Preclinical evaluation of a third-generation absorbable antibacterial envelope.

BACKGROUND: The TYRX (Medtronic) absorbable antibacterial envelope has been shown to stabilize implantable cardiac devices and reduce infection. A third-generation envelope was developed to reduce surface roughness with a redesigned multifilament mesh and enhanced form factor but identical polymer coating and antibiotic concentrations as the currently available second-generation envelope. OBJECTIVE: The purpose of this study was to compare drug elution, bacterial challenge efficacy, stabilization, and absorption of second- vs third-generation envelopes. METHODS: Antibiotic elution was assessed in vitro and in vivo. For efficacy against gram-positive/gram-negative bacteria, 40 rabbits underwent device insertions with or without third-generation envelopes. For stabilization (migration, rotation), 5 sheep were implanted with 6 devices each in second- or third-generation envelopes. Prespecified acceptance criteria were <83-mm migration and <90° rotation. Absorption was assessed via gross pathology. RESULTS: Elution curves were equivalent (similarity factors ≥50 per Food and Drug Administration guidance). Third-generation envelopes eluted antibiotics above minimal inhibitory concentration (MIC) in vivo at 2 hours postimplant through 7 days, consistent with second-generation envelopes. Bacterial challenge showed reductions (P <.05) in infection with second- and third-generation envelopes. Device migration was 5.5 ± 3.5 mm (third-generation) vs 9. 9 ±7.9 mm (second-generation) (P <.05). Device rotation was 18.9° ± 11.4° (third-generation) vs 17.6° ± 15.1° (second-generation) and did not differ (P = .79). Gross pathology confirmed the absence of luminal mesh remainders and no differences in peridevice fibrosis at 9 or 12 weeks. CONCLUSION: The third-generation TYRX absorbable antibacterial envelope demonstrated equivalent preclinical performance to the second-generation envelope. Antibiotic elution curves were similar, elution was above MIC for 7 days, infections were reduced compared to no envelope, and acceptance criteria for migration, rotation, and absorption were met.

Infants' Biological Sensitivity to the Effects of Maternal Social Support: Evidence Among Mexican American Families.

The identification of infants who are most susceptible to both negative and positive social environments is critical for understanding early behavioral development. This study longitudinally assessed the interactive effects of infant vagal tone (respiratory sinus arrhythmia; RSA) and maternal social support on behavioral problems and competence among 322 low-income Mexican American mother-infant dyads (infants: 54.1% female) and explored sex differences. Infant RSA was calculated from resting HR data at 6 weeks of age. Mothers reported on general social support, partner support, and family support at 6 months, and infant behavioral problems and competence at 1 year. Two-way interactions (RSA × support source) were evaluated to predict behavioral problems and competence, adjusting for covariates. Results indicated higher competence among infants with lower RSA whose mothers reported higher general support or higher partner support. Interactive effects on behavior problems of RSA with maternal partner or family support were only found for female infants: Girls with higher RSA showed more behavior problems when mothers reported low support, but fewer problem levels in the context of high support. Our results suggest that infant RSA is an important moderator of the effects of the early social environment on early development.

Family Support and Family Negativity as Mediators of the Relation between Acculturation and Postpartum Weight in Low-Income Mexican-Origin Women.

BACKGROUND: Obesity presents a significant health concern among low-income, ethnic minority women of childbearing age. PURPOSE: The study investigated the influence of maternal acculturation, family negativity, and family support on postpartum weight loss among low-income Mexican-origin women. METHODS: Low-income Mexican-origin women (N=322; 14% born in the U.S.) were recruited from a prenatal clinic in an urban area of the Southwest U.S. Acculturation was assessed during a prenatal home visit (26-38 weeks gestation), and post-birth family support and general family negativity were assessed at 6 weeks postpartum. Objective maternal weight measures were obtained at five time points across the first postpartum year. RESULTS: Higher acculturation predicted higher family support and family negativity. Higher family support predicted decreasing weight across the first postpartum year, and higher family negativity predicted higher weight at 6 weeks postpartum and increasing weight across the first postpartum year. In combination, family negativity and support mediated the impact of acculturation on postpartum weight gain. CONCLUSIONS: Cultural and family-related factors play a significant role in postpartum weight gain and loss for low-income Mexican-origin women.

Antibacterial Envelope Is Associated With Low Infection Rates After Implantable Cardioverter-Defibrillator and Cardiac Resynchronization Therapy Device Replacement: Results of the Citadel and Centurion Studies.

OBJECTIVES: This study sought to determine whether the nonabsorbable TYRX Antibacterial Envelope (TYRX) reduces major cardiovascular implantable electronic device (CIED) infections 12 months after implant. BACKGROUND: TYRX is a monofilament polypropylene mesh impregnated with minocycline and rifampin specifically designed to hold a CIED in place and elute antimicrobials over time. There are limited data on its ability to reduce CIED infections. METHODS: We prospectively enrolled patients who underwent generator replacement with an implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy device (CRT), treated with TYRX. The primary endpoints were major CIED infection and CIED mechanical complications. Given the differences in infection rates among ICD and CRT patients, 3 different control populations were used: a published benchmark rate for ICD patients, and both site-matched and comorbidity-matched controls groups for CRT patients. RESULTS: Overall, a major CIED infection occurred in 5 of 1,129 patients treated with TYRX (0.4%; 95% confidence interval: 0.0% to 0.9%), significantly lower than the 12-month benchmark rate of 2.2% (p = 0.0023). Among the TYRX-treated CRT cohort, the major CIED infection rate was 0.7% compared with an infection rate of 1.0% and 1.3% (p = 0.38 and p = 0.02) in site-matched and comorbidity-matched control groups, respectively. Among the ICD group, the 12-month infection rate was 0.2% compared with the published benchmark of 2.2% (p = 0.0052). The most common CIED mechanical complication in study patients was pocket hematoma, which occurred in 18 of the 1,129 patients (1.6%; 95% confidence interval: 0.8 to 2.5), which is comparable with a published rate of 1.6%. CONCLUSIONS: Use of TYRX was associated with a lower major CIED infection rate. (TYRX™ Envelope for Prevention of Infection Following Replacement With a CRT or ICD; [Centurion]; NCT01043861/NCT01043705).

Importance of cardiological evaluation for first seizures.

This paper reports two cases of long QT syndrome (LQTS) which presented with seizures as their initial feature. Case 1, AB was seen in emergency department with post-partum seizure, discharged and re-presented following cardiac arrest associated with LQTS. Case 2, CD presented initially with tonic-clonic seizure and because of experience with AB, CD was assessed for LQTS which was subsequently confirmed. The legal medicine experience re Dobler v Halverson, which involved a young boy with LQTS, who suffered cardiac arrest without prior diagnosis of LQTS, has reinforced the requirement to seriously consider LQTS as an aetiological factor in first seizure presentations.

Programming implantable cardioverter-defibrillators in patients with primary prevention indication to prolong time to first shock: results from the PROVIDE study.

BACKGROUND: Shock therapy delivery by implantable cardioverter-defibrillators (ICD) can be painful and may have adverse consequences. Reducing shock burden for patients with ICDs would be beneficial. METHODS: PROVIDE was a prospective, randomized study of primary prevention ICD patients. Patients in the experimental group received a combination of programmed parameters with higher detection rates, longer detection intervals, empiric antitachycardia pacing (ATP), and optimized supraventricular tachycardia (SVT) discriminators, while those in the control group were programmed with conventional parameters. Shock therapy and arrhythmic syncope were compared. RESULTS: Of 1,670 patients enrolled (846 in the experimental group, 824 in the control group) and monitored over a follow-up of 530 ± 241 days, 202 patients received shock therapy for any cause (82 in the experimental group and 120 in the control group). The median time to first shock was significantly prolonged (13.1 vs 7.8 months, hazard ratio [HR]: 0.62, 95% confidence interval [CI]: 0.47 to 0.82, P = 0.0005) and the 2-year shock rate significantly reduced (12.4% vs 19.4%, P < 0.001) in the experimental group compared to the control group. There was no increase in arrhythmic syncope (HR: 1.64, 95% CI: 0.69 to 3.90, P = 0.26), while the overall mortality was reduced (HR: 0.7, 95% CI: 0.50 to 0.98, P = 0.036) in the experimental group compared to the control group. CONCLUSION: A combination of programmed parameters utilizing higher detection rate, longer detection intervals, empiric ATP, and optimized SVT discriminators reduced ICD therapies without increasing arrhythmic syncope and was associated with reduction in all-cause mortality among ICD patients.

Prevalence of positive syphilis serology and meningovascular neurosyphilis in patients admitted with stroke and TIA from a culturally diverse population (2005-09).

The study aims were to determine the prevalence of positive syphilis serology and meningovascular neurosyphilis (NS) in patients admitted with transient ischaemic attack (TIA) and stroke to a tertiary hospital serving a culturally diverse community. A retrospective cohort analysis was conducted using routinely collected administrative data and medical records to identify patients admitted with TIA, stroke and other conditions, with positive syphilis serology, between 2005 and 2009. Direct medical record review confirmed diagnoses of meningovascular NS. Syphilis serology was requested in 27% (893/3270) of all patients with TIA and stroke (2005-09) of whom 4% (38/893) were positive. Thirty-seven patients with positive serology had clinical characteristics consistent with meningovascular NS. Their mean age was 72±13 years; 65% were male and 68% had a recorded place of birth in South-East Asia or the Pacific Islands. One of 12 patients with suspected meningovascular NS with cerebrospinal fluid (CSF) analysis had a positive CSF Venereal Disease Research Laboratory (VDRL) test. Three patients (8%) met diagnostic criteria for "definite or probable" meningovascular NS. All three patients with a "definite or probable" meningovascular NS and 15 (44%) of the remainder who had positive serology without confirmation of NS were treated with intravenous or intramuscular penicillin. Lumbar puncture (LP) and penicillin were underutilised in patients with TIA and stroke with positive serology. In conclusion, syphilis testing should be considered part of the diagnostic work-up of TIA and stroke, particularly in ethnically diverse populations. In patients with TIA and stroke with positive syphilis serology, it would seem appropriate to further pursue diagnosis and treatment and in patients unable to undergo LP, empiric treatment for NS should be considered.

Basilar artery occlusion in a 14-year old female successfully treated with acute intravascular intervention: case report and review of the literature.

Basilar artery occlusion (BAO) is a rare cause of paediatric stroke that may result in severe neurological disability including a 'locked-in' state. Acute interventional therapy for paediatric BAO is limited to a small number of published case reports. Of 13 previously published cases that have undergone acute intravascular therapy, six made a full neurological recovery, six had residual deficits ranging from mild dysarthria and ataxia to vegetative state and one patient died. The time from symptom onset to intervention was ≥ 12 h in 77% (10/13). We reported a 14-year-old female patient presenting with altered sensorium that progressed to a 'locked-in' state due to idiopathic BAO who made a full clinical recovery after successful mechanical thrombectomy at 24 h following symptom onset. Acute neuro-interventional therapy for paediatric BAO can result in complete neurological recovery despite the presence of severe neurological deficits and a prolonged period of time from symptom onset to clinical diagnosis.

Validation of emergency and final diagnosis coding in transient ischemic attack: South Western Sydney transient ischemic attack study.

BACKGROUND: It is important to establish the validity of diagnostic coding in administrative datasets used in stroke and transient ischemic attack (TIA) research. This study examines the accuracy of emergency department (ED) TIA diagnosis and final diagnostic coding after hospital admission. METHODS: Using administrative datasets, we identified all patients with an ED TIA diagnosis (435.9; ICD-9) admitted to Liverpool Hospital from January 2003 to December 2007. ED and hospital admission records were matched and final diagnosis codes (ICD-10-AM) recorded. All records were expertly reviewed to determine coding validity. RESULTS: 570 patients were admitted with an ED TIA diagnosis. According to ICD-10-AM coding, 46% had TIA, 29% stroke and 25% TIA mimic diagnoses. Expert review determined final diagnoses of TIA in 51.4%, stroke in 26.1% and TIA mimic in 22.5% of the patients. The positive predictive value of a final TIA diagnosis (ICD-10-AM) was 88.2% when subjected to expert review. TIA mimic disorders diagnosed after admission included serious conditions. CONCLUSIONS: Half of the emergency diagnoses retained a TIA diagnosis after hospital admission. In the setting of neurological admission there were small percentage differences between coded final diagnosis for TIA, stroke and mimic and diagnoses at expert review. Admission of ED TIA cases permitted identification of TIA mimics with serious conditions requiring non-TIA management.

Decreasing presentations of seizures to emergency departments in a large Australian population.

This study was designed (1) to compare the prevalence of emergency department (ED) presentations in Western Zone Sydney South West Area Health Service (WZS) between 1998-2002 and 2003-2007 for epilepsy (including status epilepticus (SE) and convulsions), hospital admission rates, and proportion of first seizure presentations; and (2) to compare these data with those for New South Wales (NSW) and Australia-wide figures. Using health department data sets, we found 19,834 presentations to WZS EDs between 1998 and 2007 (24.85/10,000 population/year). When the periods 2003-2007 and 1998-2002 in WZS are compared, ED presentations fell by 3% (P=0.03) and hospital admissions fell by 6% (P=0.001). The prevalence of ED presentations for seizures in NSW did not change (P=0.92), but hospital admissions fell by 3% (P<0.0001). When 1999/2000-2002/2003 was compared with 2003/2004-2006/2007, the prevalence of hospital admissions in Australia fell by 1% (P=0.0002). Rates of presentation for epilepsy in WZS have fallen over the last decade. Most presentations were first seizures rather than recurrences. The reason for this is speculative, but may reflect improved levels of education and health care delivery.

Outcomes of patients with transient ischaemic attack after hospital admission or discharge from the emergency department.

OBJECTIVE: To compare outcomes at 28 days and 1 year between patients admitted to hospital and those discharged after presenting to the emergency department (ED) with transient ischaemic attack (TIA). DESIGN AND SETTING: All TIA presentations to EDs in a large metropolitan and rural region of Sydney and its surroundings, New South Wales, between 2001 and 2005 were extracted from state health department databases and followed up over 1 year. Admission and discharge data and subsequent TIA or stroke presentations were identified. MAIN OUTCOME MEASURES: TIA recurrence or stroke. RESULTS: Of 2535 presentations to an ED with TIA during the 5-year period, 1816 patients were admitted to hospital (71.6%) and 719 were discharged from the ED (28.4%). At 28 days, the discharged group had significantly higher rates of recurrence than the admitted group for all events (TIA or stroke) (5.3% v 2.3%, P < 0.001), stroke (2.1% v 0.7%, P = 0.002), and recurrent TIA (3.2% v 1.6%, P = 0.01). During the 29-365-day follow-up period, there was no significant difference between the discharged and admitted groups for all events (4.2% v 5.1%; P = 0.37), stroke (1.3% v 2.5%; P = 0.06) or recurrent TIA (2.9% v 2.6%; P = 0.65). CONCLUSION: Patients with an ED diagnosis of TIA may benefit from admission to hospital through a reduced risk of early stroke.

Impact of race and gender on cardiac device implantations.

BACKGROUND: Pacemakers and implantable cardioverter-defibrillators (ICDs) are established therapies for life-threatening cardiac arrhythmias. Biventricular pacemakers (BiVP) can improve heart failure in selected patients as well. OBJECTIVE: This study sought to investigate the impact of gender and race on rates of implantation of pacemakers and ICDs in patients with reduced left ventricular ejection fraction (LVEF). METHODS: Data were obtained from ADVANCENT, a prospective multicenter registry enrolling patients with LVEF < or = 40% between June 2003 and November 2004. a total of 26,264 patients from 106 us centers were enrolled. the mean age was 66.4 years; 71.5% were male and 81.9% were white; 10,394 subjects (39.6%) had devices implanted. RESULTS: The overall rate of device implantation was higher in white subjects compared with nonwhite subjects (41.1% vs 32.5%, P <.0001). This was also true for the rates of implantation of all types of ICDs (28.6% vs 23.9%, P <.0001) and BiVP (11.2% vs 7.7%, P <.0001). After adjusting for age, gender, LVEF, New York Heart Association class, coronary artery disease, QRS duration, comorbidities, type of referring physician, and insurance type, nonwhite race remained an independent negative predictor of implantation of any device (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.791 to 0.927), and any ICD (OR 0.88, 95% CI 0.817 to 0.964). Female gender was also independently associated with decreased implantation of any device (OR 0.70, 95% CI 0.66 to 0.76), and any ICD (OR 0.60, 95% CI 0.55 to 0.64). CONCLUSION: In this large cohort with reduced LVEF, minorities and women were significantly less likely to receive device implants. These findings were most pronounced in nonwhite women, and could not be explained by disparities in demographic or clinical characteristics.

Lipid-lowering drug use is associated with reduced prevalence of atrial fibrillation in patients with left ventricular systolic dysfunction.

BACKGROUND: Inflammation and oxidative stress have been implicated in the pathogenesis of atrial fibrillation (AF). Lipid-lowering drugs, particularly statins and fibrates, possess anti-inflammatory and antioxidant properties. OBJECTIVES: The purpose of this study was to assess the impact of lipid-lowering drug use on AF prevalence in patients with reduced left ventricular ejection fraction (LVEF). METHODS: Data were obtained from ADVANCENT(SM), a multicenter registry of patients with reduced LVEF (

The relationship between stature and the prevalence of atrial fibrillation in patients with left ventricular dysfunction.

OBJECTIVES: This study sought to determine the influence of stature on atrial fibrillation (AF) in high-risk patients with reduced left ventricular (LV) systolic function. BACKGROUND: Left atrial (LA) enlargement is a potent risk factor for AF. Because LA size is strongly associated with stature, we hypothesized that height and body surface area (BSA) are risk factors for AF, independent of other known associations. METHODS: Data were obtained from ADVANCENT, a multicenter registry of patients with impaired LV function. Height and BSA were divided into quartiles by gender. Statistical analysis was done using the Cochran Mantel-Haenszel statistic, and multivariable logistic regressions were used to adjust for the effects of known confounders on the association between stature and AF. RESULTS: A total of 25,268 patients were enrolled. The mean age was 66 years, and the cohort consisted mostly of white men (72%) and patients with ischemic cardiomyopathy (72%). The mean left ventricular ejection fraction was 31%. A history of AF was present in 7,027 patients (27.8%). The AF prevalence increased significantly between the lowest and highest quartiles for height (32% relative increase, p < 0.0001). In the multivariable analysis, the effect of height on AF risk persisted after adjusting for age, gender, race, left ventricular ejection fraction, heart failure class and etiology, hypertension, diabetes, and medication use (odds ratio 1.026/cm, 95% confidence interval [CI] 1.022 to 1.030). In the multivariable analysis, BSA was also an independent predictor of AF risk (odds ratio 4.221/m2, 95% CI 3.358 to 5.306). CONCLUSIONS: In patients with LV dysfunction, increasing stature portends a higher risk of AF independent of other traditional risk factors for the arrhythmia. This association seems to account for the higher prevalence of AF in men and may be useful for identification of a high-risk population.

Secondary prevention of coronary heart disease in elderly patients.

Coronary heart disease remains a leading cause of mortality in the United States, with 84 percent of persons 65 years or older dying from this disease. Secondary preventive measures, including lifestyle modification and pharmacotherapy, are important for elderly patients because of the variable impacts on morbidity and mortality rates and quality of life. Participating in light to moderate activities significantly decreases mortality rates in elderly patients. Smoking cessation translates into a reduction in overall mortality and morbidity rates at least equal to that of other preventive measures such as aspirin or beta-blocker therapy. Recent studies on the effects of lowering low-density lipoprotein cholesterol levels to below 100 mg per dL have shown a substantial reduction in coronary heart disease mortality and nonfatal myocardial infarction rates, with a persistent effect in patients older than 75 years. Hypertension, manifesting mostly as isolated systolic blood pressure elevation, also should be treated aggressively. Conventional medical therapies for hypertension (e.g., diuretics, beta blockers) and newer agents (e.g., calcium channel blockers, angiotensin-converting enzyme inhibitors), together with sodium restriction, have had a positive effect on cardiovascular mortality and morbidity rates in older patients. With the increasing prevalence of obesity, insulin resistance, and type 2 diabetes, interventions targeting weight reduction and glucose control should be emphasized. Whereas weight-loss strategies are poorly defined in this population, the management of diabetes through dietary modification, exercise, and medications is similar across age groups. The target hemoglobin A1C level is less than 7 percent. Elderly patients are prone to depression and social isolation, and they are more likely to have a lower socioeconomic status than younger patients, which may negatively affect participation in rehabilitation programs and compliance with medical advice and therapy. Strategies aimed at these factors have shown variable results and remain ill-defined.

Atrial septal abnormalities and cryptogenic stroke: a paradoxical science.

Patent foramen ovale and/or atrial septal aneurysm occur in up to 20% of the general population, and have been linked to cryptogenic ischemic strokes in younger individuals. The pathophysiologic basis of this association remains unclear, with growing evidence suggesting a role for thrombosis and embolization. Aspirin and warfarin constitute the current mainstay of medical therapy, with a variety of secondary prevention studies assessing their impact on stroke recurrence. To date, the quality of published data preclude the development of strict recommendations, but a number of suggestions can be derived from available literature. Patients with isolated patent foramen ovale or atrial septal aneurysm and a first ischemic stroke respond well to either aspirin or warfarin therapy. On the other hand, oral anticoagulation seems to be the preferred medical therapy in higher-risk patients with both patent foramen ovale and atrial septal aneurysm or those with multiple strokes on aspirin. Percutaneous or surgical patent foramen ovale closures have been proposed as alternative therapies and seem effective in reducing stroke recurrence. In the absence of randomized, controlled trials comparing medical and invasive approaches, the adoption of a particular therapy should take into consideration the individual's preference, clinical presentation, risk profile, lifestyle, and the expertise of the local interventional and surgical teams.

Functional association of nox1 with p22phox in vascular smooth muscle cells.

The vascular NAD(P)H oxidases constitute important sources of ROS in the vessel wall and have been implicated in vascular disease. Vascular smooth muscle cells (VSMCs) from conduit arteries express two gp91phox homologs, Nox1 and Nox4, of which Nox1 is agonist-sensitive. Because p22phox has been shown to be functionally important in vascular cells stimulated with vasoactive hormones, the relationship of Nox1 and p22phox was investigated in VSMCs from rat and human aortas. Coimmunoprecipitation studies demonstrated that p22phox and hemagglutinin-tagged Nox1 associate in unstimulated VSMCs. These findings were confirmed by confocal microscopy, showing colocalization of the two proteins in their native states in the plasma membrane and submembrane areas of the cell. NADPH-driven superoxide production, as measured by electron spin resonance using 1-hydroxy-3-carboxypyrrolidine as a spin probe, is dependent on the coexpression of both subunits, suggesting the importance of the association for the functional integrity of the enzyme. These results indicate that in contrast to the neutrophil enzyme, VSMCs can use Nox1 rather than gp91phox as a catalytic center in the p22phox-based oxidase and that these two proteins are preassembled at or near the plasma membrane and submembrane vesicular structures in unstimulated cells.

Left atrial structure and function after percutaneous left atrial appendage transcatheter occlusion (PLAATO): six-month echocardiographic follow-up.

OBJECTIVES: This study was designed to evaluate the effects of percutaneous left atrial appendage transcatheter occlusion (PLAATO) on the anatomic and hemodynamic properties of the mitral valve (MV) and left upper pulmonary vein (LUPV). BACKGROUND: PLAATO is a device designed to seal the neck of the left atrial (LA) appendage and reduce embolization in patients with atrial fibrillation intolerant of warfarin. The impact of deployment of this device on adjacent structures has not been reported. METHODS: Patients with atrial fibrillation participating in the ongoing study for evaluation of PLAATO were enrolled. Transesophageal echocardiographies at baseline, one, and six months were reviewed to measure LA and LUPV dimensions, degree of mitral regurgitation, stability of the device, peak MV E-wave velocity, and peak systolic and diastolic flow velocities in the LUPV. Data were analyzed by a linear mixed model for repeated measures. RESULTS: Eleven patients (mean age of 72 +/- 7 years) completed six months of follow-up. Left upper pulmonary vein diameter (mean: 1.55, 1.61, 1.54 cm, p = 0.13) and peak systolic (mean: 0.38, 0.34, 0.31 m/s, p = 0.72) and diastolic flow velocities (mean: 0.39, 0.40, 0.42 m/s, p = 0.46) did not differ over the follow-up period. Left atrial size, mitral regurgitation severity, and MV peak E-wave velocities (mean: 0.94, 0.94, 0.82 m/s, p = 0.58) showed no significant change from baseline. The devices remained stable at their sites of deployment with minimal residual flow around them. CONCLUSIONS: PLAATO achieved an adequate seal of the neck of the left atrial appendage without significant effect on the structure or function of the LA and LUPV.