Risk of 30-Day All-Cause Readmission in Interstitial Lung Disease Patients after COVID-19: National-Level Data.

Rationale: Hospital readmission within 30 days poses challenges for healthcare providers, policymakers, and patients because of its impact on care quality, costs, and outcomes. Patients with interstitial lung disease (ILD) are particularly affected by readmission, which is associated with increased morbidity and mortality and reduced quality of life. Because small sample sizes have hindered previous studies, this study seeks to address this gap in knowledge by examining a large-scale dataset. Objective: To determine the rate and probability of 30-day all-cause readmission and secondary outcomes in patients with coronavirus disease (COVID-19) or ILD admitted to the hospital. Methods: This study is a nested cohort study that used the PearlDiver patient records database. Adult patients (age ⩾18 yr) who were admitted to hospitals in 28 states in the United States with COVID-19 or ILD diagnoses were included. We defined and analyzed two separate cohorts in this study. The first cohort consisted of patients with COVID-19 and was later divided into two groups with or without a history of ILD. The second cohort consisted of patients with ILD and was later divided into groups with COVID-19 or with a non-COVID-19 pneumonia diagnosis at admission. We also studied two other subcohorts of patients with and without idiopathic pulmonary fibrosis within the second cohort. Propensity score matching was employed to match confounders between groups. The Kaplan-Meier log rank test was applied to compare the probabilities of outcomes. Results: We assessed the data of 2,286,775 patients with COVID-19 and 118,892 patients with ILD. We found that patients with COVID-19 with preexisting ILD had an odds ratio of 1.6 for 30-day all-cause readmission. Similarly, an odds ratio of 2.42 in readmission rates was observed among hospitalized individuals with ILD who contracted COVID-19 compared with those who were hospitalized for non-COVID-19 pneumonia. Our study also found a significantly higher probability of intensive care admission among patients in both cohorts. Conclusions: Patients with ILD face heightened rates of hospital readmissions, particularly when ILD is combined with COVID-19, resulting in adverse outcomes such as decreased quality of life and increased healthcare expenses. It is imperative to prioritize preventive measures against COVID-19 and establish effective postdischarge care strategies for patients with ILD.

Pulmonary disease by non-tuberculous mycobacteria - clinical management, unmet needs and future perspectives.

INTRODUCTION: The number of patients with pulmonary disease caused by non-tuberculous mycobacteria (NTM) is increasing globally. Poor resistance against infections, for example, due to pre-existing lung diseases, immune deficiency and immune-modulating treatment, predisposes the population to developing pulmonary NTM disease. The incidence of pre-existing lung diseases such as chronic obstructive pulmonary disease and bronchiectasis has also increased. NTM disease diagnosis is often delayed due to non-specific symptoms. The therapeutic arsenal is limited and adherence to treatment guidelines is often low since the treatment regimens are complex, lengthy and side effects are common. Thus, current disease management is far from satisfactory and needs to be improved. Areas covered: This review provides an overview of the current knowledge of NTM infections and includes pathogenesis, disease patterns, epidemiology, disease management, unmet needs and future perspectives. Expert commentary: NTM disease is becoming more prevalent, in part with our increased awareness and improved diagnostic methods. However, our understanding of the disease pathogenesis is limited and treatment decisions are challenging, with difficult to employ drug regimens. Optimal management requires collaboration between healthcare providers, patients and expert centers.

Humoral immune profiling of mycobacterial antigen recognition in sarcoidosis and Löfgren's syndrome using high-content peptide microarrays.

INTRODUCTION: Sarcoidosis is considered an idiopathic granulomatous disease, although similar immunological and clinical features with tuberculosis (TB) suggest mycobacterial involvement in its pathogenesis. High-content peptide microarrays (HCPM) may help to decipher mycobacteria-specific antibody reactivity in sarcoidosis. METHODS: Serum samples from patients with sarcoidosis, Löfgren's syndrome, and TB, as well as from healthy individuals (12/group), were tested on HCPM containing 5964 individual peptides spanning 154 Mycobacterium tuberculosis proteins displayed as 15-amino acid stretches. Inclusion/exclusion and significance analyses were performed according to published methods. RESULTS: Each study group recognized 68-78% M. tuberculosis peptides at least once. M. tuberculosis epitope recognition by sarcoidosis patient sera was 42.7%, and by TB patient sera was 39.1%. Seven and 16 peptides were recognized in 9/12 (75%) and 8/12 (67%) sarcoidosis patient sera but not in TB patient sera, respectively. Nine (75%) and eight (67%) out of twelve TB patient sera, respectively recognized M. tuberculosis peptides that were not recognized in sarcoidosis patient sera. CONCLUSIONS: Specific IgG recognition patterns for M. tuberculosis antigens in sarcoidosis patients re-affirm mycobacterial involvement in sarcoidosis, providing biologically relevant targets for future studies pertaining to diagnostics and immunotherapy.

Discovery of AZD2716: A Novel Secreted Phospholipase A2 (sPLA2) Inhibitor for the Treatment of Coronary Artery Disease.

Expedited structure-based optimization of the initial fragment hit 1 led to the design of (R)-7 (AZD2716) a novel, potent secreted phospholipase A2 (sPLA2) inhibitor with excellent preclinical pharmacokinetic properties across species, clear in vivo efficacy, and minimized safety risk. Based on accumulated profiling data, (R)-7 was selected as a clinical candidate for the treatment of coronary artery disease.

New approaches in drug treatment for tuberculosis: Inhalation using liposomes only a future vision or soon in clinical practice?

A major change of therapy in respiratory medicine has been the transition from oral or parenteral to inhalation therapy, for example, in asthma. Inhalation of anti-infectious drugs has however not a key-role in the treatment of pulmonary infections such as tuberculosis (TB). The inhalation therapy provides several benefits; the target is reached directly with evasion of first-pass metabolism, thereby resulting in reduced systemic side effects. Furthermore, the drug is delivered to an extensive surface area that is rich in lymphoid tissue. The inhalation therapy is also easier to monitor since a more direct response is expected than orally administered drugs. Local side effects are, however, common and may depend on inadequate inhalation technique or devices. However, there are problems to consider regarding the delivery of drugs by inhalation: the anatomic structure of the tracheobronchial tree and the impact of the disease on the normal bronchial lining and the mucus. The latter may have an impact on the absorption of the inhaled drug because the mechanical and immunological defense mechanisms play a crucial role for the balance between clearance and absorption. The inhaled drug is expected to be rather effective in the overt presence of bacteria as in smear-positive cases of TB in which the bronchial tree may be directly connected with the cavitary lesions. Such compartments have more rapidly multiplying TB bacteria than other TB-infected compartments. The hypothesis is that the period of contagiousness is expected to be shorter and the recovery faster if there is an intervention directly against the major burden of TB bacteria. The size of the drug particles is essential to overcome the anatomical barriers. To improve the delivery of drugs, they should be in the form of fine particles, that it <5µm in size. Particles sized <2µm can be deposed in the alveoli. To encapsulate drugs for pulmonary delivery in liposomes has several advantages. There will be a prolonged release of the drug in the large surface area of the lungs and a high permeability of the epithelium through the liposome morphology. In general, liposomes are designed as closed spherical vesicles with a wall of a lipid bilayer that encapsulates an aqueous phase in which drugs can be stored. TB treatment with drugs administered by inhalation and liposomes is one future alternative. There are other possibilities for evaluation as well, such as high-dose rifampicin therapy and novel drugs. All new possibilities have to be considered with scientific scrutiny, proper management, and adherence. The clinical community and the patients cannot lose any more opportunities in the management of TB.

Experience of guilt and strategies for coping with guilt in patients with severe COPD: a qualitative interview study.

Guilt is associated with an increased level of mood disturbance and a poorer quality of life. The aim of this study was to explore how patients with severe COPD view and experience guilt and the ways in which they cope with this guilt. A total of 31 COPD patients were interviewed about their perceptions and experiences of guilt. Qualitative content analysis was used to examine the interviews. In the descriptive (manifest) analysis, the categories "not feeling personal guilt" and "experiencing guilt" emerged; in the interpretative (latent) analysis, various strategies for dealing with guilt were identified--for example, acceptance or blaming others. Relatively few patients reported that they felt guilt on a conscious level, but those who did expressed anguish, and remorse before God; some felt blamed by others. It is important that healthcare providers acknowledge the guilt that their patients express, since guilt may have adverse effects on the patients' overall health.

Discovery of the Fibrinolysis Inhibitor AZD6564, Acting via Interference of a Protein-Protein Interaction.

A class of novel oral fibrinolysis inhibitors has been discovered, which are lysine mimetics containing an isoxazolone as a carboxylic acid isostere. As evidenced by X-ray crystallography the inhibitors bind to the lysine binding site in plasmin thus preventing plasmin from binding to fibrin, hence blocking the protein-protein interaction. Optimization of the series, focusing on potency in human buffer and plasma clotlysis assays, permeability, and GABAa selectivity, led to the discovery of AZD6564 (19) displaying an in vitro human plasma clot lysis IC50 of 0.44 µM, no detectable activity against GABAa, and with DMPK properties leading to a predicted dose of 340 mg twice a day oral dosing in humans.

Interpersonal behaviors and socioemotional interaction of medical students in a virtual clinical encounter.

BACKGROUND: The virtual clinical encounter (VCE) may function as an important support for medical students in or prior to clinical practice to train and ease communication and socioemotional interactions with patients. Few studies have however focused on the dynamics of interpersonal behaviors in clinical interviewing with a virtual patient (VP) and the affective responses evoked by such a learning experience. The study was designed to investigate the dynamics and congruence of interpersonal behaviors and socioemotional interaction exhibited during the learning experience in a VCE, and to evaluate which interaction design characteristics contribute most to the behavioral and affective engagement in medical students. METHODS: Thirty medical students (sixth semester) participated voluntarily in an exploratory observational study with a highly interactive VP case based on a trustworthy VP encounter with a natural and realistic dialogue interface. Students worked collaboratively in pairs. They were videotaped for further behavioral analysis and self-reported (in both a survey and an interview) their personal opinions, perceptions and attitudes about the VCE. A mixed methods approach was applied. RESULTS: All participants demonstrated an adequate, respectful and relevant clinical case management and to obtain psychosocial history. The collaborative workspace played its role and led to dynamic and engaged discussions fostering thus shared understanding. The results suggest that the VCE studied was perceived as a meaningful, intrinsically motivational and activating learning environment, and was found to socially and emotionally engage learners. We also found that VCEs have the potential to support the development of relevant and congruent interpersonal communication skills in trainees. CONCLUSIONS: By taking advantage of socioemotional interaction, VCEs promote not only critical reflection skills or strategy-selection skills, but also to develop listening and nonverbal skills, induce self-awareness and target coping behaviours. We believe that, if applied in early medical education, this learning approach may facilitate clinical encounters at an early stage and contribute to responsible clinical decision making.

Palliative care in COPD--web survey in Sweden highlights the current situation for a vulnerable group of patients.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common cause of death. Despite the heavy symptom burden in late stages, these patients are relatively seldom referred to specialist palliative care. METHODS: A web-based survey concerning medical and organizational aspects of palliative care in COPD was distributed to respiratory physicians in Sweden. There were 93 respondents included in the study. RESULTS: Palliative care issues were regularly discussed with the patients according to a third of the respondents. About half of the respondents worked in settings where established routines for co-operation with palliative units were available at least to some extent. Less than half of the respondents (39%) were aware of current plans to develop palliative care, either as a co-operative effort or within the facility. Palliative care is focused on physical, psychological, social, and existential dimensions, and the proportions of respondents providing support within these dimensions, 'always' or 'often', were 83%, 36%, 32%, and 11%, respectively. Thus, to treat the physical dimensions was perceived as much more obvious than to address the other dimensions. CONCLUSIONS: The survey indicates that the priorities and resources for palliative care in COPD are insufficient in Sweden. The data, despite limitations, reveal a lack of established team-work with specialized palliative care units and actual plans for such co-operation.

Epidemiological analyses of tuberculosis in Archangelsk, Russia and implementation of a rapid assay for detection of resistance in this high burden setting.

BACKGROUND: Tuberculosis (TB) is a major problem in Russia, particularly regarding multidrug-resistant tuberculosis (MDR-TB). Rapid drug susceptibility testing methods are therefore needed. OBJECTIVES: To perform epidemiological analyses of TB in the Archangelsk region and to evaluate the molecular method GenoType®MTBDRplus in this type of setting. MATERIALS AND METHODS: Clinical and microbiological data of all TB patients in Archangelsk were collected in 2010. Smear-positive sputa were analysed by MTBDRplus and Bactec MGIT 960. RESULTS: The number of TB cases was 812 (incidence 65/105) and among these patients, 151 cases were registered in the penitentiary system (incidence 1162/105). Most patients were men, 94% had pulmonary TB and 22% were relapses. Out of all cases, 341 (42%) were smear positive and thus contagious and 176 (22%) had MDR-TB, among which one had extensively drug resistant tuberculosis (XDR-TB). Furthermore, two TB patients had strains being resistant to rifampicin, but susceptible to isoniazid. The number of cases being both contagious and MDR-TB was 128 representing 15.8% of all TB cases (incidence 10.2/105). Among these 128 TB patients 37 were relapses representing 25.7% of all the relapse cases. The results of MTBDRplus and Bactec MGIT analyses corresponded in 98.8%. CONCLUSIONS: In Archangelsk many TB patients had contagious MDR-TB thus being hazardous in society and relapsing pulmonary TB was common. The TB situation in the prisons was particularly severe. The analyses showed furthermore that MTBDRplus is of major value in this setting.

Food incentives improve adherence to tuberculosis drug treatment among homeless patients in Russia.

The aim of the study was to evaluate the impact of food incentives on adherence to tuberculosis (TB) drug treatment among homeless patients with TB. Food packages were thus given as a part of directly observed therapy to 142 homeless patients with TB at a dispensary in Saint Petersburg, Russian Federation. In addition, a social worker provided the patients with information and legal assistance, for example help with internal passports. Among the 142 patients, 66 were included in the study at the dispensary during their entire treatment period, while 76 patients were included in the study during shorter periods mainly because of transfer to inpatient care. In the first group, 59% of the patients continued the TB drug treatment without interruption in contrast to 31% in a control group. In the second group, that is those studied during shorter periods, 95% continued the TB drug treatment without interruption while attached to the dispensary. Food was introduced in the TB programme of the City of St. Petersburg as a consequence of this study. In conclusion, it can be stated that the food incentive had a strong positive impact on the adherence to TB drug treatment among these socially marginalized patients. The social support contributed in all probability also to the positive results.

Design of small molecule inhibitors of acetyl-CoA carboxylase 1 and 2 showing reduction of hepatic malonyl-CoA levels in vivo in obese Zucker rats.

Inhibition of acetyl-CoA carboxylases has the potential for modulating long chain fatty acid biosynthesis and mitochondrial fatty acid oxidation. Hybridization of weak inhibitors of ACC2 provided a novel, moderately potent but lipophilic series. Optimization led to compounds 33 and 37, which exhibit potent inhibition of human ACC2, 10-fold selectivity over inhibition of human ACC1, good physical and in vitro ADME properties and good bioavailability. X-ray crystallography has shown this series binding in the CT-domain of ACC2 and revealed two key hydrogen bonding interactions. Both 33 and 37 lower levels of hepatic malonyl-CoA in vivo in obese Zucker rats.

Impact of input parameters on the prediction of hepatic plasma clearance using the well-stirred model.

The in vitro metabolic stability assays are indispensable for screening the metabolic liability of new chemical entities (NCEs) in drug discovery. Intrinsic clearance (CL(int)) values from liver microsomes and/or hepatocytes are frequently used to assess metabolic stability as well as to quantitatively predict in vivo hepatic plasma clearance (CL(H)). An often used approximation is the so called well-stirred model which has gained widespread use. The applications of the well-stirred model are typically dependent on several measured parameters and hence with potential for error-propagation. Despite widespread use, it was recently suggested that the well-stirred model in some circumstances has been misused for in vitro in vivo extrapolation (IVIVE). In this work, we follow up that discussion and present a retrospective analysis of IVIVE for hepatic clearance prediction from in vitro metabolic stability data. We focus on the impact of input parameters on the well stirred model; in particular comparing "reference model" (with all experimentally determined values as input parameters) versus simplified models (with incomplete input parameters in the models). Based on a systematic comparative analysis and model comparison using datasets of diverse drug-like compounds and NCEs from rat and human, we conclude that simplified models, disregarding binding data, may be sufficiently good for IVIVE evaluation and compound ranking at early stage for cost-effective screening. Factors that can influence prediction accuracy are discussed, including in vitro intrinsic clearance (CL(int)) and in vivo CL(int) scaling factor used, non-specific binding to microsomes (fu(m)), blood to plasma ratio (C(B)/C(P)) and in particular fraction unbound in plasma (fu). In particular, the fu discrepancies between literature data and in-house values and between two different compound concentrations 1 and 10 µM are exemplified and its potential impact on prediction performance is demonstrated using a simulation example.

BCG scar and tuberculin reactivity in children and adults.

Bacille Calmette-Guérin (BCG) vaccination generally leads to scar formation and tuberculin skin test (TST) reactivity. This study aimed at analysing these 2 parameters and their correlation in a setting with a low prevalence of tuberculosis. Retrospectively, we analysed 314 children and 390 adults living in Sweden and known from records or individual recall to have undergone BCG vaccination. A BCG scar was present in 161 (51%) of the children and in 340 (87%) of the adults. Among children with a scar, 94 (58%) were TST-positive (>or=6 mm) compared to 23 (15%) of 154 children lacking a visible scar. Among adults with a scar, 258 (76%) were TST- positive compared to 23 (46%) of 50 with no scar. Out of 152 non-vaccinated adults, 142 (94.4%) were TST-negative. When 175 TST-negative health care students were BCG-vaccinated in a prospective part of the study, 174 (99%) were found to develop a scar. In essence, the study showed a positive correlation between scar presence and TST reactivity. Furthermore, BCG vaccination of adults in the present setting resulted in consistent scar formation, while scar prevalence in previously vaccinated children was low.

Primary vaccination and revaccination of young adults with BCG: a study using immunological markers.

Questions have been raised about the effectiveness of Bacille Calmette-Guérin (BCG) vaccination against tuberculosis (TB) in adults. We therefore analysed the immune response after BCG vaccination in primary-vaccinated and revaccinated young adults. 31 tuberculin skin test (TST) negative healthy students were BCG-vaccinated; 15 were primary-vaccinated and 16 revaccinated. Tuberculin-induced lymphocyte transformation (LT) and cytokine production of peripheral blood mononuclear cells were studied before BCG vaccination, as well as after 2 months and 1 y. In the primary-vaccinated as well as the revaccinated group the LT response increased after 2 months and remained significantly higher than baseline values after 1 y. In both groups the interferon-gamma (IFN-gamma) levels increased significantly after 2 months and the increase was maintained after 1 y. LT increased more in the revaccinated group than in the primary-vaccinated group, while the increase in IFN-gamma response did not differ between the 2 groups. Both primary vaccination and revaccination of TST negative young adults caused a significant increase in the T-helper 1-type immune response, suggesting a protective effect against TB. The present in vitro results thus support the policy in several low-endemic countries of primary vaccination as well as revaccination of young adults at risk of TB exposure.

Discovery of cyclopentane- and cyclohexane-trans-1,3-diamines as potent melanin-concentrating hormone receptor 1 antagonists.

We herein report the optimization of cyclopentane- and cyclohexane-1,3-diamine derivatives as novel and potent MCH-R1 antagonists. Structural modifications of the 2-amino-quinoline and thiophene moieties found in the initial lead compound served to improve its metabolic stability profile and MCH-R1 affinity, and revealed unprecedented SAR when compared to other 2-amino-quinoline-containing MCH-R1 antagonists.

Chest X-ray findings in relation to gender and symptoms: a study of patients with smear positive tuberculosis in Vietnam.

The aim of the study was to analyse chest X-ray (CXR) findings among men and women with smear positive pulmonary tuberculosis (TB). All new cases of smear positive pulmonary TB diagnosed during 6 months in 23 districts in Vietnam were included in a cross-sectional study. 366 cases fulfilled the inclusion criteria. Pleuritis was demonstrated in 17% of the men's CXR versus 3% of the women's, p = 0.002. A miliary pattern was seen in 11% of the men's CXR versus 3% of the women's, p = 0.04. Hilar adenopathy was common and equally distributed among men and women (65% vs 61%). Dyspnoea was common among patients with pleuritis (67%) and a miliary pattern (65%). The radiological findings were more advanced in men than women, despite a similar time from symptom onset to diagnosis. The primary manifestations of TB found among men were unexpected in this setting with an HIV prevalence <0.1% at the time. The association with other risk factors for TB in men needs further investigation. The less advanced CXR findings in women may correspond to a slower rate of progression to smear positive disease, which would have implications for the possibilities of women to obtain a timely TB diagnosis.