Driving Efficiency: Leveraging Model-Informed Approaches in 505(b)(2) Regulatory Actions.

Introduced by the Hatch-Waxman Amendments of 1984, 505(b)(2) applications permit the US Food and Drug Administration to rely, for approval of a new drug application, on information from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference. This pathway is designed to circumvent the unnecessary duplication of studies already conducted on a previously approved drug. It can lead to a considerably more efficient and expedited route to approval compared to a traditional development path. Model-informed drug development refers to the utilization of a diverse array of quantitative models in drug development to streamline the decision-making process. In this approach, diverse quantitative models that integrate knowledge of physiology, disease processes, and drug pharmacology are employed to address drug development challenges and guide regulatory decisions. Integration of these model-informed approaches into 505(b)(2) regulatory submissions and decision-making can further expedite the approval of new drugs. This article discusses some applications of model-informed approaches that were used to support 505(b)(2) drug development and regulatory actions. Specifically, various quantitative models such as population pharmacokinetic and exposure-response models have been employed to provide evidence of effectiveness, guide dosing in subgroups such as subjects with hepatic or renal impairment, and inform policies. These case study examples collectively underscore the significance of model-informed approaches in drug development and regulatory decisions associated with 505(b)(2) submissions.

ARX, PDX1, ISL1 and CDX2 expression distinguishes five subgroups of PanNETs with correlations to histology, hormone expression and outcome.

Many pancreatic neuroendocrine tumors (PanNETs) fall into two major prognostic subtypes based on DAXX/ATRX induced ALT phenotype and alpha and beta cell-like epigenomic profiles. However, these PanNETs are still flanked by other PanNETs that do not fit into either subtype. Furthermore, despite advanced genotyping, PanNETs are generally not well characterized in terms of their histological and hormonal phenotype. We aimed to identify new subgroups of PanNETs by extending the currently used transcription factor signatures and to investigate their correlation with histological, hormonal molecular and prognostic findings. 185 PanNETs (non-functioning 165, functioning 20) resected between 1996 and 2023 were classified into five subgroups (A1, A2, B, C, D) by cluster analysis based on ARX, PDX1, ISL1 and CDX2 expression and correlated with trabecular vs. solid histology, expression of insulin, glucagon, PP, somatostatin, serotonin, gastrin, calcitonin, ACTH, DAXX/ATRX, MEN1 and ALT status by FISH, and disease-free survival (DFS). A1 (46%, ARX+/ISL1+/PDX1-/CDX2-) and A2 (15%, ARX+/ISL1+/PDX1+/CDX2-) showed trabecular histology and glucagon/ PP expression, with A2 also showing gastrin expression. B (18%, PDX1+/ISL1+/ARX-/CDX2-) showed solid histology, insulin and somatostatin expression (p<0.001). It included all insulinomas and had the best outcome (p<0.01). C (15%, ARX-/PDX1-/ISL1-/CDX2-) showed solid histology and frequent expression of serotonin, calcitonin und ACTH. D (5%, PDX1+/CDX2+/ISL1-/ARX-) showed solid histology, expressed ACTH/serotonin and was an independent poor prognosticator (p<0.01). Differential expression of ARX, PDX1, ISL1 and CDX2 stratified PanNETs into five subgroups with different histology, hormone expression and outcome. Subgroups A1 and A2 resembled the alpha cell-like type, subgroup B the beta cell-like type. Subgroup C with almost a no transcription factor signature was unclear in cell lineage, while the PDX+/CDX2+ signature of subgroup D suggested a pancreatic/intestinal cell lineage. Assigning PanNETs to the subgroups may help to establish the diagnosis, predict the outcome, and guide the treatment.

Which heart failure patients benefit most from non-invasive telemedicine? An overview of current evidence and future directions.

Telemedicine in heart failure (HF) management may positively impact health outcomes, but varied effects in studies hinder guidance in HF guidelines. Evidence on the effectiveness of telemedicine in HF subpopulations is limited. We conducted a scoping review to evaluate and synthesise evidence on the effectiveness of telemedicine across HF subpopulations that could guide telemedicine strategies in routine practice. Meta-analyses concerning randomised controlled trials (RCTs) with subgroup analyses on telemedicine effectives were identified in PubMed. We identified 15 RCTs, encompassing 21 different subgroups based on characteristics of HF patients. Findings varied across studies and no definite evidence was found about which patients benefit most from telemedicine. Subgroup definitions were inconsistent, not always a priori defined and subgroups contained few patients. Some studies found heterogeneous effects of telemedicine on mortality and hospitalisation across subgroups defined by: New York Heart Association (NYHA) classification, previous HF decompensation, implantable device, concurrent depression, time since hospital discharge and duration of HF. Patients represented in the RCTs were mostly male, aged 65-75 years, with HF with reduced ejection fraction and NYHA class II/III. Traditional RCTs have not been able to provide clinicians with guidance; continuous real-world evidence generation could enhance monitoring and identify who benefits from telemedicine.

New insights into recalled parental behavior in social anxiety disorder: A cluster analytic approach.

BACKGROUND: Social Anxiety Disorder (SAD) is a highly heterogeneous disorder. To enlighten its heterogeneity, this study focused on recalled parental behavior and aimed to empirically identify if there are subgroups of SAD based on recalled parental behavior by means of cluster analysis. Further, the study investigated whether those subgroups differed on clinical, trauma, and personality variables. METHODS: This study included 505 individuals diagnosed with SAD and 98 adult controls who were asked to fill out the Parental Bonding Instrument (PBI), the Adverse Childhood Experiences Questionnaire (ACE), and the Temperament and Character Inventory (TCI). Cluster analysis determined whether there are meaningful SAD subgroups based on PBI. The clusters obtained were compared with each other and with the control group with regard to clinical, ACE, and TCI variables. RESULTS: The cluster analysis revealed two SAD clusters based on recalled parental behavior. SAD individuals in the first cluster (49.3 %) perceived their parents as intermediately caring, but not as overcontrolling. SAD individuals in the second cluster (50.7 %) perceived their parents as less caring and overcontrolling, reported more severe clinical symptoms and trauma, and had lower values in Self-Directedness and Cooperativeness. LIMITATIONS: The present study is cross-sectional, therefore unable to confirm causal interpretations. CONCLUSION: Parenting is meaningful to enlighten the heterogeneity of SAD symptomatology and to specify treatment approaches as there are two meaningful subgroups in individuals with SAD corresponding to differences in clinical presentation, trauma, and personality.

Impact of the COVID-19 Pandemic on Youth Substance Use and Substance-Related Risk Factors and Outcomes: Implications for Prevention, Treatment, and Policy.

Youth substance use and substance use disorders (SUD) are major public health issues associated with significant societal cost. The coronavirus SARS-CoV-2 (COVID-19) pandemic and pandemic-related lockdowns, school closures, and social distancing dramatically impacted the daily lives of young people worldwide, resulting in major disruptions to normal developmental trajectories and complex (and at times opposing effects) on different SUD risk and protective factors, which contributed to inconsistent outcomes. During the COVID-19 pandemic, substance use prevalence rates decreased in the general population of US youth, but increased for certain vulnerable subgroups. Additionally, overdose deaths related to fentanyl rose significantly among US youth.

How important are the cytomorphologic subtypes of the salivary gland neoplasm of uncertain malignant potential (SUMP) category in the Milan system for reporting salivary gland cytology? An institutional experience 2018-2024.

INTRODUCTION: Salivary gland neoplasm of uncertain malignant potential (SUMP) is an important diagnostic category of the Milan System for reporting salivary gland cytology (MSRSGC). Further subcategorization by cytomorphologic subtypes has been recommended to risk-stratify cases. In this study, our institutional experience with the risk of neoplasm (RON) and risk of malignancy (ROM) based on cytomorphologic subcategorization of SUMP is reported. We also report the prevalence of malignancy (POM) at our institution. METHODS: The pathology database was queried for cases of fine-needle aspiration (FNA) diagnosed as SUMP along with follow-up at our institution from 2018-February 2024. This study was approved by an institutional review board. RESULTS: Of 1159 cases of salivary gland FNA specimens reported as per MSRSGC at our institution, 14.8% (171/1159 cases) were diagnosed as SUMP, with these reports verified by at least 16 cytopathologists. Surgical follow-up was available for 139/171 (81.3%) of these cases, for which the original cytomorphologic subgroups were as follows: 65 (46.8%) basaloid, 48 (34.5%) oncocytic/oncocytoid, 14 (10.1%) myoepithelial, 9 (6.5%) other, 2 (1.4%) clear cell, and 1 (0.7%) mucinous. The POM within SUMP at our institution is within a range of 29.8%-36.7%. When considering all cases, our institutional RON for SUMP was 97.8% (136/139), and the ROM was 36.7% (51/139). Notably, a significant portion of cases (36%, 50/139) underwent review at a daily intradepartmental consensus conference. Analysis revealed that SUMP cases that underwent consensus review had a ROM of 46% (23/50), versus 31.5% (28/89) in independently verified cases (p = .13). Of the cytomorphologic subgroups, basaloid SUMP in particular was more likely to be benign on resection when the case had been independently verified than after consensus review (p = .0082). When considering only the independently verified cases, the ROM for each subgroup was as follows: 38.7% (12/31) in oncocytic/oncocytoid, 20% (9/45) in basaloid, 33.3% (2/6) in myoepithelial, 60% (3/5) in "other", and 100% (1/1) in both mucinous and clear cell (p = .0407). CONCLUSION: While the RON is high across all cytomorphologic subgroups of SUMP, the ROM does vary across the groups, with basaloid cytomorphology having the lowest ROM. This effect is seen in independently verified cases but not in cases having undergone consensus review.

The architecture of paranoia in the general population: A self-report and ecological momentary assessment study.

Paranoia is a common delusion type found in clinical and non-clinical populations. A hierarchical, dimensional model of paranoia in the general population has been proposed, with four categories representing increasing levels of paranoia: interpersonal sensitivity (IP), mistrust (M), ideas of reference (IR), persecutory ideas (PI). What is currently lacking and could provide insights into etiology is a comprehensive clinical characterization of the lower end of the paranoia spectrum, psychological domains that are associated with symptom severity, and how paranoia and its structure fluctuate over time. This study conducted both cross-sectional and longitudinal surveys with 802 participants from the German population assessing paranoia and general psychopathology. Data was collected through Ecological Momentary Assessment (EMA). Several statistical approaches were used including confirmatory factor analysis (CFA), latent class analysis (LCA) and mixed modelling analyses (ME). Paranoid experiences appear to be a common phenomenon that occur in people with and without mental illness. Subjects clustered into four paranoia severity subgroups (IP, M, IR, PI) and showed significant associations in various psychological domains like increased psychiatric symptoms and maladaptive coping. Paranoia fluctuates over time in all four severity subgroups, but the hierarchical subgrouping was stable. Both persecutory ideations and interpersonal sensitivity were significant predictors of paranoia. Findings provide important insights into the architecture of paranoia in the German population by characterizing their hierarchical, dimensional, and dynamic structure and its link to psychopathology.

Restricted health service utilization and subsequent positive self-care behavior during the early COVID-19 pandemic in China.

Background: The reallocation of health resources, epidemic prevention and control measures during the COVID-19 pandemic triggered widespread restricted health service utilization, some residents and patients tried positive self-care behavior to maintain their health, yet the efficacy of this intervention remains unclear. Object: Based on the reasoned action approach (RAA) theory, this study aimed to investigate the correlation between self-care behavior and restricted health service utilization among adults in China, trying to discover the vulnerable groups and external and intrinsic factors that affect self-care behavior among Chinese adults. Methods: Data on demographics, socioeconomic, health status, and self-care behavior were collected in "The Early China COVID-19 Survey," a cross-sectional anonymous online survey of the general population in China. Self-care behavior was measured by four indicators: weight control (WC), physical activity (PA), prevention behavior (PB), and online medical consultation (OMC). The multiple linear models and binary logistic regression were used to examine whether restricted health service utilization (RHSU) is associated with self-care behaviors; also, adjusted multivariate logistic regression was used to analyze subgroup heterogeneity. Results: In total, 8,428 adult participants completed the survey, the mean OMC score was 1.51 (SD 1.34), the mean PB score was 18.17 (SD 3.44), and the proportion of participants who engaged in WC and PA was 42.30 and 62.57%, respectively. According to the multiple regression model, the RHSU was significantly positively correlated with all four indicators of self-care (WC: OR = 1.34, p < 0.001, PA: OR = 1.34, p < 0.05, MC: OR = 1.30, p < 0.001, PB: coef = 0.16, p < 0.05). We also observed some significant differences in the intensity of this relationship by subgroup analysis, precisely, OMC (high vs. moderate vs. low infection-risk level: OR = 1.48; 1.41; 1.19, p < 0.1), PA (male vs. female: OR = 1.27;1.06; p < 0.05, high vs. Moderate and low infection-risk level: OR = 1.51; 1.17; 1.02, p < 0.05), PB (Chronic disease groups vs. no: coef = 0.46; 0.1, p < 0.05). Conclusion: Restricted health service utilization predicts more positive self-care behavior, and the intensity of partial correlation was significantly different in the subgroups of sex, actual infection risk level of the living area, and chronic diseases. These findings highlight the urgent demand for self-care behavior among Chinese adults during the pandemic and provide new insights for developing self-care and reducing the burden on the healthcare system in the long term.

Fecal bacteria and short-chain fatty acids in irritable bowel syndrome: Relations to subtype.

BACKGROUND: The relationship between gut microbiota and irritable bowel syndrome (IBS) subtype is unclear. We aimed to explore whether differences in fecal bacteria composition and short-chain fatty acid (SCFA) levels were associated with subtypes and symptoms of IBS. METHODS: All participants delivered fecal samples and self-reports on IBS Symptom Severity Score (IBS-SSS), Bristol Stool Scale (BSS), and Gastrointestinal Symptom Rating Scale (GSRS). Fecal bacteria composition was assessed by the GA-map® Dysbiosis Test based on 16S rRNA sequences of bacterial species/groups. SCFAs were analyzed by vacuum distillation followed by gas chromatography. KEY RESULTS: Sixty patients with IBS were included (mean age 38 years, 46 [77%] females): Twenty-one patients were classified as IBS-D (diarrhea), 31 IBS-M (mixed diarrhea and constipation), and eight IBS-C (constipation). Forty-two healthy controls (HCs) (mean age 35 years, 27 [64%] females) were included. Patients had a significantly higher relative frequency of dysbiosis, lower levels of Actinobacteria, and higher levels of Bacilli than HCs. Eight bacterial markers were significantly different across IBS subgroups and HCs, and 13 bacterial markers were weakly correlated with IBS symptoms. Clostridia and Veillonella spp. had a weak negative correlation with constipation scores (GSRS) and a weak positive correlation with loose stools (BSS). Diarrhea scores (GSRS) and looser stool (BSS) were weakly correlated with levels of total SCFAs, acetic and butyric acid. Levels of total SCFAs and acetic acid were weakly correlated with symptom severity (IBS-SSS). CONCLUSIONS & INFERENCES: Patients with IBS had a different fecal bacteria composition compared to HCs, and alterations of SCFAs may contribute to the subtype.

Comparative Immunohistochemical Analysis of Clinicopathological Subgroups in Hepatocellular Carcinomas from Japan and Indonesia.

Background: Standardized pathological evaluation based on immunohistochemical (IHC) analysis could improve hepatocellular carcinoma (HCC) diagnoses worldwide. We evaluated differences in clinicopathological subgroups in HCCs from two academic institutions in Tokyo-Japan, and Jakarta-Indonesia. Methods: Clinicopathological parameters and molecular expression patterns were evaluated in 35 HCCs from Indonesia and 41 HCCs from Japan. IHC analysis of biliary/stem cell (B/S) markers (cytokeratin 19, sal-like protein 4, epithelial cell adhesion molecule) and Wnt/ß-catenin (W/B) signaling-related molecules (ß-catenin, glutamine synthetase) could determine the IHC-based subgroups. For immuno-subtypes categorization, CD3/CD79α double immunohistochemistry was done to evaluate the infiltration of T and B cells. CD34 staining allowed identification of vessels that encapsulated tumor clusters (VETC). Results: Indonesian HCC patients were mostly <60 years old (66%) with a hepatitis B virus (HBV) background (82%), in contrast to Japanese HCC patients (8% and 19%, respectively, both P < 0.001). In comparison with Japanese, Indonesian cases more frequently had >5 cm tumor size (74% vs 23%, P = 0.001), poor differentiation (40% vs 24%), portal vein invasion (80% vs 61%), and α-fetoprotein levels >500 ng/ml (45% vs 13%, P = 0.005). No significant differences were found in the proportions of B/S, W/B, and -/- subgroups from both countries. No immune-high tumors were observed among Indonesian cases, and immune-low tumors (66%) were more common than in Japanese cases (54%). VETC-positive tumors in Indonesia were significantly more common (29%), and most were in the HBV (90%) and -/- subgroups (90%), whereas Japanese VETC cases (10%, P = 0.030) were nonviral (100%) and W/B subgroups (75%). Conclusion: IHC-based analysis more precisely reflected the clinicopathological differences of HCCs in Japan and Indonesia. These findings provide new insights into standardization attempts and HCC heterogeneity among countries.

Identifying subgroups of urge suppression in Obsessive-Compulsive Disorder using machine learning.

Obsessive-compulsive disorder (OCD) is phenomenologically heterogeneous. While predominant models suggest fear and harm prevention drive compulsions, many patients also experience uncomfortable sensory-based urges ("sensory phenomena") that may be associated with heightened interoceptive sensitivity. Using an urge-to-blink eyeblink suppression paradigm to model sensory-based urges, we previously found that OCD patients as a group had more eyeblink suppression failures and greater activation of sensorimotor-interoceptive regions than controls. However, conventional approaches assuming OCD homogeneity may obscure important within-group variability, impeding precision treatment development. This study investigated the heterogeneity of urge suppression failure in OCD and examined relationships with clinical characteristics and neural activation. Eighty-two patients with OCD and 38 controls underwent an fMRI task presenting 60-s blocks of eyeblink suppression alternating with free-blinking blocks. Latent profile analysis identified OCD subgroups based on number of erroneous blinks during suppression. Subgroups were compared on behavior, clinical characteristics, and brain activation during task. Three patient subgroups were identified. Despite similar overall OCD severity, the subgroup with the most erroneous eyeblinks had the highest sensory phenomena severity, interoceptive sensitivity, and subjective urge intensity. Compared to other subgroups, this subgroup exhibited more neural activity in somatosensory and interoceptive regions during the early phase (first 30 s) of blink suppression and reduced activity in the middle frontal gyrus during the late phase (second 30 s) as the suppression period elapsed. Heterogeneity of urge suppression in OCD was associated with clinical characteristics and brain function. Our results reveal potential treatment targets that could inform personalized medicine.

Differences Between RSV A and RSV B Subgroups and Implications for Pharmaceutical Preventive Measures.

INTRODUCTION: Understanding the differences between respiratory syncytial virus (RSV) subgroups A and B provides insights for the development of prevention strategies and public health interventions. We aimed to describe the structural differences of RSV subgroups, their epidemiology, and genomic diversity. The associated immune response and differences in clinical severity were also investigated. METHODS: A literature review from PubMed and Google Scholar (1985-2023) was performed and extended using snowballing from references in captured publications. RESULTS: RSV has two major antigenic subgroups, A and B, defined by the G glycoprotein. The RSV F fusion glycoprotein in the prefusion conformation is a major target of virus neutralizing antibodies and differs in surface exposed regions between RSV A and RSV B. The subgroups co-circulate annually, but there is considerable debate as to whether clinical severity is impacted by the subgroup of the infecting RSV strain. Large variations between the studies reporting RSV subgroup impact on clinical severity were observed. A tendency for higher disease severity may be attributed to RSV A but no consensus could be reached as to whether infection by one of the subgroup caused more severe outcomes. RSV genotype diversity decreased over the last two decades, and ON and BA have become the sole lineages detected for RSV A and RSV B, since 2014. No studies with data obtained after 2014 reported a difference in disease severity between the two subgroups. RSV F is relatively well conserved and highly similar between RSV A and B, but changes in the amino acid sequence have been observed. Some of these changes led to differences in F antigenic sites compared to reference F sequences (e.g., RSV/A Long strain), which are more pronounced in antigenic sites of the prefusion conformation of RSV B. Initial results from the second season after vaccination suggest specific RSV B efficacy wanes more rapidly than RSV A for RSV PreF-based monovalent vaccines. CONCLUSIONS: RSV A and RSV B both contribute substantially to the global RSV burden. Both RSV subgroups cause severe disease and none of the available evidence to date suggests any differences in clinical severity between the subgroups. Therefore, it is important to implement measures effective at preventing disease due to both RSV A and RSV B to ensure impactful public health interventions. Monitoring overtime will be needed to assess the impact of waning antibody levels on subgroup-specific efficacy.

Cluster analysis of clinical manifestations assigns systemic lupus erythematosus-phenotype subgroups: A multicentre study on 440 patients.

OBJECTIVE: Systemic lupus erythematous (SLE) is a heterogenous disease characterised by a large panel of autoantibodies and a wide spectrum of clinical signs and symptoms that engender different outcomes. We aimed to identify distinct, homogeneous SLE patients' phenotypes. METHODS: This retrospective study enrolled SLE patients meeting the Systemic Lupus International Collaborating Clinics (SLICC) classification criteria, enrolled in the French multicentre "APS (antiphospholipid syndrome) and SLE" Registry. Based on 29 variables selected to cover a broad range of clinical and laboratory (excluding autoantibodies) SLE manifestations, unsupervised multiple correspondence analysis followed by hierarchical ascendent-clustering analysis assigned different phenotypes. RESULTS: We included 440 patients, mostly women (94.3%). Median age at SLE diagnosis was 24 (IQR 19-32) years. Cluster analysis yielded three distinct subgroups based on cumulative clinical manifestations, not autoantibody pattern. Cluster 1 (n=91) comprised mostly Caucasian patients, with APS-associated clinical and biological manifestations, e.g., livedo, seizure, thrombocytopaenia and haemolytic anaemia. Cluster 2 (n=221), the largest, included patients with mild clinical manifestations, mainly articular, more frequently associated with Sjögren's syndrome and with less frequent autoantibody-positivity. Cluster 3 (n=128) consisted of patients with the largest panel of SLE-specific clinical manifestations (cutaneous, articular, proliferative nephritis, pleural, cardiac and haematological), the most frequent autoantibody-positivity, low complement levels, and more often of Asian and sub-Saharan African origin. CONCLUSION: This unsupervised clustering method distinguished three distinct SLE patient subgroups, highlighting SLE heterogeneity.

Subgroups of ICU patients identified by self-reported symptoms - A prospective multicenter study.

BACKGROUND: Intensive care unit (ICU) patients experience several symptoms, yet patterns of symptoms and their relationship with demographic and clinical characteristics have not previously been investigated. OBJECTIVES: To identify and compare subgroups (i.e. latent symptom classes) of intensive ICU patients based on prevalence of co-occurring symptoms over seven days. RESEARCH METHODOLOGY: Prospective cohort study of adult ICU patients' self-reports of five symptoms during seven days in ICU. Latent class analysis was applied to identify subgroups of ICU patients. SETTING: Multicenter study with patients from six mixed ICUs in Norway. MAIN OUTCOME MEASURES: Patient Symptom Survey was used to assess five symptoms (i.e., thirst, pain, anxiousness, tiredness, shortness of breath). RESULTS: Among 353 included patients, median age was 63 years and 60.3 % were male. Subgroups of patients were identified in a Low class (n = 126, 35.7 %), Middle Class (n = 177, 50.1 %) and High Class (n = 50, 14.2 %) based on reporting of the prevalence of five symptoms. Patients in the Low class had a low prevalence of all symptoms. Middle Class patients had a high prevalence of thirst and tiredness and a low prevalence of pain, anxiousness and shortness of breath. The High class patients had a high prevalence of all symptoms. Symptom prevalence remained stable in the Low and Middle class over time and increased over time in the High class. There were significant differences among symptom classes in use of mechanical ventilation (p = 0.012), analgesics (p < 0.001), alpha-2 agonists (p = 0.004) and fluid restriction (p = 0.006). Patients in the High class received more of these ICU-treatments. CONCLUSIONS: Findings suggest that subgroups of ICU patients with distinct symptom experiences can be identified. The High prevalence class patients had consistently high levels of all symptoms across seven ICU days and received more ICU-related interventions. IMPLICATION FOR CLINICAL PRACTICE: Some ICU patients experience a consistently high prevalence of co-occurring symptoms. Clinicians should be aware of treatment factors that could be linked to a high burden of symptoms.

Does One Measure Fit All? The Role of Experimentally Induced Pain Tests in the Assessment of Women with Provoked Vestibular Pain.

Purpose: A diagnostic algorithm was recently suggested to address the underlying mechanisms of provoked-vestibulodynia (PVD). It delineates four subgroups (Hormonal-associated, Augmented-anterior, Hymenal-associated and Hypertonicity-associated), each manifesting a distinctive vulvar pain-hypersensitivity regarding location (circumferential vs posterior-only vestibulodynia) and pain characteristics. We aimed to explore the significance of various experimentally induced vulvar pain measures in the manifestation of pain hypersensitivity in each subgroup. Methods: Women with PVD (n = 113) and 43 controls reported pain intensity provoked during vaginal penetration and tampon insertion. Vestibular tenderness (anterior and posterior) was assessed by Q-tip test, and pressure stimulation delivered to the puborectalis assessed muscle tenderness. Pain thresholds were measured using a vulvar-algesiometer. These measures were compared between patients and controls and among the PVD subgroups. Correlations between the clinical and experimentally induced-pain measures were assessed. Finally, to address whether the association between experimentally induced-pain measures and dyspareunia severity is mediated by hypertonicity, the conditional indirect effect was analyzed in each subgroup. Results: Compared to controls, augmented vulvar pain-hypersensitivity and hypertonicity were observed among patients (p < 0.001). ANOVA revealed no subgroup differences in dyspareunia severity. Nevertheless, some experimentally induced-pain measures were differently correlated with dyspareunia intensity in each subgroup, allowing discrimination of subgroups according to the unique findings of vulvar pain-hypersensitivity. The degree of pelvic floor muscle-hypertonicity mediated the association between vulvar pain-hypersensitivity and dyspareunia severity, emphasizing the key role of hypertonicity in distinguishing between subgroups. Conclusion: The findings offer more evidence of variations among PVD subtypes, demonstrating that insertional dyspareunia may originate from dissimilar alterations in the mucosal and muscular tissues. The results also emphasize the significance of utilizing a wide battery of tests to capture different experimentally induced-pain measures, revealing the unique patterns of vulvar pain-hypersensitivity in each subgroup.

Acute limbic system connectivity predicts chronic cognitive function in mild traumatic brain injury: An individualized differential structural covariance network study.

Mild traumatic brain injury (mTBI) is a known risk factor for neurodegenerative diseases, yet the precise pathophysiological mechanisms remain poorly understand, often obscured by group-level analysis in non-invasive neuroimaging studies. Individual-based method is critical to exploring heterogeneity in mTBI. We recruited 80 mTBI patients and 40 matched healthy controls, obtaining high-resolution structural MRI for constructing Individual Differential Structural Covariance Networks (IDSCN). Comparisons were conducted at both the individual and group levels. Connectome-based Predictive Modeling (CPM) was applied to predict cognitive performance based on whole-brain connectivity. During the acute stage of mTBI, patients exhibited significant heterogeneity in the count and direction of altered edges, obscured by group-level analysis. In the chronic stage, the number of altered edges decreased and became more consistent, aligning with clinical observations of acute cognitive impairment and gradual improvement. Subgroup analysis based on loss of consciousness/post-traumatic amnesia revealed distinct patterns of alterations. The temporal lobe, particularly regions related to the limbic system, significantly predicted cognitive function from acute to chronic stage. The use of IDSCN and CPM has provided valuable individual-level insights, reconciling discrepancies from previous studies. Additionally, the limbic system may be an appropriate target for future intervention efforts.

Clinically unfavorable transcriptome subtypes of non-WNT/non-SHH medulloblastomas are associated with a predominance in proliferating and progenitor-like cell subpopulations.

The non-WNT/non-SHH (Grp3/Grp4) medulloblastomas (MBs) include eight second-generation subgroups (SGS; I-VIII) each with distinct molecular and clinical characteristics. Recently, we also identified two prognostically relevant transcriptome subtypes within each SGS MB, which are associated with unique gene expression signatures and signaling pathways. These prognostic subsets may be in connection to the intra-tumoral cell landscape that underlies SGS MB clinical-molecular diversity. Here, we performed a deconvolution analysis of the Grp3/Grp4 MB bulk RNA profiles using the previously identified single-cell RNA-seq reference dataset and focusing on variability in the cellular composition of SGS MB. RNA deconvolution analysis of the Grp3/Grp4 MB disclosed the subgroup-specific neoplastic cell subpopulations. Neuronally differentiated axodendritic GP3-C1 and glutamatergic GP4-C1 subpopulations were distributed within Grp3- and Grp4-associated SGS MB, respectively. Progenitor GP3-B2 subpopulation was prominent in aggressive SGS II MB, whereas photoreceptor/visual perception GP3/4-C2 cell content was typical for SGS III/IV MB. The current study also revealed significant variability in the proportions of cell subpopulations between clinically relevant SGS MB transcriptome subtypes, where unfavorable cohorts were enriched with cell cycle and progenitor-like cell subpopulations and, vice versa, favorable subtypes were composed of neuronally differentiated cell fractions predominantly. A higher than median proportion of proliferating and progenitor cell subpopulations conferred the shortest survival of the Grp3 and Grp 4 MB, and similar survival associations were identified for all SGS MB except SGS IV MB. In summary, the recently identified clinically relevant Grp3/Grp4 MB transcriptome subtypes are composed of different cell populations. Future studies should aim to validate the prognostic and therapeutic role of the identified Grp3/Grp4 MB inter-tumoral cellular heterogeneity. The application of the single-cell techniques on each SGS MB separately could help to clarify the clinical significance of subgroup-specific variability in tumor cell content and its relation with prognostic transcriptome signatures identified before.

Characterization of High and Low IFNG-Expressing Subgroups in Atopic Dermatitis.

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases, with an increasing number of targeted therapies available. While biologics to treat AD exclusively target the key cytokines of type 2 immunity, Janus kinase inhibitors target a broad variety of cytokines, including IFN-γ. To better stratify patients for optimal treatment outcomes, the identification and characterization of subgroups, especially with regard to their IFNG expression, is of great relevance, as the role of IFNG in AD has not yet been fully clarified. This study aims to define AD subgroups based on their lesional IFNG expression and to characterize them based on their gene expression, T cell secretome and clinical attributes. RNA from the lesional and non-lesional biopsies of 48 AD patients was analyzed by RNA sequencing. Based on IFNG gene expression and the release of IFN-γ by lesional T cells, this cohort was categorized into three IFNG groups (high, medium, and low) using unsupervised clustering. The low IFNG group showed features of extrinsic AD with a higher prevalence of atopic comorbidities and impaired epidermal lipid synthesis. In contrast, patients in the high IFNG group had a higher average age and an activation of additional pro-inflammatory pathways. On the cellular level, higher amounts of M1 macrophages and natural killer cell signaling were detected in the high IFNG group compared to the low IFNG group by a deconvolution algorithm. However, both groups shared a common dupilumab response gene signature, indicating that type 2 immunity is the dominant immune shift in both subgroups. In summary, high and low IFNG subgroups correspond to intrinsic and extrinsic AD classifications and might be considered in the future for evaluating therapeutic efficacy or non-responders.

Hepatic-associated vascular morphological assessment to predict overt hepatic encephalopathy before TIPS: a multicenter study.

BACKGROUND: To provide patients the chance of accepting curative transjugular intrahepatic portosystemic shunt (TIPS) rather than palliative treatments for portal hypertension-related variceal bleeding and ascites, we aimed to assess hepatic-associated vascular morphological change to improve the predictive accuracy of overt hepatic encephalopathy (HE) risks. METHODS: In this multicenter study, 621 patients undergoing TIPS were subdivided into training (413 cases from 3 hospitals) and external validation datasets (208 cases from another 3 hospitals). In addition to traditional clinical factors, we assessed hepatic-associated vascular morphological changes using maximum diameter (including absolute and ratio values). Three predictive models (clinical, hepatic-associated vascular, and combined) were constructed using logistic regression. Their discrimination and calibration were compared to test the necessity of hepatic-associated vascular assessment and identify the optimal model. Furthermore, to verify the improved performance of ModelC-V, we compared it with four previous models, both in discrimination and calibration. RESULTS: The combined model outperformed the clinical and hepatic-associated vascular models (training: 0.814, 0.754, 0.727; validation: 0.781, 0.679, 0.776; p < 0.050) and had the best calibration. Compared to previous models, ModelC-V showed superior performance in discrimination. The high-, middle-, and low-risk populations displayed significantly different overt HE incidence (p < 0.001). Despite the limited ability of pre-TIPS ammonia to predict overt HE risks, the combined model displayed a satisfactory ability to predict overt HE risks, both in the low- and high-ammonia subgroups. CONCLUSION: Hepatic-associated vascular assessment improved the predictive accuracy of overt HE, ensuring curative chances by TIPS for suitable patients and providing insights for cirrhosis-related studies.

Utilising Behavioural and Sensory Profiles and Associated Perinatal Factors to Identify Meaningful Subgroups in Autism Spectrum Disorder.

The heterogeneity of autism spectrum disorder (ASD) clinically and aetiologically hinders intervention matching and prediction of outcomes. This study investigated if the behavioural, sensory, and perinatal factor profiles of autistic children could be used to identify distinct subgroups. Participants on the autism spectrum aged 2 to 17 years and their families were sourced via the Australian Autism Biobank (AAB). Latent class analysis was used to identify subgroups within this cohort, utilising twenty-six latent variables representing child's behavioural and sensory features and perinatal factors. Four distinct subgroups within the sample (n = 1168) distinguished by sensory and behavioural autism traits and exposure to perinatal determinants were identified. Class 2 and Class 4, which displayed the greatest behavioural and sensory impairment respectively, were associated with the highest perinatal factor exposure. Class 1, labelled "Most behavioural concerns and moderate sensory and behavioural skills concerns" had mixed exposure to perinatal determinants while Class 3, named "Least sensory and behavioural skills concerns" had the least perinatal determinant exposure, indicating a directly proportional correlation between severity of clinical features and perinatal factor exposure. Additionally, association between specific exposures such as maternal mental illness in Class 1 and significant behavioural concerns was recognised. Identifying distinct subgroups among autistic children can lead to development of targeted interventions and supports. Close monitoring of children exposed to specific perinatal determinants for developmental differences could assist early intervention and supports.