Interval ratio – ATRX Wed, 20 Oct 2021 15:42:04 +0000 en-US hourly 1 Interval ratio – ATRX 32 32 Eating nuts may reduce recurrence in breast cancer survivors – Consumer Health News Wed, 20 Oct 2021 15:03:33 +0000 WEDNESDAY, October 20, 2021 (HealthDay News) – For long-term breast cancer survivors, eating nuts is associated with better disease-free survival, according to a study published online on October 20 in the International Journal of Cancer. Cong Wang, MPH, of Vanderbilt University Medical Center in Nashville, TN, and colleagues looked at associations of nut consumption assessed […]]]>

WEDNESDAY, October 20, 2021 (HealthDay News) – For long-term breast cancer survivors, eating nuts is associated with better disease-free survival, according to a study published online on October 20 in the International Journal of Cancer.

Cong Wang, MPH, of Vanderbilt University Medical Center in Nashville, TN, and colleagues looked at associations of nut consumption assessed five years after diagnosis with overall survival (OS) and disease-free survival (DFS) among 3,449 long-term breast cancer survivors.

Researchers identified 374 deaths during a median follow-up of 8.27 years after dietary assessment, including 252 deaths from breast cancer. Two hundred and nine of the 3,274 survivors without a previous recurrence on dietary assessment developed breast cancer-specific events (recurrence, metastasis or death from breast cancer). Regular nut consumers had higher ILI (93.7 vs. 89.0 percent) and SSM (94.1 vs. 86.2 percent) rates during a five-year postdietary assessment (10 years after diagnosis). Positive associations were observed for nut consumption with OS and DFS after multivariate assessment using a dose-response pattern; for participants with more than the median nut intake, the risk ratios were 0.74 (95% confidence interval, 0.52 to 1.05) and 0.48 (95% confidence interval) , 0.31 to 0.73) for OS and DFS, respectively, compared to non-consumers. No variation was noted in these associations according to the type of nut. The associations were more evident in people with a higher total energy intake for OS and in those with early-stage breast cancer for FSD. Estrogen / progesterone receptor status and other known prognostic factors did not alter nut-DFS associations.

“Promotion of this modifiable lifestyle factor should be emphasized in the guidelines for breast cancer survivors,” the authors write.

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6 HIIT Cycling Workouts You Can Do On Your Indoor Cycle For A Fun Cardio Routine Tue, 19 Oct 2021 13:31:56 +0000 Let’s be honest: a long, steady ride on an indoor bike can take forever. HIIT cycling workouts, on the other hand, can pass the time as you challenge your body and mind with varying levels of effort, work intervals, and recovery breaks. Generally speaking, HIIT, or high intensity interval training, refers to repeated sets of […]]]>

Let’s be honest: a long, steady ride on an indoor bike can take forever. HIIT cycling workouts, on the other hand, can pass the time as you challenge your body and mind with varying levels of effort, work intervals, and recovery breaks.

Generally speaking, HIIT, or high intensity interval training, refers to repeated sets of intervals lasting between five seconds and one minute, with a relatively short rest period. Cycling trainer and certified personal trainer Marissa Axell tells SELF that while she tends to prescribe a 2: 1 work time / recovery time ratio, there are still many benefits to longer rest intervals. , especially for the more genial pop fans.

As SELF previously reported, HIIT is a type of anaerobic exercise, which means it doesn’t depend on oxygen to produce the energy your body needs for your workout. Instead, it taps into your fast-acting energy pathways to produce it, allowing you to go hard, but not for an extended period. With HIIT, the focus is on intensity, so it’s no surprise that many of its benefits relate to power, speed, and explosiveness.

“HIIT improves your VO2 max – the speed at which your body processes oxygen, a huge indicator of fitness – your anaerobic capacity, your neuromuscular power and your sprint,” said Christine D’Ercole, Peloton and cycling instructor. world track champion, Christine D’Ercole. . “Even if you are not a [competitive] cyclists, they are fun because they force you to focus on very short durations, so they are incredibly engaging.

That’s why many popular fitness apps, like Peloton and iFit, use HIIT-based protocols in their classes, which can be a great introduction to this type of workout. But the great thing about HIIT is that it also really lends itself to self-directed workouts, which can be a godsend when you want to reduce screen time during your session, or if you just want to customize. your routine depending on what your body is. research that day. After all, a self-directed workout allows you to shorten or lengthen your commute and effort depending on your needs and your energy level at that time.

Sometimes, however, you want some advice on this indoor cycling bike, especially if you are new to this particular piece of equipment, or if you had only ridden in fitness classes or via apps before. As a former certified cycling instructor, I have always incorporated high intensity intervals into every class I have taught because they are engaging, effective, and honestly quite fun. Here are six HIIT cycling workouts that you can try on your indoor bike that will pass the time.

1. A solid warm-up

Before you start your intervals, warming up with at least five to 10 minutes of easier cycling can gradually increase your heart rate and circulate blood to your muscles. This warm-up lasts less than 15 minutes and is similar to the one that D’Ercole uses for his Peloton classes. It allows your body to calm down in intensity and prepares your heart and lungs for the intense efforts to come.

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Access Denied: Inequities in Pancreatic Cancer Clinical Trial Enrollment Sat, 16 Oct 2021 22:49:50 +0000 This article was originally published here Ann Surg Oncol. October 16, 2021. doi: 10.1245 / s10434-021-10868-4. Online ahead of print. ABSTRACT Background: The influence of social determinants of health (SDH) on participation in pancreatic cancer clinical trials is not well understood. In this study, we describe trends and identify disparities in the recruitment of pancreatic […]]]>

This article was originally published here

Ann Surg Oncol. October 16, 2021. doi: 10.1245 / s10434-021-10868-4. Online ahead of print.


Background: The influence of social determinants of health (SDH) on participation in pancreatic cancer clinical trials is not well understood. In this study, we describe trends and identify disparities in the recruitment of pancreatic cancer clinical trials.

PATIENTS AND METHODS: This is a retrospective study of patients with stage I-IV pancreatic cancer in the National Cancer Database 2004-2016. The cohort was stratified between those enrolled in clinical trials during the first cycle of treatment versus those not enrolled. Bivariate analysis and logistic regression were used to understand the relationship between SDH and clinical trial participation.

RESULTS: A total of 1127 patients (0.4%) enrolled in clinical trials versus 301,340 (99.6%) not enrolled. Recruitment increased over the study period (p <0.001), but not for black patients or patients on Medicaid. The majority of participants had metastatic disease (65.8%). In multivariate analysis, in addition to the year of diagnosis (p <0.001), stage (p <0.001) and Charlson score (p <0.001), the increase in age [odds ratio (OR) 0.96, 95% confidence interval (CI) 0.96-0.97], non-white (OR 0.54, CI 0.44-0.66), living in the South (OR 0.42, CI 0.35-0.51) and Medicaid, no insurance or unknown insurance ( 0.41, CI 0.31-0.53) were predictors of lack of participation. Conversely, treatment in a university center (OR 6.36, CI 5.4-7.4) and higher education in the neighborhood predicted enrollment (OR 2.0, CI 1.55-2.67 for < 7 % sans diplôme d'études secondaires contre > 21%).

DISCUSSION: Age, race, insurance and geography are barriers to enrolling in clinical trials for patients with pancreatic cancer. While overall recruitment has increased, black patients and patients on Medicaid remain under-represented. After adjusting for cancer-specific factors, SDH is still associated with enrollment in clinical trials, suggesting the need for targeted interventions.

PMID: 34655352 | DOI: 10.1245 / s10434-021-10868-4

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Efficacy of Therapeutic Heparin Compared to Prophylactic Heparin on Death, Mechanical Ventilation, or Intensive Care Unit Admission in Moderately Ill Patients with Covid-19 Admitted to Hospital: RAPID Randomized Clinical Trial Sat, 16 Oct 2021 04:41:44 +0000 BMJ. October 14, 2021; 375: n2400. doi: 10.1136 / bmj.n2400. ABSTRACT OBJECTIVE: To assess the effects of therapeutic heparin compared to prophylactic heparin in moderately ill patients with covid-19 admitted to hospital wards. DESIGN: Randomized controlled, adaptive, open-label clinical trial. SETTING: 28 hospitals in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates and United States. […]]]>

BMJ. October 14, 2021; 375: n2400. doi: 10.1136 / bmj.n2400.


OBJECTIVE: To assess the effects of therapeutic heparin compared to prophylactic heparin in moderately ill patients with covid-19 admitted to hospital wards.

DESIGN: Randomized controlled, adaptive, open-label clinical trial.

SETTING: 28 hospitals in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates and United States.

PARTICIPANTS: 465 adults admitted to hospital wards with covid-19 and increased D-dimer levels were recruited between May 29, 2020 and April 12, 2021 and were randomized to receive a therapeutic dose of heparin (n = 228 ) or a prophylactic dose of heparin (n = 237).

INTERVENTIONS: Therapeutic dose or prophylactic dose of heparin (low molecular weight or unfractionated heparin), to be continued until hospital discharge, day 28 or death.

MAIN OUTCOME MEASURES: The primary outcome measure was a composite outcome of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or admission to an intensive care unit, evaluated for up to 28 days. Secondary outcomes included all-cause death, composite of all-cause death or any mechanical ventilation, and venous thromboembolism. Safety results included major bleeding. The results were blindly evaluated.

RESULTS: The average age of the participants was 60 years; 264 (56.8%) were male and the mean body mass index was 30.3 kg / m2. At 28 days, the composite primary outcome was observed in 37,228 (16.2%) patients assigned to therapeutic heparin and 52/237 (21.9%) to prophylactic heparin (odds ratio 0 , 69, 95% confidence interval 0.43 to 1.10; P = 0.12). Deaths occurred in four patients (1.8%) assigned to therapeutic heparin and 18 patients (7.6%) assigned to prophylactic heparin (0.22, 0.07 to 0.65; P = 0.006 ). The composite of death from any cause or from any mechanical ventilation occurred in 23 patients (10.1%) assigned to therapeutic heparin and 38 (16.0%) assigned to prophylactic heparin (0.59, 0.34 to 1.02; P = 0.06). Venous thromboembolism occurred in two patients (0.9%) assigned to therapeutic heparin and six (2.5%) assigned to prophylactic heparin (0.34, 0.07 to 1.71; P = 0 , 19). Major bleeding occurred in two patients (0.9%) assigned to therapeutic heparin and four (1.7%) assigned to prophylactic heparin (0.52, 0.09 to 2.85; P = 0 , 69).

CONCLUSIONS: In moderately ill patients with covid-19 and an increased level of D-dimer admitted to hospital wards, therapeutic heparin was not significantly associated with a reduction in the primary endpoint, but the risk death at 28 days was reduced. The risk of major bleeding appeared to be low in this trial.


PMID: 34649864 | DOI: 10.1136 / bmj.n2400

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Complainants claim Deloitte breached ERISA’s duty of care Fri, 15 Oct 2021 16:41:41 +0000 The plaintiffs filed a new Employee Retirement Income Security Act (ERISA) lawsuit in U.S. District Court for the Southern District of New York, naming as defendants Deloitte LLP, the board of directors of the company and various other related entities. The lawsuit alleges that the defendants authorized the payment of excessive administrative and record-keeping fees […]]]>

The plaintiffs filed a new Employee Retirement Income Security Act (ERISA) lawsuit in U.S. District Court for the Southern District of New York, naming as defendants Deloitte LLP, the board of directors of the company and various other related entities.

The lawsuit alleges that the defendants authorized the payment of excessive administrative and record-keeping fees in connection with the operation of a 401 (k) plan and profit-sharing plan provided to employees of Deloitte.

According to the claimants, the plans’ billions of dollars in assets under management (AUM) qualify them as jumbo plans in the defined contribution (DC) market.

“As jumbo plans, the plans had substantial negotiating power regarding fees and expenses charged on participants’ investments,” the complaint states. “The defendants, however, did not attempt to reduce the plan’s expenses or exercise proper judgment to examine every investment option that was available in the plans to ensure that they were prudent. … Based on this conduct, the plaintiffs bring forward claims against the defendants for breach of fiduciary duty of care (count one) and breach of fiduciary supervision (count two).

The plaintiffs’ arguments in this case closely resemble those in previous ERISA cases filed against large domestic employers citing ERISA’s fiduciary obligations of general prudence and fiduciary oversight. In particular, these cases gave rise to varied results, depending on the facts in question and the points of view of the courts called upon to examine them. For example, Prudential recently defeated a similarly structured lawsuit based on plaintiffs’ failure to plausibly establish standing. The same result was achieved in an ERISA lawsuit filed against TriHealth. On the other hand, the defendants’ motions to dismiss were unsuccessful in a similar lawsuit against Allstate.

Generally speaking, the success of such prosecutions is linked to the ability (or lack thereof) of the plaintiffs to demonstrate that the payment of high fees or the provision of underperforming investments was likely the result of violations. trustees. In other words, simply stating that a plan paid higher fees than its peers or offered investments that underperformed other possible investment options is not enough to establish its reputation. with ERISA.

Here, the claimants suggest that Deloitte’s plans, with more than 89,000 members and over $ 14.5 billion in assets in 2019, should have been able to negotiate a record-keeping cost of around $ 20 from the start of the proposed recourse period. The complainants allege that “poorly performing plans” pay no more than $ 60 per member for record keeping, and that Deloitte paid an annual fee of approximately $ 65 to $ 70 per member of the 401 (k) plan and more than $ 200 per participant in profit sharing. plan.

“[Given] the fact that the plans have remained with the same archivist, namely Vanguard, since at least 2004, has paid an increasing amount in record keeping fees from 2018 to present, and paid outrageous amounts for record keeping of 2015 to 2017, there is little to suggest that the defendants tendered [RFP] at reasonable intervals (or certainly any time before 2015 to present) to determine if the plans could achieve better record keeping and administration fee pricing from other service providers, as the market for record keeping is very competitive, with many vendors also able to provide a high level of service, ”the complaint states.

The applicants make very similar arguments with respect to the investment options of the plans.

“The excessive costs of funds also provide circumstantial evidence, as well as the excessive costs of record keeping and administration, that the defendants failed to use a prudent process to monitor the costs of the plans,” the lawsuit said. “Failure to select funds that do not cost more than the average expense ratios for similar funds in similar sized plans costs plan members millions of dollars in damages. “

Deloitte has yet to respond to a request for comment on the lawsuit. The full text of the complaint is available here.

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Results of a large real-world safety study of combined oral contraception published Thu, 14 Oct 2021 15:13:00 +0000 LONDON–(COMMERCIAL THREAD) –For medical and commercial / industrial media and investors outside of the United States and Canada only Theramex, a global women’s health company, today announced that safety results from the PRO-E2 real-world safety study for Zoely® (NOMAC-E2) have been published in The European Journal of Contraception and Reproductive Health Care (EJCRH).1 The Post-Authorization […]]]>

LONDON–(COMMERCIAL THREAD) –For medical and commercial / industrial media and investors outside of the United States and Canada only

Theramex, a global women’s health company, today announced that safety results from the PRO-E2 real-world safety study for Zoely® (NOMAC-E2) have been published in The European Journal of Contraception and Reproductive Health Care (EJCRH).1

The Post-Authorization Safety Study (PASS), known as PRO-E2, was a large, prospective, non-interventional, controlled cohort study involving more than 101,000 women. PRO-E2 compared the risks of using NOMAC-E2 versus COCs containing levonorgestrel (COC-LNG), a commonly prescribed contraceptive.1

The main objective of the real-world study was to assess and compare the risk of cardiovascular events * in users of NOMAC-E2 with users of COC-LNG. For the primary clinical outcome, the risk of VTE?? was at least as low with NOMAC-E2 as with COC-LNG, which is consistent with the results of previous studies (0.59 Hazard Ratio [HR]95% confidence interval [CI], 0.25-1.35).1

PRO-E2 also demonstrated that contraceptive failure (risk of unintended pregnancy), a key secondary outcome, was statistically significantly lower with NOMAC-E2 compared to COC-LNG (0.45 HR † , 95% CI, 0.34-0.60, [p<0.0001]). Further analyzes showed that the lower rate of unintended pregnancies with NOMAC-E2 was even more pronounced in women under 35.2 The shorter hormone-free interval with NOMAC-E2, its longer half-life, and its monophasic regimen can all help reduce the number of unintended pregnancies.5.6.7 These results will be published in the EJCRH later this month.

All 14 secondary endpoints of the study were met, with a risk of serious adverse events and depressive disorders or changes in weight or acne score with NOMAC-E2 comparable to COC-LNG.2

Dr Joaquim Calaf Alsina, Honorary Professor of Obstetrics and Gynecology at the Autonomous University of Barcelona, ​​Spain, said: “This is an exciting real-world study that confirms what we suspected at the both the biological profile and the experience of using NOMAC-E2. This contraceptive combination has at least the same risk of VTE as the preparation which has been shown to have the lowest risk in this regard. The data from PRO-E2 also provides patients with important and reassuring data on efficacy and other additional benefits, such as improvement in acne and low impact on body weight.

Ms Claudine Domoney, Consultant Gynecologist, Chelsea & Westminster Hospital, London, UK, said: “Contraception can be difficult for women and as clinicians we want to make it as easy as possible. To do this, there must be a range of options that provide reliable and convenient fertility control. The PRO-E2 study, which reflects the real-life experience of women, confirms that NOMAC-E2 is better at preventing unintended pregnancies than COC-LNG.

Theramex CEO Robert Stewart said, “The results of the PRO-E2 study will boost confidence in what has already proven to be a reliable and effective birth control option. As a company dedicated to improving women’s health, we are delighted that the wealth of evidence from this safety study can help clinicians and women make informed decisions about contraception.

The safety and efficacy publications were accepted by the EJCRH in September. The publication of the safety results is available online:

The efficacy publication will be available online later this month. Both publications will be available in the print journal in December.

The results have also been submitted to the European Medicines Agency (EMA) and will be presented at the congress of the European Society of Gynecology in November this year.


Notes to editor:

About the PRO-E2 study

PRO-E2 was designed to compare the risks of using NOMAC-E2 versus COC-LNG.8.9 VTE is a rare but serious adverse event associated with the use of COCs.10.11 COC-LNG was chosen as the comparator for the study as the COC associated with the lowest risk of VTE, according to treatment guidelines.12

The study, initiated by MSD and conducted by ZEG-Berlin, was requested by the European Medicines Agency (EMA).8 A PASS is performed after a medicine has been authorized to gain additional information about the safety of a medicine or to measure the effectiveness of risk management measures.

The primary outcome measure was the risk of VTE (particularly deep vein thrombosis of the lower limbs and pulmonary embolism).1 Secondary outcomes of interest were: all VTE, arterial thromboembolism, idiopathic VTE, summary of VTE results, depressive disorders, mood changes, gallstones, inflammatory bowel disease , the effect on fertility (contraceptive failure and return to fertility), pregnancy outcomes, weight change, hepatobiliary disorders and acne.2

PRO-E2 was initiated in 2014 (following a pioneering study, CELINA, initiated in 2012) and closed in December 2020.8 The results reflect the actual practice of more than 101,000 women (equivalent to 144,901 data of woman-years) from Australia, Austria, Colombia, France, Germany, Hungary, Italy, Mexico, Poland, Russia, Spain and Sweden.1

About Zoély® (NOMAC-E2)

NOMAC-E2 combines nomegestrol acetate [2.5mg] and 17β-estradiol [1.5mg]. NOMAC-E2 is the only monophasic contraceptive pill using the same 17B-estradiol in the body. Nomegestrol acetate (NOMAC) is a highly selective progestin derived from the natural hormone progesterone.3.4

MSD has been exclusively licensed by Theramex to sell Zoely® in certain territories (other than the United States and Canada) until January 2020 and held marketing authorizations for the product in non-EU markets in that territory. In January 2020, these rights were transferred back to Theramex. The rights to sell the product in the United States and Canada under a license from Teva remained with MSD until the Organon split on June 2, 2021. Zoely® and Stezza® are brand names of NOMAC Nomegestrol Acetate 2.5 mg + 17β-Estradiol E2 1.5 mg Combined Oral Contraception.

About Theramex

With a large portfolio of innovative and established brands covering contraception, fertility, menopause and osteoporosis, we support women at every stage of their lives. Our commitment is to listen and understand our patients, to meet their needs and to offer healthcare solutions to help improve their lives. Our vision is to be a lifelong partner for women and the healthcare professionals who treat them, providing innovative and effective solutions that care for and support women as they move through every stage of their lives.

The references:

  1. Reed S et al. Eur J Contracept Reprod Healthcare. Available at: Accessed October 2021

  2. PRO-E2 final report. Available at:;jsessionid=uW82EciuLgcm015Qta9_pO v1_2skaG629DgRqfNG6I5-i02w5oS0! 2052488890

  3. Theramex. (2021) Zoély® RCP. Available at: Accessed October 2021

  4. Westhoff C et al. ObstetGynecol 2012; 119 (5): 989-99.

  5. Christin-MaîtreS et al. Women’s Health (London) 2013; 9 (1): 13-23.

  6. Van Vliet HAAM, Raps M. Cochrane Database Syst Rev 2011; (11): CD009038.

  7. Duijkers IJM et al. Eur J Contracept Reprod Health Care 2010; 15 (5): 314-25.

  8. (2021) Prospective controlled cohort safety study of a monophasic oral contraceptive containing nomegestrol acetate (2.5 mg) and 17β-estradiol (1.5 mg) (PRO-E2). Available at: Accessed October 2021

  9. Reed, S. et al. Pharmacoepidemiol Drug Saf. 2020; 29 (Suppl. 3): 4.

  10. United States Food and Drug Administration. (2018). FDA Drug Safety Communication: Updated Information on the Risk of Blood Clots in Women Taking Oral Contraceptives Containing Drospirenone. Available at: Accessed October 2021

  11. de Bastos, M. et al. (2014) Cochrane Database Syst Rev (3): CD010813.

  12. Faculty of Sexual and Reproductive Health. FSRH Guideline Combined Oral Contraception. January 2019 (Modified in November 2020).

* In particular deep vein thrombosis of the lower limbs and pulmonary embolism

† HR adjusted for age, body mass index, current duration of hormonal contraceptive use, family history of VTE

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Stability of vitamin K antagonist anticoagulation after COVID‐19 diagnosis – Camilleri – 2021 – Research and Practice in Thrombosis and Haemostasis Thu, 14 Oct 2021 04:29:52 +0000 1 INTRODUCTION The novel coronavirus disease, classified as coronavirus disease 2019 (COVID-19), is a viral pneumonia caused by the newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-COV-2).1, 2 As of January 6, 2021, over 80 million cases of COVID-19 have been reported worldwide.3 Besides primarily affecting the respiratory system, COVID-19 may also affect coagulation.4, […]]]>


The novel coronavirus disease, classified as coronavirus disease 2019 (COVID-19), is a viral pneumonia caused by the newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-COV-2).1, 2 As of January 6, 2021, over 80 million cases of COVID-19 have been reported worldwide.3

Besides primarily affecting the respiratory system, COVID-19 may also affect coagulation.4, 5 The development of coagulopathy has been associated with a poor prognosis,6 and abnormal levels of coagulation parameters such as D-dimer and prolonged prothrombin time (PT) have been found in the more severely ill patients with COVID-19,7-9 yet not in all.10-12 More than half of hospital-admitted patients with COVID-19 present a PT prolongation, compared with only 28% of patients admitted with community-acquired pneumonia.13 The mechanism behind these changes in coagulation parameters is currently unclear. Reasons include a host inflammatory response, effects of viral pneumonia in general, or a specific feature of SARS-COV-2 itself.14

While these abnormalities have been recorded in hospitalized or severely ill patients, data are lacking on coagulation measures in outpatient settings. In patients treated with vitamin K antagonists (VKAs), whose anticoagulant effect is monitored through international normalized ratio (INR) measurement, the above-mentioned coagulation abnormalities could lead to unstable control of anticoagulation. This could be highly relevant, as it might influence their thrombosis and bleeding risk. A recent report showed an increase in the number of INRs above therapeutic range during the lockdown period in 30 patients treated with VKAs, of whom 10 patients were COVID-19 positive.15 Two anticoagulation clinics reported that their whole population of VKA users maintained a consistent time in therapeutic range during the first period of the COVID-19 pandemic, describing no differences with the months prior.16, 17 However, no research has been performed specifically into stability of VKA treatment in patients who are COVID-19 positive.

Our aim was to investigate the stability of anticoagulant treatment with VKAs in patients with newly diagnosed COVID-19 through a case-crossover study, in a cohort of outpatients from two anticoagulation clinics in the Netherlands.


As part of the research program initiated by the Dutch COVID & Thrombosis Coalition,18 we collected patient characteristics from two

anticoagulation clinics in the Netherlands (Leiden, Amsterdam) from their computerized patient records, consisting

of year of birth, sex, co-medication, year of VKA initiation, indication for VKA treatment and INR target range.

2.1 Study population

We included outpatients aged ≥18 years treated with a VKA for any indication, who were registered by the anticoagulation clinic as testing positive for COVID-19 between February 27, 2020, which is the date of the first reported COVID-19 case in the Netherlands, and July 10, 2020.

At the anticoagulation clinics, appointments are made to monitor the INR. Frequencies of appointments depend on the INR value and individual monitoring time: Appointments are planned at a maximum of 6 weeks apart, although they are routinely scheduled more often. At each appointment, a standardized short questionnaire is taken (and electronically stored) by a trained nurse to document changes in comedication, the occurrence of bleeding events, scheduled invasive procedure, and onset of comorbidities, among which was COVID-19. COVID-19 was defined as a positive polymerase chain reaction (PCR) test for SARS-COV-2. We retrieved this information from the electronic patient files, and all reported positive tests were checked and confirmed by the anticoagulation clinics’ treating physicians. We also included patients with suspected COVID-19, defined as patients with suspected SARS-COV-2 infection who were not tested at the time of data extraction, presumably due to the limited testing capacity in the Netherlands at that time. The date of COVID-19 positivity was defined as the day of the confirmed positive test for positive patients and the day of registered suspected infection for suspected patients.

2.2 Variables measured

To measure the INR, venous blood is drawn into vacuum tubes containing 0.1-volume 0.109 mol/L trisodium citrate as anticoagulant. Blood is centrifuged (10 minutes at 2800 g) within 4 hours of collection, upon which the INR is measured. Another performed method to measure the INR is by using a point-of-care device (CoaguChek XS PRO, Roche Diagnostics, Basel, Switzerland).

For each included patient, INR measurements were collected from 26 weeks before the diagnosis of COVID-19 up to a maximum of 12 weeks after. The time in therapeutic range (TTR) was calculated by linear interpolation according to the Rosendaal method19 in three different time frames: from 26 weeks before COVID-19 up to the date of confirmed COVID-19 positivity, from the date of COVID-19 positivity to 6 weeks after, and from 6 weeks after COVID-19 positivity to 12 weeks after. The 6-week time window was identified as a sufficiently short hazard time after COVID-19, in which we would have been able to observe an immediate risk after infection. We expected that any effect of a transient risk factor for anticoagulation instability, such as an acute infection, would be visible shortly after diagnosis. Moreover, 6 weeks is the maximum length of time between consecutive appointments, and therefore we would have been able to include at least two INR measurements for each patient. In addition, we considered a TTR >70% as sufficient anticoagulation stability, as a consensus from the European Society of Cardiology indicates that an average individual TTR should be >70% for optimal efficacy and safety outcomes while the patient is taking a VKA.20

The INR variability was assessed with two methods21, 22: the variance growth rate (VGR) of Fihn et al and of Cannegieter et al. The method of Fihn et al represents the degree to which a patient’s achieved INR deviates from the target INR, while the method of Cannegieter et al evaluates the degree to which a patient’s INR deviates from the previous one. With this second method, a patient is defined as stable if the INRs are around the same value every time, even if this means that, for example, the INR is constantly below the lower limit of the therapeutic range. INR variability assessed with the methods of Fihn et al and Cannegieter et al were calculated for the three time windows mentioned above, that is, in the 26 weeks before, in the 6 weeks after, and between 6 and 12 weeks after the confirmed positivity to COVID-19.

2.3 Statistical analysis

We defined the 26 weeks before the infection as an unexposed period for each patient, using a case-crossover design. This design, in which each patient acts as his own control, is powerful and efficient in minimizing possible confounding.23, 24 It can be used for a transient and brief exposure, such as COVID-19, which creates a hazard for an acute outcome (eg, changes in INR). Therefore, we used the paired sample t test to compare the measures of TTR and VGR in the 6 weeks and between 6 and 12 weeks after the date of infection with the measures in the 26 weeks before the date of infection that was used as a reference category. For TTR, we also calculated the relative mean difference by subtracting the measurement in the 26 weeks before infection from the measurement after infection, dividing it by the value in the 26 weeks prior and multiplying the result by 100%. Mean monitoring time of INR (ie, days between consecutive INR measurements) was also calculated for the three aforementioned times frames. Furthermore, we calculated the percentage of INRs ≥5 and ≥8 for each time window. We calculated the risk ratios (RRs) and 95% confidence intervals (95% CIs) of having an INR ≥5 or ≥8 after COVID-19, compared with the measure in the 26 weeks before infection. For each day before and after the index date, the percentage of patients in, above, and under therapeutic range was computed, using linear interpolation according to the Rosendaal methods.19 Two separate analyses were conducted: (i) including only patients with a confirmed COVID-19, and (ii) including also patients with suspicion of COVID-19.


3.1 General characteristics

Fifty-one patients were registered as positive (ie, confirmed by PCR testing) for COVID-19 by the anticoagulation clinic (Table 1), which is 0.2% of the total population followed by the anticoagulation clinic during the study period (27 853 individuals). Of those, 15 (29%) were men, and the mean age at the time of SARS-COV-2 infection was 84 years (standard deviation [SD], 11). The majority of patients were treated with VKAs because of atrial fibrillation (39; 76%) and the second-most-common indication was venous thromboembolism (6; 12%). Patients had been taking VKAs for a median of 8 years (interquartile range [IQR], 4-10) before their COVID-19 diagnosis. Acenocoumarol was the anticoagulant used in 35 patients (69%). Moreover, 13 patients were recorded as suspected of COVID-19 at the anticoagulation clinics (Table S1). Suspect patients were slightly younger than positive patients (mean age, 80 years; SD, 13) and 5 were men (39%). The indication of venous thromboembolism (6; 46%) for VKA treatment was more prevalent among suspected as compared with positive cases, and the most frequently used anticoagulant in this group was phenprocoumon (10; 77%). During the follow-up, 9 patients died (18%). These patients were older compared to the patients who survived (mean age, 88 years; SD, 8), 5 were men (56%), and the most common indication for anticoagulation was atrial fibrillation (7; 78%). The mean time until death after COVID-19 diagnosis was 12 days (SD, 6).

Demographic and clinical characteristics
Patients who were COVID-19 positive
Patients, n 51
Age, mean (SD) 84 (11)
Men, n (%) 15 (29)
Years since start of treatment, median (IQR) 8 (4-10)
Indication for anticoagulant treatment
Atrial fibrillation, n (%) 39 (76)
Venous thromboembolism, n (%) 6 (12)
Mechanic heart valve, n (%) 4 (8)
Ischemic heart disease, n (%) 1 (2)
Vascular, n (%) 2 (4)
Other, n (%) 3 (6)
INR target range
Low (2.0-3.0), n (%) 50 (98)
High (2.5-3.5), n (%) 1 (2)
Vitamin K antagonist
Acenocoumarol, n (%) 35 (69)
Phenprocoumon, n (%) 16 (31)
Antihypertensive, n (%) 25 (49)
Antidiabetic, n (%) 15 (30)
Antiplatelet, n (%) 4 (8)
  • Abbreviations: COVID-19, coronavirus disease 2019; INR, international normalized ratio; IQR, interquartile range; SD, standard deviation.

3.2 Time in therapeutic range

Mean TTR in the 26 weeks before COVID-19 diagnosis was 80% (95% CI, 75-85), whereas mean TTR in the 6 weeks after infection was 59% (95% CI, 51-68). Mean difference between the TTR calculated in the 26 weeks before and in the 6 weeks after the infection was −23% (95% CI, −32 to −14). Time above therapeutic range was 38% (95% CI, 30-47) in the 6 weeks after infection, whereas time above therapeutic range was 17% (95% CI, 13-22) in the 26 weeks before (Table 2), with a mean difference of 24% (95% CI, 14-33). In the time frame between 6 and 12 weeks after the infection, mean TTR was 79% (95% CI, 69-89), with a mean difference with the 26 weeks before infection of −1.3% (95% CI, −13 to 10). Mean TTR in the 26 weeks before COVID-19 was not different in the 9 deceased patients (80%; 95% CI, 64-95) compared with patients with COVID-19 who survived. Due to the short time to death after COVID-19 diagnosis, INR measurements were available only for 5 of the deceased patients after the index date. Of those, only 1 patient had a significant drop in TTR (from 100% to 56%), whereas for the remaining 4 patients, only a few INR measurements (1-4) were available and were all within the therapeutic range.

Stability of anticoagulation before and after COVID-19 in positive patients

TTR, % (95% CI)

Mean difference

TTR, %

(95% CI)

Relative mean

difference TTR, % (95% CI)


time above range, %

(95% CI)


difference time above range,% (95% CI)


time below range, %

(95% CI)



time below range, %

(95% CI)

26 weeks before COVID-19 80

(75 to 85)

reference reference 17

(13 to 22)

reference 3

(1 to 4)

6 weeks after COVID-19 59

(51 to 68)


(−32 to −14)


(−37 to −14)


(30 to 47)


(14 to 33)


(0.2 to 4)


(−3 to 1)

6–12 weeks after COVID-19 79

(69 to 89)


(−13 to 10)


(−11 to 21)


(8 to 27)


(−11 to 13)


(0.5 to 5)


(−2 to 3)

  • Abbreviations: CI, confidence interval; COVID-19, coronavirus disease 2019; TTR, time in therapeutic range.

We observed that the percentage of patients in therapeutic range decreased ≈9 to 11 days before the date of registered COVID-19, while we recorded a concomitant increase of patients above therapeutic range (Figure 1). After ≈30 days from the day of infection, the percentage of patients in therapeutic range rose again to values >70%.

Percentage of patients in, above and under therapeutic range over time. Day 0 is the date of positive COVID-19 test. On the right side, a blow-up figure of the time frame between 3 weeks before and after COVID-19

We repeated the aforementioned analysis combining data of patients who were COVID-19 positive with suspected patients (Table S2 and Figure S1). Results were similar to the analysis on positive patients only.

3.3 Variance growth rate of INR

The VGR calculated according to the method of Cannegieter et al in 26 weeks before COVID-19 was 1.4 (95% CI, 0.8-2.0) and increased to 5.7 (95% CI, 3.0-8.5) in the 6 weeks after infection, with a mean difference of 4.8 (95% CI, 2.1-7.5). Between 6 and 12 weeks from COVID-19, mean VGR of Cannegieter et al was 3.6 (95% CI, 0-7.4) with a mean increase of 2.5 (95% CI, −1.4 to 6.4) relative to 26 weeks before infection. Similarly, VGR calculated with the method of Fihn et al was 0.8 (95% CI, 0.5-1.1) in the 26 weeks before COVID-19 and rose to 1.9 (95% CI, 1.0-2.7) in the 6 weeks after infection, with a mean difference of 1.2 (95% CI, 0.3-2.0) (Table 3). The VGR of Fihn et al was 1.1 (95% CI, 0.2-2.0) between 6 and 12 weeks after infection, with a mean increase from 26 weeks before infection of 0.2 (95% CI, −0.8 to 1.2). We repeated both analyses including patients with suspected COVID-19 and the analyses yielded similar results (Table S3).

Variance growth rate according to Cannegieter et al and Fihn et al before and after COVID-19 in positive patients
Mean VGR

Cannegieter et al

(95% CI)

Mean difference

VGR Cannegieter et al

(95% CI)

Mean VGR

Fihn et al.

(95% CI)

Mean difference

VGR Fihn et al

(95% CI)

26 weeks before COVID-19 1.4

(0.8 to 2.0)

reference 0.8

(0.5 to 1.1)

6 weeks after



(3.0 to 8.5)


(2.1 to 7.5)


(1.0 to 2.7)


(0.3 to 2.0)

6-12 weeks after



(0 to 7.4)


(−1.4 to 6.4)


(0.2 to 2.0)


(−0.8 to 1.2)

  • Abbreviations: CI, confidence interval; COVID-19, coronavirus disease 2019; VGR, variance growth rate.

3.4 Percentage of INR ≥5.0 and INR ≥8.0

In the 26 weeks before COVID-19 diagnosis, 641 INR measurements were available, whereas 247 and 154 INR measurements were available in the 6 weeks after and between 6 and 12 after, respectively. Per patient, a median of 1.5 (IQR, 2) INR measurements were available each month in the 26 weeks before COVID-19 diagnosis. The median number of INR measurements each month per patient was instead 2 (IQR, 2) in the first 6 weeks after diagnosis and 1.3 (IQR, 1.7) between 6 and 12 weeks after. Mean monitoring time between INR was 20 days (95% CI, 17-22) in the 26 weeks before infection, whereas it was 15 days (95% CI, 13-18) in the 6 weeks after infection and remained 15 days (95% CI, 13–17) between 6 and 12 weeks after infection.

In the 26 weeks before COVID-19, 19 of 641 (3%) INR samples were ≥5.0 (13 patients) compared with 35 of 247 (14%) in 18 patients in the 6 weeks after infection (RR, 4.8; 95% CI, 2.8-8.2). Between 6 and 12 weeks after infection, we registered 10 of 154 (6%) INRs ≥5.0 in 7 patients (RR, 2.1; 95% CI, 1.0-4.6). Moreover, 3 of 641 (0.5%) of INR samples were ≥8.0 (3 patients) in the 26 weeks before the infection compared with 10 of 247 (4%) in 8 patients in the 6 weeks after (RR, 8.6; 95% CI, 2.4-31.2). Between 6 and 12 weeks after infection, we registered 6 of 154 (4%) INRs ≥8.0 in 5 patients (RR, 8.3; 95% CI, 2.1-32.9) (Table 4). The results of both analyses repeated adding suspect patients also showed a higher risk of supratherapeutic INRs after COVID-19 (Table S4).

Percentage of INR ≥5.0 and ≥8.0 before and after COVID-19 in positive patients
INR ≥5.0 INR ≥8.0
High INR/all INR



(95% CI)

High INR/all INR (%) RR

(95% CI)

26 weeks before COVID-19 19/641


Reference 3/641


6 weeks after COVID-19 35/247








6-12 weeks after COVID-19 10/154








  • Abbreviations: CI, confidence interval; COVID-19, coronavirus disease 2019; INR, international normalized ratio; RR, risk ratio.


The results of this case-crossover analysis showed that in patients using VKA treatment, 6 weeks after COVID-19, the quality of anticoagulation control was lower compared to the weeks before infection. Time in therapeutic range was 23% lower in patients who were COVID-19 positive during the 6 weeks after infection, with two times more INR values above therapeutic range. Interestingly, the mean TTR was restored between 6 and 12 weeks after infection. Moreover, the variability of the INR was increased in the 6 weeks after infection, with a more pronounced result found by the method of Cannegieter et a. than the method of Fihn et al. Between 6 and 12 weeks after infection the increase in VGR was less pronounced. In addition, in the 6 weeks after COVID-19, we registered an almost five times higher proportion of INR ≥5.0 and an eight times higher proportion of INR ≥8.0 compared to the 26 weeks before COVID-19. This is clinically relevant because INRs ≥5.0 are strongly associated with a higher risk of bleeding complications,25 and withholding of VKA or even administration of an antidote can be required.26 Between 6 and 12 weeks after infection the proportion of higher INRs was still increased but less prominently compared with the percentage in the first 6 weeks after infection. The unstable control of INR is reflected by the shorter mean number of days between consecutive INR measurements observed in the three different time frame. The mean monitoring time was 20 days in the 26 weeks before infection and dropped to 15 days in both the 6 weeks after and between 6 and 12 weeks after.

We saw that during the 26 weeks before COVID-19, the percentage of patients in therapeutic range was stable through time and sharply decreased 9 to 11 days before the actual date of registered COVID-19 positivity, with a concomitant increase in the percentage of patients above therapeutic range. This period just before the infection could reflect the latency between the day of the onset of infection and/or symptoms and the day the results of the test for SARS-COV-2 were available. Another possible explanation could be related to the interpolation assumption, that states that INRs linearly increase/decrease from one measurement to the following one. If, for example, the date of COVID-19 registered positivity is between one INR in range and one INR out of range, the linear interpolation would result in a high INR not only after but also before infection. At the end of our follow-up period, between 80 and 84 days after the infection, the percentages of patients in therapeutic range slightly decreased again, but not declining below 70%. We believe this could be due to the relatively low number of patients with such long follow-up, as only 19 patients had an INR determination between 80 and 84 days after infection.

Explanations for the unstable INR in previously stable patients during COVID-19 are probably multifactorial and difficult to identify clearly. The VGR assessed with the method of Cannegieter et al yielded the greatest mean increase, suggesting that INR instability is mainly caused by deviation from the previous measurement, rather than deviation from the target INR. A factor that could contribute to such instability is a change in diet during illness. A reduced intake of food during the illness, particularly of vitamin K–containing food, could have contributed to the higher number of supratherapeutic INRs.27 Reduced vitamin K status has also been reported in patients who were COVID-19 positive.28 Moreover, a recent review showed that patients who were COVID-19 positive are frequently treated with antibiotics.29 Changes in prescribed medication during COVID-19, some of which could have interactions with VKA, could have determined the observed instability.30 In our population, 26 (50%) patients changed medication around the time of COVID-19 diagnosis (within 14 days before until 14 days after the date of COVID-19–positive test), of whom 23 (45%) were treated with interacting medication and 24 (47%) with antibiotics. However, mean TTR in the 6 weeks after infection was lower in patients who did not initiate possible interacting medication (53%; 95% CI, 40-65) compared with patients treated with a possible interacting drug (68%; 95% CI, 57-80). Moreover, mean difference between TTR calculated in the 26 weeks before and in the 6 weeks after was similar between patients who did not initiate possible interacting medication and patients who did (−23%; 95% CI, −41 to −15; and −16%; 95% CI, −30 to 3). However, our limited sample size and the small group sizes do not allow us to draw firm conclusions on the contribution of interactive medication to the observed instability. In addition, nonadherence to prescribed VKA dosage during illness could also be a concurrent cause of deviation from the target INR. However, only a VKA overdosage could explain the observed increased rate of supratherapeutic INR. It cannot be excluded that SARS-COV-2 itself had an effect on anticoagulant intensity through its effects on coagulation parameters that are related to anticoagulant control.7-9, 13, 31 Acute respiratory infections are a demonstrated risk factor for overanticoagulation,32 independently from antibiotic treatments33; however, their exact contribution to TTR variability has not been previously evaluated in the literature. Nevertheless, as it is not possible to disentangle which component of COVID-19 illness contributes to our findings, we do not mean to infer a causal relation between SARS-COV-2 per se and decreased TTR.

Due to our relatively small sample size and follow-up time, we were not able to evaluate whether the instable INR control we found results in higher frequency of bleeding or thrombosis. However, it is established that INR instability is a general risk factor for adverse outcomes, such as bleeding and thrombotic events.21, 34, 35 For an INR of 5.0 to 5.5, the incidence of bleeding events is estimated as 4.8 per 100 patient-years, raising to 75 per 100 patient-years when the INR is ≥6.5.36 Some other limitations of our study should be noted. First, information on the severity of COVID-19 was not available in the electronic chart of the anticoagulation clinics. Therefore, we cannot comment on whether severity of disease can influence the instability of anticoagulation. Furthermore, presumably due to the strict policy of testing at the time our data were collected, some patients who were COVID-19 positive may not have been tested and were therefore not included in our analysis. This is reflected in our limited sample size of 51 patients who were COVID-19 positive. The total number of patients followed by the two anticoagulation clinics was 27 853 individuals in the study period, which means that the 0.2% of the population followed by the anticoagulation clinic tested positive for COVID-19. This percentage is similar to data from the Netherlands: as of July 14, 2020, a total of 51 146 residents in the Netherlands tested positive for COVID-19 since the beginning of the pandemic,37 which represents 0.3% of the total population (17 280 397). Regardless, we expect that missing some patients would not have influenced our results other than possibly slightly lower precision. This is further supported as repeating the analysis including suspect patients did not change our results. In addition, we observed an increased frequency of INR measurements after COVID-19 diagnosis compared with before, which could lead to an increased number of out-of-range INRs due to overtesting. However, INR controls at the anticoagulation clinics during the first wave of COVID-19 were delayed as much as possible in stable patients,38 to reduce unnecessary contact and the risk of infection. Therefore, we believe that the reduced monitoring time is a consequence of the increased rate of INRs above range and not vice versa. A strength of our study is the case-crossover design through which patients are compared with themselves. This design strongly reduces problems with incomparability of groups (minimizing confounding) and with sampling bias otherwise introduced in selection of controls.

We showed a strong reduction of anticoagulant therapy stability after COVID-19 diagnosis: TTR decreased in 23% with a doubling of time above therapeutic range. On the basis of our results, we encourage maintaining a strict INR control during COVID-19 because of the higher incidence of supratherapeutic INRs that could increase the bleeding risk.


This work was supported by the Netherlands Thrombosis Foundation.


    EC, SCC, and NvR designed the research. EC, FJvdM, and MCN collected the data. EC and NvR analyzed the data. EC and NvR wrote the manuscript. EC, SCC, NvR, FJvdM, MCN, and WML revised the article for important intellectual content.


    Dr Van der Meer reports grants from CSL Behring, Pfizer, Bayer, Novo Nordisk, Sobi, Roche, OctaPharma outside the submitted work. The other authors declare no conflict of interest.

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    The prevalence, predictors and outcomes of acute liver injury among patients with COVID‐19: A systematic review and meta‐analysis – Harapan – – Reviews in Medical Virology Thu, 14 Oct 2021 04:29:49 +0000 Abbreviations ACE2 angiotensin-converting enzyme 2 ALI acute liver injury BMI body mass index CAD coronary artery disease COVID-19 coronavirus disease 2019 DM diabetes mellitus NOS Newcastle–Ottawa Scale PRISMA Preferred Reporting Items for Systematic Review and Meta-Analysis SARS-CoV-2 severe acute respiratory syndrome coronavirus 2 1 INTRODUCTION The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute […]]]>


  1. ACE2
  2. angiotensin-converting enzyme 2
  3. ALI
  4. acute liver injury
  5. BMI
  6. body mass index
  7. CAD
  8. coronary artery disease
  9. COVID-19
  10. coronavirus disease 2019
  11. DM
  12. diabetes mellitus
  13. NOS
  14. Newcastle–Ottawa Scale
  15. PRISMA
  16. Preferred Reporting Items for Systematic Review and Meta-Analysis
  17. SARS-CoV-2
  18. severe acute respiratory syndrome coronavirus 2

    The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains the major global concern. The pathogenesis of COVID-19 is complicated1, 2 and involves multiple organs including lung, kidney, heart, neurologic system, gastrointestinal system and liver.3 Although the respiratory tract is the primary target of SARS-CoV-2, more than 50% of COVID-19 patients had nausea, vomiting, diarrhoea and loss of appetite4 suggesting the involvement of gastrointestinal and hepatobiliary system. A recent study also found that moderate microvascular steatosis was prevalent in liver biopsies of COVID-19 patients, suggesting that liver injury might occur during COVID-19.5 The involvement of liver in SARS-CoV-2 infection is mystifying,6 and it was suggested that liver involvement is mediated by several mechanisms, including direct infection of the liver, drug-induced liver injury, systemic inflammatory response or hypoxic hepatitis.7

    The optimal management of acute liver injury (ALI) in COVID-19 patients remains controversial. Although one recommendation suggested that ALI in COVID-19 is reversible and does not require specific treatment,7 liver involvement was reported to cause poor prognosis of COVID-19 patients.8 Moreover, liver involvement has been included in predicting the outcomes of patients with COVID-19.9 To date, no information is available regarding predictors of when and who among COVID-19 patients will suffer from ALI. In addition, data on the outcomes of COVID-19 patients with ALI are also limited. Therefore, the objective of this study was to determine the prevalence of ALI in COVID-19 patients, predictors of ALI occurrence and prognosis of COVID-19 patients with ALI.


    2.1 Study design and eligibility criteria

    A systematic review following the Preferred Reporting Items for Systematic Review and Meta-Analysis10 was conducted up to 10 June 2021 on four databases including PubMed, Embase, Cochrane and Web of Science. The included papers should: (1) have the design of double-arm analysis such as randomised controlled trial (RCT) and non-RCT or observational studies (case–control, cross-sectional or cohort); (2) report either the prevalence, predictor or the outcome of ALI in COVID-19 patients; (3) contain information about COVID-19 cases diagnosed using RT-PCR from nasopharyngeal or oropharyngeal swab samples; and (4) have sufficient criteria for the diagnosis of ALI.11

    2.2 Search strategy and data extraction

    All papers in English were searched using Medical Subjects Heading: (“COVID-19” OR “SARS-CoV-2”) AND (“acute liver injury” OR “liver dysfunction” OR “liver abnormality”) AND (“prevalence” OR “predictor” OR “outcome”). Additional papers from the reference list of the articles were searched and in case of dual duplication, a paper with the higher sample size was included. The following information were collected from each study: (1) first author name and publication year; (2) country and city of origin; (3) study design; (4) study setting; (5) sample size of COVID-19 patients with and without ALI; (5) the incidence of ALI; (6) the factors associated with ALI; and (7) severity and mortality rate of COVID-19 patients with and without ALI. The definition of variables and study protocols were defined prior to data collection, and a kappa test was used to assess the understanding among investigators.

    2.3 Quality assessment

    Potential articles were evaluated for their methodological quality using Newcastle–Ottawa Scale (NOS) that evaluates sample selection, comparison and exposure.12 The calculation of NOS score was used to classify the quality of articles into low (score 0–3), moderate (score 4–6) and high quality (score 7–9) and only articles with moderate and high quality were included into analysis. All letters to the editor, commentaries, case reports, case series and reviews were excluded.

    2.4 Study variables

    ALI refers to an acute abnormality of liver blood tests and the development of a coagulopathy, but does not exhibit any alteration of consciousness in an individual without underlying chronic liver disease.9 The predictor variables included age, gender, body mass index (BMI), the presence of comorbidities [diabetes mellitus (DM), coronary artery disease (CAD) and hypertension], pre-existing liver disease, as well as the levels of leucocytes, lymphocytes and neutrophils. Those variables were defined after considering the available data.

    2.5 Statistical analysis

    To assess the publication bias, an Egger test was applied and a p < 0.05 indicated potential publication bias.13 The heterogeneity among studies was assessed using a Q test and the random effect model was used if the heterogeneity across the studies were observed (p < 0.10).13 The prevalence of ALI, the associated predictors of ALI, and the association between ALI and the clinical outcomes of patients with COVID-19 were determined using a Z test. The summary of statistical analysis was presented in forest plot. A Review Manager (Revman Cochrane, London, UK) version 5.3 was used to analyse the data.


    3.1 Study eligibility results

    A total of 1331 papers were identified across the databases of which 1283 papers were excluded due to having irrelevant studies. Full-text assessment was conducted on 48 papers and additional 32 papers were excluded as they did not meet the eligibility criteria (Figure 1). 16 papers consisting of two cross-sectional studies, three prospective studies and 11 retrospective studies were finally included into meta-analysis (Table 1).5, 14-28

    A flowchart of article selection

    TABLE 1.
    Baseline characteristics of articles included in our analysis
    Author and years Country Study design Study group comparation Sample size Quality (NOS)
    ALI Non-ALI
    Bloom et al. (2021) US Prospective cohort Normal versus hepatocellular injury 10 50 6
    Cai et al. (2020) China Cross-sectional Normal liver versus ALI 22 225 6
    Cai et al. (2020) China Retrospective Normal liver versus ALI 90 327 6
    Chen et al. (2021) China Prospective cohort Normal liver versus ALI 32 603 5
    Chen et al. (2020) China Retrospective Normal liver versus ALI 13 261 6
    Chew et al. (2021) China Retrospective Normal liver versus ALI 105 729 6
    Fan et al. (2020) China Cross-sectional Normal liver versus ALI 55 93 5
    Mishra et al. (2020) US Retrospective Normal liver versus ALI 166 162 8
    Phipps et al. (2020) US Retrospective Normal liver versus ALI 145 1784 6
    Piano et al. (2020) Italy Retrospective Normal liver versus ALI 329 236 6
    Qi et al. (2020) China Prospective cohort Non-ALI versus ALI 32 38 5
    Sarin et al. (2020) India Retrospective Non-ALI versus ALI 97 88 6
    Wang et al. (2020) China Retrospective Normal liver versus ALI 96 243 6
    Xie et al. (2020) China Retrospective Non-ALI versus ALI 29 50 6
    Yang et al. (2021) China Retrospective Normal liver versus ALI 15 37 7
    Zhao et al. (2020) China Retrospective Non-ALI versus ALI 18 73 8
    • Abbreviations: ALI, acute liver injury; NOS, Newcastle–Ottawa Scale.

    3.2 The global prevalence, predictors and prognosis of ALI among patients with COVID-19

    The included studies comprised 1254 COVID-19 with ALI and 4999 COVID-19 without ALI, and the prevalence of ALI was found to be 22.8% [95% confidence interval (CI): 14.1, 34.6] (Figure 2a). A total of 10 potential predictors of ALI (age, gender, BMI; the presence of DM, CAD, and hypertension, liver disease; as well as the level of white blood cells (WBC), neutrophils and lymphocytes) were analysed (Table 2). Male and having high lymphocyte count were associated with ALI with OR: 2.70; 95% CI: 2.03, 3.60 and mean difference (MD): −125; 95% CI: −207, −43, respectively (Figures 2b,c). Our data suggested that COVID-19 patients with ALI had higher odds of suffering from severe disease compared with those without ALI, OR: 3.61; 95% CI: 2.60, 5.02 (Figure 2d and Table 2).


    The summary of acute liver injury (ALI) in patients with coronavirus disease 2019 (COVID-19). (a) The global prevalence of ALI in patients with COVID-19. (b) Association of gender (male) with ALI in COVID-19 patients. (c) Association of low level of lymphocyte with ALI in COVID-19 patients. (d) Association between ALI and the severity of COVID-19

    TABLE 2.
    The global prevalence, predictors and prognosis of acute liver injury among patients with COVID-19
    Variable NS Model Study group Point estimate 95%CI p Egger p Het p-value
    ALI Non-ALI
    ALI prevalence 16 Random 1254 (20.05) 4999 (79.94) 22.8%a 14.1, 34.6 1.1760 <0.0001 <0.0001
    ALI predictors
    Age (years), mean ± SD 5 Random 55.2 ± 8.8 53.6 ± 10.2 1.76b −3.26, 6.78 0.3260 0.0030 0.4660
    Male, n (%) 6 Fixed 194 (71.9) 1334 (48.5) 2.70c 2.03, 3.60 0.1720 0.3180 <0.0001
    BMI (kg/m2), mean ± SD 2 Fixed 28.5 ± 3.5 26.5 ± 4.9 2.63b 0.97, 4.30 <0.0001 0.3630 0.0020
    Diabetes mellitus, n (%) 6 Fixed 56 (20.7) 828 (30.1) 0.72c 0.52, 0.99 <0.0001 0.8450 0.0450
    Coronary artery disease, n (%) 4 Fixed 10 (9.7) 77 (10.4) 1.26c 0.60, 2.63 <0.0001 0.8520 0.5450
    Hypertension, n (%) 5 Random 105 (40.4) 1309 (48.5) 1.31c 0.67, 2.54 0.5790 0.0220 0.4260
    Liver disease, n (%) 4 Random 15 (7.2) 110 (4.2) 2.98c 1.00, 8.88 0.8400 0.0630 0.0500
    Leucocyte (cells/μl), mean ± SD 3 Random 7983 ± 3953 5553 ± 1700 2432b −89, 4954 0.4550 <0.0001 0.0590
    Neutrophils (cells/μl), mean ± SD 3 Random 5556 ± 2833 3893 ± 1334 166b −29, 362 0.4400 <0.0001 0.0970
    Lymphocytes (cells/μl), mean ± SD 4 Random 1097 ± 128 1222 ± 89 −125b −207, −43 0.8610 <0.0001 0.0090
    Severe versus non severe 5 Fixed 140 (27.80) 97 (11.90) 3.61b 2.60, 5.02 0.2810 0.2060 <0.0001
    Mortality 8 Random 252 (28.77) 445 (24.07) 1.38b 0.85, 2.25 0.5130 0.0060 0.1940
    • Abbreviations: ALI, acute liver injury; BMI, body mass index; CI, confidence interval; NOS, Newcastle–Ottawa Scale; NS, number of studies; p Het, p heterogeneity; WBC, white blood cells.
    • a Event rate.
    • b Odds ratio.
    • c Mean difference.

    3.3 Heterogeneity and potency of bias across the studies

    The heterogeneity was identified on data of prevalence of ALI in COVID-19 patients, mortality of COVID-19 and data of some predictors of ALI such as age, hypertension, liver disease, WBC, neutrophils and lymphocytes and therefore random effect model was used while other predictors were and the association between ALI and severity of COVID-19 was assessed using fixed effect model. The potency of publication bias was found in several predictors of ALI including BMI, DM and CAD (Table 2).


    Our study found that the cumulative prevalence of ALI among patients with COVID-19 was 22.8%. This finding is higher compared with that of a previous meta-analysis using data of five studies (prevalence 15.7%).29 Our data suggest that male and having high lymphocyte level were associated with ALI. Although the mechanism of ALI in SARS-CoV-2 infection is debatable, it is known that the expression of angiotensin-converting enzyme 2 (ACE2) receptors, the primary receptor for SARS-CoV-2 to enter human cells, was high in the liver.30 A previous investigation reported that the expression of ACE2 receptors was higher in male than female31 and ACE2 expression is mediated by androgen.32 A study revealed that ACE2 receptors were also expressed in lymphocytes,33 suggesting that SARS-CoV-2 may also attack lymphocytes leading to decreased numbers. Interestingly, our study also found that patients with higher BMI and DM had higher risk to develop ALI, although the Egger test is insufficient to support the findings. The liver abnormality in patients with the obesity and DM suggested that the metabolic associated steatohepatitis might also affect the involvement of liver injury, and this circumstance might also contribute to the severity of COVID-19 infection.31 Our findings also showed that COVID-19 patients with ALI had higher risk of developing severe disease, consistent with previous meta-analyses.29, 34-36 Therefore, patients with ALI on initial admission should be strictly monitored since they are at higher risk of developing severe outcomes including death. The involvement of liver could trigger dysregulated immune responses leading to cytokine storm,37 a pathological state associated with fatal COVID-19 outcomes.38 This presumably explains why COVID-19 patients with ALI possess higher risk of developing severe conditions.

    The present study, to the best of our knowledge, is the first to provide comprehensive data on prevalence, predictors and prognosis of ALI in COVID-19. Robust results indicated that ALI is associated with severe COVID-19. Therefore, some parameters should be monitored during COVID-19 management to anticipate the occurrence of ALI and to prevent severe outcomes. The present data might helpfully be used as the reference for the management of COVID-19 with ALI.

    There are some limitations of our study. Potential confounding factors such as previous medication, drug interactions, previous liver disease, status of metabolism and previous history of infectious disease were not reported and therefore could not be controlled. In addition, the heterogeneity of the quality of included articles in our meta-analysis might contribute to certain degree of bias. Furthermore, the limited studies on the topic led us to include only limited number of papers, and therefore the potential for publication bias should be carefully interpreted.


    The prevalence of ALI among patients with COVID-19 is 22.8%. Male and having lower lymphocyte level are more likely to be associated with ALI. COVID-19 patients with ALI have high risk for severe COVID-19 and therefore should be monitored closely to prevent the development of severe conditions. Nevertheless, further prospective studies are required to provide more robust data and to confirm the findings of the present study.


    Authors would like to thank to Lembaga Pengelola Dana Pendidikan (LPDP) Republic of Indonesia for supporting our project. Harapan is supported by the Indonesian Endowment Fund for Education and the Indonesian Science Fund through the International Collaboration RISPRO Funding Program (No. RISPRO/KI/B1/TKL/5/15448/1/2020) and Universitas Syiah Kuala (Ministry of Education, Culture, Research and Technology) through the H-Index Research Scheme (No. 169/UN11/SPK/PNBP/2021).


      Authors have no conflict of interest.


      Not applicable.


      Conceptual: Harapan Harapan, Jonny Karunia Fajar, Supriono Supriono. Design: Jonny Karunia Fajar. Control/supervision: Supriono Supriono, Gatot Soegiarto, Laksmi Wulandari. Data collection/processing: Fiha Seratin, Nyoman Gede Prayudi, Dara Puspita Dewi, Maria Theresia Monica Elsina, Lasarus Atamou, Sinta Wiranata, Dhito Pemi Aprianto, Erlin Friska, D. Fitria Sari Firdaus, Makdum Alaidin, Firdha Aprillia Wardhani, Nurdina Wahyu Hidayati, Yeni Hendriyanti, Kristia Wardani, Arde Evatta, Reizal Audi Manugan, Wiryawan Pradipto, Ade Rahmawati, Fredo Tamara, Aditya Indra Mahendra, Budi Santoso, Chandra Adi Irawan Primasatya, Nindy Tjionganata, Hendarto Arif Budiman. Extraction/analysis/interpretation: Jonny Karunia Fajar, Fredo Tamara, Aditya Indra Mahendra. Literature review: Jonny Karunia Fajar, Fredo Tamara, Aditya Indra Mahendra. Writing the article: Harapan Harapan, Jonny Karunia Fajar, Fredo Tamara, Aditya Indra Mahendra. Critical review: Harapan Harapan, Supriono Supriono, Jonny Karunia Fajar, Gatot Soegiarto, Laksmi Wulandari, Milda Husnah. All authors have read and approved the final draft.


      Not applicable.

      Data used in our study were presented in the main text.


      Directives du NCCN sur le cancer de la prostate : un focus sur la chimiothérapie, l’immunothérapie et la thérapie ciblée dans le cancer de la prostate avancé – Approches chimiothérapeutiques Thu, 14 Oct 2021 04:29:40 +0000 Lire la transcription complète de la vidéo Christophe Wallis : Bonjour et merci de vous joindre à nous pour cette discussion UroToday sur les directives de pratique clinique du NCCN en oncologie, avec un accent particulier sur les directives sur le cancer de la prostate publiées en février 2021. Je suis Chris Wallis, professeur adjoint […]]]>
      Lire la transcription complète de la vidéo

      Christophe Wallis : Bonjour et merci de vous joindre à nous pour cette discussion UroToday sur les directives de pratique clinique du NCCN en oncologie, avec un accent particulier sur les directives sur le cancer de la prostate publiées en février 2021. Je suis Chris Wallis, professeur adjoint à la division d’urologie de L’Université de Toronto. Je suis accompagné aujourd’hui de Zach Klaassen, professeur adjoint à la division d’urologie du Medical College of Georgia.

      Aujourd’hui, nous discutons du chapitre intitulé Chimiothérapie, immunothérapie et thérapie ciblée dans le cancer avancé de la prostate. Il s’agit de la première partie de ce sujet, et nous en discuterons plus en détail dans la deuxième partie.

      Pour les patients atteints de CPRCm avec ou sans symptômes, il existe maintenant une variété d’options de traitement. Et vous pouvez voir ici, le tableau des directives du NCCN, la stratification selon les lignes de thérapie antérieures. Nous allons parcourir chacun d’eux à tour de rôle.

      Dans ce contexte, nous pouvons examiner six approches thérapeutiques, dont la chimiothérapie, l’immunothérapie et les thérapies ciblées. Et dans cet exposé, nous allons nous concentrer sur les trois premiers ici, sur les approches chimiothérapeutiques.

      Le premier d’entre eux est donc le docétaxel. Le docétaxel dans le mCRPC a été introduit pour la première fois dans notre pratique sur la base de l’essai TAX-327. Il s’agit d’une étude à trois bras portant sur deux schémas posologiques différents de docétaxel, par rapport à la mitoxantrone, avec de la prednisone pour tous les patients. Et vous pouvez voir ici sur la courbe de Kaplan-Meier dans le [inaudible 00:01:34] Publication d’un journal séminal de la Nouvelle-Angleterre, selon laquelle nous obtenons une amélioration de la survie globale pour les hommes recevant du docétaxel toutes les trois semaines. Et par rapport à la mitoxantrone, la variation de la survie globale à la médiane était d’environ deux mois et demi.

      Des résultats similaires ont été observés dans l’essai SWOG 9916, qui comparait le docétaxel et l’estramustine à la mitoxantrone et à la prednisone. Et ainsi, sur cette base, le docétaxel est devenu le premier traitement de prolongation de la vie approuvé dans le mCRPC.

      L’approche standard sur la base de TAX-327 est de doser toutes les trois semaines. Cependant, une approche alternative est l’administration toutes les deux semaines, et dans les données de phase II, cette approche diminue le taux de neutropénie fébrile et peut en fait améliorer la survie globale. Cela est donc également recommandé dans le contexte des directives du NCCN. Et pour les patients qui reçoivent du docétaxel dans le cadre du mCRPC, les résultats sont meilleurs s’ils peuvent recevoir au moins huit cycles de traitement. Et le docétaxel est désormais considéré comme le traitement de stade principal pour les patients présentant une maladie symptomatique, mais peut également être envisagé chez les patients asymptomatiques qui présentent soit une progression clinique rapide, soit des métastases viscérales, ce qui suggère le bénéfice préférentiel d’un régime chimiothérapeutique. En conséquence, le docétaxel est une option thérapeutique privilégiée de catégorie un, aussi bien en première intention qu’en deuxième intention, après et pendant l’inhibition de l’accès. De plus, il convient de noter que le panel pense que le docétaxel peut être administré en deuxième intention dans le mCRPC s’il a déjà été administré dans le mCSPC. Et nous discuterons des données pour mCSPC à venir.

      Et donc il y a trois essais pertinents, dont deux forment la base des recommandations du NCCN soutenant le docétaxel.

      Et donc le premier dont nous discuterons ici est l’essai CHAARTED dirigé par le Dr Sweeney. Il s’agissait donc d’un essai contrôlé randomisé, avec un peu moins de 800 hommes atteints de CPRCm, randomisés pour recevoir ADT plus docétaxel, ou ADT seul. Et vous pouvez voir que dans l’analyse principale, la survie globale a été améliorée pour les hommes qui ont reçu l’ADT plus le docétaxel, avec un bénéfice médian de survie globale de plus d’un an, soit environ 14 mois.

      Cependant, lorsque nous examinons à la fois l’analyse initiale et le suivi avec une durée d’observation plus longue, nous voyons une stratification en fonction de la charge de morbidité. Ainsi, au sein de CHAARTED, la maladie à haut volume est définie comme quatre métastases osseuses ou plus, dont au moins une est située en dehors du bassin ou de la colonne vertébrale, ou métastase viscérale. Et dans le cas d’une maladie à haut volume, nous constatons à la fois au début et avec un suivi prolongé, qu’il y a un avantage de survie au docétaxel. Cependant, chez les patients atteints d’une maladie à faible volume, le bénéfice est moins clair. Et avec un suivi plus long, les courbes de survie se croisent.

      Nous pouvons maintenant passer à STAMPEDE, dont la plupart savent qu’il s’agit d’un essai contrôlé randomisé à plusieurs étapes et à plusieurs bras au Royaume-Uni, qui évalue une variété de nouvelles approches de traitement, en conjonction avec ADT, pour les hommes atteints d’une maladie avancée. Notamment, cette étude inclut également des patients atteints de N1 et d’une maladie localisée à haut risque, en plus d’une maladie métastatique sensible à la castration. Et donc, dans la conception de l’étude évaluant le docétaxel, il s’agit d’une étude à quatre bras avec la norme de soins étant l’ADT seul, et d’autres bras comprenant le docétaxel, l’acide zolédronique ou la combinaison de ceux-ci. La comparaison du docétaxel montre ici un avantage de survie globale à l’utilisation du docétaxel avec un rapport de risque de 0,78, ce qui est statistiquement significatif.

      Le panel du NCCN souligne spécifiquement que, bien que l’approbation du docétaxel inclue tous les volumes de maladie, le bénéfice est moins certain chez les hommes atteints de maladie à faible volume. Et donc vous pouvez le voir à partir du suivi à plus long terme, CHAARTED à gauche, de l’essai GETUG-AFU 15, qui était globalement négatif, et postulé comme tel, sur la base d’un volume global de maladie plus faible chez patients inclus, ainsi qu’un suivi plus long de l’essai GETUG-AFU 15, à l’extrême droite de l’écran.

      Le docétaxel a également été évalué dans les maladies localisées à haut risque. Et ici, nous pouvons voir deux essais, l’un du groupe GETUG en France et l’autre du RTOG aux États-Unis, évaluant le rôle de l’ajout de docétaxel à la radiothérapie externe et à l’ADT. Ainsi, dans l’essai GETUG, la survie sans rechute à huit ans a été significativement améliorée. Alors que, dans l’essai RTOG, la survie globale à quatre ans a été améliorée. Malgré ces données, le panel des directives du NCCN ne recommande pas l’ajout de docétaxel à l’ADT dans le cancer de la prostate à haut risque.

      Nous allons maintenant passer à la discussion sur le cabazitaxel, et. à ce stade, je vais le remettre à Zach.

      Zachary Klaassen : Merci, Chris. L’évaluation du cabazitaxel commence donc par l’étude TROPIC, qui était une étude randomisant les patients atteints de CPRCm progressant sous docétaxel, à leur mitoxantrone plus prednisone, versus cabazitaxel plus prednisone. Et ces patients ont été stratifiés par statut de performance ECOG, ainsi que par maladie mesurable ou non mesurable. Le critère d’évaluation principal de cette étude était la survie globale, et les critères d’évaluation secondaires clés sont la survie sans progression, le taux de réponse et la sécurité.

      Vous pouvez voir ici à droite, dans la moitié supérieure de ce panneau, la courbe de survie globale de Kaplan-Meier, en faveur du cabazitaxel, avec un risque relatif de 0,70 et un intervalle de confiance à 95 % de 0,59 à 0,83. Et encore une fois, vous pouvez voir un avantage pour le cabazitaxel avec une survie sans progression, avec un rapport de risque de 0,74 et un intervalle de confiance à 95 % de 0,64 à 0,68.

      Il est à noter dans cet essai que l’amélioration de la survie globale a été mise en balance avec une toxicité plus élevée dans le groupe cabazitaxel. Nous avons trouvé qu’il y avait une mort toxique dans 4,9% du cabazitaxel, contre 1,9% dans le groupe mitoxantrone. Ainsi qu’un taux plus élevé de neutropénie fébrile, à 7,5% contre 1,3%. Il y avait également des taux plus élevés de diarrhée sévère, de fatigue, de nausées, de vomissements, d’anémie et de thrombocytopénie dans le groupe cabazitaxel. Fait intéressant, dans l’analyse post-hoc, il a été suggéré que la neutropénie de grade 3+ était associée à une amélioration de la survie sans progression et de la survie globale.

      La deuxième étude concernant le cabazitaxel était l’étude PROSELICA. Il s’agissait d’un essai portant sur des patients atteints de CPRCm progressant pendant et après le traitement avec un schéma thérapeutique à base de docétaxel, parmi 1 200 patients randomisés pour recevoir le cabazitaxel à 20 milligrammes par mètre carré, plus prednisone, versus cabazitaxel à 25 milligrammes par mètre carré plus prednisone. Et cela a essentiellement montré qu’une dose plus faible de cabazitaxel 20 n’était pas inférieure au cabazitaxel 25, avec une survie globale médiane de 13,4 mois contre 14,5 mois. Et surtout, cela a été associé à une toxicité plus faible. Fondamentalement, cet essai suggérait que le cabazitaxel 20, toutes les trois semaines, plus ou moins le facteur de croissance, était la norme de soins. Et le cabazitaxel 25, toutes les trois semaines, peut être envisagé chez les hommes sains qui souhaiteraient être plus agressifs dans leur traitement.

      Le prochain essai sur le cabazitaxel dans l’état du mCRPC est l’essai FIRSTANA, qui a examiné des patients naïfs de chimiothérapie au mCRPC. Cet essai a évalué l’éligibilité de 1 510 patients, et a finalement attribué au hasard 1 168 au cabazitaxel 20, au cabazitaxel 25 ou au docétaxel 75. En gros, en regardant trois bras de chimiothérapie, vous pouvez voir ici à droite, la courbe de survie globale de Kaplan-Meier. En examinant les rapports de risque, cabazitaxel 20 par rapport au docétaxel, aucune différence, un rapport de risque de 1,01, avec un intervalle de confiance à 95 % de 0,85 à 1,20. Et encore, avec le cabazitaxel 25, versus docétaxel, un hazard ratio de 0,97, et un intervalle de confiance à 95 % de 0,82 à 1,16. Ainsi, le cabazitaxel, en particulier le cabazitaxel 20 milligrammes par mètre carré, présentait un taux plus faible de neuropathie sensorielle périphérique. Et l’étude suggère que cela pourrait être offert à ceux qui ne sont pas candidats à un traitement par docétaxel.

      L’essai CARD a été publié en 2019 dans le New England Journal of Medicine. Et cela a examiné les patients atteints de CPRCm qui ont été précédemment traités avec plus ou égal à trois cycles de docétaxel, et la progression de la maladie après moins ou égale à 12 mois sur l’abiratérone ou l’enzalutamide, en regardant 255 patients qui ont été randomisés pour recevoir le cabazitaxel plus la prednisone, également. Et puis également randomisés pour recevoir l’enzalutamide ou l’abiratérone plus la prednisone.

      En regardant les critères d’évaluation clés de cette étude, à gauche se trouve la survie sans progression basée sur l’imagerie, qui a profité au cabazitaxel par rapport aux inhibiteurs ciblés de signalisation des récepteurs androgènes, avec un rapport de risque de 0,54 et un intervalle de confiance à 95 % de 0,40 à 0,73. Et la survie globale a également bénéficié au cabazitaxel, avec un rapport de risque de 0,64 et un intervalle de confiance à 95 % de 0,46 à 0,89.

      Ainsi, le résumé du cabazitaxel pour le mCRPC a été approuvé chez les patients atteints de mCRPC qui ont déjà reçu du docétaxel en juin 2010. Le comité des directives du NCCN le recommande comme recommandation de catégorie 1, que le cabazitaxel soit utilisé comme traitement de deuxième intention dans le mCRPC symptomatique, après progression sous docétaxel. . Et surtout, cela devrait être administré avec des stéroïdes, et les directives concernant les facteurs de croissance prophylactiques devraient également être suivies.

      Passons brièvement à la mitoxantrone. Ceci a été évalué dans deux essais dans la population mCRPC. Malheureusement, il n’y avait aucune preuve d’avantage de survie. Elle a été associée à des réponses palliatives et à une amélioration de la qualité de vie. Et les directives recommandent qu’il puisse être utilisé pour les soins palliatifs chez les patients symptomatiques atteints de CPRCm, qui ne peuvent tolérer d’autres thérapies.

      Donc, pour résumer cette première partie de la discussion sur les directives du NCCN, examinant le traitement avancé, en particulier pour la chimiothérapie dans le cancer de la prostate métastatique, pour le docétaxel dans le cadre du mCRPC, il s’agit d’une option privilégiée de catégorie un chez les patients de première et de deuxième ligne. . Pour le cancer de la prostate métastatique sensible à la castration, il s’agit d’une option privilégiée de catégorie 1, bien que le bénéfice soit moins clair chez les patients à faible volume.

      Comme Chris l’a mentionné, pour les maladies localisées à haut risque, le docétaxel n’est actuellement pas recommandé.

      Pour le cabazitaxel, dans le cadre du CPRCm, il s’agit d’une option de catégorie 1 pour les patients présentant une maladie symptomatique après le docétaxel. Et il peut être proposé en première intention pour ceux qui ne sont pas éligibles au docétaxel. Comme nous en avons discuté dans les diapositives précédentes, la dose de C20 est préférée, en raison de sa toxicité plus faible. Bien que la dose de C25 puisse être envisagée pour les hommes en meilleure santé.

      Et enfin, la mitoxantrone dans le cadre du mCRPC peut être utilisée pour les soins palliatifs et ceux qui ne tolèrent pas d’autres thérapies.

      Merci beaucoup, et nous espérons que vous avez apprécié cette discussion du UroToday Journal Club sur les directives du NCCN sur le cancer de la prostate.

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      Introducing the All-New 2022 Lexus LX 600 Thu, 14 Oct 2021 04:29:16 +0000 PLANO, Texas, Oct. 13, 2021 /PRNewswire/ — “Good things come to those who wait,” the age-old expression goes. Following three impressive generations, the wait is now over – an all-new LX has arrived. Totally redesigned from the ground up – inside and out – the all-new 2022 LX 600 stands as the ultimate sport-utility flagship in […]]]>

      PLANO, Texas, Oct. 13, 2021 /PRNewswire/ — “Good things come to those who wait,” the age-old expression goes. Following three impressive generations, the wait is now over – an all-new LX has arrived. Totally redesigned from the ground up – inside and out – the all-new 2022 LX 600 stands as the ultimate sport-utility flagship in the luxury brand’s growing and diversified model portfolio. The full-size luxury SUV, with its newly reengineered body-on-frame platform, avant-garde style and luxurious cabin, embodies Lexus’ commitment to meeting the diversifying needs and lifestyles of customers. It is scheduled to arrive at U.S. dealers in the first quarter of 2022.

      The All-New 2022 Lexus LX 600

      Since its launch in 1995, the LX has been a luxury SUV icon shaped by an identity distinguished by an indomitable duality. Its comfortable ride quality and long list of amenities have defined it as a luxurious long-range cruiser, yet its tried-and-tested off-road specifications and equipment have taken it beyond the pavement in more than 50 countries and regions around the globe. As of August 2021, over 500,000 LX models have been sold throughout the world.

      For its fourth generation, LX offers unparalleled refinement thanks to a full optimization of nearly every component. It adopts an all-new 20% more rigid GA-F platform, which serves as a robust foundation for its body-on-frame build. Weight is reduced by 441 pounds when compared to its predecessor, and body rigidity is also increased.

      Powering LX is a high-output, high-torque 3.5-liter V6 twin-turbo gasoline engine. More refined vehicle control in both on-road and off-road situations is enabled by the new Electronically Controlled Brake (ECB) system and Electric Power Steering (EPS).

      Beyond the LX’s aluminum doors is an all-new cabin designed for the utmost in comfort and usability. The instrument panel features Lexus Interface with Lexus’ first dual display configuration. A 12.3-inch upper screen and 7-inch lower screen help to create a more comfortable driving experience with their variety of views, instrumentation and control adjustments.

      LX’s exterior design pursues a blend of athletic performance, accessible functionality and striking beauty – a combination that began with the all-new NX. Key to LX’s design are optimized proportions that combine sophistication with power and presence.

      Speaking to a wide variety of customers and diverse lifestyles is essential to the LX’s ethos. This mindset has enabled the expansion of LX’s range, which adds the all-new Ultra Luxury and F SPORT grades. The Ultra Luxury offers four independent seats for opulent travel comfort on all road surfaces. Customers preferring a sportier look and feel can select the F SPORT grade with its unique touches and handling.


      By adopting a new GA-F platform and redesigning the entire framework of the vehicle from the ground up, engineers revised the LX’s fundamental characteristics and reduced its center of gravity and weight, while increasing body rigidity to achieve a smooth composure and superior comfort level, according to Lexus Driving Signature. The new LX is 441 pounds lighter than its predecessor and realizes a predictable, balanced comportment during turning, acceleration and deceleration maneuvers, plus improves stability when driving off-road.

      To achieve both a high level of off-road driving performance and on-road handling stability, the front high-mounted double wishbone suspension, suspension geometry and optimized coil springs offer both excellent vehicle stability and ride comfort. The suspension stroke, which is an important factor for off-road driving performance, is made sufficiently long with 100 mm/3.93 in. of bound and 145 mm/5.7 in. of rebound (15 mm/0.6 in. longer than that of the previous model) to help achieve both exceptional on and off-road driving performance.

      The capable four-link axle-type suspension with rear lateral control arms is inherited from the previous model, while the suspension arms and shock absorber layout and characteristics are refined to facilitate control of axle movement, resulting in enhanced vehicle stability and ride comfort. The rebound stroke is increased by 20 mm/0.8 in. compared to the previous model to ensure excellent road-following performance.

      The rear shock absorbers are placed outside of the lower control arm, and the shock absorber mounting angle has been adjusted to match the angle at which the axle moves. This makes it easier for the shock absorbers to follow the vertical movement of the wheels, increasing their damping effect and, thus, better absorbing shocks and vibrations from the road surface to provide exceptional vehicle stability.

      The 3.5-liter V6 twin-turbo gasoline engine (V35A-FTS engine) is smaller than the outgoing naturally aspirated V8 and provides increased output and torque through turbocharging. The engine produces an output of 409 hp (415 PS) and maximum 479 lb.-ft. of torque and maintains maximum torque in a wide range up to about 3,600 rpm, making it easier to handle not only during on-road driving but also during off-road driving, which can require frequent use in the low-speed range.

      The Direct Shift-10AT produces a smooth start that only a torque converter can provide, as well as manual transmission-like direct acceleration by activating lockup in almost its entire range of operation (except when the vehicle starts from a stop). The cross gear ratio setting – which brings the gear ratios of each stage closer together – and the quick gear shift time make for crisp gear shifting at regular intervals, creating a driving rhythm that is in harmony with the sound of the engine.

      A wide range of gear ratios is employed for strong starting comfort as well as high-speed driving. The low first gear increases the driving force when starting at low speeds, providing a smooth start and powerful low speed off-road driving performance. In contrast, the high gearing in the 10th gear keeps the engine speed low during high-speed cruising, resulting in a quiet ride and lower fuel consumption.

      An oil pan guard is installed to the lower body of the automatic transmission, which has been designed for off-road performance, to help reduce the risk of oil pan damage due to unplanned hits to the underfloor that might occur when conquering rocky roads.


      LX’s fundamental dynamic characteristics are enhanced by way of Lexus’ first adoption of the GA-F platform and a weight reduction of 441 pounds. The high-output, high-torque twin-turbocharged engine, Electronically Controlled Brake (ECB), and Electric Power Steering (EPS) further deepen the Lexus Driving Signature by delivering driving performance that seamlessly connects deceleration, steering and acceleration in all situations, while the use of a new Active Height Control (AHC) system and Adaptive Variable Suspension (AVS) help provide improved grip, traction and control as well as a sense of strength and security.

      Although it is a frame-based vehicle that retains its predecessor’s traditional off-road driving performance and vehicle stability, the new LX offers a high level of vehicle control, along with supreme on-road ride comfort.

      The AHC suspension, which allows the ride height to be adjusted according to the driving environment, now comes with an expanded range of ride height positions. While ride height is still adjusted through the use of shock absorbers, gas and hydraulic springs and metal springs, a spring rate switching device – which was previously only used for the front wheels – is now used for the rear wheels as well, reducing the time needed to adjust ride height. There are three settings for vehicle height while the vehicle is in motion (Normal, Hi1 and Hi2) and a Low setting for passenger ingress and egress.

      The system automatically adjusts vehicle height depending on the activation of Drive Mode Select or Multi-Terrain Select and the selection status of the transfer case. Ride height status can now be displayed not only on the gauge panel but also on the 7-inch touch display. Additionally, AHC not only adjusts the vehicle height but also responds to changes in vehicle posture, such as the amount of pitch and roll, and it stabilizes vehicle posture during turning, acceleration and deceleration by optimizing the spring rate as needed.

      The suspension automatically adjusts to Hi1 or Hi2 in line with the road environment in coordination with the transfer case being in the L4 range or with the mode selected during the use of Multi-Terrain Select. When Hi1 or Hi2 is selected, the system automatically adjusts the vehicle height according to the vehicle’s speed to help avoid interference with the road surface and improve handling stability.

      The springs are softened to help provide a comfortable ride when overcoming bumps during in-town driving and are stiffened to help ensure a flat and stable ride when going around curves. An added benefit: Vehicle height automatically adjusts when the vehicle is in motion, and when at a standstill, lowers for easier passenger ingress and egress.

      Changing to a linear solenoid valve system offers excellent damping force switching response, providing intricate and smooth control depending on the road surface and driving conditions. The damping force can be set low to provide a comfortable ride when going over bumps during in-town driving and can be set high to provide a flat and stable feeling when going around curves.

      The new EPS uses the motor and reduction gear instead of conventional hydraulics. It enables subtle tuning and provides a light steering sensation at low speeds, such as when driving off-road, and full steering weightiness at high speeds. The vehicle responds faithfully and linearly to steering operations. At low speeds, the light steering sensation contributes to reducing driver burden, and at high speeds, a moderate steering force in line with the vehicle’s speed provides a driving experience that is distinctive of Lexus Driving Signature.

      The Electronically Controlled Brake system employs a sensor to detect the degree of brake pedal depression and creates braking force with the hydraulic brakes for more linear braking characteristics. When Multi-Terrain Select is selected for off-road driving, the system is designed to ensure a high level of driving stability through detailed braking control to counter slipping or spinning wheels.

      In addition to off-road driving performance, 22-inch forged aluminum wheels, the largest in the Lexus lineup, have been adopted for the first time to improve on-road performance. The unsprung weight of all wheels, including the available 18-inch and 20-inch wheels, has been reduced for optimized rolling resistance values.

      Exclusive to F SPORT grade, a Torsen® LSD is employed to help ensure traction performance of the rear tires. When accelerating during a turn, it optimally distributes the driving force according to the load on the rear left and right wheels to achieve a high level of control performance. In straight-line driving, it responds well to changes in road conditions, contributing to stability.


      The new LX has further evolved its proven ability to handle rough roads. In addition to refining “hardware” performance features such as its traditional body-on-frame structure and rear rigid suspension, the new LX boasts evolved software features such as Multi-Terrain Select (MTS) and Crawl Control. Furthermore, the introduction of various advanced technologies that support off-road driving, such as a Multi-Terrain Monitor (MTM) and the LX’s first dual display, enables the new LX to be driven with a greater sense of confidence in harsh environments.

      The new LX inherits the golden ratio of a 2,850 mm/112 in. wheelbase, which has been carried over from the first generation in 1995, to provide both high-level performance on rough terrain and a spacious interior. The ground obstacle angles (approach angle, departure angle and ramp break angle), maximum stable inclination angle of 44 degrees, climbing ability of 45 degrees and maximum river crossing performance of 700 mm/27.5 in. are maintained at the same level as the previous model.

      The instrument panel features Lexus’ first Lexus Interface dual display with a 12.3-inch upper screen and 7-inch lower screen designed to inform, not distract. The upper 12.3-inch display shows navigation, audio controls and the Multi-Terrain Monitor during off-road driving. The lower 7-inch touch display shows the climate control screen and serves as a driving-support screen for Multi-Terrain Select. Displaying the camera image on the upper screen while simultaneously displaying the real-time vehicle status on the lower screen allows the driver to monitor off-road driving conditions more safely without switching the display.

      The all-new LX also features Multi-Terrain Select, which allows the driver to select from six modes – Auto, Dirt, Sand, Mud, Deep Snow and Rock – to support off-road driving conditions. In addition to conventional brake hydraulics, the drive power and suspension are integrated and controlled for optimization according to the selected mode, making it possible to match driving performance to road conditions.

      In addition, the operating range of Multi-Terrain Select, which was previously limited to the low range (L4), has been extended to the high range (H4). The Auto mode, which Lexus has adopted for the first time, uses information from various sensors to estimate the road conditions while driving and to optimize brake hydraulic pressure, driving force and suspension control. This feature allows the driver to maintain ideal driving performance in various driving conditions, without having to switch modes.

      Engaged when the vehicle is in low range, Crawl Control allows LX to move forward or in reverse at one of five driver-selected low-speed settings: LO, MIDL, MID, MIDH and HIGH. Crawl Control intuitively orchestrates the engagement and disengagement of engine output and hydraulic braking pressure to help reduce tire slippage and optimize chassis behavior.

      When descending a steep slope, the system is designed to automatically control the hydraulic pressure of the brakes on all four wheels to support stable descent without locking the wheels. Because the selected vehicle speed is maintained through the operation of a switch, the driver can concentrate on steering operations without worrying about braking and accelerating, thus reducing the burden on the driver.

      The Multi-Terrain Monitor uses four cameras to help the driver see around the vehicle. The images captured by the front, side and rear cameras can be interchanged and are shown on the entire 12.3-inch display, allowing the driver to check road conditions, which are often in the driver’s blind spots.

      By switching to the Lexus-first, Back Underfloor View, images of the foreground taken in advance are provided to the driver as transparent-underfloor images. By superimposing the vehicle and wheel position over this image, the driver can check underfloor conditions and front-wheel position. In another view, the vehicle is made transparent, and an image showing the area around the rear wheels is magnified. This can enable the driver to ascertain conditions around the rear wheels and estimate distances to obstacles.


      The Lexus-first four-seat Ultra Luxury grade enhances the LX lineup with special attention paid to the rear passenger space and their experience. To help achieve an unparalleled comfort level, the front seat can move forward, and the seat reclining angle can be controlled up to 48 degrees. Additionally, the rear seat display, behind the front passenger seat, can fold down to allow for forward visibility, offering an airy VIP seating experience with a maximum leg space of 1,100 mm/43 in. This seating posture is easily achieved with the push of one rear control panel button. A footrest behind the front passenger seat can be deployed to provide maximum comfort, from head to toe.

      The rear seats feature Ultra Luxury-exclusive curved headrests, seatbacks and cushions that gently wrap around the head, hips and lower body. The all-new crafted VIP seating helps to offset any lateral G-forces and irregular road surfaces. The seats are shaped to help maintain a secure posture, while the use of soft urethane with superior vibration absorption performance helps to suppress unwanted movement – even in off-road driving conditions.

      Added comfort features such as sunshades on the side and quarter windows, reading lights and a rear seat display are standard. An Ultra Luxury-exclusive air conditioning system offers unique overhead ceiling vents for a full body comfort breeze experience.

      A product of relentless imagination and human-centered design, no surface is overlooked. The rear control panel, which centrally manages all functions and equipment of the rear passenger experience, has been carefully crafted for a seamless and intuitive guest experience. The space for wireless charging has been lowered to ensure visibility while seated in a reclined position. Cup holders are equipped with a lid, and, with the lid closed, the resulting surface, which is coated with a scratch-resistant self-healing paint, can be used as a note table. The large console box provides ample storage space, and the DC power supply, USB and headphone jacks located within provide added functionality.

      F SPORT
      Guests preferring a sportier look and feel can select the F SPORT grade – a first for LX – with its unique design touches and handling.

      Styling features of the F SPORT grade include new and exclusive 22-inch forged aluminum wheels and F mesh design spindle grille with jet-black chrome grille frame. Inside, the steering wheel and shifter feature textured genuine leather for improved style and grip, while the exclusive F SPORT emblem is applied throughout. A custom crafted F designed seat further enhances hold against lateral g-forces. Ultra White (exterior) with Circuit Red (interior) are offered as an F SPORT grade exclusive.

      Driving performance for the F SPORT grade features uniquely tuned standard front and rear performance dampers, a Torsen® LSD and a rear stabilizer. Special tuning of the EPS and AVS offers performance focused response and handling stability that only the F SPORT can provide.


      The all-new Lexus next-generation interior and exterior design marries superior function with stunning aesthetic. The front A-pillars are pulled rearward to create a cab-backward design, and a stout torso and 22-inch wheels (the largest in the Lexus lineup) express a dynamic driving image. For its spindle grille, a three-dimensional shape comprised of seven sets of floating bars creates a seamless and frame-free structure. It is style rooted in function: fine-tuning the thickness of each bar to the millimeter achieves not only a new look but also provides the high-level cooling performance required for the twin-turbo engine. The side radiator grilles also have large openings to ensure cooling performance and are shaped to provide a high-level rectifying effect.

      For the headlamps, the L-shaped clearance lamps (with daytime running lamp function) have evolved into a three-dimensional shape, and their inner lenses have been doubled, with each having a different level to give a sense of depth and change depending on the viewing angle.

      The sides portray a strong sense of unity and mass, with a thick, horizontal torso running the entirety of the profile, blending through to the muscular rear wheel arches. The LX’s quarter pillars narrow from the roof to the back window, while a distinct chiseled flow from the underside of the vehicle runs up from the lower edge of the rocker panels to behind the rear tires.

      As seen on the 2022 NX, the redesigned rear LEXUS logo symbolizes the next generation of Lexus. For the rear combination lamps, tail lamps have been adopted that combine an L-shape and a continuous axial flow from the front to the shoulders and then to the rear silhouette.

      New 22-inch forged aluminum wheels employ the high contrast of black and machined brilliance, emphasizing their largest-ever sizing for Lexus. For the Ultra Luxury grade, a deep three-dimensional effect is expressed by high-gloss paint, giving the tires and wheels a presence appropriate to the LX’s size.


      New for 2022, the North American-developed Lexus Interface multimedia system allows the LX to seamlessly integrate and navigate life’s twists and turns. The Lexus Interface’s 12.3-inch upper touchscreen with added LX-exclusive 7-inch lower touchscreen, provides intuitive technology at the occupants’ fingertips. The screen’s new Human Machine Interface (HMI) enhances user interaction through sight, touch and voice, while balancing accessibility needs.

      Lexus Interface incorporates a new Voice Assistant developed with a human-centered approach. The Voice Assistant is intended to be the primary way guests interact with the new multimedia system. Designed with dual microphones with speaker location capability and enhanced noise-cancellation, the system enables a voice-first approach allowing front seat occupants an expanded and interactive experience to access navigation, media, phone and other vehicle control settings.

      With the ubiquitous use of smart phones, an intuitive and simple guest experience is now possible with Lexus Interface. With the Lexus Interface User Profile feature, the driver’s personalized settings and experience can be retained in the cloud and accessible on the go in other Lexus Interface equipped vehicles. Once a profile is created in the Lexus App, guests can use a Bluetooth handheld device, smart key or manual login to access it.

      The Lexus Interface native navigation system was designed with ease of use and functional beauty in mind. Featuring 100% cloud capability and integrated Google Points of Interest data, the system allows faster and more accurate directions and mapping. Over-the-air (OTA) updates offer real-time updates for mapping and enriched media experiences. The native navigation is also available to occupants with or without a network connection. Offline mode detects when the vehicle is near or entering an area with low connectivity and downloads applicable maps and services in advance.


      The 2022 LX comes standard with Lexus Safety System+ 2.5, which brings a suite of key active safety features to the vehicle. For starters, the Pre-Collision System (PCS), which includes Frontal Collision Warning (FCW), Automatic Emergency Braking (AEB), Pedestrian Detection and Bicyclist Detection, features an enhancement to the lens camera and millimeter-wave radar elements to expand the response range. By enhancing the radar and camera capabilities, it is now possible for the system to help detect not only the vehicle ahead but also a preceding bicyclist in daytime and even a preceding pedestrian in daytime and low-light conditions. At intersections, the system has the capability under certain conditions to recognize an oncoming vehicle when performing a left-hand turn, or a pedestrian when performing left and right-hand turns, and is designed to activate typical PCS functions if needed. Additional PCS functions include Emergency Steering Assist (ESA), which is designed to assist steering within the vehicle’s lane as cued by the driver.

      All-Speed Dynamic Radar Cruise Control (DRCC) can be activated above 30 mph and is designed to perform vehicle-to-vehicle distance controls down to 0 mph and can resume from a stop. DRCC also includes a feature that allows for smooth overtaking of slower vehicles. If traveling behind a vehicle going slower than the preset speed, once the driver engages the turn signal, the system will provide an initial increase in acceleration in preparation for changing lanes; and, after the driver changes lanes, the vehicle will continue acceleration until it reaches the original preset driving speed.

      Lane Departure Alert with Steering Assist (LDA w/ SA) is designed to help notify the driver if it senses an inadvertent lane departure at speeds above 32 miles per hour via steering wheel vibrations or audible alert. It can also take slight corrective measures to help keep the driver within the visibly marked lane. When DRCC is set and engaged, Lane Tracing Assist (LTA) is designed to provide slight steering force to help steer to the center of the lane to assist the driver with staying in the lane using visible lane markers or a preceding vehicle. LTA alerts the driver with a visual warning and either an audible alert or steering wheel vibration.

      Additional Lexus Safety System+ 2.5 features include Intelligent High Beams, which detects preceding or oncoming vehicles and automatically switches between high beam and low beam headlights. Road Sign Assist (RSA) is designed to acquire certain road sign information using a camera and navigation maps when data is available and displays them on the multi-information display (MID).


      Lexus’ passion for brave design, imaginative technology, and exhilarating performance enables the luxury lifestyle brand to create amazing experiences for its customers. Lexus began its journey in 1989 with two luxury sedans and a commitment to pursue perfection. Since then, Lexus has developed its lineup to meet the needs of global luxury customers in more than 90 countries. In the United States, Lexus vehicles are sold through 243 dealers offering a full lineup of luxury vehicles. With six models incorporating Lexus Hybrid Drive, Lexus is the luxury hybrid leader. Lexus also offers eight F SPORT models and two F performance models. Lexus is committed to being a visionary brand that anticipates the future for luxury customers.

      Media Contact:
      Alissa Moceri    

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      Lexus Logo (PRNewsfoto/Lexus)

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