We assessed the fire trends from Moderate Resolution Imaging Spectroradiometer (MODIS) (2003–2016) and Visible Infrared Imaging Radiometer Suite (VIIRS) (2012–2016) in South/Southeast Asia (S/SEA) at a country level and vegetation types. We also quantified the fire frequencies, anomalies and climate drivers. MODIS data suggested India, Pakistan, Indonesia and Myanmar as having the most fires. Also, the VIIRS-detected fires were higher than MODIS (AQUA and TERRA) by a factor of 7 and 5 in S/SEA. Thirty percent of S/SEA had recurrent fires with the most in Laos, Cambodia, Thailand, and Myanmar. Statistically-significant increasing fire trends were found for India (p = 0.004), Cambodia (p = 0.001), and Vietnam (p = 0.050) whereas Timor Leste (p = 0.004) had a decreasing trend. An increasing trend in fire radiative power (FRP) were found for Cambodia (p = 0.005), India (0.039), and Pakistan (0.06) and declining trend in Afghanistan (0.041). Fire trends from VIIRS were not significant due to limited duration of data. In S/SEA, fires in croplands were equally frequent as in forests, with increasing fires in India, Pakistan, and Vietnam. Specific to climate drivers, precipitation could explain more variations in fires than the temperature with stronger correlations in Southeast Asia than South Asia. Our results on fire statistics including spatial geography, variations, frequencies, anomalies, trends, and climate drivers can be useful for fire management in S/SEA countries. Of the different natural factors, drought-induced fires due to El Niño-Southern Oscillation (ENSO) in southeast Asia and more specifically Indonesia are most common7. In addition to these natural factors, most of the fires in S/SEA are human initiated. For example, fire is used as a land clearing tool during the slash and burn agriculture in the Eastern Ghats and northeast India10, Chittagong hill tracts of Bangladesh11, Myanmar13, Sarawak in Malaysia14 Philippines15, Jambi, Sumatra and others in Indonesia17, northern Thailand18, northern Laos20, Cambodia21, and northern Vietnam22. Fires are also extensively used for clearing land for oil palm expansion in Indonesia24. In addition, most of the countries in S/SEA are agrarian where farmers use fire for the burning of agricultural residues to clear the land for the next crop28.Vegetation fires are a common phenomenon in many different regions of the world including South/Southeast Asia (S/SEA). Fuel type, topography, climate, weather, lightning, and other factors govern fire occurrence and spread29. Forest fires can result in the loss of biodiversity including the disruption of soil microbial processes during vegetation combustion and alter biogeochemical cycles31. Fires can create landscape disturbance resulting in a mosaic of burned and unburned forest patches, leaving complex heterogeneous patterns across the landscape32. The resulting landscape heterogeneity can further influence successional processes, which in turn may affect the spatial spread of subsequent fires33. In addition, vegetation fires can release large greenhouse gas emissions such as CO2, CO, NOx, CH4, non-methane hydrocarbons and other chemical species including aerosols impacting radiative budget, air quality and health at both local and regional scales38. Further, the pollutants can be transported over long distances impacting not only local climate, but also regional climate40. Considering these impacts, characterizing fires in different regions of the world is important, including in S/SEA countries. In particular, quantifying vegetation fire trends and anomalies can help in identifying countries where fires have been increasing or decreasing and subsequently relating the fire occurrences to driving factors such as climate, topography, vegetation and anthropogenic factors. An in-depth analysis of the type of vegetation burnt, fire intensities and also timing can help inform fire management at different spatial scales.The impacts of fire on ecosystems vary as a function of severity and management41. Some of the most commonly used satellite fire data sets include active fire detection and burnt area mapping products. In addition to the Earth Observing System Moderate Resolution Imaging Spectroradiometer (MODIS) fire products available since 2002 (http://modis-fire.umd.edu/index.php), fire products from the Joint Polar Satellite System Visible Infrared Imaging Radiometer Suite (VIIRS) data have been readily available since 2012 (http://VIIRSfire.geog.umd.edu/). These satellite fire data records provide a unique opportunity to assess fire trends in different regions of the world.Specific to mapping and monitoring of fires and related vegetation changes, remote sensing technology has been playing a vital role over the past several decades42 thus, the potential of the other  sensors designed for their continuity should be explored. The results on the vegetation fire trends can help to address fire management and mitigation related issues including drivers in different countries.Using the above satellite fire data, we address the following questions specific to vegetation fire trends in S/SEA countries: Are vegetation fires increasing or decreasing in Asian countries? Which of those countries show the highest vegetation fire concentration? Are the vegetation fire trends consistent between the MODIS and VIIRS data? How do fire trends vary across land cover types  How does fire radiative power (FRP), which is an indicator of fire intensity, vary across different vegetation types and what are the trends? We address these questions using both the MODIS and VIIRS fire datasets. Understanding the similarities and discrepancies between the MODIS and the VIIRS is important as their spatial resolutions are different. Also, the MODIS sensor on Aqua and Terra satellites are nearing the end of their liveshttp://modis-fire.umd.edu/index.php). The active fire dataset is at a 1 km nominal spatial resolution; however, it can detect flaming fires as small as 50 m2 under ideal observing conditions41. The MODIS fire product provides the latitude and longitude of the fire pixels, the date and time of the fire detection, FRP including confidence levels of fire detection. Specific to this study, we used fires with confidence greater than forty percent. The FRP parameter is a quantitative measure of radiant heat output commonly used to approximate fire intensity, which is proportional to its combustion rate and smoke emissions45.We used the latest collection 6 MODIS active fire products (MCD14ML) from the University of Maryland . In this study, we specifically used the VIIRS 375 m active fire product (VNP14IMG) reprocessed by NASA. The algorithm for this product builds on the well-established MODIS Fire and Thermal Anomalies product using a contextual approach to detect thermal anomalies41. Due to its higher spatial resolution, the VNP14IMG active fire product captures more fire pixels than MODIS MCDML product46. The confidence information is given in the data at three different levels, i.e., low, nominal and high. We used nominal and high level sorted fire data in this study. Specific to the FRP, the VNP14IMG FRP is calculated through a combination of both VIIRS 375 m and 750 m data. The former is used to identify fire, cloud (solid blue), water (dashed blue), and valid background pixels. The co-located M13 channel radiance data (750 m) coinciding with fire pixel and valid background pixels are used in the FRP calculation (https://viirsland.gsfc.nasa.gov/PDF/VIIRS_activefire_375m_ATBD.pdf).The first VIIRS instrument was launched in October 2011 aboard the Suomi-National Polar-orbiting Partnership (S-NPP) satellite. The VIIRS instrument carries two separate sets of multi-spectral channels providing global coverage at both 375 m and 750 m nominal resolutions every 12 h or less depending on the latitude. The VIIRS satellite incorporates fire-sensitive channels, including a dual-gain, high-saturation temperature 4 µm channel enabling active fire detection and characterization. Active fire products based on the 375 m (I-bands) and 750 m (M-bands) VIIRS data are currently being generated43. Fire radiative energy (FRE) is therefore FRP integrated over time and space, with units of mega joules (MJ). For the VNP14IMG product, 375 m mid-IR (I4) radiance data are not used for FRP retrieval due to frequent saturation/folding and incorrect assignment of quality flags during L1B onboard data aggregation46. Instead, FRP is retrieved using co-located dual-gain mid-IR M13 channel (750 m) for all fire pixels detected using the 375 m data. Both MODIS and VIIRS FRP (MW) retrievals are use the47 approach in which FRP is approximated as,−8 W m−2 K−4), τ4 is the atmospheric transmittance of the 4-μm channel, and a is a sensor-specific empirical constant .FRP is the rate of radiative fire energy released per unit time, measured in megawatts47, the strength of fires48 and aerosol emissions50. In this study, we used FRP as an indicator of the intensity of fires. We used trend analysis to infer if the fire intensities increased or decreased over a period in different ecosystems and countries. Details about the trend analysis are given below.FRP measurements have been previously related to the amount of biomass burnt52. We acquired the product from the ESA-CCI website for 2012–2015 (http://maps.elie.ucl.ac.be/CCI/viewer/). Because no data are available beyond 2015, we used 2015 data for 2016 in order to match it to the 2012–2016 active fire record analyzed in this study. Subsequently, we simplified the land cover classes creating five broad groups including: croplands , forest , shrubland, grassland/sparsely vegetated , and other . Specific to Indonesia, the forests also include peatlands. Land cover information was then extracted for each corresponding MODIS and VIIRS active fire datasets and used in the trend analysis.We used the latest European Space Agency Climate Change Initiative 300 m land cover product version 2.0.7 derived from a time series of MEdium Resolution Imaging Spectrometer (MERIS) surface reflectance data53. Sen’s slope estimator, which gives the trend magnitude, complemented our analysis54. The seasonal trend test is used since it assesses the data for different seasons  over a period.We used both the MODIS Aqua and Terra (2003–2016) and VIIRS fire data (2012–2016) and vegetation types retrieved from the MERIS data to assess the fire trends in S/SEA countries. For the trend analysis, we applied the non-parametric seasonal Mann-Kendall statistical test, which doesn’t require a normally-distributed sample. The method is less influenced by outliers since its calculation is based on the sign of the differences, and not directly on the variable values. Another advantage of this test is its low sensitivity to abrupt breaks due to in-homogenous time series55. The nonparametric test is used to analyze the existence of a monotonically increasing or decreasing trend. According to this test, the null hypothesis H0 states that the deseasonalized data  is a sample of n independent and identically distributed random variables. The alternative hypothesis H1 of a two-sided test is that the distributions of xk and xj are not identical for all k, j ≤ n with k ≠ j. The test statistic S, which has mean zero and variance is given as,sgn denoting the signum function, and where xj and xk are values  in years j and k respectively; n is the size of the data series. The variance of S, denoted by [VAR (S)], assumes the value of 1 when xj − xk > 0; 0 when xj − xk = 0; and −1 when xj − xk < 0, and is defined as,t is the extent of any given tie, and denotes the summation over all ties. In cases, where sample size n > 10, the standard normal variable Z is computed as,The Mann Kendall test consists of comparing each value of the data series with the subsequent values, calculating the number of times that the remaining terms are greater than the analyzed value1- α/2, obtained from the standard normal cumulative distribution tables.Positive values of Z indicate increasing trends, while negative values of Z show decreasing trends. When testing either increasing or decreasing monotonic trends at the significance level, the null hypothesis was rejected for an absolute value of Z greater than Z54 slope. The slope estimates of N pairs of data are first computed by,j and xk are data values at times j and k (j > k), respectively. The median of the N values of Qi represents the Sen’s estimator of slope. If N is odd, the Sen’s estimator is computed asIn addition, we also calculated the Sen’smed is tested with a two-sided test at the 100 (1 − α) % confidence interval and the true slope may be obtained with the non-parametric test57. The confidence interval (Cα) is given as,The QX is the active fire count for specific year and country, and Using the MODIS active fire data from 2003–2016, we computed the standardized anomalies (SD) for different countries as,We also assessed the long-term relationship between the fires and the corresponding precipitation and temperature datasets. Specifically, we used the 4.01 release of the Climate Research Unit (CRU) CY dataset available from 1901–2016. The dataset consists of country averages at a monthly, seasonal and annual frequency, for ten different variables. For the study, we used a mean monthly temperature and precipitation data from CRU and mean monthly fires from MODIS (2003–2016) for different countries to assess the fire-climate relationships.Results from averaging the MODIS fire data from 2003–2016 showed India with the highest number of annual fire counts of 73836 followed by Pakistan (8761), Nepal (3049), Bangladesh (3029) and the lowest in Afghanistan (298). Averaging the VIIRS fire data from 2012–2016 suggested India having the highest number of annual fire counts of 551649, Pakistan (53998), Nepal (32018), Bangladesh (10972), Sri Lanka (9185), Bhutan (1411), and least for Afghanistan (1075) , followed by Myanmar (70084), Laos (39666) and the lowest for Brunei (75). VIIRS detected fires (2012–2016) showed the highest number of fires for Indonesia (412080) followed by Myanmar (368533), Cambodia (199646), others and least for Singapore (32).46. The results can have significant implications concerning increased smoke release and contribution to GHG emissions and aerosols.Trends in vegetation fires in South and Southeast Asia countries retrieved using VIIRS 375 I-band data 2012–2016) are shown in Fig. 012–2016 Spatially-gridded fire return frequencies at 10-minute grid intervals for the entire S/SEA from 2003–2017 are shown in Fig. p) values  and Bhutan (75.56%) had the highest percentage of fires in forest land cover types which are mostly human initiated. The primary causes include agricultural fires spreading from farms to forests, abandoned cooking fires, carelessness due to smokers, firewood collectors60. In Afghanistan, 43.75% of total fires were in grasslands/sparsely vegetated category mostly in the Hindu Kush alpine meadow as well as the Ghorat-Hazarajat alpine meadow. In Bangladesh (42.17%) and Sri Lanka (22.39%) had relatively higher percent fires were found in shrublands suggesting degraded nature of forests which are highly vulnerable to fires , MODIS fire data has been partitioned into different land cover types to assess the major land cover types with the highest percentage of fires. In South Asia, Pakistan (91%), Sri Lanka (59.70%), and India (47.92%) had the highest percentage of fires in croplands mainly attributed to agricultural residue burning. Most of the agricultural fires in India and Pakistan are due to rice-wheat and sugarcane crop residue burning in the Indo-Ganges regionres Fig. .Figure 462, whereas Malaysia (62.65%), Cambodia (61.94%), Brunei (58.37%) and Myanmar (57.82%) had the highest percentage of fires in forests mainly due to slash and burn agriculture, and timber harvesting. Brunei also had the highest percent of fires in grassland/sparsely vegetated category, whereas, Laos (37.88%), Myanmar (25.95%), Vietnam (25.33%) and the Philippines (23.58%) had the highest percentage of fires in the shrublands category.In Southeast Asia, Thailand (51.75%), followed by Timor Leste (48.75%) and the Philippines (44.99%) had the highest percentage of fires in croplands due to rice, maize and sugarcane agricultural residue burningWe also assessed the fire and FRP trends in different land cover types . MERIS (300 m) data has been used for vegetation partition into four major categories, i.e., croplands, forests, grasslands, and shrublands. Increasing fire trends in croplands are found for India, Pakistan and Vietnam attributed to agricultural residue burning whereas decreasing trend has been found for Malaysia. In the case of forests, except Cambodia which had a positive trend, Afghanistan, Thailand, Pakistan, and Sri Lanka showed a negative trend. India, Pakistan, Indonesia, and Cambodia showed a positive fire trend in grasslands, whereas, Maldives, Nepal and Sri Lanka showed a negative trend. Further, in the case of shrub lands, Pakistan and India showed a positive trend whereas Sri Lanka, Timor Leste and Myanmar showed a negative trend. In the case of FRP, positive trends were found for forests in the Philippines and grasslands in Thailand. For rest of the countries, FRP trends in different land cover types were not significant.Except for the Philippines which showed an increasing trend in fires as well as FRP, for all other countries, the VIIRS fire data trends were not significant. We attribute the insignificant statistical trends from VIIRS to short period (2012–2016) of available data .VIIRS data did not show significant trends at a country level as well as across different land cover types. However, we found a decreasing trend in fires for Laos croplands, an increasing trend in Thailand forests and a decreasing trend in Afghanistan grasslands  values.Fire management in S/SEA countries is an increasingly complex and challenging problem that requires detailed information about the occurrence, geographic variation, trends, anomalies, and main drivers of fire within the region. Our current study provides a comprehensive analysis of the above metrics. In South Asia, India had the highest number of annual fires followed by Pakistan and others whereas in Southeast Asia, Indonesia had the highest followed by Myanmar, Laos, etc. Frequency analysis was useful to identify hotspots of grid cells having recurrent fires. Frequency analysis suggested nearly 30.5% of South/Southeast Asia with recurrent fires every year within a fifteen year time period with highest percentage in Laos (95.82%), Cambodia (78.7%), Thailand (75.0%), and Myanmar (75.1%). The frequency data can be integrated into emission models to address biomass burning impacts including transboundary air pollution. Of the different countries, increasing trend in fires were found for India (p = 0.004), Cambodia (p = 0.001), and Vietnam (p = 0.050) and decreasing trend for Timor Leste (p = 0.004). In case of FRP, Afghanistan and Sri Lanka had a negative slope value of 0.04 and 0.049 whereas Cambodia, India, and Pakistan had a positive slope with highly significant , Pakistan (p = 0.047), and Vietnam (p = 0.004) where they are increasing. Agricultural fires can be controlled through stringent and enforced policies and by promoting incorporation of residues into the soil rather than burning. Specific to forest fires, Nepal (82.84%) and Bhutan (75.56%) had the highest percentage of fires in forest land cover types which are mostly human initiated. In the hilly regions, human dependence on forests is significant, thus developing sustainable forest management plans involving local people (community based fire management) should be the priority. Also, our results suggest increasing shrub land fires in India (p = 0.054) and Pakistan (p = 0.073) and we attribute these to forest degradation and fragmentation.We also characterized anomalies in fires. In India, relatively high positive anomalies were found during 2009, 2012 and 2016 whereas negative anomalies during 2003. For Cambodia, high positive anomalies are found during 2013 and 2015. The anomaly statistics can be used to infer drivers of fires. Also, our results suggests precipitation as an important fire suppressing agent in Southeast Asian countries compared to the South Asian countries. For example, in the Philippines, 55% of variations in fires could be explained by the precipitation; similarly, 53% in Indonesia, 40% in Thailand, 41% in Vietnam, 38% percent in Cambodia, and 17% in Timor Leste. Thus, integrating precipitation data into fire-behavior models for quantifying fire risk can yield promising results. Collectively, our findings highlight essential fire metrics useful for fire management and mitigation in S/SEA countries.Supplementary Data 1


In order to maximize In vitro fertilization (IVF) success rates in advanced- age patients, it has been suggested to favor the use of intracytoplasmic sperm injection (ICSI) over conventional insemination (CI), with the notion that ICSI would serve as a tool to overcome interference in sperm oocyte interaction and sperm oocyte penetration issues that can be related to maternal age and are not due to sperm abnormalities. We therefore aim to evaluate the role of ICSI in the treatment of non-male factor infertile patients aged ≥35 in terms of fertilization and top-quality embryo rates.In this retrospective cohort study, data were collected and analyzed for all patients with non-male factor infertility, aged ≥35 treated, undergoing their first IVF cycle attempt with 6 or more oocytes yield, in whom a 50% ICSI-CI division was performed.P < 0.001). The top quality embryo rate was 62.8% following ICSI compared to 45.5% following CI (P < 0.001). Subdividing the study population to two age groups revealed that the above differences remained significant in patients aged 35–39 yrs., whereas in those aged 40–45 yrs., the differences were non-significant but still inclined in favor of ICSI.Five hundreds and four oocytes were collected from 52 eligible patients. Overall, 245 oocytes underwent ICSI and 259 oocytes underwent CI. The fertilization rate was 71.0% following ICSI, compared to 50.1% in the CI treated oocytes (This study favors the use of ICSI in the older IVF population in order to increase both the fertilization rate and the number of top quality embryos that result per IVF cycle. Further studies are needed to establish our observations and use ICSI as the preferred approach to overcome egg sperm abnormal interactions related to advanced maternal age. Intracytoplasmic sperm injection (ICSI) was developed for the treatment of couples with severe male-factor infertility to enable fertilization and pregnancy rates regardless of semen characteristics. Since its introduction , ICSI haIn addition to severe male factor infertility, ICSI is currently being applied in patients with fertilization failure or low fertilization in previous standard in vitro fertilization (IVF) procedures. Morton et al.  reportedThus, although ICSI provides a powerful tool to overcome previous reduced or total failure of fertilization in couples with unexplained infertility, its benefit for other types of infertility remains questionable. Likewise, opinions are divided regarding the notion that ICSI will be used as the procedure of choice in all couples requiring assisted reproduction techniques in order to prevent up to 30% rate of fertilization failures in the first conventional IVF attempt .Age alone has a detrimental impact on fertility, mostly due to the significant increase in aneuploidy and spontaneous abortion rates with advanced maternal age . MoreoveIn 2004, the Cochrane Group dealt with the issue of whether ICSI improves live-birth rate in comparison with CI in couples with non-male factor subfertility . It was We reviewed the computerized files of all consecutive women admitted to our IVF unit during 10-years period, and reached the ovum pick-up (OPU) stage. The elimination of bias in this selection, for the purposes of this study, was achieved by including only patients’ aged ≥35, undergoing their first IVF cycle attempt for non-male factor infertility . The preAll the accepted protocols for ovarian stimulations were included. The selection of type of controlled ovarian hyperstimulation (COH) protocol used was the decision of the treating physician and largely dependent on the fashion at the time. The oocytes retrieved from each patient were divided into two groups, those that underwent CI and those undergoing ICSI. Fertilization was confirmed by observation of two pronuclei 18 to 19 h after IVF insemination or ICSI. Total fertilization rate (per group) was calculated as the total number of zygotes divided by the total number of oocytes. Embryos classification was based on the individual embryo scoring parameters according to pre-established definitions . While aData were collected and analyzed for all patients aged ≥35 treated for non-male factor infertility in whom 6 or more oocytes were retrieved and a 50% ICSI-CI division was performed in their first IVF cycle attempt. While the ICSI\CI division policy was applied for all non-male factor infertility patients undergoing their first IVF cycle, we selected to include only those achieving a minimum of 6 oocyte, in order to enable a feasible sibling oocyte comparison.p value of less than 0.05 was considered significant.Results are presented as means + standard deviations. Differences in variables were statistically analyzed by Wilcoxon and chi-square tests, as appropriate. A + 2.6 (range 35–45) years. Causes of infertility were: unexplained in 33 (63.5%) patients, tubal factor in 17 (32.7%) and 2 patients (3.8%) with endometriosis. Thirty-four patients underwent COH using the multiple-dose GnRH-antagonist protocol and 18 underwent the long GnRH-agonist suppressive protocol. Both protocols resulted in comparable stimulation variables; e.g. similar peak estradiol levels  oocytes yield , with a significantly higher fertilization rate while using the long GnRH-agonist suppressive protocol .Fifty-two patients undergoing their first IVF cycle attempt for non-male factor infertility met the inclusion criteria and were evaluated in our analysis. Mean patients’ age during the study period was 38.7 Following the 52 IVF cycles, 504 oocytes were collected. The mean number of oocytes retrieved per cycle was 9 (range: 6–12). Overall, 245 oocytes underwent ICSI and 259 oocytes underwent CI. The median numbers of oocytes undergoing ICSI and CI were 4 .P < 0.001). Moreover, top quality embryo rate was 62.8% (154/245) following ICSI compared to 45.5% (118/259) following CI (P < 0.001). These significant differences were also maintained when comparing the mean fertilization  and top- quality embryos  per patient.The fertilization rate was 71.0% (174/245) following ICSI treated oocytes compared to 50.1% (130/259) in the CI treated oocytes (n = 31) and 40-45 yrs. (n = 21). In the 35–39 age sub-group, the fertilization and top quality rates were significantly higher in the ICSI treated oocytes compared to CI. Fertilization rate was (111/151) 73.5% vs (83/151) 54.9% (p < 0.001) and the top quality embryo rate was (93/151) 61.5% vs (75/151) 49.6% (p < 0.001) in the ICSI vs. CI oocytes, respectively.Patients were further divided into two sub-groups according to their age, 35–39  64.8% vs. (43/108) 39.8%; P < 0.057] were non-significantly higher in the ICSI vs. CI oocytes, respectively. Although result did not reach statistical significance, the numerical difference between ICSI and CI is still striking and strongly suggest of the priority of ICSI over CI in this age group.In the 40–45 age sub-group, the fertilization rate [(63/94) 67.0% vs. (47/108) 43.5%; Since the decision on which embryo should be selected for transfer, was based solely on embryo morphology and not whether, it was originated by ICSI or CI, interpretation of our data with respect to implantation, clinical pregnancy or live birth rates was limited. However, we still find it important to present IVF results for the entire IVF study population. Regarding the all study group, the implantation, clinical pregnancy, miscarriage and live birth rates were 13.9% (40/286), 30% (16/52), 11.5% (6/52) and 19% (10/52), respectively. Seven pregnancies resulted in singleton and 3 with twins’ deliveries. Since embryo transfers also consisted of embryos originated from both ICSI and CI, we could not assess the effect of ICSI vs CI on implantation or live birth rates.In 18 patients embryos originated only for CI or ICSI were transferred. Although it is a very limited comparison, we present the results without interpretation. Of the six patients who underwent a transfer of embryos following CI, 2 (33%) conceived, compared to 8 (66%) out of the 12 patients undergoing transfer of embryos solely following ICSI.In the present cohort-historical study, patients aged ≥35 years undergoing their first IVF cycle attempt for non-male factor infertility, yielded significantly higher fertilization and top-quality embryo rates, while applying ICSI vs CI on their sibling oocytes. Sub-dividing the study population by age revealed that these differences remained significant in patients aged 35–39 yrs. Although for those aged 40–45 yrs. the differences were non-significant, the results are still indicative that ICSI is beneficial.Researching the literature with regards to the comparison of ICSI vs CI in patients with non-male factor infertility reveals controversial results. Aboulghar et al.  prospect> 35 years, and demonstrated improved IVF cycle outcome using ICSI vs CI. Our observations are in contrary to those recently published by Tannus et al. (9). In their retrospective study including 745 women, they could not demonstrate any advantage for ICSI over CI in women above 40 years of age with non-male factor infertility. Although similar numbers of oocytes were retrieved in both groups, the IVF group had a higher numbers of MII oocytes, higher fertilization rates per oocyte retrieved and higher numbers of zygotes formed. A potential explanation for this discrepancy may result from the possibility that oocytes might have been scrutinized for maturity upon ICSI and immature oocytes were discarded. While in CI, the maturity of oocytes is not examined until 16–18 h after insemination and the cumulus–oocyte complex is maintained intact in culture allowing more oocytes to complete in-vitro maturation and subsequently fertilize.In contrary to the aforementioned studies, in our study we included only patients The present study was limited by its retrospective design. Moreover, one may argue that while dividing the oocytes to ICSI and CI, the embryologist may select the more “mature” oocytes for ICSI, thus, skewing the results in favor of ICSI. Moreover, due to the small sample size, we could not relate the fertilization methods to pregnancy and live birth rates. However, the results of our study strongly favour ICSI in attempting to overcome age related abnormalities in sperm egg interaction. Moreover, there is enough support for this approach in other studies presented above to encourage more research on this topic.Patients with unexplained infertility form a heterogeneous group. In those with undetected sperm abnormalities, ICSI may provide an advantage over CI. Although it does not increase the fertilization rate, it does avoid the devastating complete fertilization failure of the CI cycle, which takes an enormous physical, emotional and financial toll on affected couples.In advanced-age patients with non-male factor infertility, specifically in the 35–39 female age group, the use of ICSI should be considered in most  oocytes in the first IVF attempt in order to maximize fertilization and top-quality embryo rates. Further large prospective studies are needed to elucidate the aforementioned recommendation and prior to its routine implementation.


Cardiac output 2O) concentration was forced to oscillate sinusoidally with a fixed mean (4%), amplitude (3%), and period (60 s). 2O sinewave. The agreement and trending ability of Over successive breaths the inspired nitrous oxide . The concordance between r=0.79, P<0.05).Before lung lavage, changes in The inspired sinewave technique provides continuous and noninvasive monitoring of cardiac output, with a ‘marginal–good’ trending ability compared with cardiac output based on thermodilution. However, the trending ability can be reduced with increasing shunt fraction, such as in acute lung injury. A mathematical model of the lung processes the resultant amplitude/phase of the expired sinewave signal and recovers values for cardiopulmonary variables such alveolar volume and pulmonary blood flow The ideal cardiac output monitor should be noninvasive and automated, and generate continual, accurate, and precise measurements. Measuring cardiac output via a respiratory based method such as the inspired sinewave technique (IST) has the potential to meet these criteria. The theoretical and experimental basis for the IST originates from the work of Zwart and colleaguesThis proof-of-concept study aimed at validating the 2O is injected into inspired gas by a mass flow controller . Airflow is measured using an ultrasonic flowmeter , and N2O concentration using a rapid mainstream infrared sensor . The volume injected is proportional to inspiratory flow, and over time (i.e. successive breaths) the inspired N2O concentration oscillates sinusoidally around a fixed mean (4%), with a predetermined amplitude (3%) and period (60 s). Without venous recirculation of the N2O sinewave, which is assumed negligible at short periods (i.e. <3 min),2O concentration also oscillate in a sinewave pattern (Details of the IST and inspired sinewave device (ISD) have been detailed elsewhere, pattern . A singl−1). Relevant sections of the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines were followed.Measurements were made in eight female large white pigs with a weight of 37–53 kg (mean=43.6 kg). All procedures in the study were approved by a local ethics committee and the UK Home Office, London, UK (PPL: 30/2960) and performed at the school of Veterinary Sciences, University of Bristol, Bristol, UK. At the end of each study, the animals were killed under anaesthesia with an overdose of pentobarbital  was used for fluid maintenance. Additional boluses of the muscle relaxant were administered when spontaneous ventilatory efforts were detected from the airway gas and pressure traces. The adequacy of anaesthesia was determined during the periods of muscle relaxation by the absence of cardiovascular signs of sympathetic stimulation . Anaesthesia was maintained with continuous i.v. ketamine 32 mg kg-1 hr-1, fentanyl 4 mg kg-1 hr-1, and midazolam 0.16 mg kg-1 hr-1.All procedures have been detailed elsewhere,2, and end-tidal CO2 were continuously recorded, whereas A pulmonary artery catheter  was inserted into the internal jugular vein and advanced into the pulmonary artery. Assessment of pulmonary artery pressure (PAP) and wedge waveforms confirmed the correct position of the PAC. Arterial pressure , PAP, ECG, %SO−1 min−1), reducing −1, followed by infusions of dobutamine (15–20 μg kg−1 min−1) increasing −1 above baseline measurements.After a stabilisation period of approximately 20 min, baseline measurements were recorded for 10 min, where Measurements of −1 0.9% NaCl at approximately 38°C) until a PaO2/FIO2 ratio of 200–300 mm Hg was achieved, as determined from arterial blood gas analysis. The above experimental protocol was then repeated.After these measurements, repeated warm saline lavages were performed (30 ml kgT is the repeatability coefficient for vsr) for paired The experiments were designed in accordance with Home Office principles of RRR, essentially minimising animal use whilst preserving data fidelity. Sample sizes were estimated using Mead’s resource equation, as is typical for laboratory animal studies. We chose the sample size to give a value of E (the error degree of freedom) between 10 and 20. Since we used the same animals for measurements before and after lung injury (paired), and a quasi-factorial ‘treatment’ design (i.e. changing cardiac output from resting to higher to lower), a sample size of 8 animals yields an E value of 20. Results are displayed as means 95% confidence interval unless otherwise stated. The agreement of paired absolute . These confidence intervals can be defined as follows: Trending ability was also assessed via the trend interchangeability method (TIM).t-tests, with statistical significance set at P<0.05. All analyses were completed using standard statistical software .Differences between baseline variables were assessed via two-tailed unpaired Student's r=0.88. Bland–Altman analysis of absolute −1  with limits of agreement (LOA) ranging from 5.5  to –3.9 L min−1 . Despite this wide LOA between data points from all animals, the LOA within each animal is substantially narrower: the LOA for each animal ranged between 0.31 and 0.8 L min−1 (mean=0.61 L min−1). This is reflected in the Bland–Altman analysis of vsr=0.48. The interchangeability rate was calculated as 41%. As only poor interchangeability was observed, estimating the range of interchangeable measurements was inappropriate.Baseline haemodynamic and blood gas measurements for each animal are shown in T values a shows avsΔQ˙T b, where P<0.01). The concordance was 92.5% as assessed using four-quadrant analysis . Trending ability was examined using the same approaches discussed above . The Repeated saline lavages resulted in significant reductions in the mean baseline PaOed above . Four-quThis proof-of-concept study investigated a novel, noninvasive, and fully automated method to continuously monitor changes in cardiac output using the IST. We showed that a prototype device that utilised the IST could be integrated in a breathing circuit of mechanical ventilator, suggesting that it is feasible to use within the perioperative setting. We further demonstrated that a cardiac output based on the IST demonstrated a ‘marginal–good’ trending ability, based upon four-quadrant plot and polar analysis, compared with the pulmonary artery catheter thermodilution reference method.Thermodilution is widely considered the gold standard technique for cardiac output monitoring. However, because of its highly invasive nature and the associated complications, its clinical use is becoming less frequent.The trending ability of the IST compares well with other noninvasive or minimally invasive methods of monitoring cardiac output. Examining concordance using a four-quadrant plot against thermodilution has been commonly used. The concordance of >92% in the current investigation is commonly regarded as a ‘good’ or clinically acceptable trending ability,The findings are also similar to other recently developed respiratory-based approaches utilising the Fick principle,between animals, not within each animal. Indeed, the LOA for each individual animal was low, and so normalisation of values to each animal results in a lower bias and narrower LOA and a good trending ability, which clearly demonstrates the potential of the technique. From a practical perspective, when monitoring patients in many clinical settings absolute values only offer limited information, whereas the temporal variation in values (e.g. the % change in cardiac output) from what is ‘normal’ for each individual patient provides greater clinical insight.Despite the encouraging trending ability, the absolute agreement between 2O sinewave emerging at higher cardiac outputs and so conflicts with assumptions made by the lung model. Clearly, further work and adjustments to the model are needed to improve the trending (and absolute agreement) of vsBland–Altman analysis of Data from the IST measurements are averaged over a 3 min rolling window and updated to the monitor every 30 s. The time of 3 min was chosen because it captures three full sinewave periods and gives robust solutions, although a shorter period could be used depending on the degree of stability required. Theoretically this approach has two potential clinical consequences. The first is that it will dampen the dynamic component of the cardiac output time series, and the second is that it results in a lag between real-time cardiac output changes and their registration. Given that even under the most challenging clinical circumstances (other than sudden cardiac arrest), cardiac output changes over a time course of minutes and the ultra-dynamic component of the time series is small; so the 3 min moving average should have so significant impact. In contrast, the ‘lag’ effect will clearly result in a delay in the registration of real-time CO values. In the data presented here, this was measured as being approximately 60 s (cf. contemporaneously measured The current experiment collected data from mechanically ventilated animals and so may not necessarily apply to human participants or those spontaneously breathing. Previous work has shown that IST measures of cardiopulmonary function are both accurate and reproducible in young healthy volunteers,There are several limitations with the statistical approaches used in the current study. The exclusion zone in the four-quadrant plot and polar analysis aims to remove small 2 elimination independently of any change in cardiac output, As with other respiratory-based approaches, the presence of lung disease or injury will likely impair aspects of Conception of the protocol: AF.Design of the protocol: RB, PP, AF.Acquisition of data: RB, DC, AM, FF, PP, AF.Analysis and interpretation of the data: all authors.Development of the new technique: RB, MT, PP.Writing paper: RB.Contributed to the production of the manuscript: DC, AM, MT, FF, PP, AF.


Meloidogyne spp.) can reduce sweetpotato yields and quality. Fluensulfone is the active ingredient of the new non-fumigant nematicide Nimitz. Unlike fumigant nematicides, toxicity toward non-target organisms is low, and it does not emit volatile organic compounds which negatively impact air quality. In two field trials, the effect of fluensulfone on M. incognita levels, and on the yield and quality of sweetpotato was determined. Fluensulfone was applied as a pre-plant soil incorporated drench or as a drench followed by post-plant sprays. Fluensulfone treatments more than doubled the marketable yields over an untreated control and a metam-sodium treatment in both trials. It strongly reduced nematode symptoms on the harvested roots and nematode infestation of these roots. The lowest rate of fluensulfone was as effective as the higher rates, and post-plant sprays following a pre-plant soil incorporated drench did not result in any additional benefits. Fluensulfone did not reduce soil nematode levels at harvest. It was concluded that a pre-plant incorporated fluensulfone drench at a rate of 1.96 kg/ha could provide a viable alternative for currently used nematicides to mitigate root-knot nematode damage in sweetpotato.In California, sweetpotato is mostly grown on light sandy soils in Merced County. Root-knot nematodes ( Ipomea batatas) production in California was approximately 295 million kg annually during 2010 to 2015 grown on approximately 7,300 ha. California production is second only to North Carolina, and the crop in California is valued at $150 million, which is about 20% of the total US value. Close to 90% of the production in California is concentrated on the sandy soils of Merced County in the San Joaquin Valley (USDA/NASS). Planting material is typically produced in plastic tunnels (hotbeds) by planting sweetpotato roots from the previous year. After sprouting, the stems are cut, and these stem cuttings or ‘slips’ which do not have any roots, are used as planting material in April to May in the production fields  (Sweetpotato (hectare) . In Calihectare) .Meloidogyne spp.) are economically the most damaging nematodes in sweetpotato both on a worldwide scale as well as in California  reported a threshold level of 5 s-stage juveniles (J2) per 1 kg soil for a sandy soil. 3 soil for cracking of storage roots. Root-knot nematodes  have good RKN resistance, but under high soil temperatures, even resistant cultivars can still result in a large RKN population increase during one crop cycle . Furthermore, although storage root quality of resistant cultivars was not affected by RKN, yield losses resulting from RKN were still considerable, and additional management strategies are needed in RKN infested fields, even when growing RKN-resistant cultivars .www.adama.com). Studies on RKN control by fluensulfone in tomato, carrot, tobacco, and cucumber showed promising results , sweetpotato was among the five crops in California with the highest use of the fumigant 1,3-dichloropropene . Other fumigants used in sweetpotato in California are metam-potassium (809 ha) and metam-sodium (33 ha). As they are potential environmental and health hazards, they are limited by regulatory restrictions related to the emission of volatile organic compounds (VOC) and their toxicity. Until recently, effective, environmentally acceptable, and economically viable alternatives were not available, and this has been an important factor in the continued use of soil fumigants . Fluensu results . AlthougM. incognita-infested site.The goal of this two-year field study was to evaluate the effectiveness of fluensulfone in comparison to an untreated control and to metam-sodium in sweetpotato grown on an uniformly M. incognita race 3 population, originally isolated from cotton in the San Joaquin Valley, CA, by injecting the egg suspension through buried drip tubing (M. incognita-susceptible crops melon (Cucumis melo ‘Durango’), carrot (Daucus carota ‘Imperator 58’), tomato , and bean (Phaseolus vulgaris ‘Blue Lake 274’) were grown in sequence during the spring/summer for four years to increase and maintain an evenly distributed M. incognita infestation level before the sweetpotato trial was initiated. Wheat (Triticum aestivum) ‘Yecora Rojo’ was grown during the winter each year.The trials were located on a field with sandy-loam soil  at the University of California South Coast Research and Extension Center, Irvine, CA. The field had been inoculated five years previously with an egg suspension of a p tubing . The M. 2). All plots were pre-irrigated for 1 hr with overhead sprinklers the day prior to any pre-plant application to achieve adequate soil moisture. For each plot, Vapam and pre-plant Nimitz were suspended in 7.6 liter of water and watered evenly over the plot surface with a watering can. An additional 45.4 liter of water was applied over each plot, and the plots were tilled with a rototiller to a depth of 10 to 13 cm. Post-plant Nimitz applications were applied in 7.6 liter of water with a backpack sprayer over the crop foliage.The trials were conducted in 2016 and 2017 on different, but nearby areas of the field. In both years, 152 cm wide (center to center) beds were prepared in May and plots were laid out. Individual plots were 6.1 m long sections of bed, separated along the beds by a 91 cm border section. The experiment was designed according to a completely randomized block design with five replicates and four treatments. In both years treatments included an untreated control, a Vapam (a.i. metam-sodium) treatment at 701 liter/ha (294 liter a.i./ha), and two fluensulfone treatments. In 2016, the fluensulfone treatments were (i) Nimitz at 7 liter/ha  and (ii) Nimitz at 7 liter/ha  followed by two post-plant spray applications of 3.5 liter/ha (1.68 kg a.i./ha) at 26 and 58 d after planting. In 2017, fluensulfone treatments were (i) Nimitz at 5.8 liter/ha (2.8 kg a.i./ha) and (ii) Nimitz at 4.1 liter/ha (1.96 kg a.i./ha) both pre-plant incorporated. Vapam was applied 21 and 26 d before planting in 2016 and 2017, respectively. Pre-plant Nimitz applications were 2 and 7 d before planting in 2016 and 2017, respectively. Amounts applied per plot were based on the bed surface area of each plot  was collected from each plot just before applying Vapam  and just before harvest . Nematodes were extracted from 100 g soil subsamples in a modified Baerman-funnel technique , and RKN J2 were counted at ×40 magnification.Rootless slips of the RKN-susceptible cultivars O’Henry and Beauregard were planted on June 10, 2016 and May 18, 2017, respectively. The slips were planted in pre-wetted beds at 41 cm within-row spacing, with two rows per bed, resulting in 30 slips per plot. At planting, approximately 0.5 liter water was added to each cutting, and irrigation was through drip tubing  on top and in the center of the beds. Fertilization was according to standard practices, applied pre-plant incorporated and post-plant through the drip tubing. Weeds were removed by hand, and no fungicides or insecticides were required. In total, 20 and 50 d after planting, the general vigor of each plot was visually examined and indexed . Plots were harvested mechanically on October 9, 2016 and September 22, 2017. For each plot, total yields (weight and number of roots) were determined. In total, 20 roots were randomly collected from each plot, and assigned to one of three categories: marketable, non-marketable because of RKN damage, and non-marketable because of defects not related to RKN. The weight of these roots in each category was determined. In addition, 10 randomly selected roots from each plot were taken to the laboratory and cut in half cross-wise. One half was discarded. The 10 remaining half roots were weighed and then peeled with a potato peeler. Nematode eggs were extracted from both the peels and the peeled roots by shaking for 3 min in a 0.5% NaOCl solution  and collP ⩽ 0.05) using SAS statistical software . Percentage data were transformed by arcsin (√x) before statistical analysis, nematode counts were transformed by x1 = log10 (x + 1) before statistical analysis.Treatment effects on nematode counts, crop vigor, sweetpotato yield, and sweetpotato quality were analyzed using an analysis of variance (ANOVA) procedure, and means were compared using Fisher’s protected least significant difference (LSD) test  and that a pre-plant soil incorporated rate of fluensulfone at 1.96 kg/ha was as effective as the 2.8 kg/ha rate (2017). Surprisingly, in 2016 the percentage of culled roots that did not show obvious signs of nematode damage  was significantly higher after the two fluensulfone treatments. This suggests that fluensulfone caused some other effect on the roots, e.g., increased the number of roots with insect damage, or resulted in more misshapen or small roots. An increase in insect (wireworm) damaged roots resulting from fluensulfone seems unlikely, but it could be that in 2016 Nimitz did reduce nematode symptoms of the roots, but at the same time had some phytotoxic effect resulting in more misshapen and smaller roots. This would explain the relatively higher percentage of ‘no-nematode’ culls in the fluensulfone treatments in 2016. In 2017, when lower rates were used, this effect did not occur. Phytotoxic effects of fluensulfone in vegetable crops have been reported when used at high rates, as a post-plant spray, or too close to planting time  infested soil, significantly improves both yield and quality. Total root yields doubled, and a 10-fold increase in marketable yield occurred compared to the untreated control. The 1.96 kg/ha rate was as effective as the 2.8 kg/ha rate, and post-plant spray applications did not offer additional benefits. However, this lower rate will need to be evaluated in additional field trials before it can be recommended to sweetpotato producers. Fluensulfone failed to reduce soil RKN levels at harvest time but did reduce nematode infestation of sweetpotato roots by over 80%. We conclude that fluensulfone provides a viable new management option to growers in California for reducing RKN damage in sweetpotato that is both safe and effective.These trials show that fluensulfone when applied as an incorporated soil drench at least 2 d before planting a nematode-susceptible sweetpotato cultivar in RKN (


Regarding echocardiogram data, sST2 was correlated with left ventricular mass index , left atrial diameter , and volume index . sST2 alone did not change risk prediction of death and/or CV events compared to natriuretic peptides. Included in the Barcelona Bio-Heart Failure (BCN Bio-HF) score, sST2 added value and better stratified the risk of CV events and/or death in CKD patients (p < 0.0001). To conclude, sST2 was associated with cardiac remodeling independently of eGFR, unlike other cardiac biomarkers. Added to the BCN Bio-HF score, the risk stratification of death and/or CV events in nondialyzed CKD patients was highly improved.Heart failure is the most frequent cardiac complication of chronic kidney disease (CKD). Biomarkers help identify high-risk patients. Natriuretic peptides (BNP and NT-proBNP) are largely used for monitoring patients with cardiac failure but are highly dependent on glomerular filtration rate (GFR). Soluble suppression of tumorigenicity 2 (sST2) biomarker is well identified in risk stratification of cardiovascular (CV) events in heart failure. Furthermore, sST2 is included in a bioclinical score to stratify mortality risk. The aims of this study were to evaluate (i) the interest of circulating sST2 level in heart dysfunction and (ii) the bioclinical score  to predict the risk of composite outcome (major adverse coronary events) and mortality in the CKD population. A retrospective study was carried out on 218 CKD patients enrolled from 2004 to 2015 at Montpellier University Hospital. sST2 was measured by ELISA (Presage ST2® kit). GFR was estimated by the CKD-EPI equation (eGFR). Indices of cardiac parameters were performed by cardiac echography. No patient had reduced ejection fraction. 112 patients had left ventricular hypertrophy, and 184 presented cardiac dysfunction, with structural, functional abnormalities or both. sST2 was independent of age and eGFR ( CV events and death are associated with reduced eGFR . The preRecent studies have identified new biomarkers involved in the pathogenesis of remodeling and cardiac fibrosis. Among them is sST2, an emerging biomarker predictive of fibrosis and cardiac remodeling in HF patients without CKD. This is a marker of interest in the stratification of patients at risk as well as in the therapeutic response of HF patients –11. ST2 In patients with chronic HF episodes, sST2 acts as a predictor of both all-cause and cardiovascular death . sST2 waTo our knowledge, only few data are available regarding the prognosis value of fibrosis and myocardial remodeling biomarker in CKD patients for which the risk of a CV event constitutes the main cause of mortality. Therefore, objectives of this study were to evaluate sST2 in cardiac remodeling and to assess its role alone or in combination with other common biological parameters of HF for risk stratification of CV events or/and mortality in a nondialyzed CKD population (BCN Bio-HF score).218 patients were enrolled in the Montpellier University Hospital between 2004 and 2015. Main inclusion criteria were the ability to give informed consent, age > 18 years, cardiac echography at inclusion, and a confirmed diagnosis of CKD according to the National Kidney Foundation and KDIGO Guidelines , 20. StaAt the time of enrollment, all patients had an echocardiogram performed by a trained physician. Dry and heparinized blood samples were drawn, and serum/plasma stored at −80°C for further analyses.The follow-up of all included patients was approximatively 3 years with time-to-event analysis until the occurrence of fatal or nonfatal CV events, defined as major adverse coronary events (MACE).Written informed consent was obtained for all patients. The protocol was approved by local authorities (Ethics Committee of Montpellier) according to standards currently applied in France . A biological collection was also registered by the French government . The study was done in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.2 for men and ≥95 g/m2 for women or left atrial volume index (LAVI) > 34 mL/m2) or functional abnormality with impaired relaxation (E/A < 1) [Cardiac echocardiography was performed by a trained physician at inclusion. No patients presented signs of heart failure at inclusion. Subclinical cardiac dysfunction was defined as left ventricular ejection fraction (LVEF) > 40% with structural abnormality (left ventricular mass index (LVMI) ≥ 115 g/mBiochemical parameters, including classical cardiac variables (NT-proBNP and high-sensitivity troponin T (hs-cTnT)), were performed on a Cobas 8000/e602 immunochemistry system . C-reactive protein (CRP), urea, and IDMS traceable enzymatic creatinine were determined on a Cobas 8000/c701 . Intact aminoterminal propeptide of type I procollagen (PINP) as a biomarker of collagen synthesis was determined by chemiluminescence technology using the IDS-iSYS Multi-Discipline automated analyser .μl of standard, diluted samples (1 : 20 in sample diluent) was added to the well of a ready-to-use microtiter plate coated with mouse monoclonal anti-human sST2 antibody. The standard curve was in the concentration range 2.8–100 ng/mL. Then, the plate was incubated for 60 min at room temperature. After washing, 100 μl of biotinylated antibody reagent was added into each well and incubated for 60 min at room temperature. After washing, 100 μl of streptavidin-HRP conjugated was added into each well and incubated for 30 min at room temperature. After washing, the TMB substrate was added to each well and incubated for 20 min at room temperature in the dark. Then, stop solution was added and absorbance was read at 450 nm.sST2 was measured using a sandwich ELISA kit . In chronic HF patients, the upper reference limit for sST2 was 35 ng/mL . A recomThe Barcelona Bio-Heart Failure risk calculator  estimates the risk of death in patients with HF described by Lupón et al. . The BCNχ2 test was performed to investigate the presence of differences between proportions. The Mann-Whitney U test and Kruskal-Wallis test were used to compare groups, as appropriate. Since their distributions were skewed, logarithmic transformations of sST2, troponin, NT-proBNP, and PINP biomarkers were used. For correlation analyses, Spearman's rank correlation coefficients were computed. Composite outcome was defined as any of the following events (MACE) during follow-up: death, myocardial infarction, ischemic cardiomyopathy, angioplasty, valvular cardiomyopathy, stroke, vascular angioplasty, or cardiac arrhythmias. The Kaplan-Meier estimator of event-free survival was used to assess the ability of biomarkers to predict adverse outcome in the population. Potential predictors of composite outcome were further evaluated using the Cox proportional hazard regression. The net reclassification improvement (NRI) was used to assess the incremental value by adding a biomarker over the BCN Bio-HF score. No treatment adjustment in relation to cardiac biomarkers and kidney dysfunction was assessed in the BCN Bio-HF score analysis since they were already included in the initial score calculation.Descriptive statistics are presented as numbers (percentages) for categorical data and as medians (interquartile range (IQR)) for continuous variables. 2 (IQR 23–52). During the follow-up period, 85 out of 218 patients presented composite outcome. Demographic data, laboratory findings, and echocardiogram parameters in the global population presenting or not presenting composite outcome are shown in This study included a total of 218 patients at different stages of CKD . Median eGFR level was 37 mL/min/1.73 mρ = 0.17, p = 0.01; ρ = 0.14, p = 0.03; and ρ = 0.15, p = 0.03, respectively).Correlation between sST2 and inflammatory and cardiac biomarkers  was significant  and cardiac remodeling , LAVI , and LVMI ). No association with functional abnormality was observed ). PINP was not correlated with any echocardiographic data  or eGFR  was observed, in contrast to classical cardiac biomarkers such as hs-cTnT  and NT-proBNP . Moreover, no relationship was observed between sST2 and CKD stages (p = 0.9) whereas NT-proBNP and hs-cTnT values increased from stages 1 to 5 (p < 0.001 for both parameters) (No correlation between sST2 and both age (ameters) .During the 3 years of median follow-up (IQR 1.3–6.4), 85 (39%) patients experienced the composite outcome of death and/or CV events.In univariate Cox analysis, older age (HR 1.052 (1.031–1.072)), male gender ), increased LAVI (HR 1.050 (1.015–1.086)) and LAD (HR 1.074 (1.030–1.119)), elevated hs-cTnT (HR 5.152 (2.659–9.983)), NT-proBNP (HR = 1.650 (1.116–2.439)), and CRP (HR 2.155 (1.388–3.346)) were related to composite outcome .p < 0.0001) (p = 0.27).The Barcelona Bio-HF score was applied to assess the predictive composite outcome in our cohort. Taken together, NT-proBNP, hs-cTnT, and sST2 were highly predictive of the composite outcome of cardiovascular events and/or death ( 0.0001) . A combiThis study shows that the sST2 level is associated with cardiac remodeling features, and unlike common cardiac biomarkers, this biomarker is independent of eGFR and age. A multimarker approach including sST2 is thus reported as an appealing tool in CV risk stratification of nondialyzed CKD patients.ρ = 0.14, p = 0.03) can be explained by renal dysfunction as a confusing factor (HFpEF is associated with increased cardiac remodeling, abnormal cardiac mechanics, and poor outcomes in CKD patients , 23. Brag factor . In a stsST2 is involved in pathophysiology of cardiac fibrosis, and its increase is considered as an indirect circulating marker of cumulative fibrotic processes . RegardiTo our knowledge, this is the first time we observe that a multimarker strategy including combined sST2, NT-proBNP, and hs-cTnT biomarkers is highly associated with cardiovascular events and/or mortality and suitable in nondialyzed CKD patient risk stratification.sST2 represents a promising biomarker in prognosis mortality and CV events in chronic HF , 37. RecA multimarker strategy approach was developed and proven to be more informative than a single biomarker in HF prognosis. To date, only few clinical scores evaluating risk stratification of HF have been developed. The BCN Bio-HF score is a unique tool combining a panel of biomarkers and clinical variables . Taken tThis study presents several limitations. First of all, tissue Doppler imaging was not taken into account at the time of inclusion; consequently, the e' wave was not available. Then, a relatively small cohort of patients from a single medical center was enrolled. We only measured biomarkers at time of recruitment and did not evaluate the long-term trends of biomarkers, which could be useful for patient follow-up. Moreover, sST2 assay is not available in all laboratories, which reduces the use of the multimarker strategy.To our knowledge, this is the first study showing that sST2 is a good biomarker to evaluate the cardiac remodeling feature in nondialyzed CKD patients. Although sST2 alone is not predictive of CV events and death in this population, it plays an important role to stratify risk of all-cause mortality and CV events in a multimarker strategy combined with clinical variables.


Previous gastrectomy can lead to an increased incidence of cholecystocholedocholithiasis (CCL) and increased morbidity rate. However, the appropriate treatment strategy for patients with CCL and a history of gastrectomy remains unclear.We performed a retrospective cohort study of patients with CCL and a history of gastrectomy who underwent either one-stage laparoscopic common bile duct (CBD) exploration with stone clearance and laparoscopic cholecystectomy (LCBDE+LC) or two-stage endoscopic retrograde cholangiopancreatography followed by LC (ERCP+LC) from May 2010 to March 2018.2 = 97.67, P < 0.001, risk ratio (RR) = 3.43]. The success rate of second-step LC after successful ERCP for removal of CBD stones and the success rate of LCBDE+LC after ERCP treatment failure were 96.8 and 87.7%, respectively, in patients with preoperative intra-abdominal adhesion evaluation scores of ≤3 points. These success rates were 28.6 and 27.6%, respectively, in patients with scores of > 3 points .The success rate of ERCP for CBD stone clearance was 81.2% in patients with a history of Billroth I gastrectomy and 23.7% in patients with a history of Billroth II or Roux-en-Y esophagojejunostomy [χBased on the results of this study, ERCP+LC seems to be an attractive strategy for treatment of CCL in patients with a history of Billroth I gastrectomy, and LCBDE+LC appears to be suitable for patients with a history of Billroth II or Roux-en-Y esophagojejunostomy. Preoperative evaluation of intra-abdominal adhesions helps to reduce the conversion rate of laparoscopic surgery. Treatment options for cholecystocholedocholithiasis (CCL) include two-stage endoscopic retrograde cholangiopancreatography (ERCP) followed by laparoscopic cholecystectomy (LC) , one-stage laparoscopic common bile duct exploration (CBDE) and LC , and laparotomic CBDE and cholecystectomy , 2. WithWe performed a retrospective cohort study of patients with CCL and a history of gastrectomy in Huzhou Central Hospital and the No. 3 People’s Hospital of Changxing County, China from May 2010 to March 2018. In all patients, the diagnosis of CCL was confirmed by magnetic resonance cholangiopancreatography. The study was approved by both hospitals’ ethics committees, and written informed consent was obtained from each patient. Both hospitals provide a comprehensive general surgical service and tertiary care for patients undergoing hepatobiliary surgery among a population of 3 million people. In total, 394 consecutive patients were enrolled in this study. Of these, 342 patients underwent ERCP for removal of CBD stones first, and 289 patients who were candidates for elective LC or LCBDE+LC underwent preoperative evaluation of intra-abdominal adhesions based on our previous research , as showp-value < 0.05 was considered statistically significant.All data were prepared and compiled using the SPSS computer program . The chi square test and Fisher’s exact test were used for quantitative data. Step-wise regression was used for multivariate analysis to identify any confounding factors. Pearson’s correlation test was used for correlation analysis. A The clinical data of all 394 patients with CCL with a history of gastrectomy who underwent treatment from May 2010 to March 2018 were retrospectively reviewed. The patients’ ages ranged from 27 to 81 years . The cohort comprised 156 (39.6%) men and 238 (60.4%) women, with a male:female ratio of 0.655:1.000. No gallbladder cancer was identified. All patients had previously undergone gastrectomy for either gastric cancer [363 patients (92.1%)] or gastroduodenal ulcers [31 patients (7.9%)]. The types of gastrectomy were distal gastrectomy in 293 patients [Billroth I gastrectomy in 103 patients (26.1%) and Billroth II gastrectomy in 190 patients (48.2%)] and total gastrectomy with Roux-en-Y esophagojejunostomy in 101 patients (25.7%), as shown in Table 2 = 97.67, P < 0.001, risk ratio (RR) = 3.43], as shown in Table A total of 342 patients with CCL and a history of gastrectomy underwent ERCP for removal of CBD stones first. Of these, 139 patients underwent successful CBD stone clearance with ERCP, and without CBD stones retained which confirmed by postoperative magnetic resonance cholangiopancreatography confirmed that no stones had been retained. Among these 139 patients, 82 had previously undergone Billroth I gastrectomy and 57 had previously undergone Billroth II gastrectomy or Roux-en-Y esophagojejunostomy as shown in Fig. 2 = 59.70, P < 0.001, RR = 3.38 and χ2 = 53.41, P < 0.001, RR = 3.27), as shown in Table A total of 118 patients underwent LC after successful CBD stone removal by ERCP, and 171 patients underwent LCBDE+LC after ERCP treatment had failed Fig. . The sucP < 0.05). The incidence of postoperative bile leakage, postoperative hemorrhage, postoperative cholangitis, postoperative pancreatitis, residual CBD stones, recurrence of CBD stones, bile duct stricture, and patient death were not significantly different between the two groups (P > 0.05) (Table A total of 76 patients underwent ERCP+LC and 79 underwent LCBDE+LC for treatment of CCL after a previous gastrectomy. The hospital costs and length of hospital stay were greater in the ERCP+LC than LCBDE+LC group P < 0.0. The incIt is widely accepted that patients with a history of gastrectomy have an increased incidence of CCL and increased morbidities requiring surgery . The exaHistorically, the treatment of CCL required open laparotomy and CBDE . After tMost surgical specialists believe that either ERCP+LC or LCBDE+LC should be specifically chosen to treat patients with CCL in clinical practice based on the size and quantity of CBD stones, whether the CBD stones are combined with gallstones, the location and severity of the obstruction, and especially the level of the surgeon’s experience in ERCP or LCBDE at individual treatment centers , 26. In Regardless of whether ERCP is performed successfully, all patients with CCL will inevitably undergo second-step LC or one-stage CBDE+cholecystectomy . PreviouAt last, we collected the clinical information of the patients who were performed ERCP+LC or LCBDE+LC successfully, and we found that the postoperative complications have no differences between two groups, but the hospital costs and length of hospital stay were reduced in LCBDE+LC group. These results accord with the previous research conclusions.Although majority of carried out studies confirmed that the incidence of CCL after gastric resection is increased compared with the people without gastrectomy history, but performing prophylactic cholecystectomy during gastric cancer surgery is still being debated . In the Limitations and possible biases in this study are the lack of randomization, which may have caused some selection bias, and the small number of patients, making the detection of small differences between the study groups unreliable.This study has shown that ERCP+LC seems to be an attractive strategy for treatment of CCL in patients with a history of Billroth I gastrectomy and that LCBDE+LC is suitable for patients with a history of Billroth II or Roux-en-Y esophagojejunostomy. Introduction of preoperative evaluation of intra-abdominal adhesions is beneficial for reducing the conversion rate of laparoscopic surgery in patients with CCL and a history of gastrectomy.


To assess medication use in adult congenital heart disease (ACHD) patients compared to the age- and sex-matched general population, identify patterns of pharmacotherapy, and analyse associations between pharmacotherapy and adverse outcomes in ACHD.P < 0.001). Polypharmacy, defined as ≥5 dispensed drug types yearly, was present in 30% of ACHD and 15% of referents {odds ratio [OR] = 2.47 [95% confidence interval (CI) 2.39–2.54]}. Polypharmacy was independently associated with female sex [OR = 1.92 (95% CI 1.88–1.96)], older age , and ACHD severity . Cluster analysis identified three subgroups with distinct medication patterns; a low medication use group , and a cardiovascular and comorbidity group with lower survival . Cox regression revealed a strong association between polypharmacy and mortality [hazard ratio (HR) = 3.94 (95% CI 3.22–4.81)], corrected for age, sex, and defect severity. Polypharmacy also increased the risk of hospitalization for adverse drug events [HR = 4.58 (95% CI 2.04–10.29)].Data of 14 138 ACHD patients from the CONCOR registry  and age- and sex-matched referents (1:10 ratio) were extracted from the Dutch Dispensed Drug Register for the years 2006–14. Adult congenital heart disease patients had more cardiovascular and non-cardiovascular drugs than referents (median 3 vs. 1, Both cardiovascular and non-cardiovascular medication use is high in ACHD with twice as much polypharmacy compared with the matched general population. Patients with polypharmacy had a four-fold increased risk of mortality and adverse drug events. Recognition of distinct medication patterns can help identify patients at highest risk. Drug regimens need repeating evaluation to assess the appropriateness of all prescriptions. More high-quality studies are needed to improve ACHD care with more evidence-based pharmacotherapy. For all Dutch residents, the DDR contains all dispensed outpatient drugs reimbursed by the compulsory basic Dutch health insurance. Drugs are classified following the Anatomical Therapeutic Chemical (ATC) classification (Table S1), which classifies drugs at five levels according to the organ/system on which they act (1st) and their therapeutic (2nd), pharmacological (3rd), and chemical properties (4th and 5th level).This cohort study linked data of patients from the CONCOR registry,Figure S1). Subjects were followed from 2006 or CONCOR-inclusion until 2014 or death, using survival data from the national Cause of Death Register (CDR), which includes International Classification of Diseases (ICD) 10th revision coded causes of all deaths in Dutch citizens. From CONCOR, we obtained date of birth, inclusion date, sex, and main CHD, classified into mild, moderate, and severe CHD according to a much used consensus-based classification where proposed level of care and survival prospects differ per severity (Table S2).,Patients were matched with randomly selected age- and sex-matched reference subjects from the general population (1:10 ratio) to gain insight in the increase in medication use in ACHD compared to normal for these generally young persons  for the years 2006–12. The HDR contains person-linked discharge records of Dutch hospital admissions, including ICD-9 coded diagnoses and dates of admission. We defined hospitalizations for ADEs as admissions with ICD-9 codes 960–979  as main diagnosis. The CDR was subsequently reviewed for ADEs as cause of death in all patients (ICD-10 codes T36–T50).CONCOR was approved by the ethics boards of all participating centresn (%), mean ± standard deviation, and median [interquartile range (IQR)]. Two-sided P-values of <0.05 were considered statistically significant.Statistical analyses were performed using RStudio V.1.0.153  and SPSS V.22 . Data are summarized as Table S3) to test whether the cumulative definition of polypharmacy represented concurrent and continuous medication well.Drug use was described as percentage of years with dispensed drugs during the studied period. Generalized estimating equations with exchangeable working correlation and robust variance estimators were used to calculate odds ratios (ORs) for specific drugs and polypharmacy during the study in patients vs. matched referents, to determine whether sex, age, and CHD severity were independently associated with the presence of polypharmacy, and to plot predicted probability of polypharmacy by age in subsets per CHD severity. We performed subgroup analyses based on CHD type, sex, and age. A sensitivity analysis excluding sex hormones was performed to analyse the influence of oral contraceptives on the difference in polypharmacy between the sexes. We also performed sensitivity analysis excluding non-chronic drug types  were used at year of inclusion. Hierarchical clustering was performed with the hclust and heatmap functions in R, using binary distance to calculate the dissimilarity matrix. The optimal number of clusters was estimated by maximizing the gap statistic using the gap method.2 and analysis of variance tests. Survival was assessed using the Kaplan–Meier analysis and compared between clusters using Cox hazard regression, adjusted for age, sex, and CHD severity.To identify subgroups of patients with distinct patterns of medication relating to diseases of different organ systems, we used an unbiased machine learning approach. Of each patient, we determined whether drugs of the different anatomical classes of the ATC classification . Overall, 96 835 person-years of patients and 982 563 person-years of referents were analysed.In total, 14 138 ACHD patients  were followed for 8 (5–9) years  5.60–6.07]}, β-blockers , and renin–angiotensin–aldosterone system (RAAS) inhibitors  (Table A).Table B). Patients more commonly used drugs for thyroid disease than referents , especially patients with complete atrioventricular septal defects [OR = 15.69 (95% CI 9.53–25.83)] who often had Down syndrome [142 of 214 patients (67%)]. Antiepileptics also were more common , particularly in patients with transposition of the great arteries [OR = 4.58 (95% CI 2.87–7.33)] or a functionally univentricular heart .Remarkably, most non-cardiovascular drugs were also used more frequently in ACHD, especially systemic antibiotics , drugs for acid-related disorders  and drugs for obstructive airway disease [10 vs. 7% OR = 1.57 (95% CI 1.50–1.65)] (P < 0.001) . Twice as little patients were free of dispensed drugs at inclusion compared to referents  (most common drugs in polypharmacy: Table S5).Adult congenital heart disease patients had a median of three different dispensed drugs at year of inclusion compared to a median of one in reference subjects . It was particularly present in patients with a UVH , with many cardiovascular drugs indicating high-cardiac morbidity, and in patients with the Marfan syndrome , with notable use of cardiovascular drugs, ocular medication , and analgesics , reflecting ocular and skeletal problems (e.g. scoliosis) often seen in these syndromic patients.Mean prevalence of polypharmacy during the study was 30% in ACHD compared to 15% in referents [OR = 2.47 (95% CI 2.39–2.54)]. Polypharmacy was independently associated with older age, female sex, and CHD severity  . Already 48% of patients with severe CHD had polypharmacy at the age of 45 years, a proportion only seen for persons aged ≥70 years in the general population.Even in mild CHD, polypharmacy was already as common in 45-year-old female and 50-year-old male patients as in 65-year-old persons from the general population , with high use of antithrombotics (46%) and RAAS inhibitors (23%). These sex- and age-specific differences were seen both in patients and referents.Overall, polypharmacy was more common in women than men [OR = 1.92 (95% CI 1.88–1.96)]. It was already present in 24% of female patients under 40 years , with high use of antibiotics (41%) and sex hormones including contraceptives (31%). Even after exclusion of sex hormones, polypharmacy prevalence remained higher in women [OR = 1.88 (95% CI 1.74–1.78)]. In men, polypharmacy was less common at young age but showed a steep incline with age  when non-therapeutic and non-chronic drugs were excluded for sensitivity analysis.Figure 4). The use of drugs acting on the cardiovascular and blood & blood forming organs (mainly antithrombotics) seemed to co-occur most.The phenotype heat map created by hierarchical clustering of medication used in ACHD demonstrated heterogeneity among patients . The clusters differed significantly (Table S6). As shown in Figure 5, Cluster 1 (n = 8317) had the highest proportion of patients with drugs acting on the cardiovascular and blood & blood forming systems. This cardiovascular cluster was the oldest and had most patients with severe CHD (10%) and left sided lesions . Cluster 2 (n = 3501) mainly contained patients using anti-infectives and genito-urinary medication (sex hormones), but relative low use of other drugs, with polypharmacy in only 18% of patients. This low medication use cluster contained young, mainly female (70%) patients, mostly with mild defects (61%). In Cluster 3 (n = 2320), the comorbidity cluster, many patients used extra-cardiac medication. It had the highest proportion of patients with polypharmacy (36%) and genetic syndromes (7%).The analysis arrived at three clusters as the optimal number to reflect phenotypic variability  = 0.50 (95% CI 0.37–0.78), P < 0.001], but, despite the distinct medication patterns, did not differ between the comorbidity and cardiovascular cluster .After 8 years of follow-up, cumulative survival was 92% in the Figure 6). Eight-year mortality was higher in patients with polypharmacy at inclusion compared to those without polypharmacy . Corrected for age, sex, and defect severity, polypharmacy during the study was strongly associated with all-cause mortality in ACHD [HR = 3.94 (95% CI 3.22–4.81)]. The age- and sex-adjusted association was similar between the CHD severities (Pinteraction = 0.96 for moderate and Pinteraction = 0.70 for severe CHD compared to mild CHD) and was significantly stronger in ACHD patients than in referents (Pinteraction < 0.001).Survival analyses included 13 527 patients and 135 647 referents. During 7 (5–8) years, 595 (4%) patients and 2375 (2%) referents died  years, 21 ACHD patients were hospitalized for an ADE. Increasing drug amounts were associated with ADEs [HR = 1.20/dispensed drug (95% CI 1.10–1.32)]. Patients with polypharmacy were at markedly higher risk of hospitalization for an ADE compared to patients without polypharmacy [HR = 4.03 (95% CI 1.67–9.73)]. None of the patients that died during the study had ADEs as cause of death.This study shows that ACHD patients not only use more cardiovascular medication than the general population, but also use more extra-cardiac drugs, cumulating into polypharmacy in 30% of the patients compared to only 15% of referents. The study identified distinct medication patterns, which differed by age, sex, and CHD. Furthermore, patients with polypharmacy had an almost four-fold higher risk of all-cause mortality and almost five-fold higher risk of hospitalizations for ADEs.,,Recently, ACHD investigators have stressed the need for more evidence regarding drug therapy in this growing population.,,Previous studies focusing on other chronic conditions, such as diabetes mellitus, chronic kidney disease, and chronic heart failure, have shown comparably high odds for polypharmacy of these diseases.,Apart from common use of cardiovascular drugs, use of many non-cardiovascular drugs was increased in ACHD. Previous research showed increased prevalence of drugs related to asthma and epilepsy in patients who underwent surgery for a CHD as children.Interestingly, polypharmacy was even increased in mild CHD and at young age, reflecting decreased health even in these mildly affected patients. Alternatively, the increase in medication use may originate from intensive surveillance that facilitates early diagnosis and treatment.cardiovascular, low medication use, and comorbidity patterns. Cluster analysis based on phenotypical data has been used previously to identify distinct subgroups within other heterogeneous populations.,,comorbidity subgroup.Cluster analysis revealed three distinct patterns of medication use in ACHD, described as ,,,,This study showed, without implying causality, that patients with polypharmacy had a four-fold higher mortality risk (HR = 3.94), independent of age, sex, and defect severity. Furthermore, risk of hospitalization for adverse drug events was nearly five times higher in patients with polypharmacy (HR = 4.58). Interestingly, polypharmacy in the ACHD population was more associated with mortality than in the general population. Patients with polypharmacy may be sicker (needing therapy) than referents with polypharmacy (who e.g. often have statins as prevention). Whether an increased amount of drugs is an independent risk factor or a mere measure of poor health and multimorbidity, remains to be elucidated.The remarkably high prevalence of polypharmacy in ACHD shows that experience with managing polypharmacy is needed in the efficient management of these patients. Physicians should carefully judge drug indications in ACHD, especially as pharmacotherapy is often based on low-level evidence extrapolated from non-ACHD studies or small studies involving heterogeneous ACHD patients. Long-term use of some medication, e.g. amiodarone, may be suboptimal due to side effects.,These data from national administrative databases enable insightful comparisons with the general population. Automated data collection limits recall bias seen in questionnaires and data on dispensed drugs provide more accurate information on actual drug consumption than medical records, as these prescriptions have been filled. However, actual drug consumption may be overestimated, as we have no data on compliance. Non-compliance is of importance because it is associated with mortality and increases with treatment intensity and duration,The lack of clinical detail inherent to administrative data introduces indication bias, as no information on drug indications, comorbidities, and functional status are available. We used the consensus-based severity classification to subdivide patients with different risks. However, mortality risk may vary within specific CHDs due to late complications, such as pulmonary hypertension in patients with septal defects. Therefore, these data do not provide information about individual patients, but give insight on a population level. Furthermore, appropriateness of polypharmacy is not assessed and associations with mortality have to be interpreted with caution, as polypharmacy may mark high-risk patients with multimorbidity.,,Other limitations inherent to the data set include unavailability of data on over-the-counter medication, and data on treatment duration, daily doses, and specific distributed drugs. Our cumulative measures of polypharmacy may overestimate the prevalence of simultaneous pharmacotherapy, due to inclusion of successive and non-chronic drugs in the observed time frame. We limited this by aggregating drugs by therapeutic class, correcting for switches in pharmacological class. Such cumulative definitions of polypharmacy are common and give comparable, clinically relevant, and as reliable results as other measures of polypharmacy.In conclusion, ACHD patients used both more cardiovascular and non-cardiovascular medication compared to the general population, with polypharmacy in 30% of ACHD vs. just 15% of referents. Polypharmacy was even common in mild CHD at young ages. We identified different medication patterns that could be taken into account to help target therapies and trials in this heterogeneous population. As patients with polypharmacy had a four-fold higher risk of death and adverse drug events, daily clinical care of ACHD patients must include regular evaluation of their medication regimen, particularly in case of polypharmacy. Further clinical trials to investigate risks and benefits of pharmacotherapy remain needed to come to more evidence-based treatment in this population.pvz014_Supplementary_DataClick here for additional data file.