Prognostic genome and transcriptome signatures in colorectal cancers.

Colorectal cancer is caused by a sequence of somatic genomic alterations affecting driver genes in core cancer pathways1. Here, to understand the functional and prognostic impact of cancer-causing somatic mutations, we analysed the whole genomes and transcriptomes of 1,063 primary colorectal cancers in a population-based cohort with long-term follow-up. From the 96 mutated driver genes, 9 were not previously implicated in colorectal cancer and 24 had not been linked to any cancer. Two distinct patterns of pathway co-mutations were observed, timing analyses identified nine early and three late driver gene mutations, and several signatures of colorectal-cancer-specific mutational processes were identified. Mutations in WNT, EGFR and TGFß pathway genes, the mitochondrial CYB gene and 3 regulatory elements along with 21 copy-number variations and the COSMIC SBS44 signature correlated with survival. Gene expression classification yielded five prognostic subtypes with distinct molecular features, in part explained by underlying genomic alterations. Microsatellite-instable tumours divided into two classes with different levels of hypoxia and infiltration of immune and stromal cells. To our knowledge, this study constitutes the largest integrated genome and transcriptome analysis of colorectal cancer, and interlinks mutations, gene expression and patient outcomes. The identification of prognostic mutations and expression subtypes can guide future efforts to individualize colorectal cancer therapy.

SGLT2 Inhibition in Heart Failure with Preserved Ejection Fraction - The New Frontier.

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome with high morbidity and increasing socio-economic burden, compounded by the lack of effective treatment options available to treat this disease. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have previously been shown to improve cardiovascular and renal outcomes in patients with type 2 diabetes and patients with heart failure with reduced ejection fraction (HFrEF). Recent major clinical trials with SGLT2 inhibitors, both empagliflozin and dapagliflozin, have now demonstrated improved cardiovascular outcomes in patients with HFpEF and a significant reduction in heart failure hospitalization. Current evidence shows a potential for cardiovascular benefits with SGLT2 inhibition that is consistent across the spectrum of ejection fraction, age, New York Heart Association (NYHA) functional class, natriuretic peptide levels and diabetes status. Although the cardioprotective mechanisms behind SGLT2 inhibition remain unclear, ongoing clinical studies aim to clarify the role of SGLT2 inhibitors on biomarkers of cardiac metabolism, diastolic function and exercise capacity in HFpEF. This article analyzes current clinical evidence from randomized controlled trials and meta-analyses and explores the potential cardioprotective mechanisms of SGLT2 inhibitors, while also looking towards the future of SGLT2 inhibition in HFpEF.

FACT-seq: profiling histone modifications in formalin-fixed paraffin-embedded samples with low cell numbers.

The majority of biopsies in both basic research and translational cancer studies are preserved in the format of archived formalin-fixed paraffin-embedded (FFPE) samples. Profiling histone modifications in archived FFPE tissues is critically important to understand gene regulation in human disease. The required input for current genome-wide histone modification profiling studies from FFPE samples is either 10-20 tissue sections or whole tissue blocks, which prevents better resolved analyses. But it is desirable to consume a minimal amount of FFPE tissue sections in the analysis as clinical tissues of interest are limited. Here, we present FFPE tissue with antibody-guided chromatin tagmentation with sequencing (FACT-seq), the first highly sensitive method to efficiently profile histone modifications in FFPE tissues by combining a novel fusion protein of hyperactive Tn5 transposase and protein A (T7-pA-Tn5) transposition and T7 in vitro transcription. FACT-seq generates high-quality chromatin profiles from different histone modifications with low number of FFPE nuclei. We proved a very small piece of FFPE tissue section containing ∼4000 nuclei is sufficient to decode H3K27ac modifications with FACT-seq. H3K27ac FACT-seq revealed disease-specific super enhancers in the archived FFPE human colorectal and human glioblastoma cancer tissue. In summary, FACT-seq allows decoding the histone modifications in archival FFPE tissues with high sensitivity and help researchers to better understand epigenetic regulation in cancer and human disease.

Discontinuation of chronic benzodiazepine use in primary care: a nonrandomized intervention.

BACKGROUND: Chronic benzodiazepine use is a challenge in primary care practice. Protocols to support safe discontinuation are still needed, especially in countries with high utilization rates. OBJECTIVES: To evaluate the feasibility, effectiveness, and safety of a benzodiazepine discontinuation protocol in primary care setting. METHODS: Nonrandomized, single-arm interventional study, at primary care units. Family physicians (FPs) recruited patients (18-85 years-old) with benzodiazepine dependence and chronic daily use ≥3 months. Patients with daily dosages ≥30 mg diazepam-equivalent, taking zolpidem, with a history of other substance abuse or major psychiatric disease were excluded. After the switch to diazepam, the dosage was gradually tapered according to a standardized protocol. Primary endpoint was the percentage of patients who stopped benzodiazepine at the intervention last visit. Dosage reduction, withdrawal symptoms, patients' and FPs' satisfaction with the protocol were evaluated. RESULTS: From 66 enrolled patients (74% female; 66.7% aged >64 years; median time of benzodiazepine use was 120 months), 2 withdrew due to medical reasons and 3 presented protocol deviations. Overall, 59.4% of participants successfully stopped benzodiazepine (60.7% when excluding protocol deviations). Men had higher probability of success (relative risk = 0.51, P = 0.001). A total of 31 patients reported at least 1 withdrawal symptom, most frequently insomnia and anxiety. Most of participating FP considered the clinical protocol useful and feasible in daily practice. Among patients completing the protocol, 77% were satisfied. For the patients who reduced dosage, 85% kept without benzodiazepines after 12 months. CONCLUSION: The discontinuation protocol with standardized dosage reduction was feasible at primary care and showed long-term effectiveness.

Feasibility and performance of a combined extracorporeal assisted cardiac resuscitation and an organ donation program after uncontrolled cardiocirculatory death (Maastricht II).

INTRODUCTION: Approximately 500.000 people in Europe sustain cardiac arrest (CA) every year, being myocardial infarction the main etiology. Interest has been raised in a new approach to refractory cardiac arrest (rCA) using extra-corporeal oxygenation (ECMO). In settings where it can be rapidly implemented, ECMO assisted resuscitation (ECPR) may be considered. Additionally, donation after circulatory death, which seeks to obtain solid organs donation from patients suffering rCA, has increased its role effectively increasing the pool of donors. Combined programs with integration of ECPR and uncontrolled donation after circulatory determination of death (uDCDD) are worldwide limited and experience integrating these two techniques is lacking. METHODS: We report a 24 months experience of ECPR and uDCDD kidney transplantation based on a management protocol in a university teaching hospital in the urban area of Lisbon. RESULTS: Over a period of 24 months, 58 patients were admitted to our ICU with rCA, 6 (10%) in the ECPR program and 52 (90%) in the uDCDD. Seventy-eight percent of patients were male, with an average age of 49 year-old. CA was witnessed in 83% of cases and initial rhythm was ventricular fibrillation in 20 cases (35%). 13 (25%) patients were effective organ donors. Refusal for effective donation was mainly due to prior comorbidities. DISCUSSION: The development of an integrated program for ECPR and uDCDD is feasible and requires a well-established and efficient activation program. In an era of significant organ shortage, it provides a viable option for increasing the organ donation pool, with promising results.

The Influence of a Coherent Annotation and Synthetic Addition of Lung Nodules for Lung Segmentation in CT Scans.

Lung cancer is a highly prevalent pathology and a leading cause of cancer-related deaths. Most patients are diagnosed when the disease has manifested itself, which usually is a sign of lung cancer in an advanced stage and, as a consequence, the 5-year survival rates are low. To increase the chances of survival, improving the cancer early detection capacity is crucial, for which computed tomography (CT) scans represent a key role. The manual evaluation of the CTs is a time-consuming task and computer-aided diagnosis (CAD) systems can help relieve that burden. The segmentation of the lung is one of the first steps in these systems, yet it is very challenging given the heterogeneity of lung diseases usually present and associated with cancer development. In our previous work, a segmentation model based on a ResNet34 and U-Net combination was developed on a cross-cohort dataset that yielded good segmentation masks for multiple pathological conditions but misclassified some of the lung nodules. The multiple datasets used for the model development were originated from different annotation protocols, which generated inconsistencies for the learning process, and the annotations are usually not adequate for lung cancer studies since they did not comprise lung nodules. In addition, the initial datasets used for training presented a reduced number of nodules, which was showed not to be enough to allow the segmentation model to learn to include them as a lung part. In this work, an objective protocol for the lung mask's segmentation was defined and the previous annotations were carefully reviewed and corrected to create consistent and adequate ground-truth masks for the development of the segmentation model. Data augmentation with domain knowledge was used to create lung nodules in the cases used to train the model. The model developed achieved a Dice similarity coefficient (DSC) above 0.9350 for all test datasets and it showed an ability to cope, not only with a variety of lung patterns, but also with the presence of lung nodules as well. This study shows the importance of using consistent annotations for the supervised learning process, which is a very time-consuming task, but that has great importance to healthcare applications. Due to the lack of massive datasets in the medical field, which consequently brings a lack of wide representativity, data augmentation with domain knowledge could represent a promising help to overcome this limitation for learning models development.

Probing cortical and sub-cortical contributions to instruction-based learning: Regional specialisation and global network dynamics.

Diverse cortical networks and striatal brain regions are implicated in instruction-based learning (IBL); however, their distinct contributions remain unclear. We use a modified fMRI paradigm to test two hypotheses regarding the brain mechanisms that underlie IBL. One hypothesis proposes that anterior caudate and frontoparietal regions transiently co-activate when new rules are being bound in working memory. The other proposes that they mediate the application of the rules at different stages of the consolidation process. In accordance with the former hypothesis, we report strong activation peaks within and increased connectivity between anterior caudate and frontoparietal regions when rule-instruction slides are presented. However, similar effects occur throughout a broader set of cortical and sub-cortical regions, indicating a metabolically costly reconfiguration of the global brain state. The distinct functional roles of cingulo-opercular, frontoparietal and default-mode networks are apparent from their activation throughout, early and late in the practice phase respectively. Furthermore, there is tentative evidence of a peak in anterior caudate activity mid-way through the practice stage. These results demonstrate how performance of the same simple task involves a steadily shifting balance of brain systems as learning progresses. They also highlight the importance of distinguishing between regional specialisation and global dynamics when studying the network mechanisms that underlie cognition and learning.

Game-based interventions for neuropsychological assessment, training and rehabilitation: Which game-elements to use? A systematic review.

Game-based interventions (GBI) have been used to promote health-related outcomes, including cognitive functions. Criteria for game-elements (GE) selection are insufficiently characterized in terms of their adequacy to patients' clinical conditions or targeted cognitive outcomes. This study aimed to identify GE applied in GBI for cognitive assessment, training or rehabilitation. A systematic review of literature was conducted. Papers involving video games were included if: (1) presenting empirical and original data; (2) using video games for cognitive intervention; and (3) considering attention, working memory or inhibitory control as outcomes of interest. Ninety-one papers were included. A significant difference between the number of GE reported in the assessed papers and those composing video games was found (p < .001). The two most frequently used GE were: score system (79.2% of the interventions using video games; for assessment, 43.8%; for training, 93.5%; and for rehabilitation, 83.3%) and narrative context (79.2% of interventions; for assessment, 93.8%; for training, 73.9% and for rehabilitation, 66.7%). Usability assessment was significantly associated with six of the seven GE analyzed (p-values between p ≤ 0.001 and p. = 027). The use of GE that act as extrinsic motivation promotors (e.g., numeric feedback system) may jeopardize patients' long-term adherence to interventions, mainly if associated with progressive difficulty-increase of gaming experience. Lack of precise description of GE and absence of a theoretical framework supporting GE selection are important limitations of the available clinical literature.

Physicians' beliefs and attitudes about Benzodiazepines: a cross-sectional study.

BACKGROUND: In 2015, Portugal was the OECD country with the highest reported consumption of BZD. Physician's perceptions and attitudes regarding BZD are main determinants of related prescription habits. This study aimed to characterize beliefs and attitudes of Portuguese physicians regarding the prescription, management challenges, benefits, risks and withdrawal effects of BZD. METHODS: A cross-sectional, observational study with online data collection through anonymous self-administered questionnaire. Physicians registered with the Portuguese Medical Association were invited to participate through direct e-mail message. Physicians were asked to give their opinion (using a 5-points Likert scale) regarding the prescription of BZD, their benefits and risks in the management of insomnia and anxiety, the possible adverse effects of chronic use and alternative non-pharmacologic approaches. Descriptive statistics were used and groups were compared through logistic regression. RESULTS: A total of 329 physicians participated in the study (56% family physicians). Mean age was 44.10 ± 15.2 years, with 19.03 ± 14.9 years of clinical experience. Fifty eight percent of participants were female. Physicians reported BZD's negative impact on cognitive function (89%), association with road traffic accidents (88%) and falls (79%). Also, 58% shared the belief that chronic use is justified if the patient feels better and without adverse events. Although 68% reported to feel capable of helping patients to reduce or stop BZD, 55% recognized difficulties in motivating them. Compared to other medical specialists (altogether), family physicians were significantly more aware about the adverse effects of BZD and considered that chronic use may not be justified. Conversely, more family physicians expressed concerns about their skills to motivate patients engaging in withdrawal programs and to support them during the process. CONCLUSION: Our results show that physicians' awareness about risks of BZD chronic use is adequate though their attitudes and self-perceived skills towards promoting BZD withdrawal can be improved. Interventions in primary care are needed to capacitate physicians to better motivate patients for BZD withdrawal.

Withdrawing and Withholding Life Support in Patients With Cancer in an ICU Setting: A 5-Year Experience at a European Cancer Center.

OBJECTIVE: This was an observational retrospective study aimed to examine the frequency and associated factors of withdrawing or withholding life support (WWLS) in the intensive care unit (ICU) of a comprehensive cancer center. METHODS: Medical records of adult patients with cancer admitted to the ICU between January 2010 and December 2014 were reviewed. Patients who died during that period were classified into 2 groups: full life support and withdrawing and withholding life support. The relative impact of demographic and clinical factors was assessed using logistic regression. RESULTS: A total of 247 patients died in our unit (mortality rate of 16.3%). Their median age was 62 (interquartile range [IQR] 51-73) years, there were 142 (57.5%) male patients, and they had predominantly solid malignancies (62.3%). The median Simplified Acute Physiology Score II and Acute Physiology and Chronic Health Evaluation scores were 67 (IQR 54-80) and 29 (IQR 23-55), respectively. Ninety-six (38.9%) patients died after WWLS with no statistically significant differences in decisions to limit therapy during the study period. Patients with advanced age, solid malignancies, nonneutropenic, and longer duration of mechanical ventilation were more likely to die after WWLS. In multivariate analysis, presenting with neutropenia was independently associated with a lower likelihood of dying after WWLS (odds ratio: 0.34, 95% confidence interval: 0.15-0.80). CONCLUSION: Limitation of therapy has been a common practice in oncologic ICUs over recent years. Neutropenia is an independent predictor of limitation of therapy.

Capturing and missing the patient's story through outcome measures: A thematic comparison of patient-generated items in PSYCHLOPS with CORE-OM and PHQ-9.

BACKGROUND: There is increasing interest in individualized patient-reported outcome measures (I-PROMS), where patients themselves indicate the specific problems they want to address in therapy and these problems are used as items within the outcome measurement tool. OBJECTIVE: This paper examined the extent to which 279 items reported in an I-PROM (PSYCHLOPS) added qualitative information which was not captured by two well-established outcome measures (CORE-OM and PHQ-9). DESIGN: Comparison of items was only conducted for patients scoring above the "caseness" threshold on the standardized measures. SETTING AND PATIENTS: 107 patients were participating in therapy within addiction and general psychiatric clinical settings. MAIN RESULTS: Almost every patient (95%) reported at least one item whose content was not covered by PHQ-9, and 71% reported at least one item not covered by CORE-OM. DISCUSSION: Results demonstrate the relevance of individualized outcome assessment for capturing data describing the issues of greatest concern to patients, as nomothetic measures do not always seem to capture the whole story.

Obstructive sleep apnoea in patients with fibrotic diffuse parenchymal lung disease-characterization and treatment compliance assessment.

INTRODUCTION: Recent studies have reported a high prevalence of obstructive sleep apnoea (OSA) among patients with diffuse parenchymal lung disease (DPLD), mainly idiopathic pulmonary fibrosis (IPF). Effective OSA treatment appears to have a positive impact on morbidity and mortality in these patients. However, poor compliance to positive airway pressure (PAP) treatment in fibrotic DPLD patients has been reported. The aims of our study were to characterize patients with fibrotic DPLD and OSA and to assess their compliance to PAP treatment. METHODS: Forty-nine patients with fibrotic DPLD underwent level III polysomnography. Auto-adjusting PAP (APAP) treatment was proposed for those patients with moderate-to-severe OSA and those with mild OSA with daytime sleepiness and/or cardiovascular disease. The APAP treatment compliance was assessed after 1 month of therapy. RESULTS: The distribution of the 49 fibrotic DPLD patients included was as follows: 21 with chronic hypersensitivity pneumonitis, 12 with IPF, 10 with connective-tissue associated DPLD, 4 with stage IV sarcoidosis, 1 with idiopathic pleuropulmonary fibroelastosis, and 1 with DPLD-associated vasculitis. Thirty-four (69.4%) of the patients presented with OSA; 22 had mild OSA, and 12 had moderate-to-severe OSA. APAP treatment was prescribed in 17 of the patients. After 1 month of therapy, all patients used APAP more than 70% of the nights for more than 4 h per night. CONCLUSION: We found a high prevalence of OSA among all of the patients with fibrotic DPLD (not only IPF). Despite certain difficulties, it was possible to achieve good APAP compliance in these patients.

Cerebrovascular pathology during the progression of experimental Alzheimer's disease.

Clinical and experimental evidence point to a possible role of cerebrovascular dysfunction in Alzheimer's disease (AD). The 5xFAD mouse model of AD expresses human amyloid precursor protein and presenilin genes with mutations found in AD patients. It remains unknown whether amyloid deposition driven by these mutations is associated with cerebrovascular changes. 5xFAD and wild type mice (2 to 12months old; M2 to M12) were used. Thinned skull in vivo 2-photon microscopy was used to determine Aß accumulation on leptomeningeal or superficial cortical vessels over time. Parenchymal microvascular damage was assessed using FITC-microangiography. Collagen-IV and CD31 were used to stain basal lamina and endothelial cells. Methoxy-XO4, Thioflavin-S or 6E10 were used to visualize Aß accumulation in living mice or in fixed brain tissues. Positioning of reactive IBA1 microglia and GFAP astrocytes at the vasculature was rendered using confocal microscopy. Platelet-derived growth factor receptor beta (PDGFRß) staining was used to visualize perivascular pericytes. In vivo 2-photon microscopy revealed Methoxy-XO4(+) amyloid perivascular deposits on leptomeningeal and penetrating cortical vessels in 5xFAD mice, typical of cerebral amyloid angiopathy (CAA). Amyloid deposits were visible in vivo at M3 and aggravated over time. Progressive microvascular damage was concomitant to parenchymal Aß plaque accumulation in 5xFAD mice. Microvascular inflammation in 5xFAD mice presented with sporadic FITC-albumin leakages at M4 becoming more prevalent at M9 and M12. 3D colocalization showed inflammatory IBA1(+) microglia proximal to microvascular FITC-albumin leaks. The number of perivascular PDGFRß(+) pericytes was significantly decreased at M4 in the fronto-parietal cortices, with a trend decrease observed in the other structures. At M9-M12, PDGFRß(+) pericytes displayed hypertrophic perivascular ramifications contiguous to reactive microglia. Cerebral amyloid angiopathy and microvascular inflammation occur in 5xFAD mice concomitantly to parenchymal plaque deposition. The prospect of cerebrovascular pharmacology in AD is discussed.

Sex-based differences and risk of recurrence in patients with atrial fibrillation undergoing pulmonary vein isolation.

INTRODUCTION: Studies suggest increased likelihood of atrial fibrillation (AF) recurrence after catheter ablation (CA) in women than in men, indicating that sex may be an independent risk factor for recurrence. Nevertheless, the influence of sex on AF recurrence and underlying mechanisms remains unclear. METHODS: Retrospective, single-centre study including patients undergoing AF CA between 2017 and 2021. Late recurrence (LR) was defined as AF recurrence ≥90 days after ablation, whereas early recurrence (ER) occurred within 90 days. RESULTS: 656 patients (32% women) were included, with a median follow-up period of 26 months. Compared to men, women undergoing CA were older, had higher body mass indexes, and had higher rates of hypertension, thyroid dysfunction, and valvular disease. Women also had increased LR risk after CA (HR 1.76, 95% CI [1.19, 2.59]). A time-split multivariable analysis at one year of follow-up showed no difference in LR risk during the first 12 months after CA (HR 1.19, 95% CI [0.73, 1.94]); however, LR risk increased in women (HR 2.90, 95% CI [1.68, 5.01]) after 12 months. In a sex-stratified analysis, coronary calcium score (CCS) >100 was associated with increased LR risk in men (HR 1.81, 95% CI [1.06, 3.08]), but not in women. Cardiac adipose tissue volume was not associated with increased LR risk. CONCLUSIONS: Fewer women underwent CA than men and LR was more frequent in women, particularly one year after the procedure. CCS was associated with increased LR risk in men.

Effectiveness of a group education session on adherence with APAP in obstructive sleep apnea--a randomized controlled study.

PURPOSE: Auto-titrating continuous positive airway pressure (APAP) is an effective treatment for obstructive sleep apnea/hypopnea syndrome (OSAHS). We investigated whether a single group education session on APAP therapy is effective in promoting adherence among patients with OSAHS. METHODS: This prospective, randomized, controlled, parallel group study included patients newly diagnosed with OSAHS who met criteria for APAP therapy. Patients were randomized into a study group and a control group. All patients in the study group were assigned to a single group education session, 1 month after beginning APAP therapy. RESULTS: We evaluated 146 patients. The median percentage of APAP usage days was 88.3 %, with a median duration per day of use of 6.02 h; 59 % were classified as adherent. Overall, no significant difference in adherence was seen between the study and the control groups. Analyzing patient subgroups, the group session significantly improved APAP adherence among males and patients who were younger (<65 years old), obese (BMI ≥ 35 kg/m(2)), non-sleepy (Epworth sleepiness scale ≤ 11), smokers or past smokers, had hypertension or nocturia and those with non-severe OSAHS. CONCLUSION: To maximize the impact of group education sessions and, by that, saving resources, it may be important to select patients likely to benefit from these sessions.

Efficacy and Safety of Sufentanil Infusion for Postoperative Analgesia in Cancer Surgery: A Retrospective Cohort Study.

Background Opioids have long been the cornerstone of drugs used for perioperative analgesia. Sufentanil has an advantageous pharmacological profile for its use in continuous intravenous (IV) infusion, yet remains poorly described. Our institution has implemented analgesia protocols with IV sufentanil infusions for cancer surgery with appropriate monitoring. The aim of this study was to evaluate the efficacy and safety of IV sufentanil infusion. Methods A single-center retrospective cohort study was conducted through the analysis of patients' records and the acute pain service database. Inclusion criteria were adult patients admitted for elective cancer surgery and with postoperative IV sufentanil infusion during one year period. Descriptive and inferential statistical analysis was performed by using Software SPSS Statistics (IBM Corp., Armonk USA): Kruskal-Wallis, Mann-Whitney, Chi-square and Fisher tests; Bonferroni chi-square residual analysis, binary logistic regression; p<0.05. Results The study population of 304 patients had a median age of 66 years (22-91) and 229 (75.3%) were men. 38 (12.5%) were chronic opioid users. Head and neck/otorhinolaryngology (ORL) surgery was performed in 155 (51.0%) and abdominopelvic surgery in 123 (40.5%). The median days of IV sufentanil infusion were 2 (1-13). At rest and with movement, analgesia was considered good, i.e., over 90% of patients with visual analogue scale (VAS) pain score ≤ 3. We found that patients submitted to musculoskeletal surgery had higher VAS pain scores; this group also presented older patients with higher American Society of Anesthesiologists (ASA) physical status classification and more chronic opioid users (p<0.05). 144 patients (47.4%) had at least one adverse effect related to IV sufentanil infusion, notably transient and not requiring any specific treatment. These patients were older and had longer infusion periods (p<0.05). 237 (98.3%) of the adverse effects occurred during the first 3 days and the most common were: sedation (n=104, 42.8%), hypotension (n=32, 13.2%), hypoxemia (n=31, 12.8%) and nausea/vomiting (n=25, 10.3%). The reported incidence of respiratory depression was 2.9% (n=9), with three patients (1%) requiring advanced treatment. Conclusion Multimodal analgesic protocols with IV sufentanil infusions provided good postoperative analgesia for head and neck/ORL and abdominopelvic cancer surgeries. The adverse effects associated with the IV sufentanil infusions were mild and mainly managed with opioid dose reductions. Our study showed that this approach can be a safe option for postoperative multimodal analgesia in cancer surgery with appropriate monitoring in high-dependency units.

Association between EGF +61 genetic polymorphisms and non-small cell lung cancer increased risk in a Portuguese population: a case-control study.

Epidermal growth factor (EGF) and its receptor play critical roles in non-small cell lung cancer (NSCLC) carcinogenesis. A functional polymorphism in the EGF gene has been linked to increased cancer susceptibility. This study aimed to evaluate the role of the EGF +61A/G polymorphism as risk factors in NSCLC patients. For the present case-control study, we analyzed 112 NSCLC and 126 cancer-free controls from Portugal. Following DNA isolation from peripheral blood, EGF +61A/G polymorphism was assessed by polymerase chain reaction-restriction fragment length polymorphism. Univariate and multivariate logistic regression analyses were used to calculate odds ratio (OR) and 95 % confidence intervals (95 % CI). False-positive report probability was also assessed. The EGF +61 genotypes frequencies in NSCLC were AA (23.2 %), AG (51.8 %), and GG (25 %) and in controls, AA (40.5 %), AG (41.3 %), and GG (18.3 %). When compared to the reference genotype (EGF +61A/A), we found a statistically significant association between EGF +61 A/G (OR = 2.142, 95 % CI 1.170-3.924) and EGF +61G/G (OR = 2.398, 95 % CI 1.157-4.968) genotypes and susceptibility to development of NSCLC. Furthermore, stratification by sex revealed a trend to increased risk of males carrying +61A/G genotype for developing NSCLC (OR = 2.044, 95 % CI 0.998-4.188) when compared to A/A genotype. Our data suggest an increased risk to develop NSCLC in Portuguese population carrying the EGF +61A/G and +61G/G genotypes.

Mortality risk prediction with ILD-GAP index in a fibrotic hypersensitivity pneumonitis cohort.

BACKGROUND: Fibrotic hypersensitivity pneumonitis (fHP) is associated with significant morbidity and mortality. Interstitial lung disease-gender-age-physiology (ILD-GAP) performance in fHP outside the initial cohort was never performed. AIM: To assess the ILD-GAP index's ability to predict mortality in a Portuguese cohort of patients with fHP and analyse whether other clinical variables add value. METHODS: Retrospective analysis of fHP cohort in two Portuguese ILD centres. The baseline ILD-GAP index was calculated. Survival was analysed in months; mortality was the primary outcome. Univariate and multivariate analyses to identify mortality risk factors were performed. RESULTS: A total of 141 patients were included. Fifty-three patients (37.6%) died during the follow-up. The usual interstitial pneumonia (UIP) pattern was found in 49.6%, and their survival was inferior to non-UIP [32 months (interquartile range, IQR = 19, 60) versus 52 months (IQR = 28, 98), p = 0.048]. Patients with an ILD-GAP index higher than three double their risk of mortality [hazard ratio (HR) = 6.48, 95% confidence interval (CI) = (3.03-13.96)] when compared with the patients with an index between 2 and 3 [HR = 3.04, 95% CI = (1.62-5.71)] adjusting for acute exacerbation history. Even though UIP patients had worse survival, it did not reach statistical significance when UIP pattern was added to this model. Acute exacerbation history was an independent risk factor for mortality; however, ILD-GAP still predicted mortality after adjusting for this factor. PaO2 and 6-minute walk test desaturation were not significant risk factors. CONCLUSION: ILD-GAP index is a good predictor for mortality in fHP, even after adjusting for other mortality risk factors.

Anticoagulation therapy in patients with post-operative atrial fibrillation: Systematic review with meta-analysis.

BACKGROUND: Post-operative atrial fibrillation (POAF) is a relevant complication after surgery. Several studies have shown that POAF has important consequences for long-term morbidity and mortality, by increasing the risk of thromboembolic events. However, the use of oral anticoagulation (OAC) is not well established in this context. METHODS: We searched MEDLINE, CENTRAL, PsycInfo and Web of Science for clinical trials and observational studies evaluating anticoagulation vs. no anticoagulation in patients with POAF (after cardiac or non-cardiac surgery). Data were screened and extracted by two independent reviewers. We performed a random- effects model to estimate the pooled odds ratio (OR) with 95% Confidence Intervals (CI), and heterogeneity was evaluated by I2 statistics. The outcomes of interest were all-cause mortality, thromboembolic events, and bleeding events. RESULTS: Overall, 10 observational retrospective studies were included: 5 studies with 203,946 cardiac surgery POAF patients, and 5 studies with 29,566 patients with POAF after non-cardiac surgery. In cardiac surgery POAF, the OAC use was associated with lower risk of thromboembolic events (OR 0.68; 95%CI 0.47-0.96, I2 = 31%; 4 studies) and the bleeding risk was significantly increased (OR 4.30; 95%CI 3.69 to 5.02, 1 study). In non-cardiac surgery POAF, OAC did not significantly reduce the risk of thromboembolic events (OR 0.71, 95%CI 0.33-1.15; I2 = 79%; 5 studies) but was associated with increased risk of bleeding (OR 1.20, 95%CI 1.10-1.32, I2 = 0%; 3 studies). Mortality was not significantly reduced in both cardiac and non-cardiac surgery POAF. CONCLUSION: Oral anticoagulation was associated with a lower risk of thromboembolic events in patients with POAF following cardiac surgery but not in non-cardiac surgery. Bleeding risk was increased in both settings. The confidence on pooled results is at most low, and further data, namely randomized controlled trials are necessary to derive robust conclusions.