Abstract
Structure determination of amorphous materials remains challenging, owing to the disorder inherent to these materials. Nuclear magnetic resonance (NMR) powder crystallography is a powerful ...method to determine the structure of molecular solids, but disorder leads to a high degree of overlap between measured signals, and prevents the unambiguous identification of a single modeled periodic structure as representative of the whole material. Here, we determine the atomic-level ensemble structure of the amorphous form of the drug AZD4625 by combining solid-state NMR experiments with molecular dynamics (MD) simulations and machine-learned chemical shifts. By considering the combined shifts of all
1
H and
13
C atomic sites in the molecule, we determine the structure of the amorphous form by identifying an ensemble of local molecular environments that are in agreement with experiment. We then extract and analyze preferred conformations and intermolecular interactions in the amorphous sample in terms of the stabilization of the amorphous form of the drug.
The benefit of thyroid hormone therapy for subclinical hypothyroidism is uncertain. New evidence from recent large randomized clinical trials warrants an update of previous meta-analyses.
To conduct ...a meta-analysis of the association of thyroid hormone therapy with quality of life and thyroid-related symptoms in adults with subclinical hypothyroidism.
PubMed, EMBASE, ClinicalTrials.gov, Web of Science, Cochrane Library, CENTRAL, Emcare, and Academic Search Premier from inception until July 4, 2018.
Randomized clinical trials that compared thyroid hormone therapy with placebo or no therapy in nonpregnant adults with subclinical hypothyroidism were eligible. Two reviewers independently evaluated eligibility based on titles and abstracts of all retrieved studies. Studies not excluded in this first step were independently assessed for inclusion after full-text evaluation by 2 reviewers.
Two independent reviewers extracted data, assessed risk of bias (Cochrane risk-of-bias tool), and evaluated the quality of evidence (GRADE tool). For synthesis, differences in clinical scores were transformed (eg, quality of life) into standardized mean differences (SMDs; positive values indicate benefit of thyroid hormone therapy; 0.2, 0.5, and 0.8 correspond to small, moderate, and large effects, respectively). Random-effects models for meta-analyses were applied.
General quality of life and thyroid-related symptoms after a minimum follow-up of 3 months.
Overall, 21 of 3088 initially identified publications met the inclusion criteria, with 2192 adults randomized. After treatment (range, 3-18 months), thyroid hormone therapy was associated with lowering the mean thyrotropin value into the normal reference range compared with placebo (range, 0.5-3.7 mIU/L vs 4.6 to 14.7 mIU/L) but was not associated with benefit regarding general quality of life (n = 796; SMD, -0.11; 95% CI, -0.25 to 0.03; I2=66.7%) or thyroid-related symptoms (n = 858; SMD, 0.01; 95% CI, -0.12 to 0.14; I2=0.0%). Overall, risk of bias was low and the quality of evidence assessed with the GRADE tool was judged moderate to high.
Among nonpregnant adults with subclinical hypothyroidism, the use of thyroid hormone therapy was not associated with improvements in general quality of life or thyroid-related symptoms. These findings do not support the routine use of thyroid hormone therapy in adults with subclinical hypothyroidism.
Summary
Background: Statin treatment may be associated with adverse effects on glucose metabolism. Whether this is a class effect is not known. In contrast, ezetimibe monotherapy may beneficially ...affect insulin sensitivity.
Objective: The aim of this study was to compare the effects of three different regimens of equivalent low‐density lipoprotein cholesterol (LDL‐C) lowering capacity on glucose metabolism.
Methods: A total of 153 patients (56 men), who had not achieved the LDL‐C goal recommended by the National Cholesterol Education Program Adult Treatment Panel III (NCEP‐ATP III) despite a 3‐month dietary and lifestyle intervention, were randomly allocated to receive open‐label simvastatin 40 mg or rosuvastatin 10 mg or simvastatin/ezetimibe 10/10 mg for 12 weeks. The primary end point was changes in homeostasis model assessment of insulin resistance (HOMA‐IR). Secondary endpoints consisted of changes in fasting insulin levels, fasting plasma glucose (FPG), glycosylated haemoglobin (HbA1c), the HOMA of β‐cell function (HOMA‐B) (a marker of basal insulin secretion by pancreatic β‐cells), LDL‐C and high sensitivity C reactive protein (hsCRP).
Results: At week 12, all three treatment regimens were associated with significant increases in HOMA‐IR and fasting insulin levels (p < 0.05 compared with baseline). No significant difference was observed between groups. No change in FPG, HbA1c and HOMA‐B levels compared with baseline were noted in any of the three treatment groups. Changes in serum lipids and hsCRP were similar across groups.
Conclusion: To the extent that simvastatin 40 mg, rosuvastatin 10 mg and simvastatin/ezetimibe 10/10 mg are associated with adverse effects on insulin resistance, they appear to be of the same magnitude.
Aim
The aim of this review was to compile existing evidence on the role of platelets in the development of severe retinopathy of prematurity (ROP), highlight the strengths and weaknesses of the ...available studies and critically discuss the reported data.
Methods
A comprehensive literature search was conducted on PubMed from January 2000 to January 2022, and the reference lists of the included studies were screened manually.
Results
There were 19 primary studies that fulfilled the eligibility criteria. Experimental research indicated lower platelet count in mice oxygen‐induced retinopathy model compared with normoxia controls, while platelet transfusions suppressed neovascularisation. The latter finding was not consistently confirmed in clinical research, where a low platelet count, an increased number of thrombopenic episodes and of platelet transfusions have all been implicated in the development of ROP requiring treatment, either type I or aggressive posterior or both. However, existing studies exhibit significant clinical heterogeneity and present methodological limitations that imperil their reliability and validity.
Conclusion
Platelet deficiency has been associated with severe ROP. However, critical thresholds of platelet parameters are still unrecognised. Future research is required to determine whether platelet parameters can be predictive biomarkers for ROP requiring treatment and at what thresholds.
Several approaches to medication optimisation by identifying drug-related problems in older people have been described. Although some interventions have shown reductions in drug-related problems ...(DRPs), evidence supporting the effectiveness of medication reviews on clinical and economic outcomes is lacking. Application of the STOPP/START (version 2) explicit screening tool for inappropriate prescribing has decreased inappropriate prescribing and significantly reduced adverse drug reactions (ADRs) and associated healthcare costs in older patients with multi-morbidity and polypharmacy. Therefore, application of STOPP/START criteria during a medication review is likely to be beneficial. Incorporation of explicit screening tools into clinical decision support systems (CDSS) has gained traction as a means to improve both quality and efficiency in the rather time-consuming medication review process. Although CDSS can generate more potential inappropriate medication recommendations, some of these have been shown to be less clinically relevant, resulting in alert fatigue. Moreover, explicit tools such as STOPP/START do not cover all relevant DRPs on an individual patient level. The OPERAM study aims to assess the impact of a structured drug review on the quality of pharmacotherapy in older people with multi-morbidity and polypharmacy. The aim of this paper is to describe the structured, multi-component intervention of the OPERAM trial and compare it with the approach in the comparator arm.
This paper describes a multi-component intervention, integrating interventions that have demonstrated effectiveness in defining DRPs. The intervention involves a structured history-taking of medication (SHiM), a medication review according to the systemic tool to reduce inappropriate prescribing (STRIP) method, assisted by a clinical decision support system (STRIP Assistant, STRIPA) with integrated STOPP/START criteria (version 2), followed by shared decision-making with both patient and attending physician. The developed method integrates patient input, patient data, involvement from other healthcare professionals and CDSS-assistance into one structured intervention.
The clinical and economical effectiveness of this experimental intervention will be evaluated in a cohort of hospitalised, older patients with multi-morbidity and polypharmacy in the multicentre, randomized controlled OPERAM trial (OPtimising thERapy to prevent Avoidable hospital admissions in the Multi-morbid elderly), which will be completed in the last quarter of 2019.
Universal Trial Number: U1111-1181-9400 Clinicaltrials.gov: NCT02986425, Registered 08 December 2016. FOPH (Swiss national portal): SNCTP000002183. Netherlands Trial Register: NTR6012 (07-10-2016).
The typical linewidths of
H NMR spectra of powdered organic solids at 111 kHz magic-angle spinning (MAS) are of the order of a few hundred Hz. While this is remarkable in comparison to the tens of ...kHz observed in spectra of static samples, it is still the key limit to the use of
H in solid-state NMR, especially for complex systems. Here, we demonstrate a novel strategy to further improve the spectral resolution. We show that the anti-z-COSY experiment can be used to reduce the residual line broadening of
H NMR spectra of powdered organic solids. Results obtained with the anti-z-COSY sequence at 100 kHz MAS on thymol, β-AspAla, and strychnine show an improvement in resolution of up to a factor of two compared to conventional spectra acquired at the same spinning rate.
Cell adhesion on substrates is accompanied by significant changes in shape and cytoskeleton organization, which affect subsequent cellular and tissue responses, determining the long-term success of ...an implant. Alterations in osteoblast stiffness upon adhesion on orthopaedic implants with different surface chemical composition and topography are, thus, of central interest in the field of bone implant research. This work aimed to study the mechanical response of osteoblasts upon adhesion on chitosan-coated glass surfaces and to investigate possible correlations with the level of adhesion, spreading, and cytoskeleton reorganization. Using the micropipette aspiration technique, the osteoblast elastic modulus was found higher on chitosan-coated than on uncoated control substrates, and it was found to increase in the course of spreading for both substrates. The cell-surface contact area was measured throughout several time points of adhesion to quantify cell spreading kinetics. Significant differences were found between chitosan and control surfaces regarding the response of cell spreading, while both groups displayed a sigmoidal kinetical behavior with an initially elevated spreading rate which stabilizes in the second hour of attachment. Actin filament structural changes were confirmed after observation with confocal microscope. Biomaterial surface modification can enhance osteoblast mechanical response and induce favorable structural organization for the implant integration.
The typical linewidths of 1H NMR spectra of powdered organic solids at 111 kHz magic‐angle spinning (MAS) are of the order of a few hundred Hz. While this is remarkable in comparison to the tens of ...kHz observed in spectra of static samples, it is still the key limit to the use of 1H in solid‐state NMR, especially for complex systems. Here, we demonstrate a novel strategy to further improve the spectral resolution. We show that the anti‐z‐COSY experiment can be used to reduce the residual line broadening of 1H NMR spectra of powdered organic solids. Results obtained with the anti‐z‐COSY sequence at 100 kHz MAS on thymol, β‐AspAla, and strychnine show an improvement in resolution of up to a factor of two compared to conventional spectra acquired at the same spinning rate.
Narrow it down: A new approach to line narrowing in solid‐state 1H NMR spectra is introduced. It is based on remote correlations in anti‐z‐COSY experiments and allows an improvement in resolution of up to a factor of two compared to conventional spectra.
The analysis of complex mixtures is an important but often intractable problem. When species contain sparse fluorine atoms, NMR spectra of fluorine-containing spin systems can be efficiently ...extracted from an intact mixture using the recently proposed FESTA (Fluorine-Edited Selective TOCSY Acquisition) methodology. Here an alternative approach to the existing selective reverse INEPT FESTA (SRI-FESTA) experiment is described, based on the use of a modulated spin echo for the initial excitation. MODO-FESTA (modulated echo FESTA) is simpler and has a significant sensitivity advantage over SRI-FESTA. Comparisons are presented of the relative sensitivity and spectral purity of the two types of methods.
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