Severe communication delays are independent of seizure burden and persist despite contemporary treatments in SCN1A+ Dravet syndrome: Insights from the ENVISION natural history study.

OBJECTIVE: Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by high seizure burden, treatment-resistant epilepsy, and developmental stagnation. Family members rate communication deficits among the most impactful disease manifestations. We evaluated seizure burden and language/communication development in children with DS. METHODS: ENVISION was a prospective, observational study evaluating children with DS associated with SCN1A pathogenic variants (SCN1A+ DS) enrolled at age ≤5 years. Seizure burden and antiseizure medications were assessed every 3 months and communication and language every 6 months with the Bayley Scales of Infant and Toddler Development 3rd edition and the parent-reported Vineland Adaptive Behavior Scales 3rd edition. We report data from the first year of observation, including analyses stratified by age at Baseline: 0:6-2:0 years:months (Y:M; youngest), 2:1-3:6 Y:M (middle), and 3:7-5:0 Y:M (oldest). RESULTS: Between December 2020 and March 2023, 58 children with DS enrolled at 16 sites internationally. Median follow-up was 17.5 months (range = .0-24.0), with 54 of 58 (93.1%) followed for at least 6 months and 51 of 58 (87.9%) for 12 months. Monthly countable seizure frequency (MCSF) increased with age (median [minimum-maximum] = 1.0 in the youngest [1.0-70.0] and middle [1.0-242.0] age groups and 4.5 [.0-2647.0] in the oldest age group), and remained high, despite use of currently approved antiseizure medications. Language/communication delays were observed early, and developmental stagnation occurred after age 2 years with both instruments. In predictive modeling, chronologic age was the only significant covariate of seizure frequency (effect size = .52, p = .024). MCSF, number of antiseizure medications, age at first seizure, and convulsive status epilepticus were not predictors of language/communication raw scores. SIGNIFICANCE: In infants and young children with SCN1A+ DS, language/communication delay and stagnation were independent of seizure burden. Our findings emphasize that the optimal therapeutic window to prevent language/communication delay is before 3 years of age.

Effects of gene replacement therapy with resamirigene bilparvovec (AT132) on skeletal muscle pathology in X-linked myotubular myopathy: results from a substudy of the ASPIRO open-label clinical trial.

BACKGROUND: X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital muscle disease caused by mutations in the MTM1 gene that result in profound muscle weakness, significant respiratory insufficiency, and high infant mortality. There is no approved disease-modifying therapy for XLMTM. Resamirigene bilparvovec (AT132; rAAV8-Des-hMTM1) is an investigational adeno-associated virus (AAV8)-mediated gene replacement therapy designed to deliver MTM1 to skeletal muscle cells and achieve long-term correction of XLMTM-related muscle pathology. The clinical trial ASPIRO (NCT03199469) investigating resamirigene bilparvovec in XLMTM is currently paused while the risk:benefit balance associated with this gene therapy is further investigated. METHODS: Muscle biopsies were taken before treatment and 24 and 48 weeks after treatment from ten boys with XLMTM in a clinical trial of resamirigene bilparvovec (ASPIRO; NCT03199469). Comprehensive histopathological analysis was performed. FINDINGS: Baseline biopsies uniformly showed findings characteristic of XLMTM, including small myofibres, increased internal or central nucleation, and central aggregates of organelles. Biopsies taken at 24 weeks post-treatment showed marked improvement of organelle localisation, without apparent increases in myofibre size in most participants. Biopsies taken at 48 weeks, however, did show statistically significant increases in myofibre size in all nine biopsies evaluated at this timepoint. Histopathological endpoints that did not demonstrate statistically significant changes with treatment included the degree of internal/central nucleation, numbers of triad structures, fibre type distributions, and numbers of satellite cells. Limited (predominantly mild) treatment-associated inflammatory changes were seen in biopsy specimens from five participants. INTERPRETATION: Muscle biopsies from individuals with XLMTM treated with resamirigene bilparvovec display statistically significant improvement in organelle localisation and myofibre size during a period of substantial improvements in muscle strength and respiratory function. This study identifies valuable histological endpoints for tracking treatment-related gains with resamirigene bilparvovec, as well as endpoints that did not show strong correlation with clinical improvement in this human study. FUNDING: Astellas Gene Therapies (formerly Audentes Therapeutics, Inc.).

Safety and efficacy of gene replacement therapy for X-linked myotubular myopathy (ASPIRO): a multinational, open-label, dose-escalation trial.

BACKGROUND: X-linked myotubular myopathy is a rare, life-threatening, congenital muscle disease observed mostly in males, which is caused by mutations in MTM1. No therapies are approved for this disease. We aimed to assess the safety and efficacy of resamirigene bilparvovec, which is an adeno-associated viral vector serotype 8 delivering human MTM1. METHODS: ASPIRO is an open-label, dose-escalation trial at seven academic medical centres in Canada, France, Germany, and the USA. We included boys younger than 5 years with X-linked myotubular myopathy who required mechanical ventilator support. The trial was initially in two parts. Part 1 was planned as a safety and dose-escalation phase in which participants were randomly allocated (2:1) to either the first dose level (1·3 × 1014 vector genomes [vg]/kg bodyweight) of resamirigene bilparvovec or delayed treatment, then, for later participants, to either a higher dose (3·5 × 1014 vg/kg bodyweight) of resamirigene bilparvovec or delayed treatment. Part 2 was intended to confirm the dose selected in part 1. Resamirigene bilparvovec was administered as a single intravenous infusion. An untreated control group comprised boys who participated in a run-in study (INCEPTUS; NCT02704273) or those in the delayed treatment cohort who did not receive any dose. The primary efficacy outcome was the change from baseline to week 24 in hours of daily ventilator support. After three unexpected deaths, dosing at the higher dose was stopped and the two-part feature of the study design was eliminated. Because of changes to the study design during its implementation, analyses were done on an as-treated basis and are deemed exploratory. All treated and control participants were included in the safety analysis. The trial is registered with ClinicalTrials.gov, NCT03199469. Outcomes are reported as of Feb 28, 2022. ASPIRO is currently paused while deaths in dosed participants are investigated. FINDINGS: Between Aug 3, 2017 and June 1, 2021, 30 participants were screened for eligibility, of whom 26 were enrolled; six were allocated to the lower dose, 13 to the higher dose, and seven to delayed treatment. Of the seven children whose treatment was delayed, four later received the higher dose (n=17 total in the higher dose cohort), one received the lower dose (n=7 total in the lower dose cohort), and two received no dose and joined the control group (n=14 total, including 12 children from INCEPTUS). Median age at dosing or enrolment was 12·1 months (IQR 10·0-30·9; range 9·5-49·7) in the lower dose cohort, 31·1 months (16·0-64·7; 6·8-72·7) in the higher dose cohort, and 18·7 months (10·1-31·5; 5·9-39·3) in the control cohort. Median follow-up was 46·1 months (IQR 41·0-49·5; range 2·1-54·7) for lower dose participants, 27·6 months (24·6-29·1; 3·4-41·0) for higher dose participants, and 28·3 months (9·7-46·9; 5·7-32·7) for control participants. At week 24, lower dose participants had an estimated 77·7 percentage point (95% CI 40·22 to 115·24) greater reduction in least squares mean hours per day of ventilator support from baseline versus controls (p=0·0002), and higher dose participants had a 22·8 percentage point (6·15 to 39·37) greater reduction from baseline versus controls (p=0·0077). One participant in the lower dose cohort and three in the higher dose cohort died; at the time of death, all children had cholestatic liver failure following gene therapy (immediate causes of death were sepsis; hepatopathy, severe immune dysfunction, and pseudomonal sepsis; gastrointestinal haemorrhage; and septic shock). Three individuals in the control group died (haemorrhage presumed related to hepatic peliosis; aspiration pneumonia; and cardiopulmonary failure). INTERPRETATION: Most children with X-linked myotubular myopathy who received MTM1 gene replacement therapy had important improvements in ventilator dependence and motor function, with more than half of dosed participants achieving ventilator independence and some attaining the ability to walk independently. Investigations into the risk for underlying hepatobiliary disease in X-linked myotubular myopathy, and the need for monitoring of liver function before gene replacement therapy, are ongoing. FUNDING: Astellas Gene Therapies.

Estudio de intervención para comprobar el efecto de la música clásica en directo durante hemodiálisis sobre la calidad de vida de pacientes con enfermedad renal crónica / Intervention study to verify the effect of live classic music during hemodialysis on the quality of life of patients with chronic kidney disease

Introducción y objetivo: La música ha estado estrechamente unida a la medicina desde la antigüedad, y ha aportado numerosos beneficios a la salud de los pacientes. El paciente con enfermedad renal crónica en tratamiento de hemodiálisis (HD), generalmente, presenta una calidad de vida relacionada con la salud (CVRS) inferior a los valores de referencia de la población general. El objetivo del presente estudio es verificar si la intervención de música clásica en directo e in situ’ durante el tratamiento de HD tiene efectos sobre la CVRS de los pacientes.Materiales y métodos: Se realizó un estudio de intervención, prospectivo y aleatorizado por grupos, en pacientes con enfermedad renal crónica en tratamiento con HD. Durante 4 semanas un grupo de pacientes recibía la intervención con música clásica en directo 30 o 40min durante las sesiones de HD, mientras el grupo control realizaba el tratamiento habitual. Variables descriptivas: edad, sexo, meses en tratamiento, Kt/V, hemoglobina y albúmina. Variable resultado: CVRS, se midió con el cuestionario de salud Kidney Diseasse Quality of life (KDQOL-SF) antes y después de la intervención musical. (AU)

Introduction and objective: Music has been closely linked to medicine since ancient times, and has brought numerous benefits to the health of patients. Patients with chronic kidney disease undergoing hemodialysis (HD) generally have a health-related quality of life (HRQL) lower than the reference values of the general population. The objective of the present study is to verify if the intervention of classical music live and “in situ” during the treatment of HD has effects on the HRQL of the patients.Materials and methods: A prospective, group-randomized intervention study of 4 weeks’ duration was carried out in patients with chronic kidney disease undergoing HD. Descriptive variables are included for data analysis: age, sex, months in treatment, Kt/V, hemoglobin and albumin. Result variable: HRQL, measured with the Kidney Disease health questionnaire Quality of Life (KDQOL-SF) before and after the musical intervention. (AU)

A2 Milk: New Perspectives for Food Technology and Human Health.

Although milk consumption is increasing worldwide, in some geographical regions, its consumption has persistently declined in recent decades. This fact, together with the increase in milk production prices, has caused both milk producers and the dairy industry to be immersed in a major crisis. Some possible solutions to this problem are to get people who do not currently consume milk to start drinking it again, or to market milk and dairy products with a higher added value. In this context, a type of milk called A2 has recently received attention from the industry. This type of milk, characterized by a difference in an amino acid at position 67 of the ß-casein polypeptide chain, releases much smaller amounts of bioactive opioid peptide ß-casomorphin 7 upon digestion, which has been linked to harmful effects on human health. Additionally, A2 milk has been attributed worse technological properties in the production of some dairy products. Thus, doubts exist about the convenience for the dairy industry to bet on this product. The aim of this review is to provide an update on the effects on human health of A2 milk, as well as its different technological properties to produce dairy products.

INCEPTUS Natural History, Run-in Study for Gene Replacement Clinical Trial in X-Linked Myotubular Myopathy.

BACKGROUND: X-linked myotubular myopathy (XLMTM) is a life-threatening congenital myopathy that, in most cases, is characterized by profound muscle weakness, respiratory failure, need for mechanical ventilation and gastrostomy feeding, and early death. OBJECTIVE: We aimed to characterize the neuromuscular, respiratory, and extramuscular burden of XLMTM in a prospective, longitudinal study. METHODS: Thirty-four participants < 4 years old with XLMTM and receiving ventilator support enrolled in INCEPTUS, a prospective, multicenter, non-interventional study. Disease-related adverse events, respiratory and motor function, feeding, secretions, and quality of life were assessed. RESULTS: During median (range) follow-up of 13.0 (0.5, 32.9) months, there were 3 deaths (aspiration pneumonia; cardiopulmonary failure; hepatic hemorrhage with peliosis) and 61 serious disease-related events in 20 (59%) participants, mostly respiratory (52 events, 18 participants). Most participants (80%) required permanent invasive ventilation (>16 hours/day); 20% required non-invasive support (6-16 hours/day). Median age at tracheostomy was 3.5 months (95% CI: 2.5, 9.0). Thirty-three participants (97%) required gastrostomy. Thirty-one (91%) participants had histories of hepatic disease and/or prospectively experienced related adverse events or laboratory or imaging abnormalities. CHOP INTEND scores ranged from 19-52 (mean: 35.1). Seven participants (21%) could sit unsupported for≥30 seconds (one later lost this ability); none could pull to stand or walk with or without support. These parameters remained static over time across the INCEPTUS cohort. CONCLUSIONS: INCEPTUS confirmed high medical impact, static respiratory, motor and feeding difficulties, and early death in boys with XLMTM. Hepatobiliary disease was identified as an under-recognized comorbidity. There are currently no approved disease-modifying treatments.

The clinical, economic, and humanistic burden of Dravet syndrome - A systematic literature review.

Dravet syndrome (DS) is a developmental and epileptic encephalopathy with evolving disease course as individuals age. In recent years, the treatment landscape of DS has changed considerably, and a comprehensive systematic review of the contemporary literature is lacking. Here we synthesized published evidence on the occurrence of clinical impacts by age, the economic and humanistic (health-related quality-of-life [HRQoL]) burden, and health state utility. We provide an evidence-based, contemporary visualization of the clinical manifestations, highlighting that DS is not limited to seizures; non-seizure manifestations appear early in life and increase over time, contributing significantly to the economic and humanistic burden of disease. The primary drivers of HRQoL in DS include seizure severity, cognition, and motor and behavioral problems; in turn, these directly affect caregivers through the extent of assistance required and consequent impact on activities of daily living. Unsurprisingly, costs are driven by seizure-related events, hospitalizations, and in-home medical care visits. This systematic review highlights a paucity of longitudinal data; most studies meeting inclusion criteria were cross-sectional or had short follow-up. Nonetheless, available data illustrate the substantial impact on individuals, their families, and healthcare systems and establish the need for novel therapies to address the complex spectrum of DS manifestations.

DRAVET ENGAGE. Parent caregivers of children with Dravet syndrome: Perspectives, needs, and opportunities for clinical research.

Dravet syndrome (DS) is an intractable developmental and epileptic encephalopathy significantly impacting affected children and their families. A novel, one-time, adeno-associated virus (AAV)-mediated gene regulation therapy was designed to treat the underlying cause of DS, potentially improving the full spectrum of DS manifestations. To ensure the first-in-human clinical trial addresses meaningful outcomes for patients and families, we examined their perspectives, priorities, goals, and desired outcomes in the design phase through a mixed methods approach (quantitative and qualitative). We conducted a non-identifiable parent caregiver survey, shared through a patient advocacy organization (n = 36 parents; children age ≤6 years). Parents were also engaged via three group discussions (n = 10; children age 2-20 years) and optional follow-up in-depth individual interviews (n = 6). Qualitative data analysis followed an inductive interpretive process, and qualitative researchers conducted a thematic analysis with a narrative approach. Survey results revealed most children (94%) were diagnosed by age 1, with onset of seizures at mean age 6.2 months and other DS manifestations before 2 years. The most desired disease aspects to address with potential new disease-modifying therapies were severe seizures (ranked by 92% of caregivers) and communication issues (development, expressive, receptive; 72-83%). Qualitative results showed the need for trial outcomes that recognize the impact of DS on the whole family. Parents eventually hope for trials including children of all ages and were both excited about the potential positive impact of a one-time disease-modifying therapy and mindful of potential long-term implications. Participants reflected on the details and risks of a clinical trial design (e.g., sham procedures) and described the different factors that relate to their decision to participate in a trial. Their main aspirations were to stop neurodevelopmental stagnation, to reduce seizures, and to reduce the impact on their families' wellbeing. To our knowledge, this is the first study within a patient-oriented research framework that specifically explored parents' needs and perceptions regarding clinical trials of a potential disease-modifying therapy for children with a severe, developmental disease, such as DS.

Influential factors on dose by ionic dialysance in daily practice in chronic hemodialysis.

BACKGROUND: The determination of Kt/V by ionic dialysance is a technique that has extended its use in hemodialysis clinics. The clinical guidelines have reflected the need to validate this method as a determinant of the dose of dialysis. OBJECTIVES: Determine in daily practice, the influence of hemodialysis characteristics and medication on Kt/V results by ionic dialysance (Kt/V OCM) and compare them with Kt/V measures by serum urea (Kt/V Daugirdas). DESIGN: Cross-sectional and observational study. PARTICIPANTS: 127 patients on chronic hemodialysis. MEASUREMENTS: Descriptive variables, study variables (Kt/VOCM, Kt/VDaugidas), and the variables that modified the effect (patient temperature, serum sodium, vascular access, recirculation, blood flow, hemodialysis technique, dialyzer, acid concentrate, conductivity, dialyzate flow). RESULTS: The mean of Kt/V Daugirdas was 1.84 and the Kt/VOCM mean 1.65; Pearson's was CC r=0.54; P<0.001 and Lin CCC=0.48. In the linear regression, the variables related to hemodialysis technique showed no statistical association with the measurement obtained by Kt/VOCM. Monosodium phosphate and 20% sodium chloride dispensing were associated with a higher Kt/VOCM. CONCLUSIONS: The different technical aspects noted during HD sessions do not influence Kt/V OCM outcomes. Kt/V determined by ionic dialysance isn't similar to that determined by serum urea. When assessing dialysis doses measured by dialysance, consider that it is not the same as determined with serum urea, but it provides an approximation to estimate dialysis doses in real time. It is necessary to consider if drugs or supplements have been administered that can modify it when interpreting the results.

Use of the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) in X-Linked Myotubular Myopathy: Content Validity and Psychometric Performance.

X-linked myotubular myopathy (XLMTM) is a life-threatening, congenital myopathy characterized by extreme hypotonia, weakness, delayed motor milestones, and respiratory failure, often resulting in pediatric mortality. This study evaluated the content validity and psychometric performance of the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders as a measure of neuromuscular functioning in children with X-linked myotubular myopathy. This study was conducted in two phases. Phase I assessed the content validity of the measure for use in an XLMTM pediatric population through: literature review, clinical expert interviews, caregiver interviews, and a modified-Delphi panel among clinicians. Phase II assessed psychometric performance based on the INCEPTUS observational clinical study and the ASPIRO interventional gene therapy study, including tests of reliability (internal consistency, test-retest, and interrater), validity (construct and criterion), and responsiveness based on observational and interventional clinical trial data analyses. Data established construct validity and reliability of the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders among XLMTM patients before administration of resamirigene bilparvovec, and sensitivity to study drug administration as evidenced by the significant post-administration response in ASPIRO. Findings support the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders as an appropriate neuromuscular functioning assessment in a pediatric X-linked myotubular myopathy patient population.

Cohort study with patients older than 80 years with stage 5 chronic kidney failure on hemodialysis vs conservative treatment: Survival outcomes and use of healthcare resources.

Renal replacement treatment has not been generalized to the elderly for different reasons. The main objective of the present cohort study is to compare survival in patients older than 80 years with chronic kidney disease stage 5 on renal replacement treatment with those on conservative treatment. The use of healthcare resources is compared too. A Cox proportional hazards regression analysis was run with the outcome variable death during the follow-up period. The independent variables were treatment type, age, gender, smoking habit, serum albumin, hemoglobin, Charlson Index, diabetes mellitus, arterial hypertension, ischemic cardiopathy, and neoplasm. For outcome variable "death," renal replacement treatment obtained a hazard ratio of 0.273 (P .006, CI95% 0.108-0.686) vs conservative treatment. In conclusion, patients older than 80 years with chronic kidney disease stage 5 on renal replacement treatment presented a lower mortality risk than those receiving conservative treatment. Comorbidity and age are both associated with mortality, but do not cancel out the survival advantage. In healthcare resources, the renal replacement treatment group made greater use of tests, medical visits and consumption of hospital dispensing drugs, but there were no differences with respect to the days of hospital admission or assistance in home hospitalization.

Mortality and respiratory support in X-linked myotubular myopathy: a RECENSUS retrospective analysis.

PURPOSE: Individuals with X-linked myotubular myopathy (XLMTM) who survive infancy require extensive supportive care, including ventilator assistance, wheelchairs and feeding tubes. Half die before 18 months of age. We explored respiratory support and associated mortality risk in RECENSUS, particularly among patients ≤5 years old who received respiratory support at birth; this subgroup closely matches patients in the ASPIRO trial of gene therapy for XLMTM. DESIGN: RECENSUS is an international, retrospective study of patients with XLMTM. Descriptive and time-to-event analyses examined survival on the basis of age, respiratory support, tracheostomy use, predicted mutational effects and life-sustaining care. RESULTS: Outcomes for 145 patients were evaluated. Among 126 patients with respiratory support at birth, mortality was 47% overall and 59% among those ≤5 years old. Median survival time was shorter for patients ≤5 years old than for those >5 years old (2.2 years (IQR 0.7-5.6) vs 30.2 years (IQR 19.4-30.2)). The most common cause of death was respiratory failure (66.7%). Median survival time was longer for patients with a tracheostomy than for those without (22.8 years (IQR 8.7-30.2) vs 1.8 years (IQR 0.2-not estimable)). The proportion of patients living without a tracheostomy was 50% at age 6 months and 28% at age 2 years. Median survival time was longer with provision of life-sustaining care than without (19.4 years (IQR 3.1-not estimable) vs 0.2 years (IQR 0.1-2.1)). CONCLUSIONS: High mortality, principally due to respiratory failure, among patients with XLMTM ≤5 years old despite respiratory support underscores the need for early diagnosis, informed decision-making and disease-modifying therapies. TRIAL REGISTRATION NUMBER: NCT02231697.

Influence of Physical Exercise on the Dialytic Adequacy Parameters of Patients on Hemodialysis.

It has been suggested that physical exercise in chronic hemodialysis could improve dialysis dose and reduce postdialysis rebound. A randomized controlled trial was performed to compare a group of patients doing physical exercise during the first 2 h of hemodialysis sessions and another group doing physical exercise at home. The descriptive variables, dialysis doses measured by KtV, and rebounds (urea, creatinine, potassium, phosphorus), were recorded. For 69 patients: the mean KtV was 1.84; the 30-min rebound of creatinine was 32.37%, urea 24.39%, potassium 15.31%, and phosphorus 51.29%. For each patient, the basal measurement was compared with those determined when performing physical exercise; no statistically significant differences were observed between the changes determined to dose and rebound in the group with hemodialysis exercise compared to those of the home exercise group. In conclusion, performing physical exercise during the first 2 hours of hemodialysis sessions neither lowered postdialysis molecules rebound nor improved dialysis dose.

Red blood cells treated with the amustaline (S-303) pathogen reduction system: a transfusion study in cardiac surgery.

BACKGROUND: Nucleic acid-targeted pathogen inactivation technology using amustaline (S-303) and glutathione (GSH) was developed to reduce the risk of transfusion-transmitted infectious disease and transfusion-associated graft-versus-host disease with red blood cell (RBC) transfusion. STUDY DESIGN AND METHODS: A randomized, double-blind, controlled study was performed to assess the in vitro characteristics of amustaline-treated RBCs (test) compared with conventional (control) RBCs and to evaluate safety and efficacy of transfusion during and after cardiac surgery. The primary device efficacy endpoint was the postproduction hemoglobin (Hb) content of RBCs. Exploratory clinical outcomes included renal and hepatic failure, the 6-minute walk test (a surrogate for cardiopulmonary function), adverse events (AEs), and the immune response to amustaline-treated RBCs. RESULTS: A total of 774 RBC unis were produced. Mean treatment difference in Hb content was -2.27 g/unit (95% confidence interval, -2.61 to -1.92 g/unit), within the prespecified equivalence margins (±5 g/unit) to declare noninferiority. Amustaline-treated RBCs met European guidelines for Hb content, hematocrit, and hemolysis. Fifty-one (25 test and 26 control) patients received study RBCs. There were no significant differences in RBC usage or other clinical outcomes. Observed AEs were within the spectrum expected for patients of similar age undergoing cardiovascular surgery requiring RBCs transfusion. No patients exhibited an immune response specific to amustaline-treated RBCs. CONCLUSION: Amustaline-treated RBCs demonstrated equivalence to control RBCs for Hb content, have appropriate characteristics for transfusion, and were well tolerated when transfused in support of acute anemia. Renal impairment was characterized as a potential efficacy endpoint for pivotal studies of RBC transfusion in cardiac surgery.

Plasma treated with amotosalen and ultraviolet A light retains activity for hemostasis after 5 days post-thaw storage at 1 to 6o C.

BACKGROUND: Plasma thawed and stored at 1 to 6° C for up to 5 days (thawed plasma [TP]) provides rapid availability in emergencies and reduces plasma waste, but it carries risks of coagulation factor loss or activation, bacterial outgrowth, and viral contamination. We characterized changes in amotosalen/ultraviolet A (UVA) light pathogen-reduced, fresh-frozen plasma (FFP) and plasma frozen within 24 hours (PF24) with post-thaw storage. STUDY DESIGN AND METHODS: Amotosalen/UVA light-treated FFP and PF24 were thawed after approximately 3 to more than 12 months of frozen storage and held at 1 to 6° C for 5 days. Global assessments of coagulation and hemostatic, antithrombotic, and activation markers indicative of function were assessed. RESULTS: Day 5, thawed amotosalen/UVA light-treated FFP and PF24 contained levels of Factors II, V, VIII, IX, X, von Willebrand factor ristocetin cofactor (vWF:RCo), fibrinogen, antithrombin III (ATIII), protein C, and protein S similar to the levels measured in Day 5 TP, as described in the Circular of Information. Thrombin generation was robust on Day 5 (amotosalen/UVA: FFP = 1866 ± 402 nM/minute; PF24 = 1800 ± 277 nM/minute). Most factor activities on Day 5, including von Willebrand factor-cleaving protease (ADAMTS-13), were more than 90% of Day 0 values, except for known labile Factors V and VIII and protein S. All units contained greater than 0.4 IU/mL protein S and α2 plasmin inhibitor on Day 5. Global functional indices, including thrombin-antithrombin complexes, nonactivated thromboplastin time, and thrombin-generation peak height, did not indicate activation of the coagulation cascade, although isolated units showed raised levels of Factor VIIa and Complement 3a. CONCLUSION: Amotosalen/UVA light-treated FFP and PF24 demonstrated retention of procoagulant and antithrombotic activity after 5 days post-thaw storage at 1 to 6° C.

Pharmacodynamics assessment of Bemiparin after multiple prophylactic and single therapeutic doses in adult and elderly healthy volunteers and in subjects with varying degrees of renal impairment.

INTRODUCTION: Aging and renal impairment may prolong the half-life and lead to accumulation of low molecular weight heparins. Correct dosing is critical to prevent bleeding or thrombosis. MATERIALS AND METHODS: Open, parallel study. Healthy adult [n=13] and elderly (>65yrs) [n=12] volunteers; and subjects with mild (ClCr≥50 to ≤80mL/min, n=8), moderate (ClCr≥30 to <50mL/min, n=7), and severe (ClCr<30mL/min, n=8) renal impairment received four prophylactic doses (3,500IU/24h) and a single therapeutic dose (115IU/kg) of bemiparin with an interim washout period. Anti-FXa activity and the potential need for dose adjustment were evaluated. RESULTS: There were statistically significant differences in the severe renal impairment group vs. adult volunteers in all anti-FXa related parameters, but no significant differences in any of the anti-FXa related parameters between the adult and the elderly. Anti-FXa simulations after 10 prophylactic doses predicted mean Amax=0.59IU/mL in subjects with severe renal impairment and 0.33-0.39IU/mL in the rest. Simulations in the severe renal impairment group with dose adjustment (2,500IU/24h) predicted all individual Amax<0.60IU/mL (mean Amax=0.42IU/ml). Simulations after 10 therapeutic doses predicted mean Amax=1.22IU/mL in severe renal impairment group and 0.89-0.98IU/mL in the rest. Simulations in the severe renal impairment group with 75% dose adjustment predicted individual Amax≤1.60IU/mL (mean Amax=0.91IU/mL). CONCLUSIONS: No dose adjustments are required in elderly with preserved renal function. A dose adjustment of bemiparin is only advisable in patients with severe renal impairment when using prophylactic or therapeutic doses.

Residual effects of low-dose sublingual zolpidem on highway driving performance the morning after middle-of-the-night use.

STUDY OBJECTIVE: To evaluate next-morning driving performance after middle-of-the-night use of zolpidem 3.5 mg in a buffered sublingual formulation (ZST). DESIGN: Single-center, four-period, randomized, double-blind, placebo-controlled, crossover study. SETTING: Maastricht University, The Netherlands. PARTICIPANTS: Forty healthy volunteers (20 females). INTERVENTIONS: Single dose of ZST administered in the middle of the night at 3 and 4 h before driving, zopiclone 7.5 mg at bedtime 9 h before driving, and placebo. MEASUREMENTS: Performance in a 100-km standardized highway driving test in normal traffic measuring standard deviation of lateral position (SDLP) - an index of weaving. Drug-placebo changes in SDLP > 2.5 cm were considered to reflect clinically relevant driving impairment. RESULT: For ZST, Max McNemar symmetry analyses showed that the proportion of drivers classified as impaired was increased 3 h after dosing (P < 0.012), but not 4 h after dosing. Mean increases in SDLP from placebo, although statistically significant, were small (1.46 cm [P < 0.0001] at 3 h and 0.83 cm [P = 0.0174] at 4 h). The morning after zopiclone, 45% of the drivers were classified as impaired with a mean increase in SDLP of 2.46 cm (P < 0.0001). There were no significant sex differences in effects of ZST and zopiclone. CONCLUSION: Zolpidem 3.5 mg in a buffered sublingual formulation has a minimal risk of impairing driving performance in the morning ≥ 4 hours after middle-of-the night use. When taken 3 hours before driving, the drug may have impairing effects so caution should be exercised if medication is taken other than as indicated. CLINICAL TRIAL INFORMATION: ClinicalTrials.gov Identifier: NCT01106859; Trial Name: Driving Performance After Middle of the Night Administration of 3.5 mg Zolpidem Tartrate Sublingual Tablet; http://clinicaltrials.gov/ct2/show/NCT01106859.

Safety assessment and pharmacodynamics of a novel ultra low molecular weight heparin (RO-14) in healthy volunteers--a first-time-in-human single ascending dose study.

INTRODUCTION: RO-14 is a novel ultra low molecular heparin. The purpose of this study was to evaluate the safety and pharmacodynamic profile of RO-14 in healthy males. MATERIALS AND METHODS: We conducted a two-stage, single-center, open-label, randomized study. Two cohorts of 6 volunteers were randomly assigned to 12 single, ascending subcutaneous doses (1750-19950IU of anti-FXa activity) in an alternating crossover fashion. Safety was assessed by spontaneous/elicited adverse events, medical examination and laboratory tests. Anti-FXa activity and anti-FIIa activity were assessed throughout the 24hours after dosing. Dose proportionality and linearity of the anti-FXa activity were evaluated. RESULTS: All doses were well tolerated and there were no bleeding events. At the lowest dose, anti-FXa activity A(max) was 0.16 (±0.02) IU/mL and AUC(0-24) was 1.11 (±0.24) IU*h/mL, At the highest dose anti-FXa activity A(max) was 1.67 (±0.15) IU/mL; AUC(0-24) was 21.48 (±4.46) IU*h/mL and t½ was 8.05h. Mean T(max) (all doses) was 2.86 (±0.39) h. RO-14 showed proportional and linear pharmacodynamics [normalized A(max) among doses (p=0.594) and normalized AUC(0-24) (p=0.092), correlations between A(max-)dose (R(2)=0.89, p<0.001) and AUC(0-24)-dose (R(2)=0.86, p<0.001)]. Anti-FIIa activity was below the detection limit (0.1IU/ml) at all dose levels. No clinically significant changes were observed in the platelet count, APTT, PT, TT, fibrinogen and antithrombin. CONCLUSIONS: In this phase I study, RO-14 exhibited a good safety profile, anti-FXa activity for either prophylaxis or treatment of venous thromboembolism, linear pharmacodynamics, a longer elimination half-life than currently marketed low molecular weight heparin and no anti-FIIa activity.

¿Mejora la aproximación físico-química de Stewart-Fencl la valoración del equilibrio ácido-base en pacientes estables en hemodiafiltración? / Does Stewart-Fencl approach improve the evaluation of acidbase status in stable patients on hemodiafiltration?

Introducción: la evaluación del equilibrio ácido-base se basa en la ecuación de Henderson-Hasselbach. En 1983, P. Stewart desarrolló un análisis cuantitativo del equilibrio ácido-base en el que muestra un sistema con unas variables independientes entre las que se incluyen pCO2, diferencia iónica fuerte medida (SIDm), es decir, la diferencia entre la suma de cationes fuertes (Na+, K+, Ca++, Mg++) y la suma de aniones fuertes (Cl–, lactato) y la concentración total de todos los aniones débiles no volátiles (ATot), cuyos principales representantes son el fósforo inorgánico (P–) y la albúmina (Albúm.–). El objetivo de este estudio es evaluar desde ambas perspectivas el equilibrio ácido-base en pacientes en hemodiafiltración (HDF) crónica. Material y métodos: se estudian 35 pacientes (24 hombres y 11 mujeres, con una edad media de 67,2 ± 15,7 años y con un peso seco de 72,8 ± 19,2 kg. La duración media de la hemodiálisis (HD) fue de 253,6 ± 40,5 minutos. Se analizan los parámetros gasométricos (pH, pCO2, HCO3–y exceso de bases) y Na+, K+, Cl–, Ca++, Mg++ y lactato. Se calcularon la SIDm, la SIDe mediante la fórmula de Figge (1.000 x 2,46–11 x pCO2 /[10 – pH] + Albúm. g/dl x [0,123 x pH –0,631] + P en mmol/l x [0,309 x pH –0,469)] y gap del SID (SIDm-SIDe). Resultados: el pH pre-HD fue de 7,36 ± 0,08 y el pH post-HD de 7,44 ± 0,08 (p <0,001). No se apreciaron diferencias significativas entre pCO2 pre y post-HD. El HCO3 – y el exceso de bases se incrementaron durante la sesión (p <0,001). La SIDm descendió de manera significativa de 46,2 ± 2,9 preHD a 45 ± 2,3 post-HD (p <0,05). Por el contrario, la SIDe se elevó de 38,5 ± 3,8 a 42,9 ± 3,1 (p <0,001). El anion gap descendió de 18,6 ± 3,8 pre-HD a 12,8 ± 2,8 Eq/l post-HD (p <0,001) y el gap del SID de 7,6 ± 3 a 2,1 ± 2 (p <0,001). Se apreció una correlación entre el anion gap y el gap-SID tanto antes como después de la HDF. Asimismo, se apreció una correlación significativa entre el ?? exceso de bases y ?? del gap-SID. Conclusión: en conclusión, la aproximación físico-química de Stewart-Fencl no mejora la valoración del equilibrio ácido-base en pacientes en HDF crónica. En presencia de normocloremia la SIDm no refleja el proceso alcalinizante de la sesión de hemodiálisis. Bajo esta perspectiva, la sesión de hemodiálisis se concibe como una retirada de aniones inorgánicos no metabolizables, en especial el sulfato. El espacio dejado por estos aniones es reemplazado por OH–y secundariamente por HCO3–. La única ventaja vendría dada por una mejor valoración de los aniones no medidos mediante el gap del SID, sin el efecto de la albúmina y el fosfato (AU)

Introduction: The traditional evaluation of acid-base status relies on the Henderson-Hasselbach equation. In 1983, an alternative approach, based on physical and chemical principles was proposed by P. Stewart. In this approach, plasma pH is determined by 3 independent variables: pCO2, Strong Ion Difference (SIDm), which is the difference between the strong cations (Na+, K+, Ca++, Mg++) and the strong anions (Cl–, lactate) and total plasma concentration of nonvolatile weak acids (ATot), mainly inorganic phosphate and albumin. Bicarbonate is considered a dependent variable. The aim of this study was to evaluate the acid-base status using both perspectives, physical chemical and traditional approach. Material and methods: we studied 35 patients (24 male; 11 female) on hemodiafiltration, mean age was 67.2 ± 15.7, 8 ± 19.2 kg. We analyzed plasma chemistry including pH, pCO2, HCO3–, base excess and Na+, K+, Cl–, Ca++, Mg++, lactate and SIDm. The SID estimated (SIDe) was calculated by Figge’s formula (1,000 x 2.46–11 x pCO2/[10 – pH] + Album g/dl x [0.123 x pH –0.631] + P in mmol/l0 x [0.309 x pH –0.469]) and Gap of the SID as the difference SIDm-SIDe. Results: pH preHD was 7.36 ± 0.08 and pH post-HD 7.44 ± 0.08 (p <0.001). There was no significant differences between pCO2 pre- and post-HD. HCO3– and base excess increased during the session (p <0.001). SIDm decreased from 46.2 ± 2.9 pre-HD to 45 ± 2.3 mEq/l post-HD (p <0.05). On the opposite, SIDe increased from 38.5 ± 3.8 to 429 ± 3.1 mEq/l (p <0.001). The Gap Anion descended from 18.6 ± 3.8 pre-HD to 12.8 ± 2.8 mEq/l post-HD (p <0.001) and the Gap of the SID 7.6 ± 3 to 2.1 ± 2 (p <0.001). Anion Gap correlated with the Gap-SID so much pre-HDF as pos-HDF. ?? Base excess correlated only with ?? of the Gap SID. Conclusion: Stewart-Fencl’s approach does not improve characterization of acid-base status in patients on chronic HDF. In presence of normocloremia the SIDm does not reflect the alkalinizing process of the session of hemodialysis. According this approach, hemodialysis therapy can be viewed as a withdrawal of inorganic anions, especially the sulphate. These anions are replaced by OH– and secondarily for HCO3–. The approach only improves the evaluation of unmeasured anions by the Gap of the SID, without the effect of albumin and phosphate (AU)

[Does Stewart-Fencl improve the evaluation of acid-base status in stable patients on hemodiafiltration?]. / ¿Mejora la aproximación físico-química de Stewart-Fencl la valoración del equilibrio ácido-base en pacientes estables en hemodiafiltración?

INTRODUCTION: The traditional evaluation of acid-base status relies on the Henderson-Hasselbach equation. In 1983, an alternative approach, based on physical and chemical principles was proposed by P. Stewart. In this approach, plasma pH is determined by 3 independent variables: pCO2, Strong Ion Difference (SIDm), which is the difference between the strong cations (Na +, K +, Ca ++, Mg ++) and the strong anions (Cl-, lactate) and total plasma concentration of nonvolatile weak acids (ATot), mainly inorganic phosphate and albumin. Bicarbonate is considered a dependent variable. The aim of this study was to evaluate the acid-base status using both perspectives, physical chemical and traditional approach. MATERIAL AND METHODS: We studied 35 patients (24 M; 11F) on hemodiafiltration, mean age was 67,2+/-15,7, 8+/-19,2 kg. We analyzed plasma chemistry including pH, pCO2, HCO3-, base excess and Na+, K+, Cl-, Ca++, Mg++, lactate and SIDm. The SID estimated (SIDe) was calculated by Figge's formula (1000 x 2.46E-11 x pCO2 / (10-pH) + Album gr/dl x (0.123 x pH-0.631) + P in mmol/l x (0.309 x pH-0.469) and Gap of the SID as the difference SIDm-SIDe. RESULTS: pH preHD was 7,36+/-0,08 and pH posHD 7,44+/-0,08 (p < 0.001). There was no significant differences between pCO2 pre and pos-HD. HCO3 - and base excess increased during the session (p < 0.001). SIDm decreased from 46,2+/-2,9 preHD to 45+/-2,3 mEq/l postHD (p < 0.05). On the opposite, SIDe increased from 38,5+/-3,8 to 42,9+/-3,1 mEq/l (p < 0.001). The Gap Anion descended from 18,6+/-3,8 preHD to 12,8+/-2,8 mEq/l mEq/l postHD (p < 0.001) and the Gap of the SID 7,6+/-3 to 2,1+/-2 (p < 0.001). Anion Gap correlated with the Gap-SID so much pre-HDF as pos-HDF. Delta Base excess correlated only with Delta of the Gap SID. CONCLUSION: Stewart-Fencl's approach does not improve characterization of acid-base status in patients on chronic HDF. In presence of normocloremia the SIDm does not reflect the alkalinizing process of the session of hemodialysis. According this approach, hemodialysis therapy can be viewed as a withdrawal of inorganic anions, especially the sulphate. These anions are replaced by OH - and secondarily for HCO3-. The approach only improves the evaluation of unmeasured anions by the Gap of the SID, without the effect of albumin and phosphate.