Health-related Quality of Life in Patients With Nonalcoholic Fatty Liver Disease: A Prospective Multi-center UK Study.

BACKGROUND & AIMS: It is unclear whether health-related quality of life (HRQoL) is impaired in patients with nonalcoholic fatty liver disease (NAFLD) without advanced fibrosis and how this compares with the general population. We aimed to assess HRQoL in patients with NAFLD in comparison to the general population and any associations of fibrosis severity and metabolic comorbidities with impairments in HRQoL. METHODS: We prospectively enrolled 513 consecutive patients with NAFLD who completed the EuroQol 5-dimensional questionnaire (EQ-5D) and Chronic Liver Disease Questionnaires (CLDQ). Demographic and clinical information, liver biopsy results, and/or liver stiffness (LS) by transient elastography were recorded. A general population sub-cohort of the Health Survey for England 2018 was used as a comparator (n = 5483), and a 1:1 propensity-score (PS) matching was performed, according to age, sex, body mass index, and type 2 diabetes mellitus (T2DM). RESULTS: EQ-5D-5L utility was significantly lower in 466 PS-matched patients with NAFLD compared with PS-matched controls (0.77 ± 0.27 vs 0.84 ± 0.19; P < .001), even in those without advanced fibrosis (F ≤2 or LS <8kPa) (0.80 ± 0.24 vs 0.84 ± 0.19; P = .024). HRQoL measures (EQ-5D-5L, EQ-VAS, CLDQ) did not differ between patients with NAFLD with and without advanced fibrosis. LS was independently associated with lower EQ-5D-5L in all patients with NAFLD but not in those without advanced fibrosis. In the latter, lower EQ-5D-5L was associated with female sex, T2DM, and depression. CONCLUSIONS: Patients with NAFLD, even those without advanced fibrosis, have worse HRQoL compared with the general population. In patients with NAFLD without advanced fibrosis, HRQoL is independently associated with non-liver comorbidities but not LS. Multi-disciplinary management is therefore required in NAFLD, irrespective of fibrosis severity.

A Systematic Review of Animal Models of NAFLD Finds High-Fat, High-Fructose Diets Most Closely Resemble Human NAFLD.

BACKGROUND AND AIMS: Animal models of human disease are a key component of translational hepatology research, yet there is no consensus on which model is optimal for NAFLD. APPROACH AND RESULTS: We generated a database of 3,920 rodent models of NAFLD. Study designs were highly heterogeneous, and therefore, few models had been cited more than once. Analysis of genetic models supported the current evidence for the role of adipose dysfunction and suggested a role for innate immunity in the progression of NAFLD. We identified that high-fat, high-fructose diets most closely recapitulate the human phenotype of NAFLD. There was substantial variability in the nomenclature of animal models: a consensus on terminology of specialist diets is needed. More broadly, this analysis demonstrates the variability in preclinical study design, which has wider implications for the reproducibility of in vivo experiments both in the field of hepatology and beyond. CONCLUSIONS: This systematic analysis provides a framework for phenotypic assessment of NAFLD models and highlights the need for increased standardization and replication.

Efficacy and Complications of External and Internal Pediatric Blepharoptosis Repair Techniques: A Systematic Review.

PURPOSE: To review and evaluate the efficacy and complication rates of external and internal blepharoptosis repair techniques in pediatric patients. METHODS: The systematic review protocol was published on PROSPERO (CRD42020197343). Embase, MEDLINE, CENTRAL, and ClinicalTrials.gov were searched without date limitations. Two independent reviewers evaluated the articles for inclusion. Study quality and risk of bias were assessed using GRADE and Cochrane's ROBINS-I tool, respectively. RESULTS: Of 2,228 articles screened, 23 studies involving 730 patients were included. There were 20 case series and 3 retrospective cohort studies, but no randomized controlled studies. Overall study quality was low with serious risk of bias according to the GRADE and ROBINS-I criteria, respectively. External levator resection was the most studied procedure, evaluated in 18 studies. Seven studies investigated internal approaches including the Fasanella-Servat procedure. There was no standardized evaluation of surgical efficacy. Reoperation rates were 16.6% (range 3.6-50.9%) for external levator resection compared with 22.2% (range 0.0-25.8%) for internal approaches. The commonest postoperative complications were not sight-threatening. The most consistently reported complication was undercorrection, occurring at rates of 8.4% (range 2.4-16.7%) and 15.3% (range 2.7-75.0%) for external levator resection and internal approaches, respectively. There were no consistently applied, validated patient-reported outcomes or cosmetic outcomes. CONCLUSIONS: External and internal approaches have been successfully employed in pediatric blepharoptosis repair. However, noncomparative designs and risk-of-bias limit existing studies. Thus, prospectively designed studies with standardized outcome measures are required to minimize reporting bias, facilitate evidence synthesis, and support clinical decision making.

Evidence-Based Blepharoplasty: An Analysis of Highly Cited Research Papers.

PURPOSE: The purpose of the study was to appraise the methodological quality of the highest impact blepharoplasty research and to describe prevalent research themes. METHODS: The 100 most highly cited research papers relevant to blepharoplasty were obtained from Web of Science, with no journal or date limitations applied. Data extraction included the study design, main research topic and specialty, outcome measures, and citation count. Each paper's level of evidence was independently evaluated by 2 authors according to the Oxford Centre for Evidence-Based Medicine system. RESULTS: Overall, the 100 most cited blepharoplasty research papers were cited by 4,194 papers. The mean number of citations for each paper was 73 (range: 42-239). Most of the papers presented level 4 (n = 51) or level 5 (n = 35) evidence, which is consistent with the predominance of case series (n = 47) and expert opinions (n = 18) amongst study designs. No papers achieved level 1 (highest) evidence. Six papers presented level 2 evidence and 8 papers presented level 3. Significant research foci included innovative surgical techniques (n = 65) and anatomical considerations (n = 10), with reconstructive and cosmetic implications. Senior authors were mainly affiliated with centers of plastic (n = 53) or ophthalmic/oculoplastic (n = 34) surgery. Only 3 papers used validated subjective or objective cosmetic outcome measures. CONCLUSIONS: Despite a significant impact on current practice, the level of evidence of the highly cited blepharoplasty research was predominantly low. Robust research methodology, through well-designed studies and standardized outcome measures, is necessary to facilitate evidence synthesis and guide clinical practice.

rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis.

BACKGROUND & AIMS: A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in NAFLD; however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis. METHODS: We performed a meta-analysis of studies with data on the association between rs641738C>T genotype and liver fat, NAFLD histology, and serum alanine aminotransferase (ALT), lipids or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed a random effects meta-analysis using recessive, additive and dominant genetic models. RESULTS: Data from 1,066,175 participants (9,688 with liver biopsies) across 42 studies were included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI 0.02-0.05], pz = 4.8×10-5) and diagnosis of NAFLD (odds ratio [OR] 1.17 [95% CI 1.05-1.3], pz = 0.003) in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis (OR 1.22 [95% CI 1.03-1.45], pz = 0.021) in Caucasian adults using a recessive model of inheritance (CC + CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (pz = 0.002) and lower serum triglycerides (pz = 1.5×10-4). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD. CONCLUSIONS: Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent. LAY SUMMARY: Fatty liver disease is a common condition where fat builds up in the liver, which can cause liver inflammation and scarring (including 'cirrhosis'). It is closely linked to obesity and diabetes, but some genes are also thought to be important. We did this study to see whether one specific change ('variant') in one gene ('MBOAT7') was linked to fatty liver disease. We took data from over 40 published studies and found that this variant near MBOAT7 is linked to more severe fatty liver disease. This means that drugs designed to work on MBOAT7 could be useful for treating fatty liver disease.

CADASIL and Bipolar Affective Disorder.

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare monogenic disorder caused by mutations in the NOTCH3 gene. The clinical features are primarily neurological, which include recurrent transient ischaemic attacks, strokes, and migraines. However, psychiatric manifestations which mainly include mood disturbances have also been reported in CADASIL. Manic symptoms and bipolar disorders are rarely documented in CADASIL and existing reports generally lack detailed descriptions of the psychiatric evaluation. We discuss a case of Bipolar Affective Disorder (BD) in a British woman with a family history of CADASIL. This case provides insight into the diagnosis and management of BD as well as the possible underlying aetiologies that should be considered. The similarities between BD and CADASIL in terms of imaging, genetic, and therapeutic aspects raise the possibility of common dysfunctional pathways. BD in CADASIL may warrant greater consideration by both psychiatrists as well as non-psychiatric specialists and further studies are required to understand the pathological significance.

Nutritional Intake after Liver Transplant: Systematic Review and Meta-Analysis.

Cardiovascular disease and its concurrent risk factors are prevalent after liver transplant (LT). Most of these risk factors are modifiable by diet. We aimed to synthesise the literature reporting the nutritional intake of liver transplant recipients (LTR) and the potential determinants of intake. We performed a systematic review and meta-analyses of studies published up until July 2021 reporting the nutritional intake of LTR. The pooled daily mean intakes were recorded as 1998 (95% CI 1889, 2108) kcal, 17 (17, 18)% energy from protein, 49 (48, 51)% energy from carbohydrates, 34 (33, 35)% energy from total fat, 10 (7, 13)% energy from saturated fat, and 20 (18, 21) g of fibre. The average fruit and vegetable intake ranged from 105 to 418 g/day. The length of time post-LT and the age and sex of the cohorts, as well as the continent and year of publication of each study, were sources of heterogeneity. Nine studies investigated the potential determinants of intake, time post-LT, gender and immunosuppression medication, with inconclusive results. Energy and protein requirements were not met in the first month post-transplant. After this point, energy intake was significantly higher and remained stable over time, with a high fat intake and low intake of fibre, fruits and vegetables. This suggests that LTR consume a high-energy, low-quality diet in the long term and do not adhere to the dietary guidelines for cardiovascular disease prevention.

Evaluating multidisciplinary glaucoma care: visual field progression and loss of sight year analysis in the community vs hospital setting.

BACKGROUND: A variety of shared care models have been developed, which aim to stratify glaucoma patients according to risk of disease progression. However, there is limited published data on the rate of glaucoma progression in the hospital vs community setting. Here we aimed to compare rates of glaucomatous visual field progression in the Cambridge Community Optometrist Glaucoma Scheme (COGS) and Addenbrooke's Hospital Glaucoma Clinic (AGC). METHODS: A retrospective comparative cohort review was performed. Patients with five or more visual field tests were included. Zeiss Forum software was used to calculate the MD progression rate (dB/year). Loss of sight years (LSY) were also calculated for both COGS and AGC. RESULTS: Overall, 8465 visual field tests from 854 patients were reviewed. In all, 362 eyes from the AGC group and 210 eyes from COGS were included. The MD deterioration rate was significantly lower in the COGS patients compared with the AGC group (-0.1 vs -0.3 dB/year; p < 0.0001). No patients in the COGS group were predicted to become blind within their lifetime by LSY analysis. Fifteen patients were at risk in the AGC group. CONCLUSION: This service evaluation shows that COGS is an effective scheme to stratify lower risk glaucoma patients, increasing the capacity within hospital eye services. COGS patients have a lower rate of visual field deterioration compared to AGC patients. Effective communication between community and tertiary schemes is essential to facilitate transfer of patients requiring further hospital management reliably and efficiently, with the potential for low-risk patients to be followed safely in the community.

Weight loss, insulin resistance, and study design confound results in a meta-analysis of animal models of fatty liver.

The classical drug development pipeline necessitates studies using animal models of human disease to gauge future efficacy in humans, however there is a low conversion rate from success in animals to humans. Non-alcoholic fatty liver disease (NAFLD) is a complex chronic disease without any established therapies and a major field of animal research. We performed a meta-analysis with meta-regression of 603 interventional rodent studies (10,364 animals) in NAFLD to assess which variables influenced treatment response. Weight loss and alleviation of insulin resistance were consistently associated with improvement in NAFLD. Multiple drug classes that do not affect weight in humans caused weight loss in animals. Other study design variables, such as age of animals and dietary composition, influenced the magnitude of treatment effect. Publication bias may have increased effect estimates by 37-79%. These findings help to explain the challenge of reproducibility and translation within the field of metabolism.

Obesity and diabetes are increasingly common diseases that can lead to other complications such as fatty liver disease. Fatty liver disease affects one in five people and is caused by a built-up of fat in the liver, which can result in scarring of the liver tissue and other serious complications. There is currently no cure for fatty liver disease. Drugs that have been effective in treating the condition in mice, lack efficacy in humans. To better understand why this is the case, Hunter, de Gracia Hahn, Duret, Im et al. conducted a review of over 5,000 published studies, analysing over 600 experiments. Hunter et al. asked which drugs improved fatty liver in mice the most and if they had the same effect in humans. They also tested whether the age of the mice affected the outcome of the experiments. The analyses revealed that the drugs that work best in mice are different to the ones that show some effect in humans. In mice, many of the drugs reduced their weight or lowered their blood sugar levels, which also improved the fatty liver condition. Moreover, drugs appeared to be less effective the older the mice were. However, most of these drugs do not cause weight loss or lower blood sugar levels in humans, suggesting that factors other than the intended action of these drug could affect the outcome of a mouse study. These findings will help shape future research into obesity, diabetes and fatty liver disease using mice. They highlight that results obtained from studies with mice so far do not predict if a drug will work in humans to treat fatty liver disease. Moreover, weight loss seems to be the most important factor linked to how efficiently a drug treats fatty liver disease.

The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status.

Resistance to anaplastic lymphoma kinase (ALK)-targeted therapy in ALK-positive non-small cell lung cancer has been reported, with the majority of acquired resistance mechanisms relying on bypass signaling. To proactively identify resistance mechanisms in ALK-positive neuroblastoma (NB), we herein employ genome-wide CRISPR activation screens of NB cell lines treated with brigatinib or ceritinib, identifying PIM1 as a putative resistance gene, whose high expression is associated with high-risk disease and poor survival. Knockdown of PIM1 sensitizes cells of differing MYCN status to ALK inhibitors, and in patient-derived xenografts of high-risk NB harboring ALK mutations, the combination of the ALK inhibitor ceritinib and PIM1 inhibitor AZD1208 shows significantly enhanced anti-tumor efficacy relative to single agents. These data confirm that PIM1 overexpression decreases sensitivity to ALK inhibitors in NB, and suggests that combined front-line inhibition of ALK and PIM1 is a viable strategy for the treatment of ALK-positive NB independent of MYCN status.