Shufeng Jiedu,a promising herbal therapy for moderate COVID-19:Antiviral and anti-inflammatory properties,pathways of bioactive compounds,and a clinical real-world pragmatic study

BackgroundShufeng Jiedu capsules (SFJDC), a patented herbal drug composed of eight medicinal plants, is used for the treatment of different viral respiratory tract infectious diseases. Based on its antiviral, anti-inflammatory and immunoregulatory activity in acute lung injury, SFJDC might be a promising candidate for the treatment of COVID-19.PurposeTo evaluate the antiviral and anti-inflammatory properties and to discover the mechanism of action of SFJDC as a potential drug for the treatment of COVID-19. Furthermore, the study should determine the clinical effectiveness of SFJDC for the treatment of COVID-19.DesignWe analyzed the antiviral and anti-inflammatory effects of SFJDC in a HCoV-229E mouse model on lung index, virus load in the lung, the release of cytokines, and on T- and B-lymphocytes. The mechanism of action was further investigated by network analysis. Additionally, we investigated data from a clinical pragmatic real-world study for patients with confirmed COVID-19, to evaluate the clinical effect of SFJDC and to determine the best time to start the treatment.ResultsSFJDC significantly reduced the virus load in the lung of HCoV-229E mice (from 1109.29 ± 696.75 to 0 ± 0 copies/ml), decreased inflammatory factors IL-6, IL-10, TNF-α, and IFN-γ in the lung, and increased the amount of CD4⁺ and CD8⁺ cells in the blood compared to the model group. Network analysis revealed that SFJDC reduces the activity of NFκB via several signaling pathways. Quercetin, wogonin, and polydatin bind directly to the main protease (M^pro) of SARS-CoV-2.Clinical data showed that SFJDC, added to standard antiviral therapy (AVD), significantly reduced the clinical recovery time of COVID-19 and fatigue (from 3.55 ± 4.09 to 1.19 ± 2.28 days) as well as cough (from 5.67 ± 5.64 to 3.47 ± 3.75) days compared to AVD alone. SFJDC therapy was significantly more effective when used within the first 8 days after the onset of symptoms.ConclusionSFJDC might be a promising drug for the treatment of COVID-19, but large-scale randomized, double-blinded, placebo-controlled clinical trials are needed to complement the real-world evidence. It might be beneficial to start SFJDC treatment as early as possible in suspected cases of COVID-19.     

Obstructive lung diseases and inhaler treatment: results from a national public pragmatic survey

Background

The opinions held by the general population on obstructive lung disease and inhaler devices could influence asthma and chronic obstructive pulmonary disorder (COPD) management and treatment adherence.The aim of the present public pragmatic survey was to evaluate the opinions, beliefs and perceptions of Italian people with respect to respiratory diseases as well as their perspectives on the use of inhaler devices.

Methods

This survey was conducted on a group of 2,008 individuals forming a representative sample of the Italian population aged 15 years and over. It was based on personal interviews that were administered in the homes of the respondents using a structured questionnaire that took approximately 30 minutes.

Results

Awareness of obstructive lung diseases is poor. Asthma, but not COPD, was perceived as a common and increasingly prevalent disease by the majority of the interviewees. Allergy, pollution and smoking were considered to be responsible for both of these diseases. The rates at which the respondents claimed to be suffering from asthma and COPD were lower than expected (4% and 2%, respectively). Inhaled drugs were recognised as the main treatment by 65% of the respondents. The great majority of respondents attributed positive characteristics to the inhaler device (e.g., safety, reliability, effectiveness, ease of use and practicality). Compared to people who have never used inhaler devices, individuals who suffer from asthma or COPD were more confident in their use and showed a greater belief in their safety, reliability and trustworthiness. People older than 64 years showed less attention to the properties of these devices.

Conclusions

The present results highlight the need for public interventions aimed at improving awareness of obstructive lung disease and reveal various potentialities and critical issues for inhaler device usage. Switching of devices was considered feasible by most of the interviewees, as long as the choice is carefully explained by their physician.     

The Salford Lung Study protocol: a pragmatic,randomised phase III real-world effectiveness trial in chronic obstructive pulmonary disease

Background

New treatments need to be evaluated in real-world clinical practice to account for co-morbidities, adherence and polypharmacy.

Methods

Patients with chronic obstructive pulmonary disease (COPD), ≥40 years old, with exacerbation in the previous 3 years are randomised 1:1 to once-daily fluticasone furoate 100 μg/vilanterol 25 μg in a novel dry-powder inhaler versus continuing their existing therapy. The primary endpoint is the mean annual rate of COPD exacerbations; an electronic medical record allows real-time collection and monitoring of endpoint and safety data.

Conclusions

The Salford Lung Study is the world’s first pragmatic randomised controlled trial of a pre-licensed medication in COPD.

Trial registration

Clinicaltrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT01551758","term_id":"NCT01551758"}}NCT01551758.     

Initial experience,feasibility and safety of permanent left bundle branch pacing: results from a prospective single-centre study

BackgroundLeft bundle branch (LBB) pacing is a novel pacing technique which may serve as an alternative to both right ventricular pacing for symptomatic bradycardia and cardiac resynchronisation therapy (CRT). A substantial amount of data is reported by relatively few, highly experienced centres. This study describes the first experience of LBB pacing in a high-volume device centre.MethodsSuccess rates (i.e. the ability to achieve LBB pacing), electrophysiological parameters and complications at implant and up to 6 months of follow-up were prospectively assessed in 100 consecutive patients referred for various pacing indications.ResultsThe mean age was 71 ± 11 years and 65% were male. Primary pacing indication was atrioventricular (AV) block in 40%, CRT in 42%, and sinus node dysfunction or refractory atrial fibrillation prior to AV node ablation in 9% each. Baseline left ventricular ejection fraction was < 50% in 57% of patients, mean baseline QRS duration 145 ± 34 ms. Overall LBB pacing was successful in 83 of 100 (83%) patients but tended to be lower in patients with CRT pacing indication (69%, p = ns). Mean left ventricular activation time (LVAT) during LBB pacing was 81 ms and paced QRS duration was 120 ± 19 ms. LBB capture threshold and R‑wave sense at implant was 0.74 ± 0.4 mV at 0.4 ms and 11.9 ± 5.9 V and remained stable at 6‑month follow-up. No complications occurred during implant or follow-up.ConclusionLBB pacing for bradycardia pacing and resynchronisation therapy can be easily adopted by experienced implanters, with favourable success rates and safety profile.     

Deep-rooted vegetation, Amazonian deforestation, and climate: results from a modelling study

The depth of the root system controls the maximum amount of soil water that can be transpired by the vegetation into the atmosphere during dry periods. Water uptake from deep soil layers has been found to contribute significantly to the dry season transpiration at some sites in Amazonia and it has been estimated that large parts of the evergreen forests in Amazonia depend on deep roots to survive the dry season. Thus, the presence of deep roots might provide a significant source of atmospheric moisture during the dry season, and one which would be affected by deforestation. We investigate the role of deep-rooted vegetation and its removal in the context of Amazonian deforestation using an atmospheric General Circulation Model (GCM). A distribution of deep roots is obtained by a numerical optimization approach. The simulated climate with the use of the calculated deep roots substantially improves the seasonal characteristics of the GCM. Three additional simulations are then conducted in order to isolate the effect of rooting depth reduction from other parameter changes associated with large-scale deforestation. Most of the climatic effects occur during the dry season and are attributed to the reduction of rooting depth. Dry periods are found to last longer, being more intense with drier and warmer air, while the wet season remains fairly unchanged. The implications of these climatic effects for the re-establishment of the natural evergreen forest are discussed.     

Questioning behaviour in general practice: a pragmatic study.

OBJECTIVE: To study the extent to which general practitioners'' questioning behaviour in routine practice is likely to encourage the adoption of evidence based medicine. DESIGN: Self recording of questions by doctors during consultations immediately followed by semistructured interview. SETTING: Urban Australian general practice. SUBJECTS: Random sample of 27 general practitioners followed over a half day of consultations. MAIN OUTCOME MEASURES: Rate of recording of clinical questions about patients'' care which doctors would like answered; frequency with which doctors found answers to their questions. RESULTS: Doctors asked a total of 85 clinical questions, at a rate of 2.4 for every 10 patients seen. They found satisfactory answers to 67 (79%) of these questions. Doctors who worked in small practices (of one or two doctors) had a significantly lower rate of questioning than did those in larger practices (1.6 questions per 10 patients v 3.0 patients, P = 0.049). No other factors were significantly related to rate of questioning. CONCLUSIONS: These results do not support the view that doctors routinely generate a large number of unanswered clinical questions. It may be necessary to promote questioning behaviour in routine practice if evidence based medicine and other forms of self directed learning are to be successfully introduced.     

Raloxifene: results from the MORE study

Raloxifene is the first Selective Estrogen Receptor Modulator (SERM) approved for the prevention and treatment of osteoporosis in postmenopausal women. Acting as an estrogen agonist in the skeleton and on lipid metabolism, raloxifene maintains bone mineral density (BMD) and prevents new vertebral fractures while improving the lipid profile in postmenopausal women. In an osteoporosis prevention study, 601 women without osteoporosis, aged 45 to 60 years, were assigned to receive a placebo or raloxifene 30, 60, or 150 mg/day. All women received calcium (400 to 600 mg/day). Raloxifene 60 mg increased BMD by 2.4% at both the lumbar spine and hip compared with the placebo at 36 months. More importantly, however, raloxifene significantly reduced the risk of new vertebral fractures in Multiple Outcomes of Raloxifene Evaluation (MORE), a placebo-controlled, double-blind randomized trial of 7705 postmenopausal women with osteoporosis. The women, with a mean age of 66.5 years, and with hip or spine T-score <-2.5 and/or prevalent vertebral fractures, were assigned to receive either a placebo or 60 mg or 120 mg of raloxifene. All women were provided supplemental calcium (500 mg/day) and vitamin D (400 IU/day). After 36 months, raloxifene 60 mg/day and 120 mg/day, reduced the risk of new vertebral fractures by 55% (RR 0.45, 95% CI 0.3, 0.7; p<0.001), and 40% (RR 0.60, CI 0.4, 0.9) in women without prevalent baseline fractures, respectively; and by 31% (RR 0.7, 95% CI 0.6, 0.9; p<0.001), and 49% (RR 0.5, CI 0.4, 0.6) in women with prevalent baseline fractures compared with the placebo. There was no difference in the proportion of women reporting non-traumatic, non - spine fractures among women receiving raloxifene compared to the placebo-treated women. Compared with placebo, BMD increased after 36 months by 2.1 and 2.6% at the femoral neck and spine, respectively, in the 60mg raloxifene group, and by 2.4 and 2.7% at the femoral neck and spine, respectively, in the 120mg raloxifene group. By 40 months of follow-up, there was a higher rate of deep venous thrombosis (38 cases) and pulmonary embolus (17 cases) in the combined raloxifene groups than in the placebo group (5 and 3 cases,), with a relative risk of 3.1, (CI 1.5-6.2). By 40 months, 54 women had a confirmed diagnosis of breast cancer with a relative risk compared to placebo of 0.35, (CI, 0.21-0.58). Raloxifene therapy for 3 years maintains BMD in healthy postmenopausal women and significantly reduces the risk of new vertebral fractures by about half in postmenopausal women with osteoporosis. Raloxifene also reduces the risk of breast cancer by 65% in postmenopausal women with osteoporosis thus providing a new choice for addressing postmenopausal health concerns.     

Methods for and results from the study of design principles in molecular systems

Most aspects of molecular biology can be understood in terms of biological design principles. These principles can be loosely defined as qualitative and quantitative features that emerge in evolution and recur more frequently than one would expect by chance alone in biological systems that perform a given type of process or function. Furthermore, such recurrence can be rationalized in terms of the functional advantage that the design provides to the system when compared with possible alternatives. This paper focuses on those design features that can be related to improved functional effectiveness of molecular and regulatory networks. We begin by reviewing assumptions and methods that underlie the study of such principles in molecular networks. We follow by discussing many of the design principles that have been found in genetic, metabolic, and signal transduction circuits. We concentrate mainly on results in the context of Biochemical Systems Theory, although we also briefly discuss other work. We conclude by discussing the importance of these principles for both, understanding the natural evolution of complex networks at the molecular level and for creating artificial biological systems with specific features.     

Design of a binary biomarker study from the results of a pilot study

Biomarkers are increasingly used in clinical and epidemiologic studies. Prior to these studies, small pilot studies are often conducted to assess the reproducibility of the biomarker. This article discusses how the results of a pilot study can be used to design subsequent studies when the biomarker is a binary assessment. We consider situations in which the pilot study has two factors (e.g., laboratory and individual) that are either crossed or nested. We discuss how binary random-effects models can be used for estimating the sources of variation and how parameter estimates from these models can be used to appropriately design future studies. We also show that fitting a linear variance components model that ignores the binary nature of the data is a simple alternative method that results in nearly unbiased and moderately efficient estimators of important design parameters. We illustrate the methodology with data from a study assessing the reproducibility of p53 immunohistochemistry in bladder tumors.     

Psoriasis and hypertension severity: results from a case-control study

Background

Epidemiologic studies have provided new insights into the association between psoriasis and cardiovascular diseases. Previous population studies have examined hypertension frequency in psoriasis patients. However, the relationship between severity of hypertension and psoriasis has not been characterized.

Objective

We sought to investigate whether patients with psoriasis have more difficult-to-manage hypertension compared to non-psoriatic hypertensive patients.

Approach

We performed a case-control study using the University of California Davis electronic medical records. The cases were defined as patients diagnosed with both psoriasis and hypertension, and controls were defined as patients with hypertension and without psoriasis. In this identified population, 835 cases were matched on age, sex, and body mass index (BMI) to 2418 control patients.

Key Results

Treatment with multiple anti-hypertensives was significantly associated with the presence of psoriasis using univariate (p<0.0001) and multivariable analysis, after adjusting for diabetes, hyperlipidemia, and race (p<0.0001). Compared to hypertensive patients without psoriasis, psoriasis patients with hypertension were 5 times more likely to be on a monotherapy antihypertensive regimen (95% CI 3.607.05), 9.5 times more likely to be on dual antihypertensive therapy (95% CI 6.68–13.65), 16.5 times more likely to be on triple antihypertensive regimen (95% CI 11.01–24.84), and 19.9 times more likely to be on quadruple therapy or centrally-acting agent (95% CI 10.58–37.33) in multivariable analysis after adjusting for traditional cardiac risk factors.

Conclusions

Psoriasis patients appear to have more difficult-to-control hypertension compared to non-psoriatic, hypertensive patients.     

Pirfenidone improves survival in IPF: results from a real-life study

Background

Pirfenidone is an antifibrotic compound approved for the treatment of idiopathic pulmonary fibrosis (IPF). We present our real-world experience in terms of Pirfenidone’s effect on mortality and adverse events profile outside the restrictions of a clinical trial.

Methods

This is a retrospective observational intention to treat study of 82 consecutive IPF patients (UHH cohort).

Results

We observed a high 3-years survival rate of 73% without excluding patients who discontinued treatment for different reasons. The survival was compared to the survival of an IPF cohort from a tertiary referral center (RBH cohort). After exclusion of severe cases (DLco<?30%), in unadjusted analysis, the survival in the UHH cohort was better than in the RBH cohort (HR:0.32, 95% CI: 0.19–0.53, p?<?0.0001). After adjustment for age, gender and FVC, the survival remained higher in the UHH cohort (HR:0.28, 95% CI: 0.16–0.48, p?<?0.0001). We observed a similar safety profile compared to previously published data and a lower rate of drug discontinuation due to photosensitivity reactions. Conclusion: Pirfenidone provides a survival benefit in a real-life IPF cohort compared to previously used medications. Counselling patients and proactively managing possible adverse effects can reduce the necessity to discontinue pirfenidone.

     

Differentiation of the atrioventricular node, the atrioventricular bundle and the bundle branches in the bovine heart: an immunohistochemical and enzyme histochemical study

The previous observations of differences between different cardiac regions (ventricular myocardium, atrial myocardium, Purkinje fibre system) with respect to the maturation of the M-line region and the establishment of mature metabolic characteristics, have been extended. It was found that M-line maturation proceeds differently also between different regions of the conduction system. The M-line proteins, myomesin and MM-creatine kinase, were detected earlier, by means of immunohistochemistry, in the AV bundle and bundle branch cells than in the AV node cells. Also, a difference was observed in large foetuses. Striations in the AV node were less evident than in the AV bundle and the bundle branches in sections incubated with antibodies against myomesin as well as against MM-creatine kinase. Using enzyme histochemistry it was observed that the differences in metabolic properties between the AV node, the AV bundle and the bundle branches on the one hand, and the ordinary myocardium on the other, of adult hearts, are not established at the early stages. No clear difference in activity of succinate dehydrogenase was seen between the conduction tissues and the ordinary myocardium in the foetal hearts, while the conduction tissues showed a lower activity in the adult hearts. Furthermore, the pattern of activity of mitochondrial glycerol-3-phosphate dehydrogenase between the conduction tissues and the atrial and ventricular myocardium was quite different in early foetal stages compared with the adult stage.     

Using real-world data to monitor and improve quality of care in coronary artery disease: results from the Netherlands Heart Registration

Netherlands Heart Journal - Worldwide, quality registries for cardiovascular diseases enable the use of real-world data to monitor and improve the quality of cardiac care. In the Netherlands Heart...     

Mytilus trossulus hsp70 as a biomarker for arsenic exposure in the marine environment: Laboratory and real-world results

Acute renal papillary necrosis (RPN) in animals is characterized by increased renal lipid accumulation. The excretion of renal lipids into urine has been determined to evaluate their possible use as sensitive early biomarkers for the diagnosis of RPN. This study investigates injury induced by two model nephrotoxins, mefenamic acid (MFA), a non-steroidal anti-inflammatory drug (NSAID), and its analogue N-phenylanthranilic acid (NPAA). Oral NPAA was given repeatedly at doses of 100, 250 and 500 mg kg^-1 daily for 5 days, followed by a 2 day respite over the weekend, and then four further daily doses. The same dosing procedure was used with MFA, but at doses of 75, 150 and 300 mgkg^-1. The control groups were given vehicle orally using the same volume given to the test groups. Urinary phospholipids (PLs), notably sphingomyelin (SPM), phosphatidylcholine (PC) and phosphatidylethanolamine (PE), were measured and compared with other urinary parameters. Histopathological investigations were also performed to confirm the presence or absence of RPN. Following MFA treatment, PC, PI and PE were raised significantly (p < 0.001) on days 1 and 3 and for the remaining part of the experiment. After NPAA treatment, PI showed a transient elevation, and PC and PE levels were significantly increased from day 2 onwards. Both drugs caused a dose-related increase in PLs. There was no significant increase in the level of other urinary parameters. However, histopathological examination of the kidney on day 11 revealed lesions in the medulla and papilla following treatment with the two papillotoxins. These findings demonstrate the potential of urinary PLs as diagnostic non-invasive biomarkers for early renal injury associated with RPN, which may provide an important improvement in the approach to the therapeutic management of analgesic nephropathy.     

Male participation in family planning: results from a qualitative study in Mpigi District, Uganda

The aim of this study was to determine men's perceptions about family planning and how they participate or wish to participate in family planning activities in Mpigi District, central Uganda. Four focus group discussions were conducted with married men and with family planning providers from both the government and private sector. In addition, seven key informants were interviewed using a semi-structured interview guide. The results indicate that men have limited knowledge about family planning, that family planning services do not adequately meet the needs of men, and that spousal communication about family planning issues is generally poor. However, almost all men approved of modern family planning and expressed great interest in participating. The positive change of the beliefs and attitudes of men towards family planning in the past years has not been recognized by family planning programme managers, since available services are not in line with current public attitudes. A more couple-oriented approach to family planning is needed. Measures could include, for example, recruiting males as family planning providers, offering more family planning counselling for couples, and promoting female-oriented methods with men and vice versa.     

From coiled coils to small globular proteins: design of a native-like three-helix bundle.

A monomolecular native-like three-helix bundle has been designed in an iterative process, beginning with a peptide that noncooperatively assembled into an antiparallel three-helix bundle. Three versions of the protein were designed in which specific interactions were incrementally added. The hydrodynamic and spectroscopic properties of the proteins were examined by size exclusion chromatography, sedimentation equilibrium, fluorescence spectroscopy, and NMR. The thermodynamics of folding were evaluated by monitoring the thermal and guanidine-induced unfolding transitions using far UV circular dichroism spectroscopy. The attainment of a unique, native-like state was achieved through the introduction of: (1) helix capping interactions; (2) electrostatic interactions between partially exposed charged residues; (3) a diverse collection of apolar side chains within the hydrophobic core.     

Selenium and cognitive impairment: a brief-review based on results from the EVA study

Preventing cognitive impairment and dementia in the elderly is a major public health challenge for our century and all hypotheses should be explored. Selenium (Se) is one of the factors that may affect the risk of cognitive decline. Its importance in the health and aging process has been documented. Because of the potential of selenoproteins to protect against oxidative stress, Se raises significant expectations for the prevention of chronic diseases including cancer, cardiovascular disease, and type 2 diabetes conditions commonly associated with oxidative stress. Thus, the relationships between Se and cognitive impairment or dementia can be examined through vascular risk factors for dementia, with particular interest in diabetes and dyslipidemia. In addition, in cases of Se deficiency, the brain is the organ that remains Se replete the longest suggesting that Se plays an important role in brain functions. This article presents results obtained in the frame of a longitudinal study on Se and cognitive impairment. They are consistent with the hypothesis that low Se status is a risk factor for cognitive decline even after taking into account vascular risk factors. The concomitant evolution between plasma Se decrease over a 9-year period and cognitive decline suggested that optimal Se status is potentially important to maintain neuropsychological functions in aging people. However, as our understanding of Se biology is incomplete, epidemiological studies are needed to define the groups of population that could benefit from Se supplementation.