The average community exposure to ambient air pollutants (PM with an aerodynamic diameter of 10 μm or less (PM10), 2.5 μm or less (PM2.5), 1 μm or less (PM1) and nitrogen dioxide (NO2)) for each participant was estimated using a satellite-based spatial statistical model. Haemoglobin levels were measured for participants from dried blood spots. The models were controlled for confounders. Results: All the studied pollutants were significantly associated with increased anaemia prevalence in single pollutant model , PM2.5 , PM1  and NO2 , respectively. These air pollutants were also associated with lower concentrations of haemoglobin: PM10 ; PM2.5 ; PM1 ; NO2  respectively. Conclusions: Air pollution exposure was significantly associated with increased prevalence of anaemia and decreased haemoglobin levels in a cohort of older Chinese adults.Background: Health effects of air pollution on anaemia have been scarcely studied worldwide. We aimed to explore the associations of long-term exposure to ambient air pollutants with anaemia prevalence and haemoglobin levels in Chinese older adults. Methods: We used two-level linear regression models and modified Poisson regression with robust error variance to examine the associations of particulate matter (PM) and nitrogen dioxide (NO Anaemwn cause . In 2002wn cause . In Chinwn cause , the anawn cause ,9.Several studies have demonstrated links between anaemia and increased morbidity and mortality ,11,12 wiA number of risk factors for anaemia have been described. These include low socioeconomic status, poor dietary intake  and low Air pollution in developing countries has led to tremendous public health impacts . Driven 2.5  and NO2 (9.6 µg/m3) were associated with a 33%  1.33; 95% CI: 1.23–1.45) and 43%  increased prevalence of anaemia, respectively [Studies regarding the effects of air pollution on anaemia are scarce, with most of the prior research being focused on the short-term exposures or children population ,43,44. O2)) with anaemia prevalence and haemoglobin levels in an older (>50 years) Chinese population. PM associations were examined for PM10 , PM2.5  and PM1 .In our current study, we aim to address these gaps in the literature by examining the associations between long-term exposure to ambient particulate matter (PM) and gaseous pollutants  is a longitudinal study run by the WHO, which aims to collect and analyse extensive nationally representative cohort data on the health and well-being of adult populations and the ageing process from middle-income countries, such as China, Ghana, Mexico, India, Russia and South Africa .In our analysis, we used the data from the cross-sectional baseline survey acquired via interview from adult respondents from China during the 2007 to 2010 period (SAGE China Wave 1). A probability sampling design and a five-stage cluster sampling strategy were used. First, eight provinces from 34 eligible Chinese provinces were selected. Second, one rural county and one urban district from each of these eight provinces were randomly chosen. Third, two rural and two urban townships or communities were selected in each of the counties and districts from step 2. Fourth, from each of these townships and communities, two villages or enumerations were randomly chosen. Lastly, from each of the villages, two residential blocks were selected. All selections of the included geographic regions and districts in this multi-stage approach were performed randomly in order to minimise the possible risk of bias. Approval to conduct this study was granted through the Ethics Committee of the Chinese Centre for Disease Control and Prevention.1, PM2.5, PM10 and NO2 for China were modelled using satellite remote sensing, meteorology and land use information and other data combined with ground-monitored data on the pollutants from stations throughout China. Daily ground-level measurements of PM1 were obtained from the 77 stations of the China Atmosphere Watch Network (CAWNET) from September 2013 to December 2014. Daily ground-level measurements of PM2.5, PM10 and NO2 were obtained from 1479 stations of the China National Environmental Monitoring Centre (CNEMC) from May 2014 to December 2016. Predicted data concentrations of PM1 predictions have been previously published [1 data was linked with the AOD data, vegetation data, land use information, meteorological data and other spatial data using a generalized additive model to predict daily PM1 grid cell concentrations (2005 to 2014). A similar approach using random forest models was implemented to predict the daily PM2.5 grid cell concentrations (2005 to 2016) and daily PM10 grid cell concentrations (2005 to 2016) and the details have been published [Details of the PMublished . Brieflyublished ,49.2 (from 2013 to 2016) prediction have also been published [2 (molecules/cm2) were obtained from the OMI-NO2 level-3 data product (OMNO2d version 3) [2) resolution. Temporal convolution with Gaussian kernels, which tended to create gentle smoothing and preserve edges, was operated to filter out noise while filling data gaps because of satellite orbit, cloudy conditions, or surface reflectance. Ground-monitored NO2 data was linked with satellite NO2 data, vegetation data, land use information, meteorological data, road density and other spatial predictors using a random forest model to predict daily NO2 grid cell concentrations. Likewise, details on NOublished . In summrsion 3)  at 0.25 1, PM2.5, PM10 and NO2. The results for the adjusted coefficient of determination (R2) and root-mean-squared error (RMSE) are shown in Ten-fold cross-validation was performed using the monitored data to assess the predictive ability of the models for PM2 concentrations of the three years (2005–2007) prior to the survey. Finally, community locations of participants were geo-coded and then used to link the estimated annual PM and NO2 concentrations.We defined exposure to long-term ambient air pollution as the average PM and NOUsing the WHO criteria, anaemia was defined as the haemoglobin concentrations below 13 g/dL in men and below 12 g/dL in women ,53.We controlled for demographic, biometric, health behaviour, indoor air pollution, socioeconomic status and comorbid disease covariates based upon their previous associations with either air pollution exposure ,55, anaeThe types of fuel used at home for cooking were classified as clean  and unclean . The information on the most common type of fuel for cooking was important for assessing indoor air pollution. The highest educational attainment was categorised as: (1) no school, (2) primary school and (3) middle or high school. The participants’ socioeconomic status was categorised based on their self-reported household annual income: low ≤¥15,000; and high >¥15,000 using the median as the cut-off point. Finally, participants’ self-reported hypertension, chronic lung disease and arthritis were used for comorbidity assessment.10, PM2.5, PM1 and NO2 in single pollutant models. Haemoglobin measurements for participants in the same community may be correlated with each other, violating the independence assumption of regression models. To account this, we considered a two-level linear regression model where participants were considered as the first-level unit and the township as the second-level unit. For models, in which anaemia was treated as a dichotomous outcome, logistic regression may overestimate the prevalence ratio given anaemia’s high prevalence in the study sample; therefore, we used a modified Poisson regression with robust error variance to estimate the prevalence ratio of anaemia [We examined the association between haemoglobin and an interquartile range (IQR) increases in three-year moving averages of PM anaemia . Also, d2 by using three indicators: attributable cases, population attributable risk and population attributable fraction. The ambient NO2 level (40 μg/m3) set by the WHO Air Quality Guidelines was used as the reference concentration [We further estimated the anaemia burden attributable to ambient NOntration . The popntration ,65.bP is the proportion of participants with anaemia, and OR is the prevalence ratio of anaemia in the study population. For ease of interpretation, we will present the PAF as population attribution risk percent (PAR%) by multiplying PAF by 100. To measure the adjusted contribution of NO2 exposure above the WHO air quality guidelines on the total risk of having anaemia the ‘adjusted PAR%’ was calculated using the adjusted ORs from the final adjusted model. We estimated 95% confidence intervals for all PAR%.Here A number of sensitivity analyses were performed to ensure our findings were robust to various model specifications. First, we used average pollutants concentrations for one and five years before the baseline survey. Second, we excluded the participants with comorbidities, since respiratory and cardiovascular diseases might have had an impact on the outcomes. All analyses were conducted using STATA version 15  and p-value < 0.05 was used to determine statistical significance.2 levels , had lower BMI  and were more likely to have lower education levels and use clean cooking fuels (p < 0.01). Non-anaemic participants were more likely to live in rural areas, have lower physical activity level and have sufficient intake of fruit and vegetables  individuals had valid haemoglobin measurements; 645 additional participants were excluded because of missing covariate information, including sex, age, or type of fuel used at home. As a result, 9966 participants were included in our final analyses . Anaemiagetables . There w3 for PM10, 29–69 μg/m3 for PM2.5, 35–56 μg/m3 for PM1 and 20–46 μg/m3 for NO2. The annual average of PM10 and PM2.5 concentrations in the study regions were higher than the WHO guidelines in all eight regions of the SAGE China study , PM2.5 IQR (26.1 µg/m3) associated with a 5% : 1.02–1.09) and 11%  increased prevalence of anaemia, respectively. Associations for PM1 were positive and significant in unadjusted models, with an IQR (24.1 µg/m3) increase associated with a PR of 1.24 (95% CI: 1.17–1.31), while covariate adjustment attenuated the associations . Associations were somewhat higher for NO2, with an IQR (26.8 µg/m3) increase associated with a 46% increased prevalence  in the univariate model, and were only minimally changed in fully adjusted models . 2 and haemoglobin levels. For each PM10, PM2.5, PM1 and NO2 IQR increase corresponded to −0.53 , 0.52 , 0.55  and 1.71  mg/dL decrements in haemoglobin levels, respectively. The smoothing curves of the relationships between pollutants and haemoglobin suggest non-linear relationships for the overall population (Appendix). For PM10 and PM2.5, negative associations are approximately linear until 100 and 65 (respectively), after which they become positive. In contrast, for PM1 the strongest negative associations occur at the lowest and highest exposures, with a curvilinear association for intermediate exposures. For NO2, no association is observed until 40 ug/m3, which is the WHO air quality guideline for NO2, after which they become strongly and significantly negative. 2 and haemoglobin  and −0.80 ± 0.10 vs. −0.58 ± 0.07 (p = 0.006), respectively), suggesting that smoking may enhance this association. Also, alcohol consumption showed a significant effect modification of this association for PM1. We observed a larger magnitude of decrease in participants who reported alcohol consumption  than for those who reported that they never consumed alcohol . Region of survey was also found to be an effect modifier, participants living in northern province showed higher decrement of haemoglobin per IQR increase levels compared to southern residence (−0.29 ± 0.06 vs. −0.04 ± 0.20 p < 0.001) respectively. We did not observe any significant effect modification by age, sex, household income or history of chronic obstructive pulmonary disease (COPD).In stratified models, the association between ambient PM and NOmoglobin  suggest 2 after adjusting for confounders are summarised in 2 higher than 40 μg/m3 was 4.4% (95% CI: 3.6–5.2) corresponding to 131 (95% CI: 107–155) anaemic cases in the study population. Further, we estimated the PAF and observed that approximately 26% of the anaemic cases in the study could have been averted if all older adult participants lived in areas where NO2 levels met the WHO air quality guidelines, assuming a causal association  and 1.15 (95% CI: 1.07–1.24), respectively. Additionally, when we excluded the respiratory and cardiovascular cases from the data, the associations remained robust, with PRs of 1.26 (95% CI: 1.17–1.36) per IQR increase in PM1.The associations between PM and NOanalyses . For exa2 are significantly and consistently associated with decreased haemoglobin levels and increased prevalence of anaemia in a large scale survey of older adults in China. In addition, we observe that among current smokers, the adverse effects of PM10 and PM1, but not NO2, on haemoglobin levels were even stronger (p < 0.01). Moreover, alcohol consumption was shown to enhance this link for PM1 and NO2 (p < 0.01), but not for PM2.5 or PM10. Dose-response curves for all associations demonstrated significant non-linearity. We further estimated that 4.4% of anaemia cases in the study population could be attributed to NO2 exposure and that 26% of the anaemia cases observed in the study could have been averted if NO2 in the study locations met the WHO guidelines.The current study is the first to show that long-term exposures to PM and NO3) increase in one-year moving average PM2.5 was linked to significantly higher anaemia prevalence  and decrement in haemoglobin concentrations of 0.81 g/dL (95% CI: 0.75–0.87). Similarly, an IQR (9.6 ppb) rise in NO2 was associated with an increased prevalence of anaemia  and a decrease in average haemoglobin of 0.81 g/dL [2), soot and lead (Pb) in sediment matters in the air) was linked to an increased risk of anaemia during pregnancy [2, black smoke and SO2 had lower haemoglobin levels and RBC counts compared to those who lived in less polluted areas [Our findings of the air pollution impact on haemoglobin levels in older adults are consistent with the results of a recent US study. Honda et al. found that an IQR  [2.5 and black carbon exposures were associated with higher haemoglobin and erythrocyte counts, with a two-day average air pollution exposure associated with a 2.3% increase in RBC number, and a 2.6% increase in haemoglobin per 10 μg/m3 increase in PM2.5 in women, but not in men. In a study of children aged 6–59 months living in one of the most air-polluted cities of Latin America , investigators found that high levels of outdoor PM2.5 (25–50 μg/m3) were associated with a 39.6% of anaemia prevalence (95% CI: 39.3–39.9), were conversely males were one of the most affected groups [Studies investigating associations between short-term air pollution exposures and haemoglobin levels show inconsistent results. For instance, in a UK study of acute air pollution exposures in 112 older adults, three-day average PM in PM10 . Similar < 0.05) . In contd groups .The inconsistency of the findings from the studies mentioned above on the short-term air pollution exposures may reflect several factors. First, all these studies have a small geographically distinct and thus non-representative sample size, which limits the generalisability of the findings to other populations. Second, short-term pollutant exposure likely affects haematologic and haematopoietic physiology differently than long-term exposures , and oldAir pollution is known to cause a chronic systemic inflammatory response . This, i10 and PM2.5, the adverse effects of air pollution on haemoglobin levels were amplified in smokers (−0.78 ± 0.10 g/dL) as compared to non-smokers (−0.61 ± 0.08 g/dL). This finding is inconsistent with findings by Honda et al. (2018), who found that NO2 exposure, but not PM, was associated with higher magnitude associations in older US adults. It is possible that local immune response differences between smokers and non-smokers may underlie our result, which makes smokers more susceptible to air pollution exposures. Additionally, effect modification was observed for alcohol consumption, where increases in PM1 and NO2 among those who reported ever consuming alcohol were associated with higher magnitude associations relative to those who reported never consuming alcohol. This outcome is also unexpected, as prior literature has found that alcohol consumption is often associated with increased haemoglobin concentrations [2.5 in north China reached as high as 80–100 μg/m3, while in south, the concentration has reduced to 40–70 μg/m3 [We found that for PMtrations . Also, w70 μg/m3 ,78,79.2 were associated with decreased haemoglobin levels in Chinese older adults have significant clinical and public health implications. For instance, a 2005 study of older adults (mean 60.2 years) post-myocardial infarction found that just 1 g/dL decrease in haemoglobin levels below 14 mg/dL was linked to 21% increased odds of cardiovascular mortality (95% CI: 12–30%) [2 in a population of Chinese elderly. It also estimated the reduction of the anaemia burden when the NO2 levels meet the WHO air quality guidelines. Most of the previously published works usually quantified the association between pollutants and adverse health outcomes. The attributable risk may provide even more information from the point of public health significance. A similar approach has been applied to other research works. In a recent study of six low-to-middle income countries, Guo et al. estimated that 7.11% of stroke cases could be attributable to ambient PM2.5 [2.5 were attained [Our findings that PM and NO 12–30%) . This stnt PM2.5 . Moreoveattained . The latattained . Our study has a number of important limitations. First, as a cross-sectional study, we are not able to establish a temporal relationship between the exposures and outcomes of interest. Second, while we used a satellite-based comprehensive exposure model and assigned exposures according to the participants’ addresses at the township level, the possibility of exposure misclassification is high, as we were unable to have more detailed information to inform our exposure assessment, such as the respondents’ activity patterns regarding time spent in traffic and indoors. Third, specific components of PM that may be driving our results, such as transition and/or heavy metals, could not be considered separately. They might have had distinct chemical structures and might be associated with different health concerns. Last, some critical risk factors of anaemia, such as genetic background and cultural dietary differences among various geographic areas, were not taken into account. However, in our multilevel models, we attempted to address this by controlling for the community in which an individual lives. 1 and PM2.5 exposures enabled us to have a virtually complete spatial coverage among the study participants in the absence of air monitoring data in China for PM2.5 before the year of 2012. Third, our study is the first to investigate the PM1 association with anaemia in any settings globally. The existing air pollution standards in both the United States and China do not include regulations for PM1. Therefore, there is an urgent need to fill these gaps in the literature and our study can be used to inform public policies and guidelines in order to protect older adults from hazardous risks associated with PM1 air pollution.Several significant strengths counterbalance these limitations. First, our study encompasses a large, representative population to examine the association between ambient air pollution and anaemia among older adults in China. We collected extensive individual-level information on other risk factors, allowing us to control for individual-level confounders. Second, the use of satellite-based estimates of PM2 are warranted. Public policies and guidelines should be improved to protect the ageing population from risks associated with air pollution. Our study is the first to demonstrate that exposure to ambient air pollution is associated with an increased prevalence of anaemia and reduced levels of haemoglobin in Chinese older adults. Further studies to examine the mechanisms accounting for increased vulnerability to the PM and NO


Lactococcus lactis is a Gram-positive lactic acid bacterium commonly used in the dairy industry for the production of fermented foods such as buttermilk and a wide variety of cheeses. Here, we report the complete genome sequences of 28 bacteriophages infecting different L. lactis industrial starter strains isolated from dairy plants throughout the world. Lactococcus lactis is a Gram-positive lactic acid bacterium commonly used in the dairy industry for the production of fermented foods such as buttermilk and a wide variety of cheeses. Here, we report the complete genome sequences of 28 bacteriophages infecting different L. lactis industrial starter strains isolated from dairy plants throughout the world. Lactococcus lactis strains, which are used as starter cultures in dairy fermentation processes, is one of the main causes of fermentation failure and causes great economic losses for dairy industries , and the sequence reads were trimmed using Trimmomatic v0.36 (The bacteriophages were isolated from whey samples and plaque purified three times on their industrial lactococcal hosts at 30°C in M17 medium using the soft-agar overlay assay . A singlic v0.36 . Genome ic v0.36 . The seqic v0.36 . Bacteriic v0.36 , 16. FifThe GC contents of the analyzed bacteriophages range from 34 to 36.4%. The genome lengths of the isolates range from 20 to 23.2 kb for the c2 phages, from 25.3 to 32.6 kb for phages of the 936 species, and from 25.3 to 32.6 kb for the Bk5-T members. The numbers of predicted ORFs range from 34 to 42 among members of the c2 species, from 46 to 62 among 936 phages, and from 51 to 60 for Bk5-T isolates.PRJNA606016.The complete genomic sequences of the 28 bacteriophages described here are available at GenBank under the accession numbers reported in


Penile prothesis (PP) is the gold-standard treatment of drug-refractory erectile dysfunction (ED). While postoperative outcomes have been widely described in the literature, there are few data about patient satisfaction and intraoperative events. We aimed to assess long-term patient satisfaction and perioperative outcomes after PP implantation in a single-centre cohort of unselected patients using validated scales.p = 0.02). There were six (4.6%) non-life-threatening intraoperative events including two which resulted in non-placement of a PP (1.5%). EAUiaic grade was 0 for 124 procedures (95.4%), 1 for four procedures (3.1%) and 2 for two procedures (1.5%). Of patients who still had their PP at the end of the study, 91 (80.5%) expressed satisfaction.A total of 130 patients received a PP  score: 6 [IQR: 5–7]). Median follow-up was 6.3 years [IQR: 4–9.4]. Thirty-two (24.6%) patients underwent surgical revision, of which 20 were PP removals (15.4%). Global PP survival rate was 84.6% and previous PP placement was a risk factor for PP removal (PP implantation is a last-resort treatment for ED with a satisfactory outcome. PPs are well accepted by patients. Erectile dysfunction (ED) is a frequent condition in men which increases with age. More than 150 million men currently complain of ED and this number is expected to rise in the near future .In France, although PP implantations doubled between 2006 and 2013, less than 10% of surgeons perform a high volume of PP placements (i.e. > 20 cases/year)  and qualitative variables as number and percentage. To compare categorical variables, Pearson’s ChiInformed consent was signed by the patient at the first postoperative consultation. The study was approved by the local ethics committee (APHP) and was conducted according to the Declaration of Helsinki.n = 59, 45.4%), diabetes  and other causes . Overall, 76 patients received an AMS 700 CX device (58.5%) and 54 (41.5%) were implanted with a Coloplast Titan. The peno-scrotal approach was used in the majority of cases . Of the included patients, nine (7%) had concomitant artificial urinary sphincter (AUS) placement. During the study, there was not reported death among patients. Each patient was reachable by phone (0% lost to follow-up) and median follow-up was 6.3 years [IQR: 4–9.4]. The characteristics of the patients are summarised in Table A total of 130 patients were included in the study. Median age was 62.5 years [IQR: 58–69], median IIEF-5 score was 6 [IQR: 5–7] and 122 patients (93.8%) had received previous intracavernous injections. The causes of severe ED were: previous radical prostatectomy (EAUiaic grade was 0 for 124 procedures (95.4%), 1 for four procedures 3.1%) and 2 for two procedures (1.5%)  were achieved without PP removal in 12 cases (9.2%). A major issue was pump malfunction  that was corrected by pump replacement. Four revisions were performed at the patients’ request: two for aesthetic reasons (1.5%) and two for PP up-sizing (1.5%).n = 120 patients) was 80.7%   Table .Fig. 1Pp = 0.02) , six for urethral or skin erosions (30%) and two due to haematomas (10%). Global PP survival rate was 84.6% at the end of the study , two were grade 2 (1.5%) and 23 were grade 3 (17.7%).Two months after surgery, 85 patients (66.4%) were satisfied with the results of PP placement. The two patients who did not undergo PP placement because of urethral injury were excluded from this analysis. At the end of study, 91 (71.1%) were satisfied according to the EDITS scale. The two main complaints regarding the PP were pump manipulation and the size of their penis.In the current study, we evaluated surgical outcomes and patient satisfaction after PP placement at a single academic centre. Patient satisfaction was assessed prospectively from the beginning of the study strengthening our results.We observed a high level of satisfaction, which could be slightly lower with that described in the literature , 15. OurThe satisfaction rate increased between the first consultation and the last follow-up; this observation seems to be correlated with a necessary period of practice for patients. Patients need to become familiar with the pump but also need to relearn how to engage in sexual intercourse. In a retrospective study, Carvalheira et al. demonstrated that sexual function was associated with male satisfaction after PP placement . FactorsIn our study, the choice of PP device was left to the surgeons and > 50% of patients received an AMS 700. Previous reports have failed to demonstrate any significant difference in satisfaction between an AMS 700 and Coloplast Titan . SatisfaOur results show that a second PP placement was a risk factor for subsequent removal. Revision surgery is associated with an increased rate of post-surgical events such as infection, chronic pain or reduced PP survival . Henry eOur revision rate was superior to that reported in previous studies, , 22 but The peno-scrotal approach was more often associated with surgical revision in our study. These results are not in line with those in the literature which have shown no difference regarding the surgical approach , 25. ThiWe used the new EAUiaic scale to describe perioperative incidents during PP placement . Only twOur study has several limitations. First, patients came from a single-centre and the population size was small. In addition, the median follow-up period of 1.8 years may appear low for a study assessing satisfaction, but all of our patients did attend the last consultation.PP placement for patients with treatment refractory ED was a satisfactory procedure in our population. Intraoperative outcomes were good with a EAUiaic grade 2 reported for only two patients. Moreover, long-term surgical outcomes were acceptable with an 81% PP survival at 3 years.


Adjusted effectiveness against PPSV23-serotype IPD was 42.2%. Despite a substantial decline in the proportion of 13-valent PCV serotypes during the study period (45% to 31%), the change in effectiveness for PPSV23-serotype IPD was limited (47.1% to 39.3%) and only marginal in the elderly population (39.9% to 39.4%). The pediatric PCV program had limited impact on PPSV23 effectiveness against IPD in adults.The decline in the proportion of pneumococcal conjugate vaccine (PCV)–covered serotypes among adult invasive pneumococcal disease (IPD) patients might change the overall effectiveness of the 23-valent pneumococcal polysaccharide vaccine (PPSV23) because its effectiveness differs according to serotype. Using the indirect cohort method, we calculated the effectiveness of PPSV23 against IPD among adults in Japan to assess the impact of the national pediatric PCV program. Clinical and epidemiologic information and pneumococcal isolates were collected from IPD patients  Streptococcus pneumoniae is a major cause of illness and death among adults  and the 13-valent pneumococcal conjugate vaccine (PCV13). According to a systematic review, the effectiveness of PPSV23 against IPD among adults Discussions over adult pneumococcal vaccination programs are complicated because of differences in vaccine effectiveness (VE) by serotype and age group. Previous studies have suggested that VE of PPSV23 differs by serotype  was detected by PCR assay in samples collected from normally sterile sites, such as blood and cerebrospinal fluid. To investigate the effectiveness of PPSV23 among adults, we excluded IPD patients >15–19 years in this study. IPD patients >20 years of age who had been enrolled in the study during April 2013–December 2017 and whose clinical and epidemiologic information and microbiologic testing results were available were included in the analyses.Under the revised Infectious Disease Control Law, national IPD surveillance was implemented in Japan in 2013. Since then, physicians have been required to report all IPD patients and their basic information to the nearest local public health centers. To collect more detailed clinical and epidemiologic information and S. pneumoniae isolates were serotyped by using the capsule Quellung reaction with rabbit antisera  after culturing overnight. Clinical specimens were serotyped by using the multiplex serotyping PCR assay as described previously , the cost of vaccination is covered by health insurance. According to an estimate by Japan’s Ministry of Health, Labor, and Welfare, 33%–38% of persons >65 years of age were vaccinated with PPSV23 during 2014–2017 . In our study, only 4 of 1,121 patients reported having been vaccinated with PCV13.PCV7 was approved for the voluntary vaccination of children in February 2010, included in the routine immunization program for children in April 2013, and replaced with PCV13 in November 2013. The coverage rate of the third dose of PCV13 among children was 98% in 2017 . The indirect cohort method is a case-control design and has been used to estimate VE of pneumococcal vaccines by using pneumococcal disease surveillance data (2), normal (18.5–24.9 kg/m2), and high (>25 kg/m2). Clinical manifestations in IPD patients were classified as pneumonia, meningitis, bacteremia, and other conditions according to the physicians’ report. Because the IPD incidence is higher in the autumn and winter seasons compared with other seasons , the presence of underlying conditions, BMI group, and clinical manifestations. The stratum-specific estimates of VE were compared by using a Wald test (test for interaction).We estimated VE of IPD for PPSV23 serotypes, PCV13 serotypes excluding 6A (PCV13 non–6A serotype), including serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F, and PPSV23 serotypes excluding PCV13 serotypes (PPSV23 non–PCV13 serotypes). The serotype-specific VE was estimated for each serotype if its number of isolates was >30. To explore the potential effect of cross-immunity produced by PPSV23 on serogroup 6 (https://www.stata.com).PPSV23 vaccination history was not documented for 23% of our patients. This group was coded as no record and included in our primary analyses. In a sensitivity analysis, this group was considered to have missing data, and multiple imputations were performed. All analyses were performed by using Stata version 15  and conducted according to the principles expressed in the Declaration of Helsinki. The requirement for obtaining informed consent from all participants was waived because the data do not contain any patient identifiers, and samples were taken as part of standard patient care.>20 years of age were identified through the national IPD surveillance program in the study prefectures , and S. pneumoniae–specific DNA was detected in 4 patients (0.4%).During the study period (April 2013–December 2017), a total of 1,824 IPD patients fectures  Figure. The characteristics of the 1,121 IPD patients are summarized in After we controlled for confounders, VE against PPSV23-serotype IPD was 42.2% (95% CI 13.4 to 61.4) . VE agai>65 years of age.The trend in the proportion of vaccine-covered serotypes among adult IPD patients during the study period is shown in the >20 years of age in the first phase was 47.1% (95% CI −4.7% to 73.3%) and in the second phase was 39.3% (95% CI −2.9% to 64.2%) (p = 0.953 by test for interaction) . For persons 20–64 years of age, VE point estimates showed a decreasing trend ; however, the CIs were wide.VE against PPSV23-serotype IPD among persons raction) . When we>65 years of age, but this difference was not statistically significant level (p = 0.17 by test for interaction)  than in those with a low BMI (7.4% [95% CI −108.1% to 58.8%]) or a high BMI (−136.5% [95% CI −826.6% to 39.6%]). VE did not differ by patients’ underlying diseases. Among persons >65 years of age, VE for IPD with pneumonia was 52.8% (95% CI 16.5% to 73.3%) and for IPD without pneumonia was 9.8% (95% CI −134.4% to 65.3%)  among persons 20–64 years of age and 39.2% (95% CI 2.0% to 62.2%) among those raction) . When weo 65.3%)  Table 2.>20 years of age in Japan. VE against PCV13 non–6A-serotype IPD and that against PPSV23 non–PCV13-serotype IPD were almost comparable. Despite an observed reduction in the proportion of PCV13 serotypes among adult IPD patients during the study period, the change in VE against PPSV23-serotype IPD was limited among adults >20 years of age and only marginal among those >65 years of age.VE of PPSV23 against PPSV23-serotype IPD was 42.2% among adults >65 years of age declined by 77% and incidence of PCV13 non–PCV7-serotype IPD among the same age group declined 38% (>20 years of age was limited during the study period (47.1% in the first phase and 39.3% in the second), and no change was observed among those >65 years of age (39.9% in the first phase and 39.4% in the second). Our findings suggest that VE of PPSV23 among adults in Japan is moderate and remained constant during the 4-year study period under the impact of pediatric PCV13.Large declines in the incidence of adult pneumococcal disease caused by PCV serotypes have been reported in many countries because of the indirect effect of pediatric PCVs . A declining trend in PPSV23 effectiveness with age has been reported previously  for persons 20–64 years of age and 39.2% (95% CI 2% to 62.2%) for those >65 years of age was 52.8% (95% CI 16.5% to 73.3%), whereas among persons 20–64 years of age it was 23.0% (95% CI −272.2% to 84.1%) (p = 0.064 by test for interaction). Because pneumonia is the most common manifestation of pneumococcal disease among the elderly population (VE for bacteremic pneumococcal pneumonia among persons >65 years of age until 2023. The continued moderate PPSV23 effectiveness under the impact of the pediatric PCV13 program we observed provides supporting evidence for the current adult pneumococcal vaccination policy. However, making decisions regarding the adult PPSV23 program is still challenging for several reasons, such as its low level of efficacy in the older age group (In Japan, PPSV23 was introduced into the adult immunization program in 2014, but its vaccination coverage rate was only »30% in 2017. Recently, the Ministry of Health, Labor, and Welfare decided to extend the duration of the catch-up campaign for persons Our study has limitations. First, 37.6% of the patients identified in the local health centers were not included in our study. The inclusion rate was especially low at the beginning of the study period; however, the baseline characteristics of the patients did not differ between the enrolled and nonenrolled patients  Table 3.>20 years of age in Japan. Although the proportion of PCV13 serotypes among adult IPD patients has been substantially decreasing because of the indirect effect of the pediatric PCV program, the change in PPSV23 effectiveness was limited.In conclusion, the effectiveness of PPSV23 against IPD is moderate among adults Additional information about effectiveness of 23-valent pneumococcal polysaccharide vaccine against invasive pneumococcal disease in adults, Japan, 2013–2017.


Substituting starch with digestible fiber (dF) can improve digestive health of rabbits and reduce costs. Therefore, it is necessary to develop a criterion for dF and starch supply. Effects of the dietary dF-to-starch ratio on pellet quality, growth and cecal microbiota of Angora rabbits were evaluated.Five isoenergetic and isoproteic diets with increasing dF/starch ratios  were formulated. A total of 120 Angora rabbits with an average live weight of 2.19 kg were randomly divided into five groups with four replicates. At the end of 40 day feeding trial, cecal digesta were collected to analyse microbiota.Ruminococcus in the 0.71 dF/starch treatment was higher than that in the 0.59 dF/starch treatment (p<0.05)The results showed that the dF/starch ratio had linear effects on pellet variables (p< 0.01). When the dF/starch ratio was 1.44, the pellets had the lowest powder and highest durability. The dF/starch ratio had unfavorable linear effects on growth variables (p<0.001). When analyzed by quadratic regression, the optimal dF/starch ratios for average weight gain and feed/gain were 0.59 and 0.74, respectively. There were differences in wool yield, fiber length and fiber diameter caused by the dF/starch ratio (p<0.05), and the dF/starch ratios that ranged from 0.66 to 1.06 were appropriate for good results. The cecal microbiota operational taxonomic unit (OTU) number index in the 1.05 dF/starch treatment was higher than that in the 0.66 and 0.71 dF/starch treatments. The higher dF/starch ratio resulted in a higher cecal microbiota OTU number index (p<0.05). The proportion of The most suitable dF/starch ratio for feed pellet quality is 1.44, and for rabbit growth the optimal range of ratios is from 0.59 to 0.74. With combination of the wool growth, output cost, and cecal microbiota, we suggest that a dietary dF/starch ratio ranging from 0.74 to 1.06 is optimal. Angora rabbit produces 1.0 to 1.4 kg/yr of pure fine animal fiber. This represents about 30% of its live weight. However, there is a considerable paucity of information on Angora rabbit nutrition compared with published work on the production of meat from rabbits or wool from sheep. The special feed for Angora rabbit is also extremely rare on the market. Therefore, the nutritional research of Angora rabbit requires particular attention.vice versa on digestive parameters was described by Gidenne and Perez [The carbohydrate fraction (fiber and starch) is a major component of commercial rabbit diets. Fiber and starch both affect the stability of the microbial ecosystem and gut health. Dietary fiber accounts for 40% to 50% of the total diet. Its importance is related to the influence on feed consumption, rate of digestive passage and role as a substrate for cecal microbiota . Sufficind Perez , and Gidnd Perez . Substitnd Perez . It has nd Perez . Becausend Perez . Therefond Perez . Howeverad libitum, a transition from standard to experimental diet was followed by a 40 d feeding trial. Natural lighting and automatic ventilation were used in the rabbit house; the temperature ranged from 12°C to 24°C, and the relative humidity ranged from 40% to 50% throughout the trial. Determination of digestive energy by the endogenous indicator method was conducted in the last week of the feeding trial.The experiment was conducted in accordance with the Institutional Animal Care and Use Committee at Shenyang Agricultural University . It was carried out at the Jinhua Angora Rabbit Industrial Park , during the period from October 2016 to December 2017. A total of 120 growing female  Wan strain Angora rabbits (83 d old and 2.19±0.07 kg) were selected and randomly allocated in galvanized metal wire cages with automatic drinkers with nipples, to five treatments each with 4 replicates containing six rabbits. After an adaptation period of 7 d during which the rabbits were fed, The diets corresponded to a linear decrease in starch level (28% to 16%) and to a nearly linear increase in dF (16% to 23%); dF/starch ratios were 0.59, 0.66, 0.71, 1.05, and 1.44. The diets were approximately isoenergetic and isonitrogenous. The dietary gross energy was analyzed by a full-automatic calorimeter . Crude protein was analyzed by a semi-automated Kjeldahl technique. Neutral detergent fiber (NDF), ADF, and acid detergent lignin used detergent method of Van-Soest by an automatic fiber analyzer . Starch was measured according to national food safety standard (GB 5009.9-2016 Determination of starch in foods).We used a 150 mm long vernier caliper, with a precision of 0.02 mm, to determine particle size.We filled the feed pellets into a 1,000 mL cylinder, leveled the particles off on the top edge of the cylinder, weighed this sample, and calculated the weight to volume ratio.We used a sclerometer  to determine pellet hardness.Powder ratio determination was based on the national standard (GB/T 16765-1997). We sieved the sample with a 2-mm metal sieve, weighed the particles passing through the screen, and calculated the percentage of the weight of screened particles to the total weight of the sample.We used the national standard (GB/T 5169-91) and a pellet durability index (PDI) instrument  to score the PDI.The number of replications for particle size, bulk density, hardness, powder ratio, and PDI determination of feed pellet were 30, 5, 15, 3, and 3 respectively.At the start and end of the experiment, rabbits were weighed in the morning. The feed consumed was recorded daily. Weight gain, feed/gain (F/G), and wool yield were measured after the feeding trial.All of the hair shed by each rabbit was individually weighed.Fiber samples were collected from a 10×10 cm patch area in the rib area of the left side of each rabbit, and their lengths were measured using a ruler. A total of 200 fibers from each rabbit were measured.Diameters of fiber samples were measured using a fiber fineness meter .At 123 d of age (at the shearing period), 20 rabbits (4 per group) in apparently healthy condition were euthanized by sudden cervical dislocation. For each rabbit, the cecal digesta was collected in tube and stored at −80°C until processed.Genomic DNA from the cecal digesta (0.2 g) was extracted using the cetyltrimethylammonium bromide (CTAB) method. The extracted DNA (2 μL) was then subjected to electrophoresis on a 7 g/L agarose gel (W/V) to estimate the amount and integrity of the DNA products. The DNA solution was preserved at −20°C until further analysis.Amplification of the variable V3-V4 region of bacterial 16S rDNA was performed using the general primer sequences 340F and 805R. The details of these primers are as follows: upstream primer 340F: 5′-CCTACGGGNBGCASCAG -3′; downstream primer 805R: 5′-GACTACNVGGGTATCTAATCC -3′. Polymerase chain reaction (PCR) was performed using model PTC220  and PCR amplification kits  in reaction mixtures containing 5 μL 10× PCR buffer; 1 μL dNTP (2.5 mM); 0.2 μL rTaq (5 U/μL); 2 μL 340F (20 mM); 2 μL 805R (20 mM); 1 μL template DNA, and made up to a final volume of 50 μL using double distilled water. The thermal cycle used the following conditions: initial denaturation at 95°C for 3 min, followed by 30 cycles at 95°C for 30 s, 58°C for 30 s, and 72°C for 60 s, and final elongation at 72°C for 7 min.Samples were mixed according to the concentration of the PCR products. After complete mixing, the PCR products were purified using 0.5×tris-boric acid buffer of 1.5% agarose gel electrophoresis. The targets were then recovered using a MinElute Gel Extraction Kit .The complementary DNA Library was constructed using a NEB Next Ultra DNA Library Prep Kit  for Illumina. The constructed library was tested by Qubit quantitative and library and, after qualification, MiSeq 2500 was used for sequencing.http://ccb.jhu.edu/software/FLASH/. Paired-end reads were assigned to each sample according to the unique barcodes and follow up analysis with the processed sequence; operational taxonomic units (OTUs) cluster and Species annotation. Sequence analysis was performed by QIIME 1.8 software package [Paired-end reads assemblies: We used FastQC software to evaluate the number and quality of sequencing. Paired-end reads from the original DNA fragments were merged using FLASH v1.2.7  package . We filtData were analyzed using one-way analysis of variance with SPSS 21.0 . Contrast was established using linear and quadratic polynomial methods to determine the effects of increasing the dF/starch ratio. The data are presented as means, standard error of the mean, and p-values. Multiple comparisons were made using least significant difference method. Differences were considered significant at p<0.05.1, p<0.001) and hardness  were observed. Based on the regression equation , when the dF/starch ratio was 0.67, the pellet bulk density was the highest, and when the dF/starch was 1.53, the hardness was the greatest. When the dF/starch ratio was 1.44, the feed had the best pellet quality (the lowest powder ratio and the highest PDI).Effects of the dietary dF/starch ratio on pellet quality are presented in Effects of different dietary dF/starch ratios on growth and wool yield in Angora rabbits are shown in The wool yield in the 0.66 dF/starch treatment was the highest (140.6 g), and this was higher than that in the 1.44 dF/starch treatment by 9.37% (p<0.05), but there was no significant difference compared with the other groups (p>0.05). The fiber diameter in the 1.05 dF/starch treatment was the finest, and this was finer than that in the 0.59 dF/starch treatment (p<0.05).The shortest fiber length (5.63 cm) occurred in the 0.66 dF/starch treatment and this was shorter than that in the 1.05 dF/starch treatment by 17.81% (p<0.05). A significant favorable quadratic effect on fiber diameter was seen (p<0.05). Based on the regression equation , when thThe microbial 16S rDNA V3-V4 region of 20 cecum contents in 5 treatments were sequenced based on Illumina Miseq sequencing technology, in which 18 samples met the requirements. OTUs were classified according to the similarity of 97%; the effective sequence range of each sample was 239,496 to 963,776 and the range of OTUs was 4,403 to 10,959.Alpha diversity is the analysis of species diversity within a single sample. We annotated the microbial species found in this study. A total of 14 phyla, 24 classes, 26 orders, 25 families, and 17 genera were obtained from the 18 samples. The effect of different dF/starch ratios on the proportion of microbiota phylum is shown in The cecum microbiota was similar at the phylum level, among the different dietary dF/starch ratio treatments (p> 0.05). The dominant bacteria phyla were Firmicutes and Bacteroidetes, followed by Verrucomicrobia and Proteobacteria. The relative microbiota abundance of Bacteroidetes, Proteobacteria, Actinobacteria, Acidobacteria, Chloroflexi, Gemmatimonadetes, Planctomycetes, as well as Nitrospirae, and Crenarchaeot in the 0.59 dF/starch treatment was the highest among all other groups. The microbiota abundance of Firmicutes in the 0.66 dF/starch treatment was the highest among all other treatments. The relative microbiota abundance of Verrucomicrobia in the 0.71 dF/starch treatment was the highest among all treatments. The 1.44 dF/starch treatment had the largest proportion of Tenericutes, TM7 and Euryarchaeota.Ruminococcus (4.58%), Bacteroides (4.88%), Akkermansia (3.21%), Faecalibacterium (2.43%), and Oscillospira (1.22%). The abundance ratio of bacteria at the genus level was not affected by the dF/starch ratio (p>0.05) except for Ruminococcus. The proportion of Ruminococcus in the 0.71 dF/starch treatment was higher than that in the 0.59 dF/starch treatment (p<0.05).There were 3 genera  found only in the 0.59 dF/starch treatment.At the genus level, 14 shared bacteria taxa were identified . The perTo reflect OTU positioning among the samples, two dimensional clustering of samples and OTUs was conducted, resulting in a graphical heatmap . In the Ruminococcaceae (26.13%), S247 (10.42%), Lachnospiraceae (10.39%), Bacteroidaceae (4.63%), Verrucomicrobiaceae (3.16%), and Rikenellaceae (2.90%). Other families .At the family level, unknown bacteria accounted for 33.46% of the total, followed by The pellet quality of rabbits is mainly a function of the particle size, pellet durability and hardness. The diameter and length of the pellets affect the feeding, digestion and processing cost of rabbits. The length of pellets is preferentially between 8 to 10 mm . If pellPellet durability and hardness are major quality charac teristics of rabbit pellets because rabbits do not eat the fines between the pellets. When provided diets with a mixture of pellets of different hardness, rabbits tend to eat a greater percentage of the hard particles. However, very hard pellets with low elasticity are fragile and can produce a large amount of fines . MorisseThe digestive energy present in rabbit diet is mainly from starch and dF but excessive dF will reduce rabbit growth. Perez et al  reportedWe found that a diet combining a low dF level with rela tively high starch (dF/starch: 0.59 to 0.74) enhanced rabbit growth. These results are consistent with the results of Tazzoli et al  who obseFor regular diets, without lipid addition, growing rabbits regulate their feed intake based on the digestible energy level of the diet . If the In this paper, the highest wool yield was obtained in the 0.66 dF/starch treatment, but there was no significant difference compared with the other groups except for the 1.44 dF/starch ratio treatment. Some impairment in the performances of Angora rabbits was observed in those fed the highest dF/starch ratio (1.44). This might be explained by higher fermentation losses in the cecum . The estFiber degradation is ultimately determined by microbial activity, digesta retention time in the cecum and fiber chemical composition and structure . Jehl anWe found that the cecal microbiota remained relatively stable at the phylum level. The dominant bacteria phyla (%) were Firmicutes (59.14), Bacteroidetes (21.38), Verrucomicrobia (3.47), and Proteobacteria (3.25). This result was consistent with results of Xu et al  who repoRuminococcus spp. is the main Fibrolytic bacteria found in the rumen of cattle [Ruminococcus in the rabbit cecum in all treatments exceeded 1%, followed by Bacteroides and Akkermansia. These data could explain why both high dF and high starch diets can promote the growth of Fibrolytic bacteria. However, when the dF/starch ratio was 0.71, the abundance ratio of Ruminococcus was the highest (6.24%). So, the 0.71 dF/starch diet seems to be more beneficial to the decomposition of fiber and this result was consistent with the growth rate. We speculate that appropriate dF/starch ratio diet can provides both long and digestible fiber, which allows an adequate transit time of the digesta and a balanced growth of the cecal microbiota. There was a high percentage (77.18%) of unidentified bacteria genera in this study, indicating that there are many unidentifiable species of intestinal microbiota in Angora rabbits. More attention should be given to the characteristics and functions of unknown bacteria for a better understanding of the intestinal microbiota.f cattle . We demoIn conclusion, the most suitable dF/starch ratio for feed pellet quality is 1.44 and for rabbit growth the optimal range of ratios is from 0.59 to 0.74. In addition, for wool growth, the optimal range of ratios is from 0.66 to 1.06. With the combination of the output cost and cecal microbiota, we suggest that a dietary dF/starch ratio for Angora rabbits ranging from 0.74 to 1.06 is optimal.


The primary aim of this study was to investigate time trends of major headache diagnoses using cross-sectional data from two population-based health surveys. In addition, we aimed to perform a longitudinal assessment of baseline characteristics and subsequent risk for having headache at 22-years’ follow-up among those participating in three health surveys.Data from the Nord-Trøndelag Health Study (HUNT) performed in 1995–1997 (HUNT2), 2006–2008 (HUNT3) and 2017–2019 (HUNT4) were used. The 1-year prevalence time trends of major headache diagnoses were estimated among 41,460 participants in HUNT4 and among 39,697 participants in HUNT3, two surveys with identical headache questions. 16,118 persons participated in all three surveys, and among these, a Poisson regression was used to evaluate health-related baseline information in HUNT2 and the risk ratios (RRs) with 95% confidence interval (CIs) of consistently reporting headache during follow-up.p < 0.001), whereas a lower 1-year prevalence was found for migraine  and medication overuse headache (MOH) . Participants in the age group 20–39 years at baseline nearly three times increased risk  of reporting headache in HUNT2, HUNT3 and HUNT4 than persons aged 50 years or more. Female sex, occurrence of chronic musculoskeletal complaints and high score of depression or anxiety at baseline doubled the risk of having headache in all three surveys.Compared with the 1-year prevalence in HUNT3, a higher proportion of participants in HUNT4 had tension-type headache (20.7% vs. 15.9%, The 1-year prevalence of migraine and MOH was lower in HUNT4 than in HUNT3. Young age, female sex, and occurrence of musculoskeletal complaints and high score of anxiety and/or depression were all associated with substantially increased risk of reporting headache in all three surveys. A 1-year prevalence of 26% for tension-type headache (TTH) and of 14% for migraine have been estimated globally, higher among female and individuals aged between 20 and 50 years of age . IncreasRelatively few population-based studies have evaluated the long-term prognosis of headache. In a population-based 12-year follow-up study from Denmark, remission occurred in 40–45% of individuals with previous headache . In a 30Identification of prognostic factors of headache is important from both a clinical and a public health perspective . In the In the present study, we evaluated time trends of 1-year prevalence of major headache types using cross-sectional data from two health surveys performed with 11-years’ interval, and also evaluated the influence of health-related factors at baseline on the risk of having headache in three surveys with a 22-years’ follow-up.This is a population-based study comparing cross-sectional one-year prevalence of major headache types in two surveys performed with a 11 years’ interval. In addition, it also evaluates the impact of baseline factors on the risk of headache after 22-year follow-up in participants in all three surveys.The present study included data from three HUNT surveys conducted in Nord-Trøndelag County, Norway, in 1997–1997 (HUNT2) , in 2006HUNT3 and HUNT4 had 14 identical headache questions. The initial screening question was “Have you suffered from headache during the last 12 months?”, and those who responded “yes” answered 13 additional questions. In the present study slight modifications of the criteria of the International Classification of Headache Disorders, third edition (ICHD 3)  was usedAs to the modifications of the criteria, individuals would fulfill the migraine criteria even if the attack lasted less than 4 h, because they were not asked for untreated attacks in the question “How long does the headache usually last?” Migraine with aura was diagnosed in those who fulfilled the migraine criteria and answered “yes” to the question “Are the headaches usually characterized by or accompanied by visual disturbance before or during onset .” MOH was diagnosed in those with headache ≥15 days/month who reported use of pain killers for headache at least 4 days/week during the last month. In the present study the diagnosis of MOH excluded the diagnoses of chronic TTH, chronic migraine and the chronic part of unclassified headache. This strategy captured all participants with MOH, but it decreased the prevalence of chronic TTH, chronic migraine and unclassified headache.The headache questionnaire in Q2 of HUNT2 was quite similar to the one used in HUNT3 and HUNT4, including the screening question, except that a question about pain intensity was lacking. Consequently, the definition of migraine used in HUNT2 was stricter regarding migraine criterion C (at least two of three characteristics) than applied in the definition used in HUNT3 and HUNT4 (at least two of four characteristics). Headache sufferers not fulfilling the criteria of migraine were classified as “Unclassified headache”. To fulfil the diagnosis of MOH in HUNT2, individuals should report headache ≥15 days/month and using pain killers daily or nearly daily for at least 3 months during the last year.Individuals who participated in all three surveys were classified into four groups using categorization published previously . Those wn = 293) og HUNT4 (n = 232) gave the following results: for headache suffering, the sensitivity was 90% and specificity79% ; for migraine, the sensitivity was 54% and specificity 95% ; for migraine with aura, the sensitivity was 39% and specificity 95% ; for TTH ≥1 days/month, the sensitivity was 97% and specificity was 71% , for chronic TTH, the sensitivity was 47% and specificity was 100% , and for MOH the sensitivity was 67% and specificity was 100% . Correspondingly, in HUNT2, the validity of the questionnaire-based status of being a headache sufferer had a sensitivity of 83% and specificity of 85%  [We have previously reported the validity of the questionnaire-based headache diagnoses in HUNT2 , HUNT3 , and HUN41–0.73) . Further41–0.73) .The number of invited individuals and responders in HUNT2, HUNT3 and HUNT4 is presented in the flow diagram Fig. . As demo2. Regarding smoking the participants were divided into two categories; current daily or previously smoking, and never daily smoking. Regarding physical activity the participants were categorized into three groups based on two questions about light (no sweating or heavy breathing) and hard (sweating and heavy breathing) physical activity; none or less than 1 h of light activity, 1–2 h of light and/or hard activity; and three or more hours of hard activity. As for alcohol use, based on the non-validated question in Q1 “How many times per month do you usually drink alcohol”, the participants were divided into four groups; no use, less than 4 times per month, 4 times/month, or at least 5 times/month.HUNT2 included a wide range of health-related information, and several factors have previously been identified to be associated with any headache and migraine , 22. SexThe present study was approved by the Regional Committee for Ethics in Medical Research (2018/2428 REK midt). The HUNT Study was in addition approved by the Norwegian Data Inspectorate All participants signed a written consent.For the various headache types, the crude 1-year prevalence in men and women was estimated in HUNT4. The prevalence of all headache diagnoses was sex- and age-adjusted, using the age distributions of all inhabitants aged ≥20 years invited to HUNT3 as the standard population. Age-and sex adjusted prevalence in the HUNT4 and HUNT3 surveys were compared with the chi-square test. A modified Poisson regression with a robust error variance was used to estimate risk ratios (RRs) of headache status in HUNT4. In accordance with a pre-planned strategy, it was decided to include adjustment for age, sex and duration of education in all analyses. In this way, comparison of RR between different baseline factors was possible. Supplementary analyses were conducted to evaluate the influence of age, dividing the participants into three groups based on age in HUNT2; 20–39 years (0–33 percentile), 40–49 years (34–66 percentile), and 50 years and older (67–100 percentile). Data analyses were performed with the IBM SPSS version 25 .p < 0.001). The crude prevalence of migraine was 11.1% (95% 10.8–11.4), whereas the age-and sex adjusted 1-year prevalence was 11.2% (95% CI 10.9–11.5). The corresponding crude and age/sex-adjusted 1-year prevalence of TTH was 20.7% (95% CI 20.3–21.1). Among those with headache ≥15 days/month, 0.8% (95% CI 0.7–0.9) fulfilled our criteria of chronic migraine, 1.0% (95% CI .0.9–1.1) had chronic TTH and 0.3% (95% CI 0.2–0.3) had MOH. Lifetime prevalence of migraine was 16.2% (95% CI 15.5–16.8) (21.9% women and 9.4% men).One-year prevalence of different types of headache in HUNT4 among women and men are presented in Table p < 0.001) and TTH . In contrast, the 1-year prevalence of migraine  and MOH  were lower in HUNT4 than in HUNT3.As demonstrated in Table n = 16,118), the mean age increased from 44.2 years (95% CI 44.1–44.4) at baseline in HUNT2 to 65.9 years (95% CI 65.8–66.1) at the end of follow-up in HUNT4. As demonstrated by Table Among individuals who participated in all three surveys (n = 2136), at 21.7 years follow-up in HUNT4 a total of 40.6% were without headache, 33.2% had probable (n = 168) or definite (n = 541) migraine, 24.1% TTH, 1% MOH and 1% unclassified headache. Furthermore, among 4945 with non-migrainous headache in HUNT2, 58.8% were without headache, 28.5% had TTH, 11.6 had probable (n = 228) or definite (n = 345) migraine, 0.6% had MOH and 0.5% unclassified headache in HUNT4.Among the individuals with migraine at baseline HUNT2 (n = 147) or definite (n = 195) migraine, 0.1% had MOH and 0.1% unclassified headache.A total of 8956 individuals were without headache in HUNT2. At follow-up in HUNT4, 85.7% still were without headache, 10.3% had TTH, 3.8% had probable  of reporting headache in all three surveys compared to persons aged 50 years or more Table . Female In supplementary analyses evaluating the influence of age, highest RRs for having stable headache at follow-up were found for baseline factors like headache subtypes and self-reported complaints among those aged 50 years and older in HUNT2, and lowest RR among those aged 20–39 years in HUNT2. E.g., individuals aged 50 years or more with chronic musculoskeletal complaints at baseline had an increased RR of 3.1 (95% CI 2.5–3.8) of reporting headache in all three surveys, whereas the corresponding RR was 1.8 (95% CI 1.6–1.9) for those aged 20–40 years in HUNT2. Similarly, among persons aged 50 years or more with migraine or MOH at baseline, RRs for having stable headache were respectively 7.3 (95% CI 6.-8.2) and 6.2 (95% CI 5.2–7.3), whereas the corresponding RRs were 2.8 (95% CI 2.6–2.9) and 2.0 (95% CI 1.8–2.3) among those aged 20–39 years. Furthermore, regarding elevated systolic BP, persons aged 50 years or more had the most prominent reduced risk  of having stable headache.The main findings by using population-based data from two surveys were that the 1-year prevalence of migraine and MOH was lower in HUNT4 than in HUNT3, whereas prevalence of headache and TTH increased. In a 22-years’ follow-up among participants in three surveys, young age, female sex, and occurrence of musculoskeletal complaints and high score of anxiety and/or depression at baseline were all associated with substantially increased risk of reporting headache in all three surveys.The prevalence of TTH increased from 15.9% to 20.7% from HUNT3 to HUNT4. In accordance, in a Danish study, using a neutral screening question, the prevalence of TTH increased from 79% to 87% in the 12-year follow-up . FurtherInterestingly, we found that the prevalence of migraine decreased from 12.0% to 11.1%. In contrast, some previous studies have demonstrated an increased migraine prevalence, in Denmark from 11% to 15% from 1989 to 2001 , in SpaiWe demonstrated for the first time a recent decrease in the prevalence of MOH from 1.0% in HUNT3 to 0.3% in HUNT4. It should be highlighted that the questionnaire-based diagnosis of MOH in HUNT3 and HUNT4 was based on identical phrasing of questions regarding headache and use of analgesics. The reason for the marked decrease in MOH prevalence is unclear. In the present study we have no documentation that this is explained by better health care. On the other hand, we may hope that it reflects increased use of preventive medication and more focus on restricted use of pain killers in the primary care. In both HUNT3 and HUNT4, we could have underestimated the prevalence of MOH. Firstly, the validity of the headache screening question was not optimal, and several individuals with MOH may have been missed because they answered “no” to the screening question. Secondly, our questionnaire-based diagnosis of MOH (use of pain killers at least 4 days/week) implied use of about ≥17 days/month rather than the ≥15/days/month limit according to the ICHD 3 criteria . SimilarDuring the 22-year follow-up, 53.4% of individuals who suffered from headache in HUNT2 were without headache in HUNT4, whereas 12.5% fulfilled the migraine criteria, 27.2% TTH, 0.7% MOH and 6.2% other types of headache. In comparison, during 40-years follow-up of school children with severe migraine in Sweden, less than half did not report having migraine at follow-up . In a 12In the present study young age and female gender were important factors for poor prognosis defined as reporting headache in all three surveys. In accordance, such factors are also reported as poor prognostic factors in the follow-up study from Denmark . We idenIn this study we also found that occurrence of chronic musculoskeletal complaints and high score of depression or anxiety at baseline doubled the risk of having headache in all three surveys. This is in accordance with our previous report of a bidirectional association between headache and chronic musculoskeletal complaints , and a cWe found a slightly increased risk of stable headache in current and past smokers. The mechanism behind this finding is unclear and likely complex. However, it should be highlighted that a Mendelian randomization analysis based on the HUNT study did not find evidence of a strong relationship between smoking and headache . Thus, iFinally, we found that high systolic BP and frequent use of alcohol were associated with lower risk of having stable headache. This is in accordance with our previously results that high BP lower the risk of developing headache , and thaThe major strengths of this study are the longitudinal population-based cohort design with many participants, a wide age range, and the use of validated diagnoses of headache , 19, 20.Several study limitations should also be considered. Firstly, generalization of the results to the entire population must be made with some caution, since the participation rate was 42–55% in the three surveys, and only 17% of the invited population in HUNT2 participated in all three surveys, and we cannot be certain that loss to follow-up was random. Secondly, in the longitudinal study subjects were subclassified according to the answer to the screening question “Have you suffered from headache during the last 12 months?”. It should be highlighted that those without headache also included those who experienced headache without defining themselves as being headache sufferers. In fact, 74% of participants in the validation study of HUNT3 reported having had headache during the last year, whereas only 31% stated that they had suffered from headache during the same period .In a 11-years’ follow-up, the1-year prevalence of migraine and MOH decreased, whereas prevalence of headache and TTH increased. In a 22-years’ follow-up, young age, female sex, and occurrence of musculoskeletal complaints and high score of anxiety and/or depression at baseline increased the risk of reporting headache at end of follow-up, whereas elevated systolic blood pressure at baseline lower risk of headache at follow-up.


B12 deficiency was associated with pSS (42.9% among pSS patients vs. 11.4% among controls), even after adjustment for other causes of B12 deficiency (OR 6.45 (95%CI: 2.08–20.0)). In conclusion, pSS appeared to be associated with B12 deficiency, even after the exclusion of pernicious anemia. This justifies screening and treating B12 deficiency in pSS patients.Descriptive and retrospective studies without control groups have suggested a possible association between primary Sjögren’s syndrome (pSS) and vitamin B12 (B12) deficiency. This is of importance because several mucosal and neurological features are common to these two conditions and could be prevented or reversed in case of B12 deficiency. We aimed to evaluate the association between pSS and B12 deficiency. We prospectively assessed the B12 status of 490 patients hospitalized in an internal medicine department over a 15-week period. Patients with pernicious anemia were excluded. We extracted patients with pSS and paired them with controls according to age and sex, with a 1:5 ratio. Twenty-one pSS patients were paired with 105 control patients. The median age was 70 years old (51–75) and 95.2% of patients were women. The plasma B12 level was lower in pSS patients (329 (293–521) ng/L vs. 456 (341–587) ng/L,  Vitamin B12 (B12) or cobalamin deficiency affects around 1.5% of the general population and up to 10–15% of subjects over 60 years old  (p < 0.001) .After adjustment for age and other causes for B12 deficiency  vs. 71.5 (60.8–75) years old in pSS patients without B12 deficiency), to present more frequently with an iron deficiency (44.4% vs. 16.7%), and to have lower levels of hemoglobin (121 (113–137) vs. 135 (129–142) g/L, The association between pSS and B12 deficiency has been suggested in previous case series and descriptive studies ,9,10. ToIn the control group of this study, the prevalence of B12 deficiency was 11.4%, which is in line with previous studies about patients over 60 years of age [pSS can be associated with other immune diseases, notably pernicious anemia ,23. In tDifferent physiological mechanisms may explain how pSS could lead to B12 deficiency . We demoOur study has a few limitations. We only included hospitalized pSS patients, whose characteristics may differ from outpatients with pSS. It could be interesting to study B12 deficiency in pSS outpatients. However, the majority of pSS patients included in this study were hospitalized for planned explorations following the pSS diagnosis. Thus, they are reasonably similar to outpatients. One could notice that they were older compared to cohort studies and that B12 deficiency is more frequent in older people. However, we noticed that pSS patients with B12 deficiency in our study were younger than pSS patients without B12 deficiency and of similar age than patients described in pSS cohorts from the literature ,25. The The number of pSS patients in our study did not allow us to determine clinical differences according to B12 status. We may hypothesize that some clinical pSS manifestations could be more frequent in pSS patients with B12 deficiency. Indeed, as both pSS and B12 deficiency may cause neuropathy, we may speculate that pSS patients with B12 deficiency could be more prone to suffer from small or large fiber neuropathy .We demonstrated that pSS was independently associated with B12 deficiency, even after excluding associated pernicious anemia, with six times more B12 deficiencies in pSS patients than in controls. This justifies screening and treating B12 deficiency in pSS patients.


There is a lack of robust evidence guiding treatment options for recurrent stress urinary incontinence (SUI) and limited comparative outcome data. The aim of this study was to examine the pattern of surgery for recurrent SUI performed by gynaecologists in the UK and compare subjective success rates.Retrospective review of the British Society of Urogynaecologists database for patients having repeat incontinence procedures (2007–2015) including the number of each procedure and outcome recorded by the International Consultation on Incontinence Urinary Incontinence Short Form (ICIQ-UI-SF) questionnaire. Procedures were compared by year and outcomes by operation. Categorical comparisons were performed using Chi-squared test and numerical comparisons using appropriate non-parametric tests.p < 0.001), 81.6% felt “much better” or “very much better” on Patient Global Impression of Improvement (PGI-I), and 89.3% “cured” or “improved”. MUS, colposuspension and fascial sling showed the best results with regard to the PGI-I score and “change in SUI” (p < 0.001).A total of 2,938 records were obtained (269 were excluded) and 2,164 women (88.8%) had undergone one previous procedure, most commonly retropubic midurethral sling . Pelvic floor exercises were offered to 76.2% women. Urodynamic investigation was carried out in 96.2% women: 76.5% had urodynamic stress incontinence. Repeat MUS was the most common procedure (77.3%), followed by bladder neck injections . Follow-up details were available for 66.1%. Outcome data were poorly reported. Median ICIQ-UI-SF score fell from 16 (0–21) to 0 (0–21) (MUS and BNI were the most common repeat continence procedures. Follow-up data suggest that MUS, colposuspension and fascial sling are most effective. Urinary incontinence occurs in up to 42% of women, with Stress Urinary incontinence (SUI) accounting for about half of the cases, with a significant proportion being “socially disabling” , 2.For women in whom conservative measures are ineffective, a variety of surgical treatments are effective in about 60–90% of cases . Thus, 1Currently, treatment of recurrent SUI is varied and largely based on surgeon’s preference and experience, which may contradict women’s expectations and preferences . There iWe aimed to investigate types of surgery for recurrent SUI in the UK from 2007 to 2015, as recorded on the British Society of Urogynaecologists (BSUG) database and compare their patient-reported outcomes.This study was based on data routinely collected by the BSUG; thus, ethical approval was not required. BSUG is a section of the Royal College of Obstetricians and Gynaecologists (RCOG) that is specifically dedicated to urogynaecology, and was founded in 2001. Although highly encouraged, data input to the BSUG database is currently voluntary in the UK and is only available to subscribing members. As of October 2017, there were 486 members. Surgeons involved included gynaecologists with a special interest in urogynaecology, subspecialist urogynaecologists, and their trainees. Permission to access and use the data was obtained from the BSUG database committee. Data collected contained no patient-identifiable information. However, patients whose data were collected routinely signed a BSUG consent form before their data were collected. No specific funding was obtained for this study. U and Wilcoxon Signed Rank tests for continuous data.Patients recorded as having recurrent stress urinary incontinence (SUI) were extracted from the database. The details of how SUI was diagnosed are not included in the database; they was entered by the host surgeon. In the UK, SUI was usually diagnosed on the basis of urodynamic assessment, as per current NICE guidance, but we were unable to check the diagnosis for individual patients. Data were then cleaned removing duplicate cases, cases that did not have continence procedures and cases that were not recurrent. The total number of procedures and the relative frequency of each procedure were compared by year and the outcomes of each continence procedure type were compared by patient-reported clinical outcomes. These included Patient Global impression of Improvement (PGI-I) , change 2 , of which 269 records were excluded during the data cleaning process. Data were analysed for 2,669 cases, although in 231 cases details of previous surgery were missing. The median age of the patients at the time of surgery was 59 years (range: 20–88) and the median BMI was 28.4 kg/mData on previous procedures were available in 2,438 patients. The number of previous continence procedures was 1 in 2,164 women (88.8%), 2 in 207 (8.5%), 3 in 53 (2.2%) and ≥ 4 in 14 (0.6%) patients  where that data field was complete, of which 135 patients (6.0%) declined it. Urodynamic investigation was performed in 2,280 out of 2,370 cases (96.2%) where that data field was complete, and showed urodynamic stress incontinence (USI) in 1,802 (76.5%), mixed incontinence in 439 (18.6%), detrusor overactivity (DO) in 16 (0.7%) and the results were normal in 80 cases (2.2%).The median (range) number of repeat continence procedures per year was 273 145–500) procedures. There was a non-linear increase across the years, peaking at 500 in 2013 . All measures of improvement  differed according to the type of procedure . The method of follow-up was via the outpatient clinic in 1,573 89.2%), postal questionnaire in 100 (5.7%) and the telephone in 90 cases (5.1%). The follow-up interval was documented in 1,734 (65.0%) cases and was 6 weeks in 649 (37.4%), 3 months in 667 (38.5%), 6 months in 354 (20.4%) and 12 months in 64 cases (3.7%). The PGI-I was reported in 1,616 cases (60.5%). It was “very much better” in 988 (61.1%), “much better” in 331 (20.5%), “a little better” in 124 (7.7%), there was “no change” in 128 (7.9%), it was “a little worse” in 19 (1.2%), “much worse” in 19 (1.2%) and “very much worse” in 7 cases (0.4%). Subjective change of SUI was reported in 1,497 (56.1%). Patients reported being “cured” in 992 (66.3%), “improved” in 344 (22.9%), “no change” in 117 (7.8%), “worse” in 21 (1.4%) and that SUI was “never present” in 23 cases , repeat procedures were 77.3% MUS, 10.2% BNI and 5.7% colposuspensions. Jonsson Funk et al. reported corresponding proportions of 70.5%, 20.1% and 6.5% respectively in the USA [Data from the USA, Taiwan and Canada show that MUS are the most commonly performed secondary continence procedures, with percentages ranging between 50 and 80% , 7, 14. One of the limitations of this analysis is the high proportion of MUS as the repeat procedure (77.3% of our sample). While we can be reasonably confident of the data for these procedures, we should apply caution in the comparison between these and the other procedures, because they represent 10% or less of the whole cohort. Having said this, the outcomes do broadly reflect the relative efficacy of these procedures when performed as primary surgery.This was a UK-wide study, based on a national database, whose validity has been demonstrated (53) and included a large population, with the benefit that the success of repeat continence procedures was recorded with validated patient-reported outcomes. These have been validated against other tools measuring subjective patient outcomes . HoweverAnother factor to bear in mind when interpreting these data is that the BSUG database did not comprehensively record whether patients had SUI alone, or mixed UI. Also, there was no data field to record if the underlying aetiology was urethral hypermobility or intrinsic sphincter deficiency. The lack of aetiology does limit interpretation somewhat, although the fact that the majority of cases involved MUS, which is known to be effective regardless of aetiology, mitigates against this , 19.Success varied by the type of procedure performed, with MUS, colposuspension and fascial slings having comparable results and overall were more effective for recurrent SUI than BNI or anterior repair and bladder neck buttress suture Fig. ; Table 3Studies have shown a wide range of success rates of about 40–100% for MUS, colposuspension and fascial slings .In a recent study comparing outcomes of different repeat continence procedures, Cerniauskiene et al. have also reported that colposuspension and MUS have comparable and good success rates .Studies have reported success rates for colposuspension of 55–93%, with subjective measures generally reporting higher success rates than objective measures –25. A 20Lee et al. reported a success rate of secondary fascial slings of 65.7% using patient-reported outcomes and no reoperation as a definition of success . Amaye-OGaddi et al. reported a failure rate of BNI as a repeat continence procedure of 38.8%, i.e., success of 61.2%, where the definition of failure included both subjective and objective measures . Futyma Despite the current media and public concerns about synthetic mesh implants, MUS remained the most commonly performed procedure for recurrent SUI in the UK (until the temporary suspension enforced in 2018), with a median yearly proportion of 76.8% (range: 62.3 to 85.4%).Overall, repeat MUS, colposuspension and fascial sling procedures appear to be the best secondary procedures, based on this large cohort. Admittedly, there are few RCT data, but given the current concerns regarding mesh, these data are important to help clinicians to advise and counsel patients while RCT data from ongoing studies are awaited.


Background: Our study aims to perform a meta-analysis of benefits and risks associated with the use of non-vitamin K oral anticoagulants (NOAC) versus vitamin K antagonists (VKA) in patients with a percutaneous coronary intervention (PCI) with a particular focus on the combination type: dual vs. dual antithrombotic therapy (DAT: NOAC + single antiplatelet therapy (SAPT) vs. DAT: VKA + SAPT), dual vs. triple antithrombotic therapy ) or triple vs. triple antithrombotic therapy (TAT: NOAC+DAPT vs. TAT: VKA+DAPT). Methods: PubMed, EMBASE, and Cochrane databases were searched to identify randomized controlled trials comparing antithrombotic regimens. Four randomized studies  were included. The primary outcome was the composite of major bleeding defined by the International Society on Thrombosis and Hemostasis (ISTH) and clinically relevant bleeding requiring medical intervention (CRNM). Secondary outcomes included all-cause mortality, major adverse cardiovascular events (MACE), myocardial infarction (MI), stroke, and stent thrombosis (ST). Results: Combination strategies with NOACs were associated with reduced risk of major bleeding events across different combination strategies as compared to VKA, with the most significant risk reduction when DAT was compared with TAT, namely DAT with NOAC + SAPT was associated with a 37% relative risk reduction (RRR) of major bleeding events as compared to TAT with VKA + DAPT . The reduction of major bleeding risks is a class effect of NOACs. Combination strategies of NOACs vs. VKAs resulted in a comparable risk of MACE, MI, stroke, ST, or death. Conclusions: Antithrombotic combinations of NOACs (as DAT or TAT) are safer than VKAs with respect to bleeding risk and result in a satisfactory efficacy with no increase of ischemic or thrombotic events in patients undergoing PCI. Atrial fibrillation (AF) is a global health problem and a common arrhythmia that increases the risk of thromboembolic complications, including stroke and other cardiovascular events . ApproxiRecently, randomized controlled trials (RCTs) have been conducted to compare the safety and efficacy of NOACs versus VKA as a combination with single or dual antiplatelet agents (SAPT/DAPT) in patients with AF undergoing PCI or presenting with ACS ,11,12,13This meta-analysis was performed and reported according to established methods . We searThe primary safety outcome was the composite of major bleeding defined by the International Society on Thrombosis and Hemostasis (ISTH) and clinically relevant bleeding requiring medical intervention (CRNM). The primary efficacy outcome was “trial-defined major adverse cardiovascular events (MACE),” which followed the definition of MACE in the respective trials . SecondaI2 index and a p-value. Percentages lower than 25% (I2 = 25), 50% (I2 = 50), and 75% (I2 = 75) correlate to low, medium, and high heterogeneity, respectively [p-value of <0.05 was considered significant. The number needed to prevent major bleedings and the number needed to cause harm by increasing the risk of stent thrombosis were calculated according to the established statistical methods.Variables are reported as numbers or percentages as appropriate. Risk ratios (RR) were computed from individual studies and pooled according to the inverse variance weighted model with 95% confidence intervals (CIs) using RevMan  as appropriate . We asseectively . The metWe performed a sensitivity analysis by including subgroups for the type of comparison , and the type of NOAC (dabigatran vs. rivaroxaban vs. apixaban vs. edoxaban).A total of 237 studies were screened for eligibility, out of which 4 Phase 3–4 RCTs assessing the strategy of NOAC with either a P2Y12 inhibitor or DAPT vs. VKA (primarily represented by warfarin) with a P2Y12 inhibitor or DAPT in AF patients following PCI were included in the final analysis . All fouFollow-up ranged from 6 to 14 months. Of the P2Y12 inhibitors, clopidogrel was the most commonly used (92%), while ticagrelor and prasugrel were used in 7% and 1% cases, respectively. Details of the design of the included studies are listed in p = 0.001; I2 = 86% ISTH major or CRNM bleeding events occurred in 14.6% in the DAT (NOAC + SAPT) group vs. 23.1% in the TAT (VKA + DAPT) group. A combination strategy of DAT (NOAC + SAPT) was therefore associated with a 37% relative risk reduction (RRR) in ISTH major or CRNM bleeding events as compared to TAT. VKA + DAPT; RR 0.63; 95% CI, 0.50–0.80; p = 0.57; I2 = 0%, MACE occurred in 9.0% in the DAT (NOAC + SAPT) group vs. 8.7% in the TAT (VKA + DAPT) group, resulting in no statistical difference in the risk of MACE between the groups. RR 1.04; 95% CI, 0.91–1.19; p = 0.11; I2 = 0%, Myocardial infarction occurred in 3.6% in the DAT (NOAC + SAPT) group vs. 3.0% in the TAT (VKA + DAPT) group, resulting in no statistical difference in the risk of myocardial infarction between the groups. RR 1.21; 95% CI, 0.96–1.52; p = 0.84; I2 = 6%, Stroke occurred in 1.1% in the DAT (NOAC + SAPT) group vs. 1.2% in the TAT (VKA + DAPT) group, resulting in no statistical difference in the risk of stroke between the groups. RR 0.96; 95% CI, 0.65–1.42; p = 0.29; I2 = 0%, All-cause death occurred in 3.9% in the DAT (NOAC + SAPT) group vs. 3.5% in the TAT (VKA + DAPT) group, resulting in no statistical difference in the risk of stroke between the groups. RR 1.12; 95% CI, 0.91–1.38; p = 0.17; I2 = 0%, Stent thrombosis (ST) occurred in 1.3% in the DAT (NOAC + SAPT) group vs. 0.9% in the TAT (VKA + DAPT) group, resulting in no statistical difference in the risk of ST between the groups. RR 1.38; 95% CI, 0.87–2.20; p < 0.001; I2 = 56%, ISTH major or CRNM bleeding events occurred in 14.6% in the NOAC group vs. 21.1% in the VKA group. NOAC use was associated with a 31% RRR in ISTH major or CRNM bleeding events as compared to VKA. RR 0.69; 95% CI, 0.62–0.77; p = 0.73; I2 = 0%, MACE occurred in 8.4% in the NOAC group vs. 8.2% in the VKA group, resulting in no statistical difference in the risk of MACE between the groups. RR 1.02; 95% CI, 0.91–1.14; p = 0.61; I2 = 0%, Myocardial infarction occurred in 3.3% in the NOAC group vs. 3.2% in the VKA group, resulting in no statistical difference in the risk of myocardial infarction between the groups. RR 1.05; 95% CI, 0.87–1.27; p = 0.68; I2 = 6%, Stroke occurred in 1.1% in the NOAC group vs. 1.2% in the VKA group, resulting in no statistical difference in the risk of stroke between the groups. RR 0.93; 95% CI, 0.66–1.31; p = 0.30; I2 = 0%, All-cause death occurred in 3.6% in the NOAC group vs. 3.3% in the VKA group, resulting in no statistical difference in the risk of stroke between the groups. RR 1.10; 95% CI, 0.92–1.31; p = 0.44; I2 = 0%, ST occurred in 0.95% in the NOAC group vs. 0.82% in the VKA group, resulting in no statistical difference in the risk of ST between the groups. RR 1.17; 95% CI, 0.79–1.74; There was no difference in the direction of the effect of NOACs vs. VKA on the risk of bleeding events, but the magnitude of the effect varied for different combination strategies, NOAC + P2Y12 inhibitor was associated with a 33% RRR in ISTH major or CRNM bleeding events as compared to VKA + P2Y12 inhibitor. RR 0.67; 95% CI, 0.52–0.88; p = 0.003, Use of NOAC + P2Y12 inhibitor + aspirin was associated with a 28% RRR in ISTH major or CRNM bleeding events as compared to VKA + P2Y12 inhibitor + aspirin. RR 0.72; 95% CI, 0.62–0.83; p < 0.001; I2 = 0%, Use of NOAC + P2Y12 inhibitor was associated with 37% RRR in ISTH major and CRNM bleeding events as compared to VKA + P2Y12 inhibitor + aspirin. RR 0.63; 95% CI, 0.49–0.81; p < 0.001; I2 = 0% Use of The risk of ST did not statistically differ between NOAC vs. VKA in none of the three different combination strategies. Nevertheless, there was a trend toward a higher risk of ST when DAT with NOAC was compared against TAT with VKA The risk of MACE did not statistically differ between NOAC vs. VKA in none of the three different combination strategies .The risk of death did not statistically differ between NOAC vs. VKA in none of the three different combination strategies .The direction and the magnitude of the effect did not change after the exclusion of single studies, The direction and the magnitude of the effect did not change after the exclusion of single studies . The strOur meta-analysis in over ten thousand patients confirms that NOACs as part of diverse antithrombotic combinations are safer than VKAs with respect to major bleeding events. The magnitude of the effect was larger when NOACs were used as part of a DAT than TAT; NOACs as part of DAT were associated with a 37% RRR of major bleeding events as compared to VKA as a part of TAT. The RRR was 31% when TAT with NOAC was compared with TAT with VKA. The homogeneity in the effect of NOACs underscores their role in improving patients’ safety in the setting of AF and PCI.Of special interest, a combination of NOAC with SAPT/DAPT did not increase the risk of MACE, MI, stroke, ST, or death as compared to VKA with SAPT/DAPT in patients undergoing PCI. The neutral effect on mortality of NOAC + SAPT in comparison to VKA + DAPT might be a consequence of reduced mortality due to lower bleeding events. This is a very important finding as single studies were underpowered to make conclusions about the efficacy issues.The optimal antithrombotic strategy and especially its duration for patients with AF undergoing PCI or presenting with an ACS is still a matter of debate. DAT or TAT aims at effectively preventing thromboembolic events with an acceptable risk of bleeding complications. The pivotal clinical trials on antithrombotic therapy were designed to test efficacy in preventing thromboembolic events rather than reduction of bleeding ,20,21. IAccording to the latest consensus document on the management of antithrombotic therapy in AF patients presenting with ACS and/or undergoing PCI, TAT should be only used in patients at low bleeding risk and a very short duration (one week) of such a combination should be preferred in those at high bleeding risk . An issun = 21 vs. n = 8 in our meta-analysis), which most probably was based on authors personal communication, as the data were not available. Additionally, the meta-analysis by Gargiulo et al. [n = 21 of ST was used in both meta-analyses for the DAT group, irrespectively, whether apixaban was used with P2Y12 inhibitor or apixaban/warfarin with P2Y12 inhibitor. Another major issue is the fact that one-third of the patients in the AUGUSTUS study did not receive a stent at the index event, and therefore were not at risk for ST. In the two previous meta-analyses, the ST data from the overall cohort was used. In contrast, we used the ST data from the AUGUSTUS population receiving a coronary stent, which might result in more robust but diverging results.Several fundamental questions surrounding the risk of ST while treating patients with a NOAC and P2Y12 inhibitor and omitting aspirin also during the first weeks after stent implantation remain a matter of debate. Our meta-analysis shows that when aspirin is omitted and only DAT with NOAC+SAPT is used early after elective PCI or ACS with PCI , occurred early after PCI, and was numerically less frequent in patients receiving apixaban than VKA . A trendAnother critical question that needs to be answered is the optimal combination of NOAC with P2Y12 inhibitors i.e., clopidogrel, ticagrelor, or prasugrel in terms of safety, but also in terms of risk of thrombotic events . ClopidoFurthermore, variability in ADP-induced platelet aggregation under treatment with clopidogrel can be overcome with prasugrel and ticagrelor . It shouAnother critical issue that should be discussed here is the significant differentiation of the duration of TAT between stable CAD and ACS. The guidelines and consensus documents recommend clearly short TAT for stable CAD and longer TAT for ACS. In the PIONEER-AF PCI, RE-DUAL PCI, and ENTRUST-AF PCI, around 50% participants were presenting with ACS, in the AUGUSTUS trial this proportion was highest (60%). Moreover, in the AGUSTUS trial, almost 24% of patients had medically managed ACS with no clear indication for TAT. Moreover, according to the latest update, TAT with NOAC is recommended only for one month after elective PCI in patients with high thromboembolic risk and low risk of bleeding and for 3–6 months after ACS . In the Another interesting point that could potentially influence the risk of bleeding is the dose adjustment of a drug in patients with renal insufficiency. Rivaroxaban was reduced from 15 mg to 10 mg once daily for patients with a creatinine clearance of 30 to 50 mL per minute in the PIONEER-AF trial. It is noteworthy that this study tested two lower rivaroxaban doses (15 mg and 2.5 mg) as an alternative to approved drug regimen in AF patients (Rivaroxaban 20 mg when combined with P2Y12 inhibitor). Edoxaban was reduced to 30 mg instead of 60 mg once daily if moderate or severe renal impairment was observed  in the ENTRUST trial ,14. In tA novelty in our meta-analysis is the inclusion of all NOAC types as a part of antithrombotic therapies for AF with ACS/PCI and the unique inclusion of AUGUSTUS population receiving stent implantation. Previously published meta-analyses included studies comparing DAT vs. TAT irrespective of the oral anticoagulant type in the comparator arm ,29. CurrThere are some limitations of this study. Most importantly, different durations of TAT use and of follow-up, as well as differences in patients’ characteristics between the trials underline the heterogonous nature of included trials. Nevertheless, the sensitivity analyses underscored the robustness of the main finding.This meta-analysis shows that NOACs as a part of DAT or TAT is safer than VKA with respect to bleeding risk with a comparable risk for major adverse ischemic events in patients undergoing PCI. Nevertheless, the optimal antithrombotic regimen with a NOAC should be cautiously selected based on a number of considerations like acute vs. elective procedure, individual bleeding risk, and thromboembolic risk.Currently, vitamin K antagonists (VKA) and non–vitamin K antagonist oral anticoagulants (NOAC) are used to prevent ischemic stroke related to atrial fibrillation (AF).Recently, randomized controlled trials (RCTs) have been conducted to compare the safety and efficacy of NOACs versus VKA as a combination with single or dual antiplatelet agents (SAPT/DAPT).The evidence regarding benefits and risks associated with the use of all available NOACs  versus VKA with single (SAPT) or dual antiplatelet therapy (DAPT) in AF patients following elective percutaneous coronary intervention (PCI) or acute coronary syndrome (ACS) with stenting has not been fully investigated yet.Antithrombotic combinations of NOACs (as part of TAT or DAT) are safe and reduce the risk of bleeding events in a significant and relevant magnitude as compared to VKA (as part of DAT or TAT).The efficacy of antithrombotic combinations of NOACs (as part of TAT or DAT) is satisfactory and results in a comparable risk of major ischemic events as VKA (as part of DAT or TAT).