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.

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

This corrects the article DOI: 10.1038/nature21361.

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

Alzheimer's disease (AD) is characterized by deposition of amyloid-ß (Aß) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aß to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aß. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aß, and reduce soluble and insoluble Aß in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aß in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating-Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.

Comprehensive method to predict and quantify scald burns from beverage spills.

A comprehensive study was performed to quantify the risk of burns from hot beverage spills. The study was comprised of three parts. First, experiments were carried out to measure the cooling rates of beverages in a room-temperature environment by natural convection and thermal radiation. The experiments accounted for different beverage volumes, initial temperatures, cooling period between the time of service and the spill, the material which comprised the cup, the presence or absence of a cap and the presence or absence of an insulating corrugated paper sleeve. Among this list, the parameters which most influenced the temperature variation was the presence or absence of a cover or cap, the volume of the beverage and the duration of the cooling period. The second step was a series of experiments that provided temperatures at the surface of skin or skin surrogate after a spill. The experiments incorporated a single layer of cotton clothing and the exposure duration was 30 s. The outcomes of the experiments were used as input to a numerical model which calculated the temperature distribution and burn depth within tissue. Last was the implementation of the numerical model and a catalogue of burn predictions for various beverage volumes, beverage service temperatures, and durations between beverage service and spill. It is hoped that this catalogue can be used by both beverage industries and consumers to reduce the threat of burn injuries. It can also be used by treating medical professionals who can quickly estimate burn depths following a spill incident.

Assessment of acquired capability for suicide in clinical practice.

The Interpersonal Psychological Theory of suicide proposes that the interaction between Thwarted Belongingness, Perceived Burdensomeness, and Acquired Capability for Suicide (ACS) predicts proximal risk of death by suicide. Instruments to assess all three constructs are available. However, research on the validity of one of them, the acquired capability for suicide scale (ACSS), has been limited, especially in terms of its clinical relevance. This study aimed to explore the utility of the different versions of the ACSS in clinical assessment. Three versions of the scale were investigated, the full 20-item version, a 7-item version and a single item version representing self-perceived capability for suicide. In a sample of patients recruited from a clinic specialising in the treatment of suicidality and in a community sample, all versions of the ACSS were found to show reasonable levels of reliability and to correlate as expected with reports of suicidal ideation, self-harm, and attempted suicide. The item assessing self-perceived acquired capacity for suicide showed highest correlations with all levels of suicidal behaviour. However, no version of the ACSS on its own showed a capacity to indicate suicide attempts in the combined sample. It is concluded that the versions of the scale have construct validity, but their clinical utility is limited. An assessment using a single item on self-perceived ACS outperforms the full and shortened versions of ACSS in clinical settings and can be recommended with caution for clinicians interested in assessing this characteristic.

How do clinicians and suicide attempters understand suicide attempt impulsivity? A qualitative study.

Inconsistencies in the definition of impulsive suicide attempts hamper research integration. To expand the currently limited data on how this construct is used in clinical practice, researchers interviewed eight suicide attempters to create timelines of their suicide process, then had seven experienced clinicians review these timelines. Thematic analysis of the patient and clinician data revealed three themes: "thinking out," build-up, and unclear intentionality. The results imply that assessing build-up of agitation and exhaustion symptoms can contribute to understanding acuteness of suicide risk. In addition, uncertainty about one's intentions during the attempt should not be equated to low intent to die.

Personal Stigma in Suicide Attempters.

The aim of this study was to explore suicide attempters' experiences of personal stigma. This qualitative study included a focus group of 7 experienced clinicians and semi-structured interviews with 8 suicide attempters. Thematic analysis of the data yielded four main themes: seriousness, care, "badness," and avoidance. Experiences of stigma pervaded all contexts, but were most emotionally upsetting to the participants in interpersonal relationships. The findings show the importance of evaluating stigma for suicide attempters during suicide risk assessment and the need for specifically tailored interventions to combat suicide stigma at the individual level.

Perceived importance of prospective memory failures in adults with traumatic brain injury.

Prospective memory (PM) is the ability to carry out an intended action in the future. Failures in PM are often observed as more frequent in individuals with traumatic brain injury (TBI) than controls. However, it remains unknown how individuals with TBI and their significant others perceive the importance of these PM problems. In the current study, four groups (38 TBI, 34 TBI-other, 34 controls, 31 control-other) were recruited to report on the perceived importance of PM failures using Part B of the Comprehensive Assessments of Prospective Memory (CAPM). Individuals with TBI perceived PM failures as being more important than did their significant others. Controls' ratings did not differ from their significant others. There were no statistically significant differences in rated importance for PM problems involving the basic activities of daily living (BADL) component and those involving the instrumental activities of daily living (IADL) component. Implications of the results are discussed in terms of the motivation of people with TBI.

Geometric issues in reverse osmosis: numerical simulation and experimentation.

This investigation is a synergistic combination of laboratory experimentation and numerical simulation to quantify the practical impact of geometric imperfections in the flow channels of a reverse osmosis (RO) system. To this end, carefully executed experiments are performed to quantify the fluid flow in a system containing feed spacers which are embedded in the RO membrane. In a complementary activity, numerical simulations were performed both for an ideal geometric situation (without embedments) and the actual geometric configuration including the embedments. It was found that the presence of unaccounted embedments affected the pressure drop predictions for the system by 14-19%. When account was taken of the embedments, the simulation results were found to be virtually coincident with the experimental results. This outcome suggests that deviations between experimental and simulation results encountered in the literature might well have been due to geometrical deviations of the type investigated here. The numerical simulation of the feedwater fluid flow was based on the often-used but unverified assumption that the velocity field experiences the geometric periodicity of the feed spacer. This assumption was lent support by results from a non-periodic simulation model and by the excellent agreement between the numerically based predictions and the experimental data.

Suicide around public holidays.

OBJECTIVE: To examine the frequency of suicides on holidays and special days of the year, specifically in Queensland, Australia. METHODS: We analysed data from the Queensland Suicide Register between 1990 and 2009. The days examined were: Easter, Christmas, New Year, Valentine's Day and Anzac Day. We compared suicide cases on these days with the average counts for periods before and after the days. RESULTS: There was a statistically significant increase in suicides on Christmas Eve and on New Year's Day. Our results are discussed in light of trends reported in the literature. CONCLUSION: The beginning and end of the festive season are times when special attention is warranted for those with a heightened risk of suicide.

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.

Effects of aging, planning, and interruption on complex prospective memory.

This study examined the effects of aging, planning, and interruption on complex prospective memory (PM) using a 2 x 2 x 2 between-subjects design. Participants were 80 younger adults (65 females) aged 18-33 years and 80 older adults (70 females) aged 60-75 years. They were randomly allocated to four conditions (viz., no interruption and no planning, interruption but no planning, planning but no interruption, and both planning and interruption) and asked to undertake three PM tasks (time-, event-, and activity-based) while performing an ongoing task (viz., recipe checking and identification) in a simulated home environment. Younger adults were found to perform significantly better than older adults on time- and event-based PM. The opportunity to plan for five minutes was found to improve performances on all three types of PM. Unexpected, external interruptions, on the other hand, were found to reduce performance for time-based PM. Interestingly, planning was found to significantly improve the performance of older adults on time-based PM and to a level similar to that of younger adults. Results of the study have clarified the independent and interactive effects of the three variables on PM and have implications for understanding and enhancing this type of memory.

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.

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.

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.

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.