[Effects of pulmonary rehabilitation on dysfunctional respiratory patterns in patients with uncontrolled asthma]. / Effekte der pneumologischen Rehabilitation auf dysfunktionale Atemmuster bei Patienten mit unkontrolliertem Asthma.

PURPOSE: Dysfunctional breathing patterns (DAM) are deviations from physiologic breathing patterns. DAM seem to be associated with lower asthma control. To date, it is unclear what effect inpatient rehabilitation can have on this problem. The aim of this work is to investigate the effect of pulmonary rehabilitation (PR) on DAM. METHODS: The data are based on a randomized controlled trial with a waiting control group. The intervention group (IG) received PR 4 weeks after application approval and the control group (KG) after 5 months. Dysfunctional breathing was assessed by Nijmegen-Questionnaire (NQ). Values ≥ 23 points indicate an existing DAM. Values at the end of rehabilitation (T2) and after three months (T3) were compared (analysis of covariance). Supplemental moderator analysis was performed to examine whether the effect of PR was related to baseline NQ scores. RESULTS: Significant differences in NQ score are found between IG (n=202) and KG (n=210) at T2 (AMD=10.5; 95%CI [9; 12]; d=1.4; p<0.001) and at T3 (AMD=5.8; 95%CI [4.3; 7.3]; d=0.8; p<0.001). There is an interaction effect between the difference in NQ score between the groups at T2 and baseline at T0 (b=5.6; 95%CI [2.2; 11.9]; p<0.001). At T3, this interaction effect was no longer detectable (b=4.5; 95%CI [-3.1; 14.1]; p=807). CONCLUSION: Inpatient, multimodality, and interdisciplinary PR is associated with significant and clinically relevant improvement in DAM both at discharge and 3 months later. In the short term, patients with existing DAM benefit more from PR than patients without DAM.

Quantum Optics Measurement Scheme for Quantum Geometry and Topological Invariants.

We show how a quantum optical measurement scheme based on heterodyne detection can be used to explore geometrical and topological properties of condensed matter systems. Considering a 2D material placed in a cavity with a coupling to the environment, we compute correlation functions of the photons exiting the cavity and relate them to the hybrid light-matter state within the cavity. Different polarizations of the intracavity field give access to all components of the quantum geometric tensor on contours in the Brillouin zone defined by the transition energy. Combining recent results based on the metric-curvature correspondence with the measured quantum metric allows us to characterize the topological phase of the material. Moreover, in systems where S_{z} is a good quantum number, the procedure also allows us to extract the spin Chern number. As an interesting application, we consider a minimal model for twisted bilayer graphene at the magic angle, and discuss the feasibility of extracting the Euler number.

[Patient-Reported Outcomes (PROs) 3 and 6 Months After Pulmonary Rehabilitation Following COVID-19]. / Patient-Reported Outcomes (PROs) 3 und 6 Monate nach pneumologischer Post-COVID-Rehabilitation.

PURPOSE: If COVID-19 disease sequelae also (co-)affect the respiratory organs, national and international guidelines recommend pulmonary rehabilitation (PR). So far, however, no studies are available from Germany on the course after PR, nor on possible course differences between the two Long COVID subgroups "Ongoing symptomatic COVID-19" and "Post-COVID-19 syndrome" (PCS). METHODS: In a prospective observational study, patient-reported outcomes (PROs) regarding exertional dyspnea, quality of life, pain, fatigue, depression, and anxiety were assessed at the beginning of PR (T1), end of PR (T2), and after 3 (T3) and 6 months (T4). Statistical analyses were performed using latent difference models. RESULTS: There were 224 rehabilitation patients (MAge=54.4; SDAge=10.4; 42.0% female) included in the study. During PR, all PROs improved significantly. After PR, improvements either persisted with large pre-post effect sizes (exertional dyspnea, quality of life), decreased slightly to small pre-post effect sizes (depression, fatigue), or decreased to baseline levels (anxiety, pain). PCS patients had greater burdens in depression, fatigue, and pain at baseline, but did not differ in trajectories. Indicators of the severity of the preceding acute phase (oxygen therapy, ICU treatment, ventilation) were associated with higher burdens at T0 in depression, fatigue, and pain, but not with the courses during and after PR. In contrast, female patients showed higher burdens in both depression and fatigue at T1 and higher pre-post effects than male patients. CONCLUSION: The fact that improvements in PROs occurred in both subgroups only during PR, but not during the follow-up period suggests that the changes are not due to the natural healing process but at least partly due to PR. Moreover, the results suggest that both patient groups may benefit from PR. Persisting improvements in exertional dyspnea and quality of life and, to a reduced extent, in depression and fatigue until 6 months after PR, but not in pain and anxiety warrant study of additional multimodal interventions that may be needed to maintain these effects.

Complementary CRISPR screen highlights the contrasting role of membrane-bound and soluble ICAM-1 in regulating antigen-specific tumor cell killing by cytotoxic T cells.

Cytotoxic CD8 +T lymphocytes (CTLs) are key players of adaptive anti-tumor immunity based on their ability to specifically recognize and destroy tumor cells. Many cancer immunotherapies rely on unleashing CTL function. However, tumors can evade killing through strategies which are not yet fully elucidated. To provide deeper insight into tumor evasion mechanisms in an antigen-dependent manner, we established a human co-culture system composed of tumor and primary immune cells. Using this system, we systematically investigated intrinsic regulators of tumor resistance by conducting a complementary CRISPR screen approach. By harnessing CRISPR activation (CRISPRa) and CRISPR knockout (KO) technology in parallel, we investigated gene gain-of-function as well as loss-of-function across genes with annotated function in a colon carcinoma cell line. CRISPRa and CRISPR KO screens uncovered 187 and 704 hits, respectively, with 60 gene hits overlapping between both. These data confirmed the role of interferon-γ (IFN-γ), tumor necrosis factor α (TNF-α) and autophagy pathways and uncovered novel genes implicated in tumor resistance to killing. Notably, we discovered that ILKAP encoding the integrin-linked kinase-associated serine/threonine phosphatase 2 C, a gene previously unknown to play a role in antigen specific CTL-mediated killing, mediate tumor resistance independently from regulating antigen presentation, IFN-γ or TNF-α responsiveness. Moreover, our work describes the contrasting role of soluble and membrane-bound ICAM-1 in regulating tumor cell killing. The deficiency of membrane-bound ICAM-1 (mICAM-1) or the overexpression of soluble ICAM-1 (sICAM-1) induced resistance to CTL killing, whereas PD-L1 overexpression had no impact. These results highlight the essential role of ICAM-1 at the immunological synapse between tumor and CTL and the antagonist function of sICAM-1.

[What do health care professionals know about advance directives?] / Was wissen Fachkräfte im Gesundheitswesen über Vorsorgedokumente?

BACKGROUND: Advance directives are important to preserve the autonomy of patients for future situations in which they are uncapable of expressing their will. They are considered helpful by many healthcare professionals in their professional practice. However, their knowledge on these documents is not well known. Misconceptions can adversely affect decisions at the end of life. This study examines healthcare professionals' knowledge of advance directives and relevant correlates. METHODS: In 2021 healthcare professionals from various professions and institutions in Wuerzburg were surveyed using a standardized questionnaire on previous experiences with, advice on and use of advance directives, as well as an objective knowledge test containing 30 questions. Apart from the descriptive analysis of single questions out of the knowledge test, various parameters were screened for their influence on knowledge level. RESULTS: 363 healthcare professionals from different care settings participated in the study, including physicians, social workers, nurses and emergency services personnel. 77.5% work in patient care, of which 39.8% make decisions based on living wills daily to several times a month. High rates of incorrect answers in the knowledge test show lack in knowledge about decisions concerning patients who are unable to give consent; an average of 18 out of 30 points was achieved. Physicians, male healthcare professionals and respondents with more personal experience regarding advance directives had significantly better results in the knowledge test. CONCLUSION: Healthcare professionals have ethically and practically relevant knowledge deficits and a high need for further training on advance directives. Advance directives play an important role in maintaining patient autonomy and should receive more attention in training and further education equally involving non-medical professional groups.

High-resolution transcriptomic and epigenetic profiling identifies novel regulators of COPD.

Patients with chronic obstructive pulmonary disease (COPD) are still waiting for curative treatments. Considering its environmental cause, we hypothesized that COPD will be associated with altered epigenetic signaling in lung cells. We generated genome-wide DNA methylation maps at single CpG resolution of primary human lung fibroblasts (HLFs) across COPD stages. We show that the epigenetic landscape is changed early in COPD, with DNA methylation changes occurring predominantly in regulatory regions. RNA sequencing of matched fibroblasts demonstrated dysregulation of genes involved in proliferation, DNA repair, and extracellular matrix organization. Data integration identified 110 candidate regulators of disease phenotypes that were linked to fibroblast repair processes using phenotypic screens. Our study provides high-resolution multi-omic maps of HLFs across COPD stages. We reveal novel transcriptomic and epigenetic signatures associated with COPD onset and progression and identify new candidate regulators involved in the pathogenesis of chronic lung diseases. The presence of various epigenetic factors among the candidates demonstrates that epigenetic regulation in COPD is an exciting research field that holds promise for novel therapeutic avenues for patients.

Application of human iPSC-derived macrophages in a miniaturized high-content-imaging-based efferocytosis assay.

Macrophages play a pivotal role in drug discovery due to their key regulatory functions in health and disease. Overcoming the limited availability and donor variability of human monocyte-derived macrophages (MDMs), human induced pluripotent stem cell (iPSC)-derived macrophages (IDMs) could provide a promising tool for both disease modeling and drug discovery. To access large numbers of model cells for medium- to high-throughput application purposes, an upscaled protocol was established for differentiation of iPSCs into progenitor cells and subsequent maturation into functional macrophages. These IDM cells resembled MDMs both with respect to surface marker expression and phago- as well as efferocytotic function. A statistically robust high-content-imaging assay was developed to quantify the efferocytosis rate of IDMs and MDMs allowing for measurements both in the 384- and 1536-well microplate format. Validating the applicability of the assay, inhibitors of spleen tyrosine kinase (Syk) were shown to modulate efferocytosis in IDMs and MDMs with comparable pharmacology. The miniaturized cellular assay with the upscaled provision of macrophages opens new routes to pharmaceutical drug discovery in the context of efferocytosis-modulating substances.

Continuous symmetry breaking in a two-dimensional Rydberg array.

Spontaneous symmetry breaking underlies much of our classification of phases of matter and their associated transitions1-3. The nature of the underlying symmetry being broken determines many of the qualitative properties of the phase; this is illustrated by the case of discrete versus continuous symmetry breaking. Indeed, in contrast to the discrete case, the breaking of a continuous symmetry leads to the emergence of gapless Goldstone modes controlling, for instance, the thermodynamic stability of the ordered phase4,5. Here, we realize a two-dimensional dipolar XY model that shows a continuous spin-rotational symmetry using a programmable Rydberg quantum simulator. We demonstrate the adiabatic preparation of correlated low-temperature states of both the XY ferromagnet and the XY antiferromagnet. In the ferromagnetic case, we characterize the presence of a long-range XY order, a feature prohibited in the absence of long-range dipolar interaction. Our exploration of the many-body physics of XY interactions complements recent works using the Rydberg-blockade mechanism to realize Ising-type interactions showing discrete spin rotation symmetry6-9.

Probing magnetic orbitals and Berry curvature with circular dichroism in resonant inelastic X-ray scattering.

Resonant inelastic X-ray scattering (RIXS) can probe localized excitations at selected atoms in materials, including particle-hole transitions between the valence and conduction bands. These transitions are governed by fundamental properties of the corresponding Bloch wave functions, including orbital and magnetic degrees of freedom, and quantum geometric properties such as the Berry curvature. In particular, orbital angular momentum (OAM), which is closely linked to the Berry curvature, can exhibit a nontrivial momentum dependence. We demonstrate how information on such OAM textures can be extracted from the circular dichroism in RIXS. Based on accurate modeling with a first-principles treatment of the key ingredient-the light-matter interaction-we simulate dichroic RIXS spectra for the prototypical transition-metal dichalcogenide MoSe2 and the two-dimensional topological insulator 1T'-MoS2. Guided by an intuitive picture of the optical selection rules, we discuss how the momentum-dependent OAM manifests itself in the dichroic RIXS signal if one controls the momentum transfer. Our calculations are performed for typical experimental geometries and parameter regimes, and demonstrate the possibility of observing the predicted circular dichroism in forthcoming experiments. Thus, our work establishes a new avenue for observing Berry curvature and topological states in quantum materials.

Negative association between fatigue and signs of sleep apnoea in patients after COVID-19.

Compared to the general population, there are increased apnoea-hypopnoea indices in patients recovering from #COVID19, yet there is a negative correlation to symptoms of fatigue and no significant correlation to daytime sleepiness https://bit.ly/3pEl9C8.

Rosa26-LSL-dCas9-VPR: a versatile mouse model for tissue specific and simultaneous activation of multiple genes for drug discovery.

Transgenic animals with increased or abrogated target gene expression are powerful tools for drug discovery research. Here, we developed a CRISPR-based Rosa26-LSL-dCas9-VPR mouse model for targeted induction of endogenous gene expression using different Adeno-associated virus (AAV) capsid variants for tissue-specific gRNAs delivery. To show applicability of the model, we targeted low-density lipoprotein receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9), either individually or together. We induced up to ninefold higher expression of hepatocellular proteins. In consequence of LDLR upregulation, plasma LDL levels almost abolished, whereas upregulation of PCSK9 led to increased plasma LDL and cholesterol levels. Strikingly, simultaneous upregulation of both LDLR and PCSK9 resulted in almost unaltered LDL levels. Additionally, we used our model to achieve expression of all α1-Antitrypsin (AAT) gene paralogues simultaneously. These results show the potential of our model as a versatile tool for optimized targeted gene expression, alone or in combination.

Identification of Broadly Applicable Adeno-Associated Virus Vectors by Systematic Comparison of Commonly Used Capsid Variants In Vitro.

Adeno-associated viruses (AAVs) represent highly attractive gene therapy vectors and potent research tools for the modulation of gene expression in animal models or difficult-to-transfect cell cultures. Engineered variants, comprising chimeric, mutated, or peptide-inserted capsids, have strongly broadened the utility of AAVs by altering cellular tropism, enabling immune evasion, or increasing transduction efficiency. In this work, the performance of 50 of the most used, predominantly published, AAVs was compared on several primary cells, cell lines, and induced pluripotent stem cell-derived models from different organs, including the adipose tissue, liver, lung, brain, and eyes. To identify the most efficient capsids for each cell type, self-complementary AAVs were standardized by digital polymerase chain reaction, arrayed on 96-well plates, and screened using high-content imaging. To enable best use of the data, all results are also provided in a web app. The utility of one selected AAV variant is further exemplified in a liver fibrosis assay based on primary hepatic stellate cells, where it successfully reversed a small interfering RNA (siRNA)-induced phenotype. Most importantly, our comparative analysis revealed that a subselection of only five AAV variants (AAV2.NN, AAV9-SLRSPPS, AAV6.2, AAV6TM, and AAV1P5) enabled efficient transduction of all tested cell types and markedly outperformed other well-established capsids, such as AAV2-7m8. These findings suggest that a core panel comprising these five capsid variants is a universally applicable and sufficient tool to identify potent AAVs for gene expression modulation in cellular systems.

Self-energy dynamics and the mode-specific phonon threshold effect in Kekulé-ordered graphene.

Electron-phonon interaction and related self-energy are fundamental to both the equilibrium properties and non-equilibrium relaxation dynamics of solids. Although electron-phonon interaction has been suggested by various time-resolved measurements to be important for the relaxation dynamics of graphene, the lack of energy- and momentum-resolved self-energy dynamics prohibits direct identification of the role of specific phonon modes in the relaxation dynamics. Here, by performing time- and angle-resolved photoemission spectroscopy measurements on Kekulé-ordered graphene with folded Dirac cones at the Γ point, we have succeeded in resolving the self-energy effect induced by the coupling of electrons to two phonons at Ω1 = 177 meV and Ω2 = 54 meV, and revealing its dynamical change in the time domain. Moreover, these strongly coupled phonons define energy thresholds, which separate the hierarchical relaxation dynamics from ultrafast, fast to slow, thereby providing direct experimental evidence for the dominant role of mode-specific phonons in the relaxation dynamics.

Experiences of family caregivers 3-months after stroke: results of the prospective trans-regional network for stroke intervention with telemedicine registry (TRANSIT-Stroke).

BACKGROUND: Long-term support of stroke patients living at home is often delivered by family caregivers (FC). We identified characteristics of stroke patients being associated with receiving care by a FC 3-months (3 M) after stroke, assessed positive and negative experiences and individual burden of FC caring for stroke patients and determined factors associated with caregiving experiences and burden of FC 3 M after stroke. METHODS: Data were collected within TRANSIT-Stroke, a regional telemedical stroke-network comprising 12 hospitals in Germany. Patients with stroke/TIA providing informed consent were followed up 3 M after the index event. The postal patient-questionnaire was accompanied by an anonymous questionnaire for FC comprising information on positive and negative experiences of FC as well as on burden of caregiving operationalized by the Caregiver Reaction Assessment and a self-rated burden-scale, respectively. Multivariable logistic and linear regression analyses were performed. RESULTS: Between 01/2016 and 06/2019, 3532 patients provided baseline and 3 M-follow-up- data and 1044 FC responded to questionnaires regarding positive and negative caregiving experiences and caregiving burden. 74.4% of FC were older than 55 years, 70.1% were women and 67.5% were spouses. Older age, diabetes and lower Barthel-Index in patients were significantly associated with a higher probability of receiving care by a FC at 3 M. Positive experiences of FC comprised the importance (81.5%) and the privilege (70.0%) of caring for their relative; negative experiences of FC included financial difficulties associated with caregiving (20.4%). Median overall self-rated burden was 30 (IQR: 0-50; range 0-100). Older age of stroke patients was associated with a lower caregiver burden, whereas younger age of FC led to higher burden. More than half of the stroke patients in whom a FC questionnaire was completed did self-report that they are not being cared by a FC. This stroke patient group tended to be younger, more often male with less severe stroke and less comorbidities who lived more often with a partner. CONCLUSIONS: The majority of caregivers wanted to care for their relatives but experienced burden at the same time. Elderly patients, patients with a lower Barthel Index at discharge and diabetes are at higher risk of needing care by a family caregiver. TRIAL REGISTRATION: The study was registered at "German Clinical Trial Register": DRKS00011696. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011696.

Decreased mental health, quality of life, and utilization of professional help in cancer patients with unexpressed needs: A longitudinal analysis.

BACKGROUND: Cancer patients' mental health and quality of life can be improved through professional support according to their needs. In previous analyses of the UNSAID study, we showed that a relevant proportion of cancer patients did not express their needs during the admission interview of inpatient rehabilitation. We now examine trajectories of mental health, quality of life, and utilization of professional help in cancer patients with unexpressed needs. METHODS: We enrolled 449 patients with breast, prostate, and colon cancer at beginning (T0) and end (T1) of a 3-week inpatient rehabilitation and 3 (T2) and 9 (T3) months after discharge. We explored depression (PHQ-2), anxiety (GAD-2), emotional functioning (EORTC QLQ-C30), fear of progression (FoP-Q-SF), and global quality of life (EORTC QLQ-C30) using structuring equation models. Furthermore, we evaluated self-reports about expressing needs and utilization of professional help at follow-up. RESULTS: Patients with unexpressed needs (24.3%, n = 107) showed decreased mental health compared to other patients (e.g., depression: d T0 = 0.32, d T1-T3 = 0.39). They showed a significant decline in global quality of life at discharge and follow-up (d = 0.28). Furthermore, they had a higher need for support (Cramer's V T2 = 0.10, T3 = 0.15), talked less about their needs (Cramer's V T2 = 0.18), and made less use of different health care services at follow-up. CONCLUSION: Unexpressed needs in cancer patients may be a risk factor for decreased mental health, quality of life, and non-utilization of professional help in the long term. Further research should clarify causal relationships and focus on this specific group of patients to improve cancer care.

Effectiveness of a Three-Week Inpatient Pulmonary Rehabilitation Program for Patients after COVID-19: A Prospective Observational Study.

For COVID-19 patients who remain symptomatic after the acute phase, pulmonary rehabilitation (PR) is recommended. However, only a few studies have investigated the effectiveness of PR, especially considering the duration between the acute phase of COVID-19 and the onset of rehabilitation, as well as the initial severity. This prospective observational study evaluated the efficacy of PR in patients after COVID-19. A total of 120 still-symptomatic patients referred for PR after overcoming acute COVID-19 were asked to participate, of whom 108 (mean age 55.6 ± 10.1 years, 45.4% female) consented. The patients were assigned to three groups according to the time of referral and initial disease severity (severe acute; severe after interval; mild after interval). The primary outcome was dyspnea. Secondary outcomes included other respiratory disease symptoms, physical capacity, lung function, fatigue, quality of life (QoL), depression, and anxiety. Furthermore, patients rated the overall effectiveness of PR and their subjective change in health status. At the end of PR, we detected improvements with large effect sizes in exertional dyspnea, physical capacity, QoL, fatigue, and depression in the overall group. Other parameters changed with small to medium effect sizes. PR was effective after acute COVID-19 in all three groups analyzed.

Dynamically Induced Exceptional Phases in Quenched Interacting Semimetals.

We report on the dynamical formation of exceptional degeneracies in basic correlation functions of nonintegrable one- and two-dimensional systems quenched to the vicinity of a critical point. Remarkably, fine-tuned semimetallic points in the phase diagram of the considered systems are thereby promoted to topologically robust non-Hermitian (NH) nodal phases emerging in the coherent time evolution of a dynamically equilibrating system. Using nonequilibrium Green's function methods within the conserving second Born approximation, we predict observable signatures of these NH nodal phases both in equilibrated spectral functions and in the nonequilibrium dynamics of momentum distribution functions.

Impaired psychological well-being of healthcare workers in a German department of anesthesiology is independent of immediate SARS-CoV-2 exposure - a longitudinal observational study.

Background: The study aimed to assess the mental well-being of healthcare professionals at a German department of anesthesiology and critical care with a specialized ICU for treatment of COVID-19 patients during the first two peaks of the 2020 pandemic, and identifying risk and protective factors. Methods: A single-center longitudinal, online-based survey was conducted in healthcare workers from a department of anesthesiology and critical care in Bavaria, the most affected federal state in Germany at the time of assessment. Validated scores for depression, anxiety, somatic disorders, burnout, resilience, and self-management were used and complemented by questions about perceived COVID-19-related stressors. In parallel, patient characteristics in the ICU were collected. Results: 24 and 23 critically ill COVID-19 patients were treated during both observation periods in April/May and November/December 2020, respectively. 87.5% and 78.2% of patients had moderate to severe acute respiratory distress syndrome. From March 6, 2020 onwards, the hospital had switched to a command and control-based hospital incident command system (HICS) and increased work forces. Point prevalence of depression-like symptoms (13.6% and 12.8%) and burnout (21.6% and 17.4%) in the department's healthcare professionals was high. Exposure to SARS-CoV-2 did not increase psychological burden. Consequences of the lockdown were rated as highly distressing by a majority of all ICU personnel. High self-reported trait resilience was protective against signs of depression, generalized anxiety, and burnout. Conclusions: During the pandemic, healthcare professionals have been suffering from increased psychological distress compared to reference data for both the general population and ICU personnel. General effects of the lockdown appear more relevant than actual COVID-19 patient contact. High trait resilience has a protective effect, yet vulnerable individuals may require specific support. Prevention against potential after effects of the lockdown, and in particular measures allowing to avoid another lockdown, appear warranted.

Cost-Effectiveness of Pulmonary Rehabilitation in Patients With Bronchial Asthma: An Analysis of the EPRA Randomized Controlled Trial.

OBJECTIVES: At 3 months after the intervention, this study evaluates the cost-effectiveness of a 3-week inpatient pulmonary rehabilitation (PR) in patients with asthma compared with usual care alongside the single-center randomized controlled trial-Effectiveness of Pulmonary Rehabilitation in Patients With Asthma. METHODS: Adopting a societal perspective, direct medical costs and productivity loss were assessed using the Questionnaire for Health-Related Resource Use-Lung, a modification of the FIM in an Elderly Population. The effect side was operationalized as minimal important differences (MIDs) of the Asthma Control Test (ACT) and the Asthma Quality of Life Questionnaire (AQLQ) and through quality-adjusted life-years (QALYs) gained. Adjusted mean differences in costs (gamma-distributed model) and each effect parameter (Gaussian-distributed model) were simultaneously calculated within 1000 bootstrap replications to determine incremental cost-effectiveness ratios (ICERs) and to subsequently delineate cost-effectiveness acceptability curves. RESULTS: PR caused mean costs per capita of €3544. Three months after PR, we observed higher mean costs (Δ€3673; 95% confidence interval (CI) €2854-€4783) and improved mean effects (ACT Δ1.59 MIDs, 95% CI 1.37-1.81; AQLQ Δ1.76 MIDs, 95% CI 1.46-2.08; QALYs gained Δ0.01, 95% CI 0.01-0.02) in the intervention group. The ICER was €2278 (95% CI €1653-€3181) per ACT-MID, €1983 (95% CI €1430-€2830) per AQLQ-MID, and €312 401 (95% CI €209 206-€504 562) per QALY gained. CONCLUSIONS: Contrasting of PR expenditures with ICERs suggests that the intervention, which achieves clinically relevant changes in asthma-relevant parameters, has a high probability to be already cost-effective in the short term. However, in terms of QALYs, extended follow-up periods are likely required to comprehensively judge the added value of a one-time initial investment in PR.

Quantum simulation of 2D antiferromagnets with hundreds of Rydberg atoms.

Quantum simulation using synthetic systems is a promising route to solve outstanding quantum many-body problems in regimes where other approaches, including numerical ones, fail1. Many platforms are being developed towards this goal, in particular based on trapped ions2-4, superconducting circuits5-7, neutral atoms8-11 or molecules12,13. All of these platforms face two key challenges: scaling up the ensemble size while retaining high-quality control over the parameters, and validating the outputs for these large systems. Here we use programmable arrays of individual atoms trapped in optical tweezers, with interactions controlled by laser excitation to Rydberg states11, to implement an iconic many-body problem-the antiferromagnetic two-dimensional transverse-field Ising model. We push this platform to a regime with up to 196 atoms manipulated with high fidelity and probe the antiferromagnetic order by dynamically tuning the parameters of the Hamiltonian. We illustrate the versatility of our platform by exploring various system sizes on two qualitatively different geometries-square and triangular arrays. We obtain good agreement with numerical calculations up to a computationally feasible size (approximately 100 particles). This work demonstrates that our platform can be readily used to address open questions in many-body physics.