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Background & Aims: Successful immunosuppression withdrawal (ISW) is possible for a subfraction of liver transplant (LT) recipients but the factors that define the risk of ISW failure are largely unknown. One candidate prognostic factor for ISW success or operational tolerance (OT) is longer time between LT and ISW which we term "pre‐withdrawal time". To clarify the impact of pre‐withdrawal time span on subsequent ISW success or failure, we conducted a systematic review with meta‐analysis. Methods: We systematically interrogated the literature for LT recipient ISW studies reporting pre‐withdrawal time. Eligible articles from Embase, Medline, and the Cochrane Central Register of Controlled Trials were used for backward and forward citation searching. Pre‐withdrawal time individual patient data (IPD) was requested from authors. Pooled mean differences and time‐response curves were calculated using random‐effects meta‐analyses. Results: We included 17 studies with 691 patients, 15 of which (620 patients) with IPD. Study‐level risk of bias was heterogeneous. Mean pre‐withdrawal time was greater by 427 days [95% confidence interval (CI) 67–788] in OT compared to non‐OT patients. This increase was potentiated to 799 days (95% CI 369–1229) or 1074 days (95% CI 685–1463) when restricting analysis to adult or European study participants. In time‐response meta‐analysis for adult or European ISW candidates, likelihood of OT increased by 7% (95% CI 4–10%) per year after LT (GRADE low‐ and moderate‐certainty of evidence, respectively). Conclusions: Our data support the impact of pre‐withdrawal time in ISW decision‐making for adult and European LT recipients. PROSPERO REGISTRATION: CRD42021272995. [ABSTRACT FROM AUTHOR]

Citation tracking (CT) collects references with citation relationships to pertinent references that are already known. This scoping review maps the benefit of and the tools and terminology used for CT in health‐related systematic literature searching. We included methodological studies on evidence retrieval by CT in health‐related literature searching without restrictions on study design, language, or publication date. We searched MEDLINE/Ovid, Web of Science Core Collection, CINAHL/EBSCOhost, LLISFT/EBSCOhost, LISTA/EBSCOhost, conducted web searching via Google Scholar, backward/forward CT of included studies and pertinent reviews, and contacting of experts. Two reviewers independently assessed eligibility. Data extraction and analysis were performed by one reviewer and checked by another. We screened 11,861 references and included 47 studies published between 1985 and 2021. Most studies (96%) assessed the benefit of CT either as supplementary or primary/stand‐alone search method. Added value of CT for evidence retrieval was found by 96% of them. Science Citation Index and Social Sciences Citation Index were the most common citation indexes used. Application of multiple citation indexes in parallel, co‐citing or co‐cited references, CT iterations, or software tools was rare. CT terminology was heterogeneous and frequently ambiguous. The use of CT showed an added value in most of the identified studies; however, the benefit of CT in health‐related systematic literature searching likely depends on multiple factors that could not be assessed with certainty. Application, terminology, and reporting are heterogeneous. Based on our results, we plan a Delphi study to develop recommendations for the use and reporting of CT. [ABSTRACT FROM AUTHOR]

Background & aims: Wilson disease (WD) is a rare disorder of copper metabolism. The objective of this systematic review was to determine the comparative effectiveness and safety of common treatments of WD. Methods: We included WD patients of any age or stage and the study drugs D‐penicillamine, zinc salts, trientine and tetrathiomolybdate. The control could be placebo, no treatment or any other treatment. We included prospective, retrospective, randomized and non‐randomized studies. We searched Medline and Embase via Ovid, the Cochrane Central Register of Controlled Trials, and screened reference lists of included articles. Where possible, we applied random‐effects meta‐analyses. Results: The 23 included studies reported on 2055 patients and mostly compared D‐penicillamine to no treatment, zinc, trientine or succimer. One study compared tetrathiomolybdate and trientine. Post‐decoppering maintenance therapy was addressed in one study only. Eleven of 23 studies were of low quality. When compared to no treatment, D‐penicillamine was associated with a lower mortality (odds ratio 0.013; 95% CI 0.0010 to 0.17). When compared to zinc, there was no association with mortality (odds ratio 0.73; 95% CI 0.16 to 3.40) and prevention or amelioration of clinical symptoms (odds ratio 0.84; 95% CI 0.48 to 1.48). Conversely, D‐penicillamine may have a greater impact on side effects and treatment discontinuations than zinc. Conclusions: There are some indications that zinc is safer than D‐penicillamine therapy while being similarly effective in preventing or reducing hepatic or neurological WD symptoms. Study quality was low warranting cautious interpretation of our findings. [ABSTRACT FROM AUTHOR]

The molecular networks that control endoplasmic reticulum (ER) redox conditions in mammalian cells are incompletely understood. Here, we show that after reductive challenge the ER steady-state disulphide content is restored on a time scale of seconds. Both the oxidase Ero1α and the oxidoreductase protein disulphide isomerase (PDI) strongly contribute to the rapid recovery kinetics, but experiments in ERO1-deficient cells indicate the existence of parallel pathways for disulphide generation. We find PDI to be the main substrate of Ero1α, and mixed-disulphide complexes of Ero1 primarily form with PDI, to a lesser extent with the PDI-family members ERp57 and ERp72, but are not detectable with another homologue TMX3. We also show for the first time that the oxidation level of PDIs and glutathione is precisely regulated. Apparently, this is achieved neither through ER import of thiols nor by transport of disulphides to the Golgi apparatus. Instead, our data suggest that a dynamic equilibrium between Ero1- and glutathione disulphide-mediated oxidation of PDIs constitutes an important element of ER redox homeostasis. [ABSTRACT FROM AUTHOR]

Oxidative maturation of secretory and membrane proteins in the endoplasmic reticulum (ER) is powered by Ero1 oxidases. To prevent cellular hyperoxidation, Ero1 activity can be regulated by intramolecular disulphide switches. Here, we determine the redox-driven shutdown mechanism of Ero1α, the housekeeping Ero1 enzyme in human cells. We show that functional silencing of Ero1α in cells arises from the formation of a disulphide bond—identified by mass spectrometry—between the active-site Cys94 (connected to Cys99 in the active enzyme) and Cys131. Competition between substrate thiols and Cys131 creates a feedback loop where activation of Ero1α is linked to the availability of its substrate, reduced protein disulphide isomerase (PDI). Overexpression of Ero1α-Cys131Ala or the isoform Ero1β, which does not have an equivalent disulphide switch, leads to augmented ER oxidation. These data reveal a novel regulatory feedback system where PDI emerges as a central regulator of ER redox homoeostasis. [ABSTRACT FROM AUTHOR]