Low left ventricular ejection fraction, complication rescue, and long-term survival after coronary artery bypass grafting.

OBJECTIVES: To evaluate the association between low left ventricular ejection fraction (LVEF), complication rescue, and long-term survival after isolated coronary artery bypass grafting. METHODS: National cohort study of patients who underwent isolated coronary artery bypass grafting (2000-2016) using Veterans Affairs Surgical Quality Improvement Program data. Left ventricular ejection fraction was categorized as ≥35% (n = 55,877), 25%-34% (n = 3893), or <25% (n = 1707). Patients were also categorized as having had no complications, 1 complication, or more than 1 complication. The association between LVEF, complication rescue, and risk of death was evaluated with multivariable Cox regression. RESULTS: Among 61,477 patients, 6586 (10.7%) had a perioperative complication and 2056 (3.3%) had multiple complications. Relative to LVEF ≥35%, decreasing ejection fraction was associated with greater odds of complications (25%-34%, odds ratio, 1.30 [1.18-1.42]; <25%, odds ratio, 1.65 [1.43-1.92]). There was a dose-response relationship between decreasing LVEF and overall risk of death (≥35% [ref]; 25%-35%, hazard ratio, 1.46 [1.37-1.55]; <25%, hazard ratio, 1.68 [1.58-1.79]). Among patients who were rescued from complications, there were decreases in 10-year survival, regardless of LVEF. Among those rescued after multiple complications, LVEF was no longer associated with risk of death. CONCLUSIONS: While decreasing LVEF is associated with post-coronary artery bypass grafting complications, patients rescued from complications have worse long-term survival, regardless of left ventricular function. Prevention and timely treatment of complications should remain a focus of quality improvement initiatives, and future work is needed to mitigate their long-term detrimental impact on survival.

Long-term sequelae of drug-induced liver injury.

Drug-induced liver injury (DILI) has a very variable clinical and biochemical phenotype and differs widely in severity, from mild injury to life-threatening liver failure. Chronic injury has also been reported to occur at a variable frequency, ranging from 3.4% to 39%, 6-12 months after discontinuing the implicated agent. This wide range is probably related to various definitions of chronic liver injury and variable selection of patients. The long-term sequalae of this chronic injury in terms of morbidity and mortality are unclear, although rare vanishing bile duct syndrome is associated with an unfavourable prognosis, with increased risk of chronic liver failure and need for liver transplantation. Other forms of long-term sequalae associated with DILI are progressive fibrosis, autoimmune-like hepatitis, secondary sclerosing cholangitis, sinusoidal obstruction syndrome and, as a common final stage, the development of cirrhosis, portal hypertension and its complications. Immune checkpoint inhibitors, which can cause an autoimmune-like phenotype have also recently been shown to cause sclerosing cholangitis with cytotoxic T CD8+ cell infiltration in biliary tracts. DILI has been shown to have a significant impact on health-related quality of life but very little is known about its psychological consequences in the long-term. Further investigations with structured long-term follow-up and periodic quality of life surveys are needed to assess the impact of DILI on psychological outcomes, particularly in those with chronic sequelae.

Long-term outcomes of the arterial switch operation.

OBJECTIVES: The arterial switch operation (ASO) has excellent early outcomes in the modern era. We sought to determine the long-term outcomes in patients who underwent an ASO at a single institution. METHODS: Patients who underwent an ASO between 1983 and 2015 were identified from the hospital database and retrospectively reviewed using hospital records. RESULTS: From 1983 to 2015, 844 patients with a biventricular circulation underwent an ASO. There were 28 (3.3%, 28/844) early deaths. Follow-up was available for 94% (729/774) of local patients after hospital discharge. Median follow-up was 15 years (interquartile range, 8-20 years). There were 187 (26%, 187/729) patients with more than 20 years of follow-up and 95 (13%, 95/729) patients with more than 25 years of follow-up. Overall survival was 95% (95% confidence interval [CI], 94%-97%) at 10 and 25 years after the ASO. At 25 years after ASO, freedom from overall reintervention was 77% (95% CI, 73%-81%), freedom from reoperation on the neoaortic root or neoaortic valve was 92% (95% CI, 88%-95%), and freedom from coronary reoperation was 99% (95% CI, 98%-99.7%). Left ventricular (LV) systolic function was normal in 595 of 609 (98%) of patients who had LV function quantified at latest follow-up. Of the 95 patients with more than 25 years of follow-up after ASO, 6 (6.3%) had at least moderate neoaortic valve regurgitation (AR) and 8 (8.4%) had undergone replacement of the neoaortic valve. CONCLUSIONS: Overall, survivors of ASO have excellent late survival and normal LV systolic function into adult life. However, AR and reoperation on the neoaortic valve remains an issue for older patients.

Differential DNA methylation and changing cell-type proportions as fibrotic stage progresses in NAFLD.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is characterized by changes in cell composition that occur throughout disease pathogenesis, which includes the development of fibrosis in a subset of patients. DNA methylation (DNAm) is a plausible mechanism underlying these shifts, considering that DNAm profiles differ across tissues and cell types, and DNAm may play a role in cell-type differentiation. Previous work investigating the relationship between DNAm and fibrosis in NAFLD has been limited by sample size and the number of CpG sites interrogated. RESULTS: Here, we performed an epigenome-wide analysis using Infinium MethylationEPIC array data from 325 individuals with NAFLD, including 119 with severe fibrosis and 206 with no histological evidence of fibrosis. After adjustment for latent confounders, we identified 7 CpG sites whose DNAm associated with fibrosis (p < 5.96 × 10-8). Analysis of RNA-seq data collected from a subset of individuals (N = 56) revealed that gene expression at 288 genes associated with DNAm at one or more of the 7 fibrosis-related CpGs. DNAm-based estimates of cell-type proportions showed that estimated proportions of natural killer cells increased, while epithelial cell proportions decreased with disease stage. Finally, we used an elastic net regression model to assess DNAm as a biomarker of fibrotic stage and found that our model predicted fibrosis with a sensitivity of 0.93 and provided information beyond a model based solely on cell-type proportions. CONCLUSION: These findings are consistent with DNAm as a mechanism underpinning or marking fibrosis-related shifts in cell composition and demonstrate the potential of DNAm as a possible biomarker of NAFLD fibrosis.

Clinical Features and Outcomes of Combined Pulmonary Fibrosis and Emphysema After Lung Transplantation.

BACKGROUND: Combined pulmonary fibrosis and emphysema (CPFE) is recognized as a characteristic syndrome of smoking-related interstitial lung disease that has a worse prognosis than idiopathic pulmonary fibrosis (IPF). However, outcomes after lung transplantation for CPFE have not been reported. The aim of this study is to describe the clinical features and outcomes of CPFE after lung transplantation. RESEARCH QUESTION: What are the clinical features and outcomes of CPFE after lung transplantation? STUDY DESIGN AND METHODS: This is a single-center retrospective cohort study of patients with CPFE and IPF who underwent lung transplantation at our center between January 2011 and December 2016. We defined CPFE as ≥10% emphysema in the upper lung fields combined with fibrosis on high-resolution CT scan. We characterized the clinical features of patients with CPFE and compared their outcomes after lung transplantation with those with IPF. RESULTS: Twenty-seven of 172 (16%) patients with IPF met criteria for CPFE. Severe pulmonary hypertension was present in 16 of 27 (59%) patients with CPFE. On logistic regression analysis, CPFE was significantly associated with primary graft dysfunction (PGD) grade 3 (OR, 3.14; 95% CI, 1.18-8.37; P = .02). On competing risk regression analysis, CPFE was associated with acute cellular rejection (ACR) grade ≥ A2, and chronic lung allograft dysfunction (CLAD) (hazard ratio [HR], 1.89; 95% CI, 1.10-3.25; P = .02; HR, 1.96; 95% CI, 1.02-3.77; P = .04, respectively). Five-year survival was 79.0% for the CPFE group and 75.4% for the IPF group (log-rank P = .684). INTERPRETATION: After transplantation, patients with CPFE were more likely to develop PGD, ACR, and CLAD compared with those with IPF. However, survival was not significantly different between the two groups.

Pulmonary Apical Cap as a Potential Risk Factor for Pleuroparenchymal Fibroelastosis.

Pleuroparenchymal fibroelastosis (PPFE) is a progressive and frequently fatal interstitial lung disease that involves the upper lobes. Although its cause remains unknown, the histopathologic evidence underlying PPFE bears striking resemblance to that of the pulmonary apical cap (PAC), a relatively common and benign entity. We describe the case of a patient with PAC that evolved into distinctly asymmetric PPFE over 6 years after unilateral surgical lung injury. Given the histologic similarity between these two conditions, we propose that these two entities underlie common biologic pathways of abnormal response to lung injury, with the presence of a PAC increasing susceptibility to the development of PPFE in the face of ongoing inflammatory insults. This case describes the histopathologic evolution of PAC to PPFE before and after an inciting injury.

Outcomes in Young Adults With Tetralogy of Fallot and Pulmonary Annular Preserving or Transannular Patch Repairs.

BACKGROUND: Early surgical tetralogy of Fallot (ToF) repair involved patching across the pulmonic annulus (transannular patch [TAP] repair), which resulted in severe pulmonic regurgitation. Long-term outcome improvements were anticipated with modifications that preserved the pulmonic annulus (annulus-preserving [AP] repair). The objective of the present study was to evaluate the need for late reintervention in adults with AP repair and those with TAP repair. METHODS: We conducted a retrospective review of adults (born 1981-1996) with childhood intracardiac ToF repairs at a tertiary care center. The primary cardiovascular outcome was need for reintervention after primary intracardiac repair of ToF. Secondary outcomes included a composite of death, heart failure, and ventricular arrhythmias. RESULTS: Two hundred thirty adults were included: 104 with AP repair and 126 with TAP repair. The median age at last follow up was 25 years (interquartile range [IQR] 20-28) and the median follow-up duration was 7.9 years (IQR 3.5-12). Reintervention of any type was significantly more common in the TAP group during both childhood and adulthood (72.2% TAP vs 20.2% AP, HR 5.5, 95% CI 3.4-9.0; P < 0.001). Pulmonary valve replacement (PVR) was almost 6 times more likely in adults with TAP repair (65.1% TAP vs 16.3% AP, HR 5.7, 95% CI 3.4-9.7; P < 0.001). CONCLUSIONS: Patients who had AP ToF repair had significantly fewer late reinterventions compared with TAP repair, with the majority of reinterventions due to PVR. More long-term follow-up is required.

Clavicle Nonunion RepairWhat Can Patients Expect?

BACKGROUND: The purpose of this study was to compare the long-term functional status of patients treated surgically for a clavicular nonunion using patients treated either op-eratively or non-operatively for an acute clavicle fracture as a comparison group. METHODS: Twenty consecutive patients treated by a single surgeon for a clavicle fracture nonunion were identified. For comparison of outcomes, acute clavicle fractures were identified from an electronic medical record (EMR) query of the same orthopedic surgeon. Ninety acute clavicle fracture patients were identified and 27 (30%) patients were available for long-term follow-up. Clavicular nonunions were compared to acute clavicle fracture patients in a univariate analysis then a multivariate analysis to analyze clavicle nonunion patients against operative and non-operative acute clavicle fracture patients. The main outcome measures were time to bony union, postoperative complications, visual analog scale (VAS) pain scores, and Short Musculoskeletal Functional Assessment (SMFA) scores at long-term follow-up. RESULTS: There was no difference in time to healing or functional outcomes as assessed by SMFA and VAS pain scores between clavicle nonunion and acute fracture patients. Postoperative complications also did not differ between the groups. CONCLUSIONS: Patients who are treated surgically for clavicular nonunions ultimately regain a similar functional status as patients who are treated either operatively or non-operatively for an acute clavicle fracture and heal acutely.

Relationship of Ventricular Morphology and Atrioventricular Valve Function to Long-Term Outcomes Following Fontan Procedures.

BACKGROUND: The influence of ventricular morphology on Fontan outcomes is controversial. OBJECTIVES: This study hypothesized that dysfunction of the single right ventricle (RV) and right atrioventricular valve regurgitation (AVVR) increases over time and adversely impacts late outcomes following a Fontan operation. A single-center retrospective study was performed. METHODS: From 1985 through 2018, 1,162 patients underwent the Fontan procedure at our center and were included in this study. Transplant and takedown free survival, ventricular, and atrioventricular valve dysfunction after Fontan were analyzed. Death or heart transplantation information was obtained from the National Death Index and the Scientific Registry of Transplant Recipients. RESULTS: The follow-up rate was 99%. Morphologic RV was present in 58% of patients. Transplant and takedown free survival were 91%, 75%, and 71% at 10 years, 20 years, and 25 years, respectively. Morphologic RV was an independent risk factor for transplant, takedown free survival (hazard ratio: 2.4; p = 0.008). The AVVR, which preceded ventricular dysfunction in most cases, was associated with the development of ventricular dysfunction after Fontan (odds ratio: 4.3; 95% confidence interval: 2.7 to 6.7; p < 0.001). Furthermore, AVVR and ventricular dysfunction progressed over time after Fontan, especially in the RV (AVVR: p < 0.0001, ventricular dysfunction: p < 0.0001). CONCLUSIONS: Morphologic RV is negatively associated with the long-term survival following the Fontan, possibly due to a tendency toward progressive AVVR and deterioration of the single ventricle function. Additional volume overload caused by AVVR may be one of the main factors accelerating the dysfunction of the single RV, implying that early valve intervention may be warranted.

Aristolochia Herbs and Iatrogenic Disease: The Case of Portland's Powders.

Aristolochia herbals have a 2500-year history of medicinal use. We focused this article on Portland's Powders, an 18th-century British gout medicine containing Aristolochia herbs. The powders constitute an 18th-century iteration of an herbal remedy, which was used, with variations, since at least the fifth century BCE. The use of Portland's Powders in Great Britain may appear to be an unusual choice for investigating a public health problem currently widespread in Asia. Yet it exemplifies long-term medicinal use of Aristolochia herbs, reflecting our argument that aristolochic acid nephropathy (AAN) is a historically persistent iatrogenic disease. Moreover, we provide compelling evidence that individuals taking Portland's Powders for gout would have ingested toxic quantities of aristolochic acid, which causes AAN and cancer. Several factors, including long history of use, latency of toxic effects, and lack of effective regulation, perpetuate usage of Aristolochia herbals to the present day.

Short- and Long-term Outcomes Following Side-to-side Strictureplasty and its Modification Over the Ileocaecal Valve for Extensive Crohn's Ileitis.

BACKGROUND AND AIMS: Postoperative recurrence remains a challenging problem in patients with Crohn's disease [CD]. To avoid development of short bowel syndrome, strictureplasty techniques have therefore been proposed. We evaluated short- and long-term outcomes of atypical strictureplasties in CD patients with extensive bowel involvement. METHODS: Side-to-side isoperistaltic strictureplasty [SSIS] was performed according to the Michelassi technique or modification of this over the ileocaecal valve [mSSIS]. Ninety-day postoperative morbidity was assessed using the comprehensive complication index [CCI]. Clinical recurrence was defined as symptomatic, endoscopically or radiologically confirmed, stricture/inflammatory lesion requiring medical treatment or surgery. Surgical recurrence was defined as the need for any surgical intervention. Endoscopic remission was defined as ≤i1, according to the modified Rutgeerts score. Deep remission was defined as the combination of endoscopic remission and absence of clinical symptoms. Perioperative factors related to clinical recurrence were evaluated. RESULTS: A total of 52 CD patients [SSIS n = 12; mSSIS n = 40] were included. No mortality occurred. Mean CCI was 10.3 [range 0-33.7]. Median follow-up was 5.9 years [range 0.8-9.9]. Clinical recurrence [19 patients] was 29.7% and 39.6% after 3 and 5 years, respectively. Surgical recurrence [seven patients] was 2% and 14.1% after 3 and 5 years, respectively. At the end of the follow-up, 92% of patients kept the original strictureplasty and deep remission was observed in 25.7% of the mSSIS patients. None of the perioperative variables considered showed a significant association with clinical recurrence. CONCLUSIONS: SSIS is safe, effective, and provides durable disease control in patients with extensive CD ileitis.

Deterioration of initially accepted radiological alignment of conservatively treated AO type-C distal radius fractures: mid-term outcome.

BACKGROUND AND AIMS: It still remains controversial how often the once-accepted radiological alignment of an AO type-C distal radius fracture deteriorates after conservative treatment, and to what extent this deterioration is perhaps associated with patient-rated outcome measures (PROms). Thus, we aimed to evaluate this radiological deterioration and its association with mid-term functional follow-up. PATIENTS AND METHODS: We retrospectively reviewed 66 patients (mean age at fracture 53 years, SD 14.1, range 18-73, female 65%) with 68 C-type distal radius fractures at a mean of 6.7 years (SD 0.5 years, range 5.8-7.7 years) after primary closed reduction and cast immobilization. Radiographs of the wrists were taken and analysed for any radial shortening, dorsal tilt or step-off at the joint surface. Range of motion and grip strength were measured. In addition to the radiological result, primary outcome measures included Quick Disabilities of the Arm, Shoulder and Hand (QDash) and Patient-Rated Wrist Evaluation (PRWE). RESULTS: At mid-term follow-up, an acceptable anatomical radiological result was seen in only 22 wrists (32%). Deterioration of the once-achieved and accepted primary alignment was seen in a majority of cases (68%). Radial shortening of ≥ 2 mm was found in 34 wrists (51%, mean 4 mm, range 2-8 mm), with no association with QDash (12.8 vs. 5.5, p = 0.22) or PRWE (9.1 vs. 5.7, p = 0.40). Only four patients (6%) showed step-off at the joint surface (mean 1.1 mm, range 0.5-2 mm). Twenty-two wrists (32%) showed dorsal tilt of ≥ 10° (five with volar tilt of 15°-25°), with no effect on QDash or PRWE (14.7 vs. 6.5, p = 0.241 and 10.1 vs. 5.8, p = 0.226). Altogether, patients with dorsal tilt, step-off or shortening did not show significantly worse QDash (10.3 vs. 5.7, p = 0.213) or PRWE (8.1 vs. 5.1, p = 0.126) versus those with none. Twenty-nine (43%) of the patients had deficits in range of motion (ROM), either in extension (39%), flexion (43%), supination (16%) or pronation (4%), or combinations of these. Worse extension was associated with worse QDash (15.9 vs. 5.0, p = 0.037), flexion deficit with worse PRWE (11.5 vs. 4.4, p = 0.005) and supination deficit with both QDash (21.7 vs. 6.8, p = 0.025) and PRWE (18.9 vs. 5.2, p = 0.007). CONCLUSIONS: The initially accepted radiological alignment of AO type-C radius fractures deteriorated in a majority of cases during conservative treatment. However, this deterioration was fairly mild and showed no significant association with functional outcome. Restricted ROM showed some association with PROms. LEVEL OF EVIDENCE: IV.