How We Do It: Interdisciplinary Diagnosis and Management of Patients With Interstitial Lung Disease and Connective Tissue Disease.

A diagnosis of interstitial lung diseases (ILD) can be challenging, and the identification of an associated connective tissue disease (CTD) is crucial to estimate prognosis and to establish the optimal treatment approach. Diagnostic delay, limited expertise, and fragmented care are barriers that impede the delivery of comprehensive health care for patients with rare, complex, and multiorgan diseases such as CTD and ILD. In this article, we present our perspective on the interdisciplinary diagnosis and interprofessional treatment of patients with ILD and suspected CTD or CTD at risk of ILD. We outline the structure of our service, delineating the roles and responsibilities of the team members. Additionally, we provide an overview of our patient population, including diagnostic approaches and specific treatments, and illustrate a patient case. Furthermore, we focus on specific benefits and challenges of joint interdisciplinary and interprofessional patient consultations. The importance of rheumatology and pulmonology assessments in specific patient populations is emphasized. Finally, we explore future directions and discuss potential strategies to improve care delivery for patients with CTD-associated ILD.

Increasing implicit rationing of care in nursing homes: A time-series cross-sectional analysis.

BACKGROUND: Implicit rationing of nursing care is a socio-ecological problem where care workers, due to lack of resources, have to leave necessary nursing care activities undone. Cross-sectional studies on implicit rationing of nursing home care revealed associations with organizational and work environment characteristics. However, little is known on how implicit rationing of nursing care varies over time in nursing homes. OBJECTIVE: This study's purpose was to describe changes in levels and patterns of implicit rationing of nursing care in Swiss nursing homes over time, while accounting for key explanatory factors related to organizational, work environment, and individual characteristics. DESIGN: Time-series cross-sectional analysis. SETTING: Nursing homes in Switzerland. PARTICIPANTS: A convenience sample of 47 nursing homes and 3269 care workers from all educational levels participating in two multicenter cross-sectional studies (the Swiss Nursing Home Human Resources Project) conducted in 2013 and 2018. METHODS: To quantify implicit rationing of nursing care, care workers' data were collected via the nursing home version of the Basel Extent of Rationing of Nursing Care instrument. To control for leadership ability, staffing and resource adequacy, we used the Nursing Work Index-Practice Environment Scale. Objective measures including turnover, staffing and skill mix levels were aggregated at the nursing home level. Our analyses included multiple linear mixed models, using time as a fixed effect and nursing home as a random effect. RESULTS: We found overall increases of rationing of care activities over the five-year period studied, with documentation and social activities most rationed at both measurement points (overall coefficients varied between 0.11 and 0.23, as well as the 95%-confidence intervals between 0.05 and 0.30). Moreover, a considerable increase in rationing of activities of daily living (coefficient of 0.47 in 2013 and 0.63 in 2018) was observed. CONCLUSIONS: Alongside long-term deterioration of staff resources, increases in rationing of nursing care are a worrying development, particularly given their potential negative impacts both on residents and on care workers. To assess nursing home care quality and to determine adequate staffing levels and skill mixes, policy makers and nursing home managers should consider regular monitoring of rationing of nursing care. TWEETABLE ABSTRACT: Time-series cross-sectional analysis reveals increasing rationing of nursing care activities in Swiss nursing homes from 2013 to 2018.

Frailty assessment for COVID-19 follow-up: a prospective cohort study.

BACKGROUND: The Clinical Frailty Scale (CFS) is increasingly used for clinical decision making in acute care but little is known about frailty after COVID-19. OBJECTIVES: To investigate frailty and the CFS for post-COVID-19 follow-up. METHODS: This prospective multicentre cohort study included COVID-19 survivors aged ≥50 years presenting for a follow-up visit ≥3 months after the acute illness. Nine centres retrospectively collected pre-COVID-19 CFS and prospectively CFS at follow-up. Three centres completed the Frailty Index (FI), the short physical performance battery (SPPB), 30 s sit-to-stand test and handgrip strength measurements. Mixed effect logistic regression models accounting for repeated measurements and potential confounders were used to investigate factors associated with post-COVID-19 CFS. Criterion and construct validity were determined by correlating the CFS to other concurrently assessed frailty measurements and measures of respiratory impairment, respectively. RESULTS: Of the 288 participants 65% were men, mean (SD) age was 65.1 (9) years. Median (IQR) CFS at follow-up was 3 (2-3), 21% were vulnerable or frail (CFS ≥4). The CFS was responsive to change, correlated with the FI (r=0.69, p<0.001), the SPPB score (r=-0.48, p<0.001) (criterion validity) and with the St George's Respiratory Questionnaire score (r=0.59, p<0.001), forced vital capacity %-predicted (r=-0.25, p<0.001), 6 min walk distance (r=-0.39, p<0.001) and modified Medical Research Council (mMRC) (r=0.59, p<0.001). Dyspnoea was significantly associated with a higher odds for vulnerability/frailty (per one mMRC adjusted OR 2.01 (95% CI 1.13 to 3.58), p=0.02). CONCLUSIONS: The CFS significantly increases with COVID-19, and dyspnoea is an important risk factor for post-COVID-19 frailty and should be addressed thoroughly.

Quantification of antiangiogenic treatment effects on tissue heterogeneity in glioma tumour xenograft model using a combination of DCE-MRI and 3D-ultramicroscopy.

OBJECTIVES: This study aimed at assessing the effects of an anti-angiogenic treatment, which neutralises vascular endothelial growth factor (VEGF), on tumour heterogeneity. METHODS: Murine glioma cells have been inoculated into the right brain frontal lobe of 16 mice. Anti-VEGF antibody was administered to a first group (n = 8), while a second group (n = 8) received a placebo. Magnetic resonance acquisitions, performed at days 10, 12, 15 and 23 following the implantation, allowed the derivation of a three-dimensional features dataset characterising tumour heterogeneity. Three-dimensional ultramicroscopy and standard histochemistry analysis have been performed to verify in vivo results. RESULTS: Placebo-treated mice displayed a highly-vascularised area at the tumour periphery, a monolithic necrotic core and a chaotic dense vasculature across the entire tumour. In contrast, the B20-treated group did not show any highly vascularised regions and presents a fragmented necrotic core. A significant reduction of the number of vessel segments smaller than 17 µm has been observed. There was no difference in overall tumour volume and growth rate between the two groups. CONCLUSIONS: Region-specific analysis revealed that VEGF inhibition affects only: (1) highly angiogenic compartments expressing high levels of VEGF and characterised by small capillaries, and also (2) the formation and structure of necrotic regions. These effects appear to be transient and limited in time. KEY POINTS: • VEGF inhibition affects only the highly angiogenic region and small capillaries network • VEGF inhibition is transient in time • Tumour volume is not affected by anti-angiogenic treatment • VEGF inhibition also influences the architecture of necrotic regions.

Dynamic contrast-enhanced micro-computed tomography correlates with 3-dimensional fluorescence ultramicroscopy in antiangiogenic therapy of breast cancer xenografts.

OBJECTIVES: Dynamic contrast-enhanced (DCE) micro-computed tomography (micro-CT) has emerged as a valuable imaging tool to noninvasively obtain quantitative physiological biomarkers of drug effect in preclinical studies of antiangiogenic compounds. In this study, we explored the ability of DCE micro-CT to assess the antiangiogenic treatment response in breast cancer xenografts and correlated the results to the structural vessel response obtained from 3-dimensional (3D) fluorescence ultramicroscopy (UM). MATERIAL AND METHODS: Two groups of tumor-bearing mice (KPL-4) underwent DCE micro-CT imaging using a fast preclinical dual-source micro-CT system (TomoScope Synergy Twin, CT Imaging GmbH, Erlangen, Germany). Mice were treated with either a monoclonal antibody against the vascular endothelial growth factor or an unspecific control antibody. Changes in vascular physiology were assessed measuring the mean value of the relative blood volume (rBV) and the permeability-surface area product (PS) in different tumor regions of interest (tumor center, tumor periphery, and total tumor tissue). Parametric maps of rBV were calculated of the tumor volume to assess the intratumoral vascular heterogeneity. Isotropic 3D UM vessel scans were performed from excised tumor tissue, and automated 3D segmentation algorithms were used to determine the microvessel density (MVD), relative vessel volume, and vessel diameters. In addition, the accumulation of coinjected fluorescence-labeled trastuzumab was quantified in the UM tissue scans to obtain an indirect measure of vessel permeability. Results of the DCE micro-CT were compared with corresponding results obtained by ex vivo UM. For validation, DCE micro-CT and UM parameters were compared with conventional histology and tumor volume. RESULTS: Examination of the parametric rBV maps revealed significantly different patterns of intratumoral blood supply between treated and control tumors. Whereas control tumors showed a characteristic vascular rim pattern with considerably elevated rBV values in the tumor periphery, treated tumors showed a widely homogeneous blood supply. Compared with UM, the physiological rBV maps showed excellent agreement with the spatial morphology of the intratumoral vascular architecture. Regional assessment of mean physiological values exhibited a significant decrease in rBV (P < 0.01) and PS (P < 0.05) in the tumor periphery after anti-vascular endothelial growth factor treatment. Structural validation with UM showed a significant reduction in reduction of relative vessel volume (rVV) (P < 0.01) and MVD (P < 0.01) in the corresponding tumor region. The reduction in rBV correlated well with the rVV (R = 0.73 for single values and R = 0.95 for mean values). Spatial maps of antibody penetration showed a significantly reduced antibody accumulation (P < 0.01) in the tumor tissue after treatment and agreed well with the physiological change of PS. Examination of vessel diameters revealed a size-dependent antiangiogenic treatment effect, which showed a significant reduction in MVD (P < 0.001) for vessels with diameters smaller than 25 µm. No treatment effect was observed by tumor volume. CONCLUSIONS: Noninvasive DCE micro-CT provides valuable physiological information of antiangiogenic drug effect in the intact animal and correlates with ex vivo structural analysis of 3D UM. The combined use of DCE micro-CT with UM constitutes a complementary imaging toolset that can help to enhance our understanding of antiangiogenic drug mechanisms of action in preclinical drug research.

Apoptosis imaging for monitoring DR5 antibody accumulation and pharmacodynamics in brain tumors noninvasively.

High-grade gliomas often possess an impaired blood-brain barrier (BBB), which allows delivery of large molecules to brain tumors. However, achieving optimal drug concentrations in brain tumors remains a significant hurdle for treating patients successfully. Thus, detailed investigations of drug activities in gliomas are needed. To investigate BBB penetration, pharmacodynamics, and tumor retention kinetics of an agonistic DR5 antibody in a brain tumor xenograft model, we utilized a noninvasive imaging method for longitudinal monitoring of apoptosis induction. Brain tumors were induced by intracranial (i.c.) implantation of a luciferase-expressing tumor cell line as a reporter. To quantify accumulation of anti-DR5 in brain tumors, we generated a dosage-response curve for apoptosis induction after i.c. delivery of fluorescence-labeled anti-DR5 at different dosages. Assuming 100% drug delivery after i.c. application, the amount of accumulated antibody after i.v. application was calculated relative to its apoptosis induction. We found that up to 0.20% to 0.97% of antibody delivered i.v. reached the brain tumor, but that apoptosis induction declined quickly within 24 hours. These results were confirmed by three-dimensional fluorescence microscopy of antibody accumulation in explanted brains. Nonetheless, significant antitumor efficacy was documented after anti-DR5 delivery. We further demonstrated that antibody penetration was facilitated by an impaired BBB in brain tumors. These imaging methods enable the quantification of antibody accumulation and pharmacodynamics in brain tumors, offering a holistic approach for assessment of central nervous system-targeting drugs.

Bioluminescence imaging correlates with tumor serum marker, organ weights, histology, and human DNA levels during treatment of orthotopic tumor xenografts with antibodies.

PURPOSE: In this study, we correlate results of bioluminescence measurements with established readouts for assessing therapeutic efficacy of antibodies in orthotopic cancer xenografts. PROCEDURES: An orthotopic tumor model of pancreatic cancer (AsPC-1-luc) and experimental lung metastasis (A549-luc) were established. Whole-body bioluminescence imaging (BLI) was performed to observe tumor progression under therapy with antibodies targeting different receptor kinases (primary readout). For purpose of verification, anti-tumoral efficacy was cross-validated with results obtained by measurement of organ weights, histology, tumor serum marker analysis (CYFRA 21-1), and quantification of human DNA concentration in the organ of interest (secondary readouts). RESULTS: Anti-tumoral efficacy is demonstrated for the antibodies tested. In the pancreas xenograft, a tumor growth inhibition of 95% (p < 0.01) was achieved as compared to control. Therapeutic efficacy could be identified as soon as 1 week after initiation of treatment. In the model of experimental lung metastasis, antibody treatment significantly suppressed tumor growth up to 75% (p < 0.05). All imaging results were confirmed by correlation analysis showing excellent agreement with the secondary readouts. CONCLUSIONS: BLI was demonstrated to be a reliable tool for monitoring early drug responses in orthotopic small animal cancer models. BLI allows rapid and non-invasive assessment of tumor load in the animal over time and, thus, provides a suitable method for routine use in preclinical cancer research.