Targeted treatments of AL and ATTR amyloidosis.

The therapeutic landscape for cardiac amyloidosis is rapidly evolving. In the last decade, our focus has shifted from dealing with the inevitable complications of continued extracellular infiltration of amyloid fibrils to earlier identification of these patients with prompt initiation of targeted therapy to prevent further deposition. Although much of the focus on novel targeted therapies is within the realm of transthyretin amyloidosis, light chain amyloidosis has benefited due to an overlap particularly in the final common pathway of fibrillogenesis and extraction of amyloid fibrils from the heart. Here, we review the targeted therapeutics for transthyretin and light chain amyloidosis. For transthyretin amyloidosis, the list of current and future therapeutics continues to evolve; and therefore, it is crucial to become familiar with the underlying mechanistic pathways of the disease. Although targeted therapeutic choices in AL amyloidosis are largely driven by the hematology team, the cardiac adverse effect profiles of these therapies, particularly in those with advanced amyloidosis, provide an opportunity for early recognition to prevent decompensation and can help inform recommendations regarding therapy changes when required.

Anticoagulation strategies in extracorporeal circulatory devices in adult populations.

Extracorporeal circulatory devices such as hemodialysis and extracorporeal membrane oxygenation can be lifesaving; however, they are also prone to pathologic events including device failure, venous and arterial thrombosis, hemorrhage, and an accelerated risk for atherosclerotic disease due to interactions between blood components and device surfaces of varying biocompatibility. While extracorporeal devices may be used acutely for limited periods of time (eg, extracorporeal membrane oxygenation, continuous venovenous hemofiltration, therapeutic apheresis), some patients require chronic use of these technologies (eg, intermittent hemodialysis and left ventricular assist devices). Given the substantial thrombotic risks associated with extracorporeal devices, multiple antiplatelet and anticoagulation strategies-including unfractionated heparin, low-molecular-weight heparin, citrate, direct thrombin inhibitors, and direct oral anticoagulants, have been used to mitigate the thrombotic milieu within the patient and device. In the following manuscript, we outline the current data on anticoagulation strategies for commonly used extracorporeal circulatory devices, highlighting the potential benefits and complications involved with each.

Low Free T3 Is Associated With Worse Outcomes in Patients in the ICU Requiring Invasive Mechanical Ventilation.

OBJECTIVE: Critical illness causes a decrease in serum free triiodothyronine (T3) levels. This condition, known as nonthyroidal illness syndrome (NTIS), is associated with poor outcomes. The association of NTIS and outcomes in patients in the intensive care unit (ICU) requiring mechanical ventilation has not been well studied. This study aimed to determine the impact of NTIS on the outcomes of these patients. METHODS: This prospective study included 162 patients in the ICU who underwent mechanical ventilation. Serum free T3 levels were tested on the day of initiation of mechanical ventilation. The rates of in-hospital mortality and ventilator-free days (VFDs) at day 28 after the initiation of mechanical ventilation were compared between patients with low (<2.3 pg/mL) and normal (≥2.3 pg/mL) free T3 levels. Patients who died while on mechanical ventilation were assigned a VFD of 0. RESULTS: Low T3 was present in 60% of study patients. The in-hospital mortality rate of the entire cohort was 39%, and the mean and median VFDs at day 28 were 13.5 and 21 days, respectively. Compared to patients with normal free T3, patients with low free T3 had higher in-hospital mortality (52% vs 19%, P < .001) and less mean and median VFDs at day 28 (10.7 vs 18 and 0 vs 23, respectively. P < .001 for both mean and median VFDs). CONCLUSIONS: The presence of low T3 due to NTIS in patients in the ICU requiring mechanical ventilation is associated with poor outcomes.

Reproducibility of global electrical heterogeneity measurements on 12-lead ECG: The Multi-Ethnic Study of Atherosclerosis.

OBJECTIVE: Vectorcardiographic (VCG) global electrical heterogeneity (GEH) metrics showed clinical usefulness. We aimed to assess the reproducibility of GEH metrics. METHODS: GEH was measured on two 10-s 12­lead ECGs recorded on the same day in 4316 participants of the Multi-Ethnic Study of Atherosclerosis (age 69.4 ± 9.4 y; 2317(54%) female, 1728 (40%) white, 1138(26%) African-American, 519(12%) Asian-American, 931(22%) Hispanic-American). GEH was measured on a median beat, comprised of the normal sinus (N), atrial fibrillation/flutter (S), and ventricular-paced (VP) beats. Spatial ventricular gradient's (SVG's) scalar was measured as sum absolute QRST integral (SAIQRST) and vector magnitude QT integral (VMQTi). RESULTS: Two N ECGs with heart rate (HR) bias of -0.64 (95% limits of agreement [LOA] -5.68 to 5.21) showed spatial area QRS-T angle (aQRST) bias of -0.12 (95%LOA -14.8 to 14.5). Two S ECGs with HR bias of 0.20 (95%LOA -15.8 to 16.2) showed aQRST bias of 1.37 (95%LOA -33.2 to 35.9). Two VP ECGs with HR bias of 0.25 (95%LOA -3.0 to 3.5) showed aQRST bias of -1.03 (95%LOA -11.9 to 9.9). After excluding premature atrial or ventricular beat and two additional beats (before and after extrasystole), the number of cardiac beats included in a median beat did not affect the GEH reproducibility. Mean-centered log-transformed values of SAIQRST and VMQTi demonstrated perfect agreement (Bias 0; 95%LOA -0.092 to 0.092). CONCLUSION: GEH measurements on N, S, and VP median beats are reproducible. SVG's scalar can be measured as either SAIQRST or VMQTi. SIGNIFICANCE: Satisfactory reproducibility of GEH metrics supports their implementation.

Effect of Reverse End-to-Side (Supercharging) Neurotization in Long Processed Acellular Nerve Allograft in a Rat Model.

PURPOSE: Processed acellular nerve allograft (PNA) has been suggested as a convenient tool for overcoming short and medium nerve defects. Although the clinical implications are unclear, animal data suggest that PNA becomes less effective at longer lengths. Although reverse or supercharging end-to-side nerve transfer may improve the neurotrophic potential in chronically denervated nerve tissue, the application of this strategy to long acellular nerve allograft has not been previously investigated. We hypothesized that supercharging acellular nerve allograft would increase its effective length. METHODS: Sprague-Dawley and Thy1-green fluorescent protein Sprague-Dawley rats underwent transection of the tibial nerve, followed by immediate repair with 20-, 40-, or 60-mm acellular nerve allografts processed identically to commercially available human acellular nerve allograft (AxoGen, Inc., Alachua, FL) or isograft. Half of the allograft group was supercharged with a reverse end-to-side transfer from the ipsilateral peroneal nerve. At 10 weeks, the reconstructed nerve in the Thy1-green fluorescent rat groups were exposed and examined under a fluorescence-enabled microscope. At 20 weeks, the remaining rats underwent motor testing and tissue harvest for morphological examination. RESULTS: In comparison with a nonenhanced allograft, supercharging had a statistically significant positive impact on the reinnervated muscle normalized force generation and distal axon counts for all graft sizes. Muscles in the supercharged group were heavier than those in the allograft group for the 40-mm-length grafts and G-ratio measurements were higher in the supercharged allograft group for 60-mm-length grafts only. CONCLUSIONS: This study supports that hypothesis that supercharging nerve transfer improves axon regeneration within PNA. CLINICAL RELEVANCE: When an appropriate donor nerve is available, supercharging nerve transfer may improve nerve regeneration in PNA across long nerve defects.

Adherence to thromboprophylaxis guidelines in elderly patients with hospital acquired venous thromboembolism: a case control study.

Venous thromboembolism (VTE) remains the number one preventable cause of hospital acquired mortality and morbidity. Each year, more than 12 million patients are at risk for VTE. The delivery of appropriate and timely VTE prophylaxis is still suboptimal in many healthcare institutions and can lead to increased readmissions, morbidity, as well as costs. To clarify this issue further, we performed a retrospective case control study at our institution to determine if poor adherence to the VTE prophylaxis guidelines could lead to an increase in VTE events. This was a retrospective case control study conducted at Winthrop-University Hospital from January 2007 to December 2011. Exclusion criteria were age < 18 and concurrent use of anticoagulant agents. Out of 322 cases of hospital acquired VTE or readmission with VTE within 30 days of discharge, 289 cases were selected for final analysis and paired with age and sex matched controls. Patients with a hospital acquired VTE or a readmission for VTE within 30 days of discharge had a significantly reduced rate of VTE prophylaxis when compared to the control group (54.0 vs. 79.2 %, p < 0.0001). The VTE risk assessment rate was also lower in the VTE group (77.2 vs. 85.5 %, p = 0.035). No difference was noted in the time to prophylaxis administration between the two groups (34.8 vs. 33.1 h, p = 0.34). Lastly, sequential compression device (SCD) documentation rate was not different: 68/116 (58.6 %) vs. 44/87 (50.6 %), p = 0.32, between the two arms. Low adherence to the American College of Chest Physician (ACCP) guidelines for VTE prophylaxis correlated with an increase in hospital acquired VTE. The decreased adherence may be linked to a lower VTE risk assessment rate, and other barriers including incorrect identification of contraindications to pharmacologic prophylaxis, and poor documentation of mechanical prophylaxis. There was no difference in SCD documentation rate and timeliness to administration of initial thromboprophylaxis between the two groups. Future studies are needed to reassess adherence and documentation rates after system-wide improvements.

Comparing Length of Stay Between Patients Taking Rivaroxaban and Conventional Anticoagulants for Treatment of Venous Thromboembolism.

BACKGROUND: Recent studies have demonstrated non-inferiority of rivaroxaban when compared to warfarin for the treatment of pulmonary embolism and deep venous thrombosis. Analysis of data from the EINSTEIN trials has demonstrated that patients who received rivaroxaban had a shorter length of stay (LOS) compared to those who received warfarin. However, these trials had strict inclusion and exclusion criteria, and were designed for a different primary outcome. Also, data from these closely monitored clinical trials may not reflect the daily practice of medicine. OBJECTIVES: To clarify this issue further, we performed a retrospective analysis at our institution, comparing the LOS between patients discharged on rivaroxaban and other conventional anticoagulants (warfarin, enoxaparin, and enoxaparin with warfarin). METHODS: This was a retrospective study of consecutive patients admitted to our institution from January 2011 to July 2014 with newly diagnosed venous thromboembolism (VTE). Inclusion criteria were age > 18 years and objective confirmation of VTE. Exclusion criteria included diagnosis of VTE 24 h after admission, contraindication to anticoagulation, treatment with fibrinolytic agents, patients already on anticoagulation, and pregnancy. Out of 1553 consecutive patients diagnosed with VTE, a total of 414 patients met the eligibility criteria. These patients were further subdivided into four groups based on their discharge anticoagulant: rivaroxaban, warfarin, enoxaparin, and warfarin with enoxaparin. RESULTS: Patients discharged on rivaroxaban had a significantly shorter LOS compared with patients discharged on warfarin (3.5 vs. 7.0 days; p < 0.001), but not when compared to those discharged on enoxaparin alone (3.0 days) or enoxaparin with warfarin (4.0 days) (p > 0.05). The hospital incidence of bleeding and the 6-month readmission rates were not different among the different anticoagulants. CONCLUSIONS: In patients admitted with newly diagnosed VTE, those discharged on rivaroxaban had a significantly shorter LOS compared to those discharged on warfarin. In the appropriate subset of patients with VTE, treatment with rivaroxaban may result in significant cost savings for the hospital.

A Case of Pneumonia Caused by Pneumocystis Jirovecii and Cryptococcus Neoformans in a Patient with HTLV-1 Associated Adult T- Cell Leukemia/Lymphoma: Occam's Razor Blunted.

Adult T-cell leukemia/lymphoma (ATLL) is usually preceded by infection with human T-cell lymphotropic virus I (HTLV-I). Patients with ATLL frequently get opportunistic infections of the lungs, intestines, and central nervous system. Pneumocystis pneumonia is commonly known as an AIDS defining illness. Grocott's methenamine silver stain of bronchoalveolar lavage (BAL) samples obtained via bronchoscopy remain the gold standard for diagnosis. Pulmonary cryptococcosis is seen in patients with T-cell deficiencies and a diagnosis is made by culture of sputum, BAL, or occasionally of pleural fluid. We present the second case of coinfection with these two organisms in a patient with ATLL who was successfully treated with trimethoprim-sulfamethoxazole, corticosteroids, and fluconazole. We illustrate the need for high clinical vigilance for seeking out an additional diagnosis, especially in immunocompromised patients if they are not improving despite receiving appropriate treatment.

Multi-valvular infective endocarditis from Gemella morbillorum.

Gemella morbillorum is increasingly implicated in infectious endocarditis. Our patient presented with anaemia and renal failure with evidence of infarcts and embolic disease. He was found to have endocarditis with an organism that could not speciate with standard culture methods requiring matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF) for identification and susceptibilities. While involvement of mitral and aortic valves can be expected with Gemella, he had rare involvement of the pulmonic valve in a structurally normal heart. Although bacteriological cure was achieved, due to the locally destructive nature of Gemella, he ultimately required valve replacements for heart failure resolution. Workup for commonly implicated pathologies associated with G. morbillorum led to suspicion of gastrointestinal malignancy with findings of occult bleeding prompting an ongoing evaluation. With improved access to advanced diagnostics, G. morbillorum has been increasingly identified in infectious endocarditis. Given its destructive nature, it is important for clinicians to consider this organism is difficult to identify isolates.

Improving admission medication reconciliation with pharmacists or pharmacy technicians in the emergency department: a randomised controlled trial.

BACKGROUND: Admission medication history (AMH) errors frequently cause medication order errors and patient harm. OBJECTIVE: To quantify AMH error reduction achieved when pharmacy staff obtain AMHs before admission medication orders (AMO) are placed. METHODS: This was a three-arm randomised controlled trial of 306 inpatients. In one intervention arm, pharmacists, and in the second intervention arm, pharmacy technicians, obtained initial AMHs prior to admission. They obtained and reconciled medication information from multiple sources. All arms, including the control arm, received usual AMH care, which included variation in several common processes. The primary outcome was severity-weighted mean AMH error score. To detect AMH errors, all patients received reference standard AMHs, which were compared with intervention and control group AMHs. AMH errors and resultant AMO errors were independently identified and rated by ≥2 investigators as significant, serious or life threatening. Each error was assigned 1, 4 or 9 points, respectively, to calculate severity-weighted AMH and AMO error scores for each patient. RESULTS: Patient characteristics were similar across arms (mean±SD age 72±16 years, number of medications 15±7). Analysis was limited to 278 patients (91%) with reference standard AMHs. Mean±SD AMH errors per patient in the usual care, pharmacist and technician arms were 8.0±5.6, 1.4±1.9 and 1.5±2.1, respectively (p<0.0001). Mean±SD severity-weighted AMH error scores were 23.0±16.1, 4.1±6.8 and 4.1±7.0 per patient, respectively (p<0.0001). These AMH errors led to a mean±SD of 3.2±2.9, 0.6±1.1 and 0.6±1.1 AMO errors per patient, and mean severity-weighted AMO error scores of 6.9±7.2, 1.5±2.9 and 1.2±2.5 per patient, respectively (both p<0.0001). CONCLUSIONS: Pharmacists and technicians reduced AMH errors and resultant AMO errors by over 80%. Future research should examine other sites and patient-centred outcomes. TRIAL REGISTRATION NUMBER: NCT02026453.

Identifying the Optimal Radiation Dose in Locally Advanced Non-Small-cell Lung Cancer Treated With Definitive Radiotherapy Without Concurrent Chemotherapy.

INTRODUCTION: The optimal radiation dose for locally advanced non-small-cell lung cancer (NSCLC) is not known for patients who receive sequential chemoradiation (CRT) or definitive radiotherapy (RT) only. Our objective was to determine whether a benefit exists for radiation dose escalation for these patients. MATERIALS AND METHODS: The patients included in our retrospective analysis had undergone RT for NSCLC from 2004 to 2013, had not undergone surgery, and received a dose ≥ 50.0 Gy. Patients who received concurrent CRT were excluded from the analysis, leaving 336 patients for analysis. The primary outcomes were overall survival (OS), local failure (LF), and distant failure (DF). RESULTS: On multivariate analysis, after adjusting for age, Karnofsky performance status, gross tumor volume, and treatment modality, patients treated with a radiation dose > 66 Gy had significantly improved OS compared with those treated with < 60 Gy (hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.39-0.87; P = .008). After adjusting for smoking history and radiologic tumor size, patients treated with a radiation dose > 66 Gy had a significantly decreased risk of LF compared with those treated with < 60 Gy (HR, 0.59; 95% CI, 0.38-0.91; P = .02). The radiation dose was not an independent prognostic factor of DF on multivariate analysis. CONCLUSION: When controlling for tumor volume and/or dimensions and other independent prognostic factors, patients with locally advanced NSCLC who were not candidates for concurrent CRT benefited from a radiation dose > 66 Gy versus < 60 Gy with improved OS and reduced LF. An increased radiation dose did not appear to affect the incidence of DF.

The concentration of oxygen, lactate and glucose in the central veins, right heart, and pulmonary artery: a study in patients with pulmonary hypertension.

INTRODUCTION: Decreases in oxygen saturation (SO2) and lactate concentration [Lac] from superior vena cava (SVC) to pulmonary artery have been reported. These gradients (Delta SO2 and Delta[Lac]) are probably created by diluting SVC blood with blood of lower SO2 and [Lac]. We tested the hypothesis that Delta SO2 and Delta[Lac] result from mixing SVC and inferior vena cava (IVC) blood streams. METHODS: This was a prospective, sequential, observational study of hemodynamically stable individuals with pulmonary artery hypertension (n = 9) who were about to undergo right heart catheterization. Catheters were advanced under fluoroscopic guidance into the IVC, SVC, right atrium, right ventricle, and pulmonary artery. Samples were obtained at each site and analyzed for SO2, [Lac], and glucose concentration ([Glu]). Analysis of variance with Tukey HSD test was used to compare metabolite concentrations at each site. RESULTS: There were no differences in SO2 or [Lac] between IVC and SVC, both being greater than their respective pulmonary artery measurements (P < 0.01 for SO2 and P < 0.05 for [Lac]). SO2 and [Lac] in right atrium, right ventricle, and pulmonary artery were similar. Delta SO2 was 4.4 +/- 1.4% (mean +/- standard deviation) and Delta[Lac] was 0.16 +/- 0.11 mmol/l (both > 0; P < 0.001). Delta[Glu] was -0.19 +/- 0.31 mmol/l, which was not significantly different from zero, with SVC [Glu] being less than IVC [Glu]. CONCLUSION: Mixing of SVC with IVC blood does not account for the development of Delta SO2 and Delta[Lac] in hemodynamically stable individuals with pulmonary artery hypertension. An alternate mechanism is mixing with coronary sinus blood, implying that Delta SO2 and Delta[Lac] may reflect changes in coronary sinus SO2 and [Lac] in this patient population.

Treatment of pulmonary hypertension with left heart disease: a concise review.

Pulmonary hypertension (PH) is defined by a mean pulmonary artery pressure ≥ 25 mmHg, as determined by right heart catheterization. Pulmonary arterial hypertension (PAH) can no longer be considered an orphan disease given the increase in awareness and availability of new drugs. PH carries with it a dismal prognosis and leads to significant morbidity and mortality. Symptoms can range from dyspnea, fatigue and chest pain to right ventricular failure and death. PH is divided into five groups by the World Health Organization (WHO), based on etiology. The most common cause of PH in developed countries is left heart disease (group 2), owing to the epidemic of heart failure (HF). The data regarding prevalence, diagnosis and treatment of patients with group 2 PH is unclear as large, prospective, randomized controlled trials and standardized protocols do not exist. Current guidelines do not support the use of PAH-specific therapy in patients with group 2 PH. Prostacyclins, endothelin receptor antagonists, phosphodiesterase-5 inhibitors and guanylate cyclase stimulators have been tried in treatment of patients with HF and/or group 2 PH with mixed results. This review summarizes and critically appraises the evidence for diagnosis and treatment of patients with group 2 PH/HF and suggests directions for future research.