Non-Interferon-Dependent Role of STING Signaling in Pulmonary Hypertension.

BACKGROUND: Patients with constitutive activation of DNA-sensing pathway through stimulator of IFN (interferon) genes (STING), such as those with STING-associated vasculopathy with onset in infancy, develop pulmonary hypertension (PH). However, the role of STING signaling in general PH patients is heretofore undescribed. Here, we seek to investigate the role of STING in PH development. METHODS: STING expression in patient lung samples was examined. PH was induced in global STING-deficient mice and global type I IFN receptor 1-deficient mice using bleomycin or chronic hypoxia exposure. PH development was evaluated by right ventricular systolic pressure and Fulton index, with additional histological and flow cytometric analysis. VEGF (vascular endothelial growth factor) expression on murine immune cells was quantified and evaluated with multiplex and flow cytometry. Human myeloid-derived cells were differentiated from peripheral blood mononuclear cells and treated with either STING agonist or STING antagonist for evaluation of VEGF secretion. RESULTS: Global STING deficiency protects mice from PH development, and STING-associated PH seems independent of type I IFN signaling. Furthermore, a role for STING-VEGF signaling pathway in PH development was demonstrated, with altered VEGF secretion in murine pulmonary infiltrated myeloid cells in a STING-dependent manner. In addition, pharmacological manipulation of STING in human myeloid-derived cells supports in vivo findings. Finally, a potential role of STING-VEGF-mediated apoptosis in disease development and progression was illustrated, providing a roadmap toward potential therapeutic applications. CONCLUSIONS: Overall, these data provide concrete evidence of STING involvement in PH, establishing biological plausibility for STING-related therapies in PH treatment.

Likelihood-based tests for detecting circadian rhythmicity and differential circadian patterns in transcriptomic applications.

Circadian rhythmicity in transcriptomic profiles has been shown in many physiological processes, and the disruption of circadian patterns has been found to associate with several diseases. In this paper, we developed a series of likelihood-based methods to detect (i) circadian rhythmicity (denoted as LR_rhythmicity) and (ii) differential circadian patterns comparing two experimental conditions (denoted as LR_diff). In terms of circadian rhythmicity detection, we demonstrated that our proposed LR_rhythmicity could better control the type I error rate compared to existing methods under a wide variety of simulation settings. In terms of differential circadian patterns, we developed methods in detecting differential amplitude, differential phase, differential basal level and differential fit, which also successfully controlled the type I error rate. In addition, we demonstrated that the proposed LR_diff could achieve higher statistical power in detecting differential fit, compared to existing methods. The superior performance of LR_rhythmicity and LR_diff was demonstrated in four real data applications, including a brain aging data (gene expression microarray data of human postmortem brain), a time-restricted feeding data (RNA sequencing data of human skeletal muscles) and a scRNAseq data (single cell RNA sequencing data of mouse suprachiasmatic nucleus). An R package for our methods is publicly available on GitHub https://github.com/diffCircadian/diffCircadian.

Liver regeneration and ethanol detoxification: A new link in YAP regulation of ALDH1A1 during alcohol-related hepatocyte damage.

Yes-associated protein (YAP), a central effector in the Hippo pathway, is involved in the regulation of organ size, stem cell self-renewal, and tissue regeneration. In this study, we observed YAP activation in patients with alcoholic steatosis, hepatitis, and cirrhosis. Accumulation of this protein in the nucleus was also observed in murine livers that were damaged after chronic-plus-single binge or moderate ethanol ingestion combined with carbon tetrachloride intoxication (ethanol/CCl4 ). To understand the role of this transcriptional coactivator in alcohol-related liver injury, we knocked out the Yap1 gene in hepatocytes of floxed homozygotes through adeno-associated virus (AAV8)-mediated deletion utilizing Cre recombinase. Yap1 hepatocyte-specific knockouts (KO) exhibited hemorrhage, massive hepatic necrosis, enhanced oxidative stress, elevated hypoxia, and extensive infiltration of CD11b+ inflammatory cells into hepatic microenvironments rich for connective tissue growth factor (Ctgf) during ethanol/CCl4 -induced liver damage. Analysis of whole-genome transcriptomics indicated upregulation of genes involved in hypoxia and extracellular matrix (ECM) remodeling, whereas genes related to hepatocyte proliferation, progenitor cell activation, and ethanol detoxification were downregulated in the damaged livers of Yap1 KO. Acetaldehyde dehydrogenase (Aldh)1a1, a gene that encodes a detoxification enzyme for aldehyde substrates, was identified as a potential YAP target because this gene could be transcriptionally activated by a hyperactive YAP mutant. The ectopic expression of the human ALDH1A1 gene caused increase in hepatocyte proliferation and decrease in hepatic necrosis, oxidative stress, ECM remodeling, and inflammation during ethanol/CCl4 -induced liver damage. Taken together, these observations indicated that YAP was crucial for liver repair during alcohol-associated injury. Its regulation of ALDH1A1 represents a new link in liver regeneration and detoxification.

Fatigue and perceived fatigability, not objective fatigability, are prevalent in people with post-COVID-19.

Persistent symptoms after acute COVID-19 infection, termed post-COVID-19 fatigue, occur in 44-70% of patients. Characterizing fatigue in this population is vital to determine the etiology of post-COVID-19 fatigue symptoms and to assess the effectiveness of potential interventions. The purpose of this study was to assess differences in perceived and objective fatigability between people with post-COVID-19 symptoms (N = 29, 20 females) and people who had COVID-19 but are not experiencing persistent symptoms (N = 20, 12 females). Perceived fatigability, fatigue, pain, and quality of life were assessed with the Fatigue Severity Scale (FSS), Fatigue Assessment Scale (FAS), Visual Analog Scale for Pain (VAS), and the EQ-5D-5L, respectively. Objective fatigability was evaluated with torque and work fatigue indices (FI-T and FI-W), calculated via an isokinetic fatigue task. The results revealed that, the subjects with post-COVID-19 symptoms had significantly higher FAS (p < 0.01), FSS (p < 0.01), VAS (p < 0.01), and EQ-5D-5L VAS (p < 0.01) scores compared to subjects without post-COVID-19 symptoms, indicating greater fatigue and perceived fatigability, increased pain, and worse quality of life. However, there were no differences between the two groups for the FI-Ts (all p ≥ 0.07) or FI-W (all p ≥ 0.08), indicating no differences in objective fatigability. This study found that people with post-COVID-19 symptoms have increased fatigue and perceived fatigability, but not objective fatigability, compared to subjects without post-COVID-19 symptoms.

Residual Disease After Primary Surgical Treatment for Advanced Epithelial Ovarian Cancer, Part 2: Network Meta-analysis Incorporating Expert Elicitation to Adjust for Publication Bias.

BACKGROUND: Previous work has identified a strong association between the achievements of macroscopic cytoreduction and improved overall survival (OS) after primary surgical treatment of advanced epithelial ovarian cancer. Despite the use of contemporary methodology, resulting in the most comprehensive currently available evidence to date in this area, opponents remain skeptical. AREAS OF UNCERTAINTY: We aimed to conduct sensitivity analyses to adjust for potential publication bias, to confirm or refute existing conclusions and recommendations, leveraging elicitation to incorporate expert opinion. We recommend our approach as an exemplar that should be adopted in other areas of research. DATA SOURCES: We conducted random-effects network meta-analyses in frequentist and Bayesian (using Markov Chain Montel Carlo simulation) frameworks comparing OS across residual disease thresholds in women with advanced epithelial ovarian cancer after primary cytoreductive surgery. Elicitation methods among experts in gynecology were used to derive priors for an extension to a previously reported Copas selection model and a novel approach using effect estimates calculated from the elicitation exercise, to attempt to adjust for publication bias and increase confidence in the certainty of the evidence. THERAPEUTIC ADVANCES: Analyses using data from 25 studies (n = 20,927 women) all showed the prognostic importance of complete cytoreduction (0 cm) in both frameworks. Experts accepted publication bias was likely, but after adjustment for their opinions, published results overpowered the informative priors incorporated into the Bayesian sensitivity analyses. Effect estimates were attenuated but conclusions were robust in all analyses. CONCLUSIONS: There remains a strong association between the achievement of complete cytoreduction and improved OS even after adjustment for publication bias using strong informative priors formed from an expert elicitation exercise. The concepts of the elicitation survey should be strongly considered for utilization in other meta-analyses.

Residual Disease Threshold After Primary Surgical Treatment for Advanced Epithelial Ovarian Cancer, Part 1: A Systematic Review and Network Meta-Analysis.

BACKGROUND: We present a systematic review and network meta-analysis (NMA) that is the precursor underpinning the Bayesian analyses that adjust for publication bias, presented in the same edition in AJT. The review assesses optimal cytoreduction for women undergoing primary advanced epithelial ovarian cancer (EOC) surgery. AREAS OF UNCERTAINTY: To assess the impact of residual disease (RD) after primary debulking surgery in women with advanced EOC. This review explores the impact of leaving varying levels of primary debulking surgery. DATA SOURCES: We conducted a systematic review and random-effects NMA for overall survival (OS) to incorporate direct and indirect estimates of RD thresholds, including concurrent comparative, retrospective studies of ≥100 adult women (18+ years) with surgically staged advanced EOC (FIGO stage III/IV) who had confirmed histological diagnoses of ovarian cancer. Pairwise meta-analyses of all directly compared RD thresholds was previously performed before conducting this NMA, and the statistical heterogeneity of studies within each comparison was evaluated using recommended methods. THERAPEUTIC ADVANCES: Twenty-five studies (n = 20,927) were included. Analyses demonstrated the prognostic importance of complete cytoreduction to no macroscopic residual disease (NMRD), with a hazard ratio for OS of 2.0 (95% confidence interval, 1.8-2.2) for <1 cm RD threshold versus NMRD. NMRD was associated with prolonged survival across all RD thresholds. Leaving NMRD was predicted to provide longest survival (probability of being best = 99%). The results were robust to sensitivity analysis including only those studies that adjusted for extent of disease at primary surgery (hazard ratio 2.3, 95% confidence interval, 1.9-2.6). The overall certainty of evidence was moderate and statistical adjustment of effect estimates in included studies minimized bias. CONCLUSIONS: The results confirm a strong association between complete cytoreduction to NMRD and improved OS. The NMA approach forms part of the methods guidance underpinning policy making in many jurisdictions. Our analyses present an extension to the previous work in this area.

Single-incision sling operations for urinary incontinence in women.

BACKGROUND: Stress urinary incontinence imposes a significant health and economic burden on individuals and society. Single-incision slings are a minimally-invasive treatment option for stress urinary incontinence. They involve passing a short synthetic device through the anterior vaginal wall to support the mid-urethra. The use of polypropylene mesh in urogynaecology, including mid-urethral slings, is restricted in many countries. This is a review update (previous search date 2012). OBJECTIVES: To assess the effects of single-incision sling operations for treating urinary incontinence in women, and to summarise the principal findings of relevant economic evaluations. SEARCH METHODS: We searched the Cochrane Incontinence Specialised Register, which contains trials identified from: CENTRAL, MEDLINE, MEDLINE In-Process, MEDLINE Epub Ahead of Print, and two trials registers. We handsearched journals, conference proceedings, and reference lists of relevant articles to 20 September 2022. SELECTION CRITERIA: We included randomised or quasi-randomised controlled trials in women with stress (or stress-predominant mixed) urinary incontinence in which at least one, but not all, trial arms included a single-incision sling. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. The primary outcome was subjective cure or improvement of urinary incontinence. MAIN RESULTS: We included 62 studies with a total of 8051 women in this review. We did not identify any studies comparing single-incision slings to no treatment, conservative treatment, colposuspension, or laparoscopic procedures. We assessed most studies as being at low or unclear risk of bias, with five studies at high risk of bias for outcome assessment. Sixteen trials used TVT-Secur, a single-incision sling withdrawn from the market in 2013. The primary analysis in this review excludes trials using TVT-Secur. We report separate analyses for these trials, which did not substantially alter the effect estimates. We identified two cost-effectiveness analyses and one cost-minimisation analysis. Single-incision sling versus autologous fascial sling One study (70 women) compared single-incision slings to autologous fascial slings. It is uncertain if single-incision slings have any effect on risk of dyspareunia (painful sex) or mesh exposure, extrusion or erosion compared with autologous fascial slings. Subjective cure or improvement of urinary incontinence at 12 months, patient-reported pain at 24 months or longer, number of women with urinary retention, quality of life at 12 months and the number of women requiring repeat continence surgery or sling revision were not reported for this comparison. Single-incision sling versus retropubic sling Ten studies compared single-incision slings to retropubic slings. There may be little to no difference between single-incision slings and retropubic slings in subjective cure or improvement of incontinence at 12 months (risk ratio (RR) 0.99, 95% confidence interval (CI) 0.91 to 1.07; 2 trials, 297 women; low-certainty evidence). It is uncertain whether single-incision slings increase the risk of mesh exposure, extrusion or erosion compared with retropubic minimally-invasive slings; the wide confidence interval is consistent with both benefit and harm (RR 1.55, 95% CI 0.24 to 9.82; 3 trials, 267 women; low-certainty evidence). It is uncertain whether single-incision slings lead to fewer women having postoperative urinary retention compared with retropubic slings; the wide confidence interval is consistent with possible benefit and harm (RR 0.47, 95% CI 0.12 to 1.84; 2 trials, 209 women; low-certainty evidence). The effect of single-incision slings on the risk of repeat continence surgery or mesh revision compared with retropubic slings is uncertain (RR 4.19, 95% CI 0.31 to 57.28; 2 trials, 182 women; very low-certainty evidence). One study reported quality of life, but not in a suitable format for analysis. Patient-reported pain at more than 24 months and the number of women with dyspareunia were not reported for this comparison. We downgraded the evidence due to concerns about risks of bias, imprecision and inconsistency. Single-incision sling versus transobturator sling Fifty-one studies compared single-incision slings to transobturator slings. The evidence ranged from high to low certainty. There is no evidence of a difference in subjective cure or improvement of incontinence at 12 months when comparing single-incision slings with transobturator slings (RR 1.00, 95% CI 0.97 to 1.03; 17 trials, 2359 women; high-certainty evidence). Single-incision slings probably have a reduced risk of patient-reported pain at 24 months post-surgery compared with transobturator slings (RR 0.12, 95% CI 0.02 to 0.68; 2 trials, 250 women; moderate-certainty evidence). The effect of single-incision slings on the risk of dyspareunia is uncertain compared with transobturator slings, as the wide confidence interval is consistent with possible benefit and possible harm (RR 0.78, 95% CI 0.41 to 1.48; 8 trials, 810 women; moderate-certainty evidence). There are a similar number of mesh exposures, extrusions or erosions with single-incision slings compared with transobturator slings (RR 0.61, 95% CI 0.39 to 0.96; 16 trials, 2378 women; high-certainty evidence). Single-incision slings probably result in similar or reduced cases of postoperative urinary retention compared with transobturator slings (RR 0.68, 95% CI 0.47 to 0.97; 23 trials, 2891 women; moderate-certainty evidence). Women with single-incision slings may have lower quality of life at 12 months compared to transobturator slings (standardised mean difference (SMD) 0.24, 95% CI 0.09 to 0.39; 8 trials, 698 women; low-certainty evidence). It is unclear whether single-incision slings lead to slightly more women requiring repeat continence surgery or mesh revision compared with transobturator slings (95% CI consistent with possible benefit and harm; RR 1.42, 95% CI 0.94 to 2.16; 13 trials, 1460 women; low-certainty evidence). We downgraded the evidence due to indirectness, imprecision and risks of bias. AUTHORS' CONCLUSIONS: Single-incision sling operations have been extensively researched in randomised controlled trials. They may be as effective as retropubic slings and are as effective as transobturator slings for subjective cure or improvement of stress urinary incontinence at 12 months. It is uncertain if single-incision slings lead to better or worse rates of subjective cure or improvement compared with autologous fascial slings. There are still uncertainties regarding adverse events and longer-term outcomes. Therefore, longer-term data are needed to clarify the safety and long-term effectiveness of single-incision slings compared to other mid-urethral slings.

A wrinkle in time: circadian biology in pulmonary vascular health and disease.

An often overlooked element of pulmonary vascular disease is time. Cellular responses to time, which are regulated directly by the core circadian clock, have only recently been elucidated. Despite an extensive collection of data regarding the role of rhythmic contribution to disease pathogenesis (such as systemic hypertension, coronary artery, and renal disease), the roles of key circadian transcription factors in pulmonary hypertension remain understudied. This is despite a large degree of overlap in the pulmonary hypertension and circadian rhythm fields, not only including shared signaling pathways, but also cell-specific effects of the core clock that are known to result in both protective and adverse lung vessel changes. Therefore, the goal of this review is to summarize the current dialogue regarding common pathways in circadian biology, with a specific emphasis on its implications in the progression of pulmonary hypertension. In this work, we emphasize specific proteins involved in the regulation of the core molecular clock while noting the circadian cell-specific changes relevant to vascular remodeling. Finally, we apply this knowledge to the optimization of medical therapy, with a focus on sleep hygiene and the role of chronopharmacology in patients with this disease. In dissecting the unique relationship between time and cellular biology, we aim to provide valuable insight into the practical implications of considering time as a therapeutic variable. Armed with this information, physicians will be positioned to more efficiently use the full four dimensions of patient care, resulting in improved morbidity and mortality of pulmonary hypertension patients.

Ultra-radical (extensive) surgery versus standard surgery for the primary cytoreduction of advanced epithelial ovarian cancer.

BACKGROUND: Ovarian cancer is the seventh most common cancer among women and the leading cause of death in women with gynaecological malignancies. Opinions differ regarding the role of ultra-radical (extensive) cytoreductive surgery in ovarian cancer treatment. OBJECTIVES: To evaluate the effectiveness and morbidity associated with ultra-radical/extensive surgery in the management of advanced-stage epithelial ovarian cancer. SEARCH METHODS: We searched CENTRAL (2021, Issue 11), MEDLINE Ovid and Embase Ovid up to November 2021. We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. SELECTION CRITERIA: Randomised controlled trials (RCTs) or non-randomised studies (NRS), analysed using multivariate methods, that compared ultra-radical/extensive and standard surgery in women with advanced primary epithelial ovarian cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed whether potentially relevant studies met the inclusion criteria, abstracted data and assessed the risk of bias. We identified three NRS and conducted meta-analyses where possible. MAIN RESULTS: We identified three retrospective observational studies for inclusion in the review. Two studies included women exclusively undergoing upfront primary debulking surgery (PDS) and the other study including both PDS and interval debulking surgical (IDS) procedures. All studies were at critical risk of bias due to retrospective and non-randomised study designs. Meta-analysis of two studies, assessing 397 participants, found that women who underwent radical procedures, as part of PDS, may have a lower risk of mortality compared to women who underwent standard surgery (adjusted HR 0.60, 95% CI 0.43 to 0.82; I2 = 0%; very low-certainty evidence), but the evidence is very uncertain. The results were robust to a sensitivity analysis including women with more-extensive disease (carcinomatosis) (adjusted HR 0.61, 95% CI 0.44 to 0.85; I2 = 0%; n = 283, very low-certainty evidence), but the evidence is very uncertain. One study reported a comparison of radical versus standard surgical procedures associated with both PDS and IDS procedures, but a multivariate analysis was only undertaken for disease-free survival (DFS) and therefore the certainty of the evidence was not assessable for overall survival (OS) and remains very low. The lack of reporting of OS meant the study was at high risk of bias for selective reporting of outcomes. One study, 203 participants, found that women who underwent radical procedures as part of PDS may have a lower risk of disease progression or death compared to women who underwent standard surgery (adjusted HR 0.62, 95% CI 0.42 to 0.92; very low-certainty evidence), but the evidence is very uncertain. The results were robust to a sensitivity analysis in one study including women with carcinomatosis (adjusted HR 0.52, 95% CI 0.33 to 0.82; n = 139; very low-certainty evidence), but the evidence is very uncertain. A combined analysis in one study found that women who underwent radical procedures (using both PDS and IDS) may have an increased chance of disease progression or death than those who received standard surgery (adjusted HR 1.60, 95% CI 1.11 to 2.31; I2 = 0%; n = 527; very low-certainty evidence), but the evidence is very uncertain. In absolute and unadjusted terms, the DFS was 19.3 months in the standard surgery group, 15.8 in the PDS group and 15.9 months in the IDS group. All studies were at critical risk of bias and we only identified very low-certainty evidence for all outcomes reported in the review. Perioperative mortality, adverse events and quality of life (QoL) outcomes were either not reported or inadequately reported in the included studies. Two studies reported perioperative mortality (death within 30 days of surgery), but they did not use any statistical adjustment. In total, there were only four deaths within 30 days of surgery in both studies. All were observed in the standard surgery group, but we did not report a risk ratio (RR) to avoid potentially misleading results with so few deaths and very low-certainty evidence. Similarly, one study reported postoperative morbidity, but the authors did not use any statistical adjustment. Postoperative morbidity occurred more commonly in women who received ultra-radical surgery compared to standard surgery, but the certainty of the evidence was very low. AUTHORS' CONCLUSIONS: We found only very low-certainty evidence comparing ultra-radical surgery and standard surgery in women with advanced ovarian cancer. The evidence was limited to retrospective, NRSs and so is at critical risk of bias. The results may suggest that ultra-radical surgery could result in improved OS, but results are based on very few women who were chosen to undergo each intervention, rather than a randomised study and intention-to-treat analysis, and so the evidence is very uncertain. Results for progression/DFS were inconsistent and evidence was sparse. QoL and morbidity was incompletely or not reported in the three included studies. A separate prognostic review assessing residual disease as a prognostic factor in this area has been addressed elsewhere, which demonstrates the prognostic effect of macroscopic debulking to no macroscopic residual disease. In order to aid existing guidelines, the role of ultra-radical surgery in the management of advanced-stage ovarian cancer could be addressed through the conduct of a sufficiently powered, RCT comparing ultra-radical and standard surgery, or well-designed NRSs, if this is not possible.

Hysterectomy with radiotherapy or chemotherapy or both for women with locally advanced cervical cancer.

BACKGROUND: This is an update of the Cochrane Review published in Issue 4, 2015. Cervical cancer is one of the most frequent cause of death from gynaecological cancers worldwide. Many new cervical cancer cases in low-income countries present at an advanced stage. Standard care in Europe and the US for locally advanced cervical cancer (LACC) is chemoradiotherapy. In low-income countries, with limited access to radiotherapy, LACC may be treated with chemotherapy and hysterectomy. It is not certain if this improves survival. It is important to assess the value of hysterectomy with radiotherapy or chemotherapy, or both, as an alternative. OBJECTIVES: To determine whether hysterectomy, in addition to standard treatment with radiotherapy or chemotherapy, or both, in women with LACC (Stage IB2 to III) is safe and effective compared with standard treatment alone. SEARCH METHODS: We searched CENTRAL, MEDLINE via Ovid, Embase via Ovid, LILACS, trial registries and the grey literature up to 3 February 2022. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) that compared treatments involving hysterectomy versus radiotherapy or chemotherapy, or both, in women with LACC International Federation of Gynecology and Obstetrics (FIGO) Stages IB2 to III. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We independently assessed study eligibility, extracted data and assessed the risk of bias. Where possible, we synthesised overall (OS) and progression-free (PFS) or disease-free (DFS) survival in a meta-analysis using a random-effects model. Adverse events (AEs) were incompletely reported and we described the results of single trials in narrative form. We used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: From the searches we identified 968 studies. After deduplication, title and abstract screening, and full-text assessment, we included 11 RCTs (2683 women) of varying methodological quality. This update identified four new RCTs and three ongoing RCTs. The included studies compared: hysterectomy (simple or radical) with radiotherapy or chemoradiotherapy or neoadjuvant chemotherapy (NACT) versus radiotherapy alone or chemoradiotherapy (CCRT) alone or CCRT and brachytherapy. There is also one ongoing study comparing three groups: hysterectomy with CCRT versus hysterectomy with NACT versus CCRT. There were two comparison groups for which we were able to do a meta-analysis. Hysterectomy (radical) with neoadjuvant chemotherapy versus chemoradiotherapy alone Two RCTs with similar design characteristics (620 and 633 participants) found no difference in five-year OS between NACT with hysterectomy versus CCRT. Meta-analysis assessing 1253 participants found no evidence of a difference in risk of death (OS) between women who received NACT plus hysterectomy and those who received CCRT alone (HR 0.94, 95% CI 0.76 to 1.16; moderate-certainty evidence). In both studies, the five-year DFS in the NACT plus surgery group was worse (57%) compared with the CCRT group (65.6%), mostly for Stage IIB. Results of single trials reported no apparent difference in long-term severe complications, grade 3 acute toxicity and severe late toxicity between groups (very low-quality evidence). Hysterectomy (simple or radical) with neoadjuvant chemotherapy versus radiotherapy alone Meta-analysis of three trials of NACT with hysterectomy versus radiotherapy alone, assessing 571 participants, found that women who received NACT plus hysterectomy had less risk of death (OS) than those who received radiotherapy alone (HR 0.71, 95% CI 0.55 to 0.93; I2 = 0%; moderate-quality evidence). However, a significant number of participants who received NACT plus hysterectomy also had radiotherapy. There was no difference in the proportion of women with disease progression or recurrence (DFS and PFS) between NACT plus hysterectomy and radiotherapy groups (RR 0.75, 95% CI 0.53 to 1.05; I2 = 20%; moderate-quality evidence). The certainty of the evidence was low or very-low for all other comparisons for all outcomes. None of the trials reported quality of life outcomes. AUTHORS' CONCLUSIONS: From the available RCTs, we found insufficient evidence that hysterectomy with radiotherapy, with or without chemotherapy, improves the survival of women with LACC who are treated with radiotherapy or CCRT alone. The overall certainty of the evidence was variable across the different outcomes and was universally downgraded due to concerns about risk of bias. The certainty of the evidence for NACT and radical hysterectomy versus radiotherapy alone for survival outcomes was moderate. The same occurred for the comparison involving NACT and hysterectomy compared with CCRT alone. Evidence from other comparisons was generally sparse and of low or very low-certainty. This was mainly based on poor reporting and sparseness of data where results were based on single trials. More trials assessing medical management with and without hysterectomy may test the robustness of the findings of this review as further research is likely to have an important impact on our confidence in the estimate of effect.

Impact of residual disease as a prognostic factor for survival in women with advanced epithelial ovarian cancer after primary surgery.

BACKGROUND: Ovarian cancer is the seventh most common cancer among women and a leading cause of death from gynaecological malignancies. Epithelial ovarian cancer is the most common type, accounting for around 90% of all ovarian cancers. This specific type of ovarian cancer starts in the surface layer covering the ovary or lining of the fallopian tube. Surgery is performed either before chemotherapy (upfront or primary debulking surgery (PDS)) or in the middle of a course of treatment with chemotherapy (neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS)), with the aim of removing all visible tumour and achieving no macroscopic residual disease (NMRD). The aim of this review is to investigate the prognostic impact of size of residual disease nodules (RD) in women who received upfront or interval cytoreductive surgery for advanced (stage III and IV) epithelial ovarian cancer (EOC). OBJECTIVES: To assess the prognostic impact of residual disease after primary surgery on survival outcomes for advanced (stage III and IV) epithelial ovarian cancer. In separate analyses, primary surgery included both upfront primary debulking surgery (PDS) followed by adjuvant chemotherapy and neoadjuvant chemotherapy followed by interval debulking surgery (IDS). Each residual disease threshold is considered as a separate prognostic factor. SEARCH METHODS: We searched CENTRAL (2021, Issue 8), MEDLINE via Ovid (to 30 August 2021) and Embase via Ovid (to 30 August 2021). SELECTION CRITERIA: We included survival data from studies of at least 100 women with advanced EOC after primary surgery. Residual disease was assessed as a prognostic factor in multivariate prognostic models. We excluded studies that reported fewer than 100 women, women with concurrent malignancies or studies that only reported unadjusted results. Women were included into two distinct groups: those who received PDS followed by platinum-based chemotherapy and those who received IDS, analysed separately. We included studies that reported all RD thresholds after surgery, but the main thresholds of interest were microscopic RD (labelled NMRD), RD 0.1 cm to 1 cm (small-volume residual disease (SVRD)) and RD > 1 cm (large-volume residual disease (LVRD)). DATA COLLECTION AND ANALYSIS: Two review authors independently abstracted data and assessed risk of bias. Where possible, we synthesised the data in meta-analysis. To assess the adequacy of adjustment factors used in multivariate Cox models, we used the 'adjustment for other prognostic factors' and 'statistical analysis and reporting' domains of the quality in prognosis studies (QUIPS) tool. We also made judgements about the certainty of the evidence for each outcome in the main comparisons, using GRADE. We examined differences between FIGO stages III and IV for different thresholds of RD after primary surgery. We considered factors such as age, grade, length of follow-up, type and experience of surgeon, and type of surgery in the interpretation of any heterogeneity. We also performed sensitivity analyses that distinguished between studies that included NMRD in RD categories of < 1 cm and those that did not. This was applicable to comparisons involving RD < 1 cm with the exception of RD < 1 cm versus NMRD. We evaluated women undergoing PDS and IDS in separate analyses. MAIN RESULTS: We found 46 studies reporting multivariate prognostic analyses, including RD as a prognostic factor, which met our inclusion criteria: 22,376 women who underwent PDS and 3697 who underwent IDS, all with varying levels of RD. While we identified a range of different RD thresholds, we mainly report on comparisons that are the focus of a key area of clinical uncertainty (involving NMRD, SVRD and LVRD). The comparison involving any visible disease (RD > 0 cm) and NMRD was also important. SVRD versus NMRD in a PDS setting In PDS studies, most showed an increased risk of death in all RD groups when those with macroscopic RD (MRD) were compared to NMRD. Women who had SVRD after PDS had more than twice the risk of death compared to women with NMRD (hazard ratio (HR) 2.03, 95% confidence interval (CI) 1.80 to 2.29; I2 = 50%; 17 studies; 9404 participants; moderate-certainty). The analysis of progression-free survival found that women who had SVRD after PDS had nearly twice the risk of death compared to women with NMRD (HR 1.88, 95% CI 1.63 to 2.16; I2 = 63%; 10 studies; 6596 participants; moderate-certainty). LVRD versus SVRD in a PDS setting When we compared LVRD versus SVRD following surgery, the estimates were attenuated compared to NMRD comparisons. All analyses showed an overall survival benefit in women who had RD < 1 cm after surgery (HR 1.22, 95% CI 1.13 to 1.32; I2 = 0%; 5 studies; 6000 participants; moderate-certainty). The results were robust to analyses of progression-free survival. SVRD and LVRD versus NMRD in an IDS setting The one study that defined the categories as NMRD, SVRD and LVRD showed that women who had SVRD and LVRD after IDS had more than twice the risk of death compared to women who had NMRD (HR 2.09, 95% CI 1.20 to 3.66; 310 participants; I2 = 56%, and HR 2.23, 95% CI 1.49 to 3.34; 343 participants; I2 = 35%; very low-certainty, for SVRD versus NMRD and LVRD versus NMRD, respectively). LVRD versus SVRD + NMRD in an IDS setting Meta-analysis found that women who had LVRD had a greater risk of death and disease progression compared to women who had either SVRD or NMRD (HR 1.60, 95% CI 1.21 to 2.11; 6 studies; 1572 participants; I2 = 58% for overall survival and HR 1.76, 95% CI 1.23 to 2.52; 1145 participants; I2 = 60% for progression-free survival; very low-certainty). However, this result is biased as in all but one study it was not possible to distinguish NMRD within the < 1 cm thresholds. Only one study separated NMRD from SVRD; all others included NMRD in the SVRD group, which may create bias when comparing with LVRD, making interpretation challenging. MRD versus NMRD in an IDS setting Women who had any amount of MRD after IDS had more than twice the risk of death compared to women with NMRD (HR 2.11, 95% CI 1.35 to 3.29, I2 = 81%; 906 participants; very low-certainty). AUTHORS' CONCLUSIONS: In a PDS setting, there is moderate-certainty evidence that the amount of RD after primary surgery is a prognostic factor for overall and progression-free survival in women with advanced ovarian cancer. We separated our analysis into three distinct categories for the survival outcome including NMRD, SVRD and LVRD. After IDS, there may be only two categories required, although this is based on very low-certainty evidence, as all but one study included NMRD in the SVRD category. The one study that separated NMRD from SVRD showed no improved survival outcome in the SVRD category, compared to LVRD. Further low-certainty evidence also supported restricting to two categories, where women who had any amount of MRD after IDS had a significantly greater risk of death compared to women with NMRD. Therefore, the evidence presented in this review cannot conclude that using three categories applies in an IDS setting (very low-certainty evidence), as was supported for PDS (which has convincing moderate-certainty evidence).

Investigating the short and long-term effects of "nutritional-score" pricing on food pantry selections.

Approximately one out of ten households in the U.S. experienced food insecurity in 2019 (U. S. Department of Agriculture, 2020). Food pantries have taken on an important role in helping those with both short term and persistent food insecurity. As pantries are increasingly being arranged to allow clients to choose their own food, the question of how to encourage healthy choices is becoming an important topic for discussion. The Des Moines Area Religious Council (DMARC) implemented a "Nutritional-Score" program on September 1, 2017 as an experiment aimed at answering the above question. This program essentially changes the budgets of food pantry clients to make healthier choices cheaper and less healthy choices more expensive. We perform a Bayesian analysis using a zero-inflated Poisson (ZIP) model to help describe the effects of this program on the frequency with which clients choose less healthy items. We find evidence that the Nutritional-score program had a positive effect on the probability of rejecting less healthy items in the short and long term.

Hepatocyte nuclear factor 4α negatively regulates connective tissue growth factor during liver regeneration.

Liver regeneration after injury requires fine-tune regulation of connective tissue growth factor (Ctgf). It also involves dynamic expression of hepatocyte nuclear factor (Hnf)4α, Yes-associated protein (Yap), and transforming growth factor (Tgf)-ß. The upstream inducers of Ctgf, such as Yap, etc, are well-known. However, the negative regulator of Ctgf remains unclear. Here, we investigated the Hnf4α regulation of Ctgf post-various types of liver injury. Both wild-type animals and animals contained siRNA-mediated Hnf4α knockdown and Cre-mediated Ctgf conditional deletion were used. We observed that Ctgf induction was associated with Hnf4α decline, nuclear Yap accumulation, and Tgf-ß upregulation during early stage of liver regeneration. The Ctgf promoter contained an Hnf4α binding sequence that overlapped with the cis-regulatory element for Yap and Tgf-ß. Ctgf loss attenuated inflammation, hepatocyte proliferation, and collagen synthesis, whereas Hnf4α knockdown enhanced Ctgf induction and liver fibrogenesis. These findings provided a new mechanism about fine-tuned regulation of Ctgf through Hnf4α antagonism of Yap and Tgf-ß activities to balance regenerative and fibrotic signals.

Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines.

BACKGROUND: Repurposed medicines may have a role against the SARS-CoV-2 virus. The antiparasitic ivermectin, with antiviral and anti-inflammatory properties, has now been tested in numerous clinical trials. AREAS OF UNCERTAINTY: We assessed the efficacy of ivermectin treatment in reducing mortality, in secondary outcomes, and in chemoprophylaxis, among people with, or at high risk of, COVID-19 infection. DATA SOURCES: We searched bibliographic databases up to April 25, 2021. Two review authors sifted for studies, extracted data, and assessed risk of bias. Meta-analyses were conducted and certainty of the evidence was assessed using the GRADE approach and additionally in trial sequential analyses for mortality. Twenty-four randomized controlled trials involving 3406 participants met review inclusion. THERAPEUTIC ADVANCES: Meta-analysis of 15 trials found that ivermectin reduced risk of death compared with no ivermectin (average risk ratio 0.38, 95% confidence interval 0.19-0.73; n = 2438; I2 = 49%; moderate-certainty evidence). This result was confirmed in a trial sequential analysis using the same DerSimonian-Laird method that underpinned the unadjusted analysis. This was also robust against a trial sequential analysis using the Biggerstaff-Tweedie method. Low-certainty evidence found that ivermectin prophylaxis reduced COVID-19 infection by an average 86% (95% confidence interval 79%-91%). Secondary outcomes provided less certain evidence. Low-certainty evidence suggested that there may be no benefit with ivermectin for "need for mechanical ventilation," whereas effect estimates for "improvement" and "deterioration" clearly favored ivermectin use. Severe adverse events were rare among treatment trials and evidence of no difference was assessed as low certainty. Evidence on other secondary outcomes was very low certainty. CONCLUSIONS: Moderate-certainty evidence finds that large reductions in COVID-19 deaths are possible using ivermectin. Using ivermectin early in the clinical course may reduce numbers progressing to severe disease. The apparent safety and low cost suggest that ivermectin is likely to have a significant impact on the SARS-CoV-2 pandemic globally.

Chemotherapy versus surgery for initial treatment in advanced ovarian epithelial cancer.

BACKGROUND: Epithelial ovarian cancer presents at an advanced stage in the majority of women. These women require surgery and chemotherapy for optimal treatment. Conventional treatment has been to perform surgery first and then give chemotherapy. However, there may be advantages to using chemotherapy before surgery. OBJECTIVES: To assess whether there is an advantage to treating women with advanced epithelial ovarian cancer with chemotherapy before debulking surgery (neoadjuvant chemotherapy (NACT)) compared with conventional treatment where chemotherapy follows debulking surgery (primary debulking surgery (PDS)). SEARCH METHODS: We searched the following databases on 11 February 2019: CENTRAL, Embase via Ovid, MEDLINE (Silver Platter/Ovid), PDQ and MetaRegister. We also checked the reference lists of relevant papers that were identified to search for further studies. The main investigators of relevant trials were contacted for further information. SELECTION CRITERIA: Randomised controlled trials (RCTs) of women with advanced epithelial ovarian cancer (Federation of International Gynaecologists and Obstetricians (FIGO) stage III/IV) who were randomly allocated to treatment groups that compared platinum-based chemotherapy before cytoreductive surgery with platinum-based chemotherapy following cytoreductive surgery. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias in each included trial. MAIN RESULTS: We found 1952 potential titles, with a most recent search date of February 2019, of which five RCTs of varying quality and size met the inclusion criteria. These studies assessed a total of 1713 women with stage IIIc/IV ovarian cancer randomised to NACT followed by interval debulking surgery (IDS) or PDS followed by chemotherapy. We pooled results of the three studies where data were available and found little or no difference with regard to overall survival (OS) (1521 women; Hazard Ratio (HR) 0.95, 95% CI 0.84 to 1.07; I2 = 0%; moderate-certainty evidence) or progression-free survival in four trials where we were able to pool data (1631 women; HR 0.97, 95% CI 0.87 to 1.07; I2 = 0%; moderate-certainty evidence). Adverse events, surgical morbidity and quality of life (QoL) outcomes were poorly and incompletely reported across studies. There may be clinically meaningful differences in favour of NACT compared to PDS with regard to serious adverse effects (SAE grade 3+). These data suggest that NACT may reduce the risk of need for blood transfusion (risk ratio (RR) 0.80; 95% CI 0.64 to 0.99; four studies,1085 women; low-certainty evidence), venous thromboembolism (RR 0.28; 95% CI 0.09 to 0.90; four studies, 1490 women; low-certainty evidence), infection (RR 0.30; 95% CI 0.16 to 0.56; four studies, 1490 women; moderate-certainty evidence), compared to PDS. NACT probably reduces the need for stoma formation (RR 0.43, 95% CI 0.26 to 0.72; two studies, 581 women; moderate-certainty evidence) and bowel resection (RR 0.49, 95% CI 0.26 to 0.92; three studies, 1213 women; moderate-certainty evidence), as well as reducing postoperative mortality (RR 0.18; 95% CI 0.06 to 0.54:five studies, 1571 women; moderate-certainty evidence). QoL on the EORTC QLQ-C30 scale produced inconsistent and imprecise results in two studies (MD -1.34, 95% CI -2.36 to -0.32; participants = 307; very low-certainty evidence) and use of the QLQC-30 and QLQC-Ov28 in another study (MD 7.60, 95% CI 1.89 to 13.31; participants = 217; very low-certainty evidence) meant that little could be inferred. AUTHORS' CONCLUSIONS: The available moderate-certainty evidence suggests there is little or no difference in primary survival outcomes between PDS and NACT. NACT may reduce the risk of serious adverse events, especially those around the time of surgery, and the need for bowel resection and stoma formation. These data will inform women and clinicians and allow treatment to be tailored to the person, taking into account surgical resectability, age, histology, stage and performance status. Data from an unpublished study and ongoing studies are awaited.

Neoadjuvant chemotherapy before surgery versus surgery followed by chemotherapy for initial treatment in advanced ovarian epithelial cancer.

BACKGROUND: Epithelial ovarian cancer presents at an advanced stage in the majority of women. These women require a combination of surgery and chemotherapy for optimal treatment. Conventional treatment has been to perform surgery first and then give chemotherapy. However, there may be advantages to using chemotherapy before surgery. OBJECTIVES: To assess whether there is an advantage to treating women with advanced epithelial ovarian cancer with chemotherapy before debulking surgery (neoadjuvant chemotherapy (NACT)) compared with conventional treatment where chemotherapy follows debulking surgery (primary debulking surgery (PDS)). SEARCH METHODS: We searched the following databases up to 9 October 2020: the Cochrane Central Register of Controlled Trials (CENTRAL), Embase via Ovid, MEDLINE (Silver Platter/Ovid), PDQ and MetaRegister. We also checked the reference lists of relevant papers that were identified to search for further studies. The main investigators of relevant trials were contacted for further information. SELECTION CRITERIA: Randomised controlled trials (RCTs) of women with advanced epithelial ovarian cancer (Federation of International Gynaecologists and Obstetricians (FIGO) stage III/IV) who were randomly allocated to treatment groups that compared platinum-based chemotherapy before cytoreductive surgery with platinum-based chemotherapy following cytoreductive surgery. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias in each included trial. We extracted data of overall (OS) and progression-free survival (PFS), adverse events, surgically-related mortality and morbidity and quality of life outcomes.  We used GRADE methods to determine the certainty of evidence. MAIN RESULTS: We identified 2227 titles and abstracts through our searches, of which five RCTs of varying quality and size met the inclusion criteria. These studies assessed a total of 1774 women with stage IIIc/IV ovarian cancer randomised to NACT followed by interval debulking surgery (IDS) or PDS followed by chemotherapy. We pooled results of the four studies where data were available and found little or no difference with regard to overall survival (OS) (Hazard Ratio (HR) 0.96, 95% CI 0.86 to 1.08; participants = 1692; studies = 4; high-certainty evidence) or progression-free survival in four trials where we were able to pool data (Hazard Ratio 0.98, 95% CI 0.88 to 1.08; participants = 1692; studies = 4; moderate-certainty evidence). Adverse events, surgical morbidity and quality of life (QoL) outcomes were variably and incompletely reported across studies. There are probably clinically meaningful differences in favour of NACT compared to PDS with regard to overall postoperative serious adverse effects (SAE grade 3+): 6% in NACT group, versus 29% in PDS group, (risk ratio (RR) 0.22, 95% CI 0.13 to 0.38; participants = 435; studies = 2; heterogeneity index (I2) = 0%; moderate-certainty evidence). NACT probably results in a large reduction in the need for stoma formation: 5.9% in NACT group, versus 20.4% in PDS group, (RR 0.29, 95% CI 0.12 to 0.74; participants = 632; studies = 2; I2 = 70%; moderate-certainty evidence), and probably reduces the risk of needing bowel resection at the time of surgery: 13.0% in NACT group versus 26.6% in PDS group (RR 0.49, 95% CI 0.30 to 0.79; participants = 1565; studies = 4; I2 = 79%; moderate-certainty evidence). NACT reduces postoperative mortality: 0.6% in NACT group, versus 3.6% in PDS group, (RR 0.16, 95% CI 0.06 to 0.46; participants = 1623; studies = 5; I2 = 0%; high-certainty evidence). QoL on the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) scale produced inconsistent and imprecise results in three studies (MD -0.29, 95% CI -2.77 to 2.20; participants = 524; studies = 3; I2 = 81%; very low-certainty evidence) but the evidence is very uncertain and should be interpreted with caution. AUTHORS' CONCLUSIONS: The available high to moderate-certainty evidence suggests there is little or no difference in primary survival outcomes between PDS and NACT. NACT probably reduces the risk of serious adverse events, especially those around the time of surgery, and reduces the risk of postoperative mortality and the need for stoma formation. These data will inform women and clinicians (involving specialist gynaecological multidisciplinary teams) and allow treatment to be tailored to the person, taking into account surgical resectability, age, histology, stage and performance status. Data from an unpublished study and ongoing studies are awaited.

Interventions targeted at women to encourage the uptake of cervical screening.

BACKGROUND: This is an update of the Cochrane review published in Issue 5, 2011. Worldwide, cervical cancer is the fourth commonest cancer affecting women. High-risk human papillomavirus (HPV) infection is causative in 99.7% of cases. Other risk factors include smoking, multiple sexual partners, the presence of other sexually transmitted diseases and immunosuppression. Primary prevention strategies for cervical cancer focus on reducing HPV infection via vaccination and data suggest that this has the potential to prevent nearly 90% of cases in those vaccinated prior to HPV exposure. However, not all countries can afford vaccination programmes and, worryingly, uptake in many countries has been extremely poor. Secondary prevention, through screening programmes, will remain critical to reducing cervical cancer, especially in unvaccinated women or those vaccinated later in adolescence. This includes screening for the detection of pre-cancerous cells, as well as high-risk HPV. In the UK, since the introduction of the Cervical Screening Programme in 1988, the associated mortality rate from cervical cancer has fallen. However, worldwide, there is great variation between countries in both coverage and uptake of screening. In some countries, national screening programmes are available whereas in others, screening is provided on an opportunistic basis. Additionally, there are differences within countries in uptake dependent on ethnic origin, age, education and socioeconomic status. Thus, understanding and incorporating these factors in screening programmes can increase the uptake of screening. This, together with vaccination, can lead to cervical cancer becoming a rare disease. OBJECTIVES: To assess the effectiveness of interventions aimed at women, to increase the uptake, including informed uptake, of cervical screening. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Issue 6, 2020. MEDLINE, Embase and LILACS databases up to June 2020. We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. SELECTION CRITERIA: Randomised controlled trials (RCTs) of interventions to increase uptake/informed uptake of cervical screening. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias. Where possible, the data were synthesised in a meta-analysis using standard Cochrane methodology. MAIN RESULTS: Comprehensive literature searches identified 2597 records; of these, 70 met our inclusion criteria, of which 69 trials (257,899 participants) were entered into a meta-analysis. The studies assessed the effectiveness of invitational and educational interventions, lay health worker involvement, counselling and risk factor assessment. Clinical and statistical heterogeneity between trials limited statistical pooling of data. Overall, there was moderate-certainty evidence to suggest that invitations appear to be an effective method of increasing uptake compared to control (risk ratio (RR) 1.71, 95% confidence interval (CI) 1.49 to 1.96; 141,391 participants; 24 studies). Additional analyses, ranging from low to moderate-certainty evidence, suggested that invitations that were personalised, i.e. personal invitation, GP invitation letter or letter with a fixed appointment, appeared to be more successful. More specifically, there was very low-certainty evidence to support the use of GP invitation letters as compared to other authority sources' invitation letters within two RCTs, one RCT assessing 86 participants (RR 1.69 95% CI 0.75 to 3.82) and another, showing a modest benefit, included over 4000 participants (RR 1.13, 95 % CI 1.05 to 1.21). Low-certainty evidence favoured personalised invitations (telephone call, face-to-face or targeted letters) as compared to standard invitation letters (RR 1.32, 95 % CI 1.11 to 1.21; 27,663 participants; 5 studies). There was moderate-certainty evidence to support a letter with a fixed appointment to attend, as compared to a letter with an open invitation to make an appointment (RR 1.61, 95 % CI 1.48 to 1.75; 5742 participants; 5 studies). Low-certainty evidence supported the use of educational materials (RR 1.35, 95% CI 1.18 to 1.54; 63,415 participants; 13 studies) and lay health worker involvement (RR 2.30, 95% CI 1.44 to 3.65; 4330 participants; 11 studies). Other less widely reported interventions included counselling, risk factor assessment, access to a health promotion nurse, photo comic book, intensive recruitment and message framing. It was difficult to deduce any meaningful conclusions from these interventions due to sparse data and low-certainty evidence. However, having access to a health promotion nurse and attempts at intensive recruitment may have increased uptake. One trial reported an economic outcome and randomised 3124 participants within a national screening programme to either receive the standard screening invitation, which would incur a fee, or an invitation offering screening free of charge. No difference in the uptake at 90 days was found (574/1562 intervention versus 612/1562 control, (RR 0.94, 95% CI: 0.86 to 1.03). The use of HPV self-testing as an alternative to conventional screening may also be effective at increasing uptake and this will be covered in a subsequent review. Secondary outcomes, including cost data, were incompletely documented. The majority of cluster-RCTs did not account for clustering or adequately report the number of clusters in the trial in order to estimate the design effect, so we did not selectively adjust the trials. It is unlikely that reporting of these trials would impact the overall conclusions and robustness of the results. Of the meta-analyses that could be performed, there was considerable statistical heterogeneity, and this should be borne in mind when interpreting these findings. Given this and the low to moderate evidence, further research may change these findings. The risk of bias in the majority of trials was unclear, and a number of trials suffered from methodological problems and inadequate reporting. We downgraded the certainty of evidence because of an unclear or high risk of bias with regards to allocation concealment, blinding, incomplete outcome data and other biases. AUTHORS' CONCLUSIONS: There is moderate-certainty evidence to support the use of invitation letters to increase the uptake of cervical screening. Low-certainty evidence showed lay health worker involvement amongst ethnic minority populations may increase screening coverage, and there was also support for educational interventions, but it is unclear what format is most effective. The majority of the studies were from developed countries and so the relevance of low- and middle-income countries (LMICs), is unclear. Overall, the low-certainty evidence that was identified makes it difficult to infer as to which interventions were best, with exception of invitational interventions, where there appeared to be more reliable evidence.

Intraoperative imaging technology to maximise extent of resection for glioma: a network meta-analysis.

BACKGROUND: Multiple studies have identified the prognostic relevance of extent of resection in the management of glioma. Different intraoperative technologies have emerged in recent years with unknown comparative efficacy in optimising extent of resection. One previous Cochrane Review provided low- to very low-certainty evidence in single trial analyses and synthesis of results was not possible. The role of intraoperative technology in maximising extent of resection remains uncertain. Due to the multiple complementary technologies available, this research question is amenable to a network meta-analysis methodological approach. OBJECTIVES: To establish the comparative effectiveness and risk profile of specific intraoperative imaging technologies using a network meta-analysis and to identify cost analyses and economic evaluations as part of a brief economic commentary. SEARCH METHODS: We searched CENTRAL (2020, Issue 5), MEDLINE via Ovid to May week 2 2020, and Embase via Ovid to 2020 week 20. We performed backward searching of all identified studies. We handsearched two journals, Neuro-oncology and the Journal of Neuro-oncology from 1990 to 2019 including all conference abstracts. Finally, we contacted recognised experts in neuro-oncology to identify any additional eligible studies and acquire information on ongoing randomised controlled trials (RCTs). SELECTION CRITERIA: RCTs evaluating people of all ages with presumed new or recurrent glial tumours (of any location or histology) from clinical examination and imaging (computed tomography (CT) or magnetic resonance imaging (MRI), or both). Additional imaging modalities (e.g. positron emission tomography, magnetic resonance spectroscopy) were not mandatory. Interventions included fluorescence-guided surgery, intraoperative ultrasound, neuronavigation (with or without additional image processing, e.g. tractography), and intraoperative MRI. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the search results for relevance, undertook critical appraisal according to known guidelines, and extracted data using a prespecified pro forma. MAIN RESULTS: We identified four RCTs, using different intraoperative imaging technologies: intraoperative magnetic resonance imaging (iMRI) (2 trials, with 58 and 14 participants); fluorescence-guided surgery with 5-aminolevulinic acid (5-ALA) (1 trial, 322 participants); and neuronavigation (1 trial, 45 participants). We identified one ongoing trial assessing iMRI with a planned sample size of 304 participants for which results are expected to be published around winter 2020. We identified no published trials for intraoperative ultrasound. Network meta-analyses or traditional meta-analyses were not appropriate due to absence of homogeneous trials across imaging technologies. Of the included trials, there was notable heterogeneity in tumour location and imaging technologies utilised in control arms. There were significant concerns regarding risk of bias in all the included studies. One trial of iMRI found increased extent of resection (risk ratio (RR) for incomplete resection was 0.13, 95% confidence interval (CI) 0.02 to 0.96; 49 participants; very low-certainty evidence) and one trial of 5-ALA (RR for incomplete resection was 0.55, 95% CI 0.42 to 0.71; 270 participants; low-certainty evidence). The other trial assessing iMRI was stopped early after an unplanned interim analysis including 14 participants; therefore, the trial provided very low-quality evidence. The trial of neuronavigation provided insufficient data to evaluate the effects on extent of resection. Reporting of adverse events was incomplete and suggestive of significant reporting bias (very low-certainty evidence). Overall, the proportion of reported events was low in most trials and, therefore, issues with power to detect differences in outcomes that may or may not have been present. Survival outcomes were not adequately reported, although one trial reported no evidence of improvement in overall survival with 5-ALA (hazard ratio (HR) 0.82, 95% CI 0.62 to 1.07; 270 participants; low-certainty evidence). Data for quality of life were only available for one study and there was significant attrition bias (very low-certainty evidence). AUTHORS' CONCLUSIONS: Intraoperative imaging technologies, specifically 5-ALA and iMRI, may be of benefit in maximising extent of resection in participants with high-grade glioma. However, this is based on low- to very low-certainty evidence. Therefore, the short- and long-term neurological effects are uncertain. Effects of image-guided surgery on overall survival, progression-free survival, and quality of life are unclear. Network and traditional meta-analyses were not possible due to the identified high risk of bias, heterogeneity, and small trials included in this review. A brief economic commentary found limited economic evidence for the equivocal use of iMRI compared with conventional surgery. In terms of costs, one non-systematic review of economic studies suggested that, compared with standard surgery, use of image-guided surgery has an uncertain effect on costs and that 5-ALA was more costly. Further research, including completion of ongoing trials of ultrasound-guided surgery, is needed.

ANTECEDENTES: En múltiples estudios se ha identificado la importancia pronóstica del alcance de la resección en el tratamiento del glioma. En los últimos años han surgido diferentes tecnologías intraoperatorias con una eficacia comparativa desconocida para optimizar el alcance de la resección. Una revisión Cochrane anterior proporcionó evidencia de certeza baja a muy baja en los análisis de un solo ensayo y no fue posible la síntesis de los resultados. La función de la tecnología intraoperatoria para maximizar el alcance de la resección aún no está clara. Debido a las múltiples tecnologías complementarias disponibles, esta pregunta de investigación se presta a un enfoque metodológico de metanálisis en red. OBJETIVOS: Establecer el perfil comparativo de efectividad y riesgo de determinadas tecnologías de imagenología intraoperatorias mediante un metanálisis en red e identificar análisis de costos y evaluaciones económicas como parte de un breve comentario económico. MÉTODOS DE BÚSQUEDA: Se hicieron búsquedas en CENTRAL (2020, número 5), MEDLINE vía Ovid hasta la semana 2 de mayo de 2020, y Embase vía Ovid hasta la semana 20 de 2020. Se realizó una búsqueda retrospectiva de todos los estudios identificados. Se hicieron búsquedas manuales en dos revistas, Neuro­oncology y Journal of Neuro­oncology, desde 1990 hasta 2019, y se incluyeron todos los resúmenes de congresos. Finalmente, se estableció contacto con expertos reconocidos en neurooncología para identificar cualquier estudio elegible adicional y obtener información sobre los ensayos controlados aleatorizados (ECA) en curso. CRITERIOS DE SELECCIÓN: ECA que evaluaron a personas de todas las edades con presuntos tumores gliales nuevos o recidivantes (de cualquier ubicación o histología) a partir del examen clínico y la imagenología (tomografía computarizada [TC] o imagenología de resonancia magnética [IRM], o ambas). Las modalidades adicionales de imagenología (p.ej., tomografía de emisión de positrones, espectroscopia de resonancia magnética) no fueron obligatorias. Las intervenciones incluyeron cirugía guiada por fluorescencia, ecografía intraoperatoria, neuronavegación (con o sin procesamiento adicional de las imágenes, p.ej., tractografía) e IRM intraoperatoria. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores de la revisión, de forma independiente, evaluaron los resultados de la búsqueda en cuanto a su relevancia, realizaron la evaluación crítica según las guías conocidas y extrajeron los datos mediante un formulario predeterminado. RESULTADOS PRINCIPALES: Se identificaron cuatro ECA, que utilizaron diferentes tecnologías de imagenología intraoperatorias: la resonancia magnética (IRM) intraoperatoria (dos ensayos, con 58 y 14 participantes); la cirugía guiada por fluorescencia con ácido 5­aminolevulínico (5­ALA) (un ensayo, 322 participantes); y la neuronavegación (un ensayo, 45 participantes). Se identificó un ensayo en curso que evaluó la IRM con un tamaño de la muestra planificado de 304 participantes, del que se espera la publicación de los resultados alrededor del invierno de 2020. No se han identificado ensayos publicados sobre la ecografía intraoperatoria. Los metanálisis en red o los metanálisis tradicionales no fueron apropiados debido a la falta de ensayos homogéneos en tecnologías de imagenología. De los ensayos incluidos, hubo una notable heterogeneidad en la localización de los tumores y en las tecnologías de imagenología utilizadas en los brazos control. Hubo inquietudes significativas con respecto al riesgo de sesgo en todos los estudios incluidos. Un ensayo de IRM encontró un aumento en la extensión de la resección (razón de riesgos [RR] para la resección incompleta 0,13; intervalo de confianza [IC] del 95%: 0,02 a 0,96; 49 participantes; evidencia de certeza muy baja) y un ensayo de 5­ALA (RR para la resección incompleta 0,55; IC del 95%: 0,42 a 0,71; 270 participantes; evidencia de certeza baja). El otro ensayo que evaluó la IRM se interrumpió de forma temprana después de un análisis intermedio no planificado que incluyó 14 participantes; por lo tanto, el ensayo proporciona evidencia de calidad muy baja. El ensayo de neuronavegación no proporcionó datos suficientes para evaluar los efectos sobre el grado de resección. El informe de los eventos adversos fue incompleto e indicó la presencia de sesgo de informe significativo (evidencia de certeza muy baja). En general, la proporción de eventos informados fue baja en la mayoría de los ensayos y, por lo tanto, pueden haber estado presentes o no problemas relacionados con el poder estadístico suficiente para detectar diferencias en los desenlaces. No se informó adecuadamente sobre los desenlaces de supervivencia, aunque un ensayo no informó evidencia de mejora en la supervivencia general con 5­ALA (cociente de riesgos instantáneos [CRI] 0,82; IC del 95%: 0,62 a 1,07; 270 participantes; evidencia de certeza baja). Solo hubo datos disponibles sobre la calidad de vida de un estudio, con un sesgo de desgaste significativo (evidencia de certeza muy baja). CONCLUSIONES DE LOS AUTORES: Las tecnologías de imagenología intraoperatoria, específicamente la IRM y el 5­ALA, pueden ser beneficiosas para maximizar el grado de resección en los participantes con glioma de grado alto. Sin embargo, lo anterior se basa en evidencia de certeza baja a muy baja. Por lo tanto, los efectos neurológicos a corto y a largo plazo no están claros. No están claros los efectos de la cirugía guiada por imágenes sobre la supervivencia general, la supervivencia sin progresión ni la calidad de vida. No fue posible realizar metanálisis en red ni tradicionales debido al alto riesgo de sesgo identificado, a la heterogeneidad y a los ensayos pequeños incluidos en esta revisión. Un comentario económico breve encontró evidencia económica limitada sobre el uso equívoco de la IRM en comparación con la cirugía convencional. En cuanto a los costos, una revisión no sistemática de estudios económicos indicó que, en comparación con la cirugía estándar, el uso de la cirugía guiada por imágenes no tiene un efecto claro sobre los costos y que el ácido 5­aminolevulínico fue más costoso. Se necesitan estudios de investigación adicionales, incluida la finalización de los ensayos en curso sobre la cirugía guiada por ecografía.

Rituximab Is Ineffective for Treatment of Fatigue in Primary Biliary Cholangitis: A Phase 2 Randomized Controlled Trial.

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. Half of patients experience debilitating fatigue, which is currently untreatable. Previous studies have shown muscle bioenergetic abnormalities in PBC, including increased muscle acidosis with exercise linked to the antimitochondrial antibody (AMA) diagnostic of the disease, and reduced anaerobic threshold. In this study we addressed the hypothesis that fatigue in PBC is driven by muscle bioenergetic abnormality related to AMA, and that AMA reduction with B-cell depletion therapy will improve fatigue. In our single-center phase 2 randomized controlled trial, 57 participants aged 18 years or older with PBC and moderate to severe fatigue were randomized to receive two doses of either rituximab (1000 mg) or saline (placebo). The primary outcome measure was fatigue severity assessed using the PBC-40 fatigue domain at 3 months. Secondary outcome measures included patient-reported outcomes and immunological and bioenergetics disease parameters. Experimental outcomes included biochemical markers of disease severity. Improvement in fatigue score at 3 months was seen in both arms, with no significant difference (adjusted mean difference -0.9 [95% confidence interval -4.6 to 3.1]). Little difference was observed in other patient-reported outcomes or physical activity. Significant anaerobic threshold improvement was seen in the rituximab group, only but this was not associated with fatigue improvement. No treatment-emergent serious adverse events were seen. Conclusions: Rituximab was safe over the 12-month study period but showed no evidence of effectiveness for the treatment of fatigue in PBC. Anaerobic threshold improvement was seen, potentially linking AMA with muscle bioenergetics dysfunction; however, this was not related to improvement in fatigue. Rituximab had some evidence of a beneficial effect on alkaline phosphatase levels in this largely ursodeoxycholic acid (UDCA)-responding, early-disease stage cohort. (Hepatology 2018; 00:000-000).

Effect of ciclosporin on safety, lymphocyte kinetics and left ventricular remodelling in acute myocardial infarction.

AIMS: Following a favourable pilot trial using a single bolus of ciclosporin, it has been unclear why 2 large studies (CYCLE and CIRCUS) failed to prevent reperfusion injury and reduce infarct size in STEMI (ST elevation myocardial infarction). The purpose of this study was to assess the effect of ciclosporin on myocardial injury, left ventricular remodelling and lymphocyte kinetics in patients with acute STEMI undergoing primary percutaneous coronary intervention. METHODS: In this double-blind, single centre trial, we randomly assigned 52 acute STEMI patients with an onset of pain of <6 hours and blocked culprit artery to a single bolus of ciclosporin (n = 26) or placebo (n = 26, control group) prior to reperfusion by stent percutaneous coronary intervention. The primary endpoint was infarct size at 12 weeks. RESULTS: Mean infarct size at 12 weeks was identical in both groups (9.1% [standard deviation= 7.0] vs 9.1% [standard deviation = 7.0], P = .99; 95% confidence interval for difference: -4.0 to 4.1). CD3 T-lymphocytes dropped to similar levels at 90 minutes (867 vs 852 cells/µL, control vs ciclosporin) and increased to 1454 vs 1650 cells/µL at 24 hours. CONCLUSION: In our pilot trial, a single ciclosporin bolus did not affect infarct size or left ventricular remodelling, matching the results from CYCLE and CIRCUS. Our study suggests that ciclosporin does either not reach ischaemic cardiomyocytes, or requires earlier application during first medical contact. Finally, 1 bolus of ciclosporin is not sufficient to inhibit CD4 T-lymphocyte proliferation during remodelling. We therefore believe that further studies are warranted. (Evaluating the effectiveness of intravenous Ciclosporin on reducing reperfusion injury in pAtients undergoing PRImary percutaneous coronary intervention [CAPRI]; NCT02390674).