VOC-based detection of prostate cancer using an electronic nose and ion mobility spectrometry: A novel urine-based approach.

BACKGROUND: Many diseases leave behind specific metabolites which can be detected from breath and urine as volatile organic compounds (VOC). Our group previously described VOC-based methods for the detection of bladder cancer and urinary tract infections. This study investigated whether prostate cancer can be diagnosed from VOCs in urine headspace. METHODS: For this pilot study, mid-stream urine samples were collected from 56 patients with histologically confirmed prostate cancer. A control group was formed with 53 healthy male volunteers matched for age who had recently undergone a negative screening by prostate-specific antigen (PSA) and digital rectal exam. Headspace measurements were performed with the electronic nose Cyranose 320TM. Statistical comparison was performed using principal component analysis, calculating Mahalanobis distance, and linear discriminant analysis. Further measurements were carried out with ion mobility spectrometry (IMS) to compare detection accuracy and to identify potential individual analytes. Bonferroni correction was applied for multiple testing. RESULTS: The electronic nose yielded a sensitivity of 77% and specificity of 62%. Mahalanobis distance was 0.964, which is indicative of limited group separation. IMS identified a total of 38 individual analytical peaks, two of which showed significant differences between groups (p < 0.05). To discriminate between tumor and controls, a decision tree with nine steps was generated. This model led to a sensitivity of 98% and specificity of 100%. CONCLUSIONS: VOC-based detection of prostate cancer seems feasible in principle. While the first results with an electronic nose show some limitations, the approach can compete with other urine-based marker systems. However, it seems less reliable than PSA testing. IMS is more accurate than the electronic nose with promising sensitivity and specificity, which warrants further research. The individual relevant metabolites identified by IMS should further be characterized using gas chromatography/mass spectrometry to facilitate potential targeted rapid testing.

Pilot study for bladder cancer detection with volatile organic compounds using ion mobility spectrometry: a novel urine-based approach.

PURPOSE: Despite many efforts, no reliable urinary marker system has so far shown the potential to substitute cystoscopy. Measuring volatile organic compounds (VOCs) from urine is a promising alternative. VOCs are metabolic products which can be measured from the headspace of urine samples. Previous studies confirmed that the urine of bladder tumor patients has a different VOC profile than healthy controls. In this pilot study, the feasibility of discriminating VOCs from urine of bladder cancer patients from that of healthy control subjects was investigated. Aim of this study was to investigate whether VOC-based diagnosis of bladder cancer from urine samples is feasible using multicapillary column ion mobility spectrometry (MCC/IMS) and to identify potential molecular correlates to the relevant analytes. METHODS: Headspace measurements of urine samples of 30 patients with confirmed transitional cell carcinoma (TCC) and 30 healthy controls were performed using MCC/IMS. In the results of the measurements, peaks showing significant differences between both groups were identified and implemented into a decision tree with respect to achieve group separation. Molecular correlates were predicted using a pre-defined dataset. RESULTS: Eight peaks with significantly differing intensity were identified, 5 of which were highly significant. Using a six-step decision tree, MCC/IMS showed a sensitivity of 90% and specificity of 100% in group separation. CONCLUSION: VOC-based detection of bladder cancer is feasible. MCC/IMS is a suitable method for urine-based diagnosis and should be further validated. The molecular characteristics and metabolic background of the analytes require further workup.

Impaired Sleep in Patients with Post-COVID-19 Syndrome Compared to Healthy Controls: A Cross-Sectional Trial.

INTRODUCTION: To objectify self-reported sleep disorders in individuals with post-COVID-syndrome (PCS), we aimed to investigate the prevalence and nature of sleep disturbances by polysomnography (PSG) in PCS compared to healthy individuals. METHODS: People with PCS (n = 21) and healthy controls (CON, n = 10) were included in this prospective trial. At baseline, clinical and social anamnesis, lung function, 1 min sit-to-stand test (STST) and Pittsburgh Sleep Quality Index (PSQI) were assessed. For a single-night, sleep health was evaluated by video-PSG. The apnoea/hypopnea index (AHI) was used as the primary outcome. RESULTS: Twenty patients with PCS (50 ± 11 y, BMI 27.1 m2/kg, SARS-CoV-2 infection 8.5 ± 4.5 months ago) and 10 CON participants (46 ± 10 y, BMI 23.0 m2/kg, no SARS-CoV-2 infection in the history) completed the study. Forced vital capacity (p = 0.018), STST repetitions (p < 0.001), and symptoms of dyspnoea (at rest: p = 0.002, exertion: p < 0.001) were worse in PCS compared to CON. PSQI score (PCS: 7.5 ± 4.7 points) was higher in PCS compared to CON (Δ = 3.7 points, 95% CI [0.4-7.1] p = 0.015), indicating poor sleep in 80% of patients with PCS. Although PSG showed comparable sleep stage distributions in both groups, AHI (Δ = 9.0 n/h, 95% CI [3.3-14.8], p = 0.002), PLM index (Δ = 5.1 n/h, 95% CI [0.4-9.8], p = 0.017), and the prevalence of sleep apnoea (60% vs. 10%, p = 0.028) was significantly higher in PCS compared to CON. CONCLUSION: Quantifiable subjective limitations of sleep have been revealed by PSG data in this PCS cohort. More than half of PCS patients had signs of sleep apnoea, highlighting the importance of sleep screening in PCS.

Automatic oxygen titration versus constant oxygen flow rates during walking in COPD: a randomised controlled, double-blind, crossover trial.

RATIONALE: In patients with COPD, oxygen (O2)-supplementation via a constant flow oxygen system (CFOS) can result in insufficient oxygen saturation (SpO2 <90%) during exercise. An automatically titrating O2-system (ATOS) has been shown to be beneficial compared with an untitrated CFOS, however, it is unknown if ATOS is superior to CFOS, titrated during exercise as stipulated by guidelines. The aim was to investigate the effects of ATOS compared with titrated CFOS on walking capacity in people with hypoxaemic COPD. METHODS: Fifty participants completed this prospective randomised controlled, double-blind, crossover trial. Participants performed two endurance shuttle walk tests (ESWTs) with: (1) exercise titrated CFOS (ESWTCFOS) and (2) ATOS targeting an SpO2 of 92% (ESWTATOS). Primary outcome measure was walking time. Secondary measures were SpO2, transcutaneous-PCO2 (TcPCO2), respiratory rate (RR), heart rate (HR) at isotime (end of shortest ESWT) with blood gases and dyspnoea at rest and end exercise. RESULTS: Participants (median (IQR): age 66 (59, 70) years, FEV1 28.8 (24.8, 35.1) % predicted, PO2 54.7 (51.0, 57.7) mm Hg, PCO2 44.2 (38.2, 47.8) mm Hg) walked significantly longer with ESWTATOS in comparison to ESWTCFOS (median effect (95% CI) +144.5 (54 to 241.5) s, p<0.001). At isotime, SpO2 was significantly higher (+3 (95% CI 1 to 4) %, p<0.001) with ATOS while TcPCO2, RR and HR were comparable. End exercise, PO2 (+8.85 (95% CI 6.35 to 11.9) mm Hg) and dyspnoea (-0.5 (95% CI -1.0 to -0.5) points) differed significantly in favour of ATOS (each p<0.001) while PCO2 was comparable. CONCLUSION: In patients with hypoxaemia with severe COPD the use of ATOS leads to significant, clinically relevant improvements in walking endurance time, SpO2, PO2 and dyspnoea with no impact on PCO2. TRIAL REGISTRATION NUMBER: NCT03803384.

Using a smartphone application maintains physical activity following pulmonary rehabilitation in patients with COPD: a randomised controlled trial.

BACKGROUND: Evidence suggests that patients with COPD struggle to maintain improved physical activity (PA) after completing pulmonary rehabilitation (PR). Smartphone applications (apps) providing a comprehensive training programme have conferred healthy benefits. This study was conducted to determine whether regular usage of an app maintains PA following PR. METHODS: Patients with stage II-IV COPD were enrolled in a 6-month trial following PR. After the screening period, participants were randomised into the Kaia COPD app group (intervention group (IG)) or the control group (CG). The primary outcome was PA (daily steps), measured using an activity tracker. Secondary outcomes included the COPD Assessment Test (CAT), the Chronic Respiratory Disease Questionnaire (CRQ) and the 1 min Sit-to-Stand Test (STST). RESULTS: Sixty participants completed the study. The median steps from baseline to 6 months were significantly different between the groups, in favour of the IG (-105.3, IQR -1970.1 to 2105.8, vs CG -1173.0, IQR -3813.1 to -93.8; p=0.007). CAT was significantly decreased in the IG (15.1±8.6 vs 19.7±6.4, p=0.02), whereas the CRQ subdomains for dyspnoea (4.5±1.7 vs 3.7±1.3, p=0.033) and fatigue (4.5±1.4 vs 3.5±1.3, p=0.028) improved significantly in the IG. The STST at 6 months was not significant. Sleep duration and sleep efficiency showed no significant differences between the two groups at any time. CONCLUSIONS: A comprehensive program by using the Kaia app following PR maintained PA and improved symptoms in patients with COPD at 6 months. The app might be an important accessory tool for enhanced COPD care. TRIAL REGISTRATION NUMBER: DRKS00017275.

Rehabilitative interventions in patients with persistent post COVID-19 symptoms-a review of recent advances and future perspectives.

The SARS-CoV-2 pandemic has not only caused millions of deaths but left also millions of people with persistent symptoms behind. These long-term COVID-19 sequelae cause a considerable burden on individuals´ health, healthcare systems, and economies worldwide given the high rate of SARS-CoV-2 infections. Therefore, rehabilitative interventions and strategies are needed to counteract the post COVID-19 sequelae. The importance of rehabilitation for patients with persistent COVID-19 symptoms has been recently also highlighted in a Call for Action by the World Health Organisation. Based on previously published research, but also in line with clinical experience, COVID-19 is not one specific disease but rather presents in different phenotypes that vary in their pathophysiological mechanisms, symptomatic manifestations, and potential interventional approaches. This review provides a proposal for differentiating post COVID-19 patients in non-organ-specific phenotypes that may help clinicians to evaluate patients and to plan therapeutic options. Furthermore, we present current unmet needs and suggest a potential pathway for a specific rehabilitation approach in people with persistent post-COVID symptoms.

[Updated S1 guideline on long/post-COVID: relevant aspects for pain medicine]. / Aktualisierte S1-Leitlinie Long/Post-COVID: Relevante Aspekte für die Schmerzmedizin.

BACKGROUND: The S1 guideline on long/post-COVID of the AWMF [German Association of the Medical Scientific Societies] registration number 020-027) was updated in August 2022. METHODS: Under the coordination of the German Society of Pneumology, the guideline was updated by 21 scientific associations, two professional associations and clinical centers each and one institute and statutory accident insurance each. Each scientific association was responsible for its own chapter. The German Pain Society prepared the chapter "Pain". The coordinators of each chapter performed a selective literature search and also received approval for the chapter within their scientific association. During an internal period of comments, all representatives of the participating institutions could comment on all chapters. The AWMF task force commented on the draft of the guideline, which was then finally approved by the boards of all participating institutions. RESULTS: Coronavirus disease 2019 (COVID-19) increases the risk of persistent headache and musculoskeletal pain. Long/Post-COVID pain is frequently associated with fatigue and cognitive problems. A specialist assessment might be considered if symptoms with limitations of daily activities persist 3 months after the infection. The diagnostic workup of long/post-COVID-associated pain should be performed according to the standards of pain medicine. Management should follow the pain guidelines of the AWMF. CONCLUSIONS: The updated S1 guideline on long/post-COVID is a clinical manual which offers orientation for diagnostics and treatment despite limited data.

[Pulmonary Rehabilitation]. / Pneumologische Rehabilitation.

Reduced exercise capacity, skeletal muscle dysfunction, and a physically inactive lifestyle are linked with symptoms of fatigue and dyspnea in people suffering from chronic lung disease. Numerous such extrapulmonary manifestations have been identified as treatable aspects of pulmonary rehabilitation (PR). PR is an extensive personalized non-pharmaceutical intervention, encompassing, but not limited to, exercise training, respiratory therapy, and education. The content and goals of a PR-program are based on a comprehensive patient assessment at the time of rehabilitation admission, with personalized therapies provided by a multidisciplinary team of healthcare professionals. This article provides an overview of PR including possible indications, therapy contents (e. g. exercise training, respiratory therapy), and evidence (COPD, interstitial lung disease, COVID-19). Finally, options for pulmonary rehabilitation maintenance services in Germany are presented.

[Diagnosis and treatment of asthma: a guideline for respiratory specialists 2023 - published by the German Respiratory Society (DGP) e. V.] / S2k-Leitlinie zur fachärztlichen Diagnostik und Therapie von Asthma 2023.

The management of asthma has fundamentally changed during the past decades. The present guideline for the diagnosis and treatment of asthma was developed for respiratory specialists who need detailed and evidence-based information on the new diagnostic and therapeutic options in asthma. The guideline shows the new role of biomarkers, especially blood eosinophils and fractional exhaled NO (FeNO), in diagnostic algorithms of asthma. Of note, this guideline is the first worldwide to announce symptom prevention and asthma remission as the ultimate goals of asthma treatment, which can be achieved by using individually tailored, disease-modifying anti-asthmatic drugs such as inhaled steroids, allergen immunotherapy or biologics. In addition, the central role of the treatment of comorbidities is emphasized. Finally, the document addresses several challenges in asthma management, including asthma treatment during pregnancy, treatment of severe asthma or the diagnosis and treatment of work-related asthma.

Technical Innovations in Pneumology: E-Health, Screening, Diagnostics, and Therapy.

At the 2020 "Luftschlösser" (castles in the air) conference, experts from a wide range of pneumological fields discussed technical innovations in pneumology, which can be seen in many different areas of the field, including e-health, screening, diagnostics, and therapy. They contribute to substantial advancements ranging from the innovative use of diagnostic tools to novel treatments for chronic lung diseases. Artificial intelligence enables broader screening, which can be expected to have beneficial effects on disease progression and overall prognosis. There is still a high demand for clinical trials to investigate the usefulness and risk-benefit ratio. Open questions remain especially about the quality and utility of medical apps in an inadequately regulated market. This article weighs the pros and cons of technical innovations in specific subspecialties of pneumology based on the lively exchange of ideas among various pneumological experts.

[Pulmonary Rehabilitation in Patients with Chronic Obstructive Airway Diseases]. / Pneumologische Rehabilitation bei chronisch obstruktiven Atemwegserkrankungen.

Pulmonary rehabilitation of asthma and COPD patients can improve their physical performance and quality of life, maintain participation in social and professional life and actively promote self-help. In addition, the resources for acute medical treatment can be spared. In case of COPD, rehabilitation directly after exacerbation can also improve the poor survival prognosis and reduce the risk of emergency hospital readmission. Therefore, pulmonary rehabilitation is an essential component of evidence-based long-term management of both bronchial asthma and, in particular, COPD. In the German healthcare system, however, pneumological rehabilitation is offered only for a small fraction of patients. Despite a very good evidence of pulmonary rehabilitation, especially in COPD patients, their share in all rehabilitation services is remarkably low. It does not even amount to 3 % of all medical rehabilitation measures approved by the German Pension Insurance.

[S1 Guideline Post-COVID/Long-COVID]. / S1-Leitlinie Post-COVID/Long-COVID.

The German Society of Pneumology initiated the AWMFS1 guideline Post-COVID/Long-COVID. In a broad interdisciplinary approach, this S1 guideline was designed based on the current state of knowledge.The clinical recommendation describes current post-COVID/long-COVID symptoms, diagnostic approaches, and therapies.In addition to the general and consensus introduction, a subject-specific approach was taken to summarize the current state of knowledge.The guideline has an expilcit practical claim and will be continuously developed and adapted by the author team based on the current increase in knowledge.

TMPRSS2 Is the Major Activating Protease of Influenza A Virus in Primary Human Airway Cells and Influenza B Virus in Human Type II Pneumocytes.

Cleavage of influenza virus hemagglutinin (HA) by host cell proteases is essential for virus infectivity and spread. We previously demonstrated in vitro that the transmembrane protease TMPRSS2 cleaves influenza A virus (IAV) and influenza B virus (IBV) HA possessing a monobasic cleavage site. Subsequent studies revealed that TMPRSS2 is crucial for the activation and pathogenesis of H1N1pdm and H7N9 IAV in mice. In contrast, activation of H3N2 IAV and IBV was found to be independent of TMPRSS2 expression and supported by an as-yet-undetermined protease(s). Here, we investigated the role of TMPRSS2 in proteolytic activation of IAV and IBV in three human airway cell culture systems: primary human bronchial epithelial cells (HBEC), primary type II alveolar epithelial cells (AECII), and Calu-3 cells. Knockdown of TMPRSS2 expression was performed using a previously described antisense peptide-conjugated phosphorodiamidate morpholino oligomer, T-ex5, that interferes with splicing of TMPRSS2 pre-mRNA, resulting in the expression of enzymatically inactive TMPRSS2. T-ex5 treatment produced efficient knockdown of active TMPRSS2 in all three airway cell culture models and prevented proteolytic activation and multiplication of H7N9 IAV in Calu-3 cells and H1N1pdm, H7N9, and H3N2 IAV in HBEC and AECII. T-ex5 treatment also inhibited the activation and spread of IBV in AECII but did not affect IBV activation in HBEC and Calu-3 cells. This study identifies TMPRSS2 as the major HA-activating protease of IAV in human airway cells and IBV in type II pneumocytes and as a potential target for the development of novel drugs to treat influenza infections.IMPORTANCE Influenza A viruses (IAV) and influenza B viruses (IBV) cause significant morbidity and mortality during seasonal outbreaks. Cleavage of the viral surface glycoprotein hemagglutinin (HA) by host proteases is a prerequisite for membrane fusion and essential for virus infectivity. Inhibition of relevant proteases provides a promising therapeutic approach that may avoid the development of drug resistance. HA of most influenza viruses is cleaved at a monobasic cleavage site, and a number of proteases have been shown to cleave HA in vitro This study demonstrates that the transmembrane protease TMPRSS2 is the major HA-activating protease of IAV in primary human bronchial cells and of both IAV and IBV in primary human type II pneumocytes. It further reveals that human and murine airway cells can differ in their HA-cleaving protease repertoires. Our data will help drive the development of potent and selective protease inhibitors as novel drugs for influenza treatment.

Effects of Vibration Training in Interstitial Lung Diseases: A Randomized Controlled Trial.

BACKGROUND: Numerous studies have reported positive effects of exercise training in patients with interstitial lung disease (ILD) on physical capacity and quality of life. However, evidence is rare on the effects of specific forms of training and further pathophysiological mechanisms in these patients. OBJECTIVES: In this multicenter study we aimed to explore the clinical effects of whole-body vibration training (WBVT) in patients with ILD on various outcome measures, including proinflammatory cytokines and myostatin. METHODS: We randomly assigned 26 patients with different forms of multidisciplinary confirmed fibrotic ILDs either to the WBVT group (n = 11; 55% male, 61 ± 14 years old, forced vital capacity 83.2 ± 29.3% predicted, 6-min walking distance [6MWD] 478 ± 79 m) performing 3 months of a standardized training (3 times per week), or to a control training group (CTG, n = 15; 60% male, 63 ± 9 years old, FVC 74.6 ± 20.5% predicted, 6MWD 455 ± 85 m) performing sham WBV training. Training in the two groups was performed on a GalileoTM vibration plate (6-20 vs. 5 Hz). The functional assessments before and after the intervention period included pulmonary function, 6MWD test, chair rise test, ultrasonographic measurement of quadriceps muscle thickness (cross-sectional area), quality of life questionnaires, and serum samples. RESULTS: We observed a significant increase in 6MWD (∆Training = 30 m [12-67], p = 0.024) and a decrease of myostatin (∆Training = -465 pg/mL [-713 to -166], p = 0.008) in the WBVT group. In contrast, no significant differences were observed in the CTG. CONCLUSIONS: The present study demonstrates that WBVT is able to significantly increase 6MWD and decrease myostatin in patients with fibrotic ILDs. Therefore, WBVT seems to be a beneficial and feasible training modality in ILD patients. Clinical Trial Registry: German Clinical Trials Registry (DRKS00012930).

VOC pattern recognition of lung cancer: a comparative evaluation of different dog- and eNose-based strategies using different sampling materials.

Background: It has been reported that canine scent tests offer the possibility to screen for cancer. Assuming that breath samples can be collected with carrier materials, we tested the practicability of different carrier materials to be presented to dogs and validated and compared results with an electronic nose (eNose). Moreover, we hypothesized that cancer detection ability of dogs differs according to their working experience. Methods: In a methodological approach, two dog teams participated, one using experienced working dogs and the other ordinary household dogs to find the most qualified dogs and training method. To find best carrier material for breath sampling we compared charcoal containing glass tubes and fleece masks. In a second validating part, experienced working dogs were trained with improved training strategies. For breath sampling, two different, previously successfully tested fleece-based carrier materials were used: one was used with the dog team and both materials were compared with eNose. Results: In the methodological approach, it turned out that the charcoal-based sampling strategy qualified not sufficiently for VOC-detection. Moreover, we could determine that using experienced working dogs provided several advantages. Overall results of dogs in the validating part regarding specificity were 83%, regarding sensitivity 56%, but with great variability among dogs. Using eNose for breath analysis collected with both fleece carrier materials, specificity was 97% and sensitivity 89-100%. Conclusion: Our data confirmed that the diagnostic accuracy of dogs depended on the type of dog training and on the carrier materials. A comparison of breath samples analysis with an eNose achieved better results for both, sensitivity and specificity than for dogs. The use of fleece masks or fleeces in glass tubes as a sampling material can be recommended as successful VOC carriers, encouraging their use for clinical screenings.

Comparison of continuous flow versus demand oxygen delivery systems in patients with COPD: A systematic review and meta-analysis.

Demand oxygen delivery systems (DODS) enable prolongation of liquid oxygen cylinder life compared to continuous oxygen flow (CONT) use. Evidence is lacking, however, regarding their efficacy. This study investigated the literature comparing liquid-based CONT to DODS in patients with chronic obstructive pulmonary disease (COPD). Four electronic databases were searched from 1980 until January 2018. Primary outcomes were oxyhaemoglobin saturation (SpO2 %) at rest and during exercise and exercise performance. Risk of bias was evaluated using the Cochrane tool. Data were analysed via meta-analysis where possible using the generic inverse variance method in Revman 5.3 or narrative synthesis. Ten crossover trials involving 152 patients with moderate to severe COPD (forced expiratory volume in 1 s (FEV1 ) range: 27-42% predicted) were included. There was a large degree of uncertainty regarding potential bias related to allocation concealment and blinding for all studies. Data from three studies (n = 44) showed no significant differences between DODS and CONT in terms of SpO2 % at rest -0.2% (95% CI: -0.5% to 0.1%) or during exercise -0.3% (95% CI: -2.1% to 1.5%). The pooled mean difference of two studies (n = 56) in 6-min walk distance was 5.7 m (95% CI: -14.4 to 25.8 m). Findings were consistent between the meta-analysis and narrative synthesis. These findings from a limited number of studies suggest oxygen delivery via DODS or CONT confers similar effects in terms of SpO2 % or exercise performance in patients with COPD. However, as DODS devices use various specifications that may yield large intra-individual differences, individual SpO2 % testing appears advisable for those considering DODS use.

α1-antitrypsin mitigates NLRP3-inflammasome activation in amyloid ß1-42-stimulated murine astrocytes.

BACKGROUND: Neuroinflammation has an essential impact on the pathogenesis and progression of Alzheimer's disease (AD). Mostly mediated by microglia and astrocytes, inflammatory processes lead to degeneration of neuronal cells. The NLRP3-inflammasome (NOD-like receptor family, pyrin domain containing 3) is a key component of the innate immune system and its activation results in secretion of the proinflammatory effectors interleukin-1ß (IL-1ß) and interleukin-18 (IL-18). Under physiological conditions, cytosolic NLRP3-inflammsome is maintained in an inactive form, not able to oligomerize. Amyloid ß1-42 (Aß1-42) triggers activation of NLRP3-inflammasome in microglia and astrocytes, inducing oligomerization and thus recruitment of proinflammatory proteases. NLRP3-inflammasome was found highly expressed in human brains diagnosed with AD. Moreover, NLRP3-deficient mice carrying mutations associated with familial AD were partially protected from deficits associated with AD. The endogenous protease inhibitor α1-antitrypsin (A1AT) is known for its anti-inflammatory and anti-apoptotic properties and thus could serve as therapeutic agent for NLRP3-inhibition. A1AT protects neurons from glutamate-induced toxicity and reduces Aß1-42-induced inflammation in microglial cells. In this study, we investigated the effect of Aß1-42-induced NLRP3-inflammasome upregulation in primary murine astrocytes and its regulation by A1AT. METHODS: Primary cortical astrocytes from BALB/c mice were stimulated with Aß1-42 and treated with A1AT. Regulation of NLRP3-inflammasome was examined by immunocytochemistry, PCR, western blot and ELISA. Our studies included an inhibitor of NLRP3 to elucidate direct interactions between A1AT and NLRP3-inflammasome components. RESULTS: Our study revealed that A1AT reduces Aß1-42-dependent upregulation of NLRP3 at the mRNA and protein levels. Furthermore, A1AT time-dependently mitigated the expression of caspase 1 and its cleavage product IL-1ß in Aß1-42-stimulated astrocytes. CONCLUSION: We conclude that Aß1-42-stimulation results in an upregulation of NLRP3, caspase 1, and its cleavage products in astrocytes. A1AT time-dependently hampers neuroinflammation by downregulation of Aß1-42-mediated NLRP3-inflammasome expression and thus may serve as a pharmaceutical opportunity for the treatment of Alzheimer's disease.

The prevalence of diagnosed α1-antitrypsin deficiency and its comorbidities: results from a large population-based database.

α1-Antitrypsin deficiency (AATD) is a genetically determined disorder that is associated with different clinical manifestations. We aimed to assess the prevalence of diagnosed AATD and its comorbidities using a large healthcare database.In this retrospective longitudinal observational study, we analysed data from 4 million insurants. Using International Classification of Diseases revision 10 (ICD-10) codes, we assessed the prevalence, comorbidities and healthcare utilisation of AATD patients (E88.0 repeatedly coded) relative to non-AATD patients with chronic obstructive pulmonary disease (COPD), emphysema or asthma.In our study population, we identified 673 AATD patients (590 aged ≥30 years), corresponding to a prevalence of 23.73 per 100 000 in all age groups and 29.36 per 100 000 in those ≥30 years. Based on the number of AATD cases detected in the sample size (673 out of 2 836 585), we extrapolated that there were 19 162 AATD cases in Germany during the years studied. AATD patients had a higher prevalence of arterial hypertension, chronic kidney disease and diabetes relative to non-AATD asthma or emphysema patients. When compared to non-AATD COPD patients, AATD patients had significantly more consultations and more frequent and longer hospitalisations.Our data strengthen the assumption that AATD is associated with a variety of other diseases. Healthcare utilisation appears to be higher among AATD patients as compared to patients with non-AATD-related obstructive lung diseases.

Effect of a Three-Week Inpatient Rehabilitation Program on 544 Consecutive Patients with Very Severe COPD: A Retrospective Analysis.

BACKGROUND: Pulmonary rehabilitation improves exercise capacity, symptoms, and quality of life in chronic obstructive pulmonary disease (COPD) patients, and is therefore recommended in all stages of the disease. However, there are insufficient data on patients with very severe disease. OBJECTIVE: To describe the effect of an in-house multidisciplinary pulmonary rehabilitation program on patients with very severe COPD. METHODS: We performed a retrospective analysis of 544 consecutive patients with very severe COPD (FEV1 0.97 ± 0.26 l) that underwent an in-house pulmonary rehabilitation program (23.44 ± 4.97 days). The studied outcome parameters were the 6-min walk test (6-MWT), health-related quality of life as analyzed by the COPD Assessment Test (CAT) and a dyspnea score [modified Medical Research Council (mMRC) scale], and lung function [forced expiratory volume in 1 s (FEV1) and residual volume (RV)]. RESULTS: We found significant improvements regarding 6-MWT scores (from 321.93 ± 115.67 to 365.82 ± 111.79 m; p < 0.001), CAT scores (from 23.21 ± 6.75 to 19.57 ± 7.35; p < 0.001), mMRC scale scores (from 3.17 ± 1.14 to 2.81 ± 1.22; p < 0.001), and FEV1 (from 0.97 ± 0.26 to 1.08 ± 0.33 l; p < 0.001). A number of baseline variables were significantly correlated with the improvements that occurred during the program (Δ): baseline 6-MWT with Δ6-MWT (r = -0.316; p < 0.001), baseline CAT with ΔCAT (r = -0.302; p < 0.001), baseline mMRC with ΔmMRC (r = -0.444; p < 0.001), and baseline RV with ΔRV (r = -0.284; p < 0.001), demonstrating that improvements were more pronounced in patients with worse baseline characteristics. Patients on long-term oxygen therapy (LTOT) exhibited significantly greater improvements regarding CAT than patients not on LTOT. CONCLUSION: Patients with very severe COPD exhibit clinically meaningful improvements when undergoing pulmonary rehabilitation.