Patients Satisfied with Care Report Better Quality of Life and Self-Rated Health-Cross-Sectional Findings Based on Hospital Quality Data.

BACKGROUND: Satisfaction with care is an important indicator of health care quality. However, if this process measure is associated with patients' outcomes in real-world data is largely unknown. We, therefore, aimed to evaluate if satisfaction with physician- and nurse-related care is associated with quality of life and self-rated health among inpatients at the University Hospital Hamburg-Eppendorf in Germany. METHOD: We used standard hospital quality survey data of 4925 patients treated at various departments. We used multiple linear regressions to examine an association between satisfaction with staff-related care and quality of life as well as self-rated health, adjusted for age, gender, mother tongue, and treating ward. Patients rated their satisfaction with physician- and nurse-related care from 0 "not at all" to 9 "very much". The outcomes regarding quality of life and self-rated health were evaluated on five-point Likert scales ranking from 1 "bad" to 5 "excellent". RESULTS: We found that satisfaction with physician-related care was positively associated with quality of life (ß = 0.16; p < 0.001) as well as with self-rated health (ß = 0.16; p < 0.001). Similar findings were observed for satisfaction with nurse-related care and the two outcomes (ß = 0.13; p < 0.001 and ß = 0.14; p < 0.001, respectively). CONCLUSION: We show that patients who are more satisfied with staff-related care report better quality of life and self-rated health than patients less satisfied with care. Thus, patient satisfaction with care, is not only a process measure indicating the quality of care but is also positively associated with patient-reported outcomes.

Higher comorbidity burden is associated with lower self-reported quality of life after stroke.

Introduction: This study assesses the association of comorbidity burden and polypharmacy with self-reported quality of life after stroke. Patients and methods: We performed a post-hoc analysis of a prospective, single-center, observational study of outcome evaluation by patient-reported outcome measures in stroke clinical practice. Consecutive patients with acute ischemic stroke (AIS) were enrolled and self-reported health-related quality of life (HrQoL) was assessed 90 days after acute stroke using the Patient-reported Outcomes Measurement Information System 10-Question Short-Form (PROMIS-10). Comorbidities at baseline were assessed by the Charlson Comorbidity Index (CCI). Polypharmacy was defined as medication intake of ≥5 at baseline. We used linear regression analysis to study the association of CCI, polypharmacy and other clinical covariates with HrQoL after stroke. Results: Of 781 patients (median age 76 years, 48.4% female) enrolled, 30.2% had a CCI Score ≥2, and 31.5% presented with polypharmacy. At follow up, 71 (9.1%) had died. In 409 (52.4%) reached for outcome evaluation, Global Physical Health T-Score was 43.8 ± 10 and Global Mental Health T-Score was 43.5 ± 8.76, indicating lower HrQoL than the average population. A CCI Score ≥2, higher NIHSS Score, female sex, dependency on others for dressing, toileting and mobility before index stroke, atrial fibrillation and hypertension were independent predictors of worse physical and mental health outcomes, while polypharmacy was not. Conclusion: In patients with AIS, high comorbidity burden and polypharmacy are frequent. Comorbidity burden at admission is independently associated with worse self-reported physical and mental health three months after stroke.

Implementability of collecting patient-reported outcome data in stroke unit care - a qualitative study.

BACKGROUND: Patient-reported outcome measures (PROMs) assess patient-relevant effects of medical treatments. We aimed to evaluate the implementation of the International Consortium for Health Outcomes Measurement Standard Set for Stroke (ICHOM-SSS) into routine inpatient care of a stroke unit. METHODS: The ICHOM-SSS was administered in a certified stroke unit during and after inpatient care. Semi-structured interviews with medical staff (n = 5) and patients or their proxies (n = 19) about their experience were audio-recorded and analysed using thematic analyses. Implementation outcomes were chosen in advance and adhered to current standards of implementation science. RESULTS: Patients perceived the ICHOM-SSS to be relevant and feasible. They reported limited understanding of why the assessment was introduced. The overall acceptance of using PROMs was high. While medical staff, too, perceived the assessment to be appropriate and relevant, their appraisal of feasibility, sustainability, and their acceptance of the implementation were low. CONCLUSIONS: For a sustainable implementation of PROMs in clinical practice, IT resources need to be adapted, medical care needs to be reorganized, and additional clinical resources are required. Future research should investigate benefits of the ICHOM-SSS and a simpler, automated implementation in stroke care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03795948 , retrospectively registered on 8 January 2019.

Psychometric properties of a patient-reported outcome set in acute stroke patients.

OBJECTIVES: Impairments after stroke may affect multiple domains of health-related quality of life (HRQoL). Patient-reported outcome measures (PROMs) have proven valuable in measuring patients' well-being. We examine the psychometric properties of a standard set of PROMs assessing global health, anxiety, and depression, and functioning in a German health care setting. METHOD: We included inpatients at the Department of Neurology at the University Medical Center Hamburg-Eppendorf, diagnosed with stroke. Following the stroke-specific standard set of the International Consortium for Health Outcome Measurement, we collected demographic and clinical information at baseline, and PROMs for global health (PROMIS-10), three items for self-reported functioning, anxiety, and depression (PHQ-4) at 90 days follow-up. We calculated confirmatory factor analyses to test factorial validity and correlation analyses to test construct validity. We further conducted item and reliability analyses. RESULTS: In a sample of 487 patients (mean age, SD: 71.1, 12.6; 47% female) with mild and moderate symptoms, model fit for the PROMIS-10 was acceptable for the two-factor and single-factor models. Factor loadings ranged from 0.52 to 0.94. The postulated single-factor model for functioning was saturated with zero degrees of freedom. Factor loadings ranged from 0.90 to 0.96. For the PHQ-4, the two-factor model showed excellent model fit. Factor loadings ranged from 0.78 to 0.87. Internal consistency was acceptable to good. Construct validity was generally confirmed. CONCLUSIONS: The PROMIS-10 is a valid and reliable instrument to measure HRQoL among German stroke patients. While the PHQ-4 was confirmed as a screening measure for mental disorders, further research is needed on items assessing self-reported functioning. Results are limited to patients showing minimal functional deficits.

Outcome evaluation by patient reported outcome measures in stroke clinical practice (EPOS) protocol for a prospective observation and implementation study.

INTRODUCTION: The impact of stroke-related impairment on activities of daily living may vary between patients, and can only be estimated by applying patient-reported outcome measures. The International Consortium for Health Outcome Measurement has developed a standard set of instruments that combine clinical and longitudinal patient-reported outcome measures for stroke. The present study was designed (1) to implement and evaluate the feasibility of the use of it as a consistent outcome measure in clinical routine at the stroke center of a German university hospital, (2) to characterize impairment in everyday life caused by stroke, and (3) to identify predictive factors associated with patient-relevant outcomes. METHODS: We plan to enroll 1040 consecutive patients with the diagnosis of acute ischemic stroke, transient ischemic attack, or intracerebral hemorrhage in a prospective observational study. Demographics, cardiovascular risk factors, and living situation are assessed at inpatient surveillance. At 90 days and 12 months after inclusion, follow-up assessments take place including the Patient-reported Outcomes Measurement Information System 10-Question Short Form (PROMIS-10), the Patient- Health Questionnaire-4, and the simplified modified Ranking Scale questionnaire. The acceptance and feasibility (1) will be assessed by a process evaluation through qualitative semi-structured interviews with clinical staff and patients and quantitative analyses of the data quality evaluating practicability, acceptance, adoption, and fidelity to protocol. The primary outcome of objective 2 and 3 is health-related quality of life measured with the PROMIS-10. Additional outcomes are depressive and anxiety symptoms and patient participation in their social roles. Patient-reported outcomes will be assessed in their longitudinal course using (generalized) mixed regressions. Exploratory descriptive and inference statistical analyses will be used to find patterns of patient characteristics and predictive factors of the outcome domains. PERSPECTIVE: The results will describe and further establish the evaluation of stroke patients of a stroke center by standardized PROMs in everyday life. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (NCT03795948). Approval of the local ethics committee (Ethik-Kommission der Ärztekammer Hamburg) has been obtained.

Arylsulfatase G inactivation causes loss of heparan sulfate 3-O-sulfatase activity and mucopolysaccharidosis in mice.

Deficiency of glycosaminoglycan (GAG) degradation causes a subclass of lysosomal storage disorders called mucopolysaccharidoses (MPSs), many of which present with severe neuropathology. Critical steps in the degradation of the GAG heparan sulfate remain enigmatic. Here we show that the lysosomal arylsulfatase G (ARSG) is the long-sought glucosamine-3-O-sulfatase required to complete the degradation of heparan sulfate. Arsg-deficient mice accumulate heparan sulfate in visceral organs and the central nervous system and develop neuronal cell death and behavioral deficits. This accumulated heparan sulfate exhibits unique nonreducing end structures with terminal N-sulfoglucosamine-3-O-sulfate residues, allowing diagnosis of the disorder. Recombinant human ARSG is able to cleave 3-O-sulfate groups from these residues as well as from an authentic 3-O-sulfated N-sulfoglucosamine standard. Our results demonstrate the key role of ARSG in heparan sulfate degradation and strongly suggest that ARSG deficiency represents a unique, as yet unknown form of MPS, which we term MPS IIIE.

Multiple gains of spliceosomal introns in a superfamily of vertebrate protease inhibitor genes.

BACKGROUND: Intron gains reportedly are very rare during evolution of vertebrates, and the mechanisms underlying their creation are largely unknown. Previous investigations have shown that, during metazoan radiation, the exon-intron patterns of serpin superfamily genes were subject to massive changes, in contrast to many other genes. RESULTS: Here we investigated intron dynamics in the serpin superfamily in lineages pre- and postdating the split of vertebrates. Multiple intron gains were detected in a group of ray-finned fishes, once the canonical groups of vertebrate serpins had been established. In two genes, co-occurrence of non-standard introns was observed, implying that intron gains in vertebrates may even happen concomitantly or in a rapidly consecutive manner. DNA breakage/repair processes associated with genome compaction are introduced as a novel factor potentially favoring intron gain, since all non-canonical introns were found in a lineage of ray-finned fishes that experienced genomic downsizing. CONCLUSION: Multiple intron acquisitions were identified in serpin genes of a lineage of ray-finned fishes, but not in any other vertebrates, suggesting that insertion rates for introns may be episodically increased. The co-occurrence of non-standard introns within the same gene discloses the possibility that introns may be gained simultaneously. The sequences flanking the intron insertion points correspond to the proto-splice site consensus sequence MAG upward arrowN, previously proposed to serve as intron insertion site. The association of intron gains in the serpin superfamily with a group of fishes that underwent genome compaction may indicate that DNA breakage/repair processes might foster intron birth.

Characterization of the human sulfatase Sulf1 and its high affinity heparin/heparan sulfate interaction domain.

The extracellular sulfatases Sulf1 and Sulf2 remodel the 6O-sulfation state of heparan sulfate proteoglycans on the cell surface, thereby modulating growth factor signaling. Different from all other sulfatases, the Sulfs contain a unique, positively charged hydrophilic domain (HD) of about 320 amino acid residues. Using various HD deletion mutants and glutathione S-transferase (GST)-HD fusion proteins, this study demonstrates that the HD is required for enzymatic activity and acts as a high affinity heparin/heparan sulfate interaction domain. Association of the HD with the cell surface is sensitive to heparinase treatment, underlining specificity toward heparan sulfate chains. Correspondingly, isolated GST-HD binds strongly to both heparin and heparan sulfate in vitro and also to living cells. Surface plasmon resonance studies indicate nanomolar affinity of GST-HD toward immobilized heparin. The comparison of different mutants reveals that especially the outer regions of the HD mediate heparan sulfate binding, probably involving "tandem" interactions. Interestingly, binding to heparan sulfate depends on the presence of 6O-sulfate substrate groups, suggesting that substrate turnover facilitates release of the enzyme from its substrate. Deletion of the inner, less conserved region of the HD drastically increases Sulf1 secretion without affecting enzymatic activity or substrate specificity, thus providing a tool for the in vitro modulation of HS-dependent signaling as demonstrated here for the signal transduction of fibroblast growth factor 2. Taken together, the present study shows that specific regions of the HD influence different aspects of HS binding, cellular localization, and enzyme function.

Formylglycine aldehyde Tag--protein engineering through a novel post-translational modification.

Oxidation of a specific cysteine residue to C(alpha)-formylglycine is a novel post-translational modification that is directed by a short recognition motif commonly found in pro- and eukaryotic sulfatases. As recently shown by C. Bertozzi and co-workers, this system can be employed in protein engineering to equip proteins with genetically encoded aldehyde tags for site-specific labeling, conjugation and immobilization.

Molecular basis of multiple sulfatase deficiency, mucolipidosis II/III and Niemann-Pick C1 disease - Lysosomal storage disorders caused by defects of non-lysosomal proteins.

Multiple sulfatase deficiency (MSD), mucolipidosis (ML) II/III and Niemann-Pick type C1 (NPC1) disease are rare but fatal lysosomal storage disorders caused by the genetic defect of non-lysosomal proteins. The NPC1 protein mainly localizes to late endosomes and is essential for cholesterol redistribution from endocytosed LDL to cellular membranes. NPC1 deficiency leads to lysosomal accumulation of a broad range of lipids. The precise functional mechanism of this membrane protein, however, remains puzzling. ML II, also termed I cell disease, and the less severe ML III result from deficiencies of the Golgi enzyme N-acetylglucosamine 1-phosphotransferase leading to a global defect of lysosome biogenesis. In patient cells, newly synthesized lysosomal proteins are not equipped with the critical lysosomal trafficking marker mannose 6-phosphate, thus escaping from lysosomal sorting at the trans Golgi network. MSD affects the entire sulfatase family, at least seven members of which are lysosomal enzymes that are specifically involved in the degradation of sulfated glycosaminoglycans, sulfolipids or other sulfated molecules. The combined deficiencies of all sulfatases result from a defective post-translational modification by the ER-localized formylglycine-generating enzyme (FGE), which oxidizes a specific cysteine residue to formylglycine, the catalytic residue enabling a unique mechanism of sulfate ester hydrolysis. This review gives an update on the molecular bases of these enigmatic diseases, which have been challenging researchers since many decades and so far led to a number of surprising findings that give deeper insight into both the cell biology and the pathobiochemistry underlying these complex disorders. In case of MSD, considerable progress has been made in recent years towards an understanding of disease-causing FGE mutations. First approaches to link molecular parameters with clinical manifestation have been described and even therapeutical options have been addressed. Further, the discovery of FGE as an essential sulfatase activating enzyme has considerable impact on enzyme replacement or gene therapy of lysosomal storage disorders caused by single sulfatase deficiencies.

Sulf loss influences N-, 2-O-, and 6-O-sulfation of multiple heparan sulfate proteoglycans and modulates fibroblast growth factor signaling.

Sulf1 and Sulf2 are two heparan sulfate 6-O-endosulfatases that regulate the activity of multiple growth factors, such as fibroblast growth factor and Wnt, and are essential for mammalian development and survival. In this study, the mammalian Sulfs were functionally characterized using overexpressing cell lines, in vitro enzyme assays, and in vivo Sulf knock-out cell models. Analysis of subcellular Sulf localization revealed significant differences in enzyme secretion and detergent solubility between the human isoforms and their previously characterized quail orthologs. Further, the activity of the Sulfs toward their native heparan sulfate substrates was determined in vitro, demonstrating restricted specificity for S-domain-associated 6S disaccharides and an inability to modify transition zone-associated UA-GlcNAc(6S). Analysis of heparan sulfate composition from different cell surface, shed, glycosylphosphatidylinositol-anchored and extracellular matrix proteoglycan fractions of Sulf knock-out cell lines established differential effects of Sulf1 and/or Sulf2 loss on nonsubstrate N-, 2-O-, and 6-O-sulfate groups. These findings indicate a dynamic influence of Sulf deficiency on the HS biosynthetic machinery. Real time PCR analysis substantiated differential expression of the Hs2st and Hs6st heparan sulfate sulfotransferase enzymes in the Sulf knock-out cell lines. Functionally, the changes in heparan sulfate sulfation resulting from Sulf loss were shown to elicit significant effects on fibroblast growth factor signaling. Taken together, this study implicates that the Sulfs are involved in a potential cellular feed-back mechanism, in which they edit the sulfation of multiple heparan sulfate proteoglycans, thereby regulating cellular signaling and modulating the expression of heparan sulfate biosynthetic enzymes.

Arylsulfatase G, a novel lysosomal sulfatase.

The sulfatases constitute a conserved family of enzymes that specifically hydrolyze sulfate esters in a wide variety of substrates such as glycosaminoglycans, steroid sulfates, or sulfolipids. By modifying the sulfation state of their substrates, sulfatases play a key role in the control of physiological processes, including cellular degradation, cell signaling, and hormone regulation. The loss of sulfatase activity has been linked with various severe pathophysiological conditions such as lysosomal storage disorders, developmental abnormalities, or cancer. A novel member of this family, arylsulfatase G (ASG), was initially described as an enzyme lacking in vitro arylsulfatase activity and localizing to the endoplasmic reticulum. Contrary to these results, we demonstrate here that ASG does indeed have arylsulfatase activity toward different pseudosubstrates like p-nitrocatechol sulfate and 4-methylumbelliferyl sulfate. The activity of ASG depends on the Cys-84 residue that is predicted to be post-translationally converted to the critical active site C(alpha)-formylglycine. Phosphate acts as a strong, competitive ASG inhibitor. ASG is active as an unprocessed 63-kDa monomer and shows an acidic pH optimum as typically seen for lysosomal sulfatases. In transfected cells, ASG accumulates within lysosomes as indicated by indirect immunofluorescence microscopy. Furthermore, ASG is a glycoprotein that binds specifically to mannose 6-phosphate receptors, corroborating its lysosomal localization. ARSG mRNA expression was found to be tissue-specific with highest expression in liver, kidney, and pancreas, suggesting a metabolic role of ASG that might be associated with a so far non-classified lysosomal storage disorder.

Homogeneous stalled ribosome nascent chain complexes produced in vivo or in vitro.

Cotranslational protein maturation is often studied in cell-free translation mixtures, using stalled ribosome-nascent chain complexes produced by translating truncated mRNA. This approach has two limitations: (i) it can be technically challenging, and (ii) it only works in vitro, where the concentrations of cellular components differ from concentrations in vivo. We have developed a method to produce stalled ribosomes bearing nascent chains of a specified length by using a 'stall sequence', derived from the Escherichia coli SecM protein, which interacts with residues in the ribosomal exit tunnel to stall SecM translation. When the stall sequence is expressed at the end of nascent chains, stable translation-arrested ribosome complexes accumulate in intact cells or cell-free extracts. SecM-directed stalling is efficient, with negligible effects on viability. This method is straightforward and suitable for producing stalled ribosome complexes in vivo, permitting study of the length-dependent maturation of nascent chains in the cellular milieu.