Familial amyloid polyneuropathy, a lethal genetic disease caused by aggregation of variant transthyretin, induces progressive peripheral nerve deficits and disability. Diflunisal, a nonsteroidal ...anti-inflammatory agent, stabilizes transthyretin tetramers and prevents amyloid fibril formation in vitro.
To determine the effect of diflunisal on polyneuropathy progression in patients with familial amyloid polyneuropathy.
International randomized, double-blind, placebo-controlled study conducted among 130 patients with familial amyloid polyneuropathy exhibiting clinically detectable peripheral or autonomic neuropathy at amyloid centers in Sweden (Umeå), Italy (Pavia), Japan (Matsumoto and Kumamoto), England (London), and the United States (Boston, Massachusetts; New York, New York; and Rochester, Minnesota) from 2006 through 2012.
Participants were randomly assigned to receive diflunisal, 250 mg (n=64), or placebo (n=66) twice daily for 2 years.
The primary end point, the difference in polyneuropathy progression between treatments, was measured by the Neuropathy Impairment Score plus 7 nerve tests (NIS+7) which ranges from 0 (no neurological deficits) to 270 points (no detectable peripheral nerve function). Secondary outcomes included a quality-of-life questionnaire (36-Item Short-Form Health Survey SF-36) and modified body mass index. Because of attrition, we used likelihood-based modeling and multiple imputation analysis of baseline to 2-year data.
By multiple imputation, the NIS+7 score increased by 25.0 (95% CI, 18.4-31.6) points in the placebo group and by 8.7 (95% CI, 3.3-14.1) points in the diflunisal group, a difference of 16.3 points (95% CI, 8.1-24.5 points; P < .001). Mean SF-36 physical scores decreased by 4.9 (95% CI, -7.6 to -2.2) points in the placebo group and increased by 1.5 (95% CI, -0.8 to 3.7) points in the diflunisal group (P < .001). Mean SF-36 mental scores declined by 1.1 (95% CI, -4.3 to 2.0) points in the placebo group while increasing by 3.7 (95% CI, 1.0-6.4) points in the diflunisal group (P = .02). By responder analysis, 29.7% of the diflunisal group and 9.4% of the placebo group exhibited neurological stability at 2 years (<2-point increase in NIS+7 score; P = .007).
Among patients with familial amyloid polyneuropathy, the use of diflunisal compared with placebo for 2 years reduced the rate of progression of neurological impairment and preserved quality of life. Although longer-term follow-up studies are needed, these findings suggest benefit of this treatment for familial amyloid polyneuropathy.
clinicaltrials.gov Identifier: NCT00294671.
Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired ...glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
Abstract Objective The effect of preoperative malnutrition on outcomes in patients undergoing major vascular surgery is unclear. We investigated the effects of preoperative hypoalbuminemia, a marker ...for malnutrition, on outcomes after open abdominal aortic aneurysm repair (OAR) and endovascular abdominal aortic aneurysm repair (EVAR). Methods Patients undergoing OAR or EVAR were identified in the 2005 to 2012 American College of Surgeons National Surgical Quality Improvement Program database and stratified into three groups: normal albumin (serum albumin >3.5 g/dL), moderate hypoalbuminemia (2.8-3.5 g/dL), and severe hypoalbuminemia (<2.8 g/dL). Multivariable analyses were performed to assess the association of preoperative hypoalbuminemia with 30-day morbidity and mortality. Results We identified 15,002 patients with a recorded preoperative serum albumin who underwent OAR (n = 4956) or EVAR (n = 10,046). Patients in both cohorts with hypoalbuminemia had a higher burden of comorbidity. In OAR patients, multivariable analyses demonstrated that moderate hypoalbuminemia was associated with an increased risk of 30-day mortality (odds ratio OR, 1.32; 95% confidence interval CI, 1.02-1.70) and postoperative length of stay (LOS; means ratio MR, 1.10; 95% CI, 1.04-1.16), whereas severe hypoalbuminemia was associated with increased 30-day mortality (OR, 1.92; 95% CI, 1.37-2.70), reoperation ≤30 days (OR, 1.80; 95% CI, 1.32-2.48), pulmonary complications (OR, 1.40; 95% CI, 1.06-1.86), and postoperative LOS (MR, 1.33; 95% CI, 1.21-1.45). In EVAR patients, moderate hypoalbuminemia was associated with an increased risk of 30-day mortality (OR, 1.90; 95% CI, 1.38-2.62), pulmonary complications (OR, 1.61; 95% CI, 1.26-2.04), reoperation ≤30 days (OR, 1.39; 95% CI, 1.12-1.74), and postoperative LOS (MR, 1.23; 95% CI, 1.18-1.29), whereas severe hypoalbuminemia was associated with increased 30-day mortality (OR, 2.98; 95% CI, 1.96-4.53), pulmonary complications (OR, 1.88; 95% CI, 1.32-2.67), reoperation ≤30 days (OR, 1.54; 95% CI, 1.08-2.19), and postoperative LOS (MR, 1.52; 95% CI, 1.40-1.65). Conclusions Preoperative hypoalbuminemia is associated with increased postoperative morbidity and mortality in a severity-dependent manner among patients undergoing OAR or EVAR. Evaluation and optimization of nutritional status should be performed preoperatively in this high-risk population.
The purpose of this study is to externally validate a recently reported Vascular Study Group of New England (VSGNE) risk predictive model of postoperative mortality after elective abdominal aortic ...aneurysm (AAA) repair and to compare its predictive ability across different patients' risk categories and against the established risk predictive models using the Vascular Quality Initiative (VQI) AAA sample.
The VQI AAA database (2010-2015) was queried for patients who underwent elective AAA repair. The VSGNE cases were excluded from the VQI sample. The external validation of a recently published VSGNE AAA risk predictive model, which includes only preoperative variables (age, gender, history of coronary artery disease, chronic obstructive pulmonary disease, cerebrovascular disease, creatinine levels, and aneurysm size) and planned type of repair, was performed using the VQI elective AAA repair sample. The predictive value of the model was assessed via the C-statistic. Hosmer-Lemeshow method was used to assess calibration and goodness of fit. This model was then compared with the Medicare, Vascular Governance Northwest model, and Glasgow Aneurysm Score for predicting mortality in VQI sample. The Vuong test was performed to compare the model fit between the models. Model discrimination was assessed in different risk group VQI quintiles.
Data from 4431 cases from the VSGNE sample with the overall mortality rate of 1.4% was used to develop the model. The internally validated VSGNE model showed a very high discriminating ability in predicting mortality (C = 0.822) and good model fit (Hosmer-Lemeshow P = .309) among the VSGNE elective AAA repair sample. External validation on 16,989 VQI cases with an overall 0.9% mortality rate showed very robust predictive ability of mortality (C = 0.802). Vuong tests yielded a significant fit difference favoring the VSGNE over then Medicare model (C = 0.780), Vascular Governance Northwest (0.774), and Glasgow Aneurysm Score (0.639). Across the 5 risk quintiles, the VSGNE model predicted observed mortality significantly with great accuracy.
This simple VSGNE AAA risk predictive model showed very high discriminative ability in predicting mortality after elective AAA repair among a large external independent sample of AAA cases performed by a diverse array of physicians nationwide. The risk score based on this simple VSGNE model can reliably stratify patients according to their risk of mortality after elective AAA repair better than other established models.
Use of potentially hazardous bedding, as defined by the American Academy of Pediatrics (eg, pillows, quilts, comforters, loose bedding), is a modifiable risk factor for sudden infant death syndrome ...and unintentional sleep-related suffocation. The proportion of US infants sleeping with these types of bedding is unknown.
To investigate the US prevalence of and trends in bedding use, we analyzed 1993-2010 data from the National Infant Sleep Position study. Infants reported as being usually placed to sleep with blankets, quilts, pillows, and other similar materials under or covering them in the last 2 weeks were classified as bedding users. Logistic regression was used to describe characteristics associated with bedding use.
From 1993 to 2010, bedding use declined but remained a widespread practice (moving average of 85.9% in 1993-1995 to 54.7% in 2008-2010). Prevalence was highest for infants of teen-aged mothers (83.5%) and lowest for infants born at term (55.6%). Bedding use was also frequently reported among infants sleeping in adult beds, on their sides, and on a shared surface. The rate of decline in bedding use was markedly less from 2001-2010 compared with 1993-2000. For 2007 to 2010, the strongest predictors (adjusted odds ratio: ≥1.5) of bedding use were young maternal age, non-white race and ethnicity, and not being college educated.
Bedding use for infant sleep remains common despite recommendations against this practice. Understanding trends in bedding use is important for tailoring safe sleep interventions.
The choice for surgical revascularisation for aortoiliac occlusive disease is often tempered by patient comorbidities. This study compares peri-operative outcomes and the association between choice ...of operation and one year major adverse limb event (MALE) free survival and five year mortality.
The Vascular Study Group of New England (VSGNE) dataset for supra-inguinal bypass operations from 2009 to 2015 was queried. This study excluded cases with bypass other than aortofemoral (AFB), axillofemoral (AXB), and femorofemoral (FFB), and those with endovascular interventions or femoral endarterectomy. Cases combined with other procedures, indications other than occlusive disease, and missing pathology were also excluded. Patients were divided into three groups: AFB, AXB, and FFB. Thirty day post-operative death (POD) and adverse events were compared using univariable and multivariable analyses. One year MALE free survival was compared between groups with log rank test and Kaplan–Meier plot. Proportional hazard Cox regression was used for adjusted comparison of MALE free and five year survival.
In total, 1,602 cases were included: 207 (12.9%) AXB; 872 (54.4%) AFB; 523 (32.6%) FFB. AXB patients were older with more comorbidities. Post-operative complications and POD rates were significantly higher for AXB (p < .05). On adjusted analyses, AXB increased the hazard of one year MALE (hazard ratio HR 1.76, 95% confidence interval CI 1.12–2.78; p = .014) and five year mortality (HR 1.54; 95% CI 1.11–2.41; p = .009). Both FFB and AFB had similar one year MALE free survival but significantly better one year MALE free survival than AXB.
After adjusting for confounding variables, and while acknowledging limitations related to the VSGNE data set, FFB led to significantly lower rates of post-operative complications than AXB. FFB may serve as the extra-anatomical operation of choice in high risk patients with extensive disease, who cannot undergo AFB, provided that anatomy permits. AFB should be performed preferentially in low risk patients with appropriate anatomy. Owing to its higher complications rates, the study suggests that AXB should be limited to patients with no other option for revascularisation.
The frailty index has been linked to adverse outcomes after surgical procedures. In this study, we evaluated the association between frailty index and outcomes after elective lower extremity bypass ...(LEB) for lower extremity ischemia.
The American College of Surgeons National Surgical Quality Improvement Program data set (2005-2012) was used to identify patients who underwent elective LEB using diagnostic and procedure Current Procedural Terminology codes. Modified frailty index (mFI) scores, derived from the Canadian Study of Health and Aging, were categorized into three groups: low, medium, and high. Association of mFI with 30-day postoperative death (POD), myocardial infarction (MI), cardiopulmonary events (CPEs), deep tissue surgical site infection (SSI), and graft failure (GF) was evaluated. Both univariate and multivariable regression analyses—adjusted for age, sex, American Society of Anesthesiologists class, body mass index, and creatinine levels—were used to assess the effect of frailty on each outcome.
Of 12,677 patients (mean age, 67.7 ± 11.1 years) identified who underwent elective LEB, POD occurred in 265 (2.1% overall). Postoperative MI, SSI, CPEs, and GF occurred in 1.6%, 2.5%, 3.1%, and 4.3%, respectively. The mean mFI of the entire sample was 0.3 ± 0.1. Adjusted odds ratio for development of any morbidity in the group with the highest mFI was 1.36 (95% confidence interval, 1.08-1.72; P = .010) compared with the low frailty group. Patients with higher mFI were more likely to develop MI and CPEs but not SSI or GF. Univariate and multivariable analyses showed a significantly increased risk of POD among those in the highest mFI tertile. Female sex and age, increased American Society of Anesthesiologists class and creatinine levels, and decreased body mass index independently predicted increased mortality. The addition of categorical mFI improved models with these variables.
Higher mFI is independently associated with higher mortality and morbidity. Preoperative mFI assessment may be considered an additional screening tool for risk stratification among patients undergoing LEB.
Abstract Objective Endovascular interventions of the common femoral (CFA) and deep (DFA) femoral arteries are becoming more common. However, there is very little published data for guidance. Our ...objective was to analyze practice patterns and outcomes from these interventions. Methods The Vascular Quality Initiative (2010-2015) was queried for all endovascular interventions of the CFA and DFA. Cases that were emergent or for acute limb ischemia were excluded. Those with isolated CFA with or without DFA treatment were analyzed. Results There were 1014 patients that had either an isolated CFA intervention (946) with or without a DFA intervention (68). Average age of this isolated cohort was 67.4 ± 10.8 years, and 59% were male. Indications were claudication (67%), rest pain (16.3%), and tissue loss (16.7%). Periprocedural complications were access site hematoma (5.2%), arterial dissection (2.9%), distal embolization (0.7%), access site stenosis/occlusion (0.5%), and arterial perforation (0.6%). Thirty-day mortality was 1.6%. Survival was 92.9% at 1 year and 87.2% at 3 years. Amputation-free survival, freedom from loss of patency or death, and reintervention-free survival were 93.5%, 83%, and 87.5% at 1 year, respectively, by Kaplan-Meier analysis. Multivariable predictors of mortality were tissue loss, chronic obstructive pulmonary disease (COPD), end-stage renal disease, urgent case, and age, whereas aspirin use and non-Caucasian race were protective. Tissue loss, rest pain, COPD, end-stage renal disease, stent use, nonambulatory status, and female sex were predictive of major amputation whereas aspirin use, P2Y12 antagonist use, statin use, and initial technical success were protective. Tissue loss, case urgency and nonambulatory status predicted patency loss or death. Tissue loss, COPD, stent use, and history of prior bypass predicted reintervention. Conclusions Endovascular interventions of the CFA/DFA have a low rate of periprocedural morbidity and mortality. One-year patency is lower than historically observed for CFA endarterectomy. Stent use is associated with reinterventions and amputation. Longer-term analysis is needed to better assess durability.
Abstract Objective Despite vast improvement in the field of vascular surgery, elective abdominal aortic aneurysm (AAA) repair still leads to perioperative death. Patients with asymptomatic AAAs, ...therefore, would benefit from an individual risk assessment to help with decisions regarding operative intervention. The purpose of this study was to describe such a 30-day postoperative (POD) risk prediction model using American College of Surgeons National Surgical Quality Improvement Project (NSQIP) data. Methods The NSQIP database (2005-2011) was queried for patients undergoing elective AAA repair using open or endovascular techniques. Clinical variables and known predictors of mortality were included in a full prediction model. These variables included procedure type, patient's age, functional dependence and comorbidities, and surgeon's specialty. Backward elimination with alpha-level of 0.2 was used to construct a parsimonious model. Model discrimination was evaluated in equally sized risk quintiles. Results The overall mortality rate for 18,917 elective AAA patients was 1.7%. In this model, surgeon's specialty was not predictive of POD. The most significant factors affecting POD included open repair (odds ratio OR, 2.712; 95% confidence interval CI, 2.119-3.469; P < .001), age >70 (OR, 2.243; 95% CI, 1.695-3.033; P < .001), functional dependency (OR, 2.290; 95% CI, 1.442-3.637; P < .001), creatinine above 2.0 mg/dL (OR, 2.1; 95% CI, 1.403-3.142; P < .001) and low hematocrit levels (OR, 2.157; 95% CI, 1.365-3.408; P = .001).The discriminating ability of the NSQIP model was reasonable (C-statistic = 0.751) and corrected to 0.736 after internal validation. The NSQIP model performed well predicting mortality among risk-group quintiles. Conclusions The NSQIP risk prediction model is a robust vehicle to predict POD among patient undergoing elective AAA repair. This model can be used for risk stratification of patients undergoing elective AAA repair.
Access to medical care, by adequate insurance coverage, has a direct impact on outcomes for patients undergoing vascular procedures. We evaluated in-hospital mortality for patients undergoing index ...vascular procedures before and after the Massachusetts Healthcare Reform Law (MHRL) in 2006, which mandated insurance for all Massachusetts residents, both in Massachusetts and throughout the United States.
The National Inpatient Sample was queried to identify patients undergoing interventions for peripheral arterial disease, carotid artery stenosis, and abdominal aortic aneurysms based on International Classification of Diseases, Ninth Revision, Clinical Modification procedural and diagnostic codes. The cohort was then divided into patients treated within Massachusetts (MA) and non-Massachusetts (NMA) hospitals. Two time intervals were examined: before (2003-2006, P1) and after the MHRL (2007-2011, P2). The primary outcome of interest included in-hospital mortality. Patients in MA and NMA hospitals were described in terms of demographics and presentation by time interval (P2 vs P1) compared using χ2 and t-tests. Weighted logistic regression with term modeling change in the odds ratio (OR) for P2 was performed to test and to estimate trends in mortality. Time (year of procedure) and region interactions were investigated by inclusion of time-region interactions in our analyses. Subgroup analysis was performed for P2 vs P1 among nonwhite, nonelderly, and low-income patients.
We identified 306,438 patients who underwent repair of abdominal aortic aneurysm, lower extremity bypass, or carotid endarterectomy in MA and NMA hospitals. MA hospital patients had an increase in both Medicaid and private insurance status after the MHRL (P1 = 2.6% and 21% vs P2 = 3.3% and 21.7%, respectively; P = .034). In-hospital mortality trended down for all groups across the entire study. In comparing P2 vs P1 trends, MA hospital odds of mortality per year was lowered by 26% (OR, 0.74; 95% confidence interval CI, 0.56-0.99; P = .042) not seen in NMA hospitals (OR, 1.03; 95% CI, 0.97-1.09; P = .405). Time and region interaction terms indicated significant time trend difference in both unadjusted (P = .031) and adjusted (P = .033) analysis in MA hospitals not observed in NMA hospitals. This pattern continued when the samples were stratified by procedure. Patients undergoing vascular procedures in MA hospitals had a significantly lowered OR of mortality, with fewer patients presenting at late disease stages in P2 vs P1. Nonelderly patients in Massachusetts, who benefit from the Medicaid expansion provided by the MHRL, had a profound 92% drop in odds of mortality in P2 vs P1 (OR, 0.08; 95% CI, 0.010-0.641; P = .017) compared with the 14% drop in NMA (OR, 0.86; 95% CI, 0.709-1.032; P = .103).
The 2006 MHRL is associated with a decrease in mortality for patients undergoing index vascular surgery procedures in MA compared with NMA hospitals. This study suggests that governmental policy may play a key role in positively affecting the outcomes for patients.
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