Results from the long-term extension of PRIME: A randomized Phase 1b trial of aducanumab.

INTRODUCTION: Aducanumab selectively targets aggregated forms of amyloid beta (Aß), a neuropathological hallmark of Alzheimer's disease (AD). METHODS: PRIME was a Phase 1b, double-blind, randomized clinical trial of aducanumab. During the 12-month placebo-controlled period, participants with prodromal AD or mild AD dementia were randomized to receive aducanumab or placebo. At week 56, participants could enroll in a long-term extension (LTE), in which all participants received aducanumab. The primary endpoint was safety and tolerability. RESULTS: Amyloid-related imaging abnormalities-edema (ARIA-E) were the most common adverse event. Dose titration was associated with a decrease in the incidence of ARIA-E. Over 48 months, aducanumab decreased brain amyloid levels in a dose- and time-dependent manner. Exploratory endpoints suggested a continued benefit in the reduction of clinical decline over 48 months. DISCUSSION: The safety profile of aducanumab remained unchanged in the LTE of PRIME. Amyloid plaque levels continued to decrease in participants treated with aducanumab. HIGHLIGHTS: PRIME was a Phase 1b, double-blind, randomized clinical trial of aducanumab. We report cumulative safety and 48-month efficacy results from PRIME. Amyloid-related imaging abnormalities-edema (ARIA-E) were the most common adverse event (AE); 61% of participants with ARIA-E were asymptomatic. Dose titration was associated with a decrease in the incidence of ARIA-E. Aducanumab decreased levels of amyloid beta (Aß) in a dose- and time-dependent manner.

Genome-Wide Association Studies of ARIA From the Aducanumab Phase 3 ENGAGE and EMERGE Studies.

BACKGROUND AND OBJECTIVES: Amyloid-related imaging abnormalities (ARIA) were the most common adverse events reported in the phase 3 ENGAGE and EMERGE trials of aducanumab, an anti-amyloid monoclonal antibody. APOE ε4 carrier status has been shown to increase risk of ARIA in prior trials of aducanumab and other anti-amyloid therapies; however, the remainder of the human genome has not been evaluated for ARIA risk factors. Therefore, we sought to determine in a hypothesis-free manner whether genetic variants beyond APOE influence risk of ARIA in aducanumab-treated patients. METHODS: We performed genome-wide association studies (GWAS) of ARIA in participants in the ENGAGE and EMERGE trials. Participants had mild cognitive impairment due to Alzheimer disease or mild Alzheimer disease dementia and were amyloid-positive on PET scans. All participants underwent regular MRI monitoring to detect and diagnose ARIA. RESULTS: Of the 3,285 participants in the intent-to-treat population, this analysis included 1,691 with genotyping array data who received at least one dose of aducanumab with at least one post-baseline MRI. All participants in the study cohort were of European ancestry; 51% were female. The mean age was 70.3 years. 31% had ARIA-E, 19% had ARIA-H microhemorrhage, and 14% had ARIA-H superficial siderosis. We identified one genome-wide significant (p < 5.0 × 10-8) association at the chromosome 19 locus encompassing APOE. The APOE association with ARIA was stronger in ε4/ε4 homozygotes (OR = 4.28, 4.58, 7.84; p < 2.9 × 10-14 for ARIA-E, ARIA-H microhemorrhage, and ARIA-H superficial siderosis, respectively) than in ε3/ε4 heterozygotes (OR = 1.74, 1.46, 3.14; p ≤ 0.03). We found greater odds of radiographically severe ARIA (OR = 7.04-24.64, p ≤ 2.72 × 10-5) than radiographically mild ARIA (OR = 3.19-5.00, p ≤ 1.37 × 10-5) among ε4/ε4 homozygotes. APOE ε4 was also significantly associated with both symptomatic (ε4/ε4 OR = 3.64-9.52; p < 0.004) and asymptomatic (ε4/ε4 OR = 4.20-7.94, p < 1.7 × 10-11) cases, although among ARIA cases, APOE did not appear to modulate symptomatic status. No other genome-wide significant associations were found. DISCUSSION: We identified a strong, genome-wide significant association between APOE and risk of ARIA. Future, larger studies may be better powered to detect associations beyond APOE. These findings indicate that APOE is the strongest genetic risk factor of ARIA incidence, with implications for patient management and risk-benefit treatment decisions. TRIAL REGISTRATION INFORMATION: Both trials (ENGAGE [221AD301]: NCT02477800 and EMERGE [221AD302]: NCT02484547) were registered in June 2015 at clinicaltrials.gov and enrolled patients from August 2015 to July 2018.

TANGO: a placebo-controlled randomized phase 2 study of efficacy and safety of the anti-tau monoclonal antibody gosuranemab in early Alzheimer's disease.

In Alzheimer's disease, the spread of aberrantly phosphorylated tau is an important criterion in the Braak staging of disease severity and correlates with disease symptomatology. Here, we report the results of TANGO ( NCT03352557 ), a randomized, double-blind, placebo-controlled, parallel-group and multiple-dose long-term trial of gosuranemab-a monoclonal antibody to N-terminal tau-in patients with early Alzheimer's disease. The primary objective was to assess the safety and tolerability of gosuranemab compared to placebo. The secondary objectives were to assess the efficacy of multiple doses of gosuranemab in slowing cognitive and functional impairment (using the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores at week 78) and evaluate the immunogenicity of gosuranemab (using the incidence of anti-gosuranemab antibody responses). Participants were randomized (n = 654); received (n = 650) low-dose (125 mg once every 4 weeks (q4w), n = 58; 375 mg q12w, n = 58), intermediate-dose (600 mg q4w, n = 106) or high-dose (2,000 mg q4w, n = 214) gosuranemab or placebo (q4w, n = 214) intravenously for 78 weeks; and assigned to cerebrospinal fluid (n = 327) and/or tau positron emission tomography (n = 357) biomarker substudies. Gosuranemab had an acceptable safety profile and was generally well tolerated (incidence of serious adverse events: placebo, 12.1%; low dose, 10.3%; intermediate dose, 12.3%; high dose, 11.7%). The incidence of treatment-emergent gosuranemab antibody responses was low at all time points. No significant effects were identified in cognitive and functional tests as no dose resulted in a favorable change from the baseline CDR-SB score at week 78 compared to placebo control (adjusted mean change: placebo, 1.85; low dose, 2.20; intermediate dose, 2.24; high dose, 1.85). At week 76, all doses caused significant (P < 0.0001) reductions in the cerebrospinal fluid levels of unbound N-terminal tau compared to placebo.

The Personal Suicide Stigma Questionnaire (PSSQ): Relation to Self-Esteem, Well-Being, and Help-Seeking.

Two studies are reported that extend the evidence base for use of the Personal Stigma of Suicide Questionnaire (PSSQ). In the first study (N = 117), the Rosenberg Self-Esteem Scale, the WHO-5 measure of well-being, as well as measures of suicidality were examined in relation to the PSSQ. A self-selected sub-sample (N = 30) completed the PSSQ after an interval of two months. In line with the stigma internalization model, when demographic variables and suicidality were accounted for, the PSSQ self-blame subscale was the most significant predictor of self-esteem. As for well-being, the rejection subscale was involved as well as self-blame. The retest stability of the PSSQ for the sub-sample was 0.85 and coefficient alpha for the total sample was 0.95, indicating both good stability and internal consistency for the scale. In the second study (N = 140), PSSQ was studied in relation to intention to seek help from four sources in the case of suicidal ideation. The strongest relationship with PSSQ was with intention not to seek help from anyone (r = 0.35). When other variables were included in the prediction of help-seeking from a general medical practitioner, family or friends, or from nobody, the only significant PSSQ correlate was minimization. For help-seeking from a psychologist or psychiatrist, the most significant predictor was judged helpfulness of prior contact with them. The results from these studies strengthen previous findings of the construct validity of the PSSQ and point to its utility in understanding barriers to help-seeking among those experiencing suicidality.

The Role of Impulsivity and Self-Control in Suicidal Ideation and Suicide Attempt.

Two studies are reported examining the relation of self-control, as measured by self-report inventories, to indices of suicidal ideation and suicide attempts. In the first study (n = 113), self-control related significantly (p < 0.05) and negatively to both indices (r = -0.37 and r = -0.26), and, in a hierarchical regression analysis, added significantly to the variance in the suicidal ideation index accounted for by a measure of impulsivity. The second study (n = 223) replicated the findings of the bivariate correlations (r = -0.55 and r = -0.59) with the suicidality indices in the first study, both with the earlier measures and with alternative measures of self-control and impulsivity. Results indicated self-control added to the prediction of both indices and not just the ideation index. The second study also demonstrated that self-control acts as a moderator for perceived stress, a known risk factor for suicidality, such that, at low levels of perceived stress, there is little difference between those high and low in measured self-control, but that at high stress levels, those with high self-control had lower scores on suicidal ideation. The results are interpreted as showing that self-control is a protective factor for suicidality.

Squatting, pelvic morphology and a reconsideration of childbirth difficulties.

: Childbirth is commonly viewed as difficult in human females, encompassed by the 'Obstetrical Dilemma' (OD) described by early palaeoanthropologists as an evolved trade-off between a narrow pelvis necessitated by bipedalism and a large-brained fetal head. The OD has been challenged on several grounds. We add to these challenges by suggesting humans likely squatted regularly during routine tasks prior to the advent of farming societies and use of seats. We suggest that habitual squatting, together with taller stature and better nutrition of ancestral hunter-gatherers compared with later Neolithic and industrial counterparts, obviated an OD. Instead, difficulties with parturition may have arisen much later in our history, accompanying permanent settlements, poorer nutrition, greater infectious disease loads and negligible squatting in daily life. We discuss bioarchaeological and contemporary data that support these viewpoints, suggest ways in which this hypothesis might be tested further and consider its implications for obstetrical practice. Lay Summary: Human childbirth is viewed as universally difficult. Evidence from physical therapies/engineering and studies of living and ancestral humans illustrates habitual squatting widens the pelvis and could improve childbirth outcomes. Obstetrical difficulties emerged late in prehistory accompanying settled agriculture, poorer nutrition and less squatting. Specific physical exercises could improve obstetrical practice.

The Chain of Adherence for Incidentally Detected Pulmonary Nodules after an Initial Radiologic Imaging Study: A Multisystem Observational Study.

Rationale: Millions of people are diagnosed with incidental pulmonary nodules every year. Although most nodules are benign, it is universally recommended that all patients be assessed to determine appropriate follow-up and ensure that it is obtained. Objectives: To determine the degree of concordance and adherence to 2005 Fleischner Society guidelines among radiologists, clinicians, and patients at two Veterans Affairs healthcare systems with incidental nodule tracking systems. Methods: Trained researchers abstracted data from the electronic health records of patients with incidental pulmonary nodules as identified by interpreting radiologists from 2008 to 2016. We classified radiology reports and patient follow-up into three categories. Radiologist-Fleischner adherence was the agreement between the radiologist's recommendation in the computed tomography (CT) report and the 2005 Fleischner Society guidelines. Clinician/patient-Fleischner concordance was agreement between patient follow-up and the guidelines. Clinician/patient-radiologist adherence was agreement between the radiologist's recommendation and patient follow-up. We evaluated whether the recommendation or follow-up was more (e.g., sooner) or less (e.g., later) aggressive than recommended. Results: After exclusions, 4,586 patients with 7,408 imaging tests (n = 4,586 initial chest CT scans; n = 2,717 follow-up chest CT scans; n = 105 follow-up low-dose CT scans) were included. Among radiology reports that could be classified in terms of Fleischner Society guidelines (n = 3,150), 80% had nonmissing radiologist recommendations. Among those reports, radiologist-Fleischner adherence was 86.6%, with 4.8% more aggressive and 8.6% less aggressive. Among patients whose initial scans could be classified, clinician/patient-Fleischner concordance was 46.0%, 14.5% were more aggressive, and 39.5% were less aggressive. Clinician/patient-radiologist adherence was 54.3%. Veterans whose radiology reports were adherent to Fleischner Society guidelines had a substantially higher proportion of clinician/patient-Fleischner concordance: 52.0% concordance among radiologist-Fleischner adherent versus 11.6% concordance among radiologist-Fleischner nonadherent. Conclusions: In this multi-health system observational study of incidental pulmonary nodule follow-up, we found that radiologist adherence to 2005 Fleischner Society guidelines may be necessary but not sufficient. Our results highlight the many facets of care processes that must occur to achieve guideline-concordant care.

Development of a cognitive composite for measuring change in progressive supranuclear palsy.

INTRODUCTION: Individuals with progressive supranuclear palsy (PSP) experience cognitive changes that are challenging to follow without a validated neuropsychological test battery to measure progression. This study describes a composite measure to evaluate cognition in individuals with PSP. METHODS: Baseline cognitive test data from 486 participants with PSP in the PASSPORT (NCT03068468) study included the Repeatable Battery for Assessment of Neuropsychological Status (RBANS), Color Trails Test (CTT) parts 1 and 2, letter-number sequencing, and letter fluency. Data were analyzed using summary statistics and a matrix of Pearson correlations. A hypothetical factor structure was constructed and validated. RESULTS: Observed correlations were highest for scores between story memory and story recall (correlation coefficient = 0.78) and lowest for scores between letter fluency and picture naming (correlation coefficient = 0.11), and picture naming and figure copy (correlation coefficient = 0.12). After excluding picture naming and Color Trails Test (CTT) parts 1 and 2, a 3-factor structure was hypothesized for the remaining 13 tests. Confirmatory factor analysis demonstrated goodness of fit within acceptable limits (comparative fit index and Tucker-Lewis index = 0.98, standardized root-mean-square residual and root-mean-square error of approximation = 0.05-0.06). Mixed-model repeated-measures analysis of change from baseline to week 52 in RBANS and PSP cognitive composite score produced mean-to-standard-deviation ratios of 0.418 and 0.780, respectively. CONCLUSIONS: This novel composite endpoint, based on RBANS and designed to account for motor impairments in PSP, improves on current cognitive assessments PSP.

Safety and efficacy of anti-tau monoclonal antibody gosuranemab in progressive supranuclear palsy: a phase 2, randomized, placebo-controlled trial.

A randomized, double-blind, placebo-controlled, 52-week study (no. NCT03068468) evaluated gosuranemab, an anti-tau monoclonal antibody, in the treatment of progressive supranuclear palsy (PSP). In total, 486 participants dosed were assigned to either gosuranemab (n = 321) or placebo (n = 165). Efficacy was not demonstrated on adjusted mean change of PSP Rating Scale score at week 52 between gosuranemab and placebo (10.4 versus 10.6, P = 0.85, primary endpoint), or at secondary endpoints, resulting in discontinuation of the open-label, long-term extension. Unbound N-terminal tau in cerebrospinal fluid decreased by 98% with gosuranemab and increased by 11% with placebo (P < 0.0001). Incidences of adverse events and deaths were similar between groups. This well-powered study suggests that N-terminal tau neutralization does not translate into clinical efficacy.

Intermittent Energy Restriction Attenuates the Loss of Fat Free Mass in Resistance Trained Individuals. A Randomized Controlled Trial.

There is a lack of research into how lean, resistance trained (RT) individuals respond to intermittent energy restricted diets. Therefore, we investigated body composition changes in RT-individuals during continuous energy restriction or intermittent restriction. A total of 27 males and females (25 ± 6.1 years; 169 ± 9.4 cm; 80 ± 15.6 kg) were randomized to a ~25% caloric restricted diet Refeed (RF; n = 13) or Continuous group (CN; n = 14) in conjunction with 4-days/week resistance training for 7-weeks. RF implemented two consecutive days of elevated carbohydrate (CHO) intake, followed by 5-days of caloric restriction each week. CN adhered to a continuous 7-week caloric restriction. Body mass (BM), fat mass (FM), fat-free mass (FFM), dry fat-free mass (dFFM), and resting metabolic rate (RMR) were assessed pre/post-diet. Both groups significantly reduced BM (RF: baseline = 76.4 ± 15.6 kg, post-diet = 73.2 ± 13.8 kg, Δ3.2 kg; CN: baseline = 83.1 ± 15.4 kg, post-diet = 79.5 ± 15 kg, Δ3.6 kg) and FM (RF: baseline = 16.3 ± 4 kg, post-diet = 13.5 ± 3.6 kg, Δ2.8 kg; CN: baseline = 16.7 ± 4.5 kg, post-diet = 14.4 ± 4.9 kg, Δ2.3 kg) with no differences between groups. FFM (RF: baseline = 60.1 ± 13.8 kg, post-diet = 59.7 ± 13.0 kg, 0.4 kg; CN: baseline = 66.4 ± 15.2 kg, post-diet = 65.1 ± 15.2 kg, Δ1.3 kg p = 0.006), dFFM (RF: baseline = 18.7 ± 5.0 kg, post-diet = 18.5 ± 4.5 kg, Δ0.2 kg; CN: baseline =21.9 ± 5.7 kg, post-diet = 20.0 ± 5.7 kg, Δ1.9 kg), and RMR (RF: baseline = 1703 ± 294, post-diet = 1665 ± 270, Δ38 kcals; CN: baseline = 1867 ± 342, post-diet = 1789 ± 409, Δ78 kcals) were better maintained in the RF group. A 2-day carbohydrate refeed preserves FFM, dryFFM, and RMR during energy restriction compared to continuous energy restriction in RT-individuals.

Depression, Acquired Capability for Suicide, and Attempted Suicide.

OBJECTIVE: The study sought to replicate, with a community sample and different measures of the critical variables, the finding of Chu et al. (Cognitive Therapy and Research, 2016, 40, 22) in a military sample that suicide attempts were more frequent for those reporting higher numbers of depressive episodes if acquired capability for suicide (ACS) was also high. METHOD: An online survey (N = 251) collected data on episodes and severity of depression, number of suicide attempts, and a questionnaire measure of ACS. RESULTS: The interaction effect reported by Chu et al. (Cognitive Therapy and Research, 2016, 40, 22) was replicated, but depended on using the Fearlessness of Death component of ACS and the number and not the severity of depressive episodes. CONCLUSION: The moderating effect of ACS on the relation between depression and suicide attempts can be demonstrated beyond a military and predominately male sample. Limitations of the study are noted.

Safety of the tau-directed monoclonal antibody BIIB092 in progressive supranuclear palsy: a randomised, placebo-controlled, multiple ascending dose phase 1b trial.

BACKGROUND: Progressive supranuclear palsy is a rare neurodegenerative disease associated with dysfunctional tau protein. BIIB092 is a humanised monoclonal antibody that binds to N-terminal tau and is thus being assessed as a potential novel treatment for progressive supranuclear palsy. We aimed to investigate the safety and tolerability of BIIB092 in individuals with progressive supranuclear palsy. METHODS: This 12-week, double-blind, randomised, placebo-controlled, multiple ascending dose, phase 1b trial was done at 13 outpatient sites in the USA. Participants aged 41-86 years with probable or possible progressive supranuclear palsy with a score of 20 or greater on the Mini-Mental State Examination (MMSE) were enrolled. Three BIIB092 dose escalation cohorts (150 mg, 700 mg, or 2100 mg; eight participants per cohort) were tested sequentially. For each dose cohort, the first two participants were randomly assigned by a computer-generated scheme to receive either BIIB092 or placebo intravenously every 4 weeks for 57 days. After 2 days, the six remaining participants in each cohort were randomly assigned (5:1) to receive BIIB092 or placebo for 57 days. An additional expansion panel of 24 patients was randomly assigned (3:1) to receive 2100 mg or placebo every 4 weeks for 57 days. All participants were followed up to day 85. The primary outcome was safety, which was analysed in the treated population (all enrolled participants who received at least one dose of the study drug). This trial is registered with ClinicalTrials.gov, NCT02460094. FINDINGS: Between Oct 2, 2015, and Oct 19, 2016, 48 participants were enrolled and randomly assigned to the BIIB092 (n=36) and placebo (n=12) groups. No apparent demographic differences were observed between the two groups at baseline. All 48 participants completed the treatment phase of the study. Adverse events were generally mild to moderate in severity; the most common in the placebo and BIIB092 groups were falls (in two [17%] of 12 patients and in ten [28%] of 36 patients), urinary tract infections (in one [8%] of 12 and in six [17%] of 36), contusions (in one [8%] of 12 and in five [14%] of 36), and headaches (in none and in five [14%] of 36). Four serious adverse events resulting in admission to hospital were reported in three participants who received BIIB092 2100 mg: two severe adverse events of urinary tract infection, one severe adverse event of change in mental status, and one moderate adverse event of aspiration pneumonia. None was considered to be related to the study drug, all were resolved, and no deaths were reported. INTERPRETATION: Repeated administration of the anti-tau monoclonal antibody BIIB092, at doses of up to 2100 mg, appears to be well tolerated in participants with progressive supranuclear palsy. Results of this phase 1b trial have informed the design of the ongoing phase 2 PASSPORT (NCT03068468) study to examine the efficacy and safety of BIIB092. FUNDING: Bristol-Myers Squibb, Biogen.

Development and Validity of the Personal Suicide Stigma Questionnaire (PSSQ).

Background: The detrimental consequences of stigma have been recognized in extensive research on mental illness stigma, but experiences of suicide-related stigmatization have not received sufficient research attention. The lack of a simple self-report assessment of personal suicide-related stigma led to the work reported here. Aim: To develop and assess the validity of the Personal Suicide Stigma Questionnaire (PSSQ). Method: The item pool for PSSQ was based on qualitative data and was tested in a community sample of 224 adults (mean age = 32.68 years, 83% female, 92.9% Caucasian) who reported lifetime suicidality. Factor analysis was used for item selection. The Self-Stigma of Mental Illness Scale - Short form (SSMIS-SF) and Suicide Behaviors Questionnaire - Revised (SBQ-R) were used to assess validity of the scale. Results: Following analysis, 16 items, forming three highly interrelated factors (Rejection, Minimization, and Self-blame), were selected for the PSSQ. The PSSQ scores showed predicted relationships with mental illness stigma and suicidality, suggesting its validity. Limitations: The validity of the scale still requires further research in clinical populations. Conclusion: The newly developed PSSQ can be used to assess the levels of suicide-related stigma experiences of suicidal individuals.

Impact of Reference and Target Region Selection on Amyloid PET SUV Ratios in the Phase 1b PRIME Study of Aducanumab.

SUV ratios (SUVRs) are commonly used to quantify tracer uptake in amyloid-ß PET. Here, we explore the impact of target and reference region-of-interest (ROI) selection on SUVR effect sizes using interventional data from the ongoing phase 1b PRIME study (NCT01677572) of aducanumab (BIIB037) in patients with prodromal or mild Alzheimer disease. Methods: The florbetapir PET SUVR was calculated at baseline (screening) and at weeks 26 and 54 for patients randomized to receive placebo and each of 4 aducanumab doses (1, 3, 6, and 10 mg/kg) using the whole cerebellum, cerebellar gray matter, cerebellar white matter, pons, and subcortical white matter as reference regions. In addition to the prespecified composite cortex target ROI, individual cerebral cortical ROIs were assessed as targets. Results: Of the reference regions used, subcortical white matter, cerebellar white matter, and the pons, alone or in combination, generated the largest effect sizes. The use of the anterior cingulate cortex as a target ROI resulted in larger effect sizes than the use of the composite cortex. SUVR calculations were not affected by correction for brain volume changes over time. Conclusion: Dose- and time-dependent reductions in the amyloid PET SUVR were consistently observed with aducanumab only in cortical regions prone to amyloid plaque deposition, regardless of the reference region used. These data support the hypothesis that florbetapir SUVR responses associated with aducanumab treatment are a result of specific dose- and time-dependent reductions in the amyloid burden in patients with Alzheimer disease.

Tissue burns due to contact between a skin surface and highly conducting metallic media in the presence of inter-tissue boiling.

A numerical-based model was developed and implemented to determine the spatial and temporal temperature distributions within skin tissue resulting from thermal contact with a heated and high thermal conductivity metallic medium. In the presence of wet tissue, boiling is likely to occur, thereby affecting the probability of inducing burns. This investigation deals with how contact between a hot, highly conductive metallic material and skin gives rise to burns. In particular, the study focuses on the likelihood that metals typically used in cooking or industrial applications may cause burns. Insofar as the surfaces under consideration are above the boiling temperature of water, a mathematical model including phase change was developed. That model allowed different thermophysical properties to be respectively employed for dry and wet tissues. Multiple processes and their governing parameters were investigated to assess their impact on burn severity, including the temperature of the metal, the duration of contact, the contact resistance between the surface and the skin, the temperature range over which phase change occurred, and the cooling environment after the exposure. It was discovered that the most important parameters are the surface temperature and exposure duration. The other conditions/parameters had lesser impacts on the results.

Synergistic experimental and numerical characterization of a dry-heat, fluid-warming device.

Fluids that are infused into the human body must be at a temperature that is compatible with the internal thermal state of the body. Since infusants are typically stored at temperatures that are too low for compatibility, a heating means is required to achieve the appropriate infusion temperature. This paper sets forth a synergistic investigation involving coupled experimentation and numerical simulation of the characteristics of one of the main categories of body-fluid heating means. The methodology developed here serves equally well as a design optimization tool. The paper encompasses two stages: (a) an experimental and numerical evaluation of a generic warming device in common use and (b) a redesign utilizing the same tools to elevate the performance of devices of this category. The numerical simulation dealt with steady and unsteady three-dimensional fluid flow and heat transfer which are endemic to devices of this kind. The two-pronged approach developed here was shown to be capable of coping with an operating feature called stopflow wherein an officiating physician orders an immediate cessation of fluid flow. The thermal events following stopflow are well described by the numerical simulations.

Addendum: The antibody aducanumab reduces Aß plaques in Alzheimer's disease.

This corrects the article DOI: 10.1038/nature21361.

Use of multi-lumen catheters to preserve injected stem cell viability and injectant dispersion.

Infusion catheters, when used with balloons, are susceptible to compression of the catheter lumen. A consequence is that shear stress is increased in the fluid that passes through the lumen. When the injected fluid contains viable cells, hemolysis of the cells can result. This study investigates the effect of a new injection catheter design which is intended to resist the deleterious effect of balloon compression on cell viability for various flowrates, balloon pressures, and fluid viscosity values. Two types of catheters were employed for the study; a standard single-lumen device and a newly designed multi-lumen alternate. Experimental and numerical simulations show that for a single-lumen injection catheter, balloon pressures in excess of 7-8atm have the potential for causing hemolysis for flows of approximately 1-4ml/min. The critical balloon pressure is dependent on the viscosity of the cell-carrying fluid and the injectant flowrate. Higher injection rates and viscosities lead to lower threshold balloon pressures. The results show a sharp rise in cell death when pressures rose above approximately 7atm. On the other hand, the multi-lumen design was shown to resist hemolysis for all tested and simulated balloon pressures and flowrates up to 10ml/min. Experimental results confirmed the numerical findings that hemolysis-causing shear stress was not found with the multi-lumen, up to 12atm. This study indicates that a pressure-resistant multi-lumen catheter better preserves cell viability compared to the standard.