Experience of the first adult-focussed undiagnosed disease program in Australia (AHA-UDP): solving rare and puzzling genetic disorders is ageless.

BACKGROUND: Significant recent efforts have facilitated increased access to clinical genetics assessment and genomic sequencing for children with rare diseases in many centres, but there remains a service gap for adults. The Austin Health Adult Undiagnosed Disease Program (AHA-UDP) was designed to complement existing UDP programs that focus on paediatric rare diseases and address an area of unmet diagnostic need for adults with undiagnosed rare conditions in Victoria, Australia. It was conducted at a large Victorian hospital to demonstrate the benefits of bringing genomic techniques currently used predominantly in a research setting into hospital clinical practice, and identify the benefits of enrolling adults with undiagnosed rare diseases into a UDP program. The main objectives were to identify the causal mutation for a variety of diseases of individuals and families enrolled, and to discover novel disease genes. METHODS: Unsolved patients in whom standard genomic diagnostic techniques such as targeted gene panel, exome-wide next generation sequencing, and/or chromosomal microarray, had already been performed were recruited. Genome sequencing and enhanced genomic analysis from the research setting were applied to aid novel gene discovery. RESULTS: In total, 16/50 (32%) families/cases were solved. One or more candidate variants of uncertain significance were detected in 18/50 (36%) families. No candidate variants were identified in 16/50 (32%) families. Two novel disease genes (TOP3B, PRKACB) and two novel genotype-phenotype correlations (NARS, and KMT2C genes) were identified. Three out of eight patients with suspected mosaic tuberous sclerosis complex had their diagnosis confirmed which provided reproductive options for two patients. The utility of confirming diagnoses for patients with mosaic conditions (using high read depth sequencing and ddPCR) was not specifically envisaged at the onset of the project, but the flexibility to offer recruitment and analyses on an as-needed basis proved to be a strength of the AHA-UDP. CONCLUSION: AHA-UDP demonstrates the utility of a UDP approach applying genome sequencing approaches in diagnosing adults with rare diseases who have had uninformative conventional genetic analysis, informing clinical management, recurrence risk, and recommendations for relatives.

Femoral head decentration on hip MRI: comparison between imaging planes, methods of contrast administration, and hip deformities.

OBJECTIVES: To compare the prevalence of femoral head decentration (FHD) on different MR imaging planes in patients undergoing direct/indirect hip MR arthrography (MRA) with asymptomatic controls and to evaluate its association with osseous deformities. METHODS: IRB-approved retrospective single-center study of symptomatic hips undergoing direct or indirect hip MRA at 3 T. Asymptomatic participants underwent non-contrast hip MRI at 3 T. FHD was defined as a continuous fluid layer between the acetabulum and femoral head and assessed on axial, sagittal and radial images. The association of intra-articular/intra-venous contrast agents and the prevalence of FHD was evaluated. The association of FHD with osseous deformities and joint damage was assessed using multiple logistic regression analysis. RESULTS: Three-hundred ninety-four patients (447 hips, mean age 31 ± 9 years, 247 females) were included and compared to 43 asymptomatic controls (43 hips, mean age 31 ± 6 years, 26 females). FHD was most prevalent on radial images and more frequent in symptomatic hips (30% versus 2%, p < 0.001). FHD prevalence was not associated with the presence/absence of intra-articular contrast agents (30% versus 22%, OR = 1.5 (95% CI 0.9-2.5), p = 0.125). FHD was associated with hip dysplasia (OR = 6.1 (3.3-11.1), p < 0.001), excessive femoral torsion (OR = 3.0 (1.3-6.8), p = 0.010), and severe cartilage damage (OR = 3.6 (2.0-6.7), p < 0.001). CONCLUSION: While rare in asymptomatic patients, femoral head decentration in symptomatic patients is associated with osseous deformities predisposing to hip instability, as well as with extensive cartilage damage. CRITICAL RELEVANCE STATEMENT: Decentration of the femoral head on radial MRA may be interpreted as a sign of hip instability in symptomatic hips without extensive cartilage defects. Its presence could unmask hip instability and yield promise in surgical decision-making. KEY POINTS: The best method of identifying femoral head decentration is radial MRI. The presence/absence of intra-articular contrast is not associated with femoral head decentration. Femoral head decentration is associated with hip deformities predisposing to hip instability.

In Vitro and In Vivo Studies on a Mononuclear Ruthenium Complex Reveals It is a Highly Effective, Fast-Acting, Broad-Spectrum Antimicrobial in Physiologically Relevant Conditions.

The crystal structure of a previously reported antimicrobial RuII complex that targets bacterial DNA is presented. Studies utilizing clinical isolates of Gram-negative bacteria that cause catheter-associated urinary tract infection, (CA)UTI, in media that model urine and plasma reveal that good antimicrobial activity is maintained in all conditions tested. Experiments with a series of Staphylococcus aureus clinical isolates show that, unlike the majority of previously reported RuII-based antimicrobial leads, the compound retains its potent activity even in MRSA strains. Furthermore, experiments using bacteria in early exponential growth and at different pHs reveal that the compound also retains its activity across a range of conditions that are relevant to those encountered in clinical settings. Combinatorial studies involving cotreatment with conventional antibiotics or a previously reported analogous dinuclear RuII complex showed no antagonistic effects. In fact, although all combinations show distinct additive antibacterial activity, in one case, this effect approaches synergy. It was found that the Galleria Mellonella model organism infected with a multidrug resistant strain of the ESKAPE pathogen Acinetobacter baumannii could be successfully treated and totally cleared within 48 h after a single dose of the lead complex with no detectable deleterious effect to the host.

Gingival mesenchymal stem cells: Biological properties and therapeutic applications.

Our understanding of mesenchymal stem cells (MSCs) and their biological properties is steadily increasing, with more studies focusing on their therapeutic effects in the domains of immunology, tissue engineering and regenerative medicine. MSCs may be derived from tissues such as bone marrow, adipose, the umbilical cord, as well as from dental tissues (e.g., tooth germ, dental follicle, pulp tissue of exfoliated deciduous and permanent teeth, apical papilla, periodontal ligament, gingiva, and alveolar bone). Gingival mesenchymal stem cells (GMSCs) are non-hematopoietic adult stem cells isolated from the gingival lamina propria. When compared to MSCs purified from various dental and non-dental tissues, GMSCs are more abundant in source, relatively non-invasive to obtain, and genetically stable. In recent years, many studies have found that GMSCs possess the ability of self-renewal, multi-directional differentiation, and chemotaxis to inflammatory sites for immunity regulation. Their molecular and stem-cell properties make them highly suitable for both preclinical and clinical research. Extracellular vesicles (EVs) secreted by GMSCs are of key interest due to their ability to emulate the biological and therapeutic activity of GMSCs themselves. This paper will therefore review the current consensus on GMSCs, surveying their sources and isolation methods, their biological properties, and their therapeutic applications on inflammatory and immune-related diseases.

Quality of life in people with chronic kidney disease: focusing on modifiable risk factors.

PURPOSE OF REVIEW: With ageing populations and rising prevalence of key risk factors, the prevalence of many long-term conditions including chronic kidney disease (CKD) is increasing globally. Health-related quality of life (HRQoL) is important to people living with CKD but not all HRQoL determinants are modifiable. This review summarizes recently identified potentially modifiable factors affecting HRQoL for people with CKD and recent trials incorporating HRQoL as an outcome. RECENT FINDINGS: Considering a broad definition of 'potentially modifiable', many factors have been associated with HRQoL in recent observational studies. These include mental health conditions, symptoms, medications, health behaviours, weight-related issues, poor social support, lower education, limited literacy and directly CKD- related factors such as anaemia. Some potentially modifiable factors have been tested in CKD trials, though often with HRQoL as a secondary outcome, so may be underpowered for HRQoL. Interventions with evidence of effect on HRQoL include physical activity, education, some nutritional interventions and medications targeting CKD-related anaemia. SUMMARY: Clinicians should consider the range of potentially modifiable factors influencing HRQoL as part of a holistic approach to CKD care. High-quality, adequately-powered trials, with HRQoL as a primary outcome, with interventions focusing on the other potentially modifiable factors identified are needed.

Modified Dunn Procedure for Open Reduction of Chronic Slipped Capital Femoral Epiphysis.

Background: Abnormal femoral head anatomy following moderate-to-severe slipped capital femoral epiphysis (SCFE) can lead to femoroacetabular impingement and premature osteoarthritis4-10. Surgical correction at the deformity site through capital reorientation has the potential to fully ameliorate this but has traditionally been associated with high rates of osteonecrosis11-15. The modified Dunn procedure has the potential to restore anatomy in hips with SCFE while protecting the blood supply to the femoral head. Description: A surgical dislocation of the hip is performed according to the technique described by Ganz et al.16. The remaining posterosuperior portion of the greater trochanter is trimmed to the level of the femoral neck by subperiosteal bone removal performed in an inside-out manner. The periosteum of the femoral neck is gradually elevated. The resulting soft-tissue flap, consisting of the retinaculum and external rotators, holds the blood vessels supplying the epiphysis. The femoral epiphysis is pinned in situ (in unstable cases) with threaded Kirschner wires, the ligamentum teres is transected, and the femoral head is dislocated. With the femoral neck exposed, the epiphysis is gradually mobilized from the metaphysis, allowing exposure of the residual femoral neck and inspection of any posteroinferior callus. To avoid tension on the retinacular vessels during reduction of the epiphysis, the posterior neck callus is completely excised. The remaining physis is removed with use of a burr while holding the epiphysis stable. The epiphysis is gently reduced onto the femoral neck, avoiding tension on the retinacular vessels. If tension is noted, the femoral neck is rechecked for residual callus, which is excised. If no callus is found, the neck may be carefully shortened in order to minimize tension. Epiphyseal fixation is achieved with use of a 3-mm fully threaded wire inserted antegrade through the fovea to the lateral cortex below the greater trochanter. A second wire is inserted retrograde under fluoroscopy. After reducing the hip, the capsule is closed and the greater trochanter is reattached with use of 3.5-mm cortical screws. Alternatives: Alternatives include nonoperative treatment, in situ fixation (e.g., pinning or screw fixation), gentle closed reduction with pinning, and triplanar trochanteric osteotomy (e.g., Imhauser or Southwick osteotomies). Rationale: In situ pinning of mild-to-moderate, stable SCFE yields good long-term results with low rates of osteonecrosis9. Treatment of higher-grade SCFE without reduction aims to avoid osteonecrosis and assumes that the proximal femoral deformity will remodel; however, the head-neck offset will remain abnormal, risking impingement and early-onset osteoarthritis5,8. The procedure described in the present article allows anatomic reduction of the epiphysis with a low risk of osteonecrosis. Surgical dislocation of the hip16 with development of an extended retinacular soft-tissue flap17 provides extensive subperiosteal exposure of the circumferential femoral neck and preserves the vulnerable blood supply to the epiphysis18. The Dunn subcapital realignment procedure15 with callus removal and slip angle correction allows anatomic restoration of the proximal femur. Expected Outcomes: Reported results of various centers performing the procedure vary greatly with regard to the number of hips treated and the follow-up time. Most studies have been retrospective and have lacked a control group. The reported risk of osteonecrosis ranges from 0% to 25.9%19, with the wide range most likely because of the challenging nature of the technique, the low number of cases per surgeon, and the long learning curve associated with the procedure. In centers with extensive experience in pediatric hip-preserving surgery, the reported rate of osteonecrosis is low3. Studies with mid to long-term follow-up have shown no conversion to total hip arthroplasty3,20,21, but residual deformities can persist, and subsequent surgery is possible. Important Tips: Extensive experience in surgical hip dislocation and retinacular flap development is a prerequisite for successful outcomes and low rates of osteonecrosis.Sufficient callus and physeal remnant resections are needed to avoid tension on the retinacular vessels during epiphyseal reduction.The skin incision should be centered over the greater trochanterThe Gibson interval must be carefully prepared for adequate release and to avoid injury.Tension on the periosteal flap should be avoided to prevent stress on the retinacular vessels. Acronyms and Abbreviations: AP = anteroposteriorAVN = avascular necrosis (i.e., osteonecrosis)CI = confidence intervalCT = computed tomographyK-wire = Kirschner wireMRI = magnetic resonance imagingOA = osteoarthritisSHD = surgical hip dislocationTHA = total hip arthroplastyVTE = venous thromboembolism.

Analytical and behavioral characterization of 1-hexanoyl-LSD (1H-LSD).

The development of lysergic acid diethylamide (LSD) derivatives and analogs continues to inform the design of novel receptor probes and potentially new medicines. On the other hand, a number of newly developed LSD derivatives have also emerged as recreational drugs, leading to reports of their detection in some countries. One position in the ergoline scaffold of LSD that is frequently targeted is the N1-position; numerous N1-alkylcarbonyl LSD derivatives have been reported where the acyl chain is attached to the indole nitrogen, for example, in the form of linear n-alkane substituents, which represent higher homologs of the prototypical 1-acetyl-N,N-diethyllysergamide (1A-LSD, ALD-52). In this study, 1-hexanoyl-LSD (1H-LSD, SYN-L-027), a novel N1-acyl LSD derivative, was characterized analytically using standard techniques, followed by evaluation of its in vivo behavioral effects using the mouse head-twitch response (HTR) assay in C57BL/6J mice. 1H-LSD induced the HTR, with a median effective dose (ED50) of 192.4 µg/kg (equivalent to 387 nmol/kg), making it roughly equipotent to ALD-52 when tested previously under similar conditions. Similar to other N1-acylated analogs, 1H-LSD is anticipated to by hydrolyzed to LSD in vivo and acts as a prodrug. It is currently unknown whether 1H-LSD has appeared as on the research chemical market or is being used recreationally.

The drainome: longitudinal metagenomic characterisation of wastewater from hospital ward sinks to characterize the microbiome and resistome and assess the effects of decontamination interventions.

BACKGROUND: Hospital drains and water interfaces are implicated in nosocomial transmission of pathogens. Metagenomics can assess the microbial composition and presence of antimicrobial resistance genes in drains ('the drainome') but studies applying these methods longitudinally and to assess infection control interventions are lacking. AIM: Apply long-read metagenomics coupled with microbiological measurements to investigate the drainome and assess the effects of a peracetic acid-containing decontamination product. METHODS: 12-week study in three phases: a baseline phase, an intervention phase of enhanced decontamination with peracetic acid, and a post-intervention phase. Five hospital sink drains on an intensive care unit were sampled twice weekly. Each sample had 1) measurement of total viable count (TVC), 2) metagenomic analyses including i) taxonomic classification of bacteria and fungi ii) antibiotic resistance gene detection iii) plasmid identification, and 3) immunochromatographic detection of antimicrobial residues. FINDINGS: Overall TVCs remain unchanged in the intervention phase (+386 CFU/mL, SE 705, p=0.59). There was a small but significant increase in the microbial diversity in the intervention phase (-0.07 in Simpson's index, SE 0.03, p=0.007), which was not sustained post-intervention (-0.05, SE 0.03, p=0.08). The intervention was associated with increased relative abundance of the Pseudomonas genus (18.3% to 40.5% [+22.2%], SE 5.7%, p<0.001). Extended spectrum beta-lactamases were found in all samples, with NDM-carbapenemase found in 3 drains in 6 samples. Antimicrobial residues were detected in a large proportion of samples (31/115, 27%), suggesting use of sinks for non-handwashing activities. CONCLUSIONS: Metagenomics and other measurements can measure the composition of the drainome and assess the effectiveness of decontamination interventions.

Accelerating Formulation Design via Machine Learning: Generating a High-throughput Shampoo Formulations Dataset.

Liquid formulations are ubiquitous yet have lengthy product development cycles owing to the complex physical interactions between ingredients making it difficult to tune formulations to customer-defined property targets. Interpolative ML models can accelerate liquid formulations design but are typically trained on limited sets of ingredients and without any structural information, which limits their out-of-training predictive capacity. To address this challenge, we selected eighteen formulation ingredients covering a diverse chemical space to prepare an open experimental dataset for training ML models for rinse-off formulations development. The resulting design space has an over 50-fold increase in dimensionality compared to our previous work. Here, we present a dataset of 812 formulations, including 294 stable samples, which cover the entire design space, with phase stability, turbidity, and high-fidelity rheology measurements generated on our semi-automated, ML-driven liquid formulations workflow. Our dataset has the unique attribute of sample-specific uncertainty measurements to train predictive surrogate models.

Bioengineering from the laboratory to clinical translation in oral and maxillofacial reconstruction.

Background: Conventional techniques used in oral and maxillofacial reconstruction focus mainly on utilizing autologous tissues that have unquestionably improved function and esthetics for many patients, worldwide. However, the success depends on countless factors such as: donor and recipient sites conditions, patient's medical history, surgeon's experience, restricted availability of high-quality autogenous tissues or stem cells, and increased surgical cost and time. Materials and Methods: Lately, teaming researchers, scientists, surgeons, and engineers, to address these limitations, have allowed tremendous progress in recombinant protein therapy, cell-based therapy, and gene therapy. Results: Over the past few years, biomedical engineering has been evolving from the laboratory to clinical applications, for replacement of damaged body tissues due to trauma, cancer, congenital or acquired disorders. Conclusions: This review provides an outlook on the content, benefits, recent advances, limitations, and future expectations of biomedical engineering for salivary glands, oral mucosa, dental structures, and maxillofacial reconstruction.

The Role of Reactive Oxygen Species in Age-Related Macular Degeneration: A Comprehensive Review of Antioxidant Therapies.

This review article delves into the intricate roles of reactive oxygen species (ROS) in the pathogenesis of age-related macular degeneration (AMD). It presents a detailed analysis of the oxidative stress mechanisms that contribute to the development and progression of these diseases. The review systematically explores the dual nature of ROS in ocular physiology and pathology, underscoring their essential roles in cellular signaling and detrimental effects when in excess. In the context of AMD, the focus is on the oxidative impairment in the retinal pigment epithelium and Bruch's membrane, culminating in the deterioration of macular health. Central to this review is the evaluation of various antioxidant strategies in the prevention and management of AMD. It encompasses a wide spectrum of antioxidants, ranging from dietary nutrients like vitamins C and E, lutein, and zeaxanthin to pharmacological agents with antioxidative properties. The review also addresses novel therapeutic approaches, including gene therapy and nanotechnology-based delivery systems, aiming to enhance antioxidant defense mechanisms in ocular tissues. The article concludes by synthesizing current research findings, clinical trial data, and meta-analyses to provide evidence-based recommendations. It underscores the need for further research to optimize antioxidant therapies, considering individual patient factors and disease stages. This comprehensive review thus serves as a valuable resource for clinicians, researchers, and healthcare professionals in ophthalmology, offering insights into the potential of antioxidants in mitigating the burden of AMD.

Respiratory infection- and asthma-prone, low vaccine responder children demonstrate distinct mononuclear cell DNA methylation pathways.

BACKGROUND: Infants with frequent viral and bacterial respiratory infections exhibit compromised immunity to routine immunizations. They are also more likely to develop chronic respiratory diseases in later childhood. This study investigated the feasibility of epigenetic profiling to reveal endotype-specific molecular pathways with potential for early identification and immuno-modulation. Peripheral blood mononuclear cells from respiratory infection allergy/asthma-prone (IAP) infants and non-infection allergy/asthma prone (NIAP) were retrospectively selected for genome-wide DNA methylation and single nucleotide polymorphism analysis. The IAP infants were enriched for the low vaccine responsiveness (LVR) phenotype (Fisher's exact p-value = 0.02). RESULTS: An endotype signature of 813 differentially methylated regions (DMRs) comprising 238 lead CpG associations (FDR < 0.05) emerged, implicating pathways related to asthma, mucin production, antigen presentation and inflammasome activation. Allelic variation explained only a minor portion of this signature. Stimulation of mononuclear cells with monophosphoryl lipid A (MPL), a TLR agonist, partially reversed this signature at a subset of CpGs, suggesting the potential for epigenetic remodeling. CONCLUSIONS: This proof-of-concept study establishes a foundation for precision endotyping of IAP children and highlights the potential for immune modulation strategies using adjuvants for future investigation.

Smart Contact Lenses in Ophthalmology: Innovations, Applications, and Future Prospects.

Smart contact lenses represent a breakthrough in the intersection of medical science and innovative technology, offering transformative potential in ophthalmology. This review article delves into the technological underpinnings of smart contact lenses, emphasizing the current landscape and advancements in biosensors, power supply, biomaterials, and the transmission of ocular information. This review further applies new innovations to their emerging role in the diagnosis, monitoring, and management of various ocular conditions. Moreover, we explore the impact of technical innovations on the application of smart contact lenses in monitoring glaucoma, managing postoperative care, and dry eye syndrome, further elucidating the non-invasive nature of these devices in continuous ocular health monitoring. The therapeutic potential of smart contact lenses such as treatment through targeted drug delivery and the monitoring of inflammatory biomarkers is also highlighted. Despite promising advancements, the implementation of smart contact lenses faces technical, regulatory, and patient compliance challenges. This review synthesizes the recent advances to provide an outlook on the state of smart contact lens technology. Furthermore, we discuss future directions, focusing on potential technological enhancements and new applications within ophthalmology.

Moisture availability and groundwater recharge paced by orbital forcing over the past 750,000 years in the southwestern USA.

Quaternary climate changes are driven in part by variations in the distribution and strength of insolation due to orbital parameters. Continental climate variability is well documented for the most recent glacial-interglacial cycles, yet few records extend further back in time. Such records are critically needed to comprehensively assess the entire spectrum of natural climate variability against the backdrop of anthropogenic warming. Here, we apply uranium isotope geochronology to calcite deposits to date groundwater-table changes in Devils Hole cave, Nevada. The deposits record multi-meter groundwater-table fluctuations over the last 750,000 years, reflecting the long-term evolution of hydroclimate in this presently arid region. During periods between glacial or interglacial extremes, the water table responded sensitively to variations in 65°N summer insolation, likely caused by the increasing extent of North American ice sheets during cold period, which steered moisture-laden trajectories towards the southwestern USA. These orbitally-driven hydroclimatic changes are superimposed on a tectonically-driven long-term decline in the regional groundwater table observed prior to 438,000 ± 14,000 years ago.

Aptis Distal Radioulnar Joint Arthroplasty: A Multicenter Evaluation of Functional Outcomes, Complications, and Patient Satisfaction.

Background The Aptis distal radioulnar joint (DRUJ) implant has been commonly used to replace the DRUJ and restore wrist function in patients with a severely destroyed DRUJ. Objective Promising results have been described in the literature. However, the clinical results in a multicenter setting are sparse and variable. This study evaluates the short- to midterm clinical results of 53 patients with a (mean) follow-up of 51 months. Patients and Methods Fifty-three patients (59 implants) treated between 2011 and 2020 in three different institutions were retrospectively identified in a prospectively collected database. The main indication for Aptis DRUJ arthroplasty was a destroyed DRUJ and gross distal radioulnar instability and isolated DRUJ osteoarthritis. Functional outcome, complications, and patient satisfaction were evaluated. Patients completed the Patient-Rated Wrist Evaluation (PRWE) questionnaire and an additional questionnaire about patient satisfaction and return to hobby/work. Results Implant survival was 92%, the surgical follow-up showed many complications (64,4%), and revision surgery was needed frequently (40.7%). In 13 cases, the follow-up was longer than 5 years. Three reimplantations had to be performed and two implants were permanently explanted. In spite of this all, wrist and forearm motion as well as pain reduction was adequate and patient satisfaction was reasonable (72.2%). Conclusion The Aptis DRUJ arthroplasty is a viable option that can provide adequate wrist and forearm function after secure patient selection and surgical placement of the implant in the wrist with a good bone stock of the radius. The complication rate was found to be high, yet patient satisfaction was reasonable. In the case of secondary surgery, additional surgery seems to be needed. For primary surgery, the implant seems to be successful without complications. Different complications have been described, but further analysis is warranted to find the causes of complications and to objectify the performance of the Aptis DRUJ implant. Level of Evidence IV.

Low serum double-stranded DNA levels are associated with higher survival rates in severe COPD patients.

Introduction: Damage-associated molecular patterns (DAMPs) are endogenous danger signals that alert and activate the immune system upon cellular damage or death. It has previously been shown that DAMP release is increased in patients with COPD, leading to higher levels in extracellular fluids such as serum. In the current study we investigated whether the serum levels of DAMPs were associated with survival rates in COPD patients. Methods: A panel of seven DAMPs, consisting of HMGB1, fibrinogen, α-defensin, heat shock protein 70, S100A8, galectin-9 and double-stranded DNA (dsDNA), was measured in serum of 949 severe COPD patients. Maximally selected rank statistics was used to define cut-off values and a Cox proportional hazards model was used to evaluate the effect of high or low DAMP levels on 4-year survival. For DAMPs that were found to affect survival significantly, baseline characteristics were compared between the two DAMP groups. Results: Out of the seven DAMPs, only dsDNA was significantly associated with 4-year survival. Patients with elevated serum level of dsDNA had higher 4-year mortality rates, lower FEV1 % predicted values and higher emphysema scores. Discussion: In conclusion, in a clinical cohort of 949 patients with moderate-to-severe COPD, elevated serum levels of dsDNA were associated with a higher risk of death. This study further illustrates the potential role of circulating DAMPs, such as dsDNA, in the progression of COPD. Together, the results of this study suggest that levels of circulating dsDNA might serve as an additional prognostic biomarker for survival in COPD patients.

Reactions between ferric oxyhydroxide mineral coatings and a dimethoxyhydroquinone: A source of hydroxyl radicals.

Quinones are organic molecules that facilitate electron-transfer reactions in terrestrial environments. The reduced forms, hydroquinones, are powerful reductants that can trigger non-enzymatic radical-based decomposition of organic matter and contaminants by simultaneous reduction of iron and oxygen. Iron oxides often occur as coatings on other minerals, thus our study investigated the reactions between the ferric oxyhydroxide (FeO(OH)) surface coatings on gibbsite (Al(OH)3) and 2,6-dimethoxy-1,4-hydroquinone (2,6-DMHQ). The main aim was to investigate the oxidation of 2,6-DMHQ and the generation ∙OH in the presence of O2 at low Fe concentrations in a novel setup that allows local structural characterization. The heterogeneous redox reactions between 2,6-DMHQ and the FeO(OH) coatings were studied at pH 5.0 as a function of the amount of Fe present on the gibbsite surfaces, including the effect of aging of the FeO(OH) coatings. The results showed that reactions between 2,6-DMHQ and FeO(OH) coated gibbsite under ambient conditions can generate substantial amounts of ·OH, comparable with amounts generated on pure ferrihydrite surfaces. The ·OH is the product of two sequential reactions: hydroquinone oxidation by O2 and degradation of the formed H2O2. The calculated rate constant of the former reaction is the same regardless of amount of FeO(OH) coating suggesting a surface catalytic process where 2,6-DMHQ is oxidized by O2 resulting in formation of H2O2. Subsequently, the observed induction period, the low Fe2+ (aq) concentrations in solution and the dependency of FeO(OH) coating amount influencing ·OH formation suggest that the pathway for ∙OH is through H2O2 decomposition by the surface sites on the FeO(OH) coating. Overall, this study shows that co-existence of oxygen, FeO(OH) and organic reductants, possibly secreted by soil microorganisms, creates favorable conditions for generation of ·OH contributing to decomposition of organic matter and organic pollutants in soil environments.