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The study goal was to use a very large study cohort to establish normative data for the revised UPSIT (UPSIT-R) and to compare the resultant percentiles to those of the original UPSIT. A second study was performed to compare the performance of these two tests in a cohort of persons with and without Parkinson’s disease (PD). UPSIT-R percentiles were derived by age and sex in 16,972 volunteers. Non-parametric statistics were employed to compare the results of those with and without PD. UPSIT-R performance declined with increasing age; deficits were more pronounced in men than women. The magnitude of the difference between the original and revised test percentile scores differed by age and sex. Olfactory deficits in PD were confirmed on the UPSIT-R. This study provides normative data clinically useful for assessing the relative degree of dysfunction in persons 60 years of age and older using the UPSIT-R. Trial Registration Information: ClinicalTrials.gov NCT05065060 .

Emerging evidence shows that α-synuclein seed amplification assays (SAAs) have the potential to differentiate people with Parkinson's disease from healthy controls. We used the well characterised, multicentre Parkinson's Progression Markers Initiative (PPMI) cohort to further assess the diagnostic performance of the α-synuclein SAA and to examine whether the assay identifies heterogeneity among patients and enables the early identification of at-risk groups. This cross-sectional analysis is based on assessments done at enrolment for PPMI participants (including people with sporadic Parkinson's disease from LRRK2 and GBA variants, healthy controls, prodromal individuals with either rapid eye movement sleep behaviour disorder (RBD) or hyposmia, and non-manifesting carriers of LRRK2 and GBA variants) from 33 participating academic neurology outpatient practices worldwide (in Austria, Canada, France, Germany, Greece, Israel, Italy, the Netherlands, Norway, Spain, the UK, and the USA). α-synuclein SAA analysis of CSF was performed using previously described methods. We assessed the sensitivity and specificity of the α-synuclein SAA in participants with Parkinson's disease and healthy controls, including subgroups based on genetic and clinical features. We established the frequency of positive α-synuclein SAA results in prodromal participants (RBD and hyposmia) and non-manifesting carriers of genetic variants associated with Parkinson's disease, and compared α-synuclein SAA to clinical measures and other biomarkers. We used odds ratio estimates with 95% CIs to measure the association between α-synuclein SAA status and categorical measures, and two-sample 95% CIs from the resampling method to assess differences in medians between α-synuclein SAA positive and negative participants for continuous measures. A linear regression model was used to control for potential confounders such as age and sex. This analysis included 1123 participants who were enrolled between July 7, 2010, and July 4, 2019. Of these, 545 had Parkinson's disease, 163 were healthy controls, 54 were participants with scans without evidence of dopaminergic deficit, 51 were prodromal participants, and 310 were non-manifesting carriers. Sensitivity for Parkinson's disease was 87·7% (95% CI 84·9–90·5), and specificity for healthy controls was 96·3% (93·4–99·2). The sensitivity of the α-synuclein SAA in sporadic Parkinson's disease with the typical olfactory deficit was 98·6% (96·4–99·4). The proportion of positive α-synuclein SAA was lower than this figure in subgroups including LRRK2 Parkinson's disease (67·5% [59·2–75·8]) and participants with sporadic Parkinson's disease without olfactory deficit (78·3% [69·8–86·7]). Participants with LRRK2 variant and normal olfaction had an even lower α-synuclein SAA positivity rate (34·7% [21·4–48·0]). Among prodromal and at-risk groups, 44 (86%) of 51 of participants with RBD or hyposmia had positive α-synuclein SAA (16 of 18 with hyposmia, and 28 of 33 with RBD). 25 (8%) of 310 non-manifesting carriers (14 of 159 [9%] LRRK2 and 11 of 151 [7%] GBA) were positive. This study represents the largest analysis so far of the α-synuclein SAA for the biochemical diagnosis of Parkinson's disease. Our results show that the assay classifies people with Parkinson's disease with high sensitivity and specificity, provides information about molecular heterogeneity, and detects prodromal individuals before diagnosis. These findings suggest a crucial role for the α-synuclein SAA in therapeutic development, both to identify pathologically defined subgroups of people with Parkinson's disease and to establish biomarker-defined at-risk cohorts. PPMI is funded by the Michael J Fox Foundation for Parkinson's Research and funding partners, including: Abbvie, AcureX, Aligning Science Across Parkinson's, Amathus Therapeutics, Avid Radiopharmaceuticals, Bial Biotech, Biohaven, Biogen, BioLegend, Bristol-Myers Squibb, Calico Labs, Celgene, Cerevel, Coave, DaCapo Brainscience, 4D Pharma, Denali, Edmond J Safra Foundation, Eli Lilly, GE Healthcare, Genentech, GlaxoSmithKline, Golub Capital, Insitro, Janssen Neuroscience, Lundbeck, Merck, Meso Scale Discovery, Neurocrine Biosciences, Prevail Therapeutics, Roche, Sanofi Genzyme, Servier, Takeda, Teva, UCB, VanquaBio, Verily, Voyager Therapeutics, and Yumanity.

Isolated rapid eye movement sleep behavior disorder (iRBD) is a prodromal state for Lewy body disorders and exhibits biological heterogeneity that may influence clinical expression and progression. We examined clinical features in individuals with iRBD and biomarker-defined synucleinopathy. Parkinson's Progression Markers Initiative (PPMI) is a longitudinal, multi-center observational study. Participants included polysomnogram (PSG)-confirmed iRBD individuals who were cerebrospinal fluid (CSF) α-synuclein seed amplification assay positive with no clinical diagnosis of Parkinson's disease or dementia with Lewy bodies, along with robust healthy controls (HCs). Clinical and biological features of prodromal PD and DLB, including mild cognitive impairment (MCI), subthreshold parkinsonism, and a range of neuropsychiatric, autonomic, and sensory symptoms, were assessed. Compared with HCs (N = 136), iRBD participants (N = 197) demonstrated worse cognitive performance, including a lower cognitive summary score (p < 0.0003, effect size = 0.41), and higher odds of subthreshold parkinsonism (OR = 24.5), and neuropsychiatric (OR = 3.5), autonomic (OR = 7.2) and sensory symptoms (OR = 13.2). Common features included hyposmia (75%), pain (54%), urinary problems (52%), constipation (49%), lightheadedness (40%) and anxiety (36%), whereas rates of MCI (32%), subthreshold parkinsonism (27%) and psychosis (7%) were lower. iRBD participants with abnormal dopamine transporter imaging had higher anxiety scores and antidepressant use. Although only 10% met criteria for prodromal DLB due to the requirement for MCI, most exhibited multi-domain impairment. iRBD with synucleinopathy is associated with multi-domain clinical impairment before clinical neurodegenerative disease diagnosis, supporting broad clinical assessment in early biomarker-defined synuclein disease.

One of the primary means of communicating with a baby is through touch. Nurturing physical touch promotes healthy physiological development in social mammals, including humans. Physiology influences wellbeing and psychosocial functioning. The purpose of this paper is to explore the connections among early life positive and negative touch and wellbeing and sociomoral development. In study 1, mothers of preschoolers ( n = 156) reported their attitudes toward positive/negative touch and on their children’s wellbeing and sociomoral outcomes, illustrating moderate to strong positive correlations between positive touch attitudes and children’s sociomoral capacities and orientations and negative correlations with psychopathology. In study 2, we used an existing longitudinal dataset, with at-risk mothers ( n = 682) and their children to test touch effects on moral capacities and social behaviors in early life. Results demonstrated moderate to strong relationships between positive/negative touch and concurrent child behavioral regulation and positive correlations between low corporal punishment and child sociomoral outcomes. In a third study with adults ( n = 607), we found significant mediation processes connecting retrospective reports of childhood touch to adult moral orientation through attachment security, mental health, and moral capacities. In general across studies, more affectionate touch and less punishing touch were positively associated with wellbeing and development of moral capacities and engaged moral orientation.

RET receptor tyrosine kinase is activated in various cancers (lung, thyroid, colon and pancreatic, among others) through oncogenic fusions or gain-of-function single-nucleotide variants. Small-molecule RET kinase inhibitors became standard-of-care therapy for advanced malignancies driven by RET. The therapeutic benefit of RET inhibitors is limited, however, by acquired mutations in the drug target as well as brain metastasis, presumably due to inadequate brain penetration. Here, we perform preclinical characterization of vepafestinib (TAS0953/HM06), a next-generation RET inhibitor with a unique binding mode. We demonstrate that vepafestinib has best-in-class selectivity against RET, while exerting activity against commonly reported on-target resistance mutations (variants in RET L730 , RET V804 and RET G810 ), and shows superior pharmacokinetic properties in the brain when compared to currently approved RET drugs. We further show that these properties translate into improved tumor control in an intracranial model of RET-driven cancer. Our results underscore the clinical potential of vepafestinib in treating RET-driven cancers.

Teleost fishes and urodele amphibians can regenerate amputated appendages, whereas this ability is restricted to digit tips in adult mammals. One key component of appendage regeneration is reinnervation of the wound area. However, how innervation is regulated in injured appendages of adult vertebrates has seen limited research attention. From a forward genetics screen for temperature-sensitive defects in zebrafish fin regeneration, we identified a mutation that disrupted regeneration while also inducing paralysis at the restrictive temperature. Genetic mapping and complementation tests identify a mutation in the major neuronal voltage-gated sodium channel (VGSC) gene scn8ab. Conditional disruption of scn8ab impairs early regenerative events, including blastema formation, but does not affect morphogenesis of established regenerates. Whereas scn8ab mutations reduced neural activity as expected, they also disrupted axon regrowth and patterning in fin regenerates, resulting in hypoinnervation. Our findings indicate that the activity of VGSCs plays a proregenerative role by promoting innervation of appendage stumps.

Evolutionary systems theory identifies niches as key developmental inheritances for animals. The human evolved developmental niche (EDN) is characterized by positive touch, responsiveness, play, and social togetherness and provides the responsive, relational dynamism that optimizes development. Cross-sectional and longitudinal studies of the human EDN have demonstrated correlations between degree of EDN consistency in early childhood and positive sociomoral development and avoidance of ill-being and misbehavior. We created a brief report of children’s recent EDN experience and examined its relation to child well-being and sociomoral development. Using samples from three cultures (United States, N=574; Switzerland, N=96; China, N=382), EDN provision in the past week was related to multiple child outcomes even after controlling for parental age, education, income, responsivity, and child gender. Factor analyses indicated three sets of latent factors in each sample: Moral Socialization, Social Maladaptation, and Social Thriving. Structural equation models indicated that EDN provision significantly predicted Social Thriving in all samples beyond control variables. EDN provision may be particularly helpful in predicting optimal social development.

Objectives: In Peru, current interventions in high-risk men who have sex with men (MSM) reach a limited number of this population because they rely solely on peer education. The objective of this study was to assess the use of the internet as an alternative tool to access this population. Methods: Two nearly identical banner ads—both advertising an online survey but only one offering free HIV/syphilis tests and condoms—were displayed randomly on a Peruvian gay website. Results: The inclusion of the health incentive increased the frequency of completed surveys (5.8% vs 3.4% of delivered impressions; p<0.001), attracting high-risk MSM not previously tested for HIV but interested in a wide variety of preventive Web-based interventions. Eleven per cent (80/713) of participants who said they had completed the survey offering free testing visited our clinic: of those who attended, 6% had already been diagnosed as having HIV, while 5% tested positive for HIV. In addition, 8% tested positive for syphilis. Conclusions: The internet can be used as a tool to access MSM in Peru. The compensation of a free HIV/syphilis test increased the frequency of participation in our online survey, indicating that such incentives may be an effective means of reaching this population. However, as only a small percentage of participants actually reported for testing, future research should develop and assess tailored internet interventions to increase HIV/STI testing and delivery of other prevention services to Peruvian MSM.