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Introduction: Central vision loss due to diabetic macular edema (DME) is related to the macular edema itself, but also in some cases to alterations of the foveal avascular zone (FAZ). The aim of this trial was to study changes in macular vessels in eyes with DME treated with aflibercept using optical coherence tomography angiography (OCTA). Methods: This was a longitudinal, prospective, non-controlled, single arm study. The primary objective was the quantitative assessment of macular vessels over time in patients with DME treated with intravitreal aflibercept during a 48-week follow-up using OCTA. Results: Twenty-six DME eyes from 26 patients were included (mean age, 64.6 years; women, 53.8%; prior anti-VEGF treatment, 46.1%). Each eye received a mean (SD) of 7.2 (2.2) injections. The parameters of the FAZ did not change during the 48-week follow-up: the mean (SD) FAZ area varied from 0.19 (0.19) mm2 at baseline (n=22) to 0.23 (0.20) mm2 at week 48 (n=15), boundary from 1.54 (1.21) to 2.04 (1.20) mm and circularity from 0.45 (0.33) % to 0.57 (0.20) %. There was no change in perfusion density and vessel density of the macula in the 3-mm circle. As expected, mean central retinal thickness, macular volume and visual acuity improved during follow-up. Discussion/Conclusion: No change in macular perfusion was observed in eyes with DME during a 48-week follow-up after intravitreal injections of aflibercept. Randomized controlled trials using OCT-angiography in large populations with extended observation periods are needed to assess changes in macular vessels after intravitreal anti-VEGF treatment.

Inherited retinal diseases are a leading and untreatable cause of blindness and are therefore candidate diseases for gene therapy. Recombinant vectors derived from adeno-associated virus (rAAV) are currently the most promising vehicles forin vivotherapeutic gene delivery to the retina. However, there is a need for novel AAV-based vectors with greater efficacy for ophthalmic applications, as underscored by recent reports of dose-related inflammatory responses in clinical trials of rAAV-based ocular gene therapies. Improved therapeutic efficacy of vectors would allow for decreases in the dose delivered, with consequent reductions in immune reactions. Here, we describe the development of new rAAV vectors using bioconjugation chemistry to modify the rAAV capsid, thereby improving the therapeutic index. Covalent coupling of a mannose ligand,viathe formation of a thiourea bond, to the amino groups of the rAAV capsid significantly increases vector transduction efficiency of both rat and nonhuman primate retinas. These optimized rAAV vectors have important implications for the treatment of a wide range of retinal diseases.

Purpose The intravitreal dexamethasone implant (DEX-I) is an alternative to anti-VEGF for the first-line treatment of diabetic macular oedema (DME). However, several questions remain regarding its routine use and its place in certain situations not always specified in current recommendations. A national consensus approach was, therefore, initiated by French retinal experts. Methods An iterative Delphi consensus approach was used. A steering committee (SC) of seven experts analysed data from the literature to formulate statements divided into five key areas of treatment. These statements were submitted to the independent and anonymous electronic vote of 87 French retina experts among whom 39 expressed their opinion and therefore constituted the voting panel. Results After two rounds of voting, 22 and 7 of 38 statements received a strong consensus and a good consensus, respectively. The consensus level was higher for statements regarding first-line indications and safety of DEX-I compared to those regarding efficacy assessment, reprocessing time or pathophysiological biomarkers. The panellists recommended the preferential use of DEX-I for patients with limited availability for multiple injections, those who needed to undergo cataract surgery or who had a recent cardiovascular history, and as a therapeutic alternative to anti-VEGF in patients with a history of vitrectomy, retinal serous detachment, hyper-reflective points or dry exudates in optical coherence tomography (OCT). However, some statements proposed by SC experts were not validated. Conclusion This study provides some key recommendations to clinicians treating diabetic macular oedema, which may be useful when using intravitreal dexamethasone implants in daily practice.

Resume Objectif Evaluer le suivi et le devenir a long terme de l’acuite visuelle des patients dans les œdemes maculaires diabetiques (OMD) et lies aux occlusions veineuses retiniennes (OVR). Materiel et methode Nous avons mene une etude observationnelle retrospective de « vraie vie » monocentrique incluant 65 yeux de 47 patients traites pour OMD et 33 yeux de 33 patients traites pour œdeme maculaire compliquant une OVR entre juillet 2012 et octobre 2018. Les patients traites etaient naifs de tout traitement et ont ete suivi au moins un an. Nous avons recueilli les donnees telles que l’acuite visuelle, l’epaisseur maculaire centrale, les injections intra-vitreennes (nombre/an, schema d’injection, le nombre de switch), le nombre de visite et le nombre de perdu de vue. Resultats Pour les OMD : l’âge moyen a l’inclusion etait de 65,9 ans avec 60,4 % de femme et le suivi moyen de 28,5 mois. Le gain moyen d’acuite visuelle apres 1 an de suivi est de 6,4 lettres ETDRS pour les patients traites par anti-VEGF et de 2,6 lettres pour les patients traites par dexamethasone. Le nombre moyen d’injections intra-vitreennes d’anti-VEGF etait de 5,6/an, contre 2,9/an pour la dexamethasone. Quatorze patients initialement traites par anti-VEGF ont ete switches vers la dexamethasone. Pour les OVR, l’âge moyen a l’inclusion etait de 68,8 ans avec 54,5 % de femme et un suivi moyen de 31,1 mois. Le gain moyen d’acuite visuelle apres 1 an de suivi est de 26,7 lettres ETDRS pour les patients traites par anti-VEGF et de 7,0 lettres pour les patients traites par dexamethasone. Le nombre moyen d’injections intra-vitreennes d’anti-VEGF etait de 5,8/an, contre 2,4/an pour la dexamethasone. Cinq patients initialement traites par anti-VEGF ont ete switches vers la dexamethasone dans la premiere annee de suivi. Conclusion On retrouve dans cette etude retrospective de « vraie vie » des donnees anatomiques et fonctionnelles similaires a celles des etudes publiees, et se maintenant au cours du temps pour les patients atteints d’occlusion veineuse retinienne et d’œdeme maculaire diabetique.

Cyclopentannulation was explored as a strategy to access large, stable azaarenes. Buchwald-Hartwig coupling of previously reported di- and tetrabrominated cyclopentannulated N,N'-dihydrotetraazapentacenes furnished stable azaarenes with up to 13 six-membered rings in a row and a length of 3.1 nm. Their optoelectronic and semi-conducting properties as well as their aromaticity were investigated.

To evaluate mean change in best-corrected visual acuity (BCVA) at 52 weeks in patients with inflammatory choroidal neovascularization (CNV) treated with aflibercept.We conducted a prospective non-comparative open-label trial. Following one mandatory intravitreal injection of aflibercept, patients were treated under a pro re nata (PRN) dosing regimen with monthly visits.A total of 19 patients were included, but one presented exclusion criteria; 16 patients were followed for the whole 52-week study, and data for the primary endpoint analysis were available for 14. At baseline, mean BCVA and mean central retinal thickness (CRT) were 64.53 (±19.64) letters and 351.79 (±97.77) μm, respectively. At 52 weeks, the mean change in BCVA was +9.50 (±12.90) letters [95%CI = +2.05-+16.95]. One patient had lost more than 15-letters at 24 weeks, and another one at 52 weeks. CRT change was -62.77 (±100.73) μm at 24 weeks and -66.53 (±97.47) μm at 52 weeks. There was a mean number of 3.56 (±3.29) intravitreal injections at 52 weeks (min = 1; max = 12). No serious ocular adverse events related to the treatment were reported.Our study shows that aflibercept is clinically effective, both anatomically and functionally in the treatment of inflammatory CNV. Following the first injection, the PRN strategy appears sufficient for treating most choroidal neovessels.

Resume Introduction L’objectif de l’etude a ete d’etudier la reproductibilite ou la variabilite des delais des recidives exsudatives chez des patients ayant recu un traitement par injections intra-vitreennes (IVT) d’anti-VEGF (ranibizumab, aflibercept) dans le cadre d’une degenerescence maculaire liee a l’âge (DMLA) de type exsudative. Les donnees etudiees ont ete le nombre de recidives annuelles, la duree ecoulee entre la recidive et la derniere IVT ainsi que la fluctuation dans le temps chez un meme patient, et les modifications de prise en charge therapeutique de ces recidives exsudatives concernant la realisation d’un nouveau traitement d’induction de trois IVT, d’un changement de protocole de suivi, et d’un changement de molecule anti-VEGF. Materiels et methodes Nous avons mene une etude retrospective de « vraie-vie », monocentrique au CHU de Nantes, concernant 33 patients (42 yeux) qui ont ete inclus entre mars 2012 et mars 2017. Il s’agissait de patients naifs d’IVT, chez lesquels un traitement par IVT d’anti-VEGF a ete initie dans le cadre de la prise en charge d’une DMLA exsudative, avec une duree de suivi d’au moins deux annees consecutives. Le critere de jugement principal etait la fluctuation des delais de recidives pour un meme patient. Resultats Sur les 33 patients inclus, 9 presentaient une atteinte bilaterale, soit un total de 42 yeux. Vingt etaient des femmes (60,6 %), l’âge median a l’inclusion etait de 78,5 ans pour une duree de suivi de 3,7 annees. Le delai de recidive moyen etait de 11,6 semaines apres la derniere IVT. La 1re recidive survenait dans un delai de 9,8 semaines apres la derniere IVT. 12,3 % des yeux presentaient des delais de recidives fixes avec fluctuations inferieures a 2 semaines entre les differentes recidives sur les deux annees de suivi. Un total de 7,1 % des yeux ne presentaient aucune recidive exsudative dans la suite du suivi. La premiere recidive exsudative avait lieu en moyenne a 38,2 semaines de suivi apres le diagnostic de la pathologie soit 37,2 semaines apres la premiere IVT. Un total de 14,3 % des recidives ont conduites a la realisation d’un nouveau traitement d’induction de trois IVT d’anti-VEGF, 8,6 % ont conduites a un changement de molecule anti-VEGF, et 7,1 % a une modification du schema de traitement. Discussion Cette etude avait pour but d’etudier la variabilite des delais de recidive exsudative chez les patients traites par IVT d’anti-VEGF dans le cadre d’une DMLA exsudative, car depuis l’avenement des IVT d’anti-VEGF en 2007, peu de donnees existent concernant le suivi a long terme et les fluctuations des delais de recidive, a propos de patients qui beneficieront d’un traitement durant plusieurs annees. Conclusion Les delais de recidives ne sont pas reproductibles au cours du temps, notamment chez les patients ayant realise leur premiere recidive exsudative au-dela de 8 semaines et chez les patients presentant de nombreuses recidives exsudatives.

Resume Introduction L’objectif de cette etude est de rechercher des correlations anatomo-fonctionnelles chez les patients atteints de chorioretinopathie de Birdshot afin de mieux comprendre les mecanismes aboutissant a la perte de fonction visuelle. Materiel et methode Nous avons realise une etude prospective observationnelle monocentrique au CHU de Nantes incluant tous les patients suivis pour une maladie de Birdshot entre janvier 2019 et juillet 2019. Les parametres etudies etaient l’acuite visuelle, la microperimetrie, la perimetrie automatisee standard, l’OCT-SD, l’OCT-EDI, l’OCT-A, l’OCT-RNFL, les retinophotographies grand champ et les angiographies a la fluoresceine et a l’ICG. Resultats Quarante-quatre yeux ont ete etudies. Une correlation significative a ete retrouvee entre l’acuite visuelle et l’epaisseur retinienne (p = 0,002 r = 0,44) mais pas choroidienne (p = 0,16). Une correlation significative a egalement ete constatee entre la sensibilite retinienne et l’epaisseur maculaire de la retine totale (p Discussion Nous retrouvons des correlations significatives entre les parametres fonctionnels tels que l’acuite visuelle et la sensibilite retinienne et les parametres anatomiques retiniens et notamment avec la retine interne tandis qu’il n’y a pas de correlation mise en evidence avec les parametres anatomiques choroidiens. Conclusion Les principaux resultats de notre etude concordent en faveur d’une origine retinienne plutot que choroidienne a l’origine de la degradation de la fonction visuelle dans la maladie de Birdshot.

Background The Catquest-9SF questionnaire is a patient reported outcome measure that quantifies the visual benefits from cataract surgery. The purpose of this study was to translate and adapt the Catquest-9SF questionnaire for France, to assess its psychometric properties via Rasch analysis, and to assess its validity when completed using an electronic notepad. Methods The Catquest-9SF questionnaire was translated following the guidelines of the International Society for Pharmacoeconomics and Outcomes Research. Catquest-9SF and clinical data were collected from patients before and after routine cataract surgery. All questionnaire data were collected via an electronic notepad. Rasch analysis was performed to assess psychometric properties, and sensitivity to change was analysed for patients with complete paired pre- and post-operative questionnaires. Results A complete filled-in preoperative questionnaire was obtained for 848 patients. Rasch analysis showed good precision (person separation: 2.32, person reliability: 0.84), ordered category probability curves, no item misfit, and unidimensionality. The respondents were slightly more able than the level of item difficulty (targeting: −1.12 logits). Sensitivity was analysed on 211 paired questionnaires, and the postoperative questionnaires showed a clear ceiling effect. The effect size was 2.6. The use of an electronic notepad for completing the questionnaire worked out very well after some adjustments. Conclusions The French version of Catquest-9SF has good psychometric properties and is suitable for use in French-speaking patients. The use of the Catquest-9SF questionnaire in an electronic format showed good validity.

The aim of this study was to evaluate the impact of adherence to French coronavirus disease 2019 (COVID 19)-related guidelines for intravitreal injection (IVI) practice on the visual outcomes of patients treated with anti-vascular endothelial growth factor (VEGF) agents for macular diseases during the first lockdown period.Observational multicentre study including all patients from 18 centres with an IVI initially planned during the lockdown. Visual acuity (VA, ETDRS) was recorded at 1 and 4 months after lockdown. French COVID 19-related guidelines recommended maintaining IVI practice. We defined three groups of patients: A, adherent to guidelines; NA+, non-adherent with delayed IVIs; and NA-, non-adherent without IVIs performed during the lockdown. Risk factors for non-adherence and visual loss were studied.A total of 3020 eyes of 3020 patients, aged 77.8 ± 11.6 years, 59.8% women, were included. 59.3% were non-adherent(46.7% NA+, 12.6% NA-). A smaller decrease in VA at 4 months was observed in the A group than the NA+ and NA- group (-0.2 ± 6.7, -0.3 ± 6.9 and -1.5 ± 6.9, respectively [p 0.001]). Factors associated with non-adherence were in multivariable analysis, older age, hospital practice, low-density population areas, high viral incidence areas, longer intervals between injection and treat and extent protocol. Factors associated with visual loss at 4 months in multivariable analysis were, being in the NA- group, older age, TE and fixed regimens.Strict adherence to guidelines was associated with better visual outcome, although most of our patients did not attend as planned. Identification of patients at risk could help in the future in case of a new pandemic lockdown.

The purpose of this study is to evaluate real-world treatment outcomes in patients with neovascular age-related macular degeneration (nAMD) treated with intravitreal aflibercept (IVT-AFL) in routine clinical practice in France.RAINBOW (NCT02279537) was an ambispective, observational, 4-year study assessing IVT-AFL effectiveness, treatment patterns, and safety in patients with nAMD in France. Treatment-naïve patients prescribed IVT-AFL and treated according to local practice (pro re nata or treat-and-extend) were eligible. Three treatment cohorts were retrospectively identified based on their treatment pattern within the first 12 months: regular (3 initial monthly IVT-AFL injections received within 45-90 days after the first injection in month 0 and followed by injections every 2 months), irregular with the initial monthly injections, and irregular without the initial monthly injections. The primary endpoint was mean change in best-corrected visual acuity (BCVA) from baseline to month 12. The 48-month results are described here.Overall, the study included 516 patients (each with one study eye), and 30.2% of patients completed 48 months of IVT-AFL treatment. Mean change in BCVA from baseline (56.5 letters) to month 48 for patients with an assessment at both time points was + 1.1 (regular cohort, n = 47), + 0.1 (irregular cohort with initial monthly injections, n = 115), and - 1.3 letters (irregular cohort without initial monthly injections, n = 26), representing a decrease from the gains achieved at month 12. Mean number of IVT-AFL injections received by month 48 in the treatment cohorts was 14.9, 13.7, and 11.9, respectively. The safety profile of IVT-AFL was consistent with previous studies.In RAINBOW, the 48-month results demonstrate a lack of long-term effectiveness of IVT-AFL treatment of nAMD due to progressive undertreatment in routine clinical practice in France. These real-world findings highlight the importance of 3 initial monthly IVT-AFL injections followed by continuous proactive treatment beyond the first year to achieve optimal functional outcomes.ClinicalTrials.gov Identifier: NCT02279537.

Goldfish enter a hypometabolic state to survive chronic hypoxia. We recently described tissue-specific contributions of membrane lipid composition remodeling and mitochondrial function to metabolic suppression across different goldfish tissues. However, the molecular and especially epigenetic foundations of hypoxia tolerance in goldfish under metabolic suppression are not well understood. Here we show that components of the molecular oxygen-sensing machinery are robustly activated across tissues irrespective of hypoxia duration. Induction of gene expression of enzymes involved in DNA methylation turnover and microRNA biogenesis suggest a role for epigenetic transcriptional and post-transcriptional suppression of gene expression in the hypoxia-acclimated brain. Conversely, mechanistic target of rapamycin-dependent translational machinery activity is not reduced in liver and white muscle, suggesting this pathway does not contribute to lowering cellular energy expenditure. Finally, molecular evidence supports previously reported chronic hypoxia-dependent changes in membrane cholesterol, lipid metabolism and mitochondrial function via changes in transcripts involved in cholesterol biosynthesis, β-oxidation, and mitochondrial fusion in multiple tissues. Overall, this study shows that chronic hypoxia robustly induces expression of oxygen-sensing machinery across tissues, induces repressive transcriptional and post-transcriptional epigenetic marks especially in the chronic hypoxia-acclimated brain and supports a role for membrane remodeling and mitochondrial function and dynamics in promoting metabolic suppression.

Naked mole-rats (NMRs) are mammalian champions of hypoxia tolerance that enter metabolic suppression to survive in low oxygen environments. Common physiological mechanisms used by animals to suppress metabolic rate include downregulating energy metabolism (ATP supply) as well as ion pumps (primary cellular ATP consumers). A recent goldfish study demonstrated that remodeling of membrane lipids may mediate these responses, but it is unknown if NMR employs the same strategies; therefore, we aimed to test the hypotheses that these fossorial mammals 1) downregulate the activity of key enzymes of glycolysis, tricarboxylic acid (TCA) cycle, and β-oxidation, 2) inhibit sodium-potassium-ATPase, and 3) alter membrane lipids in response to chronic hypoxia. We found that NMRs exposed to 11% oxygen for 4 wk had a lower metabolic rate by 34%. This suppression occurs concurrently with tissue-specific 25–99% decreases in metabolic enzymes activities, a 77% decrease in brain sodium/potassium-ATPase activity, and widespread changes in membrane cholesterol abundance. By reducing glycolytic and β-oxidation fluxes, NMRs decrease the supply of acetyl-CoA to the TCA cycle. By contrast, there is a 94% upregulation of citrate synthase in the heart, possibly to support circulation and thus oxygen supply to other organs. Taken together, these responses may reflect a coordinated physiological response to hypoxia, but a clear functional link between changes in membrane composition and enzyme activities could not be established. Nevertheless, this is the first demonstration that hypometabolic NMRs alter the lipid composition of their membranes in response to chronic in vivo exposure to hypoxia.

To measure the predictive values of relative afferent pupillary defect (RAPD) assessed semi-quantitatively, and visual acuity (VA) at onset of central retinal vein occlusion (CRVO), for neovascularization.Retrospective analysis of the TROXHEMO trial that included patients with CRVO within 30 days after the onset. Inclusion criteria were as follows: semi-quantitative RAPD assessment at diagnosis and/or at one month. RAPD was 'severe' if ≥ 0.9 log. Exclusion criteria were as follows: prophylactic panretinal photocoagulation (PRP) before neovascularization.Among the 119 patients enrolled in the main centre, 101 were analysed. 26 had a neovascular complication during the twelve months of follow-up: rubeosis (19), glaucoma (7) and posterior neovascularization (15). The mean time to onset of a neovascular complication was 4.7 months (1 to 12, median 3 months). All the patients who had a neovascular complication had RAPD at first examination or at one month (negative predictive value (NPV) = 100%) but the positive predictive value (PPV) was low (31%, 95% CI [21%; 42%]). The association 'severe RAPD or VA 35 letters (ETDRS) at inclusion or at one month' was the best compromise between PPV (53%, [39%; 68%]) and NPV (96%, [92%; 100%]).To predict neovascularization, RAPD should be routinely evaluated with filters: the risk of neovascular complication is (a) almost nil if there is no RAPD, (b) very low if there is no severe RAPD and if VA is higher than 35 letters, and (c) higher than 50% if RAPD is ≥ 0.9 log or if VA is less than 35 letters.

The aim of this article is to explore the importance of biological and social networks in Whitehead’s philosophy. This exploration will involve a consideration of pluridisciplinarity in Whitehead, including a consideration of the relationship between scientific understanding and philosophical thinking, the question of method in Whitehead’s thought, and the crucial distinctions between mechanism and organicism and between nature lifeless and nature alive.

Some hypoxia-tolerant species, such as goldfish, experience intermittent and severe hypoxia in their natural habitat, causing them to develop multiple physiological adaptations. However, in fish, the metabolic impact of regular hypoxic exposure on swimming performance in normoxia is less well understood. Therefore, we experimentally tested whether chronic exposure to constant (30 days at 10% air saturation) or intermittent hypoxia (3 h in normoxia and 21 h in hypoxia, 5 days a week) would result in similar metabolic and swimming performance benefits after reoxygenation. Moreover, half of the normoxic and intermittent hypoxic fish were put on a 20-day normoxic training regime. After these treatments, metabolic rate (standard and maximum metabolic rates: SMR and MMR) and swimming performance [critical swimming speed (Ucrit) and cost of transport (COT)] were assessed. In addition, enzyme activities [citrate synthase (CS), cytochrome c oxidase (COX) and lactate dehydrogenase (LDH)] and mitochondrial respiration were examined in red muscle fibres. We found that acclimation to constant hypoxia resulted in (1) metabolic suppression (−45% SMR and −27% MMR), (2) increased anaerobic capacity (+117% LDH), (3) improved swimming performance (+80% Ucrit, −71% COT) and (4) no changes at the mitochondrial level. Conversely, the enhancement of swimming performance was reduced following acclimation to intermittent hypoxia (+45% Ucrit, −41% COT), with a 55% decrease in aerobic scope, despite a significant increase in oxidative metabolism (+201% COX, +49% CS). This study demonstrates that constant hypoxia leads to the greatest benefit in swimming performance and that mitochondrial metabolic adjustments only provide minor help in coping with hypoxia.

To evaluate real-life efficacy, safety, and treatment patterns with the dexamethasone intravitreal implant (DEX) in posterior segment inflammation due to non-infectious uveitis (treatment-naïve or not) in French clinics.In this prospective, multicenter, observational, non-comparative, post-reimbursement study, consecutive patients with posterior segment inflammation due to non-infectious uveitis were enrolled and evaluated at baseline (day 0). Those who received DEX on day 0 were re-evaluated at months 2, 6, and 18. Retreatment with DEX and/or alternative therapies was allowed during follow-up.patients (%) with at least a 15-letter gain in best corrected visual acuity (BCVA) at 2 months. Secondary outcomes included patients (%) with at least 15-letter BCVA gains at 6 and 18 months; mean BCVA change from baseline at 2, 6, and 18 months; and patients (%) retreated, mean central retinal thickness (CRT), and adverse events (AEs) at all post-baseline visits.Ninety-seven of 245 enrolled patients with posterior segment inflammation due to non-infectious uveitis (80% previously treated) and disease duration of 5 years (average) received DEX on day 0 and were included in efficacy analyses. At month 2 (n = 91), 20.5% of patients (95% CI 12.0-28.9) gained at least 15 letters from a baseline mean of 60.9 letters; the mean gain was 6.2 letters (95% CI 3.5-8.9). At month 6, 50.0% (n = 38/76) of patients did not receive alternative treatment or DEX retreatment, mostly because inflammation had sufficiently subsided (n = 27/38, 71.1%). Although early study termination prevented efficacy analysis at 18 months (n = 12), CRT reductions persisted throughout follow-up. From baseline to month 18, 21/245 (8.6%) patients had DEX-related AEs; 17/245 (6.9%) had ocular hypertension (most common AE).LOUVRE 2 confirms DEX efficacy on visual acuity and CRT in predominantly DEX-pretreated patients with relatively old/stabilized uveitis. DEX tolerability was consistent with known/published data, confirming treatment benefits in posterior segment inflammation due to non-infectious uveitis.NCT02951975.

Presburger arithmetic provides the mathematical core for the polyhedral compilation techniques that drive analytical cache models, loop optimization for ML and HPC, formal verification, and even hardware design. Polyhedral compilation is widely regarded as being slow due to the potentially high computational cost of the underlying Presburger libraries. Researchers typically use these libraries as powerful black-box tools, but the perceived internal complexity of these libraries, caused by the use of C as the implementation language and a focus on end-user-facing documentation, holds back broader performance-optimization efforts. With FPL, we introduce a new library for Presburger arithmetic built from the ground up in modern C++. We carefully document its internal algorithmic foundations, use lightweight C++ data structures to minimize memory management costs, and deploy transprecision computing across the entire library to effectively exploit machine integers and vector instructions. On a newly-developed comprehensive benchmark suite for Presburger arithmetic, we show a 5.4x speedup in total runtime over the state-of-the-art library isl in its default configuration and 3.6x over a variant of isl optimized with element-wise transprecision computing. We expect that the availability of a well-documented and fast Presburger library will accelerate the adoption of polyhedral compilation techniques in production compilers., Proceedings of the ACM on Programming Languages, 5 (OOPSLA), ISSN:2475-1421

Metabolic suppression is an essential strategy to cope with chronic hypoxia. This review examines the physiological processes used to survive in low oxygen environments. It proposes a novel mechanism–the remodeling of membrane lipids–to suppress ATP use and production. Temperature (homeoviscous adaptation), diet (natural doping in migrant birds) and body mass (membrane pacemaker of metabolism) have an impact on the lipid composition of membranes, which, in turn, modulates metabolic capacity. Vertebrate champions of hypoxia tolerance show extensive changes in membrane lipids upon in vivo exposure to low oxygen. These changes and those observed in hibernating mammals can promote the downregulation of ion pumps (major ATP consumers), ion channels, mitochondrial respiration capacity (state 3, proton leak, cytochrome c oxidase), and energy metabolism (β-oxidation and glycolysis). A common membrane signal regulating the joint inhibition of ion pumps and channels could be an exquisite way to preserve the balance between ATP supply and demand in hypometabolic states. Membrane remodeling together with more traditional mechanisms could work in concert to cause metabolic suppression.