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Few studies have assessed the impact of the COVID-19 pandemic on non-COVID diseases and healthcare quality. We aimed to evaluate changes in rates of hospitalisations, complications, in-hospital mortality, and readmissions among patients with non-COVID diseases during a one-year period after the pandemic onset. From March 2018 to February 2021 a retrospective observational study of hospital admissions in a university hospital in Spain was conducted. Non-COVID hospitalisations admitted through the emergency department were compared between the pre-COVID period (n = 28,622) and the COVID period (n = 11,904). We assessed rate ratios (RaR), comparing the weekly number of admissions and risk ratios (RR) to examine rates of complications, in-hospital mortality, readmissions, and severity. Statistical significance was set at p < 0.05. The weekly admission rate dropped by 20.8% during the complete lockdown. We observed significant reductions in admissions related to diseases of the respiratory system and circulatory system. Admissions for endocrine and metabolic diseases increased. The complication rates increased (RR = 1.21, 95% CI: 1.05;1.4), while in-hospital mortality rates held steady during the COVID period (RR = 1.09, 95% CI: 0.98;1.2). Hospital efforts to maintain quality and safety standards despite disruptions translated into a moderate increase in complications but not in in-hospital mortality. Reduced hospitalisations for conditions requiring timely treatment may have significant public health consequences.

Assessing the long-term risk of breast cancer after diagnosis of benign breast disease by mammography is of utmost importance to design personalised screening strategies. We analysed individual-level data from 778,306 women aged 50-69 years with at least one mammographic screening participation in any of ten breast cancer screening centers in Spain from 1996 to 2015, and followed-up until 2017. We used Poisson regression to compare the rates of incident breast cancer among women with and without benign breast disease. During a median follow-up of 7.6 years, 11,708 (1.5%) women had an incident of breast cancer and 17,827 (2.3%) had a benign breast disease. The risk of breast cancer was 1.77 times higher among women with benign breast disease than among those without (95% CI: 1.61 to 1.95). The relative risk increased to 1.99 among women followed for less than four years, and remained elevated for two decades, with relative risk 1.96 (95% CI: 1.32 to 2.92) for those followed from 12 to 20 years. Benign breast disease is a long-term risk factor for breast cancer. Women with benign breast disease could benefit from closer surveillance and personalized screening strategies.

Purpose: This study aimed to evaluate health service utilization in Spain among long-term breast cancer survivors and to compare it with that among women with no history of breast cancer., Methods: Study based on the SURBCAN cohort includes a sample of long-term breast cancer survivors and a sample of women without breast cancer from 5 Spanish regions. Healthcare utilization was assessed through primary care, hospital visits, and tests during the follow-up period (2012 to 2016) by using electronic health records. Annual contact rates to healthcare services were calculated, and crude and multivariate count models were fitted to estimate the adjusted relative risk of healthcare services use., Results: Data were obtained from 19,328 women, including 6512 long-term breast cancer survivors. Healthcare use was higher among breast cancer survivors (20.9 vs 16.6; p < 0.0001) and decreased from >10 years of survival. Breast cancer survivors who underwent a mastectomy were more likely to have a primary care visit (RR = 3.10 95% CI 3.08-3.11). Five to ten years survivors were more likely to have hospital inpatient visits and imaging test compared to women without breast cancer (RRa = 1.35 95% CI 1.30-1.39 and RRa = 1.27 95% CI 1.25-1.29 respectively)., Conclusion: This study shows higher use of health services in long-term breast cancer survivors than in women without breast cancer regardless of survival time., Implications for Cancer Survivors: These results help to estimate the health resources needed for the growing group of breast cancer survivors and to identify risk factors that drive higher use of health services., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Influenza NS1 is a promising anti-influenza target, considering its conserved and druggable structure, and key function in influenza replication and pathogenesis. Notwithstanding, target identification and validation, strengthened by experimental data, are lacking. Here, we further explored our previously designed structure-based antiviral rationale directed to highly conserved druggable NS1 regions across a broad spectrum of influenza A viruses. We aimed to identify NS1-mutated viruses exhibiting a reduced growth phenotype and/or an altered cell apoptosis profile. We found that NS1 mutations Y171A, K175A (consensus druggable pocket 1), W102A (consensus druggable pocket 3), Q121A and G184P (multiple consensus druggable pockets) - located at hot spots amenable for pharmacological modulation - significantly impaired A(H1N1)pdm09 virus replication, in vitro. This is the first time that NS1-K175A, -W102A, and -Q121A mutations are characterized. Our map-and-mutate strategy provides the basis to establish the NS1 as a promising target using a rationale with a higher resilience to resistance development., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: To evaluate the mammographic features in women with benign breast disease (BBD) and the risk of subsequent breast cancer according to their mammographic findings., Methods: We analyzed data from a Spanish cohort of women screened from 1995 to 2015 and followed up until December 2017 (median follow-up, 5.9 years). We included 10,650 women who had both histologically confirmed BBD and mammographic findings. We evaluated proliferative and nonproliferative BBD subtypes, and their mammographic features: architectural distortion, asymmetries, calcifications, masses, and multiple findings. The adjusted hazard ratios (aHR) and 95% confidence intervals (95% CI) for breast cancer were estimated using a Cox proportional hazards model. We plotted the adjusted cumulative incidence curves., Results: Calcifications were more frequent in proliferative disease with atypia (43.9%) than without atypia (36.8%) or nonproliferative disease (22.2%; p value < 0.05). Masses were more frequent in nonproliferative lesions (59.1%) than in proliferative lesions without atypia (35.1%) or with atypia (30.0%; p value < 0.05). Multiple findings and architectural distortion were more likely in proliferative disease (16.1% and 4.7%) than in nonproliferative disease (12.8% and 1.9%). Subsequent breast cancer occurred in 268 (2.5%) women. Compared with women who had masses, the highest risk of subsequent breast cancer was found in those with architectural distortions (aHR, 2.21; 95% CI, 1.16-4.22), followed by those with multiple findings (aHR, 1.89; 95% CI, 1.34-2.66), asymmetries (aHR, 1.66; 95% CI, 0.84-3.28), and calcifications (aHR, 1.60; 95% CI, 1.21-2.12)., Conclusion: BBD subtypes showed distinct mammographic findings. The risk of subsequent breast cancer was high in those who have shown architectural distortion, multiple findings, asymmetries, and calcifications than in women with masses., Key Points: • The presence of mammographic findings in women attending breast cancer screening helps clinicians to assess women with benign breast disease (BBD). • Calcifications were frequent in BBDs with atypia, which are the ones with a high breast cancer risk, while masses were common in low-risk BBDs. • The excess risk of subsequent breast cancer in women with BBD was higher in those who showed architectural distortion compared to those with masses., (© 2021. European Society of Radiology.)

Focused cardiac ultrasound (FoCUS) has become a valuable tool to assess unexplained hypotension in critically ill patients. Due to increasing availability of transthoracic echocardiography (TTE) equipment in the operating room, there is a widespread interest in its usefulness for intraoperative diagnosis of hypotension as an alternative to transesophageal echocardiography (TEE). The objective of this systematic review is to evaluate the utility of intraoperative FoCUS to assess patients experiencing unexplained hypotension while undergoing noncardiac surgery. We performed a systematic literature search of multiple publication databases for studies that evaluated the utility of intraoperative FoCUS for assessment and management of unexplained hypotension in patients undergoing noncardiac surgery, including retro- and prospective clinical studies. A summary of the study findings, study quality, and assessment of level of evidence is presented. We identified 2227 unique articles from the literature search, of which 27 were potentially relevant, and 9 were included in this review. The number of patients pooled from these studies was 255, of whom 228 had intraoperative diagnoses with the aid of intraoperative FoCUS. The level of evidence of all studies included was very low according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines. This systematic review has demonstrated that FoCUS may be a useful, noninvasive method to differentiate causes of intraoperative hypotension and guide correcting interventions, although the quality of evidence is very low. Further prospective high-quality studies are needed to investigate whether intraoperative FoCUS has a diagnostic utility that is associated with improved outcomes., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 International Anesthesia Research Society.)

Objectives: Assessing the combined effect of mammographic density and benign breast disease is of utmost importance to design personalized screening strategies., Methods: We analyzed individual-level data from 294,943 women aged 50-69 years with at least one mammographic screening participation in any of four areas of the Spanish Breast Cancer Screening Program from 1995 to 2015, and followed up until 2017. We used partly conditional Cox models to assess the association between benign breast disease, breast density, and the risk of breast cancer., Results: During a median follow-up of 8.0 years, 3697 (1.25%) women had a breast cancer diagnosis and 5941 (2.01%) had a benign breast disease. More than half of screened women had scattered fibroglandular density (55.0%). The risk of breast cancer independently increased with the presence of benign breast disease and with the increase in breast density (p for interaction = 0.84). Women with benign breast disease and extremely dense breasts had a threefold elevated risk of breast cancer compared with those with scattered fibroglandular density and without benign breast disease (hazard ratio [HR] = 3.07; 95%CI = 2.01-4.68). Heterogeneous density and benign breast disease was associated with nearly a 2.5 elevated risk (HR = 2.48; 95%CI = 1.66-3.70). Those with extremely dense breast without a benign breast disease had a 2.27 increased risk (95%CI = 2.07-2.49)., Conclusions: Women with benign breast disease had an elevated risk for over 15 years independently of their breast density category. Women with benign breast disease and dense breasts are at high risk for future breast cancer., Key Points: • Benign breast disease and breast density were independently associated with breast cancer. • Women with benign breast disease had an elevated risk for up to 15 years independently of their mammographic density category.

Background: Several studies have proposed personalized strategies based on women's individual breast cancer risk to improve the effectiveness of breast cancer screening. We designed and internally validated an individualized risk prediction model for women eligible for mammography screening., Methods: Retrospective cohort study of 121,969 women aged 50 to 69 years, screened at the long-standing population-based screening program in Spain between 1995 and 2015 and followed up until 2017. We used partly conditional Cox proportional hazards regression to estimate the adjusted hazard ratios (aHR) and individual risks for age, family history of breast cancer, previous benign breast disease, and previous mammographic features. We internally validated our model with the expected-to-observed ratio and the area under the receiver operating characteristic curve., Results: During a mean follow-up of 7.5 years, 2,058 women were diagnosed with breast cancer. All three risk factors were strongly associated with breast cancer risk, with the highest risk being found among women with family history of breast cancer (aHR: 1.67), a proliferative benign breast disease (aHR: 3.02) and previous calcifications (aHR: 2.52). The model was well calibrated overall (expected-to-observed ratio ranging from 0.99 at 2 years to 1.02 at 20 years) but slightly overestimated the risk in women with proliferative benign breast disease. The area under the receiver operating characteristic curve ranged from 58.7% to 64.7%, depending of the time horizon selected., Conclusions: We developed a risk prediction model to estimate the short- and long-term risk of breast cancer in women eligible for mammography screening using information routinely reported at screening participation. The model could help to guiding individualized screening strategies aimed at improving the risk-benefit balance of mammography screening programs., Competing Interests: The authors have declared that no competing interests exist.

Objective: We aimed to explore whether the type of mammographic feature prompting a false-positive recall (FPR) during mammography screening influences the risk and timing of breast cancer diagnosis, particularly if assessed with invasive procedures., Study Design: We included information on women screened and recalled for further assessment in Spain between 1994 and 2015, with follow-up until 2017, categorizing FPRs by the assessment (noninvasive or invasive) and mammographic feature prompting the recall., Main Outcome Measures: Breast cancer rates in the first two years after FPR (first period) and after two years (second period)., Results: The study included 99,825 women with FPRs. In both periods, the breast cancer rate was higher in the invasive assessment group than in the noninvasive group (first period 12 ‰ vs 1.9 ‰, p < 0.001; second period 4.4‰ vs 3.1‰, p < 0.001). During the first period, the invasive assessment group showed diverse breast cancer rates for each type of mammographic feature, with a higher rate for asymmetric density (31.9‰). When the second period was compared with the first, the breast cancer rate decreased in the invasive assessment group (from 12‰ to 4.4‰, p < 0.001) and increased in the noninvasive assessment group (from 1.9‰ to 3.1‰, p < 0.001)., Conclusion: In the context of mammography screening, the risk of breast cancer diagnosis during the first two years after FPR was particularly high for women undergoing invasive assessment; importantly, the risk was modified by type of mammographic feature prompting the recall. This information could help to individualize follow-up after exclusion of malignancy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: We aimed to assess differences in breast cancer risk across benign breast disease diagnosed at prevalent or incident screens., Materials and Methods: We conducted a retrospective cohort study with data from 629,087 women participating in a long-standing population-based breast cancer screening program in Spain. Each benign breast disease was classified as non-proliferative, proliferative without atypia, or proliferative with atypia, and whether it was diagnosed in a prevalent or incident screen. We used partly conditional Cox hazard regression to estimate the adjusted hazard ratios of the risk of breast cancer., Results: Compared with women without benign breast disease, the risk of breast cancer was significantly higher (p-value = 0.005) in women with benign breast disease diagnosed in an incident screen (aHR, 2.67; 95%CI: 2.24-3.19) than in those with benign breast disease diagnosed in a prevalent screen (aHR, 1.87; 95%CI: 1.57-2.24). The highest risk was found in women with a proliferative benign breast disease with atypia (aHR, 4.35; 95%CI: 2.09-9.08, and 3.35; 95%CI: 1.51-7.40 for those diagnosed at incident and prevalent screens, respectively), while the lowest was found in women with non-proliferative benign breast disease (aHR, 2.39; 95%CI: 1.95-2.93, and 1.63; 95%CI: 1.32-2.02 for those diagnosed at incident and prevalent screens, respectively)., Conclusion: Our study showed that the risk of breast cancer conferred by a benign breast disease differed according to type of screen (prevalent or incident). To our knowledge, this is the first study to analyse the impact of the screening type on benign breast disease prognosis., Competing Interests: Declaration of competing interest None declared., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

There are no approved target therapeutics against SARS-CoV-2 or other beta-CoVs. The beta-CoV Spike protein is a promising target considering the critical role in viral infection and pathogenesis and its surface exposed features. We performed a structure-based strategy targeting highly conserved druggable regions resulting from a comprehensive large-scale sequence analysis and structural characterization of Spike domains across SARSr- and MERSr-CoVs. We have disclosed 28 main consensus druggable pockets within the Spike. The RBD and SD1 (S1 subunit); and the CR, HR1 and CH (S2 subunit) represent the most promising conserved druggable regions. Additionally, we have identified 181 new potential hot spot residues for the hSARSr-CoVs and 72 new hot spot residues for the SARSr- and MERSr-CoVs, which have not been described before in the literature. These sites/residues exhibit advantageous structural features for targeted molecular and pharmacological modulation. This study establishes the Spike as a promising anti-CoV target using an approach with a potential higher resilience to resistance development and directed to a broad spectrum of Beta-CoVs, including the new SARS-CoV-2 responsible for COVID-19. This research also provides a structure-based rationale for the design and discovery of chemical inhibitors, antibodies or other therapeutic modalities successfully targeting the Beta-CoV Spike protein., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Authors.)

Background: Rapid sequence induction and tracheal intubation through direct laryngoscopy (DL) has been the most common approach to secure the airway in trauma patients. The introduction of video laryngoscopy (VL) has changed airway management in many clinical settings. In this retrospective study, we assessed if immediate availability of VL in the trauma suite has changed the approach and outcomes of airway management during acute resuscitation at a dedicated trauma center., Materials and Methods: We retrospectively collected data from emergency intubation in the 6 resuscitation bays at a high-volume, academic, Level 1 trauma center over a 42-month period following the introduction of immediately available VL in the resuscitation bay. We divided the data into 13-week bins to assess the trend in the use of VL over time. Our measured outcomes were the incidence of failed intubations requiring a surgical airway and the frequency of VL use for airway management., Results: Among 1328 airway management events in the resuscitation bays when intubation was attempted, the failure rate resulting in the placement of a surgical airway was 0.38% (95% confidence interval [CI], 0.12% -0.88%). This was consistent with the surgical airway rate before the introduction of VL into trauma practice (0.3%). VL use (primary or as a rescue technique) throughout the study period was 4.14% (95% CI, 2.76%-5.74%), with no temporal trend., Conclusion: The immediate availability of VL in the resuscitation bay has not changed the prevalence of its use during emergency airway management at our trauma center. DL remains a preferred primary modality for airway management by the trauma anesthesiologists working at this facility, with an acceptably low incidence of both primary failure and the need to establish a surgical airway., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 International Journal of Critical Illness and Injury Science.)

Background: The effectiveness of breast cancer screening is still under debate. Our objective was to systematically review studies assessing personalized breast cancer screening strategies based on women's individual risk and to conduct a risk of bias assessment., Methods: We followed the standard methods of The Cochrane Collaboration and PRISMA declaration and searched the MEDLINE, EMBASE and Clinical Trials databases for studies published in English. The quality of the studies was assessed using the ISPOR-AMCP-NPC Questionnaire and The Cochrane Risk of Bias Tool. Two independent reviewers screened full texts and evaluated the risk of bias., Results: Out of the 1533 initially retrieved citations, we included 13 studies. Three studies were randomized controlled trials, while nine were mathematical modeling studies, and one was an observational pilot study. The trials are in the recruitment phase and have not yet reported their results. All three trials used breast density and age to define risk groups, and two of them included family history, previous biopsies, and genetic information. Among the mathematical modeling studies, the main risk factors used to define risk groups were breast density, age, family history, and previous biopsies. Six studies used genetic information to define risk groups. The most common outcome measures were the gain in quality-adjusted life years (QALY), absolute costs, and incremental cost-effectiveness ratio (ICER), while the main outcome in the observational study was the detection rate. In all models, personalized screening strategies were shown to be effective. The randomized trials were of good quality. The modeling studies showed moderate risk of bias but there was wide variability across studies. The observational study showed a low risk of bias but its utility was moderate due to its pilot design and its relatively small scale., Conclusions: There is some evidence of the effectiveness of screening personalization in terms of QUALYs and ICER from the modeling studies and the observational study. However, evidence is lacking on feasibility and acceptance by the target population., Review Registration: PROSPERO: CRD42018110483., Competing Interests: The authors have declared that no competing interests exist

Background: We aimed to identify the risk factors associated with early, late and long-term readmissions in women diagnosed with breast cancer participating in screening programs., Methods: We performed a multicenter cohort study of 1055 women aged 50-69 years participating in Spanish screening programs, diagnosed with breast cancer between 2000 and 2009, and followed up to 2014. Readmission was defined as a hospital admission related to the disease and/or treatment complications, and was classified as early (< 30 days), late (30 days-1 year), or long-term readmission (> 1 year). We used logistic regression to estimate the adjusted odds ratios (aOR), and 95% confidence intervals (95% CI) to explore the factors associated with early, late and long-term readmissions, adjusting by women's and tumor characteristics, detection mode, treatments received, and surgical and medical complications., Results: Among the women included, early readmission occurred in 76 (7.2%), late readmission in 87 (8.2%), long-term readmission in 71 (6.7%), and no readmission in 821 (77.8%). Surgical complications were associated with an increased risk of early readmissions (aOR = 3.62; 95%CI: 1.27-10.29), and medical complications with late readmissions (aOR = 8.72; 95%CI: 2.83-26.86) and long-term readmissions (aOR = 4.79; 95%CI: 1.41-16.31)., Conclusion: Our results suggest that the presence of surgical or medical complications increases readmission risk, taking into account the detection mode and treatments received. Identifying early complications related to an increased risk of readmission could be useful to adapt the management of patients and reduce further readmissions., Trial Registration: ClinicalTrials.govIdentifier: NCT03165006. Registration date: May 22, 2017 (Retrospectively registered).

Background: Our aim was to assess the role of breast density on breast cancer mortality and recurrences, considering patient and tumour characteristics and the treatments received among women attending population-based screening programmes., Methods: We conducted a retrospective cohort study among women aged 50-69 years attending population-based screening programmes, diagnosed with invasive breast cancer between 2000 and 2009, and followed up to 2014. Breast density was categorised as low density (≤25% dense tissue), intermediate density (25-50%), and high density (≥50%). Cox proportional hazards regression models were fitted to estimate the adjusted hazard ratios (aHR) and 95% confidence intervals (95% CI) for death and recurrences, adjusting by patient characteristics, mode of detection (screen-detected vs. interval cancer), and tumour features., Results: The percentage of deaths and recurrences was higher among women with intermediate- and high-density breasts than among women with low-density breasts ( p =0.011 for death; p =0.037 for recurrences). Adjusted Cox proportional hazards regression models revealed that women with intermediate- and high-density breasts had a higher risk of death than women with low-density breasts, being statistically significant for intermediate densities (aHR = 2.19 [95% CI: 1.16-4.13], aHR = 1.44 [95% CI: 0.67-3.1], respectively). No association was found between breast density and recurrences., Conclusions: Breast density was associated with a higher risk of death, but not of recurrences, among women participating in breast cancer screening. These findings reinforce the need to improve screening sensitivity among women with dense breasts and to routinely assess breast density, not only for its role as a risk factor for breast cancer but also for its potential influence on cancer prognosis., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 Laia Domingo et al.)

The aim of this study is to determine the survival of patients with breast cancer treated with adjuvant chemotherapy (ACh) after the diagnosis by screening, taking comorbidity into account. This multicenter cohort study examined a population of patients taking part in four national screening programs for the early detection of breast cancer (localized or locally advanced), during the period 2000-2008. Of the 1248 cancers detected, 266 were prevalent (21.3%), 633 were incident (50.7%), and 349 were interval (27.9%). No significant differences were detected between the three groups in terms of the distribution of comorbidity according to the CCI. After a median follow-up of 102 months, 22.1% of the patients with interval cancer had died. The corresponding figures for the incident and prevalent cancers were 10.4% and 7.9%, respectively (P < .001). The adjusted Cox regression analysis by the stage, CCI and group revealed no differences in the risk of recurrence between the different groups according to the ACh performed. However, there were significant differences in the overall survival; for the interval cancer group without ACh, the risk of death was higher (Hazard ratio: 2.5 [1.0-6.2]) than for the other two groups. However, for the prevalent and incident groups that did not receive ACh, there was no greater risk of death. This study shows that adjuvant chemotherapy seems to benefit patients with interval breast cancer, who have a poorer prognosis than those with prevalent or incident cancer. However, the role of ACh is unclear with respect to prevalent and incident cancers when comorbidity is taken into account., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Competing Interests: There are no conflicts of interest.

To assess the cost-effectiveness of the primary prevention of fragility hip fractures through opportunistic risk-based screening using FRAX ® among women aged 70 to 89 years, and the subsequent treatment with alendronate in women at high-risk, from the Spanish national health system perspective. We performed a discrete-event simulation model. Women were categorized in low, intermediate and high-risk of fragility hip fracture through screening based on the FRAX ® risk assessment tool score (Spanish version). Low-risk women received lifestyle recommendations whereas the high-risk group was assigned to alendronate treatment. For women at intermediate-risk, treatment decision was based on a recalculated score considering bone mineral density (BMD). The cost-effectiveness analysis tested six scenarios defined by different FRAX ® cut-off values assessing the incremental costs per averted fracture in 20 years. Deterministic sensitivity analysis was performed. We included a random sample of 5146 women obtained from a Spanish cohort of women referred for BMD. The most cost-effective intervention had an Incremental Cost-effectiveness Ratio (ICER) of 57,390 € per averted hip fracture and consisted of using the FRAX ® score without BMD and treating women with a score higher than 5%. The ICER exceeded the acceptability threshold of 25,000 € in all the scenarios. Sensitivity analysis based on time to fracture, treatment efficacy, adherence to treatment and cost of dependence resulted in ICERs ranging from 39,216 € to 254,400 €. An ICER of 24,970 € was obtained when alendronate cost was reduced to 1.13 € per month. The use of FRAX ® as screening tool followed by alendronate treatment is not cost-effective in senior women in Spain. Other primary preventions strategies are advisable.

Background: The effect of changes in mammographic density over time on the risk of breast cancer remains inconclusive., Methods: We used information from four centres of the Breast Cancer Screening Program in Spain in the period 1996-2015. We analysed individual level data from 117,388 women first screened age 50-54, with at least two screening examinations. Breast density was determined using the BI-RADS classification (A to D in increasing order) at earliest and latest screening examination. Adjusted Poisson regression models were used to estimate the relative risk (RR) and 95% confidence intervals (95%CI) of the association between changes in mammographic density and breast cancer risk over time., Results: During an average 5.8 years of follow-up, 1592 (1.36%) women had a breast cancer diagnosis. An increase in density category increased breast cancer risk, and a decrease in density decreased the risk, compared with women who remained in the same BI-RADS category. Women whose density category increased from B to C or B to D had a RR of 1.55 (95%CI = 1.24-1.94) and 2.32 (95%CI = 1.48-3.63), respectively. The RR for women whose density increased from C to D was 1.51 (95%CI = 1.03-2.22). Changes in BI-RADS density were similarly associated with the risk for invasive cancer than for ductal carcinoma in situ., Conclusions: Although a modest proportion of women changed BI-RADS density category, mammographic density changes modulated the risk of breast cancer and identified women at a differential risk. Using two longitudinal measures of BI-RADS density could help target women for risk-based screening strategies., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: To describe drug-related problems identified in hospitalized patients and to assess physicians' acceptance rate of pharmacists' recommendations., Methods: Retrospective observational study that included all drug-related problems detected in hospitalized patients during 2014-2015. Statistical analysis included a descriptive analysis of the data and a multivariate logistic regression to evaluate the association between pharmacists' recommendation acceptance rate and the variable of interest., Results: During the study period 4587 drug-related problems were identified in 44,870 hospitalized patients. Main drug-related problems were prescription errors due to incorrect use of the computerized physician order entry (18.1%), inappropriate drug-drug combination (13.3%) and dose adjustment by renal and/or hepatic function (11.5%). Acceptance rate of pharmacist therapy advice in evaluable cases was 81.0%. Medical versus surgical admitting department, specific types of intervention (addition of a new drug, drug discontinuation and correction of a prescription error) and oral communication of the recommendation were associated with a higher acceptance rate., Conclusions: The results of this study allow areas to be identified on which to implement optimization strategies. These include training courses for physicians on the computerized physician order entry, on drugs that need dose adjustment with renal impairment, and on relevant drug interactions., (Copyright © 2018 SESPAS. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Individualised breast cancer risk prediction models may be key for planning risk-based screening approaches. Our aim was to conduct a systematic review and quality assessment of these models addressed to women in the general population., Methods: We followed the Cochrane Collaboration methods searching in Medline, EMBASE and The Cochrane Library databases up to February 2018. We included studies reporting a model to estimate the individualised risk of breast cancer in women in the general population. Study quality was assessed by two independent reviewers. Results are narratively summarised., Results: We included 24 studies out of the 2976 citations initially retrieved. Twenty studies were based on four models, the Breast Cancer Risk Assessment Tool (BCRAT), the Breast Cancer Surveillance Consortium (BCSC), the Rosner & Colditz model, and the International Breast Cancer Intervention Study (IBIS), whereas four studies addressed other original models. Four of the studies included genetic information. The quality of the studies was moderate with some limitations in the discriminative power and data inputs. A maximum AUROC value of 0.71 was reported in the study conducted in a screening context., Conclusion: Individualised risk prediction models are promising tools for implementing risk-based screening policies. However, it is a challenge to recommend any of them since they need further improvement in their quality and discriminatory capacity.

Introduction: Currently, variability in surgical practice is a problem to be solved. The aim of this study is to describe the variability in the surgical treatment of breast cancer and to analyze the factors associated with it., Methods: The study population included 1057 women diagnosed with breast cancer and surgically treated. Our data were from the CaMISS retrospective cohort., Results: The mean age at diagnosis was 59.3 ± 5 years. A total of 732 patients were diagnosed through screening mammograms and 325 patients as interval cancers. The mastectomy surgery was more frequent in the tumors detected between intervals (OR=2.5; [95%CI: 1.8-3.4]), although this effect disappeared when we adjusted for the rest of the variables. The most important factor associated with performing a mastectomy was TNM: tumors in stage III-IV had an OR of 7.4 [95%CI: 3.9-13.8], increasing in adjusted OR to 21.7 [95%CI: 11.4-41.8]. Histologically, infiltrating lobular carcinoma maintains significance in adjusted OR (OR=2.5; [95%CI: 1.4-4.7]). According to the screening program, there were significant differences in surgical treatment. Program 3 presented an OR of non-conservative surgery of 4.0 [95%CI: 1.8-8.9]. This program coincided with the highest percentage of reconstruction (58.3%)., Conclusions: This study shows that, despite taking into account patient and tumor characteristics, there is great variability in the type of surgery depending on the place of diagnosis., (Copyright © 2018 AEC. Publicado por Elsevier España, S.L.U. All rights reserved.)

Introduction: Increased values in the fecal immunochemical test (FIT) are correlated with increasingly severe colorectal neoplasia, but little attention has been given to FIT values below the cut-off point (negative FIT, nFIT). We analysed the relationship between the concentrations of two consecutive nFIT and the risk of following screen-detected advanced neoplasia and interval cancer (IC) in a population-based colorectal cancer screening program., Methods: FIT results were categorised into non-detectable nFIT (0-3.8 μg haemoglobin/g feces), low nFIT (3.9-9.9) and high nFIT (10.0-19.9). Multivariable adjusted logistic regression was used to estimate the odds ratios (OR) of advanced neoplasia and IC with the nFIT results in the first two screens., Results: More than 90% of the 42,524 persons had non-detectable nFIT in the first and second screen; 4.5% and 5.8% had a low nFIT, respectively, and 2.2% and 2.9% had a high nFIT. The probability of testing positive and being diagnosed of advanced neoplasia or IC rose with increasing values of nFIT. Compared with those with two non-detectable nFIT results, the highest OR were found among those who had two high nFIT results (OR 21.75; 95% confidence interval: 12.44, 38.04) and those with one low nFIT and one high nFIT (ORs around 20)., Conclusions: Participants with nFIT results above the detection limit of the test had an increased risk of advanced neoplasia and IC in subsequent participations. This information could be used in the design of personalised screening strategies., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objectives: To investigate how breast density affects screening performance indicators in a digital mammography context., Methods: We assessed the effect of breast density over the screen-detected and interval cancers rates, false-positives, specificity, sensitivity, recall rate, positive predictive value of recall (PPV-1), and PPV of invasive tests (PPV-2). Radiologists classified breast density using the BIRADS System. We used generalized estimating equations to account for within-woman correlation by means of the robust Huber-White variance estimator., Results: We included 177,164 women aged 50-69 years who underwent 499,251 digital mammograms from 2004 to 2015 in Spain. According to the fibroglandular tissue percentage, 24.7% of mammograms were classified as BI-RADS 1 (<25% glandular), 54.7% as BI-RADS 2 (25-50% glandular), 14.0% as BI-RADS 3 (51-75% glandular) and 6.6% as BI-RADS 4 (>75% glandular). Overall, women with BI-RADS 3 had the highest screen-detected cancer rate (5.9 per 1000) and BI-RADS 4 the highest interval cancer rate (2.4 per 1000). Sensitivity decreased from 89.2% in women with BI-RADS 1 to 67.9% in BI-RADS 4. Both PPV-1 and PPV-2 decreased from 10.4% to 5.7% and from 49.8% to 32.4% in women with BI-RADS 1 and BI-RADS 4, respectively. Women aged 60-69 years with BI-RADS 4 had the lowest sensitivity (54.9%) and the highest interval cancer rate (3.8 per 1000)., Conclusions: Performance screening measures are negatively affected by breast density falling to a lower sensitivity and PPV, and higher interval cancer rate as breast density increases. Particularly women aged 60-69 years with >75% glandular breasts had the worst results and therefore may be candidates for screening using other technologies., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: We aimed to evaluate survival and disease-free survival in different subtypes of interval cancers by breast density, taking into account clinical and biological characteristics. Methods: We included 374 invasive breast tumors (195 screen-detected cancers; 179 interval cancers, classified into true interval, false-negatives, occult tumors and minimal-sign cancers) diagnosed in women ages 50-69 years undergoing biennial screening from 2000-2009, followed up to 2014. Breast density was categorized into non-dense (<25% dense tissue) and mixed dense breasts (≥25%). Survival curves were generated by the Kaplan-Meier method and compared by the log-rank test. Cox proportional hazard regression models were computed to estimate the adjusted hazard ratios (aHRs) and 95% confidence intervals (95% CIs) for death and recurrences by comparing women with interval and true interval cancers versus women with screen-detected cancers, controlling for tumor and patient characteristics. All analyses were stratified by breast density. Results: Interval cancers were detected in younger women, at more advanced stages, in denser breasts and showed a higher proportion of triple-negative cancers, especially among true interval cancers. Women with interval cancer and non-dense breasts had an aHR for death of 3.40 (95% CI, 0.92-12.62). Women with true interval cancers detected in non-dense breasts had the highest adjusted risk of death (aHR, 6.55; 95% CI, 1.37-31.39). Conclusions: Women with true interval cancer in non-dense breasts had a higher risk of death than women with screen-detected cancers. Impact: These results support the advisability of routinely collecting information on breast density, both for further tailoring of screening strategies and as a prognostic factor for diagnosed breast cancers. Cancer Epidemiol Biomarkers Prev; 27(8); 908-16. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Extracorporeal membrane oxygenation has emerged as a treatment of choice for refractory hypoxemia in the intensive care unit. Severe hypoxemia unresponsive to conventional lung-protective mechanical ventilation could also occur in the operating room from severe bronchospasm, pulmonary contusions, or acute respiratory distress syndrome. We report a case of acute hypoxic respiratory failure in an adolescent with blunt chest trauma that was successfully managed with the intraoperative initiation of venovenous extracorporeal membrane oxygenation during the initial damage control surgery.

Introduction: Small bowel injury is uncommon after blunt abdominal trauma. Repeated clinical assessment is important, especially when investigative imaging is negative., Case Presentation: 39-year-old male presented to the emergency department following a blunt abdominal trauma. No initial hemodynamic abnormalities were found. Abdominal CT scan was negative for small bowel perforation. Repeated clinical assessment revealed increasing abdominal pain with tachycardia, and an emergent laparotomy was undertaken. Four grade II and one grade I small bowel perforations were found, all repaired with interrupted sutures. Patient was discharged home on day 7., Discussion/conclusion: The diagnosis of small bowel injury is difficult and a low threshold of suspicion is crucial to reduce morbidity and mortality. Hemodynamic instability or abdominal tenderness after blunt abdominal trauma are indications for immediate surgical exploration, despite negative imaging findings. Serial clinical assessment is the main decision tool to perform an abdominal exploration., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Coagulopathy induced by trauma or cirrhosis is a well-recognized entity. Viscoelastic testing has been used in either condition for goal-directed transfusion and detection of fibrinolysis since conventional coagulation tests do not correlate with clinical risk of bleeding. Hemostatic resuscitation may not be adequate for a trauma patient with liver disease due to complex alterations in coagulation systems and occasionally require adjuvant therapy. We report a case of trauma-induced coagulopathy presenting as severe hyperfibrinolysis in a cirrhotic patient who was refractory to hemostatic resuscitation but was rapidly corrected by the administration of tranexamic acid and recombinant Factor VIIa.

Growth deficits of reverse genetics vaccine seeds have compromised effective immunization. The impairment has been attributed to sub-optimal protein interactions. Some level of dependence may exist between PB1 and antigenic glycoproteins, however, further research is necessary to clarify the extent to which it can be used in favor of seed production. Our objective was to establish proof of concept on the phenotypic outcome of PB1 source in the PR8: A(H1N1)pdm09 reassortants. Reassortants were generated with the gene constellation of the classical 6:2 PR8: HA, NApdm09 seed prototype and the 5:3 reassortant PR8: HA, NA, PB1pdm09. Viral growth and antigen yield were evaluated 12-60h post-infection. The 5:3 reassortant presented statistically significant growth and antigen yield improvements when compared to the 6:2. We believe these findings to be of promising value to vaccine research towards an improvement of reverse genetic seeds, an overall more cost-effective vaccine manufacture and timely delivery., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Schwann cell (SC) transplantation exhibits significant potential for spinal cord injury (SCI) repair and its use as a therapeutic modality has now progressed to clinical trials for subacute and chronic human SCI. Although SC implants provide a receptive environment for axonal regrowth and support functional recovery in a number of experimental SCI models, axonal regeneration is largely limited to local systems and the behavioral improvements are modest without additional combinatory approaches. In the current study we investigated whether the concurrent delivery of the polyamine putrescine, started either 30 min or 1 week after SCI, could enhance the efficacy of SCs when implanted subacutely (1 week after injury) into the contused rat spinal cord. Polyamines are ubiquitous organic cations that play an important role in the regulation of the cell cycle, cell division, cytoskeletal organization, and cell differentiation. We show that the combination of putrescine with SCs provides a significant increase in implant size, an enhancement in axonal (sensory and serotonergic) sparing and/or growth, and improved open field locomotion after SCI, as compared to SC implantation alone. These findings demonstrate that polyamine supplementation can augment the effectiveness of SCs when used as a therapeutic approach for subacute SCI repair.

Following spinal cord injury (SCI), both an inhibitory environment and lack of intrinsic growth capacity impede axonal regeneration. In a previous study, prevention of cyclic adenosine monophosphate (AMP) hydrolysis by the phosphodiesterase-4 inhibitor rolipram, in combination with Schwann cell (SC) grafts, promoted significant supraspinal and proprioceptive fiber growth and/or sparing and improved locomotion. In another study, transplanted SCs transduced to generate a bifunctional neurotrophin (D15A) led to significant increases in graft SCs and axons, including supraspinal and myelinated axons. Here we studied the growth and myelination of local and supraspinal axons and functional outcome following the combination of rolipram administration and neurotrophin-transduced SC implantation after SCI. Rolipram was administered subcutaneously for 4 weeks immediately after contusion at vertebral T8 (25.0-mm weight drop, MASCIS impactor). GFP or GFP-D15A-transduced SCs were injected into the injury epicenter 1 week after SCI. GFP-D15A SC grafts and GFP SC grafts with rolipram contained significantly more serotonergic fibers compared to GFP SCs. SC myelinated axons were increased significantly in GFP SC with rolipram-treated animals compared to animals receiving SCI alone. Rolipram administered with either GFP or GFP-D15A SCs significantly increased numbers of brain stem-derived axons below the lesion/implant area and improved hindlimb function. Compared to the single treatments, the combination led to the largest SC grafts, the highest numbers of serotonergic fibers in the grafts, and increased numbers of axons from the reticular formation below the lesion/implant area and provided the greatest improvement in hindlimb function. These findings demonstrate the therapeutic potential for a combination therapy involving the maintenance of cyclic AMP levels and neurotrophin-transduced SCs to repair the subacutely injured spinal cord.

The extent of damage following spinal cord injury (SCI) can be reduced by various neuroprotective regimens that include maintaining levels of cyclic adenosine monophosphate (cyclic AMP), via administration of the phosphodiesterase 4 (PDE4) inhibitor Rolipram. The current study sought to determine the optimal neuroprotective dose, route and therapeutic window for Rolipram following contusive SCI in rat as well as its prominent PDE target and putative mechanism of protection. Rolipram or vehicle control (10% ethanol) was given subcutaneously (s.c.) daily for 2 wk post-injury (PI) after which the preservation of oligodendrocytes, neurons and central myelinated axons was stereologically assessed. Doses of 0.1 mg/kg to 1.0 mg/kg (given at 1 h PI) increased neuronal survival; 0.5 mg to 1.0 mg/kg protected oligodendrocytes and 1.0 mg/kg produced optimal preservation of central myelinated axons. Ethanol also demonstrated significant neuronal and oligo-protection; though the preservation provided was significantly less than Rolipram. Subsequent use of this optimal Rolipram dose, 1.0 mg/kg, via different routes (i.v., s.c. or oral, 1 h PI), demonstrated that i.v. administration produced the most significant and consistent cyto- and axo- protection, although all routes were effective. Examination of the therapeutic window for i.v. Rolipram (1.0 mg/kg), when initiated between 1 and 48 h after SCI, revealed maximal neuroprotection at 2 h post-SCI, although the protective efficacy of Rolipram could still be observed when administration was delayed for up to 48 h PI. Importantly, use of the optimal Rolipram regimen significantly improved locomotor function after SCI as measured by the BBB score. Lastly we show SCI-induced changes in PDE4A, B and D expression and phosphorylation as well as cytokine expression and immune cell infiltration. We demonstrate that Rolipram abrogates SCI-induced PDE4B1 and PDE4A5 production, PDE4A5 phosphorylation, MCP-1 expression and immune cell infiltration, while preventing post-injury reductions in IL-10. This work supports the use of Rolipram as an acute neuroprotectant following SCI and defines an optimal administration protocol and target for its therapeutic application.