Time since liver transplant and immunosuppression withdrawal outcomes: Systematic review and individual patient data meta-analysis.

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.

Predicting neurological outcome in adult patients with cardiac arrest: systematic review and meta-analysis of prediction model performance.

This work aims to assess the performance of two post-arrest (out-of-hospital cardiac arrest, OHCA, and cardiac arrest hospital prognosis, CAHP) and one pre-arrest (good outcome following attempted resuscitation, GO-FAR) prediction model for the prognostication of neurological outcome after cardiac arrest in a systematic review and meta-analysis. A systematic search was conducted in Embase, Medline, and Web of Science Core Collection from November 2006 to December 2021, and by forward citation tracking of key score publications. The search identified 1'021 records, of which 25 studies with a total of 124'168 patients were included in the review. A random-effects meta-analysis of C-statistics and overall calibration (total observed vs. expected [O:E] ratio) was conducted. Discriminatory performance was good for the OHCA (summary C-statistic: 0.83 [95% CI 0.81-0.85], 16 cohorts) and CAHP score (summary C-statistic: 0.84 [95% CI 0.82-0.87], 14 cohorts) and acceptable for the GO-FAR score (summary C-statistic: 0.78 [95% CI 0.72-0.84], five cohorts). Overall calibration was good for the OHCA (total O:E ratio: 0.78 [95% CI 0.67-0.92], nine cohorts) and the CAHP score (total O:E ratio: 0.78 [95% CI 0.72-0.84], nine cohorts) with an overestimation of poor outcome. Overall calibration of the GO-FAR score was poor with an underestimation of good outcome (total O:E ratio: 1.62 [95% CI 1.28-2.04], five cohorts). Two post-arrest scores showed good prognostic accuracy for predicting neurological outcome after cardiac arrest and may support early discussions about goals-of-care and therapeutic planning on the intensive care unit. A pre-arrest score showed acceptable prognostic accuracy and may support code status discussions.

Prognostic factors for the occurrence of post-operative shoulder stiffness after arthroscopic rotator cuff repair: a systematic review.

BACKGROUND: Post-operative shoulder stiffness (POSS) is one of the most frequent complications after arthroscopic rotator cuff repair (ARCR). Factors specifying clinical prediction models for the occurrence of POSS should rely on the literature and expert assessment. Our objective was to map prognostic factors for the occurrence of POSS in patients after an ARCR. METHODS: Longitudinal studies of ARCR reporting prognostic factors for the occurrence of POSS with an endpoint of at least 6 months were included. We systematically searched Embase, Medline, and Scopus for articles published between January 1, 2014 and February 12, 2020 and screened cited and citing literature of eligible records and identified reviews. The risk of bias of included studies and the quality of evidence were assessed using the Quality in Prognosis Studies tool and an adapted Grading of Recommendations, Assessment, Development and Evaluations framework. A database was implemented to report the results of individual studies. The review was registered on PROSPERO (CRD42020199257). RESULTS: Seven cohort studies including 23 257 patients were included after screening 5013 records. POSS prevalence ranged from 0.51 to 8.75% with an endpoint ranging from 6 to 24 months. Due to scarcity of data, no meta-analysis could be performed. Overall risk of bias and quality of evidence was deemed high and low or very low, respectively. Twenty-two potential prognostic factors were identified. Increased age and male sex emerged as protective factors against POSS. Additional factors were reported but do require further analyses to determine their prognostic value. DISCUSSION: Available evidence pointed to male sex and increased age as probable protective factors against POSS after ARCR. To establish a reliable pre-specified set of factors for clinical prediction models, our review results require complementation with an expert's opinion.

Outcome of right ventricular assist device implantation following left ventricular assist device implantation: Systematic review and meta-analysis.

OBJECTIVES: The main aim was a systematic evaluation of the current evidence on outcomes for patients undergoing right ventricular assist device (RVAD) implantation following left ventricular assist device (LVAD) implantation. METHODS: This systematic review was registered on PROSPERO (CRD42019130131). Reports evaluating in-hospital as well as follow-up outcome in LVAD and LVAD/RVAD implantation were identified through Ovid Medline, Web of Science and EMBASE. The primary endpoint was mortality at the hospital stay and at follow-up. Pooled incidence of defined endpoints was calculated by using random effects models. RESULTS: A total of 35 retrospective studies that included 3260 patients were analyzed. 30 days mortality was in favour of isolated LVAD implantation 6.74% (1.98-11.5%) versus 31.9% (19.78-44.02%) p = 0.001 in LVAD with temporary need for RVAD. During the hospital stay the incidence of major bleeding was 18.7% (18.2-19.4%) versus 40.0% (36.3-48.8%) and stroke rate was 5.6% (5.4-5.8%) versus 20.9% (16.8-28.3%) and was in favour of isolated LVAD implantation. Mortality reported at short-term as well at long-term was 19.66% (CI 15.73-23.59%) and 33.90% (CI 8.84-59.96%) in LVAD respectively versus 45.35% (CI 35.31-55.4%) p ⩽ 0.001 and 48.23% (CI 16.01-80.45%) p = 0.686 in LVAD/RVAD group respectively. CONCLUSION: Implantation of a temporary RVAD is allied with a worse outcome during the primary hospitalization and at follow-up. Compared to isolated LVAD support, biventricular mechanical circulatory support leads to an elevated mortality and higher incidence of adverse events such as bleeding and stroke.

Clinical parameters and biomarkers predicting spontaneous operational tolerance after liver transplantation: A scoping review.

Indefinite allograft acceptance after immunosuppression withdrawal (ISW), also known as operational tolerance (OT), can occur spontaneously after liver transplantation (LT), but reliable and reproducible prognosis of OT versus non-OT outcomes remains elusive. To prime this, systematic extraction of OT-predictive factors from the literature is crucial. We provide the first comprehensive identification and synthesis of clinical parameters and biomarkers predicting spontaneous OT in non-autoimmune/non-replicative viral LT recipients selected for ISW. We searched Embase, Medline, the Cochrane Central Register of Controlled Trials, clinicaltrials.gov, and the World Health Organization International Clinical Trials Registry Platform for articles, conference abstracts, and ongoing trials. We contacted principal investigators of stand-alone abstracts and ongoing trials for unpublished data and screened citations and references of eligible articles. Twenty-three articles reporting on 11 completed ISW studies, 13 abstracts, and five trial registry entries were included. Longer time between LT and ISW was the only clinical parameter that may increase the incidence of OT. Prognostic biomarkers conspicuously differed between pediatric and adult ISW candidates. These included allograft gene expression patterns and peripheral blood immune exhaustion markers for adults, and histological allograft scores for children. Our results will foster cross-validation efforts to facilitate safe and harmonized candidate selection for successful ISW.

Antimicrobial Prophylaxis for Postoperative Urinary Tract Infections in Transurethral Resection of Bladder Tumors: A Systematic Review and Meta-Analysis.

PURPOSE: The administration of antimicrobial prophylaxis for postoperative urinary tract infections following transurethral resection of bladder tumors is controversial. We aimed to systematically review evidence on the potential effect of antimicrobial prophylaxis on postoperative urinary tract infections and asymptomatic bacteriuria. MATERIALS AND METHODS: We conducted a systematic search in Embase®, Medline® and the Cochrane Central Register of Controlled Trials. Randomized controlled trials and nonrandomized controlled trials assessing the effect of any form of antimicrobial prophylaxis in patients with transurethral resection of bladder tumors on postoperative urinary tract infections or asymptomatic bacteriuria were included. Risk of bias was assessed using RoB 2.0 or the Newcastle-Ottawa Scale. Fixed and random effects meta-analyses were conducted. As a potential basis for a scoping review, we exploratorily searched Medline for risk factors for urinary tract infections after transurethral resection of bladder tumors. The protocol was registered on PROSPERO (CRD42019131733). RESULTS: Of 986 screened publications, 7 studies with 1,725 participants were included; the reported effect sizes varied considerably. We found no significant effect of antimicrobial prophylaxis on urinary tract infections: the pooled odds ratio of the random effects model was 1.55 (95% CI 0.73-3.31). The random effects meta-analysis examining the effect of antimicrobial prophylaxis on asymptomatic bacteriuria showed an OR of 0.43 (0.18-1.04). Risk of bias was moderate. Our exploratory search identified 3 studies reporting age, preoperative pelvic radiation, preoperative hospital stay, duration of operation, tumor size, preoperative asymptomatic bacteriuria and pyuria as risk factors for urinary tract infections following transurethral resection of bladder tumors. CONCLUSIONS: We observed insufficient evidence supporting routine antimicrobial prophylaxis in patients undergoing transurethral resection of bladder tumors for the prevention of postoperative urinary tract infections; our findings may inform harmonization of international guidelines.

Ca2+ mobilization-dependent reduction of the endoplasmic reticulum lumen is due to influx of cytosolic glutathione.

BACKGROUND: The lumen of the endoplasmic reticulum (ER) acts as a cellular Ca2+ store and a site for oxidative protein folding, which is controlled by the reduced glutathione (GSH) and glutathione-disulfide (GSSG) redox pair. Although depletion of luminal Ca2+ from the ER provokes a rapid and reversible shift towards a more reducing poise in the ER, the underlying molecular basis remains unclear. RESULTS: We found that Ca2+ mobilization-dependent ER luminal reduction was sensitive to inhibition of GSH synthesis or dilution of cytosolic GSH by selective permeabilization of the plasma membrane. A glutathione-centered mechanism was further indicated by increased ER luminal glutathione levels in response to Ca2+ efflux. Inducible reduction of the ER lumen by GSH flux was independent of the Ca2+-binding chaperone calreticulin, which has previously been implicated in this process. However, opening the translocon channel by puromycin or addition of cyclosporine A mimicked the GSH-related effect of Ca2+ mobilization. While the action of puromycin was ascribable to Ca2+ leakage from the ER, the mechanism of cyclosporine A-induced GSH flux was independent of calcineurin and cyclophilins A and B and remained unclear. CONCLUSIONS: Our data strongly suggest that ER influx of cytosolic GSH, rather than inhibition of local oxidoreductases, is responsible for the reductive shift upon Ca2+ mobilization. We postulate the existence of a Ca2+- and cyclosporine A-sensitive GSH transporter in the ER membrane. These findings have important implications for ER redox homeostasis under normal physiology and ER stress.

Abductor Muscle Strength Deficit in Patients After Total Hip Arthroplasty: A Systematic Review and Meta-Analysis.

BACKGROUND: The aims of this study were to assess and quantify hip abductor muscle strength deficits after total hip arthroplasty (THA) and to determine associations with external factors. METHODS: Studies reporting on hip abductor muscle strength before and/or after THA performed for osteoarthritis or atraumatic osteonecrosis of the hip were considered for inclusion. Data sources were Embase, Medline, and the Cochrane Central Register of Controlled Trials. Muscle strength on the affected side was compared with the healthy contralateral side or with control subjects. Study quality was assessed using a modified Newcastle-Ottawa Scale. RESULTS: Nineteen studies reporting on 875 subjects met the inclusion criteria. Patients scheduled for THA had a mean strength deficit of 18.6% (95% confidence interval (CI) [-33.9, -3.2%]) compared with control subjects. Abductor muscle strength then increased by 20.2% (CI [5.6, 34.8%]) at 4-6 months, 29.6% (CI [4.7, 54.4%]) at 9-12 months, and 49.8% (CI [-31.0, 130.6%]) at 18-24 months postoperatively compared with preoperative values. For unilateral THA, the mean torque ratio was 86.3% (CI [75.4, 97.2%]) and 93.4% (CI [75.1, 111.6%]) before and >24 months after THA, respectively. Study quality was low to moderate. CONCLUSION: Hip abductor muscle strength deficits may gradually improve during 24 months after THA possibly without complete recovery. Cautious interpretation of these findings is warranted because high-quality evidence is largely missing.

Impact of sedentary behavior on large artery structure and function in children and adolescents: a systematic review.

Sedentary behavior contributes to increased atherosclerotic risk in adults. Whether or not this can be extended to pediatric populations is unclear. This systematic review assessed associations of sedentary behavior with large artery structure and function in pediatric populations. MEDLINE, EMBASE, CENTRAL, and Web of Science were searched from the earliest available date to 31st of December 2018. Analyses of associations of sedentary behavior with large artery structure or function in a pediatric (sub-)population were included, adhering to the PRISMA guidelines. The protocol was published in advance on PROSPERO (CRD42018112996). Study quality and quality of evidence were analyzed using NHLBI Study Quality assessment tools and GRADE. Six observational studies found no association of exposure and outcome variables, and one had contradicting results. One intervention found reduced flow-mediated dilation after 3 h of uninterrupted sitting. Exposure and outcome measures were highly heterogeneous. Study quality was low to moderate. Quality of evidence was very low or low in the observational studies and high in the intervention.Conclusion: In pediatric populations, current evidence is limited and of low quality about how acute effects of sedentary behavior translate into early vascular aging and the long-term development of vascular dysfunction and atherosclerotic risk. Future studies should emphasize a careful choice of the adequate type and measurement site of a biomarker for large artery structure and function as well as conduct a detailed assessment of sedentary behavior patterns.Trial registration: PROSPERO Registration Number: CRD42018112996What is known: • An independent association of sedentary behavior and biomarkers of large artery structure and function has been demonstrated in adults. • In children, sedentary behavior is directly associated with classical cardiovascular risk factors like elevated blood glucose levels, insulin resistance, high blood pressure, obesity, and elevated blood lipids.What is new: • Currently, only few studies of low quality in children and adolescents provide limited evidence about how acute effects of sedentary behavior translate into early vascular aging and the long-term development of atherosclerosis. • The type and measurement site of vascular biomarker need to be chosen carefully, and a detailed assessment of sedentary behavior patterns is important to minimize the methodological bias.

Comparative effectiveness of common therapies for Wilson disease: A systematic review and meta-analysis of controlled studies.

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.

Human ER Oxidoreductin-1α (Ero1α) Undergoes Dual Regulation through Complementary Redox Interactions with Protein-Disulfide Isomerase.

In the mammalian endoplasmic reticulum, oxidoreductin-1α (Ero1α) generates protein disulfide bonds and transfers them specifically to canonical protein-disulfide isomerase (PDI) to sustain oxidative protein folding. This oxidative process is coupled to the reduction of O2 to H2O2 on the bound flavin adenine dinucleotide cofactor. Because excessive thiol oxidation and H2O2 generation cause cell death, Ero1α activity must be properly regulated. In addition to the four catalytic cysteines (Cys94, Cys99, Cys104, and Cys131) that are located in the flexible active site region, the Cys208-Cys241 pair located at the base of another flexible loop is necessary for Ero1α regulation, although the mechanistic basis is not fully understood. The present study revealed that the Cys208-Cys241 disulfide was reduced by PDI and other PDI family members during PDI oxidation. Differential scanning calorimetry and small angle X-ray scattering showed that mutation of Cys208 and Cys241 did not grossly affect the thermal stability or overall shape of Ero1α, suggesting that redox regulation of this cysteine pair serves a functional role. Moreover, the flexible loop flanked by Cys208 and Cys241 provides a platform for functional interaction with PDI, which in turn enhances the oxidative activity of Ero1α through reduction of the Cys208-Cys241 disulfide. We propose a mechanism of dual Ero1α regulation by dynamic redox interactions between PDI and the two Ero1α flexible loops that harbor the regulatory cysteines.

Redox controls UPR to control redox.

In many physiological contexts, intracellular reduction-oxidation (redox) conditions and the unfolded protein response (UPR) are important for the control of cell life and death decisions. UPR is triggered by the disruption of endoplasmic reticulum (ER) homeostasis, also known as ER stress. Depending on the duration and severity of the disruption, this leads to cell adaptation or demise. In this Commentary, we review reductive and oxidative activation mechanisms of the UPR, which include direct interactions of dedicated protein disulfide isomerases with ER stress sensors, protein S-nitrosylation and ER Ca(2+) efflux that is promoted by reactive oxygen species. Furthermore, we discuss how cellular oxidant and antioxidant capacities are extensively remodeled downstream of UPR signals. Aside from activation of NADPH oxidases, mitogen-activated protein kinases and transcriptional antioxidant responses, such remodeling prominently relies on ER-mitochondrial crosstalk. Specific redox cues therefore operate both as triggers and effectors of ER stress, thus enabling amplification loops. We propose that redox-based amplification loops critically contribute to the switch from adaptive to fatal UPR.

ER-luminal thiol/selenol-mediated regulation of Ca2+ signalling.

The endoplasmic reticulum (ER) is the main cellular Ca(2+)storage unit. Among other signalling outputs, the ER can release Ca(2+)ions, which can, for instance, communicate the status of ER protein folding to the cytosol and to other organelles, in particular the mitochondria. As a consequence, ER Ca(2+)flux can alter the apposition of the ER with mitochondria, influence mitochondrial ATP production or trigger apoptosis. All aspects of ER Ca(2+)flux have emerged as processes that are intimately controlled by intracellular redox conditions. In this review, we focus on ER-luminal redox-driven regulation of Ca(2+)flux. This involves the direct reduction of disulfides within ER Ca(2+)handling proteins themselves, but also the regulated interaction of ER chaperones and oxidoreductases such as calnexin or ERp57 with them. Well-characterized examples are the activating interactions of Ero1α with inositol 1,4,5-trisphosphate receptors (IP3Rs) or of selenoprotein N (SEPN1) with sarco/endoplasmic reticulum Ca(2+)transport ATPase 2 (SERCA2). The future discovery of novel ER-luminal modulators of Ca(2+)handling proteins is likely. Based on the currently available information, we describe how the variable ER redox conditions govern Ca(2+)flux from the ER.

Endoplasmic reticulum: reduced and oxidized glutathione revisited.

The reducing power of glutathione, expressed by its reduction potential EGSH, is an accepted measure for redox conditions in a given cell compartment. In the endoplasmic reticulum (ER), EGSH is less reducing than elsewhere in the cell. However, attempts to determine EGSH(ER) have been inconsistent and based on ineligible assumptions. Using a codon-optimized and evidently glutathione-specific glutaredoxin-coupled redox-sensitive green fluorescent protein (roGFP) variant, we determined EGSH(ER) in HeLa cells as -208±4 mV (at pH 7.0). At variance with existing models, this is not oxidizing enough to maintain the known redox state of protein disulfide isomerase family enzymes. Live-cell microscopy confirmed ER hypo-oxidation upon inhibition of ER Ca(2+) import. Conversely, stressing the ER with a glycosylation inhibitor did not lead to more reducing conditions, as reported for yeast. These results, which for the first time establish the oxidative capacity of glutathione in the ER, illustrate a context-dependent interplay between ER stress and EGSH(ER). The reported development of ER-localized EGSH sensors will enable more targeted in vivo redox analyses in ER-related disorders.

Endoplasmic reticulum oxidoreductin-1α (Ero1α) improves folding and secretion of mutant proinsulin and limits mutant proinsulin-induced endoplasmic reticulum stress.

Upon chronic up-regulation of proinsulin synthesis, misfolded proinsulin can accumulate in the endoplasmic reticulum (ER) of pancreatic ß-cells, promoting ER stress and type 2 diabetes mellitus. In Mutant Ins-gene-induced Diabetes of Youth (MIDY), misfolded mutant proinsulin impairs ER exit of co-expressed wild-type proinsulin, limiting insulin production and leading to eventual ß-cell death. In this study we have investigated the hypothesis that increased expression of ER oxidoreductin-1α (Ero1α), despite its established role in the generation of H2O2, might nevertheless be beneficial in limiting proinsulin misfolding and its adverse downstream consequences. Increased Ero1α expression is effective in promoting wild-type proinsulin export from cells co-expressing misfolded mutant proinsulin. In addition, we find that upon increased Ero1α expression, some of the MIDY mutants themselves are directly rescued from ER retention. Secretory rescue of proinsulin-G(B23)V is correlated with improved oxidative folding of mutant proinsulin. Indeed, using three different variants of Ero1α, we find that expression of either wild-type or an Ero1α variant lacking regulatory disulfides can rescue mutant proinsulin-G(B23)V, in parallel with its ability to provide an oxidizing environment in the ER lumen, whereas beneficial effects were less apparent for a redox-inactive form of Ero1. Increased expression of protein disulfide isomerase antagonizes the rescue provided by oxidatively active Ero1. Importantly, ER stress induced by misfolded proinsulin was limited by increased expression of Ero1α, suggesting that enhancing the oxidative folding of proinsulin may be a viable therapeutic strategy in the treatment of type 2 diabetes.

Disulphide production by Ero1α-PDI relay is rapid and effectively regulated.

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.

Effects of exercise training on cardiac output in subjects with heart failure with preserved ejection fraction (HFpEF) - a protocol for a systematic review and meta-analysis.

BACKGROUND: Patients with heart failure with preserved ejection fraction (HFpEF) commonly experience exercise intolerance, resulting in reduced cardiorespiratory fitness. This is characterised by a decreased maximal oxygen uptake (V̇O2peak), which is determined by the product of cardiac output (CO) and arteriovenous oxygen difference (a-vDO2). While exercise training has been shown to improve V̇O2peak in HFpEF patients, the effects on CO remain unclear. The aim of this study is to systematically review and analyse the current evidence on the effects of supervised exercise training on CO in patients with HFpEF. METHODS: We will systematically search for literature describing the effects of supervised exercise training on CO in patients with HFpEF. All eligible studies published before 30 June 2023 in the following electronic databases will be included: MEDLINE (Ovid), Embase (Ovid), SPORTDiscus (EBSCOhost), and CENTRAL (Cochrane Library). Effect sizes will be extracted for CO before and after a supervised exercise training intervention at rest and maximal exercise. Mass of heterogeneity (I2) will be calculated, and either fixed-effect models or random-effect models will be used for meta-analysis. To detect a potential publication bias, funnel plot analyses will be performed. DISCUSSION: While several studies have reported a positive effect of supervised exercise training on cardiorespiratory fitness, attempts to assess the underlying determinants of V̇O2peak, CO, and a-vDO2 are much scarcer, especially in patients with HFpEF. From a physiological perspective, measuring CO before and after supervised exercise training seems to be a reasonable way to accurately operationalise a potential improvement in cardiac function. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022361485.

Multidimensional versus unidimensional pain scales for the assessment of analgesic requirement in the emergency department: a systematic review.

Pain is a multidimensional experience, potentially rendering unidimensional pain scales inappropriate for assessment. Prior research highlighted their inadequacy as reliable indicators of analgesic requirement. This systematic review aimed to compare multidimensional with unidimensional pain scales in assessing analgesic requirements in the emergency department (ED). Embase, Medline, CINAHL, and PubMed Central were searched to identify ED studies utilizing both unidimensional and multidimensional pain scales. Primary outcome was desire for analgesia. Secondary outcomes were amount of administered analgesia and patient satisfaction. Two independent reviewers screened, assessed quality, and extracted data of eligible studies. We assessed risk of bias with the ROBINS-I tool and provide a descriptive summary. Out of 845 publications, none met primary outcome criteria. Three studies analyzed secondary outcomes. One study compared the multidimensional Defense and Veterans Pain Rating Scale (DVPRS) to the unidimensional Numerical Rating Scale (NRS) for opioid administration. DVPRS identified more patients with moderate instead of severe pain compared to the NRS. Therefore, the DVPRS might lead to a potential reduction in opioid administration for individuals who do not require it. Two studies assessing patient satisfaction favored the short forms (SF) of the Brief Pain Inventory (BPI) and McGill Pain Questionnaire (MPQ) over the Visual Analogue Scale (VAS) and the NRS. Limited heterogenous literature suggests that in the ED, a multidimensional pain scale (DVPRS), may better discriminate moderate and severe pain compared to a unidimensional pain scale (NRS). This potentially impacts analgesia, particularly when analgesic interventions rely on pain scores. Patients might prefer multidimensional pain scales (BPI-SF, MPQ-SF) over NRS or VAS for assessing their pain experience.

Systematic review of prognostic factors associated with progression to late age-related macular degeneration: Pinnacle study report 2.

There is a need to identify accurately prognostic factors that determine the progression of intermediate to late-stage age-related macular degeneration (AMD). Currently, clinicians cannot provide individualised prognoses of disease progression. Moreover, enriching clinical trials with rapid progressors may facilitate delivery of shorter intervention trials aimed at delaying or preventing progression to late AMD. Thus, we performed a systematic review to outline and assess the accuracy of reporting prognostic factors for the progression of intermediate to late AMD. A meta-analysis was originally planned. Synonyms of AMD and disease progression were used to search Medline and EMBASE for articles investigating AMD progression published between 1991 and 2021. Initial search results included 3229 articles. Predetermined eligibility criteria were employed to systematically screen papers by two reviewers working independently and in duplicate. Quality appraisal and data extraction were performed by a team of reviewers. Only 6 studies met the eligibility criteria. Based on these articles, exploratory prognostic factors for progression of intermediate to late AMD included phenotypic features (e.g. location and size of drusen), age, smoking status, ocular and systemic co-morbidities, race, and genotype. Overall, study heterogeneity precluded reporting by forest plots and meta-analysis. The most commonly reported prognostic factors were baseline drusen volume/size, which was associated with progression to neovascular AMD, and outer retinal thinning linked to progression to geographic atrophy. In conclusion, poor methodological quality of included studies warrants cautious interpretation of our findings. Rigorous studies are warranted to provide robust evidence in the future.