DAHEAN: A Danish nationwide study ensuring quality assurance through real-world data for suspected hereditary anemia patients.

BACKGROUND: Hereditary anemias are a group of genetic diseases prevalent worldwide and pose a significant health burden on patients and societies. The clinical phenotype of hereditary anemias varies from compensated hemolysis to life-threatening anemia. They can be roughly categorized into three broad categories: hemoglobinopathies, membranopathies, and enzymopathies. Traditional therapeutic approaches like blood transfusions, iron chelation, and splenectomy are witnessing a paradigm shift with the advent of targeted treatments. However, access to these treatments remains limited due to lacking or imprecise diagnoses. The primary objective of the study is to establish accurate diagnoses for patients with hereditary anemias, enabling optimal management. As a secondary objective, the study aims to enhance our diagnostic capabilities. RESULTS: The DAHEAN study is a nationwide cohort study that collects advanced phenotypic and genotypic data from patients suspected of having hereditary anemias from all pediatric and hematological departments in Denmark. The study deliberates monthly by a multidisciplinary anemia board involving experts from across Denmark. So far, fifty-seven patients have been thoroughly evaluated, and several have been given diagnoses not before seen in Denmark. CONCLUSIONS: The DAHEAN study and infrastructure harness recent advancements in diagnostic tools to offer precise diagnoses and improved management strategies for patients with hereditary anemias.

Oral versus intravenous empirical antibiotics in children and adolescents with uncomplicated bone and joint infections: a nationwide, randomised, controlled, non-inferiority trial in Denmark.

BACKGROUND: Bone and joint infections (BJIs) are treated with intravenous antibiotics, which are burdensome and costly. No randomised controlled studies have compared if initial oral antibiotics are as effective as intravenous therapy. We aimed to investigate the efficacy and safety of initial oral antibiotics compared with initial intravenous antibiotics followed by oral antibiotics in children and adolescents with uncomplicated BJIs. METHODS: From Sept 15, 2020, to June 30, 2023, this nationwide, randomised, non-inferiority trial included patients aged 3 months to 17 years with BJIs who presented to one of the 18 paediatric hospital departments in Denmark. Exclusion criteria were severe infection (ie, septic shock, the need for acute surgery, or substantial soft tissue involvement), prosthetic material, comorbidity, previous BJIs, or antibiotic therapy for longer than 24 h before inclusion. Patients were randomly assigned (1:1), stratified by C-reactive protein concentration (<35 mg/L vs ≥35 mg/L), to initially receive either high-dose oral antibiotics or intravenous ceftriaxone (100 mg/kg per day in one dose). High-dose oral antibiotics were coformulated amoxicillin (100 mg/kg per day) and clavulanic acid (12·5 mg/kg per day) in three doses for patients younger than 5 years or dicloxacillin (200 mg/kg per day) in four doses for patients aged 5 years or older. After a minimum of 3 days, and upon clinical improvement and decrease in C-reactive protein, patients in both groups received oral antibiotics in standard doses. The primary outcome was sequelae after 6 months in patients with BJIs, defined as any atypical mobility or function of the affected bone or joint, assessed blindly, in all randomised patients who were not terminated early due to an alternative diagnosis (ie, not BJI) and who attended the primary outcome assessment. A risk difference in sequelae after 6 months of less than 5% implied non-inferiority of the oral treatment. Safety outcomes were serious complications, the need for surgery after initiation of antibiotics, and treatment-related adverse events in the as-randomised population. This trial was registered with ClinicalTrials.gov, NCT04563325. FINDINGS: 248 children and adolescents with suspected BJIs were randomly assigned to initial oral antibiotics (n=123) or initial intravenous antibiotics (n=125). After exclusion of patients without BJIs (n=54) or consent withdrawal (n=2), 101 patients randomised to oral treatment and 91 patients randomised to intravenous treatment were included. Ten patients did not attend the primary outcome evaluation. Sequelae after 6 months occurred in none of 98 patients with BJIs in the oral group and none of 84 patients with BJIs in the intravenous group (risk difference 0, one-sided 97·5% CI 0·0 to 3·8, pnon-inferiority=0·012). Surgery after randomisation was done in 12 (9·8%) of 123 patients in the oral group compared with seven (5·6%) of 125 patients in the intravenous group (risk difference 4·2%, 95% CI -2·7 to 11·5). We observed no serious complications. Rates of adverse events were similar across both treatment groups. INTERPRETATION: In children and adolescents with uncomplicated BJIs, initial oral antibiotic treatment was non-inferior to initial intravenous antibiotics followed by oral therapy. The results are promising for oral treatment of uncomplicated BJIs, precluding the need for intravenous catheters and aligning with the principles of antimicrobial stewardship. FUNDING: Innovation Fund Denmark and Rigshospitalets Forskningsfond.

Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations.

Multiple sclerosis (MS) is a neuro-inflammatory and neurodegenerative disease that is most prevalent in Northern Europe. Although it is known that inherited risk for MS is located within or in close proximity to immune-related genes, it is unknown when, where and how this genetic risk originated1. Here, by using a large ancient genome dataset from the Mesolithic period to the Bronze Age2, along with new Medieval and post-Medieval genomes, we show that the genetic risk for MS rose among pastoralists from the Pontic steppe and was brought into Europe by the Yamnaya-related migration approximately 5,000 years ago. We further show that these MS-associated immunogenetic variants underwent positive selection both within the steppe population and later in Europe, probably driven by pathogenic challenges coinciding with changes in diet, lifestyle and population density. This study highlights the critical importance of the Neolithic period and Bronze Age as determinants of modern immune responses and their subsequent effect on the risk of developing MS in a changing environment.

Telemedicine and the assessment of clinician time: a scoping review.

OBJECTIVES: Telemedicine may improve healthcare access and efficiency if it demands less clinician time than usual care. We sought to describe the degree to which telemedicine trials assess the effect of telemedicine on clinicians' time and to discuss how including the time needed to treat (TNT) in health technology assessment (HTA) could affect the design of telemedicine services and studies. METHODS: We conducted a scoping review by searching clinicaltrials.gov using the search term "telemedicine" and limiting results to randomized trials or observational studies registered between January 2012 and October 2023. We then reviewed trial registration data to determine if any of the outcomes assessed in the trials measured effect on clinicians' time. RESULTS: We found 113 studies and of these 78 studies of telemedicine met the inclusion criteria and were included. Nine (12 percent) of the 78 studies had some measure of clinician time as a primary outcome, and 11 (14 percent) as a secondary outcome. Four studies compared direct measures of TNT with telemedicine versus usual care, but no statistically significant difference was found. Of the sixteen studies including indirect measures of clinician time, thirteen found no significant effects, two found a statistically significant reduction, and one found a statistically significant increase. CONCLUSIONS: This scoping review found that clinician time is not commonly measured in studies of telemedicine interventions. Attention to telemedicine's TNT in clinical studies and HTAs of telemedicine in practice may bring attention to the organization of clinical workflows and increase the value of telemedicine.

Communication between rehabilitation staff and people with traumatic brain injury: A systematic review.

This systematic review aimed to synthesize barriers and facilitators in communicative interactions between staff and people with traumatic brain injury (TBI) in the rehabilitation context. Searches captured published evidence up to November 2022 in MEDLINE, Embase, SCOPUS, Web of Science, CINAHL, AMED, and PsycINFO. Eligible studies reported on the communicative interaction between rehabilitation staff and adults with TBI. In total, 31 studies were included in the review; including quantitative, qualitative, and mixed-methods designs. Quality assessment was carried out using standard checklists. Quantitative studies and quantitative components of mixed-method studies were synthesized descriptively according to reported communication barriers and facilitators. Qualitative studies and qualitative components of mixed-method studies were analysed through an inductive thematic meta-synthesis; generating six main themes with four subthemes. Themes were categorized as barriers or facilitators to communicative interaction. Findings demonstrated that cognitive-communication disorders of people with TBI challenge the communicative interaction between rehabilitation staff and people with TBI. However, the extent to which these disorders create a communicative barrier is closely related to staff's communicative approach. While staff holding a collaborative and acknowledging approach and using supportive strategies may facilitate successful communicative interactions, staff using the opposite approach may exacerbate communication barriers.

Allosteric TYK2 inhibition: redefining autoimmune disease therapy beyond JAK1-3 inhibitors.

JAK inhibitors impact multiple cytokine pathways simultaneously, enabling high efficacy in treating complex diseases such as cancers and immune-mediated disorders. However, their broad reach also poses safety concerns, which have fuelled a demand for increasingly selective JAK inhibitors. Deucravacitinib, a first-in-class allosteric TYK2 inhibitor, represents a remarkable advancement in the field. Rather than competing at kinase domain catalytic sites as classical JAK1-3 inhibitors, deucravacitinib targets the regulatory pseudokinase domain of TYK2. It strikingly mirrors the functional effect of an evolutionary conserved naturally occurring TYK2 variant, P1104A, known to protect against multiple autoimmune diseases yet provide sufficient TYK2-mediated cytokine signalling required to prevent immune deficiency. The unprecedentedly high functional selectivity and efficacy-safety profile of deucravacitinib, initially demonstrated in psoriasis, combined with genetic support, and promising outcomes in early SLE clinical trials make this inhibitor ripe for exploration in other autoimmune diseases for which better, safe, and efficacious treatments are urgently needed.

Meeting the confused patient with confidence: perceived benefits of communication partner training in subacute TBI.

OBJECTIVE: This study aims to explore health professionals' perceived benefits of implementing Communication Partner Training (CPT) using Supported Conversation for Adults with Aphasia (SCA™) in a subacute rehabilitation setting with patients in post-traumatic confusional state (PTCS) after TBI. METHOD: The study was conducted in a clinical setting using a pre-post questionnaire design to explore change. One hundred and four interdisciplinary clinicians attended CPT in the SCA™ method and subsequent implementation support. Participants completed a questionnaire with both quantitative and qualitative questions before and after the training and implementation period. Data were analyzed using descriptive and inferential statistics and qualitative content analysis. RESULTS: Participants' perceived confidence and self-assessed ability to communicate with patients in PTCS significantly increased after CPT (p = 0.006). While participants still experienced communication challenges, they reported using CPT-related tools and strategies in their interactions. Participants found they could apply strategies to improve patients' comprehension of information and to confirm their understanding of patients' communication. However, using strategies to enhance patients' expressive abilities was perceived as more challenging. CONCLUSIONS: Training health professionals in CPT increase their confidence in managing communication with patients in PTCS. Further research is needed to evaluate the efficacy of CPT within a more rigorous research design.

Systematic review of the prevalence of onychomycosis in children.

Onychomycosis is one of the most common nail diseases in adults but is described as infrequent in children. Data are, however, scattered and diverse. Studies have nevertheless suggested that the prevalence of onychomycosis is increasing in children lately and the aim of this review was therefore to examine this problem. Two authors individually searched PubMed, Embase, and Cochrane Library for articles on epidemiology and prevalence of onychomycosis in children. The literature search was conducted in accordance per PRISMA guidelines. In total 1042 articles were identified of which 23 were eligible for inclusion. One of the articles presented two studies and a total of 24 studies were therefore included. Seventeen studies presented data of the prevalence of onychomycosis in children in the general population and seven studies among children visiting a dermatological and pediatric department or clinic. The prevalence ranged from 0% to 7.66% with an overall discrete increase of 0.66% during the period 1972 to 2014 in population studies (not statistically significant). This review supports a trend towards an increased prevalence of onychomycosis in children, albeit based on a paucity of studies. The data suggests an increasing prevalence of onychomycosis with age, and co-infection with tinea pedis (reported in 25% of the studies). The most common pathogen reported was Trichophyton rubrum and onychomycosis was more prevalent in toenails compared to fingernails. The general characteristics of onychomycosis in children are thus similar to those described in adults.

Communicative and Supportive Strategies: A Qualitative Study Investigating Nursing Staff's Communicative Practice With Patients With Aphasia in Stroke Care.

This study aimed to provide detailed descriptions of the influences on the nursing staff's communicative practices with patients with aphasia in the context of usual stroke care interactions, and secondly to explore the nursing staff's use or non-use of supportive techniques, including the SCATM method. A qualitative design was chosen, combining field observations and semi-structured interviews. Inductive and deductive qualitative content analysis was used. The results showed that the nursing staff's interactions with patients with aphasia were influenced by organizational and environmental influences, nurses' roles and functions and supporting patients with aphasia in communication. The role of the nursing staff in caring for the psychosocial well-being of patients is deprioritised in favor of other tasks. If there is no time or culture for prioritizing time for conversing with patients and supporting their psychosocial well-being, communication-partner training like SCATM is likely hindered.

Mouse fetal growth restriction through parental and fetal immune gene variation and intercellular communications cascade.

Fetal growth restriction (FGR) affects 5-10% of pregnancies, and can have serious consequences for both mother and child. Prevention and treatment are limited because FGR pathogenesis is poorly understood. Genetic studies implicate KIR and HLA genes in FGR, however, linkage disequilibrium, genetic influence from both parents, and challenges with investigating human pregnancies make the risk alleles and their functional effects difficult to map. Here, we demonstrate that the interaction between the maternal KIR2DL1, expressed on uterine natural killer (NK) cells, and the paternally inherited HLA-C*0501, expressed on fetal trophoblast cells, leads to FGR in a humanized mouse model. We show that the KIR2DL1 and C*0501 interaction leads to pathogenic uterine arterial remodeling and modulation of uterine NK cell function. This initial effect cascades to altered transcriptional expression and intercellular communication at the maternal-fetal interface. These findings provide mechanistic insight into specific FGR risk alleles, and provide avenues of prevention and treatment.

[Recurrent meningococcal infection in a young woman witha mutation in the C8B gene].

This is a case report of recurrent meningococcal infection in a young woman. She had no positive microbiological findings but was serologically diagnosed with the meningococcal antibody test. Investigation of the complement system showed no function of the terminal pathway. Further genetical analysis revealed a pathogen mutation in the C8B gene in the patient and her sister. They were both immunised with meningococcal vaccines. Complement deficiencies are rare but potentially fatal. Workup for complement deficiency is important for correct acute and prophylactic treatment.

The immunology of multiple sclerosis.

Our incomplete understanding of the causes and pathways involved in the onset and progression of multiple sclerosis (MS) limits our ability to effectively treat this complex neurological disease. Recent studies explore the role of immune cells at different stages of MS and how they interact with cells of the central nervous system (CNS). The findings presented here begin to question the exclusivity of an antigen-specific cause and highlight how seemingly distinct immune cell types can share common functions that drive disease. Innovative techniques further expose new disease-associated immune cell populations and reinforce how environmental context is critical to their phenotype and subsequent role in disease. Importantly, the differentiation of immune cells into a pathogenic state is potentially reversible through therapeutic manipulation. As such, understanding the mechanisms that provide plasticity to causal cell types is likely key to uncoupling these disease processes and may identify novel therapeutic targets that replace the need for cell ablation.

Ingested non-essential amino acids recruit brain orexin cells to suppress eating in mice.

Ingested nutrients are proposed to control mammalian behavior by modulating the activity of hypothalamic orexin/hypocretin neurons (HONs). Previous in vitro studies showed that nutrients ubiquitous in mammalian diets, such as non-essential amino acids (AAs) and glucose, modulate HONs in distinct ways. Glucose inhibits HONs, whereas non-essential (but not essential) AAs activate HONs. The latter effect is of particular interest because its purpose is unknown. Here, we show that ingestion of a dietary-relevant mix of non-essential AAs activates HONs and shifts behavior from eating to exploration. These effects persisted despite ablation of a key neural gut → brain communication pathway, the cholecystokinin-sensitive vagal afferents. The behavioral shift induced by the ingested non-essential AAs was recapitulated by targeted HON optostimulation and abolished in mice lacking HONs. Furthermore, lick microstructure analysis indicated that intragastric non-essential AAs and HON optostimulation each reduce the size, but not the frequency, of consumption bouts, thus implicating food palatability modulation as a mechanism for the eating suppression. Collectively, these results suggest that a key purpose of HON activation by ingested, non-essential AAs is to suppress eating and re-initiate food seeking. We propose and discuss possible evolutionary advantages of this, such as optimizing the limited stomach capacity for ingestion of essential nutrients.

The Phenotypic Responses of Vascular Smooth Muscle Cells Exposed to Mechanical Cues.

During the development of atherosclerosis and other vascular diseases, vascular smooth muscle cells (SMCs) located in the intima and media of blood vessels shift from a contractile state towards other phenotypes that differ substantially from differentiated SMCs. In addition, these cells acquire new functions, such as the production of alternative extracellular matrix (ECM) proteins and signal molecules. A similar shift in cell phenotype is observed when SMCs are removed from their native environment and placed in a culture, presumably due to the absence of the physiological signals that maintain and regulate the SMC phenotype in the vasculature. The far majority of studies describing SMC functions have been performed under standard culture conditions in which cells adhere to a rigid and static plastic plate. While these studies have contributed to discovering key molecular pathways regulating SMCs, they have a significant limitation: the ECM microenvironment and the mechanical forces transmitted through the matrix to SMCs are generally not considered. Here, we review and discuss the recent literature on how the mechanical forces and derived biochemical signals have been shown to modulate the vascular SMC phenotype and provide new perspectives about their importance.

[Acute neonatal myocarditis with cardiogenic shock caused by enterovirus infection].

In this case report, a 16-days-old boy presented with reduced feeding, vomiting, respiratory distress and pallor. He developed cardiogenic shock with cardiac arrest and was resuscitated. Echocardiography showed reduced left ventricular systolic function and he was diagnosed with enterovirus myocarditis since enterovirus RNA was found in the blood by polymerase chain reaction. After one month of hospitalization, the patient was discharged without any apparent sequelae. The condition is rare but associated with a high mortality. Early diagnosis and initiation of treatment is essential for survival.

Prevalence of SARS-CoV-2-Antibodies in Danish Children and Adults.

In Denmark, severe acute respiratory syndrome coronavirus 2 antibodies were assessed in a cross-sectional study among 1033 children visiting pediatric departments and 750 blood donors in June 2020, using a point-of-care test. Antibodies were detected in 17 children (1.6%) and 15 blood donors (2.0%) (P = 0.58). In conclusion, children and adults were infected to a similar low degree.

Mannan-MOG35-55 Reverses Experimental Autoimmune Encephalomyelitis, Inducing a Peripheral Type 2 Myeloid Response, Reducing CNS Inflammation, and Preserving Axons in Spinal Cord Lesions.

CNS autoantigens conjugated to oxidized mannan (OM) induce antigen-specific T cell tolerance and protect mice against autoimmune encephalomyelitis (EAE). To investigate whether OM-peptides treat EAE initiated by human MHC class II molecules, we administered OM-conjugated murine myelin oligodendrocyte glycoprotein peptide 35-55 (OM-MOG) to humanized HLA-DR2b transgenic mice (DR2b.Ab°), which are susceptible to MOG-EAE. OM-MOG protected DR2b.Ab° mice against MOG-EAE by both prophylactic and therapeutic applications. OM-MOG reversed clinical symptoms, reduced spinal cord inflammation, demyelination, and neuronal damage in DR2b.Ab° mice, while preserving axons within lesions and inducing the expression of genes associated with myelin (Mbp) and neuron (Snap25) recovery in B6 mice. OM-MOG-induced tolerance was peptide-specific, not affecting PLP178-191-induced EAE or polyclonal T cell proliferation responses. OM-MOG-induced immune tolerance involved rapid induction of PD-L1- and IL-10-producing myeloid cells, increased expression of Chi3l3 (Ym1) in secondary lymphoid organs and characteristics of anergy in MOG-specific CD4+ T cells. The results show that OM-MOG treats MOG-EAE in a peptide-specific manner, across mouse/human MHC class II barriers, through induction of a peripheral type 2 myeloid cell response and T cell anergy, and suggest that OM-peptides might be useful for suppressing antigen-specific CD4+ T cell responses in the context of human autoimmune CNS demyelination.