Uric acid predicts long-term cardiovascular risk in type 2 diabetes but does not mediate the benefits of fenofibrate: The FIELD study.

AIM: To explore the relationship between baseline uric acid (UA) levels and long-term cardiovascular events in adults with type 2 diabetes (T2D) and to determine whether the cardioprotective effects of fenofibrate are partly mediated through its UA-lowering effects. METHODS: Data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial were utilized, comprising 9795 adults with T2D randomly allocated to treatment with fenofibrate or matching placebo. Plasma UA was measured before and after a 6-week, active fenofibrate run-in phase in all participants. Cox proportional hazards models were used to explore the relationships between baseline UA, pre-to-post run-in reductions in UA and long-term cardiovascular outcomes. RESULTS: Mean baseline plasma UA was 0.33 mmol/L (SD 0.08). Baseline UA was a significant predictor of long-term cardiovascular events, with every 0.1 mmol/L higher UA conferring a 21% increase in event rate (HR 1.21, 95% CI 1.13-1.29, P < .001). This remained significant after adjustment for treatment allocation, cardiovascular risk factors and renal function. The extent of UA reduction during fenofibrate run-in was also a significant predictor of long-term cardiovascular events, with every 0.1 mmol/L greater reduction conferring a 14% lower long-term risk (HR 0.86, 95% CI 0.76-0.97, P = .015). This effect was not modified by treatment allocation (Pinteraction = .77). CONCLUSIONS: UA is a strong independent predictor of long-term cardiovascular risk in adults with T2D. Although greater reduction in UA on fenofibrate is predictive of lower cardiovascular risk, this does not appear to mediate the cardioprotective effects of fenofibrate.

Clinical Outcomes and Complications of Primary Fingertip Reconstruction Using a Reverse Homodigital Island Flap: A Systematic Review.

BACKGROUND: Reverse homodigital island flaps (RHIFs) are increasingly used to reconstruct traumatic fingertip injuries, but there is limited evidence on the efficacy of this technique. We performed a systematic review of the literature to establish the safety and functional outcomes of RHIF for traumatic fingertip injuries. METHODS: Electronic searches were performed using 3 databases (PubMed, Ovid Medline, Cochrane CENTRAL) from their date of inception to April 2020. Relevant studies were required to report on complications and functional outcomes for patients undergoing RHIF for primary fingertip reconstruction. Data were extracted from included studies and analyzed. RESULTS: Sixteen studies were included, which produced a total cohort of 459 patients with 495 fingertip injuries. The index and middle fingers were involved most frequently (34.6% and 34.1%, respectively), followed by the ring finger (22%), the little finger (6.7%), and the thumb (2.6%). The mean postoperative static and moving 2-point discrimination was 7.2 and 6.7 mm, respectively. The mean time to return to work was 8.4 weeks. The mean survivorship was 98.4%, with the pooled complication rate being 28%. The pooled complication rate of complete flap necrosis was 3.6%, of partial flap necrosis was 10.3%, of venous congestion was 14.6%, of pain or hypersensitivity was 11.5%, of wound infection was 7.2%, of flexion contractures was 6.3%, and of cold intolerance was 17.7%. CONCLUSIONS: Reverse homodigital island flaps can be performed safely with excellent outcomes. To minimize complications, care is taken during dissection and insetting, with extensive rehabilitation adhered to postoperatively. Prospective studies assessing outcomes of RHIF compared with other reconstruction techniques would be beneficial.

Fontan operation at less than 3 years of age is not a risk factor for long-term failure.

OBJECTIVES: The age at which the Fontan operation is performed varies globally. Over the last decade, the median age of patients having the Fontan in Australia and New Zealand has been 4.6 years, including 6% of patients younger than 3 years. Long-term outcomes of an early Fontan operation are unclear and are described in this study. METHODS: Patients from the Australian and New Zealand Fontan Registry were grouped by age at Fontan. A Fontan before 3 years (early Fontan) was compared to the combined second and third quartiles by age at surgery in the Registry (3.6-6.1 years; control). Outcomes included Fontan failure (death, transplant, New York Heart Association functional group III/IV heart failure, Fontan takedown or conversion, protein losing enteropathy and plastic bronchitis), arrhythmias, thromboembolism and reinterventions. RESULTS: A total of 191 patients who had early Fontan operations were compared to 781 controls. Profound or progressive cyanosis was noted more frequently in the early than in the control group (63% vs 23%; P < 0.001). The early group was followed up for a median 22.1 years. The incidence of long-term failure was similar between the 2 groups (early, 1.08 failures per 100 patient-years of follow-up vs control, 0.99; log-rank P = 0.79). Adjusted for risk factors, early age at Fontan was not a risk factor for long-term failure [hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.77-1.76; P = 0.48], new-onset arrhythmia (HR 0.93, 95% CI 0.63-1.39; P = 0.73), thromboembolism (HR 0.50, 95% CI 0.28-0.91; P = 0.024) or reintervention (HR 1.08, 95% CI 0.80-1.45; P = 0.62). CONCLUSIONS: Having the Fontan operation at an early age was not a risk factor for short- or long-term adverse outcomes in our cohort.

The case for extended thromboprophylaxis in medically hospitalised patients - not yet made.

BACKGROUND: The role of extended thromboprophylaxis is established for surgical patients, but not yet for hospitalised medical patients. DESIGN: This systematic review and meta-analysis sought to explore the role of extended thromboprophylaxis for medically ill hospitalised patients. METHODS: Medline, EMBASE and Cochrane Libraries were searched and five randomised controlled trials were identified, comprising 20,046 extended and 20,078 standard duration thromboprophylaxis patients. RESULTS: Allocation to extended treatment, compared with standard duration therapy, significantly reduced the risk of symptomatic deep vein thrombosis (relative risk (RR) 0.47, 95% confidence interval (CI) 0.29-0.78, P = 0.003) and non-fatal pulmonary embolism (RR 0.59, 95% CI 0.39-0.91, P = 0.02). The risk of venous thromboembolism-related death was comparable between the extended and standard duration treatment groups (RR 0.81, 95% CI 0.6-1.09, P = 0.16). Extended treatment also doubled the risk of major bleeding (RR 2.04, 95% CI 1.42-2.91, P < 0.001), without significantly affecting the risk of intracranial bleeding or bleeding-associated death. The cost of preventing one symptomatic deep vein thrombosis and non-fatal pulmonary embolism was found to be £24,972 (€27,969) and £45,148 (€50,566), respectively, which outweigh the direct cost of managing established venous thromboembolism as previously reported. CONCLUSIONS: Extended duration thromboprophylaxis caused a reduction in the risk of venous thromboembolic events, but also a numerically comparable increase in major bleeding. Further trials are required in high-risk subpopulations who may derive mortality benefits from treatment. Only then could a change in current policy and practice be supported.

Impact of adiposity on clinical outcomes in people living with a Fontan circulation.

BACKGROUND: To assess the association between body composition and the risk of adverse outcomes in Fontan patients. METHODS: Participants from the Australian and New Zealand Fontan Registry with dual-energy X-ray absorptiometry scans were included. Appendicular lean mass (ALM), appendicular lean mass index (ALM divided by height squared; ALMI) and total body fat mass percentage (%BF) were calculated. ALMI and %BF z-scores were derived using age- and sex-matched reference ranges. The primary outcome was Fontan failure (death, transplantation, New York Heart Association functional class III/IV, protein-losing enteropathy, and plastic bronchitis) or moderate-or-severe ventricular dysfunction. RESULTS: 144 patients were included. Mean %BF was 29% (SD 10) with 50% having increased adiposity. Mean ALMI z-score was -1.4 (SD 1.1); one third of patients had skeletal muscle deficiency (ALMI z-score < -1 and -2) and another third had Fontan-associated myopaenia (ALMI z-score < -2). Age and %BF were associated with the risk of the endpoint in univariable regression (age: HR 1.09 per year, 95% CI 1.02-1.17, p = 0.01; %BF: HR 1.08, 95% CI 1.01-1.17, p = 0.03). On multivariable regression, every 1% increase in %BF was associated with a 10% increased risk of reaching the clinical endpoint (HR 1.10, 95% CI 1.01-1.19; p = 0.03). ALM was not associated with the endpoint (HR 1.02 per kg, 95% CI 0.88-1.20, p = 0.77). CONCLUSIONS: Increased adiposity is associated with higher risk for adverse outcomes. Prospective studies to assess lifestyle interventions to optimise body composition should be prioritised.

Metabolic Reprogramming of Nasal Airway Epithelial Cells Following Infant Respiratory Syncytial Virus Infection.

Respiratory syncytial virus (RSV) is a seasonal mucosal pathogen that infects the ciliated respiratory epithelium and results in the most severe morbidity in the first six months of life. RSV is a common cause of acute respiratory infection during infancy and is an important early-life risk factor strongly associated with asthma development. While this association has been repeatedly demonstrated, limited progress has been made on the mechanistic understanding in humans of the contribution of infant RSV infection to airway epithelial dysfunction. An active infection of epithelial cells with RSV in vitro results in heightened central metabolism and overall hypermetabolic state; however, little is known about whether natural infection with RSV in vivo results in lasting metabolic reprogramming of the airway epithelium in infancy. To address this gap, we performed functional metabolomics, 13C glucose metabolic flux analysis, and RNA-seq gene expression analysis of nasal airway epithelial cells (NAECs) sampled from infants between 2-3 years of age, with RSV infection or not during the first year of life. We found that RSV infection in infancy was associated with lasting epithelial metabolic reprogramming, which was characterized by (1) significant increase in glucose uptake and differential utilization of glucose by epithelium; (2) altered preferences for metabolism of several carbon and energy sources; and (3) significant sexual dimorphism in metabolic parameters, with RSV-induced metabolic changes most pronounced in male epithelium. In summary, our study supports the proposed phenomenon of metabolic reprogramming of epithelial cells associated with RSV infection in infancy and opens exciting new venues for pursuing mechanisms of RSV-induced epithelial barrier dysfunction in early life.

A comparison of aspirin against rivaroxaban for venous thromboembolism prophylaxis after hip or knee arthroplasty: A meta-analysis.

PURPOSE: Total knee arthroplasty (TKA) and total hip arthroplasty (THA) patients are at an elevated risk of post-operative venous thromboembolism (VTE). Newer thromboprophylactic agents such as rivaroxaban are increasingly used and effective in preventing thromboembolic events but may worsen bleeding risk. Recent studies have suggested that the more cost-effective aspirin may also be effective in preventing VTE. This systematic review and meta-analysis aimed to compare the efficacy of aspirin against rivaroxaban for the prevention of VTE following TKA and THA. METHODS: Electronic searches were performed using five databases from their date of inception to August 2018. Relevant studies were identified, with data extracted and meta-analyzed from the studies. RESULTS: Five studies were included, which consisted of 2257 in the aspirin group and 2337 in the rivaroxaban group. There were no differences between aspirin and rivaroxaban for either VTE (p = 0.48) or its components deep vein thrombosis (p = 0.44) and pulmonary embolism (p = 0.98). Also, there were no differences between groups for either major bleeding (p = 0.17), any bleeding (p = 0.62), readmissions (p = 0.37) or wound complications (p = 0.17). CONCLUSION: Aspirin was not significantly different to rivaroxaban for prevention of VTE or adverse events after TKA or THA. However, this study was limited by the significant heterogeneity of the included studies. More large randomized studies are needed to add to this body of evidence.

Comparison of outpatient versus inpatient total hip and knee arthroplasty: A systematic review and meta-analysis of complications.

INTRODUCTION: Patients undergoing TKA or THA have traditionally been managed post-operatively as inpatients. However, with current surgical techniques and pain management, there is evidence that outpatient joint arthroplasty can be safely performed in selected patient. This systematic review and meta-analysis aimed to compare the post-operative complication rates of outpatient and inpatient TJA with subgroup analysis of TKA and THA. METHODS: Electronic searches were performed using five databases from their date of inception to October 2018. Relevant studies were identified, with data extracted and meta-analyzed from the studies. RESULTS: From seven included studies, 176,179 patients were inpatient TJA and 1613 were outpatient TJA. The outpatient and inpatient TJA cohorts had similar mean age and BMI, with a greater proportion of females in the inpatient group. For TJA we found no significant difference in total complications (P = 0.06), major complications (P = 0.59), readmissions (P = 0.60), DVT (P = 0.94), UTI (P = 0.50), pneumonia (P = 0.42) and wound complications (P = 0.50) between the outpatient and inpatient groups. However, there were fewer transfusions (P = 0.05) but increased reoperations (P = 0.02) in the outpatient TJA group. Subgroup analysis of TKA (P = 0.25) and THA (P = 0.39) also found no significant differences in total complications between the outpatient and inpatient groups. CONCLUSION: Outpatient TJA had comparable total complication rates to inpatient TJA. Along with that outpatient TJA can significantly reduce costs to healthcare systems but careful pre-operative patient selection is required to optimize outcomes. More quality randomized controlled trials with longer follow-up periods are needed to add to this body of evidence.

Outcomes of the Fontan Operation for Patients With Heterotaxy: A Meta-Analysis of 848 Patients.

BACKGROUND: Heterotaxy is considered a risk factor for adverse events at all stages in the pre-Fontan pathway, and Fontan outcomes are expected to be worse in patients with heterotaxy. The aim of this study was to review existing literature reporting outcomes of the Fontan operation systematically in patients with heterotaxy. METHODS: A systematic review and meta-analysis was performed to identify and synthesize early mortality and medium- and long-term survival in heterotaxy patients after the Fontan procedure. Subsequent outcome analyses were stratified by study period era, cohort size, and proportion of right versus left atrial isomerism to explore predictors of outcome. RESULTS: A total of 21 studies were included for analysis, which were composed of 848 post-Fontan heterotaxy patients. Early mortality varied between 1% and 30% with a weighted event rate of 14% (95% confidence interval [CI], 10%-19%). Survival at 1, 5, and 10 years was 86% (95% CI, 79%-91%), 80% (95% CI, 71%-87%), and 74% (95% CI, 59%-85%), respectively. Stratification by study period highlighted that studies with a median study period year of 1995 or later had similar early mortality and 1- and 5-year survival, but superior 10-year survival (P = .02) compared with earlier studies. Stratification by cohort size and right versus left atrial isomerism did not reveal subgroup differences. CONCLUSIONS: Compared with existing literature, in patients with heterotaxy, early mortality after Fontan is higher than for the overall Fontan population. Long-term survival is comparable to the overall Fontan cohort. When heterotaxy patients are successfully transitioned to Fontan, subsequent survival is acceptable and predictable. Long-term follow-up is lacking.

Repair of Less Than Severe Tricuspid Regurgitation During Left-Sided Valve Surgery: A Meta-Analysis.

BACKGROUND: This systematic review and meta-analysis was undertaken to investigate the short- and long-term clinical outcomes of concurrent repair of mild or moderate tricuspid regurgitation (TR) during left-sided valve surgery. METHODS: Medline, PubMed, EMBASE, and Cochrane Libraries were searched, and 12 studies were identified, comprising 1373 patients who underwent TR repair during left-sided valve surgery and 1553 patients who did not. Of these studies, 6 were classified as having a low risk of bias (randomized controlled trials or propensity-matched studies), and 6 were considered as having a high risk of bias (nonmatched observational studies). The primary analysis included only studies with a low risk of bias (399 repair and 426 nonrepair). RESULTS: Primary analysis of studies at low risk of bias demonstrated that the addition of TR repair compared with nonrepair was associated with reduced risks of cardiovascular mortality, all-cause mortality, and progression of TR over a median of 5.3 years of follow-up (cardiovascular mortality: relative risk [RR], 0.46; 95% confidence interval [CI], 0.28 to 0.75; P = .002; all-cause mortality: RR, 0.68; 95% CI, 0.49 to 0.96; P = .03; and TR progression: RR, 0.26; 95% CI, 0.12 to 0.56; P < .001). Cardiopulmonary bypass time was significantly shorter in the nonrepair group (mean weighted difference, 18 minutes; 95% CI, 6 to 30; P = .003), although the risk of perioperative mortality was comparable between the 2 groups (RR, 0.72; 95% CI, 0.27 to 1.97; P > .05). CONCLUSIONS: Concurrent repair of mild or moderate TR during left-sided valve surgery is associated with improved long-term clinical outcomes without adversely affecting early survival. Should these results be validated by ongoing trials, there should be a revision of current guidelines to recommend a more aggressive approach toward TR repair.

Heterotaxy Is Not a Risk Factor for Adverse Long-Term Outcomes After Fontan Completion.

BACKGROUND: Heterotaxy is considered a risk factor for poor outcomes after the Fontan operation. However, long-term data to support this notion are lacking. The aims of this study were to ascertain the long-term outcomes of patients with heterotaxy after hospital discharge after Fontan completion and to compare these outcomes with those of a contemporary nonheterotaxy cohort. METHODS: A binational Fontan registry (n = 1540) was analyzed to identify patients with heterotaxy and compare them with patients without heterotaxy. The primary composite end point was Fontan failure, encompassing death, heart transplantation, Fontan takedown or conversion, protein-losing enteropathy, plastic bronchitis, or New York Heart Association functional class III or IV. RESULTS: A total of 109 patients with heterotaxy were identified and they were compared with 1431 nonheterotaxy patients after Fontan completion. There was no difference in unadjusted 15-year freedom from Fontan failure (heterotaxy, 78% vs nonheterotaxy, 85%; P = .2). Patients in the heterotaxy group had a significantly higher cumulative incidence of post-Fontan arrhythmias (P < .001). Propensity-score matching for confounders yielded 73 patients with heterotaxy matched with 439 patients without heterotaxy, in whom 15-year freedom from Fontan failure was also not different (heterotaxy, 76% vs nonheterotaxy, 81%; P = .2). There was no difference in 15-year freedom from Fontan failure in patients with right vs left isomerism (right isomerism, 80% vs left isomerism, 76%; P = .7). CONCLUSIONS: Although heterotaxy may complicate the pre-Fontan course, once the Fontan procedure is successfully completed, heterotaxy does not appear to be an important risk factor for Fontan failure. Patients with heterotaxy are at a higher risk of post-Fontan arrhythmias compared with patients without heterotaxy.

Long term survival of hypoplastic left heart syndrome infants: Meta-analysis comparing outcomes from the modified Blalock-Taussig shunt and the right ventricle to pulmonary artery shunt.

BACKGROUND: Stage 1 palliation of hypoplastic left heart syndrome (HLHS) involves the Norwood procedure combined with a modified Blalock-Taussig shunt (mBTS) or right ventricle to pulmonary artery shunt (RVPAS). Short-term survival has been described previously, whereas longer-term outcomes remain a subject of debate. This meta-analysis aimed to describe the short and long-term survival outcomes of these two shunts, and explore factors that might influence survival. METHODS: Medline, Cochrane Libraries and EMBASE were systematically searched, and 32 studies were included for statistical synthesis, comprising 1348 mBTS and 1258 RVPAS patients. RESULTS: While early in-hospital survival was superior in the RVPAS group (RR=1.5, p<0.05, 95% CI: 1.21-1.85), this difference was lost from 2years post-stage 1 palliation (RR=0.91, p>0.05, 95% CI: 0.79-1.04), and maintained unchanged up to 6years. This shift in survival was also reflected in inter-stage survival, with superior RVPAS outcomes between stage 1 and 2 (RR=1.62, p<0.05, 95% CI: 1.39-1.88), and equivalent outcomes between stage 2 and 3. Potential contributors to this included a significantly higher rate of pulmonary artery stenosis in the RVPAS group and an increased requirement for shunt re-intervention in this group prior to stage 2. CONCLUSIONS: Despite early advantages, RVPAS and mBTS for palliation of hypoplastic left heart syndrome produced comparable long-term survival. The RVPAS patients experienced more pulmonary artery stenosis and requirement for shunt re-intervention. The impact of shunt type on quality and survival with a Fontan is yet to be assessed.

Renin-angiotensin-aldosterone inhibition improves right ventricular function: a meta-analysis.

The benefits of inhibiting the renin-angiotensin-aldosterone system (RAAS) are well established for left ventricular dysfunction, but remain unknown for right ventricular (RV) dysfunction. The aim of the current meta-analysis is to investigate the role of RAAS inhibition on RV function in those with or at risk of RV dysfunction. Medline, PubMed, EMBASE and Cochrane Libraries were systematically searched and 12 studies were included for statistical synthesis, comprising 265 RAAS inhibition treatment patients and 265 placebo control patients. The treatment arm showed a trend towards increased RV ejection fraction (weighted mean difference (WMD)=0.95, 95% CI -0.12 to 2.02, p=0.08) compared with the control arm. Subgroup analysis demonstrated a trend towards improvement in RV ejection fraction in patients receiving angiotensin receptor blockers compared with control (WMD=1.11, 95% CI -0.02 to 2.26, p=0.06), but not in the respective comparison for ACE inhibitors (WMD=0.07, 95% CI -2.74 to 2.87, p>0.05). No differences were shown between the two groups with regard to maximal oxygen consumption, RV end-systolic volume, RV end-diastolic volume, duration of cardiopulmonary exercise testing, and resting and maximal heart rate. Mild adverse drug reactions were common but evenly distributed between the treatment and control groups. The current meta-analysis highlights that there may be a role for RAAS inhibition, particularly treatment with angiotensin receptor blockers, in those with or at risk of RV dysfunction. However, further confirmation will be required by larger prospective trials.

Early Outcomes of Hypoplastic Left Heart Syndrome Infants: Meta-Analysis of Studies Comparing the Hybrid and Norwood Procedures.

The hybrid strategy is an alternative to the traditional Norwood procedure for initial palliation of infants with hypoplastic left heart syndrome (HLHS) who are deemed to be at high surgical risk. Numerous single-center studies have compared the two procedures, showing similar early outcomes, although the cohort sizes are likely insufficiently powered to detect significant differences. The current meta-analysis aims to explore the early morbidity and mortality associated with the hybrid compared to the Norwood procedure. MEDLINE, Cochrane Libraries, and Embase were systematically searched, and 14 studies were included for statistical synthesis, comprising 263 hybrid and 426 Norwood patients. Early mortality was significantly higher in the hybrid patients (relative risk [RR] = 1.54, P < .05, 95% confidence interval [CI]: 1.02-2.34), whereas interstage mortality was comparable between the two groups (RR = 0.88, P > .05, 95% CI: 0.46-1.70). Six-month (RR = 0.89, P < .05, 95% CI: 0.80-1.00) and one-year (RR = 0.88, P < .05, 95% CI: 0.78-1.00) transplant-free survival was also inferior among the hybrid patients. Furthermore, the hybrid patients required more reinterventions following initial surgical palliation (RR = 1.48, P < .05, 95% CI: 1.09-2.01), although the two groups had comparable length of hospital and intensive care unit stay postoperatively. In conclusion, our results suggest that the hybrid procedure is associated with worse early survival compared to the traditional Norwood when used for initial palliation of infants with HLHS. However, due to the hybrid being used preferentially for high-risk patients, definitive conclusions regarding the efficacy of the procedure cannot be drawn.

Pulmonary vasodilator therapies are of no benefit in pulmonary hypertension due to left heart disease: A meta-analysis.

BACKGROUND: Pulmonary hypertension complicating left heart disease (PH-LHD) is the most common cause of PH. Off-label use of pulmonary arterial hypertension (PAH) medications for PH-LHD is prevalent, despite a lack of clinical data supporting their use. METHODS: A systematic review and meta-analysis was performed. Comprehensive search of all available literature to date identified ten randomised, placebo controlled trials comprising 439 treated (Phosphodiesterase 5 inhibitors: n = 206; guanylate cyclase stimulators: n = 132; endothelin receptor antagonists: n = 101) and 338 placebo patients. Random effects model was employed to assess outcomes in the treatment compared to the placebo control arm. RESULTS: The risks of all-cause mortality, cardiovascular mortality and worsening heart failure were numerically higher in the treated compared to the control group, although not statistically (all-cause mortality: RR = 1.97, 95% CI: 0.64-6.05, p = 0.24; cardiovascular mortality: RR = 2.01, 95% CI: 0.39-10.34, p = 0.4; worsening heart failure: RR = 1.23, 95% CI: 0.68-2.25, p = 0.49). Conversely, right heart hemodynamics improved numerically in the treated group, also without being significant (mean pulmonary artery pressure: MWD = -5.13 mm Hg, 95% CI: -13.2-2.9, p = 0.21; pulmonary vascular resistance: MWD = -0.87 WU, 95% CI: -1.75-0.1, p = 0.053). CONCLUSIONS: The current meta-analysis demonstrated that there is no current evidence to support the widespread use of PAH therapy in PH-LHD. On the basis of a numerically increased risk of clinical harm, these agents should not be prescribed in this setting, unless further evidence of benefit arises in the future.