Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1 progenitor CD8 T cells to improve immunotherapy.

TCF1 progenitor CD8 T cells mediate the efficacy of immunotherapy; however, the mechanisms that govern their generation and maintenance are poorly understood. Here, we show that targeting glycolysis through deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a TCF1 progenitor-exhausted-like phenotype and increased responsiveness to PD-1 blockade in vivo. PKM2 CD8 T cells showed reduced glycolytic flux, accumulation of glycolytic intermediates and PPP metabolites and increased PPP cycling as determined by 1,2-C glucose carbon tracing.

SARS-CoV-2 Omicron XBB lineage spike structures, conformations, antigenicity, and receptor recognition.

A recombinant lineage of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant, named XBB, appeared in late 2022 and evolved descendants that successively swept local and global populations. XBB lineage members were noted for their improved immune evasion and transmissibility. Here, we determine cryoelectron microscopy (cryo-EM) structures of XBB.

Vaccine induction of heterologous HIV-1-neutralizing antibody B cell lineages in humans.

A critical roadblock to HIV vaccine development is the inability to induce B cell lineages of broadly neutralizing antibodies (bnAbs) in humans. In people living with HIV-1, bnAbs take years to develop. The HVTN 133 clinical trial studied a peptide/liposome immunogen targeting B cell lineages of HIV-1 envelope (Env) membrane-proximal external region (MPER) bnAbs (NCT03934541).

SARS-CoV-2 Omicron XBB lineage spike structures, conformations, antigenicity, and receptor recognition.

A recombinant lineage of the SARS-CoV-2 Omicron variant, named XBB, appeared in late 2022 and evolved descendants that successively swept local and global populations. XBB lineage members were noted for their improved immune evasion and transmissibility. Here, we determine cryo-EM structures of XBB.

Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve checkpoint blockade.

TCF1 progenitor CD8+ T cells mediate the efficacy of PD-1 blockade, however the mechanisms that govern their generation and maintenance are poorly understood. Here, we show that targeting glycolysis through deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a TCF1 central memory-like phenotype and increased responsiveness to PD-1 blockade . PKM2 CD8+ T cells showed reduced glycolytic flux, accumulation of glycolytic intermediates and PPP metabolites, and increased PPP cycling as determined by 1,2 C glucose carbon tracing.

Neonatal SHIV infection in rhesus macaques elicited heterologous HIV-1-neutralizing antibodies.

Infants and children infected with human immunodeficiency virus (HIV)-1 have been shown to develop neutralizing antibodies (nAbs) against heterologous HIV-1 strains, characteristic of broadly nAbs (bnAbs). Thus, having a neonatal model for the induction of heterologous HIV-1 nAbs may provide insights into the mechanisms of neonatal bnAb development. Here, we describe a neonatal model for heterologous HIV-1 nAb induction in pathogenic simian-HIV (SHIV)-infected rhesus macaques (RMs).

An assessment of the dose and image quality difference between AP and PA positioned adult radiographic knee examinations.

Introduction: Knee X-rays are a standard examination to diagnose multiple conditions ranging from traumatic injuries, degeneration, and cancer. This study explores the differences between adult Anterior-Posterior (AP) and Posterior-Anterior (PA) weight-bearing knee examinations using absorbed radiation dose data and image quality.

Methods: The study modelled and compared AP and PA knee X-ray radiation dose data using Monte-Carlo software, an Ion Chamber, and thermoluminescence dosemeters (TLDs) on a Rando phantom.

Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer.

IRE1α-XBP1 signaling is emerging as a central orchestrator of malignant progression and immunosuppression in various cancer types. Employing a computational XBP1s detection method applied to TCGA datasets, we demonstrate that expression of the XBP1s mRNA isoform predicts poor survival in non-small cell lung cancer (NSCLC) patients. Ablation of IRE1α in malignant cells delays tumor progression and extends survival in mouse models of NSCLC.

Cryo-EM structures of SARS-CoV-2 Omicron BA.2 spike.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.2 sub-lineage has gained in proportion relative to BA.1.

Structural diversity of the SARS-CoV-2 Omicron spike.

Aided by extensive spike protein mutation, the SARS-CoV-2 Omicron variant overtook the previously dominant Delta variant. Spike conformation plays an essential role in SARS-CoV-2 evolution via changes in receptor-binding domain (RBD) and neutralizing antibody epitope presentation, affecting virus transmissibility and immune evasion. Here, we determine cryo-EM structures of the Omicron and Delta spikes to understand the conformational impacts of mutations in each.

Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: a phase 1b/2 trial.

CEP290-associated Leber congenital amaurosis type 10 (LCA10) is a retinal disease resulting in childhood blindness. Sepofarsen is an RNA antisense oligonucleotide targeting the c.2991+1655A>G variant in the CEP290 gene to treat LCA10.

Structural diversity of the SARS-CoV-2 Omicron spike.

Aided by extensive spike protein mutation, the SARS-CoV-2 Omicron variant overtook the previously dominant Delta variant. Spike conformation plays an essential role in SARS-CoV-2 evolution via changes in receptor binding domain (RBD) and neutralizing antibody epitope presentation affecting virus transmissibility and immune evasion. Here, we determine cryo-EM structures of the Omicron and Delta spikes to understand the conformational impacts of mutations in each.

Can Total Hip Arthroplasty for Hip Fracture Be Safely Performed by Trainees? A Retrospective Cohort Study.

Background: No research is available comparing trainee and consultant outcomes for total hip arthroplasty (THA) for hip fracture. The aim of our study is to determine whether trainee-performed and consultant-performed THA produced equivalent radiological outcomes and complication rates for this patient cohort.

Methods: We performed a retrospective cohort study at our institution, with inclusion of patients who underwent a primary THA for hip fracture between March 30, 2017 and February 07, 2019.

Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multicentre cohort study.

Background: In neonatal encephalopathy, the clinical manifestations of injury can only be reliably assessed several years after an intervention, complicating early prognostication and rendering trials of promising neuroprotectants slow and expensive. We aimed to determine the accuracy of thalamic proton magnetic resonance (MR) spectroscopy (MRS) biomarkers as early predictors of the neurodevelopmental abnormalities observed years after neonatal encephalopathy.

Methods: We did a prospective multicentre cohort study across eight neonatal intensive care units in the UK and USA, recruiting term and near-term neonates who received therapeutic hypothermia for neonatal encephalopathy.

A novel technique for estimating component sizes in total knee arthroplasty.

Introduction: Intra-operative assessment of total knee arthroplasty (TKA) components is performed with manufacturer specific jigs. Pre-operative templating, patient specific knee cutting blocks and computer-assisted surgeries have also been used to improve alignment and sizing; although the literature shows marginal improvement in functional scores. We propose pre-operative shoe size as a simple measurement tool for estimating the component sizes required for TKA.

Lesser Trochanter Avulsion Fracture in an Adolescent after Seizure.

Background: Injury secondary to epileptic seizure is widely documented in the literature. In particular, uncontrolled muscular contractions generated during a seizure can lead to a variety of musculoskeletal injuries.

Case Report: We present the case of a 16-year-old male who presented on two separate occasions after a tonic-clonic seizure with hip pain, an antalgic gait, and marked discomfort on hip flexion.

New insights into phase distribution, phase composition and disorder in Y2(Zr,Sn)2O7 ceramics from NMR spectroscopy.

A combination of (89)Y and (119)Sn NMR spectroscopy and DFT calculations are used to investigate phase evolution, local structure and disorder in Y2Zr2-xSnxO7 ceramics, where a phase change is predicted, from pyrochlore to defect fluorite, with increasing Zr content. The ability of NMR to effectively probe materials that exhibit positional and compositional disorder provides insight into the atomic-scale structure in both ordered and disordered phases and, by exploiting the quantitative nature of the technique, we are able to determine detailed information on the composition of the phase(s) present and the average coordination number (and next-nearest neighbour environment) of the cations. In contrast to previous studies, a more complex picture of the phase variation with composition emerges, with single-phase pyrochlore found only for the Sn end member, and a single defect fluorite phase only for x = 0 to 0.

Accelerated polyethylene wear and early failure of the uncemented Reflection acetabular component: a ten to fifteen-year follow-up study.

Purpose: The Reflection® second-generation uncemented acetabular component was designed to address increased rates of failure observed with the early acetabular designs. However, the reported survivorship of this acetabular component has been conflicting. The aim of this study was to describe the ten to 15-year survivorship and polyethylene wear rate for the uncemented Reflection® acetabular component performed as part of a primary total hip replacement.

IL-6 pathway-driven investigation of response to IL-6 receptor inhibition in rheumatoid arthritis.

Objectives: To determine whether heterogeneity in interleukin-6 (IL-6), IL-6 receptor and other components of the IL-6 signalling pathway/network, at the gene, transcript and protein levels, correlate with disease activity in patients with rheumatoid arthritis (RA) and with clinical response to tocilizumab.

Design: Biomarker samples and clinical data for five phase 3 trials of tocilizumab were analysed using serum (3751 samples), genotype (927 samples) and transcript (217 samples) analyses. Linear regression was then used to assess the association between these markers and either baseline disease activity or treatment response.

Variation in physical development in schoolboy rugby players: can maturity testing reduce mismatch?

Objectives: This study set out to pursue means of reducing mismatch in schoolboy rugby players. The primary objective was to determine whether application of previously reported thresholds of height and grip strength could be used to distinguish those 15-year-old boys appropriate to play under-18 school rugby from their peers. A secondary objective was to obtain normative data for height, weight and grip strength and to assess the variation within that data of current schoolboy rugby players.

Effects of plant flavonoids on Manduca sexta (tobacco hornworm) fifth larval instar midgut and fat body mitochondrial transhydrogenase.

The reversible, membrane-associated transhydrogenase that catalyzes hydride-ion transfer between NADP(H) and NAD(H) was evaluated and compared to the corresponding NADH oxidase and succinate dehydrogenase activities in midgut and fat body mitochondria from fifth larval instar Manduca sexta. The developmentally significant NADPH-forming transhydrogenation occurs as a nonenergy- or energy-linked activity with energy for the latter derived from either electron transport-dependent NADH or succinate utilization, or ATP hydrolysis by Mg++-dependent ATPase. In general, the plant flavonoids examined (chyrsin, juglone, morine, quercetin, and myricetin) affected all reactions in a dose-dependent fashion.

Association of the PPARG Pro12Ala polymorphism with type 2 diabetes and incident coronary heart disease in a Hong Kong Chinese population.

Aims: We examined the risk association between single nucleotide polymorphisms (SNPs) in eleven candidate genes with type 2 diabetes (T2D). T2D-associated polymorphisms were also examined for prediction of incident CHD.

Methods: 113 tagging SNPs were genotyped in stage 1 (467 T2D cases, 290 controls), and 15 SNPs were analyzed in the final cohort (1462 T2D cases, 600 controls).

Resistance to selective BRAF inhibition can be mediated by modest upstream pathway activation.

A high percentage of patients with BRAF(V600E) mutant melanomas respond to the selective RAF inhibitor vemurafenib (RG7204, PLX4032) but resistance eventually emerges. To better understand the mechanisms of resistance, we used chronic selection to establish BRAF(V600E) melanoma clones with acquired resistance to vemurafenib. These clones retained the V600E mutation and no second-site mutations were identified in the BRAF coding sequence.

Genetic variation in UGT1A1 typical of Gilbert syndrome is associated with unconjugated hyperbilirubinemia in patients receiving tocilizumab.

Objective: Tocilizumab, a monoclonal antibody to interleukin-6 receptor, was recently approved for the treatment of moderate-to-severe rheumatoid arthritis. Two patients during clinical development met laboratory, but not clinical, criteria for Hy's law with bilirubin elevations suspected as a result of genetic variation in uridine diphosphoglucose glucuronosyltransferase (UGT1A1) typical of Gilbert syndrome.

Methods: Genotyping of the two cases potentially meeting with Hy's law was performed using commercially available procedures.