Matthew S.

Environmental Microbial and Food Safety Laboratory, Beltsville Agricultural Research Center, Northeast Area, Agricultural Research Service, U.S.

Targeting tumor-specific molecular alterations has shown significant clinical benefit. Molecular tumor boards (MTBs) connect cancer patients with personalized treatments and clinical trials. However, rural cancer centers often have limited access to MTB expertise. We established an academic–community partnership expanding our academic MTB to affiliated rural community cancer centers. We developed a centralized molecular registry of tumors (MRT) to aggregate the comprehensive genomic profiling (CGP) results and facilitate multidisciplinary MTB review. Of the 151 patients included, 87 (58%) had actionable genomic biomarkers, 42 (28%) were eligible for a targeted off-label therapy, and 27 (18%) were matched to a clinical trial. Of those with a clinical trial match, only 1 of 27 (3%) was enrolled in the identified trial. One year into implementation, community oncology providers were anonymously surveyed on persistent barriers to precision treatment utilization. The primary barriers to clinical trial enrollment were the distance to the trial center (70%), lack of transportation (55%), and lack of local trials (50%). This study offers a framework to improve access to molecular expertise, but significant barriers to the equitable use of CGP and trial enrollment persist.

Antibiotic resistance is a global healthcare crisis. Bacteria are highly adaptable and can rapidly acquire mechanisms of resistance towards conventional antibiotics. The permeability barrier conferred by the Gram-negative bacteria cell envelope constitutes a first line of defence against the action of antibiotics. Exposure to extracytoplasmic stresses can negatively affect cell envelope homoeostasis and this causes localised protein misfolding, compromised envelope integrity and impairs barrier function. The CpxA-CpxR two-component regulatory system has evolved to sense extracytoplasmic stresses and to regulate processes that restore homoeostasis of the cell envelope. Hence, controlled Cpx-signalling assists bacteria in adapting, surviving and proliferating in harsh environments, including exposure to antibiotics. Herein, we determined that an intact Cpx-signalling is key to maintaining the Yersinia pseudotuberculosis resistance to colistin and polymyxin B. The susceptibility displayed by Cpx-signalling defective mutants, correlated with cell-envelope deformity and specific modifications of Lipid-A. In vivo transcriptional analysis and in vitro protein-DNA binding studies demonstrated that these modifications were dependent on the direct regulation of Lipid-A biogenesis and modifications of operons by the active phosphorylated CpxR~P isoform. Altogether, our work defines the regulatory mechanism that enables Cpx-signalling to actively control cell envelope remodelling and the permeability of antibiotics in the clinically relevant enteropathogen Y. pseudotuberculosis.

Abstract Portable, low-field magnetic resonance imaging (LF-MRI) of the brain may facilitate point-of-care assessment of patients with

A new multi-speleothem record from Guatemala demonstrates that Atlantic Ocean circulation and sea surface temperature controlled Central American monsoon convection during the last glacial cycle, with a limited role for orbital summer insolation.

Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA

Kaposi sarcoma-associated herpes virus (KSHV), also known as human herpes virus 8 (HHV-8), is the primary etiologic cause of Kaposi sarcoma (KS) and KSHV Inflammatory Cytokine Syndrome (KICS). Patients with KICS demonstrate symptoms of systemic inflammation, high KSHV viral load, elevation of inflammatory markers, and increased mortality. Management requires rapid diagnosis, treatment of underlying HIV, direct treatment of KS, and addressing the hyperimmune response. While a case definition based on clinical presentation, imaging findings, laboratory values, KSHV viral load, and lymph-node biopsy has been proposed, some of the required investigations are frequently unavailable in resource-constrained settings. Due to these challenges, KICS likely remains underdiagnosed and undertreated in these settings. We report a case of a 19-year-old woman living with HIV, and intermittent adherence to her ART, who presented with hypotension and acute hypoxemic respiratory failure. She was found to have high KSHV and HIV viral loads, low CD4 count, anemia, thrombocytopenia, hypoalbuminemia, and elevated inflammatory markers. On bedside ultrasound, she was found to have bilateral pleural effusions, ascites, an enlarged spleen, and hyperechoic splenic lesions. The diagnosis of KICS was made based on this constellation of findings. Weighing the risk and benefits of steroid administration in KS patients, the patient was successfully treated by the continuation of ART and the initiation of paclitaxel chemotherapy and steroids. We propose an adapted case definition relevant to the resource-constrained context. Due to the dual burden of KSHV and HIV in sub-Saharan Africa, additional cases of KICS are likely, and this syndrome will contribute to the burden of early mortality in newly diagnosed HIV patients. Addressing the diagnostic and therapeutic challenges of KICS must be a part of the overall management of the HIV pandemic.

Posada-Quintero et al. study the dynamics of the electrodermal activity and heart rate while breathing at elevated oxygen partial pressures in a hyperbaric environment. Electrodermal activitycan be used to predict the onset of central nervous system oxygen toxicity symptoms in divers resulting from prolonged exposure to a hyperbaric environment.

Abstract Nutrient recycling by marine megafauna is a key ecosystem service that has been disturbed by anthropogenic activity.

Background Seasonal vaccination is the mainstay of human influenza prevention. Licensed influenza vaccines are regularly updated to account for viral mutations and antigenic drift and are standardised for their haemagglutinin content. However, vaccine effectiveness remains suboptimal. Neuraminidase (NA) evolves more gradually than hemagglutinin and has been demonstrated to provide added clinical benefits. However, NA is not currently a mandated or standardised component of influenza vaccines. Methods Here, we collated expert opinions on the importance of NA in influenza vaccines in a two-stage Delphi survey. Nine statements about NA were formulated by a steering committee based on a targeted literature review. In the survey’s first round, panellists recruited from three continents were requested to report on their agreement with each statement and estimate the strength of evidence for each statement. Panellists were also requested to explain their choice of answer and suggest revisions to the statements. Consensus was considered reached if ≥ 75% of panellists agreed with a statement. If consensus was not reached for a statement, this statement was revised and included in the survey’s second round. Results Nine panellists with a broad range of NA-related expertise, including clinical, research, and public health experience, completed the survey. They agreed that anti-NA responses acquired via natural infection or vaccination are associated with protective immunity independently of haemagglutinin and that NA provided additional advantages including improving disease severity metrics. The experts identified several knowledge gaps concerning heterologous cross-reactivity of vaccine-induced anti-NA antibodies, correlations between anti-NA titres and reduced transmission or infection risks, and differences in anti-NA responses to seasonal influenza vaccines. Conclusions NA is an important influenza vaccine component and is associated with specific benefits. These benefits would likely be greater if NA content were standardised. Additional research is needed to optimise vaccines for anti-NA effects.