The highest regression was obtained for the FM values vs. vol. %. SEM images of the tested FRCs showed hybrid inorganic filler for Filtek Supreme XT (A3) and StarFlow (A2) and a homogeneous type of inorganic filler for the other investigated materials. All of the FS values were above 50 MPa, the ISO 4049/2019 limit for FRCs.The aim of this study was to evaluate the correlation between the percent of inorganic filler by weight (wt. %) and by volume (vol. %) of 11 flowable resin composites (FRCs) and their mechanical properties. To establish the correlation, the quantity of inorganic filler was determined by combustion and shape/size analyzed by SEM images. The compressive strength (CS), flexural strength (FS), and flexural modulus (FM) were determined. The CS values were between 182.87-310.38 MPa, the FS values ranged between 59.59 and 96.95 MPa, and the FM values were between 2.34 and 6.23 GPa. The percentage of inorganic filler registered values situated between 52.25 and 69.64 wt. % and 35.35 and 53.50 vol. %. There was a very good correlation between CS, FS, and FM vs. the inorganic filler by wt. % and vol. %. (R Flowable resin composites (FRCs) have been popular since 1995 because of their light cure and low viscosity. FRCs have a reduced filler content (37–53 vol. %) , which gThe major clinical indications of FRCs are preventive resin restorations, pit and fissure sealants, cavity liners, Class V abfraction lesions, minimally invasive Class II restorations, and an inner layer for posterior Class II restorations . The widn = 8) from 11 commercially available FRCs were prepared. n = 8) obtained in a Teflon mold with an internal dimension of 2 mm × 2 mm × 25 mm by curing them from the top and bottom in five 60-s stages along the length of the samples and storing the specimens as previously described. Samples (n = 10) were dried at room temperature in a desiccator for 1 day before combustion and weighed to an accuracy of 0.00001 g. The combustion of the specimens was performed at 700 °C for 3 h. The resulting powder was stored for another day in the desiccator and weighed with the same accuracy. The percentage of inorganic fillers by weight was determined by investigating the differences in the weight of the specimens before and after the combustion. The inorganic filler weight percent was then transformed to a volume percent by applying the formula from Equation (1) . Th. Th23]. The FM (GPa) was determined from the slope in the elastic portion of the stress–strain curve.FRC disks of Accolade SRO (A2), Filtek Supreme XT (A3), ELS , PermaFlo (A1), StarFlow (A2), and Wave (A3) measuring 8 mm diameter and 1 mm (±0.01) thickness were obtained by curing with an XL3000 photocuring source  for 60 s. The FRC samples were polished using #800 and #1200 carbide paper. The specimen surfaces were evaluated by SEM  at an operating voltage of 15 kV and a magnification of 10.000×. The data were statistically evaluated using one-way analysis of variance (ANOVA) with SPSS  software package, with a Tukey’s test with the level of significance set at 0.05 to calculate the significant differences between the mean values of the tested FRCs. The combustion analysis that was conducted showed that the inorganic filler fraction ranged between 52.25 and 69.64 wt. % and 35.35 and 53.50 vol. % . The CS The SEM analysis of the FRC surfaces  showed ap > 0.05) from the materials with the lowest CS: Accolade PV A2 , Wave A3 (SDI), Starfill 2B , Wave mv A2 , Tetric EvoFlow Bleach L (Ivoclar Vivadent), and Tetric EvoFlow A3  from the materials with lower FS values: Accolade PV A2 , ELS (Extra Low Shrinkage) A3 op , Accolade SRO , StarFlow A2 , and Wave A3  from all of the other tested materials. The materials with the lowest FM values were StarFlow A2  and Wave A3 (SDI) (2 = 0.8899 and R2 = 0.8899). The highest correlation coefficients were also found for FS values and FM values vs. the values of inorganic filler by wt. % and vol. %. (R2 = 0.9483 and R2 = 0.9237). To calculate the correlation between the FM values vs. the inorganic filler values by vol. %, we excluded PermaFlo DC . The null hypothesis, that the percentage of fillers by weight and volume could be correlated with the mechanical properties was accepted. The FS test was associated with the fracture behavior, which occurs more often in I, II, and III Class restorations . Due to omposite . The FM A3 (SDI) . The FM o DC A2; . In our o DC A2;  for PermThe SEM images  demonstrThe percentage of inorganic filler registered was very well correlated with the mechanical properties and influenced the mechanical properties of the FRC. The highest regression was obtained for the FS values vs. the inorganic filler fraction vol. %. The tested FRC demonstrated FS values, which certificate them to be used as restorative materials as stated in ISO 4049/2019. The presence of hybrid inorganic fillers in the composition of some materials confirmed better mechanical properties.


This data article describes the attitudes of German and Chinese respondents to some measures taken against the COVID-19 pandemic such as social distancing and face masks wearing, as well as their trust in government actions. The data were collected through six online surveys conducted between March 23 to September 15 2020 from 865 participants in Germany, 135 in China and 169 participants with Chinese roots in Germany. The data were partly used in related research papers in which the theoretical background, analysis of the survey variables and the interpretation of the findings are presented in detail  During this time period, different measures and restrictions were introduced in Germany. This allows to measure changes in these parameters induced by the changing pandemic situation as well as by changes in policy measures.•The data also allow making comparisons across countries (China and Germany) that show interesting differences. It should be emphasized, however, that the data are not representative, thus we cannot generalize sample means to the national populations of China or Germany. The primary goal is therefore the detection of associative relationships between the variables.1The attached dataset contains six sub-datasets. Our data were collected through six self-administered anonymous questionnaire-based surveys on the Internet platform Unipark. As shown in ,3,5,6,The samples in our data are obviously not representative for the overall population of Germany or China. 2To see whether they are aware of the exponential growth of cases during a pandemic, the respondents were asked to estimate the number of cases in one month, assuming that the numbers double in four days.Questions in To measure the attitude towards foreigners  and globalization, participants were asked to state whether they agree with the following statements : “I coulAs regards face masks, the questions can be divided into three groups. In the first group, the general opinion of the respondents on face masks was asked: whether it is weird when someone wears a mask in public; whether others would think strange of them if they wear a mask; how well wearing a face mask can protect oneself from getting infected; how well it can protect others from getting infected. In the second part, they were asked whether they would wear a face mask voluntarily when they were at a supermarket, on a bus, at the University, on the street and on a plain, respectively. Too see whether they would change their decisions when face mask wearing was a legal obligation, the same questions were asked again in the third part but under the condition that it were required by law.Last but not least, to assess the participants’ satisfaction with the government performance during the pandemic, they were asked, as listed in 2There was one questionnaire for each wave of sample 1 and sample 3, and one for sample 2 respectively. Each questionnaire consisted of two parts. The first part included general information on the respondents  which is summarized in (age) What is your age?1.Male2.Female3.Other(gender) What is your gender?1.Pupil2.Student3.Employed (public sector)4.Employed (private sector)5.Self-employed6.Homemaker7.Unemployed8.Other(job) What is your current occupation?1.Secondary general school (Hauptschule)/Middle School (Mittlere Reife)/Abitur2.Bachelor's degree3.Master's degree, Magister degree, Diploma4.PhD5.Other(degree) What is the highest degree or level of school you have completed?1.Yes2.No(econ_experience) Are you currently pursuing or do you already have a degree in Economics?1.Yes2.No(pre_results) Have you had the opportunity to get acquainted with the results of our previous survey on the Coronavirus crisis?(known_old_people) How many people aged 70 or above do you personally know?1.Yes2.No(known_case) Did any of your relatives, acquaintances or friends get infected with the novel Coronavirus?1.Yes2.No(known_suspected) Does any of your relatives, acquaintances or friends suspect to have been infected with the novel Coronavirus?1.Very little2.Little3.Somewhat4.Quite a bit5.A great deal(worries_corona) How worried are you personally about the consequences of the Coronavirus?(german_deaths) How many people do you think will die from Coronavirus in Germany until the end of this year?(chinese_deaths) How many people do you think have died from Coronavirus in China until now ?Which of the following statements do you think are correct?(ways_transmission) Coronaviruses can be spread when the infected person coughs, sneezes but also speaks or breathes.(coronavirus_history) Coronaviruses have always been there and mostly cause a harmless cold.(pathogen) The correct name of the ongoing virus is SARS-CoV-19.(new_influenza_virus) Coronavirus is a new form of the flu virus.(spread_with_symptom) Only those with symptoms can spread the virus.(mild_illness) In most cases, the virus leads to a mild cold.(death_rate) The mortality rate of the virus is 0.1% among young people and in the double-digit percent range among older people.(length_vaccine) According to the experts, the development of a vaccine will take about a year. If the number of infected people in a given country is 1000 on March 20 and 1000 new cases are reported on March 24, how many new cases can be expected in a month (given that no measures are being undertaken to curb the spread of the virus).To what extent do you agree or disagree with the following statements?1.Strongly disagree2.Somewhat disagree3.Neither agree nor disagree4.Somewhat agree5.Strongly agree(one_soure_info) While searching for new information on a specific topic, I am normally satisfied with one single source.1.Strongly disagree2.Somewhat disagree3.Neither agree nor disagree4.Somewhat agree5.Strongly agree While searching for new information, I search both for information that supports my opinion as well as for information that contradicts my opinion and I weigh the arguments against one another.1.Strongly disagree2.Disagree3.Agree4.Strongly agree(problem_sovling) It is not very important to insist on trying to solve a difficult problem.1.Strongly disagree2.Disagree3.Agree4.Strongly agree(supportive_arguments) I search for arguments that support my point of view and not for arguments that contradict it.1.Strongly disagree2.Disagree3.Agree4.Strongly agree(time_wasting) Analyzing the arguments of other people is a waste of time.1.Strongly disagree2.Disagree3.Agree4.Strongly agree(own_thought) I am aware of my own opinions, why should I pretend to be considering other options?1.Strongly disagree2.Disagree3.Agree4.Strongly agree(no_own_ideas) Taking into account the opinions of other people means that you are not able to have your own.1.0=very high risk aversion2.13.24.35.46.57.68.79.810.911.10=very high risk loving(risk_taking) How would you personally assess yourself? Are you generally willing to take risks or do you try to avoid taking risks?1.0=very high risk aversion2.13.24.35.46.57.68.79.810.911.10=very high risk loving How would assess your willingness to take risks in situations related to your health?1.A payment of 3400 € this month2.A payment of 3800 € next month(patience) Which of the following offers would you prefer?1.A payment of 1700 € this month2.A payment of 1900 € next month(patience) Which of the following offers would you prefer?Where do you think does the COVID-19 origin from?1.No2.Rather unlikely3.Rather likely4.Yes(cov_from_china) China1.No2.Rather unlikely3.Rather likely4.Yes(cov_from_usa) The USA1.No2.Rather unlikely3.Rather likely4.Yes(cov_from_elsewhere) ElsewhereHave you heard or read any of the following theories about the origins of COVID-19?1.Yes, I have.2.No, never. The virus originated in animals (bats or pangolins) and spread to humans.1.Yes, I have.2.No, never.(wuhan_origin) The virus emanated in Wuhan (China).1.Yes, I have.2.No, never.(wuhan_lab) The first patient was an employee of a virus lab in Wuhan who got infected by accident.1.Yes, I have.2.No, never.(us_secret_service) The US Secret Agency developed the virus and imported it into Wuhan to damage China.1.Yes, I have.2.No, never.(china_bioweapon) The virus was developed by China at a laboratory for biological weapons and spread due to an accident.1.Yes, I have.2.No, never.(caused_by_5G) The spread of COVID-19 is related to the rollout of 5G networks.1.Yes, I have.2.No, never.(pharma_companies) Pharmaceutical companies and Bill Gates spread the virus to make money from their patented vaccine.1.Yes, I have.2.No, never.(wuhan_market) The first patients supposedly got infected at a live animal market in Wuhan.How likely do you think these theories about the origins of COVID-19 are?1.Very unlikely2.Unlikely3.Somewhat likely4.Likely5.Very likely The virus originated in animals (bats or pangolins) and spread to humans.1.Very unlikely2.Unlikely3.Somewhat likely4.Likely5.Very likely(prob_wuhan_origin) The virus emanated in Wuhan (China).1.Very unlikely2.Unlikely3.Somewhat likely4.Likely5.Very likely(prob_wuhan_lab) The first patient was an employee of a virus lab in Wuhan who got infected by accident.1.Very unlikely2.Unlikely3.Somewhat likely4.Likely5.Very likely(prob_US) The US Secret Agency developed the virus and imported it into Wuhan to damage China.1.Very unlikely2.Unlikely3.Somewhat likely4.Likely5.Very likely(prob_China_bioweapon) The virus was developed by China at a laboratory for biological weapons and spread due to an accident.1.Very unlikely2.Unlikely3.Somewhat likely4.Likely5.Very likely(prob_5G) The spread of COVID-19 is related to the rollout of 5G networks.1.Very unlikely2.Unlikely3.Somewhat likely4.Likely5.Very likely(prob_pharma_companies) Pharmaceutical companies and Bill Gates spread the virus to make money from a patented vaccine developed by them.1.Very unlikely2.Unlikely3.Somewhat likely4.Likely5.Very likely(prob_wuhan_market) The first patients supposedly got infected at a live animal market in Wuhan.To what extent do you agree or disagree with the following statements?1.Disagree2.Somewhat agree3.Mostly agree4.Strongly agree(trust_offi_info) I trust the official information on the Coronavirus in Germany.1.Disagree2.Somewhat agree3.Mostly agree4.Strongly agree(media_hide_info) The media try to hide information about the Coronavirus from the public.1.Disagree2.Somewhat agree3.Mostly agree4.Strongly agree(german_media_hide_info) The German media try to hide information about the Coronavirus from the public.1.Disagree2.Somewhat agree3.Mostly agree4.Strongly agree(chinese_media_hide_info) The Chinese media try to hide information about the Coronavirus from the public.1.Disagree2.Somewhat agree3.Mostly agree4.Strongly agree(profit_pharma) The hype about the Coronavirus was caused by pharmaceutical companies and other groups that benefit from it.1.Disagree2.Somewhat agree3.Mostly agree4.Strongly agree(rights_undermining) The virus is just an excuse for our politicians to trample on our fundamental human rights.1.Disagree2.Somewhat agree3.Mostly agree4.Strongly agree I can understand why someone would avoid sitting next to an Italian person on the bus.1.Disagree2.Somewhat agree3.Mostly agree4.Strongly agree(avoid_french) I can understand why someone would avoid sitting next to a French person on the bus.1.Disagree2.Somewhat agree3.Mostly agree4.Strongly agree(avoid_chinese) I can understand why someone would avoid sitting next to a Chinese person on the bus.1.Disagree2.Somewhat agree3.Mostly agree4.Strongly agree(chinese_responsible) Ultimately, it is the Chinese that are responsible for the pandemic.1.Disagree2.Somewhat agree3.Mostly agree4.Strongly agree(econ_relations_reduction) We should limit our economic relations with China to avoid such problems in the future.1.Disagree2.Somewhat agree3.Mostly agree4.Strongly agree(less_chinese) It would be better if there were less Chinese people in Germany.1.Disagree2.Somewhat agree3.Mostly agree4.Strongly agree Our lives would be better without globalization.1.Disagree2.Somewhat agree3.Mostly agree4.Strongly agree(china_better) China's response to the pandemic was better than that of Germany.1.Disagree2.Somewhat agree3.Mostly agree4.Strongly agree(lern_eastasia) We can generally learn from East Asia how to handle pandemics.1.Disagree2.Somewhat agree3.Mostly agree4.Strongly agree(wuhan_response) Wuhan was too slow in its response to the pandemic.How would you characterize the behavior of the following students last weekend?1.Perfectly OK2.Not optimal but understandable3.Rather bad4.Unacceptable(hypo_birthday_party) A student celebrates his birthday with his friends on the university campus. None of the friends is in a high-risk group.1.Perfectly OK2.Not optimal but understandable3.Rather bad4.Unacceptable(hypo_soccer) A student meets his friends for a soccer game. None of them is showing any symptoms.1.Perfectly OK2.Not optimal but understandable3.Rather bad4.Unacceptable(hypo_grandma_visiting) Despite having a cold, a student visits his grandmother in a nursing home because she is feeling lonely.1.Perfectly OK2.Not optimal but understandable3.Rather bad4.Unacceptable(hypo_distance_keeping) A student meets his friends for a jog and does not greet them by hugging as usual and insists that they keep distance, even though his friends tell him that they are not feeling sick.1.Perfectly OK2.Not optimal but understandable3.Rather bad4.Unacceptable(hypo_blaming) A student tells her friend that it is irresponsible of him to continue to meet his friends, knowing that it may hurt his feelings.(estimated_restriction_duration) How many weeks do you think the ongoing restrictions due to the Coronavirus will last in Germany?1.Disagree2.Somewhat agree3.Mostly agree4.Strongly agree(weird_masks) It is weird when someone wears a face mask in public.1.Yes, for sure2.Rather yes3.Rather no4.No, certainly not(seen_as_weird) Would others  think strange of you if you wore a face mask?1.Very well2.Well3.Somewhat4.Very little5.Not at all(self_protection) How well do you think wearing a face mask protects one from getting infected with the new Coronavirus?1.Very well2.Well3.Somewhat4.Very little5.Not at all(protection_others) How well do you think wearing a face mask prevents one from infecting others with the new Coronavirus?Would you wear a face mask in the following situations (assuming you had one)?1.No2.Probably no3.Probably yes4.Yes(mask_supermarket) At the supermarket1.No2.Probably no3.Probably yes4.Yes(mask_bus) On the bus1.No2.Probably no3.Probably yes4.Yes(mask_university) At the university1.No2.Probably no3.Probably yes4.Yes(mask_street) On the street1.No2.Probably no3.Probably yes4.Yes(mask_plane) On the planeIf wearing a face mask were legally required, would you wear one in the following situations (assuming you had one)?1.No2.Probably no3.Probably yes4.Yes(law_mask_supermaket) At the supermarket1.No2.Probably no3.Probably yes4.Yes(law_mask_bus) On the bus1.No2.Probably no3.Probably yes4.Yes(law_mask_university) At the university1.No2.Probably no3.Probably yes4.Yes(law_mask_street) On the street1.No2.Probably no3.Probably yes4.Yes(law_mask_plane) On the planeHow satisfied are you with the performance of the Federal Government on the following aspects?1.1=very dissatisfied2.23.34.45.56.67.7=very satisfied(gov_info_provision) Provision of information on the novel Coronavirus1.1=very dissatisfied2.23.34.45.56.67.7=very satisfied(gov_measures_pandemic) Measures aimed at managing the Coronavirus crisis 1.1=very dissatisfied2.23.34.45.56.67.7=very satisfied(gov_measures_daily_life) Measures that ensure the normal course of daily life of the citizens during the ongoing pandemic 1.Far too slow and lax2.Rather slow and lax3.Well-balanced4.Rather fast and restrictive5.Far too fast and restrictive(germany_gov_slow_fast) All in all, how would you rate the response of the German government to the novel Coronavirus?1.Far too slow and lax2.Rather slow and lax3.Well-balanced4.Rather fast and restrictive5.Far too fast and restrictive(china_gov_slow_fast) All in all, how would you rate the response of the Chinese government to the novel Coronavirus?1.Far too slow and lax2.Rather slow and lax3.Well-balanced4.Rather fast and restrictive5.Far too fast and restrictive(wuhan_gov_slow_fast) All in all, how would you rate the response of the Wuhan government to the novel Coronavirus?Informed consent was obtained for experimentation with human subjects.The authors declare that they have no known competing financial interests or personal relationships which have, or could be perceived to have, influenced the work reported in this article.


Studies of morbidity compression routinely report the average number of years spent in an unhealthy state but do not report variation in age at morbidity onset. Variation was highlighted by Fries (1980) as crucial for identifying disease postponement. Using incidence of first hospitalization after age 60, as one working example, we estimate variation in morbidity onset over a 27-year period in Denmark. Annual estimates of first hospitalization and the population at risk for 1987 to 2014 were identified using population-based registers. Sex-specific life tables were constructed, and the average age, the threshold age, and the coefficient of variation in age at first hospitalization were calculated. On average, first admissions lasting two or more days shifted towards older ages between 1987 and 2014. The average age at hospitalization increased from 67.8 years (95% CI 67.7–67.9) to 69.5 years (95% CI 69.4–69.6) in men, and 69.1 (95% CI 69.1–69.2) to 70.5 years (95% CI 70.4–70.6) in women. Variation in age at first admission increased slightly as the coefficient of variation increased from 9.1 (95% CI 9.0–9.1) to 9.9% (95% CI 9.8–10.0) among men, and from 10.3% (95% CI 10.2–10.4) to 10.6% (95% CI 10.5–10.6) among women. Our results suggest populations are ageing with better health today than in the past, but experience increasing diversity in healthy ageing. Pensions, social care, and health services will have to adapt to increasingly heterogeneous ageing populations, a phenomenon that average measures of morbidity do not capture.The online version of this article (10.1007/s10654-020-00642-3) contains supplementary material, which is available to authorized users. Remaining life expectancy at age 60 has increased across developed countries . WhetherKey to Fries (1980) theory of morbidity compression is that the years spent with bad health or disability would become increasingly concentrated at the end of life. This implies that the age at morbidity onset should become increasingly homogenous within populations. This dimension is well established in mortality compression research, which focuses on changes to the variation in age at death , 16. HowReducing rates of morbidity onset at any age increases the average age at morbidity onset. Variation in age at onset reductions depend on the balance between reducing rates at younger ages, which compresses the age-at-morbidity-onset distribution into a narrower age span, and reducing rates at older ages, which increases variation by pulling out the right tail of the age-at-morbidity-onset distribution. For variation in the age at morbidity onset to decrease, onset at younger ages needs to be reduced faster than onset at older ages . This woThere is no universal indicator of morbidity. Most estimates of DFLE or HLE use prevalence based estimates of disability or functional limitations, typically derived from self-reported health surveys , 17. In In this paper, we calculate variation in the age at morbidity onset, using hospital admissions data for all individuals aged 60 + between 1987 and 2014 in Denmark, as a working example. The ageing population structure in Denmark is comparable to many other developed countries. Unique to Denmark is that data exist for constructing individual-level hospitalization trajectories for the total population covering a substantial period of time , 25.We linked individual level records, covering the total Danish population, from the National Patient Register (NPR) with data from the Central Population Register (CPR) using the unique personal identification number (CPR-Number). The NPR contains information on all treatments provided in Danish hospitals since 1977 . ReportiAs hospitalization data for Denmark began in 1977, we were not able to identify admissions before this year. To ensure comparability throughout the study period, we created an identical cohort study population and consistently applied the same method for each calendar year between 1987  and 2014. Figure First, we linked CPR and NPR information on all inpatient admissions and the population alive and residing in Denmark aged 60 + . Second, we identified all individuals hospitalized within the previous 7-year period—irrespective of length of stay, and excluded these individuals from the analyses for that particular year. This 7-year washout period was used to limit the chance that a first event is a readmission or a follow-up treatment , 27. ThiFrom the number of first hospital admissions and the population at risk, we estimated age-specific risks of first admission  and reported values as a percentage. The CoefV is a standard measure of dispersion and is defined as the ratio of the standard deviation to the average. Here, the CoefV reflects the variability in age at first hospital admission relative to the average age at first hospital admission. We calculated 95% Confidence Intervals (95% CI) for nd CoefV .Figure The trend declined throughout the 1990s before rebounding in the 2000s, resulting in a subtle u-shaped pattern. In 1987, the average age at first admission for men was 67.8 years (95% CI 67.7–67.9). At the midpoint, 2001, the average age had increased only slightly to 67.9 years (95% CI 67.8–67.9). By 2014, the average age at first admission had increased to 69.5 years (95% CI 69.4–69.6). For women, the average age decreased slightly between 1987 and 2001: from 69.1 years (95% CI 69.1–69.2) to 68.5 years (95% CI 68.4–68.6). By 2014, the average age for women had increased to 70.5 years (95% CI 70.4–70.6).Figure The threshold age and the proportion of individuals experiencing an admission below the threshold age increased over time among men and women. In 1987, the threshold age was 62.0 years for men and 17.3% experienced their first admission to hospital below the threshold age. The remaining 82.7% experienced a first admission to hospital above the threshold age. By 2001, the threshold age for men had increased to 62.4 years and the proportion which experienced a first admission to hospital below the threshold age increased to 19.3%. In 2014, the threshold age for men increased further to 63.3 years and 21.3% experienced a first admission to hospital below the threshold age. For women, the threshold age in 1987 was 62.6 years and 19.5% of women experienced a first admission to hospital below the threshold age. The remaining 80.5% of women experienced a first admission to hospital above the threshold age. By 2001, the threshold age for women and the percentage of women being admitted to hospital below the threshold age remained unchanged. The threshold age reached 64.0 years in 2014 and the percentage of women who experienced a first admission to hospital below the threshold age was 22.9%. The remaining 77.1% experienced a first admission to hospital above the threshold age.We estimated the CoefV to quantify variation in the average age at first hospital admission. Figure Among men, the CoefV in average age at first admission to hospital decreased from 9.1% (95% CI 9.0–9.1) in 1987 to 8.7% (95% CI 8.6–8.7) in 2001. For women, the corresponding change was from 10.3% (95% CI 10.2–10.4) to 9.4% (95% CI 9.4–9.5). In the early 2000s, the trends in variation changed to slightly increasing. In 2014, the CoefV was 9.9% (95% CI 9.8–10.0) for men and 10.6% (95% CI 10.5–10.6) for women.Our main results reflect hospital stays lasting a minimum of 2 days, including all fatal events. We tested the sensitivity of our results by systematically altering three features of the analysis: (I) varying the minimum length of stay, (II) excluding fatal cases that occurred during admission, and (III) changing the washout period length. The substantive conclusions were generally consistent across the different sensitivity tests. However, the choice of cut-off for length of stay did have an impact. Stays lasting 1 day showed a slightly decreasing trend as opposed to the increasing trend found for all other lengths of stay that were analyzed. Results of sensitivity analyses are provided in Appendices 2 and 3 .We found the average age at first hospital admission at ages 60, for admissions lasting more than 2 days, to be higher in 2014 than in 1987, suggesting that people on average tend to live for longer without being admitted to hospital. At the same time, there may have been an increase in the proportion of first events occurring below the threshold age, and variation in age at first hospital admission may have increased. These findings indicate that individuals may face greater uncertainty in the timing of morbidity onset and that health at older ages may have become increasingly heterogeneous.A shift of hospital admissions towards older ages would suggest that people are ageing with better health today than in the past. Healthy ageing is due to multiple factors, including improved health during childhood, reduced exposure to hazardous working conditions, and changes in health behaviors such as smoking or diet , 35. AnoAt the same time, increasing variation in age at morbidity onset would indicate increasing diversity in healthy aging. The same technological advancements that have postponed adverse health events, have also enabled individuals to live for longer while managing chronic conditions, resulting in populations with more heterogeneous health profiles , 38, 39.Changes to population health are not the only factor which could have contributed to the changes in hospital admissions. Differences over time in admission and treatment strategies will have had an impact . In an aStudies of morbidity traditionally use self-reports of functional limitation, disability, or poor health from survey data to capture the concept of morbidity , 41–44. Unfortunately, there are few longitudinal data sources covering an entire population that enable the identification of morbidity onset required to estimate variation. Even for a country with an established register based system, such as Denmark, options were limited. We identified first admission to hospital after age 60 as one illustrative example. From hospital admissions data we were able to estimate the incidence rate of a medical diagnosis as a proxy indicator of morbidity , 19. HowIn Denmark, General Practitioners are gate keepers for determining access to hospital care , 49 and Morbidity compression studies have consistently calculated the average number of years spent in an unhealthy state, compared with life expectancy , 51–55. Supplementary file1 (PDF 253 kb)Supplementary file2 (PDF 1744 kb)Supplementary file3 (PDF 749 kb)Supplementary file4 (PDF 273 kb)Below is the link to the electronic supplementary material.


Populus nigra) on seven different late blight strains was tested under laboratory and field conditions. The growth rate of hyphae was found to be significantly lower in vitro after 3 and 4 v/v% populin applications. Stain M16 was resistant to populin treatment under lab conditions, however. Both 5% and 10% concentration populin reduced the M16 strain’s severity on potato leaves under field conditions and proved to be even more effective than conventionally used fungicides Infinito 687 Sc and Valis M. Higher infection intensity at the 1% level was observed after 24 h using Valis M, and the same trend toward 10% infection remained after 48 and 72 h as well. Low, almost-no-infection intensity was detected after populin 5% and 10% treatment under an open field condition. Altogether, it can be concluded that populin extract can be a low-cost option for growers and an environmentally friendly approach in late blight control.The effect of populin extract from black poplar ( Phytophthora infestans (Mont.) de Bary is one of the most severe and economically important diseases of the Solanaceae family worldwide . ThP. infestans were previously maintained on pea-broth agar (PBA) [v/v% of the extract from black poplar buds (here termed populin) were prepared by the addition of the required volume of filter sterilized , concentrated extract with 20% populin and varying volumes of sterile distilled water to a total of 67.5 mL combined volume to the medium after autoclaving. Plates containing no extract, only distillate water, were used as controls and received only 67.5 mL sterile distilled water. First, PBA glass plates were inoculated with 8-mm-diameter mycelial agar blocks excised from actively growing colonies of P. infestans. Altogether 100 plates were inoculated with each strain , meaning 20 plates/strain/treatment (four treatments and control). Inoculated plates were then incubated for 14 days at 20 °C in darkness. Colony growth of P. infestans in each plate was measured daily in two directions  over a 10 day period after the 14 days incubation using a digital caliper in units of mm, which were collected as quantitative data up to 55 mm (the plate diameter). The whole experiment was carried out twice with the same number of replicates and followed along each 10-day period. The parameters of the treatments were as follows:The whole lab experiment was carried out in 2016 and 2017. The seven strains of ar (PBA) . PBA tesv/v%-11.25 mL 20% populin + 140 g pea agar + 56.25 mL sterile distillate water.v/v%-22.5 mL 20% populin + 140 g pea agar + 45 mL sterile distillate water.v/v%-33.75 mL 20% populin + 140 g pea agar + 33.75 mL sterile distillate water.v/v%-45 mL 20% populin + 140 g pea agar + 22.5 mL sterile distillate water.Control-no populin + 140 g pea agar + 67.5 mL sterile distillate water.v/v% populin extract on the mycelial growth was low, the experiment was repeated again two more times  using only 3 and 4 v/v% extracts and water control. The experimental conditions, data assessment and number of replicates were the same as describe above.When the inhibitory effect of 1 and 2 2 area. First the area was surrounded by a 1.5-m plastic fence to prevent the experimental plot from unknown late blight strains present in the neighboring fields. The potato variety Carrera was used in the experiment, because it is one of the most frequently cultivated varieties and is often used in experiments dealing with foliage and tuber blight [Field application of populin treatment was carried out during a complete vegetation period in Central Transylvania  in 2018. This area is dominated by potato fields in which traditional cultivating methods are applied. The experimental plot was established in a 1000-mr blight ,23. StraInfinito 687 SC (62.5 g/L fluopicolid + 625 g/L propamocarb) doze: 1.4 L/300 L water (1.9 mL/200 mL water) synthetic fungicide.Valis M  doze: 2.5 kg/300 L water (1.7 g/200 mL water) synthetic fungicide.Populin 10%: 100 mL extract 20% + 100 mL water.Populin 5%: 50 mL extract 20% + 150 mL water.Control-no populin or synthetic fungicide, only distilled water 200 mL.The late blight inoculum M16 was prepared and plant infestations made according to Bálint et al., 2014 . Potato 0% = healthy (0 foliar damage).1% = up to 10 spots per plant or up to 1 leaflet in 10 attacked.10% = up to 4 leaflets in 10 affected; plants still retaining normal form.25% = nearly every leaflet with lesions but plants still retaining normal form; plot may look green though every plant affected.50% = every plant affected and about half of leaf area destroyed by blight; plot looks green, flecked with brown.Field assessments of late blight infestation were made according to the EPPO protocol . During All applicable international, national, and/or institutional guidelines for the care and use of plant pathogens were followed. The article does not contain any studies with human and animal participants performed by any of the authors.The data from the lab experiments did not follow the assumption of normality; therefore, the Kruskal-Wallis test, followed by a Mann-Whitney test, was used to assess differences for each day during the 10-day assessment period. The effects of populin treatments were compared with controls using the average value of daily diameter data recorded during the 10-day growing period for 20 plates/strains/treatments, and 99% confidence intervals were used as statistically significant differences.Because data from field experiment did not meet the assumption of normality, again the nonparametric Kruskal-Wallis test was used, followed by a Mann-Whitney test to compare the effect of populin, synthetic fungicide treatment and control. To compare infection rate and intensity, average data of 10 plants/blocks/treatments were used, and 95% confidence intervals were used as statistically significant differences. All analyses were run in R .v/v% populin treatments or their absence (control) under lab conditions on mycelial growth of different late blight strains. This was done by subjecting data on the relative amount of each strain’s dimensions in plates after 3 and 4 v/v% application and control. PCA was also used to test the effect of either populin, synthetic fungicide or its absence (control) as an environmental variable on late blight infection rate and intensity under experimental field conditions. Before analyses, all data were first averaged and log10 transformed, then PCA covariance analyses were run using Community Analysis Package 4 in R [Principal Components Analyses (PCAs) were used to determine the effect of 3 and 4 e 4 in R .P. infestans hyphae under lab conditions in the control, the most intensive growth was detected for strain NY34 (average of 46.3 mm), reaching the maximum area of 55 mm on the 5th day. This was followed by strains S40 (mean of 43.6 mm), T17 (mean of 41.4 mm), T2 (mean of 41.6 mm), H-1/2005 (mean of 36.3 mm) and M16 (mean of 33.3 mm). The lowest growth rate was detected for strain 13/08/21 (mean of 28.7 mm), which did not reach the maximum size of the plate even at day 10. By comparing the growth rate under different populin treatments and their controls, it could be detected that the 1 v/v% populin did not affect the growth of strains 13/08/21 , M16  and T17 , but had a moderate effect on other strains after the first days and reduced the growth of mycelium significantly until the end of the experiment  and M16 , while the 3 v/v% concentration reduced the growth rate of all strains  and small colonies with an average of 11 to 32 mm were observed at the end of day 10 , S40 , T17  and T2  compared with control  positive correlation values between PCA scores of treatments and late blight colony dimensions were detected for all strains except for M16 (rho < 0.62) (Considering the average growth rate of periment . Populin strains . Populinf day 10 . Running control . Delayed control . The 4 v for M16 . PCA rev < 0.62) .Considering assessment of the field experiment, 0% infection rate was detected after 24 and 48 h when populin 5 and 10% were applied A,B. InhiHigher infection intensity at the 1% level was observed after 24 h using Valis M D. The saP. infestans. The extract considerably reduced the hyphal growth of six isolates out of seven in culture, and was significantly more effective against leaf blight in the field experiment than the two synthetic fungicides used in late blight control. Because all of the major diseases of Populus species are caused by true fungi, it is possible that Populus species  generally produce compounds as populin that inhibit oomycete pathogens. Based on this, it can be concluded that the disease severity may be significantly reduced by the use of populin extract in a 5% or 10% concentration. It is also a less expensive yet available natural material that could replace fungicides under field conditions. Strain M16, however, seems to have developed resistance against populin, and the background of this resistance needs further assessment. For many growers, the repeated application of synthetic fungicides throughout the growing season has been the only available approach to managing late blight. Therefore, resistance against these fungicides now exists in many of the potato growing areas throughout the world [Venturia inaequalis) conidia, and that infestation levels furthermore were lower than in cases of conventional treatments [Our aim was to test the effect of poplar bud extract on the potato late blight pathogen he world ,8. Accoreatments .P. infestans in laboratory bioassays [Galla chinensis, Potentilla erecta, Rheum rhabarbarum, Salviae officinalis, Sophora flavescens and Terminalia chebula) [Podophyllum hexandrum, Withania somnifera and Xanthium strumarium) at a 3-day interval significantly reduced disease severity and resulted in a higher tuber yield [P. infestans. Unfortunately, little is known about the biological mechanisms leading to the inhibitory effect of populin [P. infestans isolates, direct inhibition of hyphal growth might be a possible mode of action. However, there must be other mechanism(s) too, because disease severity caused by the isolate which was insensitive to populin in vitro was greatly reduced in the field trials. Germination of sporangia and/or encysted zoospores could have been inhibited by populin, but we cannot exclude the role of antagonistic organisms in the phyllosphere either. Further investigations are needed to answer these questions. According to our results, including those of the apple scab [Compounds of plant extracts may have direct inhibitory effects on plant pathogens , or they can help in the establishment of favorable conditions for antagonistic microbes . Extractioassays ,28. Wangchebula) . In the er yield . Accordi populin ,16. Sincple scab ,16,17, w


Experiments occurred in Nebraska, Oklahoma, Washington, and Texas. Similar arrival processing was used across experiments where 17,675 heifers [initial body weight = 333 kg SEM (4.1)] were enrolled into 180 pens (90 pens per treatment with 65–240 heifers per pen) and fed for 145–222 d. Only REPEATED heifers were removed from their pen at reimplant. Diets contained monensin and tylosin, consisted of ingredients common to each region, and contained greater than 90% concentrate. Ractopamine hydrochloride was fed for a minimum of 28 d prior to harvest. Linear mixed models were used for all analyses; model-adjusted means for each implant group and the corresponding SEM were generated. Distributions of U.S. Department of Agriculture (USDA) quality grade (QG) and yield grade (YG) were analyzed as ordinal outcomes. No differences (P ≥ 0.11) were detected for any performance parameters except dry matter intake (DMI), where SINGLE had greater (P = 0.02) DMI (9.48 vs. 9.38 ± 0.127 kg) compared with REPEATED. Heifers implanted with REPEATED had greater (P ≤ 0.02) hot carcass weight , dressing percentage (64.54 vs. 64.22 ± 0.120%), and ribeye area (91.87 vs. 89.55 ± 0.839 cm2) but less (P ≤ 0.01) rib fat (1.78 vs. 1.83 ± 0.025 cm) and calculated YG (2.82 vs. 2.97 ± 0.040) and similar (P = 0.74) marbling scores (503 vs. 505 ± 5.2) compared with SINGLE heifers. Distributions of USDA YG and QG were impacted (P ≤ 0.03) by treatment such that REPEATED had fewer USDA Prime and YG 4 and 5 carcasses. Heifer growth performance did not differ between implant regimens, but HCW and muscling did, perhaps indicating that REPEATED may be suited for grid-based marketing, and SINGLE might be suited for heifers sold on a live basis depending upon market conditions and value-based grid premiums and discounts. However, these decisions are operational dependent and also may be influenced by factors including animal and employee safety, stress on animals, processing facilities, time of year, labor availability, and marketing strategies.Randomized complete block design experiments ( Trials were conducted (n = 1), Oklahoma (n = 1), Washington (n = 1), and Texas (n = 3), and all heifers used in these experiments were of breed type respective of their feeding region. All heifers were vaccinated and treated for internal and external parasites according to processing protocols at each specific feed yard. A total of 17,675 heifers were enrolled into 180 pens (n = 90 pens per implant program), pen sizes ranged from 65 to 240 heifers per pen, and DOF ranged from 145 to 222. Heifers in the Revalor-XH treatment group remained in their home pens from start to finish, while heifers that were reimplanted were removed from their pen on the day of reimplanting. Diets fed in these studies consisted of common ingredients to the specific geographic area of the commercial feedlot and contained greater than 90% concentrate. Ractopamine hydrochloride was fed to all heifers for a minimum of 28 d prior to harvest.Large-pen feedlot studies  included:2) administered on arrival followed by Revalor-200 .1) Revalor-IH  administered on arrival (SINGLE).2) Revalor-XH  and assigned randomly to one of two treatments as they passed through the processing shed, resulting in six pen replications per treatment (n = 73 heifers on average per pen and 435 heifers per treatment) and were used in a randomized complete block design. Heifers were housed in outdoor, soil-surfaced pens, with a concrete bunk apron, and pens were stocked so that each animal had approximately 7.1 m2 and 27.9 cm of bunk space.Starting in May of 2018, intact crossbred heifers (from four unique sources) were received from Nebraska (two replications), North Dakota, and Montana (two replications), as well as spayed feeder heifers from Canada (two replications) to a commercial research feedyard near Farnam, NE. At initial processing, heifers were vaccinated against viral respiratory pathogens  and the parasiticides oral fenbendazole  and moxidectin pour-on  were given for the control of internal and external parasites. Heifers were excluded from the study if they were considered unfit for the experiment  or pregnant as identified via ultrasonography. A total of 870 heifers  were blocked by arrival load  was done using a series of four step-up diets over a 27-d period. The finish ration was prepared in the on-site feed mill and contained 65.3% steam-flaked corn, 18.0% wet distillers grains plus solubles, 5.5% corn silage, 4.5% mixed hay, 1.7% tallow, and 5.0% supplement on a DM basis. Feed calls were made to provide feed to appetite and such that feed carryover in the bunk was minimized.Monensin sodium  was included in the finish ration to provide 340 mg/heifer/d throughout the experiment. Tylosin phosphate  was included at 8 g/907 kg. To control the outbreak of heifers cycling, melengestrol acetate  was included in the diet to provide 0.45 mg/heifer/d. All heifers were fed 250 mg/heifer/d of ractopamine hydrochloride for 29 d with a 2-d withdrawal period prior to slaughter. Feed ingredients were collected weekly for DM determination on site, and these DMs were used for the calculation of DMI. The finishing diet provided protein and minerals to meet or exceed requirements .Heifers were weighed as a group by pen using a platform scale at study initiation and the morning of shipment for the calculation of live growth performance. Body weights were measured prior to the morning feeding and a 4% pencil shrink was applied to the final BW measure, and carcass-adjusted performance was calculated from HCW/dressing percentage (DP) in decimal form.Individual animal ID was tracked through the harvest floor, and HCW was captured as the carcass exited the harvest floor. Carcasses were graded after approximately 24-h chill. United States Department of Agriculture (USDA) quality grade  and YG (assigned by camera system), HCW, and grading camera measurements were obtained from the packing plant records. Dressing percentage for each pen was calculated as the mean HCW/final shrunk BW × 100.n = 12 blocks) and assigned to one of four implant treatments as they passed through the squeeze chute at initial processing, resulting in 12 pen replications per treatment . The implant treatments included: 1) Revalor-IH  at initial processing and reimplanted with a Revalor-200  after 90 d, 2) Revalor-200 at initial processing and reimplanted with a Revalor-200 after 90 d, 3) Revalor-XH  at initial processing, or 4) Synovex ONE Feedlot  at initial processing; only implant treatments 1 and 3 were used in the present analysis.Between January 25, 2018 and February 23, 2018, heifers were received at a commercial feed yard in Oklahoma. The yearling crossbred beef heifers were sourced from Arkansas, Colorado, Kansas, Mississippi, New Mexico, Oklahoma, and Texas. A total of 6,239 heifers were enrolled in the study. Heifers were arranged into blocks by arrival date  or if they were determined to be bred at the time of processing. Initial processing also included vaccination against viral respiratory pathogens  and clostridial species , as well as the application the of parasiticides injectable Ivermectin  and Safe-Guard oral drench  given for the control of internal and external parasites according to label instructions.2 and 23.1 cm of bunk space. Heifers were fed twice daily a milled ration consisting of steam-flaked corn (75.9%), wheat, and/or corn silage (9.2%), corn-milling byproducts (7.9%), and supplemental ingredients (7.0%). Heifers were fed a starter ration and were gradually adapted to a finish ration using a single intermediate ration and a series of step-up feeding schedules. Monensin sodium  was included in the finish ration at 34 g/907 kg (dry basis) and tylosin phosphate  was included at 9 g/907 kg (dry basis). Additionally, MGA was included in the finish ration at a rate sufficient to provide melengestrol at 50 mg/907 kg (dry basis). Heifers were fed ractopamine hydrochloride at a target level of 27 g/907 kg (dry basis) for 34 d followed by a 4-d withdrawal prior to harvest. Feed ingredients were collected weekly for DM determination on site, and these DMs were used for the calculation of DMI. Feed calls were made to provide feed to appetite and such that feed carryover in the bunk was minimized.Heifers were housed in outdoor, soil-surfaced pens, and pens were stocked so that each animal had approximately 11.9 mIndividual BW was recorded for each animal at the time of initial processing. Heifers were weighed as a group by pen using a platform scale the morning of shipment for the calculation of live growth performance. Body weights were measured prior to the morning feeding and a 4% pencil shrink was applied to initial weight and final BW. In addition, carcass-adjusted performance was calculated using carcass-adjusted final BW calculated from HCW/DP in decimal form.All heifers were shipped by block to a commercial abattoir  as they became market ready from July to August 2018. Camera plant data was obtained, and DP for each pen was calculated as the mean HCW/mean final shrunk live weight (4% shrink) × 100.n = 8 blocks) and assigned to one of two treatments as they passed through the processing shed, resulting in eight pen replications per treatment  and were used in a randomized complete block design. Heifers were housed in outdoor, soil-surfaced pens, and pens were stocked so that each animal had approximately 18.6 m2 and 25.4 cm of bunk space.Between February 7, 2018 and March 3, 2018, a total of 3,686 heifers were transported 24 km from a backgrounding facility in Washington State. Heifers were of English and English × Continental breeding. At initial processing, heifers were vaccinated against viral respiratory pathogens  and the parasiticides Safe-Guard oral drench and Synergized Delice pour-on  were given for the control of internal and external parasites. Heifers were excluded from the study if they were considered unfit for the experiment  or bred, identified via ultrasonography; these heifers remained at the backgrounding yard and were not included in the potential pool of study candidates. A total of 3,686 heifers  were blocked by arrival date (Transition to the finishing diet was done using a two-ration approach. The finish ration was prepared in the on-site feed mill and contained (DM basis) steam-flaked corn (62.0%) and high-moisture corn (14.0%) in a 4:1 ratio, alfalfa hay (2.7%), triticale silage (6.1%) condensed corn distiller’s solubles (3.6%), canola meal (4.3%), tallow (3.2%), and a liquid supplement (4.2%). Monensin sodium  was included in the finish ration (36 g/907 kg) throughout the experiment. Tylosin phosphate  was included at 8.3 g/907 kg. To control the outbreak of heifers cycling, MGA was included in the diet to provide 0.50 mg/heifer/d. All heifers were fed 19-g/907-kg ractopamine hydrochloride for 31–34 d prior to slaughter. All feed additives were included via a micromachine. Samples of each ration were collected daily from the feed bunk and dried at 100 °C. Daily DMs were averaged weekly and used for the calculation of DMI. The finishing diet provided protein and minerals to meet or exceed requirements .Heifers were weighed as a group by pen using a platform scale at study initiation and the morning of shipment for the calculation of live growth performance. Body weights were measured prior to the morning feeding and a 4% pencil shrink was applied to final BW. In addition, the carcass-adjusted performance was calculated using carcass-adjusted final BW calculated from HCW/DP in decimal form.Beef Carcass Research Center  personnel recorded individual animal ear tag numbers in the sequence of harvest and affixed a harvest sequence number to each carcass. Plant carcass ID and HCW were recorded and verified by carcass sequence number during the harvest procedure. Carcasses were graded after approximately 36-h chill. United States Department of Agriculture QG (assigned by USDA Grader) and YG (assigned by camera system), HCW, and grading camera measurements were obtained from the packing plant records. Dressing percentage for each pen was calculated as the mean HCW/mean final shrunk live weight (4% shrink) × 100.n = 10 blocks) and assigned to one of two treatments as they passed through the processing shed, resulting in 10 pen replications per treatment  and were used in a randomized complete block design.Between January 18, 2018 and January 31, 2018, a total of 3,048 heifers were received at the commercial feed yard in Texas. Heifers were received from the Texas Panhandle, Oklahoma, Eastern New Mexico, and Kentucky and were mostly black-hided in color and of English and English × Continental breeding. At initial processing, heifers were vaccinated against viral respiratory pathogens  and the parasiticides Dectomax Injectable (Zoetis) and Safe-Guard oral drench  were given for the control of internal and external parasites. On the day of initial processing and randomization, heifers were excluded from the candidate population due to extremes in BW. Heifers were also excluded if they were considered unfit for the experiment  or if they were determined to be bred at the time of processing. A total of 2,500  heifers were blocked by arrival date . In addition, loose hay was top-dressed to the feed bunk for at least 3 d after arrival. Transition to the finishing diet was done using a two-ration approach where replacement of 10–15% of the daily feed call of RAMP was replaced with the finishing ration. Increases in the amount of finish ration were made every 2–4 d.The finish ration was prepared in the on-site feed mill and contained (DM basis) steam-flaked corn (55.2%), Sweet Bran Plus , wet distiller’s grains plus solubles (17.2%), cotton burrs initially then ground cornstalks (7.2%), corn oil (1.5%), glycerin (1.0%), and microingredients (0.03%). Monensin sodium  was included in the RAMP (20 g/907 kg) and finish ration (42.1 g/907 kg) throughout the experiment. Tylosin phosphate  was included at 9.6 g/907 kg. To control the outbreak of heifers cycling, MGA (Zoetis) was included in the diet to provide 0.40 mg/heifer/d. Feed calls were made to provide feed to appetite and such that feed carryover in the bunk was minimized. All heifers were fed 27.3-g/907-kg ractopamine hydrochloride for 29 d prior to slaughter. Samples of each ration were collected daily from the feed bunk and subsamples dried at 100°C. Daily DMs were averaged weekly and used for the calculation of DMI. The finishing diet provided protein and minerals to meet or exceed requirements .Individual BW was recorded for each animal at the time of initial processing. Heifers were weighed as a group by pen using a platform scale on study day 0 and the morning of shipment for the calculation of live growth performance. Body weights were measured prior to the morning feeding and a 4% pencil shrink was applied to day 0 and final BW, and carcass-adjusted performance was calculated from HCW/DP in decimal form.Trained personnel recorded individual animal ear tag numbers in the sequence of harvest and affixed a harvest sequence number to each carcass. Plant carcass ID and HCW were recorded and verified by carcass sequence number. Carcasses were graded after approximately 36-h chill. United States Department of Agriculture QG (assigned by USDA Grader) and YG, HCW, and actual and camera grading measurements were obtained from the packing plant records. Dressing percentage for each pen was calculated as the mean HCW/mean shrunk live weight × 100.n = 9 blocks) and assigned to one of six treatments as they passed through the processing shed, resulting in nine pen replications per simple-effect treatment (n = 70 heifers per pen and 630 heifers per simple-effect treatment) and were used in a randomized complete block design. The study was originally designed as a 2 × 3 factorial treatment arrangement with three serial harvest dates and two implant treatments. Heifer growth performance and carcass traits from this experiment have been published previously  and clostridia species  and administered the parasiticides Cydectin Injectable  and Ultra Saber Pour-On  for the control of internal and external parasites according to label directions. On the day of initial processing and randomization, heifers were excluded from the candidate population due to extremes in BW. Heifers were also excluded if they were considered unfit for the experiment  or if they were determined to be bred at the time of processing. A total of 3,780  heifers were blocked by arrival date . In addition, loose hay was top-dressed to the feed bunk for at least 3 d after arrival. Transition to the finishing diet was done using a two-ration approach where replacement of 10–15% of the daily feed call of RAMP was replaced with the finishing ration. Increases in the amount of finish ration were made every 2–4 d.The finish diet was prepared in the on-site feed mill and contained (DM basis): steam-flaked corn (48.5%), Sweet Bran Plus at 11.0% (Cargill Corn Milling), wet distiller’s grains plus solubles (34.2%), corn stalks (5.6%), yellow grease (0.72%), and microingredients (0.03%). Monensin sodium  was included in the RAMP (20.0 g/907 kg) and finish diet (42.0 g/907 kg) throughout the experiment. Tylosin phosphate  was included at 9.6 g/907 kg. To control the outbreak of heifers, cycling MGA was included in the diet at 0.40 mg/heifer/d. All heifers were fed 27.3-g/907-kg ractopamine hydrochloride for approximately 28 d prior to slaughter . Feed calls were made to provide feed to appetite and such that feed carryover in the bunk was minimized. Samples of each ration were collected daily from the feed bunk and subsamples dried at 100 °C. Daily DM was averaged weekly and used for the calculation of DMI. The finishing diet provided protein and minerals to meet or exceed requirements .2 of pen space and 25 cm of bunk space. Feed bunks were visually checked three times daily for the presence of residual feed. Feed calls were made to provide feed to appetite and such that feed carryover in the bunk was minimized.Heifers were housed in outdoor, soil-surfaced, pipe-constructed pens measuring 53 m deep and 18 m wide in Exp. 1. Pens were stocked so that each animal had approximately 14 mHeifers were weighed as a group by pen using a platform scale on study day 0 and the morning of shipment for the calculation of live growth performance. Body weights were measured prior to the morning feeding and a 4% pencil shrink was applied to initial and final BW. Carcass-adjusted performance was calculated from HCW/DP in decimal form.Trained personnel from the Beef Carcass Research Center recorded individual animal ear tag numbers in the sequence of harvest and affixed a harvest sequence number to each carcass. Plant carcass ID and HCW were recorded and verified by carcass sequence number. Carcasses were graded after chilling for approximately 36 h and USDA QG (assigned by USDA Grader) and YG (assigned by camera system) were obtained from the packing plant records. Dressing percentage for each pen was calculated as the mean HCW/mean shrunk live weight × 100.Bos indicus breeding. At initial processing, heifers were vaccinated against viral respiratory pathogens  and the parasiticides Dectomax (Zoetis) and Safe-Guard oral drench  were given for the control of internal and external parasites according to label directions. On the day of initial processing and randomization, heifers were excluded from the candidate population due to extremes in BW. Heifers were also excluded if they were considered unfit for the experiment  or if they were determined to be bred at the time of initial processing. A total of 3,719  heifers were blocked by arrival date (n = 9 blocks) and assigned to one of six treatments as they passed through the processing shed, resulting in nine pen replications per simple-effect treatment (n = 65–70 heifers per pen and 585–630 heifers per simple-effect treatment) and were used in a randomized complete block design. The study was originally designed as a 2 × 3 factorial treatment arrangement with three serial harvest dates and two implant treatments. Heifer growth performance and carcass traits from this experiment have been published previously . In addition, loose hay was top-dressed to the feed bunk for at least 3 d after arrival. Transition to the finishing diet was done using a two-ration approach where replacement of 10–15% of the daily feed call of RAMP was replaced with the finishing ration. Increases in the amount of finish ration were made every 2–4 d.The finishing diet was prepared in the on-site feed mill and contained (DM basis) steam-flaked corn (55.2%), Sweet Bran Plus , wet distiller’s grains plus solubles (17.2%), cotton burrs initially, then ground corn stalks (7.2%), corn oil (1.5%), glycerin (1.0%), and microingredients (0.03%). Monensin sodium  was included in the RAMP (20.0 g/907 kg) and finish diet (40.0 g/907 kg) throughout the experiment. Tylosin phosphate  was included only in the finish diet at 9.2 g/907 kg. To control the outbreak of heifers cycling, MGA was included in the diet at 0.40 mg per heifer daily. All heifers were fed 27.3-g/907-kg ractopamine hydrochloride for approximately 31 d prior to slaughter . Samples of each diet were collected daily from the feed bunk and subsamples dried at 100 °C. Daily DM was averaged weekly and used for the calculation of DMI. The finishing diets provided protein and minerals to meet or exceed requirements .Heifers were weighed as a group by pen using a platform scale on study day 0 and the morning of shipment for the calculation of live growth performance. Body weights were measured prior to the morning feeding and a 4% pencil shrink was applied to initial and final BW. Carcass-adjusted performance was calculated from HCW/DP in decimal form.Trained personnel from the Beef Carcass Research Center recorded individual animal ear tag numbers in the sequence of harvest and affixed a harvest sequence number to each carcass. Plant carcass ID and HCW were recorded and verified by carcass sequence number. Carcasses were graded after approximately 36-h chill. United States Department of Agriculture QG (assigned by USDA Grader) and YG (assigned by camera system) and grading camera measurements were obtained from the packing plant records. The DP for each pen was calculated as the mean HCW/mean shrunk live weight (4% shrink) × 100.P > 0.10) except for DMI , as such, only the main effect of the implant is discussed in this analysis. Random intercepts were used to account for trial (location) and block within trials. Model-adjusted treatment means for each implant group and corresponding SEM are reported. Comparisons of the distributions of quality and YG data among treatment groups were analyzed in generalized linear mixed models for ordinal outcomes  with similar fixed effects as those described above . Fixed effects included implant treatment, serial slaughter time, and interaction. No interaction was detected for any dependent variables (ed above . Random P ≥ 0.11) for initial BW (333 vs. 333 ± 941 kg); final BW calculated with deads and removals—excluded (599 vs. 600 ± 4.5 kg), ADG (1.51 vs. 1.51 ± 0.022 kg) or gain-to-feed ratio ; final BW calculated with deads and removals—included analysis for ADG (1.44 vs. 1.44 ± 0.022 kg) or G:F (0.153 vs. 0.152 ± 0.0020); mortality (0.83 vs. 0.94 ± 0.160 %), removals (1.43 vs. 1.17 ± 0.220 %), or realizers (1.99 vs. 1.89 ± 0.270 %) for REPEATED and SINGLE, respectively. Daily DMI was influenced by implant program, and heifers administered the SINGLE implant had greater (P = 0.02) DMI (9.46 vs. 9.38 ± 0.127 kg) compared to heifers administered REPEATED.Heifer growth performance, mortality, removals, and realizers are presented in P = 0.74; 503 vs. 505 ± 5.2) for REPEATED and SINGLE heifers. Heifers in REPEATED had greater (P ≤ 0.02) DP (64.54 vs. 64.22 ± 0.120 %), HCW (384 vs. 382 ± 2.8 kg), and ribeye area (91.87 vs. 89.55 ± 0.839 cm2), as well as lesser (P ≤ 0.01) rib fat (1.78 vs. 1.83 ± 0.025 cm) and calculated YG (2.82 vs. 2.97 ± 0.040) compared to heifers administered SINGLE. The distribution of USDA YG was impacted (P = 0.03) by implant regimen: 6.61 % vs. 4.26 % for YG 1, 31.04 % vs. 25.71 % for YG 2, 43.24 % vs. 45.80 % for YG 3, 16.38 % vs. 20.75 % for YG 4, and 2.72 % vs. 3.48 % for YG 5 in heifers from REPEATED compared to SINGLE. Distribution of USDA QG also was altered (P = 0.01) by implant program: 5.41 % vs. 7.02 % for USDA Prime, 78.41 % vs. 79.70 % for USDA Choice, 14.47 % vs. 11.98 % for USDA Select, and 1.71 % vs. 1.30 % for all other possible grades in heifers administered REPEATED compared to SINGLE.Carcass characteristics are presented in A primary challenge to using steroidal implants to improve cattle growth performance is the payout period of steroidal hormone from the implant pellets. Payout-period duration from cholesterol and polyethylene glycol excipient matrices is typically from 60 to 120 d following implantation . The DOF2 implants have been demonstrated to increase the final BW by upward of 30 kg over nonimplanted cattle  213 d prior to harvest had greater final BW, ADG, and improved G:F compared to steers administered a single Revalor-200  at either 213 or 143 d prior to harvest  were administered to beef steers, no reduction in cumulative DMI was noted  and heifer outcome  are not altered by a single, coated implant or noncoated reimplant regimen given the DOF employed in the present analysis. Carcass measures of leanness and muscling were improved in REPEATED. These data may indicate that REPEATED may be suited for grid-based marketing, and SINGLE might be suited for heifers sold on a live basis depending upon market conditions and value-based grid premiums and discounts. However, these decisions are operational dependent and also may be influenced by factors including animal and employee safety, stress on animals, processing facilities, time of year, labor availability, and marketing strategies.


Cabazitaxel is a novel taxane that might be active in breast cancer resistant to first-generation taxanes.The purpose of the current multicentre phase II trial was to evaluate the activity and safety of cabazitaxel, as second-line treatment, in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) previously treated with taxanes. The primary endpoint was objective response rate (ORR).Eighty-four patients were enrolled between October 2012 and November 2016. Taxane resistance to previous treatment was detected in 43 cases. The ORR was 22.6% in the intent-to-treat population, 23.3% in taxane-resistant and 20.5% in taxane-non-resistant cases. At a median follow-up of 39.6 months, the median progression-free survival and overall survival were 3.7 months (95% CI 2.2–4.4) and 15.2 months (95% CI 11.3–19.4), respectively. Regarding toxicity, grade 3–4 neutropenia was reported in 22.6% and febrile neutropenia in 6% of the patients, respectively. Two fatal events (one febrile neutropenia and one sepsis) were reported as being related to study treatment.This phase II trial suggests that cabazitaxel is active as second-line treatment in taxane-pretreated patients with HER2-negative MBC, with manageable toxicity. In this clinical setting, the role of systemic treatment is to palliate symptoms, maintain quality of life and prolong patient survival. In patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative MBC, international guidelines support the administration of endocrine therapy (with or without targeted agents) in the majority of cases, excluding only those with visceral crisis or endocrine resistance.2 When progression of the disease develops following first-line chemotherapy, further lines of systemic therapy may be administered.3 However, in patients with MBC resistant to anthracyclines and/or taxanes, well documented active treatments are limited. Furthermore, with the extensive use of anthracyclines and taxanes in chemotherapy regimens administered as adjuvant therapy in early breast cancer, the development of active options in patients with MBC, particularly those pretreated with taxanes, is considered important.The application of anthracyclines and taxanes in the first-line treatment has been associated with an improvement in the survival of patients with advanced breast cancer.4 The greater activity of cabazitaxel as compared to other taxanes is attributed to a faster uptake and longer retention by tumour cells.5Cabazitaxel (XRP6258) is a recent taxane, showing activity in vitro and in vivo in cell lines and tumours resistant to docetaxel and paclitaxel. Cabazitaxel is also able to penetrate the blood–brain barrier.6Weekly and every 3-week schedules of administration of cabazitaxel were evaluated in phase I studies. In one trial, cabazitaxel was administered on a weekly regimen as a 1-h i.v. infusion on days 1, 8, 15 and 22 every 5 weeks, in patients with advanced solid tumours.8Two additional trials (TED6188 and TED6190) evaluated cabazitaxel given as a 1-h i.v. infusion every 3 weeks. The dose-limiting toxicity of cabazitaxel was neutropenia and its infectious complications at the highest dose tested, 30 mg/m² in TED6188 and 25 mg/m² in TED6190.Consequently, the dose levels of 25 mg/m² and 20 mg/m² every 3 weeks were defined as the recommended doses for further clinical development.9 Preclinical and limited clinical data indicate that cabazitaxel might also be effective in patients with breast cancer resistant to first-generation taxanes.11A phase III clinical trial has documented the activity of cabazitaxel in patients with castration-resistant metastatic prostate cancer and disease progression during or following previous treatment with docetaxel.We conducted a multicentre, non-randomised Phase 2 trial to assess the activity and safety of cabazitaxel as second-line treatment in patients with HER2-negative MBC, previously treated with taxanes. The primary objective was to evaluate the clinical efficacy of cabazitaxel regarding the objective response rate (ORR). Secondary objectives included duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety.12 All cases were to have received first-line chemotherapy for locally recurrent/metastatic disease. Moreover, eligible patients should have received prior taxane-containing treatment , either for advanced disease or as neoadjuvant/adjuvant chemotherapy. Additional eligibility criteria included: age 18–75 years, an Eastern Cooperative Oncology Group performance status (PS) of 0–1, life expectancy of at least 12 weeks, adequate organ function including haemoglobin ≥ 9.0 g/dL; absolute neutrophil count of ≥1.5 × 109/L; thrombocyte count of ≥100 × 109/L; serum creatinine ≤ 1.5 upper limit of normal (ULN); SGOT (AST), SGPT (ALT) ≤ 2.5 × ULN; alkaline phosphatase ≤ 2.5 × ULN; total bilirubin ≤ ULN. The enrolment of patients with controlled brain metastases was allowed.Eligible patients were women with HER2-negative metastatic breast adenocarcinoma, who had measurable disease by the Response Criteria in Solid Tumors 1.1 (RECIST 1.1).Patients who had received more than one line of chemotherapy for locally recurrent/metastatic disease were excluded. Furthermore, patients were not eligible for study enrolment in the following cases: neuropathy CTC grade 2 or greater at baseline; history of severe hypersensitivity reaction (≥grade 3) to docetaxel or polysorbate 80 containing drugs; spinal cord compression or carcinomatous meningitis; any concurrent active malignancy other than non-melanoma skin cancer or in situ carcinoma of the cervix; clinically significant cardiac disease within 6 months from study entry; uncontrolled severe illness or medical condition; any other significant acute or chronic medical or psychiatric condition or abnormal laboratory finding; pregnancy or lactation; concurrent or planned treatment with strong inhibitors or strong inducers of cytochrome P450.9/L and the platelet count was at least 75 × 109/L, and non-haematological toxicities  had improved. Toxicities required resolution to grade 1 or to baseline before the next cycle of treatment could be administered. A maximum of 2-week delay was allowed between treatment cycles. Patients would come off treatment if treatment had to be delayed by more than 2 weeks. Dose could be reduced for cabazitaxel when necessary. The dose, which had been reduced for toxicity, should not be re-escalated. Only one dose reduction (20 mg/m²) was allowed per patient. If a second dose reduction was required, the patient had to discontinue study treatment.Cabazitaxel (XRP6258) was administered on day 1 of each cycle at a dose of 25 mg/m², as an i.v. 1-h infusion. Cycle length for cabazitaxel was 3 weeks. At least 30 min prior to each administration of cabazitaxel, patients were given i.v. premedication for hypersensitivity prophylaxis including: an anti-histamine, a corticosteroid and an H2 antagonist. Anti-emetic prophylaxis was also recommended. Primary prophylaxis with granulocyte-colony stimulating factor (G-CSF) was recommended in all patients, due to the high incidence of cabazitaxel-associated neutropenia. Treatment was continued until consent withdrawal by the patient, intolerable toxicity or documented disease progression. Patients could not begin a new cycle of treatment unless the neutrophil count was at least 1.5 × 10Measurable disease was assessed by imaging studies, preferably CT scans, during the duration of the treatment using the RECIST 1.1 criteria. Imaging evaluation included CT scans of the brain, lungs, upper/lower abdomen, as well as bone scans. Patients underwent baseline imaging during the 2 weeks preceding treatment initiation and were rescanned, using the same method, 8, 16 and 24 weeks after the initiation of the treatment and every 3 months thereafter. The radiological assessment of response rate was performed centrally according to the RECIST 1.1 criteria upon completion of the study, after review of the imaging tests by two experienced radiologists . Toxicities were assessed using the NCI Common Terminology Criteria for Adverse Events version 4 at baseline and at the conclusion of each cycle of treatment.The primary endpoint of the study was to assess the clinical activity of cabazitaxel regarding the ORR. According to the Simon’s optimal two-stage design, assuming that the expected ORR would be at least 25% and the minimum acceptable response rate was 15%, with a type I and II error of 10 and 20%, respectively, a total of 29 patients was required for the first stage of the study. Upon enrolment of the 29th patient, recruitment was halted in order to perform an interim analysis for response assessment. Given the number of responses observed in the first stage, 55 additional patients were enrolled, leading to a total of 84 patients. Secondary endpoints included assessment of PFS, OS, DOR and the safety profile of cabazitaxel. Time to treatment failure (TTF) and time to response (TTR) were also assessed.Progression-free survival was calculated from the date of study entry to the date of first documented disease progression, death (from any cause) without prior documented progression or last contact (whichever occurred first). Overall survival was calculated from the date of study entry to the date of patient’s death or last contact, while TTF was measured from the date of study entry to the date of treatment discontinuation for any reason, including disease progression, treatment toxicity and death. Alive patients without progression, that did not discontinue treatment due to toxicity or any other reason, were censored at the date of last contact. Time to response was measured from the date of study entry until measurement criteria were first met for a partial or complete response. Duration of response was measured as the time from the date of onset of complete or partial response until the date of progression, death from any cause or last contact, whichever occurred first. Time to event data were analysed using the Kaplan–Meier product limit method and compared across groups with the log-rank test.The study was conducted on an intent-to-treat (ITT) basis and therefore all enrolled patients were included in the analysis. Analysis of response was conducted separately in the intent-to-treat population as well as in the subgroup of patients with measurable disease who received at least two cycles of cabazitaxel . In addition, cases with early disease progression (prior to cycle 2) were not excluded from this subgroup of patients. The safety profile of cabazitaxel was assessed in the safety population consisting of patients who received at least one dose of the investigational product.10In an unplanned analysis, we evaluated the efficacy of cabazitaxel in patients with and without taxane-resistant disease. Taxane resistance was defined as: For advanced disease, progressive disease as the best overall response on first-line treatment with a taxane; or, progressive disease within 4 months following discontinuation of first-line treatment with a taxane, after an initial objective response or disease stabilisation. For patients who had received an adjuvant or neoadjuvant taxane-containing regimen, a disease-free interval of ≤12 months from the end of treatment.Moreover, we evaluated the activity of cabazitaxel in the subgroups of patients with triple-negative and luminal disease.All tests were two-sided and the significance level was set at 5%. The data cut-off date for the analysis was June 20, 2018. The SAS version 9.3 (SAS Institute) was used for statistical analysis and the R studio version 3.5.0 was used for generation of survival plots.Eighty-four patients with a median age of 57.5 years  were enrolled between October 2012 and November 2016. Among them, 3 (3.6%) were ineligible  but received at least two cycles of treatment. Patient and tumour characteristics at study entry are summarised in Table All patients enrolled in the study received at least one cycle of treatment. In total, 499 cycles of cabazitaxel were administered . The median relative dose intensity was 0.99 (range 0.79–1.49), while dose reduction was required in 13 patients due to adverse events (11 patients) or other reasons (two patients). In nine of them, the dose of cabazitaxel was reduced during the first eight cycles of treatment. In total, 25 patients (29.8%) completed eight cycles of treatment, while the rest of the patients (70.2%) discontinued treatment before the completion of eight cycles. The main reasons for treatment discontinuation were death in three patients , non-fatal adverse events in four patients, investigator’s decision in two patients, disease progression in 44 patients, informed consent withdrawal in three patients and other reasons in three cases  was 20% (95% CI 6.8–40.7%) and among those with luminal disease (N = 57) 22.8% (95% CI 12.7–35.8%).Among the 84 patients enrolled in the study, objective response was observed in 19 patients  , as assessed by the investigators in the local institutions (Supplementary Table 1). Twenty-six patients presented with stable disease (31.0%), whereas 33 patients (39.3%) had disease progression. Six patients were not evaluated for response due to treatment discontinuation prior to evaluation (four patients), early toxic death (one patient) and early death due to cancer (one patient). Ten of the 43 taxane-resistant patients  achieved an objective response , while objective  response was observed in eight of the 39 patients  with no resistance to previous taxane treatment. One of the 19 patients with objective response according to the investigators’ assessment in the local hospitals had not received previous taxane treatment. The ORR in patients with triple-negative tumours (The median time to objective response for the 19 patients was 60 days (range 35.0–128.0), while the median duration of response was 5.6 months (range 0.7–23.2). Taxane-resistant patients (10 cases) achieved an objective response in a median of 64 days (range 36.0–120.0), while the median TTR for the eight taxane-non-resistant patients was 59.5 days (range 37.0–128.0). Taxane-resistant patients had a median duration of response of 5.1 months (range 1.9–23.2), which was shorter than that of non-resistant cases who had a median DOR of 8.6 months (range 1.4–20.4).Central radiological review according to RECIST 1.1 criteria was available for 53 cases. Among them, two patients (3.8%) had a complete response, 15 patients 28.3%) achieved a partial response, while stable disease was observed in 15 patients (28.3%) and disease progression in 21 patients (39.6%). A waterfall plot of responses is depicted in Fig. 8.3% achiWithin a median follow-up of 39.6 months (95% CI 30.6–48.7), 73 patients (86.9%) had experienced disease progression and 62 patients (73.8%) had died. Sixty patients died from their disease, while in two patients death was attributed to an adverse event. Six patients (7.1%) were lost to follow-up. The median PFS was 3.7 months (95% CI 2.2–4.4) and the median OS was 15.2 months (95% CI 11.3–19.4), while the median TTF was 3.0 months (95% CI 2.1–3.9)  and 13 months (95% CI 9.4–19.3), respectively, while the median TTF was 2.1 months (95% CI 1.6–3.7). In the subgroup of patients with luminal disease, the median PFS, OS and TTF was 4.1 (95% CI 2.6–5.6), 17.7 (95% CI 11.3–21.6) and 3.6 months (95% CI 2.2–4.9), respectively.During the reporting period of the study, 443 events were recorded in 72 patients (85.7%), which were consistent with the already known safety profile of cabazitaxel and other taxanes, as well as the study disease and its complications. Selected grade 1–2 adverse events occurring in more than 10% of patients are depicted in Supplementary Table 2, while Table 13Metastatic breast cancer still remains an incurable disease and the effective long-term management of patients represents a major challenge. Taxanes constitute a mainstay of treatment both in the early-stage, as well as in the advanced setting. However, the clinical use of these compounds is often associated with primary or acquired resistance. Consequently, the development of additional effective therapeutic options for patients previously treated with taxanes is important. So far, there are no standardised treatment regimens following the failure of anthracycline and taxane therapy. Capecitabine, gemcitabine, vinorelbine, eribulin, etc. are reasonable alternatives. Capecitabine has been the only approved treatment for anthracycline- and taxane-pretreated MBC for many years, since the majority of Phase 3 studies in this setting failed to demonstrate superior clinical outcomes with new agents, compared or combined with capecitabine. More recently, eribulin was approved for MBC progressing after chemotherapy regimens including anthracyclines and taxanes, following a Phase 3 trial, which showed significantly improved OS for eribulin in comparison with investigators’ treatment of choice.14In the current multicentre, single-arm Phase 2 study, cabazitaxel showed promising activity as second-line treatment in taxane-pretreated patients with MBC. Among the 84 patients enrolled in the study, the ORR was 22.6%, while the disease-control rate was 53.6%. These results are considered encouraging taking into account that cabazitaxel was given in a pretreated patient population. Moreover, the median OS of 15.2 months is considered particularly promising, although the median PFS was 3.7 months. These findings are comparable with the results of phase 3 studies evaluating eribulin versus treatment of physician’s choice or capecitabine, in pretreated patients with MBC.10 The ORR was 14%, whereas 25% of patients had stable disease. The median time to progression (TTP) was 2.7 months, while the median OS was 12.3 months. Moreover, another Phase 1/2 dose-escalating study assessed the combination of cabazitaxel with capecitabine in patients with MBC pretreated with anthracyclines and taxanes.11 In the 21 evaluable patients at the maximum tolerated dose, the ORR was 23.8%, and the median TTP was 4.9 months. The results of our study compare favourably with the findings in the above mentioned, previously published studies in pretreated patients with MBC. On the other hand, a randomised Phase 2 study comparing cabazitaxel versus weekly paclitaxel as neoadjuvant therapy in patients with early HER2-negative breast cancer demonstrated inferior activity of cabazitaxel with respect to the pathological complete response rate.15 The efficacy of cabazitaxel in other types of cancer has also been evaluated with encouraging results in recent studies.17 Regarding toxicity, cabazitaxel was tolerated fairly well in most of the patients. The incidence of grade 3–4 neutropenia was relatively high (22.6%), considering that primary prophylaxis with G-CSF was recommended in all patients. Recent studies evaluating cabazitaxel in pretreated patients with non-small-cell lung cancer and head and neck carcinoma, have also reported similar rates of severe (grade 3–4) neutropenia, despite primary prophylaxis with G-CSF.17 However, the rates of grade 3–4 neutropenia were considerably lower compared with the reported incidence in the pivotal study in prostate cancer.9 Nevertheless, in the pivotal study neutropenia was measured at the nadir in all patients and prophylactic G-CSF was not allowed at cycle 1. In general, severe neutropenic events were manageable in the majority of cases in our study. The safety profile of the study drug was similar to the known toxicity profile of cabazitaxel, no serious adverse events were assessed as unexpected and no new safety issues were revealed.Regarding the efficacy of cabazitaxel according to resistance to previous taxane treatment, no difference was demonstrated in ORR . Moreover, the median time to objective response was also similar . However, the duration of response was shorter in patients with taxane-resistant disease, compared with taxane-non-resistant cases (5.1 months vs. 8.6 months). Similarly, taxane-resistant patients had numerically shorter PFS (median 3.1 months vs. 4.3 months), as well as worse OS (median 12.7 months vs. 19.4 months) in comparison with those with taxane-non-resistant disease. Clinical data assessing the activity of cabazitaxel in patients with MBC is very limited. A Phase 2 study has evaluated the efficacy of cabazitaxel in 71 patients with taxane-resistant MBC.In conclusion, this Phase 2 trial suggests that cabazitaxel is active with a manageable toxicity profile when administered as second-line treatment in patients with HER2-negative MBC, who have received prior taxane therapy. These promising results support further evaluation of cabazitaxel in Phase 3 studies in patients with MBC.