A Healthy Conversation Skills intervention to support changes to physical activity and dietary behaviours in community-dwelling older adults during the COVID-19 pandemic.

AIMS: Physical activity (PA) and nutrition are important determinants of health in late adulthood. However, low levels of PA and poor nutrition are common in older adults and have become more prevalent during the COVID-19 pandemic. We hypothesised that Healthy Conversation Skills could be used to support health behaviour changes beneficial for health in older adults and thus conducted a study nested within the UK Hertfordshire Cohort Study. METHODS: Between November 2019 and March 2020, 176 participants were visited at home. A trained researcher administered a questionnaire and undertook anthropometric and physical performance tests. A total of 89 participants were randomised to the control group and received a healthy living leaflet; 87 participants in the intervention group were interviewed using Healthy Conversation Skills at the initial visit with follow-up telephone calls at 1, 3, 6 and 9 months. Follow-up at 1 year by postal questionnaire assessed change in PA and diet. In total, 155 participants (79 control and 76 intervention) completed the baseline and 1-year follow-up. RESULTS: At baseline, median (lower quartile, upper quartile) age (years) was 83.1 (81.5, 85.5) and median PA time (min/day) from walking, cycling and sports was 30.0 (15.0, 60.0). In total, 95% of participants completed the intervention; the total response rate for postal questionnaires was 94%. There were no statistically significant differences in outcomes between the trial arms. In women, there was a tendency for greater increases in diet quality in the intervention group compared to the control group (p = 0.075), while among men, there was a tendency for reduced decline in self-reported physical function in the intervention group compared to the control group (p = 0.081). CONCLUSION: We have shown that it is viable to utilise Healthy Conversation Skills via telephone to promote healthier lifestyles in older adults. Larger appropriately powered studies to determine the efficacy of such an intervention are now warranted.

Developing and Evaluating a Situated Assessment Instrument for Trichotillomania: The SAM2 TAI.

Measuring trichotillomania is essential for understanding and treating it effectively. Using the Situated Assessment Method (SAM2), we developed a psychometric instrument to assess hair pulling in situations where it occurs. In two studies, pullers evaluated their pulling in relevant situations, along with how much they experience factors that potentially influence it (e.g., external triggers, reduction in negative emotion, negative self-thoughts). Individual measures of pulling, averaged across situations, exhibited high test reliability, construct validity, and content validity. Large differences between situations in pulling were observed, along with large individual-situation interactions (with limited evidence distinguishing focused versus automatic pulling subtypes). In linear regressions for individual participants, factors that influence pulling tended to correlate with pulling as predicted, explaining a median 74%-83% of its variance. By identifying factors that predict pulling for each individual across situations, the SAM2 Trichotillomania Assessment Instrument (TAI) offers a rich understanding of an individual's pulling experience, potentially supporting individualized pulling interventions.

Deletion in RMST lncRNA impairs hypothalamic neuronal development in a human stem cell-based model of Kallmann Syndrome.

Rhabdomyosarcoma 2-associated transcript (RMST) long non-coding RNA has previously been shown to cause Kallmann syndrome (KS), a rare genetic disorder characterized by congenital hypogonadotropic hypogonadism (CHH) and olfactory dysfunction. In the present study, we generated large deletions of approximately 41.55 kb in the RMST gene in human pluripotent stem cells using CRISPR/Cas9 gene editing. To evaluate the impact of RMST deletion, these cells were differentiated into hypothalamic neurons that include 10-15% neurons that express gonadotrophin-releasing hormone (GnRH). We found that deletion in RMST did not impair the neurogenesis of GnRH neurons, however, the hypothalamic neurons were electro-physiologically hyperactive and had increased calcium influx activity compared to control. Transcriptomic and epigenetic analyses showed that RMST deletion caused altered expression of key genes involved in neuronal development, ion channels, synaptic signaling and cell adhesion. The in vitro generation of these RMST-deleted GnRH neurons provides an excellent cell-based model to dissect the molecular mechanism of RMST function in Kallmann syndrome and its role in hypothalamic neuronal development.

Effectiveness of Influenza Vaccination During Pregnancy Against Laboratory-Confirmed Seasonal Influenza Among Infants Under 6 Months of Age in Ontario, Canada.

BACKGROUND: Randomized trials conducted in low- and middle-income settings demonstrated efficacy of influenza vaccination during pregnancy against influenza infection among infants <6 months of age. However, vaccine effectiveness (VE) estimates from settings with different population characteristics and influenza seasonality remain limited. METHODS: We conducted a test-negative study in Ontario, Canada. All influenza virus tests among infants <6 months from 2010 to 2019 were identified and linked with health databases to ascertain information on maternal-infant dyads. VE was estimated from the odds ratio for influenza vaccination during pregnancy among cases versus controls, computed using logistic regression with adjustment for potential confounders. RESULTS: Among 23 806 infants tested for influenza, 1783 (7.5%) were positive and 1708 (7.2%) were born to mothers vaccinated against influenza during pregnancy. VE against laboratory-confirmed infant influenza infection was 64% (95% confidence interval [CI], 50%-74%). VE was similar by trimester of vaccination (first/second, 66% [95% CI, 40%-80%]; third, 63% [95% CI, 46%-74%]), infant age at testing (0 to <2 months, 63% [95% CI, 46%-75%]; 2 to <6 months, 64% [95% CI, 36%-79%]), and gestational age at birth (≥37 weeks, 64% [95% CI, 50%-75%]; < 37 weeks, 61% [95% CI, 4%-86%]). VE against influenza hospitalization was 67% (95% CI, 50%-78%). CONCLUSIONS: Influenza vaccination during pregnancy offers effective protection to infants <6 months, for whom vaccines are not currently available.

Deep autoencoder as an interpretable tool for Raman spectroscopy investigation of chemical and extracellular vesicle mixtures.

Surface-enhanced Raman spectroscopy (SERS) is a powerful tool that provides valuable insight into the molecular contents of chemical and biological samples. However, interpreting Raman spectra from complex or dynamic datasets remains challenging, particularly for highly heterogeneous biological samples like extracellular vesicles (EVs). To overcome this, we developed a tunable and interpretable deep autoencoder for the analysis of several challenging Raman spectroscopy applications, including synthetic datasets, chemical mixtures, a chemical milling reaction, and mixtures of EVs. We compared the results with classical methods (PCA and UMAP) to demonstrate the superior performance of the proposed technique. Our method can handle small datasets, provide a high degree of generalization such that it can fill unknown gaps within spectral datasets, and even quantify relative ratios of cell line-derived EVs to fetal bovine serum-derived EVs within mixtures. This simple yet robust approach will greatly improve the analysis capabilities for many other Raman spectroscopy applications.

Preventing Exertional Heat Stroke in Football: Time for a Paradigm Shift.

CONTEXT: Among American sports, football has the highest incidence of exertional heat stroke (EHS), despite decades of prevention strategies. Based on recent reports, 100% of high school and college EHS football fatalities occur during conditioning sessions. Linemen are the at-risk population, constituting 97% of football EHS deaths. Linemen heat up faster and cool down slower than other players. EVIDENCE ACQUISITION: Case series were identified from organized, supervised football at the youth, high school, and collegiate levels and compiled in the National Registry of Catastrophic Sports Injuries. Sources for event occurrence were media reports and newspaper clippings, autopsy reports, certificates of death, school-sponsored investigations, and published medical literature. Articles were identified through PubMed with search terms "football," "exertional heat stroke," and "prevention." STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 5. RESULTS: Football EHS is tied to (1) high-intensity drills and conditioning that is not specific to individual player positions, (2) physical exertion as punishment; (3) failure to modify physical activity for high heat and humidity, (4) failure to recognize early signs and symptoms of EHS, and (5) death when cooling is delayed. CONCLUSION: To prevent football EHS, (1) all training and conditioning should be position specific; (2) physical activity should be modified per the heat load; (3) understand that some players have a "do-or-die" mentality that supersedes their personal safety; (4) never use physical exertion as punishment; (5) eliminate conditioning tests, serial sprints, and any reckless drills that are inappropriate for linemen; and (6) consider air-conditioned venues for linemen during hot practices. To prevent EHS, train linemen based on game demands. STRENGTH-OF-RECOMMENDATION TAXONOMY: n/a.

Blue-Detuned Magneto-optical Trap of CaF Molecules.

A key method to produce trapped and laser-cooled molecules is the magneto-optical trap (MOT), which is conventionally created using light red detuned from an optical transition. In this work, we report a MOT for CaF molecules created using blue-detuned light. The blue-detuned MOT (BDM) achieves temperatures well below the Doppler limit and provides the highest densities and phase-space densities reported to date in CaF MOTs. Our results suggest that BDMs are likely achievable in many relatively light molecules including polyatomic ones, but our measurements suggest that BDMs will be challenging to realize in substantially heavier molecules due to sub-mK trap depths. In addition to record temperatures and densities, we find that the BDM substantially simplifies and enhances the loading of molecules into optical tweezer arrays, which are a promising platform for quantum simulation and quantum information processing. Notably, the BDM reduces molecular number requirements ninefold compared to a conventional red-detuned MOT, while not requiring additional hardware. Our work therefore substantially simplifies preparing large-scale molecular tweezer arrays, which are a novel platform for simulation of quantum many-body dynamics and quantum information processing with molecular qubits.

2D and 3D Self-Assembly of Fluorine-Free Pillar-[5]-Arenes and Perfluorinated Diacids at All-Aqueous Interfaces.

The interaction of perfluorinated molecules, also known as "forever chemicals" due to their pervasiveness, with their environment remains an important yet poorly understood topic. In this work, the self-assembly of perfluorinated molecules with multivalent hosts, pillar-[5]-arenes, is investigated. It is found that perfluoroalkyl diacids and pillar-[5]-arenes rapidly and strongly complex with each other at aqueous interfaces, forming solid interfacially templated films. Their complexation is shown to be driven primarily by fluorophilic aggregation and assisted by electrostatic interactions, as supported by the crystal structure of the complexes, and leads to the formation of quasi-2D phase-separated films. This self-assembly process can be further manipulated using aqueous two-phase system microdroplets, enabling the controlled formation of 3D micro-scaffolds.

Antiphospholipid-exposed trophoblast-derived extracellular vesicles express elevated levels of TLR7/8-activating microRNAs and induce endometrial endothelial activation, in part, through TLR7.

Women with antiphospholipid syndrome (APS) are at high risk for miscarriage and preeclampsia. Unlike pro-thrombotic systemic APS, obstetric APS is associated with insufficient placentation, as well as inflammation and vascular dysfunction at the maternal-fetal interface. Antiphospholipid antibodies (aPL) can target the placental trophoblast and induce inflammation. We reported that aPL trigger trophoblast cells to produce elevated levels of IL-8 through activation of Toll-like receptor 4 (TLR4). Downstream of TLR4, we found this IL-8 response is mediated by a TLR8-activating microRNA (miR), miR-146a-3p, which is also released by the trophoblast via extracellular vesicles (EVs). Since endothelial dysfunction is a feature of obstetric APS, we sought to determine if other miRs that can activate the RNA sensors, TLR7 and/or TLR8, are released by the trophoblast via EVs after exposure to aPL, and if these EVs can activate human endometrial endothelial cells (HEECs). Using a human first trimester extravillous trophoblast cell line we found that aPL elevated their release of small EVs (<150 nm). These extracellular vesicles released from trophoblast cells exposed to aPL expressed elevated levels of TLR7/8-activating miR-21a and miR-29a, in addition to the previously reported miR-146a-3p. Extracellular vesicles from aPL-exposed human trophoblast cells triggered human endometrial endothelial cells to generate an inflammatory IL-8 response, in part through TLR7. This study highlights EVs as a mode of communication between the placenta and the maternal vasculature, as well as a potential role for TLR7/8-activating miRs in contributing to inflammation at the maternal-fetal interface in obstetric APS.

Type III Vasa Previa Associated with Resolution of a Low-Lying Placenta: Case Report and Literature Review.

Vasa previa occurs when fetal vessels lie above the cervical os. A novel type of vasa previa, known as type III, is characterized by an abnormal branching of fetal vessels from the placenta in the absence of velamentous cord insertion (as seen in type I) or multilobed placenta (as seen in type II). Here, we present a case of a type III vasa previa after a resolution of a low-lying placenta. The presence of any known risk factors of vasa previa, including low-lying placenta, should prompt screening for vasa previa in the third trimester. Accurate and timely diagnosis of vasa previa will confer significant survival benefit for the neonate.

Extracellular vesicles and their effect on vascular haemodynamics: a systematic review.

Extracellular vesicles (EVs) are released from all cell types studied to date and act as intercellular communicators containing proteins, nucleic acids and lipid cargos. They have been shown to be involved in maintaining homoeostasis as well as playing a role in the development of pathology including hypertension and cardiovascular disease. It is estimated that there is 109-1010 circulating EVs/mL in the plasma of healthy individuals derived from various sources. While the effect of EVs on vascular haemodynamic parameters will be dependent on the details of the model studied, we systematically searched and summarized current literature to find patterns in how exogenously injected EVs affected vascular haemodynamics. Under homoeostatic conditions, evidence from wire and pressure myography data demonstrate that injecting isolated EVs derived from cell types found in blood and blood vessels resulted in the impairment of vasodilation in blood vessels ex vivo. Impaired vasodilation was also observed in rodents receiving intravenous injections of human plasma EVs from cardiovascular diseases including valvular heart disease, acute coronary syndrome, myocardial infarction and end stage renal disease. When EVs were derived from models of metabolic syndromes, such as diabetes, these EVs enhanced vasoconstriction responses in blood vessels ex vivo. There were fewer publications that assessed the effect of EVs in anaesthetised or conscious animals to confirm whether effects on the vasculature observed in ex vivo studies translated into alterations in vascular haemodynamics in vivo. In the available conscious animal studies, the in vivo data did not always align with the ex vivo data. This highlights the importance of in vivo work to determine the effects of EVs on the integrative vascular haemodynamics.

Pseudoprogression in a patient with metastatic melanoma treated with PD-1 and LAG-3 inhibition.

Pseudoprogression encapsulates a process of temporary radiographic growth followed by subsequent regression of metastatic melanoma lesions in response to immune checkpoint blockade (ICB), such as the combination of anti-programmed cell death protein 1 (PD-1) and anticytotoxic T-lymphocyte-associated antigen 4 therapy. This occurs in approximately 5-10% of ICB-treated patients, but has not yet been described in the context of novel combination therapies. Here, we report a case of an 89-year-old patient with metastatic melanoma to the liver, lung and lymph nodes, who underwent treatment with Opdualag (combining anti-PD-1 nivolumab and anti-lymphocyte-activation gene 3 relatlimab ICBs), and developed pseudoprogression after two cycles of therapy. The patient experienced a radiographic increase in liver metastatic lesion size, but was found to have a subsequent reduction in these lesions. The patient has been on therapy for 18 months without evidence of disease progression and continues to be clinically well-appearing.

Biosensing with Oleosin-Stabilized Liquid Crystal Droplets.

Liquid crystals (LCs) are emerging as novel platforms for chemical, physical, and biological sensing. They can be used to detect biological amphiphiles such as lipids, fatty acids, digestive surfactants, and bacterial endotoxins. However, designing LC-based sensors in a manner that preserves their sensitivity and responsiveness to these stimuli, and possibly improves biocompatibility, remains challenging. In this work, the stabilization of LC droplets by oleosins, plant-sourced and highly surface active proteins due to their extended amphipathic helix, is investigated. Purified oleosins, at sub-micromolar concentrations, are shown to readily stabilize nematic LC droplets without switching their alignment, allowing them to detect surfactants at micromolar concentrations. Direct evidence of localization of oleosins at the LC-water interface is provided with fluorescent labeling, and the stabilized droplets remain stable over months. Interestingly, chiral LC droplets readily switch in the presence of nanomolar oleosin concentrations, an unexpected behavior that is explained by accounting for the energy barriers required for switching the alignment between the two cases. This leads thus to a twofold conclusion: oleosin-stabilized nematic LC droplets present a biocompatible alternative for bioanalyte detection, while chiral LCs can be further investigated for use as highly sensitive sensors for detecting amphipathic helices in biological systems.

Power-Doppler Ultrasonic Imaging of Peripheral Perfusion in Diabetic Mice.

OBJECTIVE: We explored the capabilities of power-Doppler ultrasonic (PD-US) imaging without contrast enhancement for monitoring changes in muscle perfusion over time. METHODS: Ischemic recovery was observed in healthy and type II diabetic male and female mice with and without exercise. In separate studies, perfusion was measured during and after 5-min ischemic periods and during four-week recovery periods following irreversible femoral ligation. A goal was to assess how well PD-US estimates tracked the diabetic-related changes in endothelial function that influenced perfusion. RESULTS: The average perfusion recovery time following femoral ligation increased 47% in diabetic males and 74% in diabetic females compared with non-diabetic mice. Flow-mediated dilation in conduit arteries and the reactive hyperemia index in resistive vessels each declined by one half in sedentary diabetic mice compared with sedentary non-diabetic mice. We found that exercise reduced the loss of endothelial function from diabetes in both sexes. The reproducibility of perfusion measurements was limited primarily by our ability to select the same region in muscle and to effectively filter tissue clutter. CONCLUSIONS/SIGNIFICANCE: PD-US measurements can precisely follow site-specific changes in skeletal muscle perfusion related to diabetes over time, which fills the need for techniques capable of regularly monitoring atherosclerotic changes leading to ischemic vascular pathologies.

The Impact of LY487379 or CDPPB on eNOS Expression in the Mouse Brain and the Effect of Joint Administration of Compounds with NO• Releasers on MK-801- or Scopolamine-Driven Cognitive Dysfunction in Mice.

The role of endothelial nitric oxide synthase (eNOS) in the regulation of a variety of biological processes is well established, and its dysfunction contributes to brain pathologies, including schizophrenia or Alzheimer's disease (AD). Positive allosteric modulators (PAMs) of metabotropic glutamate (mGlu) receptors were shown to be effective procognitive compounds, but little is known about their impact on eNOS expression and stability. Here, we investigated the influence of the acute and chronic administration of LY487379 or CDPPB (mGlu2 and mGlu5 PAMs), on eNOS expression in the mouse brain and the effect of the joint administration of the ligands with nitric oxide (NO) releasers, spermineNONOate or DETANONOate, in different combinations of doses, on MK-801- or scopolamine-induced amnesia in the novel object recognition (NOR) test. Our results indicate that both compounds provoked eNOS monomer formation, and CDPPB at a dose of 5 mg/kg exaggerated the effect of MK-801 or scopolamine. The coadministration of spermineNONOate or DETANONOate enhanced the antiamnesic effect of CDPPB or LY487379. The best activity was observed for ineffective or moderate dose combinations. The results indicate that treatment with mGluR2 and mGluR5 PAMs may be burdened with the risk of promoting eNOS uncoupling through the induction of dimer dissociation. Administration of the lowest possible doses of the compounds with NO• donors, which themselves have procognitive efficacy, may be proposed for the treatment of schizophrenia or AD.

The Association of Agent Orange Exposure with the progression of monoclonal gammopathy of undetermined significance to multiple myeloma: a population-based study of Vietnam War Era Veterans.

Herbicide and pesticide exposure [e.g., agent orange (AO)] is associated with an increased risk of multiple myeloma (MM) due to the contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, it is unclear whether TCDD/AO exposure (AO exposure hereafter) increases the risk of progression of monoclonal gammopathy of undetermined significance (MGUS) to MM. We sought to evaluate the association in a nationwide study of US Veterans. A natural language processing algorithm was used to confirm MGUS and progression to MM. We included Veterans who were diagnosed with MGUS from 10/1/1999 to 12/31/2021 and served during the Vietnam War Era from 1/9/1962 to 5/7/1975. AO exposure was stratified according to three TCDD exposure levels: high (1/9/1962-11/30/1965), medium (12/1/1965-12/31/1970), or low (1/1/1971-5/7/1975). The association between AO exposure and progression was analyzed using multivariable Fine-Gray subdistribution hazard model with death as a competing event. The analytic cohort included 10,847 Veterans with MGUS, of whom 26.3% had AO exposure and 7.4% progressed to MM over a median follow-up of 5.2 years. In multivariable analysis, high exposure was associated with an increased progression rate (multivariable-adjusted hazard ratio 1.48; 95% confidence interval 1.02-2.16), compared to Veterans with no exposure. This information is critical to inform progression risk in patients diagnosed with MGUS and prior AO exposure. It is also applicable to MGUS patients with occupational TCDD exposure from herbicides and pesticides.

Diverse array of neutralizing antibodies elicited upon Spike Ferritin Nanoparticle vaccination in rhesus macaques.

The repeat emergence of SARS-CoV-2 variants of concern (VoC) with decreased susceptibility to vaccine-elicited antibodies highlights the need to develop next-generation vaccine candidates that confer broad protection. Here we describe the antibody response induced by the SARS-CoV-2 Spike Ferritin Nanoparticle (SpFN) vaccine candidate adjuvanted with the Army Liposomal Formulation including QS21 (ALFQ) in non-human primates. By isolating and characterizing several monoclonal antibodies directed against the Spike Receptor Binding Domain (RBD), N-Terminal Domain (NTD), or the S2 Domain, we define the molecular recognition of vaccine-elicited cross-reactive monoclonal antibodies (mAbs) elicited by SpFN. We identify six neutralizing antibodies with broad sarbecovirus cross-reactivity that recapitulate serum polyclonal antibody responses. In particular, RBD mAb WRAIR-5001 binds to the conserved cryptic region with high affinity to sarbecovirus clades 1 and 2, including Omicron variants, while mAb WRAIR-5021 offers complete protection from B.1.617.2 (Delta) in a murine challenge study. Our data further highlight the ability of SpFN vaccination to stimulate cross-reactive B cells targeting conserved regions of the Spike with activity against SARS CoV-1 and SARS-CoV-2 variants.

Spatial synchrony cascades across ecosystem boundaries and up food webs via resource subsidies.

Cross-ecosystem subsidies are critical to ecosystem structure and function, especially in recipient ecosystems where they are the primary source of organic matter to the food web. Subsidies are indicative of processes connecting ecosystems and can couple ecological dynamics across system boundaries. However, the degree to which such flows can induce cross-ecosystem cascades of spatial synchrony, the tendency for system fluctuations to be correlated across locations, is not well understood. Synchrony has destabilizing effects on ecosystems, adding to the importance of understanding spatiotemporal patterns of synchrony transmission. In order to understand whether and how spatial synchrony cascades across the marine-terrestrial boundary via resource subsidies, we studied the relationship between giant kelp forests on rocky nearshore reefs and sandy beach ecosystems that receive resource subsidies in the form of kelp wrack (detritus). We found that synchrony cascades from rocky reefs to sandy beaches, with spatiotemporal patterns mediated by fluctuations in live kelp biomass, wave action, and beach width. Moreover, wrack deposition synchronized local abundances of shorebirds that move among beaches seeking to forage on wrack-associated invertebrates, demonstrating that synchrony due to subsidies propagates across trophic levels in the recipient ecosystem. Synchronizing resource subsidies likely play an underappreciated role in the spatiotemporal structure, functioning, and stability of ecosystems.

A Randomized Phase 3 Study Comparing P2B001 to its Components (Low-Dose Extended-Release Rasagiline and Pramipexole) and to Optimized Doses of Marketed Extended-Release Pramipexole in Early Parkinson's Disease.

BACKGROUND: There remains uncertainty as to the optimal way to initiate therapy for Parkinson's disease (PD) to maximize benefit and minimize adversity. OBJECTIVES: The objective was to determine if P2B001 (a fixed, low-dose, extended-release [ER] combination of pramipexole 0.6 mg and rasagiline 0.75 mg) is superior to each of its components and compare its safety and efficacy to optimized treatment with marketed doses of pramipexole-ER. METHODS: This was a 12-week, double-blind study (NCT03329508). Total of 544 untreated patients with PD were randomized (2:2:2:1) to treatment with P2B001, its individual components (pramipexole-ER 0.6 mg or rasagiline-ER 0.75 mg), or commercial doses of pramipexole-ER titrated to optimal dose (1.5-4.5 mg). The primary endpoint was change from baseline to week 12 in Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III. The key secondary endpoint was the change from baseline in the Epworth Sleepiness Scale (ESS) for P2B001 versus the titrated dose of pramipexole-ER. RESULTS: P2B001 provided superior efficacy compared to each of its components; mean (95% CI) treatment differences in UPDRS II + III scores were -2.66 (95% CI, -4.33 to -1.00) versus pramipexole-ER 0.6 mg (P = 0.0018) and - 3.30 (95% CI, -4.96 to -1.63) versus rasagiline-ER 0.75 mg (P < 0.0001). P2B001 had comparable efficacy with the titrated dose of pramipexole-ER (mean, 3.2 mg), but significantly less worsening in daytime-sleepiness (ESS treatment difference: -2.66 [95% CI, -3.50 to -1.81]; P < 0.0001). P2B001 was well-tolerated with fewer sleep-related and dopaminergic adverse events than titrated doses of pramipexole-ER including somnolence, orthostatic hypotension, and neuropsychiatric side effects. CONCLUSIONS: P2B001 had superior efficacy to its individual components and was comparable with commercially used doses of pramipexole-ER with less worsening of sleepiness and fewer dopaminergic adverse events. These findings support considering once-daily P2B001 as initial therapy for patients with early PD. © 2023 International Parkinson and Movement Disorder Society.