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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.

Progressive apraxia of speech is a neurodegenerative syndrome affecting spoken communication. Molecular pathology, biochemistry, genetics, and longitudinal imaging were investigated in 32 autopsy-confirmed patients with progressive apraxia of speech who were followed over 10 years. Corticobasal degeneration and progressive supranuclear palsy (4R-tauopathies) were the most common underlying pathologies. Perceptually distinct speech characteristics, combined with age-at-onset, predicted specific 4R-tauopathy; phonetic subtype and younger age predicted corticobasal degeneration, and prosodic subtype and older age predicted progressive supranuclear palsy. Phonetic and prosodic subtypes showed differing relationships within the cortico-striato-pallido-nigro-luysial network. Biochemical analysis revealed no distinct differences in aggregated 4R-tau while tau H1 haplotype frequency (69%) was lower compared to 1000+ autopsy-confirmed 4R-tauopathies. Corticobasal degeneration patients had faster rates of decline, greater cortical degeneration, and shorter illness duration than progressive supranuclear palsy. These findings help define the pathobiology of progressive apraxia of speech and may have consequences for development of 4R-tau targeting treatment., Progressive apraxia of speech (PAOS) is a neurodegenerative syndrome of multiple etiologies which affects spoken communication. Here, the authors characterized the molecular pathology, biochemistry, genetics and longitudinal neuroimaging of 32 autopsy-confirmed patients with PAOS who were followed over 10 years.

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

Highlights • Gait and balance impairments correlated to various imaging abnormalities. • Stride length, cadence and balance varied independently in PSP. • PSP phenotype affects the associations between gait and imaging., Progressive supranuclear palsy is a neurodegenerative disorder characterized primarily by tau inclusions and neurodegeneration in the midbrain, basal ganglia, thalamus, premotor and frontal cortex. Neurodegenerative change in progressive supranuclear palsy has been assessed using MRI. Degeneration of white matter tracts is evident with diffusion tensor imaging and PET methods have been used to assess brain metabolism or presence of tau protein deposits. Patients with progressive supranuclear palsy present with a variety of clinical syndromes; however early onset of gait impairments and postural instability are common features. In this study we assessed the relationship between multimodal imaging biomarkers (i.e., MRI atrophy, white matter tracts degeneration, flortaucipir-PET uptake) and laboratory-based measures of gait and balance abnormalities in a cohort of nineteen patients with progressive supranuclear palsy, using univariate and multivariate statistical analyses. The PSP rating scale and its gait midline sub-score were strongly correlated to gait abnormalities but not to postural imbalance. Principal component analysis on gait variables identified velocity, stride length, gait stability ratio, length of gait phases and dynamic stability as the main contributors to the first component, which was associated with diffusion tensor imaging measures in the posterior thalamic radiation, external capsule, superior cerebellar peduncle, superior fronto-occipital fasciculus, body and splenium of the corpus callosum and sagittal stratum, with MRI volumes in frontal and precentral regions and with flortaucipir-PET uptake in the precentral gyrus. The main contributor to the second principal component was cadence, which was higher in patients presenting more abnormalities on mean diffusivity: this unexpected finding might be related to compensatory gait strategies adopted in progressive supranuclear palsy. Postural imbalance was the main contributor to the third principal component, which was related to flortaucipir-PET uptake in the left paracentral lobule and supplementary motor area and white matter disruption in the superior cerebellar peduncle, putamen, pontine crossing tract and corticospinal tract. A partial least square model identified flortaucipir-PET uptake in midbrain, basal ganglia and thalamus as the main correlate of speed and dynamic component of gait in progressive supranuclear palsy. Although causality cannot be established in this analysis, our study sheds light on neurodegeneration of brain regions and white matter tracts that underlies gait and balance impairment in progressive supranuclear palsy.

Purpose Individuals with primary progressive apraxia of speech have apraxia of speech (AOS) as the initial and predominant symptom. Many develop aphasia and/or dysarthria later in the disease course. It was previously demonstrated that patients with neurodegenerative AOS experience reduced participation in communication that is further exacerbated by co-occurring language deficits ( Utianski et al., 2020 ). Measures of disease severity did not necessarily correlate with measures of participation restrictions. The aim of this follow-up study was to describe changes in communication limitations in these patients, again measured by (a) the patient via the Communicative Participation Item Bank (CPIB) and (b) the speech-language pathologist via the American Speech-Language-Hearing Association's (ASHA's) Functional Communication Measures (FCMs) and an adapted motor speech disorder (MSD) severity rating to determine if there are significant changes in these and other objective speech and language measures at follow-up after 1 year. Method Of the 24 patients reported in the study of Utianski et al. (2020) , 17 (10 men, seven women) returned for a second visit approximately 1 year following the first visit. Identical procedures were utilized; the communication measures collected at each visit were statistically compared. Correlations were calculated between the participation ratings and other clinical assessment measures at the second visit and for the change in scores on those measures between the first and second visits. Results There were statistically significant differences in AOS and aphasia severity between visits. There were significant changes in clinical assessments, MSD severity rating, and all ASHA FCMs between visits, but not the CPIB. Correlation analyses suggest the relationships among clinical and participation measures are complex; overall, patients with more severe changes in AOS experienced greater changes in participation restrictions. Conclusions The findings of this study support the use of patient-reported outcome measures as they may better reflect the patient experience, including the influence of factors such as ongoing speech therapy and the emergence of neuropsychiatric features, and associated changes in day-to-day functioning, when other measures may simply index the progression of the disease. Supplemental Material https://doi.org/10.23641/asha.16528512

ObjectiveTo assess and compare demographic, clinical, neuroimaging, and pathologic characteristics of a cohort of patients with right hemisphere–predominant vs left hemisphere–predominant logopenic progressive aphasia (LPA).MethodsThis is a case-control study of patients with LPA who were prospectively followed at Mayo Clinic and underwent [18F]-fluorodeoxyglucose (FDG) PET scan. Patients were classified as rLPA if right temporal lobe metabolism was ≥1 SD lower than left temporal lobe metabolism. Patients with rLPA were frequency-matched 3:1 to typical left-predominant LPA based on degree of asymmetry and severity of temporal lobe metabolism. Patients were compared on clinical, imaging (MRI, FDG-PET, β-amyloid, and tau-PET), and pathologic characteristics.ResultsOf 103 prospectively recruited patients with LPA, 8 (4 female) were classified as rLPA (7.8%); all patients with rLPA were right-handed. Patients with rLPA had milder aphasia based on the Western Aphasia Battery–Aphasia Quotient (p = 0.04) and less frequent phonologic errors (p = 0.015). Patients with rLPA had shorter survival compared to typical LPA: hazard ratio 4.0 (1.2–12.9), p = 0.02. There were no other differences in demographics, handedness, genetics, or neurologic or neuropsychological tests. Compared to the 24 frequency-matched patients with typical LPA, patients with rLPA showed greater frontotemporal hypometabolism of the nondominant hemisphere on FDG-PET and less atrophy in amygdala and hippocampus of the dominant hemisphere. Autopsy evaluation revealed a similar distribution of pathologic findings in both groups, with Alzheimer disease pathologic changes being the most frequent pathology.ConclusionsrLPA is associated with less severe aphasia but has shorter survival from reported symptom onset than typical LPA, possibly related to greater involvement of the nondominant hemisphere.

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 For reproductive-age women, medications for opioid use disorder (OUD) decrease risk of overdose death and improve outcomes but are underutilized. Our objective was to provide a qualitative description of reproductive-age women's experiences of seeking an appointment for medications for OUD. Methods Trained female callers placed telephone calls to a representative sample of publicly listed opioid treatment clinics and buprenorphine providers in Florida, Kentucky, Massachusetts, Michigan, Missouri, North Carolina, Tennessee, Virginia, Washington, and West Virginia to obtain appointments to receive medication for OUD. Callers were randomly assigned to be pregnant or non-pregnant and have private or Medicaid-based insurance to assess differences in the experiences of access by these characteristics. The callers placed 28,651 uniquely randomized calls, 10,117 to buprenorphine-waivered prescribers and 754 to opioid treatment programs. Open-ended, qualitative data were obtained from the callers about the access experiences and were analyzed using a qualitative, iterative inductive-deductive approach. From all 28,651 total calls, there were 17,970 unique free-text comments to the question “Please give an objective play-by-play of the description of what happened in this conversation.” Findings Analysis demonstrated a common path to obtaining an appointment. Callers frequently experienced long hold times, multiple transfers, and difficult interactions. Clinic receptionists were often mentioned as facilitating or obstructing access. Pregnant callers and those with Medicaid noted more barriers. Obtaining an appointment was commonly difficult even for these persistent, trained callers. Conclusions Interventions are needed to improve the experiences of reproductive-age women as they enter care for OUD, especially for pregnant women and those with Medicaid coverage.

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.

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.

Over the past decade, the transactive response DNA-binding protein of 43 kDa (TDP-43) has been recognized as a major protein in normal and pathological ageing, increasing the risk of cognitive impairment and dementia. In conditions distinct from the frontotemporal lobar degenerations, TDP-43 appears to progress in a stereotypical pattern. In the present study, we aimed at providing a better understanding of the effects of TDP-43 and other age-related neuropathologies on cross-sectional grey matter volume in a cohort of non-FTLD subjects. We included 407 individuals with an antemortem MRI and post-mortem brain tissue from the Mayo Clinic Alzheimer's Disease Research Center, Mayo Clinic Alzheimer's Disease Patient Registry, or the Mayo Clinic Study of Aging. All individuals were assigned pathological stages for TDP-43, tau, amyloid-β, Lewy bodies, argyrophilic grain disease and vascular pathologies. Robust regressions were performed in regions of interest and voxel-wise to explore the relationships between TDP-43 stages and grey matter volume while controlling for other pathologies. Grey matter volumes adjusted for pathological and demographic variables were also computed for each TDP-43-positive case to further characterize the sequential involvement of brain structures associated with TDP-43, irrespective of the TDP-43 staging scheme. Robust regressions showed that the extent of TDP-43 pathology was associated with the extent of grey matter atrophy. Specifically, we found that the volume in medial temporal regions (i.e. amygdala, entorhinal cortex, hippocampus) decreased progressively with advancing TDP-43 stages. Importantly, these effects were of similar magnitude to those related to tau stages. Additional analyses using adjusted grey matter volume demonstrated a sequential pattern of volume loss associated with TDP-43, starting within the medial temporal lobe, followed by early involvement of the temporal pole, and eventually encompassing additional temporal and frontal regions. Altogether, this study demonstrates the major and independent contribution of TDP-43 pathology on neurodegeneration and provides further insight into the regional distribution of TDP-43 in non-FTLD subjects. Along with previous studies, these findings emphasized the importance of targeting TDP-43 in future clinical trials to prevent its detrimental effect on grey matter volume and, eventually, cognition.

The aims of this study were: to examine regional rates of change in tau-PET uptake and grey matter volume in atypical Alzheimer's disease (AD); to investigate the role of age in such changes; to describe multimodal regional relationships between tau accumulation and atrophy. Thirty atypical AD patients underwent baseline and one-year follow-up MRI, [18F]AV-1451 PET and PiB PET. Region- and voxel-level rates of tau accumulation and grey matter atrophy relative to cognitively unimpaired individuals, and the influence of age on such rates, were assessed. Univariate and multivariate analyses were performed between baseline measurements and rates of change, between baseline tau and atrophy, and between the two rates of change. Regional patterns of change in tau and volume differed, with highest rates of tau accumulation in frontal lobe and highest rates of atrophy in temporoparietal regions. Age had a negative effect on disease progression, predominantly on tau, with younger patients having a more rapid accumulation. Baseline tau uptake and regions of tau accumulation were disconnected, with high baseline tau uptake across the cortex correlated with high rates of tau accumulation in frontal and sensorimotor regions. In contrast, baseline volume and atrophy were locally related in the occipitoparietal regions. Higher tau uptake at baseline was locally related to higher rates of atrophy in frontal and occipital lobes. Tau accumulation rates positively correlated with rates of atrophy. In summary, our study showed that tau accumulation and atrophy presented different regional patterns in atypical AD, with tau spreading into the frontal lobes while atrophy remains in temporoparietal and occipital cortex, suggesting a temporal disconnect between protein deposition and neurodegeneration. Keywords: Longitudinal tau-PET, Atrophy, Atypical AD, Multimodal imaging

Introduction Little is known about the role of age on neurodegeneration and protein deposition in atypical variants of Alzheimer's disease (AD). Methods Regional tau and β-amyloid positron emission tomography standard uptake value ratios and gray matter volumes were calculated in a cohort of 42 participants with atypical AD. The relationship between regional metrics and age was modeled using a Bayesian hierarchical linear model. Results Age was strongly associated with tau uptake across all cortical regions, particularly parietal, with greater uptake in younger participants. Younger age was associated with smaller parietal and lateral temporal volumes. Regional β-amyloid differed little by age. Age showed a stronger association with tau than volume and β-amyloid in all cortical regions. Age was not associated with cognitive performance. Discussion Age is an important determinant of severity of cortical tau uptake in atypical AD, with young participants more likely to show widespread and severe cortical tau uptake.

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.

Agrammatic aphasia affects grammatical language production and can result from a neurodegenerative disease. Although it typically presents with concomitant apraxia of speech, this is not always the case. Little is known about the clinical course and imaging features of patients that present with agrammatism in the absence of apraxia of speech, which we will refer to as progressive agrammatic aphasia. We aimed to make a detailed description of the longitudinal clinical, linguistic, and neuroimaging features of a cohort of 11 patients with progressive agrammatic aphasia to provide a complete picture of this syndrome. All patients underwent detailed speech and language, neurological and neuropsychological assessments, 3 T structural and diffusion tensor imaging MRI, 18F-fluorodeoxyglucose and Pittsburgh compound B PET. The 11 patients were matched by age and gender to 22 patients who had mixed apraxia of speech and agrammatism. The progressive agrammatic aphasia patients performed abnormally on tests of language, general cognition, executive function, and functional ability at baseline and declined in these measures over time. Only two patients eventually developed apraxia of speech, while parkinsonism was absent-to-mild throughout all visits for all patients. When compared to the patients with mixed apraxia of speech and agrammatism, the patients with progressive agrammatic aphasia performed better on tests of motor speech and parkinsonism but more poorly, and declined faster over time, on tests of general aphasia severity, agrammatism, and naming. The patients with progressive agrammatic aphasia also showed different neuroimaging abnormalities, with greater atrophy, hypometabolism and white matter tract degeneration in the prefrontal and anterior temporal lobes compared to patients with mixed apraxia of speech and agrammatism. These differences were more pronounced as the disease progressed. These results demonstrate that progressive agrammatic aphasia has a different clinical disease course and different underlying neuroanatomical abnormalities than patients with the more common syndrome of mixed agrammatism and apraxia of speech. This supports the distinction of progressive agrammatic aphasia and has implications for the classification of patients with agrammatic aphasia.

Background In 2017, the International Parkinson and Movement Disorder Society put forward new clinical criteria for the diagnosis of PSP, recognizing diverse PSP phenotypes. In this study, we compared the sensitivity and specificity of the new criteria with the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy criteria at different times. Methods Patients with clinical parkinsonism, clinical and/or neuropathological diagnosis of PSP, were identified from the Society for Progressive Supranuclear Palsy brain bank. All patients had neuropathologic diagnoses and detailed clinical examination performed by a neurologist at 1 of the 3 Mayo Clinic sites, in Florida, Arizona, and Minnesota. Clinical symptoms and signs were abstracted retrospectively in a blinded fashion and used to determine whether patients met either diagnostic criterion. Patients were divided into early and late disease stage groups using a 3-year cutoff. Results A total of 129 patients were included, of whom 66 had PSP pathology (51%). The remainder had other neurodegenerative diseases. The overall sensitivity of the International Parkinson and Movement Disorder Society criteria was 87.9%, compared with 45.5% for the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy criteria, whereas the specificity of the International Parkinson and Movement Disorder Society probable PSP criteria was 85.7%, compared with 90.5% for the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy. Individual patients were noted to have features of multiple PSP phenotypes. Conclusion The International Parkinson and Movement Disorder Society criteria recognize several phenotypes of progressive supranuclear palsy and hence have higher sensitivity than the previous criteria. © 2019 International Parkinson and Movement Disorder Society.

Alzheimer's disease (AD) can present with atypical clinical forms where the prominent domain of deficit is not memory, that is, atypical AD. Atypical AD patients show cortical atrophy on MRI, hypometabolism on [18 F]fluorodeoxyglucose (FDG) PET, tau uptake on [18 F]AV-1451 PET, and white matter tract degeneration on diffusion tensor imaging (DTI). How these disease processes relate to each other locally and distantly remains unclear. We aimed to examine multimodal neuroimaging relationships in individuals with atypical AD, using univariate and multivariate techniques at region- and voxel-level. Forty atypical AD patients underwent MRI, FDG-PET, tau-PET, beta-amyloid PET, and DTI. Patients were all beta-amyloid positive. Partial Pearson's correlations were performed between tau and FDG standardized uptake value ratios, gray matter MRI-volumes and white matter tract fractional anisotropy. Sparse canonical correlation analysis was applied to identify multivariate relationships between the same quantities. Voxel-level associations across modalities were also assessed. Tau showed strong local negative correlations with FDG metabolism in the occipital and frontal lobes. Tau in frontal and parietal regions was negatively associated with temporoparietal gray matter MRI-volume. Fractional anisotropy in a set of posterior white matter tracts, including the splenium of the corpus callosum, cingulum, and posterior thalamic radiation, was negatively correlated with parietal and occipital tau, atrophy and, predominantly, with hypometabolism. These results support the view that tau is the driving force behind neurodegeneration in atypical AD, and that a breakdown in structural connectivity is related to cortical neurodegeneration, particularly hypometabolism.

Corticobasal syndrome (CBS) is a phenotypic manifestation of diverse pathologies, including Alzheimer’s disease and 4-repeat tauopathies. Predicting pathology in CBS is unreliable and, hence, molecular neuroimaging may prove to be useful. The aim of this study was to assess regional patterns of uptake on [18F] AV-1451 PET in CBS and determine whether patterns of uptake differ according to beta-amyloid deposition or differing clinical presentations. Fourteen patients meeting criteria for CBS underwent Pittsburgh Compound B (PiB) and [18F] AV-1451 PET. Seven patients presented as CBS and seven presented with apraxia of speech (AOS) and later evolved into CBS. A global PiB summary was calculated and used to classify patients as PiB (−) or PiB (+). AV-1451 uptake was calculated in fourteen regions-of-interest, with values divided by uptake in cerebellar crus grey matter to generate standard uptake value ratios. AV-1451 uptake was considered elevated if it fell above the 95th percentile from a group of 476 cognitively unimpaired normal controls. Six of the 14 CBS patients (43%) were PiB (+), with three of these patients showing strikingly elevated AV-1451 uptake across many cortical regions. Of the eight PiB (−) patients, only those with AOS showed elevated AV-1451 uptake in supplementary motor area and precentral cortex compared to controls. No region of elevated AV-1451 uptake were observed in PiB (−) typical CBS patients without AOS. These results suggest that regional [18F] AV-1451 is variable in CBS and depends on the presence of beta-amyloid as well as clinical presentation such as AOS. PiB (+) CBS does not necessarily reflect underlying Alzheimer’s disease; however, the possibility some of these patients will evolve into Alzheimer’s disease over time cannot be excluded.

Background Neuropsychological assessment can add essential information to the characterization of individuals presenting with the logopenic variant of primary progressive aphasia (lvPPA). Objective This study examined the neuropsychological characteristics of lvPPA patients. We also examined differences in regional and whole brain atrophy based on neuropsychological profiles. Methods We conducted a hierarchical cluster analysis on memory, executive functioning, and visuospatial neuropsychological test data for 56 individuals with lvPPA. We then compared resultant clusters to left middle temporal, inferior parietal, and superior parietal regions-of-interest using multivariate analysis of covariance. We also performed voxel-level analyses. Results We identified three clusters characterized as lvPPA with no neurocognitive impairment (n = 5), lvPPA with mild neurocognitive deficits (n = 23), and lvPPA with marked cognitive deficits (n = 28). WAB-AQ was associated with left middle temporal volume. Superior parietal volumes were smaller for the lvPPA group with marked cognitive symptoms compared to the less severe groups. Voxel-level analyses showed greater atrophy in temporal, parietal, lateral occipital, and frontal regions, left worse than right. Age, disease duration, gender, WAB-AQ, and PiB-PET did not account for differences between groups. Conclusions LvPPA patients without cognitive deficits in other domains were relatively uncommon while 50% of our sample exhibited pronounced neurocognitive deficits outside the language domain. Pronounced cognitive deficits in lvPPA are associated with widespread atrophy, left worse than right. Our study underscores the importance of examining neuropsychological function in addition to language in patients with lvPPA.

Methadone and buprenorphine are highly effective and commonly prescribed for the treatment of opioid use disorder. Both medications are also efficacious for the treatment of pregnant women with this disorder. In one third of states, however, Medicaid reimbursement will cover the cost of buprenorphine, but not methadone, to treat opioid use disorder in pregnant women. This commentary will explore the clinical and policy rational and consequences of this policy, with the opinion that this approach is guided by political expediency rather than sound clinical research. The commentary will focus on the pharmacological management of prescription opioid dependence during pregnancy in Tennessee, one of the states that restrict Medicaid coverage of pregnant women to buprenorphine. Tennessee is also relevant in that this state ranks second nationally in the rate of prescriptions written for opioid pain relievers; in contrast to injection opioid use in urban populations, opioid addiction in rural and southeastern regions of the US is characterized by use of non-injection prescription opioids. Until recently, most research-based recommendations for the management of opioid use disorder during pregnancy have derived from studies of women using opioids intravenously. The lack of research in non-injection opioid-using pregnant women may partially explain why policy rather than scientific evidence guides Medicaid reimbursement. It is hoped that future research in pregnant women addicted to prescription opioids will clarify which opioid addicted pregnant women have better outcomes with buprenorphine or methadone treatment and these findings, in turn, will inform Medicaid reimbursement.

BACKGROUND AND OBJECTIVES: Although opioid pain relievers are commonly prescribed in pregnancy, their association with neonatal outcomes is poorly described. Our objectives were to identify neonatal complications associated with antenatal opioid pain reliever exposure and to establish predictors of neonatal abstinence syndrome (NAS). METHODS: We used prescription and administrative data linked to vital statistics for mothers and infants enrolled in the Tennessee Medicaid program between 2009 and 2011. A random sample of NAS cases was validated by medical record review. The association of antenatal exposures with NAS was evaluated by using multivariable logistic regression, controlling for maternal and infant characteristics. RESULTS: Of 112 029 pregnant women, 31 354 (28%) filled ≥1 opioid prescription. Women prescribed opioid pain relievers were more likely than those not prescribed opioids (P < .001) to have depression (5.3% vs 2.7%), anxiety disorder (4.3% vs 1.6%) and to smoke tobacco (41.8% vs 25.8%). Infants with NAS and opioid-exposed infants were more likely than unexposed infants to be born at a low birth weight (21.2% vs 11.8% vs 9.9%; P < .001). In a multivariable model, higher cumulative opioid exposure for short-acting preparations (P < .001), opioid type (P < .001), number of daily cigarettes smoked (P < .001), and selective serotonin reuptake inhibitor use (odds ratio: 2.08 [95% confidence interval: 1.67–2.60]) were associated with greater risk of developing NAS. CONCLUSIONS: Prescription opioid use in pregnancy is common and strongly associated with neonatal complications. Antenatal cumulative prescription opioid exposure, opioid type, tobacco use, and selective serotonin reuptake inhibitor use increase the risk of NAS.

Purpose Magnetic resonance imaging (MRI)-targeted, three-dimensional (3D) transrectal ultrasound (TRUS)-guided prostate biopsy aims to reduce the 21-47% false-negative rate of clinical two-dimensional (2D) TRUS-guided systematic biopsy, but continues to yield false-negative results. This may be improved via needle target optimization, accounting for guidance system errors and image registration errors. As an initial step toward the goal of optimized prostate biopsy targeting, we investigated how needle delivery error impacts tumor sampling probability for two targeting strategies. Methods We obtained MRI and 3D TRUS images from 49 patients. A radiologist and radiology resident assessed these MR images and contoured 81 suspicious regions, yielding tumor surfaces that were registered to 3D TRUS. The biopsy system's root-mean-squared needle delivery error (RMSE) and systematic error were modeled using an isotropic 3D Gaussian distribution. We investigated two different prostate tumor-targeting strategies using (a) the tumor's centroid and (b) a ring in the lateral-elevational plane. For each simulation, targets were spaced at equal arc lengths on a ring with radius equal to the systematic error magnitude. A total of 1000 biopsy simulations were conducted for each tumor, with RMSE and systematic error magnitudes ranging from 1 to 6 mm. The difference in median tumor sampling probability and probability of obtaining a 50% core involvement was determined for ring vs centroid targeting. Results Our simulation results indicate that ring targeting outperformed centroid targeting in situations where systematic error exceeds RMSE. In these instances, we observed statistically significant differences showing 1-32% improvement in sampling probability due to ring targeting. Likewise, we observed statistically significant differences showing 1-39% improvement in 50% core involvement probability due to ring targeting. Conclusions Our results suggest that the optimal targeting scheme for prostate biopsy depends on the relative levels of systematic and random errors in the system. Where systematic error dominates, a ring-targeting scheme may yield improved probability of tumor sampling. The findings presented in this paper may be used to aid in target selection strategies for clinicians performing targeted prostate biopsies on any MRI targeted, 3D TRUS-guided biopsy system and could support earlier diagnosis of prostate cancer while it remains localized to the gland and curable.

Background Methadone and buprenorphine are recommended to treat opioid use disorders during pregnancy. However, the literature on the relationship between longer-term effects of prenatal exposure to these medications and childhood development is both spare and inconsistent. Methods Participants were 96 children and their mothers who participated in MOTHER, a randomized controlled trial of opioid-agonist pharmacotherapy during pregnancy. The present study examined child growth parameters, cognition, language abilities, sensory processing, and temperament from 0 to 36 months of the child’s life. Maternal perceptions of parenting stress, home environment, and addiction severity were also examined. Results Tests of mean differences between children prenatally exposed to methadone vs. buprenorphine over the three-year period yielded 2/37 significant findings for children. Similarly, tests of mean differences between children treated for NAS relative to those not treated for NAS yielded 1/37 significant finding. Changes over time occurred for 27/37 child outcomes including expected child increases in weight, head and height, and overall gains in cognitive development, language abilities, sensory processing, and temperament. For mothers, significant changes over time in parenting stress (9/17 scales) suggested increasing difficulties with their children, notably seen in increasing parenting stress, but also an increasingly enriched home environment (4/7 scales) Conclusions Findings strongly suggest no deleterious effects of buprenorphine relative to methadone or of treatment for NAS severity relative to not-treated for NAS on growth, cognitive development, language abilities, sensory processing, and temperament. Moreover, findings suggest that prenatal opioid agonist exposure is not deleterious to normal physical and mental development.

We compared fitness-for-duty assessment findings of physicians who subsequently engaged in suicidal behavior and those who did not.Assessments of 141 physicians evaluated at the Vanderbilt Comprehensive Assessment Program were retrospectively compared between those who later either attempted (n = 2) or completed (n = 5) suicide versus the remainder of the sample.Subsequent suicidal behaviors were associated with being found unfit to practice (86% vs. 31%, P.05), being in solo practice (71% vs. 33%) and chronically using benzodiazepines (57% vs. 11%, Fisher's Exact Test, P.05).Being found unfit for practice may trigger a cascade of adverse social and financial consequences. Those engaged in solo practice may be particularly vulnerable due to isolation and lack of oversight by supportive colleagues. Finally, chronic benzodiazepine use may impair resilience due to associated brain dysfunction. Although these characteristics must be investigated prospectively, our observations suggest that they may be important signals of increased risk for suicidal behavior in physicians. The intense stress associated with medical practice and the relatively high rates of suicidal behavior among physicians make it important to be able to identify physicians who are at risk, so that appropriate preventive actions can be taken.

Background and Objectives Despite the dramatic increase in the use of buprenorphine for the treatment of opioid dependence, clinical outcomes of this treatment approach continue to need evaluation. This study examines factors associated with relapse and retention during buprenorphine treatment in a sample of opioid dependent outpatients. Methods In a retrospective chart review of 62 patients with opioid dependence, relapse was determined by self-report, urine toxicology screens, and by checking the state controlled substance monitoring database. Data was analyzed using two-way tests of association and logistic regression. Results Patients with comorbid anxiety disorders, active benzodiazepine use (contrary to clinic policy), or active alcohol abuse, were significantly more likely to relapse. Patients who relapsed were also more likely to be on a higher buprenorphine maintenance dose. Conclusion This study identifies relapse risk factors during buprenorphine treatment for opioid dependence. Future research is needed to determine whether modifying these factors may lead to improved treatment outcomes. (Am J Addict 2014;23:62–67)

Introduction Little is known about the relationship between cigarette smoking and agonist treatment in opioid-dependent pregnant patients. The objective of this study is to examine the extent to which cigarette smoking profiles differentially changed during the course of pregnancy in opioid-dependent patients receiving either double-blind methadone or buprenorphine. Patients were participants in the international, randomized controlled Maternal Opioid Treatment: Human Experimental Research (MOTHER) study. Methods A sample of opioid-maintained pregnant patients (18-41 years old) with available smoking data who completed a multisite, double-blind, double-dummy, randomized controlled trial of methadone (n = 67) and buprenorphine (n = 57) between 2005 and 2008. Participants were compared on smoking variables based on opioid agonist treatment condition. Results Overall, 95% of the sample reported cigarette smoking at treatment entry. Participants in the two medication conditions were similar on pretreatment characteristics including smoking rates and daily cigarette amounts. Over the course of the pregnancy, no meaningful changes in cigarette smoking were observed for either medication condition. The fitted difference in change in adjusted cigarettes per day between the two conditions was small and nonsignificant (β = -0.08, SE = 0.05, p = .132). Conclusions Results support high rates of smoking with little change during pregnancy among opioid-dependent patients, regardless of the type of agonist medication received. These findings are consistent with evidence that suggests nicotine effects, and interactions may be similar for buprenorphine compared with methadone. The outcomes further highlight that aggressive efforts are needed to reduce/eliminate smoking in opioid-dependent pregnant women.

Magnetic resonance imaging (MRI)-targeted, 3D transrectal ultrasound (TRUS)-guided "fusion" prostate biopsy aims to reduce the 21–47% false negative rate of clinical 2D TRUS-guided sextant biopsy, but still has a substantial false negative rate. This could be improved via biopsy needle target optimization, accounting for uncertainties due to guidance system errors, image registration errors, and irregular tumor shapes. As an initial step toward the broader goal of optimized prostate biopsy targeting, in this study we elucidated the impact of biopsy needle delivery error on the probability of obtaining a tumor sample, and on the core involvement. These are both important parameters to patient risk stratification and the decision for active surveillance vs. definitive therapy. We addressed these questions for cancer of all grades, and separately for high grade (≥ Gleason 4+3) cancer. We used expert-contoured gold-standard prostatectomy histology to simulate targeted biopsies using an isotropic Gaussian needle delivery error from 1 to 6 mm, and investigated the amount of cancer obtained in each biopsy core as determined by histology. Needle delivery error resulted in variability in core involvement that could influence treatment decisions; the presence or absence of cancer in 1/3 or more of each needle core can be attributed to a needle delivery error of 4 mm. However, our data showed that by making multiple biopsy attempts at selected tumor foci, we may increase the probability of correctly characterizing the extent and grade of the cancer.

Background and Objectives: How best to measure the occurrence of adverse events during a randomized clinical trial is an issue that has not been adequately examined in the research literature. Focus of this study was on the examination of the relative frequency of occurrence of adverse events directly recorded during the conduct of the trial compared to an indirect determination of adverse events derived from data collected as part of the trial. Methods: A secondary analysis of nonserious adverse events that occurred in the Maternal Opioid Treatment: Human Experimental Research (MOTHER) Study was undertaken. MOTHER was a randomized clinical trial of methadone versus buprenorphine in 175 opioid-dependent pregnant women. Results: The two methods of recording adverse events failed to agree on where differences in the frequency of occurrence of adverse events between the medication conditions might exist. Moreover, indirect assessment indicated all participants had experienced at least one adverse event, yet indirect coverage of adverse events was incomplete. Conclusions: Findings suggest indirect examination of occurrence of adverse events should be cautiously undertaken, because indirect assessment of adverse events makes no distinction between what might be simply typical variation in behavior rather than systematic changes in behavior attributable to study condition, and lacks coverage of the full spectrum of adverse events. Scientific Significance: Contemporaneous direct measurement of adverse events likely yield reasonably valid estimates of the rate of occurrence of the adverse events, while indirect measu-rement of adverse events may not be sufficiently reliable. (Am J Addict 2012;21:S1–S4)

Aims This paper reviews the published literature regarding outcomes following maternal treatment with buprenorphine in five areas: maternal efficacy, fetal effects, neonatal effects, effects on breast milk and longer-term developmental effects. Methods Within each outcome area, findings are summarized first for the three randomized clinical trials and then for the 44 non-randomized studies (i.e. prospective studies, case reports and series and retrospective chart reviews), only 28 of which involve independent samples. Results Results indicate that maternal treatment with buprenorphine has comparable efficacy to methadone, although difficulties may exist with current buprenorphine induction methods. The available fetal data suggest buprenorphine results in less physiological suppression of fetal heart rate and movements than methadone. Regarding neonatal effects, perhaps the single definitive conclusion is that prenatal buprenorphine treatment results in a clinically significant less severe neonatal abstinence syndrome (NAS) than treatment with methadone. The limited research suggests that, like methadone, buprenorphine is compatible with breastfeeding. Data available thus far suggest that there are no deleterious effects of in utero buprenorphine exposure on infant development. Conclusions While buprenorphine produces a less severe neonatal abstinence syndrome than methadone, both methadone and buprenorphine are important parts of a complete comprehensive treatment approach for opioid-dependent pregnant women.

Aim To determine pre- and post-dosing effects of prenatal methadone compared to buprenorphine on fetal wellbeing. Design A secondary analysis of data derived from the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study, a double-blind, double-dummy, randomized clinical trial. Setting Six United States sites and one European site that provided comprehensive opioid-dependence treatment to pregnant women. Participants Eighty-one of the 131 opioid-dependent pregnant women completing the MOTHER clinical trial, assessed between 31 and 33 weeks of gestation. Measurements Two fetal assessments were conducted, once before and once after study medication dosing. Measures included mean fetal heart rate (FHR), number of FHR accelerations, FHR reactivity in the fetal non-stress test (NST) and biophysical profile (BPP) score. Findings Significant group differences were found for number of FHR accelerations, non-reactive NST and BPP scores (all Ps

Aims To examine the relationship of anxiety and depression symptoms with treatment outcomes (treatment discontinuation, rates of ongoing use of illicit drugs and likelihood of preterm delivery) in opioid-dependent pregnant women and describe their use of psychotropic medications. Design and setting Secondary data analysis from a randomized clinical trial of treatment for opioid dependence during pregnancy. Participants A total of 175 opioid-dependent pregnant women, of whom 131 completed treatment. Measurements Symptoms of anxiety and depression were captured with the 15-item Mini International Neuropsychiatric Interview (MINI) screen. Use of illicit drugs was measured by urine drug screening. Preterm delivery was defined as delivery prior to 37 weeks' gestation. Self-reported use of concomitant psychotropic medication at any point during the study was recorded. Findings Women reporting only anxiety symptoms at study entry were more likely to discontinue treatment [adjusted odds ratio (OR) = 4.56, 95% confidence interval (CI): 1.91–13.26, P = 0.012], while those reporting only depression symptoms were less likely to discontinue treatment (adjusted OR = 0.14, 95% CI: 0.20–0.88, P = 0.036) compared to women who reported neither depression nor anxiety symptoms. No statistically significant between-group differences were observed for ongoing illicit drug use or preterm delivery. A majority (61.4%) of women reported use of concomitant psychotropic medication at some point during study participation. Conclusions Opioid agonist-treated pregnant patients with co-occurring symptoms of anxiety require additional clinical resources to prevent premature discontinuation.

Aims To compare the profile of signs of neonatal abstinence syndrome (NAS) in methadone- versus buprenorphine- exposed infants. Design, setting and participants Secondary analysis of NAS data from a multi-site, double-blind, double-dummy, flexible-dosing, randomized clinical trial. Data from a total of 129 neonates born to opioid-dependent women who had been assigned to receive methadone or buprenorphine treatment during pregnancy were examined. Measurements For 10 days after delivery, neonates (methadone = 72, buprenorphine = 57) were assessed regularly using a 19-item modified Finnegan scale. Data from neonates who required pharmacological treatment (metha- done = 41, buprenorphine = 27) were included up to the time treatment was initiated. The incidence and mean severity of the total NAS score and each individual sign of NAS were calculated and compared between medication conditions, as was the median time until morphine treatment initiation among treated infants in each condition. Findings Two NAS signs (undisturbed tremors and hyperactive Moro reflex) were observed significantly more frequently in methadone-exposed neonates and three (nasal stuffiness, sneezing, loose stools) were observed more frequently in buprenorphine-exposed neonates. Mean severity scores on the total NAS score and five individual signs (disturbed and undisturbed tremors, hyperactive Moro reflex, excessive irritability, failure to thrive) were significantly higher among methadone-exposed neonates, while sneezing was higher among buprenorphine-exposed neonates. Among treated neonates, methadone-exposed infants required treatment significantly earlier than buprenorphine- exposedinfants(36versus59hourspostnatal,respectively).Conclusions Theprofileof neonatalabstinencesyndrome differs in methadone- versus buprenorphine-exposed neonates, with significant differences in incidence, severity and treatment initiation time. Overall, methadone-exposed neonates have a more severe neonatal abstinence syndrome.