Ritlecitinib, an orally available Janus kinase 3 and tyrosine kinase inhibitor being developed for the treatment of alopecia areata (AA), is highly soluble across the physiological pH range at the therapeutic dose. As such, it is expected to dissolve rapidly in any in vitro dissolution conditions. However, in vitro dissolution data showed slower dissolution for 100-mg capsules, used for the clinical bioequivalence (BE) study, compared with proposed commercial 50-mg capsules. Hence, a biowaiver for the lower 50-mg strength using comparable multimedia dissolution based on the f2 similarity factor was not possible. The in vivo relevance of this observed in vitro dissolution profile was evaluated with a physiologically based pharmacokinetic (PBPK) model. This report describes the development, verification, and application of the ritlecitinib PBPK model to translate observed in vitro dissolution data to an in vivo PK profile for ritlecitinib capsule formulations. Virtual BE (VBE) trials were conducted using the Simcyp VBE module, including the model-predicted within-subject variability or intra-subject coefficient of variation (ICV). The results showed the predicted ICV was predicted to be smaller than observed clinical ICV, resulting in a more optimistic BE risk assessment. Additional VBE assessment was conducted by incorporating clinically observed ICV. The VBE trial results including clinically observed ICV demonstrated that proposed commercial 50-mg capsules vs clinical 100-mg capsules were bioequivalent, with > 90% probability of success. This study demonstrates a PBPK model-based biowaiver for a clinical BE study while introducing a novel method to integrate clinically observed ICV into VBE trials with PBPK models. Trial registration: NCT02309827, NCT02684760, NCT04004663, NCT04390776, NCT05040295, NCT05128058.

Gerstmann-Sträussler disease (GSD) is a very rare autosomal dominant late-onset neurodegenerative disorder related to prion protein gene PRNP. Mutation p.Pro102Leu produces about 80% of cases, which are often named GSD-102. DNA testing provides exact diagnosis. In the presented Russian family there were 3 patients: a female index case, age 32 years, her brother, age 37 years (age of onset in both is 27 years) and their deceased father (onset in 35 years, death in 44 years). GSD was not suspected until whole exome sequencing in the female detected PRNP mutation p.Pro102Leu confirmed in her and in the brother by Sanger sequencing. Atypical features of the case are: early onset in siblings, absence of mental and behavioral problems in the female and in the father and mild disturbances in the brother; epilepsy in the brother; atypical onset with transient signs in the brother. Other intrafamilial differences are prevailing spastic paraparesis in the female in contrast to predominant ataxia in the brother and dysarthria absence in the female. The case illustrates GSD-102 variability, complicating clinical diagnostics.
Болезнь Герстмана—Штросслера (БГШ) — очень редкое аутосомно-доминантное нейродегенеративное заболевание взрослого возраста, обусловленное мутациями гена прионного белка PRNP. Мутация p.Pro102Leu вызывает около 80% случаев, часто обозначаемых как БГШ-102, анализ ДНК — основной метод диагностики. В описанной русской семье 3 больных: женщина-пробанд 32 лет, брат 37 лет (начало у обоих в 27 лет) и отец (начало в 35 лет, смерть в 44 года). БГШ не предполагали до полноэкзомного секвенирования у пробанда, выявившего мутацию PRNP p.Pro102Leu, подтвержденную секвенированием по Сэнгеру у нее и брата. Особенности случая: раннее начало у сибсов; отсутствие когнитивных и психических расстройств у пробанда и отца и легкие нарушения у брата; у него же эпилепсия, а также атипичное начало с преходящих расстройств. Другие внутрисемейные различия — ведущий спастический парапарез у пробанда и преобладающая атаксия у брата, отсутствие дизартрии у пробанда. МРТ у сибсов, включая диффузионно-взвешенную МРТ у пробанда, без значимых изменений. Случай демонстрирует разнообразие проявлений БГШ-102, затрудняющее клиническую диагностику.

Even though a mutation in monogenic diseases leads to a \"classic\" manifestation, many disorders exhibit great clinical variability that could be due to modifying genes also called minor genes. Fabry disease (FD) is an X-linked inborn error resulting from the deficient or absent activity of alpha-galactosidase A (α-GAL) enzyme, that leads to deposits of globotriaosylceramide. With our proprietary software SNPclinic v.1.0, we analyzed 110 single nucleotide polymorphisms (SNPs) in the proximal promoter of 14 genes that could modify the FD phenotype FD. We found seven regulatory-SNP (rSNPs) in three genes (IL10, TGFB1 and EDN1) in five cell lines relevant to FD (Cardiac myocytes and fibroblasts, Astrocytes-cerebellar, endothelial cells and T helper cells 1-TH1). Each SNP was confirmed as a true rSNP in public eQTL databases, and additional software suggested the prediction of variants. The two proposed rSNPs in IL10, could explain components for the regulation of active B cells that influence the fibrosis process. The three predicted rSNPs in TGFB1, could act in apoptosis-autophagy regulation. The two putative rSNPs in EDN1, putatively regulate chronic inflammation. The seven rSNPs described here could act to modulate Fabry\'s clinical phenotype so we propose that IL10, TGFB1 and EDN1 be considered minor genes in FD.

BACKGROUND: Progranulin (PGRN) is a secreted glycoprotein encoded in humans by the GRN gene, located on chromosome 17q21. Several nonsense and missense pathogenetic GRN mutations have been described.
OBJECTIVE: We herein describe two sisters carrying a rare GRN mutation with extremely different clinical features and family history of dementia and behavioral disorders, with a novel presentation with stridor and dysphonia.
METHODS: Patients underwent a multidimensional assessment including neurological and neuropsychological evaluation, structural and functional imaging, and genetic screening.
RESULTS: The younger sister presented at the age of 64 with inspiratory stridor, dysphonia and exercise-induced dyspnea. Transnasal fiberoptic laryngoscopy showed bilateral adduction of the vocal cords at rest and paradoxical further adduction of the vocal cords during forced inspiration, suggesting the hypothesis of an adductor laryngeal dystonia. The older sister presented at the age of 63 with a rapidly progressive corticobasal syndrome. The only clinical feature common to both sisters was a dysexecutive syndrome. The c.893G > A mutation in exon 9 of GRN was found in heterozygosis in both sisters, causing a missense Arginine to Histidine substitution in position 298 of the protein (p.R298H).
CONCLUSIONS: Our report supports the pathogenicity of the GRN p.R298H mutation, which is first detected in two members from the same family, showing an extremely different phenotypes. Moreover, we report the first case of an FTD-associated mutation presenting with inspiratory stridor and dysphonia linked to adductor laryngeal dystonia, thus expanding the clinical spectrum of GRN-related disorders.

To evaluate changes in the disconnection of mechanical ventilation in Spain from 1998 to 2016.
Post-hoc analysis of four cohort studies.
138 Spanish ICUs.
2141 patients scheduled extubated.
None.
Demographics, reason for mechanical ventilation, complications, methods for disconnection, failure on the first attempt at disconnection, duration of weaning, reintubation, post-reintubation tracheotomy, ICU stay and mortality.
There was a significant increase (p < 0.001) in the use of gradual reduction of support pressure. The adjusted probability of using the gradual reduction in pressure support versus a spontaneous breathing trial has increased over time, both for the first attempt at disconnection (taking the 1998 study as a reference: odds ratio 0.99 in 2004, 0.57 in 2010 and 2.43 in 2016) and for difficult/prolonged disconnection (taking the 1998 study as a reference: odds ratio 2.29 in 2004, 1.23 in 2010 and 2.54 in 2016). The proportion of patients extubated after the first attempt at disconnection has increased over time. There is a decrease in the ventilation time dedicated to weaning (from 45% in 1998 to 36% in 2016). However, the duration in difficult/prolonged weaning has not decreased (median 3 days in all studies, p = 0.435).
There have been significant changes in the mode of disconnection of mechanical ventilation, with a progressive increase in the use of gradual reduction of pressure support. No relevant changes in outcomes have been observed.

OBJECTIVE: Atrial fibrillation (AF) carries substantial morbidity and mortality. Evidence-based guidelines have been synthesized into emergency department (ED) AF care pathways, but the effectiveness and scalability of such approaches are not well established. We thus evaluated the impacts of an algorithmic care pathway for ED management of non-valvular AF (EDAFMP) on hospital use and care process measures.
METHODS: We deployed a voluntary-use EDAFMP in 4 EDs (1 tertiary hospital, 1 cardiac hospital, 2 community hospitals) of an integrated delivery organization using a multifaceted implementation approach. We compared outcomes between patients with AF treated using the EDAFMP and historical and contemporaneous \"usual care\" controls, using a propensity-score adjusted generalized estimating equation. Patients with an index ED encounter for a primary visit reason of non-valvular AF (and no excluding concurrent diagnoses) were eligible for inclusion.
RESULTS: Preimplementation (January 1, 2016-December 31, 2016), 628 AF patients were eligible; postimplementation (September 1, 2017-June 30, 2019), 1296, including 271 (20.9%) treated with the EDAFMP, were eligible. EDAFMP patients were less likely to be admitted than both historical (adjusted odds ratio [aOR], 95% confidence interval [CI]: 0.45, 0.29-0.71) and contemporaneous controls (aOR, 95%CI: 0.63, 0.46-0.86). ED visits and hospital readmissions over 90 days subsequent to index ED encounters were similar between postimplementation EDAFMP and usual care groups. EDAFMP patients were more likely to be prescribed anticoagulation (38% v. 5%, P < 0.001) and be referred to a cardiologist (93% vs 29%, P < 0.001) versus the comparator group.
CONCLUSIONS: EDAFMP use is associated with decreased hospital admission during an index ED encounter for non-valvular AF, and improved delivery of AF care processes.

Brain heterotopia is a group of rare malformations with a heterogeneous phenotype, ranging from asymptomatic to a severe clinical picture (drug-resistant epilepsy, severe developmental delay). The etiology is multifactorial, including both genetic and environmental factors. In the present study, a cohort of 15 pediatric patients with brain heterotopia were investigated by clinical examination, electroencephalographic studies, brain imaging, and genomic tests. Most of the patients had epileptic seizures, often difficult to control with one antiepileptic drug; another frequent characteristic in the cohort was developmental delay or intellectual disability, in some cases associated with behavioral problems. The genomic studies revealed an interstitial 22q11.2 microduplication, an anomaly not reported previously in heterotopia patients. Comparing the cohort of the present study with that of a previous series of heterotopia patients, both adult and pediatric, similar aspects, such as the high frequency of drug-resistant epilepsy were observed as well as some differences, such as no systemic malformations and no cases with fatal evolution. The current findings add new data to existing knowledge on a rare heterogeneous disorder. The detailed clinical description, including the epilepsy phenotypes, and genomic profiles bring new insights into a group of disorders, yet to be fully understood.

Neurofibromatosis type 1 (NF1) is a tumor predisposition genetic disorder that directly affects more than 1 in 3,000 individuals worldwide. It results from mutations of the NF1 gene and shows almost complete penetrance. NF1 patients show high phenotypic variabilities, including cafe-au-lait macules, freckling, or other neoplastic or non-neoplastic features. Understanding the underlying mechanisms of the diversities of clinical symptoms might contribute to the development of personalized healthcare for NF1 patients. Currently, studies have shown that the different types of mutations in the NF1 gene might correlate with this phenomenon. In addition, genetic modifiers are responsible for the different clinical features. In this review, we summarize different genetic mutations of the NF1 gene and related genetic modifiers. More importantly, we focus on the genotype-phenotype correlation. This review suggests a novel aspect to explain the underlying mechanisms of phenotypic heterogeneity of NF1 and provides suggestions for possible novel therapeutic targets to prevent or delay the onset and development of different manifestations of NF1.

Accurate medical triage is essential for improving patient outcomes and efficient healthcare delivery. Patients increasingly rely on artificial intelligence (AI)-based applications to access healthcare information, including medical triage advice. We assessed the accuracy of triage decisions provided by an AI-based application. We presented 50 clinical vignettes to the AI-based application, seven emergency medicine providers, and five internal medicine physicians. We compared the triage decisions of the AI-based application to those of the individual providers as well as their consensus decisions. When compared to the human clinicians\' consensus triage decisions, the AI-based application performed equal or better than individual human clinicians.

OBJECTIVE: To evaluate changes in the disconnection of mechanical ventilation in Spain from 1998 to 2016.
METHODS: Post-hoc analysis of four cohort studies.
UNASSIGNED: 138 Spanish ICUs.
METHODS: 2141 patients scheduled extubated.
METHODS: None.
METHODS: Demographics, reason for mechanical ventilation, complications, methods for disconnection, failure on the first attempt at disconnection, duration of weaning, reintubation, post-reintubation tracheotomy, ICU stay and mortality.
RESULTS: There was a significant increase (p<0.001) in the use of gradual reduction of support pressure. The adjusted probability of using the gradual reduction in pressure support versus a spontaneous breathing trial has increased over time, both for the first attempt at disconnection (taking the 1998 study as a reference: odds ratio 0.99 in 2004, 0.57 in 2010 and 2.43 in 2016) and for difficult/prolonged disconnection (taking the 1998 study as a reference: odds ratio 2.29 in 2004, 1.23 in 2010 and 2.54 in 2016). The proportion of patients extubated after the first attempt at disconnection has increased over time. There is a decrease in the ventilation time dedicated to weaning (from 45% in 1998 to 36% in 2016). However, the duration in difficult/prolonged weaning has not decreased (median 3 days in all studies, p=0.435).
CONCLUSIONS: There have been significant changes in the mode of disconnection of mechanical ventilation, with a progressive increase in the use of gradual reduction of pressure support. No relevant changes in outcomes have been observed.