Effects of Low pH on Lactate Dehydrogenase Kinetics of Diving and Nondiving Reptiles

The properties of lactate dehydrogenase were examined in two snake species, Nerodia rhombifera and Elaphe obsoleta, and a turtle species, Pseudemys scripta. Our purpose was to compare the LDH activity of reptiles with limited anaerobic capabilities with that of the well established diver Pseudemys. The Michaelis-Menten kinetics of LDH and its susceptibility to inhibition by elevated pyruvate concentrations were investigated in the brain and heart of the three species. All tissue incubations and enzyme activity determinations were done at a pH of 7.0 in order to stimulate a diving blood pH in the three species. In both tissues the LDH activity of the snakes was higher than that of Pseudemys at pyruvate concentrations ranging between .03 mM and .50 mM. The Km values of the snakes were lower than those of Pseudemys, suggesting a greater enzyme-substrate affinity in the snake tissues. The Vmax values were higher in the snake tissues indicating a faster conversion of substrate to product. Heart LDH activity was reduced to an equal extent by high pyruvate concentrations in each of the three species. Elaphe brain LDH was most susceptible to pyruvate inhibition, but Nerodia and Pseudemys brain LDH were inhibited to an equal extent. The results indicate that the kinetic behavior of brain and heart LDH of the three species is similar at a pH of 7.4 and a pH of 7.0. The results also suggest that the LDH of Pseudemys is no better adapted to withstand anaerobic conditions than that of Nerodia or Elaphe at a pH of 7.0

SN 2010ay is a Luminous and Broad-lined Type Ic Supernova within a Low-metallicity Host Galaxy

We report on our serendipitous pre-discovery detection and detailed follow-up of the broad-lined Type Ic supernova (SN) 2010ay at z = 0.067 imaged by the Pan-STARRS1 3pi survey just ~4 days after explosion. The SN had a peak luminosity, M_R ~ -20.2 mag, significantly more luminous than known GRB-SNe and one of the most luminous SNe Ib/c ever discovered. The absorption velocity of SN 2010ay is v_Si ~ 19,000 km/s at ~40 days after explosion, 2-5 times higher than other broad-lined SNe and similar to the GRB-SN 2010bh at comparable epochs. Moreover, the velocity declines ~2 times slower than other SNe Ic-BL and GRB-SNe. Assuming that the optical emission is powered by radioactive decay, the peak magnitude implies the synthesis of an unusually large mass of 56 Ni, M_Ni = 0.9 M_solar. Modeling of the light-curve points to a total ejecta mass, M_ej ~ 4.7 M_sol, and total kinetic energy, E_K ~ 11x10^51 ergs. The ratio of M_Ni to M_ej is ~2 times as large for SN 2010ay as typical GRB-SNe and may suggest an additional energy reservoir. The metallicity (log(O/H)_PP04 + 12 = 8.19) of the explosion site within the host galaxy places SN 2010ay in the low-metallicity regime populated by GRB-SNe, and ~0.5(0.2) dex lower than that typically measured for the host environments of normal (broad-lined) Ic supernovae. We constrain any gamma-ray emission with E_gamma < 6x10^{48} erg (25-150 keV) and our deep radio follow-up observations with the Expanded Very Large Array rule out relativistic ejecta with energy, E > 10^48 erg. We therefore rule out the association of a relativistic outflow like those which accompanied SN 1998bw and traditional long-duration GRBs, but place less-stringent constraints on a weak afterglow like that seen from XRF 060218. These observations challenge the importance of progenitor metallicity for the production of a GRB, and suggest that other parameters also play a key role.Comment: 19 pages, 10 figures, V3 has revisions following referee's report; more information at http://www.cfa.harvard.edu/~nsanders/papers/2010ay/summary.htm

Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all &gt;0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

Enabling equitable and affordable access to novel therapeutics for pandemic preparedness and response via creative intellectual property agreements

The COVID-19 pandemic demonstrated that the current purely market-driven approaches to drug discovery and development alone are insufficient to drive equitable access to new therapies either in preparation for, or in response to, pandemics. A new global framework driven by equity is under negotiation at the World Health Organization to support pandemic preparedness and response. Some believe that the global intellectual property (IP) system itself is part of the problem and propose a purely Open Science approach. In this article, we discuss how existing IP frameworks and contractual agreements may be used to create rights and obligations to generate a more effective global response in future, drawing on experience gained in the COVID Moonshot program, a purely Open Science collaboration, and the ASAP AViDD drug discovery consortium, which uses a hybrid, phased model of Open Science, patent filing and contractual agreements. We conclude that ‘straight to generic’ drug discovery is appropriate in some domains, and that targeted patent protection, coupled with open licensing, can offer a route to generating affordable and equitable access for therapy areas where market forces have failed. The Extended Data contains a copy of our model IP policy, which can be used as a template by other discovery efforts seeking to ensure their drug candidates can be developed for globally equitable and affordable access

Statin effects on the lipidome: Predicting statin usage and implications for cardiovascular risk prediction

Statin therapy is a highly successful and cost-effective strategy for the prevention and treatment of cardiovascular diseases (CVD). Adjusting for statin usage is crucial when exploring the association of the lipidome with CVD to avoid erroneous conclusions. However, practical challenges arise in real-world scenarios due to the frequent absence of statin usage information. To address this limitation, we demonstrate that statin usage can be accurately predicted using lipidomic data. Using three large population datasets and a longitudinal clinical study, we show that lipidomic-based statin prediction models exhibit high prediction accuracy in external validation. Furthermore, we introduce a re-weighted model, designed to overcome a ubiquitous limitation of prediction models, namely the need for predictor alignment between training and target data. We demonstrated that the re-weighted models achieved comparable prediction accuracy to ad hoc models which use the aligned predictor between training and target data. This innovation holds promise for significantly enhancing the transferability of statin prediction and other ‘omics prediction models, especially in situations where predictor alignment is incomplete. Our statin prediction model now allows for the inclusion of statin usage in lipidomic analyses of cohorts even where statin use is not available, improving the interpretability of the resulting analyses

Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA-KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all &gt;0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council