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Objective: To compare initiation of PTSD evidence-based psychotherapy (EBP) between Veterans with and without a co-occurring substance use disorder (SUD), and identify factors associated with EBP initiation among Veterans with PTSD-SUD., Method: A national sample of Veterans with PTSD ( n = 301,872) and PTSD-SUD ( n = 94,515) were identified from VA Electronic Health Record data. Treatment initiation was defined as having at least one mental health encounter associated with Cognitive Processing Therapy or Prolonged Exposure therapy. Generalized estimating equations were used to compare EBP initiation between Veterans with and without co-occurring SUD, and to identify patient- and facility characteristics associated with EBP initiation among Veterans with PTSD-SUD., Results: The majority of Veterans were 30 - 44 years old, male sex, and Non-Hispanic White. No significant differences were observed in EBP initiation between Veterans with and without a co-occurring SUD ( OR =1.00, p =0.985). Among Veterans with PTSD-SUD, co-occurring bipolar disorder ( OR =0.83, p =.000), co-occurring psychotic disorder ( OR =0.69, p =.000), service connection ( OR =0.94, p =.001), female sex ( OR =0.87, p =.000), and being 60 years or older ( OR =0.57, p =.000) were associated with a reduced likelihood of initiating a PTSD EBP. Having a co-occurring anxiety disorder ( OR =1.06, p =.020), MST history ( OR =1.95, p =.000), and high risk for suicide ( OR =1.15, p =.000) were associated with an increased likelihood of initiating EBP., Discussion: These findings support VA provision of EBP for Veterans with PTSD regardless of the presence of co-occurring SUD. Identifying characteristics that increase or reduce the likelihood of EBP initiation may provide insight into treatment pathways and subgroups warranting augmented outreach., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Somohano, Cameron, Lewis, O’Neill, Phillips, Kaplan and O’Neil.)

Introduction: The substantia nigra pars compacta (SNc) is the key pathologic locus in neurodegenerative parkinsonian disorders. Recently, in vivo susceptibility MRI metrics were associated with postmortem glial cell density and tau burden in the SNc of parkinsonism subjects. This study investigated the red nucleus (RN), another iron-rich region adjacent to the SNc and a potential site of higher functionality in parkinsonisms., Methods: In vivo MRI and postmortem data were obtained from 34 parkinsonism subjects and 3 controls. Neuron density, glial cell density, and percentages of area occupied by α-synuclein and tau were quantified using digitized midbrain slides. R2* and quantitative susceptibility mapping (QSM) metrics in the RN and SNc were derived from multi-gradient echo images. Histopathology data were compared between the RN and SNc using paired t-tests. MRI-histology associations were analyzed using partial Pearson correlations., Results: The RN had greater neuron (t 23  = 3.169, P = 0.004) and glial cell densities (t 23  = 2.407, P = 0.025) than the SNc, whereas the SNc had greater α-synuclein (t 28  = 4.614, P < 0.0001) and tau burden (t 24  = 4.513, P = 0.0001). In both the RN (R2*: r = 0.47, P = 0.043; QSM: r = 0.52, P = 0.024) and SNc (R2*: r = 0.57, P = 0.01; QSM: r = 0.58, P = 0.009), MRI values were associated with glial cell density but not neuron density or α-synuclein (Ps > 0.092). QSM associated with tau burden (r = 0.49, P = 0.038) in the SNc, but not the RN., Conclusions: The RN is resilient to parkinsonian-related pathological processes compared to the SNc, and susceptibility MRI captured glial cell density in both regions. These findings help to further our understanding of the underlying pathophysiological processes in parkinsonisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Patients in late-stage Parkinson's disease (PD LS ) are caregiver-dependent, have low quality of life, and higher healthcare costs., Objective: To estimate the prevalence of PD LS patients in the current US healthcare system., Methods: We downloaded the 2010-2022 data from the TriNetX Diamond claims network that consists of 92 US healthcare sites. PD was identified using standard diagnosis codes, and PD LS was identified by the usage of wheelchair dependence, personal care assistance, and/or presence of diagnoses of dementia. Age of PD LS identification and survival information were obtained and stratified by demographic and the disability subgroups., Results: We identified 1,031,377 PD patients in the TriNetX database. Of these, 18.8% fitted our definition of PD LS (n = 194,297), and 10.2% met two or more late-stage criteria. Among all PD LS , the mean age of PD LS identification was 78.1 (±7.7) years, and 49% were already reported as deceased. PD LS patients were predominantly male (58.5%) with similar distribution across PD LS subgroups. The majority did not have race (71%) or ethnicity (69%) information, but for the available information >90% (n = 53,162) were White, 8.2% (n = 5121) Hispanic/Latino, 7.8% (n = 4557) Black, and <0.01% (n = 408) Asian. Of the PD LS cohort, 71.6% identified with dementia, 12.9% had personal care assistance, and 4.8% were wheelchair-bound., Conclusions: Late-stage patients are a significant part of the PD landscape in the current US healthcare system, and largely missed by traditional motor-based disability staging. It is imperative to include this population as a clinical, social, and research priority. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: DICER1 mutations, though infrequent, are encountered on preoperative molecular testing of indeterminate adult and pediatric thyroid fine-needle aspiration (FNA) specimens. Yet, published cytomorphologic features of DICER1-altered thyroid lesions are limited. Cytomorphological features of DICER1-altered thyroid lesions were examined in a multipractice FNA cohort with clinical, radiological, and histologic data., Methods: The cohort comprised 18 DICER1-altered thyroid FNAs, with 14 having slides available and eight having corresponding surgical resections. Smears, ThinPrep, and formalin-fixed cell block slides were reviewed and correlated with histology, when available. Clinical and radiologic data were obtained from the medical record., Results: Most DICER1-altered FNAs were classified as atypia of undetermined significance (94.4%). DICER1 mutations occurred in codons 1709 (50%), 1810 (27.8%), and 1813 (22.2%). One patient had an additional DICER1 p.D1822N variant in both of their FNAs. Lesions were often hypoechoic (35.3%) and solid (47.1%) on ultrasound. Notable cytomorphologic features include mixed but prominent microfollicular or crowded component, variable colloid, and insignificant nuclear atypia. On resection (n = 10), histologic diagnoses ranged from benign follicular adenoma and low-risk follicular thyroid carcinoma to high-grade follicular-derived nonanaplastic thyroid carcinoma. Subcapsular infarct-type change was the most common histologic change. There was no evidence of recurrence or metastasis in eight patients on limited follow-up., Conclusion: DICER1-altered thyroid lesions occurred frequently in young females and FNAs show RAS-like cytomorphology including crowded, mixed macro-/microfollicular pattern, and bland nuclear features. On resection, DICER1-altered thyroid lesions include benign (50%), low-risk lesions (30%), or high-risk malignancies (20%)., (© 2024 American Cancer Society.)

Background: Omnidirectional treadmills (ODTs) offer a promising solution to the virtual reality (VR) locomotion problem, which describes the mismatch between visual and somatosensory information and contributes to VR sickness. However, little is known about how walking on ODTs impacts the biomechanics of gait. This project aimed to compare overground and ODT walking and turning in healthy young adults., Methods: Fifteen young adults completed forward walk, 180° turn, and 360° turn tasks under three conditions: (1) overground, (2) on the Infinadeck ODT in a virtual environment without a handrail, and (3) on the ODT with a handrail. Kinematic data for all walking trials were gathered using 3D optical motion capture., Results: Overall, gait speed was slower during ODT walking than overground. When controlling for gait speed, ODT walking resulted in shorter steps and greater variability in step length. There were no significant differences in other spatiotemporal metrics between ODT and overground walking. Turning on the ODT required more steps and slower rotational speeds than overground turns. The addition of the stability handrail to the ODT resulted in decreased gait variability relative to the ODT gait without the handrail., Conclusion: Walking on an ODT resembles natural gait patterns apart from slower gait speed and shorter step length. Slower walking and shorter step length are likely due to the novelty of physically navigating a virtual environment which may result in a more conservative approach to gait. Future work will evaluate how older adults and those with neurological disease respond to ODT walking., (© 2023. The Author(s).)

Background: Telecommunicator CPR (T-CPR), whereby emergency dispatch facilitates cardiac arrest recognition and coaches CPR over the telephone, is an important strategy to increase early recognition and bystander CPR in adult out-of-hospital cardiac arrest (OHCA). Little is known about this treatment strategy in the pediatric population. We investigated the role of T-CPR and related performance among pediatric OHCA., Methods and Results: This study was a retrospective cohort investigation of OHCA among individuals <18 years in King County, Washington, from April 1, 2013, to December 31, 2019. We reviewed the 911 audio recordings to determine if and how bystander CPR was delivered (unassisted or T-CPR), key time intervals in recognition of arrest, and key components of T-CPR delivery. Of the 185 eligible pediatric OHCAs, 23% (n=43) had bystander CPR initiated unassisted, 59% (n=109) required T-CPR, and 18% (n=33) did not receive CPR before emergency medical services arrival. Among all cases, cardiac arrest was recognized by the telecommunicator in 89% (n=165). Among those receiving T-CPR, the median (interquartile range) interval from start of call to OHCA recognition was 59 seconds (38-87) and first CPR intervention was 115 seconds (94-162). When stratified by age (≤8 versus >8), the older age group was less likely to receive CPR before emergency medical services arrival (88% versus 69%, P =0.002). For those receiving T-CPR, bystanders spent a median of 207 seconds (133-270) performing CPR. The median compression rate was 93 per minute (82-107) among those receiving T-CPR., Conclusions: T-CPR is an important strategy to increase early recognition and early CPR among pediatric OHCA.

Background: Antiretroviral adherence is essential to achieve viral suppression and limit HIV-related morbidity and mortality; however, antiretroviral adherence thresholds to achieve viral suppression in clinical practice have not been fully characterized using administrative claims data., Objective: The purpose of this study was to assess the relationship between medication adherence and viral suppression among adult persons with HIV/AIDS (PWH) receiving antiretroviral therapy (ART) for ≥6 months., Methods: This historical cohort, real-world investigation assessed maintenance of viral load suppression and viral load area-under-the-curve (vAUC) in PWH ≥18 years of age based on ART adherence. A marginal effects model was used to determine the predicted probabilities of final plasma HIV-1 RNA <50 copies/mL or vAUC <1,000 copy-days/mL according to the medication possession ratio (MPR), estimated using a Jackknife model variance estimator and a delta-method for marginal effects standard error. Tests for statistical significance used a Šidák method to correct for multiple comparisons., Results: The mean MPR for ART was 86.7% (95% CI: 85.0%-88.4%) for the 372 PWH included in the study. The marginal effects analysis indicated that an MPR ≥82% was associated with a predicted probability of viral suppression <50 copies/mL ( P < 0.05). Significant predicted probabilities for vAUC <1,000 copy-days/mL were observed with an MPR ≥90% ( P < 0.05)., Conclusion and Relevance: Medication possession ratio as a proxy for drug exposure was significantly and consistently associated with viral suppression using a longitudinal measure of HIV viremia. These findings can aid clinicians in the clinical management of PWH and inform future studies of adherence-viral suppression relationships with contemporary antiretroviral regimens., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: We investigated changes in indices of muscle synergies prior to gait initiation and the effects of gaze shift in patients with Parkinson's disease (PD). A long-term objective of the study is to develop a method for quantitative assessment of gait-initiation problems in PD., Methods: PD patients without clinical signs of postural instability and two control groups (age-matched and young) performed a gait initiation task in a self-paced manner, with and without a quick prior gaze shift produced by turning the head. Muscle groups with parallel scaling of activation levels (muscle modes) were identified as factors in the muscle activation space. Synergy index stabilizing center of pressure trajectory in the anterior-posterior and medio-lateral directions (indices of stability) was quantified in the muscle mode space. A drop in the synergy index in preparation to gait initiation (anticipatory synergy adjustment, ASA) was quantified., Results: Compared to the control groups, PD patients showed significantly smaller synergy indices and ASA for both directions of the center of pressure shift. Both PD and age-matched controls, but not younger controls, showed detrimental effects of the prior gaze shift on the ASA indices., Conclusions: PD patients without clinically significant posture or gait disorders show impaired stability of the center of pressure and its diminished adjustment during gait initiation., Significance: The indices of stability and ASA may be useful to monitor pre-clinical gait disorders, and lower ASA may be relevant to emergence of freezing of gait in PD., (Copyright © 2023 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Although mRNA lipid nanoparticles (LNPs) are highly effective as vaccines, their efficacy for pulmonary delivery has not yet fully been established. A major barrier to this therapeutic goal is their instability during aerosolization for local delivery. This imparts a shear force that degrades the mRNA cargo and therefore reduces cell transfection. In addition to remaining stable upon aerosolization, mRNA LNPs must also possess the aerodynamic properties to achieve deposition in clinically relevant areas of the lungs. We addressed these challenges by formulating mRNA LNPs with SM-102, the clinically approved ionizable lipid in the Spikevax COVID-19 vaccine. Our lead candidate, B-1, had the highest mRNA expression in both a physiologically relevant air-liquid interface (ALI) human lung cell model and in healthy mice lungs upon aerosolization. Further, B-1 showed selective transfection in vivo of lung epithelial cells compared to immune cells and endothelial cells. These results show that the formulation can target therapeutically relevant cells in pulmonary diseases such as cystic fibrosis. Morphological studies of B-1 revealed differences in the surface structure compared to LNPs with lower transfection efficiency. Importantly, the formulation maintained critical aerodynamic properties in simulated human airways upon next generation impaction. Finally, structure-function analysis of SM-102 revealed that small changes in the number of carbons can improve upon mRNA delivery in ALI human lung cells. Overall, our study expands the application of SM-102 and its analogs to aerosolized pulmonary delivery and identifies a potent lead candidate for future therapeutically active mRNA therapies., Competing Interests: Dedadyuti Ghosh and Mae M. Lewis have filed a provisional patent on this work., (© 2023 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of The American Institute of Chemical Engineers.)

Background: Circulating small RNAs (smRNAs) originate from diverse tissues and organs. Previous studies investigating smRNAs as potential biomarkers for Parkinson's disease (PD) have yielded inconsistent results. We investigated whether smRNA profiles from neuronally-enriched serum exosomes and microvesicles are altered in PD patients and discriminate PD subjects from controls., Methods: Demographic, clinical, and serum samples were obtained from 60 PD subjects and 40 age- and sex-matched controls. Exosomes and microvesicles were extracted and isolated using a validated neuronal membrane marker (CD171). Sequencing and bioinformatics analyses were used to identify differentially expressed smRNAs in PD and control samples. SmRNAs also were tested for association with clinical metrics. Logistic regression and random forest classification models evaluated the discriminative value of the smRNAs., Results: In serum CD171 enriched exosomes and microvesicles, a panel of 29 smRNAs was expressed differentially between PD and controls (false discovery rate (FDR) < 0.05). Among the smRNAs, 23 were upregulated and 6 were downregulated in PD patients. Pathway analysis revealed links to cellular proliferation regulation and signaling. Least absolute shrinkage and selection operator adjusted for the multicollinearity of these smRNAs and association tests to clinical parameters via linear regression did not yield significant results. Univariate logistic regression models showed that four smRNAs achieved an AUC ≥ 0.74 to discriminate PD subjects from controls. The random forest model had an AUC of 0.942 for the 29 smRNA panel., Conclusion: CD171-enriched exosomes and microvesicles contain the differential expression of smRNAs between PD and controls. Future studies are warranted to follow up on the findings and understand the scientific and clinical relevance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Aguilar, Ebanks, Markus, Lewis, Midya, Vrana, Huang, Hall and Kawasawa.)

Current pharmacotherapy has limited efficacy and/or intolerable side effects in late-stage Parkinson's disease (LsPD) patients whose daily life depends primarily on caregivers and palliative care. Clinical metrics inadequately gauge efficacy in LsPD patients. We explored if a D 1/5 dopamine agonist would have efficacy in LsPD using a double-blind placebo-controlled crossover phase Ia/b study comparing the D 1/5 agonist PF-06412562 to levodopa/carbidopa in six LsPD patients. Caregiver assessment was the primary efficacy measure because caregivers were with patients throughout the study, and standard clinical metrics inadequately gauge efficacy in LsPD. Assessments included standard quantitative scales of motor function (MDS-UPDRS-III), alertness (Glasgow Coma and Stanford Sleepiness Scales), and cognition (Severe Impairment and Frontal Assessment Batteries) at baseline (Day 1) and thrice daily during drug testing (Days 2-3). Clinicians and caregivers completed the clinical impression of change questionnaires, and caregivers participated in a qualitative exit interview. Blinded triangulation of quantitative and qualitative data was used to integrate findings. Neither traditional scales nor clinician impression of change detected consistent differences between treatments in the five participants who completed the study. Conversely, the overall caregiver data strongly favored PF-06412562 over levodopa in four of five patients. The most meaningful improvements converged on motor, alertness, and functional engagement. These data suggest for the first time that there can be useful pharmacological intervention in LsPD patients using D 1/5 agonists and also that caregiver perspectives with mixed method analyses may overcome limitations using methods common in early-stage patients. The results encourage future clinical studies and understanding of the most efficacious signaling properties of a D 1 agonist for this population.

Introduction: Chronic excessive welding exposure may be related to higher metal accumulation and structural differences in different subcortical structures. We examined how welding affected brain structures and their associations with metal exposure and neurobehavioral consequences., Methods: Study includes 42 welders and 31 controls without a welding history. Welding-related structural differences were assessed by volume and diffusion tensor imaging (DTI) metrics in basal ganglia, red nucleus (RN), and hippocampus. Metal exposure was estimated by both exposure questionnaires and whole blood metal levels. Brain metal accumulations were estimated by R1 (for Mn) and R2* (for Fe). Neurobehavioral status was assessed by standard neuropsychological tests., Results: Compared to controls, welders displayed higher hippocampal mean (MD), axial (AD), and radial diffusivity (RD) (p's < 0.036), but similar DTI or volume in other ROIs (p's > 0.117). Welders had higher blood metal levels (p's < 0.004), higher caudate and RN R2* (p's < 0.014), and lower performance on processing/psychomotor speed, executive function, and visuospatial processing tasks (p's < 0.046). Higher caudate and RN R2* were associated with higher blood Fe and Pb (p's < 0.043), respectively. RN R2* was a significant predictor of all hippocampal diffusivity metrics (p's < 0.006). Higher hippocampal MD and RD values were associated with lower Trail Making Test-A scores (p's < 0.025). A mediation analysis of both groups revealed blood Pb indirectly affected hippocampal diffusivity via RN R2* (p's < 0.041)., Discussion: Welding-related higher hippocampal diffusivity metrics may be associated with higher RN R2* and lower psychomotor speed performance. Future studies are warranted to test the role of Pb exposure in these findings., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Susceptibility magnetic resonance imaging (MRI) is sensitive to iron-related changes in the substantia nigra pars compacta (SNc), the key pathologic locus of parkinsonisms. It is unclear, however, if iron deposition in the SNc is associated with its neurodegeneration., Objective: The objective of this study was to test whether susceptibility MRI metrics in parkinsonisms are associated with SNc neuropathologic features of dopaminergic neuron loss, gliosis, and α-synuclein and tau burden., Methods: This retrospective study included 27 subjects with both in vivo MRI and postmortem data. Multigradient echo imaging was used to derive the apparent transverse relaxation rate (R2*) and quantitative susceptibility mapping (QSM) in the SNc. Archived midbrain slides that were stained with hematoxylin and eosin, anti-α-synuclein, and anti-tau were digitized to quantify neuromelanin-positive neuron density, glial density, and the percentages of area occupied by positive α-synuclein and tau staining. MRI-histology associations were examined using Pearson correlations and regression., Results: Twenty-four subjects had postmortem parkinsonism diagnoses (Lewy body disorder, progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration), two had only Alzheimer's neuropathology, and one exhibited only mild atrophy. Among all subjects, both R2* and QSM were associated with glial density (r ≥ 0.67; P < 0.001) and log-transformed tau burden (r ≥ 0.53; P ≤ 0.007). Multiple linear regression identified glial density and log-transformed tau as determinants for both MRI metrics (R 2 ≥ 0.580; P < 0.0001). Neither MRI metric was associated with neuron density or α-synuclein burden., Conclusions: R2* and QSM are associated with both glial density and tau burden, key neuropathologic features in the parkinsonism SNc. © 2023 International Parkinson and Movement Disorder Society., (© 2023 International Parkinson and Movement Disorder Society.)

Background and Purpose: The circuitry underlying heterogenous cognitive profiles in Parkinson's disease (PD) remains unclear. The purpose of this study is to investigate whether structural changes in frontostriatal and limbic pathways contribute to different cognitive trajectories in PD., Methods: We obtained clinical and multimodal MRI data from 120 control and 122 PD subjects without dementia or severe motor disability. T1/T2-weighted images estimated volume, and diffusion imaging evaluated fractional anisotropy (FA) of frontostriatal (striatum and frontostriatal white matter [FSWM]) and limbic (hippocampus and fornix) structures. Montreal Cognitive Assessment (MoCA) gauged total and domain-specific (attention/executive and memory) cognitive function. Linear mixed-effects models were used to compare MRI and cognitive progression over 4.5 years between controls and PD and evaluate associations between baseline MRI and cognitive changes in PD., Results: At baseline, control and PD groups were comparable, except PD participants had smaller striatal volume (p < 0.001). Longitudinally, PD showed faster decline in hippocampal volume, FSWM FA, and fornix FA (ps < .016), but not striatal volume (p = .218). Total and domain-specific MoCA scores declined faster in PD (ps < .030). In PD, lower baseline hippocampal volume (p = .005) and fornix FA (p = .032), but not striatal volume (p = .662) or FSWM FA (p = .143), were associated with faster total MoCA decline. Baseline frontostriatal metrics of striatal volume and FSWM FA were associated with faster attention/executive decline (p < .038), whereas lower baseline hippocampal volume was associated with faster memory decline (p = .005)., Conclusion: In PD, frontostriatal structural metrics are associated with attention/executive tasks, whereas limbic changes correlated with faster global cognitive decline, particularly in memory tasks., (© 2022 American Society of Neuroimaging.)

Motor synergies, i.e., neural mechanisms that organize multiple motor elements to ensure stability of actions, are affected by several neurological condition. Asymptomatic welders showed impaired synergy controlling the stability of multi-finger action compared to non-welders and this impairment was associated with microstructural damage in the globus pallidus. We further explored the effect of welding-related metal exposure on multi-finger synergy and extended our investigation to posture-stabilizing synergy during a standing task. Occupational, MRI, and performance-stabilizing synergies during multi-finger accurate force production and load releasing while standing were obtained from 29 welders and 19 age- and sex-matched controls. R2* and R1 relaxation rate values were used to estimate brain iron and manganese content, respectively, and diffusion tensor imaging was used to reflect brain microstructural integrity. Associations of brain MRI (caudate, putamen, globus pallidus, and red nucleus), and motor synergy were explored by group status. The results revealed that welders had higher R2* values in the caudate (p = 0.03), putamen (p = 0.01), and red nucleus (p = 0.08, trend) than controls. No group effect was revealed on multi-finger synergy index during steady-state phase of action (ΔV Z ss). Compared to controls, welders exhibited lower ΔV Z ss (-0.106 ± 0.084 vs. 0.160 ± 0.092, p = 0.04) and variance that did not affect the performance variable (V UCM , 0.022 ± 0.003 vs. 0.038 ± 0.007, p = 0.03) in the load releasing, postural task. The postural synergy index, ΔV Z ss, was associated negatively with higher R2* in the red nucleus in welders (r = -0.44, p = 0.03), but not in controls. These results suggest that the synergy index in the load releasing during a standing task may reflect welding-related neurotoxicity in workers with chronic metals exposure. This finding may have important clinical and occupational health implications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Methylphenidate is used widely to treat symptoms of attention-deficit/hyperactivity disorder (ADHD), but like other stimulants has significant side effects. This study used a rodent model (spontaneously hypertensive rat) of spatial working memory (sWM) to compare the effects of methylphenidate with the novel dopamine D 1 -like receptor agonist 2-methyldihydrexidine. Acute oral administration of methylphenidate (1.5 mg/kg) caused sWM improvement in half of the tested rats, but impairment in the others. Both improvement or impairment were eliminated by administration of the D 1 antagonist SCH39266 directly into the prefrontal cortex (PFC). Conversely, 2-methyldihydrexidine showed greater sWM improvement compared with methylphenidate without significant impairment in any subject. Its effects correlated negatively with vehicle-treated baseline performance (i.e., rats with lower baseline performance improved more than rats with higher baseline performance). These behavioral effects were associated with neural activities in the PFC. Single neuron firing rate was changed, leading to the alteration in neuronal preference to correct or error behavioral responses. Overall, 2-methyldihydrexidine was superior to methylphenidate in decreasing the neuronal preference, prospectively, in the animals whose behavior was improved. In contrast, methylphenidate, but not 2-methyldihydrexidine, significantly decreased neuronal preference, retrospectively, in those animals who had impaired performance. These results suggest that a D 1 agonist may be more effective than methylphenidate in regulating sWM-related behavior through neural modulation of the PFC, and thus may be superior to methylphenidate or other stimulants as ADHD pharmacotherapy. SIGNIFICANCE STATEMENT: Methylphenidate is effective in ADHD by its indirect agonist stimulation of dopamine and/or adrenergic receptors, but the precise effects on specific targets are unclear. This study compared methylphenidate to a dopamine D 1 receptor-selective agonist by investigating effects on working memory occurring via neural modulation in the prefrontal cortex. The data suggest that pharmacological treatment selectively targeting the dopamine D 1 may offer a superior approach to ADHD pharmacotherapy., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Higher nigral iron has been reported in Parkinson's disease (PD)., Objective: The aim is to understand the dynamics of nigral iron accumulation in PD and its association with drug treatment., Methods: Susceptibility magnetic resonance imaging data were obtained from 79 controls and 18 drug-naive (PD DN ) and 87 drug-treated (PD DT ) PD patients. Regional brain iron in basal ganglia and cerebellar structures was estimated using quantitative susceptibility mapping. Nigral iron was compared between PD DN and PD DT subgroups defined by disease duration (early [PDE, <2 years], middle [PDM, 2-6 years], and later [PDL, >6 years]). Associations with both disease duration and types of antiparkinson drugs were explored using regression analysis., Results: Compared to controls, PD DN had lower iron in the substantia nigra (P = 0.018), caudate nucleus (P = 0.038), and globus pallidus (P = 0.01) but not in the putamen or red nucleus. In contrast, PD DT had higher iron in the nigra (P < 0.001) but not in other regions, compared to either controls or PD DN . Iron in the nigra increased with disease duration (PDE > PD DN [P = 0.001], PDM > PDE [P = 0.045]) except for PDM versus PDL (P = 0.226). Levodopa usage was associated with higher (P = 0.013) nigral iron, whereas lower nigral iron was correlated with selegiline usage (P = 0.030)., Conclusion: Nigral iron is lower before the start of dopaminergic medication and then increases throughout the disease until it plateaus at late stages, suggesting increased iron may not be an etiological factor. Interestingly, PD medications may have differential associations with iron accumulation that need further investigation. © 2022 International Parkinson and Movement Disorder Society., (© 2022 International Parkinson and Movement Disorder Society.)

The awareness of the potential importance of functional selectivity/biased signaling has led to the discovery of biased compounds as both research tools and novel drugs. A major pan-receptor focus has been to identify GPCR-selective ligands that have bias in G protein-dependent vs. β-arrestin related signaling. Although this field has exploded during the past two decades, it is only recently that highly β-arrestin biased ligands for the dopamine D 1 receptor were reported. We now summarize important pharmacological, molecular, and cellular studies relevant to D 1 -mediated β-arrestin-related signaling. It is intriguing that many results emerged from behavioral and physiological studies implying that bias toward or against D 1 -mediated β-arrestin either can improve or impair functional outcomes. We discuss the importance of understanding the translatability of cell and animal models to have more precise functional targeting to harness the value of this signaling pathway., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Low doses of dopamine D 1 agonists improve working memory-related behavior, but high doses eliminate the improvement, thus yielding an 'inverted-U' dose-response curve. This dose-dependency also occurs at the single neuron level in the prefrontal cortex where the cellular basis of working memory is represented. Because signaling mechanisms are unclear, we examined this process at the neuron population level. Two D 1 agonists (2-methyldihydrexidine and CY208,243) having different signaling bias were tested in rats performing a spatial working memory-related T-maze task. 2-Methyldihydrexidine is slightly bias toward D 1 -mediated β-arrestin-related signaling as it is a full agonist at adenylate cyclase and a super-agonist at β-arrestin recruitment, whereas CY208,243 is slightly bias toward D 1 -mediated cAMP signaling as it has relatively high intrinsic activity at adenylate cyclase, but is a partial agonist at β-arrestin recruitment. Both compounds had the expected inverted U dose-dependency in modulating prefrontal neuronal activities, albeit with important differences. Although CY208,243 was superior in improving the strength of neuronal outcome sensitivity to the working memory-related choice behavior in the T-maze, 2-methyldihydrexidine better reduced neuron-to-neuron variation. Interestingly, at the neuron population level, both drugs affected the percentage, uniformity, and ensemble strength of neuronal sensitivity in a complicated dose-dependent fashion, but the overall effect suggested higher efficiency and potency of 2-methyldihydrexidine compared to CY208,243. The differences between 2-methyldihydrexidine and CY208,243 may be related to their specific D 1 signaling. These results suggest that D 1 -related dose-dependent regulation of working memory can be modified differentially by functionally selective ligands, theoretically increasing the balance between desired and undesired effects., Competing Interests: RM has interests in issued and pending patents related to dopamine D1 receptor mechanisms that constitute a conflict of interest for which there is University oversight. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Kocher, Lewis and Mailman.)

Lead is a nonessential metal and may be a coexposure in welding fumes. Preclinical data indicate lead may affect iron regulation. The current study investigated blood lead concentrations and their association with brain iron accumulation in workers with chronic welding fume exposure, with a focus on iron-rich subcortical regions of the cerebellum and basal ganglia. Occupational exposure, whole blood metal, and brain MRI data were obtained from 29 controls and 42 welders. R2* (1/T2*) and R1 (T1 relaxation rate) values were used to estimate brain iron and manganese content, respectively. Blood metals and brain R2* (in the red nucleus [RN], dentate nucleus, caudate, putamen, globus pallidus, and substantia nigra) were compared between groups. Associations between brain R2* values and exposure metrics were tested within each group, and analyses were adjusted for potential confounders. Welders had significantly higher levels of whole blood lead, manganese, iron, and copper. Welders also had higher R2* RN (p = .002), but not R1. A 2nd-order polynomial modeled the association between R2* RN and a long-term welding exposure metric. In welders, but not controls, R2* RN was associated positively with whole blood lead (r = 0.54, p = .003), and negatively with whole blood manganese (r = -0.43, p = .02). Higher blood Pb and lower blood Mn independently accounted for variance in high RN R2*. Together, these data suggest that higher RN R2* values may mark lead exposure in welders. Because lead is a known neurotoxicant, additional studies are warranted to confirm this finding, and ascertain its scientific and public/occupational health implications., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Recent randomized clinical trials using hydrophobic statins reported no influence on Parkinson's disease (PD) clinical progression. Hydrophobicity is a key determinant for blood-brain barrier penetrance., Objective: Investigate a potential effect of statins on PD progression., Methods: Statin use was determined at baseline and subtyped according to hydrophobicity in 125 PD patients participating in the PD Biomarker Program (PDBP, 2012-2015) at our site. Clinical (N = 125) and susceptibility MRI (N = 86) data were obtained at baseline and 18-months. Movement Disorders Society-Unified PD Rating Scales were used to track progression of non-motor (MDS-UPDRS-I) and motor (MDS-UPDRS-II) symptoms, and rater-based scores (MDS-UPDRS-III) of patients in the "on" drug state. R2* values were used to capture pathological progression in the substantia nigra. Associations between statin use, its subtypes, and PD progression were evaluated with linear mixed effect regressions., Results: Compared to statin non-users, overall statin or lipophilic statin use did not significantly influence PD clinical or imaging progression. Hydrophilic statin users, however, demonstrated faster clinical progression of non-motor symptoms [MDS-UPDRS-I (β= 4.8, p = 0.010)] and nigral R2* (β= 3.7, p = 0.043). A similar trend was found for MDS-UPDRS-II (β= 3.9, p = 0.10), but an opposite trend was observed for rater-based MDS-UPDRS-III (β= -7.3, p = 0.10). Compared to lipophilic statin users, hydrophilic statin users also showed significantly faster clinical progression of non-motor symptoms [MDS-UPDRS-I (β= 5.0, p = 0.020)], but R2* did not reach statistical significance (β= 2.5, p = 0.24)., Conclusion: This study suggests that hydrophilic, but not lipophilic, statins may be associated with faster PD progression. Future studies may have clinical and scientific implications.

A growing body of evidence suggests nigral iron accumulation plays an important role in the pathophysiology of Parkinson's disease (PD), contributing to dopaminergic neuron loss in the substantia nigra pars compacta (SNc). Converging evidence suggests this accumulation might be related to, or increased by, serotonergic dysfunction, a common, often early feature of the disease. We investigated whether lower plasma serotonin in PD is associated with higher nigral iron. We obtained plasma samples from 97 PD patients and 89 controls and MRI scans from a sub-cohort (62 PD, 70 controls). We measured serotonin concentrations using ultra-high performance liquid chromatography and regional iron content using MRI-based quantitative susceptibility mapping. PD patients had lower plasma serotonin (p < 0.0001) and higher nigral iron content (SNc: p < 0.001) overall. Exclusively in PD, lower plasma serotonin was correlated with higher nigral iron (SNc: r(58) =  - 0.501, p < 0.001). This correlation was significant even in patients newly diagnosed (< 1 year) and stronger in the SNc than any other region examined. This study reveals an early, linear association between low serotonin and higher nigral iron in PD patients, which is absent in controls. This is consistent with a serotonin-iron relationship in the disease process, warranting further studies to determine its cause and directionality., (© 2021. The Author(s).)

Background: Deposition and spreading of misfolded proteins (α-synuclein and tau) have been linked to Parkinson's disease cognitive dysfunction. The glymphatic system may play an important role in the clearance of these toxic proteins via cerebrospinal fluid (CSF) flow through perivascular and interstitial spaces. Recent studies discovered that sleep-dependent global brain activity is coupled to CSF flow, which may reflect glymphatic function., Objective: The objective of this current study was to determine if the decoupling of brain activity-CSF flow is linked to Parkinson's disease cognitive dysfunction., Methods: Functional and structural MRI data, clinical motor (Unified Parkinson's Disease Rating Scale), and cognitive (Montreal Cognitive Assessment [MoCA]) scores were collected from 60 Parkinson's disease and 58 control subjects. Parkinson's disease patients were subgrouped into those with mild cognitive impairment (MoCA < 26), n = 31, and those without mild cognitive impairment (MoCA ≥ 26), n = 29. The coupling strength between the resting-state global blood-oxygen-level-dependent signal and associated CSF flow was quantified, compared among groups, and associated with clinical and structural measurements., Results: Global blood-oxygen-level-dependent signal-CSF coupling decreased significantly (P < 0.006) in Parkinson's disease patients showing mild cognitive impairment, compared with those without mild cognitive impairment and controls. Reduced global blood-oxygen-level-dependent signal-CSF coupling was associated with decreased MoCA scores present in Parkinson's disease patients (P = 0.005) but not in controls (P = 0.65). Weaker global blood-oxygen-level-dependent signal-CSF coupling in Parkinson's disease patients also was associated with a thinner right entorhinal cortex (Spearman's correlation, -0.36; P = 0.012), an early structural change often seen in Alzheimer's disease., Conclusions: The decoupling between global brain activity and associated CSF flow is related to Parkinson's disease cognitive impairment. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Background: Brain MRI is a promising technique for Parkinson's disease (PD) biomarker development. Its analysis, however, is hindered by the high-dimensional nature of the data, particularly when the sample size is relatively small., New Method: This study introduces a folded concave penalized machine learning scheme with spatial coupling fused penalty (fused FCP) to build biomarkers for PD directly from whole-brain voxel-wise MRI data. The penalized maximum likelihood estimation problem of the model is solved by local linear approximation., Results: The proposed approach is evaluated on synthetic and Parkinson's Progression Marker Initiative (PPMI) data. It achieves good AUC scores, accuracy in classification, and biomarker identification with a relatively small sample size, and the results are robust for different tuning parameter choices. On the PPMI data, the proposed method discovers over 80 % of large regions of interest (ROIs) identified by the voxel-wise method, as well as potential new ROIs., Comparison With Existing Methods: The fused FCP approach is compared with L1, fused-L1, and FCP method using three popular machine learning algorithms, logistic regression, support vector machine, and linear discriminant analysis, as well as the voxel-wise method, on both synthetic and PPMI datasets. The fused FCP method demonstrated better accuracy in separating PD from controls than L1 and fused-L1 methods, and similar performance when compared with FCP method. In addition, the fused FCP method showed better ROI identification., Conclusions: The fused FCP method can be an effective approach for MRI biomarker discovery in PD and other studies using high dimensionality data/low sample sizes., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Paraquat is an herbicide whose use is associated with Parkinson's disease (PD), a neurodegenerative disorder marked by neuron loss in the substantia nigra pars compacta (SNc). We recently observed that the murine homolog to the human H63D variant of the homeostatic iron regulator (HFE) may decrease paraquat-associated nigral neurotoxicity in mice. The present study examined the potential influence of H63D on paraquat-associated neurotoxicity in humans. Twenty-eight paraquat-exposed workers were identified from exposure histories and compared with 41 unexposed controls. HFE genotypes, and serum iron and transferrin were measured from blood samples. MRI was used to assess the SNc transverse relaxation rate (R2*), a marker for iron, and diffusion tensor imaging scalars of fractional anisotropy (FA) and mean diffusivity, markers of microstructural integrity. Twenty-seven subjects (9 exposed and 18 controls) were H63D heterozygous. After adjusting for age and use of other PD-associated pesticides and solvents, serum iron and transferrin were higher in exposed H63D carriers than in unexposed carriers and HFE wildtypes. SNc R2* was lower in exposed H63D carriers than in unexposed carriers, whereas SNc FA was lower in exposed HFE wildtypes than in either unexposed HFE wildtypes or exposed H63D carriers. Serum iron and SNc FA measures correlated positively among exposed, but not unexposed, subjects. These data suggest that H63D heterozygosity is associated with lower neurotoxicity presumptively linked to paraquat. Future studies with larger cohorts are warranted to replicate these findings and examine potential underlying mechanisms, especially given the high prevalence of the H63D allele in humans., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Manganese (Mn)-induced parkinsonism involves motor symptoms similar to those observed in Parkinson's disease (PD). Previous literature suggests that chronic Mn- exposure may increase PD risk, although Mn-induced clinical syndromes are considered atypical for PD. This study investigated whether asymptomatic welders display differences in the substantia nigra (SN), the key pathological locus of PD., Method: Brain MRI data and occupational exposure history were obtained in welders (N = 43) and matched controls (N = 31). Diffusion tensor imaging fractional anisotropy (FA; estimate of microstructural integrity) and R2* (estimate of iron and other PD-related brain differences) values in the SN pars compacta (SNc), SN reticulata (SNr), and globus pallidus (GP) were compared between the two groups. The MRI markers of the SN and GP within welders were related to exposure estimates., Results: Compared to controls, welders who had chronic, but low-level, Mn-exposure had similar FA and R2* values in both SN regions (p's > 0.082), but significantly lower FA (p = 0.0013), although not R2* (p = 0.553), in the GP. In welders, FA values in the SN and GP showed a second-order polynomial relationship with cumulative lifetime welding exposure (p's < 0.03)., Conclusion: Neurotoxic processes associated with Mn-exposure may be different from those in PD when the exposure-level is relatively low. Greater welding duration and level, however, were associated with FA differences in the GP and SN, indicating that welding exposures above a certain level may induce neurotoxicity in the SN, a finding that should be explored further in future studies., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Pharmacotherapy considerations are often a concern for transgender individuals who are living with human immunodeficiency virus (HIV) due to concerns for drug-drug interactions between their hormone and antiretroviral therapies. Many of the first-line therapies offered to patients for the management of HIV have reduced concerns for safety, resistance, and drug-drug interactions. In this review, we highlight common medications and important considerations for caring for transgender people living with HIV., (© 2021 Pharmacotherapy Publications, Inc.)

Background: Parkinson's disease (PD) is marked clinically by motor symptoms and pathologically by Lewy bodies and dopamine neuron loss in the substantia nigra pars compacta (SNc). Higher iron accumulation, assessed by susceptibility MRI, also is observed as PD progresses. Recently, evidence has suggested that PD affects the retina., Objective: To better understand retinal alterations in PD and their association to clinical and SNc iron-related imaging metrics., Methods: Ten PD and 12 control participants (2 eyes each) from an ongoing PD imaging biomarker study underwent enhanced depth imaging optical coherence tomography evaluation. Choroidal (vascular) thickness and nerve layers were measured in 4 subregions [superior, temporal, inferior, and nasal] and at 3 foveal distances (1, 1.5, and 3 mm). These metrics were compared between PD and control groups. For significantly different metrics, their associations with clinical [levodopa equivalent daily dosage (LEDD), motor and visuospatial function] and SNc susceptibility MRI metrics [R2* and quantitative susceptibility mapping (QSM)] were explored., Results: Compared to control participants, PD participants had a thicker choroid (p = 0.005), but no changes in nerve layers. Higher mean choroidal thickness was associated with lower LEDD (p < 0.01) and better visuospatial function (p < 0.05). Subregion analyses revealed higher choroidal thickness correlated with lower LEDD and better motor and visuospatial measures. Higher mean choroidal thickness also was associated with lower nigral iron MRI (p < 0.05)., Conclusion: A small cohort of PD research participants displayed higher choroidal thickness that was related to better clinical performance and less nigral pathology. These intriguing findings warrant further investigation.

Postural instability is a major disabling feature in Parkinson's disease (PD). We quantified the organization of leg and trunk muscles into synergies stabilizing the center of pressure (COP) coordinate within the uncontrolled manifold hypothesis in levodopa-naïve patients with PD and age-matched control subjects. The main hypothesis was that changes in the synergic control of posture are present early in the PD process even before levodopa exposure. Eleven levodopa-naïve patients with PD and 11 healthy controls performed whole-body cyclical voluntary sway tasks and a self-initiated load-release task during standing on a force plate. Surface electromyographic activity in 13 muscles on the right side of the body was analyzed to identify muscle groups with parallel scaling of activation levels (M-modes). Data were collected both before ("off-drug") and approximately 60 min after the first dose of 25/100 carbidopa/levodopa ("on-drug"). COP-stabilizing synergies were quantified for the load-release task. Levodopa-naïve patients with PD showed no COP-stabilizing synergy "off-drug", whereas controls showed posture-stabilizing multi-M-mode synergy. "On-drug", patients with PD demonstrated a significant increase in the synergy index. There were no significant drug effects on the M-mode composition, anticipatory postural adjustments, indices of motor equivalence, or indices of COP variability. The results suggest that levodopa-naïve patients with PD already show impaired posture-stabilizing multi-muscle synergies that may be used as promising behavioral biomarkers for emerging postural disorders in PD. Moreover, levodopa modified synergy metrics differently in these levodopa-naïve patients compared to a previous study of patients on chronic antiparkinsonian medications (Falaki et al. in J Electromyogr Kinesiol 33:20-26, 2017a), suggesting different neurocircuitry involvement.

The development of novel π-conjugated charge transfer mediators is at the forefront of current research efforts and interests. Among the plethora of building blocks, diketopyrrolopyrroles have been widely employed, associated to the ease of tailoring their optoelectronic properties by systematic peripheral substitutions. It is somehow of surprise to us that their six-member ring bis-lactam analogues, naphthyridines have been overlooked and reports are scarce and almost solely limited to their use in polymeric materials. Herein we report a comprehensive theoretical analysis of the charge transfer properties of 1,5-naphthyridine-based materials by means of a number of bespoke model systems, further able to quantitatively predict experimental mobility observations. Our results imply that thiophene substituted naphthyridine crystalline materials represent a promising class of organic π-conjugated systems with an experimentally observed ability to self-assemble in the solid state conforming to one dimensional stacking motifs. These highly sought-after charge propagation channels are characterised by large wavefunction overlap and thermal integrity and have as a result the potential to outperform currently exploited alternatives. We anticipate this work to be of interest to materials scientists and hope it will pave the way towards the realisation of novel charge transfer mediators exploiting naphthyridine chemistries.

Background: The objective of this study was to determine whether neurotoxic kynurenine metabolites, induced by inflammation, in plasma and cerebrospinal fluid (CSF) are associated with symptom severity and nigral pathology in Parkinson's disease (PD)., Methods: Clinical and MRI data were obtained from 97 PD and 89 controls. We used ultra-performance liquid chromatography to quantify kynurenine metabolites and high-sensitivity multiplex assays to quantify inflammation in plasma and CSF. We evaluated group-wise differences as well as associations between the biomarkers, motor and nonmotor symptoms, and nigral R2* (MRI metric reflecting iron content)., Results: PD subjects had >100% higher 3-hydroxykynurenine and 14% lower 3-hydroxyanthranilic acid in plasma. The 3-HK in plasma was closely associated with both symptom severity and disease duration. PD subjects also had 23% lower kynurenic acid in the CSF. Higher CSF levels of the excitotoxin quinolinic acid were associated with more severe symptoms, whereas lower levels of the neuroprotective kynurenic acid were linked to olfactory deficits. An elevated quinolinic acid/picolinic acid ratio in the CSF correlated with higher R2* values in the substantia nigra in the entire cohort. Plasma C-reactive protein and serum amyloid alpha were associated with signs of increased kynurenine pathway activity in the CSF of PD patients, but not in controls., Conclusions: In PD, the kynurenine pathway metabolite levels are altered in both the periphery and the central nervous system, and these changes are associated with symptom severity. Replication studies are warranted in other cohorts, and these can also explore if kynurenine metabolites might be PD biomarkers and/or are involved in PD pathogenesis. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Parkinson's disease (PD) is characterized by dopaminergic cell loss and reduced striatal volume. Prior studies have demonstrated striatal involvement in access to lexical-semantic knowledge and damage to this structure may be evident in the lexical properties of responses. Semantic fluency task responses from early stage, non-demented PD participants with right (PD-R) or left (PD-L) lateralizing symptoms were compared to matched controls on lexical properties (word frequency, age of acquisition) and correlated with striatal volumes segmented from T1-weighted brain MR images. PD-R participants produced semantic fluency responses of a lower age of acquisition than PD-L and control participants (p < 0.05). PD-R age of acquisition responses correlated positively with putamen volume (p < 0.05), while age of acquisition of responses correlated negatively with caudate volume in controls (p < 0.05). Findings provide evidence for a role of the striatum in lexical-semantic access and qualitative changes in lexical access in select PD patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Inc.)

Introduction: An integrated collaborative care intervention was successful for treating comorbid obesity and depression. The effect of the integrated intervention on secondary outcomes of quality of life and psychosocial functioning were examined, as well as whether improvements in these secondary outcomes were correlated with improvements in the primary outcomes of weight and depressive symptoms., Study Design: This RCT compared an integrated collaborative care intervention for obesity and depression to usual care. Data were analyzed in 2018., Setting/participants: Adult primary care patients (n=409) with a BMI ≥30 (≥27 if Asian) and 9-Item Patient Health Questionnaire score ≥10 were recruited from September 30, 2014 to January 12, 2017 from primary care clinics in Northern California., Intervention: The 12-month intervention integrated a behavioral weight loss program and problem-solving therapy with as-needed antidepressant medications for depression., Main Outcome Measures: A priori secondary outcomes included health-related quality of life (Short Form-8 Health Survey), obesity-specific quality of life (Obesity-Related Problems Scale), sleep disturbance and sleep-related impairment (Patient-Reported Outcomes Measurement Information System), and functional disability (Sheehan Disability Scale) at baseline and 6 and 12 months., Results: Participants randomized to the intervention experienced significantly greater improvements in obesity-specific problems, mental health-related quality of life, sleep disturbance, sleep-related impairment, and functional disability at 6 months but not 12 months. Improvements in obesity-related problems (β=0.01, 95% CI=0.01, 0.02) and sleep disturbance (β= -0.02, 95% CI= -0.04, 0) were associated with lower BMI. Improvements in the physical (β= -0.01, 95% CI= -0.01, 0) and mental health components (β= -0.02, 95% CI= -0.03, -0.02) of the Short Form-8 Health Survey as well as sleep disturbance (β=0.01, 95% CI=0.01, 0.02) and sleep-related impairment (β=0.01, 95% CI=0, 0.01) were associated with fewer depressive symptoms., Conclusions: An integrated collaborative care intervention for obesity and depression that was shown previously to improve weight and depressive symptoms may also confer benefits for quality of life and psychosocial functioning over 6 months., Trial Registration: This study is registered at clinicaltrials.gov NCT02246413., (Copyright © 2019 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

We explored the origin of the impaired control of action stability in Parkinson's disease (PD) by testing levodopa-naïve PD patients to disambiguate effects of PD from possible effects of long-term exposure to levodopa. Thirteen levodopa-naïve PD patients and 13 controls performed single- and multi-finger force production tasks, including producing a self-paced quick force pulse into a target. A subgroup of patients (n = 10) was re-tested about 1 h after the first dose of levodopa. Compared to controls, PD patients showed lower maximal forces and synergy indices stabilizing total force (reflecting the higher inter-trial variance component affecting total force). In addition, PD patients showed a trend toward shorter anticipatory synergy adjustments (a drop in the synergy index in preparation to a quick action) and larger non-motor equivalent finger force deviations. Lower maximal force, higher unintentional force production (enslaving) and higher inter-trial variance indices occurred in PD patients after one dosage of levodopa. We conclude that impairment in synergies is present in levodopa-naïve patients, mainly in indices reflecting stability (synergy index), but not agility (anticipatory synergy adjustments). A single dose of levodopa, however, did not improve synergy indices, as it did in PD patients on chronic anti-PD medication, suggesting a different mechanism of action. The results suggest that indices of force-stabilizing synergies may be used as an early behavioral sign of PD, although it may not be sensitive to acute drug effects in drug-naïve patients.

Background: Current drug treatments have little efficacy in advanced-to-end-stage Parkinson's disease (advPD), yet there are no reports of interventional trials in advPD. D1 dopamine agonists have the potential to provide benefit., Objective: To determine the feasibility and safety of the selective D1/D5 dopamine partial agonist PF 06412562 in advPD., Methods: A two-week, randomized, double blind, crossover phase Ib study in advPD patients compared standard-of-care (SoC) carbidopa/levodopa with PF 06412562. Each week, there was a Day 1 baseline evaluation with overnight levodopa washout, then treatment on Days 2 and 3 with either SoC or PF-06412562 (split dose 25 + 20 mg), followed by discharge on Day 4. Primary endpoints were safety and tolerability. Secondary endpoints were global clinical impression of change (GCI-C) rated by clinicians and caregivers., Results: Eight advPD patients and their caregivers consented to participate and six were randomized (average disease duration: 22 y). None withdrew voluntarily. One participant with baseline Day 1 dehydration, pre-renal kidney injury, and autonomic dysfunction experienced symptomatic and serious hypotension after receiving PF-06412562 in Week 1 and was discontinued from the study. All other adverse events were rated mild (PF-06412562: n = 1, SoC: n = 0), moderate (PF-06412562: n = 1, SoC: n = 1), or severe but non-serious (PF-06412562: n = 3, SoC: n = 2). No clinically meaningful laboratory changes were observed. Among the five participants who completed the study, GCI-C favored PF-06412562 in two per clinicians' and four participants per caregivers' rating., Conclusion: PF-06412562 was tolerated in advPD patients. This study provides the feasibility for future safety and efficacy studies in this population with unmet needs.

Background/objective: To synchronize data collection, the National Institute of Neurological Disorders and Stroke (NINDS) recommended Common Data Elements (CDEs) for use in Parkinson's disease (PD) research. This study delineated the progression patterns of these CDEs in a cohort of PD patients., Methods: One hundred-twenty-five PD patients participated in the PD Biomarker Program (PDBP) at Penn State. CDEs, including MDS-Unified PD Rating Scale (UPDRS)-total, questionnaire-based non-motor (-I) and motor (-II), and rater-based motor (-III) subscales; Montreal Cognitive Assessment (MoCA); Hamilton Depression Rating Scale (HDRS); University of Pennsylvania Smell Identification Test (UPSIT); and PD Questionnaire (PDQ-39) were obtained at baseline and three annual follow-ups. Annual change was delineated for PD or subgroups [early = PDE, disease duration (DD) <1 y; middle = PDM, DD = 1-5 y; and late = PDL, DD > 5 y] using mixed effects model analyses., Results: UPDRS-total, -II, and PDQ-39 scores increased significantly, and UPSIT decreased, whereas UPDRS-I, -III, MoCA, and HDRS did not change, over 36 months in the overall PD cohort. In the PDE subgroup, UPDRS-II increased and UPSIT decreased significantly, whereas MoCA and UPSIT decreased significantly in the PDM subgroup. In the PDL subgroup, UPDRS-II and PDQ-39 increased significantly. Other metrics within each individual subgroup did not change. Sensitivity analyses using subjects with complete data confirmed these findings., Conclusion: Among CDEs, UPDRS-total, -II, PDQ-39, and UPSIT all are sensitive metrics to track PD progression. Subgroup analyses revealed that these CDEs have distinct stage-dependent sensitivities, with UPSIT for DD < 5 y, PDQ-39 for DD > 5 y, UPDRS-II for early (DD < 1) or later stages (DD > 5).

Class 2 CRISPR-Cas systems, such as Cas9 and Cas12, have been widely used to target DNA sequences in eukaryotic genomes. However, class 1 CRISPR-Cas systems, which represent about 90% of all CRISPR systems in nature, remain largely unexplored for genome engineering applications. Here, we show that class 1 CRISPR-Cas systems can be expressed in mammalian cells and used for DNA targeting and transcriptional control. We repurpose type I variants of class 1 CRISPR-Cas systems from Escherichia coli and Listeria monocytogenes, which target DNA via a multi-component RNA-guided complex termed Cascade. We validate Cascade expression, complex formation and nuclear localization in human cells, and demonstrate programmable CRISPR RNA (crRNA)-mediated targeting of specific loci in the human genome. By tethering activation and repression domains to Cascade, we modulate the expression of targeted endogenous genes in human cells. This study demonstrates the use of Cascade as a CRISPR-based technology for targeted eukaryotic gene regulation, highlighting class 1 CRISPR-Cas systems for further exploration.

Experiential avoidance (EA) is receiving attention as an emotion regulation strategy and critical factor in the development and maintenance of posttraumatic stress disorder (PTSD) Evidence suggests that EA explains co-varying relationships among topographically dissimilar problem behaviors. The transmission of emotion regulatory strategies is important to understanding the development of these problems. EA may be a learned response style. This conceptual framework was used to test parent EA as a predictor of young adult/older adolescent (offspring) EA, posttraumatic stress symptoms (PTSS), and problem behaviors in a university context as well as to test the best predictors of these outcomes individually for parents and offspring. Two measures of experiential avoidance, the unwillingness to be in contact with distressing emotions, thoughts, and memories were used to predict the outcomes of interest. The Acceptance and Action Questionnaire-II (AAQ-II) was the strongest and only statistically significant predictor of PTSS and problem behaviors for parents and offspring above and beyond trauma history, while the Multidimensional Experiential Avoidance Questionnaire (MEAQ) remained non-significant. Implications regarding measurement discrepancies, PTSS, and harmful behavior trajectories are discussed.

Background: Development of valid, non-invasive biomarkers for parkinsonian syndromes is crucially needed. We aimed to assess whether non-invasive diffusion-weighted MRI can distinguish between parkinsonian syndromes using an automated imaging approach., Methods: We did an international study at 17 MRI centres in Austria, Germany, and the USA. We used diffusion-weighted MRI from 1002 patients and the Movement Disorders Society Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) to develop and validate disease-specific machine learning comparisons using 60 template regions and tracts of interest in Montreal Neurological Institute space between Parkinson's disease and atypical parkinsonism (multiple system atrophy and progressive supranuclear palsy) and between multiple system atrophy and progressive supranuclear palsy. For each comparison, models were developed on a training and validation cohort and evaluated in an independent test cohort by quantifying the area under the curve (AUC) of receiving operating characteristic curves. The primary outcomes were free water and free-water-corrected fractional anisotropy across 60 different template regions., Findings: In the test cohort for disease-specific comparisons, the diffusion-weighted MRI plus MDS-UPDRS III model (Parkinson's disease vs atypical parkinsonism had an AUC 0·962; multiple system atrophy vs progressive supranuclear palsy AUC 0·897) and diffusion-weighted MRI only model had high AUCs (Parkinson's disease vs atypical parkinsonism AUC 0·955; multiple system atrophy vs progressive supranuclear palsy AUC 0·926), whereas the MDS-UPDRS III only models had significantly lower AUCs (Parkinson's disease vs atypical parkinsonism 0·775; multiple system atrophy vs progressive supranuclear palsy 0·582). These results indicate that a non-invasive imaging approach is capable of differentiating forms of parkinsonism comparable to current gold standard methods., Interpretations: This study provides an objective, validated, and generalisable imaging approach to distinguish different forms of parkinsonian syndromes using multisite diffusion-weighted MRI cohorts. The diffusion-weighted MRI method does not involve radioactive tracers, is completely automated, and can be collected in less than 12 min across 3T scanners worldwide. The use of this test could positively affect the clinical care of patients with Parkinson's disease and parkinsonism and reduce the number of misdiagnosed cases in clinical trials., Funding: National Institutes of Health and Parkinson's Foundation., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Chronic high-level manganese (Mn)-induced neurotoxicity has been associated with Mn accumulation in the basal ganglia and higher risk for developing parkinsonism. Recent studies in Mn-exposed animals revealed Mn accumulation in the hippocampus, the presence of Aβ diffuse plaques, and deficits in associative learning, the latter being hallmarks of Alzheimer's disease (AD) or related disorders. This and recent evidence of hippocampal Mn accumulation in welders prompted us to test the hypothesis that welders with chronic Mn exposure would display changes in the hippocampus. Subjects with (welders; n = 42) or without (controls; n = 31) welding history were studied. Mn exposure was estimated by occupational questionnaires, whole blood Mn, and R1 imaging (estimate of short-term brain Mn accumulation). Hippocampal diffusion tensor imaging (DTI; estimate of microstructural brain changes) and volume were determined. Compared with controls, welders displayed no significant difference in hippocampal volume (p = .165). Welders, however, exhibited higher DTI hippocampal mean diffusivity (MD) values compared with controls (p = .035) that was evident particularly in older welders (>50 years, p = .002). Hippocampal MD was associated significantly with age in welders (R = 0.59; p < .001) but not in controls (p = .16). Moreover, higher hippocampal MD values (age adjusted) were associated with long-term cumulative Mn exposure (R = 0.36, p = .021). Welders with chronic exposure have higher MD values in the hippocampus that become greater with increasing age, a brain change that is similar to that observed in those at risk for AD. The current results suggest that Mn exposure, coupled with aging, may make welders more vulnerable to AD or AD-like changes., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)