The past three million years: Evolution of climatic variability in the north atlantic region : edited by N. J. Shackleton, R. G. West, and D. Q. Bowen. The royal society, 1988, 278p., [UK pound]47.50 (ISBN 0-85403-348-3)

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29613/1/0000702.pd

LungBEAM: A prospective multicenter study to monitor stage IV NSCLC patients with EGFR mutations using BEAMing technology

Mutacions de l'EGFR; Biòpsia líquida; Carcinoma de pulmó de cèl·lules no petitesMutaciones de EGFR; Biopsia liquida; Carcinoma de pulmón de células no pequeñasEGFR mutations; Liquid biopsy; Non-small cell lung carcinomaObjectives The aim of LungBEAM was to determine the value of a novel epidermal growth factor receptor (EGFR) mutation test in blood based on BEAMing technology to predict disease progression in advanced non-small cell lung cancer (NSCLC) patients treated with first- or second-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Another goal was to monitor the dynamics of EGFR mutations, as well as to track EGFR exon 20 p.T790M (p.T790M) resistance during treatment, as critical indicators of therapeutic efficacy and patient survival. Methods Stage IV NSCLC patients with locally confirmed EGFR-TKI sensitizing mutations (ex19del and/or L858R) in biopsy tissue who were candidates to receive first- or second-generation EGFR-TKI as first-line therapy were included. Plasma samples were obtained at baseline and every 4 weeks during treatment until a progression-free survival (PFS) event or until study completion (72-week follow-up). The mutant allele fraction (MAF) was determined for each identified mutation using BEAMing. Results A total of 68 of the 110 (61.8%) patients experienced a PFS event. Twenty-six patients (23.6%) presented with an emergent p.T790M mutation in plasma at some point during follow-up, preceding radiologic progression with a median of 76 (interquartile ratio: 54–111) days. Disease progression correlated with the appearance of p.T790M in plasma with a hazard ratio (HR) of 1.94 (95% confidence interval [CI], 1.48–2.54; p < 0.001). The HR for progression in patients showing increasing plasma sensitizing mutation levels (positive MAF slope) versus patients showing either decreasing or unchanged plasma mutation levels (negative or null MAF slopes) was 3.85 (95% CI, 2.01–7.36; p < 0.001). Conclusion Detection and quantification of EGFR mutations in circulating tumor DNA using the highly sensitive BEAMing method should greatly assist in optimizing treatment decisions for advanced NSCLC patients.This work was supported by Sysmex Inostics GmbH. The sponsor and the study coordinating investigators were involved in the study design and data interpretation. Writing and editorial assistance was funded by Sysmex Inostics GmbH

Incidence and characteristics of adverse drug reactions in a cohort of patients treated with PD-1/PD-L1 inhibitors in real-world practice

Adverse reaction; Immunotherapy; PharmacovigilanceReacción adversa; Inmunoterapia; FarmacovigilanciaReacció adversa; Immunoteràpia; FarmacovigilànciaBackground: Data related to adverse drug reactions (ADRs), specifically immune-related adverse events (irAEs), in long-term treatment with immunotherapy in real-world practice is scarce, as is general information regarding the management of ADRs. Objectives: To characterize and describe the incidence of ADRs in patients who began immunotherapy treatment in clinical practice. Methods: In a prospective observational study cancer patients ≥18 years of age who were treated with a monotherapy regime of PD-1/PD-L1 inhibitors were evaluated. The study period was from November 2017 to June 2019 and patients were followed up until June 2021. Patients were contacted monthly by telephone and their electronic health records were reviewed. Each ADR was graded according to the Common Terminology Criteria for Adverse Events (CTCAE 5.0). Results: Out of 99 patients, 86 met the inclusion criteria. Most were male (67.4%), with a median age of 66 (interquartile range, IQR: 59–76). The most frequent cancer was non-small cellular lung cancer (46 cases, 53.5%), followed by melanoma (22, 25.6%). A total of 74 patients (86%) were treated with anti-PD-1 drugs and 12 (14%) were treated with anti-PD-L1 drugs. The median treatment durations were 4.9 (IQR: 1.9–17.0) and 5.9 months (IQR: 1.2–12.3), respectively. Sixty-three patients (73%) developed from a total of 156 (44% of the total number of ADR) irADRs, wherein the most frequent were skin disorders (50 cases, 32%, incidence = 30.5 irADRs/100 patients per year [p-y]), gastrointestinal disorders (29, 19%, 17.7 irADRs/100 p-y), musculoskeletal disorders (17, 11%, 10.4 irADRs/100 p-y), and endocrine disorders (14, 9%, 8.6 irADRs/100 p-y). A total of 22 irADRs (14%) had a latency period of ≥12 months. Twelve irADRs (7.7%) were categorized as grade 3–4, and while 2 (1.3%) were categorized as grade 5 (death). Sixty-one irADRs (39.1%) in 36 patients required pharmacological treatment and 47 irADRs (30.1%) in 22 patients required treatment with corticosteriods. Conclusion: The majority of patients treated with anti-PD1/PDL1-based immunotherapy experienced adverse reactions. Although most of these reactions were mild, 11.5% were categorized as grade 3 or above. A high percentage of the reactions were immune-related and occurred throughout the treatment, thereby indicating that early identification and close monitoring is essential

Coping Strategies and Social Support in a Mobile Phone Chat App Designed to Support Smoking Cessation : Qualitative Analysis

Smoking is one of the most significant factors contributing to low life expectancy, health inequalities, and illness at the worldwide scale. Smoking cessation attempts benefit from social support. Mobile phones have changed the way we communicate through the use of freely available message-oriented apps. Mobile app-based interventions for smoking cessation programs can provide interactive, supportive, and individually tailored interventions. This study aimed to identify emotions, coping strategies, beliefs, values, and cognitive evaluations of smokers who are in the process of quitting, and to analyze online social support provided through the analysis of messages posted to a chat function integrated into a mobile app. In this descriptive qualitative study, informants were smokers who participated in the chat of Tobbstop. The technique to generate information was documentary through messages collected from September 2014 through June 2016, specifically designed to support a smoking cessation intervention. A thematic content analysis of the messages applied 2 conceptual models: the Lazarus and Folkman model to assess participant's experiences and perceptions and the Cutrona model to evaluate online social support. During the study period, 11,788 text messages were posted to the chat by 101 users. The most frequent messages offered information and emotional support, and all the basic emotions were reported in the chat. The 3 most frequent coping strategies identified were physical activity, different types of treatment such as nicotine replacement, and humor. Beliefs about quitting smoking included the inevitability of weight gain and the notion that not using any type of medications is better for smoking cessation. Health and family were the values more frequently described, followed by freedom. A smoke-free environment was perceived as important to successful smoking cessation. The social support group that was developed with the app offered mainly emotional and informational support. Our analysis suggests that a chat integrated into a mobile app focused on supporting smoking cessation provides a useful tool for smokers who are in the process of quitting, by offering social support and a space to share concerns, information, or strategies

BIM and mTOR expression levels predict outcome to erlotinib in EGFR-mutant non-small-cell lung cancer

Altres ajuts: Fellowship Award of the International Association for the Study of Lung Cancer i grant of the Italian Association for Cancer Research (AIRC My First AIRC Grant n° 14282).Abstract.BIM is a proapoptotic protein that initiates apoptosis triggered by EGFR tyrosine kinase inhibitors (TKI). mTOR negatively regulates apoptosis and may influence response to EGFR TKI. We examined mRNA expression of BIM and MTOR in 57 patients with EGFR-mutant NSCLC from the EURTAC trial. Risk of mortality and disease progression was lower in patients with high BIM compared with low/intermediate BIM mRNA levels. Analysis of MTOR further divided patients with high BIM expression into two groups, with those having both high BIM and MTOR experiencing shorter overall and progression-free survival to erlotinib. Validation of our results was performed in an independent cohort of 19 patients with EGFR-mutant NSCLC treated with EGFR TKIs. In EGFR-mutant lung adenocarcinoma cell lines with high BIM expression, concomitant high mTOR expression increased IC50 of gefitinib for cell proliferation. We next sought to analyse the signalling pattern in cell lines with strong activation of mTOR and its substrate P-S6. We showed that mTOR and phosphodiesterase 4D (PDE4D) strongly correlate in resistant EGFR-mutant cancer cell lines. These data suggest that the combination of EGFR TKI with mTOR or PDE4 inhibitors could be adequate therapy for EGFR-mutant NSCLC patients with high pretreatment levels of BIM and mTOR

Procediment d'higiene de mans

Higiene de mans; Mesures de prevenció; Antisèpsia de mans; InfeccionsHigiene de manos; Medidas de prevención; Antisepsia de manos; InfeccionesHand hygiene; Prevention measures; Hand antisepsis; InfectionsL’objectiu d'aquest document és fer un treball de revisió, actualització i consens de diversos documents sobre la higiene de mans en l'àmbit hospitalari i a l'atenció primària, per crear-ne un de sol que faciliti la informació i la consulta als professionals, amb la finalitat de millorar el seu compliment de la higiene de mans

Analgesia intra y postoperatoria prolongada mediante fentanilo percutáneo en artrodesis de columna tóraco lumbar

El uso de fentanilo transdérmico (FT) en el tratamiento del dolor postoperatorio es controvertido debido a sus características farmacocinéticas. Nuestro estudio postula que la aplicación de un parche FT ocho horas antes de la intervención, proporciona analgesia segura y eficaz durante las primeras 72 horas del postoperatorio, en pacientes intervenidos de artrodesis vertebral. En un estudio prospectivo, aleatorizado, doble ciego, evaluamos 52 pacientes que recibieron una dosis de FT de 1,5 ug/kg/h (grupo FT) o un parche placebo (grupo C). El parche se aplico en el tórax, 8h antes de la intervención y fue retirado a las 72h. Los pacientes recibieron anestesia general con profofol, remifentanilo, N2O y cisatracurio, y antes de finalizar la intervención recibieron 30mg de ketorolaco intravenoso. Como analgesia postoperatoria utilizamos PCA-intravenosa de ketorolaco con rescate mediante tramadol ± morfina. Se evaluó periódicamente la intensidad del dolor/analgesia mediante escalas analgésicas (EVA, ECN, alivio del dolor), el consumo de analgésicos y los efectos indeseables. Como variables secundarias registramos los niveles plasmáticos de fentanilo, la satisfacción del paciente y la estancia hospitalaria. La intensidad del dolor en reposo y movimiento fue significativamente menor en el grupo FT, excepto al final del estudio en que se aproximan los valores de ambos grupos (a partir de las 44-56 h). El FT disminuyó en un 60% el consumo postoperatorio de analgésicos, que convertidos en equivalentes de morfina corresponden a 39 y 101 mg para los grupos FT y control, respectivamente (p<0,001). Ocho horas después de aplicar el parche FT e inmediatamente antes de la inducción anestésica, el grupo FT presentó una disminución significativa de la frecuencia respiratoria y somnolencia. La sedación se prolongó durante las primeras 16h del estudio disminuyendo gradualmente, mientras que la frecuencia respiratoria permaneció significativamente más baja en el grupo FT durante las primeras 32h del postoperatorio (p<0,01). Los cambios observados, aunque estadísticamente significativos, fueron de escasa magnitud y no tuvieron relevancia clínica. Un paciente del grupo FT (3,8%) presentó sedación y depresión respiratoria a las 46h que remitió con naloxona, y fue retirado del estudio. El grupo FT presentó también una mayor incidencia de nausea y prurito (p<0,05), aunque los pacientes mostraron menos temblor al despertar (p<0,001). La mínima concentración plasmática analgésica de fentanilo para el dolor postoperatorio, se alcanzó a las 16h (0,67 ng/ml), coincidiendo con la aparición de analgesia en reposo y movimiento; sin embargo concentraciones plasmáticas no analgésicas (0,46 ng/ml) obtenidas a las 10h, fueron capaces de inducir sedación y disminución de la frecuencia respiratoria. El FT no modificó el tiempo de despertar de la anestesia, ni la duración del ingreso hospitalario. La satisfacción de los pacientes fue similar con ambos tratamientos analgésicos. En conclusión, el FT aplicado 8h antes de la cirugía de artrodesis de columna, proporciona analgesia efectiva de larga duración y disminuye significativamente los requerimientos de analgésicos. La analgesia va acompañada de una disminución significativa de la frecuencia respiratoria, así como de incrementos de la sedación, las nauseas y el prurito. En relación al riesgo de depresión respiratoria, el FT sólo está indicado en el postoperatorio de intervenciones que cursan con dolor intenso y persistente. Es aconsejable ajustar la dosis de FT al peso del paciente y mantener una monitorización continua durante las primeras 48 h después de la aplicación del parche.The administration of transdermal fentanyl (TF) for postoperative analgesia is controversial due to the pharmacokinetic profile of the opioid preparation. Our study hypothesized that TF treatment started eight hours before spine fusion, provides safe and effective postoperative analgesia during 72h. In this randomized, prospective and double blind study, 52 patients received a transdermal fentanyl patch of 1,5 ug/kg/h (TF group) or a placebo patch (C group). The patch was applied 8 h before surgery in the chest wall and removed after 72 h. Patients had general anaesthesia with propofol, remifentanil, nitrous oxide and cis-atracurium, and before the end of surgery they received a bolus of 30 mg of intravenous ketorolac. For postoperative analgesia, we administered intravenous PCA with ketorolac and for rescue analgesia with tramadol ± morphine were used. We periodically evaluated pain intensity (PI) using a visual analogical scale (VAS), a verbal rating scale (VRS), and a pain relief scale. Postoperative analgesic requirements and adverse effects were registered. As secondary variables, we measured the plasma fentanyl concentrations, the satisfaction degree of the patients and the hospitalization duration. The TF group had significantly lower PI at rest and on movement, except during the last hours of the study, when the values of both groups were similar (from 44-56h). TF reduced by 60% the postoperative analgesics requirements than converted to morphine equivalents were 39 mg and 101 mg for the TF and C groups, respectively (p<0,001). Eight hours after the application of the TF patch and just before the anaesthetic induction, the TF group showed a significant reduction of respiratory rate and somnolence. Sedation was present during the first 16 hrs of the study and gradually disappeared, while respiratory rate remained significantly lower in the FT group during the first 32 postoperative hours (p<0,01). However, these changes, were of small magnitude and without clinical relevance. One patient in the TF group (3,8%) had intense sedation and respiratory depression at 46h that resolved after naloxone administration, and had to be removed from the study. Nausea and pruritus were higher in the TF group (p<0,05), while the incidence of shivering was significantly lower (p=0,001) in the same group. The minimum effective plasma concentration of fentanyl (0,67 ng /ml) for postoperative pain was reached at 16 h, concurring with significant analgesia rest and on movement; however, sub-analgesic plasma concentrations (0,46 ng/ml) observed at 10h were able to induce significant sedation and reduction of respiratory rate. The TF treatment did not change the time of awakening from the anaesthesia or the length of hospital stay. Patient satisfaction was similar with both analgesic treatments. In conclusion, applying the TF patch 8 hours before spine fusion surgery, produces an effective and long lasting analgesic effect, significantly reducing the analgesics requirements. The analgesia is associated with a significant reduction in respiratory rate, and increased sedation, nausea and pruritus. Due to the risk of respiratory depression, TF analgesia is only suitable for use in the postoperative care of surgeries that induce intense and persistent pain. It is recommended to adjust the TF dose to the patient weight, and maintain a continuous monitoring during the first 48 hours after FT patch application

(Table 1) Oxygen and carbon isotope data of bulk carbonate and foraminiferal species across the Cretaceous/Tertiary boundary at ODP Site 119-738

In low and middle latitudes, the Cretaceous/Tertiary boundary is marked by a sudden and pronounced decrease in d13C values of near-surface-water carbonates and a reduction in the surface-to-bottom d13C gradient. These isotopic data have been interpreted as evidence of a decline in surface-water productivity that was responsible for the extinction of many planktic foraminiferal species and other marine organisms at or near the K/T boundary. We present planktic and benthic foraminiferal isotopic data from two almost biostratigraphically complete sections at Ocean Drilling Program Site 738 in the antarctic Indian Ocean and at Nye Kløv in Denmark. These data suggest that planktic carbonate d13C values in high latitudes may not have decreased dramatically at the K/T boundary; thus, surface-water productivity may not have been reduced as much as in low and middle latitudes. Comparison of the records of Site 738 with those of ODP Sites 690 and 750 indicates a pronounced decline in d13C values of planktic and benthic foraminifera and fine-fraction/bulk carbonate ~200 000 yr after the K/T boundary. This reflects a regional shift in the carbon isotopic composition of oceanic total dissolved carbon (TDC) and correlates with a similar change in benthic foraminiferal d13C values at mid- and low-latitude Deep Sea Drilling Project Sites 527 and 577. This oceanographic event was followed by the ecosystem's global recovery ~500 000 yr after the K/T boundary. These data suggest that the environmental effects of the K/T boundary may have been less severe in the high-latitude oceans than in tropical and subtropical regions

Isotopic composition and Strontium/Calcium ratios of foraminifera of ODP Holes 113-689B and 113-690C

Oxygen and carbon isotopic ratios were measured from Maestrichtian benthic and planktonic foraminifer species and bulk carbonate samples from ODP Sites 689 and 690, drilled on the Maud Rise during Leg 113. Careful scanning electron microscope observations reveal that test calcite in some intervals was diagenetically altered, although Sr/Ca and isotopic ratios of these tests do not appear to have been modified significantly. Foraminifer d18O values at both sites document a cooling trend during early Maestrichtian time, a rapid drop in water temperatures at the time of the first appearance of Abathomphalus mayaroensis in the high southern latitude regions (about 69.9 Ma), and lower water temperatures during late Maestrichtian time. d13C values record a depletion in 13C in the latest early Maestrichtian time beginning at about 72.2 Ma, just prior to the sharp late Maestrichtian increase in d18O values. These trends are similar to those previously reported for well-preserved benthic foraminifer species from Seymour Island, in the Antarctic Peninsula. Paleotemperature estimates are also comparable to those at Seymour Island and suggest temperate climatic conditions in Antarctica and that bottom waters in the southern South Atlantic region were of Antarctic origin. Benthic and planktonic foraminifer 613C values fluctuate sympathetically and are higher in upper Maestrichtian sediments than in the lower Maestrichtian sequence