Solid-phase synthesis of coralmycin A/-coralmycin A and desmethoxycoralmycin A.

The total synthesis of the natural product coralmycin A/epi-coralmycin A, as well as a desmethoxy analogue is described. Synthesis was achieved via a divergent, bidirectional solid-phase strategy, including a key on-resin O-acylation, O to N acyl shift, and O-alkylation protocol to incorporate the unusual 4-amino-2-hydroxy-3-isopropoxybenzoic acid motifs. The synthetic natural product was generated as a 1 : 1 mixture of epimers at the central β-methoxyasparagine residue and exhibited potent antibacterial activity against a panel of ten Gram-negative and seven Gram-positive organisms.

Preparation, validation and use of a vasoactive tryptophan-derived hydroperoxide and relevant control compounds.

The L-tryptophan-derived tricyclic hydroperoxide cis-WOOH was recently identified as a novel and biologically important factor for regulating vascular tone and blood pressure under inflammatory conditions and potentially other cellular redox signaling events. cis-WOOH is highly labile and currently not available commercially. In this protocol, we provide procedures for the synthesis, purification, quantification and characterization of cis-WOOH, its epimer trans-WOOH and their respective alcohols (cis-WOH and trans-WOH).

Thyroidectomy for Graves' Disease Predicts Postoperative Neck Hematoma and Hypocalcemia: A North American cohort study.

Objective: Examine the association of Graves' disease with the development of postoperative neck hematoma.

Design: A cohort of patients participating in the Thyroid Procedure-Targeted Database of the National Surgical Quality Improvement Program from January 1, 2016 to December 31, 2018.

Setting: A North American surgical cohort study.

Potent Cyclic Peptide Inhibitors of FXIIa Discovered by mRNA Display with Genetic Code Reprogramming.

The contact system comprises a series of serine proteases that mediate procoagulant and proinflammatory activities the intrinsic pathway of coagulation and the kallikrein-kinin system, respectively. Inhibition of Factor XIIa (FXIIa), an initiator of the contact system, has been demonstrated to lead to thrombo-protection and anti-inflammatory effects in animal models and serves as a potentially safer target for the development of antithrombotics. Herein, we describe the use of the Randomised Nonstandard Peptide Integrated Discovery (RaPID) mRNA display technology to identify a series of potent and selective cyclic peptide inhibitors of FXIIa.

GPs' mindlines on deprescribing antihypertensives in older patients with multimorbidity: a qualitative study in English general practice.

Background: Optimal management of hypertension in older patients with multimorbidity is a cornerstone of primary care practice. Despite emphasis on personalised approaches to treatment in older patients, there is little guidance on how to achieve medication reduction when GPs are concerned that possible risks outweigh potential benefits of treatment. Mindlines - tacit, internalised guidelines developed over time from multiple sources - may be of particular importance in such situations.

Glycosylation Regulates N-Terminal Proteolysis and Activity of the Chemokine CCL14.

Chemokines are secreted proteins that regulate leukocyte migration during inflammatory responses by signaling through chemokine receptors. Full length CC chemokine ligand 14, CCL14(1-74), is a weak agonist for the chemokine receptor CCR1, but its activity is substantially enhanced upon proteolytic cleavage to CCL14(9-74). CCL14 is O-glycosylated at Ser7, adjacent to the site of proteolytic activation.

Blood Pressure Changes Following Antihypertensive Medication Reduction, by Drug Class and Dose Chosen for Withdrawal: Exploratory Analysis of Data From the OPTiMISE Trial.

Deprescribing of antihypertensive drugs is recommended for some older patients with polypharmacy, but there is little evidence to inform which drug (or dose) should be withdrawn. This study used data from the OPTiMISE trial to examine whether short-term outcomes of deprescribing vary by drug class and dose of medication withdrawn. The OPTiMISE trial included patients aged ≥80 years with controlled systolic blood pressure (SBP; <150 mmHg), receiving ≥2 antihypertensive medications.

Molecular testing for cytologically suspicious and malignant (Bethesda V and VI) thyroid nodules to optimize the extent of surgical intervention: a retrospective chart review.

Background: Molecular testing has been used for cytologically indeterminate thyroid nodules (Bethesda III and IV), where the risk of malignancy is 10-40%. However, to date, the role of molecular testing in cytologically suspicious or positive for malignancy (Bethesda V and VI) thyroid nodules has been controversial. The aim of this study was to determine whether patients who had molecular testing in Bethesda V and VI thyroid nodules had the optimal extent of surgery performed more often than patients who did not have molecular testing performed.

Evaluating perceptions of social determinants of health and Part D star performance of Medicare Advantage-contracted primary care providers serving a South Texas market.

Socioeconomic factors can have a significant impact on a patient's health status and could be responsible for as much as 70%-80% of a patient's overall health. These factors, called the social determinants of health (SDoH), define a patient's day-to-day experiences. While the influence of such factors is well recognized, who ultimately is responsible for addressing SDoH in health care remains unclear.

Single-cell multi-omics analysis of the immune response in COVID-19.

Analysis of human blood immune cells provides insights into the coordinated response to viral infections such as severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19). We performed single-cell transcriptome, surface proteome and T and B lymphocyte antigen receptor analyses of over 780,000 peripheral blood mononuclear cells from a cross-sectional cohort of 130 patients with varying severities of COVID-19. We identified expansion of nonclassical monocytes expressing complement transcripts (CD16C1QA/B/C) that sequester platelets and were predicted to replenish the alveolar macrophage pool in COVID-19.

Key periods of peatland development and environmental changes in the middle taiga zone of Western Siberia during the Holocene.

The response of peatlands to climate change can be highly variable. Through understanding past changes we can better predict the response of peatlands to future climate change. We use a multi-proxy approach to reconstruct the surface wetness and carbon accumulation of the Mukhrino mire (Western Siberia), describing the development of the mire since peat formation in the early Holocene, around 9360 cal.

Chemical Synthesis of Phosphorylated Insulin-like Growth Factor Binding Protein 2.

Chemical protein synthesis is a powerful avenue for accessing homogeneously modified proteins. While a significant number of small modified proteins bearing native post-translational modifications and non-natural modifications have been generated to date, access to larger targets has proved challenging. Herein, we describe the use of two ligation manifolds, namely, diselenide-selenoester ligation and native chemical ligation, to assemble a 31.

Protein/AS01 vaccination elicits stronger, more Th2-skewed antigen-specific human T follicular helper cell responses than heterologous viral vectors.

Interactions between B cells and CD4 T follicular helper (Tfh) cells are key determinants of humoral responses. Using samples from clinical trials performed with the malaria vaccine candidate antigen merozoite protein (PfRH5), we compare the frequency, phenotype, and gene expression profiles of PfRH5-specific circulating Tfh (cTfh) cells elicited by two leading human vaccine delivery platforms: heterologous viral vector prime boost and protein with AS01 adjuvant. We demonstrate that the protein/AS01 platform induces a higher-magnitude antigen-specific cTfh cell response and that this correlates with peak anti-PfRH5 IgG concentrations, frequency of PfRH5-specific memory B cells, and antibody functionality.

The Use of Primary Care Big Data in Understanding the Pharmacoepidemiology of COVID-19: A Consensus Statement From the COVID-19 Primary Care Database Consortium.

The use of big data containing millions of primary care medical records provides an opportunity for rapid research to help inform patient care and policy decisions during the first and subsequent waves of the coronavirus disease 2019 (COVID-19) pandemic. Routinely collected primary care data have previously been used for national pandemic surveillance, quantifying associations between exposures and outcomes, identifying high risk populations, and examining the effects of interventions at scale, but there is no consensus on how to effectively conduct or report these data for COVID-19 research. A COVID-19 primary care database consortium was established in April 2020 and its researchers have ongoing COVID-19 projects in overlapping data sets with over 40 million primary care records in the United Kingdom that are variously linked to public health, secondary care, and vital status records.

Phrenic Nerve Stimulator Placement via the Cervical Approach: Technique and Anatomic Considerations.

Background: Diaphragmatic pacing via phrenic nerve stimulation can help improve breathing and facilitate mechanical ventilation weaning in patients with respiratory failure secondary to brainstem injury, high cervical spinal cord injury, or congenital central hypoventilation. Devices can be placed utilizing several techniques; however, nuances regarding placement are not well published.

Objective: To describe our experience with phrenic nerve stimulator placement via the cervical approach with a focus on surgical anatomy, variations, and technique.

Mapping immune variation and gene switching in naive hosts infected with .

Falciparum malaria is clinically heterogeneous and the relative contribution of parasite and host in shaping disease severity remains unclear. We explored the interaction between inflammation and parasite variant surface antigen (VSA) expression, asking whether this relationship underpins the variation observed in controlled human malaria infection (CHMI). We uncovered marked heterogeneity in the host response to blood challenge; some volunteers remained quiescent, others triggered interferon-stimulated inflammation and some showed transcriptional evidence of myeloid cell suppression.

BET-Family Bromodomains Can Recognize Diacetylated Sequences from Transcription Factors Using a Conserved Mechanism.

Almost all eukaryotic proteins receive diverse post-translational modifications (PTMs) that modulate protein activity. Many histone PTMs are well characterized, heavily influence gene regulation, and are often predictors of distinct transcriptional programs. Although our understanding of the histone PTM network has matured, much is yet to be understood about the roles of transcription factor (TF) PTMs, which might well represent a similarly complex and dynamic network of functional regulation.

Association between antihypertensive treatment and adverse events: systematic review and meta-analysis.

Objective: To examine the association between antihypertensive treatment and specific adverse events.

Design: Systematic review and meta-analysis.

Eligibility Criteria: Randomised controlled trials of adults receiving antihypertensives compared with placebo or no treatment, more antihypertensive drugs compared with fewer antihypertensive drugs, or higher blood pressure targets compared with lower targets.

Promoting Ethical Payment in Human Infection Challenge Studies.

To prepare for potential human infection challenge studies (HICS) involving SARS-CoV-2, we convened a multidisciplinary working group to address ethical questions regarding whether and how much SARS-CoV-2 HICS participants should be paid. Because the goals of paying HICS participants, as well as the relevant ethical concerns, are the same as those arising for other types of clinical research, the same basic framework for ethical payment can apply. This framework divides payment into reimbursement, compensation, and incentives, focusing on fairness and promoting adequate recruitment and retention as counterweights to concerns about undue inducement.

Association of prior lymphopenia with mortality in pneumonia: a cohort study in UK primary care.

Background: Lymphopenia (reduced lymphocyte count) during infections, such as pneumonia, is common and is associated with increased mortality. Little is known about the relationship between lymphocyte count before developing infections and mortality risk.

Aim: To identify whether patients with lymphopenia who develop pneumonia have increased risk of death.

Synthetic protein conjugate vaccines provide protection against in mice.

The global incidence of tuberculosis remains unacceptably high, with new preventative strategies needed to reduce the burden of disease. We describe here a method for the generation of synthetic self-adjuvanted protein vaccines and demonstrate application in vaccination against Two vaccine constructs were designed, consisting of full-length ESAT6 protein fused to the TLR2-targeting adjuvants PamCys-SK or PamCys-SK These were produced by chemical synthesis using a peptide ligation strategy. The synthetic self-adjuvanting vaccines generated powerful local CD4 T cell responses against ESAT6 and provided significant protection in the lungs from virulent aerosol challenge when administered to the pulmonary mucosa of mice.

A multi-stakeholder approach to the co-production of the research agenda for medicines optimisation.

Background: Up to 50% of medicines are not used as intended, resulting in poor health and economic outcomes. Medicines optimisation is 'a person-centred approach to safe and effective medicines use, to ensure people obtain the best possible outcomes from their medicines'. The purpose of this exercise was to co-produce a prioritised research agenda for medicines optimisation using a multi-stakeholder (patient, researcher, public and health professionals) approach.

Potent anti-SARS-CoV-2 activity by gallinamide A and analogues via inhibition of cathepsin L.

The emergence of SARS-CoV-2 in late 2019, and the subsequent COVID-19 pandemic, has led to substantial mortality, together with mass global disruption. There is an urgent need for novel antiviral drugs for therapeutic or prophylactic application. Cathepsin L is a key host cysteine protease utilized by coronaviruses for cell entry and is recognized as a promising drug target.