City-wide lockdowns and school closures have demonstrably impacted COVID-19 transmission. However, simulation studies have suggested an increased risk of COVID-19 related morbidity for older individuals inoculated by house-bound children. This study examines whether the March 2020 lockdown in New York City (NYC) was associated with higher COVID-19 hospitalization rates in neighborhoods with larger proportions of multigenerational households.We obtained daily age-segmented COVID-19 hospitalization counts in each of 166 ZIP code tabulation areas (ZCTAs) in NYC. Using Bayesian Poisson regression models that account for spatiotemporal dependencies between ZCTAs, as well as socioeconomic risk factors, we conducted a difference-in-differences study amongst ZCTA-level hospitalization rates from February 23 to May 2, 2020. We compared ZCTAs in the lowest quartile of multigenerational housing to other quartiles before and after the lockdown.Among individuals over 55 years, the lockdown was associated with higher COVID-19 hospitalization rates in ZCTAs with more multigenerational households. The greatest difference occurred three weeks after lockdown: Q2 vs. Q1: 54% increase ; Q3 vs. Q1: 48% (17–89%); Q4 vs. Q1: 66% (30–211%). After accounting for pandemic-related population shifts, a significant difference was observed only in Q4 ZCTAs: 37% (7–76%).By increasing house-bound mixing across older and younger age groups, city-wide lockdown mandates imposed during the growth of COVID-19 cases may have inadvertently, but transiently, contributed to increased transmission in multigenerational households. Since COVID-19’s first appearance in December 2019, knowledge of transmission dynamics of SARS-CoV2 has rapidly advanced. Studies show that both proximity to infected patients and the concentration of inoculum play important roles in acquisition and subsequent severity of COVID-19 . For thiEvidence suggests that the organization of households and housing structure may also play a role in COVID-19 transmission. Ecological studies that examined links between housing conditions and COVID-19 rates describe associations between poorer housing conditions and COVID-19 cases , as wellNon-pharmaceutical interventions (NPIs) such as city-wide lockdowns and school closures have had demonstrable impacts on COVID-19 transmission –17. HoweWe conducted a retrospective difference-in-difference analysis of weekly COVID-19 hospitalizations per 10,000 population in each NYC ZCTA between February 23 and May 23, 2020. Beginning in late February 2020, NYC became the global epicenter of the COVID-19 pandemic, with a first wave that crested in late March/early April 2020 . A city-Our dependent variable was weekly COVID-19 hospitalization counts in each ZCTA, which were aggregated from daily hospitalization counts obtained from the NYC Department of Health and Mental Hygiene (NYC DOHMH). These counts were used to calculate weekly hospitalization rates per 10,000 population in each ZCTA, both across all patients and those over 55 years of age. We then calculated as our primary independent variable the proportion of households in each ZCTA that are multigenerational (defined as the percentage of households occupied by a grandparent and a grandchild less than 18 years of age), using the American Community Survey 5-year 2018 estimates. The primary analysis focused on hospitalized patients aged 55 years and older to reflect the average age of grandparents in the US . SecondaAlthough several socioeconomic factors have been reported to be associated with increased rates of COVID-19 cases, we were careful to consider the potentially mediating effect of these factors in order to avoid over-adjusting our model of hospitalization rates over time and space. To account for socioeconomic conditions that likely confound the ecological-level association between the lockdown, COVID-19 hospitalization rates in ZCTAs, and multigenerational households, we modified the conceptual model used by Nalfilyan et al. ; this stOur primary analysis therefore included, by ZCTA, the proportion of residents who are White, the proportion of residents living under the federal poverty line (both as a percentage), and the median income (in 2018 US dollars). Furthermore, as we did in prior work on the first COVID-19 wave in NYC , we alsoIn order to undertake inferential spatial analyses, spatial shapefiles of NYC’s ZCTAs were downloaded from the New York City Department of City Planning.The primary outcome of interest was the adjusted COVID-19 weekly hospitalization rate per 10,000 population within each ZCTA for a) hospitalized patients over 55 years old, and b) for all hospitalized patients. We binned the ZCTA-level proportions of multigenerational households into quartiles and then calculated these hospitalization rates for each quartile, using the first (lowest) quartile as the reference group.Upon dividing NYC ZCTAs into quartiles of multigenerational housing percentages, we first compared the number of COVID-19 hospitalizations per 10,000 population in each quartile with the quartile’s socioeconomic characteristics . Visual Using a modified difference-in-difference analysis, we then estimated the association between the city-wide lockdown and hospitalization rates within each quartile of multigenerational household percentages. A typical difference-in-difference analysis defines an unexposed control group and an exposed treatment group; in our analysis, the exposure is the city-wide lockdown beginning with school closures on March 16, 2020. Our modified difference-in-difference analysis hypothesized an effect of increasing magnitude on COVID-19 hospitalization rates for ZCTAs with higher proportions of multigenerational households (quartiles 2–4) relative to quartile 1. Therefore, for the purposes of this analysis, we defined the control group as the ZCTAs in the first quartile of multigenerational households.We could not test the parallel trend assumption of the difference-in-difference methodology directly. However, we assessed trends in the daily and weekly COVID-19 hospitalization rates by multigenerational housing quartile prior to the lockdown. Furthermore, we believe the parallel trend assumption holds as the decision for the lockdown was unlikely to be associated with other factors; it was abruptly implemented at the same time across all ZCTAs.In our analysis, we estimated multivariable generalized linear models specifying a Poisson distribution for the weekly COVID-19 hospitalization counts. We included in these models a binary indicator that denoted whether each week under consideration occurred before or after the city-wide lockdown order. This allowed us to compare the COVID-19 hospitalization rates across the quartiles of multigenerational housing in weekly increments before and after the lockdown took effect. In light of the known spatial clustering of COVID-19 cases in NYC, we used the Moran’s I statistic to formally assess spatial autocorrelation of the cumulative COVID-19 hospitalizations rates by ZCTA over the study period. Details of our model specification are provided in the Upon finding that there was significant spatial autocorrelation in our dependent variable , asThe study protocol was approved by Weill Cornell Medical College of Cornell University Institutional Review Board (IRB), protocol # 20–03021681, with consent given in writing. All analyses were conducted in GeoDa version 1.16, QGIS version 3.16.2, and R version 3.6.2. Data were analyzed between January 20 and May 25, 2021.Across 166 ZCTAs in NYC, there were 51,008 individuals during the study period who were hospitalized with COVID-19, 71.05% of whom were patients over 55 years. In moving from the first to the fourth quartile of multigenerational housing prevalence , the total number of COVID-19 hospitalizations in each quartile increased overall, as well as per 10,000 population . CompareAs ZCTAs contained more multigenerational households, the median income fell by more than half , the proportion of White residents fell by more than a third (Q1: 72.49% vs. Q4: 20.68%), the proportion of residents below the federal poverty line approximately doubled (Q1: 11.01% vs. Q4: 25.62%), and the proportion of those residing in overcrowded housing increased (Q1: 4.92% vs. Q4: 13.53%).For ZCTAs in each quartile of multigenerational housing prevalence, Secondary analyses of all patients hospitalized with COVID-19 demonstrated similar findings to the primary analysis . RelativEstimates from the sensitivity analyses were largely consistent with those from the primary analysis . When weThis first empirical study examines the relationship between city-wide lockdown and COVID-19 hospitalization rates amongst older adults in multigenerational households in NYC. We found that the lockdown was associated with a transient and disproportionate increase in hospitalizations among individuals older than 55 years residing in ZCTAs with higher proportions of multigenerational households, after adjusting for socioeconomic characteristics. The estimated association was consistent with the known transmission dynamics in multigenerational households during the exponential growth phase of COVID-19 in NYC, and had its greatest effect three weeks after lockdown measures were implemented. These results were attenuated by pandemic-related flight, but remained significant in the ZCTAs with the highest proportions of multigenerational households.Our results add crucial ecological evidence to the emerging literature on household structure and COVID-19 risk. Moreover, they add empirical evidence to simulation studies that postulated deleterious effects of school closures, which were the first city-wide lockdown measure introduced . By asseOur findings should not be interpreted to suggest that NPIs, such as city-wide lockdowns, do not work. They clearly do. Instead, they suggest that the impact of such measures is not uniform across households and neighborhoods. Early reports in the pandemic underlined the age-dependent morbidity related to SARS-CoV2 infection . TherefoThis study has five limitations. First, despite attempts to address unobservable confounding influences, we cannot rule out the role of residual confounding due to the observational nature of the study. This is particularly relevant in the use of control covariates which acted as proxies for socioeconomic risk at the ZCTA level. Although we were careful to note which factors may act to mediate and confound the relationship under study, there could be other unmeasured time-varying factors. Second, because our data was collected at the ZCTA level, we were not able to evaluate individual COVID-19 hospitalization risk. Third, our analysis does not quantify the relative hospitalization risk in multigenerational households incurred by not undertaking city-wide lockdown; this risk is likely to outweigh the impact of lockdown. Nonetheless, our results indicate that the risks and benefits of lockdown vary across different populations, with particularly stark consequences for multigenerational households. Fourth, hospitalization rates may not accurately reflect the remaining population base of ZCTAs in NYC because of pandemic-related flight, which favored wealthier neighborhoods . This maIn its first COVID-19 wave, NYC’s lockdown was associated with increases in COVID-19 hospitalization rates for individuals over 55 years of age in ZCTAs with higher proportions of multigenerational households. These findings highlight unanticipated interactions between structural factors such as housing and social distancing measures that may have contributed to greater transmission risks for select vulnerable groups in the pandemic.S1 Fig(DOCX)Click here for additional data file.S2 Fig2), adults who smoke, and adults with coronary heart disease, hypertension, diabetes, asthma, or chronic obstructive pulmonary disease (COPD)–taken from the CDC 500 Cities Dataset; additional socioeconomic factors: ZCTA-level estimates of total population, percentage of residents living below the federal poverty line (FPL), median income in 2018 USD, percentage of White residents, and percentage of overcrowded households —all taken from the ACS 5-year estimates 2018; and percentage of essential workers by ZCTA, identified from service-oriented non-public roles using Census Industrial Classification Codes in the following categories: 1) public transit workers, 2) grocery, convenience and drug store workers, 3) trucking, warehouse and postal service workers, 4) healthcare workers, 5) childcare, homeless, food and family service workers, and 6) building cleaning service workers–we replicated the same methodology employed by the New York City Office of the Comptroller .This model controlled for the following covariates: ZCTA-level prevalence, as a percentage, of: adults who are obese (defined as body mass index [BMI] ≥ 30 kg/m(DOCX)Click here for additional data file.S3 Figt = 0 for the week of school closure) and the quartile of overcrowded housing proportions that each ZCTA belongs to, after accounting for the interaction effect between time and the ZCTA’s quartile of multigenerational housing.A. Adjusted difference-in-difference estimates of the association between school closure and COVID-19 hospitalization rates for all age groups, with ZCTAs grouped by quartiles of multigenerational housing proportions (with quartile 1 as reference), and with quartiles of overcrowded ZCTAs also included as a covariate. This model controlled for the following covariates: percentage of residents living below the federal poverty line (FPL), median income in 2018 USD, percentage of White residents, percentage of overcrowded households —all taken from the ACS 5-year estimates 2018. B. Adjusted difference-in-difference estimates of the association between school closure and COVID-19 hospitalization rates for all age groups, with ZCTAs grouped by quartiles of multigenerational housing proportions (with quartile 1 as reference), and with quartiles of overcrowded ZCTAs also included as a covariate. This model controlled for the same covariates as described in S3A Fig. This plot presents the coefficients and 95% Bayesian credible intervals of the interaction between time in weeks (indexed at (DOCX)Click here for additional data file.S1 File(DOCX)Click here for additional data file.S1 Data(XLSX)Click here for additional data file.


Lung cancer survivors who experienced severe radiotherapy-related fatigue presented higher impairments after COVID-19 voluntary isolation than lung cancer patients who did not experience severe radiotherapy-related fatigue, and showed high levels of anxiety, depression and disability, and a poor self-perceived health status.The main objective of this study was to investigate the impairments presented after COVID-19 voluntary isolation by lung cancer survivors that experienced radiotherapy-related fatigue. In this observational study, data were collected after COVID-19 voluntary isolation. Patients were divided into two groups according to their fatigue severity reported with the Fatigue Severity Scale. Health status was assessed by the EuroQol-5D, anxiety and depression by the Hospital Anxiety and Depression Scale, and disability by the World Health Organization Disability Assessment Schedule 2.0. A total of 120 patients were included in the study. Patients with severe fatigue obtained higher impairment results compared to patients without severe fatigue, with significant differences in all the variables ( Concurrent chemo-radiation remains the standard treatment for most cancer patients . RadiothRadiotherapy is an oncological treatment that implies the apoptosis of both tumoral cells  and normCancer-related fatigue (CRF) damages the quality of life of cancer patients . Tt inteThe COVID-19 pandemic has impacted lives around the world, causing high physical and psychological suffering, such that 40% of lung cancer patients have had their quality of life affected by home confinement . The phyConsidering the scientific background that relates perceived fatigue and presented disability with voluntary isolation, and the lack of awareness of the impact of the COVID-19 lockdown on lung cancer patients, the purpose of this study was to investigate the impairment presented after COVID-19 voluntary isolation in lung cancer survivors that experienced radiotherapy-related fatigue.We hypothesized that lung cancer patients who experienced severe radiotherapy-related fatigue present higher impairments during COVID-19 voluntary isolation than lung cancer patients who did not experience severe radiotherapy-related fatigue.A cross-sectional observational study was performed. Patients were recruited from the Oncological Radiotherapy Service of the “Hospital Universitario San Cecilio” , between June 2020 and May 2021. The included lung cancer survivors were aged 18–80 years, treated by radiotherapy treatment, and all were informed and signed the informed consent. Exclusion criteria were a diagnosis of fibromyalgia or similar condition, diagnosis of any psychiatric disorder, diagnosis of COVID-19 in the previous year, being in actual chemotherapy treatment, and any cognitive impairment affecting the possible completion of the evaluation protocol. We conducted this study in accordance with the Declaration of Helsinki 1975, revised in 2013. The study protocol was reviewed and approved by the Biomedical Research Ethics Committee of Granada . Patients were divided into two groups—a group with severe fatigue and another group without severe fatigue—according to the cut-off point of the Fatigue Severity Scale (FSS), which was recorded after COVID-19 voluntary isolation. The FSS has been used in different chronic conditions ,32,33, iThe FSS has been used in previous cancer populations in more than 400 occasions . It has Data were recorded after COVID-19 voluntary isolation. Anthropometric data, characteristics of the pathology, adjuvant treatment, and characteristics of radiotherapy treatment  were colThe main study outcomes evaluated the patient affectation including anxiety and depression levels, disability, and self-perceived health status.The Hospital Anxiety and Depression Scale (HADS) was used to assess anxiety and depression. The HADS is a self-reported measure that contains 14 statements ranging from 0 to 3, which result in two subscales: anxiety (0–21) and depression (0–21). A score of 8 is an indicator of possible anxiety or depression . This scDisability was measured by the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). WHODAS 2.0 has good validity and high reliability ,42. ThisThe EuroQol-5D was used to assess self-perceived health status . It has t test) was used; when any conditions were not achieved, a nonparametric test (Mann–Whitney test) was used. In any cases, α = 5%. Previous to the between group comparison, two groups were created according to fatigue status: having (≥42 FSS score) or not having (<42 FSS score) severe fatigue. IBM SPSS version 23.0 was used to perform the statistical analysis . The KolA sample of 130 patients lung cancer survivors treated with radiotherapy was screened in this study. From that sample, 10 patients were excluded due to difficulties communicating with the interviewers (n = 6) or not accomplishing the voluntary isolation (n = 4). Finally, 120 were included in the study. The 120 participants gave their consent to be evaluated and all completed the evaluation. When the presence of fatigue was evaluated, 80 patients did not present severe fatigue and 40 participants presented severe fatigue. The characteristics of the participants are summarized in t test and the Mann–Whitney test, are presented in p < 0.001), with higher results in the group with severe fatigue.The comparison of the main study outcomes between groups, using Student’s p < 0.001), presenting worse results in the group with severe fatigue for each domain and the total score.All the domains of the presented disability questioner also had significant differences (p = 0.003), self-care (p = 0.036), activities of daily living, pain and anxiety, and depression (p < 0.001) subscores.The group with severe fatigue presented worse results in the Euroqol-5D scale, with significant differences in the mobility  as “a distressing persistent, subjective sense of physical, emotional and/or cognitive tiredness related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning” . AlthougThe high prevalence of radiotherapy-related severe fatigue found in this study is similar to that found in other studies, such as Tombal et al. Our study showed that lung cancer survivors who experienced severe fatigue presented higher level of anxiety and depression than those who did not experience severe fatigue. Our results are in line with previous studies  that repThe studies previous to the COVID-19 era  have invWith respect to the Euroqol-5D results, our study found significant differences between groups. A recent study of Presley CJ et al. , which sOur study results explore a possible effect of COVID-19 isolation on lung cancer survivors. Studies in healthy populations ,30 have The stressors  are directly related with the development of symptoms, given the high comorbid nature of mood disorders in patients with fatigue . It has Future studies might focus on psychological disorders and the presented disability. A shared-decision care plan could improve the recovery of these disorders, helping cancer patients to improve and deal with impairments related to radiotherapy treatment, especially lung cancer survivors who present severe fatigue. Guidelines on detection and treatment of CRF during active treatment, follow-up, and at end-of-life  have beeThis study presents several strengths, such as the high significance of the results, a high response rate, and the use of a validated and used CRF tool with a cut-off point that has good agreement with the current CRF diagnostic criteria . HoweverLung cancer survivors who experience severe radiotherapy-related fatigue present higher impairments after COVID-19 voluntary isolation than lung cancer patients who do not experience severe radiotherapy-related fatigue, show higher levels of anxiety, depression and disability, and have a poorer self-perceived health status.An important finding of this study is that presented severe fatigue and the high psychological suffering of lung cancer patients are associated during COVID-19 voluntary isolation. Clinicians can use the findings of this study to identify lung cancer survivors who have a higher risk for developing greater radiotherapy-related impairments during voluntary isolation, permitting the early initiation of management interventions. In this line, therapeutic approaches need to, first, screen for fatigue in lung cancer patients routinely, and second, propose therapeutic intervention including exercise, psychological assessment, and functional training.


Most co-culture models depart from synovial lining and cartilage culture, but also fat pad and bone have been included. Not all of the models appear to reflect the postulated in vivo OA pathophysiology, although some of the discrepancies may indicate current assumptions on this process are not entirely valid. Systematic analysis of the mutual influence the separate compartments in a given model exert on each other and validation against in vivo or ex vivo observation is still largely lacking and would increase their added value as in vitro OA models.Osteoarthritis (OA) is a highly prevalent disease and a major health burden. Its development and progression are influenced by factors such as age, obesity or joint overuse. As a whole organ disease OA affects not only cartilage, bone and synovium but also ligaments, fatty or nervous tissue surrounding the joint. These joint tissues interact with each other and understanding this interaction is important in developing novel treatments. To incorporate and study these interactions in OA research, several co-culture models have evolved. They combine two or more cell types or tissues and investigate the influence of amongst others inflammatory or degenerative stimuli seen in OA. This review focuses on co-cultures and the differential processes occurring in a given tissue or cell as a consequence of being combined with another joint cell type or tissue, and/or the extent to which a co-culture mimics the  Osteoarthritis (OA) is a degenerative and progressive joint disease affecting approximately 500 million people worldwide . High agOA is a whole organ disease affecting all tissues in and adjacent to the joint. The pathology of OA includes degradation of articular cartilage and ligaments, synovial inflammation (synovitis), malformation of subchondral bone and osteophyte formation. Adjoining muscles and nerves can also be affected by OA . The mosin vivo studies are carried out, recently the interest in the use of in vitro models to replace in vivo studies in joint research has intensified, especially against the backdrop of the societal demand to reduce animal use /cells, and/or if a culture system was shown to reflect in vivo pathophysiological phenomena. Also co-cultures combining cells or tissues as part of regenerative approaches (e.g. MSCs and chondrocytes) were excluded.Although for final proof of the relevance of these interactions commonly imal use . SeveralThe interplay of different cell types can be investigated using co-culture. Indirect co-culture models, so culturing one cell type in conditioned medium of another cell type of interest can provide valuable insights. To add more complexity to a monolayer culture, a second cell type is added to form a direct co-culture system. Cells can either be mixed directly and seeded into a monolayer culture or separated using cell culture inserts . A benef+CD127dim/- enriched PBMCs. A significant increase of MMP-1 and ADAMTS-5 was found upon co-culture, compared to chondrocytes cultured alone  in non-arthritic chondrocytes compared to chondrocytes in conditioned medium from non-arthritic osteoblasts or medium only . The infed alone .in vivo in OA, cannot be verified with certainty, however.As rupture of anterior cruciate ligaments (ACL) can result in OA development, the impact of synoviocytes on ligament fibroblasts upon stimulation with TNFα and/or mechanical stress was investigated . Synovio2D culture fails to recapitulate the three-dimensional organization of cartilage and other tissues of the joint. Therefore, usually 3D cultures of chondrocytes or cells encapsulated into hydrogels are utilized. Both natural and synthetic hydrogels are used for the bioengineering of tissues  Figure . They arin vitro OA models, indicating the validity of the model -diacrylate (PEGDA) using culture inserts, a significant increase of MMP-1, MMP-3, MMP-9, MMP-13, IL-1β, TNF-α, IL-6, IL-8, and IFN-γ compared to OA chondrocytes in monoculture was observed . Convershe model . Whetherhe model . Activat testing . The inhIn vivo, mechanical stress of bone lead to increased TGFβ signaling, which in turn could promote OA , an enzyme involved in glucosamine production, can influence matrix production. Rat synovial fibroblasts were adenovirally transduced with GFAT cDNA, co-cultured with alginate-encapsulated chondrocytes and stimulated with IL-1β to investigate the influence of GFAT on the response to IL-1β . While i changes . Therebyin vivo situation to a certain extent. Additional TNFα treatment of the endothelial cells synergistically increased ICAM expression. Addition of a chemokine mix  to the synovial fluid-mimicking compartment further stimulated monocyte extravasation. OA synovial fluid was similarly able to increase monocyte extravasation significantly, suggesting that synovial fluid might be relevant for monocyte extravasation in vivo -based co-culture of a mix of immortalized mesenchymal stromal cell line (MSOD) and HUVEC cells was utilized. MSOD cells underwent osteogenic differentiation by the presence of the HUVEC cells  MSOD monAlthough cell-based co-culture is a versatile strategy, one of the clear disadvantage is the change in phenotype occurring as a consequence of isolation and expansion of primary cells . In ordein vivo is not clear.Upon exposure to mechanically injured equine cartilage, primary equine healthy synovial fibroblasts reduced their ADAMTS-4 and 5 expression while increasing expression of MMP-1 as compared to co-culture with normal cartilage . Vice veIn an elegant study where healthy rat chondrocytes were co-cultured with synovium harvested at different time points after OA induction, addition of synovium initially showed higher aggrecan production of the chondrocytes, suggesting injury induced a transient anabolic effect. With increased OA stage of the isolated synovium, however, this changed into an increase of monocyte chemoattractant protein 1 (MCP-1), a chemokine initiating inflammation . The effin vivo disease  agonist lipopolysaccharide (LPS) was tested on human osteochondral explants to see whether it could be used to create an OA model for drug testing. LPS activates TLR-4 in a similar fashion as damage-associated molecular patterns (DAMP) which are thought to play a key role in the inflammatory processes in OA . In the in vivo , could rin vivo . Unfortuartments . Moreoveartments . A co-cuartments . A porciartments . Combiniin vivo levels, whereas in cartilage monoculture staining was more faint, suggesting proteoglycan loss (2 (PGE2) in culture medium of co-cultures, but not in cartilage monoculture. Moreover, MMP-13 secretion was increased to a higher extent after IL-1β stimulation in co-culture compared to cartilage monoculture, in line with the postulated role of the inflamed synovial lining in vivo. Gene expression of collagens, aggrecan and catabolic enzymes  of canine OA cartilage in co-culture with OA synovial tissue was more in line with tissue directly derived from OA patients than of cartilage in monoculture  was shown in co-culture. TAA prevented the decrease in GAG production induced by the presence of synovium, while in cartilage monoculture it decreased GAG production . Using sus PGE2. . The relus PGE2. . Thus, cly valid .in vivo situation closer than the corresponding model of osteochondral explants alone  obtained from healthy rats . In co-cin vivo . HoweverCo-culture systems have also been used for drug development. So far, various types of treatments, ranging from drugs to platelet-rich plasma and stem cells to biomechanics-changing additives were investigated in OA models . Most ofin vivo drug response was not explained as no comparison of NAPA treatment on mono and co-culture was performed  as a drug targeting the NFκB pathway involved in OA. The addition of synoviocytes to chondrocytes induced increased phosphorylation on serine 10 in histone 3, suggesting higher NFκB pathway activity and a shift to a more inflammatory state . NAPA trerformed . Even thsynovium . In contsynovium . The dissynovium .in vitro effects of these biologicals are in contrast with the poor level of evidence of efficacy of HA treatment , which was able to dose-dependently inhibit the bovine synovium-induced GAG breakdown in bovine cartilage explants and in human OA cartilage monoculture . This inNon-sclerotic and sclerotic osteoblasts were used in co-culture with chondrocytes to study the effect of carnosol, a polyphenol extracted from rosemary. Pretreatment of sclerotic osteoblasts with carnosol could prevent and even partially reverse the reduced aggrecan production by chondrocytes induced by untreated sclerotic osteoblasts. Carnosol pretreatment furthermore decreased MMP-3, ADAMTS-4 and ADAMTS-5 in chondrocytes compared to co-culture with non-pretreated osteoblasts. However, the reduced collagen II gene expression in chondrocytes could not be mitigated by pretreatment .2 produced by the human OA synovium correlated with proteoglycan degradation in OA cartilage  technology, which has advanced recently to the possibility of generating different cell types.Co-cultures of joint cells and tissues have been widely used in OA research and have replaced animal models to a certain extent. Essential to their applicability is the degree to which they reflect the solation . Also thsolation . Achievi in vivo . Tissue  in vivo . Anothertrations . Using ctrations  and therThe utilization of co-culture models is key to reduce the animal use in OA research and to gain more understanding of the interplay in OA joints at the cell and tissue level. This can be a useful tool in drug development, but also in other research questions such as the role of biomechanical loading. The model should reflect respective characteristics of and processes in OA. Better validation of models is key here. Moreover, ideally more complex models incorporating more tissues and cell types are introduced.


The coronavirus disease 2019 (COVID-19) pandemic has spread across the world in a relentless and merciless way. As the pandemic escalates, varied presentations and complications of the disease have been reported from all over the world. Pregnant women fall into a vulnerable group who have been reported to have more severe disease and need of intensive care when compared to non-pregnant women of the same age group. Preeclampsia is one of the most common co-morbidity seen in pregnant women with COVID-19 infection. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to worsening of pre-existing co-morbidities and extra vigilance is required in such cases. Here we present a case of a pregnant woman with COVID-19 infection with preeclampsia complicated by acute fatty liver of pregnancy and acute kidney injury. Although a rare diagnosis, a prompt multidisciplinary approach helped in achieving a favorable maternal and neonatal outcome. The ongoing coronavirus disease 2019 (COVID-19) pandemic has spread across the globe in an alarming rate and is responsible for the death of more than two million people worldwide. Pregnancy affected with COVID-19 initially presented with uncertainties but with time more information is available about its effect on pregnancy outcome. Although respiratory symptoms are the most commonly observed clinical manifestation of the disease, a substantial number of infected patients may develop involvement of other systems and present with extra-respiratory manifestations like cardiac, gastrointestinal, hepatic, renal, neurological, ocular and hematological symptoms [Preeclampsia in pregnancy can lead to grave complications such as hemolysis, elevated liver enzymes and low platelet (HELLP) syndrome, acute fatty liver of pregnancy (AFLP) and acute kidney injury. AFLP is rare, usually presents in the third trimester of pregnancy or early post-partum period. It is a potentially lethal complication for both the mother and fetus, with an approximate incidence of one in 7,000 to 16,000 pregnancies .Recent data shows that pregnant women infected with SARS-CoV-2 are more likely to need intensive care treatment when compared to non-pregnant women of reproductive age . FurtherA 27-year-old primigravida with di-chorionic di-amniotic twin pregnancy was admitted at 35 weeks of gestation with pain abdomen for two hours. She gave history of low-grade fever for four days associated with mild cough. On admission she was icteric and afebrile, pulse rate was 88/minute, blood pressure was 142/94 mmHg, respiratory rate was 20/minute and oxygen saturation was 98% in room air. Prior to admission patient had regular antenatal visits, with no history of any medical disorder. Patient was admitted in COVID-19 suspect isolation ward and nasal swab was sent to test for COVID-19. Her ultrasound abdomen showed twin live fetus, first in cephalic and second in breech position, with normal liquor volume. Her urine dipstick test was done and showed +2 protein level. She was started on tablet labetalol 200 milligram twice daily. The routine blood investigations sent on admission were collected (Table Patient tested positive for COVID-19 (by rapid antigen test) and was shifted to the positive isolation ward. She tested negative for viral hepatitis, and an ultrasound upper abdomen was done which showed a normal study. As her platelet level was normal, provisional diagnosis of preeclampsia complicated by atypical HELLP syndrome and acute kidney injury was made. Decision of termination of pregnancy was taken and prophylactic magnesium sulfate was started for prevention of eclampsia. After two hours of admission, the patient had spontaneous rupture of membranes and thick meconium stained liquor. Her cervix was 2 cm dilated and 40% effaced. An emergency caesarean section was done under spinal anesthesia, twin babies were delivered weighing 2 kilogram (kg) and 2.1 kg, with APGAR  score at birth of 8/10 each. Blood loss during the procedure was approximately 800 milliliters. All the healthcare professionals wore adequate personal protective equipment (PPE) during the procedure.Both the babies were tested within 24 hours of delivery and reported negative for COVID-19 and were roomed in with the mother. Immediate post-operative period was uneventful. After 12 hours of caesarean section, patient complained of pain abdomen and vomiting and developed restlessness, confusion and breathlessness. On examination patient was disoriented, her pulse rate was 110/min, blood pressure was 130/90 mmHg, oxygen saturation in room air was 90% and blood sugar level was 47 mg/dl. Patient was started on oxygen inhalation and dextrose infusion. Emergency blood investigations were sent which showed worsening of bilirubin levels and deranged electrolyte levels (Table Her chest X-ray was done which showed bilateral basal opacities. A provisional diagnosis of AFLP was made according to Swansea criteria . As thisPreeclampsia is one of the most commonly associated co-morbidity with COVID-19 infection in pregnancy . As placAFLP is a rare life-threatening disease. Majority of women with AFLP present in the third trimester of pregnancy; however, there are isolated case reports with presentation in early post-partum period . PotentiThe Swansea criteria  for the Hepatic dysfunction has been commonly associated with COVID-19 infection . Deng etMorton  had repoThis case illustrates the complexities of COVID-19 in pregnancy, the overlap of symptoms and the increased severity of associated co-morbidities. As COVID-19 in pregnancy predisposes to hepatic dysfunction, health care workers should be extra vigilant in cases of pregnancy with preeclampsia or existing hepatic disorders, as the synergistic effect may lead to worsening of the patient, AFLP and multiorgan dysfunction.


We investigated the impact of earlier military combat on ability to cope with the COVID-19 pandemic in 379 male Vietnam veterans who responded to surveys in 1984, 1998, and 2020. Combat exposure was scored with a validated scale, contrasting lowest tertile (8-15) vs. medium/high (16-40). About one-fourth of veterans (26%) reported that their military experience made it easier to cope with the pandemic, while over half (59%) said it had no effect. Medium/high-combat veterans were more likely to report that their military experience made coping easier , but were less likely to report no effect of service on their coping than low-combat veterans . All 19 respondents (5%) who said military experience made coping more difficult were medium/high combat veterans. Military experience, and combat particularly, affected many of these veterans’ ability to cope with the pandemic decades after their service.


COVID-19 mortality has disproportionately affected specific occupations and industries. The Occupational Safety and Health Administration (OSHA) protects the health and safety of workers by setting and enforcing standards for working conditions. Workers may file OSHA complaints about unsafe conditions. Complaints may indicate poor workplace safety during the pandemic. We evaluated COVID-19-related complaints filed with California /OSHA between January 1, 2020 and December 14, 2020 across seven industries. To assess whether workers in occupations with high COVID-19-related mortality were also most likely to file Cal/OSHA complaints, we compared industry-specific per-capita COVID-19 confirmed deaths from the California Department of Public Health with COVID-19-related complaints. Although 7820 COVID-19-related complaints were deemed valid by Cal/OSHA, only 627 onsite inspections occurred, and 32 citations were issued. Agricultural workers had the highest per-capita COVID-19 death rates  but were least represented among workplace complaints . Health Care workers had the highest complaint rates  but the second lowest COVID-19 death rate . Industries with the highest inspection rates also had high COVID-19 mortality. Our findings suggest complaints are not proportional to COVID-19 risk. Instead, higher complaint rates may reflect worker groups with greater empowerment, resources, or capacity to advocate for better protections. This capacity to advocate for safe workplaces may account for relatively low mortality rates in potentially high-risk occupations. Future research should examine factors determining worker complaints and complaint systems to promote participation of those with the greatest need of protection. •COVID-19 mortality disproportionately affected specific occupations and industries.•Cal/OSHA workplace complaint system may indicate poor workplace safety during the pandemic.•Overall, complaints varied markedly by industry and rarely resulted in inspection or citation.•High COVID-19-related complaint rates did not align with the highest COVID-19 death rates.•Complaints filed to Cal/OSHA may better reflect employee resources than COVID-19 risk. One yeaMany factors might have contributed to the breakdown of workplace safety during the pandemic, but the role of the worker complaint response system merits special scrutiny. Previous studies indicate that examining occupational health and safety complaint and citation records within the workplace setting may serve as a unique data source in helping to identify risky workplace settings that have inadequate worker protections . Health During the pandemic, thousands of COVID-19-related worker complaints were submitted to In this manuscript, we describe the distribution of COVID-19-related 2We obtained data from Using 2017 data from the North American Industry Classification System (NAICS) , we matcWe restricted our analysis to valid Potential temporal alignment between COVID-19-related complaints and outcomes was evaluated using California death certificates. Individual death records were obtained from the California Department of Public Health. Each death certificate contained information on the cause of death, date of death, and decedent occupation, among other data. We assigned NAICS industry codes to the entries in the open text field for decedent occupation using an automated system developed by the National Institute for Occupational Safety and Health . Confirm3Of the 8736 COVID-19-related complaints made through December 14, 2020, 7820 complaints were deemed valid by The number of workers in a given industry varied widely: Health Care & Social Assistance = 2,243,345; Retail Trade = 1,842,446; Manufacturing = 1,602,690; Accommodation & Food Service = 1,381,409; Transportation & Warehousing = 920,798; Agricultural = 363,181; and Other = 9,752,178. Complaints from workers in the health care sector accounted for the largest proportion of all complaints (23%) and highest complaint rate (81 per 100K). The health care sector had the second lowest death rate (81 per 100K). Health Care complaints were also the most likely to be rated as severe (31%) followed by Agricultural worker complaints (19%) . Agricultural complaints were the most likely to be formal (15%) and exclusively health-related (96%). Death rates were highest for Agricultural workers (402 per 100K) although the sector had amongst the lowest rate of worker complaints (44 per 100K). The total number of inspections exceeded the total number of formal complaints filed in industries with highest death rates: Agricultural and Manufacturing. Conversely, formal complaints were fewer than inspections in Health Care that had the lowest death rate.Fifteen employers had the highest number of alleged COVID-19-related violations (≥30) . Three iAmong the employers that received an onsite inspection (n = 627), 32 citations were issued . Apart fAmong the 32 citations issued, fines ranged from $560 to $105,000 with some establishments being cited multiple times . Nearly As shown in The number of complaints in Health Care far exceeded all other industries during the first wave of infection, and then lowered steadily through the second wave. Retail, Manufacturing, and Accommodation & Food Service complaints were low during the first wave and increases during wave two. Similarly, ‘other’ industries showed the largest combined increase during wave two. Agricultural and Transportation & Warehousing complaints remained relatively low across all waves.4Using all valid COVID-19 occupational safety complaints filed in the state of California during the first year of the pandemic, we found that complaints were common but rarely triggered inspections or citations. The industries with the highest COVID-19 mortality rates were not the industries from which complaints were most likely to originate. Although spikes in complaint counts preceded the first two major mortality surges, occupational complaints did not provide any early warning for the third wave of the pandemic starting in late fall.due to workplace exposures or violations, our findings suggest that complaints may not adequately capture COVID-19 exposure or mortality risk. The absence of complaints from worker groups that are known to be at high-risk of COVID-19 exposure, infection, and mortality, such as agricultural and manufacturing workers, is concerning, and warrants further investigation to determine if violations have gone unreported.To our knowledge, this is the first study documenting the correspondence between industry-specific Another reason the proactive guideline dissemination, inspections, and enforcement beyond reactive protocols that respond to the workers that are most vocal rather than the most vulnerable.Alternatively, worker complaints may be a weak indicator of workplace risk of COVID-19 exposure, either because workers are not aware of the risks in their workplace or because they are hesitant or discouraged by employers to report workplace risks . Worker While complaints were not indicative of the industries with the highest COVID-19 mortality rates, industries with the highest inspection rates did align with those with the highest mortality. For example, inspections were most common in Agriculture (21.5%) and comparatively less common in other industries (6.5–9.4%). Further research is needed to quantify COVID-19 mortality that can be causally linked to ill-addressed workplace citations.if and howUnlike inspections, no discernible pattern emerged between fines and COVID-19 mortality rates across industries. For instance, Health Care had the lowest mortality rate and received the highest total fines  followed by Manufacturing  which had the second highest mortality rate. This lack of correlation between We also found that surges in worker complaint rates in spring and summer were followed by surges in COVID-19 mortality across industries, consistent with patterns previously documented by Hanage and colleagues . This paWorkplace exposure to COVID-19 is avoidable with adoption of protective equipment and other prevention measures, hence essential worker status does not imply an inevitable increase in COVID-19 mortality risk. Indeed, some essential worker groups in California experienced no increased mortality risk . In our Our descriptive study has notable considerations. Complaints filed to 5In this novel study, we leveraged publicly available data of 2020 COVID-19-related Existing data suggest that even occupations with high COVID-19 exposure risk  do not necessarily have elevated COVID-19 mortality risk. Rather, differences in COVID-19 infection and mortality risk likely exist in part because of inadequate adoption and enforcement of COVID-19-safe procedures in the workplace. This study suggests that complaints may be indicative of worker representation, power, and capacity to file a complaint within a given industry or establishment. If MD Thomas, primary investigator, conceptualized the study, coordinated all logistics related to data collection, cleaning, and coding, designed and performed all statistical analyses , and took final responsibility for drafting and revising the manuscript; EC Matthay assisted in the study design, data collection and cleaning, coding review, and editing and approval of the revised manuscript; KA Duchowny assisted in the study design, data cleaning and coding, coding review, and editing and approval of the revised manuscript; AR Riley assisted in the study design, data coding, code review, and editing and approval of the revised manuscript; H Khela assisted in data collection, data cleaning, and editing and approval of the revised manuscript; YH Chen assisted in data collection, data cleaning, and editing and approval of the revised manuscript; K Bibbins-Domingo assisted in data collection and editing and approval of the revised manuscript; MM Glymour assisted in study design, data collection, and editing and approval of the revised manuscript.1)This material is the authors' own original work, which has not been previously published elsewhere.2)The paper is not currently being considered for publication elsewhere.3)The paper reflects the authors' own research and analysis in a truthful and complete manner.4)The paper properly credits the meaningful contributions of co-authors and co-researchers.5)The results are appropriately placed in the context of prior and existing research.6)All sources used are properly disclosed.7)All authors have been personally and actively involved in substantial work leading to the paper, and will take public responsibility for its content.Hereby, I, Marilyn D. Thomas, consciously assure that for the manuscript “A descriptive analysis of 2020 California Occupational Safety and Health Administration COVID-19-related complaints”, the following is fulfilled:The violation of the Ethical Statement rules may result in severe consequences.I agree with the above statements and declare that this submission follows the policies of Solid State Ionics as outlined in the Guide for Authors and in the Ethical Statement.10.13039/100008069UCSF Chancellors Fund, awarded to Kirsten Bibbins-Domingo. Marilyn D. Thomas was supported by an unrelated award from the 10.13039/100000057National Institute of General Medical Sciences (UL1GM118985).This work was supported by the None.


Successful irido-zonulo-hyaloidotomy in combination with complete pars plana vitrectomy in malignant glaucoma may lead to better intraocular pressure (IOP) control and a promising visual outcome. We report a case of an 81-year-old woman who presented with a ten-day history of right eye redness and blurring of vision associated with throbbing pain. An ocular examination revealed right-eye visual acuity (VA) of 6/60. The cornea was oedematous with a shallow anterior chamber (AC) and a grade 0 (Shaffer’s grading) by gonioscopy. The intraocular pressure at presentation was 52 mmHg. The optic disc was pink, with a cup-disc ratio of 0.3. Complete pars plana vitrectomy with irido-zonulo-hyaloidotomy was performed in view of poorly controlled intraocular pressure despite aggressive medical therapies, laser treatment, and the Chandler procedure. Postoperatively, the IOP was maintained at mid-teens without intraocular pressure-lowering agents. The visual acuity improved to 6/9. The early decision for irido-zonulo-hyaloidotomy with complete pars plana vitrectomy leads to resolution of malignant glaucoma with a lower relapse risk. Malignant glaucoma is a form of angle-closure glaucoma, characterised by intraocular pressure (IOP) elevation with a shallow anterior chamber (AC) despite patent peripheral iridotomy (PI), in the absence of posterior segment pathology, causes the forward movement of the lens-iris diaphragm . It is aAn 81-year-old woman with underlying hypertension presented with right eye redness and blurring of vision associated with throbbing pain for ten days. She had undergone uneventful cataract surgery in the right eye ten years ago. She had no history of trauma or glaucoma.Ocular examination revealed the VA of 6/60 in the affected eye improved with pinhole to 6/36 and the left eye VA was 6/18 improved to 6/12 with pinhole. The relative afferent pupillary defect was negative. Examination of the right eye showed injected conjunctiva. The cornea was oedematous with epithelial bedewing. The AC was shallow with gonioscopic findings of Shaffer’s grading grade zero in all four quadrants, and peripheral anterior synaechiae (PAS) was absent. The IOP was 52 mmHg. The left eye examination was unremarkable with a deep anterior chamber, Shaffer’s grading grade four (open) in all four quadrants with an IOP of 12 mmHg. Both eyes' optic discs were pink, with a cup-disc ratio of 0.3. Both the retinae and the maculae were normal.She was started on an oral carbonic anhydrase inhibitor, topical aqueous suppressants, and topical prostaglandin analogue. A laser PI was performed in the 2 o’clock area. Post-procedure, the PI was patent; however, the AC remained shallow with an IOP ranging from 32 to 40 mmHg. She was then administered with topical cycloplegic, oral glycerol and was subjected to Nd: YAG laser posterior capsulotomy and anterior hyaloidotomy. Unfortunately, the IOP remained high post-procedure.The Chandler procedure was performed subsequently. The IOP was lower than pre-procedure (24 mmHg) but the cornea was still oedematous as shown in Figure Ultrasound biomicroscopy was done after the Chandler procedure, showing a slightly widened angle but persistent bowing of the iris with reduced iris-lens distance and ciliary sulcus collection, as can be seen in Figure Two days post Chandler procedure, the IOP rebounded to 30 mmHg, the AC was shallow, and only transiently responded to intravenous mannitol infusion. In view of the refractory response to prior therapies, complete PPV with irido-zonulo-hyaloidotomy was performed on day 14 of diagnosis. A clear corneal incision was made, and a viscoelastic agent was used to reform the AC. Three side ports of 23-gauge were inserted, and a core vitrectomy was done. Iridectomies at the 6 and 10 o’clock positions were created using a vitreous cutter through the anterior approach. Hyaloidotomy followed by zonulectomy and posterior capsulotomy was performed using a vitreous cutter through the pars plana approach under direct visualization through the patent iridectomies. A complete vitrectomy with 360-degree shaving of the vitreous base was performed and deepening of AC was observed at the end of the surgery.Post-operatively, the cornea was clear, the AC was deep, and surgical iridectomies at 6 o’clock and 10 o’clock were patent, as shown in Figure Malignant glaucoma, also known as aqueous misdirection, is a rare condition. Its incidence ranges from 0.6% to 4% in eyes treated surgically for angle-closure glaucoma, with a higher prevalence after penetrating glaucoma surgeries .One of the theories behind the pathogenesis of malignant glaucoma is that the laxity of lens zonules coupled with vitreous pressure leads to forward lens movement . The higOur patient presented with a VA of 6/60, a closed-angle, and an IOP of 52 mmHg. A laser PI was performed to exclude a possible pupillary block angle closure mechanism. Pseudophakic malignant glaucoma was diagnosed when the AC remained shallow despite a patent iridotomy. Topical cycloplegic, oral, and topical IOP-lowering agents, as well as an intravenous hyperosmotic agent, were initiated, but the IOP remained high. Subsequent Nd: YAG laser posterior capsulotomy and anterior hyaloidotomy procedures also failed to reduce the IOP, although a transient deepening of the central AC depth was observed. In malignant glaucoma, Nd: YAG laser posterior capsulotomy in conjunction with hyaloidotomy aims to disrupt the posterior capsule and anterior hyaloid membrane to allow communication between the drainage angle of the AC and vitreous cavity. However, the relapse rate is as high as 75% . AnotherThe vast variability of surgical options for malignant glaucoma has been reported with variable success and a relapse rate. Options include lens extraction for the phakic patient, conventional vitrectomy without tunnelling, anterior vitrectomy with tunnelling, and vitrectomy with tunnelling. Conventional vitrectomy without tunnel construction theoretically does not reverse the pathology as the absence of communication between the AC and posterior vitreous cavity will lead to future build-up of posterior vitreous pressure and a relapse rate of 75% was described, although initially success might be observed .Irido-zonulo-hyaloido-vitrectomy can be performed via the anterior or pars plana approach . For theOn day 14, after the diagnosis of malignant glaucoma, a 23-gauge complete PPV with irido-zonulo-hyaloidotomy was performed on our patient. Similar procedures were described and the majority of patients observed no or very low recurrence throughout the follow-ups . During The prognosis of complete PPV with irido-zonulo-hyaloidotomy is promising and favours a low relapse rate. In this 10-year retrospective study, a 90.3% anatomical success rate with deepening of AC after PPV and irido-zonulo-hyaloidectomy was described . Case reThe stepladder approach for the treatment of malignant glaucoma is commonly practiced, starting with medical therapies, followed by laser therapies, and finally, vitrectomy. However, a longer interval of more than a month from diagnosis to the timing of vitrectomy has been shown to significantly reduce the post-operative success rate and visual outcome . In our Malignant glaucoma is a relatively rare condition. Thus, the variability of treatment modalities and approaches makes it difficult to decide on the exact timing for complete PPV with irido-zonulo-hyaloidotomy. We believe that this option will add value to the small number of reported literature on the successful management of malignant glaucoma with early complete vitrectomy alongside irido-zonulo-hyaloidotomy during an early course of treatment with a promising visual outcome.


Spermidine showed higher concentration in CVS-AKI  and had a strong association with the outcome . uKIM-1 and particularly spermidine predict in-hospital AKI associated with CVS in preoperative samples. These findings may aid in preventing postoperative AKI and improve prognosis of CVS.Acute Kidney Injury (AKI) affects up to 30% of the patients who undergo cardiac surgery (CVS) and is related to higher mortality. We aim to investigate molecular features associated with in-hospital AKI development and determine the predictive value of these features when analyzed preoperatively. This is a case-control study. From an initial cohort of 110 recruited subjects, a total of 60 patients undergoing cardiac surgery were included: 20 (33%) developed in-hospital AKI (CVS-AKI) and 40 did not . Pre- and post-surgery samples were collected and a prospective study was carried out. A total of 312 serum samples and 258 urine samples were analyzed by nuclear magnetic resonance, mass spectrometry and ELISA. Six features predicted AKI development in pre-surgery samples: urinary kidney functional loss marker kidney injury molecule-1 (uKIM-1), 2-hydroxybutyric acid, 2-hydroxyphenylacetic acid, hippuric acid, phosphoethanolamine and spermidine. Two of them stood out as powerful predictors. Pre-surgery uKIM-1 levels were increased in CVS-AKI vs. CVS-C (AUC = 0.721,  Acute Kidney Injury (AKI) is a serious postoperative complication affecting up to 30% of cardiac surgery patients . It is aIn recent years, there has been a growing interest in the early prevention of post-surgery AKI, with particular emphasis on finding novel markers that contribute to early detection. Research has mainly been focused on kidney tubular damage indicators such as urinary neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury molecule-1 (uKIM-1), in addition to markers of kidney function such as serum cystatin C (sCysC). These markers have shown promising results for an early post-surgery detection, especially when combined . AdditioAlthough useful, postoperative prediction is still too late. The gold standard for AKI diagnosis, serum creatinine (sCr), is not a predictor but rather an indicator of established renal damage. Additionally, AKI develops shortly after surgery , which gives physicians a very narrow window in which to act. As a result, more research is needed to identify molecular predictors that can be used to evaluate risk of post-surgery AKI when analyzed in pre-surgery samples.The usefulness of metabolites as potential predictors of in-hospital AKI has shown promising results in plasma samples collected at 24 h post-surgery . Our groIn the present study, we aimed to investigate molecular features that can predict in-hospital AKI after CVS, even before surgery. For such purpose, known markers of tubular damage and kidney dysfunction, together with a novel metabolite panel here identified in association with post-surgery AKI, were investigated in pre-surgery urine to predict the outcome. The post-surgery variation of those molecules was also evaluated over time.A total of 110 subjects with cardiovascular disease who were admitted for cardiac surgery at University Hospital Marqués de Valdecilla in Santander were considered for this observational study. Inclusion criteria were patients of both sex and ages between 18 and 85 years who underwent extracorporeal cardiac surgery of any etiology. All patients were subjected to previous catheterization. Exclusion criteria were patients with active immunological disease under treatment, visceral neoplastic disease within the last 5 years patients on chronic dialysis , patients with solid organ transplant and patients with an expected survival of less than one year. Patients fulfilling the inclusion and exclusion criteria who consented to participate in the study were prospectively studied. All patients were informed that their participation in the study would not jeopardize the treatment in any way or put them at risk and signed the informed consent form. The study was conducted according to the recommendations of the Declaration of Helsinki and was approved by local ethics committee (PIC181-19).g for 10 min. Similarly, urine samples were centrifuged at 1300× g for 5 min to remove cell debris. Processed samples were frozen and stored at −80 °C until analysis.Analytical and clinical data were collected from clinical records and electronic databases of the hospital and primary care, including patient characteristics and comorbidities. Urine and serum samples were collected from patients at different time points during admission: pre-surgery (P), followed by 6, 24, 48 and 72 h post-surgery and at discharge (D), resulting in a total of 312 serum samples and 258 urine samples . Serum was obtained from blood samples by centrifugation at 3000× n = 40), or in the AKI group (CVS-AKI) (n = 20) if the increment in sCr was ≥0.3 mg/dL. In all cases, CVS-AKI patients had sCr levels corresponding to stage 1 of the AKI KDIGO classification.The primary outcome of this study was in-hospital post-surgical AKI defined by the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines as an increase in serum Creatinine (sCr) concentration of ≥0.3 mg/dL within 48 h after surgery . Creatin1H Nuclear Magnetic Resonance (NMR) as described before ·[IGFBP7] reduced the risk of AKI related to cardiac surgery from 71.7% to 55.1% (lgorithm .The present study fulfills the requirements of an omics study in terms of group size and technical workflow; however, one limitation could be the relatively low number of patients from a clinical perspective. To overcome this, two phases were used, screening and confirmation by absolute quantitation. Further studies are warranted in larger cohorts before considering the use of these new urinary biomarkers in clinical practice.The urinary metabolome reflects the effects of CVS and predicts AKI outcome. In pre-surgery urine samples, specific metabolites and tubular damage proteins may anticipate AKI development. Particularly, urinary spermidine significantly correlates with and predicts AKI after cardiac surgery in preoperative stage, thus allowing very early prediction of the outcome. Spermidine is a polyamine with known antioxidant properties and the most significant alteration found in pre-surgery urine of patients developing post-surgical AKI. This study gives evidence of a potential imbalance in the oxidative status of these patients, encouraging novel research in pre-operative antioxidant treatments as new therapeutic avenues for AKI prevention. This knowledge may be used to bring substantial improvements to patient management and the prognosis of patients with cardiovascular disease.


Purpose: Asymmetric cerebral representation of autonomic function could help to stratify cardiac complications in people with epilepsy, as some seizures are associated with potentially deleterious arrhythmias including bradycardia and atrioventricular (AV) conduction block. We investigated seizure-related changes in AV conduction and ascertained whether these alterations depend on the hemisphere in mesial temporal lobe epilepsy (mTLE).Methods: EEG and ECG data of people with pharmacoresistant mTLE undergoing pre-surgical video-EEG telemetry with seizures independently arising from both hippocampi, as determined by intracranial depths electrodes were reviewed. RR and PR intervals were measured using one-lead ECG. Statistics were done with paired student's t-tests and linear regression analysis. Data are given as mean ± SD.Results: Fifty-six seizures of 14 patients  were included (2 seizures per hemisphere and patient). There were no differences of absolute PR intervals and HR before and during unilateral ictal activity between left- and right-sided hippocampal seizures. Peri-ictal modulation of AV conduction, however, appeared greater with left-sided seizures, as the slope of the PR/HR correlations was significantly steeper with seizures originating in the left hippocampus. PR lengthening >200 ms or full block did not occur in any seizure.Conclusions: Our data show that on average, PR intervals shortens with mesial temporal lobe seizures with more prominent effects in seizures with left-sided onset, supporting the notion of lateralized cerebral control of cardiac function. The clinical relevance of this subtle finding is unclear but may indicate a lateralized susceptibility to seizure-related AV node dysfunction in mTLE. Given the intricate overlap of regions involved in the central autonomic nervous system (CAN) and networks that generate or maintain epileptic activity, seizures are frequently accompanied by alterations of cardiac properties and heart activity , 2. ThesPrevious studies have predominantly reported increases and decreases of sinus node activity with subsequent changes in heart rate (HR) as well as lengthening or shortening of cardiac repolarization and QT intervals in association with seizures , 5. WhilIn view of these observations, we hypothesized that seizure-related modulation of AV conduction depends on the side of ictal activity. Such an asymmetric representation of AV node control may serve as lateralizing hint during assessment of seizure-onset zone, but may also help to identify people at an elevated risk for ictal AV block and asystole. In the present study, we investigated seizure-related changes in AV conduction in patients with medically refractory bilateral mTLE who underwent intracranial video-EEG telemetry for pre-surgical diagnostics.This study is a retrospective audit of EEG and ECG data recorded during standard clinical procedures and was approved as such by the local medical ethics committee . Patient data of a 12-year period (2000–2011) collected at our tertiary epilepsy center  were reviewed. All patients suffered from pharmacoresistant mTLE and underwent pre-surgical video-EEG telemetry, with seizures arising from both hippocampi, as assessed by intracranial EEG recordings with depth electrodes. Patients with known cardiac diseases were excluded.A total of 205 patients with bilateral hippocampal electrodes was eligible. Of these, 32 patients displayed hippocampal seizures with onsets from both hemispheres and 14 patients showed at least two seizures from each hippocampus and had EEG- and ECG-recordings of sufficient quality  to be included in the final analysis , Table 1preictal: 1 min before EEG seizure-onset, early ictal: within the first seconds of seizure activity and late ictal: at the end of the unilateral course of the seizure, before spread to the contralateral side or seizure termination). The respective values of RR and PR interval were calculated as a mean of 2–3 successive ECG intervals. After calculating HR values from RR intervals, statistical analyses were performed to compare preictal and ictal data of seizures originating from the left and right hippocampus using paired student's t-tests. Furthermore, a bivariate linear regression of HR and PR intervals for right and left-sided seizures was performed. Resulting correlations were considered as a measure of peri-ictal modulation of AV conduction. Analyses and graphs were generated using GraphPad Prism 4 . The data underlying the study are available from the corresponding author on reasonable request.RR and PR intervals were manually determined at different timepoints (Recordings of 56 seizures (2 seizures per hemisphere and patient) in 14 patients with refractory mTLE  were analyzed. Hippocampal sclerosis was found in 12 patients , 2 patients had no apparent lesions .t = −7.34, df = 27, p < 0.001) and right-sided  hippocampal seizures.Changes of HR were observed during all seizures . In 64.3At the level of individual patients, PR intervals during seizures were consistently shortened  in right-hippocampal seizures of 4 patients and left-hippocampal seizures of 3 patients. Consistent lengthening of PR intervals was found in right-hippocampal seizures of 5 patients and left-hippocampal seizures of 4 patients. Consistent shortening of PR intervals of all seizures of both sides was not observed in any patients, whereas consistent lengthening of PR intervals in all 4 seizures was seen in 1 patient.t = −0.13, df = 54, p = 0.894; HR: left 84 ± 15 bpm, right 83 ± 13 bpm, t = 0.07, df = 54, p = 0.947) as well as during early  or late  unilateral seizure activity , there were no significant differences between left- and right-sided hippocampal seizures regarding absolute PR intervals and HR before (PR intervals: left 146 ± 20 ms, right 146 ± 24 ms, activity . Peri-icIn this retrospective clinical study, peri-ictal PR intervals and HR were assessed in patients with pharmacoresistant bilateral mTLE. Importantly, these patients were bilaterally implanted and at least two seizures per side were registered, allowing a comparison between left-and right-hippocampal seizure-related changes of PR intervals, and minimizing the effects of inter- and intra-individual variability. Moreover, the simultaneous iEEG-ECG recording provides optimal ECG resolution regarding time and localization of seizure onsets. While this investigation of seizure and hemisphere related changes of PR-Intervals follows an original approach, it does not come without limitations. Firstly, several other regions involved in the CAN such as the insular cortex, hypothalamus, thalamus and cingulate gyrus were not covered by intracranial EEG electrodes, so that spreading of ictal activity could not be recorded and excluded . SecondlIn-vivo experiments in rodents and neuroimaging studies in humans provide structural correlates that link the left mesial temporal lobe to the control of cardiac properties. At the brain stem level, the nucleus ambiguus and raphe nuclei are involved in the modulation of AV conduction (As expected, all seizures were associated with alterations of HR, mainly chronotropic changes with tachycardia, or mixed patterns, supporting the notion of the hippocampus as an important element within the CAN. Overall, the absolute changes of HR and PR intervals were similar in seizures originating from the left and right hippocampus. Previous studies in apparently healthy subjects revealed an inverse correlation between PR intervals and HR, i.e., PR intervals shorten with increasing HR . Intrigunduction –12 whichnduction , which mIn conclusion, left-hippocampal seizures appear to be linked to greater changes in cardiac repolarization and AV conduction . These aThe data underlying the study are available from the corresponding author on reasonable request.The studies involving human participants were reviewed and approved by Medinizische Fakultaet Bonn. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.LMB and AJ have collected and analyzed data. MP has analyzed the data and drafted the manuscript. RS has designed and supervised the study. All authors have reviewed the draft.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.


N = 10) or enzalutamide (N = 21). Additional potential prognostic factors were extracted from clinical records and outcome was evaluated as overall survival (OS) and progression-free survival (PFS). cfmiRNAs were measured in plasma samples using quantitative real-time RT-PCR. Linear correlation among clinical factors and cfmiRNAs was assessed using the Spearman's rank correlation coefficient. The association with survival was studied using univariate and multivariate Cox proportional hazards models. Continuous variables were dichotomized with the cut points corresponding to the most significant relation with the outcome. Univariate analysis indicated that plasma levels of miR-21-5p, miR-141-3p and miR-223-3p, time to development of castration-resistance (tCRPC), and blood hemoglobin (Hb) levels strongly correlated with both PFS and OS. Multivariate analysis revealed that low plasma levels of miR-21, shorter tCRPC, and lower Hb values were independent factors predicting reduced PFS and OS. These findings suggest that the integrated analysis of cfmiRNAs, tCRPC, and Hb may provide a promising, non-invasive tool for the prognostic stratification of mCRPC patients treated with ARTA.Androgen Receptor-Targeted Agents (ARTA) have dramatically changed the therapeutic landscape of metastatic Castration-Resistant Prostate Cancer (mCRPC), but 20–40% of these patients progress early after start of ARTA treatment. The present study investigated the potential utility of plasma cell-free microRNAs (cfmiRNAs) as prognostic markers by analyzing a prospective cohort of 31 mCRCP patients treated with abiraterone ( TherefoSeveral studies have highlighted the role of microRNAs (miRNAs) in the pathogenesis of PCa ; among tThis exploratory prospective observational study was performed on a cohort of 31 mCRPC patients treated with abiraterone (10 patients) or enzalutamide (21 patients); ARTA was administered either as first-line therapy (26 patients) or after treatment with docetaxel (five patients). All consecutive patients who were candidates to receive ARTA and were eligible according to the study criteria were enrolled between September 2016 and October 2017 at the Veneto Institute of Oncology. The study was conducted according to the Declaration of Helsinki and approved by the local Ethics Committee; all patients signed an informed consent form prior to their inclusion.Patients were selected according to the following inclusion criteria: (i) histological diagnosis of prostate cancer; (ii) metastatic disease at any site; (iii) mCRPC according to the Prostate Cancer Working Group 3 (PCWG3) definition ; (iv) atAt the start of ARTA treatment blood samples were collected for the miRNA analyses. All the patients were then treated as per clinical practice, according to the drugs' current label authorization and international guidelines for the treatment of mCRPC. ARTA therapy was administered until progression and clinical need to start another therapy, or when the patient experienced unacceptable toxicity or decided to withdraw from treatment. Disease progression was defined according to the PCWG3 criteria. No change in patients' management was introduced based on the results of the biomarker analysis. Comorbidities and contraindications to steroids guided the choice between abiraterone and enzalutamide. Adverse events were documented and treated in line with the best clinical practice.18F-choline. Plasma samples for miRNA analysis were obtained within 1 day before the start of ARTA. After disease progression, all the patients were followed up for survival, and received further lines of therapy or only best supportive care (BSC) according to their performance status and fitness to treatment, as indicated by the national and international guidelines for mCRPC.Clinical examination and assessment of hematological and biochemical parameters were performed on a monthly basis during treatment. Disease restaging was performed every 3 to 4 months with serum PSA quantification and contrast-enhanced CT scan of the thorax, abdomen and pelvis plus bone scan, or with a total body CT/PET scan with −ΔCt= 2CtmiRx−CtmiR1228)− was calculated from the start of treatment with ARTA to the date of radiological/clinical disease progression, or death. Patients who did not develop an event during the study period were censored at the date of the last observation. The cfmiRNAs were dichotomized with cut points corresponding to the most significant relation with the outcome, estimated from maximally selected log-rank statistic for values between the 10 and 90% quantiles using the upper bound of the d Lausen .p-values were adjusted by applying the Benjamini-Hochberg correction  for the median survival was calculated according to Brookmeyer and Crowley. Hazard ratios (HR) and 95% CI for each group were estimated using univariate Cox proportional hazards models with Efron's method of tie handling. No deviation from the proportional hazards assumption was found by the test statistic of Grambsch and Therneau . To asserrection .p-value <0.05 was considered statistically significant. Statistical analyses were performed using RStudio .The independent role of each covariate in predicting survival was verified in a multivariable model considering all characteristics significantly associated with the outcome in the univariate analyses. All statistical tests were two-sided and a 223, 1 with a second ARTA (abiraterone) and 1 with oral cyclophosphamide.Thirty-one mCRPC patients were enrolled in the present study, 10 of whom were treated with abiraterone acetate and 21 with enzalutamide . The medA series of statistical analyses was performed to interrogate the possible prognostic value of plasma levels of miR-21, miR-141, and miR-223  measured for mCRPC patients at the start of ARTA treatment .Ct−Δ ≤2.69) and miR-223 (2Ct−Δ ≤4.35) and high plasma miR-141 values (2Ct−Δ>0.20) were significantly associated with shorter PFS in all patients. In addition, shorter tCRPC (≤15.2 months) and low blood hemoglobin (≤127 g/L) were also significantly correlated with reduced PFS. N/L, PSA values, and the Gleason score at the start of ARTA treatment were not related to clinical outcome in our cohort.Univariate analysis indicated a significant association between plasma levels of miR-21, miR-141, miR-223 and PFS . Low plaFigure 3A).The median PFS was 2.1 months for patients with shorter tCRPC and low miR-21 values (95%CI: 2.1-NE), 11.7 months for patients with one risk factor  (95%CI: 8.7-NE) and 29.3 months for patients with longer tCRPC and high miR-21 values (95%CI: 20.1_NE) . The median OS was 36.0 months (95%CI: 12.3-NE) for patients with one risk factor, 18.7 months (95%CI: 8.4-NE) for patients with two risk factors, and 4.6 months (95%CI: 3.4-NE) for patients with shorter tCRPC, low Hb concentration and low plasma miR-21 values .r = 0.71; p < 0.001)  .The present study explored the relationship between circulating miR-21, miR-141 and miR-223 and clinical outcome of patients with mCRPC treated with ARTA. Among the miRNAs tested, high expression of miR-21 was the best predictor of favorable PFS and OS after treatment with abiraterone or enzalutamide in our cohort of patients.To date, few studies have analyzed circulating miR-21 in mCRPC. In an analysis of plasma/serum samples from 97 mCRPC patients, Lin et al.  found thThe relationship between miR-21 and androgen-responsive signaling pathways was investigated by Mishra et al. who proposed a positive feedback loop mechanism in prostate cancer cells . AndrogeOur finding of higher plasma levels of miR-141 in patients with shorter PFS and OS in the univariate analysis is in line with the results of previous studies showing increased plasma/serum levels of miR-141 in patients with mCRPC compared to healthy/benign prostatic hyperplasia (BPH) subjects , 27 or pWe previously reported downregulation of cfmiR-223 in plasma from patients with localized PC compared to BPH controls , which iMultivariable analysis showed that the plasma level of miR-21 (but not miR-223 or miR-141) was associated with outcome (OS and PFS), independently of other clinical variables. In our evaluation of different clinical parameters usually included in prognostic/predictive models of metastatic prostate cancer  time to The results presented here are promising, but must be considered preliminary, due to the limited number of patients examined, which reflects the exploratory nature of the study that implies the lack of any previous information required to carry out a power analysis and determine the appropriate sample size. In addition, our cohort included five patients who were previously treated with docetaxel. Although it is possible that docetaxel may alter tumor biology and influence miRNA expression, in the context of our study, docetaxel-treated patients did not show a significant difference in the levels of the cfmiRNA examined compared to chemonaïve patients; furthermore chemotherapy is currently administered at very early stages of disease and is not considered cross-resistant with ARTA.Taken together, our findings suggest that the integration of the analysis of cfmiR-21 with the clinical parameters tCRPC and Hb levels may provide useful information for the prognostic stratification of mCRCP patients receiving ARTA treatment, and lay the ground for a large prospective validation study.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Ethics Committee of the Veneto Institute of Oncology. The patients/participants provided their written informed consent to participate in this study.ES, VC, UB, and MM conceived and designed the experiments. ES performed the experiments. MM, UB, and FP followed the patients, including planning clinical visits and blood sample collection, follow-up and clinical data collection. PDB performed statistical analysis. ES, IC, PDB, VC, MM, and VZ analyzed the results. ES, MM, UB, and VC wrote and revised the paper. All authors reviewed the manuscript.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.


Carbidopa is a peripheral enzyme inhibitor. Carbidopa premedication increases the radiotracer uptake on static images. None of the evidence-based data available to date recommends carbidopa premedication. Our study therefore determined the impact of carbidopa premedication on static, radiomics and dynamic parameters for 18F-FDOPA PET brain tumor imaging. We show that carbidopa premedication leads to higher SUV and TTP dynamic parameters and impacts SUV-dependent radiomics by the same magnitude in healthy brains and tumors. The carbidopa effect is therefore compensated for by correcting for the tumor-to-healthy-brain ratio, a significant advantage for harmonizing data for multicentric studies. Results were obtained from simulations of time-activity curves using compartmental modeling.18F-FDOPA PET in brain tumors. Methods: The study included 54 patients, 18 of whom received carbidopa, who underwent 18F-FDOPA PET for newly diagnosed gliomas. SUV-derived, 105 radiomics features and TTP dynamic parameters were extracted from volumes of interest in healthy brains and tumors. Simulation of the effects of carbidopa on time-activity curves were generated. Results: All static and TTP dynamic parameters were significantly higher in healthy brain regions of premedicated patients . Furthermore, carbidopa impacted 81% of radiomics features, of which 92% correlated with SUVmean (absolute correlation coefficient ≥ 0.4). In tumors, premedication with carbidopa was an independent predictor of SUVmean  and TTP . All parameters were no longer significantly modified by carbidopa premedication when using ratios to healthy brain. Simulated data confirmed that carbidopa leads to higher tumor TTP values, corrected by the ratios. Conclusion: In 18F-FDOPA PET, carbidopa induces similarly higher SUV and TTP dynamic parameters and similarly impacts SUV-dependent radiomics in healthy brain and tumor regions, which is compensated for by correcting for the tumor-to-healthy-brain ratio. This is a significant advantage for multicentric study harmonization.Purpose: This study aimed to determine the impact of carbidopa premedication on static, dynamic and radiomics parameters of  Its use as a premedication therefore results in higher plasma concentrations of -L-DOPA) . As the ters, K1 , are notters, K1 . The proters, K1 .18F-FDOPA PET for brain tumor imaging, solely based on the fact that most of the published studies do not use it. There is currently no evidence-based data to determine whether carbidopa should be used in the clinical setting of brain tumor imaging, particularly in the current era of routine semi-quantitative analyses [In contrast to movement disorder PET imaging , internaanalyses .18F-FDOPA PET imaging.The objective of this study is therefore to determine the impact of carbidopa premedication on static, radiomics and dynamic parameters in brain tumor 18F-FDOPA PET at the CHRU of Nancy between January 2013 and October 2017. Carbidopa premedication data were available for all patients included in the study and depended on the routine examination protocol performed; patients analyzed from March 2016 to October 2017 were premedicated with carbidopa, and patients analyzed from January 2013 to February 2016 were not premedicated prior to PET imaging. The data evaluation process was approved by the local ethics committee (Comité d’Éthique du CHRU de Nancy) on 26 August 2020. The trial was registered at ClinicalTrials.gov (NCT04469244). This research complied with the principles of the Declaration of Helsinki. Informed consent was obtained from all individuals included in the study. We retrospectively selected newly diagnosed gliomas, which were all classified or re-classified according to the WHO 2016 classification . All new18F-FDOPA PET-computed tomography (CT) scans were performed on a Biograph hybrid system involving a six-detector CT for attenuation correction . All patients were instructed to fast for at least 4 h, and patients analyzed from March 2016 to October 2017 received 100 mg of carbidopa 1 h prior to their examination. A CT scan was first recorded for each patient, immediately followed by a 30 min 3D list mode PET recording, initiated during the bolus injection of 3 MBq of 18F-FDOPA per kilogram of body weight. Static PET images were reconstructed from the list mode data acquired 10 to 30 min post-injection, while dynamic PET images consisted of 30 frames of one minute each [3). All images were corrected for attenuation using CT, dead time, random and scattered coincidences during the reconstruction process.ute each . Static The LIFEx software (lifexsoft.org) was used to define volumes of interest (VOIs) for tumors and contralateral healthy brains . To measure healthy brain uptake, patient-specific crescent-shaped contours for the healthy brain VOI were drawn on three consecutive image slices and encompassed both white and grey matter on the semi-oval center of the unaffected hemisphere, as previously recommended .mean [In tumors, VOIs were segmented semi-automatically using a threshold of 1.6 healthy brain SUVmean . For tummean, SUVmax and SUVpeak parameters were extracted from the previously described VOIs for healthy brains and tumors. SUVpeak was defined as the highest mean uptake in a 1 cm3 sphere, centered on each voxel of the VOI.For static images, the SUVFor the radiomics analysis, 105 features were extracted from the same brain and tumor VOIs. These included morphological, local intensity, intensity-based statistical, intensity histogram and textural parameters. In accordance with the guidelines and benchmark values of the image standard biomarker initiative , 103 parmean of healthy brain VOI, to compute the Tumor-to-normal-Brain Ratio (TBR) parameters. To potentially correct for any carbidopa premedication effects in our population, all static and radiomics parameters, except morphological features, in tumors were re-extracted after normalizing each static image for the SUVmean values for each frame were respectively computed in the brain VOI and in the VOI corresponding to the tumor SUVpeak on the static image to extract the brain and tumor time activity curves (TACs). TACs were fitted to overcome noise effects [To take into account any potential patient movement during the dynamic acquisition, each dynamic frame was first registered to the associated CT image . The SUV effects . As prev effects . As for parameters extracted from static images, a normalized version of the parameters was extracted from a TAC, representing the evolution of the ratio between tumor and brain fitted TACs to potentially correct for any carbidopa premedication effect .18F-FDOPA PET, both without and with premedication, simulations were performed. Simulated TACs of the carbidopa premedication status were computed based on the TACs of 15 patients without premedication, for which raw data were available  years, 5 women). Five patients were classified as IDH mutant astrocytomas (3 anaplastic), 4 as IDH wildtype astrocytomas (2 anaplastic), 2 as IDH mutant and 1p/19q co-deleted oligodendrogliomas (1 anaplastic) and 4 as IDH wildtype glioblastomas.To indirectly confirm our hypotheses and compare the effects of carbidopa premedication on dynamic analysis in the same brain tumor of patients who underwent 18F-FDOPA PET imaging without any premedication were extracted from VOIs placed into the internal carotid by an experienced physician (A.V.), using initial dynamic frames to identify early vascular phases [18F-FDOPA input functions were computed after metabolite correction, according to the methodology described by Wardak et al. [18F-labeled metabolites determined by Melega et al. [18F-FDOPA PET imaging in gliomas [b fixed at 5% [4 set to 0).This was performed using a compartmental model analysis. Dynamic PET images were reconstructed using 26 frames of 8 × 15 s, 2 × 30 s, 2 × 60 s, and 5 × 300 s . Total br phases . The spir phases . These br phases . Plasma k et al.  and by ua et al.  were use gliomas , as it s gliomas  or to a 18F-FDOPA PET imaging without any premedication. Compartmental models were fitted to these TACs using the previously described input function to obtain the four rate constants  as well as the blood volume fraction (Vb)  were assumed to be unchanged compared to those calculated for the patients without any premedication, given that the 18F-FDOPA K1 [18F-FDOPA input function corresponding to the carbidopa premedication  B. For thFDOPA K1  are not on C100, C. TTP and slope were extracted from healthy brain and tumor TACs for the patients as well as for the simulated TACs. A normalized version of these parameters was also extracted.mean were assessed using the Spearman correlation coefficient. Correction of multiples tests was performed with the Benjamini-Hochberg correction, and p < 0.05 was considered significant. For tumor VOIs, linear regression analyses were performed to predict the parameters using carbidopa status and histo-molecular diagnosis as covariates, as histo-molecular diagnosis is known to influence static and dynamic parameters  [Categorical variables are expressed as percentages and continuous variables as medians and interquartile ranges. Intergroup comparisons were performed with the Chi-squared test for categorical variables and the Mann-Whitney test for continuous variables. Mann-Whitney tests were performed to compare carbidopa-naïve and premedicated patients in healthy brain VOIs. Correlations between radiomics features and SUVastomas) . The sigFifty-four patients with a median age of 44  years, comprised of 19 (35%) women and 18 (33%) patients who were premedicated with 100 mg of carbidopa, were included in the study. Dynamic acquisitions were available for 41 of these patients  years, 14 (34%) women, 11 (27%) patients premedicated with carbidopa). Detailed patient characteristics are provided in mean = +53%, ΔTTP = +48% and Δslope = +88%  (mean (absolute correlation coefficient ≥ 0.4)  . Furthert ≥ 0.4) .mean  and TTP . Histo-molecular diagnosis was predictive of TTP (p = 0.010) and slope (p < 0.001), and a trend was observed for the SUVmean (p = 0.07). Interestingly, all static, dynamic and radiomics parameters were no longer significantly modified by carbidopa premedication when using tumor-to-healthy-brain image ratios or time-activity curve ratios  parametric images are shown in 18F-FDOPA, without modifying the rate constants. Results of these simulations are provided in To confirm our hypotheses about the impact of carbidopa premedication on TTP and to better understand its effect on slope, simulated TACs were performed with carbidopa premedication, on the assumption that carbidopa premedication induces an increase of radiotracer availability through the input function, i.e., the plasma concentration of Examples of simulated carbidopa premedication leading to higher TTP are displayed in 18F-FDOPA PET imaging of brain tumors is associated with higher SUV, SUV-related radiomics and TTP dynamic parameters, of the same order of magnitude as in healthy brains. For neuro-oncological PET indications, the effect of the costly and time-consuming carbidopa premedication is thus limited when using TBR images and TAC ratios, which are efficient tools for multicentric study harmonization. This study shows that carbidopa premedication before mean in healthy brain tissue as well as and in brain tumors  . Beyond the impact of a threshold effect, we presume that these parameters are less correlated with SUVmean because they mainly depend on the bin spread effect, for which the impact on radiomics parameters is less directly correlated with SUVmean than the bin shift effect. The bin spread effect on the involved matrices is illustrated in mean values  . This unc et al. . As we an values . 18F-FDOPA without modifying the rate constants (In our study, carbidopa also induced changes in the dynamic analysis parameters, with higher TTP in healthy brains and in tumors. In tumors, this effect was independent of the histo-molecular diagnosis, which is known to affect the TTP of the dynamic analysis ,26,27,28onstants . These sInterestingly, when extracted from TBR images and TAC ratios, all static, dynamic and radiomics parameters were no longer significantly modified by the carbidopa premedication . This is18F-FDOPA PET guidelines for imaging of Parkinsonian syndromes [18F-FDOPA, this recommendation is completely different in brain tumors, given that, unlike striatum, brain tumor cells do not metabolize 18F-FDOPA [18F-FDOPA PET imaging do not include mandatory carbidopa premedication prior to brain tumor scans. This recommendation is however not founded on any evidence-based data from the literature, and our study therefore provides additional information that supports the current recommendation. It should be noted that premedication with Carbidopa before PET imaging increases 18F-FDOPA bioavailability, leading to higher uptake and thus improved image quality. This was a particularly significant issue in older low-sensitivity PET scanners and is therefore a problem encountered in studies that use retrospective data. Today’s state-of-the-art high-resolution scanners have eliminated this issue. This means that the only remaining rationale for using carbidopa premedication would be to reduce patients’ radiation exposure to an absolute minimum, which is not a key concern in glioma patients, for whom radiotherapy is one of the treatments of choice.Glioma is a rare pathology, which relies on multicentric studies to gather high enough patient numbers. Such multicentric studies can only be conducted after harmonizing data obtained from the participating centers. Although the use of carbidopa premedication is very heterogenous between individual centers, the harmonization process may only entail using TBR images and TAC ratios, which have been shown to be insensitive to carbidopa premedication in this study, without modifying the protocols used by participating centers. While the yndromes  recommen8F-FDOPA . This is18F-FDOPA and premedication with carbidopa are not ubiquitously available in all parts of the world, with other PET tracers also yielding excellent performances in brain tumor detection [Our retrospective study was performed on a heterogeneous population of patients, therefore limiting the ability to directly compare the effects of carbidopa premedication in tumors. Our hypotheses on the effects of carbidopa premedication were nevertheless confirmed by using simulated data. In our department, the patient carbidopa status was predicated by the recruitment period; this may have introduced an inclusion bias. However, no significant differences were observed between the characteristics of the two groups of patients . Finallyetection .18F-FDOPA PET imaging of brain tumors. As carbidopa premedication leads to higher SUV, SUV-dependent radiomics and TTP dynamic parameters in the same order of magnitude in healthy brains as in tumor, these effects are compensated for after taking into account the tumor-to-healthy-brain ratios in static images or in time-activity curves, which is an important point for multicentric study harmonization.Our current study documents the effects of carbidopa premedication on the