Smartphone Voice Calls Provide Early Biomarkers of Parkinsonism in Rapid Eye Movement Sleep Behavior Disorder.

BACKGROUND: Speech dysfunction represents one of the initial motor manifestations to develop in Parkinson's disease (PD) and is measurable through smartphone. OBJECTIVE: The aim was to develop a fully automated and noise-resistant smartphone-based system that can unobtrusively screen for prodromal parkinsonian speech disorder in subjects with isolated rapid eye movement sleep behavior disorder (iRBD) in a real-world scenario. METHODS: This cross-sectional study assessed regular, everyday voice call data from individuals with iRBD compared to early PD patients and healthy controls via a developed smartphone application. The participants also performed an active, regular reading of a short passage on their smartphone. Smartphone data were continuously collected for up to 3 months after the standard in-person assessments at the clinic. RESULTS: A total of 3525 calls that led to 5990 minutes of preprocessed speech were extracted from 72 participants, comprising 21 iRBD patients, 26 PD patients, and 25 controls. With a high area under the curve of 0.85 between iRBD patients and controls, the combination of passive and active smartphone data provided a comparable or even more sensitive evaluation than laboratory examination using a high-quality microphone. The most sensitive features to induce prodromal neurodegeneration in iRBD included imprecise vowel articulation during phone calls (P = 0.03) and monopitch in reading (P = 0.05). Eighteen minutes of speech corresponding to approximately nine calls was sufficient to obtain the best sensitivity for the screening. CONCLUSION: We consider the developed tool widely applicable to deep longitudinal digital phenotyping data with future applications in neuroprotective trials, deep brain stimulation optimization, neuropsychiatry, speech therapy, population screening, and beyond. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Linguistic Abnormalities in Isolated Rapid Eye Movement Sleep Behavior Disorder.

BACKGROUND: Patients with synucleinopathies frequently display language abnormalities. However, whether patients with isolated rapid eye movement sleep behavior disorder (iRBD) have prodromal language impairment remains unknown. OBJECTIVE: We examined whether the linguistic abnormalities in iRBD can serve as potential biomarkers for conversion to synucleinopathy, including the possible effect of mild cognitive impairment (MCI), speaking task, and automation of analysis procedure. METHODS: We enrolled 139 Czech native participants, including 40 iRBD without MCI and 14 iRBD with MCI, compared with 40 PD without MCI, 15 PD with MCI, and 30 healthy control subjects. Spontaneous discourse and story-tale narrative were transcribed and linguistically annotated. A quantitative analysis was performed computing three linguistic features. Human annotations were compared with fully automated annotations. RESULTS: Compared with control subjects, patients with iRBD showed poorer content density, reflecting the reduction of content words and modifiers. Both PD and iRBD subgroups with MCI manifested less occurrence of unique words and a higher number of n-grams repetitions, indicating poorer lexical richness. The spontaneous discourse task demonstrated language impairment in iRBD without MCI with an area under the curve of 0.72, while the story-tale narrative task better reflected the presence of MCI, discriminating both PD and iRBD subgroups with MCI from control subjects with an area under the curve of up to 0.81. A strong correlation between manually and automatically computed results was achieved. CONCLUSIONS: Linguistic features might provide a reliable automated method for detecting cognitive decline caused by prodromal neurodegeneration in subjects with iRBD, providing critical outcomes for future therapeutic trials. © 2022 International Parkinson and Movement Disorder Society.

Unified Total Synthesis of Diverse Meroterpenoids from Ganoderma Applanatum.

A unified approach to meroterpenoids applanatumols B, V, W, X, and Y produced by the medicinal fungus Ganoderma applanatum and 2'-epi-spiroapplanatumine O is presented. The key synthetic sequence consists of a tandem anionic ketone allylation/oxy-Cope rearrangement/α-oxygenation furnishing an α-aminoxy ketone and a persistent radical effect-based 5-exo-trig cyclization leading to the trisubstituted cyclopentane core. The relative configuration of applanatumol V has to be revised. Some compounds display significant cytotoxic and antioxidant properties.

Validation of cepstral peak prominence in assessing early voice changes of Parkinson's disease: Effect of speaking task and ambient noise.

Although the cepstral peak prominence (CPP) and its variant, the cepstral peak prominence smooth (CPPS), are considered to be robust acoustic measures for the evaluation of dysphonia, whether they are sensitive to capture early voice changes in Parkinson's disease (PD) has not yet been explored. This study aimed to investigate the voice changes via the CPP measures in the idiopathic rapid eye movement sleep behavior disorder (iRBD), a special case of prodromal neurodegeneration, and recently diagnosed and advanced-stage Parkinson's disease (AS-PD) patients using different speaking tasks across noise-free and noisy environments. The sustained vowel phonation, reading of passages, and monologues of 60 early stage untreated PD, 30 advanced-stage Parkinson's disease, 60 iRBD, and 60 healthy control (HC) participants were evaluated. Significant differences were found between the PD groups and controls in sustained phonation via the CPP (p < 0.05) and CPPS (p < 0.01) and the monologue via the CPP (p < 0.01), although neither the CPP nor CPPS measures were sufficiently sensitive to capture the possible prodromal dysphonia in the iRBD. The quality of the CPP and CPPS measures was influenced substantially by the addition of ambient noise. It was anticipated that the CPP measures might serve as a promising digital biomarker in assessing the dysphonia from the early stages of PD.

Tandem Anionic oxy-Cope Rearrangement/Oxygenation Reactions as a Versatile Method for Approaching Diverse Scaffolds.

Tandem anionic oxy-Cope rearrangement/radical oxygenation reactions provide δ,ϵ-unsaturated α-(aminoxy) carbonyl compounds, which serve as convenient precursors to diverse compound classes. Functionalized carbocycles are accessible by very rare all-carbon 5-endo-trig cyclizations, but also common 5-exo-trig radical cyclizations, based on the persistent radical effect. The tandem reactions can be further extended by highly diastereoselective allylation or reduction steps to give complex scaffolds.

Decarboxylative Organocatalytic Allylic Amination of Morita-Baylis-Hillman Carbamates.

The present study reports the organocatalytic enantioselective allylic amination of Morita-Baylis-Hillman carbamates efficiently catalyzed by a chiral amine in the presence of a Brønsted acid. Chiral allylic amines were produced in high yields (up to 98 %) and enantioselectivities (up to 97 % ee). This method provides an efficient and easily performed route to prepare α-methylene-ß-lactams, and other optically active ß-lactams, such as the cholesterol-lowering drug Ezetimibe.

Asymmetric organocatalytic synthesis of tertiary azomethyl alcohols: key intermediates towards azoxy compounds and α-hydroxy-ß-amino esters.

A series of peracylated glycosamine-derived thioureas have been synthesized and their behavior as bifunctional organocatalysts has been tested in the enantioselective nucleophilic addition of formaldehyde tert-butyl hydrazone to aliphatic α-keto esters for the synthesis of tertiary azomethyl alcohols. Using the 1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-ß-d-glucosamine derived 3,5-bis-(trifluoromethyl)phenyl thiourea the reaction could be accomplished with high yields (75-98%) and moderate enantioselectivities (50-64% ee). Subsequent high-yielding and racemization-free tranformations of both aromatic- and aliphatic-substituted diazene products in a one pot fashion provide a direct entry to valuable azoxy compounds and α-hydroxy-ß-amino esters.

Salt-kneading: alternative sizing of active pharmaceutical ingredients?

The most of currently produced active pharmaceutical ingredients (APIs) are poorly soluble in the human body. One of the options how to increase their dissolution rate is reducing their particle size. If very small particles of API are desired, traditional milling methods often cause smeared, agglomerated or non-flowing particles due to the forces applied. We tried to compare some of milling methods with the salt-kneading method, which is not typically used in the pharmaceutical industry. Salt-kneading process is driven by several variable parameters (e.g. the amount, hardness and particle size of the salt-kneading material), which influence the degree of size reduction of API particles which are chafed by a surplus of salt-kneading material. A model poorly-soluble API was separately processed with oscillation mill, vibratory mill and kneader; and the morphology, size distribution and solid form of prepared particles were analyzed. Our basic variation of salt-kneading parameters showed the potential of the salt-kneading method, which appears a very effective method of API controlled reduction. The final size can be modified according to the amount and properties of the salt-kneading material. The availability of such a method equips pharmaceutical scientists with a size-reduction method that provides very small, rounded and free-flowing particles of the poorly soluble API and reduces non-preferred needle shape.

Hot-stage microscopy for determination of API fragmentation: comparison with other methods.

Although the fragmentation of the active pharmaceutical ingredient (API) is a phenomenon that is mentioned in many literature sources, no well-suited analytical tools for its investigation are currently known. We used the hot-stage microscopy method, already presented in our previous work, and studied the real fragmentation of the tadalafil particles in model tablets which were prepared under different compaction pressures. The morphology, spectral imaging and evaluation of plastic and elastic energies were also analyzed to support the hot-stage method. The prepared blend of tadalafil and excipients was compacted under a several forces from 5 to 35 kN to reveal the trend of fragmentation. The exact fragmentation of tadalafil with increased compaction pressure was revealed by the hot-stage microscopic method and it was in good agreement with plastic and elastic energies. Conversely, spectral imaging, which is being used for this analysis, was considered to be inaccurate methodology as mainly agglomerates, not individual particles, were measured. The availability of the hot-stage microscopic method equips pharmaceutical scientists with an in vitro assessment technique that will more reliably determine the fragmentation of the API in finished tablets and the behavior of the particles when compacted.

Hot-stage microscopy for determination of API particles in a formulated tablet.

Although methods exist to readily determine the particle size distribution (PSD) of an active pharmaceutical ingredient (API) before its formulation into a final product, the primary challenge is to develop a method to determine the PSD of APIs in a finished tablet. To address the limitations of existing PSD methods, we used hot-stage microscopy to observe tablet disintegration during temperature change and, thus, reveal the API particles in a tablet. Both mechanical and liquid disintegration were evaluated after we had identified optimum milling time for mechanical disintegration and optimum volume of water for liquid disintegration. In each case, hot-stage micrographs, taken before and after the API melting point, were compared with image analysis software to obtain the PSDs. Then, the PSDs of the APIs from the disintegrated tablets were compared with the PSDs of raw APIs. Good agreement was obtained, thereby confirming the robustness of our methodology. The availability of such a method equips pharmaceutical scientists with an in vitro assessment method that will more reliably determine the PSD of active substances in finished tablets.

A new way of solid dosage form samples preparation for SEM and FTIR using microtome.

Rapid and correct production of generic solid dosage forms requires a large amount of analytical data and conclusions. Modern analytical techniques have a good resolution and accuracy and allow obtaining a lot of information about the original product. Scanning electron microscopy (SEM) is used for observation and assessing individual layers, core and surface of solid dosage forms. Fourier transform infrared (FTIR) spectroscopy mapping allows determining the distribution and characterization of individual components in a solid dosage form. However, the samples prepared by common way, using scalpel or tablet splitter, are not good enough. It was the reason for development of a new and better method of sample preparation, which uses microtome. Well-prepared samples analyzed by SEM and FTIR mapping allow to determine a solid dosage form formulation, excipient content and distribution of excipient and active pharmaceutical ingredient.