Management and outcome of cutaneous diphtheria in adolescent refugees in Germany, June 2022 - October 2023.

OBJECTIVES: From September 2022 an increase in Corynebacterium diphtheriae (C. diphtheriae) infections was reported in Europe. Our study focuses on 31 adolescent and young adult refugees with cutaneous C. diphtheriae infections detected in Germany. We examined treatment regimens and outcomes to provide targeted insights into the management of this infection. METHODS: We distributed a standardized survey, focused on children and adolescents presenting to paediatric clinics through the German Paediatric Infectious Diseases Society (DGPI) and additional professional contacts in Germany. Data were extracted from routine medical documentation and reported anonymously. RESULTS: A total of 31 individuals with cutaneous C. diphtheriae infection were reported by 9 centres. Two of these showed diphtheria toxin (DT) related systemic symptoms and four exhibited systemic inflammation requiring complex management. The remaining 25 cases, with exclusively cutaneous manifestations, were afebrile. Treatment with topical antiseptics and systemic antibiotics, mainly aminopenicillin/beta-lactamase inhibitors (BLI) (35%) or clindamycin (25%), achieved eradication in all but two cases treated with aminopenicillin/BLI. Treatment duration varied between 5 and 17 days. CONCLUSIONS: In refugees presenting with chronic skin wounds, C. diphtheriae should be included into the differential diagnosis. Fever seems to be a valuable marker to differentiate severe cases with potentially DT-mediated sequelae from exclusively cutaneous diphtheria (CD). For afebrile CD, topical antiseptics and oral antibiotic therapy with clindamycin for 7 days, followed by clinical surveillance appears to be a safe treatment regimen. Patients with CD who present with fever or pharyngitis should be thoroughly investigated including blood and pharyngeal swab cultures.

Individual factors determine landing impacts in rested and fatigued cheerleaders.

High vertical ground reaction forces (VGRF) during landings following acrobatic elements in artistic gymnastics is associated with trunk and lower extremity injury risk. As similar data regarding injury risk factors in cheerleading are scarce, the purpose of this study was to assess VGRF in pop-off dismounts of rested and fatigued flyers in cheerleaders. Fifteen German cheerleaders were recruited for this study, including seven female flyers and eight male bases. It was expected that performance would change in fatiguing athletes, potentially increasing the risk for injuries. However, neither the mean VGRF (rested: 6.0 ± 1.9 BW, fatigued: 6.2 ± 1.3 BW, overall range: 2.1-14.9 BW) nor the individual VGRF-time courses of the flyers changed significantly after the workout. Instead, we show that the flyers' ability to land - but not the bases' ability to catch - significantly influences the maximum and time-resolved impacts.

The burdens and benefits of managing and engaging: a diary study approach to person-centred risk assessment of top executives and works council members.

The present diary study investigates the impact of daily effort-reward imbalance (ERI), subjective stress and the cortisol awakening response (CAR) as an objective measure on work engagement of top managers and high-level works council members (N = 45) on three consecutive working days. In the scope of psychosocial risk assessment, we argue that focusing on ERI as a generalized work characteristic might be more suitable for work re-design of higher leadership positions because of their highly dynamic and unpredictable psychosocial work characteristics, while at the same time having more access to job resources. The analyses reveal that both baseline and daily ERI, as well as subjective stress, influence work engagement. Our results suggest that interventions to reduce daily levels of ERI may improve the work environment of top managers and works councils by promoting work engagement and related positive health outcomes in the scope of person-centred risk assessment.

The components of arginine and methylarginine metabolism are indicative of altered kidney function in intrauterine growth-restricted neonates.

BACKGROUND: Intrauterine fetal growth restriction (IUGR) affects up to 10% of all pregnancies. Severe IUGR is associated with impaired kidney development, reduced nephron endowment, and chronic kidney disease later in life. Currently, no early predictive biomarker exists for detecting altered kidney function in neonates with IUGR. Because nephrons produce key enzymes for the metabolism of arginine and methylarginine components, we quantified and compared the concentrations of arginine and methylarginine metabolites between IUGR and non-IUGR neonates to identify potential biomarkers for the early detection of altered kidney function in IUGR neonates. METHODS: Seventy-one IUGR and 123 non IUGR neonates were examined. Serum and Urine samples were obtained between 30 h and 5 days of life and between 5 and 70 days of life. Serum concentrations of creatinine, urea, symmetric and asymmetric-dimethylarginine metabolites (SDGV, SDMA, ADGV, and ADMA), guanidino-2-oxo-caproic acid (GOCA), citrulline, homocitrulline, arginine, and homoarginine were quantified using LC-MS/MS and standard clinical laboratory methods. Datasets were compared by Mann-Whitney--Wilcoxon or Chi-square tests for continuous and discrete parameters. P values were corrected for multiple comparisons using the Bonferroni method. RESULTS: After Bonferroni correction, we found that serum creatinine, urea, SDGV, ADGV, and GOCA levels were significantly lower in neonates with IUGR. Consequently, the ratios of SDGV/SDMA, ADGV/ADMA, and GOCA/homoarginine were significantly lower in IUGR neonates. CONCLUSION: Our study suggests that arginine and methylarginine are possible early biomarkers for detecting altered kidney function in IUGR neonates.

Is electrical cardioversion independently associated with infarcts on brain magnetic resonance imaging or clinical outcomes in patients with atrial fibrillation?

BACKGROUND: Electrical cardioversion (ECV) is frequently performed in symptomatic atrial fibrillation. OBJECTIVE: This study aimed to assess the association of ECV with infarcts on brain magnetic resonance imaging (bMRI) and clinical outcomes. METHODS: The Swiss Atrial Fibrillation Cohort Study included 2386 patients; 1731 patients were evaluated by bMRI. ECVs were recorded by questionnaire. Patients were assigned to categories by number of ECVs performed before enrollment (0, 1, ≥2). A bMRI study was conducted at baseline and after 2 years (n = 1227) and analyzed for large noncortical or cortical infarcts and small noncortical infarcts. Clinical outcomes were recorded during follow-up. Associations of ECV and outcome measures were assessed by multivariate analyses. RESULTS: There was no independent association between the number of ECVs and infarct prevalence (large noncortical or cortical infarcts and small noncortical infarcts) on baseline bMRI (ECV 1 vs 0: odds ratio [OR], 0.95 [95% CI, 0.68-1.24]; ECV ≥2 vs 0: OR, 1.04 [0.72-1.44]) or between ECVs performed during follow-up and new infarcts on bMRI at 2 years (OR, 1.46 [0.54-3.31]). ECVs were not associated with overt stroke or transient ischemic attack (ECV 1 vs 0: hazard ratio [HR], 1.36 [0.88-2.10]; ECV ≥2 vs 0: HR, 1.53 [0.94-2.48]), hospitalization for heart failure (ECV 1 vs 0: HR, 1.06 [0.82-1.37]; ECV ≥2 vs 0: HR, 1.03 [0.77-1.38]), or death (ECV 1 vs 0: HR, 0.90 [0.70-1.15]; ECV ≥2 vs 0: HR, 0.91 [0.69-1.20]). CONCLUSION: There was no association between ECV performed before enrollment and cerebral infarcts on baseline bMRI or between ECV performed during follow-up and new infarcts at 2 years. Moreover, ECV was not associated with clinical events.

Influence of Critical Shoulder Angle and Rotator Cuff Tear Type on Load-Induced Glenohumeral Biomechanics: A Sawbone Simulator Study.

Glenohumeral (GH) biomechanics after rotator cuff (RC) tears are not fully understood. The purpose of our study was to determine if the critical shoulder angle (CSA), type of RC tears, and level of weight bearing increase GH translation, instability based on the instability ratio, muscle forces and joint reaction force (JRF), and shifts the center of force (CoF) superiorly. A GH simulator with muscle-mimicking cable systems was used to simulate 30° abduction in the scapular plane. A Sawbone humerus and five specimen-specific scapular anthropometries were used to test six types of RC tears, three weight-bearing loads, and the native and adjusted (to different CSAs) deltoid origin sites. Linear mixed effects models (CSA, RC tear type, and weight bearing) with random effects (specimen and sex) were used to assess differences in GH biomechanics. With increasing CSA, GH translation increased, JRF decreased, and the CoF position was more inferior. RC tears did not significantly alter GH translation but shifted the CoF position superiorly, close to where glenoid erosion occurs in patients with RC tears with secondary osteoarthritis. Weight bearing significantly increased GH translation and JRF. RC and deltoid muscle forces increased with the presence of RC tears and increased weight bearing. The remaining RC muscles of intact tendons compensated for the torn RC tendons but not for the altered CoF position. GH translation remained comparable to shoulders with intact RC. These findings highlight the importance of early detection, clinical management, and targeted rehabilitation strategies for patients with RC tears.

[Ruptured pulmonary Echinococcus granulosus cyst: A rare cause of severe pneumogenic sepsis]. / Rupturierte pulmonale Echinococcus granulosus-Zyste ­ Eine seltene Ursache für eine schwere pneumogene Sepsis.

Parasitic infections by Echinococcus granulosus are rare in Germany, and predominantly affect individuals with a migration background. Liver and lungs are the most commonly affected organs. Pulmonary cysts often remain asymptomatic until rupture, at which point symptoms may manifest. The diagnostic approach typically involves a combination of imaging modalities and serological tests, occasionally supplemented by molecular genetic methods. Given the global movements of migration, considerations of the epidemiology of common diseases in the country of origin should also be taken into account in the differential diagnosis. We present the unusual case of a pneumogenic sepsis in a young man from Syria, where the combination of medical history alongside radiological, serological, and molecular genetic investigations ultimately led to the diagnosis of a severe pulmonary echinococcosis with rupture.

Microsurgical central lymphatic reconstruction-the role of thoracic duct lymphovenous anastomoses at different anatomical levels.

Introduction: In recent years advances have been made in the microsurgical treatment of congenital or acquired central lymphatic lesions. While acquired lesions can result from any surgery or trauma of the central lymphatic system, congenital lymphatic lesions can have a variety of manifestations, ranging from singular thoracic duct abnormalities to complex multifocal malformations. Both conditions may cause recurrent chylous effusions and downstream lymphatic congestion depending on the anatomical location of the thoracic duct lesion and are associated with an increased mortality due to the permanent loss of protein and fluid. Methods: We present a case series of eleven patients undergoing central lymphatic reconstruction, consisting of one patient with a cervical iatrogenic thoracic duct lesion and eleven patients with different congenital thoracic duct lesions or thrombotic occlusions. Results: Anastomosis of the thoracic duct and a nearby vein was performed on different anatomical levels depending on the underlying central lymphatic pathology. Cervical (n = 4), thoracic (n = 1) or abdominal access (n = 5) was used for central lymphatic reconstruction with promising results. In 9 patients a postoperative benefit with varying degrees of symptom regression was reported. Conclusion: The presented case series illustrates the current rapid advances in the field of central microsurgical reconstruction of lymphatic lesions alongside the relevant literature.

Neutrophil-specific expression of JAK2-V617F or CALRmut induces distinct inflammatory profiles in myeloproliferative neoplasia.

BACKGROUND: Neutrophils play a crucial role in inflammation and in the increased thrombotic risk in myeloproliferative neoplasms (MPNs). We have investigated how neutrophil-specific expression of JAK2-V617F or CALRdel re-programs the functions of neutrophils. METHODS: Ly6G-Cre JAK2-V617F and Ly6G-Cre CALRdel mice were generated. MPN parameters as blood counts, splenomegaly and bone marrow histology were compared to wild-type mice. Megakaryocyte differentiation was investigated using lineage-negative bone marrow cells upon in vitro incubation with TPO/IL-1ß. Cytokine concentrations in serum of mice were determined by Mouse Cytokine Array. IL-1α expression in various hematopoietic cell populations was determined by intracellular FACS analysis. RNA-seq to analyse gene expression of inflammatory cytokines was performed in isolated neutrophils from JAK2-V617F and CALR-mutated mice and patients. Bioenergetics of neutrophils were recorded on a Seahorse extracellular flux analyzer. Cell motility of neutrophils was monitored in vitro (time lapse microscopy), and in vivo (two-photon microscopy) upon creating an inflammatory environment. Cell adhesion to integrins, E-selectin and P-selection was investigated in-vitro. Statistical analysis was carried out using GraphPad Prism. Data are shown as mean ± SEM. Unpaired, two-tailed t-tests were applied. RESULTS: Strikingly, neutrophil-specific expression of JAK2-V617F, but not CALRdel, was sufficient to induce pro-inflammatory cytokines including IL-1 in serum of mice. RNA-seq analysis in neutrophils from JAK2-V617F mice and patients revealed a distinct inflammatory chemokine signature which was not expressed in CALR-mutant neutrophils. In addition, IL-1 response genes were significantly enriched in neutrophils of JAK2-V617F patients as compared to CALR-mutant patients. Thus, JAK2-V617F positive neutrophils, but not CALR-mutant neutrophils, are pathogenic drivers of inflammation in MPN. In line with this, expression of JAK2-V617F or CALRdel elicited a significant difference in the metabolic phenotype of neutrophils, suggesting a stronger inflammatory activity of JAK2-V617F cells. Furthermore, JAK2-V617F, but not CALRdel, induced a VLA4 integrin-mediated adhesive phenotype in neutrophils. This resulted in reduced neutrophil migration in vitro and in an inflamed vessel. This mechanism may contribute to the increased thrombotic risk of JAK2-V617F patients compared to CALR-mutant individuals. CONCLUSIONS: Taken together, our findings highlight genotype-specific differences in MPN-neutrophils that have implications for the differential pathophysiology of JAK2-V617F versus CALR-mutant disease.

Severity of rotator cuff disorders and additional load affect fluoroscopy-based shoulder kinematics during arm abduction.

BACKGROUND: Rotator cuff disorders, whether symptomatic or asymptomatic, may result in abnormal shoulder kinematics (scapular rotation and glenohumeral translation). This study aimed to investigate the effect of rotator cuff tears on in vivo shoulder kinematics during a 30° loaded abduction test using single-plane fluoroscopy. MATERIALS AND METHODS: In total, 25 younger controls, 25 older controls and 25 patients with unilateral symptomatic rotator cuff tears participated in this study. Both shoulders of each participant were analysed and grouped on the basis of magnetic resonance imaging into healthy, rotator cuff tendinopathy, asymptomatic and symptomatic rotator cuff tears. All participants performed a bilateral 30° arm abduction and adduction movement in the scapular plane with handheld weights (0, 2 and 4 kg) during fluoroscopy acquisition. The range of upward-downward scapular rotation and superior-inferior glenohumeral translation were measured and analysed during abduction and adduction using a linear mixed model (loads, shoulder types) with random effects (shoulder ID). RESULTS: Scapular rotation was greater in shoulders with rotator cuff tendinopathy and asymptomatic rotator cuff tears than in healthy shoulders. Additional load increased upward during abduction and downward during adduction scapular rotation (P < 0.001 in all groups but rotator cuff tendinopathy). In healthy shoulders, upward scapular rotation during 30° abduction increased from 2.3° with 0-kg load to 4.1° with 4-kg load and on shoulders with symptomatic rotator cuff tears from 3.6° with 0-kg load to 6.5° with 4-kg load. Glenohumeral translation was influenced by the handheld weights only in shoulders with rotator cuff tendinopathy (P ≤ 0.020). Overall, superior glenohumeral translation during 30° abduction was approximately 1.0 mm with all loads. CONCLUSIONS: The results of glenohumeral translation comparable to control but greater scapular rotations during 30° abduction in the scapular plane in rotator cuff tears indicate that the scapula compensates for rotator cuff deficiency by rotating. Further analysis of load-dependent joint stability is needed to better understand glenohumeral and scapula motion. LEVEL OF EVIDENCE: Level 2. TRIAL REGISTRATION: Ethical approval was obtained from the regional ethics committee (Ethics Committee Northwest Switzerland EKNZ 2021-00182), and the study was registered at clinicaltrials.gov on 29 March 2021 (trial registration number NCT04819724, https://clinicaltrials.gov/ct2/show/NCT04819724 ).

Retinopathy of prematurity in Germany over 13 years: incidences, treatment preferences and effects of national guideline changes.

OBJECTIVE: Retinopathy of prematurity (ROP) is a leading yet avoidable cause of childhood blindness. Screening for ROP is highly effective in preventing blindness secondary to ROP. We provide epidemiological data on ROP screening and treatment in Germany since 2010 and evaluate the effects of recently adopted as well as potential future screening guideline adaptations. METHODS: Data sets of the German Quality Assurance Procedure in Neonatology, the ROP screening programme of two German university hospitals, and the German section of the EU-ROP Registry were analysed. RESULTS: Over the 13-year period from 2010 to 2022, 141 550 infants received ROP screening in Germany. Mean annual incidences of ROP were 3.5% (±0.2%) in premature infants and 19.6% (±2.3%) in screened infants. Of screened infants, 2.0% (±0.3%) received treatment for ROP. Treatment preferences shifted from laser coagulation (46.2% in 2015) to anti-vascular endothelial growth factor therapy (83.7% in 2022). A revision of national screening criteria in 2020 with a reduction of the gestational age limit from <32 to <31 weeks resulted in a decrease of the annual number of infants requiring screening by 25.8% (p<0.001). Infants with a birth weight ≥1500 g accounted for 35.2% of the screening population but only for 0.4% of ROP stage 3-5 cases. CONCLUSIONS: Collection of epidemiological data on ROP in national and international registries enables the continuous surveillance and adaptation of ROP screening and treatment criteria. In Germany, infants with a birth weight ≥1500 g have a very low risk of developing treatment-requiring ROP, supporting an upper birth weight limit for ROP screening.

Heart rate variability and stroke or systemic embolism in patients with atrial fibrillation.

BACKGROUND: Stroke remains one of the most serious complications in atrial fibrillation (AF) patients and has been linked to disturbances of the autonomic nervous system. OBJECTIVE: The purpose of this study was to test the hypothesis that impaired cardiac autonomic function might be associated with an enhanced stroke risk in AF patients. METHODS: A total of 1922 AF patients who were in either sinus rhythm (SR group; n = 1121) or AF (AF group; n = 801) on a 5-minute resting electrocardiographic (ECG) recording were enrolled in the study. Heart rate variability triangular index (HRVI), standard deviation of normal-to-normal intervals, root mean square root of successive differences of normal-to-normal intervals, mean heart rate, 5-minute total power, and power in the high-frequency, low-frequency, and very-low-frequency ranges were calculated. Cox regression models were constructed to examine the association of heart rate variability (HRV) parameters with the composite endpoint of stroke or systemic embolism. RESULTS: Mean age was 71 ± 8 years in the SR group and 75 ± 8 years in the AF group. Thirty-seven patients in the SR group (3.4%) and 60 patients in the AF group (8.0%) experienced a stroke or systemic embolism during follow-up of 5 years. In patients with SR, HRVI <15 was the strongest HRV parameter to be associated with stroke or systemic embolism (hazard ratio 3.04; 95% confidence interval 1.3-7.0; P = .009) after adjustment for multiple confounders. In the AF group, no HRV parameter was found to be associated with the composite endpoint. CONCLUSION: HRVI measured during SR on a single 5-minute ECG recording is independently associated with stroke or systemic embolism in AF patients. HRV analysis in SR may help to improve risk stratification in AF patients.

Long-term stimulation by implanted pacemaker enables non-atrophic treatment of bilateral vocal fold paresis in a human-like animal model.

A wide variety of treatments have been developed to improve respiratory function and quality of life in patients with bilateral vocal fold paresis (BVFP). One experimental method is the electrical activation of the posterior cricoarytenoid (PCA) muscle with a laryngeal pacemaker (LP) to open the vocal folds. We used an ovine (sheep) model of unilateral VFP to study the long-term effects of functional electrical stimulation on the PCA muscles. The left recurrent laryngeal nerve was cryo-damaged in all animals and an LP was implanted except for the controls. After a reinnervation phase of six months, animals were pooled into groups that received either no treatment, implantation of an LP only, or implantation of an LP and six months of stimulation with different duty cycles. Automated image analysis of fluorescently stained PCA cross-sections was performed to assess relevant muscle characteristics. We observed a fast-to-slow fibre type shift in response to nerve damage and stimulation, but no complete conversion to a slow-twitch-muscle. Fibre size, proportion of hybrid fibres, and intramuscular collagen content were not substantially altered by the stimulation. These results demonstrate that 30 Hz burst stimulation with duty cycles of 40% and 70% did not induce PCA atrophy or fibrosis. Thus, long-term stimulation with an LP is a promising approach for treating BVFP in humans without compromising muscle conditions.

Trace Analysis of C4F7N Insulating Gas Mixtures by Spontaneous Raman Spectroscopy and Gas Chromatography.

2,3,3,3-Tetrafluoro-2-(trifluoromethyl) propanenitrile (C4F7N) is being researched as an alternative to sulfur hexafluoride (SF6) for applications in gas-insulated switchgear. We independently assessed the effectiveness of gas chromatography-mass spectrometry (GC-MS) and a novel method of feedback-assisted multipass cavity spontaneous Raman spectroscopy (SRS) for the trace quantification of impurities in C4F7N and its related byproducts. A total of 14 gases were identified with estimated concentrations as low as 20 ppm (ppm) for C3F6 using GC-MS and 7.4 ppm for CH4 using SRS and as high as 500 ppm for CF4 using GC-MS and 1430 ppm for CO using SRS. While GC-MS is highly effective in selectively detecting and quantifying trace contaminants, it necessitates separate detectors for various gases, such as CH4 and H2. SRS succeeded in detecting CF4 and C2F6 at concentrations of 465 and 100 ppm, respectively, and in placing an upper bound of several hundred ppm for the other analytes. Crucially, SRS holds potential for portability-and thus for field applications-in gas-insulated switchgear equipment diagnostics.

Oncological and functional outcome after laryngectomy for laryngeal and hypopharyngeal cancer: a population-based analysis in Germany from 2001 to 2020.

Prognostic factors for overall survival (OS), percutaneous endoscopic gastrostomy (PEG) dependency, and long-term speech rehabilitation via voice prosthesis (VP) after laryngectomy for laryngeal or hypopharyngeal cancer were investigated in a retrospective population-based study in Thuringia, Germany. A total of 617 patients (68.7% larynx; hypopharynx; 31.3%; 93.7% men; median age 62 years; 66.0% stage IV) from 2001 to 2020 were included. Kaplan-Meier and Cox multivariable regression analyses were performed. 23.7% of patients received a PEG. 74.7% received a VP. Median OS was 131 months. Independent factors for lower OS were stage IV (compared to stage II; hazard ratio [HR] = 3.455; confidence interval [CI] 1.395-8.556) and laryngectomy for a recurrent disease (HR = 1.550; CI 1.078-2.228). Median time to PEG removal was 7 months. Prior partial surgery before laryngectomy showed a tendency for independent association for later PEG removal (HR = 1.959; CI 0.921-4.167). Postoperative aspiration needing treatment was an independent risk factor (HR = 2.679; CI 1.001-7.167) for later definitive VP removal. Laryngectomy continuously plays an important role in a curative daily routine treatment setting of advanced laryngeal or hypopharyngeal cancer in Germany. Long-term dependency on nutrition via PEG is an important issue, whereas use of VP is a stable long-term measure for voice rehabilitation.

ChatGPT-4 generates orthopedic discharge documents faster than humans maintaining comparable quality: a pilot study of 6 cases.

BACKGROUND AND PURPOSE: Large language models like ChatGPT-4 have emerged. They hold the potential to reduce the administrative burden by generating everyday clinical documents, thus allowing the physician to spend more time with the patient. We aimed to assess both the quality and efficiency of discharge documents generated by ChatGPT-4 in comparison with those produced by physicians. PATIENTS AND METHODS: To emulate real-world situations, the health records of 6 fictional orthopedic cases were created. Discharge documents for each case were generated by a junior attending orthopedic surgeon and an advanced orthopedic resident. ChatGPT-4 was then prompted to generate the discharge documents using the same health record information. The quality assessment was performed by an expert panel (n = 15) blinded to the source of the documents. As secondary outcome, the time required to generate the documents was compared, logging the duration of the creation of the discharge documents by the physician and by ChatGPT-4. RESULTS: Overall, both ChatGPT-4 and physician-generated notes were comparable in quality. Notably, ChatGPT-4 generated discharge documents 10 times faster than the traditional method. 4 events of hallucinations were found in the ChatGPT-4-generated content, compared with 6 events in the human/physician produced notes. CONCLUSION: ChatGPT-4 creates orthopedic discharge notes faster than physicians, with comparable quality. This shows it has great potential for making these documents more efficient in orthopedic care. ChatGPT-4 has the potential to significantly reduce the administrative burden on healthcare professionals.

Early-life vitamin A treatment rescues neonatal infection-induced durably impaired tolerogenic properties of celiac lymph nodes.

Gut-draining mesenteric and celiac lymph nodes (mLNs and celLNs) critically contribute to peripheral tolerance toward food and microbial antigens by supporting the de novo induction of regulatory T cells (Tregs). These tolerogenic properties of mLNs and celLNs are stably imprinted within stromal cells (SCs) by microbial signals and vitamin A (VA), respectively. Here, we report that a single, transient gastrointestinal infection in the neonatal, but not adult, period durably abrogates the efficient Treg-inducing capacity of celLNs by altering the subset composition and gene expression profile of celLNSCs. These cells carry information about the early-life pathogen encounter until adulthood and durably instruct migratory dendritic cells entering the celLN with reduced tolerogenic properties. Mechanistically, transiently reduced VA levels cause long-lasting celLN functional impairment, which can be rescued by early-life treatment with VA. Together, our data highlight the therapeutic potential of VA to prevent sequelae post gastrointestinal infections in infants.

Early postnatal high-dose fat-soluble enteral vitamin A supplementation for moderate or severe bronchopulmonary dysplasia or death in extremely low birthweight infants (NeoVitaA): a multicentre, randomised, parallel-group, double-blind, placebo-controlled, investigator-initiated phase 3 trial.

BACKGROUND: Vitamin A plays a key role in lung development, but there is no consensus regarding the optimal vitamin A dose and administration route in extremely low birthweight (ELBW) infants. We aimed to assess whether early postnatal additional high-dose fat-soluble enteral vitamin A supplementation versus placebo would lower the rate of moderate or severe bronchopulmonary dysplasia or death in ELBW infants receiving recommended basic enteral vitamin A supplementation. METHODS: This prospective, multicentre, randomised, parallel-group, double-blind, placebo-controlled, investigator-initiated phase 3 trial conducted at 29 neonatal intensive care units in Austria and Germany assessed early high-dose enteral vitamin A supplementation (5000 international units [IU]/kg per day) or placebo (peanut oil) for 28 days in ELBW infants. Eligible infants had a birthweight of more than 400 g and less than 1000 g; gestational age at birth of 32+0 weeks postmenstrual age or younger; and the need for mechanical ventilation, non-invasive respiratory support, or supplemental oxygen within the first 72 h of postnatal age after admission to the neonatal intensive care unit. Participants were randomly assigned by block randomisation with variable block sizes (two and four). All participants received basic vitamin A supplementation (1000 IU/kg per day). The composite primary endpoint was moderate or severe bronchopulmonary dysplasia or death at 36 weeks postmenstrual age, analysed in the intention-to-treat population. This trial was registered with EudraCT, 2013-001998-24. FINDINGS: Between March 2, 2015, and Feb 27, 2022, 3066 infants were screened for eligibility at the participating centres. 915 infants were included and randomly assigned to the high-dose vitamin A group (n=449) or the control group (n=466). Mean gestational age was 26·5 weeks (SD 2·0) and mean birthweight was 765 g (162). Moderate or severe bronchopulmonary dysplasia or death occurred in 171 (38%) of 449 infants in the high-dose vitamin A group versus 178 (38%) of 466 infants in the control group (adjusted odds ratio 0·99, 95% CI 0·73-1·55). The number of participants with at least one adverse event was similar between groups (256 [57%] of 449 in the high-dose vitamin A group and 281 [60%] of 466 in the control group). Serum retinol concentrations at baseline, at the end of intervention, and at 36 weeks postmenstrual age were similar in the two groups. INTERPRETATION: Early postnatal high-dose fat-soluble enteral vitamin A supplementation in ELBW infants was safe, but did not change the rate of moderate or severe bronchopulmonary dysplasia or death and did not substantially increase serum retinol concentrations. FUNDING: Deutsche Forschungsgemeinschaft and European Clinical Research Infrastructures Network (ECRIN).