Tuberculosis disease in immunocompromised children and adolescents: a pTBnet multi-centre case-control study.

BACKGROUND: In high-resource settings the survival of immunocompromised (IC) children has increased and immunosuppressive therapies are increasingly being used. This study aimed to determine the clinical characteristics, performance of diagnostic tools and outcome of IC children with TB in Europe. METHODS: Multicentre, matched case-control study within the Paediatric Tuberculosis Network European Trials Group (ptbnet), capturing TB cases <18 years diagnosed 2000-2020. RESULTS: 417 TB cases were included, comprising 139 children with IC (HIV, inborn errors of immunity, drug-induced immunosuppression and other immunocompromising conditions) and 278 non-IC children as controls. Non-respiratory TB was more frequent among cases than controls (32.4% vs. 21.2%; p = 0.013). IC patients had an increased likelihood of presenting with severe disease (57.6% vs. 38.5%; p < 0.001; OR [95% CI]: 2.073 [1.37-3.13]). Children with IC had higher rates of false-negative tuberculin skin test (31.9% vs. 6.0%; p < 0.001) and QuantiFERON-TB Gold assay (30.0% vs. 7.3%; p < 0.001) results at diagnosis. Overall, the microbiological confirmation rate was similar in IC and non-IC cases (58.3% vs. 49.3%; p = 0.083). Although the mortality in IC children was <1%, the rate of long-term sequelae was significantly higher than in non-IC cases (14.8% vs. 6.1%; p = 0.004). CONCLUSIONS: IC children with TB disease in Europe have increased rates of non-respiratory TB, severe disease, and long-term sequelae. Immune-based TB tests have poor sensitivity in those children. Future research should focus on developing improved immunological TB tests that perform better in IC patients, and determining the reasons for the increased risk of long-term sequelae, with the aim to design preventive management strategies.

[Medical societies in Germany call for a ban on flavors in e-cigarettes - A Position Paper of the German Respiratory Society (DGP) in cooperation with other professional associations and organizations]. / Medizinische Fachgesellschaften fordern ein Verbot von Aromen in E-Zigaretten.

E-cigarettes are primarily used by teenagers and young adults. Flavors in e-cigarettes increase their attractiveness and encourage young people and adults to start using them. This exposes young people in particular to the risk of nicotine addiction and various toxic substances from the aerosol of e-cigarettes. There are indications that various flavors in e-cigarettes are harmful to health, although toxicological studies are still lacking for the majority of flavors. There is a need for independent scientific investigations in this area. The scientific societies involved are calling for a ban on flavors in e-cigarettes, a ban on disposable e-cigarettes, effective regulation of the sale of e-cigarettes and effective control and implementation of the provisions for the protection of minors.

Longitudinal changes in habitual physical activity in adult people with cystic fibrosis in the presence or absence of treatment with elexacaftor/tezacaftor/ivacaftor.

Background: Habitual physical activity (PA) and exercise training are accepted as important aspects of care for people with cystic fibrosis (pwCF) to improve health-related measures of physical fitness, which in turn have a positive impact on quality of life and prognosis. In the last decade, effective CFTR modulator therapies have become a promising treatment for pwCF by targeting the underlying cause of CF. This highly effective therapy improves clinical outcomes and quality of life in people with specific CFTR mutations. Little is known about the longitudinal pattern of PA or the impact of the highly effective modulator therapy with Elexacaftor/Tezacaftor/Ivacaftor (ETI) on PA in adult pwCF. This study assessed the course of device-based PA measurement in adult pwCF and evaluated the effects of ETI on habitual physical activity in those who were eligible for ETI. Methods: Data from adult pwCF (aged ≥18 years) were analysed at baseline and follow-up, using identical assessments at both time points. Outcome parameters were PA in steps/day and the intensity of PA. The group that received ETI was treated for an average of 33 weeks and not for the entire duration of the period. The data were collected between 2021 and 2022, following the removal of absolute pandemic restrictions/lockdowns. Results: Follow-up duration was 5.6 years in pwCF with ETI (ETI group, n = 21) and 6.5 years in pwCF without ETI (non-ETI group, n = 6). From baseline to follow-up, pwCF treated with ETI had a significant increase in steps/day (+25%, p = 0.019) and a non-significant increase in moderate-to-vigorous intensity time (+5.6%, p = 0.352). Conversely, individuals in the non-ETI group showed a non-significant decrease in both steps/day -3.2%, p = 0.893) and moderate-to-vigorous intensity time (-25%, p = 0.207). The ETI group showed a significant decrease in percent predicted forced expiratory volume in 1 s (ppFEV1) and FEV1 z-score before the start of ETI treatment, both of which improved significantly after therapy initiation. Body weight and body mass index also improved significantly with ETI use. Conclusions: These data suggest that ETI treatment has a positive effect on habitual physical activity behavior in the adult pwCF studied.

Longitudinal Evaluation of Physical Fitness in Adults with Cystic Fibrosis in the Era of CFTR-Modulating-Therapies.

Purpose: Maintaining physical fitness plays an important role in the management of people with cystic fibrosis (pwCF). Longitudinal data on the course of physical fitness and the potential impact of the introduction of highly effective CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor (ETI) in adult pwCF are scarce. Methods: Health-related and skill-related components of physical fitness were assessed using an incremental cycle test (Wpeak), plus forward bend (FB), prone bent knee hip extension (HE), plank leg raise (PLR), standing long jump (SLJ), and standing on one leg (OLS). Relevant disease-specific clinical data (body mass index [BMI] and forced expiratory volume in 1 second [FEV1]) were recorded. Results: Twenty-eight adult pwCF (age 26.0 ± 7.8 years) were followed over 5.6 ± 0.9 years; 21 started ETI therapy during this period. Significant improvements from baseline were noted in BMI (p < 0.001) and health-related fitness components (HE, p = 0.002; PLR, p = < 0.001), whereas Wpeak and FB remained stable over time (all p > 0.05). Skill-related components (SLJ, OLS) showed no change (all p > 0.05). Subgroup analysis revealed significant improvements in BMI, FEV1, and health-related fitness measures of muscular strength and endurance (HE, p = 0.009; PLR, p < 0.001) only in pwCF using ETI. Conclusion: Despite the improvements, the impact of ETI on the individual parameters was small. Other factors than implementation of ETI alone need to be considered on the way to a high level of physical fitness in adult pwCF.

Prevalence of infectious diseases, immunity to vaccine-preventable diseases and chronic medical conditions among Ukrainian refugees in Germany - A cross sectional study from the German Network University Medicine (NUM).

BACKGROUND: Vulnerability to infectious diseases in refugees is dependent on country of origin, flight routes, and conditions. Information on specific medical needs of different groups of refugees is lacking. We assessed the prevalence of infectious diseases, immunity to vaccine-preventable diseases, and chronic medical conditions in children, adolescents, and adult refugees from Ukraine who arrived in Germany in 2022. METHODS: Using different media, we recruited Ukrainian refugees at 13 sites between 9-12/2022. An antigen test for acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection, serologies for a range of vaccine-preventable diseases, as well as interferon gamma release assays (IGRAs) for tuberculosis (TB), and SARS-CoV-2 were performed. We assessed personal and family history of chronic medical conditions, infectious diseases, vaccination status, and conditions during migration. RESULTS: Overall, 1793 refugees (1401 adults and 392 children/adolescents) were included. Most participants were females (n = 1307; 72·3%) and from Eastern or Southern Ukraine. TB IGRA was positive in 13% (n = 184) of the adults and in 2% (n = 7) of the children. Serology-based immunological response was insufficient in approximately 21% (360/1793) of the participants for measles, 32% (572/1793) for diphtheria, and 74% (1289/1793) for hepatitis B. CONCLUSIONS: We show evidence of low serological response to vaccine-preventable infections and increased LTBI prevalence in Ukrainian refugees. These findings should be integrated into guidelines for screening and treatment of infectious diseases in migrants and refugees in Germany and Europe. Furthermore, low immunity for vaccine-preventable diseases in Ukrainians independent of their refugee status, calls for tailor-made communication efforts.

TB or not TB? Diagnostic Sensitivity, Specifity and Interobserver Agreement in the Radiological Diagnosis of Pulmonary Tuberculosis in Children.

BACKGROUND: The differentiation between latent tuberculosis infection (LTBI) and tuberculosis (TB) relies on radiological changes. Confirming the diagnosis remains a challenge because typical findings are often missing in children. This study evaluates diagnostic sensitivity, specifity and interobserver agreement on the radiological diagnosis of TB by chest-x-rays in accordance to professional specialization and work experience. METHODS: Chest x-rays of 120 children with proven tuberculosis infection were independently evaluated by general radiologists, paediatric radiologists and paediatric pulmonologists. Results were compared to a reference diagnosis created by group of experienced paediatric radiologists and paediatric pulmonologists. Primary endpoints were diagnostic sensitivity and specificity and interobserver variability defined as Krippendorfs alpha of thesel groups compared to the reference diagnosis. RESULTS: Of the 120 chest x-rays 33 (27,5%) were diagnosed as TB by the reference standard . Paediatric pulmonologist had the highest diagnostic sensitivity (90%) but were less specific (71%) whereas general radiologist were less sensitive (68%) but more secific (95%). The best diagnostic accuracy was achieved by pediatric radiologists with a diagnostic sensitivity of 77% and specificity 95% respectively. CONCLUSIONS: We demonstrated significant interobserver variability and relevant differences in sensitivity and specificity in the radiological diagnosis of TB between the groups. Paediatric radiologists showed the best diagnostic performance. As the diagnosis of pulmonary TB has significant therapeutic consequences for children they should be routinely involved in the diagnostic process.

Long COVID in pediatrics-epidemiology, diagnosis, and management.

This review summarizes current knowledge on post-acute sequelae of COVID-19 (PASC) and post-COVID-19 condition (PCC) in children and adolescents. A literature review was performed to synthesize information from clinical studies, expert opinions, and guidelines. PASC also termed Long COVID - at any age comprise a plethora of unspecific symptoms present later than 4 weeks after confirmed or probable infection with severe respiratory syndrome corona virus type 2 (SARS-CoV-2), without another medical explanation. PCC in children and adolescents was defined by the WHO as PASC occurring within 3 months of acute coronavirus disease 2019 (COVID-19), lasting at least 2 months, and limiting daily activities. Pediatric PASC mostly manifest after mild courses of COVID-19 and in the majority of cases remit after few months. However, symptoms can last for more than 1 year and may result in significant disability. Frequent symptoms include fatigue, exertion intolerance, and anxiety. Some patients present with postural tachycardia syndrome (PoTS), and a small number of cases fulfill the clinical criteria of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). To date, no diagnostic marker has been established, and differential diagnostics remains challenging. Therapeutic approaches include appropriate self-management as well as the palliation of symptoms by non-pharmaceutical and pharmaceutical strategies.    Conclusion: PASC in pediatrics present with heterogenous severity and duration. A stepped, interdisciplinary, and individualized approach is essential for appropriate clinical management. Current health care structures have to be adapted, and research was extended to meet the medical and psychosocial needs of young people with PASC or similar conditions. What is Known: • Post-acute sequelae of coronavirus 2019 (COVID-19) (PASC) - also termed Long COVID - in children and adolescents can lead to activity limitation and reduced quality of life. • PASC belongs to a large group of similar post-acute infection syndromes (PAIS). Specific biomarkers and causal treatment options are not yet available. What is New: • In February 2023, a case definition for post COVID-19 condition (PCC) in children and adolescents was provided by the World Health Organization (WHO), indicating PASC with duration of at least 2 months and limitation of daily activities. PCC can present as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). • Interdisciplinary collaborations are necessary and have been established worldwide to offer harmonized, multimodal approaches to diagnosis and management of PASC/PCC in children and adolescents.

Necessity of Tobramycin trough Levels in Once Daily Iv-Treatment in Patients with Cystic Fibrosis.

BACKGROUND: Once daily intravenous (iv) treatment with tobramycin for Pseudomonas aeruginosa infection in patients with cystic fibrosis (pwCF) is frequently monitored by measuring tobramycin trough levels (TLs). Although the necessity of these TLs is recently questioned in pwCF without renal impairment, no study has evaluated this so far. The aim of this observational study was to evaluate the frequency of increased tobramycin TLs in pwCF treated with a once daily tobramycin dosing protocol. METHODS: Patient records of all consecutive once daily iv tobramycin courses in 35 pwCF between 07/2009 and 07/2019 were analyzed for tobramycin level, renal function, co-medication and comorbidity. RESULTS: Eight elevated TLs (2.9% of 278 courses) were recorded in four patients, two with normal renal function. One of these resolved without adjustment of tobramycin dosages suggesting a test timing or laboratory error. In the other patient the elevated tobramycin level decreased after tobramycin dosage adjustment. Six of the elevated levels occurred in two patients with chronic renal failure. In 15 other patients with reduced glomerular filtration rate (GFR) (36 courses) but normal range creatinine no case of elevated tobramycin trough levels was detected. Neither cumulative tobramycin dosages nor concomitant diabetes or nutritional status were risk factors for elevated TLs. CONCLUSION: Our data show that elevated tobramycin TLs are rare but cannot be excluded, so determination of tobramycin TLs is still recommended for safety.

Impact of habitual physical activity and exercise capacity on quality of life in adolescents and adults with cystic fibrosis.

BACKGROUND: The influence of habitual physical activity and exercise capacity on health-related quality of life (HRQoL) in people with cystic fibrosis (pwCF) is poorly characterized. This study investigated the influence of habitual physical activity, exercise capacity, lung function, and body mass index (BMI) on HRQoL in adolescent and adult pwCF. METHOD: Subjects were fitted with an accelerometer to determine habitual physical activity (steps/day), including time spent at different intensities, for up to 4 weeks. Then bicycle ergometry (maximal exercise capacity; Wpeak), lung function (percent predicted forced expiratory volume in 1 s, ppFEV1), BMI, and response to the Cystic Fibrosis Questionnaire-Revised (CFQ-R) were determined. RESULTS: Sixty-five pwCF participated in the study. Physically active pwCF had significantly higher ppFEV1 (p < .001) and exercise capacity (p < .001) than inactive pwCF, and had significantly higher scores on the CFQ-R physical (p = .006), emotional (p = .015), role (p = .008), health (p = .006), and weight (p = .004) subscales. On multiple linear regression analysis, ppFEV1 and, to a lesser extent, exercise capacity, were the most important determinants of HRQoL in pwCF. Time spent in moderate-to-vigorous intensity physical activity did not influence any of the CFQ-R subscales, whereas time spent in vigorous-intensity influenced CFQ-R scores for role (p = .007), body (p = .001), health (p = .009), and weight (p = .01). CONCLUSION: HRQoL in adolescent and adult pwCF was influenced by several factors. Avoiding sedentary behavior and spending time in vigorous-intensity levels positively influenced HRQoL, whereas the total number of steps per day played only a minor role in determining HRQoL. Both ppFEV1 and exercise capacity markedly influenced HRQoL.

Subjective Smell Disturbances in Children with Sars-Cov-2 or Other Viral Infections do not Correspond with Olfactory Test Results.

BACKGROUND: Olfactory dysfunction associated with SARS-CoV-2 infection in children has not been verified by a validated olfactory test. We aimed to determine whether these complaints are objectifiable (test-based hyposmia), how often they occur during acute SARS-CoV-2 infection compared to other upper respiratory tract infections (URTI), as well as in children recovered from COVID-19 compared to children with long COVID. METHODS: Olfactory testing (U-sniff test; hyposmia<8 points) and survey-based symptom assessments were performed in 434 children (5-17 years; 04/2021-06/2022). 186 symptom-free children served as controls. Of the children with symptoms of acute respiratory tract infection, SARS-CoV-2 PCR test results were positive in 45 and negative in 107 children (URTI group). Additionally, 96 children were recruited at least 4 weeks (17.6±15.2 weeks) after COVID-19, of whom 66 had recovered and 30 had developed long COVID. RESULTS: Compared to controls (2.7%), hyposmia frequency was increased in all other groups (11-17%, p<0.05), but no between-group differences were observed. Only 3/41 children with hyposmia reported complaints, whereas 13/16 children with complaints were normosmic, with the largest proportion being in the long-COVID group (23%, p<0.05). CONCLUSION: Questionnaires are unsuitable for assessing hyposmia frequency in children. Olfactory complaints and hyposmia are not specific for SARS-CoV-2 infection. The number of complaints in the long-COVID group could result from aversive olfactory perception, which is undetectable with the U-sniff test.

17q21 Variants Disturb Mucosal Host Defense in Childhood Asthma.

Rationale: The strongest genetic risk factor for childhood-onset asthma, the 17q21 locus, is associated with increased viral susceptibility and disease-promoting processes.Objectives: To identify biological targets underlying the escalated viral susceptibility associated with the clinical phenotype mediated by the 17q21 locus.Methods: Genome-wide transcriptome analysis of nasal brush samples from 261 children (78 healthy, 79 with wheezing at preschool age, 104 asthmatic) within the ALLIANCE (All-Age-Asthma) cohort, with a median age of 10.0 (range, 1.0-20.0) years, was conducted to explore the impact of their 17q21 genotype (SNP rs72163891). Concurrently, nasal secretions from the same patients and visits were collected, and high-sensitivity mesoscale technology was employed to measure IFN protein levels.Measurements and Main Results: This study revealed that the 17q21 risk allele induces a genotype- and asthma/wheeze phenotype-dependent enhancement of mucosal GSDMB expression as the only relevant 17q21-encoded gene in children with preschool wheeze. Increased GSDMB expression correlated with the activation of a type-1 proinflammatory, cell-lytic immune, and natural killer signature, encompassing key genes linked to an IFN type-2-signature (IFNG, CXCL9, CXCL10, KLRC1, CD8A, GZMA). Conversely, there was a reduction in IFN type 1 and type 3 expression signatures at the mRNA and protein levels.Conclusions: This study demonstrates a novel disease-driving mechanism induced by the 17q21 risk allele. Increased mucosal GSDMB expression is associated with a cell-lytic immune response coupled with compromised airway immunocompetence. These findings suggest that GSDMB-related airway cell death and perturbations in the mucosal IFN signature account for the increased vulnerability of 17q21 risk allele carriers to respiratory viral infections during early life, opening new options for future biological interventions.The All-Age-Asthma (ALLIANCE) cohort is registered at www.clinicaltrials.gov (pediatric arm, NCT02496468).

Estimates of protection levels against SARS-CoV-2 infection and severe COVID-19 in Germany before the 2022/2023 winter season: the IMMUNEBRIDGE project.

PURPOSE: Despite the need to generate valid and reliable estimates of protection levels against SARS-CoV-2 infection and severe course of COVID-19 for the German population in summer 2022, there was a lack of systematically collected population-based data allowing for the assessment of the protection level in real time. METHODS: In the IMMUNEBRIDGE project, we harmonised data and biosamples for nine population-/hospital-based studies (total number of participants n = 33,637) to provide estimates for protection levels against SARS-CoV-2 infection and severe COVID-19 between June and November 2022. Based on evidence synthesis, we formed a combined endpoint of protection levels based on the number of self-reported infections/vaccinations in combination with nucleocapsid/spike antibody responses ("confirmed exposures"). Four confirmed exposures represented the highest protection level, and no exposure represented the lowest. RESULTS: Most participants were seropositive against the spike antigen; 37% of the participants ≥ 79 years had less than four confirmed exposures (highest level of protection) and 5% less than three. In the subgroup of participants with comorbidities, 46-56% had less than four confirmed exposures. We found major heterogeneity across federal states, with 4-28% of participants having less than three confirmed exposures. CONCLUSION: Using serological analyses, literature synthesis and infection dynamics during the survey period, we observed moderate to high levels of protection against severe COVID-19, whereas the protection against SARS-CoV-2 infection was low across all age groups. We found relevant protection gaps in the oldest age group and amongst individuals with comorbidities, indicating a need for additional protective measures in these groups.

[Treatment of MDR, pre-XDR, XDR and rifampicin resistant tuberculosis or in case of intolerance to at least rifampicin in Austria, Germany and Switzerland - Amendment dated 19.09.2023 to the Sk2-Guideline: Tuberculosis in adulthood of the German Central Committee against Tuberculosis (DZK) on behalf of the German Respiratory Society (DGP)]. / Therapie bei MDR-, prä-XDR-, XDR-Tuberkulose und Rifampicin-Resistenz oder bei Medikamentenunverträglichkeit gegenüber mindestens Rifampicin.

In December 2022, based on the assessment of new evidence, the World Health Organization (WHO) updated its guidelines for the treatment of drug-resistant tuberculosis (TB). The evaluation of both, these recommendations, and the latest study data, makes it necessary to update the existing guidelines on the treatment of at least rifampicin-resistant tuberculosis for the German-speaking region, hereby replacing the respective chapters. A shortened MDR-TB treatment of at least 6 month using the fixed and non-modifiable drug combination of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) is now also recommended for Germany, Austria, and Switzerland under certain conditions. This recommendation applies to TB cases with proven rifampicin resistance, including rifampicin monoresistance. For treatment of pre-extensively drug resistant TB (pre-XDR-TB), an individualized treatment for 18 months adjusted to resistance data continues to be the primary recommendation. The non-modifiable drug combination of bedaquiline, pretomanid, and linezolid (BPaL) may be used alternatively in pre-XDR TB if all prerequisites are met. The necessary prerequisites for the use of BPaLM and BPaL are presented in this amendment to the S2k guideline for 'Tuberculosis in adulthood'.

Motivations for Adolescent COVID-19 Vaccination: A Comparative Study of Adolescent and Caregiver Perspectives in Germany.

Given the crucial role of vaccination in halting the COVID-19 pandemic, it is imperative to understand the factors that motivate adolescents to get vaccinated. We surveyed adolescents and their accompanying guardians scheduled to receive a COVID-19 vaccination (Comirnaty) in an urban region in Germany in mid-2021 regarding their motivation for getting vaccinated and collected data on their sociodemographic characteristics, medical history, vaccination status, and any history of COVID-19 infection in the family. We also queried information strategies related to the SARS-CoV-2 pandemic. Motivations for getting vaccinated were similar among adolescents and their parents. The primary reasons for vaccination were protection against SARS-CoV-2-related illness and gaining access to leisure facilities. This was not influenced by gender, health status, migration background, or the presence of chronic or acute diseases. The percentage of parents who had received SARS-CoV-2 immunization and the proportion of parents with a high level of education were higher among study participants than in the general population. Adolescents were especially willing to be vaccinated if they came from a better educational environment and had a high vaccination rate in the family. Emphasizing the importance of vaccination among all segments of the population and removing barriers to vaccines may lead to an ameliorated acceptance of COVID-19 vaccines.

Long-Term Follow-Up of Health-Related Quality of Life and Short-Term Intervention with CFTR Modulator Therapy in Adults with Cystic Fibrosis: Evaluation of Changes over Several Years with or without 33 Weeks of CFTR Modulator Therapy.

BACKGROUND: Longitudinal data on changes in health-related quality of life (HRQoL) in adult people with cystic fibrosis (pwCF) and the longitudinal effects of Elexacaftor/Tezacaftor/Ivacaftor therapy (ETI) on HRQoL or HRQoL domains are currently scarce. This study aimed to investigate the effects of ETI on HRQoL and compare them with those of pwCF who did not receive highly effective CFTR modulators over a longer period. METHODS: Baseline assessment and follow-up data for 5.6 years in pwCF with (n = 21) and 6.5 years in pwCF without (n = 6) ETI (≥18 years) were evaluated. The assessment of HRQoL and clinical parameters was identical at both time points. HRQoL was assessed using the CFQ-R, and clinical outcomes included BMI, ppFEV1, and FEV1 z-score. RESULTS: ETI was found to improve all HRQoL domains at more than four points over time, and their increases were significant except for vitality, digestion, treatment burden, and social functioning (p < 0.05). Without ETI, psychosocial domains remained almost constant, whereas most physical domains decreased over time. CONCLUSIONS: The results of the present study show that ETI therapy has a positive effect on HRQoL and clinical outcomes over time but not in pwCF without ETI treatment. Furthermore, our results suggest that disease progression over time affects the physical domains of HRQoL more than the psychosocial domains. Due to the small sample size and the heterogeneity of the study population (CFTR mutation genotype), the results should be interpreted with some caution.

Impaired Nitric Oxide Synthetase Activity in Primary Ciliary Dyskinesia-Data-Driven Hypothesis.

Low nasal nitric oxide (nNO) is a typical feature of Primary Ciliary Dyskinesia (PCD). nNO is part of the PCD diagnostic algorithm due to its discriminative power against other lung diseases, such as cystic fibrosis (CF). However, the underlying pathomechanisms are elusive. To better understand NO dysregulation in PCD, the L-arginine/NO (Arg/NO) pathway in patients with PCD (pwPCD) and CF (pwCF) and in healthy control (HC) subjects was investigated. In a prospective, controlled study, we measured in 24 pwPCD, 25 age-matched pwCF, and 14 HC the concentrations of the NO precursors Arg and homoarginine (hArg), the arginase metabolite ornithine (Orn), the NO inhibitor asymmetric dimethylarginine (ADMA), and the major NO metabolites (nitrate, nitrite) in sputum, plasma, and urine using validated methods. In comparison to HC, the sputum contents (in µmol/mg) of L-Arg (PCD 18.43 vs. CF 329.46 vs. HC 9.86, p < 0.001) and of ADMA (PCD 0.055 vs. CF 0.015 vs. HC 0.010, p < 0.001) were higher. In contrast, the sputum contents (in µmol/mg) of nitrate and nitrite were lower in PCD compared to HC (nitrite 4.54 vs. 9.26, p = 0.023; nitrate 12.86 vs. 40.33, p = 0.008), but higher in CF (nitrite 16.28, p < 0.001; nitrate 56.83, p = 0.002). The metabolite concentrations in urine and plasma were similar in all groups. The results of our study indicate that PCD, unlike CF, is associated with impaired NO synthesis in the lung, presumably due to mechano-chemical uncoupling.

Pediatric multi-drug-resistant tuberculosis in Germany - diagnostic and therapeutic challenges of an "orphan disease".

Delay in diagnosing multidrug-resistant tuberculosis (MDR-pTB) in children prolongs time to effective treatment. Data on risk factors for pediatric MDR from low-incidence countries are scarce. Retrospective nationwide case-control study to analyze MDR-pTB cases in Germany between 2010 and 2020 in comparison to a drug-susceptible (DS)-pTB group. We included 52 MDR cases (24 tuberculosis (TB), 28 TB infection (TBI); mean age 7.3 years) and 56 DS cases (31 TB, 26 TBI; mean age 7.9 years). Groups were similar for sex, household size, and migration background. Compared to the DS group, more children with MDR were born in the Commonwealth of Independent States (CIS) (22% MDR-pTB vs. 13% DS-pTB, n.s.) and had more MDR index cases (94% MDR-pTB, 5% DS-pTB, p < 0.001). The interval between first healthcare contact and initiation of effective therapy was significantly longer in MDR-pTB (47 days) than in DS-pTB (11 days, p < 0.001), correlating with disease progression. Treatment for MDR-pTB was successful in 74%, but 22% experienced long-term adverse effects (e.g., hepatopathy, hearing loss). CONCLUSIONS: Close contact to MDR cases or birth in MDR-TB-high-incidence countries are risk factors for MDR-pTB. Early identification of potential MDR index cases by contact investigation, and susceptibility testing in children from high-burden MDR-TB countries are essential for timely diagnosis and treatment, reducing the severity of disease and treatment side effects. TRIAL REGISTRATION: Deutsches Register Klinischer Studien ( https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00023817 ), DRKS00023817, 2020-09-08. WHAT IS KNOWN: •Management of children with MDR-TB remains challenging due to difficulties in diagnosing MDR-TB (lack of information on MDR index case, lack of microbiological confirmation in paucibacillary disease). •Choice of treatment regimen and monitoring of side effects. WHAT IS NEW: •Children with an MDR-TB index or born in a MDR-TB-high-incidence country are at higher risk of developing MDR-TB in a low incidence country. •The time lag to initiate treatment in MDR-TB is longer than in DS-TB and MDR-TB treatment involves a higher risk of adverse effects in longer treatment regimens especially with injectables.

Impact of elexacaftor/tezacaftor/ivacaftor on lung function, nutritional status, pulmonary exacerbation frequency and sweat chloride in people with cystic fibrosis: real-world evidence from the German CF Registry.

Background: Treatment with elexacaftor/tezacaftor/ivacaftor (ETI) improves multiple clinical outcomes in people with cystic fibrosis (pwCF) with at least one F508del allele. This study evaluated the real-world impact of ETI on lung function, nutritional status, pulmonary exacerbation frequency, and sweat chloride concentrations in a large group of pwCF. Methods: This observational cohort study used data from the German CF Registry for pwCF who received ETI therapy and were followed up for a period of 12 months. Findings: The study included 2645 pwCF from 67 centres in Germany (mean age 28.0 ± 11.5 years). Over the first year after ETI was initiated, percent predicted forced expiratory volume in 1 s (ppFEV1) increased by 11.3% (95% confidence interval [CI] 10.8-11.8, p < 0.0001), body mass index (BMI) z-score increased by 0.3 (95% CI 0.3-0.4, p < 0.0001) in individuals aged 12 to <18 years and BMI in adults increased by 1.4 kg/m2 (95% CI 1.3-1.4, p < 0.0001), pulmonary exacerbations decreased by 75.9% (p < 0.0001) and mean sweat chloride concentration decreased by 50.9 mmol/L (95% CI -52.6, -49.3, p < 0.0001). Improvements in ppFEV1 over the first year of therapy were greater in pwCF who had not previously received cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy (12.6% [95% CI 11.9-13.4] vs. 9.7% [95% CI 9.0-10.5] in those with prior CFTR modulator treatment. Interpretation: These real-world data are consistent with the findings of randomised clinical trials, and support the use of ETI as a highly effective treatment option for pwCF who have at least one F508del allele. Funding: None.

Effects of Physical Activity in the High School Curriculum on Cardiovascular Health, Cognitive and Physical Performance.

Cardiovascular health at a young age has implications for preventing cardiovascular disease, and it is associated with improved physical and cognitive performance during the aging process. Sports are well known to prevent cardiovascular disease; however, school-based interventions have mostly been neglected. This cross-sectional study aimed to compare groups of high school students, stratified by the amount of physical activity in their high school curriculum and downtime. Comparisons concerning physical and cognitive performance and arterial stiffness were made. A total of 63 senior-year students were investigated. Arterial stiffness was assessed using the oscillometric technique with ArteriographTM detection. Three-kilometer and pendulum runs were conducted as typical training loads. Cognitive performance was evaluated via the visual and verbal memory and number connection tests. Regarding cognitive skills, extracurricular physical activity improved the number connection test in male participants (p = 0.004). For physical performance, female students with a sports-focused curriculum were faster in the 3 km run (p < 0.001). Concerning arterial stiffness, the measurements yielded a lower mean arterial pressure (p = 0.015) and aortic pulse wave velocity (p = 0.04) in male students with a sports-focused curriculum. In summary, extracurricular physical activity and enrollment in a sports-focused curriculum may be associated with lower cardiovascular risk due to lower arterial stiffness and better physical and cognitive abilities.

SARS-CoV-2 sero-immunity and quality of life in children and adolescents in relation to infections and vaccinations: the IMMUNEBRIDGE KIDS cross-sectional study, 2022.

PURPOSE: The study evaluates the effects on sero-immunity, health status and quality of life of children and adolescents after the upsurge of the Omicron variant in Germany. METHODS: This multicenter cross-sectional study (IMMUNEBRIDGE Kids) was conducted within the German Network University Medicine (NUM) from July to October 2022. SARS-CoV-2- antibodies were measured and data on SARS-CoV-2 infections, vaccinations, health and socioeconomic factors as well as caregiver-reported evaluation on their children's health and psychological status were assessed. RESULTS: 497 children aged 2-17 years were included. Three groups were analyzed: 183 pre-schoolchildren aged 2-4 years, 176 schoolchildren aged 5-11 years and 138 adolescents aged 12-18 years. Positive antibodies against the S- or N-antigen of SARS-CoV-2 were detected in 86.5% of all participants (70.0% [128/183] of pre-schoolchildren, 94.3% of schoolchildren [166/176] and 98.6% of adolescents [136/138]). Among all children, 40.4% (201/497) were vaccinated against COVID-19 (pre-schoolchildren 4.4% [8/183], schoolchildren 44.3% [78/176] and adolescents 83.3% [115/138]). SARS-CoV-2 seroprevalence was lowest in pre-school. Health status and quality of life reported by the parents were very positive at the time of the survey (Summer 2022). CONCLUSION: Age-related differences on SARS-CoV-2 sero-immunity could mainly be explained by differences in vaccination rates based on the official German vaccination recommendations as well as differences in SARS-CoV-2 infection rates in the different age groups. Health status and quality of life of almost all children were very good independent of SARS-CoV-2 infection and/or vaccination. TRIAL REGISTRATION: German Registry for Clinical Trials Identifier Würzburg: DRKS00025546 (registration: 11.09.2021), Bochum: DRKS00022434 (registration:07.08.2020), Dresden: DRKS 00022455 (registration: 23.07.2020).