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The nsP3 macrodomain is a conserved protein interaction module that plays essential regulatory roles in host immune response by recognizing and removing posttranslational ADP-ribosylation sites during SARS-CoV-2 infection. Thus, targeting this protein domain may offer a therapeutic strategy to combat the current and future virus pandemics. To assist inhibitor development efforts, we report here a comprehensive set of macrodomain crystal structures complexed with diverse naturally-occurring nucleotides, small molecules as well as nucleotide analogues including GS-441524 and its phosphorylated analogue, active metabolites of remdesivir. The presented data strengthen our understanding of the SARS-CoV-2 macrodomain structural plasticity and it provides chemical starting points for future inhibitor development.
Background: To study neoadjuvant chemoradiotherapy (nCRT) and potential predictive factors for response in locally advanced oral cavity cancer (LA-OCC).
Methods: The INVERT trial is an ongoing single-center, prospective phase 2, proof-of-principle trial. Operable patients with stage III-IVA squamous cell carcinomas of the oral cavity were eligible and received nCRT consisting of 60 Gy with concomitant cisplatin and 5-fluorouracil. Surgery was scheduled 6-8 weeks after completion of nCRT. Explorative, multiplex immunohistochemistry (IHC) was performed on pretreatment tumor specimen, and diffusion-weighted magnetic resonance imaging (DW-MRI) was conducted prior to, during nCRT (day 15), and before surgery to identify potential predictive biomarkers and imaging features. Primary endpoint was the pathological complete response (pCR) rate.
Results: Seventeen patients with stage IVA OCC were included in this interim analysis. All patients completed nCRT. One patient died from pneumonia 10 weeks after nCRT before surgery. Complete tumor resection (R0) was achieved in 16/17 patients, of whom 7 (41%, 95% CI: 18-67%) showed pCR. According to the Clavien-Dindo classification, grade 3a and 3b complications were found in 4 (25%) and 5 (31%) patients, respectively; grade 4-5 complications did not occur. Increased changes in the apparent diffusion coefficient signal intensities between MRI at day 15 of nCRT and before surgery were associated with better response (p=0.022). Higher abundances of programmed cell death protein 1 (PD1) positive cytotoxic T-cells (p=0.012), PD1+ macrophages (p=0.046), and cancer-associated fibroblasts (CAFs, p=0.036) were associated with incomplete response to nCRT.
Conclusion: nCRT for LA-OCC followed by radical surgery is feasible and shows high response rates. Larger patient cohorts from randomized trials are needed to further investigate nCRT and predictive biomarkers such as changes in DW-MRI signal intensities, tumor infiltrating immune cells, and CAFs.
Children’s and adolescents’ lives drastically changed during COVID lockdowns worldwide. To compare accident- and injury-related admissions to pediatric intensive care units (PICU) during the first German COVID lockdown with previous years, we conducted a retrospective multicenter study among 37 PICUs (21.5% of German PICU capacities). A total of 1444 admissions after accidents or injuries during the first lockdown period and matched periods of 2017–2019 were reported and standardized morbidity ratios (SMR) were calculated. Total PICU admissions due to accidents/injuries declined from an average of 366 to 346 (SMR 0.95 (CI 0.85–1.05)). Admissions with trauma increased from 196 to 212 (1.07 (0.93–1.23). Traffic accidents and school/kindergarten accidents decreased (0.77 (0.57–1.02 and 0.26 (0.05–0.75)), whereas household and leisure accidents increased (1.33 (1.06–1.66) and 1.34 (1.06–1.67)). Less neurosurgeries and more visceral surgeries were performed (0.69 (0.38–1.16) and 2.09 (1.19–3.39)). Non-accidental non-suicidal injuries declined (0.73 (0.42–1.17)). Suicide attempts increased in adolescent boys (1.38 (0.51–3.02)), but decreased in adolescent girls (0.56 (0.32–0.79)). In summary, changed trauma mechanisms entailed different surgeries compared to previous years. We found no evidence for an increase in child abuse cases requiring intensive care. The increase in suicide attempts among boys demands investigation.
Introduction: Dravet syndrome (DS) is a rare developmental and epileptic encephalopathy. This study estimated cost, cost-driving factors and quality of life (QoL) in patients with Dravet syndrome and their caregivers in a prospective, multicenter study in Germany.
Methods: A validated 3–12-month retrospective questionnaire and a prospective 3-month diary assessing clinical characteristics, QoL, and direct, indirect and out-of-pocket (OOP) costs were administered to caregivers of patients with DS throughout Germany.
Results: Caregivers of 93 patients (mean age 10.1 years, ±7.1, range 15 months–33.7 years) submitted questionnaires and 77 prospective diaries. The majority of patients (95%) experienced at least one seizure during the previous 12 months and 77% a status epilepticus (SE) at least once in their lives. Over 70% of patients had behavioural problems and delayed speech development and over 80% attention deficit symptoms and disturbance of motor skills and movement coordination. Patient QoL was lower than in the general population and 45% of caregivers had some form of depressive symptoms. Direct health care costs per three months were a mean of €6,043 ± €5,825 (median €4054, CI €4935-€7350) per patient. Inpatient costs formed the single most important cost category (28%, €1,702 ± €4,315), followed by care grade benefits (19%, €1,130 ± €805), anti-epileptic drug (AED) costs (15%, €892 ± €1,017) and ancillary treatments (9%, €559 ± €503). Total indirect costs were €4,399 ±€ 4,989 (median €0, CI €3466-€5551) in mothers and €391 ± €1,352 (median €0, CI €195-€841) in fathers. In univariate analysis seizure frequency, experience of SE, nursing care level and severe additional symptoms were found to be associated with total direct healthcare costs. Severe additional symptoms was the single independently significant explanatory factor in a multivariate analysis.
Conclusions: This study over a period up to 15 months revealed substantial direct and indirect healthcare costs of DS in Germany and highlights the relatively low patient and caregiver QoL compared with the general population.
Tumor cells frequently overexpress heat shock protein 70 (Hsp70) and present it on their cell surface, where it can be recognized by pre‐activated NK cells. In our retrospective study the expression of Hsp70 was determined in relation to tumor‐infiltrating CD56+ NK cells in formalin‐fixed paraffin embedded (FFPE) tumor specimens of patients with SCCHN (N = 145) as potential indicators for survival and disease recurrence. All patients received radical surgery and postoperative cisplatin‐based radiochemotherapy (RCT). In general, Hsp70 expression was stronger, but with variable intensities, in tumor compared to normal tissues. Patients with high Hsp70 expressing tumors (scores 3–4) showed significantly decreased overall survival (OS; p = 0.008), local progression‐free survival (LPFS; p = 0.034) and distant metastases‐free survival (DMFS; p = 0.044), compared to those with low Hsp70 expression (scores 0–2), which remained significant after adjustment for relevant prognostic variables. The adverse prognostic value of a high Hsp70 expression for OS was also observed in patient cohorts with p16‐ (p = 0.001), p53‐ (p = 0.0003) and HPV16 DNA‐negative (p = 0.001) tumors. The absence or low numbers of tumor‐infiltrating CD56+ NK cells also correlated with significantly decreased OS (p = 0.0001), LPFS (p = 0.0009) and DMFS (p = 0.0001). A high Hsp70 expression and low numbers of tumor‐infiltrating NK cells have the highest negative predictive value (p = 0.00004). In summary, a strong Hsp70 expression and low numbers of tumor‐infiltrating NK cells correlate with unfavorable outcome following surgery and RCT in patients with SCCHN, and thus serve as negative prognostic markers.
Purpose: Seizures pose a significant burden in patients with primary and secondary brain tumors during the end-of-life period. A wide range of 6 to 56% of clinically observed epileptic seizures at the end of life has been reported. We aimed to analyse the incidence of epileptic seizures at the end of life in brain tumor patients more accurately using not only clinical but also electrophysiological findings.
Methods: This retrospective, single center study included brain tumor patients who died during the stay on the ward or within 7 days after discharge between 01/2015 and 08/2020. Clinical observation of seizures derived from the original medical records and EEG findings (within 45 days prior to death) were analyzed to determine the incidence of seizures in that period.
Results: Of the 68 eligible patients, 50 patients (73.5%) suffered from seizures within 45 days prior to death, of which n = 24 had a status epilepticus. The diagnosis of seizures/ status epilepticus was determined either by the presentation of clinical signs in 45 patients and if not, by the detection of a (possible) non-convulsive status epilepticus in the EEG of five patients.
Conclusion: In the presence of neurologically trained staff and with the frequent use of routine EEG, we were able to identify seizures and to distinguish status epilepticus from encephalopathy/ hypoactive delirium. We detected a higher incidence of seizures and status epilepticus at the end of life in neurooncological patients than previously reported.
Local anesthetics are commonly administered by nuchal infiltration to provide a temporary interscalene brachial plexus block (ISB) in a surgical setting. Although less commonly reported, local anesthetics can induce central nervous system toxicity. In this case study, we present three patients with acute central nervous system toxicity induced by local anesthetics applied during ISB with emphasis on neurological symptoms, key neuroradiological findings and functional outcome. Medical history, clinical and imaging findings, and outcome of three patients with local anesthetic-induced toxic left hemisphere syndrome during left ISB were analyzed. All patients were admitted to our neurological intensive care unit between November 2016 and September 2019. All three patients presented in poor clinical condition with impaired consciousness and left hemisphere syndrome. Electroencephalography revealed slow wave activity in the affected hemisphere of all patients. Seizure activity with progression to status epilepticus was observed in one patient. In two out of three patients, cortical FLAIR hyperintensities and restricted diffusion in the territory of the left internal carotid artery were observed in magnetic resonance imaging. Assessment of neurological severity scores revealed spontaneous partial reversibility of neurological symptoms. Local anesthetic-induced CNS toxicity during ISB can lead to severe neurological impairment and anatomically variable cerebral lesions.
The SARS-CoV-2 virus is the cause of the respiratory disease COVID-19. As of today, therapeutic interventions in severe COVID-19 cases are still not available as no effective therapeutics have been developed so far. Despite the ongoing development of a number of effective vaccines, therapeutics to fight the disease once it has been contracted will still be required. Promising targets for the development of antiviral agents against SARS-CoV-2 can be found in the viral RNA genome. The 5′- and 3′-genomic ends of the 30 kb SCoV-2 genome are highly conserved among Betacoronaviruses and contain structured RNA elements involved in the translation and replication of the viral genome. The 40 nucleotides (nt) long highly conserved stem-loop 4 (5_SL4) is located within the 5′-untranslated region (5′-UTR) important for viral replication. 5_SL4 features an extended stem structure disrupted by several pyrimidine mismatches and is capped by a pentaloop. Here, we report extensive 1H, 13C, 15N and 31P resonance assignments of 5_SL4 as the basis for in-depth structural and ligand screening studies by solution NMR spectroscopy.
The SARS-CoV-2 (SCoV-2) virus is the causative agent of the ongoing COVID-19 pandemic. It contains a positive sense single-stranded RNA genome and belongs to the genus of Betacoronaviruses. The 5′- and 3′-genomic ends of the 30 kb SCoV-2 genome are potential antiviral drug targets. Major parts of these sequences are highly conserved among Betacoronaviruses and contain cis-acting RNA elements that affect RNA translation and replication. The 31 nucleotide (nt) long highly conserved stem-loop 5a (SL5a) is located within the 5′-untranslated region (5′-UTR) important for viral replication. SL5a features a U-rich asymmetric bulge and is capped with a 5′-UUUCGU-3′ hexaloop, which is also found in stem-loop 5b (SL5b). We herein report the extensive 1H, 13C and 15N resonance assignment of SL5a as basis for in-depth structural studies by solution NMR spectroscopy.