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Comprehensive analysis of mRNA-microRNA-lncRNA expression profiles in post-traumatic elbow heterotopic ossification using RNA sequencing and experimental validation.

BACKGROUND: This study aimed to profile the molecular signatures of post-traumatic elbow heterotopic ossification (HO) to identify key regulators and potential therapeutic targets. METHODS: Total RNA from post-traumatic elbow HO tissues (n=4) and normal bone tissues (n=6) was subjected to high-throughput sequencing to identify differentially expressed mRNAs (DEGs), microRNAs (DEMs), and lncRNAs (DELs). Bioinformatics analyses included Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, protein-protein interaction network construction, and transcription factor (TF)-microRNA-mRNA network analysis. The expression trends of four most upregulated and four most downregulated DEGs were validated by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: We identified 2,138 DEGs, 40 DEMs, and 905 DELs. DEGs were significantly enriched in biological process "bone mineralization," cellular component "plasma membrane," molecular function "integrin binding," and pathways including PI3K-Akt, NF-κB, JAK-STAT, and TNF signaling pathways. Hub genes with high connectivity included MMP9, IL6, MMP3, CTSK, and BGLAP. Integrated network analysis highlighted the transcription factor JUN and key microRNAs (hsa-miR-124-3p, hsa-miR-548c-3p, and hsa-miR-135b). The qRT-PCR results confirmed the expression trends of selected DEGs. CONCLUSIONS: This study, for the first time, profiled the differentially expressed mRNAs, microRNAs, and lncRNAs in post-traumatic elbow HO using high-throughput RNA sequencing. These findings provide valuable insights into the molecular mechanisms of HO following elbow trauma. The identified hub genes (MMP9, IL6, MMP3, CTSK, and BGLAP), key TF (JUN), and key microRNAs (hsa-miR-124-3p, hsa-miR-548c-3p, and hsa-miR-135b) may serve as potential therapeutic targets for preventing and treating post-traumatic elbow HO.

Humans

Access to maternity services for women asylum seekers and refugees: A transnational document analysis of international, European regional, and United Kingdom governance.

Women asylum seekers and refugees face persistent barriers to maternity care (antenatal, intrapartum and postnatal care) across high-income countries, yet the upstream governance shaping access remains under-examined. Although legally distinct, both groups share protection-seeking experiences and are addressed jointly in governance documents. This study examined and synthesised how international (macro), European regional (meso), and United Kingdom (UK, micro) governance documents frame and operationalise maternity service access. Sixty-four documents were analysed using the READ framework. Inductive analysis of macro and meso documents identified six access dimensions: universal coverage; cultural and linguistic adaptation; rights-based approaches; multi-agency collaboration; data, monitoring and accountability; and quality of care. These dimensions structured assessment of UK governance, with jurisdictions rated strong, moderate or weak. Alignment was fragmented: Wales, Scotland and Northern Ireland exempted asylum seekers from charging, whereas England retained charging provisions. Multi-agency collaboration was consistently articulated, yet none of the 35 UK government documents focused on maternity access for this population, and none required outcome monitoring disaggregated by asylum or refugee status. UK governance appears coordinated in form but fragmented in substance. UK-wide minimum standards and routine recording of these data, with safeguards against immigration-related use, could strengthen coherence and accountability and improve visibility of inequities.

Refugees

Pretreatment EBV-DNA/TLG-Based Risk Stratification Is Associated With Survival Outcomes in Nonmetastatic Nasopharyngeal Carcinoma: An Exploratory Study.

Whether combining pretreatment plasma Epstein-Barr virus DNA (EBV-DNA) with 18F-FDG PET/CT-derived total lesion glycolysis (TLG) improves prognostic stratification in nonmetastatic nasopharyngeal carcinoma (NPC) is unclear, particularly in nonendemic populations. We retrospectively analyzed 86 eligible nonmetastatic NPC patients treated with definitive radiotherapy (2010-2024) at a single nonendemic-region institution. EBV-DNA (prespecified cutoff 3500 copies/mL) and TLG (cutoff 200, ROC-derived within this cohort) were dichotomized. Both were available in 59/86 patients (68.6%), who differed from the rest in nodal and overall stage and in RT technique. Baseline PET/CT was in-house in 57 of 86 patients, and a robustness analysis in that subgroup is reported. Given limited events (13 PFS, 9 OS), Cox analyses are exploratory and were supplemented with penalized regression and bootstrap validation. At a median follow-up of 75.5 months, 5-year PFS and OS for the whole cohort (n = 86) were 81.1% and 85.9%. The EBV-DNAhigh/TLGhigh subgroup remained associated with inferior PFS after adjustment in an exploratory model (adjusted HR = 3.97, 95% CI: 1.32-11.93) and, in a single-variable model, with inferior OS (HR = 4.13, 95% CI: 1.10-15.52). Discrimination was comparable to the individual-biomarker model for PFS and lower for OS. Five-year PFS fell monotonically across the four risk groups in the complete-case cohort (n = 59; 89.7%-58.3%). OS differed across groups (log-rank p = 0.044) but was not strictly monotonic, with wide, overlapping confidence intervals. This two-biomarker model is hypothesis-generating and needs prospective, multicenter validation before any consideration of risk-adapted treatment.

Epstein–Barr virus DNA

The Thyroid-Brain Network: Exploring Inflammation, Immune Mechanisms and Common Triggers in Thyroid-Related Neurological Dysfunction.

Autoimmune thyroid diseases (AITD), including Hashimoto's thyroiditis and Graves' disease, represent the most prevalent endocrine disorders worldwide, affecting hundreds of millions with profound but often under recognized neurological consequences. There are emerging lines of evidence establishing inflammation and immunity as the critical missing link connecting peripheral thyroid dysfunction to central nervous system manifestations. Thyroid hormones function as essential neuromodulators governing neurodevelopment, synaptic plasticity, and cognitive processing through integrated genomic and non-genomic mechanisms, with region-specific cerebral metabolic disturbances correlating with distinct neuropsychiatric symptoms. The immunological perspective reveals that AITD propagates neuroinflammation through convergent pathways: molecular mimicry enabling cross-reactivity between thyroid and neural antigens, cytokine-mediated disruption of neurotransmitter metabolism, HMGB1-driven glial activation, and blood-brain barrier compromise facilitating immune cell infiltration. The thyroid-gut-microbiota axis emerges as a critical mediator wherein dysbiosis perpetuates both thyroid autoimmunity and neuroinflammation through impaired serotonin precursor availability and increased intestinal permeability. Mitochondrial dysfunction represents an energetic common denominator, as thyroid hormone dysregulation directly impairs oxidative phosphorylation, producing region-specific cerebral metabolic disturbances. Simultaneous compromise of monoamine systems, cholinergic signaling abnormalities, and glutamate excitotoxicity creates a particularly toxic neurochemical state in untreated thyroid dysfunction. Common triggers such as psychological stress, gut dysbiosis, and mitochondrial impairment may activate interconnected pathways that simultaneously compromise thyroid and brain function, revealing that these disorders share fundamental mechanistic origins. These insights have been discussed in the current review to enhance the understanding of thyroid-brain function, the core mechanisms and consequences of functional deficits.

Journal Article

Transcriptomic and RNAi analyses reveal chloride channel 3-associated osmoregulation in Litopenaeus vannamei under low-salinity stress.

Chloride channels and transporters are important for cellular volume regulation and salinity adaptation in euryhaline crustaceans, yet the intestinal transcriptional relationship between plasma-membrane and intracellular chloride pathways remains unclear in Litopenaeus vannamei. In this study, RNA interference of anoctamin 1 (ANO1) was combined with intestinal transcriptome sequencing under the production-relevant low-salinity condition of salinity 3. ANO1 silencing produced a focused transcriptional response, with 16 differentially expressed genes (DEGs) identified (11 upregulated and 5 downregulated). Functional enrichment indicated that these genes were associated with transporter activity, cytoskeletal organization, extracellular matrix-receptor interaction, membrane lipid metabolism, and vesicular processes. Notably, a transcript encoding chloride channel protein 3 (CLC-3) was significantly upregulated following ANO1 knockdown, suggesting a potential transcriptional relationship between ANO1 and CLC-3 in chloride homeostasis. Based on this finding, CLC-3 was selected for full-length cDNA cloning, sequence characterization, salinity-gradient expression analysis, and RNAi-based functional assessment. The cloned CLC-3 cDNA was 2883 bp in length and encoded an 850 amino acid protein containing a conserved voltage-gated chloride channel (Voltage-CLC) domain and two cystathionine β-synthase domains. Phylogenetic analysis placed LvCLC-3 within the intracellular CLC-c clade, and tissue distribution analysis showed the highest CLC-3 expression in the intestine. Intestinal CLC-3 expression responded nonlinearly to salinity variation, peaking at salinity 20. Under salinity 3, CLC-3 knockdown reduced ANO1, Na+/K+-ATPase alpha subunit, and Na+-K+-2Cl- cotransporter transcript levels, whereas glutamate-gated chloride channel expression increased. Mild hepatopancreatic structural alterations were also observed after CLC-3 knockdown. These findings suggest that CLC-3 is a salinity-responsive intracellular chloride-transporter candidate associated with intestinal ion-transport-related transcriptional responses after ANO1 suppression in L. vannamei, although the underlying physiological mechanism requires further validation.

Animals

Diagnostic value of blood p-tau subtypes in Alzheimer's disease progression and pathology: systematic review and meta-analysis.

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease and the most likely to lead to dementia. With the availability of the latest therapies, the need for Alzheimer's disease diagnosis is now gradually increasing. Whereas blood phosphorylated-tau (p-tau) has demonstrated excellent performance in the prediction and diagnosis of disease progression and A&#x3b2; positivity in AD, there are differences between different p-tau subtypes. Therefore, a pooled analysis of different blood p-tau subtypes is of more important clinical value. METHOD: Relevant literature was screened by complete search in four databases, Pubmed, Embase, Cochrane Library and Scopus. Relevant data and AUC and their confidence intervals of the included literature were extracted and analyzed by classification according to p-tau subtypes. Quality assessment was performed using the QUADAS-2 tool. RESULT: Our results reveal that p-tau217 performs better in the diagnostic performance in most stages of AD, which is consistent with the guidelines. However, our results concluded that p-tau217 has poorer diagnostic performance in the stages of cognitive unimpaired or less cognitively impaired, especially in the A&#x3b2; positivity diagnosis of SCD and CU. Head-to-head meta-analyses formally confirmed that p-tau217 significantly outperforms p-tau181 across AD dementia, A&#x3b2; positivity, tau positivity, and biological staging (all P&#x2009;<&#x2009;0.05), whereas no significant difference was observed between p-tau231 and p-tau181. CONCLUSION: By integrating single-arm pooled AUC estimates with formal head-to-head statistical comparisons, our study provides evidence-based support for plasma p-tau217 as the subtype with the most robust diagnostic performance across AD pathology and biological staging. Head-to-head analyses formally confirmed that p-tau217 significantly outperforms p-tau181 in A&#x3b2; positivity, Tau positivity, and biological staging.

Humans

ALG-020572, an Antisense Oligonucleotide for the Treatment of Chronic Hepatitis B Virus Infection Discontinued for Drug-Induced Liver Injury.

Current treatment options for chronic HBV infection are suboptimal in that they fail to suppress HBsAg levels. ALG-020572 is an antisense oligonucleotide designed to reduce viral protein synthesis through degradation of HBV mRNA. ALG-020572-401 was a double-blind, randomized, placebo-controlled trial consisting of two parts. Part 1 (single-ascending doses) evaluated the pharmacokinetics, safety and tolerability of single doses of ALG-020572 or placebo in healthy participants. In Part 2 (multiple dosing), participants with non-cirrhotic HBeAg-negative, virologically suppressed chronic HBV infection were administered up to 7 doses of ALG-020572 to evaluate safety, pharmacokinetics and antiviral activity. In Part 1, 32 participants were randomized to ALG 020572 or placebo. Single doses of ALG-020572 up to 480&#x2009;mg were well tolerated. The most common treatment-emergent adverse event reported was injection site reaction. ALG-020572 was rapidly absorbed and plasma exposures increased with dose. In Part 2, 8 participants with non-cirrhotic HBeAg-negative virologically suppressed chronic hepatitis B infection were enrolled and received up to 7 doses of ALG-020572. The study was prematurely discontinued after 4 participants experienced significant alanine aminotransferase elevations that were subsequently attributed to drug-induced liver injury. Single doses of ALG-020572 demonstrated a favourable pharmacokinetic and safety profile in healthy participants. Unexpectedly, ALG-020572 was poorly tolerated in participants with chronic HBV infection, resulting in the early termination of the study and further development of ALG-020572 due to idiosyncratic drug-induced liver injury, suggesting caution is required in the development of this class of drugs. Trial Registration: Registered at clinicaltrials.gov: NCT0500102.

Adult

Understanding FDA's reasons for nonapproval: A systematic review of complete response letters in cell and gene therapy.

BACKGROUND AIMS: Cell and gene therapy products face unique regulatory challenges due to their biological complexity and the stringent expectations for manufacturing control, analytical testing, and clinical assessment. As the pipeline grows, understanding the drivers of FDA non&#x2011;approval is increasingly important for improving first&#x2011;cycle success and reducing development delays. In this study, we aimed to characterize the frequency and impact of refuse&#x2011;to&#x2011;file actions, major amendments, and complete response letters issued for biologics licensing applications; and to identify recurring patterns of deficiencies contributing to delayed approval. METHODS: Publicly available documents were extracted from the FDA website. Data from each approved cell and gene therapy product's regulatory history-including complete responses, major amendments, inspection timing, and cited deficiencies-were compiled and categorized across clinical, quality, and labeling domains. RESULTS: Analysis showed that informational deficiencies were common across modalities. Major amendments occurred in roughly half of applications, and complete responses had the most significant impact. Quality deficiencies appeared in all complete responses and were the predominant barrier, while clinical and labeling issues were less frequent but meaningful when present. CONCLUSION: Overall, these findings highlight the need for proactive FDA engagement, comprehensive readiness, and early inspection preparation to reduce regulatory risk and improve first cycle approval outcomes.

Humans

Bi-compartmental CSF-serum analysis of NfL and GFAP differentiates central and peripheral pathology in neuroinfectious diseases: A monocentric real-world cohort study.

Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), established biomarkers of neuroaxonal injury and astroglial pathology, are frequently only assessed in blood, which limits conclusions regarding their origin. Bi-compartmental analyses of CSF and serum may help differentiate central or peripheral origin of biomarker elevation. Moreover, studies on NfL and GFAP in distinct neuroinfectious disease (NID) phenotypes, particularly those based on real-world cohorts, are limited. This retrospective monocentric study analyzed CSF and serum from patients with (meningo-)encephalitis/myelitis (TI+; n&#xa0;=&#xa0;48), meningitis (TI-; n&#xa0;=&#xa0;80), (cranial) nerve palsies/polyradiculitis (PND; n&#xa0;=&#xa0;61), and 113 non-neuroinflammatory/non-neurodegenerative controls. A bi-compartmental model using scatter plots and simple linear regression was applied to assess the origin of blood biomarker levels and discriminate between central and peripheral pathology. CSF and serum NfL and GFAP z-scores were significantly higher in TI+ compared with TI- (CSF-GFAP p&#xa0;<&#xa0;0.001/sGFAP p&#xa0;=&#xa0;0.0083; CSF-NfL p&#xa0;=&#xa0;0.003/sNfL p&#xa0;=&#xa0;0.0004). TI+ and PND differed only in GFAP levels, which were higher in TI+ (CSF-GFAP p&#xa0;=&#xa0;0.0049/sGFAP p&#xa0;=&#xa0;0.003). The overall group effect (p&#xa0;&#x2264;&#xa0;0.003) and principal findings remained significant after adjustment for age, sex, QAlb, and time since (symptom) onset to LP. Bi-compartmental analysis revealed simultaneous elevation of CSF and serum NfL in TI+, indicating predominantly central origin, whereas PND demonstrated a shift toward higher sNfL levels suggesting peripheral origin. Higher clinical severity (modified Rankin Scale 3-5) was associated with elevated serum and CSF GFAP and NfL (sGFAP p&#xa0;=&#xa0;0.012/sNfL p&#xa0;=&#xa0;0.002; CSF-GFAP p&#xa0;<&#xa0;0.0001/CSF-NfL p&#xa0;=&#xa0;0.0001), which also predicted unfavorable outcome at discharge (sGFAP p&#xa0;=&#xa0;0.006/sNfL p&#xa0;=&#xa0;0.004; CSF-GFAP p&#xa0;=&#xa0;0.003/CSF-NfL p&#xa0;=&#xa0;0.012). NfL and GFAP were associated with brain/myelon involvement in NID, predominantly reflecting central pathology. Despite strong CSF-serum correlations, bi-compartmental approaches provide additional insight into biomarker origin and disease compartment.

Humans

Comparison of Adult Tracheostomy Outcomes Before and After Implementation of a Dedicated Tracheostomy Team.

OBJECTIVE: (A) Determine patient and institutional factors associated with increased length of stay (LOS) and complications of tracheostomy, (B) Develop data-driven quality improvement in tracheostomy care. DESIGN: Mixed methods protocol used cross-sectional survey assessing institutional trends in tracheostomy-specific care. Retrospective chart review compared tracheostomy patient outcomes prior to and during implementation of a multidisciplinary tracheostomy care team and standardized guidelines. PARTICIPANTS: Patients undergoing tracheostomy from January 2019 to December 2021 at a tertiary hospital. METHODS: Patient factors, procedure type and indication, tracheostomy tube size, management timeline, insurance, and disease severity using Acute Physiology and Chronic Health Evaluation II (APACHE II) score were analyzed for associations with LOS and adverse events. Multivariate analyses controlled for APACHE II score and payer source. LOS and complications were compared between patients before and during implementation of multidisciplinary tracheostomy care team and standardized guidelines. RESULTS: Three-hundred and eighteen patients met criteria with a 21.7% complication rate, average LOS of 24 days (SD&#x2009;=&#x2009;28.523), and median LOS post-tracheostomy of 14 days (IQR 7, 29). Departments without standardized protocols had greater LOS (F[1,316]&#x2009;=&#x2009;28.706, P&#x2009;<&#x2009;.001]) and complication odds (OR&#x2009;=&#x2009;2.92, P&#x2009;=&#x2009;.015, 95% CI[1.231, 6.930]). Larger tracheostomy tube size was linked to increased LOS (&#x3b2;&#x2009;=&#x2009;.253, t(314)&#x2009;=&#x2009;4.741, P&#x2009;<&#x2009;.001, 95% CI[4.137, 10.081]). Delays from ventilation discontinuation to cuffless tube exchange and decannulation correlated with increased LOS (&#x3b2;&#x2009;=&#x2009;.406, t(184)&#x2009;=&#x2009;6.321, P&#x2009;<&#x2009;.001, 95% CI[.928, 1.771]); (&#x3b2;&#x2009;=&#x2009;.554, t(129)&#x2009;=&#x2009;7.625, P&#x2009;<&#x2009;.001, 95% CI[1.008, 1.715]). When focusing on a single department, comparing 2019 patients to 2021 patients (pre- and post-guideline and care team), overall, LOS decreased from 33.08 to 30.83 days (P&#x2009;=&#x2009;.586). When excluding patients discharged on a ventilator, the 2019 group had average LOS of 37.938 days versus 33.41 days in 2021 (P&#x2009;=&#x2009;.344). CONCLUSIONS: Standardized tracheostomy care guidelines and multidisciplinary care teams are critical to improving institutional outcomes. Data-driven approaches to quality improvement ensure efficient and targeted methods to improving patient care. LEVEL OF EVIDENCE: 4.

Humans

Prevalence of Breastfeeding in Infants With Down Syndrome: A Systematic Review and Meta-Analysis.

AIM: To estimate the prevalence of breastfeeding-overall, exclusive, partial and depending on infants' age-in infants with Down syndrome, and to investigate associated factors. METHODS: A systematic literature search was conducted in Medline, Cochrane Library, Web of Science, Embase, CINAHL and SciELO up to 1 August 2024. Original articles that estimated the prevalence of breastfeeding in infants with Down syndrome, written in French, English or Spanish, were included. Study quality was assessed using the Joanna Briggs Institute (JBI) scale. Meta-analyses were performed for breastfeeding outcomes and meta-regression explored heterogeneity. The review was registered in PROSPERO (CRD42021278019). RESULTS: Twenty-six studies (3463 infants) were included. The estimated prevalence of overall breastfeeding regardless of duration was 71.6% (95% CI [60.3; 80.7]; 25 studies, 3351 infants) with high heterogeneity, I2&#x2009;=&#x2009;94%. The estimated prevalence of exclusive breastfeeding was 38.4% (95% CI [22.4; 57.3]; 10 studies, 1099 infants). No factor assessed in meta-regression was significantly associated with overall breastfeeding. CONCLUSION: The estimated breastfeeding prevalence in infants with Down syndrome is similar to that reported in the general population, despite high heterogeneity. Further studies using standardised methodology to assess breastfeeding barriers and facilitators in the context of Down syndrome would allow us to improve support for breastfeeding.

Humans

The psychosocial supports and interventions accessed by family members of patients with developmental and epileptic encephalopathies: A systematic review.

AIM: Family members of patients with developmental and epileptic encephalopathies (DEEs) face profound emotional, social and practical challenges, yet little is known about how they access psychosocial support. We synthesised the literature on the psychosocial support accessed by family members of patients with DEEs, including evidence-based interventions. METHOD: Four databases were searched. Two reviewers independently screened and extracted data, appraised study quality (QualSyst Tool), and determined certainty of evidence (GRADE-CERQual Framework). Data were synthesised using inductive thematic analysis. RESULTS: 28 papers comprising 27 unique studies were included and methodological quality was high overall (median&#xa0;=&#xa0;0.91, IQR&#xa0;=&#xa0;0.85-1.00). Most studies focused on parent experiences; only two included siblings' perspectives. Families reported high psychological needs which were rarely met by psychological support. Clinicians rarely provided adequate information, quality communication or addressed mental health. Families valued respite care, but experienced barriers to access. Peer support was the most common and valued resource. Three studies tested interventions and appeared feasible and acceptable for parents. However, evidence for intervention effectiveness is preliminary and limited to small, uncontrolled pilot studies. INTERPRETATION: Gaps exist in psychosocial support provision for families of patients with DEEs, including insufficient research on siblings' and grandparents' needs, and lack of evidence-based interventions. We propose evidence-informed research and implementation strategies to address these gaps.

Humans

Association between Kidney Tubular Secretory Clearance with Cognitive Function among Adults with CKD in the Systolic Blood Pressure Intervention Trial.

BACKGROUND: Persons with CKD are disproportionally affected with cognitive impairment, yet the pathophysiology linking the two conditions is unclear. Because kidney tubule secretion is essential for clearance of medications, uremic toxins, and metabolites, we hypothesized that worse tubular secretion would be associated with reduced cognitive function in CKD. METHODS: The Systolic Blood Pressure Intervention Trial tested a systolic blood pressure target <120 mmHg vs. <140 mmHg in hypertensive individuals at high cardiovascular risk. In paired blood and urine specimens from 1,937 participants with eGFR <60 ml/min/1.73m2, we measured 10 endogenous tubule-secreted metabolites and calculated a urine/plasma ratio for each, then averaged these to generate a summary secretion score. We used unadjusted and multivariable-adjusted linear regression and mixed models to evaluate cross-sectional and longitudinal associations of the secretion score with the Montreal Cognitive Assessment, Digit Symbol Coding, and Logical Memory immediate and delayed tests-measured at baseline and months 24 and 48 of follow-up. Multivariable Cox regression evaluated associations with incident probable dementia and mild cognitive impairment, adjudicated by prespecified criteria. RESULTS: Mean age was 73 &#xb1; 9 years, 41% were women, mean eGFR was 48.2 &#xb1; 11.4 ml/min/1.73m2, median albuminuria was 14.8 [7.1-48.6] mg/g. Lower secretion score was associated with a 0.06 higher adjusted logical memory delayed score (95% CI: 0.02, 0.11) but not with other cognitive tests at baseline or longitudinal cognitive decline. After a median 4.1 years of follow-up, 118 developed probable dementia and 187 developed mild cognitive impairment. Each 1-SD lower secretion score was associated with lower risk of probable dementia (HR 0.78, 95% CI: 0.63, 0.98) but not mild cognitive impairment. CONCLUSIONS: Among Systolic Blood Pressure Intervention Trial participants with CKD, lower estimated tubular secretion was not associated with worse cognition at baseline or during longitudinal follow-up.

Journal Article

Trio-based whole-exome sequencing identifies convergent epithelial junction-related pathways in syndromic hidradenitis suppurativa.

INTRODUCTION: Hidradenitis suppurativa (HS)-related autoinflammatory syndromes, simply termed as syndromic HS (sHS), represent a group of rare immune-mediated inflammatory disorders in which HS coexists with systemic or cutaneous autoinflammatory features like PASH (pyoderma gangrenosum-PG-, acne and HS), PAPASH (PASH, pyogenic arthritis), PASS (PG, acne, HS, and ankylosing spondylitis), and SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis). In recent years, genetic studies identified several novel pathogenic variants underlying sHS; however, most investigations rely exclusively on affected individuals sequencing and the absence of parental genomic information limits the possibility to determine inheritance patterns. METHODS: To address these gaps, we performed trio-based whole-exome sequencing (WES) on five individuals diagnosed with sHS and their unaffected parents. RESULTS: The pathway related to epidermal adhesion and desmosome organization was the most represented across our cohort, encompassing seven genes: DSC3, DSG1, FAT1, LAMA3, MICALL2, PLEC and TJP2. Integrin-extracellular matrix (ECM) adhesion signaling pathway, represented by ten genes (CSPG4, FERMT3, ITGA3, LAMA3, LAMA5, LIMS2, LTBP3, PLEC, TGM2, TNC) was also retrieved. Also, variants affecting innate immune pathways, including cytokine signalling and antigen presentation, have been observed. CONCLUSION: Our exploratory findings suggest that genetically heterogeneous variants in syndromic HS converge on biological processes involving epithelial junction organisation, extracellular matrix interactions and innate immune regulation. Although not establishing a unique pathogenic mechanism, these observations identify epithelial barrier biology as a candidate pathway warranting validation in larger cohorts and functional studies.

Journal Article

Continuous Intraperitoneal Insulin Infusion for People With Type 1 Diabetes: A Literature Review and International Position Statement.

Achieving glucose targets without hypoglycaemia is the treatment goal in type 1 diabetes. Structured education, intensified insulin injection regimens, continuous glucose monitoring, automated insulin delivery, and ongoing support from a multidisciplinary team all support people with type 1 diabetes to achieve this goal. Despite these advances, significant barriers to achieving optimal management remain. Continuous intraperitoneal insulin infusion has comparable or better glucose outcomes to continuous subcutaneous insulin infusion and may reduce the frequency of hypoglycaemia, including severe episodes. Intraperitoneal insulin may be considered as a treatment modality for children and adults with type 1 diabetes using optimised intensive insulin therapy for whom subcutaneous insulin has failed due to lipoatrophy, -dystrophy or -hypertrophy, local allergy, subcutaneous insulin resistance or co-existing skin conditions. Failure of subcutaneous insulin may result in recurrent or unexplained severe hypoglycaemia or hyperglycaemia. Intraperitoneal insulin may also be considered as a treatment modality for people with type 1 diabetes with severe needle-phobia, and for those being considered for islet cell or pancreatic transplantation, or where transplantation is not available. This paper summarises current intraperitoneal insulin delivery technology, its potential risks and benefits, and an expert position statement. It is intended for use by diabetes specialist healthcare professionals, and as a reference for other healthcare professionals, commissioners, payors, people with diabetes, their carers, and advocates.

Humans

Electrospun Nanofiber Dressings for Diabetic Wounds: From Single-Layer to Intelligent Composite Systems.

Diabetic chronic wounds have become a major challenge for clinical treatment due to their complex pathological microenvironment, including persistent inflammatory response, angiogenesis disorder, excessive oxidative stress, and susceptible infection. Traditional dressings as a passive barrier have difficulty meeting the above multiple treatment needs. Electrospinning technology, with its ability to mimic the fibrous network structure of the natural extracellular matrix (ECM), offers a high specific surface area, controllable porosity, and excellent drug-loading capacity, making it an ideal platform for developing a new generation of multifunctional wound dressings. This article provides a systematic review of the research progress on electrospun nanofiber dressings in the treatment of diabetic wounds, focusing on the design evolution from basic single-layer structures to advanced complex structures and elucidating the mechanisms of action and quantifiable effects of each structural type in addressing specific pathological challenges. We also compared the current status of clinical translation for electrospun dressings with that of other advanced wound care platforms and proposed a standardized preclinical evaluation framework. A large number of research data show that these advanced designs can effectively improve the quality of healing. Finally, this paper points out the challenges faced by this field, such as scalable fabrication, in vivo reliability of smart systems, and long-term biosafety, and provides theoretical basis and technical reference for the design of efficient and intelligent electrostatic spinning diabetic wound dressings.

Nanofibers

The Interrelationship between Cadmium, Smoking, and Migraine in the ELSA-Brasil Study.

This study explored the relationship between serum cadmium (Cd), smoking exposure, and migraine in the ELSA-Brasil cohort (2008-2010). The analysis included 2,750 participants whose serum Cd levels were measured using inductively coupled plasma mass spectrometry. Smoking exposure was assessed using self-report data of active smoking and second-hand smoke. Migraine, including definite and probable migraine, was diagnosed according to the International Classification of Headache Disorders, 3rd edition (ICHD-3). Logistic regression was used to estimate the odds of migraine across serum Cd quintiles, using the third quintile as the reference category, while linear regression examined the relationship between smoking exposure and Cd levels. Polynomial contrasts tested linear trends. Participants had a mean (SD) age of 53.2 (9.0) years and 53.1% were women. Migraine prevalence was 29.1% (including probable migraine). Individuals with migraine had slightly higher median serum Cd levels than controls [0.050&#xa0;&#xb5;g/L (IQR 0.035-0.077) vs. 0.048&#xa0;&#xb5;g/L (0.035-0.066); p&#x2009;=&#x2009;0.021], although smoking exposure scores did not differ between groups. Smoking exposure showed a strong positive association with serum Cd concentrations (p-trend&#x2009;<&#x2009;0.001). Participants in the highest Cd quintile had greater odds of migraine [aOR 1.51 (95% CI 1.09-2.08), p&#x2009;=&#x2009;0.011] after adjustment for smoking exposure and sociodemographic and clinical confounders. Sex-stratified analysis yielded even stronger associations among males [aOR 1.84 (95% CI 1.07-3.16), p&#x2009;=&#x2009;0.027]. However, in the sensitivity analysis including definite migraine cases only, this association was no longer significant [aOR: 1.14 (0.71, 1.83), p&#x2009;=&#x2009;0.579]. Main findings suggest that Cd exposure from smoking may contribute to migraine occurrence, particularly in males. However, other sources of Cd that could influence migraine should not be disregarded, and future investigation in this field is warranted.

Cadmium

Artificial Intelligence Technologies in Nursing Clinical Decision-Making: An Umbrella Review.

AIM: To describe contemporary peer-reviewed literature on artificial intelligence in nurses' clinical decision-making. METHODS: An umbrella review of literature reviews. DATA SOURCES: Four major databases were searched for reviews published between 2019 and 2024. RESULTS: Sixteen literature reviews reported on 965 nursing artificial intelligence primary studies. The studies focused on technology development and emerging performance evaluations, whilst real-world testing or implementation in nursing clinical settings was rare. Rigorous comparative analyses were lacking. While artificial intelligence demonstrates promise in decision-making, challenges such as a lack of controlled studies, algorithmic bias, limited reproducibility and insufficient clinical trials hinder its practical impact. Ethical concerns, transparency and patient data privacy issues pose barriers to AI integration in nursing practice. Ethical and legal guidelines for patient privacy are needed and should be taught along with AI literacy training for nurses. CONCLUSIONS: Artificial intelligence has the potential to enhance clinical nursing decision-making, although evidence is limited by too few examples of nurse participation during development. Underutilisation in administrative nursing functions hinders implementation. Nurses should assume a central role in the design and development of AI applications to ensure that these technologies address the realities of nursing practice. With such improvements, artificial intelligence can transform nursing practice, improve nurses' clinical decision-making and ultimately enhance consumer healthcare outcomes. PATIENT OR PUBLIC INVOLVEMENT: No Patient or Public Involvement. REPORTING METHOD: While there is no reporting checklist for umbrella reviews, the PRISMA guide for systematic reviews was followed.

Artificial Intelligence