IMPORTANCE: Coronary plaques that are prone to rupture and cause adverse cardiac events are characterized by large plaque burden, large lipid content, and thin fibrous caps. Statins can halt the ...progression of coronary atherosclerosis; however, the effect of the proprotein convertase subtilisin kexin type 9 inhibitor alirocumab added to statin therapy on plaque burden and composition remains largely unknown. OBJECTIVE: To determine the effects of alirocumab on coronary atherosclerosis using serial multimodality intracoronary imaging in patients with acute myocardial infarction. DESIGN, SETTING, AND PARTICIPANTS: The PACMAN-AMI double-blind, placebo-controlled, randomized clinical trial (enrollment: May 9, 2017, through October 7, 2020; final follow-up: October 13, 2021) enrolled 300 patients undergoing percutaneous coronary intervention for acute myocardial infarction at 9 academic European hospitals. INTERVENTIONS: Patients were randomized to receive biweekly subcutaneous alirocumab (150 mg; n = 148) or placebo (n = 152), initiated less than 24 hours after urgent percutaneous coronary intervention of the culprit lesion, for 52 weeks in addition to high-intensity statin therapy (rosuvastatin, 20 mg). MAIN OUTCOMES AND MEASURES: Intravascular ultrasonography (IVUS), near-infrared spectroscopy, and optical coherence tomography were serially performed in the 2 non–infarct-related coronary arteries at baseline and after 52 weeks. The primary efficacy end point was the change in IVUS-derived percent atheroma volume from baseline to week 52. Two powered secondary end points were changes in near-infrared spectroscopy–derived maximum lipid core burden index within 4 mm (higher values indicating greater lipid content) and optical coherence tomography–derived minimal fibrous cap thickness (smaller values indicating thin-capped, vulnerable plaques) from baseline to week 52. RESULTS: Among 300 randomized patients (mean SD age, 58.5 9.7 years; 56 18.7% women; mean SD low-density lipoprotein cholesterol level, 152.4 33.8 mg/dL), 265 (88.3%) underwent serial IVUS imaging in 537 arteries. At 52 weeks, mean change in percent atheroma volume was −2.13% with alirocumab vs −0.92% with placebo (difference, −1.21% 95% CI, −1.78% to −0.65%, P < .001). Mean change in maximum lipid core burden index within 4 mm was −79.42 with alirocumab vs −37.60 with placebo (difference, −41.24 95% CI, −70.71 to −11.77; P = .006). Mean change in minimal fibrous cap thickness was 62.67 μm with alirocumab vs 33.19 μm with placebo (difference, 29.65 μm 95% CI, 11.75-47.55; P = .001). Adverse events occurred in 70.7% of patients treated with alirocumab vs 72.8% of patients receiving placebo. CONCLUSIONS AND RELEVANCE: Among patients with acute myocardial infarction, the addition of subcutaneous biweekly alirocumab, compared with placebo, to high-intensity statin therapy resulted in significantly greater coronary plaque regression in non–infarct-related arteries after 52 weeks. Further research is needed to understand whether alirocumab improves clinical outcomes in this population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03067844
Aims:
The development of effective interventions to reduce inappropriate use of antibiotics in the elderly population requires knowledge on who can benefit from such interventions. Thus, we aimed to ...identify and characterise antibiotic heavy users among elderly patients in general practice with respect to sociodemographic variables.
Methods:
We conducted a retrospective nationwide register-based study on all Danish elderly citizens (⩾65 years) who redeemed an antibiotic prescription in 2017. Heavy users were defined as the 10% with the highest excess use, that is, their recorded use minus the average use for their sex, age group and comorbidity level as estimated from a linear regression model. Comparative analyses of sociodemographic characteristics (civil status, employment status, urbanity, educational level and country of origin) of heavy users and non-heavy users were performed using logistic regression models.
Results:
The study population consisted of 251,733 elderly individuals, who in total redeemed 573,265 prescriptions of antibiotics. Heavy users accounted for 68% of all excess use of antibiotics. In multivariable analyses, individuals with an educational level above basic schooling, non-retired, residing in an urban municipality and being born in a country outside Scandinavia all had lower odds of being a heavy user. Widowed, divorced or single individuals had higher odds of being a heavy user compared with married individuals. Relative importance analyses showed that civil status and educational level contributed considerably to the explained variance.
Conclusions:
This study found an association between sociodemographic characteristics and risk of being a heavy user, indicating that sociodemographic variation exists with regard to antibiotic prescribing.
Recent studies suggest that alterations in the female urinary microbiota is associated to development of bladder disease. However, the normal microbiota composition and variation in healthy women are ...poorly described. Moreover, the effects of hormonal changes on microbiota during menopause is not well understood. The aim of our study was to investigate the urinary microbiota in healthy pre- and postmenopausal women without urinary tract symptoms. Microbiota composition in catheterized urine samples was mapped using 16S rRNA gene sequencing. In total, 41 premenopausal and 42 postmenopausal women were initially included. Samples with first PCR amplification concentration below level of the negative control were excluded, resulting in 34 premenopausal and 20 postmenopausal women included in data analysis. Urine from postmenopausal women showed significantly higher alpha diversity compared to premenopausal women. Lactobacillus was the most abundant bacteria in both groups, however the relative abundance of Lactobacillus accounted for 77.8% in premenopausal versus 42.0% in postmenopausal women. In conclusion, urine from premenopausal mostly presented with Lactobacillus dominated urotypes, whereas urine from postmenopausal women presented a more diverse urinary microbiota with higher abundance of the genera Gardnerella and Prevotella. The clinical and pathophysiological implications of this difference remain to be elucidated.
The Niemann-Pick C2 protein (NPC2) is a sterol transfer protein in the lumen of late endosomes and lysosomes (LE/LYSs). Absence of functional NPC2 leads to endo-lysosomal buildup of cholesterol and ...other lipids. How NPC2’s known capacity to transport cholesterol between model membranes is linked to its function in living cells is not known. Using quantitative live-cell imaging combined with modeling of the efflux kinetics, we show that NPC2-deficient human fibroblasts can export the cholesterol analog dehydroergosterol (DHE) from LE/LYSs. Internalized NPC2 accelerated sterol efflux extensively, accompanied by reallocation of LE/LYSs containing fluorescent NPC2 and DHE to the cell periphery. Using quantitative fluorescence loss in photobleaching of TopFluor-cholesterol (TF-Chol), we estimate a residence time for a rapidly exchanging sterol pool in LE/LYSs localized in close proximity to the plasma membrane (PM), of less than one min and observed non-vesicular sterol exchange between LE/LYSs and the PM. Excess sterol was released from the PM by shedding of cholesterol-rich vesicles. The ultrastructure of such vesicles was analyzed by combined fluorescence and cryo soft X-ray tomography (SXT), revealing that they can contain lysosomal cargo and intraluminal vesicles. Treating cells with apoprotein A1 and with nuclear receptor liver X-receptor (LXR) agonists to upregulate expression of ABC transporters enhanced cholesterol efflux from the PM, at least partly by accelerating vesicle release. We conclude that NPC2 inside LE/LYSs facilitates non-vesicular sterol exchange with the PM for subsequent sterol efflux to acceptor proteins and for shedding of sterol-rich vesicles from the cell surface.
Purpose
Particle therapy is becoming increasingly available world‐wide for precise tumor targeting, its favorable depth dose deposition, and increased biological damage to tumor tissue compared to ...conventional photon therapy. As demand increases for improved robustness and conformality, next‐generation secondary dose calculation engines are needed to verify treatment plans independently and provide estimates for clinical decision‐making factors, such as dose‐averaged linear energy transfer (LETd) and relative biological effectiveness (RBE).
Method
FRoG (Fast dose Recalculation on GPU) has been installed and commissioned at the Danish Centre for Particle Therapy (DCPT). FRoG was developed for synchrotron‐based facilities and has previously demonstrated good agreement with gold‐standard Monte Carlo simulations and measurements. In this work, additions and modifications to FRoG’s pencil beam algorithm to support the ion beam delivery with cyclotron‐based technology as used at the DCPT, range shifter (RS) implementation, and robustness analysis methods are presented. FRoG dose predictions are compared to measurements and predictions of the clinical treatment planning system (TPS) Eclipse (Varian Medical Systems, Palo Alto, United States of America, CA, v.13.7.16) in both homogenous and heterogeneous scenarios using a solid‐water/water and a half‐head anthropomorphic phantom, respectively. Additional capabilities of FRoG are explored by performing a plan robustness analysis, analyzing dose and LETd for ten patients.
Results
Mid‐target measurements in spread‐out Bragg Peaks (SOBP) were on average within −0.19% ± 0.30% and ≤0.5% of FRoG predictions for irradiations without and with RS, respectively. Average 3%/2mm 3D γ‐analysis passing rates were 99.1% for ~200 patient plan QA comparisons. Measurement with an anthropomorphic head‐phantom yielded a γ‐passing rate >98%. Overall, maximum target differences in D02% of <2% between the TPS and FRoG were observed for patient plans. The robustness analysis study accounting for range, delivery, and positioning uncertainties revealed small differences in target dose and a maximum LETdVH02% (LETd received by 2% of the volume having dose larger than 1% of maximum dose) values below 10.1 keV/µm to the brain stem.
Conclusion
We demonstrate that auxiliary dose calculation systems like FRoG can yield excellent agreement to measurements comparable to clinical beam models. Through this work, application of FRoG as a secondary engine at third party cyclotron‐based particle treatment facilities is now established for dose verification as well as providing further insight on LETd and variable RBE distributions for protons, currently absent from the standard clinical TPS.
To describe the use and perceived usefulness of implementation support provided to general practice during an accreditation process and to explore potential variations across clinic characteristics.
...Cross-sectional questionnaire study.
All Danish general practice clinics undergoing an accreditation survey from 27 September 2016 to 15 December 2017 (n = 608).
Use and perceived usefulness of seven types of implementation support as reported by general practitioners (GPs). Clinic characteristics included practice type, number of GP partners and staff and employment of GP trainees.
The total response rate was 74% (n = 447). Most clinics (99.5%) used some type of implementation support (average: 4.8 different types). The most used types of support were peer support (80-92%) and various accreditation documents (85-92%). Support tailored to the individual clinic was most often considered useful (91-97%). However, this type of support was used relatively infrequently (16-40%). In most cases, clinic characteristics were neither significantly associated with the use of support nor with the perceived usefulness of the available support.
During the accreditation processes, each clinic used a broad variety of implementation support. Support tailored to the individual clinic was highly appreciated and should be promoted in future quality interventions in general practice. Discussions with peers were widely used, and it should be investigated further how peer discussions are best facilitated. The study calls for a multifactorial approach to future quality interventions in general practice to target the needs and capacities of the individual clinics.
Currently available injectable drugs that target proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce serum LDL cholesterol and improve cardiovascular outcomes. This phase 2 study assessed ...NNC0385-0434, an oral PCSK9 inhibitor, in individuals receiving oral lipid-lowering therapy.
In this randomised, double-blind, placebo-controlled and active-controlled trial, 42 research sites across seven countries (Belgium, Germany, Greece, Japan, the Netherlands, Poland, and the USA) recruited individuals with established atherosclerotic cardiovascular disease (aged ≥40 years) or at high risk of atherosclerotic cardiovascular disease (aged >50 years), who had LDL cholesterol concentration of at least 1·8 mmol/L and were receiving maximum tolerated statins and stable lipid-lowering therapy. The study randomly allocated participants (3:1) with an interactive web response system to receive either NNC0385-0434 (15 mg, 40 mg, or 100 mg) once a day co-formulated with the oral absorption enhancer sodium N-8-(2-hydroxybenzoyl)amino caprylate (500 mg); placebo; or open-label evolocumab (140 mg) every 2 weeks administered subcutaneously. Blinding was performed within each dose level. The primary endpoint was percentage change from baseline in LDL cholesterol measured by β quantification at week 12. All randomly assigned participants received at least one dose of treatment and were included in both safety and efficacy analyses. The trial was registered on ClinicalTrials.gov, NCT04992065, and is completed.
Between Aug 16, 2021, and Jan 28, 2022, we randomly assigned 267 patients to one of the three NNC0385-0434 dose cohorts (n=53 per cohort), matching placebo (n=54), or open-label evolocumab (n=54). The study population comprised 82 (31%) women and 185 (69%) men; mean age was 64·3 years (SD 9·0). Baseline mean LDL cholesterol concentration was 2·7 mmol/L (SD 0·8). Treatment with NNC0385-0434 resulted in reductions in LDL cholesterol from baseline to week 12, of 32·0 percentage points (95% CI 20·9 to 43·0) in the 15 mg cohort, 44·9 percentage points (33·8 to 56·0) in the 40 mg cohort, and 61·8 percentage points (50·7 to 72·9) in the 100 mg cohort, compared with the placebo group (p<0·0001 for each). Patients treated with evolocumab had similar LDL cholesterol reductions (59·6% SE 4·1 decrease from baseline) to patients receiving NNC0385-0434 100 mg (56·2% 4·0). The estimated treatment difference between NNC0385-0434 100 mg and evolocumab 140 mg was 3·4 percentage points 95% CI -7·8 to 14·7. The most frequently reported adverse event was COVID-19, which affected 31 (12%) of 267 patients, with similar numbers across treatment groups. Investigative sites reported gastrointestinal disorders as the most frequent treatment-related adverse event (26 patients and 35 events total in the three NNC0385 cohorts and one patient and one event each in the placebo and evolocumab cohorts). No deaths or treatment-related serious adverse events occurred.
This study showed excellent 12-week LDL cholesterol lowering efficacy and good patient tolerance of an oral PCSK9 inhibitor, NNC0835-0434, similar to an injectable drug. However, the sponsor chose to discontinue further development of NNC0835-0434 due to portfolio considerations.
Novo Nordisk.
During the Devonian, the Svalbard Archipelago lay at low latitudes, occupying a paleogeographic position at the intersection of Caledonian and Ellesmerian orogens. Provenance analysis, including ...detrital zircon U‐Pb age studies, of Devonian (ca. 420–360 Ma) strata from the Andrée Land Basin, Svalbard, help reconstruct sediment sources to understand the assembly of the three basement provinces that make up Svalbard, which are presently separated by Devonian sedimentary basins and(or) faults with syn‐to post‐Devonian displacement. The studied Andrée Land Group strata, which are part of the North Atlantic's Old Red Sandstone, consist of the Early Devonian Wood Bay Formation and Middle to Late Devonian Mimerdalen subgroup. Paleocurrent indicators from Lower to lower‐Middle Devonian strata record north‐directed sediment transport. Detrital zircon U‐Pb ages indicate a prominent “Caledonian” signal and include sources from Svalbard's Northwestern and(or) Southwestern basement provinces. In Middle and Upper Devonian strata, paleocurrents and detrital zircon ages record a shift to a predominantly eastern‐northeastern provenance, likely from the uplifting Ny‐Friesland block along the Billefjorden Fault Zone. Late Ediacaran‐early Cambrian detrital zircons in the uppermost Planteryggen Formation (Frasnian) indicate extrabasinal sources possibly associated with the Timanian orogen of Northern Baltica. The combined provenance data suggest Svalbard may have already been assembled, similar to the modern block, with the Andrée Land Basin located between modern exposures of the Southwestern/Northwestern and the Northeastern basement provinces. Comparison of detrital zircon ages from Andrée Land Group strata with those from other circum Arctic Devonian strata provides constraints on Svalbard's paleogeographic position in the Devonian.
Key Points
Provenance analysis of the Andrée Land Basin identifies N‐NE paleodrainage in the Early Devonian and W‐SW in the Middle‐Late Devonian
Svalbard's three basement provinces were likely juxtaposed into a relative position similar to the present day by the end of the Devonian
Detrital zircon U‐Pb age comparisons of circum Arctic Devonian strata further constrain Svalbard's paleogeographic position in the Devonian
The investigation of large-scale intrinsic connectivity networks in antipsychotic-naïve first-episode schizophrenia increases our understanding of system-level cerebral dysfunction in schizophrenia ...while enabling control of confounding effects of medication and disease progression. Reports on functional connectivity in antipsychotic-naïve patients have been mixed and the relation between network alterations, psychopathology and cognition is unclear.
A total number of 47 patients with first-episode schizophrenia who had never received antipsychotic medication and 47 healthy controls were scanned with functional magnetic resonance imaging under resting conditions. Main outcome measures were differences in functional connectivity between groups and the relationship between network alterations, psychopathology and cognition.
Altered connectivity was found between right central executive network (CEN) and right ventral attention network (VAN) (patients > controls, P = .001), left CEN and left VAN (P = .002), and between posterior default mode network and auditory network (P = .006). Association between network connectivity and clinical characteristics was found as interactions between the effects of group and sustained attention (P = .005) and between group and processing speed (P = .007) on the connectivity between right CEN and right VAN.
Our findings suggest that the early phase of schizophrenia is characterized by increased connectivity between fronto-parietal networks suggested to be involved in the control of cognitive and sensory functions. Moreover, the present study suggests that the problem of not disengaging the VAN leads to difficulties with attention and possibly subjective awareness.
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