≤100 colonies) and E. faecalis (<10 colonies). These results suggest that adding tetrathionate as a lyophilisate (S/L) is a feasible alternative to the use of Lugol's solution for the preparation of MKTTn enrichment broth and does not affect the properties of the medium.

A systematic review of cost-effectiveness evidence of endoscopic saphenous vein harvesting: is it efficient?

OBJECTIVE: Greater saphenous vein harvest for coronary and lower extremity bypass requires the longest incision of any surgical procedure. Endoscopic vein harvest allows better results in some clinical variables compared to open harvesting techniques. The objective of this study is to present the results of a systematic review of the scientific evidence about the efficiency of endoscopic saphenous vein harvest. METHODS: We performed a systematic review in the bibliographical databases Pubmed, National Health Service Economic Evaluation Database, and NHS Health Technology Assessment Database. The search strategy was "endoscopic AND harvesting", in the period January 1970-December 2009. RESULTS: We identified only 3 economic evaluation studies, 2 cost analyses with some methodological limitations, and 1 cost-utility analysis. All of them suggest lower hospital costs for endoscopic harvesting. CONCLUSIONS: Available evidence does not allow recommendations to be made based on the efficiency of endoscopic saphenous vein harvest, although it suggests lower costs for endoscopic harvesting. More scientific evidence about the long-term efficacy and the effectiveness of this technique is necessary, with studies measuring final outcomes, and carrying out complete and rigorous economic evaluations.

[Molecular and biological aspects of Arterivirus]. / Aspects moléculaires et biologiques des artérivirus.

Arteriviruses are a group of small enveloped viruses with a genome composed of a positive, single-stranded, 5'-capped and 3'-polyadenylated RNA molecule. These viruses belong to the Arteriviridae family which together with the Coronaviridae and Roniviridae families constitutes the order Nidovirales. Arteriviruses have a marked tropism for macrophages and induce persistent infections. Several studies have reported the unique genomic organization of these viruses together with replication and transcription mechanisms for the synthesis of genomic and sub-genomic viral RNAs which, for the latter, encode viral structural proteins. Several sequences are now available for these viruses. Recent studies about the modulation of innate immune response by arteriviruses also demonstrated a key-role of particular non structural proteins in that process. Finally, certain pro- and anti-apoptotic mechanisms associated to Arteriviruses have been elucidated; however the exact significance of theses apoptotic processes in arterivirus pathogenesis has yet to be determined.

LOXL2-mediated H3K4 oxidation reduces chromatin accessibility in triple-negative breast cancer cells.

Oxidation of H3 at lysine 4 (H3K4ox) by lysyl oxidase-like 2 (LOXL2) generates an H3 modification with an unknown physiological function. We find that LOXL2 and H3K4ox are higher in triple-negative breast cancer (TNBC) cell lines and patient-derived xenografts (PDXs) than those from other breast cancer subtypes. ChIP-seq revealed that H3K4ox is located primarily in heterochromatin, where it is involved in chromatin compaction. Knocking down LOXL2 reduces H3K4ox levels and causes chromatin decompaction, resulting in a sustained activation of the DNA damage response (DDR) and increased susceptibility to anticancer agents. This critical role that LOXL2 and oxidized H3 play in chromatin compaction and DDR suggests that functionally targeting LOXL2 could be a way to sensitize TNBC cells to conventional therapy.

Waveguiding properties of a photonic crystal fiber with a solid core surrounded by four large air holes.

The polarization-dependent guiding properties of a hexagonal-lattice photonic crystal fiber with a solid-core surrounded by four large air holes are investigated. The appearance of a polarization dependent cutoff frequency, together with several parameters as the birefringence, the modal effective area, the group velocity dispersion and the polarization dependent loss are analyzed. A collection of fibers with different structural parameters were fabricated and characterized. An effective anti-guide structure from at least 450 nm to 1750 nm, a polarizing fiber with a polarization dependent loss of 16 dB/m at 1550 nm, and an endlessly singlemode polarization-maintaining fiber with group birefringence of 2.1x10(-3) at 1550 nm are reported. Experimental results are compared with accurate numerical modeling of the fibers.

[Medication errors in a tertiary hospital with three different drug delivery systems]. / Errores de medicación en un hospital terciario con tres sistemas de distribución de medicamentos diferentes.

OBJECTIVE: To estimate the proportion of medication errors in a tertiary hospital, global and for each delivery medication system, to describe the error types and the implied medications, and to analyze the factors associated to the same ones. METHODS: Errors were identified from direct observation of 2,242 opportunities for error (administered doses or prescribed doses not given) by 6 couples of observers. Delivery medication systems were stock in ward, unit dose with electronic prescription and unit dose with computerized transcription. Logistic regression was used to evaluate the association between errors and certain factors. RESULTS: The medication error rate was of 7.2% (CI 95%: 6.1-8.3), and 4.4% (CI 95%: 3.6-5.3) of them reached the patient. For delivery systems, the error rate was of 9.5% (CI 95%: 7.4-11.9) for stock in ward, 7.8% (CI 95%: 5.9-10.0) for electronic prescription and 4.7% (CI 95%: 3.4-6.4) for computerized transcription. The highest error frequency was observed in the administration phase (58.4%) and the omitted dose was the most prevalent error (31.7%). The error rate was associated to the pharmacotherapeutic process, the schedule of administration and the unit of hospitalization. CONCLUSIONS: In one of each 14 opportunities for error a medication error takes place. The different delivery medication systems have different error rates.

Nerve growth factor activation of the extracellular signal-regulated kinase pathway is modulated by Ca(2+) and calmodulin.

Nerve growth factor is a member of the neurotrophin family of trophic factors that have been reported to be essential for the survival and development of sympathetic neurons and a subset of sensory neurons. Nerve growth factor exerts its effects mainly by interaction with the specific receptor TrkA, which leads to the activation of several intracellular signaling pathways. Once activated, TrkA also allows for a rapid and moderate increase in intracellular calcium levels, which would contribute to the effects triggered by nerve growth factor in neurons. In this report, we analyzed the relationship of calcium to the activation of the Ras/extracellular signal-regulated kinase pathway in PC12 cells. We observed that calcium and calmodulin are both necessary for the acute activation of extracellular signal-regulated kinases after TrkA stimulation. We analyzed the elements of the pathway that lead to this activation, and we observed that calmodulin antagonists completely block the initial Raf-1 activation without affecting the function of upstream elements, such as Ras, Grb2, Shc, and Trk. We have broadened our study to other stimuli that activate extracellular signal-regulated kinases through tyrosine kinase receptors, and we have observed that calmodulin also modulates the activation of such kinases after epidermal growth factor receptor stimulation in PC12 cells and after TrkB stimulation in cultured chicken embryo motoneurons. Calmodulin seems to regulate the full activation of Raf-1 after Ras activation, since functional Ras is necessary for Raf-1 activation after nerve growth factor stimulation and calmodulin-Sepharose is able to precipitate Raf-1 in a calcium-dependent manner.

Adherence to oral anticoagulants in patients with atrial fibrillation-a population-based retrospective cohort study linking health information systems in the Valencia region, Spain: a study protocol.

INTRODUCTION: Adherence to oral anticoagulation (OAC) treatment, vitamin K antagonists or new oral anticoagulants, is an essential element for effectiveness. Information on adherence to OAC in atrial fibrillation (AF) and the impact of adherence on clinical outcomes using real-world data barely exists. We aim to describe the patterns of adherence to OAC over time in patients with AF, estimate the associated factors and their impact on clinical events, and assess the same issues with conventional measures of primary and secondary adherence-proportion of days covered (PDC) and persistence-in routine clinical practice. METHODS AND ANALYSIS: This is a population-based retrospective cohort study including all patients with AF treated with OAC from 2010 to date in Valencia, Spain; data will be obtained from diverse electronic records of the Valencia Health Agency. PRIMARY OUTCOME MEASURE: adherence trajectories. SECONDARY OUTCOMES: (1) primary non-adherence; (2) secondary adherence: (a) PDC, (b) persistence. Clinical outcomes: hospitalisation for haemorrhagic or thromboembolic events and death during follow-up. ANALYSIS: (1) description of baseline characteristics, adherence patterns (trajectory models or latent class growth analysis models) and conventional adherence measures; (2) logistic or Cox multivariate regression models, to assess the associations between adherence measures and the covariates, and logistic multinomial regression models, to identify characteristics associated with each trajectory; (3) Cox proportional hazard models, to assess the relationship between adherence and clinical outcomes, with propensity score adjustment applied to further control for potential confounders; (4) to estimate the importance of different healthcare levels in the variations of adherence, logistic or Cox multilevel regression models. ETHICS AND DISSEMINATION: This study has been approved by the corresponding Clinical Research Ethics Committee. We plan to disseminate the project's findings through peer-reviewed publications and presentations at relevant health conferences. Policy reports will also be prepared in order to promote the translation of our findings into policy and clinical practice.

Activation of Raf-1 is defective in annexin 6 overexpressing Chinese hamster ovary cells.

Annexin 6 is a Ca2+-dependent phospholipid-binding protein involved in membrane trafficking. In this study we demonstrate the association of Raf-1 with recombinant rat annexin 6. Raf-annexin 6 interaction was shown to be independent of cell activation by epidermal growth factor (EGF) or phorbol esters (12-O-tetradecanoyl-phorbol-13-acetate (TPA)). A stable Chinese hamster ovary (CHO)-anx6 cell line overexpressing annexin 6 was established to examine the function of annexin 6. In these cells, no increase of Ras-GTP levels, induced by EGF or TPA, was detected. In addition, the activity of Raf was completely inhibited, whereas the mitogen-activated protein kinase-P was unaffected.

Chronic comorbidity and outcomes of hospital care: length of stay, mortality, and readmission at 30 and 365 days.

This article evaluates the behavior of an adaptation of the Charlson Index (CHI) applied to administrative databases to measure the relationship between chronic comorbidity and the hospital care outcomes of length of stay (LOS), in-hospital mortality, and emergency readmissions at 30 and 365 days. These outcomes were analyzed in 106,673 hospitalization episodes whose records are registered in a minimum basic data set maintained by the public health authorities of the community of Valencia, Spain. The highest comorbidity measured by the CHI was associated with greater LOS and in-hospital mortality and increased readmission at 30 and 365 days. The rate of readmissions at 1 year dropped, however, in the group with the greatest comorbidity, probably owing to an increase in mortality after hospitalization. While comorbidity does appear to increase the risk of adverse outcomes in general and mortality and readmission specifically, the second outcome is only possible if the first has not occurred. For this reason, information and selection biases derived from administrative databases, or from the CHI itself, should be taken into account when using and interpreting the index.

Quantitative determination of endotoxins on surgical gloves.

The amount of endotoxin on surgical gloves was investigated by the limulus chromogenic substrate method. Heavy endotoxin contamination was observed on the outside of certain surgical gloves sold in Sweden. Given an endotoxin absorption of 10% to the patients, one of the types of gloves studied would cause fever, chills, headache and muscle pain. The amount of endotoxin on the gloves could be minimized by rinsing in endotoxin-free water. We conclude that the manufacturing process of latex gloves should be checked microbiologically for Gram-negative bacteria before sterilization. Alternatively, the amount of endotoxin should be checked on the product by the limulus ameobocyte lysate test before release.

Inter-hospital variations in caesarean sections. A risk adjusted comparison in the Valencia public hospitals.

BACKGROUND: The aim of this study was to describe the variability in caesarean rates in the public hospitals in the Valencia Region, Spain, and to analyse the association between caesarean sections and clinical and extra-clinical factors. METHODS: Analysis of data contained in the Minimum Basic Data Set (MBDS) compiled for all births in 11 public hospitals in Valencia during 1994-1995 (n=36 819). Bivariate and multivariate analyses were used to evaluate the association between caesarean section rates and specific risk factors. The multivariate model was used to construct predictions about caesarean rates for each hospital, for comparison with rates observed. RESULTS: Caesarean rates were 17.6% (inter-hospital range: 14.7% to 25.0%), with ample variability between hospitals in the diagnosis of maternal-fetal risk factors (particularly dystocia and fetal distress), and the indication for caesarean in the presence of these factors. Multivariate analysis showed that maternal-fetal risk factors correlated strongly with caesarean section, although extra-clinical factors, such as the day of the week, also correlated positively. After adjusting for the risk factors, the inter-hospital variation in caesarean rates persisted. CONCLUSIONS: Although certain limitations (imprecision of some diagnoses and information biases in the MBDS) make it impossible to establish unequivocal conclusions, results show a high degree of variability among hospitals when opting for caesarean section. This variability cannot be justified by differences in obstetric risks.