Public hospitals have set adapted strategies dedicated to overcoming the overload of COVID-19 patients, and our Oncology and Hematology Center (OHC) has implemented a flexible adapted strategy aiming to reduce the burden of COVID-19. We report our single-center experience on the detailed infection control measures undertaken to minimize virus transmission.nd to April 20th, 2020 as measures were taken since the detection of the first COVID-19 case to ensure the protection of patients and healthcare providers, especially a screening zone for any patient entering the center. The patient's data were retrospectively collected and anonymized.we reviewed all patients treated at the OHC from March 2we notified a significant decrease in patients' admissions during the lockdown period at the different units of our center. The screening area received a total of 5267 patients during our study period, with an average of 105 patients per day. Interestingly, no healthcare professional was infected and only 8 patients showed symptoms of fever and cough, and all of them had a negative test for COVID-19 (RT-PCR). Thus, the OHC is considered as a COVID-19 free center with zero cases among patients and healthcare providers.by having a 0% rate of infection, the efficiency of our measures is proven, but efforts are still needed as we have to measure the impact of this pandemic in our cancer management. Thus, a lockdown has been applied with restriction of movements within and between the cities along with sealing the national borders. During this crisis, the Moroccan Health System underwent an important pressure and remarkable efforts were spent to provide efficient reactions to this emergency. Public hospitals have set adapted strategies dedicated to overcoming the overload of COVID-19 patients. Currently, the Emergency Medical System is being implemented with material supplies such as respirators, personal protection equipment (PPE), and treatment. But also with healthcare providers. For this purpose, medical doctors from different departments and specialties were recruited to provide their assistance in managing patients suffering from COVID-19.Since December 2019, the world has known the outbreak of a novel coronavirus named SARS-CoV-2 that first appeared in Wuhan . Since then, the spread of coronavirus disease 2019 (COVID-19) has progressively involved countries outside China leading the World Health Organization (WHO) to recognize it as a pandemic. It is therefore considered an emerging health threat  [et al. were the first to focus on oncological cases affected by COVID-19, through their study they concluded that the risk of SARS-CoV-2 infection was higher in cancer patients deteriorating more rapidly and presenting higher risks of severe events including the necessity for admission to the ICU and death. Interestingly, older adults and patients with pre-existing comorbidities (commonly diabetes and cardiovascular disease) are facing the most severe and critical consequences of the SARS-CoV-2 infection. Hence, the current emergency is of particular concern to medical oncologists, radiotherapists, and their patients [nd and April 20th, 2020.In this very unusual situation, cancer patients are considered as a highly vulnerable group and more susceptible to infections as compared to general population due to systemic immunosuppression secondary to both the malignancy and anticancer treatments. In the literature, Gwan patients . The OncPatients' cohort: we reviewed all patients who were treated at the Oncology and Hematology Center (OHC) of Mohammed VIth University Teaching Hospital of Marrakesh, Morocco, from March 2nd to April 20th, 2020. The starting date of this study preceded the country lockdown by 18 days, as measures were taken since the detection of the first COVID-19 case to ensure the protection of patients and healthcare providers. Patient´s data such as medical history, contact with a COVID-19 positive patient, suspected symptoms and clinical examination, biological investigations, and possible chest imaging, were retrospectively collected and anonymized.Infection control measures: strong infection control measures were implemented all over the OHC, including a new sorting area dedicated to patient screening, a special clinical unit to manage suspected COVID-19 cases, and adapted schedules for healthcare workers and treatment administration.Screening/sorting zone: the sorting zone was an interface area situated at the entrance of the OHC. A strict and safe triaging procedure was performed to assess any COVID-19 symptoms as shown in Organization measures: during the COVID-19 pandemic, the units of OHC were managed to ensure both, the protection and good care delivery for all cancer patients as shown in Statistical analysis: for descriptive analysis, continuous variables were presented as the mean with standard deviation or as median with interquartile range (IQR), as appropriate. Categorical variables are presented as percentages (%). The Shapiro-Wilk test was used to test the normality of data distribution.nd to April 20th, 2020, and are summarized in All the demographic features included in the present study describe the period from March 2Outpatient visits unit: a total number of 343 new cases were admitted in the OHC, with 214 (62.3%) confirmed solid tumors and 103 (37.7%) hematological diseases. Telemedicine allowed us to reach 1440 patients mainly cancer survivors for surveillance visits. The median age was 54 years old (IQR: 15-88) for oncology patients and 49 years old  for hematology patients. Gender was evenly distributed. Interestingly, we reported a decrease of 40% of newly admitted cases compared to the same period of the year 2019  were managed since the beginning of the pandemic. The median age was 68 and 45 years old respectively . In the oncology emergencies, 20% of patients required a blood transfusion, 20% received intravenous antibiotic treatment while 4% needed ascites or pleural evacuation puncture. In the Hematological Unit, the patients needed mainly blood transfusion (70%).Ambulatory care unit: we had a total of 1912 admissions (1236 in oncology and 676 in hematology) which represents a decrease of 24% compared to the March-April 2019 period . Head and Neck cancers (68 cases), gynecological cancers (39 cases), lung cancers (30 cases), and Upper gastrointestinal cancers (23 cases) were the most common localizations admitted to this unit. For the hematological department, we registered a total of 91 admissions and the median age was 45 years old (IQR: 17-66).Radiation therapy unit: a total of 167 patients were admitted for CT-scanner simulation and 142 for treatment. The median age was 51 years old (IQR: 4-84). Breast cancer (35%), Head and Neck Cancer mainly nasopharyngeal and laryngeal cancer (22%), and Gynecological Tumors including Cervix cancer (14%) comprised the majority of the cases. Among these patients, 47% received Adjuvant RT, 39% received definitive RT while 14% received palliative treatments. Before and during the lockdown, the mean number of admitted patients per day was relatively constant (96 ± 3 patients).nd to April 20th, 2020, with an average of 105 patients per day. Interestingly, only 8 patients showed symptoms of fever and cough, after deep investigations we report that: 1) One patient had a contact history with a confirmed COVID-19 case, the Rt-PCR result was negative and the patient displayed a normal chest CT scan. 2) One patient had tuberculosis with a negative Rt-PCR. 3) Two patients presented suspected CT scan profiles (ground-glass opacity) but the Rt-PCR results were negative. 4) Four patients underwent Rt-PCR for unexplained fever and respiratory symptoms but all came back negative. However, since those 8 patients were admitted mainly for chemotherapy, their treatment was postponed and they remained on quarantine for 14 days. Concerning healthcare providers, one staff member (A Radiation therapist) presented suspect symptoms including fever and cough with no previous contact history with a COVID-19 patient. He underwent an Rt-PCR and chest CT scan that came out negative. Thus, the OHC is considered as a COVID-19 free center with zero cases among patients and healthcare providers.The screening area received a total of 5267 patients from March 2th University Teaching Hospital of Marrakesh, Morocco. We shared our single-institution experience in the safety and management of cancer patients in the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak. Overall, the national COVID-19 situation is particularly under control in Morocco, this was challenging to achieve and to maintain for both national healthcare system and OHC which attracts patients from all the southern regions of the country. It is well established that due to their immunosuppressive state, cancer patients present higher vulnerability for infections [et al. cohort describing that cancer patients had a higher risk of developing severe events  compared with general population . Moreover, according to the same study, patients who received antitumor treatment within 14 days before COVID-19 diagnosis, including, radiotherapy, systemic therapies, and surgery had a higher risk of developing severe events with borderline statistical significance [The present report describes the contingency plan established by the Oncology and Hematology Center (OHC) of Mohammed VIfections -6. This ificance . SeveralAssuming these implications, several international guidelines were published concerning the management of cancer patients´ treatment during COVID-19 pandemic  along wiObviously, delayed or interrupted oncology treatments  may lead to disease progression and compromise survival outcomes. It was a major concern for us during this difficult period. We reported a diminishing number of outpatient visits and performed chemotherapy sessions, mainly because of the health emergency state and the inter-cities transport being suspended. It is mandatory, especially in the context of a limited resource system, to balance the potential benefit of containment measures, such as postponing scheduled procedures, with negative health and social costs. COVID-19 infection Diagnosis in cancer patients was particularly challenging, due to multiple factors. First of them would be the similarities of symptoms between the infection and the underlying disease, especially in lung cancer patients and patients with pulmonary metastasis which can hide an underlying COVID-19 infection causing a delay of diagnosis . Adding Our main goal was to develop an adapted strategy to protect our patients and healthcare workers from contracting the novel coronavirus disease without impacting the quality of our healthcare services. By having 0% rate of infection, the efficiency of our measures is proven, but efforts are still needed as we have to measure the impact of this pandemic in our cancer management, and certainly more studies are yet to come to show this impact in our patients.COVID-19 pandemic needed efficient screening protocols to prevent infected patients from harming other patients or healthcare professionals;According to a recently published Chinese cohort, patients with cancer had a higher risk of developing severe events  compared with patients without cancer  (7);Cancer patients need continuous care, and interrupting their treatment in this outbreak could impact seriously their cancer prognosis, whereas their potential COVID-19 exposure could be very risky.Even a developing country with limited health resources could have managed this outbreak by setting a good approach dealing with cancer patients during COVID-19 pandemic. Mainly with implementing an efficient screening protocol at the entrance of the center, and referring any suspected case to COVID-19 facilities;The main result was that our patients were well educated and informed about the risks of COVID-19 infection and how to prevent from it, and this leaded our center to be a free-COVID-19 facility during the first period of the country's lockdown.


Ten (0.18%) of 5512 prevalent Austrian kidney transplant recipients were diagnosed with SARS-CoV-2. The case fatality rate  in renal transplant patients was less than in other countries but higher than in Austria’s general population (2.4%). We conclude that early and strict general lockdown measures imposed by the government allowed an early, however cautious, re-opening of Austrian transplant programs and played a crucial role for the favorable outcomes of SARS-CoV-2 in Austrian kidney transplant patients. Even though it may be uncertain whether similar results may be obtainable in other countries, the findings may support early intervention strategies during similar episodes in the future.SARS-CoV-2 led to considerable morbidity/mortality worldwide and tremendously impacted on daily life. Strict lockdown measures were implemented early to contain the viral outbreak in Austria. Massive changes in organizational structures of healthcare facilities followed with unclear implications on the care of non-COVID-19-affected patients. We studied the nationwide impact of COVID-19 on kidney transplantation in Austria during the first six months of 2020. Concurrent with general lockdown measures, all kidney transplant activity was suspended from 13 March to 9 April. Nevertheless, between January and June, total transplant ( Among he world . In partOn 25 February 2020, the first two cases of SARS-CoV-2 infections were recorded in Innsbruck. During the subsequent days, Austria saw an exponential increase in cases, congruent with increases seen in other countries worldwide. The government promoted strict adherence to personal hygiene as well as social distancing measures, and followed a “stay-at-home testing” strategy  to spare hospitals and healthcare facilities to the utmost degree from unnecessary exposure to infected patients. SARS-CoV-2-positive, mildly symptomatic subjects had to home quarantine. Contact tracing went into effect to test contact persons and impose quarantine on them.By 11 March, the daily new SARS-CoV-2 cases had reached 206 in Austria. Consequently, the government imposed far-reaching restrictions, which were implemented in a stepwise fashion see . HospitaThese regulations affected kidney transplant programs, as transplantation  was classified as a non-lifesaving, semi-elective surgical procedure that could be postponed to after the resolution of the viral threat. The decision to pause transplant programs on 13 March was corroborated by the uncertainty regarding possible virus transmission from a donor (if not adequately tested) and the unclear effect of intense post-transplant immunosuppression on viral defense mechanisms of the recipient.We retrospectively studied the effects of the pandemic on kidney transplantation and on incident and prevalent transplant recipients in Austria. Transplant activity in the four Austrian transplant centers  during the first half year of 2020 was compared to preceding years. Timely correlations with the general governmental regulations and the specifications imposed on organizational structures in Austrian hospitals were analyzed. This included total transplant activity, national organ procurement and issues concerning post-transplant patient care. Austria is part of Eurotransplant  which is serving a total population of approximately 137 million. Organs are procured and distributed within the member states.Incident kidney transplants performed in the first half of 2020  were evaluated and compared to preceding years (2016–2019).The clinical course and outcome of all COVID-19-infected kidney transplant recipients, who were reported to the Austrian Dialysis and Transplant Registry (OEDTR), were recorded. All infected patients were followed for a median of 94 days (range 19 to 107 days) until 30 June. The incidence rate of SARS-CoV-2 in Austrian patients was calculated based on the total number of prevalent kidney transplant recipients.The effect of COVID-19 on post-transplant care was evaluated at the four transplant centers. The weekly outpatient activities for each center were recorded from 1 January to 30 June and compared to the respective weeks in 2019.t-tests for all four centers. p-values < 0.05 were considered statistically significant, however, as they serve only descriptive purposes, no multiplicity correction is applied.The study was approved by the local ethics committee (EK Nr: 1704/2020) and conducted in accordance with the Helsinki Declarations. Total transplant and donor numbers for the periods January–June 2016–2020 were visualized using grouped barplots and boxplots. To compare the average monthly transplant numbers between the years 2016 and 2020, an ANOVA was used. No post hoc tests were conducted. The number of weekly outpatient visits during the first six months of 2019 and 2020 in the four transplant centers was visualized as line graphs and compared by paired In the light of rapidly rising numbers of SARS-CoV-2 infections throughout Europe and after a thorough discussion between representatives of the four Austrian transplant centers, it was convened on 13 March 2020 to suspend all kidney transplant activity in the country. Daily reports on SARS-CoV-2 case numbers in the Austrian general population were closely monitored. When Austria saw a sustained reduction (118 new cases on 14 April) and the SARS-CoV-2 situation within most Eurotransplant member states was equally easing up, all centers agreed to restart the deceased donor programs. Initially, only low-risk transplants were considered. Antibody induction therapy is generally not used in patients with a lower immunological risk in Austria. In these patients, immunosuppression did not differ from patients transplanted in the pre-COVID period. The first deceased donor transplant after the lockdown was performed in Innsbruck on 9 April. The living donor programs were resumed at different times . Vienna has accepted highly sensitized patients  since 14 May . The protocols for higher-dose immunosuppression  were not adapted from pre-COVID times. Pre-transplant evaluations, a prerequisite for being accepted to the waiting list, resumed during mid-April.p = 0.483), as shown in The monthly rate of kidney transplants (January to June 2016–2020) at the four centers is shown in From 1 January to 30 June, 151 deceased donor kidney transplants were performed in Austria . Until 13 March 2020 (when the transplant activity was intermittently stopped), 84 kidney transplants were performed in Austria . Following the re-opening of the program on April 9 in Innsbruck, 15 April in Vienna and Linz and 4 May  in Graz until 30 June, 67 patients received a kidney in Austria .n = 1, and June n = 2), and the other centers restarted the evaluation of new donor/recipient pairs on May 18, but did not perform living donor transplants in May. In June, Linz performed one living donor, and in Vienna, an initially re-scheduled transplantation was performed.The living donor transplant programs in Austria were equally paused on 13 March and were resumed at different times in the four centers. Before the lockdown, seven living donor transplants were performed in Innsbruck, five in Vienna and one in Linz. After the lockdown, Innsbruck resumed the living program in April with two transplants (May p = 0.604) . The average monthly donor numbers did not change significantly from 2016 to 2020 (= 0.604) . The meaAccording to the Austrian Dialysis and Transplantation registry, 5512 kidney transplant recipients were alive at the end of February 2020. From the start of the outbreak until 30 June, ten patients tested positive for SARS-CoV-2. The time of diagnosis of the individual patients in relation to the general Austrian SARS-CoV-2 situation is depicted in n = 173, Innsbruck n = 45, Graz n = 71 and Linz n = 55. During the COVID-19-induced lockdown, Austrian hospitals were requested to limit outpatient contacts to emergency visits only. Therefore, non-essential visits to the transplant outpatient clinics were actively postponed. The centers remained accessible for emergencies and by phone or video consultations, whenever necessary. Weekly outpatient numbers differed significantly between 2019 and 2020 in Vienna and Graz (both p < 0.01), but not in Linz and Innsbruck (p = 0.069 and p = 0.129), as shown in The majority of transplant recipients are followed as outpatients by their transplant center , amounting to considerable numbers of patients treated in outpatient clinics. In 2019, the average number of patients seen per week in the centers were Vienna SARS-CoV-2 and its associated disease, COVID-19, have led to widespread consequences for all aspects of daily life, as well as for national economic and healthcare systems. The official response to the viral threat differed significantly between countries ,16. The In fear that the hospital and intensive care capacity could be overwhelmed by the ongoing pandemic, Austrian hospitals started to take precautions, which included the provision of treatment capacity for SARS-CoV-2-infected patients. All elective surgical procedures were cancelled by 12 March. Simultaneously, all planned non-essential outpatient visits were postponed. Despite missing empirical evidence at the time , it was A reason for pausing the transplant activity was the unclear situation regarding the prevalence of SARS-CoV-2 in other Eurotransplant member states that would be part of the organ exchange program. Furthermore, the available test capacities in different countries were unknown and it was uncertain whether all potential organ donors can be adequately tested for SARS-CoV-2. Thus, a potential virus transmission from the donor to the recipient could not be excluded and remained another obstacle to a safe organ retrieval. Travel restrictions and the grounding of air travel made organ transport virtually impossible or would have led to prolonged cold ischemic times of unacceptable lengths in most instances. In addition, it was unforeseeable to which degree of risk an individual patient would be exposed by the typically intensive immunosuppression immediately post-transplant.Contrary to the expectations, the four-week intermission until mid-April did not have a significant impact on the mean monthly number of transplants in Austria, when compared to the first six months in preceding years. To our knowledge, this is the first complete report at a national level on the effect of SARS-CoV-2 in kidney transplantation. Due to the current lack of equally concise national transplant data during the early months of the pandemic elsewhere, it is yet beyond the scope of our manuscript to compare the Austrian data with other nations. A similar advantageous recovery of transplant numbers, however, was reported on a regional basis for Cantabria, Spain . This isThe reason for these advantageous results in Austria may be the favorable general virus situation in the country, which was critically influenced by early testing and home care strategies and the restrictions implemented by the government. COVID-19 patients, once identified, were admitted to designated COVID hospitals or wards according to the national pandemic plan. This strategy helped to keep transplant centers COVID-free during the observation period. This successful way helped our decision to re-start the transplant programs early after freezing them and to provide organs for our patients again. Thus, SARS-CoV-2 showed only a mitigated effect on the Austrian transplant activity . Admitten= 627) to 2020 (n= 595).As elsewhere , the livSARS-CoV-2 had a demonstrable impact on the post-transplant care of patients in Austria. Significantly less patients than in 2019 were seen in the outpatient clinics during the lockdown, as non-essential control visits were postponed in order to free resources for inpatients. At the time, when the prevalence of the virus was still unknown, it was considered equally important to limit the exposure of patients to a potential infectious environment . We believe that by that measure we could contribute to limit the spread of the disease among the transplant population, as later also suggested by others . WhetherUntil 30 June, only ten of 5512 prevalent patients  contracted COVID-19, representing 0.18% of the transplant population. This rate did not differ from the general Austrian population . Several reasons could have led to this favorable outcome. First, transplant patients are well informed about their increased infection risk by their physicians. In addition, risk groups were addressed early through widely distributed information by Austrian health authorities and instructed to be particularly careful. Furthermore, the timely stay-at-home order imposed during the lockdown of the country may have been crucial, specifically for the protection of transplant patients.https://coronavirus.jhu.edu/data/mortality, accessed on 12 September 2020).The case fatality rate in Austrian kidney transplant patients  was much lower than in other series of transplant patients with COVID-19 . Likely Data on the total number of Austrian kidney transplant patients who were tested for SARS-CoV-2 are lacking. Due to the national “stay-at-home” orders proclaimed by the government and the reduction in outpatient visits, it cannot be ruled out that some patients with mild symptoms did not report to their respective transplant center and remained undetected infected cases. Thus, it will be interesting to perform widescale SARS-CoV-2 antibody testing in the group of kidney transplant recipients in the future.Taken together, our observations suggest that the effect of SARS-CoV-2 on the Austrian transplant activity was mitigated and could be contained within acceptable limits. The timely actions by the government and health authorities, which were based on scientific advice, and strategies instituted by hospitals and transplant centers were important contributors, as was the active contribution of the patients and their families, who complied with the recommendations. These observations are an important lesson that shows for the well-defined field of kidney transplantation how public measures can be of direct benefit for individual patient groups. The observations may be extrapolated to other specialized fields of medicine. Furthermore, the Austrian experience may serve as an example—at least for kidney transplant patients—of how the pandemic could be successfully navigated, at least in regions with similar population densities and transplant activities . At the The importance of combined general and specific actions, integrating science and policy, should be respected by governments and healthcare providers in preparation for impending threats caused by a significant re-emergence of SARS-CoV-2 or other future deadly viruses.The study describes the influence of COVID-19 on kidney transplant activity in Austria and the effect of SARS-CoV-2 on Austrian transplant patients. While 10 patients were identified as SARS-CoV-2-positive during the study, data on the number of negative tests in Austrian kidney transplant patients are not available.Our results demonstrate favorable transplant results. Whether the delay of outpatient visits did or will result in transplant-specific or general medical problems that went undetected in our patients during the cessation period remains to be evaluated.The Austrian experience may serve as an example—at least for kidney transplant patients—of how the pandemic could be successfully navigated. Whether this strategy is equally effective in regions or countries with different population densities and transplant activities remains to be elucidated.Due to the lack of other complete country data, we were not yet able to compare our findings with transplant populations of other nations that followed divergent strategies to fight the pandemic.


B-cell lymphoma 2 (BCL-2) family proteins primarily work as a programmed cell death regulator, whereby multiple interactions between them determine cell survival. This explains the two major classes of BCL-2 proteins which are anti-apoptotic and pro-apoptotic proteins. The anti-apoptotic proteins are attractive targets for BCL-2 family inhibitors, which result in the augmentation of the intrinsic apoptotic pathway. BCL-2 family inhibitors have been studied extensively for novel targeted therapies in various cancer types, fibrotic diseases, aging-related as well as autoimmune diseases. Navitoclax is one of them and it has been discovered to have a high affinity toward BCL-2 anti-apoptotic proteins, including BCL-2, BCL-W and B-cell lymphoma-extra-large. Navitoclax has been demonstrated as a single agent or in combination with other drugs to successfully ameliorate tumor progression and fibrosis development. To date, navitoclax has entered phase I and phase II clinical studies. Navitoclax alone potently treats small cell lung cancer and acute lymphocytic leukemia, whilst in combination therapy for solid tumors, it enhances the therapeutic effect of other chemotherapeutic agents. A low platelet count has always associated with single navitoclax treatments, though this effect is tolerable. Moreover, the efficacy of navitoclax is determined by the expression of several BCL-2 family members. Here, we elucidate the complex mechanisms of navitoclax as a pro-apoptotic agent, and review the early and current clinical studies of navitoclax alone as well as with other drugs. Additionally, some suggestions on the development of navitoclax clinical studies are presented in the future prospects section. Navitoclax is one of the B-cell lymphoma 2 (BCL-2) family protein inhibitors which has been generated during the clinical development of ABT-737 . This orThe BCL-2 family members are categorized into three groups which represent their respective structure and function : i) ExecL) and BCL-W but low potency to A1 and no association with myeloid cell leukemia (MCL-1). In contrast, NOXA only showed interaction with MCL-1 and A1  domains which play a crucial role in activating cell apoptosis . In fact1 and A1 . Concurr1 and A1 . This se1 and A1 . Another members . Neverthactivity . This evOver the decade, further investigations and clinical studies involving navitoclax in cancer treatment have been carried out to evaluate its efficacy and toxicology. In addition, many existing investigations attempt to explore the apoptotic effect of navitoclax on other diseases such as chronic lymphocytic leukemia, epithelial cancer, breast cancer and fibrosis. Nevertheless, a comprehensive review of navitoclax pharmacological properties has yet to be presented. This review aims to clearly elucidate and compile the potential therapeutic use of navitoclax on various cancer types, tumor progression, and fibrosis. The discussion will center on the mechanisms and available clinical reports of navitoclax in treating those diseases in order to evaluate its pharmacological profile as well as tolerability in patients. Furthermore, the combination therapy of navitoclax with other drugs will also be reviewed. Lastly, suggestions on how to improve navitoclax clinical studies and other potential targets for navitoclax treatment will be included in the future prospects section.L, and BCL-W in multiple myeloma cell lines  and xenograft models (in vivo). Navitoclax efficacy on different SCLC xenograft models was varied, yet the treatment showed the induction of BAX translocation, cytochrome c release and caspase-3 stimulation were dose-dependent through the cellular level. Nonetheless, the results displayed a good correlation between in vitro cellular potency and in vivo tumor efficacy where the cell lines with the higher potency (EC50 <200 nmol/L) exhibited 100% objective response rate [ORR: the proportion of patients with tumor size reduction of a predefined amount and for a minimum time period  cell lines and xenograft models have revealed a high potency of this prodrug to mitigate tumor progression , which aims to minimize the platelet toxicity effect and increase the selectivity toward tumors-accumulating senescent cells . The modgression . Besides that activate stromal fibroblasts. Continual activation of fibroblast is the key factor of liver fibrosis. Activated stromal fibroblasts express a lower level of BCL-2, causing them to become BCL-XL-dependent. Since BCL-XL is the key to survival of senescent cholangiocytes and activated stromal fibroblasts, treatment with navitoclax, which is a BCL-XL inhibitor is potent in reducing biliary liver fibrosis  mouse model of biliary liver fibrosis. The reduction of senescent cholangiocytes and activated stromal fibroblasts due to apoptosis reversed established biliary liver fibrosis in Mdr2−/− mice.Senescent cholangiocytes consistently secrete growth factors that stimulate stromal fibroblasts, which contribute to the progression of fibrosis . The actAccording to L proteins, navitoclax can induce apoptosis not only in myofibroblasts, but also in senescent cells. The specificity of navitoclax enables the eradication of both myofibroblasts and related senescent cells, hence resolving fibrosis in the affected organs. This widens the potential of navitoclax in treating a variety of fibrotic diseases.Since both senescent cells and activated myofibroblasts express BCL-XTo date, most studies on navitoclax with the presence of other drugs have been conducted against various solid tumors and lymphoid malignancies. Researches intend to amplify the anti-tumor activity of chemotherapeutic drugs with navitoclax through multiple simultaneous protein interactions. This could be achieved as the chemotherapeutic agents commonly display distinct target proteins from navitoclax. The preclinical and clinical studies on navitoclax in combination treatment are summarized in V600E mutation in papillary thyroid cancer (PTC) highly corresponds to aggressive tumor features, including metastasis, cancer relapse, and failure of radioiodine treatment  with co-existing NUP98-NSD1 and FLT3-ITD mutation is accompanied by poor prognosis and a low chance of survival . Kivioja and Fgr .Navitoclax alone adequately exhibits therapeutic response against CLL and lymphoma as described above. In vitro, lymphoma clones with resistance to rituximab show elevated expression of anti-apoptotic BCL-2 family proteins and increased level of resistance to a range of chemotherapeutic drugs. These findings suggest that by reducing the apoptotic threshold, navitoclax as a BCL-2 inhibitor may produce a synergistic effect with rituximab against B-cell malignancies . Elucidation of this interaction would assist in determining the potential of navitoclax as a single agent or can be used in combinational regimens for these cancers' treatment. Other than that, following in vitro studies of navitoclax on various primary cell lines  has to be done in order to evaluate the potency of navitoclax.Most of the previous, as well as ongoing clinical studies on navitoclax are focusing more on its therapeutic effect as a pro-apoptotic agent on cancer and tumor therapies. However, cell apoptotic activity mediated by navitoclax may also provide a therapeutic outcome on cardiovascular diseases. Some of the cardiovascular diseases such as atherosclerosis, myocardial infarction, and stroke are exacerbated due to excessive cellular proliferation. On that account, pro-apoptotic agents like navitoclax may play a role in ameliorating the progression of those diseases. In order to approach this matter, L activities, with MCL-1 expression having minor influence However, further downstream signaling of the intrinsic apoptotic pathway through BCL-2 family members is modulated by the expression of proapoptotic activators such as BIM, and executioner proteins as well. This downstream signaling has contributed to the complex mechanism of navitoclax as those proteins’ expressions should be considered in evaluating the effectiveness of single navitoclax treatments. Otherwise, a combination of navitoclax with other cytotoxic agents would be the best strategy to enhance its anti-tumor effect. Most of the combination treatment clinical studies have also shown a tremendous therapeutic effect of navitoclax as a proapoptotic agent with very minimal unfavorable effects. Furthermore, accumulating findings on solid tumors have uncovered several novel molecular mechanisms targeted by navitoclax to induce cell killing activity such as survivin and CHOP. These data suggest that navitoclax has a diverse mechanism with multiple molecular targets that are not only limited through BCL-2 family members in order to exhibit its role as a pro-apoptotic agent. Therefore, clear elucidation and understanding of potential molecular targets by navitoclax is essential and highly beneficial for further development of navitoclax treatment in cancer as well as other diseases including cardiovascular disease.Based on the evidence discussed in this review paper, the navitoclax mechanism is shown to be complex and diverse. Through SCLC and several lymphoid malignancies, navitoclax can be well-explained to have an effect through the inhibition of either BCL-2, BCL-W or BCL-XNSNH and LSL searched the literature and drafted the manuscript. AU and NMA edited and revised the manuscript. All authors approved the final version of the manuscript.This review was supported by a grant from Ministry of Education, Malaysia (FRGS/1/2019/SKK06/UKM/02/7) and Universiti Kebangsaan Malaysia (UKM).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Significant declines in the mental health and wellbeing of children and adolescents have been reported during the coronavirus COVID-19) pandemic, with the closure of schools and subsequent disruption to learning and assessment, loss of social contacts, routines and services accessed through schools playing a pivotal role [9 pandemiPrior to the pandemic, hospital admissions relating to manifestations of stress in secondary school aged adolescents were positively correlated with term times . Stress-We aimed to investigate the impact of the pandemic and lockdown (including school closures) on rates of emergency hospital admissions with a stress-related presentation. Our study examined secondary school aged children to better characterise the relationships between schools and stress.st-August 31st) of 2018/19, 2019/20 and 2020/21. These years were selected to cover pre-pandemic and pandemic periods. We excluded records for adolescents of unknown sex or who were not resident in England.We used Hospital Episodes Statistics (HES) data for all adolescents aged 11 to 17 who were admitted to an NHS hospital in England in the academic years  version 10. Stress-related presentations were defined as emergency hospital admissions with a primary diagnosis relating to mental health, pain without a medical cause, or potentially psychosomatic symptoms (e.g. fatigue), or where a diagnostic code indicating self-harm was recorded in any diagnostic position. Codes are outlined in We estimated weekly rates of admissions with a stress-related presentation  using Office for National Statistics mid-year population estimates for England stratified into 1 year age bands. Weekly rates of stress-related presentations were plotted and visualised against school term times, which were defined from a sample of school timetables published online by local authorities in England. Incident rate ratios (IRRs) for term vs holiday time occurrence of stress-related presentations were estimated using separate negative binomial regression models that were age- and sex-specific, and adjusted for academic year .Approvals for the use of HES data were obtained from NHS Digital through the standard approval process. This study is exempt from NHS Research Ethics Committee approval and participant consent was not applicable because we analysed an existing dataset of deidentified data that was collected as part of routine care.We identified a total of 662,000 emergency admissions for adolescents aged 11-17 years. Of these, 21,818 were excluded because they related to; exact duplicates (n=260), adolescents not residing in England , or with unrecorded sex (n=196), maternity care  or for adolescents who died in hospital (n=498). A further 8,942 admissions with abdominal pain were excluded because a likely medical cause was recorded. We analysed the remaining 210,441 admissions  with a stress-related presentation.th 2020. This was followed by a rebound in rates of stress-related presentations and resumption of term-time peaks to historic levels by July 2020. The small number of pandemic holiday periods  when schools were closed limits scope for formal evaluation of changes in term versus holiday presentations.Across the three years investigated, mean weekly term-time rates of stress-related presentations were higher than holiday-time rates for girls of all ages and boys aged 11-16 years  and 2. COur main findings are that following the start of the pandemic, rates of hospital admission with stress-related presentations have increased substantially for girls aged 11-15 years, reflecting higher rates in both term-time and holiday periods. In boys, stress-related admission rates were much lower than for girls and remain at pre-pandemic levels. The observed increase for girls corroborates reports of declining levels of adolescent wellbeing exacerbated by insufficient support, as illustrated by a 94% increase in referrals to Child and Adolescent Mental Health services in 2021 relative to 2019 [We found that term-time rates of stress-related admissions were higher than holiday periods for girls and boys aged 11-16 years. This is similar to pre-pandemic data for England  and Irelth 2020 [We also identified a rapid drop in stress-related presentations that preceded the closure of schools on March 20th 2020 . This isth 2020 . This shAs our data on hospitalisations captures only the tip of the iceberg of stress manifestations the true burden will be substantially greater and warrants ongoing action from researchers, schools and clinicians. Stress-related presentations accounted for almost one third of all emergency hospital admissions in 11 to 17 year olds. This indicates a real need for earlier intervention in other settings as well as interdisciplinary support at admission - potentially through mental health liaison service - to address the bio-psycho-social factors that are likely contributing to the need for emergency care. Further research should use linked clinical data to examine referral patterns and service use associated with these stress presentations [Supplementary material


The purpose of this study was to determine the effect of fatigue level and sex on the range of motions of the lower extremities and impulses during the jump-landing phase after performing bilateral fatiguing tasks.In total, 41 healthy young adults volunteered for this study. Participants’ jump-landing trajectories were monitored using nine cameras, and ground reaction forces were measured using a force plate. Participants performed five maximal bilateral countermovement jumps as prefatiguing tasks. The fatiguing tasks consisted of maximal effort contractions of the knee extensor at 60°/s on a dynamometer until task failure, defined as the inability to reach 50% of the peak knee extension torque for three consecutive times. The post-task maximal bilateral jumps were immediately captured after the participants failed the fatiguing task. Participants were asked to perform this cycle again, performing the fatiguing contraction task until failure to reach 30% of the peak knee extension torque.It was found that the knee joint was more extended in the post-30% fatiguing task, which was due to the reduction of the flexion angle of the hip and knee joints in response to fatigue level. The impulses for both sexes were reduced at the severe fatigue level. Fatigability altered jump-landing kinematics, jump heights and impulses in response to fatigue level. The post-30% fatiguing task elicited more fatigue than the post-50% fatiguing task. Vertical jump height was related to fatigue level in both sexes.Extension of the knee joint occurred in the 30% fatiguing task, and the flexion angle of the hip and knee joints was reduced in response to muscle fatigue level.Reduction of impulses occurred at severe fatigue levels for both sexes.Fatigability was altered in response to fatigue level, with the post-30% fatiguing task generating more obvious fatigue than the post-50% task.Jumping and landing movements are major skill components in sports as well as in human movement.Muscle fatigue can be defined as an exercise-induced temporary reduction in the force and power production of the skeletal muscles.Fundamentally, jump-landing performance is influenced by kinetic, kinematic and physical parameters, in addition to muscle fatigue.Forty-one healthy young adults who exercise at least 3 days a week  volunteered. Participants were excluded from the study if they had musculoskeletal injuries or surgery on their lower extremities within the last 6 months.The marker trajectories data captured jump-landing using the three-dimensional motion analysis system of nine cameras , with a sampling frequency of 100 Hz. The ground reaction force (GRF) was collected with a force plate  at 2000 Hz. The marker trajectories data were captured using the Vicon Nexus software package (Oxford Metrics). Twenty-six retroreflective markers (with a diameter of 14.0 mm) were placed according to the modified Plug-in Gait model of the Helen Hayes marker set.This study was split into two sessions, with a 7-day interval between sessions. All participants attended a familiarisation session that involved biometric tests, measurement of the lower extremity joint centre and knee extension peak torque, and practice of the jump and landing. The participant’s dominant leg  was placed on the force plate, and then they performed the maximal bilateral countermovement jump with their hands on the hips and then landing back on the force plate.Participants rode a stationary bike at their preferred speed for 10 min and practised the jumps for a few times as a warm-up exercise for the lower extremities in order to reduce the risk of injury. Following this warm-up, the prefatiguing task, involving five maximal bilateral countermovement jumps, was captured prior to starting the fatiguing contraction task. Participants then moved to the dynamometer to perform the fatiguing contraction task, which was similar to the method of testing the knee extension peak torque. Participants were asked to maximally extend their legs on the dynamometer to the full range of motion (0°–90°). The lower leg was then passively returned to the start position of 90° of knee flexion. The participants performed maximal effort contractions of the knee extensor at 60°/s until they failed to reach 50% of the previously measured peak knee extension torque for three consecutive times.Jump-landing data were interpreted as the average values of three successful trials in which participants landed on the force plate correctly from five bilateral jump-landing trials. Analysis of the jump-landing phase was carried out prior to the commencement of the fatiguing task to provide vertical jump heights as a baseline measurement for comparisons. The vertical jump heights were calculated by subtracting the height of the pelvis centre of mass during the static position from the maximum height during the jump. This measurement was repeated after failure at 50% and 30% of peak torque was observed in the fatiguing task. The joint angles were calculated based on the Euler/Cardan angles in the flexion/extension, adduction/abduction, and internal/external rotation order, namely y-x-z-axis rotation sequence. The kinematic and impulse data were filtered with a second-order Butterworth low-pass filter with a cut-off frequency of 10 Hz and 25 Hz, respectively. Data were analysed from the initial contact to the maximum flexion angle at the ankle, knee and hip joints of landing. The initial contact was defined as the moment when >10 N of vertical GRF  was exerted by foot contact on the force plate.Statistical analysis was conducted using IBM SPSS Statistics V.20. Results are expressed as mean±SD. After confirmation of normality using the Shapiro-Wilk test, we performed a two-way repeated measures analysis of variance to evaluate fatigue level  and sex. For the post-hoc analysis, the difference between fatigue levels was evaluated using a one-way analysis of variance, with the p value adjusted for multiple comparisons, using the Bonferroni method, to 0.0167 (0.05/3). The difference between male and female participants was evaluated using an independent t-test analysis. Values of p<0.05 were considered significant.39=0.010, p>0.05). In addition, there was no sex-related or fatigue-related difference in the number of repetitions compared with baseline measurements   .F2,78=22.079, p<0.001), further to the main observed effects of sex  and fatigue level . Post-hoc analysis indicated that men had significantly higher jump heights than women at baseline as well as after the post-50% and post-30% fatiguing tasks . Additionally, the post-50% and post-30% fatiguing task data revealed significantly decreased jump heights in women compared with baseline values . The jump height in men also decreased significantly in the following order: baseline, post-50% and post-30% fatiguing task causing the greatest reduction in jump height   .F2,78=3.276, p=0.043). Post-hoc analysis indicated a significantly smaller dorsiflexion angle during the post-30% fatiguing task than at baseline or during the post-50% fatiguing task in men . Fatigue level had no significant effect on the ankle flexion angle in women. There were no interactive effects between sex and fatigue level, and no effect was observed for sex alone . Post-hoc analysis indicated that women had a significantly greater knee flexion angle than men at baseline and during the post-50% fatiguing task . During fatigue, the knee flexion angle was significantly greater in the post-50% fatiguing task than at baseline and the post-30% fatiguing task in women . Fatigue level had no significant effect on the knee flexion angle in men. There were no interactive effects between sex and fatigue level. Fatigue level had a significant effect on the knee rotation angle . Post-hoc analysis indicated that significantly greater internal rotation occurred during the post-30% fatiguing task than at baseline for both sexes . However, there were no significant interactive effects between sex and fatigue level . Post-hoc analysis indicated that women had a significantly greater hip flexion angle than men in the post-50% fatiguing task . Hip flexion angles were significantly smaller in the following order in both sexes: post-30%, post-50 and baseline . However, there were no significant interactive effects between sex and fatigue level. The main effect of fatigue level on hip rotation angle  was a significantly greater hip external rotation angle in both sexes during the post-30% fatiguing task compared with baseline . There were no significant interactive or main effects of sex on the hip rotation angle . Post-hoc analysis indicated that impulses during the post-30% fatiguing tasks were smaller than the baseline in men . For women, jump-landing impulses were smaller during the post-30% fatiguing task than the post-50% fatiguing task . However, sex and fatigue level had no significant interactive effect  that was normalised by body weight. The primary effects of fatigue level were observed in the jump-landing impulses (e effect .This study demonstrates the differences between men and women in responses to fatigue level of the knee extensor during jump-landing. The following are the main findings of this study: (1) vertical jump height is related to fatigue level in both sexes; (2) extension of the knee joint occurs more in the post-30% fatiguing task, and reductions in the flexion angle of the hip and knee joint occur in response to muscle fatigue level; (3) a reduction of impulses occurs at severe fatigue levels for both sexes; and (4) jump-landing kinematics/impulses are altered in response to fatigue level, with the post-30% fatiguing task generating more obvious fatigue than the post-50% task. These findings are discussed in detail in the sections that follow.No differences were observed between men and women with regard to the number of repetitions required to reach failure in the fatiguing tasks. The fatiguing protocol used in the present study can be related to the bilateral limb deficit (BLD) phenomenon.In both sexes, a more extended knee joint was apparent in the post-30% fatiguing task. This was due to a reduced change in the flexion angle of the hip and knee joints during landing in response to fatigue level. We also observed more extended hip and knee joints as well as decreased ankle range of motion during jump-landing according to fatigue level in men. This indicated a diminished shock absorption capacity in the more extended joints, which was dependent on sex and fatigue level as previously reported.The internal rotation angles of the knee joint were significantly affected by fatigue level. Specifically, the results showed that the greater the fatigue, the greater the internal rotation angle of the knee joint, although there was no interaction between sex and fatigue level. Previous studies have reported that a greater internal rotation angle of the knee joint is a risk factor for knee injury.We also found that the higher jump height in men was due to the greater peak torque of men in maximal voluntary contraction than in women.The impulses for both sexes were diminished following the fatiguing tasks compared with baseline, with the post-30% fatiguing task having the greatest effect. This leads us to suggest that severe fatigue levels are related to the recruitment threshold of motor units in the knee extensors. In a previous study, regression analysis of the average motor unit firing rate versus the recruitment threshold relationship showed that as the muscle became more fatigued, the y-intercept decreased and the slope became shallower.This study and its experimental design have a few limitations that should be considered when interpreting the results. First, some of the results, especially the rotation angle of the hip joint in the post-50% fatiguing task, were greater in the post-30% fatiguing task. We speculate that this could be due to a recovery in the force production between fatiguing tasks and moving to the jumping task, as previous studies have reported,This study investigated the range of motions of the lower extremities and impulse changes during jump-landing related to different bilateral fatigue levels and sex. The results of this study showed differences in the range of motion of the knee and hip joints, as well as the landing impulse, for both sexes and muscle fatigue levels. This indicates that fatigability altered jump-landing kinematics, jump heights and impulses for both sexes in response to fatigue level. The post-30% fatiguing task elicited more fatigue than the post-50% fatiguing task. This study may provide insights into preventing lower limb injuries due to high fatigue levels.


The current coronavirus disease 2019 (COVID-19) pandemic highlights the importance of a mindful utilization of financial and human resources. Preventing infections and preserving resources and manpower are crucial in healthcare. It is important to ensure the ability of the surgeons and the specialized interventionalists to function through this pandemic. A tremendous effort should be achieved to minimize cross-infections in this sector. In addition, more efforts should be conducted to monitor surgical patients diagnosed with COVID-19 because they have higher mortality rates. A study by Lei et al. was conducted retrospectively on 34 patients with COVID-19 who underwent surgery. They reported that all patients developed COVID-19 pneumonia shortly after surgery with abnormal findings on chest computed tomographic scans. Also, they reported that 15 (44.1%) patients required admission to the intensive care unit (ICU) during disease progression, and 7 patients (20.5%) died after admission to the ICU [Another study was conducted in Italy regarding the protocols of dealing with operative patients in the era of COVID-19 pandemic. They recommended that the designated COVID-19 operating areas must be allocated to the operating room closest to the entrance of the theater block entrance . Also, tTheoretically and practically, the aforementioned protocols carry a risk for hospital facilities contamination, and healthcare staff and other admitted patients cross-infection. Patients with COVID-19 are transferred in an “open circuit” even with the maximal strict adherence to the protocols , 7. In aHealthcare staff and hospital facilities cross-infections are a major concern which can affect the strongest healthcare systems in the world. The current pandemic of the COVID-19 has a significant risk of viral transmission to healthcare workers who take care of infected patients, with high reported mortality rates –10. Prop


While transcatheter aortic valve replacement (TAVR) has revolutionized the treatment of aortic valve stenosis, wearable health-monitoring devices are gradually transforming digital patient care.The aim of this study was to develop a simple, efficient, and economical method for preprocedural frailty assessment based on parameters measured by a wearable health-monitoring device.In this prospective study, we analyzed data of 50 consecutive patients with mean (SD) age of 77.5 (5.1) years and a median (IQR) European system for cardiac operative risk evaluation (EuroSCORE) II of 3.3 (4.1) undergoing either transfemoral or transapical TAVR between 2017 and 2018. Every patient was fitted with a wrist-worn health-monitoring device (Garmin Vivosmart 3) for 1 week prior to the procedure. Twenty different parameters were measured, and threshold levels for the 3 most predictive categories  were calculated. Patients were assigned 1 point per category for exceeding the cut-off value and were then classified into 4 stages . Furthermore, the FItness-tracker assisted Frailty-Assessment Score (FIFA score) was compared with the scores of the preprocedural gait speed category derived from the 6-minute walk test (GSC-6MWT) and the Edmonton Frail Scale classification (EFS-C). The primary study endpoint was hospital mortality.P=.02), minutes of high stress per day (P=.02), minutes of rest per day (P=.045), and daily heart rate maximum (P=.048) as single parameters were the strongest predictors of hospital mortality. When comparing the different frailty scores, the FIFA score demonstrated the greatest predictive power for hospital mortality .The overall preprocedural stress level (This proof-of-concept study demonstrates the strong predictive performance of the FIFA score compared to that of the conventional frailty assessments. Since the first transcatheter aortic valve replacement (TAVR) performed in 2002 by Alain Cribier, little development has taken place in the field of frailty assessment . DespiteWearable health-monitoring devices have already been used for patient-related basic measurements in different specialties. Several studies have proven that such devices can reliably predict flares in patients with rheumatic diseases or reverse remodeling in patients with heart failure treated with resynchronization therapy -4. TheseThe present open-label, nonrandomized proof-of-concept study features permanent preprocedural activity monitoring with a wearable health-monitoring device  during the week prior to the intervention. All patients treated between March and December 2018 at the Heart Center Hietzing  were invited to participate and they provided written informed consent. Baseline patient characteristics, as well as procedural and outcome data, were obtained from the VIennaCardioThOracic Aortic Valve RegistrY. The Ethics Committee of the City of Vienna approved the study (protocol EK-048-0318).The indication for TAVR was assessed by a multidisciplinary Heart Team, consisting of cardiologists, cardiac surgeons, anesthetists, radiologists, and geriatricians. Intermediate-risk or high-risk patients with severe aortic stenosis were subject to evaluation and were included, conforming to the current guidelines of the European Association of Cardio-Thoracic Surgery . Hence, The EFS includes an objective evaluation of the patient’s health status as well as the quality of life and clinical frailty. It comprises 5 categories: 0-5 points, not frail; 6-7 points, vulnerable; 8-9 points, mild frailty; 10-11 points, moderate frailty; and >12 points, severe frailty [The Vivosmart 3 continuously measures daily physical activity. It assesses the daily step count, distance covered (in kilometers), calories burned, the time spent in different stress levels, the hours and depth of sleep, the minimum and maximum heart rate, and the number of flights of stairs climbed. Several reports have validated the accuracy of the heart rate measurement by Garmin Vivosmart devices with simultaneous electrocardiogram readings ,14, and The waterproof device was worn for at least one week prior to the procedure around the wrist of the nondominant hand to avoid additional step count through repetitive gestures during daily activities. Patients were encouraged to follow their regular routines and activities while continuously wearing the device and they were instructed not to remove it temporarily for bathing, swimming, or sleeping.On the day of admission, the device was removed, and the activity data were uploaded via password-encrypted Bluetooth transfer to anonymous accounts in the Garmin Connect app (version 3.22.0.1-4.20). The device had no GPS-tracking function, thereby ensuring maximum data security.The objective of this study was to develop a modern, easy-to-use, time-saving, and resource-saving frailty assessment method that allows accurate prediction of adverse outcomes after TAVR. The daily output was used to calculate the weekly average values, excluding the incomplete activity data available from the first and last day of monitoring. Threshold levels in 3 predefined categories  were calculated. The patients were assigned 1 point per category when exceeding (in categories with positive correlation) or subceeding (in categories with negative correlation) the threshold levels and then grouped into 4 categories . Sleep pattern parameters were assessed for their discriminatory power but not included in the FItness-tracker assisted Frailty-Assessment (FIFA) score, as currently, no evidence exists that such parameters are correlated with adverse postoperative outcomes.Continuous data were expressed as mean (SD) or median (IQR) depending on the normal distribution. The comparison of continuous data between groups was performed using the Kruskal-Wallis test (H test) or univariate analysis when appropriate. A chi-square or Fisher exact test was performed to compare categorical data. Posthoc testing was performed using the Bonferroni corrected z test, Duncan, or Scheffé test depending on variance homogeneity and sample size.(J = sensitivity + specificity –1). The different frailty and risk assessment tools were then again compared for their predictive power of hospital mortality with ROC and AUC analysis. The alpha level was set at less than .05. All tests were two-tailed. Statistical calculations were performed using the SPSS statistical software version 24.0 (IBM Corp).For the development of the FIFA score, different parameters identifying frail patients and positively predicting hospital mortality were determined by receiver operating characteristic (ROC) analysis. The discriminatory ability was assessed via the area under the curve (AUC). Threshold values were calculated retrospectively with the Youden Index P=.005). Apart from the serum albumin levels, the baseline characteristics, including echocardiographic parameters, were similar among the groups.The baseline characteristics of the cohort are outlined in The procedural outcomes are shown in P=.02), the minutes spent in high stress , the minutes at rest , and the heart rate maximum  as individual parameters were the strongest predictors of hospital mortality in the ROC analysis. High preprocedural stress levels, long periods spent in high stress, and an elevated maximum heart rate correlated positively with hospital mortality, whereas the amount of time at rest had an inverse correlation with hospital mortality  when compared to 6MWT gait speed classification  and EFS-C   and 60.6% (EFS-C) to 62.5% (gait speed category). Therefore, frailty was defined as either “moderate frailty” or “severe frailty” in the FIFA score classification, as “mild frailty,” “moderate frailty,” and “severe frailty” in the EFS-C or as unfeasible 6MWT or gait speed less than 0.83 m/s. The FIFA score demonstrated the highest predictability of hospital mortality  .This study demonstrates the strong predictive performance of a modern health-monitoring device–based frailty assessment, and, to the best of our knowledge, this is the first trial to investigate the potential of a wearable activity-monitoring device in this specific clinical setting. The main findings of our study were as follows. The FIFA score correctly identifies frail patients, as demonstrated by the strong correlation with baseline serum albumin levels—a well-established biomarker for frailty. Device-recorded preprocedural stress and heart rates in patients with TAVR are independent predictors with increased postprocedural hospital mortality. The FIFA score outperformed conventional frailty assessment methods by correctly identifying patients at higher risk for procedure-related mortality.The FIFA trial has developed a modern, intuitive, and efficient frailty assessment tool that adds substantially to the growing body of evidence on the relevance of frailty in the selection of patients with TAVR. Its potential in clinical practice is substantiated by its relationship with established measures of frailty such as serum albumin levels, which play a prominent role in the estimation of frailty by reflecting the extent of muscle weakness and malnutrition. Preoperative serum albumin levels <3.5 g/dl have been proven to be an independent predictor of mortality and the inverse and proportional correlation between baseline serum albumin levels and the FIFA score is thus indicative of the assessment tool’s ability to correctly identify frail patients .Furthermore, it has also been shown for the first time that several preprocedural stress parameters  are independent predictors of postprocedural mortality. Establishing the link between stress measurements and postprocedural outcomes was enabled by wearable devices and represents a novel finding. The physiological basis for this relationship may be underpinned by the pivotal role that heart rate variability has in deriving the stress parameters. Several studies have verified the association between deviations in heart rate variability scores and postoperative outcomes. The standard deviation of normal to normal intervals has been established as an independent predictor of increased postprocedural mortality in various clinical populations -19. VaraConventional frailty scores (the EFS-C and the 6MWT gait speed classification) showed limited association with hospital mortality compared to the FIFA score, but given the fact that these criteria were designed to predict long-term outcomes, correlations may improve, as the study progresses over time. In contrast to our findings, gait speed as a single measure was shown to be independently associated with mortality after TAVR procedures. Alfredsson et al  reportedThere are several limitations to this study. As this is a proof-of-concept study, benchmark data had to be established for comparison with conventional frailty assessment methods; hence, the open-label, nonrandomized, prospective trial design. Owing to the lack of existing data, the concept was established and tested in a relatively small number of patients. Even though the primary endpoint is sufficiently powered, the concept needs to be validated in a larger patient population. Furthermore, the short postprocedural observation period may lead to underestimation of the predictive value of the FIFA score as most frailty-related studies assess long-term outcomes, including 1-year mortality.For the first time, the strong predictive performance of wearable health-monitoring device–related assessment compared to that of conventional frailty methods has been shown. The ease of use, objectivity, and high predictive performance may not only save valuable clinical resources but ultimately improve patient selection and safety. The promising initial results warrant further evaluation of the FIFA score classification as a predictor of short-term and long-term mortality after structural heart interventions or conventional surgery.


Recent evidence is focusing on the presence of a hypercoagulable state with development of both venous and arterial thromboembolic complications in patients infected with SARS-CoV-2. The ongoing activation of coagulation related to the severity of the illness is further characterized by thrombotic microangiopathy and endotheliitis. These microangiopathic changes cannot be classified as classical disseminated intravascular coagulation (DIC). In this short review we describe the interaction between coagulation and inflammation with focus on the possible mechanisms that might be involved in SARS-CoV-2 infection associated coagulopathy in the critically ill. The clinical course in the critically ill infected with SARS-CoV-2 is defined by the development of severe hypoxia based on acute respiratory distress syndrome and multiple organ failure necessitating intensive care support.11 The ongoing activation of coagulation related to the severity of the illness in SARS-CoV-2 infected patients is further characterized by thrombotic microangiopathy and endotheliitis as described in autopsies.13 There are however important reasons to not classify these microangiopathic changes as classical disseminated intravascular coagulation, possibly in part based on local plasma leakage in the lungs.15 Based on evidence from clinical course, SARS-CoV-2 infection associated coagulopathy occurs in two distinct phases. The ongoing coagulation might be caused by prekallikrein dependent contact activation, which is exacerbated by gradually increasing intravascular (micro)angiopathy caused by ongoing endothelial activation. In this short review we describe the interaction between coagulation and inflammation emphasizing the possible mechanisms that might be involved in SARS-CoV-2 infection associated coagulopathy in the critically ill. These mechanisms are summarized in Figure Besides these important mechanisms, recent evidence is focusing on the presence of a hypercoagulable state with development of both venous and arterial thromboembolic events such as pulmonary embolism, deep vein thrombosis and ischemic stroke.16 Tissue factor (TF) plays a pivotal role as initiator of this system in case of vascular injury, known as the extrinsic pathway.17 TF expressed after the endothelial cell damage activates coagulation locally.18 Coagulation factor (F)VII, present in the blood circulation, contacts with TF forming the extrinsic tenase complex.19 This complex initiates thrombin generation but is inhibited by tissue factor pathway inhibitor (TFPI) after sufficient formation of activated FX (FXa). The amplicification loop, known as the intrinsic pathway,20 can be activated through feedback amplification of thrombin via FXI, which in turn activates the intrinsic tenase complex (FVIIIa:FIXa:FX) leading to amplification of thrombin generation. The intrinsic pathway can also be triggered directly through contact activation, in which FXII is the initiator. FXII is activated spontaneously when negatively charged surfaces contact the blood21 and directly activates FXI. Thrombin in turn stimulates several other factors  in order to accelerate prothrombin generation and convert fibrinogen to fibrin. Subsequently fibrin clot is formed. Although the role of FXII in bleeding complications seems not to be clinically relevant, its role in inflammation is apparent in acute and chronic inflammation.25The haemostatic system is based on consecutive activation of precursor proteins.28 The crosstalk between inflammation and coagulation in sepsis takes place at different levels and is bidirectional with the endothelium being at the center of the process. The interaction between coagulation and activated endothelial cells in sepsis is well defined and is essential for a properly functioning haemostatic system.31 The extrinsic tenase complex (TF: FVIIa) formed after endothelial cell damage initiates thrombin generation by activating FX or FIX. This tenase complex connects the extrinsic and intrinsic route via FIX. The expression of TF on monocytes, macrophages and endothelial cells is induced by proinflammatory cytokines .33 Increased levels of these proinflammatory cytokines have been observed in severely ill patients infected with SARS-CoV-2.35 Thrombin results in the recruitment of leucocytes and platelets and stimulates the production of proinflammatory cytokines.41 Second crosstalk is at the level of the protein C system. Thrombin binds to thrombomodulin on the endothelial cell surface which in turn enhances the generation of activated protein C (aPC).42 The aPC acts as anticoagulant agent by inactivating FV and FVIII and has been suggested to act as anti-inflammatory factor by downregulation of proinflammatory cytokine production and decreasing leucocyte adherence and apoptosis.43 Decreased levels of aPC results in decreased inactivation of FV and FVIII, which in particular might cause a limited anticoagulant response. The anticoagulant effect of aPC is well defined, however its use in microangiopathic patients, such as in sepsis, did not improve outcome.45 Third crosstalk is at the level of fibrinolysis where aPC has been suggested to neutralize fibrinolysis inhibitors TAFI and PAI-1 resulting in the activation of the fibrinolysis.46 Decreased levels of aPC might in turn limit the fibrinolytic response. The haemostatic system is a complex and dynamic process and continuously subject to changes based on inflammation related factors, especially in critically ill.A systemic infection, like sepsis, is commonly associated with systemic inflammation and activation of coagulation which can result in microthrombosis, a process called immunothrombosis or thromboinflammation.50 which in turn might lead to activation of FXII. Prekallikrein (PK) generates FXIIa on the surface of activated endothelial cells, in a receptor-dependent manner. The binding of FXIIa, PK and high molecular weight kininogen to endothelial cells results in generation of kallikrein  activity in relation to high vWF antigen may contribute to microangiopathic changes in critically ill patients infected with SARS-CoV-2.61 An additional important mechanism contributing to the SARS-CoV-2 associated coagulopathy might be the SARS-CoV-2 infection induced severe hypoxia. Hypoxia has been linked to augmentation of thrombosis.64 Hypoxia-inducible factor-1 (HIF-1) is activated under hypoxic conditions resulting in upregulation of plasminogen activator inhibitor-1 (PAI-1) and TF as well as inhibition of protein S.64 Hypoxia inducible factor-2 (HIF-2) is also upregulated and stimulates PAI-1 and inhibits TFPI.66 Finally, from another angle obesity influences the risk of a hypercoagulable state. Obese subjects have shown to have enhanced coagulation by elevated levels of vWF, TF, FVII, FVIII and fibrinogen, and impaired fibrinolysis by increased secretion of plasminogen activator inhibitor (PAI)-1 and thrombin activatable fibrinolysis inhibitor (TAFI).69 A significant number of patients infected with SARS-CoV-2 has been described to be obese indicating that being obese may be a predisposing risk factor for the hypercoagulable state. Taken together, all these mechanisms may contribute to the complex hypercoagulable state of the critically ill patients infected with SARS-CoV-2 having severe hypoxia and ongoing endothelial activation.The observed massive coagulopathy in critically ill patients infected with SARS-CoV-2 may also be played by the activation of endothelial cells. The very high plasma levels of FVIII and von Willebrand factor (vWF) and the histological post-mortem analysis of different organs indicate the profound endothelial activation in SARS-CoV-2 associated coagulopathy in critically ill.70 These data are in contrast to what is known about evolving disseminated intravascular coagulation (DIC) where platelet counts, AT, protein C and fibrinogen levels are clearly diminished. As the focus of this perspective is restricted to SARS-CoV-2 infection associated coagulopathy in critically ill, the reader is referred to several recent articles emphasizing the differences between DIC and SARS-CoV-2 associated coagulopathy.72 Moreover, several AT-binding proteins  on human monocytes have been identified and indicated to be involved in blocking the activity of nuclear factor-κβ.73 AT also seemed to possess antiviral activity against HIV, HSV and HCV.77 Therefore, normal to high levels of AT might hypothetically be caused by SARS-CoV-2 infection itself and be due to its possible role in anti-inflammation. Another interesting observation is the increased level of d-dimer during the severe clinical course of SARS-CoV-2 infection.9 D-dimer is a fibrin degradation product. Factors enhancing the degradation of fibrin clot by plasmin might influence the production of d-dimer. Annexin A2, a calcium- and phospholipid-binding protein, is an endothelial surface co-receptor for tissue plasminogen activator (tPA) and plasminogen that stimulates the profibrinolytic state.78 There is increasing evidence for a role of annexin A2 at the first phase of viral life cycle known as cell attachment and entry in a variety of viral infections.79 SARS-associated cytokines (IL-6 and IFN-gamma) have been shown to upregulate the expression of annexin A2.80 The plasma kallikrein is involved in many proteolytic activities. One of the additional functions of kallikrein is to stimulate the production of plasmin.81 Plasmin in turn can generate d-dimer from fibrin clots. Although available data is limited, this may imply that factors interfering either with this co-receptor and/or stimulating plasmin might modulate the production of d-dimer.Surprisingly, the platelet counts, antithrombin (AT), fibrinogen and protein C levels ranged between normal to slightly increased levels in SARS-CoV-2 infected patients who are severely ill.82 However, despite the use of thrombosis prophylaxis and therapeutic anticoagulation, the risk of thromboembolic events remained high and appeared not to be sufficient.9 Pharmacological targeting of the different pathophysiological mechanisms other than routine anticoagulation therapies might improve the severe clinical course seen in patients with SARS-CoV-2 infection at several of them are currently clinically being tested. At the level of platelets, anti-polyP antibodies have the potential to ameliorate the hyperinflammatory and prothrombotic state.83 Although successful in animal models,84 no human drug currently exists. Blocking FXI or FXII is an appealing option and both have been shown to prevent contact activated thrombosis in animal models. Considering its role in the bradykinin pathway, FXII is the attractive target in SARS-CoV-2 related pathology. From this point of view, blocking FXIIa by its strong inhibitor C1-esterase inhibitor (C1-INH) is of interest and is currently been explored by Osthoff and colleagues at the University Hospital Basel in Switzerland. The potential role of plasma kallikrein in case of SARS-CoV-2 infection may be summarized as (1) the activation of FXII with the end-product thrombin (2) the generation of bradykinin with subsequent vascular permeability and leakage, (3) the activation of the renin-angiotensin system through conversion of renin from pre-renin leading to a pro-inflammatory state through increased angiotensin 1 receptor activation and (4) the activation of C5, in part through activation of C1 via FXII and in part through activation of C3 via plasmin. The inhibition of plasma kallikrein might therefore play a central role as target treatment, especially as 2 drugs are already on the market . The use of these agents, alone or in combination with other agents acting on complement, coagulation and/or renin-angiotensin systems, might be an attractive treatment strategy. At the level of the complement system, the risk of thrombotic complications in patients with paroxysmal nocturnal hemoglobinuria, a rare life threatening disease manifesting with hemolytic anemia, bone marrow failure and thrombosis, has well been established.85 Even more so, treatment with the C5 blocking agent eculizumab decreases these thrombotic risk significantly indicating the inhibition of complement activation as a possible target to reduce the risk of thrombotic complications.86 Finally, the interplay between inflammation and thrombosis has already being stressed. Interfering with anti-inflammatory agents, such as tocilizumab, anti-IL-6, anti-IL-1 and others, could have a beneficial effect on the level of coagulopathy as well. Future research to prevent or treat the SARS-CoV-2 infection related coagulopathy should therefore focus on targets other than regular antithrombotic treatment.The use of pharmacological thrombosis prophylaxis decreases the risk of thrombotic events in COVID-19.The severe critical illness as seen in patients infected with SARS-CoV-2 is characterized by multiple organ failure and a deep hypoxia related to ARDS and pulmonary embolism. Central in the pathogenesis are the activation of the renin-angiotensin, the kallikrein-kinin, the complement and the coagulation system. Pharmacological interventions aimed at these mechanisms may alter the clinical course in these patients.