Quality of life in Dutch patients with primary biliary cholangitis:Discrepancies between patients’ perspectives and objective disease parameters

Aim: This study aims to assess the health-related quality of life (HRQoL) in a Dutch population of patients with primary biliary cholangitis (PBC) in relation to the prognosis and need for second line-therapy, based on both objective disease parameters and patients’ perspectives. Methods: In this cross-sectional multicenter study, HRQoL was assessed by using the Dutch PBC-40 according to objective clinical parameters and patients’ perspectives on treatment and prognosis. Results: In total, 178/269 (66%) patients responded; mean age 61.2 (SD 9.9) years and 165 (92.7%) women. The PBC-40 domain scores did not differ according to the GLOBE score response (p &gt; 0.05 for all) or according to the POISE criteria (p &gt; 0.05), except for the domain itch (p = 0.031). Patients who considered their survival to be impaired scored higher on all domains as compared to those expecting a normal prognosis (p &lt; 0.05). Similarly, PBC-40 domain scores were higher among patients who considered that they were in need of additional therapy compared to those who did not (p &lt; 0.05 for all, except for domain itch [p = 0.056]). However, 45/62 (72.6%) patients with a self-expected impaired prognosis had a GLOBE score indicative of a normal prognosis. Twenty-five of the 40 (62.5%) patients who believed they needed additional therapy were below POISE criteria. Conclusion: The HRQoL of patients with PBC was impaired in terms of nonfavorable disease status according to the expectations of patients, but not according to objective disease parameters. Substantial discrepancies between patients’ perspectives and objective parameters were observed, which highlights the need for better patient guidance among patient with PBC.</p

The Role of PIVKA-II as a Predictor of Early Hepatocellular Carcinoma Recurrence-Free Survival after Liver Transplantation in a Low Alpha-Fetoprotein Population

Introduction: AFP and the RETREAT score are currently used to predict HCC recurrence after LT. However, superior discriminating models are needed for low AFP populations. The aim of this study is to investigate the predictive value of PIVKA-II on recurrence-free survival after LT in a low AFP population and microvascular invasion on explant. Methods: A retrospective cohort study including all consecutive patients transplanted for HCC between 1989 and 2019 in the Erasmus MC University Medical Center in Rotterdam, the Netherlands, was used. AFP and PIVKA-II levels were determined in serum samples collected at the time of transplantation. Data on tumor load and microvascular invasion were retrieved from patients’ records. Results: The study cohort consisted of 121 patients, with HCC recurrence in 15 patients (12.4%). The median AFP was 7.7 ng/mL (4.4–20.2), and the median PIVKA-II was 72.0 mAU/mL (41.0–213.5). Patients with low AFP (≤8 ng/mL) and PIVKA-II (≤90 mAU/mL) had a 5-year recurrence-free survival of 100% compared to 85.7% in patients with low AFP and high PIVKA-II (p = 0.026). Regardless of the AFP level, patients within the Milan criteria (based on explant pathology) with a low PIVKA-II level had a 5-year recurrence-free survival of 100% compared to patients with a high PIVKA-II level of 81.1% (p = 0.002). In patients with microvascular invasion, the AUC for PIVKA-II was slightly better than the AUC for AFP (0.775 vs. 0.687). Conclusions: The dual model of PIVKA-II ≤ 90 mAU/mL with either AFP ≤ 8 ng/mL or with patients within the Milan criteria identifies patient groups which can be exempted from HCC surveillance after LT in a low AFP population. PIVKA-II may be a better predictor for explant microvascular invasion than AFP and could play a role in future models identifying LT candidates with the highest risk for HCC recurrence.</p

The Role of PIVKA-II as a Predictor of Early Hepatocellular Carcinoma Recurrence-Free Survival after Liver Transplantation in a Low Alpha-Fetoprotein Population

Introduction: AFP and the RETREAT score are currently used to predict HCC recurrence after LT. However, superior discriminating models are needed for low AFP populations. The aim of this study is to investigate the predictive value of PIVKA-II on recurrence-free survival after LT in a low AFP population and microvascular invasion on explant. Methods: A retrospective cohort study including all consecutive patients transplanted for HCC between 1989 and 2019 in the Erasmus MC University Medical Center in Rotterdam, the Netherlands, was used. AFP and PIVKA-II levels were determined in serum samples collected at the time of transplantation. Data on tumor load and microvascular invasion were retrieved from patients’ records. Results: The study cohort consisted of 121 patients, with HCC recurrence in 15 patients (12.4%). The median AFP was 7.7 ng/mL (4.4–20.2), and the median PIVKA-II was 72.0 mAU/mL (41.0–213.5). Patients with low AFP (≤8 ng/mL) and PIVKA-II (≤90 mAU/mL) had a 5-year recurrence-free survival of 100% compared to 85.7% in patients with low AFP and high PIVKA-II (p = 0.026). Regardless of the AFP level, patients within the Milan criteria (based on explant pathology) with a low PIVKA-II level had a 5-year recurrence-free survival of 100% compared to patients with a high PIVKA-II level of 81.1% (p = 0.002). In patients with microvascular invasion, the AUC for PIVKA-II was slightly better than the AUC for AFP (0.775 vs. 0.687). Conclusions: The dual model of PIVKA-II ≤ 90 mAU/mL with either AFP ≤ 8 ng/mL or with patients within the Milan criteria identifies patient groups which can be exempted from HCC surveillance after LT in a low AFP population. PIVKA-II may be a better predictor for explant microvascular invasion than AFP and could play a role in future models identifying LT candidates with the highest risk for HCC recurrence.</p

Tight cooperation between Mot1p and NC2β in regulating genome-wide transcription, repression of transcription following heat shock induction and genetic interaction with SAGA

TATA-binding protein (TBP) is central to the regulation of eukaryotic transcription initiation. Recruitment of TBP to target genes can be positively regulated by one of two basal transcription factor complexes: SAGA or TFIID. Negative regulation of TBP promoter association can be performed by Mot1p or the NC2 complex. Recent evidence suggests that Mot1p, NC2 and TBP form a DNA-dependent protein complex. Here, we compare the functions of Mot1p and NC2βduring basal and activated transcription using the anchor-away technique for conditional nuclear depletion. Genome-wide expression analysis indicates that both proteins regulate a highly similar set of genes. Upregulated genes were enriched for SAGA occupancy, while downregulated genes preferred TFIID binding. Mot1p and NC2β depletion during heat shock resulted in failure to downregulate gene expression after initial activation, which was accompanied by increased TBP and RNA pol II promoter occupancies. Depletion of Mot1p or NC2β displayed preferential synthetic lethality with the TBP-interaction module of SAGA. Our results support the model that Mot1p and NC2β directly cooperate in vivo to regulate TBP function, and that they are involved in maintaining basal expression levels as well as in resetting gene expression after induction by stress

Type of calcineurin inhibitor and long-term outcomes following liver transplantation in patients with primary biliary cholangitis – an ELTR study

Background &amp; Aims: Tacrolimus has been associated with recurrence of primary biliary cholangitis (PBC) after liver transplantation (LT), which in turn may reduce survival. This study aimed to assess the association between the type of calcineurin inhibitor used and long-term outcomes following LT in patients with PBC. Methods: Survival analyses were used to assess the association between immunosuppressive drugs and graft or patient survival among adult patients with PBC in the European Liver Transplant Registry. Patients who received a donation after brain death graft between 1990 and 2021 with at least 1 year of event-free follow-up were included. Results: In total, 3,175 patients with PBC were followed for a median duration of 11.4 years (IQR 5.9–17.9) after LT. Tacrolimus (Tac) was registered in 2,056 (64.8%) and cyclosporin in 819 (25.8%) patients. Following adjustment for recipient age, recipient sex, donor age, and year of LT, Tac was not associated with higher risk of graft loss (adjusted hazard ratio [aHR] 1.07, 95% CI 0.92-1.25, p = 0.402) or death (aHR 1.06, 95% CI 0.90-1.24, p = 0.473) over cyclosporin. In this model, maintenance mycophenolate mofetil (MMF) was associated with a lower risk of graft loss (aHR 0.72, 95% CI 0.60-0.87, p &lt;0.001) or death (aHR 0.72, 95% CI 0.59-0.87, p &lt;0.001), while these risks were higher with use of steroids (aHR 1.31, 95% CI 1.13-1.52, p &lt;0.001, and aHR 1.34, 95% CI 1.15-1.56, p &lt;0.001, respectively). Conclusions: In this large LT registry, type of calcineurin inhibitor was not associated with long-term graft or recipient survival, providing reassurance regarding the use of Tac post LT in the population with PBC. Patients using MMF had a lower risk of graft loss and death, indicating that the threshold for combination treatment with Tac and MMF should be low. Impact and implications: This study investigated the association between immunosuppressive drugs and the long-term survival of patients with primary biliary cholangitis (PBC) following donation after brain death liver transplantation. While tacrolimus has previously been related to a higher risk of PBC recurrence, the type of calcineurin inhibitor was not related to graft or patient survival among patients transplanted for PBC in the European Liver Transplant Registry. Additionally, maintenance use of mycophenolate was linked to lower risks of graft loss and death, while these risks were higher with maintenance use of steroids. Our findings should provide reassurance for physicians regarding the continued use of Tac after liver transplantation in the population with PBC, and suggest potential benefit from combination therapy with mycophenolate.</p

A global experiment on motivating social distancing during the COVID-19 pandemic

Finding communication strategies that effectively motivate social distancing continues to be a global public health priority during the COVID-19 pandemic. This cross-country, preregistered experiment (n = 25,718 from 89 countries) tested hypotheses concerning generalizable positive and negative outcomes of social distancing messages that promoted personal agency and reflective choices (i.e., an autonomy-supportive message) or were restrictive and shaming (i.e., a controlling message) compared with no message at all. Results partially supported experimental hypotheses in that the controlling message increased controlled motivation (a poorly internalized form of motivation relying on shame, guilt, and fear of social consequences) relative to no message. On the other hand, the autonomy-supportive message lowered feelings of defiance compared with the controlling message, but the controlling message did not differ from receiving no message at all. Unexpectedly, messages did not influence autonomous motivation (a highly internalized form of motivation relying on one’s core values) or behavioral intentions. Results supported hypothesized associations between people’s existing autonomous and controlled motivations and self-reported behavioral intentions to engage in social distancing. Controlled motivation was associated with more defiance and less long-term behavioral intention to engage in social distancing, whereas autonomous motivation was associated with less defiance and more short- and long-term intentions to social distance. Overall, this work highlights the potential harm of using shaming and pressuring language in public health communication, with implications for the current and future global health challenges

A global experiment on motivating social distancing during the COVID-19 pandemic

Finding communication strategies that effectively motivate social distancing continues to be a global public health priority during the COVID-19 pandemic. This cross-country, preregistered experiment (n = 25,718 from 89 countries) tested hypotheses concerning generalizable positive and negative outcomes of social distancing messages that promoted personal agency and reflective choices (i.e., an autonomy-supportive message) or were restrictive and shaming (i.e. a controlling message) compared to no message at all. Results partially supported experimental hypotheses in that the controlling message increased controlled motivation (a poorly-internalized form of motivation relying on shame, guilt, and fear of social consequences) relative to no message. On the other hand, the autonomy-supportive message lowered feelings of defiance compared to the controlling message, but the controlling message did not differ from receiving no message at all. Unexpectedly, messages did not influence autonomous motivation (a highly-internalized form of motivation relying on one’s core values) or behavioral intentions. Results supported hypothesized associations between people’s existing autonomous and controlled motivations and self-reported behavioral intentions to engage in social distancing: Controlled motivation was associated with more defiance and less long-term behavioral intentions to engage in social distancing, whereas autonomous motivation was associated with less defiance and more short- and long-term intentions to social distance. Overall, this work highlights the potential harm of using shaming and pressuring language in public health communication, with implications for the current and future global health challenges

Measurement properties of the PBC-40 and PBC-27: A Dutch validation study

Objective Patients with primary biliary cholangitis (PBC) have an impaired health-related quality of life (HRQoL). Practice guidelines recommend evaluating the HRQoL in all patients with PBC. The aim of this study was to assess the reliability and validity of our Dutch translation of the PBC-40, a PBC-specific measure of the HRQoL. Design The PBC-40 was translated into Dutch following standardised forward-backward procedures. Participants received the Dutch PBC-40 and the RAND-36 (a validated Dutch version of the 36-Item Short Form Health Survey) through postal mail. The PBC-27 is an abridged version of the PBC-40. Internal consistency between the items within the PBC-40/PBC-27 domains was assessed by Cronbach's alpha. In addition, score distributions were analysed on floor and ceiling effects. Construct validity was assessed by hypotheses testing using Pearson's correlation between the PBC-40/PBC-27 domains and RAND-36 scales. Results 177 patients with PBC were included. The mean age was 61.1 (SD 9.9) years and the majority of patients was female (n=164, 92.7%). From the 7080 PBC-40 items, 61 items (0.9%) were missing and 342 items (4.8%) were answered with the € does not apply' option. Each PBC-40 domain had a Cronbach's α of >0.70, with the highest in the domain fatigue (0.95). For the PBC-27, the lowest Cronbach's α was 0.69. Floor effects were present in three domains (cognition 19.3%, itch 27.0% and social 25.0% (only for PBC-27)). No ceiling effects were observed. All domains were significantly correlated with the corresponding RAND-36 scale(s) (p<0.001 for all). The strongest correlation was between the PBC-40 domain fatigue and the RAND-36 vitality scale (r=-0.834). Conclusion Our findings demonstrate the reliability and validity of the Dutch PBC-40 and PBC-27 for the assessment of the HRQoL in patients with PBC. This PBC-specific measure can be used in Dutch-speaking patients with PBC for both research and clinical purposes

External Validation of the RETREAT Score for Prediction of Hepatocellular Carcinoma Recurrence after Liver Transplantation

Background. We aimed to externally validate the performance of the RETREAT score in a European population. Methods. This single center retrospective cohort study enrolled all consecutive patients with HCC who underwent LT between 1989 and 2019. The performance of RETREAT was assessed in the overall population and after stratification between being within or beyond the Milan criteria based on the explant pathology report. Recurrence probabilities were estimated by using the Kaplan&ndash;Meier method and compared by log-rank test. Results. We studied 203 patients; 42 patients were beyond the Milan criteria based on explant pathology. The median follow-up was 26.8 months (IQR 7.2&ndash;60.7). Overall cumulative HCC recurrence rates were 10.6%, 21.3%, and 23.0% at 2, 5, and 10 years, with the majority of recurrences extrahepatic and at multiple sites. Higher RETREAT scores were associated with higher recurrence rates, with a 10-year recurrence rate of 60.5% in patients with RETREAT &ge; 3 (n = 65), compared to 6.2% in those with RETREAT &le;2 (n = 138; p &lt; 0.001). HCC recurrence rates were even lower in patients within the Milan criteria who also had a low RETREAT score (n = 122; 2.7% at 10 years). Conclusion. Low RETREAT scores identify patients at low risk of HCC recurrence after LT in patients within the Milan criteria based on explant pathology