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From 2025, Health Technology Developers (HTDs) have to submit EU HTA dossiers. The joint clinical assessment (JCA) aims to streamline HTA processes and access to medicinal products across Europe. Currently, German HTA bodies IQWiG and G-BA actively shape the JCA methodology. Here we examine if German HTA dossier requirements are suitable for the JCA. We compare the number of safety endpoint and subgroup analyses in German dossiers with analyses considered in IQWIG's benefit assessment and evaluate if these analyses were considered by the G-BA. We further investigated how the number of analyses was affected by the latest change in the German dossier template. With the current template, HTDs report in median 2.6 times more analyses on adverse events (AE) and 1.1 times more subgroup categories than in the previous template. IQWiG does not consider 33% of AE analyses and 73% of the subgroup categories presented by the HTD under the current template. G-BA considered the same AE as IQWiG in 76% of cases. Subgroups were uncommented by G-BA in most cases, independent of the template (previous: 93%, current 85%) and unconsidered in the conclusion on additional benefit (previous: 77%, current 69%). Thus, changes in the dossier template drastically increased HTD workload, but additional analyses seem unconsidered by the HTA bodies. With a broader scope in JCA, this effect could be amplified. To mitigate duplicative efforts and ensure prompt availability of medicinal products as envisioned by the HTAR, we suggest well-chosen and precise dossier requirements, early consultations, and early HTD engagement., (© 2023. The Author(s).)

The mechanical muscular oscillations are rarely the objective of investigations regarding the identification of a biomarker for Parkinson's disease (PD). Therefore, the aim of this study was to investigate whether or not this specific motor output differs between PD patients and controls. The novelty is that patients without tremor are investigated performing a unilateral isometric motor task. The force of armflexors and the forearm acceleration (ACC) were recorded as well as the mechanomyography of the biceps brachii (MMGbi), brachioradialis (MMGbra) and pectoralis major (MMGpect) muscles using a piezoelectric-sensor-based system during a unilateral motor task at 70% of the MVIC. The frequency, a power-frequency-ratio, the amplitude variation, the slope of amplitudes and their interlimb asymmetries were analysed. The results indicate that the oscillatory behavior of muscular output in PD without tremor deviates from controls in some parameters: Significant differences appeared for the power-frequency-ratio (p = 0.001, r = 0.43) and for the amplitude variation (p = 0.003, r = 0.34) of MMGpect. The interlimb asymmetries differed significantly concerning the power-frequency-ratio of MMGbi (p = 0.013, r = 0.42) and MMGbra (p = 0.048, r = 0.39) as well as regarding the mean frequency (p = 0.004, r = 0.48) and amplitude variation of MMGpect (p = 0.033, r = 0.37). The mean (M) and variation coefficient (CV) of slope of ACC differed significantly (M: p = 0.022, r = 0.33; CV: p = 0.004, r = 0.43). All other parameters showed no significant differences between PD and controls. It remains open, if this altered mechanical muscular output is reproducible and specific for PD.

Surface temperature is a fundamental parameter of Earth's climate. Its evolution through time is commonly reconstructed using the oxygen isotope and the clumped isotope compositions of carbonate archives. However, reaction kinetics involved in the precipitation of carbonates can introduce inaccuracies in the derived temperatures. Here, we show that dual clumped isotope analyses, i.e., simultaneous ∆ 47 and ∆ 48 measurements on the single carbonate phase, can identify the origin and quantify the extent of these kinetic biases. Our results verify theoretical predictions and evidence that the isotopic disequilibrium commonly observed in speleothems and scleractinian coral skeletons is inherited from the dissolved inorganic carbon pool of their parent solutions. Further, we show that dual clumped isotope thermometry can achieve reliable palaeotemperature reconstructions, devoid of kinetic bias. Analysis of a belemnite rostrum implies that it precipitated near isotopic equilibrium and confirms the warmer-than-present temperatures during the Early Cretaceous at southern high latitudes.

Thermal shift assays measure the stability of macromolecules and macromolecular assemblies as a function of temperature. The Particle Stability Thermal Release Assay (PaSTRy) of picornaviruses is based on probes becoming strongly fluorescent upon binding to hydrophobic patches of the protein capsid (e.g., SYPRO Orange) or to the viral RNA genome (e.g., SYTO-82) that become exposed upon heating virus particles. PaSTRy has been exploited for studying the stability of viral mutants, viral uncoating, and the effect of capsid-stabilizing compounds. While the results were usually robust, the thermal shift assay with SYPRO Orange is sensitive to surfactants and EDTA and failed at least to correctly report the effect of excipients on an inactivated poliovirus 3 vaccine. Furthermore, interactions between the probe and capsid-binding antivirals as well as mutual competition for binding sites cannot be excluded. To overcome these caveats, we assessed differential scanning fluorimetry with a nanoDSF device as a label-free alternative. NanoDSF monitors the changes in the intrinsic tryptophan fluorescence (ITF) resulting from alterations of the 3D-structure of proteins as a function of the temperature. Using rhinovirus A2 as a model, we demonstrate that nanoDFS is well suited for recording the temperature-dependence of conformational changes associated with viral uncoating with minute amounts of sample. We compare it with orthogonal methods and correlate the increase in viral RNA exposure with PaSTRy measurements. Importantly, nanoDSF correctly identified the thermal stabilization of RV-A2 by pleconaril, a prototypic pocket-binding antiviral compound. NanoDFS is thus a label-free, high throughput-customizable, attractive alternative for the discovery of capsid-binding compounds impacting on viral stability., (Copyright © 2020 Real-Hohn, Groznica, Löffler, Blaas and Kowalski.)

Reconstructing long-term continental temperature change provides the required counterpart to age equivalent marine records and can reveal how terrestrial and marine temperatures were related during times of extreme climate change such as the Miocene Climatic Optimum (MCO) and the following Middle Miocene Climatic Transition (MMCT). Carbonate clumped isotope temperatures (T(Δ 47 )) from 17.5 to 14.0 Ma Central European paleosols (Molasse Basin, Switzerland) display a temperature pattern during the MCO that is similar to coeval marine temperature records. Maximum temperatures in the long-term soil T(Δ 47 ) record (at 16.5 and 14.9 Ma) lag maximum ocean bottom water temperatures, lead global ice volume, and mark the initiation of minimum global ice volume phases. The suggested onset of the MMCT, deduced by a marked and rapid decline in Molasse Basin soil temperatures is coeval with cooling reported in high-latitudinal marine records. This is best explained by a change in the seasonal timing of soil carbonate formation that was likely driven by a modification of rainfall seasonality and thus by a major reorganization of mid-latitude atmospheric circulation across Central Europe. In particular, our data suggest a strong climate coupling between the North Atlantic and Central Europe already in the middle Miocene.

Brachiopod shells are the most widely used geological archive for the reconstruction of the temperature and the oxygen isotope composition of Phanerozoic seawater. However, it is not conclusive whether brachiopods precipitate their shells in thermodynamic equilibrium. In this study, we investigated the potential impact of kinetic controls on the isotope composition of modern brachiopods by measuring the oxygen and clumped isotope compositions of their shells. Our results show that clumped and oxygen isotope compositions depart from thermodynamic equilibrium due to growth rate-induced kinetic effects. These departures are in line with incomplete hydration and hydroxylation of dissolved CO 2 . These findings imply that the determination of taxon-specific growth rates alongside clumped and bulk oxygen isotope analyses is essential to ensure accurate estimates of past ocean temperatures and seawater oxygen isotope compositions from brachiopods.

It is well known that a subtle nonlinearity can occur during clumped isotope analysis of CO2 that - if remaining unaddressed - limits accuracy. The nonlinearity is induced by a negative background on the m/z 47 ion Faraday cup, whose magnitude is correlated with the intensity of the m/z 44 ion beam. The origin of the negative background remains unclear, but is possibly due to secondary electrons. Usually, CO2 gases of distinct bulk isotopic compositions are equilibrated at 1000 °C and measured along with the samples in order to be able to correct for this effect. Alternatively, measured m/z 47 beam intensities can be corrected for the contribution of secondary electrons after monitoring how the negative background on m/z 47 evolves with the intensity of the m/z 44 ion beam. The latter correction procedure seems to work well if the m/z 44 cup exhibits a wider slit width than the m/z 47 cup. Here we show that the negative m/z 47 background affects precision of dual inlet-based clumped isotope measurements of CO2 unless raw m/z 47 intensities are directly corrected for the contribution of secondary electrons. Moreover, inaccurate results can be obtained even if the heated gas approach is used to correct for the observed nonlinearity. The impact of the negative background on accuracy and precision arises from small imbalances in m/z 44 ion beam intensities between reference and sample CO2 measurements. It becomes the more significant the larger the relative contribution of secondary electrons to the m/z 47 signal is and the higher the flux rate of CO2 into the ion source is set. These problems can be overcome by correcting the measured m/z 47 ion beam intensities of sample and reference gas for the contributions deriving from secondary electrons after scaling these contributions to the intensities of the corresponding m/z 49 ion beams. Accuracy and precision of this correction are demonstrated by clumped isotope analysis of three internal carbonate standards. The proposed correction scheme can be easily applied if the slit width of the m/z 49 Faraday cup is bigger than that of the m/z 47 cup.

Introduction: Studies analysing the frequency of rhythm disorders in patients with cirrhosis are rare. Nevertheless, factors triggering rhythm disorders occur frequently in cirrhosis. Therefore, a retrospective case control study was performed investigating the frequency of cardiac arrhythmia in a population of patients with cirrhosis while evaluating several associated factors., Methods: The files of patients with cirrhosis (n  =  293) in the period 2004 - 2008 were analysed retrospectively regarding cardiac arrhythmia. The frequency of cardiac arrhythmia in the presence of relevant risk factors was analysed using χ ²tests and logistic regression models., Results: 61.1  % of all patients were male (mean age 61.7 years) and 38.9  % female (mean age 62.8 years). The severity of cirrhosis according to the Child-Pugh score (CP) was as follows: CP A 43.3  %, CP B 32.8  % and CP C 23.9  %. Altogether, rhythm disorders were diagnosed in 16.4  % (48/293) of the study population, most frequently atrial fibrillation (68.8  %) and atrial flutter (6.7  %). An advanced age and comorbidities such as arteriosclerotic diseases, hypercholesterinemia (p  <  0.001, each) and diabetes mellitus (p  =  0.013) correlated significantly with the frequency of rhythm disorders which occurred more often in males than in females (p  = 0.066). Ongoing alcohol abuse, the severity of cirrhosis and arterial hypertension were not associated significantly with the onset of rhythm disorders. 84.4  % of all patients with cardiac arrhythmia were treated by diuretics. Decreased (<  3.5 mmol/L) and elevated (>  5 mmol/L) potassium values were observed in 60.6  % of the study collective. Rhythm disorders were more often observed in patients with hyperkalemia (especially atrioventricular block, p  < 0.01)., Conclusion: Compared to the average population, the prevalence of atrial fibrillation was increased in our cirrhotic cohort. The occurrence of rhythm disorders was significantly associated with arteriosclerotic diseases, hypercholesterinaemia and diabetes mellitus. Additionally, cardiac arrhythmia must be considered under diuretic therapy and in the presence of electrolyte disturbances., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Nonhepatic cancer risk of cirrhotic patients seems to be increased. Major surgery and chemotherapy in cirrhosis are associated with increased mortality and morbidity, which limits treatment., Aim: The aims of this study were analysis of (a) prevalence, (b) outcome after treatment, (c) of survival rate and (d) predictors of survival in a cirrhotic population., Patients and Methods: The study population was assembled retrospectively from a database of hospitalized patients (n=354). The Kaplan-Meier method was used to calculate the survival rate, and Cox regression analysis was performed to identify prognostic parameters., Results: Altogether, 84 neoplasms in 70 patients were observed. A total of 54 were nonhepatic (15.3%) mainly colorectal carcinoma, prostate cancer and tobacco-related neoplasms. TNM stage was the best prognostic parameter (p<0.0001). Low bilirubin (p=0.01), normal albumin (p=0.005) and absence of ascites (p<0.0001) were also related significantly to longer survival. The rate of postinterventional death after specific treatment was high. A proportion of patients received no specific therapy due to reduced physical performance, even in cases of limited disease., Conclusion: Our data confirm the increased risk of cirrhotic patients for developing nonhepatic cancer. Advanced TNM stage was associated with reduced long-term survival. Scoring systems, such as Child's classification and Model of Elevated Liver Disease (MELD) score, were suitable parameters to predict mortality. Oncological management in patients with cirrhosis must be on an individual basis, independent from TNM classification.

Uip to 20% of patients with liver cirrhosis develop hepatogenous diabetesdue to the hepatocellular functional loss and insulin resistance. Optimizing diabetic metabolic conditions is not only important to avoid typical late complications of diabetes, but also cirrhosis-associated complications e.g. gastrointestinal bleeding, hepatic encephalopathy or the occurence of hepatocellular carcinoma. So far there have beenno recommendations orguidelines for the diagnosis and treatmentof hepatogenous diabetes. The medical teatment of a diabetic condition is mainly influenced by its side effects. The risk of hypoglycemia must be considered carefully during drug treatment, especially in patients with chronic alcohol abuse. Suitable oral antidiabetics are glinides and short-acting sulfonylureas or possibly meal-related insulin administration with short-acting insulins or rapid-acting insulin analogues. Biguanide and PPAR-gamma agonists are contraindicated because of side effects in liver cirrhosis. Regarding basic treatment, an adequate daily energy and protein supply should be ensuredbecause the majority of patients with liver cirrhosis are malnourished., (Georg Thieme Verlag KG Stuttgart, New York.)

Medical treatment of patients with liver cirrhosis consists mainly of symptomatic therapy of associated complications. Apart from the classical complications of cirrhosis, e. g. ascites, portal hypertension or hepatic encephalopathy, other frequent complications are neglected in everyday medicine. The incidence of metabolic disturbances seems to be similar to the prevalence of classical complications of liver cirrhosis, such as portal hypertension or ascites. Osteoporosis is an important manifestation of hepatic osteopathy, especially in chronic cholestatic diseases and in candidates for liver transplantation, which necessitates timely adequate diagnostic test (e. g. osteodensitometry) and treatment (pre-emptive and causal). Malnutrition, especially when related to protein- and energy supply, is very common in patients with liver cirrhosis and has prognostic significance regarding mortality and complication rates. A sufficient daily energy and protein supply should be ensured, one which is higher than that for the normal population. Additional substitution of vitamins and trace elements is indicated when symptoms of deficiency became apparent., (Georg Thieme Verlag KG Stuttgart, New York.)

A total of 1202 orthopantograms of young dental patients were analyzed to assess the correlation of third molar root development with chronological age. The investigated patients were treated at a university dental clinic on an outpatient basis, included a variety of demographic characteristics (600 males and 602 females, 28% of other than central European background), and were 15-24 years old when the radiographs were obtained. Radiographs in which more than one third molar were either missing due to agenesia or extraction, or not evaluable because of deep destruction or marked tilting, were not included in the analysis. Our findings show that the growth patterns of third molars, based on seven defined stages of root development, did correlate with chronological age; age estimation when applied to a specific individual would involve a margin of error of +/- 2-4 years. There were no significant differences between the left and right jaw segments, but the stage of root development was generally more advanced in the upper than in the lower third molars. Root development was also more advanced among boys than among girls of the same age. There were no apparent differences in growth patterns based on national/ethnic background. While only 2.5% of 18-year-olds revealed fully developed third molars in all four quadrants, this percentage leaped to 38.4% among the 21-year-olds. To summarize, while the developmental stage of third molars is not per se a highly useful indicator of chronological age in juveniles and young adults, it is nevertheless a valuable supplementary parameter given the scarcity of other available age indicators.

Unlabelled: 38 totally or partially incontinent patients following imperforate anus repair (age 6-15 years) tested a new polyurethane (PU) anal plug against another, widely used anal plug (PVA) in a randomized crossover trial. Plugs were tested 3 weeks each, data concerning bowel habits, handling and plug-related problems were collected by questionnaire before trial, at time of product change and after trial., Results: 15 of 38 patients did not complete the protocol, among them 6 with anal canal diameters too small for the smallest plug. During plug use, patients experienced enhanced awareness of repletion and urge. Stool consistence did not change in 82% of patients. There were no changes in children constipated prior to study (n = 8/23). 12,123 children were absolutely clean during use of either plug. 15 patients (68%) using the PU plug and 10 (45%) using the PVA plug felt secure from soiling during plug use. 74% of patients preferred the PU plug. Painful plug insertion, a feeling of pressure inside the anal canal and painful plug removal were reported with both plugs, but were less frequent with the PU plug., Conclusion: Anal plugs, regardless of their make, offer absolute cleanliness for periods of several hours to 66% of our incontinent patients. The PU plug (Conveen, Coloplast) is preferred by the patients and offers greater security than the PVA plug.