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Immediately after the start of the COVID-19 pandemic in Early 2020, most affected countries reacted with strict lockdown to limit the spread of the virus. Since that time, the measures were adapted on a short time basis according to certain numbers (i.e., number of infected, utilization of intensive care units). Implementing a long-term optimal strategy was not possible since a forecast when R&D will succeed in developing an effective vaccination was not available. Our paper closes this gap by assuming a stochastic arrival rate of the COVID-19 vaccine with the corresponding change in the optimal policy regarding the accompanying optimal lockdown measures. The first finding is that the lockdown should be intensified after the vaccine approval if the pace of the vaccination campaign is rather slow. Secondly, the anticipation of the vaccination arrival also leads to a stricter lockdown in the period without vaccination. For both findings, an intuitive explanation is offered.

In this paper we compare several types of economic dependency ratios for a selection of European countries. These dependency ratios take into account not only the demographic structure of the population, but also the differences in agespecific economic behaviour such as labour market activity, income and consumption as well as age-specific public transfers. In selected simulations where we combine patterns of age-specific economic behaviour and transfers with population projections, we show that in all countries population ageing would lead to a pronounced increase in dependency ratios if present age-specific patterns were not to change. Our analysis of cross-country differences in economic dependency demonstrates that these differences are driven by both differences in age-specific economic behaviour and in the age composition of the populations. The choice of which dependency ratio to use in a specific policy context is determined by the nature of the question to be answered. The comparison of our various dependency ratios across countries gives insights into which strategies might be effective in mitigating the expected increase in economic dependency due to demographic change.

In this paper we compare several types of economic dependency ratios for a selection of European countries. These dependency ratios take not only into account the demographic structure of the population, but also the differences in age-specific economic behaviour such as labour market activity, income and consumption. In simulations where we combine patterns of age-specific economic behaviour with population projections, we show that in all countries population ageing would lead to a pronounced increase in dependency ratios if present age-specific patterns were not to change. Our analysis of cross-country differences in economic dependency demonstrates that these differences are driven by both differences in age-specific economic behaviour and in the age composition of the populations. In addition, the specific deffinitions of the ratios will result in different interpretations of dependency. The choice which dependency ratio to use in a specific policy context is determined by the nature of the question to be answered. The comparison of our various dependency ratios across countries gives insights into which strategies might be effective in mitigating the expected increase in economic dependency due to demographic change.

Paola Bronson, Lennart Hammarström and colleagues report a genome-wide association study meta-analysis of selective IgA immunodeficiency in Europeans. They identify four new loci and a rare variant of a previously associated gene, IFIH1 . Selective immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in Europeans. Our genome-wide association study (GWAS) meta-analysis of 1,635 patients with IgAD and 4,852 controls identified four new significant ( P < 5 × 10 −8 ) loci and association with a rare IFIH1 variant (p.Ile923Val). Peak new variants ( PVT1 , P = 4.3 × 10 −11 ; ATG13 – AMBRA1 , P = 6.7 × 10 −10 ; AHI1 , P = 8.4 × 10 −10 ; CLEC16A , P = 1.4 × 10 −9 ) overlapped with autoimmune markers (3/4) and correlated with 21 putative regulatory variants, including expression quantitative trait loci (eQTLs) for AHI1 and DEXI and DNase hypersensitivity sites in FOXP3 + regulatory T cells. Pathway analysis of the meta-analysis results showed striking association with the KEGG pathway for IgA production (pathway P < 0.0001), with 22 of the 30 annotated pathway genes containing at least one variant with P ≤ 0.05 in the IgAD meta-analysis. These data suggest that a complex network of genetic effects, including genes known to influence the biology of IgA production, contributes to IgAD.

Immune checkpoint inhibitor treatment has the potential to prolong survival in non-small cell lung cancer (NSCLC), however, some of the patients develop resistance following initial response. Here, we analyze the immune phenotype of matching tumor samples from a cohort of NSCLC patients showing good initial response to immune checkpoint inhibitors, followed by acquired resistance at later time points. By using imaging mass cytometry and whole exome and RNA sequencing, we detect two patterns of resistance¨: One group of patients is characterized by reduced numbers of tumor-infiltrating CD8 +  T cells and reduced expression of PD-L1 after development of resistance, whereas the other group shows high CD8 +  T cell infiltration and high expression of PD-L1 in addition to markedly elevated expression of other immune-inhibitory molecules. In two cases, we detect downregulation of type I and II IFN pathways following progression to resistance, which could lead to an impaired anti-tumor immune response. This study thus captures the development of immune checkpoint inhibitor resistance as it progresses and deepens our mechanistic understanding of immunotherapy response in NSCLC. Acquired resistance to immune checkpoint inhibitors limits therapeutic success in non-small-cell lung cancer, however, the underpinning immune parameters are largely unknown. Here authors distinguish resistance types based on immune cell infiltration, immune checkpoint molecule and cytokine expression level, using paired samples from patients in the sensitive and in the resistant disease phase.

Proteomics, lipidomics and metabolomics of single gene deletion yeast strains sheds light on mitochondrial protein biology. Mitochondrial dysfunction is associated with many human diseases, including cancer and neurodegeneration, that are often linked to proteins and pathways that are not well-characterized. To begin defining the functions of such poorly characterized proteins, we used mass spectrometry to map the proteomes, lipidomes, and metabolomes of 174 yeast strains, each lacking a single gene related to mitochondrial biology. 144 of these genes have human homologs, 60 of which are associated with disease and 39 of which are uncharacterized. We present a multi-omic data analysis and visualization tool that we use to find covariance networks that can predict molecular functions, correlations between profiles of related gene deletions, gene-specific perturbations that reflect protein functions, and a global respiration deficiency response. Using this multi-omic approach, we link seven proteins including Hfd1p and its human homolog ALDH3A1 to mitochondrial coenzyme Q (CoQ) biosynthesis, an essential pathway disrupted in many human diseases. This Resource should provide molecular insights into mitochondrial protein functions.

Adenoid cystic carcinoma (AdCC) is a salivary gland neoplasm that infrequently appears in the sinonasal region. The aim of this study was to evaluate the outcome and clinicopathological parameters of sinonasal AdCC. A retrospective analysis was conducted on all cases of AdCC affecting the nasal cavity or paranasal sinuses between 2000 and 2018 at the University Hospital Zurich. Tumor material was examined for morphological features and analyzed for molecular alterations. A total of 14 patients were included. Mean age at presentation was 57.7 years. Sequencing revealed MYB::NFIB gene fusion in 11/12 analyzable cases. Poor prognostic factors were solid variant (p < 0.001), histopathological high-grade transformation (p < 0.001), and tumor involvement of the sphenoid sinus (p = 0.02). The median recurrence-free survival (RFS) and OS were 5.2 years and 11.3 years. The RFS rates at 1-, 5-, and 10-year were 100%, 53.8%, and 23.1%. The OS rates at 1-, 5-, and 10- years were 100%, 91.7%, and 62.9%, respectively. In Conclusion, the solid variant (solid portion > 30%), high-grade transformation, and sphenoid sinus involvement are negative prognostic factors for sinonasal AdCC. A high prevalence of MYB::NFIB gene fusion may help to correctly classify diagnostically challenging (e.g. metatypical) cases.

Sarcopenic obesity (SO) is a geriatric syndrome characterized by the disproportion between the amount of lean mass and fat mass. Exercise decreases fat and maintains muscle mass; however, older people fail to exercise at doses sufficient to affect musculoskeletal and cardiometabolic risk factors. The aim of this study was to evaluate the effect of whole-body electromyostimulation (WB-EMS), a time-efficient, joint-friendly and highly individualized exercise technology, on sarcopenia and SO in older men. A total of 100 community-dwelling northern Bavarian men aged ≥70 years with sarcopenia and obesity were randomly (1-1-1) assigned to either 16 weeks of 1) WB-EMS and protein supplementation (WB-EMS&P), 2) isolated protein supplementation or 3) nonintervention control. WB-EMS consisted of 1.5×20 min (85 Hz, 350 µs, 4 s of strain to 4 s of rest) applied with moderate-to-high intensity while moving. We further generated a daily protein intake of 1.7-1.8 g/kg/body mass per day. The primary study end point was Sarcopenia Z-Score, and the secondary study end points were body fat rate (%), skeletal muscle mass index (SMI) and handgrip strength. Intention-to-treat analysis determined a significantly favorable effect of WB-EMS&P ( <0.001) and protein ( =0.007) vs control. Both groups significantly ( <0.001) lost body fat (WB-EMS&P: 2.1%; protein: 1.1%) and differed significantly ( ≤0.004) from control (0.3%). Differences between WB-EMS&P and protein were significant for the Sarcopenia Z-Score ( =0.39) and borderline nonsignificant ( =0.051) for body fat. SMI increased significantly in both groups ( <0.001 and =0.043) and decreased significantly in the control group (CG; =0.033); differences between the verum groups and control were significant ( ≤0.009). Handgrip strength increased in the WB-EMS group (1.90 kg; <0.001; =0.050 vs control) only. No adverse effects of WB-EMS or protein supplementation were recorded. WB-EMS&P is a safe and efficient method for tackling sarcopenia and SO in older men. However, the suboptimum effect on functional parameters should be addressed by increased voluntary activation during WB-EMS application.

Haematoma expansion is a major cause of mortality in intracranial haemorrhage related to vitamin K antagonists (VKA-ICH). Normalisation of the international normalised ratio (INR) is recommended, but optimum haemostatic management is controversial. We assessed the safety and efficacy of fresh frozen plasma (FFP) versus prothrombin complex concentrate (PCC) in patients with VKA-ICH. We did an investigator-initiated, multicentre, prospective, randomised, open-label, blinded-endpoint trial. Patients aged at least 18 years with VKA-ICH who presented within 12 h after symptom onset with an INR of at least 2·0 were randomly assigned (1:1) by numbered sealed envelopes to 20 mL/kg of intravenous FFP or 30 IU/kg of intravenous four-factor PCC within 1 h after initial cerebral CT scan. The primary endpoint was the proportion of patients with INR 1·2 or lower within 3 h of treatment initiation. Masking of treatment was not possible, but the primary analysis was observer masked. Analyses were done using a treated-as-randomised approach. This trial is registered with EudraCT, number 2008-005653-37, and ClinicalTrials.gov, number NCT00928915. Between Aug 7, 2009, and Jan 9, 2015, 54 patients were randomly assigned (26 to FFP and 28 to PCC) and 50 received study drug (23 FFP and 27 PCC). The trial was terminated on Feb 6, 2015, after inclusion of 50 patients after a safety analysis because of safety concerns. Two (9%) of 23 patients in the FFP group versus 18 (67%) of 27 in the PCC group reached the primary endpoint (adjusted odds ratio 30·6, 95% CI 4·7–197·9; p=0·0003). 13 patients died: eight (35%) of 23 in the FFP group (five from haematoma expansion, all occurring within 48 h after symptom onset) and five (19%) of 27 in the PCC group (none from haematoma expansion), the first of which occurred on day 5 after start of treatment. Three thromboembolic events occurred within 3 days (one in the FFP group and two in the PCC group), and six after day 12 (one and five). 43 serious adverse events (20 in the FFP group and 23 in the PCC group) occurred in 26 patients. Six serious adverse events were judged to be FFP related (four cases of haematoma expansion, one anaphylactic reaction, and one ischaemic stroke) and two PCC related (ischaemic stroke and pulmonary embolism). In patients with VKA-related intracranial hemorrhage, four-factor PCC might be superior to FFP with respect to normalising the INR, and faster INR normalisation seemed to be associated with smaller haematoma expansion. Although an effect of PCC on clinical outcomes remains to be shown, our data favour the use of PCC over FFP in intracranial haemorrhage related to VKA. Octapharma.

The purpose of this retrospective study was to investigate response of sinonasal mucosal melanoma (SMM) patients to treatment with immune checkpoint inhibitors (ICI), using hybrid PET imaging. Fifteen SMM patients underwent hybrid PET imaging before and three months after initiation of ICI. The disease-specific survival (DSS) was calculated. Quantitative PET parameters of the primary tumor and their association with DSS and therapy response were investigated. Nine of the fifteen (60%) patients responded to ICI therapy. Patients with therapy response depicted on hybrid PET imaging had better DSS than those without ( p  = 0.0058). Quantitative PET parameters of the initial PET harbored no association with DSS or therapy response. However, these findings lack of sufficient statistical power and must be interpreted with caution. The first restaging PET-imaging after ICI initiation can help stratify patients with regard to DSS.