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Multiple sclerosis (MS) is a chronic neuroinflammatory disease characterized by central nervous system demyelination and axonal degeneration. Fatigue affects a major portion of MS patients, significantly impairing their daily activities and quality of life. Despite its prevalence, the mechanisms underlying fatigue in MS are poorly understood, and measuring fatigue remains a challenging task. This study evaluates the efficacy of automated speech analysis in detecting fatigue in MS patients. MS patients underwent a detailed clinical assessment and performed a comprehensive speech protocol. Using features from three different free speech tasks and a proprietary cognition score, our support vector machine model achieved an AUC on the ROC of 0.74 in detecting fatigue. Using only free speech features evoked from a picture description task we obtained an AUC of 0.68. This indicates that specific free speech patterns can be useful in detecting fatigue. Moreover, cognitive fatigue was significantly associated with lower speech ratio in free speech (ρ = −0.283, p = 0.001), suggesting that it may represent a specific marker of fatigue in MS patients. Together, our results show that automated speech analysis, of a single narrative free speech task, offers an objective, ecologically valid and low-burden method for fatigue assessment. Speech analysis tools offer promising potential applications in clinical practice for improving disease monitoring and management.

IntroductionDysarthria, a motor speech disorder caused by muscle weakness or paralysis, severely impacts speech intelligibility and quality of life. The condition is prevalent in motor speech disorders such as Parkinson's disease (PD), atypical parkinsonism such as progressive supranuclear palsy (PSP), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Improving intelligibility is not only an outcome that matters to patients but can also play a critical role as an endpoint in clinical research and drug development. This study validates a digital measure for speech intelligibility, the ki: SB-M intelligibility score, across various motor speech disorders and languages following the Digital Medicine Society (DiMe) V3 framework.MethodsThe study used four datasets: healthy controls (HCs) and patients with PD, HD, PSP, and ALS from Czech, Colombian, and German populations. Participants’ speech intelligibility was assessed using the ki: SB-M intelligibility score, which is derived from automatic speech recognition (ASR) systems. Verification with inter-ASR reliability and temporal consistency, analytical validation with correlations to gold standard clinical dysarthria scores in each disease, and clinical validation with group comparisons between HCs and patients were performed.ResultsVerification showed good to excellent inter-rater reliability between ASR systems and fair to good consistency. Analytical validation revealed significant correlations between the SB-M intelligibility score and established clinical measures for speech impairments across all patient groups and languages. Clinical validation demonstrated significant differences in intelligibility scores between pathological groups and healthy controls, indicating the measure's discriminative capability.DiscussionThe ki: SB-M intelligibility score is a reliable, valid, and clinically relevant tool for assessing speech intelligibility in motor speech disorders. It holds promise for improving clinical trials through automated, objective, and scalable assessments. Future studies should explore its utility in monitoring disease progression and therapeutic efficacy as well as add data from further dysarthrias to the validation.

Introduction: Progressive cognitive decline is the cardinal behavioral symptom in most dementia-causing diseases such as Alzheimer’s disease. While most well-established measures for cognition might not fit tomorrow’s decentralized remote clinical trials, digital cognitive assessments will gain importance. We present the evaluation of a novel digital speech biomarker for cognition (SB-C) following the Digital Medicine Society’s V3 framework: verification, analytical validation, and clinical validation. Methods: Evaluation was done in two independent clinical samples: the Dutch DeepSpA (N = 69 subjective cognitive impairment [SCI], N = 52 mild cognitive impairment [MCI], and N = 13 dementia) and the Scottish SPeAk datasets (N = 25, healthy controls). For validation, two anchor scores were used: the Mini-Mental State Examination (MMSE) and the Clinical Dementia Rating (CDR) scale. Results: Verification: The SB-C could be reliably extracted for both languages using an automatic speech processing pipeline. Analytical Validation: In both languages, the SB-C was strongly correlated with MMSE scores. Clinical Validation: The SB-C significantly differed between clinical groups (including MCI and dementia), was strongly correlated with the CDR, and could track the clinically meaningful decline. Conclusion: Our results suggest that the ki:e SB-C is an objective, scalable, and reliable indicator of cognitive decline, fit for purpose as a remote assessment in clinical early dementia trials.

The Ethnologisches Museum: Staatliche Museen zu Berlin (formerly the Museum für Völkerkunde, and referred to here as the Berlin Ethnological Museum) contains over 1,000 artifacts fashioned by California Indians, collected between 1837 and 1914. The collection is rich and varied; it represents one of the earliest ethnographic collections from Native California and includes ethnological treasures of great aesthetic quality and rarity. The collection is an invaluable source of scientific information and cultural renewal. The objects are highly regarded by living descendants of the Native Californians who long ago sold, traded, and exchanged these artifacts with collectors. They are heirlooms reflecting tribal history and culture, and are worthy of remembrance and study. In this paper we offer first-hand observations on a small sample (n =10) of the Berlin Ethnological Museum’s California Indian collection, with a particular emphasis on baskets. We describe and discuss these objects in detail in order to bring to life the people and cultures that brilliantly produced such exquisite, artistic objects and ethnographic treasures. We also attempt to identify their historical context and the circumstances motivating their collection, so as to better understand how they came to be curated in Berlin. Finally, we provide a brief overview of the history and development of the Berlin Ethnological Museum’s California Indian collection, because the intriguing interconnections and influential coincidences associated with it provide insights into the history and nature of the early development of California Indian studies and particularly illuminate the evolution of the science of anthropology as an academic discipline in America.

Auditory nerve fibers (ANFs) innervating the same inner hair cell (IHC) may have identical frequency tuning but different sound response properties. In cat and guinea pig, ANF response properties correlate with afferent synapse morphology and position on the IHC, suggesting a causal structure-function relationship. In mice, this relationship has not been fully characterized. Here we measured the emergence of synaptic morphological heterogeneities during maturation of the C57BL/6J mouse cochlea by comparing postnatal day 17 (p17, ∼3 days after hearing onset) with p34, when the mouse cochlea is mature. Using serial block face scanning electron microscopy and three-dimensional reconstruction we measured the size, shape, vesicle content, and position of 70 ribbon synapses from the mid-cochlea. Several features matured over late postnatal development. From p17 to p34, presynaptic densities (PDs) and post-synaptic densities (PSDs) became smaller on average (PDs: 0.75 to 0.33; PSDs: 0.58 to 0.31 μm2) and less round as their short axes shortened predominantly on the modiolar side, from 770 to 360 nm. Membrane-associated synaptic vesicles decreased in number from 53 to 30 per synapse from p17 to p34. Anatomical coupling, measured as PSD to ribbon distance, tightened predominantly on the pillar side. Ribbons became less spherical as long-axes lengthened only on the modiolar side of the IHC, from 372 to 541 nm. A decreasing gradient of synaptic ribbon size along the modiolar-pillar axis was detected only at p34 after aligning synapses of adjacent IHCs to a common reference frame (median volumes in nm3 × 106: modiolar 4.87; pillar 2.38). The number of ribbon-associated synaptic vesicles scaled with ribbon size (range 67 to 346 per synapse at p34), thus acquiring a modiolar-pillar gradient at p34, but overall medians were similar at p17 (120) and p34 (127), like ribbon surface area (0.36 vs. 0.34 μm2). PD and PSD morphologies were tightly correlated to each other at individual synapses, more so at p34 than p17, but not to ribbon morphology. These observations suggest that PDs and PSDs mature according to different cues than ribbons, and that ribbon size may be more influenced by cues from the IHC than the surrounding tissue.

Background: The role of angioembolization (AE) and pre-peritoneal pelvic packing (PPP) for pelvic hemorrhage control in the era of resuscitative endovascular balloon occlusion of the aorta (REBOA) has not been well described. Our aim was to investigate outcomes of PPP and AE after REBOA. Methods: Patients who received aortic occlusion (AO) at Zone 3 (distal abdominal aorta) plus PPP and/or AE at three high-volume REBOA centers between February 2013 and December 2018 were identified. Outcomes were compared between three groups based on procedures performed: REBOA with PPP only (RPPP), REBOA with angioembolization only (RAE), and REBOA with PPP and AE (RPPPAE). Results: Fifty-eight patients underwent REBOA at Zone 3; 37 RPPP, 13 RAE, 8 RPPPAE. Mean age was 45 ± 16 years, mean injury severity score (ISS) 35 ± 13, mean systolic blood pressure (SBP) pre-AO was 71 ± 19 mmHg, and post-AO SBP was 110 ± 34 mmHg. In-hospital mortality was 28%, with the majority of deaths occurring in the intensive care unit. Age, ISS, admission SBP, physiology on admission and at the time of AO, response to AO, admission hemoglobin, blood products transfused, and rate of local wound infections were not different between RPPP and RAE groups. Comparing RPPP to RAE groups, duration of AO was significantly lower in the RPPP group (45 + 34 vs 81 + 37 mins, p = 0.012), while rates of acute kidney injury (14% vs 46%) and distal embolism (8% vs 31%) were higher in the RAE group (p = 0.015, 0.04, respectively).There was no statistical difference in mortality between RPPP (22%) and RAE patients (39%), including on regression analysis controlling for duration of AO and ongoing CPR at the time of AO. Conclusion: Despite a longer duration of AO and higher rates of ongoing CPR at the time of AO in RAE patients, mortality rates are similar whether hemostasis is achieved after REBOA with pelvic packing or angioembolization. RPPP results in significantly lower systemic and local complication rates.

Bassem Sadek,1 Ali Saad,1 Johannes Stephan Schwed,2,3 Lilia Weizel,2 Miriam Walter,2 Holger Stark2,3 1Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates; 2Biocenter, Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany; 3Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University, Düsseldorf, Germany Abstract: Phenytoin (PHT), valproic acid, and modern antiepileptic drugs (AEDs), eg, remacemide, loreclezole, and safinamide, are only effective within a maximum of 70%–80% of epileptic patients, and in many cases the clinical use of AEDs is restricted by their side effects. Therefore, a continuous need remains to discover innovative chemical entities for the development of active and safer AEDs. Ligands targeting central histamine H3 receptors (H3Rs) for epilepsy might be a promising therapeutic approach. To determine the potential of H3Rs ligands as new AEDs, we recently reported that no anticonvulsant effects were observed for the (S)-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propanamide (1). In continuation of our research, we asked whether anticonvulsant differences in activities will be observed for its R-enantiomer, namely, (R)-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propaneamide (2) and analogs thereof, in maximum electroshock (MES)-, pentylenetetrazole (PTZ)-, and strychnine (STR)-induced convulsion models in rats having PHT and valproic acid (VPA) as reference AEDs. Unlike the S-enantiomer (1), the results show that animals pretreated intraperitoneally (ip) with the R-enantiomer 2 (10 mg/kg) were moderately protected in MES and STR induced models, whereas proconvulsant effect was observed for the same ligand in PTZ-induced convulsion models. However, animals pretreated with intraperitoneal doses of 5, 10, or 15 mg/kg of structurally bulkier (R)-enantiomer (3), in which 3-piperidinopropan-1-ol in ligand 2 was replaced by (4-(3-(piperidin-1-yl)propoxy)phenyl)methanol, and its (S)-enantiomer (4) significantly and in a dose-dependent manner reduced convulsions or exhibited full protection in MES and PTZ convulsions model, respectively. Interestingly, the protective effects observed for the (R)-enantiomer (3) in MES model were significantly greater than those of the standard H3R inverse agonist/antagonist pitolisant, comparable with those observed for PHT, and reversed when rats were pretreated with the selective H3R agonist R-(α)-methyl-histamine. Comparisons of the observed antagonistic in vitro affinities among the ligands 1–6 revealed profound stereoselectivity at human H3Rs with varying preferences for this receptor subtype. Moreover, the in vivo anticonvulsant effects observed in this study for ligands 1–6 showed stereoselectivity in different convulsion models in male adult rats. Keywords: histamine, H3 receptor, isomeric antagonists, anticonvulsant activity, stereo­selectivity

Bassem Sadek,1 Annemarie Schreeb,2 Johannes Stephan Schwed,2,3 Lilia Weizel,2 Holger Stark3 1Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates; 2Biocenter, Institute of Pharmaceutical Chemistry, Johann-Wolfgang Goethe University, Frankfurt, Germany; 3Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University, Duesseldorf, Germany Abstract: A small series of compounds containing derivatives of 2,4-diamino- and 2,4,6-triaminopyrimidine (compounds 2–7) was synthesized and tested for binding affinity to human histamine H3 receptors (hH3Rs) stably expressed in HEK-293 cells and human H4Rs (hH4Rs) co-expressed with Gαi2 and Gβ1γ2 subunits in Sf9 cells. Working in part from the lead compound 6-(4-methylpiperazin-1-yl)-N4-(3-(piperidin-1-yl)propyl)pyrimidine-2,4-diamine (compound 1) with unsatisfactory affinity and selectivity to hH3Rs, our structure-activity relationship studies revealed that replacement of 4-methylpiperazino by N-benzylamine and substitution of an amine group at the 2-position of the 2-aminopyrimidine core structure with 3-piperidinopropoxyphenyl moiety as an hH3R pharmacophore resulted in N4-benzyl-N2-(4-(3-(piperidin-1-yl)propoxy)phenyl)pyrimidine-2,4-diamine (compound 5) with high hH3R affinity (ki =4.49±1.25 nM) and H3R receptor subtype selectivity of more than 6,500×. Moreover, initial metric analyses were conducted based on their target-oriented drug-likeness for predictively quantifying lipophilicity, ligand efficiency, lipophilicity-dependent ligand efficiency, molecular size-independent efficiency, and topological molecular polar surface. As to the development of potential H3R ligands, results showed that integration of the hH3R pharmacophore in hH4R-affine structural scaffolds resulted in compounds with high hH3R affinity (4.5–650 nM), moderate to low hH4R affinity (4,500–30,000 nM), receptor subtype selectivity (ratio hH4R/hH3R; 8–6,500), and promising calculated drug-likeness properties. Keywords: histamine, H3 receptors, H4 receptors, drug-likeness

Amine Bahi,1,* Johannes Stephan Schwed,2,3 Miriam Walter,2 Holger Stark,3 Bassem Sadek,4,* 1Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates; 2Institut für Pharmazeutische Chemie, Biozentrum, Johann Wolfgang Goethe University, Frankfurt, 3Heinrich Heine University Duesseldorf, Institut fuer Pharmazeutische and Medizinische Chemie, Düsseldorf, Germany; 4Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates *These authors contributed equally to this work Abstract: Previous studies have suggested a potential link between histamine H3 receptors (H3R) signaling and anxiolytic-like and antidepressant-like effects. The aim of this study was to investigate the acute effects of ST-1283, a novel H3R antagonist, on anxiety-related and depression-related behaviors in comparison with those of diazepam and fluoxetine. The effects of ST-1283 were evaluated using the elevated plus maze test, open field test, marbles burying test, tail suspension test, novelty suppressed feeding test, and forced swim test in male C57BL/6 mice. The results showed that, like diazepam, ST-1283 (7.5 mg/kg) significantly modified all the parameters observed in the elevated plus maze test. In addition, ST-1283 significantly increased the amount of time spent in the center of the arena without altering general motor activity in the open field test. In the same vein, ST-1283 reduced the number of buried marbles as well as time spent digging in the marbles burying test. The tail suspension test and forced swim test showed that ST-1283 was able to reduce immobility time, like the recognized antidepressant drug fluoxetine. In the novelty suppressed feeding test, treatment with ST-1283 decreased latency to feed with no effect on food intake in the home cage. Importantly, pretreatment with the H3R agonist R-α-methylhistamine abrogated the anxiolytic and antidepressant effects of ST-1283. Taken together, the present series of studies demonstrates the novel effects of this newly synthesized H3R antagonist in a number of preclinical models of psychiatric disorders and highlights the histaminergic system as a potential therapeutic target for the treatment of anxiety-related and depression-related disorders. Keywords: anxiety, depression, histamine, H3 receptor, R-α-methylhistamine, ST-1283

A Medicina Legal tem por objetivo auxiliar a Justiça em matéria técnico-científica. Assim, para que o perito possa atuar da forma mais adequada em perícias de ordem criminal, cível, trabalhista, administrativa, previdenciária, securitária e/ou nas auditorias médicas (públicas e privadas) é necessária uma formação ampla e sólida. O Programa de Residência Médica em Medicina Legal e Perícias Médicas é a opção mais completa e segura para a formação acadêmica de peritos médicos, conforme o conteúdo programático de atividades práticas e teóricas. Implementado em 2004, o programa tem a duração de três anos e, atualmente, oferece cinco vagas por ano credenciadas pela Comissão Nacional de Residência Médica. Até a presente data já formou 16 médicos peritos que atuam nas diversas áreas da perícia médica e no meio acadêmico (graduação e pós-graduação).

Charmstones are some of the more mysterious objects in California's archaeological record. They were described as early as 1885 by Henshaw, while the term 'charmstone' first appeared in an article by Yates (1889). These early accounts adopted the term based on information provided by Native California consultants, who reported that these were "charms" rather than mundane, utilitarian objects. This paper provides an interpretive overview and synthesis of data on a rare and recently defined type of charmstone-a biconical object, shaped somewhat like an American football. Sometimes fashioned from opaque white quartz, these rare artifacts have been found across a broad swath of California. In this paper, we expand the known geographic distribution of these artifacts and review the nine known examples from California, supplying new information on their age, function, and cultural context. We agree with the researchers who first defined this new type of charmstone that they comprised part of a shaman's ritual bundle at times and were used in various ceremonies. Some charmstones were associated with California Indian weather shamanism. In addition, new evidence now suggests that the use of charmstones extends for at least 9,000 years into the past. However, they were also sometimes procured as "heirloom" objects scavenged from earlier archaeological sites and later re-introduced into the archaeological record. [ABSTRACT FROM AUTHOR]

A survey of 59 daily newspapers indicates the increased dominance on newspaper staffs of persons with college training in journalism. (RL)

Numerous genetic alterations of HSA 11q13 are found frequently in several cancer types, including breast cancer (BC). The 11q13 locus harbors FADS2 encoding Δ6 desaturation which is not functional in several cancer cell lines, including hormone positive MCF7 BC cells. In vitro, the non-functional FADS2 activity unmasks 18:2n−6 elongation to 20:2n−6 and Δ5 desaturation by FADS1 to yield 5Z,11Z,14Z–20:3 (sciadonic acid) rather than 5Z,8Z,11Z,14Z–20:4 (arachidonic acid). In this pilot study we aimed to determine whether 5,11,14–20:3 appears in vivo in hormone positive human BC tissue. Fatty acids were profiled in surgically removed human breast tumor and adjacent normal tissue (n = 9). Sciadonic acid was detected in three of nine breast tumor samples and was below detect limits in normal breast tissue. The internal Δ8 double bond of arachidonic acid is required for normal eicosanoid synthesis but is missing in sciadonic acid. This pilot study demonstrates for the first time in vivo sciadonic acid in hormone positive BC tissue, warranting a larger survey study to further evaluate its appearance and the functional implications. [ABSTRACT FROM AUTHOR]

The Ethnologisches Museum: Staatliche Museen zu Berlin (formerly the Museum für Völkerkunde, and referred to here as the Berlin Ethnological Museum) contains over 1,000 artifacts fashioned by California Indians, collected between 1837 and 1914. The collection is rich and varied; it represents one of the earliest ethnographic collections from Native California and includes ethnological treasures of great aesthetic quality and rarity. The collection is an invaluable source of scientific information and cultural renewal. The objects are highly regarded by living descendants of the Native Californians who long ago sold, traded, and exchanged these artifacts with collectors. They are heirlooms reflecting tribal history and culture, and are worthy of remembrance and study. In this paper we offer first-hand observations on a small sample (n=10) of the Berlin Ethnological Museum’s California Indian collection, with a particular emphasis on baskets. We describe and discuss these objects in detail in order to bring to life the people and cultures that brilliantly produced such exquisite, artistic objects and ethnographic treasures. We also attempt to identify their historical context and the circumstances motivating their collection, so as to better understand how they came to be curated in Berlin. Finally, we provide a brief overview of the history and development of the Berlin Ethnological Museum’s California Indian collection, because the intriguing interconnections and influential coincidences associated with it provide insights into the history and nature of the early development of California Indian studies and particularly illuminate the evolution of the science of anthropology as an academic discipline in America. [ABSTRACT FROM AUTHOR]