Development of an effective immune response in adults with Down Syndrome after SARS-CoV-2 vaccination

Immune dysregulation in individuals with Down syndrome (DS) leads to an increased risk for hospitalization and death due to COVID-19 and may impair the generation of protective immunity after vaccine administration. The cellular and humoral responses of 55 DS patients who received a complete SARS-CoV-2 vaccination regime at one to three (V1) and six (V2) months were characterised. SARS-CoV-2-reactive CD4+ and CD8+ T lymphocytes with a predominant Th1 phenotype were observed at V1, and increased at V2. Likewise, a sustained increase of SARS-CoV-2-specific circulating Tfh (cTfh) cells was observed one to three months after vaccine administration. Specific IgG antibodies against SARS-CoV-2 S protein were detected in 96% and 98% of subjects at V1 and V2, respectively, though IgG titers decreased significantly between both timepoints.

Fluvial processes and landforms

The period 1965-2000 saw a sustained increase in research and publication on fluvial processes and landforms. The trend toward generalisation and/or mechanistic understanding, rather than site-specific history, continued. Research was multi-disciplinary, with important contributions from hydraulic engineers, geologists and physical geographers and from experimental and theoretical approaches as well as geomorphological and sedimentological fieldwork. Rapidly increasing computer power underpinned new measurement methods and greatly increased the scope of data analysis and numerical modelling. There were major advances in understanding the interaction of river process and form at reach scale, with growing recognition of differences between sand-bed and coarse-bed rivers. Field studies outside Europe and North America led to greater awareness of the diversity of river planforms and deposition landforms. Conceptual models of how rivers respond to natural or anthropogenic change in boundary conditions at different timescales were refined, taking advantage of studies of response to land use change, major floods, and volcanic eruptions. Dating of sediments allowed greater appreciation of fluctuations in the incidence of extreme driving events over centuries and thousands of years. Towards the end of the period research on bedrock rivers began to take off.

163. MIC Shifts in Response to Increased Antibiotic Utilization During COVID-19 Pandemic

Background Multiple studies have shown that antibiotic utilization increased during the COVID-19 pandemic. However, the impact of this increased utilization has not been well established. The aim of this study is to describe the trends in minimum inhibitory concentrations for various antibiotics against common gram-negative pathogens observed since the start of the COVID-19 pandemic as compared to previous years. Methods This retrospective study was conducted at the Memphis VA. All respiratory, urine, and blood culture MicroScan results run from October 2017-March 2021 were analyzed. Only inpatient and emergency department data was included. The MIC50 and MIC90 of seven antibiotics for four of the most common pathogens were trended by quarterly intervals. Results MIC50 and MIC90 were compared using standardized breakpoints. As compared to previous years, Pseudomonas aeruginosa was noted to have the most sustained increase in MIC90 across various antibiotics. In the last 3 quarters of the study time frame, piperacillin-tazobactam mean MIC90 increased from 32 to 64, cefepime from 8 to > 16, and meropenem from 4 to > 8. Escherichia coli had a sustained increase in ceftriaxone MIC90 from < 1 to > 8 in the final quarter of 2020 and beginning of 2021. Klebsiella pneumonia was also found to have a sustained increase in cefepime mean MIC90 from < 1 to > 16 during the year of 2020, with return to previous MIC90 the following quarters. Conclusion Previous studies have clearly demonstrated a widespread increase in antibiotic utilization during the COVID era. Our study demonstrates how even short-term increases in antibiotic use can lead to shifts in MIC, if not outright resistance. This was demonstrated across multiple common gram-negative pathogens and to various broad-spectrum antibiotics which were commonly used more frequently during COVID-19. Further analysis will be needed to determine whether these trends continue or whether the decrease in antibiotic utilization in the recent months will lead to similar decrease in MIC. Disclosures All Authors: No reported disclosures

Double peroxidase and histone acetyltransferase AgTip60 maintain innate immune memory in primed mosquitoes

Immune priming in Anopheles gambiae is mediated by the systemic release of a hemocyte differentiation factor (HDF), a complex of lipoxin A4 bound to Evokin, a lipid carrier. HDF increases the proportion of circulating granulocytes and enhances mosquito cellular immunity. Here, we show that Evokin is present in hemocytes and fat-body cells, and messenger RNA (mRNA) expression increases significantly after immune priming. The double peroxidase (DBLOX) enzyme, present in insects but not in vertebrates, is essential for HDF synthesis. DBLOX is highly expressed in oenocytes in the fat-body tissue, and these cells increase in number in primed mosquitoes. We provide direct evidence that the histone acetyltransferase AgTip60 (AGAP001539) is also essential for a sustained increase in oenocyte numbers, HDF synthesis, and immune priming. We propose that oenocytes may function as a population of cells that are reprogrammed, and orchestrate and maintain a broad, systemic, and long-lasting state of enhanced immune surveillance in primed mosquitoes.

Impact of Energy Price Stabilization Mechanism on Regulated Clients’ Tariffs: The Case of Chile

The Chilean socio-political explosion in October 2019 embodies a milestone in Chile’s national history, challenging the current government’s administration and the management of state resources. One of the triggering factors of this crisis was the increase in electricity prices for those clients previously subject to flat pricing. As an example, in 2019, electricity fees increased by 25% at the national level. In order to solve the conflict, the Ministry of Energy proposed a mechanism, applicable for two years, which would freeze energy charges for companies, industries and domestic customers subject to a regulated tariff. This mechanism was employed and would produce a debt favoring generation companies, which could not exceed CLD 1.350 million. This article analyzes the effectiveness of the energy price stabilization mechanism and the effects of the Chilean socio-economic instability—resulting from the aggregated debt generated by the mechanism applicability—on the exchange rate over its duration of operation. The results suggest that the effects of the current law will not fulfill the purpose of tariff stabilization until 2024; additionally, there will be a sustained increase in tariffs until the year 2027.

Regulation of Liver Regeneration by hepatocyte O-GlcNAcylation in mice

The liver has a unique capacity to regenerate after injury in a highly orchestrated and regulated manner. Here we report that O-GlcNAcylation, an intracellular posttranslational modification (PTM) regulated by two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), is a critical termination signal for liver regeneration (LR) following partial hepatectomy (PHX). We studied liver regeneration after PHX on hepatocyte specific OGT and OGA knockout mice (OGT-KO and OGA-KO), which caused a significant decrease (OGT-KO) and increase (OGA-KO) in hepatic O-GlcNAcylation, respectively. OGA-KO mice had normal regeneration, but the OGT-KO mice exhibited substantial defects in termination of liver regeneration with increased liver injury, sustained cell proliferation resulting in significant hepatomegaly, hepatic dysplasia and appearance of small nodules at 28 days after PHX. This was accompanied by a sustained increase in expression of cyclins along with significant induction in pro-inflammatory and pro-fibrotic gene expression in the OGT-KO livers. RNA-Seq studies revealed inactivation of hepatocyte nuclear 4 alpha (HNF4α), the master regulator of hepatic differentiation and a known termination signal, in OGT-KO mice at 28 days after PHX, which was confirmed by both Western blot and IHC analysis. Furthermore, a significant decrease in HNFα target genes was observed in OGT-KO mice, indicating a lack of hepatocyte differentiation following decreased hepatic O-GlcNAcylation. Immunoprecipitation experiments revealed HNF4α is O-GlcNAcylated in normal differentiated hepatocytes. These studies show that O-GlcNAcylation plays a critical role in the termination of LR via regulation of HNF4α in hepatocytes.

Efficacy and Safety of Subcutaneous Infusion of Non-formulated Furosemide in Patients with Worsening Heart Failure: a Real-World Study

We aimed to evaluate the efficacy (short-term changes in surrogates of decongestion) and safety following the ambulatory administration of subcutaneous furosemide (SCF) in patients with WHF. Fifty-five ambulatory patients were treated with SCF administered by an elastomeric pump for at least 72 h. Surrogates of congestion were assessed at baseline, 72 h, and 30 days. Spot urinary sodium (uNa+) was assessed at baseline, 24-48-72 h, and 30 days. The median (IQI) of NT-proBNP and uNa+ at baseline was 5218 pg/mL (2856-10878) and 68±3 mmol/L, respectively. Following administration of SCF (median dose of 100 mg/daily), we found a sustained increase in uNa+ during the first 72 h of treatment compared to baseline, paralleled with evidence of decongestion at 72 h, and 30 days. No significant safety concerns were observed. SCF was an effective and safe diuretic strategy for outpatient congestion management. Graphical abstract

The effect of the COVID-19 pandemic on mental health calls for police service

Drawing upon seven years of police calls for service data (2014–2020), this study examined the effect of the COVID-19 pandemic on calls involving persons with perceived mental illness (PwPMI) using a Bayesian Structural Time Series. The findings revealed that PwPMI calls did not increase immediately after the beginning of the pandemic in March 2020. Instead, a sustained increase in PwPMI calls was identified in August 2020 that later became statistically significant in October 2020. Ultimately, the analysis revealed a 22% increase in PwPMI calls during the COVID-19 pandemic than would have been expected had the pandemic not taken place. The delayed effect of the pandemic on such calls points to a need for policymakers to prioritize widely accessible mental health care that can be deployed early during public health emergencies thus potentially mitigating or eliminating the need for increased police intervention, as was the case here.

Acute and sustained increase in endothelial biomarkers in COVID-19

Endothelial injury is related to poor outcomes in respiratory infections yet little is known in relation to COVID-19. Performing a longitudinal analysis (on emergency department admission and post-hospitalisation follow-up), we evaluated endothelial damage via surrogate systemic endothelial biomarkers, that is, proadrenomedullin (proADM) and proendothelin, in patients with COVID-19. Higher proADM and/or proendothelin levels at baseline were associated with the most severe episodes and intensive care unit admission when compared with ward-admitted individuals and outpatients. Elevated levels of proADM or proendothelin at day 1 were associated with in-hospital mortality. High levels maintained after discharge were associated with reduced diffusing capacity.

THE PLASTICITY OF NERVE FIBRES: THE PROLONGED EFFECTS OF POLARIZATION OF AFFERENT FIBRES

The review surveys various aspects of the plasticity of nerve fibres, in particular the prolonged increase in their excitability evoked by polarization, focusing on a long-lasting increase in the excitability of myelinated afferent fibres traversing the dorsal columns of the spinal cord. We review the evidence that increased axonal excitability (i) follows epidurally applied direct current as well as relatively short (5 or 10 ms) current pulses and synaptically evoked intrinsic field potentials; (ii) critically depends on the polarization of branching regions of afferent fibres at the sites where they bifurcate and give off axon collaterals entering the spinal grey matter in conjunction with actions of extrasynaptic GABAA membrane receptors; and (iii) shares the feature of being activity-independent with the short-lasting effects of polarization of peripheral nerve fibres. A comparison between the polarization evoked sustained increase in the excitability of dorsal column fibres and spinal motoneurons (plateau potentials) indicates the possibility that they are mediated by partly similar membrane channels (including non-inactivating type L Cav++ 1.3 but not Na+ channels) and partly different mechanisms. We finally consider under which conditions trans-spinally applied DC (tsDCS) might reproduce the effects of epidural polarization on dorsal column fibres and the possible advantages of increased excitability of afferent fibres for the rehabilitation of motor and sensory functions after spinal cord injuries.