Publications

Organ fibrosis, including idiopathic pulmonary fibrosis, is associated with significant morbidity and mortality. Because currently available therapies have limited effect, there is a need to better understand the mechanisms by which organ fibrosis occurs. We have recently reported that transforming growth factor (TGF)-β, a key cytokine that promotes fibrogenesis, induces the expression of the enzymes of the de novo serine and glycine synthesis pathway in human lung fibroblasts, and that phosphoglycerate dehydrogenase (PHGDH; the first and rate-limiting enzyme of the pathway) is required to promote collagen protein synthesis downstream of TGF-β. In this study, we investigated whether inhibition of de novo serine and glycine synthesis attenuates lung fibrosis in vivo. We found that TGF-β induces mRNA and protein expression of PHGDH in murine fibroblasts. Similarly, intratracheal administration of bleomycin resulted in increased expression of PHGDH in mouse lungs, localized to fibrotic regions. Using a newly developed small molecule inhibitor of PHGDH (NCT-503), we tested whether pharmacologic inhibition of PHGDH could inhibit fibrogenesis both in vitro and in vivo. Treatment of murine and human lung fibroblasts with NCT-503 decreased TGF-β-induced collagen protein synthesis. Mice treated with the PHGDH inhibitor beginning 7 days after intratracheal instillation of bleomycin had attenuation of lung fibrosis. These results indicate that the de novo serine and glycine synthesis pathway is necessary for TGF-β-induced collagen synthesis and bleomycin-induced pulmonary fibrosis. PHGDH and other enzymes in the de novo serine and glycine synthesis pathway may be a therapeutic target for treatment of fibrotic diseases, including idiopathic pulmonary fibrosis.

Importance

Frailty is a measure of decreased physiological reserve that is associated with morbidity and mortality in major elective and emergency general surgery operations, independent of chronological age. To date, the association of frailty with outcomes in ambulatory general surgery has not been established.

Objective

To determine the association between frailty and perioperative morbidity in patients undergoing ambulatory general surgery operations.

Design, Setting, and Participants

A retrospective cohort study was conducted of 140 828 patients older than 40 years of age from the 2007-2010 American College of Surgeons National Surgical Quality Improvement Program Participant Use File who underwent ambulatory and 23-hour-stay hernia, breast, thyroid, or parathyroid surgery. Data analysis was performed from August 18, 2016, to June 21, 2017.

Main Outcomes and Measures

The association between the National Surgical Quality Improvement Program modified frailty index and perioperative morbidity was determined via multivariable logistic regression with random-effects modeling to control for clustering within Current Procedural Terminology codes.

Results

A total of 140 828 patients (80 147 women and 60 681 men; mean [SD] age, 59.3 [12.0] years) underwent ambulatory hernia (n = 71 455), breast (n = 51 267), thyroid, or parathyroid surgery (n = 18 106). Of these patients, 2457 (1.7%) experienced any type of perioperative complication and 971 (0.7%) experienced serious perioperative complications. An increasing modified frailty index was associated with a stepwise increase in the incidence of complications. In multivariable analysis adjusting for age, sex, race/ethnicity, anesthesia type, tobacco use, renal failure, corticosteroid use, and clustering by Current Procedural Terminology codes, an intermediate modified frailty index score (0.18-0.35, corresponding to 2-3 frailty traits) was associated with statistically significant odds ratios of 1.70 (95% CI, 1.54-1.88; P < .001) for any complication and 2.00 (95% CI, 1.72-2.34; P < .001) for serious complications. A high modified frailty index score (≥0.36, corresponding to ≥4 frailty traits) was associated with statistically significant odds ratios of 3.35 (95% CI, 2.52-4.46; P < .001) for any complication and 3.95 (95% CI, 2.65-5.87; P < .001) for serious complications. Anesthesia with local and monitored anesthesia care was the only modifiable covariate associated with decreased odds of serious 30-day complications, with an adjusted odds ratio of 0.66 (95% CI, 0.53-0.81; P < .001).

Conclusions and Relevance

Frailty is associated with increased perioperative morbidity in common ambulatory general surgery operations, independent of age, type of anesthesia, and other comorbidities. Surgeons should consider frailty rather than chronological age when counseling and selecting patients for elective ambulatory surgery.

Background

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the United States. Binge eating disorder (BED) is the most common form of eating disorder. NAFLD and BED have similar risk factors, including obesity, insulin resistance, and metabolic syndrome. The aim of our study was to examine prevalence of BED in NAFLD patients.

Methods

We administered the Binge Eating Scale (BES), a questionnaire validated to screen for BED, to NAFLD patients at our Fatty Liver Center. Demographics were retrieved retrospectively from our electronic medical record.

Results

Of the total 95 NAFLD patients screened, 22 (23.1%) had binge eating tendencies; 6 of the 22 (6.3%) scored 27 or more points, suggestive of severe binge eating. Patient demographics included 59 females and 36 males (14 females and 8 males positive for BED). Liver disease severity and of metabolic syndrome presence were similar in both groups: 45 patients had steatosis, 25 steatohepatitis, and 24 cirrhosis, of which 10 steatosis, 5 steatohepatitis, and 7 cirrhosis patients screened positive for BED. Of the NAFLD patients with BED, 50.0% had insulin resistance, 68.2% hypertension, and 50.0% hyperlipidemia, whereas among non-BED NAFLD patients 58.9% had insulin resistance, 63.0% hypertension, and 67.1% hyperlipidemia.

Conclusions

This pilot study suggests that BED may have a higher prevalence among NAFLD patients than in the general population. Based on these preliminary results, further study into the prevalence of BED is recommended. More data is need to identify effects of BED on the progression of NAFLD and role of BED treatment.