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PARP and ATR inhibitors also induced cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) innate immune signaling in PBRM1-defective tumor cells. Overall, these findings provide the preclinical basis for using PARP inhibitors in PBRM1-defective cancers. SIGNIFICANCE This study demonstrates that PARP and ATR inhibitors are synthetic lethal with the loss of PBRM1, a PBAF-specific subunit, thus providing the rationale for assessing these inhibitors in patients with PBRM1-defective cancer. GRAPHICAL ABSTRACT http//cancerres.aacrjournals.org/content/canres/81/11/2888/F1.large.jpg.The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of heme metabolism, with nanomolar affinity. Using cryo-electron microscopy and x-ray crystallography, we mapped the tetrapyrrole interaction pocket to a deep cleft on the spike N-terminal domain (NTD). At physiological concentrations, biliverdin significantly dampened the reactivity of SARS-CoV-2 spike with immune sera and inhibited a subset of neutralizing antibodies. Access to the tetrapyrrole-sensitive epitope is gated by a flexible loop on the distal face of the NTD. Accompanied by profound conformational changes in the NTD, antibody binding requires relocation of the gating loop, which folds into the cleft vacated by the metabolite. Our results indicate that SARS-CoV-2 spike NTD harbors a dominant epitope, access to which can be controlled by an allosteric mechanism that is regulated through recruitment of a metabolite.
This document aimed to summarise the key components of exertional heat stroke (EHS) prehospital management.
Members of the International Olympic Committee Adverse Weather Impact Expert Working Group for the Olympic Games Tokyo 2020 summarised the current best practice regarding the EHS prehospital management.
Sports competitions that are scheduled under high environmental heat stress or those that include events with high metabolic demands should implement and adopt policy and procedures for EHS prehospital management. The basic principles of EHS prehospital care are early recognition, early diagnosis, rapid, on-site cooling and advanced clinical care. In order to achieve these principles, medical organisers must establish an area called the heat deck within or adjacent to the main medical tent that is optimised for EHS diagnosis, treatment and monitoring. Once admitted to the heat deck, the rectal temperature of the athlete with suspected EHS is assessed to confirm an elevated core body temperature. After EHS is diagnosed, the athlete must be cooled on-site until the rectal temperature is below 39°C. Cy7 DiC18 concentration While cooling the athlete, medical providers are recommended to conduct a blood analysis to rule out exercise-associated hyponatraemia or hypoglycaemia, provided that this can be safely performed without interrupting cooling. The athlete is transported to advanced care for a full medical evaluation only after the treatment has been provided on-site.
A coordination of care among all medical stakeholders at the sports venue, during transport, and at the hospital is warranted to ensure effective management is provided to the EHS athlete.
A coordination of care among all medical stakeholders at the sports venue, during transport, and at the hospital is warranted to ensure effective management is provided to the EHS athlete.
The aim of this study was to develop a risk model for intraoperative complication (IC) during cataract surgery, defined as posterior capsule rupture and/or zonular dehiscence, and to include previous intravitreal therapy (pIVT) in the model.
This retrospective register-based study covered patients reported to the Swedish National Cataract Register (SNCR) between 1 January 2010 and 30 June 2018. Odds ratios (ORs) were used to quantify association strength of each variable with IC. Data from the SNCR were cross referenced with the Swedish Macula Register to include data on pIVT. Variables statistically significant in the univariate analyses (p<0.05) were included in a multivariate logistic regression model.
The inclusion criteria were met by 907 499 eyes. The overall rate of IC was 0.86%. Variables significantly associated with IC were best corrected visual acuity ≥1.0 LogMAR (OR (adjusted) 1.75, p<0.001), age ≥90 years (OR 1.25, p<0.001), male sex (OR 1.09, p<0.01), pseudoexfoliation (OR 1.33, p<0.001), glaucoma (OR 1.11, p<0.05), diabetic retinopathy (OR 1.35, p<0.001), pIVT (OR 1.45, p<0.05), surgeon's experience <600 surgeries (OR 2.77, p<0.001), use of rhexis hooks (OR 6.14, p<0.001), blue staining (OR 1.87, p<0.001) and mechanical pupil dilation (OR 1.52, p<0.001).
The risk model can be used in the preoperative setting to predict the probability of IC, to facilitate planning of surgery and improving patient communication. Patients who have undergone intravitreal therapy prior to cataract surgery have an increased risk of IC during cataract surgery.
The risk model can be used in the preoperative setting to predict the probability of IC, to facilitate planning of surgery and improving patient communication. Patients who have undergone intravitreal therapy prior to cataract surgery have an increased risk of IC during cataract surgery.
To characterise the association between visual field (VF) defects and myopic macular degeneration (MMD) in highly myopic adults without glaucoma.
Participants (n=106; 181 eyes) with high myopia (HM; spherical equivalent ≤-5.0 D or axial length (AL) ≥26 mm), after excluding glaucoma and glaucoma suspects, from the Singapore Epidemiology of Eye Diseases-HM study were included in this cross-sectional study. Humphrey VF (central 24-2 threshold), cup-disc ratio (CDR) and intraocular pressure (IOP) measurements were performed. Mean deviation (MD) and pattern SD (PSD), VF defects (normal or abnormal; p<0.05 in ≥3 non-edge contiguous locations) and pattern (eg, generalised sensitivity loss) were analysed. MMD presence was diagnosed from fundus photographs. Generalised estimating equations were used for analysing factors (MD, PSD, VF defects, CDR and IOP) associated with MMD.
Mean age was 55.4±9.9 years and 51.9% were women (AL=26.7±1.1 mm). MMD eyes had lower MD (-3.8±2.9 dB vs -1.1±1.4 dB) and higher PSD (2.