New treatment modalities are urgently needed for patients with COVID-19. The World Health Organization (WHO) Solidarity trial showed no effect of remdesivir or hydroxychloroquine (HCQ) on mortality, ...but the antiviral effects of these drugs are not known.
To evaluate the effects of remdesivir and HCQ on all-cause, in-hospital mortality; the degree of respiratory failure and inflammation; and viral clearance in the oropharynx.
NOR-Solidarity is an independent, add-on, randomized controlled trial to the WHO Solidarity trial that included biobanking and 3 months of clinical follow-up (ClinicalTrials.gov: NCT04321616).
23 hospitals in Norway.
Eligible patients were adults hospitalized with confirmed SARS-CoV-2 infection.
Between 28 March and 4 October 2020, a total of 185 patients were randomly assigned and 181 were included in the full analysis set. Patients received remdesivir (
= 42), HCQ (
= 52), or standard of care (SoC) (
= 87).
In addition to the primary end point of WHO Solidarity, study-specific outcomes were viral clearance in oropharyngeal specimens, the degree of respiratory failure, and inflammatory variables.
No significant differences were seen between treatment groups in mortality during hospitalization. There was a marked decrease in SARS-CoV-2 load in the oropharynx during the first week overall, with similar decreases and 10-day viral loads among the remdesivir, HCQ, and SoC groups. Remdesivir and HCQ did not affect the degree of respiratory failure or inflammatory variables in plasma or serum. The lack of antiviral effect was not associated with symptom duration, level of viral load, degree of inflammation, or presence of antibodies against SARS-CoV-2 at hospital admittance.
The trial had no placebo group.
Neither remdesivir nor HCQ affected viral clearance in hospitalized patients with COVID-19.
National Clinical Therapy Research in the Specialist Health Services, Norway.
Severe chronic postsurgical pain has a prevalence of 4-10% in the surgical population. The underlying nociceptive mechanisms have not been well characterized. Following the late resolution phase of ...an inflammatory injury, high-dose μ-opioid-receptor inverse agonists reinstate hypersensitivity to nociceptive stimuli. This unmasking of latent pain sensitization has been a consistent finding in rodents while only observed in a limited number of human volunteers. Latent sensitization could be a potential triggering venue in chronic postsurgical pain. The objective of the present trial was in detail to examine the association between injury-induced secondary hyperalgesia and naloxone-induced unmasking of latent sensitization. Healthy volunteers (n = 80) received a cutaneous heat injury (47°C, 420 s, 12.5 cm2). Baseline secondary hyperalgesia areas were assessed 1 h post-injury. Utilizing an enriched enrollment design, subjects with a magnitude of secondary hyperalgesia areas in the upper quartile ('high-sensitizers' n = 20) and the lower quartile ('low-sensitizers' n = 20) were selected for further study. In four consecutive experimental sessions (Sessions 1 to 4), the subjects at two sessions (Sessions 1 and 3) received a cutaneous heat injury followed 168 h later (Sessions 2 and 4) by a three-step target-controlled intravenous infusion of naloxone (3.25 mg/kg), or normal saline. Assessments of secondary hyperalgesia areas were made immediately before and stepwise during the infusions. Simple univariate statistics revealed no significant differences in secondary hyperalgesia areas between naloxone and placebo treatments (P = 0.215), or between 'high-sensitizers' and 'low-sensitizers' (P = 0.757). In a mixed-effects model, secondary hyperalgesia areas were significantly larger following naloxone as compared to placebo for 'high-sensitizers' (P < 0.001), but not 'low-sensitizers' (P = 0.651). Although we could not unequivocally demonstrate naloxone-induced reinstatement of heat injury-induced hyperalgesia, further studies in clinical postsurgical pain models are warranted.
According to drug labels, the frequency of thiazide-induced hyponatremia is unknown or uncommon to very rare (that is, <1 in 10 000 to <1 in 100), but the exact burden remains unclear.
To estimate ...the increase in the cumulative incidence of hyponatremia using thiazide diuretics compared with nonthiazide antihypertensive drugs in routine clinical practice.
Population and register-based cohort study using target trial emulation.
Denmark, 1 January 2014 to 31 October 2018.
Two target trials were emulated among persons aged 40 years or older who had no recent prescription for any antihypertensive drug, had no previous hyponatremia, and were eligible for the studied antihypertensive treatments. The first target trial emulation compared new use of bendroflumethiazide (BFZ) versus a calcium-channel blocker (CCB). The second target trial emulation compared new use of hydrochlorothiazide plus a renin-angiotensin system inhibitor (HCTZ-RASi; that is, combination pill) versus a RASi alone.
Two-year cumulative incidences of sodium levels less than 130 mmol/L using stabilized inverse probability of treatment-weighted survival curves.
The study compared 37 786 new users of BFZ with 44 963 of a CCB and 11 943 new users of HCTZ-RASi with 85 784 of a RASi. The 2-year cumulative incidences of hyponatremia were 3.83% for BFZ and 3.51% for HCTZ-RASi. The risk differences were 1.35% (95% CI, 1.04% to 1.66%) between BFZ and CCB and 1.38% (CI, 1.01% to 1.75%) between HCTZ-RASi and RASi; risk differences were higher with older age and higher comorbidity burden. The respective hazard ratios were 3.56 (CI, 2.76 to 4.60) and 4.25 (CI, 3.23 to 5.59) during the first 30 days since treatment initiation and 1.26 (CI, 1.09 to 1.46) and 1.29 (CI, 1.05 to 1.58) after 1 year.
The study assumed that filled prescriptions equaled drug use, and residual confounding is likely.
Treatment initiation with thiazide diuretics suggests a more substantial excess risk for hyponatremia, particularly during the first months of treatment, than indicated by drug labeling.
Independent Research Fund Denmark.
Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of the metabolic syndrome and is rapidly emerging as the leading cause of liver-related morbidity and mortality. ...Macrophages play an essential role in the development and progression of NAFLD.
In this review, we provide an update on recent studies of drugs, which directly or indirectly affect macrophages in NAFLD, and discuss the implication of macrophage biomarkers to monitor the disease stage and progression/regression.
There is an unmet need for a better understanding of disease pathogenesis from hepatic fat accumulation to disease progression with inflammation and fibrosis. We expect that future research will uncover additional objects/pathways as treatment targets. We speculate that this will involve better characterization of the gut microbiome, damage-associated molecular patterns (DAMPS) or molecules and pathways involved in the development of DAMPS, and advanced molecular biology studies including single-cell sequencing of macrophage subpopulations. In addition, we speculate that studies focusing on pharmaceuticals that improve insulin resistance, diminish the metabolic syndrome, and reduce fibrosis will prevail.
Medial unicompartmental knee arthroplasties (UKAs) have good clinical outcomes but implant survival is inferior to that of total knee arthroplasties (TKAs). Conversion to a TKA is a reliable option ...when UKA fails. However, there is controversy regarding these conversions. The aim of this study was to analyze the survival of TKAs converted from UKAs when compared with both primary and revision TKAs.
On the basis of registrations in the Danish Knee Arthroplasty Registry from 1997 to 2017, 1,012 TKAs converted from UKAs were compared with 73,819 primary TKAs and 2,572 revision TKAs. The primary outcome was the risk of revision. Secondarily, the study analyzed the influence of different implants, the indication for the UKA conversion, and surgical volume on the survival of TKA converted from UKA. Third, the study compared the indications for revision.
The converted UKAs were mainly mobile-bearing (85%) and, at the time of conversion, the patients were younger (mean standard deviation, 66 ± 10 years) and more were Charnley class A (55%) compared with patients with primary TKA (70 ± 9 years and 35% class A) or revision TKA (70 ± 10 years and 42% class A) (all p < 0.001). The survival of TKAs converted from UKAs was comparable with that of revision TKAs (p = 0.42) and significantly inferior to the survival of primary TKAs (p < 0.001). This relationship was unaffected by differences between the groups, with an adjusted hazard ratio of 0.94 (95% confidence interval CI: 0.74 to 1.19) compared with revision TKAs and 3.00 (95% CI: 2.47 to 3.66) compared with primary TKAs. The survival of TKA converted from UKA was unaffected by differences in the conversion implants (all p ≥ 0.47), experience with revision surgery (all p ≥ 0.06), and the indications for the UKA-to-TKA conversion (all p ≥ 0.27). Instability (26%) and unexplained pain (13%) were more frequent indications for revisions of TKA converted from UKA (p < 0.001).
TKA converted from medial UKA has a 3-fold higher risk of revision when compared with primary TKA. The implant survival resembled that of revision TKA but with a higher prevalence of unexplained pain and instability.
Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
Research into new advanced district heating concepts has increased since the first four generations of district heating were defined in 2014. This definition created a common framework for research ...and industry alike, and pointed to potential futures for district heating which could benefit from low-temperature heating in buildings. The fully developed fourth-generation district heating includes the cross-sectoral integration into the smart energy system. This paper defines four generations of district cooling to make a similar useful framework for district cooling. The first generation being pipeline refrigeration systems that were first introduced in the late 19th century, the second generation being mainly based on large compression chillers and cold water as distribution fluid, the third generation having a more diversified cold supply such as natural cooling, and the fourth generation combining cooling with other energy sectors sometimes into a renewable energy-based smart energy systems context, including combined heating and cooling.
•Definition of four generations of district cooling.•District cooling systems from first developments to contemporary state-of-the-art.•District cooling and energy system integration.
Prevalent diabetes at the time of heart failure (HF) diagnosis is associated with a higher risk of death, but the incidence and prognostic importance of new-onset diabetes in patients with ...established HF remains unknown.
Patients with a first hospitalization for HF in the period 2003-2014 were included and stratified according to history of diabetes. Annual incidence rates of new-onset diabetes were calculated and time-dependent multivariable Cox regression models were used to compare the risk of death in patients with prevalent and new-onset diabetes with patients without diabetes as reference. The model was adjusted for age, sex, duration of HF, educational level and comorbidity. Covariates were continuously updated throughout follow-up.
A total of 104,522 HF patients were included in the study, of which 21,216 (19%) patients had diabetes at baseline, and 8164 (10%) developed new-onset diabetes during a mean follow-up of 3.9 years. Patients with new-onset diabetes and prevalent diabetes were slightly younger than patients without diabetes (70 vs. 74 and 77, respectively), more likely to be men (62% vs. 60% and 54%), and had more comorbidities expect for ischemic heart disease, hypertension and chronic kidney disease which were more prevalent among patients with prevalent diabetes. Incidence rates of new-onset diabetes increased from around 2 per 100 person-years in the first years following HF hospitalization up to 3 per 100 person-years after 5 years of follow-up. A total of 61,424 (59%) patients died during the study period with event rates per 100 person-years of 21.5 for new-onset diabetes, 17.9 for prevalent diabetes and 13.9 for patients without diabetes. Compared to patients without diabetes, new-onset diabetes was associated with a higher risk of death (adjusted HR 1.47; 95% CI 1.42-1.52) and prevalent diabetes was associated with an intermediate risk (HR 1.19; 95% CI, 1.16-1.21).
Following the first HF hospitalization, the incidence of new-onset diabetes was around 2% per year, rising to 3% after 5 years of follow-up. New-onset diabetes was associated with an increased risk of death, compared to HF patients with prevalent diabetes (intermediate risk) and HF patients without diabetes.
Objective: Investigate direct and indirect associations between markers of socioeconomic position (SEP) across the life course and midlife cognitive ability while addressing methodological ...limitations in prior work. Method: Longitudinal data from the Danish Metropolit cohort of men born in 1953 (N = 2,479) who completed ability tests at age 12, 18, and 56-58 linked to register-based information on paternal occupational class, educational attainment, and occupational level. Associations were assessed using structural equation models, and different models were estimated to examine the importance of accounting for childhood ability and measurement error. Results: Associations between adult SEP measures and midlife ability decreased significantly when adjusting for childhood ability and measurement error. The association between childhood and midlife ability was by far the strongest. Discussion: The impact of adult SEP on later life ability may be exaggerated when not accounting for the stability of individual differences in cognitive ability and measurement error in test scores.
Equations of state (EoS) are essential in the modeling of a wide range of industrial and natural processes. Desired qualities of EoS are accuracy, consistency, computational speed, robustness, and ...predictive ability outside of the domain where they have been fitted. In this work, we review present challenges associated with established models, and give suggestions on how to overcome them in the future. The most accurate EoS available, multiparameter EoS, have a second artificial Maxwell loop in the two-phase region that gives problems in phase-equilibrium calculations and excludes them from important applications such as treatment of interfacial phenomena with mass-based density functional theory. Suggestions are provided on how this can be improved. Cubic EoS are among the most computationally efficient EoS, but they often lack sufficient accuracy. We show that extended corresponding state EoS are capable of providing significantly more accurate single-phase predictions than cubic EoS with only a doubling of the computational time. In comparison, the computational time of multiparameter EoS can be orders of magnitude larger. For mixtures in the two-phase region, however, the accuracy of extended corresponding state EoS has a large potential for improvement. The molecular-based SAFT family of EoS is preferred when predictive ability is important, for example, for systems with strongly associating fluids or polymers where few experimental data are available. We discuss some of their benefits and present challenges. A discussion is presented on why predictive thermodynamic models for reactive mixtures such as CO2–NH3 and CO2–H2O–H2S must be developed in close combination with phase- and reaction equilibrium theory, regardless of the choice of EoS. After overcoming present challenges, a next-generation thermodynamic modeling framework holds the potential to improve the accuracy and predictive ability in a wide range of applications such as process optimization, computational fluid dynamics, treatment of interfacial phenomena, and processes with reactive mixtures.
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