Health-related quality of life (HRQoL) in German early benefit assessment: The importance of disease-specific instruments.

INTRODUCTION: Health-Related Quality of Life (HRQoL) data is frequently requested in early benefit assessment in Germany. To test the hypothesis that the importance of HRQoL in general and the significance of disease-specific instruments in particular has increased since the introduction of AMNOG in Germany, we analysed all early benefit assessments between 2011 and 2022. METHODS: All 793 early benefit assessments completed between 01/01/2011 and 03/11/2022 were systematically analysed. The HRQoL instruments featured in the dossier submissions were extracted for all assessments and categorized into generic and specific instruments. All G-BA resolutions were likewise assessed for consideration and acceptance of generic and specific HRQoL instruments. In addition, it was examined whether there was an association between HRQoL data and the extent of additional benefit. RESULTS: Since 2014 HRQoL data have continuously been submitted in 70% to 80% of assessments per year with the exception of 2022 (63%). Generally, disease-specific instruments are favoured, regarding submissions by industry but especially with higher acceptance by the G-BA in the resolution. Subgroup analyses revealed oncology as a major contributor to the submission and acceptance rates of disease-specific instruments. Disease-specific instruments were submitted in 81% of all oncology assessments and accepted in 53% of assessments. Overall, assessments with accepted HRQoL data tend to reach a higher overall benefit. Procedures with accepted HRQoL were most likely to receive a considerable benefit (31%), while for procedures in which HRQoL data were not accepted, a benefit was most often (65%) not proven. DISCUSSION: Industry has followed the request for submission of specific HRQoL instruments early on. Higher submission rates of specific instruments over time which at the same time meet the methodological requirements indicate that industry has learned from early assessments. A potential reason for the high submission- and acceptance rates of specific HRQoL instruments in oncology might be the particularly high relevance of HRQoL in this indication. Possible effects of changes in legislature on the future development of submission and acceptance of HRQoL data need to be monitored. CONCLUSION: In Germany, HRQoL has gained a relevant position in early benefit assessment over time. Overall specific instruments are favoured, regarding submissions by industry but especially through consideration by the G-BA in the resolution. Furthermore, HRQoL data can be supportive for benefit assessments, in particular to show that advantages in morbidity and/or mortality are reflected in HRQoL and not at the expense of HRQoL.

Author Correction: Glomerulocapillary miRNA response to HLA-class I antibody in vitro and in vivo.

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Recommendations for mRNA analysis of micro-dissected glomerular tufts from paraffin-embedded human kidney biopsy samples.

BACKGROUND: Glomeruli are excellent pre-determined natural structures for laser micro-dissection. Compartment-specific glomerular gene expression analysis of formalin-fixed paraffin-embedded renal biopsies could improve research applications. The major challenge for such studies is to obtain good-quality RNA from small amounts of starting material, as applicable for the analysis of glomerular compartments. In this work, we provide data and recommendations for an optimized workflow of glomerular mRNA analysis. RESULTS: With a proper resolution of the camera and screen provided by the next generation of micro-dissection systems, we are able to separate parietal epithelial cells from glomerular tufts. Selected compartment-specific transcripts (WT1 and GLEPP1 for glomerular tuft as well as PAX2 for parietal epithelial cells) seem to be reliable discriminators for these micro-dissected glomerular substructures. Using the phenol-chloroform extraction and hemalaun-stained sections (2 µm), high amounts of Bowman's capsule transections (> 300) reveal sufficient RNA concentrations (> 300 ng mRNA) for further analysis. For comparison, in unstained sections from a number of 60 glomerular transections upwards, a minimum amount of 157 ng mRNA with a reasonable mRNA purity [A260/A280 ratio of 1.5 (1.4/1.7) median (25th/75th percentiles)] was reversely transcribed into cDNA. Comparing the effect of input RNA (20, 60, 150 and 300 micro-dissected glomerular transections), transcript expression of POLR2A significantly correlated when 60 and 150 laser micro-dissected glomerular transections were used for analysis. There was a lower inter-assay coefficient of variability for ADAMTS13, when at least 60 glomerular transections were used. According to the algorithms of geNormPlus and NormFinder, PGK1 and PPIA are more stable glomerular reference transcripts compared to GUSB, GAPDH, POLR2A, RPLPO, TBP, B2M, ACTB, 18SrRNA and HMBS. CONCLUSIONS: Our approach implements compartment-specific glomerular mRNA expression analysis into research applications, even regarding glomerular substructures like parietal epithelial cells. We recommend using of at least 60 micro-dissected unstained glomerular or 300 hemalaun-stained Bowman's capsule transections to obtain sufficient input mRNA for reproducible results. Hereby, the range of RNA concentrations in 60 micro-dissected glomeruli is low and appropriate normalization of Cq values using our suggested reference transcripts (PGK1 and PPIA) allows compensation with respect to different amounts of RNA purity and quantity.

Glomerulocapillary miRNA response to HLA-class I antibody in vitro and in vivo.

Changes in miRNA expression glomerular of capillaries during antibody-mediated rejection (ABMR) are poorly understood and could contribute to the deleterious inflammation and fibrosis of ABMR via suppression of target genes. A better understanding could lead to novel diagnostic tools and reveal novel therapeutic targets. We explored deregulated miRNAs in an glomeruloendothelial in vitro model of ABMR due to class I human leukocyte antigen (HLA) with and without complement activation. We studied a set of 16 promising candidate miRNAs in microdissected glomeruli a confirmation set of 20 human transplant biopsies (DSA+) compared to 10 matched controls without evidence for ABMR. Twelve out of these 16 glomerulocapillary miRNAs could successfully be confirmed as dysregulated in vivo with 10 upregulated (let-7c-5p, miR-28-3p, miR-30d-5p, miR-99b-5p, miR-125a-5p, miR-195-5p, miR-374b-3p, miR-484, miR-501-3p, miR-520e) and 2 downregulated (miR29b-3p, miR-885-5p) in DSA+ vs. CONTROLS: A random forest analysis based on glomerular miRNAs identified 18/20 DSA+ and 8/10 controls correctly. This glomerulocapillary miRNA signature associated with HLA class I-DSA could improve our understanding of ABMR and be useful for diagnostic or therapeutic purposes.

Automated first-principles mapping for phase-change materials.

Plotting materials on bi-coordinate maps according to physically meaningful descriptors has a successful tradition in computational solid-state science spanning more than four decades. Equipped with new ab initio techniques introduced in this work, we generate an improved version of the treasure map for phase-change materials (PCMs) as introduced previously by Lencer et al. which, other than before, charts all industrially used PCMs correctly. Furthermore, we suggest seven new PCM candidates, namely SiSb4 Te7 , Si2 Sb2 Te5 , SiAs2 Te4 , PbAs2 Te4 , SiSb2 Te4 , Sn2 As2 Te5 , and PbAs4 Te7 , to be used as synthetic targets. To realize aforementioned maps based on orbital mixing (or "hybridization") and ionicity coordinates, structural information was first included into an ab initio numerical descriptor for sp3 orbital mixing and then generalized beyond high-symmetry structures. In addition, a simple, yet powerful quantum-mechanical ionization measure also including structural information was introduced. Taken together, these tools allow for (automatically) generating materials maps solely relying on first-principles calculations. © 2017 Wiley Periodicals, Inc.

Comparison of different normalization strategies for the analysis of glomerular microRNAs in IgA nephropathy.

Small nucleolar RNAs (snoRNAs) have been used for normalization in glomerular microRNA (miRNA) quantification without confirmation of validity. Our aim was to identify glomerular reference miRNAs in IgA nephropathy. We compared miRNAs in human paraffin-embedded renal biopsies from patients with cellular-crescentic IgA-GN (n = 5; crescentic IgA-GN) and non-crescentic IgA-GN (n = 5; IgA-GN) to mild interstitial nephritis without glomerular abnormalities (controls, n = 5). Laser-microdissected glomeruli were used for expression profiling of 762 miRNAs by low-density TaqMan arrays (cards A and B). The comparison of different normalization methods (GeNormPlus, NormFinder, global mean and snoRNAs) in crescentic IgA-GN, IgA-GN and controls yielded similar results. However, levels of significance and the range of relative expression differed. In median, two normalization methods demonstrated similar results. GeNormPlus and NormFinder gave different top ranked reference miRNAs. Stability ranking for snoRNAs varied between cards A and B. In conclusion, we suggest the geometric mean of the most stable reference miRNAs found in GeNormPlus (miR-26b-5p), NormFinder (miR-28-5p) and snoRNAs (RNU44) as reference. It should be considered that significant differences could be missed using one particular normalization method. As a starting point for glomerular miRNA studies in IgA nephropathy we provide a library of miRNAs.

Assessment of utilization and pharmacovigilance based on spontaneous adverse event reporting of gadopentetate dimeglumine as a magnetic resonance contrast agent after 45 million administrations and 15 years of clinical use.

PURPOSE: Although contrast agents have become indispensable tools in magnetic resonance and their safe and effective use the foundation of many essential diagnostic procedures, only limited summary information on their utilization and pharmacovigilance is available to the community. After voluntary access to the manufacturer spontaneous adverse event database, we assessed the available data for gadopentetate dimeglumine. MATERIAL AND METHODS: Gadopentetate dimeglumine (Gd-DTPA, Magnevist; Berlex/Schering AG, Berlin, Germany) became commercially available in 1988 and is currently marketed in 101 countries. Using the manufacturer's continuous and cumulative database on product distribution and spontaneous adverse event (AE) reporting, we categorized AEs and assessed their cumulative occurrence after 10, 20, and 45 million applications that occurred in 1993, 1997, and 2002, respectively. Furthermore, we reviewed publications in Medline to assess prevalence of the 4 most common MR contrast agents in the indexed literature. RESULTS: Gd-DTPA has been used in more than 45 million magnetic resonance imaging procedures since 1988 and is currently used globally in more than 5 million applications annually. The broadest category of spontaneously reported AEs, subjective symptoms, occurs in less than 0.01% of procedures. Within the total AEs reported, the distribution of serious and nonserious reports was 9.3% and 90.7%, respectively. The rates of AE reporting have changed over time, with increased rates in the second reporting period (1993 to 1997), followed by substantially lower rates in subsequent years. AE reporting rates are the most comprehensive data available; however, there will always be some underestimation of the true event rates. Although no substantial differences were noted among major age groups, substantial differences in reporting frequency were found among regions, with the United States reporting nearly twice as many AEs as Europe in the postmarketing phase. CONCLUSION: The postmarketing utilization and pharmacovigilance analysis of Gd-DTPA has revealed temporal changes and regional differences, overall with an excellent safety profile. Its extensive utilization and safety information have firmly established it as highly used and safe magnetic resonance imaging agent.

Economic evaluations of granulocyte colony-stimulating factor: in the prevention and treatment of chemotherapy-induced neutropenia.

The prevailing uncertainty about the pharmacoeconomic positioning of granulocyte colony-stimulating factor (G-CSF) in the prevention and treatment of chemotherapy-induced febrile neutropenia has resulted in a number of pharmacoeconomic evaluations published in the past 10 years. These studies vary considerably regarding the approaches used and the results presented. In order to contribute to a clearer pharmacoeconomic positioning of G-CSF, a systematic review of economic evaluations was carried out. The focus of the review was prophylaxis and therapy of chemotherapy-induced neutropenia in patients with cancer. A computerised bibliography search of several databases was conducted yielding 33 studies. The findings demonstrated the cost-saving potential of G-CSF in standard-dose chemotherapy to be limited, with lower costs often seen in the control group. The results of these studies were too heterogeneous to extract a clear recommendation from a cost-saving point of view. The administration of G-CSF after high-dose chemotherapy with stem cell support resulted more often in cost savings in the G-CSF group as compared with standard-dose chemotherapy, illustrating a possible cost-saving potential of G-CSF. In the treatment of established chemotherapy-induced febrile neutropenia, cost savings were found in all studies. This result is surprising but hampered by the small number of studies (n = 5) and remains to be confirmed by more rigourously designed prospective economic analyses. Despite the substantial research on this topic, the economic evaluation of G-CSF is far from being settled and needs further investigation.