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INTRODUCTION: Irritable bowel syndrome (IBS) is common, affecting 12% of the population. However, the quality of evidence in support of current medical interventions has been rated as very low, and the majority of those with IBS report their symptoms as being unchanged or worsened over time. Diet is thought to play a significant role in IBS, and there is increasing focus on the therapeutic benefit of diet and supplementation. This study aims to compare dietary composition and serologic markers of nutritional status in those with and without IBS to determine potential targets for therapeutic supplementation. METHODS: All 17 national surveys between 1959 and 2019 were screened and only one, the Second National Health and Nutrition Examination Survey (NHANES II) (1976-1980), provided comprehensive data on IBS. We performed a cross-sectional analysis of serology and dietary composition of 12,295 individuals, aged 18 to 74 in NHANES II. Dietary composition was drawn from dietary recall questionnaires, and the diagnosis of IBS was based on self-reporting. RESULTS: Individuals with IBS had significantly higher copper-zinc ratios (1.70 versus 1.55, P = 0.048) and were more likely to have ratios above 1.8 (odds ratio 1.79, 95% confidence interval 1.02-3.13), suggestive of an underlying zinc deficiency. This deficiency may be due to their avoidance of milk, which was the largest source of dietary zinc in the study population. While they were significantly more likely to report dietary avoidances, they had no other serologic evidence of nutritional deficiencies. Additionally, dietary recall showed that they consumed significantly more daily calories ( P = 0.02), were more likely to take vitamin supplements ( P = 0.003) and that their macro and micronutrient intake was not significantly different. CONCLUSION: The findings suggest that individuals with IBS should be screened for zinc deficiency. Zinc deficiency may perpetuate the underlying pathophysiology of IBS and may contribute to the associated psychiatric conditions through zinc's role in the immune system, “brain-gut” axis, and gastrointestinal barrier integrity. This suggests that zinc supplementation may be a potential therapy both to mitigate underlying pathology as well as improve symptoms. Our findings should be confirmed in future studies, and the association of copper-zinc ratios with symptom severity, and the response of symptoms to supplementation could be investigated.

Accurate right ventricle functional analysis prior to mechanical circulatory support continues to be valuable for preoperative stratification of patients at risk for developing right ventricular (RV) failure. While cardiac magnetic resonance imaging (CMR) remains the gold standard, CMR is limited by availability and patient-specific contraindications. Further investigation of other imaging modalities would be beneficial as it may serve as a surrogate to identifying RV systolic dysfunction. A single-center, retrospective study including 29 patients with advanced heart failure was performed. All patients underwent ventricular functional analysis with both CMR and echocardiography, and 19 patients underwent right heart catheterization. Predictability with multimodal assessment of RV function was determined using logistic regression methods. Of the 29 participants, 10 had severe RV dysfunction. Tricuspid annular plane of systolic excursion was a modest predictor of RV dysfunction with odd ratio (OR) of 0.07 (0.01–0.72) and c-statistic of 0.79. Invasive hemodynamic measurement of cardiac index by thermodilution method was also predictive of RV dysfunction but failed to reach statistical significance (OR of 0.03, <0.001–1.28) with c-statistic of 0.83. The role of invasive hemodynamic data in predicting RV function compared with CMR should be further explored among patients with advanced heart failure.

Abstract Context SDHB mutations are found in an increasing number of neoplasms, most notably in paragangliomas and pheochromocytomas (PPGLs). SDHB-PPGLs are slow-growing tumors, but ∼50% of them may develop metastasis. The molecular basis of metastasis in these tumors is a long-standing and unresolved problem. Thus, a better understanding of the biology of metastasis is needed. Objective This study aimed to identify gene methylation changes relevant for metastatic SDHB-PPGLs. Design We performed genome-wide profiling of DNA methylation in diverse clinical and genetic PPGL subtypes, and validated protocadherin γ-C3 (PCDHGC3) gene promoter methylation in metastatic SDHB-PPGLs. Results We define an epigenetic landscape specific for metastatic SDHB-PPGLs. DNA methylation levels were found significantly higher in metastatic SDHB-PPGLs than in SDHB-PPGLs without metastases. One such change included long-range de novo methylation of the PCDHA, PCDHB, and PCDHG gene clusters. High levels of PCDHGC3 promoter methylation were validated in primary metastatic SDHB-PPGLs, it was found amplified in the corresponding metastases, and it was significantly correlated with PCDHGC3 reduced expression. Interestingly, this epigenetic alteration could be detected in primary tumors that developed metastasis several years later. We also show that PCDHGC3 down regulation engages metastasis-initiating capabilities by promoting cell proliferation, migration, and invasion. Conclusions Our data provide a map of the DNA methylome episignature specific to an SDHB-mutated cancer and establish PCDHGC3 as a putative suppressor gene and a potential biomarker to identify patients with SDHB-mutated cancer at high risk of metastasis who might benefit from future targeted therapies.

Background:Hereditary transthyretin amyloidosis (hATTR) is a rare protein misfolding disorder that causes progressive and debilitating polyneuropathy. A randomized, controlled phase 3 trial (NEURO‐TTR; NCT01737398) demonstrated efficacy and safety of inotersen in patients with hATTR polyneuropathy (Benson 2018 NEJM).Aims:To provide an update on the long‐term efficacy and safety of inotersen, an antisense oligonucleotide inhibitor of transthyretin protein production, in patients with hereditary transthyretin amyloidosis (hATTR) with polyneuropathy.Methods:Patients who completed NEURO‐TTR were eligible to enroll in an ongoing open‐label extension (OLE) study (NCT02175004). We report an update on the long‐term efficacy and safety of inotersen in patients with hATTR polyneuropathy after 24 months in the OLE. Assessments included modified Neuropathy Impairment Score +7 neurophysiologic tests composite score (mNIS+7), Norfolk Quality of Life–Diabetic Neuropathy questionnaire total score (Norfolk QoL‐DN), Short Form 36 Health Survey version 2 (SF‐36v2) physical component summary (PCS), and safety monitoring.Results:Of 139 patients who completed NEURO‐TTR, 135 (97.1%) enrolled in the OLE. As of 5/31/2018, some patients were ongoing but had not yet completed 24 months in the OLE, and longest inotersen exposure in both studies was 5.2 years. Patients who switched from placebo to inotersen in the OLE demonstrated slowing of neurologic disease progression by mNIS+7 and Norfolk QoL‐DN as early as 6 months after starting inotersen (mean change from OLE baseline to month 6/year 2: 6.22/5.08 for mNIS+7 and 0.54/2.26 for Norfolk QoL‐DN). Patients who received inotersen for 39 months (15 months NEURO‐TTR + 24 months OLE) continued to show benefit (mean change from OLE baseline to year 2: 11.18 for mNIS+7 and 5.22 for Norfolk QoL‐DN). Patients who continued inotersen also showed stabilization of health‐related quality of life measured by SF‐36v2 PCS. No evidence of increased risk for grade 4 thrombocytopenia or severe renal events has been observed with increased exposure duration; no new safety concerns have been identified.Summary/Conclusion:In the OLE, inotersen improved, halted, or slowed progression of hATTR polyneuropathy, with greater stabilization observed in patients who initiated inotersen earlier.

529 Background: The effect of metformin on sex hormones (SHs) levels that may impact breast cancer (BC) outcome, is unclear. We evaluated the effect of metformin on SHs in a subgroup of women enrolled in the placebo-controlled MA.32 trial, a phase III randomized study of nondiabetic subjects with T1-3, N0-3 BC randomized to receive metformin 850 mg po bid or placebo for 5 years. Methods: Our substudy was conducted on the group of post-menopausal women with estrogen receptor (ER) and progesterone receptor (PR) negative BC and not receiving endocrine treatment enrolled in the trial. Post-menopausal was defined as prior bilateral oophorectomy or > 12 months since last menses without prior hysterectomy. Fasting blood and adherence to study drug at baseline and 6 months was required. Sex hormone binding globulin (SHBG), free testosterone and estradiol serum levels were evaluated using Roche Modular competitive ECLIA (electrochemiluminescense immunoassay). We compared change from baseline to 6 months in estradiol, SHBG and free testosterone between study arms using Wilcoxon sum rank tests and regression models to adjust for baseline BMI and weight change. Results: 304 women were eligible, 135 metformin vs 169 placebo; tumor stage and prior (neo)adjuvant chemotherapy (98% in both arms) and HER2 targeted treatment were well balanced between arms. At baseline mean age was 58.2±6.9 vs 57.6±7.9 years, mean BMI 26.9±4.9 vs 28.6±6.2 Kg/m2, median estradiol 29.82 vs 31.01 pmol/L, SHBG 80.6 vs 73.7 nmol/L and free testosterone 0.02 vs 0.03 nmol/L in metformin vs placebo patients, respectively. In univariable analysis, median estradiol decreased significantly between baseline and 6 months on the metformin vs placebo arm (-4.81 vs 0 pmol/L, p = < 0.0001); this difference remained significant after controlling for baseline BMI (p = 0.0001) and weight change (mean weight change -1.8±3.5 vs 0.4±3.5 Kg, p = < 0.0001 for metformin vs placebo respectively) between baseline and 6 months (p = 0.0007). In contrast, there was no significant change in SHBG or free testosterone (median change SHBG -5.5 vs -5.9 nmol/L, p = 0.33; median change free testosterone 0 vs 0 nmol/L, p = 0.33 for metformin vs placebo respectively). Conclusions: Metformin lowered estradiol levels, independent of weight change in non-diabetic post-menopausal women with ER and PR negative BC enrolled onto MA.32 trial. This observation suggests a new metformin action that has potential relevance to BC management.