Validation and implementation of whole-genome sequencing-based analytical methods for molecular surveillance and relatedness analysis of complex isolates at a national reference laboratory.

Whole genome sequencing-based methodologies have become extremely relevant for the molecular surveillance of human pathogens and are being increasingly introduced into national reference laboratory services. In this study, we describe the validation and implementation of core-genome Multi-Locus Sequence Typing (cgMLST) and whole genome single-nucleotide polymorphism (wgSNP) analysis at the Irish Mycobacteria Reference Laboratory, as a replacement for Mycobacterial Interspersed Repetitive Unit-Variable Number Tandem Repeat (MIRU-VNTR) typing. Concordance of clustering, discriminatory power, and ease-of-use of both WGS analytical methods were evaluated.

An alternative route for β-hydroxybutyrate metabolism supports fatty acid synthesis in cancer cells.

Cancer cells are exposed to diverse metabolites in the tumor microenvironment that are used to support the synthesis of nucleotides, amino acids, and lipids needed for rapid cell proliferation. Recent work has shown that ketone bodies such as β-hydroxybutyrate (β-OHB), which are elevated in circulation under fasting conditions or low glycemic diets, can serve as an alternative fuel that is metabolized in the mitochondria to provide acetyl-CoA for the tricarboxylic acid (TCA) cycle in some tumors. Here, we discover a non-canonical route for β-OHB metabolism, in which β-OHB can bypass the TCA cycle to generate cytosolic acetyl-CoA for fatty acid synthesis in cancer cells.

An unnatural amino acid dependent, conditional Pseudomonas vaccine prevents bacterial infection.

Live vaccines are ideal for inducing immunity but suffer from the need to attenuate their pathogenicity or replication to preclude the possibility of escape. Unnatural amino acids (UAAs) provide a strategy to engineer stringent auxotrophies, yielding conditionally replication incompetent live bacteria with excellent safety profiles. Here, we engineer Pseudomonas aeruginosa to maintain auxotrophy for the UAA p-benzoyl-L-phenylalanine (BzF) through its incorporation into the essential protein DnaN.

Passive infusion of an S2-Stem broadly neutralizing antibody protects against SARS-CoV-2 infection and lower airway inflammation in rhesus macaques.

The continued evolution of SARS-CoV-2 variants capable of subverting vaccine and infection-induced immunity suggests the advantage of a broadly protective vaccine against betacoronaviruses (β-CoVs). Recent studies have isolated monoclonal antibodies (mAbs) from SARS-CoV-2 recovered-vaccinated donors capable of neutralizing many variants of SARS-CoV-2 and other β-CoVs. Many of these mAbs target the conserved S2 stem region of the SARS-CoV-2 spike protein, rather the receptor binding domain contained within S1 primarily targeted by current SARS-CoV-2 vaccines.

Polymerase Chain Reaction on Respiratory Tract Specimens of Immunocompromised Patients to Diagnose Pneumocystis Pneumonia: A Systematic Review and Meta-analysis.

Background: This meta-analysis examines the comparative diagnostic performance of polymerase chain reaction (PCR) for the diagnosis of Pneumocystis pneumonia (PCP) on different respiratory tract samples, in both human immunodeficiency virus (HIV) and non-HIV populations.

Methods: A total of 55 articles met inclusion criteria, including 11 434 PCR assays on respiratory specimens from 7835 patients at risk of PCP. QUADAS-2 tool indicated low risk of bias across all studies.

Deep repertoire mining uncovers ultra-broad coronavirus neutralizing antibodies targeting multiple spike epitopes.

The development of vaccines and therapeutics that are broadly effective against known and emergent coronaviruses is an urgent priority. We screened the circulating B cell repertoires of COVID-19 survivors and vaccinees to isolate over 9,000 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific monoclonal antibodies (mAbs), providing an expansive view of the SARS-CoV-2-specific Ab repertoire. Among the recovered antibodies was TXG-0078, an N-terminal domain (NTD)-specific neutralizing mAb that recognizes diverse alpha- and beta-coronaviruses.

Lipid availability influences ferroptosis sensitivity in cancer cells by regulating polyunsaturated fatty acid trafficking.

Ferroptosis is a form of cell death caused by lipid peroxidation that is emerging as a target for cancer therapy, highlighting the need to identify factors that govern ferroptosis susceptibility. Lipid peroxidation occurs primarily on phospholipids containing polyunsaturated fatty acids (PUFAs). Here, we show that even though extracellular lipid limitation reduces cellular PUFA levels, lipid-starved cancer cells are paradoxically more sensitive to ferroptosis.

Delayed Onset of Symptoms After a Rattlesnake Bite in a Renal Transplant Patient: A Case Report.

Introduction: The United States is home to two major families of venomous snakes, Crotalids and Elapids. The Crotalid family, also known as pit vipers, is well known for being among the most frequent causes of snakebites reported. Crotalid envenomation can present with local findings, hematologic toxicity, and systemic toxicity.

Discovery of CMX990: A Potent SARS-CoV-2 3CL Protease Inhibitor Bearing a Novel Warhead.

There remains a need to develop novel SARS-CoV-2 therapeutic options that improve upon existing therapies by an increased robustness of response, fewer safety liabilities, and global-ready accessibility. Functionally critical viral main protease (M, 3CL) of SARS-CoV-2 is an attractive target due to its homology within the coronaviral family, and lack thereof toward human proteases. In this disclosure, we outline the advent of a novel SARS-CoV-2 3CL inhibitor, , bearing an unprecedented trifluoromethoxymethyl ketone warhead.

An Overview of Systematic Reviews of Polymerase Chain Reaction (PCR) for the Diagnosis of Invasive Aspergillosis in Immunocompromised People: A Report of the Fungal PCR Initiative (FPCRI)-An ISHAM Working Group.

This overview of reviews (i.e., an umbrella review) is designed to reappraise the validity of systematic reviews (SRs) and meta-analyses related to the performance of PCR tests for the diagnosis of invasive aspergillosis in immunocompromised patients.

Tumor lipid metabolism: a mechanistic link between diet and cancer progression.

The potential for 'anti-cancer' diets to markedly alter cancer risk and prognosis has captured the imagination of patients, physicians, and researchers alike, but many of these dietary recommendations come from correlative studies that attribute certain diets to altered cancer risk. While provocative, little is known about the molecular mechanisms behind how these dietary interventions impact cancer progression. Within this context, however, changes in tumor lipid metabolism are emerging as a key contributor.

Characterization of Food Chain Isolates in Terms of Ribotype and Antimicrobial Resistance.

The aim of this study was to characterize isolates from the farm, abattoir, and retail outlets in Ireland in terms of ribotype and antibiotic resistance (vancomycin, erythromycin, metronidazole, moxifloxacin, clindamycin, and rifampicin) using PCR and E-test methods, respectively. The most common ribotype in all stages of the food chain (including retail foods) was 078 and a variant (RT078/4). Less commonly reported (014/0, 002/1, 049, and 205) and novel (RT530, 547, and 683) ribotypes were also detected, but at lower frequencies.

Supernatants Disrupt Bronchial Epithelial Monolayers: Potential Role for Enhanced Invasion in Cystic Fibrosis.

is the most commonly isolated fungus in chronic lung diseases, with a prevalence of up to 60% in cystic fibrosis patients. Despite this, the impact of colonisation on lung epithelia has not been thoroughly explored. We investigated the influence of supernatants and the secondary metabolite, gliotoxin, on human bronchial epithelial cells (HBE) and CF bronchial epithelial (CFBE) cells.

Transdermal Detection of MB-102 and Correlation to Meropenem Pharmacokinetics During Continuous Renal Replacement Therapy: In Vivo Results.

Critically ill patients undergoing continuous renal replacement therapy (CRRT) have medical conditions requiring extensive pharmacotherapy. Continuous renal replacement therapy impacts drug disposition. Few data exist regarding drug dosing requirements with contemporary CRRT modalities and effluent rates.

Deep repertoire mining uncovers ultra-broad coronavirus neutralizing antibodies targeting multiple spike epitopes.

Development of vaccines and therapeutics that are broadly effective against known and emergent coronaviruses is an urgent priority. Current strategies for developing pan-coronavirus countermeasures have largely focused on the receptor binding domain () and S2 regions of the coronavirus Spike protein; it has been unclear whether the N-terminal domain () is a viable target for universal vaccines and broadly neutralizing antibodies (). Additionally, many RBD-targeting Abs have proven susceptible to viral escape.

The effect of cold storage and cooking on the viability of Clostridioides difficile spores in consumer foods.

The increased detection of clinical cases of Clostridioides difficile coupled with the persistence of clostridial spores at various stages along the food chain suggest that this pathogen may be foodborne. This study examined C. difficile (ribotypes 078 and 126) spore viability in chicken breast, beef steak, spinach leaves and cottage cheese during refrigerated (4 °C) and frozen (-20 °C) storage with and without a subsequent sous vide mild cooking (60 °C, 1 h).

Broadly neutralizing anti-S2 antibodies protect against all three human betacoronaviruses that cause deadly disease.

Pan-betacoronavirus neutralizing antibodies may hold the key to developing broadly protective vaccines against novel pandemic coronaviruses and to more effectively respond to SARS-CoV-2 variants. The emergence of Omicron and subvariants of SARS-CoV-2 illustrates the limitations of solely targeting the receptor-binding domain (RBD) of the spike (S) protein. Here, we isolated a large panel of broadly neutralizing antibodies (bnAbs) from SARS-CoV-2 recovered-vaccinated donors, which targets a conserved S2 region in the betacoronavirus spike fusion machinery.

Rotator cuff repair in patients with inflammatory arthritis: satisfactory midterm outcomes.

Background: We aimed to evaluate midterm patient-reported outcomes and reoperation rates following rotator cuff repair in patients with either rheumatoid arthritis (RA) or other inflammatory arthritis (nonRA-IA) diagnoses.

Methods: We identified all patients with either RA or nonRA-IA who underwent a rotator cuff repair at our institution between 2008 and 2018. IA diagnoses included RA, systemic lupus erythematosus, psoriatic arthritis, and other unspecified inflammatory arthritis.

Long-Term Patient-Reported Outcomes After Arthroscopic Debridement of Grade 3 or 4 Capitellar Osteochondritis Dissecans Lesions.

Background: Arthroscopic debridement for osteochondritis dissecans (OCD) lesions of the capitellum is a relatively common and straightforward surgical option for failure of nonoperative management. However, the long-term outcomes of this procedure remain unknown.

Hypothesis: Arthroscopic debridement of capitellar OCD would provide satisfactory long-term improvement in patient-reported outcomes.

Targeted protein S-nitrosylation of ACE2 inhibits SARS-CoV-2 infection.

Prevention of infection and propagation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a high priority in the Coronavirus Disease 2019 (COVID-19) pandemic. Here we describe S-nitrosylation of multiple proteins involved in SARS-CoV-2 infection, including angiotensin-converting enzyme 2 (ACE2), the receptor for viral entry. This reaction prevents binding of ACE2 to the SARS-CoV-2 spike protein, thereby inhibiting viral entry, infectivity and cytotoxicity.