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Background: Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations.Methods: In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran.Results: No thromboembolic events were observed during the study. The most common adverse events were mild injection-site reactions. Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants.Conclusions: Once-monthly subcutaneous administration of fitusiran resulted in dose-dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02035605 .). [ABSTRACT FROM AUTHOR]

Background: The focus of much Intensive Care research has been on short-term survival, which has demonstrated clear improvements over time. Less work has investigated long-term survival, and its correlates. This study describes long-term survival and identifies factors associated with time to death, in patients who initially survived an Intensive Care admission in Victoria, Australia., Methods: We conducted a retrospective cohort study of adult patients discharged alive from hospital following admission to all Intensive Care Units (ICUs) in the state of Victoria, Australia between July 2007 and June 2018. Using the Victorian Death Registry, we determined survival of patients beyond hospital discharge. Comparisons between age matched cohorts of the general population were made. Cox regression was employed to investigate factors associated with long-term survival., Results: A total of 130,775 patients from 23 ICUs were included (median follow-up 3.6 years post-discharge). At 1-year post-discharge, survival was 90% compared to the age-matched cohort of 98%. All sub-groups had worse long-term survival than their age-matched general population cohort, apart from elderly patients admitted following cardiac surgery who had better or equal survival. Multiple demographic, socio-economic, diagnostic, acute and chronic illness factors were associated with long-term survival., Conclusions: Australian patients admitted to ICU who survive to discharge have worse long-term survival than the general population, except for the elderly admitted to ICU following cardiac surgery. These findings may assist during goal-of-care discussions with patients during an ICU admission., Competing Interests: The authors have declared that no competing interests exist.

Different approaches for the determination of the 87 Sr/ 86 Sr isotope ratio of high-Rb glass are compared in this work to assess the suitability of minimally invasive approaches for applications on medieval stained glass (from the ancient Abbey of Stavelot in Belgium). It was found that pneumatic nebulization multicollector inductively coupled plasma-mass spectrometry (PN-MC-ICP-MS) after acid digestion and chromatographic isolation of the target analyte out of the sample matrix can still be seen as the preferred method for the high-precision isotopic analysis of Sr in glass with high Rb and rare-earth element (REE) concentrations. Alternatively, the use of laser ablation (LA) for sample introduction is a powerful technique for the direct analysis of solid samples. However, both the high Rb/Sr ratios in the samples of interest and the presence of REEs at sufficiently high concentrations lead to a large bias in LA-MC-ICP-MS, which cannot be corrected for, even by operating the MC-ICP-MS instrument at higher mass resolution and/or using mathematical corrections. It was demonstrated that LA tandem-ICP-MS (LA-ICP-MS/MS) using CH 3 F/He as the reaction gas to overcome spectral overlap in a mass-shift approach (chemical resolution) provides a viable alternative when (quasi) nondestructive analysis is required. This approach relies on the monitoring of Sr + ( m/z = 86, 87, and 88) ions as the corresponding SrF + reaction product ions ( m/z = 105, 106, and 107), thus avoiding the occurrence of spectral interference. Self-evidently, the isotope ratio precision attainable using sequential quadrupole-based ICP-MS instrumentation (0.3% RSD) was found to be significantly worse than that of high-precision MC-ICP-MS (0.03% RSD) with simultaneous detection, although it was still fit for the purpose of current applications. In addition to Sr isotopic analysis, the REE patterns and their potential influence on the Sr isotopic composition were evaluated by LA-ICP-MS., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

We document the utility for in situ Rb-Sr dating of a one-of-a-kind tribrid mass spectrometer, 'Proteus', coupled to a UV laser ablation system. Proteus combines quadrupole mass-filter, collision cell and sector magnet with a multicollection inductively-coupled plasma mass spectrometer (CC-MC-ICPMS/MS). Compared to commercial, single collector, tribrid inductively-coupled plasma mass spectrometers (CC-ICPMS/MS) Proteus has enhanced ion transmission and offers simultaneous collection of all Sr isotopes using an array of Faraday cups. These features yield improved precision in measured 87 Sr/ 86 Sr ratios, for a given mass of Sr analysed, approximately a factor of 25 in comparison to the Thermo Scientific™ iCAP TQ™ operated under similar conditions. Using SF 6 as a reaction gas on Proteus, measurements of Rb-doped NIST SRM (standard reference material) 987 solutions, with Rb/Sr ratios from 0.01-100, yield 87 Sr/ 86 Sr that are indistinguishable from un-doped NIST SRM 987, demonstrating quantitative 'chemical resolution' of Rb from Sr. We highlight the importance of mass-filtering before the collision cell for laser ablation 87 Sr/ 86 Sr analysis, using an in-house feldspar standard and a range of glass reference materials. By transmitting only those ions with mass-to-charge ratios 82-92 u/e into the collision cell, we achieve accurate 87 Sr/ 86 Sr measurements without any corrections for atomic or polyatomic isobaric interferences. Without the pre-cell mass-filtering, measured in situ 87 Sr/ 86 Sr ratios are inaccurate. Combining in situ measurements of Rb/Sr and radiogenic Sr isotope ratios we obtain mineral isochrons. We utilise a sample from the well-dated Dartmoor granite (285 ± 1 Ma) as a calibrant for our in situ ages and, using the same conditions, produce accurate Rb-Sr isochron ages for samples of the Fish Canyon tuff (28 ± 2 Ma) and Shap granite pluton (397 ± 1 Ma). Analysing the same Dartmoor granite sample using identical laser conditions and number of spot analyses using the Thermo Scientific™ iCAP TQ™ yielded an isochron slope 5× less precise than Proteus. We use an uncertainty model to illustrate the advantage of using Proteus over single collector CC-ICPMS/MS for in situ Rb-Sr dating. The results of this model show that the improvement is most marked for samples that have low Rb/Sr (<10) or are young (<100 Ma). We also report the first example of an in situ , internal Rb-Sr isochron from a single potassium-feldspar grain. Using a sample from the Shap granite, we obtained accurate age and initial 87 Sr/ 86 Sr with 95% confidence intervals of ±1.5% and ±0.03% respectively. Such capabilities offer new opportunities in geochronological studies., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The serine protease factor XI (FXI) is a prominent drug target as it holds promise to deliver efficacious anticoagulation without an enhanced risk of major bleeds. Several efforts have been described targeting the active form of the enzyme, FXIa. Herein, we disclose our efforts to identify potent, selective, and orally bioavailable inhibitors of FXIa. Compound 1 , identified from a diverse library of internal serine protease inhibitors, was originally designed as a complement factor D inhibitor and exhibited submicromolar FXIa activity and an encouraging absorption, distribution, metabolism, and excretion (ADME) profile while being devoid of a peptidomimetic architecture. Optimization of interactions in the S1, S1β, and S1' pockets of FXIa through a combination of structure-based drug design and traditional medicinal chemistry led to the discovery of compound 23 with subnanomolar potency on FXIa, enhanced selectivity over other coagulation proteases, and a preclinical pharmacokinetics (PK) profile consistent with bid dosing in patients.

Matrix metalloproteinases (MMP) are a family of more than 25 zinc-dependent enzymes that are centrally involved in cellular migration, tissue remodeling, cancer invasion and metastasis. Besides degrading extracellular matrix proteins, MMPs are crucial for growth factor and cytokine release and activation. At the same time, they can inactivate inflammatory mediators and enzymes themselves through protein degradation. Subclasses of MMPs include collagenases, gelatinases, stromelysins, membrane-bound MMPs, and others. With regard to the stromelysin subfamily, three members exist, e.g., stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11). MMP-3, and MMP-10 share extensive similarities at the amino acid level that made it difficult to develop specific antibodies distinguishing between MMP-3 and MMP-10. Scrutinizing published data on and performing different analyses with detection of both stromelysins with commercially available or lab-made antibodies showed ambiguous results with regard to specificity of antibodies used to date. We developed new specific antibodies against the most divergent parts of the active forms of both proteins. We assessed the specificity of our novel specific anti-human and anti-mouse MMP-3 and MMP-10 antibodies in cell lysates and different human and murine skin tissues. Tests analyzing specificity of the novel antibodies included Western immunoblotting, immunofluorescence, and immunohistochemistry on paraffin sections. Analyses demonstrated specific detection of respective protein for human or mouse samples except for the anti-human MMP-3 antibody. The aim of this summary was to call attention the MMP research community to distinguish clearly between both enzymes. Our new specific anti-mouse MMP-3 and both MMP-10 antibodies allow us to address this detection problem and to enable comparative studies between both stromelysins with regard to their respective location and function in the tissue., (© 2019 by the Wound Healing Society.)

Objectives: To estimate the potential impact of the addition of culture-based screening for group B streptococcus (GBS) carriage in pregnancy to a risk-based prevention policy in the UK. We aimed to establish agreement within a multidisciplinary group of key stakeholders on the model input parameters., Design: Deterministic model using a consensus approach for the selection of input parameters., Setting and Participants: A theoretical annual cohort of 711 999 live births in the UK (excluding births by elective caesarean section)., Interventions: Culture-based screening for GBS at 35-37 weeks of pregnancy added to the recommended risk-based prevention policy in place on the date of modelling., Outcome Measures: Outcomes assessed included use of intrapartum antibiotic prophylaxis (IAP), early onset GBS (EOGBS), EOGBS mortality, severe EOGBS-related morbidity and maternal penicillin anaphylaxis., Results: With no prophylaxis strategy, the model estimated that there would be 421 cases of culture positive EOGBS in a year (0.59/1000 live births). In the risk-based prophylaxis scenario, 30 666 women were estimated to receive IAP and 70 cases of EOGBS were prevented. Addition of screening resulted in a further 96 260 women receiving IAP and the prevention of an additional 52 to 57 cases of EOGBS. This resulted in the prevention of three EOGBS deaths and four cases of severe disability. With screening, an additional 1675 to 1854 women receive IAP to prevent one EOGBS case and 24 065 to 32 087 receive IAP to prevent one EOGBS death., Conclusions: The evidence base available for a broad range of model input parameters was limited, leading to uncertainty in the estimates produced by the model. Where data was limited, the model input parameters were agreed with the multidisciplinary stakeholder group, the first time this has been done to our knowledge. The main impact of screening is likely to be on the large group of low-risk women where the clinical impact of EOGBS tends to be less severe. This model suggests that the reduction in mortality and severe disability due to EOGBS with antenatal GBS screening is likely to be very limited, with a high rate of overdetection and overuse of antibiotics., Competing Interests: Competing interests: CP chaired the expert group. JM and DB were both employees of the UK National Screening Committee at the time of preparation of the model. AW is an employee of Bazian Ltd. who received payment to develop the model and write up the project through contracts with the UK National Screening Committee. Bazian Ltd. have also been paid to carry out other literature searches, reviews and models for the National Screening Committee, including reviews of the evidence on antenatal GBS screening. Bazian Ltd. is part of The Economist Group, and holds contracts with public and private organisations within the healthcare industry., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The Blood-Brain Barrier (BBB) is a highly specialised interface separating the Central Nervous System (CNS) from circulating blood. Dysregulation of the BBB is a key early event in pathological conditions such as inflammation, in which the entry of activated leukocytes into the CNS is facilitated by BBB breakdown. The metzincin family of metalloproteinases (MPs) is one of the major contributors to BBB permeability as they cleave endothelial cell-cell contacts and underlying basal lamina components. However, the mechanisms by which MPs regulate BBB integrity has not yet been fully elucidated. The aim of this review is to provide an overview of pathways by which MPs could regulate the BBB in the context of neuroinflammation.

Think back; think wayyy back: before laptops, internet and smartphones. Bank machines didn't exist, tele-phones were permanently plugged into the wall, airport security meant only checking that you paid for your ticket and medical journals came in the mail (as did the bills for the journals). As it turned out, the 1970s was not a kind decade for medical journals, and several were struggling financially. Even the New England Journal of Medicine (NEJM), desperate for cash, was forced to offer a lifetime subscription to anyone who could pay the princely sum of $350! (A colleague of ours, now retired, still receives the weekly NEJM by mail, 45 years later!).

Soluble guanylate cyclase (sGC), the endogenous receptor for nitric oxide (NO), has been implicated in several diseases associated with oxidative stress. In a pathological oxidative environment, the heme group of sGC can be oxidized becoming unresponsive to NO leading to a loss in the ability to catalyze the production of cGMP. Recently a dysfunctional sGC/NO/cGMP pathway has been implicated in contributing to elevated intraocular pressure associated with glaucoma. Herein we describe the discovery of molecules specifically designed for topical ocular administration, which can activate oxidized sGC restoring the ability to catalyze the production of cGMP. These efforts culminated in the identification of compound (+)-23, which robustly lowers intraocular pressure in a cynomolgus model of elevated intraocular pressure over 24 h after a single topical ocular drop and has been selected for clinical evaluation.

Non-alcoholic fatty liver disease (NAFLD) affects 25% of adults and at present no licensed medication has been approved. Despite its complex patho-physiology, dietary strategies aiming at delaying or preventing NAFLD have taken a reductionist approach, examining the impact of single components. Accumulating evidence suggests that n-3 LC-PUFAs are efficacious in regulating lipogenesis and fatty acid oxidation. In addition, plant derived flavonoids are also emerging as a dietary strategy for NAFLD prevention, with efficacy attributed to their insulin sensitising and indirect antioxidant effects. Based on knowledge of their complementary molecular targets, we aimed to demonstrate that the combination of n-3 LC-PUFA (n-3) and flavan-3-ols (FLAV) prevents NAFLD. In a high-fat high-fructose (HF/HFr) fed C57Bl/6J mouse model, the independent and interactive impact of n-3 and FLAV on histologically defined NAFLD, insulin sensitivity, weight gain, intestinal and hepatic gene expression, intestinal bile acids were examined. Only the combination of FLAV and n-3 (FLAVn-3) prevented steatosis as evidenced by a strong reduction in hepatocyte ballooning. While FLAV reduced body (-28-30%), adipose tissue (-45-50%) weights and serum insulin (-22-25%) as observed following an intra-peritoneal glucose tolerance test, n-3 downregulated the expression of Srebf1 and the lipogenic genes (Acaca, Fasn). Significant impacts of interventions on intestinal bile acid metabolism, farnesoid X receptor (Fxr) signalling in the intestine and liver, and hepatic expression of fatty acid transporters (Fabp4, Vldlr, Cd36) were also evident. FLAVn-3 may be a novel intervention for NAFLD. Future research should aim to demonstrate its efficacy in the prevention and treatment of human NAFLD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Osteogenesis imperfecta (OI) is an inherited disorder, which causes brittle bones resulting in recurrent fractures. The associated poor mobility of children with OI increases susceptibility to obesity, and obesity further dramatically limits mobility and increases fracture risk., Objectives: The aim of this report is to describe outcomes of weight loss surgery (WLS) in 2 adolescents with severe obesity and OI., Setting: Two University Hospitals (in the United Kingdom and in the United States)., Methods: Two cases of OI treated with WLS were identified. Pre- and postoperative anthropometric and biochemical data and clinical course were reviewed., Results: In these 2 cases, preoperative Body Mass Index (BMI) values were 38 and 46 kg/m 2 . Following laparoscopic sleeve gastrectomy (LSG), BMI decreased by 55% and 60% by 26 and 24 months, respectively. There were no surgical complications, and both patients experienced improvement in their mobility and ability to perform activities of daily living., Conclusion: WLS effectively treated severe obesity in 2 OI patients and substantially improved mobility and quality of life, theoretically reducing fracture risk., (Copyright © 2017 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

The ATPase subunit of DNA gyrase B is an attractive antibacterial target due to high conservation across bacteria and the essential role it plays in DNA replication. A novel class of pyrazolopyridone inhibitors was discovered by optimizing a fragment screening hit scaffold using structure guided design. These inhibitors show potent Gram-positive antibacterial activity and low resistance incidence against clinically important pathogens.