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"text": "\n108268\nEffective use of cinacalcet for the treatment of secondary hyperparathyroidism in Austrian dialysis patients--results of the Austrian cohort of the ECHO study.\n\nZitt, E\n\nJäger, C\n\nRosenkranz, AR\n\nEigner, M\n\nKodras, K\n\nKovarik, J\n\nGraf, H\n\nPétavy, F\n\nHorn, S\n\nWatschinger, B\n\nBeiträge in Fachzeitschriften\nISI:000287497700010\n21253777.0\n10.1007/s00508-010-1515-x\nNone\nDespite extensive use of standard therapy for secondary hyperparathyroidism (sHPT) in dialysis patients, still most patients do not achieve the recommended treatment targets. In a pan-European observational study (ECHO), the effectiveness of the calcimimetic cinacalcet for the treatment of sHPT was evaluated in real-world clinical practice. A sub-analysis of the entire Austrian study cohort is presented.\n Adult dialysis patients who had initiated cinacalcet therapy were included. Data on biochemical parameters of bone and mineral metabolism (intact parathyroid hormone [iPTH], calcium [Ca] and phosphorus [P]) and concurrent medication were collected 6 months prior to the initiation of cinacalcet, at initiation (baseline) and after up to 12 months of active treatment.\n A total of 320 patients (mean age (±SD): 56 (±14) years) from 34 Austrian dialysis centres were enrolled. At baseline, patients presented with elevated serum iPTH (median 605 pg/ml) and hyperphosphataemia (median 2.1 mmol/l). After 12 months of cinacalcet treatment, serum iPTH (median percentage change -48%), calcium (-2%) and phosphorus (-6%) decreased. The greatest iPTH reduction (-66%) was found in patients with most severe sHPT (>800 pg/ml at baseline). The proportion of patients achieving the recommended NKF/K-DOQI(™) treatment targets increased from baseline to month 12 for iPTH (3-36%) and phosphorus (24 to 39%) and remained stable for calcium (51 to 50%), respectively. No patient had all 3 parameters simultaneously within NKF/K-DOQI(™) treatment targets at baseline, while 7% of patients achieved this treatment goal after 12 months. During the study the use of the phosphate binder sevelamer remained fairly stable, while the relative percentage use of calcium-based phosphate binders increased and the usage of aluminium-containing binders decreased; vitamin D analogue use remained stable.\n Additional use of cinacalcet improved biochemical parameters of bone and mineral metabolism and enabled more patients to achieve and maintain the KDOQI(™) treatment targets for serum iPTH, calcium and phosphorus.\n\nHorn, Sabine\n\nRosenkranz, Alexander\n\n\n"
},
{
"text": "\n119025\nHydrocortisone improved haemodynamics and fluid requirement in surviving but not non-surviving of severely burned patients.\n\nWinter, W\n\nKamolz, L\n\nDonner, A\n\nHoerauf, K\n\nBlaicher, A\n\nAndel, H\n\nBeiträge in Fachzeitschriften\nISI:000186242500013\n14556732.0\n10.1016/S0305-4179(03)00148-7\nNone\nRecent studies have shown that administration of hydrocortisone may lead to a reduction of catecholamines and to an improved outcome in septic patients. However, there are no data on the use of hydrocortisone in burn patients although in these patients reduction of vasopressors might be even more crucial for outcome due to improvement of skin perfusion. This study presents the first results on the impact of hydrocortisone administration in norepinephrine dependent severely burned patients. In a prospective cohort study fourteen consecutive severely burned patients received, 12h after norepinephrine dependency, a hydrocortisone bolus of 100mg followed by 0.18mg/(kgh) hydrocortisone. The course of the necessary norepinephrine dose, as well as the fluid balance was documented 12h prior and after the first dosage of hydrocortisone. Statistical analysis showed an unexpected increase of the required norepinephrine dosage. A statistical post hoc evaluation of surviving and non-surviving patients revealed a significant increase of norepinephrine in non-survivors whereas in survivors it was possible to reduce norepinephrine significantly. Furthermore, the median fluid requirement of surviving patients could be significantly reduced whereas in the group of non-survivors there was no change of volume needed. Our data suggests that hydrocortisone might be useful in selected patients with severe burn injuries. However, patients not responding to hydrocortisone administrations seem to have a poor prognosis. Our findings are in contrast to previously published data on septic patients, in whom hydrocortisone administration resulted in a reduction of norepinephrine. In burned patients the severity of trauma seems to have more profound influence on the pathophysiological mechanism of sepsis. Due to the high number of non-responders, the potential immune suppression and impaired wound healing caused by the side effects of hydrocortisone, further selection criteria seem to be necessary. A short ACTH-test might be considered prior to hydrocortisone administration to select patients who might benefit from this therapy. In summary, further prospective controlled studies will be necessary to establish hydrocortisone in the routine therapy of severely burned patients.\n\nKamolz, Lars-Peter\n\n\n"
},
{
"text": "\n127379\nComplex tumor genomes inferred from single circulating tumor cells by array-CGH and next-generation sequencing.\n\nHeitzer, E\n\nAuer, M\n\nGasch, C\n\nPichler, M\n\nUlz, P\n\nHoffmann, EM\n\nLax, S\n\nWaldispuehl-Geigl, J\n\nMauermann, O\n\nLackner, C\n\nHöfler, G\n\nEisner, F\n\nSill, H\n\nSamonigg, H\n\nPantel, K\n\nRiethdorf, S\n\nBauernhofer, T\n\nGeigl, JB\n\nSpeicher, MR\n\nBeiträge in Fachzeitschriften\nISI:000318903700006\n23471846.0\n10.1158/0008-5472.CAN-12-4140\nNone\nCirculating tumor cells (CTC) released into blood from primary cancers and metastases reflect the current status of tumor genotypes, which are prone to changes. Here, we conducted the first comprehensive genomic profiling of CTCs using array-comparative genomic hybridization (CGH) and next-generation sequencing. We used the U.S. Food and Drug Administration-cleared CellSearch system, which detected CTCs in 21 of 37 patients (range, 1-202/7.5 mL sample) with stage IV colorectal carcinoma. In total, we were able to isolate 37 intact CTCs from six patients and identified in those multiple colorectal cancer-associated copy number changes, many of which were also present in the respective primary tumor. We then used massive parallel sequencing of a panel of 68 colorectal cancer-associated genes to compare the mutation spectrum in the primary tumors, metastases, and the corresponding CTCs from two of these patients. Mutations in known driver genes [e.g., adenomatous polyposis coli (APC), KRAS, or PIK3CA] found in the primary tumor and metastasis were also detected in corresponding CTCs. However, we also observed mutations exclusively in CTCs. To address whether these mutations were derived from a small subclone in the primary tumor or represented new variants of metastatic cells, we conducted additional deep sequencing of the primary tumor and metastasis and applied a customized statistical algorithm for analysis. We found that most mutations initially found only in CTCs were also present at subclonal level in the primary tumors and metastases from the same patient. This study paves the way to use CTCs as a liquid biopsy in patients with cancer, providing more effective options to monitor tumor genomes that are prone to change during progression, treatment, and relapse.\n\nAuer, Martina\n\nBauernhofer, Thomas\n\nEisner, Florian\n\nGeigl, Jochen Bernd\n\nHeitzer, Ellen\n\nHöfler, Gerald\n\nLackner, Karoline\n\nPichler, Martin\n\nSamonigg, Hellmut\n\nSill, Heinz\n\nSpeicher, Michael\n\nUlz, Peter\n\nWaldispühl-Geigl, Julie\n\n\n"
},
{
"text": "\n141900\nPharmacological disruption of the outer limiting membrane leads to increased retinal integration of transplanted photoreceptor precursors.\n\nWest, EL\n\nPearson, RA\n\nTschernutter, M\n\nSowden, JC\n\nMacLaren, RE\n\nAli, RR\n\nBeiträge in Fachzeitschriften\nISI:000255454100006\n18294631.0\n10.1016/j.exer.2008.01.004\nPMC2394572\nRetinal degeneration is the leading cause of untreatable blindness in the developed world. Cell transplantation strategies provide a novel therapeutic approach to repair the retina and restore sight. Previously, we have shown that photoreceptor precursor cells can integrate and form functional photoreceptors after transplantation into the subretinal space of the adult mouse. In a clinical setting, however, it is likely that far greater numbers of integrated photoreceptors would be required to restore visual function. We therefore sought to assess whether the outer limiting membrane (OLM), a natural barrier between the subretinal space and the outer nuclear layer (ONL), could be reversibly disrupted and if disruption of this barrier could lead to enhanced numbers of transplanted photoreceptors integrating into the ONL. Transient chemical disruption of the OLM was induced in adult mice using the glial toxin, dl-alpha-aminoadipic acid (AAA). Dissociated early post-natal neural retinal cells were transplanted via subretinal injection at various time-points after AAA administration. At 3 weeks post-injection, the number of integrated, differentiated photoreceptor cells was assessed and compared with those found in the PBS-treated contralateral eye. We demonstrate for the first time that the OLM can be reversibly disrupted in adult mice, using a specific dose of AAA administered by intravitreal injection. In this model, OLM disruption is maximal at 72 h, and recovers by 2 weeks. When combined with cell transplantation, disruption of the OLM leads to a significant increase in the number of photoreceptors integrated within the ONL compared with PBS-treated controls. This effect was only seen in animals in which AAA had been administered 72 h prior to transplantation, i.e. when precursor cells were delivered into the subretinal space at a time coincident with maximal OLM disruption. These findings suggest that the OLM presents a physical barrier to photoreceptor integration following transplantation into the subretinal space in the adult mouse. Reversible disruption of the OLM may provide a strategy for increasing cell integration in future therapeutic applications.\n\n\n"
},
{
"text": "\n163850\nDiscontinuation of Denosumab therapy for osteoporosis: A systematic review and position statement by ECTS.\n\nTsourdi, E\n\nLangdahl, B\n\nCohen-Solal, M\n\nAubry-Rozier, B\n\nEriksen, EF\n\nGuañabens, N\n\nObermayer-Pietsch, B\n\nRalston, SH\n\nEastell, R\n\nZillikens, MC\n\nBeiträge in Fachzeitschriften\nISI:000413994500002\n28789921.0\n10.1016/j.bone.2017.08.003\nNone\nThe optimal duration of osteoporosis treatment is controversial. As opposed to bisphosphonates, denosumab does not incorporate into bone matrix and bone turnover is not suppressed after its cessation. Recent reports imply that denosumab discontinuation may lead to an increased risk of multiple vertebral fractures.\n The European Calcified Tissue Society (ECTS) formed a working group to perform a systematic review of existing literature on the effects of stopping denosumab and provide advice on management.\n Data from phase 2 and 3 clinical trials underscore a rapid decrease of bone mineral density (BMD) and a steep increase in bone turnover markers (BTMs) after discontinuation of denosumab. Clinical case series report multiple vertebral fractures after discontinuation of denosumab and a renewed analysis of FREEDOM and FREEDOM Extension Trial suggests, albeit does not prove, that the risk of multiple vertebral fractures may be increased when denosumab is stopped due to a rebound increase in bone resorption.\n There appears to be an increased risk of multiple vertebral fractures after discontinuation of denosumab although strong evidence for such an effect and for measures to prevent the occurring bone loss is lacking. Clinicians and patients should be aware of this potential risk. Based on available data, a re-evaluation should be performed after 5years of denosumab treatment. Patients considered at high fracture risk should either continue denosumab therapy for up to 10years or be switched to an alternative treatment. For patients at low risk, a decision to discontinue denosumab could be made after 5years, but bisphosphonate therapy should be considered to reduce or prevent the rebound increase in bone turnover. However, since the optimal bisphosphonate regimen post-denosumab is currently unknown continuation of denosumab can also be considered until results from ongoing trials become available. Based on current data, denosumab should not be stopped without considering alternative treatment in order to prevent rapid BMD loss and a potential rebound in vertebral fracture risk.\n Copyright © 2017 Elsevier Inc. All rights reserved.\n\nObermayer-Pietsch, Barbara\n\n\n"
},
{
"text": "\n164828\nEuropean Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2017 Update.\n\nRouprêt, M\n\nBabjuk, M\n\nCompérat, E\n\nZigeuner, R\n\nSylvester, RJ\n\nBurger, M\n\nCowan, NC\n\nGontero, P\n\nVan Rhijn, BWG\n\nMostafid, AH\n\nPalou, J\n\nShariat, SF\n\nBeiträge in Fachzeitschriften\nISI:000419428900026\n28867446.0\n10.1016/j.eururo.2017.07.036\nNone\nThe European Association of Urology (EAU) Guidelines Panel on Upper Urinary Tract Urothelial Carcinoma (UTUC) has prepared updated guidelines to aid clinicians in the current evidence-based management of UTUC and to incorporate recommendations into clinical practice.\n To provide an overview of the EAU guidelines on UTUC as an aid to clinicians.\n The recommendations provided in the current guidelines are based on a thorough review of available UTUC guidelines and articles identified following a systematic search of Medline. Data on urothelial malignancies and UTUC were searched using the following keywords: urinary tract cancer; urothelial carcinomas; upper urinary tract, carcinoma; renal pelvis; ureter; bladder cancer; chemotherapy; ureteroscopy; nephroureterectomy; adjuvant treatment; instillation; recurrence; risk factors; and survival. References were weighted by a panel of experts.\n Owing to the rarity of UTUC, there are insufficient data to provide strong recommendations (ie, grade A). However, the results of recent multicentre studies are now available, and there is a growing number of retrospective articles in UTUC. The 2017 tumour, node, metastasis (TNM) classification is recommended. Recommendations are given for diagnosis and risk stratification, as well as for radical and conservative treatment; prognostic factors are also discussed. A single postoperative dose of intravesical mitomycin after radical nephroureterectomy reduces the risk of bladder tumour recurrence. Kidney-sparing management should be offered as a primary treatment option to patients with low-risk tumours and two functional kidneys.\n These guidelines contain information on the management of individual patients according to a current standardised approach. Urologists should take into account the specific clinical characteristics of each patient when determining the optimal treatment regimen, based on the proposed risk stratification of these tumours.\n Urothelial carcinoma of the upper urinary tract is rare, but because 60% of these tumours are invasive at diagnosis; appropriate diagnosis and management is most important. We present recommendations based on current evidence for optimal management.\n Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.\n\nZigeuner, Richard\n\n\n"
},
{
"text": "\n169814\nUrine proteome analysis reflects atherosclerotic disease in an ApoE-/- mouse model and allows the discovery of new candidate biomarkers in mouse and human atherosclerosis.\n\nvon zur Muhlen, C\n\nSchiffer, E\n\nSackmann, C\n\nZürbig, P\n\nNeudorfer, I\n\nZirlik, A\n\nHtun, N\n\nIphöfer, A\n\nJänsch, L\n\nMischak, H\n\nBode, C\n\nChen, YC\n\nPeter, K\n\nBeiträge in Fachzeitschriften\nISI:000306411300006\n22371488.0\n10.1074/mcp.M111.013847\nPMC3394942\nNoninvasive diagnosis of atherosclerosis via single biomarkers has been attempted but remains elusive. However, a previous polymarker or pattern approach of urine polypeptides in humans reflected coronary artery disease with high accuracy. The aim of the current study is to use urine proteomics in ApoE(-/-) mice to discover proteins with pathophysiological roles in atherogenesis and to identify urinary polypeptide patterns reflecting early stages of atherosclerosis. Urine of ApoE(-/-) mice either on high fat diet (HFD) or chow diet was collected over 12 weeks; urine of wild type mice on HFD was used to exclude diet-related proteome changes. Capillary electrophoresis coupled to mass spectrometry (CE-MS) of samples identified 16 polypeptides specific for ApoE(-/-) mice on HFD. In a blinded test set, these polypeptides allowed identification of atherosclerosis at a sensitivity of 90% and specificity of 100%, as well as monitoring of disease progression. Sequencing of the discovered polypeptides identified fragments of α(1)-antitrypsin, epidermal growth factor (EGF), kidney androgen-regulated protein, and collagen. Using immunohistochemistry, α(1)-antitrypsin, EGF, and collagen type I were shown to be highly expressed in atherosclerotic plaques of ApoE(-/-) mice on HFD. Urinary excretion levels of collagen and α(1)-antitrypsin fragments also significantly correlated with intraplaque collagen and α(1)-antitrypsin content, mirroring plaque protein expression in the urine proteome. To provide further confirmation that the newly identified proteins are relevant in humans, the presence of collagen type I, α(1)-antitrypsin, and EGF was also confirmed in human atherosclerotic disease. Urine proteome analysis in mice exemplifies the potential of a novel multimarker approach for the noninvasive detection of atherosclerosis and monitoring of disease progression. Furthermore, this approach represents a novel discovery tool for the identification of proteins relevant in murine and human atherosclerosis and thus also defines potential novel therapeutic targets.\n\nZirlik, Andreas\n\n\n"
},
{
"text": "\n179222\nPrognostic Value of a New Lung Ultrasound Score to Predict Intensive Care Unit Stay in Pediatric Cardiac Surgery.\n\nCantinotti, M\n\nGiordano, R\n\nScalese, M\n\nMarchese, P\n\nFranchi, E\n\nViacava, C\n\nMolinaro, S\n\nAssanta, N\n\nKoestenberger, M\n\nKutty, S\n\nGargani, L\n\nAit-Ali, L\n\nBeiträge in Fachzeitschriften\nISI:000502619500048\n31400328.0\n10.1016/j.athoracsur.2019.06.057\nNone\nLung ultrasound (LUS) in pediatric cardiac surgery is gaining consensus. We (1) evaluated the prognostic value of a new LUS-score in pediatric cardiac surgery, and (2) compared LUS-score to conventional risk factors including age, The Society of Thoracic Surgeons/European Association of Cardio-Thoracic Surgery (STAT) score, cardiopulmonary bypass time, and prognostic biomarkers including brain natriuretic peptide and cystatin-C.\n LUS examinations were performed in 237 children (median age, 0.55 years; interquartile range, 0.09-4.15 years) at 12 to 36 hours after surgery. For each hemithorax, 3 areas (anterior/lateral/posterior) were evaluated in the upper and lower halves, constituting 12 total scanning areas. For each site a score was assigned: 0 (rare B lines), 1 (separated B lines), 2 (coalescent B lines), 3 (loss of aeration), and total LUS score was calculated as sum of all sites. The primary endpoints were intensive care unit length of stay and extubation time.\n The mean total LUS score was 12.88 ± 6.41 (range, 0-26) and was higher in newborns (16.77 ± 5.25) compared with older children (5.36 ± 5.57; P < .001). On univariate analysis, LUS score was associated inversely with age (beta 0.26; P = .004) and body surface area (beta 3.41 P = .006) and positively with brain natriuretic peptide (beta 1.65; P < .001) and cystatin-C (beta 2.41; P < .001). The LUS score, when added as continuous predictor to a conventional risk model (age, STAT score, and cardiopulmonary bypass time) emerged significant both for intensive care unit length of stay (beta 0.145, P = .047) and extubation time (beta 1.644; P = .024). When single quadrants were analyzed, only anterior LUS score was significant (intensive care unit length of stay beta, 0.471; P = .020; extubation time beta 5.530; P = .007).\n Our data show the prognostic incremental value of a new LUS score over traditional risk factors in pediatric cardiac surgery.\n Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.\n\nKoestenberger, Martin\n\n\n"
},
{
"text": "\n179663\nTetracycline-regulated expression of VEGF-A in beta cells induces angiogenesis: improvement of engraftment following transplantation.\n\nMathe, Z\n\nDupraz, P\n\nRinsch, C\n\nThorens, B\n\nBosco, D\n\nZbinden, M\n\nMorel, P\n\nBerney, T\n\nPepper, MS\n\nBeiträge in Fachzeitschriften\nISI:000242553500006\n17176614.0\n10.3727/000000006783981675\nNone\nEarly revascularization of pancreatic islet cells after transplantation is crucial for engraftment, and it has been suggested that vascular endothelial growth factor-A (VEGF-A) plays a significant role in this process. Although VEGF gene therapy can improve angiogenesis, uncontrolled VEGF secretion can lead to vascular tumor formation. Here we have explored the role of temporal VEGF expression, controlled by a tetracycline (TC)-regulated promoter, on revascularization and engraftment of genetically modified beta cells following transplantation. To this end, we modified the CDM3D beta cell line using a lentiviral vector to promote secretion of VEGF-A either in a TC-regulated (TET cells) or a constitutive (PGK cells) manner. VEGF secretion, angiogenesis, cell proliferation, and stimulated insulin secretion were assessed in vitro. VEGF secretion was increased in TET and PGK cells, and VEGF delivery resulted in angiogenesis, whereas addition of TC inhibited these processes. Insulin secretion by the three cell types was similar. We used a syngeneic mouse model of transplantation to assess the effects of this controlled VEGF expression in vivo. Time to normoglycemia, intraperitoneal glucose tolerance test, graft vascular density, and cellular mass were evaluated. Increased expression of VEGF resulted in significantly better revascularization and engraftment after transplantation when compared to control cells. In vivo, there was a significant increase in vascular density in grafted TET and PGK cells versus control cells. Moreover, the time for diabetic mice to return to normoglycemia and the stimulated plasma glucose clearance were also significantly accelerated in mice transplanted with TET and PGK cells when compared to control cells. VEGF was only needed during the first 2-3 weeks after transplantation; when removed, normoglycemia and graft vascularization were maintained. TC-treated mice grafted with TC-treated cells failed to restore normoglycemia. This approach allowed us to switch off VEGF secretion when the desired effects had been achieved. TC-regulated temporal expression of VEGF using a gene therapy approach presents a novel way to improve early revascularization and engraftment after islet cell transplantation.\n\n\n"
},
{
"text": "\n187780\nOncogenic stress induced by acute hyper-activation of Bcr-Abl leads to cell death upon induction of excessive aerobic glycolysis.\n\nDengler, MA\n\nStaiger, AM\n\nGutekunst, M\n\nHofmann, U\n\nDoszczak, M\n\nScheurich, P\n\nSchwab, M\n\nAulitzky, WE\n\nvan der Kuip, H\n\nBeiträge in Fachzeitschriften\nNone\n21949869.0\n10.1371/journal.pone.0025139\nPMC3176818\nIn response to deregulated oncogene activation, mammalian cells activate disposal programs such as programmed cell death. To investigate the mechanisms behind this oncogenic stress response we used Bcr-Abl over-expressing cells cultivated in presence of imatinib. Imatinib deprivation led to rapid induction of Bcr-Abl activity and over-stimulation of PI3K/Akt-, Ras/MAPK-, and JAK/STAT pathways. This resulted in a delayed necrosis-like cell death starting not before 48 hours after imatinib withdrawal. Cell death was preceded by enhanced glycolysis, glutaminolysis, and amino acid metabolism leading to elevated ATP and protein levels. This enhanced metabolism could be linked to induction of cell death as inhibition of glycolysis or glutaminolysis was sufficient to sustain cell viability. Therefore, these data provide first evidence that metabolic changes induced by Bcr-Abl hyper-activation are important mediators of oncogenic stress-induced cell death.During the first 30 hours after imatinib deprivation, Bcr-Abl hyper-activation did not affect proliferation but resulted in cellular swelling, vacuolization, and induction of eIF2α phosphorylation, CHOP expression, as well as alternative splicing of XPB, indicating endoplasmic reticulum stress response. Cell death was dependent on p38 and RIP1 signaling, whereas classical death effectors of ER stress, namely CHOP-BIM were antagonized by concomitant up-regulation of Bcl-xL.Screening of 1, 20 compounds for their potential effects on oncogenic stress-induced cell death uncovered that corticosteroids antagonize cell death upon Bcr-Abl hyper-activation by normalizing cellular metabolism. This protective effect is further demonstrated by the finding that corticosteroids rendered lymphocytes permissive to the transforming activity of Bcr-Abl. As corticosteroids are used together with imatinib for treatment of Bcr-Abl positive acute lymphoblastic leukemia these data could have important implications for the design of combination therapy protocols.In conclusion, excessive induction of Warburg type metabolic alterations can cause cell death. Our data indicate that these metabolic changes are major mediators of oncogenic stress induced by Bcr-Abl.\n\nDengler, Michael Andreas\n\n\n"
},
{
"text": "\n5757\nQualitative effect of fenofibrate and quantitative effect of atorvastatin on LDL profile in combined hyperlipidemia with dense LDL.\n\nWinkler, K\n\nWeltzien, P\n\nFriedrich, I\n\nSchmitz, H\n\nNickell, HH\n\nHauck, P\n\nHoffmann, MM\n\nBaumstark, MW\n\nWieland, H\n\nMärz, W\n\nBeiträge in Fachzeitschriften\nISI:000221695000004\n15146369.0\n10.1055/s-2004-817970\nNone\nINTRODUCTION: The association of elevated plasma triglyceride concentrations, decreased HDL-cholesterol, and dense LDL (dLDL) is referred to as the atherogenic lipoprotein phenotype. dLDL particularly plays a role in the metabolic syndrome and type 2 diabetes and may be one of the factors responsible for the increased risk for coronary artery disease in these patients. The effect of fenofibrate and atorvastatin on the LDL subfraction profile in patients with combined hyperlipidemia and a preponderance of dLDL was studied in a sequential design. METHODS: Six male patients with combined hyperlipidemia and dLDL received 160 mg/die supra-bioavailable fenofibrate. After a washout phase of 8 weeks all patients received 10 mg/die atorvastatin for another 8 weeks. At baseline, after fenofibrate, and after atorvastatin treatment LDL subfractions were analyzed by equilibrium density gradient ultracentrifugation. RESULTS: Treatment with atorvastatin and fenofibrate reduced serum cholesterol by 30 % and 21 % (p = 0.046) (p-values for differences between treatment groups), triglycerides by 32 % and 45 %, LDL cholesterol by 28 % and 16 %, and increased HDL cholesterol by 3 % and 6 %, respectively. Atorvastatin and fenofibrate treatment resulted in the following changes of apoB and LDL subfractions: LDL-1 (1.019 - 1.031 kg/L) - 31 % and + 15 % (p = 0.028); LDL-2 (1.031 - 1.034 kg/L) - 14 % and + 57 % (p = 0.028); LDL-3 (1.034 - 1.037 kg/L) - 20 % and + 30 % (p = 0.028); LDL-4 (1.037 - 1.040 kg/L) - 25 % and - 6 %; LDL-5 (1.040 - 1.044 kg/L) - 29 % and - 38 %; and LDL-6 (1.044 - 1.063 kg/L) - 39 % and - 55 % (p = 0.028). As a consequence, fenofibrate reduced LDL density significantly (p = 0.028 versus atorvastatin). CONCLUSIONS: Atorvastatin decreased all LDL-subfractions to a similar extent (quantitative effect) whereas fenofibrate reduced predominantly dLDL and changed the LDL profile towards medium dense LDL-particles (qualitative effect). Since medium dense LDL have a higher affinity to the LDL-receptor fenofibrate may have a higher antiatherogenic potential than assessed by the reduction of total LDL-cholesterol and triglycerides alone.\n\nMärz, Winfried\n\n\n"
},
{
"text": "\n61339\nSerum gastrin in Zollinger-Ellison syndrome: I. Prospective study of fasting serum gastrin in 309 patients from the National Institutes of Health and comparison with 2229 cases from the literature.\n\nBerna, MJ\n\nHoffmann, KM\n\nSerrano, J\n\nGibril, F\n\nJensen, RT\n\nBeiträge in Fachzeitschriften\nISI:000242251500001\n17108778.0\n10.1097/01.md.0000236956.74128.76\nNone\nThe assessment of fasting serum gastrin (FSG) is essential for the diagnosis and management of patients with the Zollinger-Ellison syndrome (ZES). Although many studies have analyzed FSG levels in patients with gastrinoma, limited information has resulted from these studies because of their small size, different methodologies, and lack of correlations of FSG levels with clinical, laboratory, or tumor features in ZES patients. To address this issue, we report the results of a prospective National Institutes of Health (NIH) study of 309 patients with ZES and compare our results with those of 2229 ZES patients in 513 small series and case reports in the literature. In the NIH and literature ZES patients, normal FSG values were uncommon (0.3%-3%), as were very high FSG levels >100-fold normal (4.9%-9%). Two-thirds of gastrinoma patients had FSG values <10-fold normal that overlap with gastrin levels seen in more common conditions, like Helicobacter pylori infection or antral G-cell hyperplasia/hyperfunction. In these patients, FSG levels are not diagnostic of ZES, and gastrin provocative tests are needed to establish the diagnosis. Most clinical variables (multiple endocrine neoplasia type 1 status, presence or absence of the most common symptoms, prior medical treatment) are not correlated with FSG levels, while a good correlation of FSG values was found with other clinical features (prior gastric surgery, diarrhea, duration from onset to diagnosis). Increasing basal acid output, but not maximal acid output correlated closely with increasing FSG. Numerous tumoral features correlated with the magnitude of FSG in our study, including tumor location (pancreatic > duodenal), primary size (larger > smaller) and extent (liver metastases > local disease). In conclusion, this detailed analysis of FSG in a large number of patients with ZES allowed us to identify important clinical guidelines that should contribute to improved diagnosis and management of patients with ZES.\n\nHoffmann, Karl Martin\n\n\n"
},
{
"text": "\n80010\nCirculating and skeletal insulin-like growth factor-I (IGF-I) concentrations in two inbred strains of mice with different bone mineral densities.\n\nRosen, CJ\n\nDimai, HP\n\nVereault, D\n\nDonahue, LR\n\nBeamer, WG\n\nFarley, J\n\nLinkhart, S\n\nLinkhart, T\n\nMohan, S\n\nBaylink, DJ\n\nBeiträge in Fachzeitschriften\nISI:A1997XT24200003\n9276086.0\n10.1016/S8756-3282(97)00143-9\nNone\nRecent work has demonstrated differences in femoral bone mineral density between two common inbred strains of mice, C3H/HeJ (C3H) and C57BL/6J (B6), across a wide age range. To investigate one possible mechanism that could affect acquisition and maintenance of bone mass in mice, we studied circulatory and skeletal insulin-like growth factor-I (IGF-I) and femoral bone mineral density (F-BMD) by pQCT in C3H and B6 progenitor strains, as well as serum IGF-I obtained from matings between these two strains and mice bred from subsequent F1 intercrosses (F2). Serum IGF-I measured by radioimmunoassay was more than 35% higher in virgin progenitor C3H than virgin B6 at 1, 4, 8, and 10 months of age, and in 8-month-old C3H compared with B6 retired breeders (p < 0.001). In the progenitors, there was also a strong correlation between serum IGF-I and serum alkaline phosphatase (r = 0.51, p = 0.001). In the 4 month F1 females IGF-I levels and F-BMD were intermediate between C3H and B6 progenitors. In contrast, groups of F2 mice with the highest or lowest BMD also had the highest or lowest serum IGF-I (p = 0.0001). IGF-I accounted for > 35% of the variance in F-BMD among the F2 mice. Conditioned media from newborn C3H calvarial cultures had higher concentrations of IGF-I than media from B6 cultures, and cell layer extracts from C3H calvariae exhibited greater alkaline phosphatase activity than cultures from B6 calvarial cells (p < 0.0001). The skeletal content of IGF-I in C3H tibiae, femorae, and calvariae (6-14 weeks of age) was also significantly higher than IGF-I content in the same bones of the B6 mice (p < 0.05). These data suggest that a possible mechanism for the difference in acquisition and maintenance of bone mass between these two inbred strains is related to systemic and skeletal IGF-I synthesis.\n\nDimai, Hans\n\n\n"
},
{
"text": "\n119056\nThe need for flaps in burn surgery.\n\nHold, A\n\nKamolz, L\n\nFrey, M\n\nBeiträge in Fachzeitschriften\nISI:000273768300006\n19639541.0\n10.1055/s-0029-1220761\nNone\nBACKGROUND: Due to the improvement of surgery and intensive care more and more patients survive even severe burn injuries. Therefore we have to pay attention not only to survival alone but also to the achievement of a good quality of life. Thereby, one of the most important aspects is sufficient tissue coverage. After appropriate debridement functionally important structures may be exposed. Therefore, these areas require more than split skin coverage. These cases necessitate flap coverage for preservation of function or, respectively, limb salvage. In secondary reconstruction flaps are commonly used for scar revision. The aim of this study is to give more detailed information about the need for flaps in burn surgery. PATIENTS AND METHODS: All burn patients of our burn centre who received free or local flap coverage between January 1997 and February 2008 were analysed retrospectively. We evaluated the following parameters: indication (acute or late), flap type (pedicled or free flap), localisation, cause of accident and complication rate. Small local flaps like Z-plasties have been excluded. RESULTS: 45 patients have been included into this study. They received 53 flaps. In 53% the cause of accident was flame, in 22% scald and in 24% electrical burn, whereby electrical burn injuries most frequently required flap coverage related to their incidence. Most of the flaps have been performed for primary reconstruction. More than half of all flaps have been used for the upper extremity, concerning just the hand in 36%, 19% for the lower extremity, 15% for the trunk and 11% for the head. There have been three total flap failures during the study period. In all other cases we reached good results. Two of these flap failures occurred during the vulnerable phase between the 6th and the 21st day after trauma. CONCLUSION: Limb salvage was the dominant indication for primary reconstruction compared to the improvement of function and aesthetics for secondary reconstruction. The timing of reconstruction has an important influence on the flap outcome and has to be considered when the decision for reconstruction is made. So, if possible, the period between the 6th and the 21st day should not be chosen for flap coverage.\n\nKamolz, Lars-Peter\n\n\n"
},
{
"text": "\n127083\nComparable analgesic efficacy of transdermal buprenorphine in patients over and under 65 years of age.\n\nLikar, R\n\nVadlau, EM\n\nBreschan, C\n\nKager, I\n\nKorak-Leiter, M\n\nZiervogel, G\n\nBeiträge in Fachzeitschriften\nISI:000257198800008\n18574363.0\n10.1097/AJP.0b013e3181673b65\nNone\nObjectives: To compare the efficacy and tolerability of transdermal buprenorphine in elderly patients and 2 younger populations, all requiring analgesic treatment for moderate-to-severe chronic pain. Methods: Three equally sized age-groups (A >= 65, n = 30; B = 51 to 64, n = 27; C < 50 y, n = 25) were examined during 28-day treatment periods to detect potential differences in responsiveness (pain intensity, rescue medication, sleep duration) to the transdermal opioid. Results: Distribution of pain causing diagnoses was comparable between age-groups, predominantly musculoskeletal disorders (65% of all diagnoses), diseases of the nervous system (13%), injuries (8%); and cancer (5%). Mean buprenorphine patch.. doses were 35, 50, and 40 mu g/h (groups A, B, and C) at end of study. Pain intensity significantly decreased from pretreatment [visual analog scale (VAS) = 57% and numerical rating pain scale = 5.9 points) until the end of the study (day 28: 34% and 3.8 points; n = 55), without differences between age-groups (VAS day 28: A = 34%; B = 34%; C = 33%). Two-third of patients (A = 67%; B = 67%; C = 68%) completed the study at day 28; the rates and reasons for premature study termination were similar in all age-groups. Daily mean pain intensities (days 10 to 28) were even lower (P < 0.005) in elderly patients (VAS A = 35.8%) as compared with both younger age-groups (B = 39.8%; C = 39.9%). Sleep duration incidences above 6 hours improved from 34% to a plateau above 50% (A = 68%; B = 38%; C = 57%) for patients terminating the study as planned. The need for rescue medication was lowest in elderly patients (A = 107; B = 136; C = 253 mu g/d, days 10 to 28). The opioid typical adverse event profile (predominantly dizziness and nausea) and local skin tolerability were both comparable for younger and elderly patients. Conclusions: This investigation showed that the treatment of chronic pain with transdermal buprenorphine in elderly patients above the age of 65 years is at least as effective, tolerable, and safe as in patients studied in 2 age-groups below that age.\n\nBreschan, Christian\n\n\n"
},
{
"text": "\n127217\nImpact of clinical and histopathological parameters on disease specific survival in patients with collecting duct renal cell carcinoma: development of a disease specific risk model.\n\nMay, M\n\nFicarra, V\n\nShariat, SF\n\nZigeuner, R\n\nChromecki, T\n\nCindolo, L\n\nBurger, M\n\nGunia, S\n\nFeciche, B\n\nWenzl, V\n\nAziz, A\n\nChun, F\n\nBecker, A\n\nPahernik, S\n\nSimeone, C\n\nLongo, N\n\nZucchi, A\n\nAntonelli, A\n\nMirone, V\n\nStief, C\n\nNovara, G\n\nBrookman-May, S\n\nCORONA and SATURN projects\n\nYoung Academic Urologists Renal Cancer Group\n\nBeiträge in Fachzeitschriften\nISI:000321436600019\n23434943.0\n10.1016/j.juro.2013.02.035\nNone\nPurpose: Collecting duct renal cell carcinoma is a rare, aggressive histological subtype of renal cell carcinoma. Since few groups have evaluated the oncological prognosis in these patients based on clinical and pathological parameters, we assessed parameters prognostic for disease specific mortality. Materials and Methods: From a cohort of 14, 47 patients with renal cell carcinoma we retrieved the records of 95 with collecting duct renal cell carcinoma at a total of 16 European and American centers of the CORONA (Collaborative Research on Renal Neoplasms Association) and SATURN (Surveillance and Treatment Update Renal Neoplasms) projects, and another 2 centers. Multivariable Cox regression analysis was applied to determine the influence of parameters on disease specific mortality. Median followup was 48.1 months (IQR 24-103). Results: The disease specific survival rate at 1, 2, 5 and 10 years was 60.4%, 47.3%, 40.3% and 32.8%, respectively. American Society of Anesthesiologists (ASA) score 3-4, tumor size greater than 7 cm, stage M1, Fuhrman grade 3-4 and lymphovascular invasion independently predicted disease specific mortality. Based on these parameters, patients were divided into 26 (27%) at low, 13 (14%) at intermediate and 56 (59%) at high risk with a 5-year disease specific survival rate of 96%, 62% and 8%, respectively (bootstrap corrected c-index 0.894, 95% CI 0.820-0.967, p < 0.001). Conclusions: While patients with collecting duct renal cell carcinoma are commonly diagnosed at advanced stage and have poor prognosis after surgery, a subset has excellent survival. Histopathological features can help risk stratify patients based on the described, highly accurate risk model to predict disease specific mortality, facilitating patient counseling and risk based clinical decision making for adjuvant therapy and clinical trial inclusion.\n\nZigeuner, Richard\n\n\n"
},
{
"text": "\n127771\nPostoperative B-type natriuretic peptide for prediction of major cardiac events in patients undergoing noncardiac surgery: systematic review and individual patient meta-analysis.\n\nRodseth, RN\n\nBiccard, BM\n\nChu, R\n\nLurati Buse, GA\n\nThabane, L\n\nBakhai, A\n\nBolliger, D\n\nCagini, L\n\nCahill, TJ\n\nCardinale, D\n\nChong, CP\n\nCnotliwy, M\n\nDi Somma, S\n\nFahrner, R\n\nLim, WK\n\nMahla, E\n\nLe Manach, Y\n\nManikandan, R\n\nPyun, WB\n\nRajagopalan, S\n\nRadovic, M\n\nSchutt, RC\n\nSessler, DI\n\nSuttie, S\n\nVanniyasingam, T\n\nWaliszek, M\n\nDevereaux, PJ\n\nBeiträge in Fachzeitschriften\nISI:000329062100007\n23528538.0\n10.1097/ALN.0b013e31829083f1\nNone\nBackground: It is unclear whether postoperative B-type natriuretic peptides (i.e., BNP and N-terminal proBNP) can predict cardiovascular complications in noncardiac surgery. Methods: The authors undertook a systematic review and individual patient data meta-analysis to determine whether postoperative BNPs predict postoperative cardiovascular complications at 30 and 180 days or more. Results: The authors identified 18 eligible studies (n = 2, 51). For the primary outcome of 30-day mortality or nonfatal myocardial infarction, BNP of 245 pg/ml had an area under the curve of 0.71 (95% CI, 0.64-0.78), and N-terminal proBNP of 718 pg/ml had an area under the curve of 0.80 (95% CI, 0.77-0.84). These thresholds independently predicted 30-day mortality or nonfatal myocardial infarction (adjusted odds ratio [AOR] 4.5; 95% CI, 2.74-7.4; P < 0.001), mortality (AOR, 4.2; 95% CI, 2.29-7.69; P < 0.001), cardiac mortality (AOR, 9.4; 95% CI, 0.32-254.34; P < 0.001), and cardiac failure (AOR, 18.5; 95% CI, 4.55-75.29; P < 0.001). For greater than or equal to 180-day outcomes, natriuretic peptides independently predicted mortality or nonfatal myocardial infarction (AOR, 3.3; 95% CI, 2.58-4.3; P < 0.001), mortality (AOR, 2.2; 95% CI, 1.67-86; P < 0.001), cardiac mortality (AOR, 2.1; 95% CI, 0.051, 85.17; P < 0.001), and cardiac failure (AOR, 3.5; 95% CI, 1.0-9.34; P = 0.022). Patients with BNP values of 0-250, greater than 250-400, and greater than 400 pg/ml suffered the primary outcome at a rate of 6.6, 15.7, and 29.5%, respectively. Patients with N-terminal proBNP values of 0-300, greater than 300-900, and greater than 900 pg/ml suffered the primary outcome at a rate of 1.8, 8.7, and 27%, respectively. Conclusions: Increased postoperative BNPs are independently associated with adverse cardiac events after noncardiac surgery.\n\nMahla, Elisabeth\n\n\n"
},
{
"text": "\n132123\nRenewal of the air-water interface as a critical system parameter of protein stability: aggregation of the human growth hormone and its prevention by surface-active compounds.\n\nWiesbauer, J\n\nPrassl, R\n\nNidetzky, B\n\nBeiträge in Fachzeitschriften\nISI:000328437000014\n24224491.0\n10.1021/la4028223\nNone\nSoluble proteins are often highly unstable under mixing conditions that involve dynamic contacting between the main liquid phase and a gas phase. The recombinant human growth hormone (rhGH) was recently shown to undergo aggregation into micrometer-sized solid particles composed of non-native (mis- or unfolded) protein, once its solutions were stirred or shaken to generate a continuously renewed air-water interface. To gain deepened understanding and improved quantification of the air-water interface effect on rhGH stability, we analyzed the protein's aggregation rate (r(agg)) at controlled specific air-water surface areas (a(G/L)) established by stirring or bubble aeration. We show that in spite of comparable time-averaged values for a(G/L) (≈ 100 m(2)/m(3)), aeration gave a 40-fold higher r(agg) than stirring. The enhanced r(agg) under aeration was ascribed to faster macroscopic regeneration of free a(G/L) during aeration as compared to stirring. We also show that r(agg) was independent of the rhGH concentration in the range 0.67 - 6.7 mg/mL, and that it increased linearly dependent on the available a(G/L). The nonionic surfactant Pluronic F-68, added in 1.6-fold molar excess over rhGH present, resulted in complete suppression of r(agg). Foam formation was not a factor influencing r(agg). Using analysis by circular dichroism spectroscopy and small-angle X-ray scattering, we show that in the presence of Pluronic F-68 under both stirring and aeration, the soluble protein retained its original fold, featuring native-like relative composition of secondary structural elements. We further provide evidence that the efficacy of Pluronic F-68 resulted from direct, probably hydrophobic protein-surfactant interactions that prevented rhGH from becoming attached to the air-water interface. Surface-induced aggregation of rhGH is suggested to involve desorption of non-native protein from the air-water interface as the key limiting step. Proteins or protein aggregates released back into the bulk liquid appear to be essentially insoluble.\n\nPrassl, Ruth\n\n\n"
},
{
"text": "\n156284\nGenetic Variants Associated with Circulating Parathyroid Hormone.\n\nRobinson-Cohen, C\n\nLutsey, PL\n\nKleber, ME\n\nNielson, CM\n\nMitchell, BD\n\nBis, JC\n\nEny, KM\n\nPortas, L\n\nEriksson, J\n\nLorentzon, M\n\nKoller, DL\n\nMilaneschi, Y\n\nTeumer, A\n\nPilz, S\n\nNethander, M\n\nSelvin, E\n\nTang, W\n\nWeng, LC\n\nWong, HS\n\nLai, D\n\nPeacock, M\n\nHannemann, A\n\nVölker, U\n\nHomuth, G\n\nNauk, M\n\nMurgia, F\n\nPattee, JW\n\nOrwoll, E\n\nZmuda, JM\n\nRiancho, JA\n\nWolf, M\n\nWilliams, F\n\nPenninx, B\n\nEcons, MJ\n\nRyan, KA\n\nOhlsson, C\n\nPaterson, AD\n\nPsaty, BM\n\nSiscovick, DS\n\nRotter, JI\n\nPirastu, M\n\nStreeten, E\n\nMärz, W\n\nFox, C\n\nCoresh, J\n\nWallaschofski, H\n\nPankow, JS\n\nde Boer, IH\n\nKestenbaum, B\n\nBeiträge in Fachzeitschriften\nISI:000400225100024\n27927781.0\n10.1681/ASN.2016010069\nPMC5407713\nParathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29, 55 participants of European ancestry from 13 cohort studies (n=22, 53 and n=6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry. We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 (P=4.2 × 10-53), a gene that encodes the primary catabolic enzyme for 1, 5-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of the minor allele at this SNP associated with 7% higher serum PTH concentration. The other SNPs associated with serum PTH concentration included rs4074995 within RGS14 (P=6.6 × 10-17), rs219779 adjacent to CLDN14 (P=3.5 × 10-16), rs4443100 near RTDR1 (P=8.7 × 10-9), and rs73186030 near CASR (P=4.8 × 10-8). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued.\n Copyright © 2017 by the American Society of Nephrology.\n\nMärz, Winfried\n\nPilz, Stefan\n\n\n"
},
{
"text": "\n184846\nFactors influencing daily treatment choices in multiple sclerosis: practice guidelines, biomarkers and burden of disease.\n\nBerger, T\n\nAdamczyk-Sowa, M\n\nCsépány, T\n\nFazekas, F\n\nFabjan, TH\n\nHoráková, D\n\nLedinek, AH\n\nIlles, Z\n\nKobelt, G\n\nJazbec, SŠ\n\nKlímová, E\n\nLeutmezer, F\n\nRejdak, K\n\nRozsa, C\n\nSellner, J\n\nSelmaj, K\n\nŠtouracˇ, P\n\nSzilasiová, J\n\nTurcˇáni, P\n\nVachová, M\n\nVanecková, M\n\nVécsei, L\n\nHavrdová, EK\n\nBeiträge in Fachzeitschriften\nISI:000597939700001\n33335562.0\n10.1177/1756286420975223\nPMC7724259\nAt two meetings of a Central European board of multiple sclerosis (MS) experts in 2018 and 2019 factors influencing daily treatment choices in MS, especially practice guidelines, biomarkers and burden of disease, were discussed. The heterogeneity of MS and the complexity of the available treatment options call for informed treatment choices. However, evidence from clinical trials is generally lacking, particularly regarding sequencing, switches and escalation of drugs. Also, there is a need to identify patients who require highly efficacious treatment from the onset of their disease to prevent deterioration. The recently published European Committee for the Treatment and Research in Multiple Sclerosis/European Academy of Neurology clinical practice guidelines on pharmacological management of MS cover aspects such as treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and are based on expert consensus statements. However, the recommendations constitute an excellent framework that should be adapted to local regulations, MS center capacities and infrastructure. Further, available and emerging biomarkers for treatment guidance were discussed. Magnetic resonance imaging parameters are deemed most reliable at present, even though complex assessment including clinical evaluation and laboratory parameters besides imaging is necessary in clinical routine. Neurofilament-light chain levels appear to represent the current most promising non-imaging biomarker. Other immunological data, including issues of immunosenescence, will play an increasingly important role for future treatment algorithms. Cognitive impairment has been recognized as a major contribution to MS disease burden. Regular evaluation of cognitive function is recommended in MS patients, although no specific disease-modifying treatment has been defined to date. Finally, systematic documentation of real-life data is recognized as a great opportunity to tackle unresolved daily routine challenges, such as use of sequential therapies, but requires joint efforts across clinics, governments and pharmaceutical companies.\n © The Author(s), 2020.\n\nFazekas, Franz\n\n\n"
}
]
}