Pomalidomide is a 2nd-generation chiral immunomodulatory (IMiDs) drugs and have antiangiogenic activity. Despite being teratogenic, it has been shown to be effective in treating multiple myeloma. Enantioselectivity, chemical structure, and biological activity have been investigated using molecular docking. In silico docking simulations to confirm the enantioselective binding of pomalidomide to immunomodulator targets, namely, CRBN, TNF- α11, Pg G/H synthase 2, and Cadeherin-5 Protein. The protein was preprocessed using hydrogen addition, disulphide treatment, and bond order assignment. The Ligand Preparation Module was used to optimize all of the chosen ligands, and OPLS3e Forcefield was used to optimize the geometry. Site map analysis module was used to determine the top-ranked receptor binding sites for the enzymes. Molecules were docked by using Schrodinger 2020_3 software. Docking study confirms the enantioselective binding of pomalidomide to immunomodulator targets (CRBN, TNF-α_11, Pg G/H synthase 2, and Cadeherin-5 Protein). Out of all four targets S- (-) enantiomer of pomalidomide had significant binding with CRBN and TNF-α 11, while R-(+)enantiomer of pomalidomide had significant binding with Pg G/H synthase 2, and Cadeherin-5 Protein. The result suggests that, chemical interactions of S-enantiomer of pomalidomide have better binding with residues at the active site of CRBN and TNF-α 11. This concludes that S-enantiomer of pomalidomide could be a better choice for multiple myeloma therapy.
To investigate the causal effects of antidiabetic drug targets on Bell's palsy risk using Mendelian randomization (MR), addressing limitations of observational studies and informing therapeutic strategies for diabetic patients. A 2-sample MR analysis was conducted using genetic instruments for 5 major antidiabetic drug classes: sulfonylureas (ABCC8/KCNJ11), metformin (GPD1), thiazolidinediones (PPARG), GLP1-RAs (GLP1R), and SGLTi (SLC5A1/2). Instrumental variables were selected from cis-regions (±500 kb) of target genes using HbA1c-associated single nucleotide polymorphisms (GWAS ID: ebi-a-GCST90014006) with stringent clumping (P < 5 × 10-8, r2 < 0.2) and F-statistic > 10 to ensure robustness. Bell's palsy data were sourced from FinnGen (finn-b-G6_BELLPA) including. Causal effects were assessed via inverse variance weighted, MR-Egger, and weighted median methods, complemented by sensitivity analyses (MR-Pleiotropy RESidual Sum and Outlier, Cochran's Q). Genetically proxied sulfonylurea (via ABCC8/KCNJ11) and metformin (via GPD1) targets exhibited significant protective effects against Bell's palsy, with odds ratios of 0.19 (95% CI: 0.04-0.92, P = .039) and 0.16 (0.03-0.87, P = .034), respectively. Sensitivity analyses confirmed minimal pleiotropy (MR-Egger intercept P > .05) and heterogeneity (Cochran's Q P > .05). No associations were observed for thiazolidinediones, GLP1-RAs, or SGLTi. Scatter plots and inverse variance weighted median concordance supported robustness for ABCC8/KCNJ11, though limited single nucleotide polymorphisms for GPD1 warranted cautious interpretation. This MR analysis provides genetic evidence that sulfonylureas and metformin may confer neuroprotection against Bell's palsy, supporting potential repurposing of these agents to mitigate neurological complications in diabetic patients.
A large number of functional disorders and uncomfortable symptoms often remain following ischemic stroke (IS). Existing drug therapy is not ideal for the direct improvement of symptoms, which often leads to poor patient compliance with physical rehabilitation therapy. Buyang Huanwu Decoction (BYHWD) is a famous prescription that is effective in treating IS, especially during the sequela stage of IS. We analyzed the therapeutic mechanism of BYHWD through network pharmacology. This study aims to investigate the potential active ingredients, targets, and signaling pathways of BYHWD for the treatment of IS, utilizing network pharmacology and molecular docking technology. The active ingredients of 7 Chinese herbs in BYHWD were obtained from the Traditional Chinese Medicine Systems Pharmacology and HERB databases, and IS-related disease targets were searched in the DisGeNET, GeneCards, and OMIM databases. The protein-protein interaction network was constructed using the STRING database and analyzed by Cytoscape 3.10.2 software. Additionally, the target genes were uploaded to the Database for Annotation, Visualization, and Integrated Discovery website for Gene Ontology alongside Kyoto Encyclopedia of Genes and Genomes analyses. With the assistance of AutoDockTools and PyMOL software (Schrödinger, Inc.), a validation of molecular docking results and a visualization of the results were performed. The results showed that there were 190 intersection targets between the active drug components and IS, corresponding to 61 active components, among which the top 5 target genes were tumor suppressor protein 53, Jun proto-oncogene, AKT serine/threonine kinase 1, mitogen-activated protein kinase 1, and estrogen receptor alpha. The PI3K-Akt signaling pathway is one of the top 10 pathways. The molecular docking results indicated that most of the top 5 targets had good affinities for the 8 core compounds. This computational analysis suggests that BYHWD may treat IS through multiple targets and pathways. It may play a neuroprotective role by regulating the inflammatory response, oxidative stress, apoptosis, autophagy, and vascular endothelial homeostasis. The identification of core effective components provides a theoretical foundation and candidate compounds for further investigation into new drugs for the treatment of sequelae after IS.
To identify the active compounds of Platycladus orientalis leaf extract (POE) and quantify its efficacy against androgenetic alopecia (AGA) via vascular endothelial growth factor A (VEGFA)/B-cell lymphoma 2 (Bcl-2) signaling. Active compounds and their potential targets in POE were first identified. A compound-target interaction network was constructed using network pharmacology approaches, and molecular docking was employed to evaluate the binding affinities of key compounds to their predicted targets. Furthermore, in vitro experiments were conducted to assess the effects of key bioactive constituents on the expression levels of proteins involved in the VEGFA/Bcl2 pathway. POE promotes dermal papilla cell proliferation and angiogenesis by activating VEGFA/Bcl-2 signaling. Network pharmacology screened 28 compounds against 506 androgenetic alopecia targets; the top 6 (amentoflavone, isoquercitrin, afzelin, phloretin, pinusolide, and quinic acid) were docked to VEGFA (threshold Vina score < -7.0). POE at 3.13 µg mL-1 increased dermal papilla cell number by 15.6 ± 1.2% versus control (P < .01) and up-regulated VEGFA (0.76 ± 0.02 vs 0.64 ± 0.03), Bcl-2 (0.86 ± 0.01 vs 0.79 ± 0.01) and phosphorylated B-cell lymphoma 2 (0.81 ± 0.01 vs 0.71 ± 0.01); all P < .01. Efficacy matched 10 µg mL-1 minoxidil (P > .05).
This study aimed to assess the association between early nutritional support - specifically the attainment of predefined energy targets - and the risk of hospital-acquired infections (HAIs) in critically ill neonates. We conducted a retrospective cohort study involving 200 critically ill neonates admitted to a tertiary neonatal intensive care unit between January 2022 and December 2023. Participants were stratified into 2 exposure groups according to the timing of nutritional initiation and adequacy of energy/protein intake during the first postnatal week: an early-adequate nutrition group (n = 92) and a delayed or insufficient nutrition group (n = 108). A multivariable logistic regression model was fitted to evaluate the independent effect of energy target achievement on HAI risk, with additional subgroup and sensitivity analyses to assess robustness. The cohorts were largely comparable at baseline, although birth weight was significantly higher in the early-adequate nutrition group (1605 ± 390 vs 1470 ± 440 g, P = .02). Initiation of nutritional support occurred earlier in the early-adequate group, resulting in significantly greater cumulative energy and protein intake by day 7. The energy target achievement rate was 100% in the early-adequate group, compared with 33.3% in the delayed/insufficient group (P < .001). Throughout the follow-up period, 48 neonates (24.0%) developed HAIs, with a significantly lower incidence observed in the early-adequate nutrition group (15.2% vs 31.5%, P = .008). Quartile-based analysis demonstrated a clear inverse dose-response relationship between energy intake and infection incidence (P for trend = .001). After adjusting for potential confounders, achievement of the energy target (≥60 kcal/kg/d) remained independently associated with reduced HAI risk (adjusted odds ratio = 0.45, 95% confidence interval = 0.22-0.89, P = .02). Subgroup analyses revealed a more pronounced protective effect among very low birth weight infants and those born at <28 weeks' gestation. Sensitivity analyses confirmed the consistency of these findings across alternative energy thresholds (60, 70, and 80 kcal/kg/d). Early attainment of energy targets is independently associated with a reduced incidence of HAIs in critically ill neonates, underscoring the vital role of timely and sufficient nutritional support in mitigating infectious complications in the neonatal intensive care unit setting.
Facial spastic synkinesis (FSS) is a disabling sequela of facial nerve palsy, with current treatments limited by transient efficacy, severe side effects, poor precision, and lack of quantifiable targets/objective evaluation. This study used ultrasound shear wave elastography combined with Canggui Tanxue needling to precisely locate lesioned muscles, exploring a safer, more effective targeted strategy to address the gap of insufficient precision and quantitative evidence in clinical practice. A single-blind randomized controlled trial was conducted at Chongqing Traditional Chinese Medicine Hospital's Acupuncture Department (June 2022 to May 2023), enrolling 64 FSS patients randomized into an ultrasound-guided group (n = 31) and a control group (n = 33). The former received Canggui Tanxue needling at hypertonic muscles (Young modulus > 10 kPa) under real-time shear wave elastography, the latter received traditional syndrome differentiation-based acupuncture. Both groups had 6 sessions (twice weekly for 3 weeks). Outcome measures included primary (Young modulus of target muscles) and secondary (House-Brackmann grading, Facial Disability Index, and total effective rate) indicators. SPSS 26.0 was used for statistical analysis. A total of 64 patients aged 27 to 66 years were enrolled, including 25 males (39.06%) and 39 females (60.94%). Baseline characteristics were comparable between groups (P > .05). Post-intervention, the ultrasound-guided group had significantly larger reductions in Young modulus of depressor anguli oris (3.00 vs 1.10 kPa) and levator labii superioris (5.60 vs 1.00 kPa) versus controls (P < .001). It also showed superior facial nerve recovery (House-Brackmann grading: P = .013), a higher total effective rate (87.1% vs 42.4%, P < .001), and greater improvement in physical function scores (74.84 ± 8.42 vs 68.94 ± 13.68, P = .04). Psychosocial function scores decreased in both groups (P = .92). Only 2 mild subcutaneous hematomas occurred in the ultrasound-guided group, confirming good safety. Ultrasound-guided Canggui Tanxue needling precisely targets hypertonic muscles, reduces pathological tension, improves FSS patients' facial function, and is safe, offering an effective targeted strategy. Clinical promotion of this precise acupuncture technology is recommended, especially for late-stage facial nerve palsy patients with abnormal muscle tension. Future studies should extend follow-up to assess long-term efficacy/recurrence and combine neurophysiological/multimodal imaging to clarify its mechanism.
The treatment with immune checkpoint inhibitors is not universally effective, and the efficacy is challenging to predict using a single biomarker. Breast cancer (BC) cells develop within a complex microenvironment, which includes tumor cells, immune cells, and extracellular matrix, and they may interact through paracrine signaling. Elucidating the mechanisms of immune microenvironment regulation and intercellular interactions in BC is fundamental for screening efficacy markers and developing new immunotherapeutic targets. Based on the immune phenotype cellular infiltration characteristics and transcriptomic changes, we constructed a two-way orthogonal partial least square (O2PLS) model to identify immune cell infiltration (ICI) genes, quantitatively characterizing the immune microenvironment within BC to predict patient prognosis, select sensitive populations for immunotherapy, and provide a theoretical basis for the combination of immunotherapy with radiotherapy and chemotherapy. We described the T cell differentiation trajectories and intercellular communication landscapes and revealed the synergistic effects of receptors and ligands (CXCL9-CXCR3, CCL5-ACKR1, and GZMA-F2R) on the immune microenvironment and prognosis. These findings may contribute to elucidating the factors that shape the immune microenvironment and identifying new therapeutic targets.
Developmental programming, a permanent adaptation of the fetus/neonate to maternal environmental signals, underlies many adult physiological and psychiatric disorders. Prenatal stress induced by the synthetic glucocorticoid dexamethasone has been shown to increase anxiety- and depressive-like behaviors and lead to hyperreactive neuroendocrine and autonomic nervous system (ANS) responses to stress in adult female offspring. Prenatal stressors can also cause maternal immune activation (MIA), impact mood/stress circuitry, and program neural development. One way to engage molecular immune signals is to activate toll-like receptors (TLRs). Developmental changes have been seen following gestational exposure to lipopolysaccharide (LPS; TLR4), poly I:C (TLR3), and, most recently, TLR7 agonists resiquimod (RQ) or imiquimod (IMQ). Studies have identified changes in ANS function that may be tied to blood-brain barrier (BBB) changes in the paraventricular nucleus of the hypothalamus (PVN) that coincide with anxiety- /depressive-like behaviors that manifest after fetal programming. These adult dysfunctions are a consequence of prenatal stressors and may have a common underlying mechanism related to the dysregulation of communication between the PVN and critical ANS centers in the brainstem. Studies in humans indicate that brainstem loci may be important centers of ANS regulation that can be targeted to attenuate major depressive disorder (MDD) symptoms in adults. Furthermore, data suggest that select immune and BBB characteristics in PVN and autonomic nuclei in the brainstem are critical targets for future studies, aligning with the hypothesis that immune signaling plays a major role in the development and expression of psychiatric disorders. The overarching goal of this review is to outline the cellular and physiological pathways by which prenatal stressors, mainly synthetic glucocorticoid exposure and MIA, produce long-term, sex-biased programming of adult behavior and ANS function relevant to physiological and psychiatric disorders.
In popular discourse, personal success is often attributed to mindset. In psychological science, such claims correspond to self-related core beliefs-generalized self-representations. However, the lack of a comprehensive framework has prevented systematic investigation of their links to socioeconomic inequality. The present study aimed to provide the first systematic mapping of how socioeconomic status (SES) is reflected in individuals' core beliefs. Building on the CorBel model-an integrative taxonomy of 97 belief nuances derived via natural language processing-we analyzed two preregistered, SES-representative national samples (Germany: N = 435, UK: N = 266). Positive beliefs (e.g., competence, autonomy, trust) were associated with higher SES, whereas negative beliefs (e.g., insecurity, unworthiness, pessimism) were associated with lower SES. These associations replicated across SES indicators (education, income, wealth) and across countries, explaining up to 20% of the variance in SES outcomes. The findings offer the first systematic mapping of how socioeconomic inequalities are mirrored in individuals' innermost psychological constitution. Core beliefs emerge as potential targets for interventions with both societal and policy relevance.
Huangkui capsule (HKC), the ethanol extract of Abelmoschus Manihot (L.) Medicus, is well known for its nephroprotective effects against chronic kidney diseases, but its therapeutic potential in acute kidney injury (AKI) and the underlying mechanisms remain largely unexplored. In this study, a simple and reliable LC-Q-TOF/MS method was developed to detect HKC metabolites in rat serum and urine. A metabolite-disease target network was constructed to predict the pharmacological activities of the serum metabolites, followed by PPI network analysis for hub target identification and GO/KEGG enrichment analyses. A total of 41 urine and 28 serum metabolites were identified. Network pharmacology analysis revealed 50 targets associated with 15 metabolites in the context of HKC treatment of AKI. AKT1 and its related pathways were predicted to serve as a central hub, and molecular docking analysis further predicted favorable binding affinity between AKT1 and all six screened key metabolites. This study established a practical approach for identifying HKC metabolites in vivo and provided a systematic framework for predicting the anti-AKI mechanism of HKC.
Evidence on the long-term durability of glycemic control beyond the first year of automated insulin delivery therapy remains limited, particularly in large multicenter pediatric cohorts. The present study aimed to evaluate long-term effectiveness and identify determinants of sustained optimal outcomes over 3 years of MiniMed™ 780G use in youth with type 1 diabetes (T1D). In this longitudinal, multicenter, real-world study, 359 youth with T1D (median age 12.2 years, 50.9% female) from 20 Italian pediatric diabetes centers were followed for 3 years after MiniMed 780G initiation. Glucose metrics, insulin delivery parameters, device settings, and engagement indicators were analyzed at 1, 2, and 3 years. Longitudinal changes were assessed using linear mixed-effects models. Multivariable logistic regression identified predictors of achieving time in tight range target (TITR ≥ 50%) at 3 years. Median time in range (TIR) remained within international targets but declined modestly from 75% at 1 year to 74% at 3 years (P = 0.002). The percentage of automatic correction boluses increased over time, whereas user-initiated boluses and carbohydrate entries declined (P < 0.001). Youth with higher TIR at 1 year showed a progressive reduction in TIR and greater increase in automated corrections (time × group interaction P < 0.001). At 3 years, higher SmartGuard use (odds ratio [OR]: 1.13, 95% confidence interval [CI]: 1.03-1.23; P = 0.007), optimal system settings (OR: 3.21, 95% CI: 1.33-7.77; P = 0.010), and lower automatic correction boluses (OR: 0.84, 95% CI: 0.80-0.89; P < 0.001) were independently associated with achieving TITR ≥50%. MiniMed 780G provides sustained glycemic control over 3 years. However, progressive reliance on automated corrections and reduced user engagement may attenuate tight glycemic control, highlighting the need for ongoing education and proactive device optimization.
Research on intimate partner violence has traditionally focused on discrete aggressive acts and their frequency, with less attention to how appraisal, emotion, and response readiness are organized within specific conflict episodes. This study advances an event-based structural model of conflict escalation in intimate relationships by examining how appraisal processes, negative emotional activation, escalation tendency, and behavioral responding cohere within standardized conflict events. Using a vignette-based survey of 2,702 adults in long-term intimate relationships, participants responded to scenarios involving potentially offensive partner demands. Path analyses tested associations among appraisal components, anger and fear activation, escalation tendency, behavioral responses, and expectations of partner escalation. To explicitly evaluate the robustness of the proposed structural configuration, behavioral responding was modeled in two alternative ways: as differentiated decision and response style components and as a unified ordinal severity index, with the full structural model estimated under both specifications. Appraisal components were positively associated with negative emotional activation, particularly anger, which in turn was linked to escalation tendency and to more confrontational behavioral indicators, whereas fear was not associated with escalation tendency. This differentiation between anger and fear indicates that not all negative emotional activation within conflict events carries the same escalation potential. The overall pattern of associations remained substantively consistent across both behavioral representations. Gender differences emerged in levels of several components, with women reporting higher perceived hurt, anger, and escalation tendency, and men reporting higher compliance. By conceptualizing escalation as a structurally embedded response orientation within conflict events, the study clarifies how event-specific appraisal and emotion relate to both readiness and behavioral expression in intimate partner conflict and highlights anger-focused, rather than globally emotion-focused, targets for de-escalation efforts.
Kidney stones and sepsis have a complex pathological association. Urinary obstruction and infection caused by kidney stones can easily induce sepsis, leading to increased mortality and poor prognosis. However, the molecular mechanism underlying their comorbidity remains unclear, and there is a lack of specific biomarkers for early prediction and targeted therapy. This study aims to explore the molecular regulatory network of their comorbidity, screen key genes, and clarify their roles in disease progression. Transcriptome, single-cell ribonucleic acid sequencing (scRNA-seq), and spatial transcriptome data of kidney stones and sepsis were downloaded from the Gene Expression Omnibus database. Differential expression analysis was performed using the Limma package to screen for shared differentially expressed genes between the 2 diseases. Least absolute shrinkage and selection operator regression and random forest algorithms were applied for feature selection to identify key regulatory genes. Functional enrichment analyses (Gene Ontology, KEGG) were conducted to explore biological processes and signaling pathways associated with these genes. ScRNA-seq was used to determine cell-type-specific expression patterns, while spatial transcriptome combined with robust cell-type decomposition was employed to validate their spatial distribution. Additionally, transcriptional regulation analysis, drug-gene interaction prediction (via DGIdb), and molecular docking were performed to investigate potential regulatory mechanisms and therapeutic targets. Five key genes (FCER1A, LEF1, NELL2, SBK1, ZC3H8) were identified through integrative analysis. Functional enrichment showed these genes are primarily involved in bacterial response, immune effector processes, and inflammation-related pathways such as IL6-JAK-STAT3 signaling. ScRNA-seq revealed cell-type specificity: FCER1A was enriched in immune cells, LEF1 localized to T cells, and NELL2 was highly expressed in renal tubular epithelial cells. Spatial transcriptome and robust cell-type decomposition confirmed their spatial distribution - NELL2 was overexpressed in epithelial-damaged regions of kidney stones, while FCER1A accumulated around blood vessels in sepsis. Transcriptional regulation analysis indicated FCER1A is regulated by the cisbp__M2925 motif. DGIdb predicted 14 potential drugs targeting FCER1A, and molecular docking showed a binding energy of -5.0 kcal/mol between FCER1A (1j88) and ROME. This study identified 5 key genes and their regulatory networks in the comorbidity of kidney stones and sepsis, revealing their roles in immune regulation and inflammatory responses.
Olfactory dysfunction (OD) and Alzheimer disease (AD) represent significant global public health challenges. Growing evidence underscores the need to clarify the neuropathological mechanisms underlying their association. Our study intends to analyze global research trends and overlapping molecular mechanisms underlying OD and AD. Reviews and articles on OD and AD published between 2008 and 2024 were extracted from the Web of Science Core Collection. CiteSpace and VOSviewer were applied to for the analysis and visualization of the publication outputs, as well as the distribution of countries/regions, institutions and authors, the journals output, keywords co-occurrence, and reference citations. Molecular targets and associated pathways were investigated by GeneCards, STRING, and Metascape databases. One thousand nine hundred sixteen publications were identified, demonstrating steady growth in research output across 7006 institutions from 398 countries. The USA emerged as the top contributor, excelling in both publication output and citation impact. The University of Pennsylvania, University of California San Francisco, and Chinese Academy of Sciences stood out as the top influential institutions. Among 10,476 authors, Thomas Hummel from Technische Universität Dresden, Germany, emerged as the most prominent scholar. In terms of journals, Journal of Alzheimer's Disease leaded in publications in this field. Keywords including "Alzheimer's disease," "olfactory bulb," and "cognitive impairment" represent the current research focuses. A total of 1779 overlapping genes were identified between OD and AD. ACTB, AKT1, TP53, CTNNB1, and INS were identified as the most central regulatory genes. Enrichment analyses revealed involvement in PI3K-Akt, mitogen-activated protein kinases, and cyclic adenosine monophosphate signaling pathways, as well as biological functions related to signaling receptor activator activity, growth factor activity, and cytokine activity. Our study uncovers the dynamic research trends on OD and AD, while we further identified shared molecular mechanisms underlying these 2 disorders. Early olfactory risk assessment, diagnosis, and intervention may serve as critical components in the prevention and management in AD.
Disparities in breast cancer care access and outcomes are persistent and globally recognized issues driven by a complex interplay of socioeconomic, geographical, and systemic factors. Given the complex psychosocial effects on this patient group, it is crucial to incorporate Patient and Public Involvement and Engagement (PPIE) into care models. PPIE is a collaborative approach that involves patients, caregivers, and community members. It engages diverse populations and addresses the needs of underrepresented and disadvantaged groups, thereby promoting health equity. However, the multifaceted connection between health equity and PPIE programs must be strengthened. This narrative review critically explores research and organizational models that describe how PPIE informs health equity in breast cancer care. Our focus is on adaptability: as patient needs, treatments, and technologies evolve, so must the strategies employed to ensure equitable care. We discuss how PPIE is crucial for tailoring efforts to provide equity in two areas of intervention: community-driven and data and targeted-driven approaches. Integrating PPIE into flexible organizational models and research projects has emerged as a critical driver for achieving health equity in breast cancer care in both areas. Community-led initiatives ensure that interventions are culturally relevant and address fundamental social determinants of health. Conversely, data-driven approaches provide the evidence needed to target resources effectively and measure progress. Advancing PPIE reporting in rigorous study designs is the first step to ensuring effective and reproducible implementation. Furthermore, the models' adaptive features may reduce health inequities, increasing their reach, and strengthening community collaborations. PPIE can address several reasons for inequities in breast cancer care, such as a lack of health literacy, supportive infrastructure and policy priority. Regardless of whether the initial approach was more community- or data-oriented, PPIE has informed health equity by promoting the dynamism and appropriateness of interventions, and by revealing actionable barriers. These models emphasise bottom-up participation, multi-stakeholder partnerships, co-designed projects and the use of health data and targets to build equity. Advancing PPIE reporting in rigorous study designs is the first step to ensuring effective and reproducible implementation. Furthermore, the models' adaptive features may reduce health inequities, increasing their reach, and strengthening community collaborations.
Posterior tibial slope (PTS) is a key determinant of sagittal knee mechanics, cruciate ligament loading, and flexion-extension behavior after total knee arthroplasty (TKA). Accurate reproduction of the intended PTS is therefore an important objective in contemporary TKA, particularly when patient-specific alignment targets are used. The aim of this study was to evaluate the radiographic agreement among planned, robot-validated, and postoperative PTS values in ROSA-assisted TKA using standardized true lateral radiographs and blinded repeated measurements, and to determine the reliability of postoperative radiographic measurements. This retrospective observational radiological study, reported in accordance with the STrengthening the Reporting of OBservational studies in Epidemiology statement, included knees that underwent robotic-assisted primary TKA using the ROSA system and had complete intraoperative robotic records and adequate postoperative true lateral radiographs. Postoperative true lateral radiographs were obtained at 6-week follow-up. Planned PTS values were obtained from the robotic planning interface, and final robot-validated PTS values were recorded intraoperatively after tibial preparation. Postoperative PTS was measured on standardized true lateral radiographs by 2 independent blinded orthopedic surgeons, each performing repeated measurements at a 2-week interval. Agreement was assessed using paired comparisons, mean absolute differences, outlier analysis, and Bland-Altman evaluation. A total of 73 knees from 64 patients were initially reviewed, and 72 knees with complete paired measurements were included in the final analysis. There was no statistically significant difference between planned and robot-validated PTS values. The mean absolute difference between planned and robot-validated PTS was 0.57°, and 80.6% of knees were within ±1° of the planned target, while all knees were within ±2° and ±3°. Similarly, no statistically significant difference was observed between robot-validated and postoperative mean radiographic PTS values. Radiographic measurement reliability was excellent, with ICC(3,1) = 0.983 (95% confidence interval = 0.976-0.989) and ICC(3,k) = 0.996 (95% confidence interval = 0.994-0.997). ROSA-assisted TKA demonstrated close radiographic agreement among planned, robot-validated, and postoperative PTS values, with low absolute deviations and excellent measurement reliability. Because this study lacked a comparator group and did not assess clinical outcomes, these findings should be interpreted as evidence of radiographic reproducibility rather than evidence of superiority over conventional instrumentation or proof of clinical benefit.
Mycobacteria have long posed a threat to human health, being responsible for a range of hard-to-treat infections such as tuberculosis, leprosy, and other chronic diseases caused by nontuberculous mycobacteria. Their intrinsic resistance to antibiotics and resilience when exposed to environmental stress complicate treatment and underscore the need for discovering novel drug targets and developing new therapeutic strategies. Mycobacterium hassiacum, a thermophilic mycobacterium, is a promising source of stable proteins suitable for detailed structural analysis. In this study, we investigated its glucosyl-3-phosphoglycerate synthase (GpgS), an enzyme that plays a key role in the biosynthesis of methylglucose lipopolysaccharides in Mycobacterium tuberculosis and is implicated in responses to nitrogen starvation and thermal stress in different mycobacterial species. We confirmed the potential of M. hassiacum as a source of enzymes amenable to structural studies, as its GpgS ortholog yielded not only the first mycobacterial GpgS crystallographic structure at near-atomic resolution (1.10 Å) but also multiple high-resolution structures under different pH conditions and in complex with various substrates. These structural insights revealed a previously unrecognized aromatic binding pocket that is not only cryptic in nature but also capable of accommodating the substrates p-aminobenzoic acid and p-hydroxybenzaldehyde, which have been found to be relevant in its genetic context, thereby establishing a direct link between GpgS activity and broader metabolic pathways in mycobacteria. Our findings establish M. hassiacum as a valuable model for structural enzymology in mycobacteria and highlight GpgS as a potential drug target. The detailed structural data provided here offer a foundation for rational drug design, opening new avenues for the development of inhibitors targeting this key, potentially pleiotropic enzyme.
The purpose of this study was to identify older siblings' responses to their younger siblings' peer conflict situations and reasons for their responses. Findings will contribute to a gap in the field of violence prevention, which rarely considers siblings' roles as socialization agents. Qualitative interviews were completed with 20 Black sibling pairs (M = 11.08, SD = 2.81) from high-violence, under-resourced communities in the southeastern U.S. Younger siblings recalled an experience of peer conflict of which their older sibling was aware, and siblings discussed their responses to that situation. Themes that emerged during the interviews suggested that older siblings were likely to be present for and consulted about their younger siblings' conflict situations, which primarily involved physical aggression. Younger siblings valued their older siblings' input, as evidenced by older siblings' responses being highly influential in younger siblings' behavioral decisions. A conceptual model was proposed whereby older siblings' responses to younger siblings' conflict mediate the relation between older siblings' roles and responsibilities, older siblings' goals for their younger siblings, and older siblings' beliefs about fighting and younger siblings' responses to conflict. Moderators, such as younger siblings' preferred support, sibling dyad characteristics, and sibling relationship processes, are proposed for the relation between older and younger siblings' responses to peer conflict. Sibling relationships are a promising and underexplored avenue for effective youth violence prevention. These findings have the potential to inform prevention and intervention strategies by identifying older siblings as additional targets for programming.
We aimed to estimate the association of air pollution and term low birth weight (LBW) by maternal education and assess the distributional impact of meeting European Union and World Health Organization air pollution targets and universal tertiary maternal education on LBW cases. We analyzed administrative data on 1 409 084 term births in Spain (2010-18) and high spatial resolution estimates of maternal particulate matter with a diameter of 2.5 micrometers or less (PM2.5) and nitrogen dioxide (NO2) exposure. Single-exposure distributed lag non-linear models were used to estimate exposure-response functions (ERF) for LBW (<2500 g) overall and by maternal education. We then applied G-computation to estimate changes in LBW cases under counterfactual scenarios: target levels of PM2.5 (10 and 5 µg/m³) and NO2 (20 and 10 µg/m³), and universal tertiary maternal education. A 10 µg/m³ increase in PM2.5 and NO2 was associated with 6% [95% confidence interval (CI): 0%-11%] and 1% (95% CI: 0%-3%) higher odds of LBW. Relative to tertiary education, secondary and primary education were associated with increased LBW odds [1.32 (95% CI: 1.30-1.35); 1.76 (95% CI: 1.71-1.82)]. Meeting the 10 and 5 µg/m³ PM2.5 limits would have prevented 662 (95% CI: -4 to 1271) and 2032 (95% CI: -74 to 3900) LBW cases in 2010-18. Meeting the 20 and 10 µg/m³ NO2 limits would have prevented 432 (95% CI: -16 to 848) and 938 (95% CI: -50 to 1860) LBW cases in 2010-18. Universal attainment of tertiary education would have prevented over 9200 LBW cases. The primary maternal education group showed the highest shares of LBW cases, but they also experienced the largest relative reductions under air pollution intervention scenarios. Expanding access to higher education may yield large reductions in the burden of LBW. Reducing air pollution exposure could also meaningfully reduce LBW burden, particularly among infants from lower educated mothers, and contribute to narrowing related health inequalities.
Systemic lupus erythematosus (SLE)-associated thrombotic microangiopathy with features of atypical hemolytic uremic syndrome (aHUS) is a rare but life-threatening complication. Early recognition is challenging because of its overlapping clinical manifestations with other thrombotic microangiopathies. A 49-year-old man with SLE presented with anemia, thrombocytopenia, and multi-system involvement. Despite initial immunosuppressive therapy, his hematologic parameters progressively deteriorated, with hemoglobin decreasing to 89 g/L and the platelet count to 54 × 109/L. Laboratory investigations demonstrated elevated lactate dehydrogenase (501 U/L) and markedly increased soluble complement membrane attack complex (sC5b-9, >1790 ng/mL). ADAMTS13 activity was normal (75.41%), excluding thrombotic thrombocytopenic purpura. Based on the clinical and laboratory findings, the patient was diagnosed with SLE-associated aHUS. Following the diagnosis, the patient received eculizumab, a monoclonal antibody targeting complement component C5. Within 6 days of eculizumab treatment, hemoglobin increased to 102 g/L, and the platelet count recovered to 108 × 109/L, indicating a rapid hematologic response. This case highlights that aHUS can occur as a severe complication of SLE, even in male patients. Complement-mediated thrombotic microangiopathy may coexist with and be triggered by immune hemolysis in SLE. Early recognition and prompt complement inhibition with eculizumab can produce an ultra-rapid hematologic response and may be critical for improving patient outcomes.