Perinatal asphyxia: current status and approaches towards neuroprotective strategies, with focus on sentinel proteins

Delivery is a stressful and risky event menacing the newborn. The mother-dependent respiration has to be replaced by autonomous pulmonary breathing immediately after delivery. If delayed, it may lead to deficient oxygen supply compromising survival and development of the central nervous system. Lack of oxygen availability gives rise to depletion of NAD+ tissue stores, decrease of ATP formation, weakening of the electron transport pump and anaerobic metabolism and acidosis, leading necessarily to death if oxygenation is not promptly re-established. Re-oxygenation triggers a cascade of compensatory biochemical events to restore function, which may be accompanied by improper homeostasis and oxidative stress. Consequences may be incomplete recovery, or excess reactions that worsen the biological outcome by disturbed metabolism and/or imbalance produced by over-expression of alternative metabolic pathways. Perinatal asphyxia has been associated with severe neurological and psychiatric sequelae with delayed clinical onset. No specific treatments have yet been established. In the clinical setting, after resuscitation of an infant with birth asphyxia, the emphasis is on supportive therapy. Several interventions have been proposed to attenuate secondary neuronal injuries elicited by asphyxia, including hypothermia. Although promising, the clinical efficacy of hypothermia has not been fully demonstrated. It is evident that new approaches are warranted. The purpose of this review is to discuss the concept of sentinel proteins as targets for neuroprotection. Several sentinel proteins have been described to protect the integrity of the genome (e.g. PARP-1; XRCC1; DNA ligase IIIα; DNA polymerase β, ERCC2, DNA-dependent protein kinases). They act by eliciting metabolic cascades leading to (i) activation of cell survival and neurotrophic pathways; (ii) early and delayed programmed cell death, and (iii) promotion of cell proliferation, differentiation, neuritogenesis and synaptogenesis. It is proposed that sentinel proteins can be used as markers for characterising long-term effects of perinatal asphyxia, and as targets for novel therapeutic development and innovative strategies for neonatal care

Effect of SGLT2 inhibitors on stroke and atrial fibrillation in diabetic kidney disease: Results from the CREDENCE trial and meta-analysis

BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-Analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus. METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-Analysis. RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: Total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]). CONCLUSIONS: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Geological, Physical and Chemical Foundations

Modern tidal flats are coastal geomorphological features with a recentgeologic history (Holocene period, 10,000 YBP) that are found globally, underdifferent climatic, hydrodynamic and sedimentological regimes. They are primarilycharacterized by fine-grained sedimentary deposits (silt and clay) that present uniquephysical and chemical properties, in comparison to other sediment types. The input ofsediments to mudflats can be either riverine, from offshore, and/or from the erosion ofcoastal sedimentary deposits. Tides and tidal currents are the dominant hydrodynamicforces shaping mudflats, with wave action playing a secondary role. Theoccurrence of intermittent or temporary flooding and the presence of variable redox(oxidation-reduction) conditions are typical features of mudflat sediments. Thetemporally and spatially variable changes from aerobic, oxidized states of mudflatsediment and porewater to anaerobic, reduced states drive particular redox reactionsthat govern the characteristic chemical processes and biogeochemical functioningthat distinguish mudflats from other coastal settings. Mudflat sediments are not inert;the high surface area:volume ratio of fine-grained sediment particles offers a vast andstructurally-complex landscape for colonization by microbes that rely on surfaceadhesionprocesses. Photosynthetic microalgae belonging to several taxonomicgroups (collectively known as microphytobenthos MPB) are the dominant microorganismsgrowing in association with sedimentary particles, and forming a biofilmlayer on top. In addition to physical forces, living benthic communities modifysediment properties as part of their normal physiology (micro- and macro-biota)and feeding, movement, and burrowing activity (meio- and macrofauna), especiallyin relation to stabilization and destabilization processes. These may ultimately havemarked effects on sediment stability and geomorphology. The interplay between suchbiological processes and sediments in mudflats is currently an active field of research.Fil: Pan, Jeronimo. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Geología de Costas y del Cuaternario. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto de Geología de Costas y del Cuaternario; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; ArgentinaFil: Pratolongo, Paula Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto Argentino de Oceanografía. Universidad Nacional del Sur. Instituto Argentino de Oceanografía; ArgentinaFil: Cuadrado, Diana Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto Argentino de Oceanografía. Universidad Nacional del Sur. Instituto Argentino de Oceanografía; Argentin

Effect of SGLT2 Inhibitors on Stroke and Atrial Fibrillation in Diabetic Kidney Disease: Results From the CREDENCE Trial and Meta-Analysis

BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus.METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-analysis.RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (&lt;45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]).CONCLUSIONS: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02065791

The ATLAS experiment at the CERN Large Hadron Collider: a description of the detector configuration for Run 3

Abstract The ATLAS detector is installed in its experimental cavern at Point 1 of the CERN Large Hadron Collider. During Run 2 of the LHC, a luminosity of  ℒ = 2 × 1034 cm-2 s-1 was routinely achieved at the start of fills, twice the design luminosity. For Run 3, accelerator improvements, notably luminosity levelling, allow sustained running at an instantaneous luminosity of  ℒ = 2 × 1034 cm-2 s-1, with an average of up to 60 interactions per bunch crossing. The ATLAS detector has been upgraded to recover Run 1 single-lepton trigger thresholds while operating comfortably under Run 3 sustained pileup conditions. A fourth pixel layer 3.3 cm from the beam axis was added before Run 2 to improve vertex reconstruction and b-tagging performance. New Liquid Argon Calorimeter digital trigger electronics, with corresponding upgrades to the Trigger and Data Acquisition system, take advantage of a factor of 10 finer granularity to improve triggering on electrons, photons, taus, and hadronic signatures through increased pileup rejection. The inner muon endcap wheels were replaced by New Small Wheels with Micromegas and small-strip Thin Gap Chamber detectors, providing both precision tracking and Level-1 Muon trigger functionality. Trigger coverage of the inner barrel muon layer near one endcap region was augmented with modules integrating new thin-gap resistive plate chambers and smaller-diameter drift-tube chambers. Tile Calorimeter scintillation counters were added to improve electron energy resolution and background rejection. Upgrades to Minimum Bias Trigger Scintillators and Forward Detectors improve luminosity monitoring and enable total proton-proton cross section, diffractive physics, and heavy ion measurements. These upgrades are all compatible with operation in the much harsher environment anticipated after the High-Luminosity upgrade of the LHC and are the first steps towards preparing ATLAS for the High-Luminosity upgrade of the LHC. This paper describes the Run 3 configuration of the ATLAS detector.</jats:p

The ATLAS experiment at the CERN Large Hadron Collider: a description of the detector configuration for Run 3

Abstract The ATLAS detector is installed in its experimental cavern at Point 1 of the CERN Large Hadron Collider. During Run 2 of the LHC, a luminosity of  ℒ = 2 × 1034 cm-2 s-1 was routinely achieved at the start of fills, twice the design luminosity. For Run 3, accelerator improvements, notably luminosity levelling, allow sustained running at an instantaneous luminosity of  ℒ = 2 × 1034 cm-2 s-1, with an average of up to 60 interactions per bunch crossing. The ATLAS detector has been upgraded to recover Run 1 single-lepton trigger thresholds while operating comfortably under Run 3 sustained pileup conditions. A fourth pixel layer 3.3 cm from the beam axis was added before Run 2 to improve vertex reconstruction and b-tagging performance. New Liquid Argon Calorimeter digital trigger electronics, with corresponding upgrades to the Trigger and Data Acquisition system, take advantage of a factor of 10 finer granularity to improve triggering on electrons, photons, taus, and hadronic signatures through increased pileup rejection. The inner muon endcap wheels were replaced by New Small Wheels with Micromegas and small-strip Thin Gap Chamber detectors, providing both precision tracking and Level-1 Muon trigger functionality. Trigger coverage of the inner barrel muon layer near one endcap region was augmented with modules integrating new thin-gap resistive plate chambers and smaller-diameter drift-tube chambers. Tile Calorimeter scintillation counters were added to improve electron energy resolution and background rejection. Upgrades to Minimum Bias Trigger Scintillators and Forward Detectors improve luminosity monitoring and enable total proton-proton cross section, diffractive physics, and heavy ion measurements. These upgrades are all compatible with operation in the much harsher environment anticipated after the High-Luminosity upgrade of the LHC and are the first steps towards preparing ATLAS for the High-Luminosity upgrade of the LHC. This paper describes the Run 3 configuration of the ATLAS detector.</jats:p