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Introduction: This study aimed to assess the effects of a monoclonal antibody (mAb) combination on symptoms, daily function, and overall health-related quality of life., Methods: We analyzed patient-reported outcomes data from symptomatic outpatients in a phase 1/2/3 trial. Patients with confirmed SARS-CoV-2 infection and ≥ 1 risk factor for severe COVID-19 received mAb treatment (casirivimab plus imdevimab 1200 mg) or placebo. Prespecified exploratory assessments included time to sustained symptoms resolution, usual health, and return to usual activities (assessed daily for 29 days). The trial was conducted from September 2020 to February 2021, prior to widespread COVID-19 vaccination programs and Omicron-lineage variants against which casirivimab + imdevimab is not active., Results: In this analysis 736 outpatients received mAb and 1341 received placebo. Median time to sustained symptoms resolution was consistently shorter with mAb versus placebo (≥ 2 consecutive days: 14 vs 17 days, [nominal p = 0.0017]; ≥ 3 consecutive days: 17 vs 21 days, [nominal p = 0.0046]). Median time to sustained return to usual health and usual activities were both consistently shorter with mAb versus placebo (≥ 2 consecutive days: 12 vs 15 days [nominal p = 0.0001] and 9 vs 11 days [nominal p = 0.0001], respectively; ≥ 3 consecutive days: 14 vs 18 days [nominal p = 0.0003] and 10 vs 13 days [nominal p = 0.0041], respectively)., Conclusions: mAb treatment against susceptible SARS-CoV-2 strains improved how patients feel and function, as evidenced by shortened time to sustained symptoms resolution and return to usual health and activities. Future studies are warranted to assess the patient experience with next generation mAbs., Clinicaltrials: GOV: Registration number, NCT04425629; Submission date June 11, 2020., (© 2024. The Author(s).)

Upon melting, the molecules in a crystal explore numerous configurations, reflecting an increase in disorder. The molar entropy of disorder can be defined by Boltzmann's formula Δ S d = R ln( W d ), where W d is the increase in the number of microscopic states, so far inaccessible experimentally. We found that the Arrhenius frequency factor A of the electron diffraction signal decay provides W d through an experimental equation A = A INT W d , where A INT is an inelastic scattering cross section. The method connects Clausius and Boltzmann experimentally and supplements the Clausius approach, being applicable to a femtogram quantity of thermally unstable and biomolecular crystals. The data also showed that crystal disordering and crystallization of melt are reciprocal, both governed by the entropy change but manifesting in opposite directions.

Infrequent Metadynamics is a popular method to obtain the rates of long time-scale processes from accelerated simulations. The inference procedure is based on rescaling the first-passage times of the Metadynamics trajectories using a bias-dependent acceleration factor. While useful in many cases, it is limited to Poisson kinetics, and a reliable estimation of the unbiased rate requires slow bias deposition and prior knowledge of efficient collective variables. Here, we propose an improved inference scheme, which is based on two key observations: (1) the time-independent rate of Poisson processes can be estimated using short trajectories only. (2) Short trajectories experience minimal bias, and their rescaled first-passage times follow the unbiased distribution even for relatively high deposition rates and suboptimal collective variables. Therefore, by basing the inference procedure on short time scales, we obtain an improved trade-off between speedup and accuracy at no additional computational cost, especially when employing suboptimal collective variables. We demonstrate the improved inference scheme for a model system and two molecular systems.

Controlling the size distribution in the nucleation of copper particles is crucial for achieving nanocrystals with desired physical and chemical properties. However, their synthesis involves a complex system of solvents, ligands, and copper precursors with intertwining effects on the size of the nanoclusters. We combine molecular dynamics simulations and density functional theory calculations to provide insights into the nucleation mechanism in the presence of a triphenyl phosphite ligand. We identify the crucial role of the strength of the metal-phosphine interaction in inhibiting the cluster's growth. We demonstrate computationally several practical routes to fine-tune the interaction strength by modifying the side groups of the additive. Our work provides molecular insights into the complex nucleation process of protected copper nanocrystals, which can assist in controlling their size distribution and, eventually, their morphology., (© 2024 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).)

Background: A high-dose formulation of intravitreal aflibercept (8 mg) could improve treatment outcomes in diabetic macular oedema (DMO) by requiring fewer injections than the standard comparator, aflibercept 2 mg. We report efficacy and safety results of aflibercept 8 mg versus 2 mg in patients with DMO., Methods: PHOTON was a randomised, double-masked, non-inferiority, phase 2/3 trial performed at 138 hospitals and specialty retina clinics in seven countries. Eligible patients were adults aged 18 years or older with type 1 or 2 diabetes and centre-involved DMO. Patients were randomly assigned (1:2:1) to intravitreal aflibercept 2 mg every 8 weeks (2q8), aflibercept 8 mg every 12 weeks (8q12), or aflibercept 8 mg every 16 weeks (8q16), following initial monthly dosing. From week 16, dosing intervals for the aflibercept 8 mg groups were shortened if patients met prespecified dose regimen modification criteria denoting disease activity. The primary endpoint was change from baseline in best-corrected visual acuity (BCVA) at week 48 (non-inferiority margin of 4 letters). Efficacy and safety analyses included all randomly assigned patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov (NCT04429503)., Findings: Between June 29, 2020, and June 28, 2021, 970 patients were screened for eligibility. After exclusions, 660 patients were enrolled and randomly assigned to receive aflibercept 8q12 (n=329), 8q16 (n=164), or 2q8 (n=167); two patients were randomly assigned in error and did not receive treatment. 658 (99·7%) patients were treated and included in the full analysis set and safety analysis set (8q12 n=328, 8q16 n=163, and 2q8 n=167). Mean patient age was 62·3 years (SD 10·4). 401 (61%) patients were male. 471 (72%) patients were White. Aflibercept 8q12 and 8q16 demonstrated non-inferior BCVA gains to aflibercept 2q8 (BCVA mean change from baseline 8·8 letters [SD 9·0] in the 8q12 group, 7·9 letters [8·4] in the 8q16 group, and 9·2 letters [9·0] in the 2q8 group). The difference in least squares means was -0·57 letters (95% CI -2·26 to 1·13, p value for non-inferiority <0·0001) between 8q12 and 2q8 and -1·44 letters (-3·27 to 0·39, p value for non-inferiority 0·0031) between aflibercept 8q16 and 2q8. Proportions of patients with ocular adverse events in the study eye were similar across groups (8q12 n=104 [32%], 8q16 n=48 [29%], and 2q8 n=46 [28%])., Interpretation: Aflibercept 8 mg demonstrated efficacy and safety with extended dosing intervals and could decrease treatment burden in patients with DMO., Funding: Regeneron Pharmaceuticals and Bayer., Competing Interests: Declaration of interests DMB serves as a scientific adviser for Regeneron/Bayer and Genentech/Roche and as a member of the Regeneron Combination Products Steering Committee. DSB has served as a consultant for Adverum, Allergan, Bayer, Genentech, Graybug, Novartis, Regeneron Pharmaceuticals, REGENXBIO, and Roche. DVD is a consultant to Allergan, AsclepiX, Boehringer Ingelheim, Clearside, Genentech, Kodiak Sciences, and Regeneron Pharmaceuticals and has received research funding from AsclepiX, Boehringer Ingelheim, Genentech, and Regeneron Pharmaceuticals. CCW is a consultant for 4DMT, AbbVie, Adverum, Aerie, AGTC, Alcon, Annexon, Apellis, Arrowhead, Bausch + Lomb, Boehringer Ingelheim, Cholgene, Clearside, Curacle, EyePoint, Genentech, Gyroscope, IACTA, Iveric Bio, Janssen, Kato, Kiora, Kodiak Sciences, Kriya, Merck, Nanoscope, NGM, Novartis, Ocular Therapeutix, OcuTerra, ONL, Opthea, Oxular, Palatin, PerceiveBio, Perfuse, Ray, RecensMedical, Regeneron Pharmaceuticals, REGENXBIO, Roche, and Stealth and has received research support from 4DMT, Adverum, AffaMed, Alexion, Alimera, Alkahest, Allgenesis, Amgen, Annexin, Annexon, Apellis, AsclepiX, Bayer, Boehringer Ingelheim, Clearside, Curacle, EyePoint, Gemini, Genentech, GlaxoSmithKline, Gyroscope, IONIS, iRENIX, Iveric Bio, Kodiak Sciences, LMRI, Nanoscope, Neurotech, NGM, Novartis, Ocular Therapeutix, Ocuphire, OcuTerra, Opthea, Ophthotech, Oxurion, Oxular, Oyster Point, PerceiveBio, Regeneron Pharmaceuticals, REGENXBIO, Roche, and UNITY. TSa is a consultant for Bayer, Boehringer Ingelheim, Chugai/Roche, Novartis, and Senju. ASe is a consultant for Syneos Health and Novartis; has served as an adviser for Roche; and has contributed to the industry-sponsored international multicentre studies for Allergan, Amgen, Bayer, Formycon, Hexal, Iveric Bio, Kodiak Sciences, Oculis, Opthea, Novartis, Qilu Pharma, Regeneron Pharmaceuticals, Roche, and Sam Chun Dang Pharma. AJB, RV, KWC, KR, RR, YC, WS, DV, RB, and BH are employees and stockholders of Regeneron Pharmaceuticals. SL, US-O, TSc, ASc, and XZ are employees of Bayer. GDY is the founding scientist, President, and Chief Scientific Officer of Regeneron Pharmaceuticals. SS is an adviser and contributes to the industry-sponsored international multicentre studies for AbbVie, Bayer, Boehringer Ingelheim, Novartis, Optos, and Roche and has received consultancy fees from Allergan, Apellis, Bayer, Biogen, Boehringer Ingelheim, Eyebiotech, Novartis Pharma, Optos, and Roche. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Intravitreal aflibercept 8 mg could improve treatment outcomes and provide sustained disease control in patients with neovascular age-related macular degeneration (nAMD), with extended dosing compared with aflibercept 2 mg., Methods: PULSAR is a phase 3, randomised, three-group, double-masked, non-inferiority, 96-week trial conducted across 223 sites worldwide. Adults with nAMD were randomised 1:1:1 to aflibercept 8 mg every 12 weeks (8q12), aflibercept 8 mg every 16 weeks (8q16), or aflibercept 2 mg every 8 weeks (2q8), following three initial monthly doses in all groups. From week 16, patients in the aflibercept 8 mg groups had their dosing interval shortened if pre-specified dose regimen modification criteria denoting disease activity were met. The primary endpoint was change from baseline in best-corrected visual acuity (BCVA) at week 48. All patients with at least one dose of study treatment were included in the efficacy and safety analyses. This trial is registered with ClinicalTrials.gov (NCT04423718) and is ongoing., Findings: Of 1011 patients randomised to aflibercept 8q12 (n=336), 8q16 (n=338), or 2q8 (n=337) between Aug 11, 2020, and July 30, 2021, 1009 patients received study treatment (aflibercept 8q12 n=335; aflibercept 8q16 n=338; and aflibercept 2q8 n=336). Aflibercept 8q12 and 8q16 showed non-inferior BCVA gains versus aflibercept 2q8 (mean BCVA change from baseline +6·7 [SD 12·6] and +6·2 [11·7] vs +7·6 [12·2] letters). The least squares mean differences between aflibercept 8q12 versus 2q8 and 8q16 versus 2q8, respectively, were -0·97 (95% CI -2·87 to 0·92) and -1·14 (-2·97 to 0·69) letters (non-inferiority margin at 4 letters). The incidence of ocular adverse events in the study eye was similar across groups (aflibercept 8q12 n=129 [39%]; aflibercept 8q16 n=127 [38%]; and aflibercept 2q8 n=130 [39%])., Interpretation: Aflibercept 8 mg showed efficacy and safety with extended dosing intervals, which has the potential to improve the management of patients with nAMD., Funding: Bayer AG and Regeneron Pharmaceuticals., Competing Interests: Declaration of interests PL is a consultant for Aerie, Allergan, Apellis, Bausch + Lomb, Bayer, Biogen, Boehringer Ingelheim, I-Care, Genentech, Novartis, Ocular Therapeutix, Outlook Therapeutics, and Roche. J-FK receives consulting fees from AbbVie, Apellis, Bayer, Janssen, Nano Retina, Roche, Théa Pharmaceuticals, and Carl Zeiss Meditec; and is a member of data and safety monitoring boards or advisory boards for Alexion, Novo Nordisk, and Oxular. JSH receives consulting fees for 4D Molecular Therapeutics, Abpro, Adverum, AffaMed Therapeutics, Applied Genetics Technologies Corporation, Akouos, Allegro, Annexon, Apellis, AsclepiX Therapeutics, Bausch + Lomb, Biovisics, Clearside, Curacle, DTx Pharma, Exegenesis, Roche and Genentech, Glaukos, Gyroscope Therapeutics, ImmunoGen, Iveric Bio, Janssen R&D, jCyte, Kriya, Nanoscope, NGM Bio, Notal Vision, Novartis, Ocular Therapeutix, Ocuphire, OcuTerra, OliX, ONL Therapeutics, Outlook Therapeutics, Palatin Technologies, Perceive Biotherapeutics, Ray Therapeutics, Regeneron Pharmaceuticals, REGENXBIO, RetinAI, RevOpsis Therapeutics, Stealth BioTherapeutics, Théa Pharmaceuticals, and Vanotech; receives grants or contracts for 4D Molecular Technologies, Annexon, Apellis, AsclepiX Therapeutics, Ashvattha, Bayer, Cognition Therapeutics, Curacle, Roche and Genentech, Gyroscope Therapeutics, Iveric Bio, Janssen R&D, Kodiak, NGM, Notal Vision, Novartis, OcuTerra, Perceive Bio, Regeneron Pharmaceuticals, and REGENXBIO; has equity in Adverum, Aldeyra Therapeutics, Allegro, Aviceda, DTx Pharma, jCyte, Ocuphire, Ocular Therapeutix, RevOpsis Therapeutics, Vinci Pharmaceuticals, and Vitranu; and is on the Board of Directors for Ocular Therapeutix. FGH has served as a consultant for Acucela, Apellis, Bayer, Boehringer Ingelheim, Bioeq/Formycon, Roche and Genentech, Graybug Vision, IvericBio, Lin BioScience, Novartis, and Stealth BioTherapeutics; has received research support from Acucela, Apellis, Bayer, Bioeq/Formycon, and Roche and Genentech; has received honoraria from Bayer, Ellex, Roche and Genentech, Graybug Vision, Lin BioScience, Novartis, Oxurion, and Stealth BioTherapeutics; has received support for attending meetings or travel from Bayer, Roche and Genentech, Heidelberg Engineering, Lin BioScience, Novartis, and Stealth BioTherapeutics; has been a member of EURETINA and the German Ophthalmology Society (DOG); has other financial or non-financial interests in Acucela, Allergan, Apellis, Bayer, Bioeq/Formycon, CenterVue, Ellex, Roche and Genentech, Geuder, Heidelberg Engineering, IvericBio, Chengdu Kanghong Pharmaceuticals, NightStarX, Novartis, Optos, Pixium Vision, and Zeiss. WLC serves as a consultant for Genentech and Regeneron Pharmaceuticals; has received research support from Genentech; is a lecturer for Bayer, Genentech, and Regeneron Pharmaceuticals; and has received travel support from Bayer, Genentech, and Regeneron Pharmaceuticals. TYW receives consulting fees from Aldropika Therapeutics, Bayer, Boehringer Ingelheim, Genetech, Iveric Bio, Novartis, Oxurion, Plano, Roche, Sanofi, and Shanghai Henlius; and holds patents and is the co-founder of EyRiS and Visre. DE is a speaker for Allergan, Apellis, Bausch + Lomb, Bayer, the Dutch Ophthalmic Research Center, EyePoint, Genentech, and Novartis; is a consultant for Alimera Sciences, Allergan, Apellis, Bausch + Lomb, Coherus, Crinetics, DORC, EyePoint, Genentech, Gyroscope Therapeutics, Iveric Bio, KKR, Kodiak, Novartis, Ocular Therapeutix, Opthea, Outlook Therapeutics, RecensMedical, Regeneron Pharmaceuticals, REGENXBIO, Revive Pharmaceuticals, USRetina, and Vial; is an investigator for 4D Molecular Therapeutics, Alexion, Alkahest, Allgenesis, Annexon, AsclepiX Therapeutics, Bayer, Chengdu Kanghong Biotech (PANDA Trial stopped April, 2021), EyePoint, Gemini Therapeutics, Genentech, Gyroscope Therapeutics, Ionis, Iveric Bio, Kodiak, Mylan, NGM Bio, Novartis, Ocular Therapeutix, Opthea, RecensMedical, Regeneron Pharmaceuticals, REGENXBIO, and UNITY Biotechnology; is a stockholder for or has equity in Boston Image Reading Center, Clearside Biomedical, Hemera Biosciences, Network Eye, Revive Pharmaceuticals, and USRetina; and is a founder of Network Eye. TI has received financial support from NIDEK, Topcon Healthcare, Santen Pharmaceutical, Novartis, Senju Pharmaceutical, Alcon Japan, HOYA Vision Care, and AMO Pharma; has received consultancy fees from Bayer Yakuhin, Chugai Pharmaceutical, Nippon Boehringer Ingelheim, Janssen Pharmaceutical, Novartis Pharma, Senju Pharmaceutical, and Kyowa Kirin; has received lecture fees from Bayer Yakuhin, Novartis, Alcon Japan, Santen Pharmaceuticals, Senju Pharmaceutical, Topcon Healthcare, Chugai Pharmaceutical, Canon, NIDEK, Otsuka Pharmaceutical, and Nikon; has a patent with Topcon; and has received rewards from Kyowa Kirin. SX has received consulting fees from Alcon, Allergan, Bayer, Innovent Biologics, Chengdu Kanghong Biotech, Novartis, Roche, and Carl Zeiss Meditec. US-O and TS are employees and stockholders of Bayer. SL, AS, and XZ are employees of Bayer. AJB, RV, KWC, KR, RR, YC, WS, RB, and BH are employees and stockholders of Regeneron Pharmaceuticals. GDY is the Founding Scientist, President, and Chief Scientific Officer of Regeneron Pharmaceuticals., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels due to profoundly defective LDL receptor (LDLR) function. Given that severely elevated LDL-C starts in utero, atherosclerosis often presents during childhood or adolescence, creating a largely unmet need for aggressive LDLR-independent lipid-lowering therapies in young patients with HoFH. Here we present the first evaluation of the efficacy and safety of evinacumab, a novel LDLR-independent lipid-lowering therapy, in pediatric patients with HoFH from parts A and B of a 3-part study., Methods: The phase 3, part B, open-label study treated 14 patients 5 to 11 years of age with genetically proven HoFH (true homozygotes and compound heterozygotes) with LDL-C >130 mg/dL, despite optimized lipid-lowering therapy (including LDLR-independent apheresis and lomitapide), with intravenous evinacumab 15 mg/kg every 4 weeks., Results: Evinacumab treatment rapidly and durably (through week 24) decreased LDL-C with profound reduction in the first week, with a mean (SE) LDL-C reduction of -48.3% (10.4%) from baseline to week 24. ApoB (mean [SE], -41.3% [9.0%]), non-high-density lipoprotein cholesterol (-48.9% [9.8%]), and total cholesterol (-49.1% [8.1%]) were similarly decreased. Treatment-emergent adverse events were reported in 10 (71.4%) patients; however, only 2 (14.3%) reported events that were considered to be treatment-related (nausea and abdominal pain). One serious treatment-emergent adverse event of tonsillitis occurred (n=1), but this was not considered treatment-related., Conclusions: Evinacumab constitutes a new treatment for pediatric patients with HoFH and inadequately controlled LDL-C despite optimized lipid-lowering therapy, lowering LDL-C levels by nearly half in these extremely high-risk and difficult-to-treat individuals., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04233918., Competing Interests: Disclosures A.W. reports payment or honoraria for lectures, presentations, speakers’ bureaus, article writing, or educational events from Novartis and Algorithm; participation in a data safety monitoring board or advisory board for Amryt Pharma; leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, for Novartis; and research support for pharmaceutical trials from Amgen, Regeneron Pharmaceuticals, Inc, Novartis, Silence Therapeutics, Esperion, and Ultragenyx. S.G.-P. reports receiving research support from Amgen. S.A., J.M., S.B., P.B., R.T.G., B.H., and R.P. are employees of and stockholders in Regeneron Pharmaceuticals, Inc. E.A.B. is a steering committee member for the REDUCE-IT (Amarin) and PROMINENT (Kowa) trials, and receives research support from Regeneron Pharmaceuticals, Inc. He has received speaking or consulting honoraria from 89Bio, Amarin, Amgen, Amryt, Dalcor, Esperion, Immunovant, Ionis, Merck, New Amsterdam, and Pfizer. M.-J.C. reports honoraria from AstraZeneca, Merck Sharp & Dohme, Pfizer, Amgen, and Sanofi. C.B.-S. reports honoraria for presentations from the National Association of Continuing Medical Education and the Cardiometabolic Health Congress. S.B. reports funding or consulting fees from Amgen, Altimmune, Axcella, Regeneron Pharmaceuticals, Inc, Ionis Pharmaceuticals, Boehringer Ingelheim, Esperion, Lilly, Madrigal, Merck, and Novartis. J.B. reports funding or consulting fees from Regeneron Pharmaceuticals, Inc. P.M.M. reports receipt of research grants to his institution for the participation in the ODYSSEY OUTCOMES trial, as well as financial fees for serving as a medical monitor for the trial and associated support for travel related to trial meetings from Sanofi; consulting fees from Regeneron Pharmaceuticals, Inc, Amgen, Esperion, Kaneka, and Stage II Innovations; advisor fees from Novartis for serving on their advisory committee; and research grants to his institution from Ionis, FH Foundation, GB Life Sciences, Aegerion, Amgen, Kowa, Novartis, and Regeneron Pharmaceuticals, Inc. The other authors report no conflicts.

Metadynamics is a powerful method to accelerate molecular dynamics simulations, but its efficiency critically depends on the identification of collective variables that capture the slow modes of the process. Unfortunately, collective variables are usually not known a priori and finding them can be very challenging. We recently presented a collective variables-free approach to enhanced sampling using stochastic resetting. Here, we combine the two methods, showing that it can lead to greater acceleration than either of them separately. We also demonstrate that resetting Metadynamics simulations performed with suboptimal collective variables can lead to speedups comparable with those obtained with optimal collective variables. Therefore, applying stochastic resetting can be an alternative to the challenging task of improving suboptimal collective variables, at almost no additional computational cost. Finally, we propose a method to extract unbiased mean first-passage times from Metadynamics simulations with resetting, resulting in an improved tradeoff between speedup and accuracy. This work enables combining stochastic resetting with other enhanced sampling methods to accelerate a broad range of molecular simulations., (© 2024. The Author(s).)

Background: Virologic determinants of seroconversion to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were defined in a post hoc analysis of prospectively studied vaccine- and infection-naïve individuals at high risk for coronavirus disease 2019 (COVID-19)., Methods: This phase 3 COVID-19 prevention trial (NCT04452318) with casirivimab and imdevimab was conducted in July 2020-February 2021, before widespread vaccine availability. Placebo-treated participants who were uninfected (SARS-CoV-2 quantitative reverse transcription polymerase chain reaction [RT-qPCR] negative) and seronegative were assessed weekly for 28 days (efficacy assessment period [EAP]) for COVID-19 symptoms and SARS-CoV-2 infection by RT-qPCR of nasopharyngeal swab samples and for serostatus by antinucleocapsid immunoglobulin (Ig) G. Regression-based modeling, including causal mediation analysis, estimated the effects of viral load on seroconversion., Results: Of 157/1069 (14.7%) uninfected and seronegative (for antispike IgG, antispike IgA, and antinucleocapsid IgG) participants who became infected during the EAP, 105 (65%) seroconverted. The mean (SD) maximum viral load of seroconverters was 7.23 (1.68) log 10 copies/mL vs 4.8 (2.2) log 10 copies/mL in those who remained seronegative; viral loads of ∼6.0   log 10 copies/mL better predicted seroconversion. The mean of the maximum viral load was 7.11 log 10  copies/mL in symptomatic participants vs 5.58 log 10  copies/mL in asymptomatic participants. The mean duration of detectable viral load was longer in seroconverted vs seronegative participants: 3.24 vs 1.63 weeks., Conclusions: Maximum SARS-CoV-2 viral load is a major driver of seroconversion and symptomatic COVID-19, with high viral loads (∼6.0 log 10  copies/mL) better predicting seroconversion. Serology underestimates infection rates, incidence, and prevalence of SARS-CoV-2 infection., Competing Interests: Potential conflicts of interest. M.X., K.-C.C., B.H., and B.J.M. are Regeneron Pharmaceuticals, Inc., employees/shareholders and report grants from BARDA. M.P.O. and G.A.H. are Regeneron Pharmaceuticals, Inc., employees/stockholders who report having a patent pending, which has been licensed and for which they are receiving royalties, with Regeneron Pharmaceuticals, Inc., as well as a pending patent application, and report grants from BARDA. A.T.H. is a Regeneron Pharmaceuticals, Inc., employee/stockholder and a Pfizer stockholder and has a patent pending, which has been licensed and for which they are receiving royalties, with Regeneron Pharmaceuticals, Inc., and reports grants from BARDA. E.F.-N. was an employee of and holds stocks and shares in Regeneron Pharmaceuticals, Inc., and reports having a patent pending, which has been licensed and for which they are receiving royalties, with Regeneron Pharmaceuticals, Inc., as well as a pending patent application, and reports grants from BARDA. F.I. and J.D.H. are Regeneron Pharmaceuticals, Inc., employees/stockholders who report having a patent pending, which has been licensed and for which they are receiving royalties, with Regeneron Pharmaceuticals, Inc., and report grants from BARDA. P.H. is a former Regeneron Pharmaceuticals, Inc., employee and current stockholder and reports grants from BARDA. M.A.M. reports being an employee of the federal government, which, as part of USG, through Operation Warp Speed, supported the clinical trial network involved in implementation of this effort. M.S.C. reports a relationship with the National Institutes for Health for study funding and Regeneron Pharmaceuticals, Inc., for drug studies; reports receiving consulting fees from Aerium for a Scientific Advisory Board and Atrea for a Medical Advisory Board; reports receiving payment for lectures from NY Course, MJH Life Sciences, Clinical Care Solutions, Virology Education, Amgen, Medscape, and UpToDate; reports receiving payment for an educational panel from AstraZeneca and GSK; reports receiving support for attending meetings with Krog Healthcare-GSK and Trinity Health Sciences; and has a leadership role for the HIV Prevention Trials Network, COVID-19 Prevention Network., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The ab initio path integral Monte Carlo (PIMC) method is one of the most successful methods in statistical physics, quantum chemistry and related fields, but its application to quantum degenerate Fermi systems is severely hampered by an exponential computational bottleneck: the notorious fermion sign problem. Very recently, Xiong and Xiong [J. Chem. Phys. 157, 094112 (2022)] have suggested to partially circumvent the sign problem by carrying out simulations of fictitious systems guided by an interpolating continuous variable ξ ∈ [-1, 1], with the physical Fermi- and Bose-statistics corresponding to ξ = -1 and ξ = 1. It has been proposed that information about the fermionic limit might be obtained by calculations within the bosonic sector ξ > 0 combined with an extrapolation throughout the fermionic sector ξ < 0, essentially bypassing the sign problem. Here, we show how the inclusion of the artificial parameter ξ can be interpreted as an effective penalty on the formation of permutation cycles in the PIMC simulation. We demonstrate that the proposed extrapolation method breaks down for moderate to high quantum degeneracy. Instead, the method constitutes a valuable tool for the description of large Fermi-systems of weak quantum degeneracy. This is demonstrated for electrons in a 2D harmonic trap and for the uniform electron gas (UEG), where we find excellent agreement (∼0.5%) with exact configuration PIMC results in the high-density regime while attaining a speed-up exceeding 11 orders of magnitude. Finally, we extend the idea beyond the energy and analyze the radial density distribution (2D trap), as well as the static structure factor and imaginary-time density-density correlation function (UEG)., (© 2023 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).)

Bosonic exchange symmetry leads to fascinating quantum phenomena, from exciton condensation in quantum materials to the superfluidity of liquid 4He. Unfortunately, path integral molecular dynamics (PIMD) simulations of bosons are computationally prohibitive beyond ∼100 particles, due to a cubic scaling with the system size. We present an algorithm that reduces the complexity from cubic to quadratic, allowing the first simulations of thousands of bosons using PIMD. Our method is orders of magnitude faster, with a speedup that scales linearly with the number of particles and the number of imaginary time slices (beads). Simulations that would have otherwise taken decades can now be done in days. In practice, the new algorithm eliminates most of the added computational cost of including bosonic exchange effects, making them almost as accessible as PIMD simulations of distinguishable particles., (© 2023 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).)

Importance: Aflibercept, 8 mg, may have greater therapeutic benefits compared with aflibercept, 2 mg, in patients with neovascular age-related macular degeneration (nAMD), including potentially improved outcomes and decreased treatment burden., Objective: To assess safety and efficacy of aflibercept, 8 mg, in patients with nAMD., Design, Setting, and Participants: The CANDELA trial was a phase 2, randomized, single-masked, open-label, 44-week clinical trial conducted in the US. Treatment-naive patients with active subfoveal choroidal neovascularization secondary to nAMD and a best-corrected visual acuity score of 78 to 24 letters (approximately 20/32 to 20/320) in the study eye were enrolled between November 2019 and November 2021., Interventions: Eligible participants were randomized 1:1 to receive 3 monthly doses of 8 mg (70 μL) or 2 mg (50 μL) of aflibercept followed by doses at weeks 20 and 32., Main Outcomes and Measures: Coprimary end points were the proportion of eyes without fluid (absence of intraretinal and subretinal fluid) in the central subfield at week 16 and safety., Results: All 106 eligible eyes were randomized to receive aflibercept, 8 mg (n = 53), or aflibercept, 2 mg (n = 53). Overall, 66 participants (62.3%) were female. The proportion of eyes without fluid in the central subfield with 8-mg vs 2-mg aflibercept was 50.9% (n = 27) vs 34.0% (n = 18) (difference, 17.0 [95% CI, -1.6 to 35.5] percentage points; P = .08) at week 16 and 39.6% (n = 21) vs 28.3% (n = 15) (difference, 11.3 [95% CI, -6.6 to 29.2] percentage points; nominal P = .22) at week 44. At week 44, mean (SE) change in central retinal thickness was -159.4 (16.4) vs -137.2 (22.8) μm with 8 mg vs 2 mg of aflibercept, respectively (least squares mean difference, -9.5 [95% CI, -51.4 to 32.4]; nominal P = .65) and mean (SE) change in best-corrected visual acuity score was +7.9 (1.5) vs +5.1 (1.5) letters (least squares mean difference, +2.8 [95% CI, -1.4 to +7.0]; nominal P = .20). No differences in safety profiles between the groups were observed., Conclusions and Relevance: Although aflibercept, 8 mg, did not achieve the primary efficacy end point at week 16 at the 2-sided significance level of 5%, the observed trends in anatomic and visual improvements over 44 weeks with aflibercept, 8 mg, indicate potential additional therapeutic benefit over aflibercept, 2 mg. No new safety signals were observed over 44 weeks. These findings support further evaluation of aflibercept, 8 mg, in pivotal trials of exudative retinal diseases including nAMD and diabetic macular edema., Trial Registration: ClinicalTrials.gov Identifier: NCT04126317.

Background: Individuals who are immunocompromised (IC) are at high risk for severe coronavirus disease 2019 (COVID-19)., Methods: Post hoc analyses of a double-blind trial conducted prior to Omicron (June 2020-April 2021), in hospitalized patients with COVID-19 assessed viral load, clinical outcomes, and safety of casirivimab plus imdevimab (CAS + IMD) versus placebo in IC versus overall study patients., Results: Ninety-nine of 1940 (5.1%) patients were IC. IC versus overall patients were more frequently seronegative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies (68.7% vs 41.2%) and had higher median baseline viral loads (7.21 vs 6.32 log 10 copies/mL). On placebo, IC versus overall patients had slower viral load declines. CAS + IMD reduced viral load in IC and overall patients; least-squares mean difference versus placebo in time-weighted average change from baseline viral load at day 7 was -0.69 (95% confidence interval [CI], -1.25 to -.14) log 10 copies/mL for IC patients and -0.31 (95% CI, -.42 to -.20) log 10 copies/mL for overall patients. For IC patients, the cumulative incidence of death or mechanical ventilation at day 29 was lower with CAS + IMD (11.0%) versus placebo (17.2%), consistent with overall patients (15.7% CAS + IMD vs 18.3% placebo). IC and overall patients receiving CAS + IMD exhibited similar rates of treatment-emergent adverse events (30.4% and 26.6%, respectively), grade ≥2 hypersensitivity or infusion-related reactions (1.4% and 2.5%), and deaths (8.7% and 12.2%)., Conclusions: IC patients were more likely to exhibit high viral loads and be seronegative at baseline. For susceptible SARS-CoV-2 variants, CAS + IMD reduced viral load and resulted in fewer death or mechanical ventilation events in IC and overall study patients. There were no new safety findings among IC patients. Clinical Trials Registration. NCT04426695., Competing Interests: Potential conflicts of interest. S. S.-K., J. M., V. M. C., A. M., M. H., S. A., R. B., and B. H. are employees/stockholders of Regeneron Pharmaceuticals, and report grants from BARDA. E. M. reports payments to his institution received from the National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIH), National Institute of General Medical Sciences/NIH, SciClone Pharmaceuticals, Regeneron Pharmaceuticals, Pfizer, Chemic Labs/KODA Therapeutics, Cidara, and Leidos Biomedical Research Inc/National Cancer Institute. E. O.-O. was an employee of and holds stocks and shares in Regeneron Pharmaceuticals, and reports grants from BARDA. M. P. O. and G. A. H. are employees/stockholders of Regeneron Pharmaceuticals and report having a patent pending, which has been licensed and receiving royalties, with Regeneron Pharmaceuticals, as well as a pending patent application; and report grants from BARDA. A. T. H. is an employee/stockholder of Regeneron Pharmaceuticals, a former Pfizer employee and current stockholder, has a patent pending with Regeneron Pharmaceuticals, and reports grants from BARDA. F. M. M. reports payments to his institution received from Regeneron Pharmaceuticals, F2G, Gilead, Merck, Shire, Syneos, and the Bill & Melinda Gates Foundation; reports grants or contracts from Ansun, Chimerix, Cidara, Scynexis, Shire (a Takeda company), WHISCON, AlloVir, Amplyx, F2G, Gilead, and Merck; reports consulting fees from AlloVir, Amplyx, Avir, Emcure, F2G, Gilead, Janssen, Kyorin, Merck, Regeneron, ReViral, Symbio, United Medical, ADMA Biologics, Astellas, Behring, Cidara, Octapharma, Partner Therapeutics, Shionogi, Shire (a Takeda company), and Siemens Healthineers; reports payment for honoraria from Basilea, Merck, and Merck Sharp & Dohme Europe; and reports grants from BARDA. E. F.-N. was an employee of and holds stocks and shares in Regeneron Pharmaceuticals and reports having a patent pending, which has been licensed and receiving royalties from Regeneron Pharmaceuticals, as well as a pending patent application; and reports grants from BARDA. J. D. H. is an employee/stockholder of Regeneron Pharmaceuticals and has a patent pending, which has been licensed and receiving royalties, with Regeneron Pharmaceuticals. D. M. W. was an employee of and holds stocks and shares in Regeneron Pharmaceuticals and reports having a pending patent application; and reports grants from BARDA., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Controlling polymorphism in molecular crystals is crucial in the pharmaceutical, dye, and pesticide industries. However, its theoretical description is extremely challenging, due to the associated long time scales (>1 μs). We present an efficient procedure for identifying collective variables that promote transitions between conformational polymorphs in molecular dynamics simulations. It involves applying a simple dimensionality reduction algorithm to data from short (∼ps) simulations of the isolated conformers that correspond to each polymorph. We demonstrate the utility of our method in the challenging case of the important energetic material, CL-20, which has three anhydrous conformational polymorphs at ambient pressure. Using these collective variables in Metadynamics simulations, we observe transitions between all solid polymorphs in the biased trajectories. We reconstruct the free energy surface and identify previously unknown defect and intermediate forms in the transition from one known polymorph to another. Our method provides insights into complex conformational polymorphic transitions of flexible molecular crystals.

Background: Chronic pain is prevalent but difficult to treat in patients undergoing hemodialysis (HD). Effective and safe analgesics are limited in this patient population. Our aim in this feasibility study was to evaluate the safety of sublingual oil based medical cannabis for pain management in patients undergoing HD., Methods: In a prospective randomized, double-blind, cross-over design, patients undergoing HD with chronic pain were assigned to one of three arms: BOL-DP-o-04-WPE whole-plant extract (WPE), BOL-DP-o-04 cannabinoid extraction (API) or placebo. WPE and API contained trans-delta-9-‏tetrahydrocannabinol (THC) and cannabidiol (CBD) in a 1:6 ratio (1:6, THC:CBD). Patients were treated for 8 weeks, with subsequent 2-week wash out, followed by a cross-over to a different arm. The primary endpoint was safety., Results: Eighteen patients were recruited and 15 were randomized. Three did not complete drug titration period due to adverse events (AEs) and one patient died during titration due to sepsis (WPE). Of those who completed at least one treatment period, seven patients were in the WPE arm, five in the API and nine receiving placebo. The most common AEs were sleepiness, which improved after dose reduction or patient adaptation. Most AEs were mild to moderate and resolved spontaneously. Serious AEs considered related to study drug included one episode of accidental overdose (WPE) leading to hallucinations. Liver enzymes were stable during cannabis treatment., Conclusions: Short-term medical cannabis use in patients treated with HD was generally well tolerated. The safety data supports further studies to assess the overall risk-benefit of a treatment paradigm utilizing medical cannabis to control pain in this patient population., Competing Interests: N.A. is an employee of BOL Pharma Ltd. N.V. and B.H. are former employees of BOL Pharma Ltd. O.M. is a former employee of BOL; Advisory Board: Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, Novartis, AstraZeneca, Bayer, BOL Pharma; Research grant: Novo Nordisk, AstraZeneca; Speakers Bureau: Novo Nordisk, AstraZeneca, Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Objective: To assess the real-world effectiveness of casirivimab and imdevimab (CAS+IMD) versus no COVID-19 antibody treatment among patients diagnosed with COVID-19 in the ambulatory setting, including patients diagnosed during the Delta-dominant period prior to Omicron emergence., Design: Retrospective cohort study., Setting: Komodo Health closed claims database., Participants: 13 273 128 patients diagnosed with COVID-19 (December 2020 through September 2021) were treated with CAS+IMD or untreated but treatment eligible under the Emergency Use Authorization (EUA). Each treated patient was exact and propensity score matched without replacement to up to five untreated EUA-eligible patients., Interventions: CAS+IMD., Primary and Secondary Outcome Measures: Composite endpoint of 30-day all-cause mortality or COVID-19-related hospitalisation. Kaplan-Meier estimators were used to calculate outcome risks overall and across subgroups: age, COVID-19 vaccination status, immunocompromised status, and timing of diagnosis (December 2020 to June 2021, and July to September 2021). Cox proportional hazards models were used to estimate adjusted HRs (aHRs) and 95% CIs., Results: Among 75 159 CAS+IMD-treated and 1 670 338 EUA-eligible untreated patients, 73 759 treated patients were matched to 310 688 untreated patients; matched patients were ~50 years, ~60% were women and generally well balanced across risk factors. The 30-day risk of the composite outcome was 2.1% and 5.2% in the CAS+IMD-treated and CAS+IMD-untreated patients, respectively; equivalent to a 60% lower risk (aHR 0.40; 95% CI, 0.38 to 0.42). The effect of CAS+IMD was consistent across subgroups, including those who received a COVID-19 vaccine (aHR 0.48, 95% CI, 0.41 to 0.56), and those diagnosed during the Delta-dominant period (aHR 0.40, 95% CI, 0.38 to 0.42)., Conclusions: The real-world effectiveness of CAS+IMD is consistent with the efficacy for reducing all-cause mortality or COVID-19-related hospitalisation reported in clinical trials. Effectiveness is maintained across patient subgroups, including those prone to breakthrough infections, and was effective against susceptible variants including Delta. ., Competing Interests: Competing interests: All authors are employees and stockholders of Regeneron Pharmaceuticals, Inc., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We present a method for enhanced sampling of molecular dynamics simulations using stochastic resetting. Various phenomena, ranging from crystal nucleation to protein folding, occur on time scales that are unreachable in standard simulations. They are often characterized by broad transition time distributions, in which extremely slow events have a non-negligible probability. Stochastic resetting, i.e., restarting simulations at random times, was recently shown to significantly expedite processes that follow such distributions. Here, we employ resetting for enhanced sampling of molecular simulations for the first time. We show that it accelerates long time scale processes by up to an order of magnitude in examples ranging from simple models to a molecular system. Most importantly, we recover the mean transition time without resetting, which is typically too long to be sampled directly, from accelerated simulations at a single restart rate. Stochastic resetting can be used as a standalone method or combined with other sampling algorithms to further accelerate simulations.

Introduction: Data on real-world effectiveness of subcutaneous (SC) casirivimab and imdevimab (CAS+IMD) for the treatment of coronavirus disease 2019 (COVID-19) are limited. The objective of this study was to assess the effectiveness of SC CAS+IMD versus no antibody treatment among patients with COVID-19., Methods: This retrospective cohort study linked Komodo Health and CDR Maguire Health and Medical data. Patients diagnosed with COVID-19 in ambulatory settings (August 1-October 30, 2021) treated with SC CAS+IMD were exact- and propensity score-matched to fewer than five untreated treatment-eligible patients and followed for the composite endpoint of 30-day all-cause mortality or COVID-19-related hospitalization. Kaplan-Meier estimators were used to calculate outcome risk overall and across subgroups. Cox proportional-hazards models were used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI)., Results: Of 13,522 patients treated with CAS+IMD, 12,972 were matched to 41,848 untreated patients. The 30-day composite outcome risk was 1.9% (95% CI 1.7-2.2) and 4.4% (95% CI 4.2-4.6) in the treated and untreated cohorts, respectively; treated patients had a 49% lower relative risk of the composite outcome (aHR 0.51; 95% CI 0.46-0.58) and a 67% relative risk of 30-day mortality (aHR 0.33, 95% CI 0.18-0.60). Effectiveness was consistent across vaccination status and various subgroups., Discussion: Patients with COVID-19 benefitted from treatment with SC CAS+IMD versus untreated patients. The results were consistent across subgroups of patients, including older adults, immunocompromised patients, and patients vaccinated against COVID-19. Results were robust across numerous sensitivity analyses., Conclusion: SC CAS+IMD is effective in reducing 30-day COVID-19-related hospitalization or mortality in real-world outpatient settings during the Delta-dominant period., (© 2022. The Author(s).)

Background: High-density lipoprotein plays a key role in reverse cholesterol transport. In addition, high-density lipoprotein particles may be cardioprotective and reduce infarct size in the setting of myocardial injury. Lecithin-cholesterol acyltransferase is a rate-limiting enzyme in reverse cholesterol transport. MEDI6012 is a recombinant human lecithin-cholesterol acyltransferase that increases high-density lipoprotein cholesterol. Administration of lecithin-cholesterol acyltransferase has the potential to reduce infarct size and regress coronary plaque in acute ST-segment-elevation myocardial infarction., Methods: REAL-TIMI 63B (A Randomized, Placebo‑controlled Phase 2b Study to Evaluate the Safety and Efficacy of MEDI6012 in Acute ST Elevation Myocardial Infarction) was a phase 2B multinational, placebo-controlled, randomized trial. Patients with ST-segment-elevation myocardial infarction within 6 hours of symptom onset and planned for percutaneous intervention were randomly assigned 2:1 to MEDI6012 (2- or 6-dose regimen) or placebo and followed for 12 weeks. The primary outcome was infarct size as a percentage of left ventricular mass by cardiac MRI at 10 to 12 weeks, with the primary analysis in patients with TIMI Flow Grade 0 to 1 before percutaneous intervention who received at least 2 doses of MEDI6012. The secondary outcome was change in noncalcified plaque volume on coronary computed tomographic angiography from baseline to 10 to 12 weeks with the primary analysis in patients who received all 6 doses of MEDI6012., Results: A total of 593 patients were randomly assigned. Patients were a median of 62 years old, 77.9% male, and 95.8% statin naive. Median time from symptom onset to randomization was 146 (interquartile range [IQR], 103-221) minutes and from hospitalization to randomization was 12.7 (IQR, 6.6-24.0) minutes, and the first dose of drug was administered a median of 8 (IQR, 3-13) minutes before percutaneous intervention. The index myocardial infarction was anterior in 69.6% and TIMI Flow Grade 0 to 1 in 65.1% of patients. At 12 weeks, infarct size did not differ between treatment groups (MEDI6012: 9.71%, IQR 4.79-16.38; placebo: 10.48%, [IQR, 4.92-16.61], 1-sided P =0.79. There was also no difference in noncalcified plaque volume (geometric mean ratio, 0.96 [95% CI, NA-1.10], 1-sided P =0.30). There was no significant difference in treatment emergent serious adverse events., Conclusions: Administration of MEDI6012 in patients with acute ST-segment-elevation myocardial infarction did not result in a significant reduction in infarct size or noncalcified plaque volume at 12 weeks. MEDI6012 was well tolerated with no excess in overall serious adverse events., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT03578809.

Aims: Reverse cholesterol transport (RCT) removes cholesterol and stabilizes vulnerable plaques. In addition, high-density lipoprotein (HDL) may be cardioprotective in acute myocardial infarction (MI). Lecithin-cholesterol acyltransferase (LCAT) may enhance RCT. The objective of this study was to investigate the pharmacokinetics, pharmacodynamics, and safety of multiple ascending doses of recombinant human LCAT (MEDI6012) to inform a Phase 2b programme., Methods and Results: This was a randomized, blinded, placebo-controlled, dose-escalation Phase 2a study of MEDI6012. Patients were randomized into one of four cohorts (40, 120, 300 mg IV weekly ×3 doses, or 300 mg IV-push, 150 mg at 48 h and 100 mg at 7 days). All cohorts were planned to randomize 6:2 (MEDI6012 vs. placebo). The primary endpoints were baseline-adjusted area under the curve (AUC) from 0 to 96 h post dose 3 (AUC 0-96 h) for HDL-C, HDL cholesteryl ester (HDL-CE), and total cholesteryl ester (CE). The primary safety endpoints were treatment-emergent adverse events. A total of 32 patients were randomized. MEDI6012 significantly increased AUC 0-96 h for HDL-C, HDL-CE and CE in a graded fashion with increasing doses. Relative to placebo, MEDI6012 increased HDL-C at Day 19 by 66% (95% CI 33-99, P = 0.014) with 120 mg and 144% (95% CI 108-181, P < 0.001) with 300 mg. An IV-push increased HDL-C by 40.8% at 30 min. Overall adverse events were similar between groups with no severe, life-threatening/fatal adverse events, or neutralizing antibodies., Conclusions: Multiple ascending doses of MEDI6012 were safe and well tolerated and significantly increased HDL-C, HDL-CE and CE in a dose-related manner. These data support the ongoing Phase 2b programme investigating MEDI6012 in ST-elevation MI., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021.)

Supersolid is a mysterious and puzzling state of matter whose possible existence has stirred a vigorous debate among physicists for over 60 years. Its elusive nature stems from the coexistence of two seemingly contradicting properties, long-range order and superfluidity. We report computational evidence of a supersolid phase of deuterium under high pressure (p>800  GPa) and low temperature (T<1.0  K). In our simulations, that are based on bosonic path integral molecular dynamics, we observe a highly concerted exchange of atoms while the system preserves its crystalline order. The exchange processes are favored by the soft core interactions between deuterium atoms that form a densely packed metallic solid. At the zero temperature limit, Bose-Einstein condensation is observed as the permutation probability of N deuterium atoms approaches 1/N with a finite superfluid fraction. Our study provides concrete evidence for the existence of a supersolid phase in high-pressure deuterium and could provide insights on the future investigation of supersolid phases in real materials.

Objective: Functional HDL (high-density lipoprotein) particles that facilitate cholesterol efflux may be cardioprotective. EL (endothelial lipase) hydrolyzes phospholipids promoting catabolism of HDL and subsequent renal excretion. MEDI5884 is a selective, humanized, monoclonal, EL-neutralizing antibody. We sought to determine the safety, pharmacokinetics, and pharmacodynamic effects of multiple doses of MEDI5884 in patients with stable coronary artery disease. Approach and Results: LEGACY was a phase 2a, double-blind, placebo-controlled, parallel-design trial that randomized 132 patients with stable coronary artery disease receiving high-intensity statin therapy to 3 monthly doses of 1 of 5 dose levels of MEDI5884 (50, 100, 200, 350, or 500 mg SC) or matching placebo. The primary end point was the safety and tolerability of MEDI5884 through the end of the study (day 151). Additional end points included change in HDL cholesterol and cholesterol efflux from baseline to day 91, hepatic uptake of cholesterol at day 91, changes in various other lipid parameters. The incidence of adverse events was similar between the placebo and MEDI5884 groups. In a dose-dependent manner, MEDI5884 increased HDL cholesterol up to 51.4% ( P <0.0001) and global cholesterol efflux up to 26.2% ([95% CI, 14.3-38.0] P <0.0001). MEDI5884 increased HDL particle number up to 14.4%. At the highest dose tested, an increase in LDL (low-density lipoprotein) cholesterol up to 28.7% ( P <0.0001) and apoB (apolipoprotein B) up to 13.1% ( P =0.04) was observed with MEDI5884. However, at the potential target doses for future studies, there was no meaningful increase in LDL cholesterol or apoB., Conclusions: Inhibition of EL by MEDI5884 increases the quantity and quality of functional HDL in patients with stable coronary artery disease on high-intensity statin therapy without an adverse safety signal at the likely dose to be used. These data support further clinical investigation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03351738.

Background MEDI6012 is recombinant human lecithin cholesterol acyltransferase, the rate-limiting enzyme in reverse cholesterol transport. Infusions of lecithin cholesterol acyltransferase have the potential to enhance reverse cholesterol transport and benefit patients with coronary heart disease. The purpose of this study was to test the safety, pharmacokinetic, and pharmacodynamic profile of MEDI6012. Methods and Results This phase 2a double-blind study randomized 48 subjects with stable coronary heart disease on a statin to a single dose of MEDI6012 or placebo (6:2) (NCT02601560) with ascending doses administered intravenously (24, 80, 240, and 800 mg) and subcutaneously (80 and 600 mg). MEDI6012 demonstrated rates of treatment-emergent adverse events that were similar to those of placebo. Dose-dependent increases in high-density lipoprotein cholesterol were observed with area under the concentration-time curves from 0 to 96 hours of 728, 1640, 3035, and 5318 should be: mg·h/mL in the intravenous dose groups and 422 and 2845 mg·h/mL in the subcutaneous dose groups. Peak mean high-density lipoprotein cholesterol percent change was 31.4%, 71.4%, 125%, and 177.8% in the intravenous dose groups and 18.3% and 111.2% in the subcutaneous dose groups, and was accompanied by increases in endogenous apoA1 (apolipoprotein A1) and non-ATP-binding cassette transporter A1 cholesterol efflux capacity. Decreases in apoB (apolipoprotein B) were observed across all dose levels and decreases in atherogenic small low-density lipoprotein particles by 41%, 88%, and 79% at the 80-, 240-, and 800-mg IV doses, respectively. Conclusions MEDI6012 demonstrated an acceptable safety profile and increased high-density lipoprotein cholesterol, endogenous apoA1, and non-ATP-binding cassette transporter A1 cholesterol efflux capacity while reducing the number of atherogenic low-density lipoprotein particles. These findings are supportive of enhanced reverse cholesterol transport and a functional high-density lipoprotein phenotype. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02601560.

Objective: Cotadutide, a dual GLP-1 and glucagon receptor agonist, is under development for nonalcoholic steatohepatitis (NASH) and chronic kidney disease with type 2 diabetes. The effects of cotadutide on hepatic and metabolic parameters were evaluated in participants with overweight/obesity and type 2 diabetes., Research Design and Methods: In this phase 2b study, 834 adults with BMI ≥25 kg/m 2 and type 2 diabetes inadequately controlled with metformin (glycated hemoglobin A 1c [HbA 1c ] of 7.0%-10.5% [53-91 mmol/mol]) were randomized to double-blind cotadutide 100 μg ( n = 100), 200 μg ( n = 256), or 300 μg ( n = 256); placebo ( n = 110); or open-label liraglutide 1.8 mg ( n = 110)-all administered subcutaneously. Coprimary end points were changes in HbA 1c and body weight at week 14. The originally randomized interventions were continued to week 54. Liver damage biomarkers and liver fibrosis algorithms were assessed., Results: Cotadutide significantly decreased HbA 1c and body weight at weeks 14 and 54 versus placebo (all P < 0.001). Improvements in lipid profile, AST and ALT levels, propeptide of type III collagen level, fibrosis-4 index, and nonalcoholic fatty liver disease fibrosis score were observed with cotadutide 300 μg versus placebo, but not with liraglutide. Weight loss with cotadutide 200 μg was similar to that with liraglutide 1.8 mg and greater with cotadutide 300 μg versus liraglutide 1.8 mg. The most common adverse events with cotadutide (nausea, 35%; vomiting, 17%) decreased over time., Conclusions: Cotadutide treatment for 54 weeks improved glycemic control and weight loss in participants with overweight/obesity and type 2 diabetes. Ad hoc analyses demonstrated improvements in hepatic parameters and support further evaluation of cotadutide in NASH., (© 2021 by the American Diabetes Association.)

Cardiovascular disease (CVD) is the leading global cause of death, and treatments that further reduce CV risk remain an unmet medical need. Epidemiological studies have consistently identified low high-density lipoprotein cholesterol (HDL-C) as an independent risk factor for CVD, making HDL elevation a potential clinical target for improved CVD resolution. Endothelial lipase (EL) is a circulating enzyme that regulates HDL turnover by hydrolyzing HDL phospholipids and driving HDL particle clearance. Using MEDI5884, a first-in-class, EL-neutralizing, monoclonal antibody, we tested the hypothesis that pharmacological inhibition of EL would increase HDL-C by enhancing HDL stability. In nonhuman primates, MEDI5884 treatment resulted in lasting, dose-dependent elevations in HDL-C and circulating phospholipids, confirming the mechanism of EL action. We then showed that a favorable lipoprotein profile of elevated HDL-C and reduced low-density lipoprotein cholesterol (LDL-C) could be achieved by combining MEDI5884 with a PCSK9 inhibitor. Last, when tested in healthy human volunteers, MEDI5884 not only raised HDL-C but also increased HDL particle numbers and average HDL size while enhancing HDL functionality, reinforcing EL neutralization as a viable clinical approach aimed at reducing CV risk., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Accurate thermodynamic simulations of correlated fermions using path integral Monte Carlo (PIMC) methods are of paramount importance for many applications such as the description of ultracold atoms, electrons in quantum dots, and warm-dense matter. The main obstacle is the fermion sign problem (FSP), which leads to an exponential increase in computation time both with an increase in the system size and with a decrease in the temperature. Very recently, Hirshberg et al. [J. Chem. Phys. 152, 171102 (2020)] have proposed to alleviate the FSP based on the Bogoliubov inequality. In the present work, we extend this approach by adding a parameter that controls the perturbation, allowing for an extrapolation to the exact result. In this way, we can also use thermodynamic integration to obtain an improved estimate of the fermionic energy. As a test system, we choose electrons in 2D and 3D quantum dots and find in some cases a speed-up exceeding 10 6 , as compared to standard PIMC, while retaining a relative accuracy of ∼0.1%. Our approach is quite general and can readily be adapted to other simulation methods.

In this review, we will discuss and illustrate the pathophysiology, presentation, and multidetector computed tomography findings associated with emergent bladder conditions, limiting our discussion to traumatic, infectious, and obstructive etiologies. After reviewing computed tomography cystographic technique, the commonly utilized classification systems for bladder trauma will be presented with illustrative examples of associated typical and more infrequent secondary injuries and complications. Next, the pathogenesis and imaging appearance of both mechanical and neurogenic acute urinary retention will be addressed, including less common though potentially pathognomonic obstructive etiologies including urethral calculi and ectopic ureteroceles. Finally, we will review and illustrate the imaging features of both inflammatory and infectious cystitis, including hemorrhagic and emphysematous variants, as well as the potentially encountered secondary complications., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We present a method to sample reactive pathways via biased molecular dynamics simulations in trajectory space. We show that the use of enhanced sampling techniques enables unconstrained exploration of multiple reaction routes. Time correlation functions are conveniently computed via reweighted averages along a single trajectory and kinetic rates are accessed at no additional cost. These abilities are illustrated analyzing a model potential and the umbrella inversion of NH&#95;{3} in water. The algorithm allows a parallel implementation and promises to be a powerful tool for the study of rare events.

We present a method for performing path integral molecular dynamics (PIMD) simulations for fermions and address its sign problem. PIMD simulations are widely used for studying many-body quantum systems at thermal equilibrium. However, they assume that the particles are distinguishable and neglect bosonic and fermionic exchange effects. Interacting fermions play a key role in many chemical and physical systems, such as electrons in quantum dots and ultracold trapped atoms. A direct sampling of the fermionic partition function is impossible using PIMD since its integrand is not positive definite. We show that PIMD simulations for fermions are feasible by employing our recently developed method for bosonic PIMD and reweighting the results to obtain fermionic expectation values. The approach is tested against path integral Monte Carlo (PIMC) simulations for up to seven electrons in a two-dimensional quantum dot for a range of interaction strengths. However, like PIMC, the method suffers from the sign problem at low temperatures. We propose a simple approach for alleviating it by simulating an auxiliary system with a larger average sign and obtaining an upper bound to the energy of the original system using the Bogoliubov inequality. This allows fermions to be studied at temperatures lower than would otherwise have been feasible using PIMD, as demonstrated in the case of a three-electron quantum dot. Our results extend the boundaries of PIMD simulations of fermions and will hopefully stimulate the development of new approaches for tackling the sign problem.

Context: Cotadutide is a dual receptor agonist with balanced glucagon-like peptide-1 and glucagon activity., Objective: To evaluate different doses of cotadutide and investigate underlying mechanisms for its glucose-lowering effects., Design/setting: Randomized, double-blind, phase 2a study conducted in 2 cohorts at 5 clinical trial sites., Patients: Participants were 65 adult overweight/obese patients with type 2 diabetes mellitus; 63 completed the study; 2 were withdrawn due to AEs., Intervention: Once-daily subcutaneous cotadutide or placebo for 49 days. Doses (50-300 µg) were uptitrated weekly (cohort 1) or biweekly (cohort 2)., Main Outcome Measures: Co-primary end points (cohort 1) were percentage changes from baseline to end of treatment in glucose (area under the curve from 0 to 4 hours [AUC0-4h]) post-mixed-meal tolerance test (MMTT) and weight. Exploratory measures included postprandial insulin and gastric emptying time (GET; cohort 2)., Results: Patients received cotadutide (cohort 1, n = 26; cohort 2, n = 20) or placebo (cohort 1, n = 13; cohort 2, n = 6). Significant reductions were observed with cotadutide vs placebo in glucose AUC0-4h post MMTT (least squares mean [90% CI], -21.52% [-25.68, -17.37] vs 6.32% [0.45, 12.20]; P < 0.001) and body weight (-3.41% [-4.37, -2.44] vs -0.08% [-1.45, 1.28]; P = 0.002). A significant increase in insulin AUC0-4h post MMTT was observed with cotadutide (19.3 mU.h/L [5.9, 32.6]; P = 0.008) and GET was prolonged on day 43 with cotadutide vs placebo (t½: 117.2 minutes vs -42.9 minutes; P = 0.0392)., Conclusion: These results suggest that the glucose-lowering effects of cotadutide are mediated by enhanced insulin secretion and delayed gastric emptying., Trial Registration: ClinicalTrials.gov, NCT03244800., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The complexity and costs associated with traditional randomized, controlled trials have increased exponentially over time, and now threaten to stifle the development of new drugs and devices. Nevertheless, the growing use of electronic health records, mobile applications, and wearable devices offers significant promise for transforming clinical trials, making them more pragmatic and efficient. However, many challenges must be overcome before these innovations can be implemented routinely in randomized, controlled trial operations. In October of 2018, a diverse stakeholder group convened in Washington, DC, to examine how electronic health record, mobile, and wearable technologies could be applied to clinical trials. The group specifically examined how these technologies might streamline the execution of clinical trial components, delineated innovative trial designs facilitated by technological developments, identified barriers to implementation, and determined the optimal frameworks needed for regulatory oversight. The group concluded that the application of novel technologies to clinical trials provided enormous potential, yet these changes needed to be iterative and facilitated by continuous learning and pilot studies.

Trapped bosons exhibit fundamental physical phenomena and are at the core of emerging quantum technologies. We present a method for simulating bosons using path integral molecular dynamics. The main difficulty in performing such simulations is enumerating all ring-polymer configurations, which arise due to permutations of identical particles. We show that the potential and forces at each time step can be evaluated by using a recurrence relation which avoids enumerating all permutations, while providing the correct thermal expectation values. The resulting algorithm scales cubically with system size. The method is tested and applied to bosons in a 2-dimensional (2D) trap and agrees with analytical results and numerical diagonalization of the many-body Hamiltonian. An analysis of the role of exchange effects at different temperatures, through the relative probability of different ring-polymer configurations, is also presented., Competing Interests: The authors declare no competing interest.

The anharmonic frequencies of O-H, C-H, and N-H stretching modes of hydrogen-bonded glycine-H 2 O complexes are calculated using ab initio classical separable potential approximation. In this approach, ab initio molecular dynamic simulations are used to determine an effective classical potential for each of the normal modes of the system. The frequencies are calculated by solving the time-independent Schrödinger equation for each mode using time-averaged potentials. Three complex structures are studied, which differ in the location of the water molecule on the amino acid. Significant differences are found between the spectra of the three structures, and signatures of individual complexes are established. It is demonstrated that anharmonic effects are essential in the discrimination between different structures, while frequency differences at the harmonic level are much smaller. Intensities are also computed and found to carry information on differences between structures, but the role of anharmonicity in this is small.

Over the past 40 years since the first in vitro fertilization was performed, both the role of assisted reproductive technology (ART) in establishing viable pregnancy as well as the available treatment options have expanded enormously. Annually in the USA, nearly 2% of pregnancies now employ some form of ART assistance, with in vitro fertilization (IVF) being the most commonly utilized methodology. Both maternal and fetal risks are elevated in ART pregnancies, the latter including adverse outcome due to both increased gestational number as well as advanced maternal age. Maternal risks may be divided into locoregional and systemic complications. Adverse pelvic complications include those relating to gamete harvesting and transfer, ovarian hyperstimulation, the sequela of ectopic and heterotopic pregnancies, as well as ovarian torsion, all of which are elevated in the ART cohort. Ovarian hyperstimulation syndrome is the most commonly encountered complication, with both systemic and pelvic features relating to increased vascular permeability, hemoconcentration, and ascites. While life-threatening cases are relatively rare, moderate and severe manifestations may occur in up to 10% of ART cycles and, as such, are a not infrequent cause for ER visitation. Familiarity with the clinical and imaging manifestations of ART complications as well as their prognostic implications will facilitate a timely diagnosis and assist the interpreting radiologist in best expediting appropriate clinical care. In this article, we will briefly discuss the current methodology of ART then present an imaging-based multimodality review of the potentially encountered adverse maternal sequela, highlighting key diagnostic features and differential considerations as well as potential prognostic implications.

Aims/hypothesis: Cardiovascular disease is the leading cause of morbidity and mortality in people with type 2 diabetes. MEDI4166 is a proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody and glucagon-like peptide-1 (GLP-1) analogue fusion molecule designed to treat patients with type 2 diabetes who are at risk for cardiovascular disease. In this completed, first-in-human study, we evaluated the safety and efficacy of single or multiple doses of MEDI4166 in participants with type 2 diabetes., Methods: In this phase 1 study that was conducted across 11 clinics in the USA, eligible adults had type 2 diabetes, a BMI of ≥25 kg/m 2 to ≤42 kg/m 2 , and LDL-cholesterol levels ≥1.81 mmol/l. Participants were randomised 3:1 to receive MEDI4166 or placebo using an interactive voice/web response system, which blinded all participants, investigators and study site personnel to the study drug administered. In 'Part A' of the study, five cohorts of participants received a single s.c. injection of MEDI4166 at 10 mg, 30 mg, 100 mg, 200 mg or 400 mg, or placebo. 'Part B' of the study consisted of three cohorts of participants who received an s.c. dose of MEDI4166 once weekly for 5 weeks at 50 mg, 200 mg or 400 mg, or placebo. The primary endpoint in Part A was safety. The co-primary endpoints in Part B were change in LDL-cholesterol levels and area under the plasma glucose concentration-time curve (AUC 0-4h ) post-mixed-meal tolerance test (MMTT) from baseline to day 36. The pharmacokinetics and immunogenicity of MEDI4166 were also evaluated., Results: MEDI4166 or placebo was administered to n = 30 or n = 10 participants, respectively, in Part A of the study, and n = 48 or n = 15 participants, respectively, in Part B. The incidence of treatment-emergent adverse events (TEAEs) were comparable between MEDI4166 and placebo in both Part A (60% vs 50%) and Part B (79% vs 87%) of the study. Common TEAEs with MEDI4166 included injection-site reactions, diarrhoea and headache; there was no evidence for dose-related increases in TEAEs. In Part B of the study, at all tested doses of MEDI4166, there was a significant decrease in LDL-cholesterol levels vs placebo (least squares mean [95% CI]; MEDI4166 50 mg, -1.25 [-1.66, -0.84]; MEDI4166 200 mg, -1.97 [-2.26, -1.68]; MEDI4166 400 mg, -1.96 [-2.23, -1.70]; placebo, -0.03 [-0.35, 0.28]; all p < 0.0001). However, there were no clinically relevant reductions or significant differences between MEDI4166 vs placebo in glucose AUC 0-4h post-MMTT (least squares mean [95% CI]; MEDI4166 50 mg, -10.86 [-17.69, -4.02]; MEDI4166 200 mg, -4.23 [-8.73, 0.28]; MEDI4166 400 mg, -2.59 [-7.14, 1.95]; placebo, -4.84 [-9.95, 0.28]; all p > 0.05). MEDI4166 was associated with a pharmacokinetic profile supportive of weekly dosing and an overall treatment-induced anti-drug antibody-positive rate of 22%., Conclusions/interpretation: MEDI4166 was associated with an acceptable tolerability profile and significantly decreased LDL-cholesterol levels in a dose-dependent manner in overweight or obese patients with type 2 diabetes. However, there were no significant reductions in postprandial glucose levels at any dose of MEDI4166., Trial Registration: ClinicalTrials.gov NCT02524782 FUNDING: This study was funded by MedImmune LLC, Gaithersburg, MD, USA.

We sought to assess the prevalence of polyvascular disease in patients with type 2 diabetes mellitus (T2DM) and its impact on ischemic events. Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53, a large contemporary, randomized trial, evaluated the effect of saxagliptin versus placebo in 16,492 patients with T2DM and a history of or at risk for cardiovascular (CV) events. Polyvascular disease was defined as a history of clinical events involving 2 or more vascular beds (coronary, peripheral, or cerebrovascular system) at the time of randomization. The primary composite endpoint of CV death, myocardial infarction, or ischemic stroke was compared according to the number of diseased arterial beds. At the time of randomization, 3,667 (22.2%) patients had risk factors for CV events; 11,423 (69.3%) had established 1 arterial bed disease; 1,298 (7.9%) had 2 bed disease; and 104 (0.6%) had 3 bed disease. Compared with diabetic patients with no established atherosclerosis, the adjusted hazard ratio for the composite primary end point in 1, 2, or 3 diseased beds was 1.95, 3.54, and 4.64, respectively (trend p < 0.0001). The adjusted risk for overall mortality increased in a similar stepwise fashion from 1.47 to 2.33 to 3.12, respectively (trend p = 0.0001) with each additional diseased arterial territory. In conclusion, in patients with confirmed atherosclerosis enrolled in SAVOR-TIMI 53, 11% had polyvascular disease; and compared with diabetic patients with single bed disease, the risk of ischemic events and overall mortality was substantially higher in patients with T2DM and polyvascular disease., (Copyright © 2018. Published by Elsevier Inc.)

Aims: MEDI0382 is a balanced glucagon-like peptide-1/glucagon receptor dual agonist under development for the treatment of type 2 diabetes mellitus and non-alcoholic steatohepatitis. The primary objective was to assess the safety of MEDI0382 in healthy subjects., Methods: In this placebo-controlled, double-blind, Phase 1 study, healthy subjects (aged 18-45 years) were randomized (3:1) to receive a single subcutaneous dose of MEDI0382 or placebo after ≥8 h of fasting. The study consisted of six cohorts that received study drug at 5 μg, 10 μg, 30 μg, 100 μg, 150 μg or 300 μg. The primary objective was safety and tolerability. Secondary endpoints included assessments of pharmacokinetics and immunogenicity. All subjects were followed for up to 28 days., Results: A total of 36 subjects received MEDI0382 (n = 6 per cohort) and 12 subjects received placebo (n = 2 per cohort). Treatment-emergent adverse events (TEAEs) occurred more frequently with MEDI0382 vs. placebo, which was mostly due to an increased occurrence at MEDI0382 doses ≥150 μg. All TEAEs were mild or moderate in severity. The most common TEAEs were vomiting, nausea and dizziness. There appeared to be a dose-dependent increase in heart rate with MEDI0382 treatment. MEDI0382 showed linear pharmacokinetic profile (time to maximum plasma concentration: 4.50-9.00 h; elimination half-life: 9.54-12.07 h). No immunogenicity was observed in the study., Conclusions: In this single-dose, Phase 1 study in healthy subjects, the safety and pharmacokinetic profiles of MEDI0382 support once-daily dosing and further clinical development of MEDI0382., (© 2018 The British Pharmacological Society.)

Interactions of N2O5 with water media are of great importance in atmospheric chemistry and have been the topic of extensive research for over two decades. Nevertheless, many physical and chemical properties of N2O5 at the surface or in bulk water are unknown or not microscopically understood. This study presents extensive new results on the physical properties of N2O5 in water and at the surface of water, with a focus on their microscopic basis. The main results are obtained using ab initio molecular dynamics and calculations of a potential of mean force. These include: (1) collisions of N2O5 with water at 300 K lead to trapping at the surface for at least 20 ps and with 95% probability. (2) During that time, there is no N2O5 hydrolysis, evaporation, or entry into the bulk. (3) Charge separation between the NO2 and NO3 groups of N2O5, fluctuates significantly with time. (4) Energy accommodation of the colliding N2O5 at the surface takes place within picoseconds. (5) The binding energy of N2O5 to a nanosize amorphous ice particle at 0 K is on the order of 15 kcal mol-1 for the main surface site. N2O5 binding to the cluster is due to one weak hydrogen bond and to interactions between partial charges on the N2O5 and on water. (6) The free-energy profile was calculated for transporting N2O5 from the gas phase through the interface and into bulk water. The corresponding concentration profile exhibits a propensity for N2O5 at the aqueous surface. The free energy barrier for entry from the surface into the bulk was determined to be 1.8 kcal mol-1. These findings are used to interpret recent experiments. We conclude with implications of this study for atmospheric chemistry.

Background: Weight loss is often key in the management of obese or overweight patients with type 2 diabetes, yet few treatments for diabetes achieve clinically meaningful weight loss. We aimed to assess the efficacy, tolerability, and safety of treatment with MEDI0382, a balanced glucagon-like peptide-1 and glucagon receptor dual agonist developed to provide glycaemic control and weight loss, in patients with type 2 diabetes., Methods: This randomised, placebo-controlled, double-blind, combined multiple-ascending dose (MAD) and phase 2a study was done at 11 study sites (hospitals and contract research organisations) in Germany. We enrolled patients aged 18-65 years with controlled type 2 diabetes (glycated haemoglobin A 1c [HbA 1c ] levels of 6·5-8·5% at screening) and a body-mass index between 27 kg/m 2 and 40 kg/m 2 . An interactive web-response system was used to randomly assign patients to receive MEDI0382 or placebo. Patients were randomly assigned 2:1 in cohorts A-C and 3:1 in cohorts D and E in the MAD portion of the study, and 1:1 in the phase 2a portion. Randomisation was done by a contracted third-party operator who was not involved in the clinical operations of the study. The pharmacists, participants, and study site personnel involved in treating and assessing participants were masked to treatment allocation. Patients received once-daily subcutaneous injections of the study drug at doses of no more than 300 μg for 22 days or less in the MAD portion of the study, and a dose of no more than 200 μg for 41 days or less in the phase 2a portion. The two primary endpoints of the phase 2a portion were the change from baseline to day 41 in glucose area under the curve at 0-4 h (AUC 0-4 h ) after a mixed-meal tolerance test (MMTT), assessed in all participants who received at least one dose of study drug and whose measurements were taken at baseline and day 41, and change from baseline in bodyweight, assessed in the intention-to-treat (ITT) population. Safety analyses were done in all participants who received any study drug analysed according to the treatment they received. This study is registered with ClinicalTrials.gov, number NCT02548585., Findings: Patients were recruited between Dec 9, 2015, and Feb 24, 2017. 61 patients were randomly assigned to the MAD part of the study (42 to MEDI0382 and 19 to placebo). 51 patients were randomly assigned to the phase 2a part, of whom 25 were randomly assigned to MEDI0382 and 26 to placebo. In the phase 2a study, three patients in the MEDI0382 group and one in the placebo group discontinued, all as a result of adverse events. 22 (88%) patients in the MEDI0382 group and 25 (96%) in the placebo group received at least one dose and had measurements taken at baseline and day 41. Glucose AUC 0-4 h post MMTT decreased significantly with MEDI0382 versus placebo (least squares [LS] mean -32·78% [90% CI -36·98 to -28·57] vs -10·16% [-14·10 to -6·21], and the mean difference was -22·62% [-28·40 to -16·85]; p<0·0001). In the ITT population, reduction in bodyweight was significantly greater with MEDI0382 than with placebo (LS mean -3·84 kg [90% CI -4·55 to -3·12] vs -1·70 kg [-2·40 to -1·01] and mean difference of 2·14 kg [-3·13 to -1·31]; p=0·0008). The proportion of patients who had a treatment-emergent adverse event (TEAE) was similar between treatment groups (22 [88%] of 25 in the MEDI0382 group vs 23 [88%] of 26 in the placebo group); gastrointestinal disorders (18 [72%] vs 13 [40%]) and decreased appetite (five [20%] vs none) occurred more frequently with MEDI0382 than placebo. No participants in the MEDI0382 group had a grade 3 or worse TEAE (vs two [8%] in the placebo group)., Interpretation: MEDI0382 has the potential to deliver clinically meaningful reductions in blood glucose and bodyweight in obese or overweight individuals with type 2 diabetes., Funding: MedImmune., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The heterogeneous reaction of N 2 O 5 with sea spray aerosols yields the ClNO 2 molecule, which is postulated to occur through water-mediated charge separation into NO 3 - and NO 2 + ions followed by association with Cl - . Here we address an alternative mechanism where the attack by a halide ion can yield XNO 2 by direct insertion in the presence of water. This was accomplished by reacting X - (D 2 O) n (X = Cl, Br, I) cluster ions with N 2 O 5 to produce ions with stoichiometry [XN 2 O 5 ] - . These species were cooled in a 20 K ion trap and structurally characterized by vibrational spectroscopy using the D 2 messenger tagging technique. Analysis of the resulting band patterns with DFT calculations indicates that they all correspond to exit channel ion-molecule complexes based on the association of NO 3 - with XNO 2 , with the NO 3 - constituent increasingly perturbed in the order I > Br > Cl. These results establish that XNO 2 can be generated even when more exoergic reaction pathways involving hydrolysis are available and demonstrate the role of the intermediate [XN 2 O 5 ] - in the formation of XNO 2 .

Background: In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) trial in patients with type 2 diabetes mellitus (T2D) at high risk of cardiovascular (CV) disease, saxagliptin did not increase the risk for major CV adverse events. However, there was an unexpected imbalance in events of hospitalization for heart failure (hHF), one of six components of the secondary CV composite endpoint, with a greater number of events observed with saxagliptin. Here, we examined findings from nonclinical safety and clinical pharmacology studies of saxagliptin with the aim of identifying any potential signals of myocardial injury., Methods: In vitro and in vivo (rat, dog, monkey) safety pharmacology and toxicology studies evaluating the potential effects of saxagliptin and its major active metabolite, 5-hydroxy saxagliptin, on the CV system are reviewed. In addition, results from saxagliptin clinical studies are discussed: one randomized, 2-period, double-blind, placebo-controlled single-ascending-dose study (up to 100 mg); one randomized, double-blind, placebo-controlled, sequential, multiple-ascending-high-dose study (up to 400 mg/day for 14 days); and one randomized, double-blind, 4-period, 4-treatment, cross-over thorough QTc study (up to 40 mg/day for 4 days) in healthy volunteers; as well as one randomized, placebo-controlled, sequential multiple-ascending-dose study in patients with T2D (up to 50 mg/day for 14 days)., Results: Neither saxagliptin nor 5-hydroxy saxagliptin affected ligand binding to receptors and ion channels (e.g. potassium channels) or action potential duration in in vitro studies. In animal toxicology studies, no changes in the cardiac conduction system, blood pressure, heart rate, contractility, heart weight, or heart histopathology were observed. In healthy participants and patients with T2D, there were no findings suggestive of myocyte injury or fluid overload. Serum chemistry abnormalities indicative of cardiac injury, nonspecific muscle damage, or fluid homeostasis changes were infrequent and balanced across treatment groups. There were no QTc changes associated with saxagliptin. No treatment-emergent adverse events suggestive of heart failure or myocardial damage were reported., Conclusions: The saxagliptin nonclinical and clinical pharmacology programs did not identify evidence of myocardial injury and/or CV harm that may have predicted or may explain the unexpected imbalance in the rate of hHF observed in SAVOR.

Background: The impact of cardiovascular complications on health-related quality-of-life (HRQoL) in type 2 diabetes mellitus has not been clearly established. Using EQ5D utility data from SAVOR-TIMI 53, a large phase IV trial of saxagliptin versus placebo, we quantified the impact of cardiovascular and other major events on HRQoL., Methods: EQ5D utilities were recorded annually and following myocardial infarction (MI) or stroke. Utilities among patients experiencing major cardiovascular events were analyzed using linear mixed-effects regression, adjusting for baseline characteristics (including EQ5D utility), and compared to those not experiencing major cardiovascular events. Mean utility decrements with standard errors (SE) were estimated as the difference in utility before and after the event., Findings: The mean EQ5D utility of the sample was 0.776 at all time points, and did not differ by treatment. However, mean baseline and month 12 utilities among those with a major cardiovascular event were 0.751 and 0.714. Mean utilities were 0.691 within 3months of, 0.691 3-6months after, and 0.714 6-12months after, a major cardiovascular event. Cardiovascular event-specific utility decrements were 0.05 (0.007) for major cardiovascular events over the same time periods. Decrements of 0.051 (0.012; myocardial infarction), 0.111 (0.022; stroke), 0.065 (0.014; hospitalization for heart failure) 0.019 (0.024; hospitalization for hypoglycemia) were estimated; all coefficients were statistically significant., Interpretation: Consistent with clinical outcomes reported elsewhere, saxagliptin did not improve HRQoL. Cardiovascular complications were associated with significantly decreased HRQoL, most substantial earlier after the event., Funding: BMS/AZ., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Hypoglycaemia is a well-known risk associated with the use of sulphonylureas and insulin, often limiting achievement of glycaemic goals. Recognizing the precipitants and recurrence patterns of hypoglycaemic events, particularly major events, is therefore clinically important. The SAVOR-TIMI-53 trial was a cardiovascular outcome study of 16 492 patients allocated to saxagliptin vs placebo added to conventional care for a median of 2.1 years. Hypoglycaemic events were a prespecified outcome in the study and were defined as a symptomatic episode that recovered with carbohydrates or any recorded blood glucose <3.0 mmol/l (<54 mg/dL). A major event was defined as one that required third-party assistance. Analysis of the features of the first hypoglycaemic event for each patient showed that a precipitant for the event was recognized by fewer than half of the patients, with the precipitant most often being a missed meal. In 40% of patients reporting major hypoglycaemic events, no precipitating factor was recognized, and in >60%, no previous hypoglycaemic event was reported during the timespan of the study, underscoring the lack of predictability of such an event., (© 2017 John Wiley & Sons Ltd.)

Introduction: This meta-analysis of data from 14 phase 2 and 3, double-blind, randomized, controlled 12- and 24-week studies (N = 4632) summarizes saxagliptin efficacy in patients with type 2 diabetes (T2D) across treatment regimens., Methods: Patients received saxagliptin 5 mg/d or control as either monotherapy (n = 1196 vs placebo), add-on therapy (n = 2139 vs placebo and n = 514 vs uptitrated sulfonylurea), or initial combination therapy (n = 619 vs control monotherapy). Patients with renal impairment received saxagliptin 2.5 mg/d or placebo (n = 164)., Results: Mean baseline glycated hemoglobin (A1C) ranged from 8.07% to 9.43% for the saxagliptin and control groups across treatment regimens. A1C reduction from baseline was greater with saxagliptin versus control for all studies combined (mean treatment difference [95% CI]: -0.55% [-0.63%, -0.47%]) and when used as monotherapy (-0.52% [-0.63, -0.40%]), add-on (-0.55% [-0.69%, -0.40%] vs placebo; -0.72% [-0.88%, -0.56%] vs uptitrated sulfonylurea), initial combination therapy (-0.54% [-0.73%, -0.35%] vs control monotherapy), and in patients with renal impairment (-0.42% [-0.75%, -0.09%]). Similar reductions in A1C versus control were noted for patients <65 years (-0.55% [-0.67%, -0.43%]) and ≥65 years (-0.54% [-0.69%, -0.38%]) and for men (-0.54% [-0.69%, -0.40%]) and women (-0.55% [-0.64%, -0.47%]) across treatment regimens. More patients achieved A1C <7% (39% vs 23%) and A1C ≤6.5% (24% vs 14%) with saxagliptin than with placebo or active-control treatment. Saxagliptin versus control was associated with a reduction in glucagon area under the curve (AUC) from baseline and increases in insulin AUC, C-peptide AUC, and the homeostasis model assessment of β-cell function., Conclusion: Results of this meta-analysis demonstrate the consistency of saxagliptin efficacy in different subgroups of patients with T2D across treatment regimens., Funding: AstraZeneca.

Algorithms for quantum molecular dynamics simulations that directly use ab initio methods have many potential applications. In this article, the ab initio classical separable potentials (AICSP) method is proposed as the basis for approximate algorithms of this type. The AICSP method assumes separability of the total time-dependent wave function of the nuclei and employs mean-field potentials that govern the dynamics of each degree of freedom. In the proposed approach, the mean-field potentials are determined by classical ab initio molecular dynamics simulations. The nuclear wave function can thus be propagated in time using the effective potentials generated "on the fly". As a test of the method for realistic systems, calculations of the stationary anharmonic frequencies of hydrogen stretching modes were carried out for several polyatomic systems, including three amino acids and the guanine-cytosine pair of nucleobases. Good agreement with experiments was found. The method scales very favorably with the number of vibrational modes and should be applicable for very large molecules, e.g., peptides. The method should also be applicable for properties such as vibrational line widths and line shapes. Work in these directions is underway.

Objective: To determine if reduction in serum insulin with dapagliflozin plus saxagliptin or dapagliflozin add-on to metformin contributed to increased insulin clearance and to assess the effects of these treatments on β-cell function., Methods: Patients (glycated hemoglobin, 8 to 12%; 64 to 108 mmol/mol) were randomized to 24-week, double-blind treatment with saxagliptin 5 mg/day plus dapagliflozin 10 mg/day (n = 179), saxagliptin 5 mg/day plus placebo (n = 176), or dapagliflozin 10 mg/day plus placebo (n = 179) added to metformin. C-peptide to insulin ratio was used as an index of insulin clearance during a meal tolerance test, and β-cell function was evaluated by Homeostasis Model Assessment 2., Results: At 24 weeks, compared with baseline, saxagliptin + dapagliflozin and saxagliptin + placebo increased mean (95% confidence interval [CI]) C-peptide area under the curve (AUC 0-180 min ) (40.2 [9.2 to 71.3] ng/mL and 95.4 [63.4 to 127.4] ng/mL, respectively); no change was noted with dapagliflozin + placebo (14.5 [-17.6 to 46.8] ng/mL). Insulin AUC was reduced from baseline with saxagliptin + dapagliflozin (-1,120.4 [-1,633.9 to -606.9] μU/mL) and dapagliflozin + placebo (-1,018.6 [-1550.5 to -486.8] μU/mL) but increased with saxagliptin + placebo (661.2 [131.1 to 1,191.3] μU/mL). C-peptide to insulin ratio did not change versus baseline with saxagliptin + placebo but increased after saxagliptin + dapagliflozin and dapagliflozin + placebo, largely due to decreased insulin AUC with dapagliflozin. All treatments improved β-cell function (mean change [95% CI] from baseline, saxagliptin+dapagliflozin: 20.6% [16.5% to 24.8%]; dapagliflozin + placebo: 17.0% [12.7% to 21.4%]; saxagliptin + placebo: 11.0% [6.6% to 15.5%])., Conclusion: Increased C-peptide to insulin ratio with saxagliptin + dapagliflozin and dapagliflozin + placebo add-on to metformin compared with saxagliptin + placebo add-on to metformin suggests that dapagliflozin increases insulin clearance and may contribute to lower circulating insulin. All treatments improved β-cell function, with the greatest improvements with saxagliptin + dapagliflozin and dapagliflozin + placebo., Abbreviations: A1c = glycated hemoglobin AUC 0-180 min = area under the curve from 0 to 180 minutes HOMA-2β = homeostasis model assessment-2 β-cell function SGLT-2 = sodium-glucose cotransporter-2 T2D = type 2 diabetes.

Objective: Dipeptidyl peptidase 4 inhibitors may have a protective effect in diabetic nephropathy., Research Design and Methods: We studied renal outcomes of 16,492 patients with type 2 diabetes, randomized to saxagliptin versus placebo and followed for a median of 2.1 years in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial., Results: At baseline, 9,696 (58.8%) subjects had normoalbuminuria (albumin/creatinine ratio [ACR] <30 mg/g), 4,426 (26.8%) had microalbuminuria (ACR 30-300 mg/g), and 1,638 (9.9%) had macroalbuminuria (ACR >300 mg/g). Treatment with saxagliptin was associated with improvement in and/or less deterioration in ACR categories from baseline to end of trial (EOT) (P = 0.021, P < 0.001, and P = 0.049 for individuals with baseline normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively). At 2 years, the difference in mean ACR change between saxagliptin and placebo arms was -19.3 mg/g (P = 0.033) for estimated glomerular filtration rate (eGFR) >50 mL/min/body surface area per 1.73 m 2 (BSA), -105 mg/g (P = 0.011) for 50 ≥ eGFR ≥ 30 mL/min/BSA, and -245.2 mg/g (P = 0.086) for eGFR <30 mL/min/BSA. Analyzing ACR as a continuous variable showed reduction in ACR with saxagliptin (1 year, P < 0.0001; 2 years, P = 0.0143; and EOT, P = 0.0158). The change in ACR did not correlate with that in HbA 1c (r = 0.041, 0.052, and 0.036; 1 year, 2 years, and EOT, respectively). The change in eGFR was similar in the saxagliptin and placebo groups. Safety renal outcomes, including doubling of serum creatinine, initiation of chronic dialysis, renal transplantation, or serum creatinine >6.0 mg/dL, were similar as well., Conclusions: Treatment with saxagliptin improved ACR, even in the normoalbuminuric range, without affecting eGFR. The beneficial effect of saxagliptin on albuminuria could not be explained by its effect on glycemic control., (© 2017 by the American Diabetes Association.)

Purpose: The management of hyperglycemia is challenging in older patients with type 2 diabetes owing to excess fragility and risk for adverse outcomes should hypoglycemia episodes occur. We evaluated baseline β-cell function as a potential risk factor for the development of hypoglycemia when saxagliptin or glimepiride was added in patients aged ≥65 years whose type 2 diabetes was poorly controlled on stable metformin monotherapy., Methods: A post hoc analysis of data from the GENERATION (Efficacy and Tolerability of Saxagliptin Compared with Glimepiride in Elderly Patients with Type 2 Diabetes: A Randomized, Controlled Study) trial, which enrolled 720 patients aged ≥65 years, was conducted. β-Cell function was assessed using homeostasis model assessment-2%β (HOMA-2%β)., Findings: The percentage of patients experiencing any hypoglycemia event (ie, symptomatic event or event of plasma glucose concentration <54 mg/dL regardless of symptoms) was lower with saxagliptin compared with glimepiride (5.8% vs 34.8%). Regardless of treatment, patients with lower (median HOMA-2%β ≤39.1% [≤median]) versus higher (HOMA-2%β above median value [>median]) baseline β-cell function had a higher hypoglycemia event rate (1.27 vs 0.82 events/patient-year; adjusted incidence rate ratio [IRR] = 1.800; 95% CI, 1.501-2.159). In patients receiving glimepiride, the hypoglycemia event rate was higher in patients with baseline HOMA-2%β ≤median versus >median (2.29 vs 1.60 events/patient-year; adjusted IRR = 1.737; 95% CI, 1.439-2.097); corresponding saxagliptin hypoglycemia event rates were too low to draw meaningful conclusions (0.16 vs 0.09 events/patient-year; adjusted IRR = 2.457; 95% CI, 1.148-5.256). The association between lower β-cell function at baseline and increased prevalence of hypoglycemia was particularly strong in patients aged ≥75 years (adjusted IRR = 2.409; 95% CI, 1.686-3.442; P < 0.001), although it was also significant in patients aged 65 to <75 years old (adjusted IRR, 1.654; 95% CI, 1.339-2.043; P < 0.001)., Implications: In patients with lower β-cell function, the addition of a sulfonylurea to a metformin regimen was associated with an increased risk for hypoglycemia compared with that in patients with higher β-cell function; low hypoglycemia event rates with the addition of saxagliptin limited equivalent assessments. These findings in older patients are especially relevant because morbidity associated with hypoglycemia is higher in this age group. ClinicalTrials.gov identifier: NCT01006603 (ClinicalTrials.gov)., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)