Cystic Fibrosis Reprograms Airway Epithelial IL-33 Release and Licenses IL-33-Dependent Inflammation.

Rationale: Type 2 inflammation has been described in people with cystic fibrosis (CF). Whether loss of CFTR (cystic fibrosis transmembrane conductance regulator) function contributes directly to a type 2 inflammatory response has not been fully defined. Objectives: The potent alarmin IL-33 has emerged as a critical regulator of type 2 inflammation. We tested the hypothesis that CFTR deficiency increases IL-33 expression and/or release and deletion of IL-33 reduces allergen-induced inflammation in the CF lung. Methods: Human airway epithelial cells (AECs) grown from non-CF and CF cell lines and Cftr+/+ and Cftr-/- mice were used in this study. Pulmonary inflammation in Cftr+/+ and Cftr-/- mice with and without IL-33 or ST2 (IL-1 receptor-like 1) germline deletion was determined by histological analysis, BAL, and cytokine analysis. Measurements and Main Results: After allergen challenge, both CF human AECs and Cftr-/- mice had increased IL-33 expression compared with control AECs and Cftr+/+ mice, respectively. DUOX1 (dual oxidase 1) expression was increased in CF human AECs and Cftr-/- mouse lungs compared with control AECs and lungs from Cftr+/+ mice and was necessary for the increased IL-33 release in Cftr-/- mice compared with Cftr+/+ mice. IL-33 stimulation of Cftr-/- CD4+ T cells resulted in increased type 2 cytokine production compared with Cftr+/+ CD4+ T cells. Deletion of IL-33 or ST2 decreased both type 2 inflammation and neutrophil recruitment in Cftr-/- mice compared with Cftr+/+ mice. Conclusions: Absence of CFTR reprograms airway epithelial IL-33 release and licenses IL-33-dependent inflammation. Modulation of the IL-33/ST2 axis represents a novel therapeutic target in CF type 2-high and neutrophilic inflammation.

Patient Perspectives of High-Quality Care on the Liver Transplant Waiting List: A Qualitative Study.

The prevalence of advanced liver disease and listing for liver transplantation is increasing. Prior assessments of quality of care neither incorporate nor emphasize the patient perspective on quality of care, which may impact clinical outcomes. Our aim was to identify patients' perceptions on what constitutes high quality of care, comparing the findings to existing frameworks and assessments to determine if a patient-derived tool assessing quality of care could facilitate efforts to improve health care. We conducted semistructured interviews of patients wait-listed for liver transplantation, asking patients to describe the quality of their health care with a specific focus on how coordination, communication, office visits, hospitalizations, and cost affect their perceptions of the quality of their care. Data collection conducted concurrently with analyses determined emerging themes and saturation. Themes were mapped to an existing quality-of-care conceptual framework. Qualitative analysis revealed thematic saturation after 15 interviews, and an additional 15 interviews were analyzed that confirmed thematic saturation, maximizing the strength of the results. The 30 patients had a median age of 56 years (range, 32-72 years) and included 15 (50%) men. Although patients believed they received a high quality of care, which was substantiated on current existing measures, a qualitative analysis suggested that patient priorities emphasized 5 themes not currently assessed: managing expectations, providing education, responding to patient needs, executing the care plan efficiently, and utilizing interdisciplinary communication and coordination of care. In conclusion, transplant candidates perceived 5 themes that constitute quality of care, and existing quality-of-care measures do not assess these domains, suggesting a role for creating a patient-derived quality-of-care tool to improve health care and clinical outcomes.

The impact of histopathology and NAB2-STAT6 fusion subtype in classification and grading of meningeal solitary fibrous tumor/hemangiopericytoma.

Meningeal solitary fibrous tumor (SFT)/hemangiopericytoma (HPC) is a rare tumor with propensity for recurrence and metastasis. Although multiple classification schemes have been proposed, optimal risk stratification remains unclear, and the prognostic impact of fusion status is uncertain. We compared the 2016 WHO CNS tumor grading scheme (CNS-G), a three-tier system based on histopathologic phenotype and mitotic count, to the 2013 WHO soft-tissue counterpart (ST-G), a two-tier system based on mitotic count alone, in a cohort of 133 patients [59 female, 74 male; mean age 54 years (range 20-87)] with meningeal SFT/HPC. Tumors were pathologically confirmed through review of the first tumor resection (n = 97), local recurrence (n = 35), or distant metastasis (n = 1). A STAT6 immunostain showed nuclear expression in 132 cases. NAB2-STAT6 fusion was detected in 99 of 111 successfully tested tumors (89%) including the single STAT6 immunonegative tumor. Tumors were classified by CNS-G as grade 1 (n = 43), 2 (n = 41), or 3 (n = 49), and by ST-G as SFT (n = 84) or malignant SFT (n = 49). Necrosis was present in 16 cases (12%). On follow-up, 42 patients had at least one subsequent recurrence or metastasis (7 metastasis only, 33 recurrence only, 2 patients had both). Twenty-nine patients died. On univariate analysis, necrosis (p = 0.002), CNS-G (p = 0.01), and ST-G (p = 0.004) were associated with recurrence-free (RFS) but not overall survival (OS). NAB2-STAT6 fusion type was not significantly associated with RFS or OS, but was associated with phenotype. A modified ST-G incorporating necrosis showed higher correlation with RFS (p = 0.0006) and remained significant (p = 0.02) when considering only the primary tumors. From our data, mitotic rate and necrosis appear to stratify this family of tumors most accurately and could be incorporated in a future grading scheme.

Salvage therapy outcomes for atypical meningioma.

Atypical menginomas demonstrate increased clinical aggressiveness characterized by recurrence and diminished survival. The optimal management of atypical meningioma in the recurrent setting is especially not well defined. To characterize outcomes following salvage treatment of recurrent atypical meningioma and to identify risk factors for further recurrence. Retrospective chart review was performed on 65 patients who underwent salvage treatment of atypical meningioma at a single institution. Data were analyzed using the Kaplan-Meier method and Cox proportional hazards modeling. Sixty-five patients with recurrent atypical meningioma and median imaging follow-up of 4.0 years (range 1.9-6.6 years) underwent 62 surgeries and 114 radiation treatments (RT) for salvage therapy. Salvage modality was surgery (21%), surgery/RT (25%), or RT alone (54%), associated with 2 year local freedom from recurrence (LFFR) of 36, 59, and 73%, respectively (P = 0.01). Twenty percent of patients experienced CTCAE grade ≥ 3 toxicity with salvage therapy. Thirty-nine percent of patients experienced ≥ 3 recurrences. The median disease-free survival intervals after first and second salvage treatments were 2.9 and 1.3 years, respectively. On univariate Cox analysis, prior subtotal resection, prior RT, tumor diameter > 2.5 cm, and multifocal local recurrence were associated with recurrence after salvage therapy. On multivariate logistic regression, only multifocal local recurrence was associated with further recurrence. Recurrent atypical meningioma is clinically and pathologically more aggressive than primary atypical meningioma, and the likelihood of durable local control with salvage therapy is lower. Future efforts should identify patients at risk of recurrence, and aggressive upfront treatment should be employed.

Cell-type-specific activation of the oligoadenylate synthetase-RNase L pathway by a murine coronavirus.

Previous studies have demonstrated that the murine coronavirus mouse hepatitis virus (MHV) nonstructural protein 2 (ns2) is a 2',5'-phosphodiesterase that inhibits activation of the interferon-induced oligoadenylate synthetase (OAS)-RNase L pathway. Enzymatically active ns2 is required for efficient MHV replication in macrophages, as well as for the induction of hepatitis in C57BL/6 mice. In contrast, following intranasal or intracranial inoculation, efficient replication of MHV in the brain is not dependent on an enzymatically active ns2. The replication of wild-type MHV strain A59 (A59) and a mutant with an inactive phosphodiesterase (ns2-H126R) was assessed in primary hepatocytes and primary central nervous system (CNS) cell types-neurons, astrocytes, and oligodendrocytes. A59 and ns2-H126R replicated with similar kinetics in all cell types tested, except macrophages and microglia. RNase L activity, as assessed by rRNA cleavage, was induced by ns2-H126R, but not by A59, and only in macrophages and microglia. Activation of RNase L correlated with the induction of type I interferon and the consequent high levels of OAS mRNA induced in these cell types. Pretreatment of nonmyeloid cells with interferon restricted A59 and ns2-H126R to the same extent and failed to activate RNase L following infection, despite induction of OAS expression. However, rRNA degradation was induced by treatment of astrocytes or oligodendrocytes with poly(I·C). Thus, RNase L activation during MHV infection is cell type specific and correlates with relatively high levels of expression of OAS genes, which are necessary but not sufficient for induction of an effective RNase L antiviral response.

Dormancy-like Phenotype of Aggregatibacter actinomycetemcomitans: Survival during Famine.

Microbes frequently experience nutrient deprivations in the natural environment and may enter dormancy. Aggregatibacter actinomycetemcomitans is known to establish long-term infections in humans. This study examined the dormancy-like phenotype of an A. actinomycetemcomitans strain D7S-1 and its isogenic smooth-colony mutant D7SS. A tissue culture medium RPMI-1640 was nutrient-deficient (ND) and unable to support A. actinomycetemcomitans growth. RPMI-1640 amended with bases was nutrient-limited (NL) and supported limited growth of A. actinomycetemcomitans less than the nutrient-enriched (NE) laboratory medium did. Strain D7S-1, after an initial 2-log reduction in viability, maintained viability from day 4 to day 15 in the NL medium. Strain D7SS, after 1-log reduction in viability, maintained viability from day 3 to day 5. In contrast, bacteria in the NE medium were either non-recoverable (D7S-1; >6-log reduction) or continued to lose viability (D7SS; 3-log reduction) on day 5 and beyond. Scanning and transmission electron microscopy showed that A. actinomycetemcomitans in the NL medium formed robust biofilms similar to those in the NE medium but with evidence of stress. A. actinomycetemcomitans in the ND medium revealed scant biofilms and extensive cellular damage. We concluded that A. actinomycetemcomitans grown in the NL medium exhibited a dormancy-like phenotype characterized by minimum growth, prolonged viability, and distinct cellular morphology.

NAB2::STAT6 fusions and genome-wide DNA methylation profiling: Predictors of patient outcomes in meningeal solitary fibrous tumors.

Meningeal solitary fibrous tumors (SFT) are rare and have a high frequency of local recurrence and distant metastasis. In a cohort of 126 patients (57 female, 69 male; mean age at surgery 53.0 years) with pathologically confirmed meningeal SFTs with extended clinical follow-up (median 9.9 years; range 15 days-43 years), we performed extensive molecular characterization including genome-wide DNA methylation profiling (n = 80) and targeted TERT promoter mutation testing (n = 98). Associations were examined with NAB2::STAT6 fusion status (n = 101 cases; 51 = ex5-7::ex16-17, 26 = ex4::ex2-3; 12 = ex2-3::exANY/other and 12 = no fusion) and placed in the context of 2021 Central Nervous System (CNS) WHO grade. NAB2::STAT6 fusion breakpoints (fusion type) were significantly associated with metastasis-free survival (MFS) (p = 0.03) and, on multivariate analysis, disease-specific survival (DSS) when adjusting for CNS WHO grade (p = 0.03). DNA methylation profiling revealed three distinct clusters: Cluster 1 (n = 38), Cluster 2 (n = 22), and Cluster 3 (n = 20). Methylation clusters were significantly associated with fusion type (p < 0.001), with Cluster 2 harboring ex4::ex2-3 fusion in 16 (of 20; 80.0%), nearly all TERT promoter mutations (7 of 8; 87.5%), and predominantly an "SFT" histologic phenotype (15 of 22; 68.2%). Clusters 1 and 3 were less distinct, both dominated by tumors having ex5-7::ex16-17 fusion (respectively, 25 of 33; 75.8%, and 12 of 18; 66.7%) and with variable histological phenotypes. Methylation clusters were significantly associated with MFS (p = 0.027), but not overall survival (OS). In summary, NAB2::STAT6 fusion type was significantly associated with MFS and DSS, suggesting that tumors with an ex5::ex16-17 fusion may have inferior patient outcomes. Methylation clusters were significantly associated with fusion type, TERT promoter mutation status, histologic phenotype, and MFS.

The Relationship between the Sexual Double Standard and Women's Sexual Health and Comfort.

The current research explores the relationship between Sexual Double Standard (SDS) endorsement and women's sexual health and attitudes. Women (n = 705) completed an SDS endorsement scale, and then answered a variety of questions in three main categories of outcome variables: sexual comfort, sexual reputation, and sexual health. Results suggest that women's SDS endorsement was not related to women's sexual comfort. Further, SDS endorsement was slightly positively related to how concerned women were about their sexual reputation. Regarding sexual health, SDS endorsement was related to a shorter timespan since women's last OBGYN screening, and unrelated to women's discomfort discussing birth control with their OBGYN. Results suggest there is much more to explore in targeted studies on the relationship of SDS endorsement to women's perceptions of their sexual reputations and their interactions with OBGYNs with respect to the SDS. Previous and related research is discussed, along with implications of the current research.

Evaluating the glucagon-like peptide-1 receptor in managing asthma.

PURPOSE OF REVIEW: The aim of this study was to discuss the role of glucagon-like peptide-1 (GLP-1) receptor signalling in reducing lung inflammation and potential use for GLP-1 receptor agonists (GLP-1RAs) in management of asthma. RECENT FINDINGS: Although GLP-1RA are currently used for the treatment of type 2 diabetes (T2D) and weight loss in obesity, there is much interest in expanding the indications for use in other diseases, including inflammatory pulmonary disease. In animal models of both acute and chronic pulmonary disease, use of GLP-1RA reduces airway inflammation, obstruction and fibrosis. In particular, GLP-1 receptor (GLP-1R) signalling seems to inhibit allergen-induced type 2 inflammation, making it an attractive agent for asthma. Results are especially promising in disease processes with disturbed metabolic regulation, such as T2D or metabolic syndrome. Retrospective clinical studies demonstrate promising evidence for the use of GLP-1RAs in comorbid diabetes and asthma, although prospective human studies are limited. SUMMARY: Here, we discuss the biology of GLP-1 and GLP-1R signalling, review the preclinical and mechanistic evidence for how GLP-1R signalling may reduce pulmonary inflammation, and summarize recent and upcoming clinical studies. Ultimately, targeting GLP-1R signalling may represent a novel approach for asthma therapy that is glucocorticoid sparing and possibly disease modifying.

Organizational Best Practices Supporting Mental Health in the Workplace.

OBJECTIVE: To provide a narrative review of best and promising practices for achieving exemplary mental health in the workplace as the foundation for the inaugural Carolyn C. Mattingly Award for Mental Health in the Workplace. METHODS: Research was drawn from peer-reviewed articles using the search terms associated with workplace mental health. RESULTS: Eight categories of best practices were identified: (1) culture, (2) robust mental health benefits, (3) mental health resources, (4) workplace policies and practices, (5) healthy work environment, (6) leadership support, (7) outcomes measurement, and (8) innovation. CONCLUSION: The review provided the scientific backing to support criteria developed for the Carolyn C. Mattingly Award for Mental Health in the Workplace. By recognizing organizations that apply evidence-based practices in their health and well-being programs, the Mattingly Award may inspire employers to adopt best practices.

Self-administered oral glucose tolerance test with capillary glucose measurements for the screening of diabetes mellitus in high-risk adults: a feasibility study.

INTRODUCTION: Early diagnosis of prediabetes based on blood sampling for the oral glucose tolerance test (OGTT) is crucial for intervention but multiple barriers hinder its uptake. This study aimed to assess the feasibility and precision of a self-administered capillary OGTT for type-2 diabetes mellitus (T2DM) in high-risk individuals. RESEARCH DESIGN AND METHODS: Participants with history of gestational diabetes or prediabetes were recruited in primary care. Due to their prediabetic status and previous diagnosis of gestational diabetes mellitus, a proportion of participants had previous experience doing OGTT. They self-administered the capillary OGTT and concurrently their venous glucose samples were obtained. They filled a questionnaire to collect their demographic information, views of their capillary OGTT, and their preferred site of the test. RESULTS: Among 30 participants enrolled in this feasibility study, 93.3% of them felt confident of performing the capillary OGTT themselves, and 70.0% preferred the test at home. Older, less educated participants found it less acceptable. Mean capillary glucose values were significantly higher than venous glucose values, with mean difference at 0.31 mmol/L (95% CI 0.13 to 0.49) at fasting, and 0.47 mmol/L (95% CI 0.12 to 0.92) 2 hours post-OGTT. Capillary and venous glucose measurements were correlated for fasting (r=0.95; p<0.001) and 2-hour-post-OGTT (r=0.95;p<0.001). The Fleiss-Kappa Score (0.79, p<0.0001) indicated fair agreement between the two methods. The capillary OGTT had excellent sensitivity (94.1%) and negative predictive value (NPV=91.7%) in identifying prediabetes or T2DM status, vis-a-vis to venous glucose samples. CONCLUSION: Self-administered capillary OGTT is feasible and acceptable, especially among younger adults, with excellent sensitivity and NPV compared with plasma-based OGTT.

Smartphone apps for depression and anxiety: a systematic review and meta-analysis of techniques to increase engagement.

Meta-analyses have shown that digital mental health apps can be efficacious in reducing symptoms of depression and anxiety. However, real-world usage of apps is typically not sustained over time, and no studies systematically examine which features increase sustained engagement with apps or the relationship between engagement features and clinical efficacy. We conducted a systematic search of the literature to identify empirical studies that (1) investigate standalone apps for depression and/or anxiety in symptomatic participants and (2) report at least one measure of engagement. Features intended to increase engagement were categorized using the persuasive system design (PSD) framework and principles of behavioral economics. Twenty-five studies with 4159 participants were included in the analysis. PSD features were commonly used, whereas behavioral economics techniques were not. Smartphone apps were efficacious in treating symptoms of anxiety and depression in randomized controlled trials, with overall small-to-medium effects (g = 0.2888, SE = 0.0999, z(15) = 2.89, p = 0.0119, Q(df = 14) = 41.93, p < 0.0001, I2 = 66.6%), and apps that employed a greater number of engagement features as compared to the control condition had larger effect sizes (ß = 0.0450, SE = 0.0164, t(15) = 2.7344, p = 0.0161). We observed an unexpected negative association between PSD features and engagement, as measured by completion rate (ß = -0.0293, SE = 0.0121, t(17) = 02.4142, p = 0.0281). Overall, PSD features show promise for augmenting app efficacy, though engagement, as reflected in study completion, may not be the primary factor driving this association. The results suggest that expanding the use of PSD features in mental health apps may increase clinical benefits and that other techniques, such as those informed by behavioral economics, are employed infrequently.

Peptide-Conjugated Phosphorodiamidate Morpholino Oligomers Retain Activity against Multidrug-Resistant Pseudomonas aeruginosa In Vitro and In Vivo.

Most antimicrobials currently in the clinical pipeline are modifications of existing classes of antibiotics and are considered short-term solutions due to the emergence of resistance. Pseudomonas aeruginosa represents a major challenge for new antimicrobial drug discovery due to its versatile lifestyle, ability to develop resistance to most antibiotic classes, and capacity to form robust biofilms on surfaces and in certain hosts such as those living with cystic fibrosis (CF). A precision antibiotic approach to treating Pseudomonas could be achieved with an antisense method, specifically by using peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs). Here, we demonstrate that PPMOs targeting acpP (acyl carrier protein), lpxC (UDP-(3-O-acyl)-N-acetylglucosamine deacetylase), and rpsJ (30S ribosomal protein S10) inhibited the in vitro growth of several multidrug-resistant clinical P. aeruginosa isolates at levels equivalent to those that were effective against sensitive strains. Lead PPMOs reduced established pseudomonal biofilms alone or in combination with tobramycin or piperacillin-tazobactam. Lead PPMO dosing alone or combined with tobramycin in an acute pneumonia model reduced lung bacterial burden in treated mice at 24 h and reduced morbidity up to 5 days postinfection. PPMOs reduced bacterial burden of extensively drug-resistant P. aeruginosa in the same model and resulted in superior survival compared to conventional antibiotics. These data suggest that lead PPMOs alone or in combination with clinically relevant antibiotics represent a promising therapeutic approach for combating P. aeruginosa infections.IMPORTANCE Numerous Gram-negative bacteria are becoming increasingly resistant to multiple, if not all, classes of existing antibiotics. Multidrug-resistant Pseudomonas aeruginosa bacteria are a major cause of health care-associated infections in a variety of clinical settings, endangering patients who are immunocompromised or those who suffer from chronic infections, such as people with cystic fibrosis (CF). Herein, we utilize antisense molecules that target mRNA of genes essential to bacterial growth, preventing the formation of the target proteins, including acpP, rpsJ, and lpxC We demonstrate here that antisense molecules targeted to essential genes, alone or in combination with clinically relevant antibiotics, were effective in reducing biofilms and protected mice in a lethal model of acute pneumonia.

One-year outcomes with ustekinumab therapy in infliximab-refractory paediatric ulcerative colitis: a multicentre prospective study.

BACKGROUND: The phase 3 (UNIFI) trial of ustekinumab (anti-interleukin 12/23) demonstrated efficacy even after prior biologic failure in adult ulcerative colitis (UC), but paediatric data are lacking. AIM: To prospectively monitor efficacy and serum concentrations of ustekinumab given to children with UC refractory to other biologics. METHODS: Children with anti-TNF refractory UC initiating ustekinumab intravenously at sites of the Canadian Children IBD Network prior to 12/2019 are included. The primary endpoint was steroid-free clinical remission with subcutaneous ustekinumab at 52 weeks (Paediatric Ulcerative Colitis Activity Index <10, no steroids ≥4 weeks). Ustekinumab levels were measured after week 20. Endoscopic improvement was defined as Mayo endoscopic subscore ≤1, or faecal calprotectin (FCP) <250 µg/g if not re-colonoscoped. RESULTS: At six sites between 01/2018 and 11/2019, 25 children (median [IQR] age 14.8 years [12.3-16.2], 72% female) with UC duration 2.3 years (1.1-4.2) received intravenous ustekinumab (median dose/kg of 6.4 [5.5-7.5] mg). All patients had failed prior infliximab therapy, and 12 (48%) also vedolizumab. Five patients discontinued ustekinumab after IV induction (four undergoing colectomy). On intent to treat basis, 44% achieved the primary endpoint of steroid-free remission at week 52, including nine (69%) of 13 who previously treated with anti-TNF only vs two (17%) of 12 who previously failed also by vedolizumab (P = 0.008). Seven of 11 remitters met the criteria for endoscopic improvement. The median (IQR) trough levels (µg/mL) were greater with q4 vs q8 weekly dosing (8.7 [4.6-9.9] vs 3.8 [12.7-4.8]) P = 0.02, but greater exposure was not associated with a superior rate of clinical remission. No adverse events were associated with therapy. CONCLUSION: Ustekinumab demonstrated efficacy in this paediatric cohort with otherwise treatment-refractory UC. Treatment failure was not due to inadequate drug exposure.

PSEUDOHYPOPHOSPHATEMIA IN A PATIENT WITH MULTIPLE MYELOMA.

OBJECTIVE: To discuss the diagnosis and management of paraprotein interference in the setting of multiple myeloma (MM). METHODS: We discuss the evaluation of hypophosphatemia in a patient with MM and present a review of the relevant literature. RESULTS: Our patient, who had a history of MM, was found to have persistently undetectable serum phosphate which did not respond to aggressive phosphate replacement. His clinical condition was not consistent with severe phosphate depletion and hence paraprotein interference secondary to MM was suspected. Re-analyzation of samples on a different machine showed normal serum inorganic phosphate levels. CONCLUSION: Paraprotein interference from MM causing pseudohypophosphatemia can be overlooked and lead to unnecessary treatment. Recognition of this phenomenon is important to all clinicians, especially in light of potential complications of unnecessary treatment.

Systematic review with meta-analysis on transplantation for alcohol-related liver disease: Very low evidence of improved outcomes.

BACKGROUND: Alcohol-related liver disease (ALD) is a leading cause of liver failure and indication for liver transplantation that arises in the setting of alcohol use disorder (AUD). Previous reviews of transplantation for ALD are limited in scope of outcomes and type of ALD studied. A comprehensive systematic review could improve use of transplantation in ALD and improve future research. We hypothesize that while transplanting ALD may improve mortality and relapse, findings will be limited by pre-specified causes of heterogeneity - assessment and treatment of AUD, definition of ALD, spectrum of ALD studied, assessment and rates of relapse, and study quality and bias. AIM: To optimize liver transplantation for ALD, understanding existing research to guide future research, we conducted a systematic review with meta-analysis. METHODS: We conducted a systematic review, comparing liver transplant to no-transplant in patients with ALD, with a primary outcome of both short- and long-term mortality and relapse. We performed a comprehensive search of MEDLINE, EMBASE, Web of Science, and The Cochrane Library databases for peer-reviewed journal articles comparing use of liver transplant in ALD to no-transplant. Two reviewers independently conducted screening, full text review, and data extraction according to the PRISMA guidelines. We report the quality of the evidence according to the GRADE criteria. RESULTS: We analyzed data from 10 studies. Of 1332 participants, 34.2% (456/1332) had undergone liver transplantation, while 65.8% (876/1332) had not. While random effects meta-analysis suggested transplant in comparison to no-transplant had an association of reduced mortality that did not reach statistical significance, relative risk (RR) = 0.51 (0.25-1.05), but not relapse risk, RR = 0.52 (0.18-1.53), significant heterogeneity limited these findings. When restricted to prospective data, transplant compared to no-transplant significantly reduced mortality, RR = 0.25 (0.13-0.46, P < 0.01), and relapse, RR = 0.25 (0.14-0.45, P < 0.01), with insignificant heterogeneity but persistent small-study effects. The overall quality of the evidence was Very Low. Heterogeneity analysis suggested that AUD assessment and treatment was often not reported while ALD, relapse assessment and rate, and data collection were institutionally rather than standardly defined. CONCLUSION: Systematic review of liver transplantation for ALD suggests reduced mortality and relapse in heterogeneous, institution-specific populations with inherent bias. To understand efficacy of transplanting ALD, our research approach must change.

Integrated models incorporating radiologic and radiomic features predict meningioma grade, local failure, and overall survival.

BACKGROUND: We investigated prognostic models based on clinical, radiologic, and radiomic feature to preoperatively identify meningiomas at risk for poor outcomes. METHODS: Retrospective review was performed for 303 patients who underwent resection of 314 meningiomas (57% World Health Organization grade I, 35% grade II, and 8% grade III) at two independent institutions, which comprised primary and external datasets. For each patient in the primary dataset, 16 radiologic and 172 radiomic features were extracted from preoperative magnetic resonance images, and prognostic features for grade, local failure (LF) or overall survival (OS) were identified using the Kaplan-Meier method, log-rank tests and recursive partitioning analysis. Regressions and random forests were used to generate and test prognostic models, which were validated using the external dataset. RESULTS: Multivariate analysis revealed that apparent diffusion coefficient hypointensity (HR 5.56, 95% CI 2.01-16.7, P = .002) was associated with high grade meningioma, and low sphericity was associated both with increased LF (HR 2.0, 95% CI 1.1-3.5, P = .02) and worse OS (HR 2.94, 95% CI 1.47-5.56, P = .002). Both radiologic and radiomic predictors of adverse meningioma outcomes were significantly associated with molecular markers of aggressive meningioma biology, such as somatic mutation burden, DNA methylation status, and FOXM1 expression. Integrated prognostic models combining clinical, radiologic, and radiomic features demonstrated improved accuracy for meningioma grade, LF, and OS (area under the curve 0.78, 0.75, and 0.78, respectively) compared to models based on clinical features alone. CONCLUSIONS: Preoperative radiologic and radiomic features such as apparent diffusion coefficient and sphericity can predict tumor grade, LF, and OS in patients with meningioma.