Selective Serotonin Reuptake Inhibitors and Risk of Noncardioembolic Ischemic Stroke: A Nested Case-Control Study.

BACKGROUND: Multiple studies have reported that the use of selective serotonin reuptake inhibitors (SSRIs) is associated with an increased risk of ischemic stroke; however, this finding may be the result of a confounding by indication. We examined the association using different approaches to minimize such potential bias. METHODS: A nested case-control study was carried out in a Spanish primary health-care database over the study period 2001 to 2015. Cases were patients sustaining an ischemic stroke with no sign of cardioembolic or unusual cause. For each case, up to 5 matched controls (for exact age, sex, and index date) were randomly selected. Antidepressants were divided in 6 pharmacological subgroups according to their mechanism of action. The current use of SSRIs (use within a 30-day window before index date) was compared with nonuse, past use (beyond 365 days) and current use of other antidepressants through a conditional logistic regression model to obtain adjusted odds ratios and 95% CI. Only initiators of SSRIs and other antidepressants were considered. RESULTS: A total of 8296 cases and 37 272 matched controls were included. Of them, 255 (3.07%) were current users of SSRIs among cases and 834 (2.24%) among controls, yielding an adjusted odds ratio of 1.14 (95% CI, 0.97-1.34) as compared with nonusers, 0.94 (95% CI, 0.77-1.13) as compared with past-users and 0.74 (95% CI, 0.58-0.93) as compared with current users of other antidepressants. No relevant differences were found by duration (≤1, >1 year), sex, age (<70, ≥70 years old) and background vascular risk. CONCLUSIONS: The use of SSRIs was not associated with an increased risk of noncardioembolic ischemic stroke. On the contrary, as compared with other antidepressants, SSRIs appeared to be protective.

Trends in the use of oral anticoagulants, antiplatelets and statins in four European countries: a population-based study.

PURPOSE: To evaluate time trends in the prevalence of antithrombotic and statin use in four European countries. METHODS: Using population-based data from the United Kingdom, Denmark, Spain and Italy between 2010 and 2018, we calculated standardized annual prevalence proportions of antithrombotics and statin use, and changes in prevalence proportions (2018 vs. 2010). RESULTS: Prevalence proportion of statins increased from 24.8% to 24.6% (UK), 21.0% to 22.3% (Region of Southern Denmark [RSD]), 12.9% to 14.3% (Udine, Italy), and 20.3% to 23.2% (Spain). Prevalence proportions of antithrombotics declined in all four countries: 18.7% to 15.9% (UK; - 2.8% points), 18.9% to 18.1% (RSD; - 0.8% points), 17.7% to 16.6% (Udine; - 1.1% points) and 15.0% to 13.6% (Spain; - 1.4% points). These declines were driven by reductions in low-dose aspirin use: 15.3% to 8.9% (UK; - 6.4% points), 16.3% to 9.5% (RSD; - 6.8% points), 13.5% to 11.6% (Udine; - 1.9% points), and 10.2% to 8.8% (Spain; - 1.4% points). In the UK, low-dose aspirin use declined from 9.1% to 4.3% (- 4.8% points) for primary CVD prevention, and from 49.6% to 36.9% (- 12.7% points) for secondary prevention. Oral anticoagulant use gradually increased but did not fully account for the decrease in low-dose aspirin use. CONCLUSIONS: Antithrombotic use in the UK, RSD, Udine and Spain declined between 2010 and 2018, driven by a reduction in use of low-dose aspirin that is not completely explained by a gradual increase in OAC use. Use of statins remained constant in the UK, and increased gradually in the RSD, Udine and Spain.

Use of renin-angiotensin-aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study.

BACKGROUND: Concerns have been raised about the possibility that inhibitors of the renin-angiotensin-aldosterone system (RAAS) could predispose individuals to severe COVID-19; however, epidemiological evidence is lacking. We report the results of a case-population study done in Madrid, Spain, since the outbreak of COVID-19. METHODS: In this case-population study, we consecutively selected patients aged 18 years or older with a PCR-confirmed diagnosis of COVID-19 requiring admission to hospital from seven hospitals in Madrid, who had been admitted between March 1 and March 24, 2020. As a reference group, we randomly sampled ten patients per case, individually matched for age, sex, region (ie, Madrid), and date of admission to hospital (month and day; index date), from Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP), a Spanish primary health-care database, in its last available year (2018). We extracted information on comorbidities and prescriptions up to the month before index date (ie, current use) from electronic clinical records of both cases and controls. The outcome of interest was admission to hospital of patients with COVID-19. To minimise confounding by indication, the main analysis focused on assessing the association between COVID-19 requiring admission to hospital and use of RAAS inhibitors compared with use of other antihypertensive drugs. We calculated odds ratios (ORs) and 95% CIs, adjusted for age, sex, and cardiovascular comorbidities and risk factors, using conditional logistic regression. The protocol of the study was registered in the EU electronic Register of Post-Authorisation Studies, EUPAS34437. FINDINGS: We collected data for 1139 cases and 11 390 population controls. Among cases, 444 (39·0%) were female and the mean age was 69·1 years (SD 15·4), and despite being matched on sex and age, a significantly higher proportion of cases had pre-existing cardiovascular disease (OR 1·98, 95% CI 1·62-2·41) and risk factors (1·46, 1·23-1·73) than did controls. Compared with users of other antihypertensive drugs, users of RAAS inhibitors had an adjusted OR for COVID-19 requiring admission to hospital of 0·94 (95% CI 0·77-1·15). No increased risk was observed with either angiotensin-converting enzyme inhibitors (adjusted OR 0·80, 0·64-1·00) or angiotensin-receptor blockers (1·10, 0·88-1·37). Sex, age, and background cardiovascular risk did not modify the adjusted OR between use of RAAS inhibitors and COVID-19 requiring admission to hospital, whereas a decreased risk of COVID-19 requiring admission to hospital was found among patients with diabetes who were users of RAAS inhibitors (adjusted OR 0·53, 95% CI 0·34-0·80). The adjusted ORs were similar across severity degrees of COVID-19. INTERPRETATION: RAAS inhibitors do not increase the risk of COVID-19 requiring admission to hospital, including fatal cases and those admitted to intensive care units, and should not be discontinued to prevent a severe case of COVID-19. FUNDING: Instituto de Salud Carlos III.

Impact of in-hospital discontinuation with angiotensin receptor blockers or converting enzyme inhibitors on mortality of COVID-19 patients: a retrospective cohort study.

BACKGROUND: In the first wave of the COVID-19 pandemic, the hypothesis that angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) increased the risk and/or severity of the disease was widely spread. Consequently, in many hospitals, these drugs were discontinued as a "precautionary measure". We aimed to assess whether the in-hospital discontinuation of ARBs or ACEIs, in real-life conditions, was associated with a reduced risk of death as compared to their continuation and also to compare head-to-head the continuation of ARBs with the continuation of ACEIs. METHODS: Adult patients with a PCR-confirmed diagnosis of COVID-19 requiring admission during March 2020 were consecutively selected from 7 hospitals in Madrid, Spain. Among them, we identified outpatient users of ACEIs/ARBs and divided them in two cohorts depending on treatment discontinuation/continuation at admission. Then, they were followed-up until discharge or in-hospital death. An intention-to-treat survival analysis was carried out and hazard ratios (HRs), and their 95%CIs were computed through a Cox regression model adjusted for propensity scores of discontinuation and controlled by potential mediators. RESULTS: Out of 625 ACEI/ARB users, 340 (54.4%) discontinued treatment. The in-hospital mortality rates were 27.6% and 27.7% in discontinuation and continuation cohorts, respectively (HR=1.01; 95%CI 0.70-1.46). No difference in mortality was observed between ARB and ACEI discontinuation (28.6% vs. 27.1%, respectively), while a significantly lower mortality rate was found among patients who continued with ARBs (20.8%, N=125) as compared to those who continued with ACEIs (33.1%, N=136; p=0.03). The head-to-head comparison (ARB vs. ACEI continuation) yielded an adjusted HR of 0.52 (95%CI 0.29-0.93), being especially notorious among males (HR=0.34; 95%CI 0.12-0.93), subjects older than 74 years (HR=0.46; 95%CI 0.25-0.85), and patients with obesity (HR=0.22; 95%CI 0.05-0.94), diabetes (HR=0.36; 95%CI 0.13-0.97), and heart failure (HR=0.12; 95%CI 0.03-0.97). CONCLUSIONS: The discontinuation of ACEIs/ARBs at admission did not improve the in-hospital survival. On the contrary, the continuation with ARBs was associated with a trend to a reduced mortality as compared to their discontinuation and to a significantly lower mortality risk as compared to the continuation with ACEIs, particularly in high-risk patients.

Differential effects of antidepressant subgroups on risk of acute myocardial infarction: A nested case-control study.

The primary objective of this study was to investigate the association between antidepressants use and the risk of acute myocardial infarction (AMI). METHODS: We conducted a nested case-control study using a primary care database over the period 2002-2015. From a cohort of patients aged 40-99 years, we identified incident AMI cases and randomly selected 5 controls per case, matched to cases for exact age, sex and index date. Exposure to antidepressants were categorised as current, recent, past and nonusers. Adjusted odds ratio (AOR) and 95% confidence interval (CI) were computed using conditional logistic regression to assess the association between the current use of different antidepressants subgroups and AMI as compared to nonuse. Dose and duration effects were explored. RESULTS: Totals of 24 155 incident AMI cases and 120 775 controls were included. The current use of antidepressants as a group was associated with a reduced risk (AOR = 0.86; 95% CI: 0.81-0.91), but mainly driven by selective serotonin reuptake inhibitors (AOR = 0.86; 95% CI:0.81-0.93). A reduced risk was also observed with trazodone (AOR = 0.76;95% CI: 0.64-0.91), and clomipramine (AOR = 0.62; 95% CI: 0.40-0.96), whereas no significant effect was observed with other antidepressants. A duration-dependent effect was suggested for selective serotonin reuptake inhibitors, trazodone and clomipramine, while there was no clear dose-dependency. CONCLUSION: This study suggests that current use of antidepressants interfering selectively with the reuptake of serotonin, and those antagonizing the 5-HT2A receptor, are associated with a decrease in AMI risk and should be the antidepressants of choice in patients at cardiovascular risk.

Clopidogrel and Low-Dose Aspirin, Alone or Together, Reduce Risk of Colorectal Cancer.

BACKGROUND & AIMS: The antiplatelet effect of low-dose aspirin, via inhibition of cyclooxygenase-1, might contribute to its ability to reduce the risk of colorectal cancer (CRC). Antiplatelet agents with a different mechanism, such as clopidogrel, might have the same effects. We aimed to quantify the effects of low-dose aspirin and clopidogrel on the risk of CRC in a Mediterranean population. METHODS: We performed a nested case-control study using a primary care database (Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria) in Spain. We collected data, from 2001 through 2014, on 15,491 incident cases of CRC and 60,000 randomly selected individuals (controls), frequency-matched to cases by age, sex, and year. To estimate the association between exposure to different antiplatelet agents and the risk of colorectal cancer, we built multiple logistic regression models and computed the adjusted-odds ratios (AORs) and their respective 95% CIs. RESULTS: Use of low-dose aspirin was associated with a reduced risk of CRC overall (AOR, 0.83; 95% CI, 0.78-0.89) and in patients receiving treatment for more than 1 year (AOR, 0.79; 95% CI, 0.73-0.85). Use of clopidogrel was associated with a decreased risk of CRC overall (AOR, 0.8; 95% CI, 0.69-0.93) and in patients receiving treatment for more than 1 year (AOR, 0.65; 95% CI, 0.55-0.78). Dual antiplatelet therapy had the same effect as either drug taken as monotherapy. No modification by sex or age was observed. CONCLUSIONS: In a nested case-control study of a primary care database in Spain, we found clopidogrel use, alone or in combination with low-dose aspirin, to reduce the risk of CRC by 20% to 30%, a magnitude similar to that of low-dose aspirin alone. These data support the concept that inhibiting platelets is an effective strategy for prevention of CRC.

Incidence of Stevens-Johnson syndrome/toxic epidermal necrolysis among new users of different individual drugs in a European population: a case-population study.

PURPOSE: To estimate the specific incidences of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) among new users of drugs frequently reported to be associated with this serious event. METHODS: We performed a case-population approach, which combined data from a registry of SJS/TEN cases from the Madrid region (numerator) during the study period 2005-2015 and a primary healthcare database from the same catchment population. The proportion of new users of drugs estimated in the primary healthcare database was stratified by calendar year, sex and age (5-year bands), and then applied to the same strata of Madrid's population census to compute the number of new users (denominator). Incidences were re-estimated using only cases in which the concerned drug had a probable or very probable causal relationship. RESULTS: A total of 44 SJS/TEN cases aged > 14 years were registered during the study period. The highest SJS/TEN incidence was found for phenytoin with 68.9 per 100,000 new users (95% CI 27.7-141.9), followed by dexamethasone (5.48; 1.49-14.03), allopurinol (3.29; 1.07-7.67) and cotrimoxazole (3.19; 0.87-8.16). Considering only probable and very probable cases, the incidences hardly changed, except for dexamethasone, which was left without cases. Pantoprazole, levofloxacin and lorazepam showed incidences between 1 per 100,000 and 1 per 1,000,000 new users. Ibuprofen, amoxicillin-clavulanic acid, metamizole, amoxicillin, paracetamol and omeprazole showed incidences around 1 per one million new users. CONCLUSIONS: Phenytoin was the drug with the highest incidence of SJS/TEN, followed by allopurinol and cotrimoxazole. For the rest of the drugs, the estimated incidences were below 1 in 100,000 new users.

Validation study of colorectal cancer diagnosis in the Spanish primary care database, BIFAP.

PURPOSE: To define and validate a case-finding algorithm to identify incident colorectal cancer (CRC) in the Spanish primary care database BIFAP. METHODS: All potential incident CRC cases recorded during the study period 2001 to 2014 among patients 20 to 89 years old were identified using a defined case-finding algorithm tailored to BIFAP database characteristics and based on codes plus text mining strategies. Potential CRC cases identified by the algorithm were classified into eight homogeneous groups according to recording characteristics. Random samples of 100 cases per group were obtained, and electronic medical records were manually reviewed by two independent researchers. Positive predictive values (PPVs) were estimated per each group and for the whole sample taking into account the stratified sampling. Standardized incidence rate (SIR) of CRC was estimated and compared with that reported by the National Cancer Registry. Negative predictive value (NPV) was also estimated in a random sample of 100 non-CRC patients by the algorithm. RESULTS: A total of 17 008 potential CRC cases were identified. Most of them (14793; 87%) were recorded as incident diagnosis with linked clinical notes as free text, having this group a PPV of 92.1% (95%CI: 87.1%-95.3%). The overall PPV including all groups was 87.3% (95%CI: 83.3%-90.4%). SIR of CRC was 55.5 per 100.000 person-years. SIR increased with age and was higher in men as compared with women (77.7 vs 38.1 per 100.000 py, respectively) which were in line with those reported by the Network of Cancer Registries in Spain. NPV was of 100% (96.3%-100%). CONCLUSIONS: This study shows a high validity of the CRC cases identified by the algorithm and a high level of CRC recording in BIFAP database and supports its appropriateness to validly identify incident CRC cases in BIFAP.

Active surveillance of severe cutaneous adverse reactions: A case-population approach using a registry and a health care database.

PURPOSE: The "case-population" design has been proposed for the surveillance of rare events like Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), wherein a registry of cases is combined with sales data from the source population in order to estimate crude odds ratios (ORs). A major drawback of this method is the inability to distinguish between new and non-new users of drugs, which for the study of hypersensitivity reactions is of utmost importance. METHODS: We have explored an approach in which the exposure to the drugs of interest in the source population is inferred from a primary health care database (BIFAP), which helped us to identify drug initiators among all users and additionally adjust for potential confounders. A total of 44 SJS/TEN cases from the Registry and 44 000 controls randomly sampled from BIFAP and matched with cases for index date were included. We estimated the adjusted ORs (AORs) and 95% confidence intervals (CI) of SJS/TEN associated with the new use of 13 drugs (for which we had at least two exposed cases) through a conditional logistic regression model. RESULTS: AORs (95% CI) were estimated for phenytoin, 4618 (434-49112); cotrimoxazole, 1142 (163-8015); allopurinol, 160 (36-709); dexamethasone, 38 (1.33-1077); ibuprofen, 33 (8.6-124); lorazepam, 27 (5.8-124); paracetamol, 13 (2.8-62); levofloxacine, 12 (1.24-120); amoxicillin, 6.9 (1.39-35); pantoprazole, 6.5 (0.10-420); metamizole, 6.3 (0.69-57); amoxicillin clavulanic acid, 4.2 (0.53-34); and omeprazole, 1.34 (0.06-31). The inclusion of non-new users dramatically decreased the AORs for all drugs. CONCLUSIONS: The case-population approach using a registry of cases and a primary health care database proved feasible and efficient for the active surveillance of SJS/TEN.

Ablation of the regulatory IE1 protein of murine cytomegalovirus alters in vivo pro-inflammatory TNF-alpha production during acute infection.

Little is known about the role of viral genes in modulating host cytokine responses. Here we report a new functional role of the viral encoded IE1 protein of the murine cytomegalovirus in sculpting the inflammatory response in an acute infection. In time course experiments of infected primary macrophages (MΦs) measuring cytokine production levels, genetic ablation of the immediate-early 1 (ie1) gene results in a significant increase in TNFα production. Intracellular staining for cytokine production and viral early gene expression shows that TNFα production is highly associated with the productively infected MΦ population of cells. The ie1- dependent phenotype of enhanced MΦ TNFα production occurs at both protein and RNA levels. Noticeably, we show in a series of in vivo infection experiments that in multiple organs the presence of ie1 potently inhibits the pro-inflammatory cytokine response. From these experiments, levels of TNFα, and to a lesser extent IFNß, but not the anti-inflammatory cytokine IL10, are moderated in the presence of ie1. The ie1- mediated inhibition of TNFα production has a similar quantitative phenotype profile in infection of susceptible (BALB/c) and resistant (C57BL/6) mouse strains as well as in a severe immuno-ablative model of infection. In vitro experiments with infected macrophages reveal that deletion of ie1 results in increased sensitivity of viral replication to TNFα inhibition. However, in vivo infection studies show that genetic ablation of TNFα or TNFRp55 receptor is not sufficient to rescue the restricted replication phenotype of the ie1 mutant virus. These results provide, for the first time, evidence for a role of IE1 as a regulator of the pro-inflammatory response and demonstrate a specific pathogen gene capable of moderating the host production of TNFα in vivo.

Host defense against viral infection involves interferon mediated down-regulation of sterol biosynthesis.

Little is known about the protective role of inflammatory processes in modulating lipid metabolism in infection. Here we report an intimate link between the innate immune response to infection and regulation of the sterol metabolic network characterized by down-regulation of sterol biosynthesis by an interferon regulatory loop mechanism. In time-series experiments profiling genome-wide lipid-associated gene expression of macrophages, we show a selective and coordinated negative regulation of the complete sterol pathway upon viral infection or cytokine treatment with IFNγ or ß but not TNF, IL1ß, or IL6. Quantitative analysis at the protein level of selected sterol metabolic enzymes upon infection shows a similar level of suppression. Experimental testing of sterol metabolite levels using lipidomic-based measurements shows a reduction in metabolic output. On the basis of pharmacologic and RNAi inhibition of the sterol pathway we show augmented protection against viral infection, and in combination with metabolite rescue experiments, we identify the requirement of the mevalonate-isoprenoid branch of the sterol metabolic network in the protective response upon statin or IFNß treatment. Conditioned media experiments from infected cells support an involvement of secreted type 1 interferon(s) to be sufficient for reducing the sterol pathway upon infection. Moreover, we show that infection of primary macrophages containing a genetic knockout of the major type I interferon, IFNß, leads to only a partial suppression of the sterol pathway, while genetic knockout of the receptor for all type I interferon family members, ifnar1, or associated signaling component, tyk2, completely abolishes the reduction of the sterol biosynthetic activity upon infection. Levels of the proteolytically cleaved nuclear forms of SREBP2, a key transcriptional regulator of sterol biosynthesis, are reduced upon infection and IFNß treatment at both the protein and de novo transcription level. The reduction in srebf2 gene transcription upon infection and IFN treatment is also found to be strictly dependent on ifnar1. Altogether these results show that type 1 IFN signaling is both necessary and sufficient for reducing the sterol metabolic network activity upon infection, thereby linking the regulation of the sterol pathway with interferon anti-viral defense responses. These findings bring a new link between sterol metabolism and interferon antiviral response and support the idea of using host metabolic modifiers of innate immunity as a potential antiviral strategy.

Strategies and interventions used to provide communication education for midwifery students. A scoping review.

AIM: To examine the current literature on educational strategies and interventions developed with the objective of teaching or enhancing communication skills of student midwives during their pre-registration education programmes. DESIGN: A scoping review based on the Joanna Briggs Institute framework was conducted using predefined criteria and reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist. METHODS: A comprehensive search was conducted using various databases (Medline, Cumulative Index to Nursing and Allied Health Literature (CINAHL), EMBASE, PsycINFO, Maternity and Infant Care Database (MIDIRS), Web of Science and Education Resources Information Centre (ERIC)) in October 2023. RESULTS: A total of 120 titles and abstracts were screened. A final number of eight articles were subjected to quality appraisal and included in the scoping review. Five themes were identified which describe educational strategies and interventions including: simulation-based training, the use of role-play, pedagogical approaches, theory-based information workshops and debrief and reflection. CONCLUSIONS: This review highlights a gap in research focusing on the importance of communication skills training for student midwives throughout midwifery education. Despite the limited numbers of studies, different interventions and educational strategies have been recognized for enhancing these skills. To equip midwives with strong communication skills, a combination of interventions is recommended, including communication-focused workshops tailored for midwifery education and debriefing and student reflection sessions specifically designed to enhanced communication skills. REGISTRATION NUMBER: to be included in abstract after acceptance.

Risk of Ischemic Stroke Associated with Calcium Supplements and Interaction with Oral Bisphosphonates: A Nested Case-Control Study.

Conflicting results about the association of calcium supplements (CS) with ischemic stroke (IS) have been reported. We tested this hypothesis by differentiating between CS alone (CaM) and CS with vitamin D (CaD) and between cardioembolic and non-cardioembolic IS. We examined the potential interaction with oral bisphosphonates (oBs). A nested case-control study was carried out. We identified incident IS cases aged 40-90 and randomly sampled five controls per case matched by age, sex, and index date. Current users were compared to non-users. An adjusted odds ratios (AOR) and 95% CI were computed through conditional logistic regression. Only new users were considered. We included 13,267 cases (4400 cardioembolic, 8867 non-cardioembolic) and 61,378 controls (20,147 and 41,231, respectively). CaM use was associated with an increased risk of cardioembolic IS (AOR = 1.88; 95% CI: 1.21-2.90) in a duration-dependent manner, while it showed no association with non-cardioembolic IS (AOR = 1.05; 95% CI: 0.74-1.50); its combination with oBs increased the risk of cardioembolic IS considerably (AOR = 2.54; 95% CI: 1.28-5.04), showing no effect on non-cardioembolic. CaD use was not associated with either cardioembolic (AOR = 1.08; 95% CI: 0.88-1.31) or non-cardioembolic IS (AOR = 0.98; 95% CI: 0.84-1.13) but showed a small association with cardioembolic IS when combined with oBs (AOR = 1.35; 95% CI: 1.03-1.76). The results support the hypothesis that CS increases the risk of cardioembolic IS, primarily when used concomitantly with oBs.

Association of oral bisphosphonates with cardioembolic ischemic stroke: a nested case-control study.

Background: Bisphosphonates have been reported to increase the risk of atrial fibrillation. Therefore, it is conceivable that they may increase the risk of cardioembolic ischemic stroke (IS). However, most epidemiological studies carried out thus far have not shown an increased risk of IS, though none separated by the main pathophysiologic IS subtype (cardioembolic and non-cardioembolic) which may be crucial. In this study, we tested the hypothesis that the use of oral bisphosphonates increases specifically the risk of cardioembolic IS, and explored the effect of treatment duration, as well as the potential interaction between oral bisphosphonates and calcium supplements and anticoagulants. Methods: We performed a case-control study nested in a cohort of patients aged 40-99 years, using the Spanish primary healthcare database BIFAP, over the period 2002-2015. Incident cases of IS were identified and classified as cardioembolic or non-cardioembolic. Five controls per case were randomly selected, matched for age, sex, and index date (first recording of IS) using an incidence-density sampling. The association of IS (overall and by subtype) with the use of oral bisphosphonates within the last year before index date was assessed by computing the adjusted odds ratios (AOR) and their 95% CI using a conditional logistic regression. Only initiators of oral bisphosphonates were considered. Results: A total of 13,781 incident cases of IS and 65,909 controls were included. The mean age was 74.5 (SD ± 12.4) years and 51.6% were male. Among cases, 3.15% were current users of oral bisphosphonates, while among controls they were 2.62%, yielding an AOR of 1.15 (95% CI:1.01-1.30). Of all cases, 4,568 (33.1%) were classified as cardioembolic IS (matched with 21,697 controls) and 9,213 (66.9%) as non-cardioembolic IS (matched with 44,212 controls) yielding an AOR of 1.35 (95% CI:1.10-1.66) and 1.03 (95% CI: 0.88-1.21), respectively. The association with cardioembolic IS was clearly duration-dependent (AOR≤1 year = 1.10; 95% CI:0.82-1.49; AOR>1-3 years = 1.41; 95% CI:1.01-1.97; AOR>3 years = 1.81; 95% CI:1.25-2.62; p for trend = 0.001) and completely blunted by anticoagulants, even in long-term users (AOR>1 year = 0.59; 0.30-1.16). An interaction between oral bisphosphonates and calcium supplements was suggested. Conclusion: The use of oral bisphosphonates increases specifically the odds of cardioembolic IS, in a duration-dependent manner, while leaves materially unaffected the odds of non-cardioembolic IS.

Reversible inhibition of murine cytomegalovirus replication by gamma interferon (IFN-γ) in primary macrophages involves a primed type I IFN-signaling subnetwork for full establishment of an immediate-early antiviral state.

Activated macrophages play a central role in controlling inflammatory responses to infection and are tightly regulated to rapidly mount responses to infectious challenge. Type I interferon (alpha/beta interferon [IFN-α/ß]) and type II interferon (IFN-γ) play a crucial role in activating macrophages and subsequently restricting viral infections. Both types of IFNs signal through related but distinct signaling pathways, inducing a vast number of interferon-stimulated genes that are overlapping but distinguishable. The exact mechanism by which IFNs, particularly IFN-γ, inhibit DNA viruses such as cytomegalovirus (CMV) is still not fully understood. Here, we investigate the antiviral state developed in macrophages upon reversible inhibition of murine CMV by IFN-γ. On the basis of molecular profiling of the reversible inhibition, we identify a significant contribution of a restricted type I IFN subnetwork linked with IFN-γ activation. Genetic knockout of the type I-signaling pathway, in the context of IFN-γ stimulation, revealed an essential requirement for a primed type I-signaling process in developing a full refractory state in macrophages. A minimal transient induction of IFN-ß upon macrophage activation with IFN-γ is also detectable. In dose and kinetic viral replication inhibition experiments with IFN-γ, the establishment of an antiviral effect is demonstrated to occur within the first hours of infection. We show that the inhibitory mechanisms at these very early times involve a blockade of the viral major immediate-early promoter activity. Altogether our results show that a primed type I IFN subnetwork contributes to an immediate-early antiviral state induced by type II IFN activation of macrophages, with a potential further amplification loop contributed by transient induction of IFN-ß.

Influenza vaccine and risk of acute myocardial infarction in a population-based case-control study.

OBJECTIVE: To assess the relationship between influenza vaccination and risk of a first acute myocardial infarction (AMI) in the general population by different epidemic periods. METHODS: This is a population-based case-control study carried out in BIFAP (Base de datos para la investigación farmacoepidemiológica en atención primaria), over 2001-2015, in patients aged 40-99 years. Per each incident AMI case, five controls were randomly selected, individually matched for exact age, sex and index date (AMI diagnosis). A patient was considered vaccinated when he/she had a recorded influenza vaccination at least 14 days before the index date within the same season. The association between influenza vaccination and AMI risk was assessed through a conditional logistic regression, computing adjusted ORs (AOR) and their respective 95% CIs. The analysis was performed overall and by each of the three time epidemic periods per study year (pre-epidemic, epidemic and postepidemic). RESULTS: We identified 24 155 AMI cases and 120 775 matched controls. Of them, 31.4% and 31.2%, respectively, were vaccinated, yielding an AOR of 0.85 (95% CI 0.82 to 0.88). No effect modification by sex, age and background cardiovascular risk was observed. The reduced risk of AMI was observed shortly after vaccination and persisted over time. Similar results were obtained during the pre-epidemic (AOR=0.87; 95% CI 0.79 to 0.95), epidemic (AOR=0.89; 95% CI 0.82 to 0.96) and postepidemic (AOR=0.83; 95% CI 0.79 to 0.87) periods. No association was found with pneumococcal vaccine (AOR=1.10; 95% CI 1.06 to 1.15). CONCLUSIONS: Results are compatible with a moderate protective effect of influenza vaccine on AMI in the general population, mostly in primary prevention, although bias due to unmeasured confounders may partly account for the results.

Influenza Vaccination and Risk of Ischemic Stroke: A Population-Based Case-Control Study.

BACKGROUND AND OBJECTIVES: To assess the relationship between influenza vaccination in the general population and risk of a first ischemic stroke (IS) during pre-epidemic, epidemic and post-epidemic periods. METHODS: A nested case-control study was carried out in a Spanish primary care database over 2001-2015. Subjects aged 40-99 years with at-least 1-year registry and no history of stroke or cancer were selected to conform the source cohort, from which incident IS cases were identified and classified as cardioembolic or non-cardioembolic. Five controls per case were randomly selected, individually matched with cases for exact age, sex and date of stroke diagnosis (index date). A patient was considered vaccinated when he/she had a recorded influenza vaccination at least 14 days before the index date within the same season. Adjusted odds ratios (AOR) and their respective 95% confidence intervals (CI) were computed through a conditional logistic regression. Pneumococcal vaccination was used as a negative control. RESULTS: From a cohort of 3,757,621 patients, we selected 14,322 incident IS cases (9,542 non-cardioembolic and 4,780 cardioembolic) and 71,610 matched controls. Of them, 41.4% and 40.5%, respectively, were vaccinated yielding a crude OR of 1.05(95%CI:1.01-1.10). Vaccinated subjects presented a higher prevalence of vascular risk factors, diseases and comedication than non-vaccinated and, after full adjustment, the association of influenza vaccination with IS yielded an AOR of 0.88(95%CI:0.84-0.92) was found, appearing early (AOR15-30 days=0.79;95%CI:0.69-0.92) and slightly declining over time (AOR>150 days=0.92;95%CI:0.87-0.98). A reduced risk of similar magnitude was observed with both types of IS, in the three epidemic periods and in all subgroups analyzed (men, women, subjects below and over 65 years of age, and subjects with intermediate and high vascular risk). By contrast, pneumococcal vaccination was not associated with a reduced risk of IS (AOR=1.08;95%CI:1.04-1.13). DISCUSSION: Results are compatible with a moderate protective effect of influenza vaccine on IS appearing early after vaccination. The finding that a reduced risk was also observed in pre-epidemic periods suggests that either the "protection" is not totally linked to prevention of influenza infection, or it may be partly explained by unmeasured confounding factors.

Risk of ischaemic stroke among new users of glucosamine and chondroitin sulphate: a nested case-control study.

Background: Several studies have reported that the use of chondroitin sulphate (CS) and glucosamine may reduce the risk of acute myocardial infarction. Although it is thought that this potential benefit could be extended to ischaemic stroke (IS), the evidence is scarce. Objective: To test the hypothesis that the use of prescription glucosamine or CS reduces the risk of IS. Design: Case-control study nested in an open cohort. Methods: Patients aged 40-99 years registered in a Spanish primary healthcare database (BIFAP) during the 2002-2015 study period. From this cohort, we identified incident cases of IS, applying a case-finding algorithm and specific validation procedures, and randomly sampled five controls per case, individually matched with cases by exact age, gender and index date. Adjusted odds ratios (AORs) and 95% confidence interval (CI) were computed through a conditional logistic regression. Only new users of glucosamine or CS were considered. Results: A total of 13,952 incident cases of IS and 69,199 controls were included. Of them, 106 cases (0.76%) and 803 controls (1.16%) were current users of glucosamine or CS at index date, yielding an AOR of 0.66 (95% CI: 0.54-0.82) (for glucosamine, AOR: 0.55; 95% CI: 0.39-0.77; and for CS, AOR: 0.77; 95% CI: 0.60-0.99). The reduced risk among current users was observed in both sexes (men, AOR: 0.69; 95% CI: 0.49-0.98; women, AOR: 0.65; 95% CI: 0.50-0.85), in individuals above and below 70 years of age (AOR: 0.69; 95% CI: 0.53-0.89 and AOR: 0.59; 95% CI: 0.41-0.85, respectively), in individuals with vascular risk factors (AOR: 0.53; 95% CI: 0.39-0.74) and among current/recent users of nonsteroidal anti-inflammatory drugs (NSAIDs) (AOR: 0.71; 95% CI: 0.55-0.92). Regarding duration, the reduced risk was observed in short-term users (<365 days, AOR: 0.61; 95% CI: 0.48-0.78) while faded and became nonsignificant in long-term users (>364 days AOR: 0.86; 95% CI: 0.57-1.31). Conclusions: Our results support a protective effect of prescription CS and glucosamine in IS, which was observed even in patients at vascular risk. Mini abstract: Our aim was to analyse whether the use of glucosamine or chondroitin sulphate (CS) reduces the risk of ischaemic stroke (IS). We detected a significant decrease.

Relationship Between Influenza, Temperature, and Type 1 Myocardial Infarction: An Ecological Time-Series Study.

Background Previous studies investigating the relationship of influenza with acute myocardial infarction (AMI) have not distinguished between AMI types 1 and 2. Influenza and cold temperature can explain the increased incidence of AMI during winter but, because they are closely related in temperate regions, their relative contribution is unknown. Methods and Results The temporal relationship between incidence rates of AMI with demonstrated culprit plaque (type 1 AMI) from the regional primary angioplasty network and influenza, adjusted for ambient temperature, was studied in Madrid region (Spain) during 5 influenza seasons (from June 2013 to June 2018). A time-series analysis with quasi-Poisson regression models and distributed lag-nonlinear models was used. The incidence rate of type 1 AMI according to influenza vaccination status was also explored. A total of 8240 cases of confirmed type 1 AMI were recorded. The overall risk ratio (RR) of type 1 AMI during epidemic periods, adjusted for year, month, and temperature, was 1.23 (95% CI, 1.03-1.47). An increase of weekly influenza rate of 50 cases per 100 000 inhabitants resulted in an RR for type 1 AMI of 1.16 (95% CI, 1.09-1.23) during the same week, disappearing 1 week after. When adjusted for influenza, a decrease of 1ºC in the minimum temperature resulted in an increase of 2.5% type 1 AMI. Influenza vaccination was associated with a decreased risk of type 1 AMI in subjects aged 60 to 64 years (RR, 0.58; 95% CI, 0.47-0.71) and ≥65 years (RR, 0.53; 95% CI, 0.49-0.57). Conclusions Influenza and cold temperature were both independently associated with an increased risk of type 1 AMI, whereas vaccination was associated with a reduced risk among older patients.