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Purpose: The purpose of this study was to examine the interrater reliability and validity of the Apraxia of Speech Rating Scale (ASRS-3.5) as an index of the presence and severity of apraxia of speech (AOS) and the prominence of several of its important features. Method: Interrater reliability was assessed for 27 participants. Validity was examined in a cohort of 308 participants (120 with and 188 without progressive AOS) through item analysis; item-Total score correlations; correlations among ASRS Total score and component subscores and independent clinical ratings of AOS, dysarthria and aphasia severity, intelligibility, and articulatory errors, as well as years postonset and age; and regression models assessing item and Total score prediction of AOS presence. Results: Interrater reliability was good or excellent for most items and excellent for the Total score. Item and Total score analyses revealed good separation of participants with versus without AOS. Inter-item and item-Total score correlations were generally moderately high as were correlations between the ASRS Total score and independent ratings of AOS severity, intelligibility, and articulatory errors. The Total score was not meaningfully correlated with ratings of aphasia and dysarthria severity, years postonset, or age. Total scores below 7 and above 10 revealed excellent diagnostic sensitivity and specificity for AOS. The presence of eight or more abnormal features was also highly predictive of AOS presence. Conclusions: The ASRS-3.5 is a reliable and valid scale for identifying the presence and severity of AOS and its predominant features. It has excellent sensitivity to AOS presence and excellent specificity relative to aphasia and dysarthria in patients with neurodegenerative disease. Supplemental Material: https://doi.org/10.23641/asha.21817584

Purpose: The purpose of this study was to describe, compare, and understand speech modulation capabilities of patients with varying motor speech disorders (MSDs) in a paradigm in which patients made highly cued attempts to speak faster or slower. Method: Twenty-nine patients, 12 with apraxia of speech (AOS; four phonetic and eight prosodic subtype), eight with dysarthria (six hypokinetic and two spastic subtype), and nine patients without any neurogenic MSD completed a standard motor speech evaluation where they were asked to repeat words and sentences, which served as their “natural” speaking rate. They were then asked to repeat lower complexity (counting 1–5; repeating “cat” and “catnip” 3 times each) and higher complexity stimuli (repeating “catastrophe” and “stethoscope” 3 times each and “My physician wrote out a prescription” once) as fast/slow as possible. Word durations and interword intervals were measured. Linear mixed-effects models were used to assess differences related to MSD subtype and stimuli complexity on bidirectional rate modulation capacity as indexed by word duration and interword interval. Articulatory accuracy was also judged and compared. Results: Patients with prosodic AOS demonstrated a reduced ability to go faster; while they performed similarly to patients with spastic dysarthria when counting, patients with spastic dysarthria were able to increase rate similar to controls during sentence repetition; patients with prosodic AOS could not and made increased articulatory errors attempting to increase rate. AOS patients made more articulatory errors relative to other groups, regardless of condition; however, their percentage of errors reduced with an intentionally slowed speaking rate. Conclusions: The findings suggest comparative rate modulation abilities in conjunction with their impact on articulatory accuracy may support differential diagnosis between healthy and abnormal speech and among subtypes of MSDs (i.e., type of dysarthria or AOS). Findings need to be validated in a larger, more representative cohort encompassing several types of MSDs. Supplemental Material: https://doi.org/10.23641/asha.22044632

Purpose: Prior studies have shown that communication-related participation restrictions in patients with degenerative disease do not always match clinician judgment or objective indices of symptom severity. Although there is a growing body of literature documenting that discrepancies between patients with dementia and their care partners' perception of participation restrictions exist, it is not known how care partner perceptions of communication participation restrictions specifically match or diverge from the patients' experiences, which may inform the use of care partner proxy in the context of degenerative diseases. Method: Thirty-eight patients with progressive neurologic conditions (progressive supranuclear palsy, corticobasal syndrome, and primary progressive aphasia or apraxia of speech) and, in most instances, focal cognitive-communication disorders were included. The patients and their accompanying care partners independently completed the Communicative Participation Item Bank, short form, a 10-question survey about communication participation restrictions in different contexts. Care partners were instructed to complete the form with their perception of the patient's experience. The difference between patient and care partner total scores were calculated and analyzed relative to clinical and demographic variables of interest. Results: Care partner ratings modestly tracked with patient experience and objective indices of symptom severity but did not exactly match patient ratings. The presence of aphasia increased, but did not fully account for, the likelihood of a discrepancy between care partner and patient ratings. Conclusion: Although careful consideration should be given prior to using care-partner report as a proxy for patient experience, it is worthwhile to include care partner ratings as a means of supporting conversations about differing perceptions, guiding joint intervention planning, and monitoring care-partner perceptions of change along with the implementation of supported conversation strategies.

This article examines a cartographic encounter that took place in 1850 between Kallihirua, a member of Inughuit community of Northern Greenland, and members of the British Admiralty. Drawing on recent literatures that critically assess histories of indigenous mapping, the article explores the troubling circumstances that surrounded this encounter and analyses two maps which were produced as a result. Informed by ongoing debates pertaining to the decolonization of geographical knowledge, the article also reflects critically upon the extent to which historical indigenous cosmologies were commensurate with non-indigenous cartographic traditions and thus reassesses the motivations that lay behind the production and circulation of these maps. The article thus concludes by arguing that while Kallihirua certainly did contribute various types of geographical knowledge during this encounter, to label him as the sole author of these maps would be a problematic act of “cartographic ventriloquism.”

America's opioid epidemic has spawned an epidemic of neonatal abstinence syndrome (NAS). Studies have not tested approaches to promoting contraceptive services for women with opioid use disorder (OUD) along with treatment for this disorder. This pilot study examined the promotion of medication for OUD (MOUD) treatment and contraception use, primarily long-acting reversible contraception (LARC), for women with OUD.In Appalachia, a peer-delivered contraception and MOUD promotion intervention was delivered to a sample of 30 women with OUD. Primary outcomes were attendance of initial appointments to receive MOUD and counseling about contraceptive options. Peer recovery coaches also offered to help the women schedule appointments and attend the appointment with them or give them a ride if necessary and requested by the patients.Two-thirds experienced all seven symptoms of opioid dependence. Within 30 days of a brief counseling session, over one-half of the women (56.7%) were referred to MOUD, with all of them initiating treatment within 30 days. Just under one-half of the women (46.7%) were referred to a contraception consultation, with 85.7% of those receiving a LARC implant.Study findings indicate the potential efficacy of a single-session, peer-delivered counseling intervention for linking women with OUD and at high risk of unintended pregnancy to MOUD and to services that provide women with highly reliable contraceptives.This study is unique in exploring the efficacy of linking high-risk opioid-using women to contraceptive options and treatment for MOUD to prevent NAS.

Accurate genome replication is essential for all life and a key mechanism of disease prevention, underpinned by the ability of cells to respond to replicative stress (RS) and protect replication forks. These responses rely on the formation of Replication Protein A (RPA)-single stranded (ss) DNA complexes, yet this process remains largely uncharacterized. Here we establish that actin nucleation-promoting factors (NPFs) associate with replication forks, promote efficient DNA replication and facilitate association of RPA with ssDNA at sites of RS. Accordingly, their loss leads to deprotection of ssDNA at perturbed forks, impaired ATR activation, global replication defects and fork collapse. Supplying an excess of RPA restores RPA foci formation and fork protection, suggesting a chaperoning role for actin nucleators (ANs) (i.e., Arp2/3, DIAPH1) and NPFs (i.e, WASp, N-WASp) in regulating RPA availability upon RS. We also discover that β-actin interacts with RPA directlyin vitro, andin vivoa hyper-depolymerizing β-actin mutant displays a heightened association with RPA and the same dysfunctional replication phenotypes as loss of ANs/NPFs, which contrasts with the phenotype of a hyper-polymerizing β-actin mutant. Thus, we identify components of actin polymerization pathways that are essential for preventing ectopic nucleolytic degradation of perturbed forks by modulating RPA activity.

Prior studies have shown communication-related participation restrictions in patients with degenerative disease do not always match clinician judgment of symptom severity. Relatedly, there is a growing body of literature documenting discrepancies between patients with dementia and care partner perception of participation restrictions. However, it is not known how care partner perceptions of communication participation restrictions match or diverge from the patient's experience, which was the topic of this study. Toward that end, 28 patients with apraxia of speech and/or dysarthria associated with primary progressive apraxia of speech, nonfluent/agrammatic primary progressive aphasia, or progressive supranuclear palsy, all types of frontotemporal dementia, were seen for speech-language examinations. The patients and their care partners were asked to independently complete the Communication Participation Item Bank (CPIB), short form, which is a 10-question survey about communication in different contexts; higher scores reflect less interference from their condition on communication. Care partners were instructed to complete the form with their perception of the patient's restrictions. The total CPIB score (maximum 30) and difference scores were calculated and visualized. The data (Figure) suggest mismatches exist in care partner and patient ratings of communication participation restrictions. Of 28 patients, only 1 pair had identical scores, each rating severe interference in all communication contexts. 57% of patients rated communication as less impacted (higher scores) compared to their family member, leaving 39% of family members rating communication as less impacted than their loved one's perception. This study lays the foundation for future research to include patient and care partner ratings when examining the benefit of impairment-based therapy, utilization of compensatory speech strategies, effectiveness of such strategies, and impact of other augmentative or alternative means of communication. The CPIB may be useful to document reduced psychosocial impact of disease and diminished burden and burnout on care partners with different intervention options. Future studies will explore possible differences between FTD phenotypes and, more specifically, whether 1) the motor speech disorder (MSD) disorder is primary or secondary to other motor impairment, 2) the nature or severity of the MSD, or 3) concomitant cognitive-communication impairment predict the existence of and/or direction of a discrepancy.

Introduction Progressive supranuclear palsy (PSP) variants other than PSP-Richardson Syndrome (PSP-RS) have been recognized, including PSP with speech and language problems (PSP-SL). Given the reported sleep disruptions in PSP-RS, we investigated sleep abnormalities in PSP-SL. Methods Four sleep-related screening questions were given to the caregivers of 90 patients with PSP-SL (59 suggestive of PSP-SL and 31 possible PSP-SL) and 71 probable PSP-RS (prob. PSP-RS) patients. Results At least one sleep-related disturbance was observed in 35.6% of suggestive of PSP-SL, 38.7% of possible PSP-SL, and 67.6% of prob. PSP-RS, the most common being “unable to fall or stay asleep”. Prob. PSP-RS showed higher frequency of “screaming or talking in sleep”, “acting out dreams”, and “unable to fall or stay asleep” compared to both PSP-SL groups, but did not differ from possible PSP-SL in “excessive daytime sleepiness”. Conclusion Sleep abnormalities are common in PSP-SL, but less frequent than prob.PSP-RS.

Objective:To characterize and compare the neuropsychological profiles of patients with primary progressive apraxia of speech (PPAOS) and apraxia of speech with progressive agrammatic aphasia (AOS-PAA).Method:Thirty-nine patients with PPAOS and 49 patients with AOS-PAA underwent formal neurological, speech, language, and neuropsychological evaluations. Cognitive domains assessed included immediate and delayed episodic memory (Wechsler Memory Scale-Third edition; Logical Memory; Visual Reproduction; Rey Auditory Verbal Learning Test), processing speed (Trail Making Test A), executive functioning (Trail Making Test B; Delis-Kaplan Executive Functioning Scale – Sorting), and visuospatial ability (Rey-Osterrieth Complex Figure copy).Results:The PPAOS patients were cognitively average or higher in the domains of immediate and delayed episodic memory, processing speed, executive functioning, and visuospatial ability. Patients with AOS-PAA performed more poorly on tests of immediate and delayed episodic memory and executive functioning compared to those with PPAOS. For every 1 unit increase in aphasia severity (e.g. mild to moderate), performance declined by 1/3 to 1/2 a standard deviation depending on cognitive domain. The degree of decline was stronger within the more verbally mediated domains, but was also notable in less verbally mediated domains.Conclusion:The study provides neuropsychological evidence further supporting the distinction of PPAOS from primary progressive aphasia and should be used to inform future diagnostic criteria. More immediately, it informs prognostication and treatment planning.

Quantitative susceptibility mapping (QSM) can detect iron distribution in the brain by estimating local tissue magnetic susceptibility properties at every voxel. Iron deposition patterns are well studied in typical Alzheimer's disease (tAD), but little is known about these patterns in atypical clinical presentations of AD such as logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA). Seventeen PCA patients and eight LPA patients were recruited by the Neurodegenerative Research Group at Mayo Clinic, Rochester, MN, and underwent MRI that included a five-echo gradient echo sequence for calculation of QSM. Mean QSM signal was extracted from gray and white matter for regions-of-interest across the brain using the Mayo Clinic Adult Lifespan Template. Bayesian hierarchical models were fit per-region and per-hemisphere to compare PCA, LPA, 63 healthy controls, and 20 tAD patients. Strong evidence (posterior probability 0.99) was observed for greater susceptibility in the middle occipital gyrus and amygdala in both LPA and PCA, and in the right inferior parietal, inferior temporal, and angular gyri in PCA and the caudate and substantia nigra in LPA compared to controls. Moderate evidence for greater susceptibility (posterior probability 0.90) was also observed in the inferior occipital gyrus, precuneus, putamen and entorhinal cortex in both LPA and PCA, along with superior frontal gyrus in PCA and inferior temporal gyri, insula and basal ganglia in LPA, when compared to controls. Between phenotypic comparisons, LPA had greater susceptibility in the caudate, hippocampus, and posterior cingulate compared to PCA, while PCA showed greater susceptibility in the right superior frontal and middle temporal gyri compared to LPA. Both LPA and PCA showed moderate and strong evidence for greater susceptibility than tAD, particularly in medial and lateral parietal regions, while tAD showed greater susceptibility in the hippocampus and basal ganglia. This study proposes the possibility of unique iron profiles existing between LPA and PCA within cortical and subcortical structures. These changes match well with the disease-related changes of the clinical phenotypes, suggesting that QSM could be an informative candidate marker to study iron deposition in these patients.

OBJECTIVE The aim was to analyze the timeline, prevalence, and survival of rapid eye movement (REM) sleep behavior disorder (RBD) in patients who developed alpha-synucleinopathies (Parkinson disease, dementia with Lewy bodies, and Parkinson disease dementia) compared with age- and sex-matched controls in a population-based incident-cohort study. METHODS We used a population-based, 1991 to 2010 incident-cohort study of alpha-synucleinopathies. A movement-disorder specialist reviewed medical records to confirm diagnoses. RBD was diagnosed by reported dream-enactment symptoms or polysomnography. Probable RBD and polysomnographically confirmed RBD were analyzed separately and combined. RESULTS Among the 444 incident cases of alpha-synucleinopathy, 86 were clinically diagnosed with RBD (19.8%), including 30 (35%) by polysomnography and 56 (65%) as probable. The prevalence of idiopathic RBD at alpha-synucleinopathy diagnosis was 3.4%, increasing to 23.8% after 15 years. Cumulative lifetime incidence was 53 times greater in alpha-synucleinopathy patients than in controls (odds ratio [OR] = 53.1, 95% confidence interval [CI]: 13.0-217.2, p

Alzheimer’s disease is characterized by the presence of amyloid-β and tau deposition in the brain, hippocampal atrophy and increased rates of hippocampal atrophy over time. Another protein, TAR DNA binding protein 43 (TDP-43) has been identified in up to 75% of cases of Alzheimer’s disease. TDP-43, tau and amyloid-β have all been linked to hippocampal atrophy. TDP-43 and tau have also been linked to hippocampal atrophy in cases of primary age-related tauopathy, a pathological entity with features that strongly overlap with those of Alzheimer’s disease. At present, it is unclear whether and how TDP-43 and tau are associated with early or late hippocampal atrophy in Alzheimer’s disease and primary age-related tauopathy, whether either protein is also associated with faster rates of atrophy of other brain regions and whether there is evidence for protein-associated acceleration/deceleration of atrophy rates. We therefore aimed to model how these proteins, particularly TDP-43, influence non-linear trajectories of hippocampal and neocortical atrophy in Alzheimer’s disease and primary age-related tauopathy. In this longitudinal retrospective study, 557 autopsied cases with Alzheimer’s disease neuropathological changes with 1638 ante-mortem volumetric head MRI scans spanning 1.0–16.8 years of disease duration prior to death were analysed. TDP-43 and Braak neurofibrillary tangle pathological staging schemes were constructed, and hippocampal and neocortical (inferior temporal and middle frontal) brain volumes determined using longitudinal FreeSurfer. Bayesian bivariate-outcome hierarchical models were utilized to estimate associations between proteins and volume, early rate of atrophy and acceleration in atrophy rates across brain regions. High TDP-43 stage was associated with smaller cross-sectional brain volumes, faster rates of brain atrophy and acceleration of atrophy rates, more than a decade prior to death, with deceleration occurring closer to death. Stronger associations were observed with hippocampus compared to temporal and frontal neocortex. Conversely, low TDP-43 stage was associated with slower early rates but later acceleration. This later acceleration was associated with high Braak neurofibrillary tangle stage. Somewhat similar, but less striking, findings were observed between TDP-43 and neocortical rates. Braak stage appeared to have stronger associations with neocortex compared to TDP-43. The association between TDP-43 and brain atrophy occurred slightly later in time (∼3 years) in cases of primary age-related tauopathy compared to Alzheimer’s disease. The results suggest that TDP-43 and tau have different contributions to acceleration and deceleration of brain atrophy rates over time in both Alzheimer’s disease and primary age-related tauopathy.

To assess volume loss and flortaucipir uptake in patients with semantic dementia (SD) over time. Eight SD patients (3 female) underwent clinical evaluations, flortaucipir positron emission tomography, and brain magnetic resonance imaging at 2 visits. Voxel-level comparisons of magnetic resonance imaging gray and white matter volume loss and flortaucipir positron emission tomography uptake were performed in SPM12, comparing SD patients to controls at each visit. T-tests on difference images and paired t-tests of flortaucipir uptake were also performed. At the voxel level, SD patients showed asymmetric, bilateral gray volume loss in the temporal lobes, which, via visual inspection, extended posteriorly at follow-up. White matter loss and flortaucipir uptake were noted in SD patients in the left temporal lobe only, which appeared to extend posteriorly, without involvement of the right hemisphere at follow-up. Longitudinal analyses did not support significant changes in flortaucipir uptake between visits. The biological mechanisms of flortaucipir signal in suspected underlying TAR-DNA binding protein 43 pathology are unknown. A 1-year interval is not sufficient time to demonstrate significant longitudinal flortaucipir uptake changes in SD.

Alzheimer’s disease can present clinically with either the typical amnestic phenotype or with atypical phenotypes, such as logopenic progressive aphasia and posterior cortical atrophy. We have recently described longitudinal patterns of flortaucipir PET uptake and grey matter atrophy in the atypical phenotypes, demonstrating a longitudinal regional disconnect between flortaucipir accumulation and brain atrophy. However, it is unclear how these longitudinal patterns differ from typical Alzheimer’s disease, to what degree flortaucipir and atrophy mirror clinical phenotype in Alzheimer’s disease, and whether optimal longitudinal neuroimaging biomarkers would also differ across phenotypes. We aimed to address these unknowns using a cohort of 57 participants diagnosed with Alzheimer’s disease (18 with typical amnestic Alzheimer’s disease, 17 with posterior cortical atrophy and 22 with logopenic progressive aphasia) that had undergone baseline and 1-year follow-up MRI and flortaucipir PET. Typical Alzheimer’s disease participants were selected to be over 65 years old at baseline scan, while no age criterion was used for atypical Alzheimer’s disease participants. Region and voxel-level rates of tau accumulation and atrophy were assessed relative to 49 cognitively unimpaired individuals and among phenotypes. Principal component analysis was implemented to describe variability in baseline tau uptake and rates of accumulation and baseline grey matter volumes and rates of atrophy across phenotypes. The capability of the principal components to discriminate between phenotypes was assessed with logistic regression. The topography of longitudinal tau accumulation and atrophy differed across phenotypes, with key regions of tau accumulation in the frontal and temporal lobes for all phenotypes and key regions of atrophy in the occipitotemporal regions for posterior cortical atrophy, left temporal lobe for logopenic progressive aphasia and medial and lateral temporal lobe for typical Alzheimer’s disease. Principal component analysis identified patterns of variation in baseline and longitudinal measures of tau uptake and volume that were significantly different across phenotypes. Baseline tau uptake mapped better onto clinical phenotype than longitudinal tau and MRI measures. Our study suggests that optimal longitudinal neuroimaging biomarkers for future clinical treatment trials in Alzheimer’s disease are different for MRI and tau-PET and may differ across phenotypes, particularly for MRI. Baseline tau tracer retention showed the highest fidelity to clinical phenotype, supporting the important causal role of tau as a driver of clinical dysfunction in Alzheimer’s disease.

BACKGROUND Few studies have investigated the incidence of PSP and CBS in the population. OBJECTIVE To examine the incidence of and trends in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) in a population-based cohort of residents of Olmsted County, MN. METHODS We used the 1991-2005 population-based, Olmsted County Parkinsonism-cohort study, defined via the Rochester Epidemiology Project. A movement-disorder specialist reviewed medical records, to confirm PSP and CBS diagnoses. RESULTS We identified 21 patients with these diagnoses 1991-2005 : 18 (85.7%), PSP; 3 (14.3%), CBS. The median diagnosis age was 78 (range: 66-88). 13/21 (62.0%) were male. MRI was performed pre-diagnosis in 11 patients (8 PSP and 3 CBD); 10 showed atrophy consistent with clinical diagnoses. We observed concordance between clinical and pathological diagnoses in two PSP patients who underwent autopsy. Combined incidence for PSP and CBS in Olmsted County was 3.1 per 100,000 person-years (2.6 per 100,000 person-years, PSP; 0.4 per 100,000 person-years, CBS). Incidence was higher in men (4.5, 95% CI, 2.0-7.0) than women (1.8, 95% CI, 0.5-2.9). A combined, significant trend of increasing incidence was observed between 1991 and 2005 (B=0.69, 95% CI 0.42, 0.96, p

INTRODUCTION: Frontotemporal-dementia disorders (FTDs) are heterogeneous phenotypical behavioral and language disorders usually associated with frontal and/or temporal lobe degeneration. We investigated their incidence in a population-based cohort. METHODS: Using a records-linkage system, we identified all patients with a diagnostic code for dementia in Olmsted County, MN, 1995–2010, and confirmed the diagnosis of FTD. A behavioral neurologist verified the clinical diagnosis and determined phenotypes. RESULTS: We identified 35 FTDs cases. Overall, the incidence of FTDs was 4.3/100,000/year (95% CI 2.9, 5.7). Incidence was higher in men (6.3/100,000, 95% CI 3.6, 9.0) than women (2.9/100,000; 95% CI 1.3, 4.5); we observed an increased trend over time (B= 0.83, 95% CI 0.54, 1.11, P

On 13th November 1905, the Danish sea captain Ejnar Mikkelsen presented his detailed plans to survey a hitherto uncharted region of the Beaufort Sea before the fellows of the Royal Geographical Society. Although much coveted ‘undiscovered land’ in this icy polar region had been hypothesised within geographical debates across Europe and the United States, no ‘intelligent and scientific’ geographical explorer had yet managed to conduct the essential surveying work required to prove or disprove this theory. With his planned expedition being met with approval, Mikkelsen then ventured into the frozen landscape of the American High North hoping to correct this intriguing geographical lacuna. It is here that the inexperienced Arctic explorer was to have a series of encounters with the indigenous inhabitants of the region from whom he learned more about the hypothetical landmass. Updating the RGS on his progress and communicating the details of these moments of indigenous encounter, Mikkelsen relayed a series of tales that had been gleaned from these local people. Considering these tales in terms of the circulation of geographical knowledge, this article will contribute to the growing body of literature that has highlighted the significant role that indigenous people have played in the exploration of the Arctic regions. More importantly, it will also highlight the ways in which these contributions have regularly been obscured or omitted from the prevailing historical record of Arctic exploration.

Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy with neurodegeneration typically observed in the superior cerebellar peduncle (SCP) and dentatorubrothalamic tracts (DRTT). However, it is unclear how these tracts are differentially affected in different clinical variants of PSP.To determine whether diffusion tractography of the SCP and DRTT can differentiate autopsy-confirmed PSP with Richardson's syndrome (PSP-RS) and PSP with predominant speech/language disorder (PSP-SL).We studied 22 autopsy-confirmed PSP patients that included 12 with PSP-RS and 10 with PSP-SL. We compared these two groups to 11 patients with autopsy-confirmed Alzheimer's disease with SL problems, i.e., logopenic progressive aphasia (AD-LPA) (disease controls) and 10 healthy controls. Whole brain tractography was performed to identify the SCP and DRTT, as well as the frontal aslant tract and superior longitudinal fasciculus. We assessed fractional anisotropy and mean diffusivity for each tract. Hierarchical linear modeling was used for statistical comparisons, and correlations were assessed with clinical disease severity, ocular motor impairment, and parkinsonism. DRTT connectomics matrix analysis was also performed across groups.The SCP showed decreased fractional anisotropy for PSP-RS and PSP-SL and increased mean diffusivity in PSP-RS, compared to controls and AD-LPA. Right DRTT fibers showed lower fractional anisotropy in PSP-RS and PSP-SL compared to controls and AD-LPA, with PSP-RS also showing lower values compared to PSP-SL. Reductions in connectivity were observed in infratentorial DRTT regions in PSP-RS vs cortical regions in PSP-SL. PSP-SL showed greater abnormalities in the frontal aslant tract and superior longitudinal fasciculus compared to controls, PSP-RS, and AD-LPA. Significant correlations were observed between ocular motor impairment and SCP in PSP-RS (p = 0.042), and DRTT in PSP-SL (p = 0.022). In PSP-SL, the PSP Rating Scale correlated with the SCP (p = 0.045) and DRTT (p = 0.008), and the Unified Parkinson's Disease Rating Scale correlated with the DRTT (p = 0.014).Degeneration of the SCP and DRTT are diagnostic features of both PSP-RS and PSP-SL and associations with clinical metrics validate the role of these tracts in PSP-related clinical features, particularly in PSP-SL.

Introduction: Benzodiazepine tapering and cessation has been associated with diverse symptom constellations of varying duration. Although described in the literature decades ago, the mechanistic underpinnings of enduring symptoms that can last months or years have not yet been elucidated. Objective: This secondary analysis of the results from an Internet survey sought to better understand the acute and protracted withdrawal symptoms associated with benzodiazepine use and discontinuation. Methods: An online survey ( n = 1207) was used to gather information about benzodiazepine use, including withdrawal syndrome and protracted symptoms. Results: The mean number of withdrawal symptoms reported by a respondent in this survey was 15 out of 23 symptoms. Six percent of respondents reported having all 23 listed symptoms. A cluster of least-frequently reported symptoms (whole-body trembling, hallucinations, seizures) were also the symptoms most frequently reported as lasting only days or weeks, that is, short-duration symptoms. Symptoms of nervousness/anxiety/fear, sleep disturbances, low energy, and difficulty focusing/distractedness were experienced by the majority of respondents (⩾85%) and, along with memory loss, were the symptoms of longest duration. Prolonged symptoms of anxiety and insomnia occurred in many who have discontinued benzodiazepines, including over 50% who were not originally prescribed benzodiazepines for that indication. It remains unclear if these symptoms might be caused by neuroadaptive and/or neurotoxic changes induced by benzodiazepine exposure. In this way, benzodiazepine withdrawal may have acute and long-term symptoms attributable to different underlying mechanisms, which is the case with alcohol withdrawal. Conclusions: These findings tentatively support the notion that symptoms which are acute but transient during benzodiazepine tapering and discontinuation may be distinct in their nature and duration from the enduring symptoms experienced by many benzodiazepine users.

Magnetic resonance brainstem measurements are useful structural biomarkers in the Richardson's syndrome variant of progressive supranuclear palsy (PSP). However, it is unclear how these biomarkers differ across the phenotypic spectrum of PSP and how they relate to underlying pathology.The aim of this study was to compare brainstem imaging measures across clinical variants of PSP and determine sensitivity and specificity based on pathologically diagnosed cases.A total of 153 patients with PSP who represented eight clinical variants were recruited at Mayo Clinic (Rochester, MN, USA) and underwent structural magnetic resonance imaging (MRI). Midbrain and pons area and superior and middle cerebellar peduncle width measurements were performed, and midbrain/pons ratio and Magnetic Resonance Parkinsonism Index (MRPI) were calculated. Among the 43 patients who later died, PSP pathology was confirmed in 29, whereas 14 had other pathology.Brainstem measurements varied across PSP clinical variants and were most abnormal in PSP-Richardson's syndrome and frontal variants, followed by PSP-corticobasal, PSP-speech/language, and PSP-parkinsonism variants. All these variants showed abnormalities compared with controls. The PSP-gait freezing variant and patients with prominent corticospinal tract signs showed normal brainstem measures. Among cases with confirmed PSP pathology, the midbrain area, midbrain/pons ratio, and MRPI were all more abnormal compared to those with other pathologies, with best differentiation obtained with the MRPI (sensitivity = 83%; specificity = 85%).MRI brainstem measures show utility as diagnostic biomarkers across PSP clinical variants and have the potential to be useful in predicting underlying pathology. © 2021 International Parkinson and Movement Disorder Society.

Background and aims Opioid agonist therapies (OATs) are highly effective treatments for opioid use disorders (OUDs), especially for pregnant women; thus, improving access to OAT is an urgent public policy goal. Our objective was to determine if insurance and pregnancy status were barriers to obtaining access to OAT in 4 Appalachian states disproportionately impacted by the opioid epidemic. Methods Between April and May 2017, we conducted phone surveys of OAT providers, opioid treatment programs (OTPs), and outpatient buprenorphine providers, in Kentucky, North Carolina, Tennessee, and West Virginia. Survey response rates were 59%. Logistic models for dichotomous outcomes (e.g., patient acceptance) and negative binomial models were created for count variables (e.g., wait time), overall and for pregnant women. Results The majority of OAT providers were accepting new patients; however, providers were less likely to treat pregnant women (91% vs. 75%; p Conclusions We found that OAT providers frequently did not accept any insurance and frequently did not treat pregnant women in an area of the country disproportionately affected by the opioid epidemic. Policymakers could prioritize improvements in provider training (e.g., training of obstetricians to become buprenorphine prescribers) as a means to enhance access to pregnant women or enhancing reimbursement rates as a means of improving insurance acceptance for OAT.

Background: Published safety data in pregnant epileptic women suggests that oxcarbazepine (OXC) may be a treatment option in nonepileptic pregnant women with substance use disorders (SUDs) and psychiatric symptomatology. Objective: To compare safety outcomes associated with OXC exposure versus non-exposure in nonepileptic pregnant women with SUD and comorbid psychiatric symptomatology. Methods: A retrospective chart review was conducted to identify pregnant women 18 years or older with a SUD who delivered at the study site. Exclusion criteria included a current diagnosis of epilepsy/seizure disorder; concurrent use of lithium, anticonvulsants, medications with a Risk Evaluation and Mitigation Strategy program or a black box warning for potential fetal toxicity; and multi-parity. Eligible patients were divided into two groups based on OXC exposure. Results: The OXC group included 94 mother-neonate pairs versus 194 mother-neonate pairs in the non-OXC group. Baseline characteristics differed in mean number of prior pregnancies (2.8 vs 2.2 in the OXC and non-OXC group, respectively, P = .03). No significant differences were found regarding emergent cesarean or maternal hyponatremia. Average gestational age at OXC initiation was 19.8 weeks. No significant differences were found in the rates of prematurity, physical characteristics, malformation, and neonatal abstinence syndrome. Conclusion: OXC may be considered for management of SUD with comorbid psychiatric symptomatology in nonepileptic pregnant women. Further studies should be conducted to determine statistical significance in larger sample sizes.

Background The Movement Disorder Society clinical criteria for progressive supranuclear palsy (PSP) provide a framework for assessing the presence/severity of clinical symptoms and define a speech/language variant of PSP. Objectives To evaluate the clinical criteria in a cohort of speech/language patients with longitudinal follow-up. Methods A total of 52 patients presenting with progressive apraxia of speech and/or agrammatic aphasia were followed longitudinally for up to 6 visits with clinical assessments and magnetic resonance imaging. We assessed oculomotor, postural instability, and akinesia diagnostic levels and determined whether patients met criteria for possible PSP-speech/language or probable PSP at each visit. Kaplan-Meier curves assessed time-to-event probabilities according to age. Statistical parametric mapping and midbrain volume were assessed according to disease progression. Results Few PSP symptoms were observed early in the disease, with oculomotor abnormalities and falls first observed 2 years after onset. Falls were more common than vertical supranuclear gaze palsy. Bradykinesia and rigidity commonly developed but axial was rarely greater than appendicular rigidity. During follow-up, 54% met criteria for possible PSP-speech/language, 38% for probable PSP-Richardson's syndrome, and 38% for probable PSP-parkinsonism, most commonly 6 to 6.9 years after onset. The probability of developing PSP was greater when onset was at an age older than 70 years. Patients who progressed to probable PSP had more parkinsonism and oculomotor impairment at baseline and greater midbrain atrophy when compared with those who did not develop probable PSP. Conclusions Symptoms typical of PSP commonly develop in patients presenting with a progressive speech/language disorder. Older age appears to be an important prognostic factor in these patients.

ObjectiveTo compare [18F]AV-1451 uptake in the semantic variant of primary progressive aphasia (svPPA) to Alzheimer dementia, and determine whether increased uptake in svPPA is associated with the presence of β-amyloid (Aβ).MethodsThirty-one participants with svPPA underwent MRI and Pittsburgh compound B–PET scanning, and 17 of these also underwent [18F]AV-1451 tau-PET. A global Pittsburgh compound B standardized uptake value ratio was calculated for all participants, with a cutoff of 1.42 used to define Aβ(+) participants. We assessed region and voxel-level [18F]AV-1451 uptake in the whole svPPA cohort and separately in Aβ(+) and Aβ(−) svPPA groups, compared to 12 Aβ(+) participants with Alzheimer dementia and 170 cognitively normal, Aβ(−) controls.ResultsOf the entire cohort of participants with svPPA, 26% were Aβ(+). The Aβ(+) participants were older at scan compared to the Aβ(−) participants. svPPA showed elevated [18F]AV-1451 uptake in anteromedial temporal regions but the degree of uptake was lower than in Alzheimer dementia. After controlling for age, Aβ(+) status in svPPA was associated with significantly higher uptake in all anteromedial and inferior/middle lateral temporal regions, but uptake was still lower than in Alzheimer dementia.ConclusionAlthough [18F]AV-1451 uptake is focally elevated in svPPA, the level of uptake is much less than what occurs in Alzheimer dementia and appears to be at least partially related to Aβ. Therefore, it is possible that some of the increased uptake of [18F]AV-1451 in svPPA is related to binding paired helical filament tau.

This study examined the rate of producing alternating motion rates, sequential motion rates (SMRs), and repeated words in 27 individuals with the semantic variant of Primary Progressive Aphasia (svPPA). Only the rate of producing SMRs was significantly elevated in svPPA compared to controls. This may be associated with concomitant neuropsychiatric symptoms in svPPA, as correlation analysis showed a relationship between increased SMR rate and the Neuropsychiatric Inventory Questionnaire, which documented anxiety and disinhibition. Future studies will assess these findings in a larger cohort and work to better understand if this phenomenon is a manifestation of behavioral and/or motor changes.

Purpose Individuals with primary progressive apraxia of speech (PPAOS) have apraxia of speech (AOS) in which disruptions in articulation or prosody predominate the speech pattern, referred to, respectively, as phonetic or prosodic subtypes. Many develop aphasia and/or dysarthria. Past research has demonstrated that simple temporal acoustic measures are sensitive to the presence of AOS. The aim of this study was to describe the change in temporal acoustic measures over time and assess if specific patterns of AOS or co-occurring aphasia or dysarthria impact the rate of change over time. Method Durations for multiple productions of the words cat , catnip , catapult , and catastrophe , in an imitative speech task, were recorded for 73 patients, with two to six visits each. A linear mixed-effects model was used to assess the cross-sectional differences and longitudinal influence of AOS subtype and presence of aphasia/dysarthria on speech rate. Pearson correlations were calculated between rate measures and performance on other clinical measures. Results Cross-sectionally, patients with prosodic-predominant PPAOS produced words more slowly than those with phonetic-predominant PPAOS. Patients with either aphasia or dysarthria produced words more slowly than those without. Longitudinally, the speech rate of patients with phonetic-predominant PPAOS had a reduction of 0.5 syllables per second per year. Patients with prosodic-predominant AOS changed less quickly, as did those who developed aphasia. Dysarthria did not impact rate of change. There were strong associations between speech rate measures and other clinical indices of speech and language functioning. Conclusion Simple temporal acoustic measures may reflect the subtype of AOS (phonetic or prosodic predominant), serve as an index of progression of AOS, and inform prognostication relative to the presenting combination of speech and language features. Supplemental Material https://doi.org/10.23641/asha.13564724

Importance Medications for opioid use disorder, including buprenorphine hydrochloride and methadone hydrochloride, are highly effective at improving outcomes for individuals with the disorder. For pregnant women, use of these medications also improves pregnancy outcomes, including the risk of preterm birth. Despite the known benefits of medications for opioid use disorder, many pregnant and nonpregnant women with the disorder are not receiving them. Objective To determine whether pregnancy and insurance status are associated with a woman’s ability to obtain an appointment with an opioid use disorder treatment clinician. Design, Setting, and Participants In this cross-sectional study with random assignment of clinicians and simulated-patient callers (performed in “secret shopper” format), outpatient clinics that provide buprenorphine and methadone were randomly selected from publicly available treatment lists in 10 US states (selected for variability in opioid-related outcomes and policies) from March 7 to September 5, 2019. Pregnant vs nonpregnant woman and private vs public insurance assigned randomly to callers to create unique patient profiles. Simulated patients called the clinics posing as pregnant or nonpregnant women to obtain an initial appointment with a clinician. Main Outcomes and Measures Appointment scheduling, wait time, and out-of-pocket costs. Results A total of 10 871 unique patient profiles were assigned to 6324 clinicians. Among all women, 2312 of 3420 (67.6%) received an appointment with a clinician who prescribed buprenorphine, with lower rates among pregnant vs nonpregnant callers (1055 of 1718 [61.4%] vs 1257 of 1702 [73.9%]; relative risk, 0.83; 95% CI, 0.79-0.87). For clinicians who prescribed methadone, there was no difference in appointment access for pregnant vs nonpregnant callers (240 of 271 [88.6%] vs 237 of 265 [89.4%]; relative risk, 0.99; 95% CI, 0.93-1.05). Insurance was frequently not accepted, with 894 of 3420 buprenorphine-waivered prescribers (26.1%) and 174 of 536 opioid treatment programs (32.5%) granting appointments only when patients agreed to pay cash. Median wait times did not differ between pregnant and nonpregnant callers among buprenorphine prescribers (3 days [interquartile range, 1-7 days] vs 3 days [interquartile range, 1-7 days];P = .43) but did differ among methadone prescribers (1 day [interquartile range, 1-4 days] vs 2 days [interquartile range, 1-6 days];P = .049). For patients agreeing to pay cash, the median out-of-pocket costs for initial appointments were $250 (interquartile range, $155-$300) at buprenorphine prescribers and $34 (interquartile range, $15-$120) at methadone prescribers. Conclusions and Relevance In this cross-sectional study with random assignment of clinicians and simulated-patient callers, many women, especially pregnant women, faced barriers to accessing treatment. Given the high out-of-pocket costs and lack of acceptance of insurance among many clinicians, access to affordable opioid use disorder treatment is a significant concern.

The mechanisms through which tau and amyloid-beta (Aβ) accumulate in the brain of Alzheimer’s disease patients may differ but both are related to neuronal networks. We examined such mechanisms on neuroimaging in 58 participants with atypical Alzheimer’s disease (posterior cortical atrophy or logopenic progressive aphasia). Participants underwent Aβ-PET, longitudinal tau-PET, structural MRI and resting-state functional MRI, which was analyzed with graph theory. Regions with high levels of Aβ were more likely to be functional hubs, with a high number of functional connections important for resilience to cascading network failures. Regions with high levels of tau were more likely to have low clustering coefficients and degrees, suggesting a lack of trophic support or vulnerability to local network failures. Regions strongly functionally connected to the disease epicenters were more likely to have higher levels of tau and, less strongly, of Aβ. The regional rate of tau accumulation was associated with tau levels in functionally connected regions, in support of tau accumulation in a functional network. This study elucidates the relations of tau and Aβ to functional connectivity metrics in atypical Alzheimer’s disease, strengthening the hypothesis that the spread of the 2 proteins is driven by different biological mechanisms related to functional networks.

Background: Over 92 million prescriptions for benzodiazepines are dispensed in the United States annually, yet little is known about the experiences of those taking and discontinuing them. Objective: The aim of this study is to assess the experiences of those taking, tapering, or having discontinued benzodiazepines. Methods: An online survey ( n = 1207) elicited information about benzodiazepine use, including long-term use, tapering, discontinuation, and withdrawal symptoms. Results: Symptoms associated with benzodiazepine use, tapering, and discontinuation were numerous and ranged from symptoms such as anxiety, insomnia, and nervousness to digestive problems, irregular heart rhythms, uncontrollable anger, photosensitivity, balance problems, and others. When asked how benzodiazepine symptoms affected their lives, 82.9% reported work problems, 86.3% had problems with social interactions and friendships, and 88.8% had problems with fun, recreation, and hobbies. Suicidal thoughts or attempted suicide was reported by 54.4%, and 46.8% said benzodiazepines caused lost employment. Most of the respondents for whom benzodiazepines were prescribed (76.2%) stated they had not been informed that benzodiazepines were indicated for short-term use only and that discontinuation might be difficult. About a third (31.5%) reported food allergies and/or seasonal allergies that occurred only after benzodiazepine use. Conclusion: The trajectory of those who taper or discontinue benzodiazepines is unpredictable, and many patients experience a range of protracted and severe symptoms, even years after benzodiazepines were completely discontinued. Greater awareness is needed for both prescribers and patients about the potential for a difficult withdrawal from benzodiazepines.

BACKGROUND Overtreatment of prostate cancer (PCa) is a healthcare issue. Development of noninvasive imaging tools for improved characterization of prostate lesions might reduce overtreatment. PURPOSE To measure the distribution of tissue sodium concentration (TSC), proton T2 -weighted signal, and apparent diffusion coefficient (ADC) values in human PCa and to test the presence of a correlation between regional differences in imaging metrics and the Gleason grade of lesions determined from histopathology. STUDY TYPE Cross-sectional. SUBJECTS Ten men with biopsy-proven PCa. SEQUENCES/FIELD STRENGTH Sodium, proton T2 -weighted, and diffusion-weighted MRI data were acquired using Broad-Band 3D-Fast-Gradient-Recalled, 3D Cube (Isotropic 3D-Fast-Turbo-Spin-Echo acquisition) and 2D Spin-Echo sequences, respectively, with a 3.0T MR scanner. ASSESSMENT All imaging data were coregistered to Gleason-graded postprostatectomy histology, as the standard for prostate cancer lesion characterization. Regional TSC and T2 data were assessed using percent changes from healthy tissue of the same patient (denoted ΔTSC, ΔT2 ). STATISTICS Differences in ΔTSC, ADC, and ΔT2 as a function of Gleason score were analyzed for each imaging contrast using a one-way analysis of variance or a nonparametric t-test. Correlations between imaging data measures and Gleason score were assessed using a Spearman's ranked correlation. RESULTS Evaluation of the correlation of ΔTSC, ADC, and ΔT2 datasets with Gleason scoring revealed that only the correlation between ΔTSC and Gleason score was statistically significant (rs = 0.791, p

ObjectiveTo compare survival among patients with different combinations of apraxia of speech (AOS) and agrammatic aphasia, including those with isolated AOS (primary progressive AOS, PPAOS), both AOS and agrammatic aphasia (AOS + progressive agrammatic aphasia [PAA]), and isolated agrammatic aphasia (PAA).MethodsOne hundred nine patients were recruited who had any combination of AOS and agrammatic aphasia (42 PPAOS, 56 AOS + PAA, and 11 PAA) and were followed longitudinally, with 57 patients having since died. Cox proportional hazard models were used to quantify the relative risk of death across diagnoses. Adjusted survival curves are presented based on this model. We also assessed the influence of AOS and aphasia severity on survival.ResultsPPAOS had the longest survival (median survival of 5.97 years from the baseline visit), followed by PAA (5.26 years) and then AOS + PAA (4.33 years). AOS + PAA had a greater risk of death than PPAOS, with a hazard ratio of 3.01 (lower/upper confidence interval = 1.66/5.46, p < 0.001). Risk of death did not differ between PAA and the other groups. All results accounted for age and time from onset to baseline visit. AOS severity, independent of syndromic diagnosis, was associated with greater risk of death, with a hazard ratio of 1.35 for a 1-point increase in severity. Aphasia severity was not associated with risk of death.ConclusionsIndividuals with PPAOS have better survival and reduced risk of death compared with individuals with AOS + PAA. This finding will help improve prognostic estimates for these patients and supports the value of distinguishing PPAOS from AOS + PAA.

Background Despite common pathology, Alzheimer's disease (AD) can have multiple clinical presentations which pathological studies suggest result from differences in the regional distribution of tau pathology. Positron emission tomography (PET) ligands are now available that can detect tau proteins in vivo and hence can be used to investigate the biological mechanisms underlying atypical AD. Objective To assess regional patterns of tau uptake on PET imaging in two atypical AD variants, posterior cortical atrophy (PCA) and logopenic progressive aphasia (lvPPA). Methods Eighteen PCA and 19 lvPPA subjects that showed amyloid-β deposition on PET underwent tau-PET imaging with [18F]AV-1451. Group comparisons of tau uptake in PCA and lvPPA were performed using voxel-level and regional-level analyses. We also assessed the degree of lobar tau asymmetry and correlated regional tau uptake to age and performance on clinical evaluations. Results Both syndromes showed diffuse tau uptake throughout all cortical regions, although PCA showed greater uptake in occipital regions compared to lvPPA, and lvPPA showed greater uptake in left frontal and temporal regions compared to PCA. While lvPPA showed predominant left-asymmetric tau deposition, PCA was more bilateral. Younger subjects showed greater tau uptake bilaterally in frontal and parietal lobes than older subjects, and sentence repetition, Boston naming test, simultanagnosia, and visuoperceptual function showed specific regional tau correlates. Conclusion Tau deposition is closely related to clinical presentation in atypical AD with age playing a role in determining the degree of cortical tau deposition.

Objectives To assess [18 F]AV-1451 tau-PET (positron emission tomography) uptake patterns across the primary progressive aphasia (PPA) variants (logopenic, semantic, and agrammatic), examine regional uptake patterns of [18 F]AV-1451 independent of clinical diagnosis, and compare the diagnostic utility of [18 F]AV-1451, [18 F]-fluorodeoxygluclose (FDG)-PET and MRI (magnetic resonance imaging) to differentiate the PPA variants. Methods We performed statistical parametric mapping of [18 F]AV-1451 across 40 PPA patients (logopenic-PPA = 14, semantic-PPA = 13, and agrammatic-PPA = 13) compared to 80 cognitively normal, Pittsburgh compound B-negative controls, age and gender matched 2:1. Principal component analysis of regional [18 F]AV-1451 tau-PET standard uptake value ratio was performed to understand underlying patterns of [18 F]AV-1451 uptake independent of clinical diagnosis. Penalized multinomial regression analyses were utilized to assess diagnostic utility. Results Logopenic-PPA showed striking uptake throughout neocortex, particularly temporoparietal, compared to controls, semantic-PPA, and agrammatic-PPA. Semantic-PPA and agrammatic-PPA showed milder patterns of focal [18 F]AV-1451 uptake. Semantic-PPA showed elevated uptake (left>right) in anteromedial temporal lobes, compared to controls and agrammatic-PPA. Agrammatic-PPA showed elevated uptake (left>right) throughout prefrontal white matter and in subcortical gray matter structures, compared to controls and semantic-PPA. The principal component analysis of regional [18 F]AV-1451 indicated two primary dimensions, a severity dimension that distinguished logopenic-PPA from agrammatic-PPA and semantic-PPA, and a frontal versus temporal contrast that distinguishes agrammatic-PPA and semantic-PPA cases. Diagnostic utility of [18 F]AV-1451was superior to MRI and at least equal to FDG-PET. Interpretation [18 F]AV-1451binding characteristics differ across the PPA variants and were excellent at distinguishing between the variants. [18 F]AV-1451binding characteristics were as good or better than other brain imaging modalities utilized in clinical practice, suggesting that [18 F]AV-1451 may have clinical diagnostic utility in PPA. Ann Neurol 2018 Ann Neurol 2018;83:599-611.

Background Lofexidine is an alpha-2-adrenergic receptor agonist approved in the United Kingdom (UK) for the treatment of opioid withdrawal symptoms. Lofexidine has demonstrated better efficacy than placebo for reducing opioid withdrawal symptoms in patients undergoing opioid withdrawal with less reported hypotension than clonidine. Methods Designed as an FDA registration trial, this 8-day, randomized, double-blind, placebo-controlled, parallel-group study in 264 patients dependent on short-acting opioids evaluated the efficacy of lofexidine hydrochloride in reducing withdrawal symptoms in patients undergoing opioid withdrawal. The primary efficacy measures were SOWS-Gossop on Day 3 and time-to-dropout. Secondary endpoints included the proportion of participants who were completers; area under the 5-day SOWS-Gossop – time curve (i.e., AUC 1–5 ), and daily mean SOWS-Gossop, OOWS‐Handelsman, MCGI (subject and rater), and VAS-E scores. Participants received lofexidine HCl 3.2 mg daily in four divided doses or matching placebo on Days 1–5, followed by 2 days of placebo. Results Lofexidine significantly decreased mean Day 3 SOWS scores compared to placebo, 6.32 versus 8.67, respectively, p = 0.0212. Fewer lofexidine patients were early terminators compared to placebo (59 versus 80, respectively); and non-completers in the lofexidine group remained in the study longer than those assigned to placebo (p = 0.0034). Secondary endpoints consistently favored lofexidine. Lofexidine was well tolerated in this trial. Conclusion Lofexidine significantly decreased SOWS scores compared to placebo and demonstrated better retention rates in participants undergoing opioid withdrawal. Lofexidine potentially offers a useful non-opioid alternative to treat opioid withdrawal symptoms.

Since the 1980s, studying histories of exploration has become an increasingly prominent area of scholarship and has attracted critical attention from a range of different academic perspectives. Whether framed as a process of imperial expansion, as a quest for the production of new knowledge, or as a means for certain individuals to establish or advance their reputations, the complex motivations that lay behind European travellers' desire to venture overseas has been examined and critiqued by scholars situated in a number of different disciplines. Growing attention has been paid to those groups or individuals who have historically been written out of traditional, hagiographic exploration accounts, and we have seen the key roles played by women explorers, “indigenous intermediaries,” and various others exposed and investigated more thoroughly. The purpose of this paper is to review these diverse scholarly literatures, with a particular focus on those which centre their analysis on the long nineteenth century. In doing so, we demonstrate that the study of exploration is not just of narrow historical interest, but rather offers a means in which to shed new light on many wider social, political, and cultural processes that were taking place during this period.

To assess volume loss and flortaucipir uptake in patients with semantic dementia (SD) over time. Eight SD patients (3 female) underwent clinical evaluations, flortaucipir positron emission tomography, and brain magnetic resonance imaging at 2 visits. Voxel-level comparisons of magnetic resonance imaging gray and white matter volume loss and flortaucipir positron emission tomography uptake were performed in SPM12, comparing SD patients to controls at each visit. T-tests on difference images and paired t-tests of flortaucipir uptake were also performed. At the voxel level, SD patients showed asymmetric, bilateral gray volume loss in the temporal lobes, which, via visual inspection, extended posteriorly at follow-up. White matter loss and flortaucipir uptake were noted in SD patients in the left temporal lobe only, which appeared to extend posteriorly, without involvement of the right hemisphere at follow-up. Longitudinal analyses did not support significant changes in flortaucipir uptake between visits. The biological mechanisms of flortaucipir signal in suspected underlying TAR-DNA binding protein 43 pathology are unknown. A 1-year interval is not sufficient time to demonstrate significant longitudinal flortaucipir uptake changes in SD.

Scientific understandings of how coffee affects health have been closely linked to the moral and political discourses of the changing times. Inquiries into coffee began in the 16th century, as Europeans wrestled with understanding the effects of this newly introduced beverage. These early studies built on the nascent fields of chemistry and physiology to examine how coffee stimulated the body. Coffee invoked strong scientific and moral opinions about its effects, and its portrayal in the literature has swung from seeing it as the cause of a variety of conditions to seeing it as a potential cure for an equally impressive range of ailments. Most recent studies on the bioactivity of coffee emphasize its salubrious potential, and popular opinion and health promotion policies are changing their recommendations accordingly.

Objectives To develop and validate clinical risk prediction tools for neonatal abstinence syndrome (NAS). Study design We developed prediction models for NAS based on a set of 30 demographic and antenatal exposure covariates collected during pregnancy. Data (outpatient prescription, vital, and administrative records), were obtained from enrollees in the Tennessee Medicaid Program from 2009 to 2014. Models were created using logistic regression and backward selection based on improvement in the Akaike information criterion, and internally validated using bootstrap cross-validation. Results A total of 218 020 maternal and infant dyads met inclusion criteria, of whom 3208 infants were diagnosed with NAS. The general population model included age, hepatitis C virus infection, days of opioid used by type, number of cigarettes used daily, and the following medications used in the last 30 day of pregnancy: bupropion, antinausea medicines, benzodiazepines, antipsychotics, and gabapentin. Infant characteristics included birthweight, small for gestational age, and infant sex. A high-risk model used a smaller number of predictive variables. Both models discriminated well with an area under the curve of 0.89 and were well-calibrated for low-risk infants. Conclusions We developed 2 predictive models for NAS based on demographics and antenatal exposure during the last 30 days of pregnancy that were able to risk stratify infants at risk of developing the syndrome.