Development of nitroalkene-based inhibitors to target STING-dependent inflammation.

Stimulator of Interferon Genes (STING) is essential for the inflammatory response to cytosolic DNA. Despite that aberrant activation of STING is linked to an increasing number of inflammatory diseases, the development of inhibitors has been challenging, with no compounds in the pipeline beyond the preclinical stage. We previously identified endogenous nitrated fatty acids as novel reversible STING inhibitors. With the aim of improving the specificity and efficacy of these compounds, we developed and tested a library of nitroalkene-based compounds for in vitro and in vivo STING inhibition. The structure-activity relationship study revealed a robustly improved electrophilicity and reduced degrees of freedom of nitroalkenes by conjugation with an aromatic moiety. The lead compounds CP-36 and CP-45, featuring a ß-nitrostyrene moiety, potently inhibited STING activity in vitro and relieved STING-dependent inflammation in vivo. This validates the potential for nitroalkene compounds as drug candidates for STING modulation to treat STING-driven inflammatory diseases, providing new robust leads for preclinical development.

Actionability and familial uptake following opportunistic genomic screening in a pediatric cancer cohort.

The care for patients with serious conditions is increasingly guided by genomic medicine, and genomic medicine may equally transform care for healthy individual if genomic population screening is implemented. This study examines the medical impact of opportunistic genomic screening (OGS) in a cohort of patients undergoing comprehensive genomic germline DNA testing for childhood cancer, including the impact on their relatives. Medical actionability and uptake after cascade testing in the period following disclosure of OGS results was quantified. A secondary finding was reported to 19/595 (3.2%) probands primarily in genes related to cardiovascular and lipid disorders. After a mean follow up time of 1.6 years (Interquartile range (IQR): 0.57-1.92 yrs.) only 12 (63%) of these variants were found to be medically actionable. Clinical follow up or treatment was planned in 16 relatives, and as in the probands, the prescribed treatment was primarily betablockers or cholesterol lowering therapy. No invasive procedures or implantation of medical devices were performed in probands or relatives, and no reproductive counseling was requested. After an average of 1.6 years of follow-up 2.25 relatives per family with an actionable finding had been tested. This real-world experience of OGS grants new insight into the practical implementation effects and derived health care demands of genotype-first screening. The resulting health care effect and impact on demand for genetic counseling and workup in relatives extends beyond the effect in the probands.

Breastfeeding Duration Is Not Associated With Offspring Inflammatory Bowel Disease Risk in Three Population-Based Birth Cohorts.

BACKGROUND & AIMS: Breastfeeding is critical for offspring health and development. Although many observational studies report a protective effect between breastfeeding and inflammatory bowel disease (IBD), the relationship is not well-understood. METHODS: We used prospectively collected data from 3 population-based birth cohorts (Danish National Birth Cohort, Norwegian Mother, Father, and Child Cohort, and All Babies in Southeast Sweden) and cross-linked national registers to ascertain the impact of breastfeeding duration on offspring IBD risk in each country, using adjusted Cox proportional regression analyses. We performed meta-analyses to determine pooled estimates. RESULTS: We included 148,737 offspring and 169,510 offspring in analyses of exclusive and any breastfeeding duration, respectively. During median follow-up of 16.3-22.3 years, between 1996 and 2021, 543 offspring were diagnosed with IBD. In each country, there was no association between exclusive breastfeeding duration and offspring IBD risk after adjusting for birth year (Denmark), offspring sex, parental IBD status, maternal education, smoking during pregnancy, age at delivery, mode of delivery, preterm birth, and small for gestational age. The pooled adjusted hazard ratio for IBD was 1.24 (95% confidence interval, 0.94-1.62; Q = 0.16, I2 = 0.0%) and 1.02 (95% confidence interval, 0.85-1.21; Q = 1.45, I 2= 0.0%) among offspring breastfed exclusively for ≥6 months and <4 months, respectively, compared with 4-5 months. Similarly, we found null associations in pooled analyses of any breastfeeding duration and IBD, subtypes Crohn's disease and ulcerative colitis, as well as in cohort-specific analyses. CONCLUSIONS: In prospectively collected data from 3 population-based birth cohorts, the duration of exclusive or any breastfeeding was not associated with offspring IBD risk.

Familial occurrences of cardiac wild-type transthyretin amyloidosis: a case series.

Background: Cardiomyopathy caused by aggregation and deposition of transthyretin amyloid fibrils in the heart (ATTR-CM) is divided into a hereditary (ATTRv) and a wild-type (ATTRwt) forms. While ATTR-CM has been considered a rare disease, recent studies suggest that it is severely underdiagnosed and an important cause of heart failure in elderly patients. Familial occurrence is implicit in ATTRv, but it is not expected in ATTRwt. Case summary: We report a case series of two unrelated families each with two brothers diagnosed with ATTRwt. Genetic testing did not reveal mutations in the transthyretin gene. Family screening with electrocardiogram, echocardiography, and genetic testing did not raise any suspicion of ATTR in first-line family members. Discussion: Familial occurrence of a rare, non-hereditary disease is statistically unlikely. Two siblings in two different families diagnosed with ATTRwt highlight that the aetiology of ATTRwt is poorly understood, and that genetic factors distinct from mutations in the transthyretin gene, as well as environmental factors, might contribute to the pathogenesis. Identifying such factors might reveal new therapeutic targets. To investigate this further, clinicians need to be aware of the possibility of familial occurrence of ATTRwt.

Inflammatory Markers in Children and Adolescents with Functional Somatic Disorders: A Systematic Review.

Functional somatic disorders (FSDs) are common in children and adolescents. Recent findings suggest that low-grade inflammation has a role in the development and maintenance of pediatric FSDs. This systematic review included studies with original data on systemic inflammatory markers in children and adolescents with an FSD compared to individuals without an FSD. The literature search identified 1374 articles. After assessment, a total of 15 studies met the inclusion criteria. In total, 41 serum or plasma cytokines were assayed in a population of 696 children and adolescents. Altered cytokine levels in patients with FSDs were reported in 12 studies, whereas three studies found no significant differences when comparing patients with FSDs and controls. The cytokine levels were significantly elevated in nine studies (i.e., IL-2, IL-6, IL-8, IL-12 (p70), CRP, hsCRP, IP-10, MCP-1, sTIM-3, sCD25 and TNF-α). The findings indicate that inflammatory response may have a role in the pathophysiology of pediatric FSDs. However, the included studies showed limited quality with potential risk of bias, small study populations and a narrow spectrum of included FSDs, which limits the generalizability of the results. To further explore the potential link between inflammatory markers and pediatric FSDs, future research using a longitudinal study design is recommended.

Cardiovascular risk factors and aortic valve stenosis: towards 10-year absolute risk charts for primary prevention.

AIM: Due to aging populations the incidence of aortic valve stenosis (AVS) is increasing steeply. Since no medical therapy is available but only surgical interventions, it is highly warranted to identify modifiable risk factors for early prevention. The aim of the study was to investigate the associations of cardiovascular risk factors with AVS and to create 10-year absolute risk scores for use in primary prevention. METHODS: In the Copenhagen General Population Study (N=93,979) lifestyle data, biochemical measures, and confounders were assessed at baseline. Risk factors with the strongest association with aortic valve stenosis from Cox regression analyses were included in ten-year risk prediction models. Ten-year absolute risk scores were conducted using the method of Fine-Gray proportional sub-hazards models, accounting for competing events. RESULTS: 1,132 individuals developed AVS during follow-up. Of well-known cardiovascular risk factors, those that associated with AVS included increasing levels of remnant cholesterol, triglycerides, lipoprotein(a), systolic blood pressure, and body mass index, low adherence to Danish dietary guidelines, current smoking, high alcohol consumption, lipid-lowering therapy and diabetes mellitus. Ten-year absolute risk scores increased when compiling the most important risk factors for AVS; age, sex, body mass index, systolic blood pressure, lipoprotein(a), and diabetes. Ten-year absolute risk increased from <1% to 19%. CONCLUSIONS: The presence of cardiovascular risk factors is associated with AVS, supporting that this disease, at least partly, may be modifiable through lifestyle changes. Risk charts combining cardiovascular risk factors have the potential to identify high-risk individuals, offering opportunities for preventive strategies. (Word count 245).

This study investigates the impact of common cardiovascular risk factors on aortic valve stenosis (AVS) and introduces a risk score to predict the likelihood of developing AVS within ten years. We identified strong links between AVS and several risk factors, including lipid traits, high blood pressure, obesity, smoking, increased alcohol intake, low adherence to dietary guidelines, and diabetes. A ten-year risk score combining age, sex, body mass index, blood pressure, the lipid trait lipoprotein(a), and diabetes estimates an individual's future risk of AVS, which can range from 1% to 19%. Such risk scores enable identification of individuals at highest risk, where early prevention is most effective.

Asthma and pregnancy.

Managing asthma during pregnancy is crucial for both the mother and the developing child. Adequate control lowers risks as do continuation of prescribed medication and maintaining of regular check-ups. Signs of deterioration should not be ignored and treating asthma during pregnancy should follow guidelines for non-pregnant women with asthma as described in this review. Effective medication and counseling are essential for a safe pregnancy, emphasizing that well-controlled asthma is key.

Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis.

We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase. Using data from 12 cohorts, including 18,265 cases with cirrhosis, 1,782,047 controls, up to 1 million individuals with liver function tests and a validation cohort of 21,689 cases and 617,729 controls, we identify and validate 14 risk associations for cirrhosis. Many variants are located near genes involved in hepatic lipid metabolism. One of these, PNPLA3 p.Ile148Met, interacts with alcohol intake, obesity and diabetes on the risk of cirrhosis and hepatocellular carcinoma (HCC). We develop a polygenic risk score that associates with the progression from cirrhosis to HCC. By focusing on prioritized genes from common variant analyses, we find that rare coding variants in GPAM associate with lower ALT, supporting GPAM as a potential target for therapeutic inhibition. In conclusion, this study provides insights into the genetic underpinnings of cirrhosis.

To disinfect or not to disinfect that is the question - Procedure when drawing blood for alcohol measurements in Denmark.

Swabbing with ethanol to disinfect the skin before venipuncture does not bias measurements of blood ethanol, as previously suspected. International evidence-based theory may not always be successfully integrated into local practices, where old customs may remain. So how are the local protocols for swabbing in practice - if they even do swab? Not disinfecting may risk patient safety. We aim to put a focus on the venipuncture disinfection procedure in practice when measuring blood alcohol for clinical matters and if their procedure refers to a guideline. Specialized biomedical laboratory scientists (BLS) are typically responsible for the phlebotomy procedure in Denmark, thus questionnaires were sent to the relevant BLS in 2020 to map disinfection procedures in all Danish hospitals and affiliated blood draw clinics (n = 58). The response rate was 93% (54/58). We observed an inter-laboratory dissimilarity in swabbing procedures, when measuring blood alcohol: A quarter did not use any disinfectant (26%), while the remaining disinfected with ethanol 55%, isopropanol 13%, and 6% with ethanol/chlorhexidine. Of the five Danish regions, three had a regional guideline (3/5), otherwise the swabbing protocol was locally based. There was a regional difference in disinfecting or not (Chi2 p < 0,0001). Danish protocols do not always parallel international literature and international guidelines. Not applying disinfectant may jeopardize patient safety. Laboratories are encouraged to work with evidence-based practice or follow newest standardized international guidelines.

Association between early life exposure to agriculture, biodiversity, and green space and risk of inflammatory bowel disease: a population-based cohort study.

Background: Specific pollutants and environmental exposures are implicated in modulating inflammatory bowel disease (IBD) risk. However, the role of environmental exposures, particularly during the early life period, towards IBD risk, has not been systematically evaluated. Methods: We conducted a nationwide population-based cohort study during the study period extending from January 1, 1995, to September 1, 2020, using cross-linked Danish registers, maps, and inventories to ascertain the impact of agricultural land use, biodiversity, green space, urban space, blue space, and normalized difference vegetation index during pregnancy and the first two years of life on IBD, Crohn's disease (CD), and ulcerative colitis (UC) risk, using adjusted Cox proportional hazards regression analyses. We adjusted for covariates sex, maternal age at delivery, calendar year of birth, municipal-level socioeconomic status, and first-degree relative with IBD. Findings: Of 1,438,487 individuals included in the study who were followed from age 2 years until a median (IQR) age of 14 (8-20) years, 3768 individuals were diagnosed with IBD. Exposure to the second, third and highest quartiles of agriculture land use during early life, relative to the lowest quartile, were associated with increased CD risk (aHR 1.12, 95% CI 1.01, 1.26, 1.19, 95% CI 1.05, 1.34 and, 1.24 95% CI 1.06, 1.46, respectively). There was no association of agriculture land use with UC risk. Conversely, exposure to the third quartile of biodiversity in early life, compared to the lowest quartile, were associated with a lower CD risk (aHR 0.86, 95% CI 0.75, 0.98). A protective effect of greenspace was noted in the highest quartile for CD (aHR 0.87, 95% CI 0.78, 0.98). Interpretation: In a nationwide cohort with long-term follow up data, early life environmental exposures were associated with modulation of CD risk, with a harmful effect of agriculture land use and protective effect of biodiversity and green space. Funding: Danish National Research Foundation, the International Organization for the Study of Inflammatory Bowel Disease, the National Institute of Diabetes and Digestive and Kidney Diseases.

Introduction of a novel neonatal warming device in Malawi: an implementation science study.

BACKGROUND: Neonatal hypothermia significantly contributes to infant morbidity and mortality in low-resource settings like Malawi. Kangaroo mother care (KMC) is essential but faces challenges in providing continuous thermal support. The Dream Warmer is a neonatal warming device that was developed to complement KMC. We studied its implementation outside a research environment. METHODS: Using an implementation science approach, we conducted a prospective interventional cohort study in two hospitals and four health centres in Malawi. Through audits and surveys, we assessed the effect of the Dream Warmer on neonatal hypothermia as well as healthcare provider (HCP) and parent attitudes regarding thermoregulation and related issues. RESULTS: The Dream Warmer raised no safety concerns and effectively treated hypothermia in 90% of uses. It was positively received by HCPs and parents, who reported it had a favourable effect on the care of small and sick newborns. Challenges identified included a scarcity of water and electricity, lack of availability of the device and HCPs forgetting to prepare it in advance of need or to use it when indicated. Feedback for future training was obtained. The Dream Warmer's strong safety and effectiveness performance is consistent with results from strict research studies. Training materials can be adapted to optimize integration into daily practice and provide educational content for parents. CONCLUSIONS: The Dream Warmer is a safe and effective device to treat neonatal hypothermia, particularly when KMC is insufficient. We gained an understanding of how to optimize implementation through robust HCP and family education to help combat hypothermia.

Establishing a regional registry for neonatal encephalopathy: impact on identification of gaps in practice.

BACKGROUND: Neonatal encephalopathy (NE) continues to be a significant risk for death and disability. To address this risk, regional guidelines were developed with the support of a malpractice insurance patient safety organization. A NE registry was also established to include 14 centers representing around 50% of deliveries in the state of Massachusetts. The aim of this study was to identify areas of variation in practice that could benefit from quality improvement projects. METHODS: This manuscript reports on the establishment of the registry and the primary findings to date. RESULTS: From 2018 to 2020, 502 newborns with NE were evaluated for Therapeutic Hypothermia (TH), of which 246 (49%) received TH, representing a mean of 2.91 per 1000 live births. The study reports on prenatal characteristics, delivery room resuscitation, TH eligibility screening, and post-natal management of newborns with NE who did and did not receive TH. CONCLUSIONS: The registry has allowed for the identification of areas of variation in clinical practices, which have guided ongoing quality improvement projects. The authors advocate for the establishment of local and regional registries to standardize and improve NE patient care. They have made the registry data collection tools freely available for other centers to replicate this work. IMPACT: Malpractice insurance companies can take an active role in supporting clinicians in establishing clinical practice guidelines and regional registries. Establishing a collaborative regional neonatal encephalopathy (NE) registry is feasible. Data Collection tools for a NE registry have been made publicly available to be adopted and replicated by other groups. Establishing a regional NE registry allowed for the identification of gaps in knowledge, variations in practice, and the opportunity to advance care through quality improvement projects.

Participatory ergonomics: What works for whom and why? A realist review.

Participatory workplace interventions to improve workforce musculoskeletal health are infrequently analysed regarding why they work, for whom or under what circumstances. This review sought to identify intervention strategies which achieved genuine worker participation. In total, 3388 articles on participatory ergonomic (PE) interventions were screened; 23 were suitable to analyse within a realist framework identifying contexts, mechanisms of change, and outcomes. The interventions which succeeded in achieving worker participation were characterised by one or more of these contexts: workers' needs as a core starting point; a positive implementation climate; clear distribution of roles and responsibilities; allocation of sufficient resources; and managerial commitment to and involvement in occupational safety and health. Interventions that were organised and delivered in this way generated relevance, meaning, confidence, ownership and trust for the workers in an interrelated and multi-directional manner. With such information, PE interventions may be carried out more effectively and sustainably in the future.Practitioner summary: This review focuses on the question: which mechanisms support genuine worker participation, in what context and with which necessary resources, to reduce musculoskeletal disorders. Results emphasise the importance of starting with workers' needs, making the implementation climate egalitarian, clarifying the roles and responsibilities of all involved, and providing sufficient resources.Abbreviations: PE: participatory ergonomic(s); WMSD: Work-related musculoskeletal disorders; EU: European Union; MSD: Muskuloskeletal disorders; OSH: Occupational health and safety; C: context; M: mechanism; O: outcome; CMOCs: CMO configurations; NPT: Normalization process theory; OECD: The Organisation for Economic Co-operation and Development: EU-OSHA: European Occupational Safety and Health Agency.

Telomere length and risk of cirrhosis, hepatocellular carcinoma, and cholangiocarcinoma in 63,272 individuals from the general population.

BACKGROUND AND AIMS: Inherited short telomeres are associated with a risk of liver disease, whereas longer telomeres predispose to cancer. The association between telomere length and risk of HCC and cholangiocarcinoma remains unknown. APPROACH AND RESULTS: We measured leukocyte telomere length using multiplex PCR in 63,272 individuals from the Danish general population. Telomere length and plasma ALT concentration were not associated (ß = 4 ×10 -6 , p -value = 0.06) in a linear regression model, without any signs of a nonlinear relationship. We tested the association between telomere length and risk of cirrhosis, HCC, and cholangiocarcinoma using Cox regression. During a median follow-up of 11 years, 241, 76, and 112 individuals developed cirrhosis, HCC, and cholangiocarcinoma, respectively. Telomere length and risk of cirrhosis were inversely and linearly associated ( p -value = 0.004, p for nonlinearity = 0.27). Individuals with telomeres in the shortest vs. longest quartile had a 2.25-fold higher risk of cirrhosis. Telomere length and risk of HCC were nonlinearly associated ( p -value = 0.009, p -value for nonlinearity = 0.01). This relationship resembled an inverted J-shape, with the highest risk observed in individuals with short telomeres. Individuals with telomeres in the shortest versus longest quartile had a 2.29-fold higher risk of HCC. Telomere length was inversely and linearly associated with the risk of cholangiocarcinoma. Individuals with telomeres in the shortest versus longest quartile had a 1.86-fold higher risk of cholangiocarcinoma. CONCLUSIONS: Shorter telomere length is associated with a higher risk of cirrhosis, HCC, and cholangiocarcinoma.

The Fusion Clinic: Integrating the care of people with severe mental illness and diabetes.

AIM: People with coexisting severe mental illness (SMI) and type 2 diabetes have a shorter life expectancy and poorer diabetes outcomes than those without SMI. This is partly explained by the separate treatment of diabetes and SMI, which occurs in parallel silos in many healthcare systems. The Steno Diabetes Center Sjaelland and Region Zealand established the Fusion Clinic to offer combined psychiatric and diabetes care delivered by both diabetes and mental healthcare professionals. This study describes how the clinic was established and the initial diabetes outcomes. METHODS: The Fusion Clinic was co-designed by people with diabetes and SMI and healthcare professionals to improve the care of adults with diabetes and SMI. The clinic approach utilised the F-ACT model. The 63 people referred to the Fusion Clinic between 01.02.2020 and 01.01.2022 who attended the clinic for more than 6 months were included in this study. Diabetes outcomes were recorded in the electronic medical records (Sundhedsplatformen EPIC). RESULTS: There was a high prevalence of diabetes complications at baseline. Furthermore, 70% had one or more additional concomitant diseases, as well as SMI and diabetes. Assessment of diabetes complications and measurements of HbA1c and lipid profile improved after referral to the clinic. HbA1c declined during the first 6 months of attendance at the clinic. CONCLUSIONS: This model of service delivery has the potential to improve the quality of care for people with SMI and type 2 diabetes.

Extreme Reticulocytosis After Splenectomy in a Patient With Hemoglobin Mizuho.

BACKGROUND: Patients with Hb Mizuho may be splenectomized at a young age to decrease their need for blood transfusions. OBSERVATIONS: Transfusion-dependency decreased dramatically in a 4-year-old white boy with Hb Mizuho after splenectomy. Surprisingly, he developed reticulocytosis (>1000×10 9 /L) with a peak reticulocyte percentage of 49%, and erythrocyte abnormalities, including Heinz bodies, Howell-Jolly bodies, and basophilic stippling. Manual reticulocyte counting and flow cytometric measurement with anti-CD71 antibodies supported a truly elevated reticulocyte count. CONCLUSIONS: We propose possible explanations for the extreme reticulocytosis that arose postsplenectomy and compare the reticulocyte count in the present case with previously published cases.

Classification of fetal and adult red blood cells based on hydrodynamic deformation and deep video recognition.

Flow based deformation cytometry has shown potential for cell classification. We demonstrate the principle with an injection moulded microfluidic chip from which we capture videos of adult and fetal red blood cells, as they are being deformed in a microfluidic chip. Using a deep neural network - SlowFast - that takes the temporal behavior into account, we are able to discriminate between the cells with high accuracy. The accuracy was larger for adult blood cells than for fetal blood cells. However, no significant difference was observed between donors of the two types.

Pharmacologic and Genetic Downregulation of Proprotein Convertase Subtilisin/Kexin Type 9 and Survival From Sepsis.

OBJECTIVES: Treatments that prevent sepsis complications are needed. Circulating lipid and protein assemblies-lipoproteins play critical roles in clearing pathogens from the bloodstream. We investigated whether early inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) may accelerate bloodstream clearance of immunogenic bacterial lipids and improve sepsis outcomes. DESIGN: Genetic and clinical epidemiology, and experimental models. SETTING: Human genetics cohorts, secondary analysis of a phase 3 randomized clinical trial enrolling patients with cardiovascular disease (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY OUTCOMES]; NCT01663402), and experimental murine models of sepsis. PATIENTS OR SUBJECTS: Nine human cohorts with sepsis (total n = 12,514) were assessed for an association between sepsis mortality and PCSK9 loss-of-function (LOF) variants. Incident or fatal sepsis rates were evaluated among 18,884 participants in a post hoc analysis of ODYSSEY OUTCOMES. C57BI/6J mice were used in Pseudomonas aeruginosa and Staphylococcus aureus bacteremia sepsis models, and in lipopolysaccharide-induced animal models. INTERVENTIONS: Observational human cohort studies used genetic PCSK9 LOF variants as instrumental variables. ODYSSEY OUTCOMES participants were randomized to alirocumab or placebo. Mice were administered alirocumab, a PCSK9 inhibitor, at 5 mg/kg or 25 mg/kg subcutaneously, or isotype-matched control, 48 hours prior to the induction of bacterial sepsis. Mice did not receive other treatments for sepsis. MEASUREMENTS AND MAIN RESULTS: Across human cohort studies, the effect estimate for 28-day mortality after sepsis diagnosis associated with genetic PCSK9 LOF was odds ratio = 0.86 (95% CI, 0.67-1.10; p = 0.24). A significant association was present in antibiotic-treated patients. In ODYSSEY OUTCOMES, sepsis frequency and mortality were infrequent and did not significantly differ by group, although both were numerically lower with alirocumab vs. placebo (relative risk of death from sepsis for alirocumab vs. placebo, 0.62; 95% CI, 0.32-1.20; p = 0.15). Mice treated with alirocumab had lower endotoxin levels and improved survival. CONCLUSIONS: PCSK9 inhibition may improve clinical outcomes in sepsis in preventive, pretreatment settings.