This themed issue follows a meeting held at the Royal College of Physicians in London in November 2019 entitled “Avoiding harm from overprescribing: how to reduce waste and dependence on prescription drugs.” Here we summarize the existing challenges faced by healthcare professionals and attempt to present solutions to the expanding problem associated with a vast therapeutic arsenal and increasing medical complexity.
Multi-channel food webs are shaped by the ability of apex predators to link asymmetric energy flows in mesohabitats differing in productivity and community traits. While body size is a fundamental trait underlying life histories and demography, its implications for structuring multi-channel food webs are unexplored. To fill this gap, we develop a framework that links population responses to predation and resource availability to community-level patterns using a tri-trophic food web model with two populations of intermediate consumers and a size-selective top predator. We show that asymmetries in mesohabitat productivities and consumer body sizes drive food web structure, merging previously separate theory on apparent competition and emergent Allee effects (i.e., abrupt collapses of top predator populations). Our results yield theoretical support for empirically observed stability of asymmetric multi-channel food webs and discover three novel types of emergent Allee effects involving intermediate consumers, multiple populations or multiple alternative stable states.
Introduction: Prevalence of insomnia is higher in females and increases with higher age. Besides primary insomnia, comorbid sleep disorders are also common, accompanying different conditions. Considering the possible adverse effects of commonly used drugs to promote sleep, a nonpharmacologic approach should be preferred in most cases. Although generally considered first-line treatment, the nonpharmacologic approach is often underestimated by both patients and physicians. Objective: To provide primary care physicians an up-to-date approach to the nonpharmacologic treatment of insomnia. Methods: PubMed, Web of Science, and Scopus databases were searched for relevant articles about the nonpharmacologic treatment of insomnia up to December 2020. We restricted our search only to articles written in English. Main Message: Most patients presenting with sleep disorder symptoms can be effectively managed in the primary care setting. Primary care physicians may use pharmacologic and nonpharmacologic approaches, while the latter should be generally considered first-line treatment. A primary care physician may opt to refer the patient to a sleep medicine specialist for refractory cases. Conclusions: This paper provides an overview of current recommendations and up-to-date evidence for the nonpharmacologic treatment of insomnia. This article emphasizes the importance of cognitive-behavioral therapy for insomnia, likewise, exercise and relaxation techniques. Complementary and alternative approaches are also covered.
Objectives: To externally validate and compare Resorlu-Unsal stone score(RUSS), modified Seoul National University Renal Stone Complexity Score(S-ReSC), Ito’s nomogram and R.I.R.S. scoring systems for predicting capabilities of both the stone-free status and complications in a multi-institutional study. Materials and Methods: We performed a retrospective analysis of 949 patients who were underwent flexible ureterorenoscopy (f-URS) and laser lithotripsy for renal stones in two institutions between March-2015 and June-2020. The RUSS, modified S-ReSC, Ito’s nomogram and R.I.R.S. scores were calculated for each patient by same surgeon on imaging methods. Results were compared for their predictive capability of stone-free status and complications. Results: Of 949 patients 603 were male and 346 were female with a mean age of 47.2±14.3 (range 2-84years). Mean stone burden was 102.6±42.2 (48-270mm2). All nomograms predicted stone-free status (AUC were 0.689, 0.657, 0.303 and 0.690, respectively). All four scoring systems predicted complications with AUC values of 0.689, 0.646, 0.286 and 0.664 for RUSS, modified S-ReSC, Ito’s nomogram, R.I.R.S., respectively. Although all scoring systems were able to predict complications only Ito’s nomogram was able to predict Clavien ≥2 complications. Conclusion: All four scoring systems (RUSS, modified S-ReSC, Ito’s nomogram and R.I.R.S.) could predict stone-free status after f-URS, however the AUC values are not satisfactory in our large patient cohort. Although these scoring systems were not developed for predicting post-operative complications, they were associated with complications in our study. However, these four scoring systems have some significant limitations. The ideal scoring system is yet to be developed.
Abstract Aims of the study: The aim of this study was to investigate the impact of testosterone deficiency on cognitive functions in metastatic prostate cancer patients receiving androgen deprivation therapy (ADT). Methods: In this multicentric prospective study, 65 metastatic prostate cancer patients were evaluated. Demographic and clinical data were recorded. Cognitive functions were assessed using the Symbol Digit Modalities Test, the California Verbal Learning Test Second Edition, the Brief Visuospatial Memory Test - Revised, and the Trail Making Test. Depressive symptoms were assessed using the Beck Depression Inventory. Cognitive functions and depressive symptoms were recorded before the androgen deprivation therapy and at the 3- and 6-month follow ups. Results: At the basal cognitive assessment, the mean Symbol Digit Modalities Test, the California Verbal Learning Test Second Edition, the Brief Visuospatial Memory Test - Revised scores were 25.84 ± 17.54, 32.68 ± 10.60, and 17.63 ± 11.23, respectively, and the mean time for the Trail Making Test was 221.56 ± 92.44 s., and were similar at the 3-month, and 6-month controls (p > 0.05). The mean pretreatment, third and sixth month testosterone levels were 381.40 ± 157.53 ng/dL, 21.61 ± 9.09 ng/dL, and 12.25 ± 6.45 ng/dL (p < 0.05), and the total PSA levels were 46.46 ± 37.83 ng/mL, 1.41 ± 3.31 ng/mL, and 0.08 ± 0.14 ng/mL (p < 0.05), respectively. Conclusion: The ADT in patients with metastatic prostate cancer does not affect patients’ cognitive functions and depressive symptoms. However, further prospective randomized studies with higher cohorts and longer follow up periods are needed.
Background and aim of the study The Valiant NavionTM stent graft system is a third-generation low profile thoracic endograft designed for thoracic endovascular aortic repair. In this population analysis, we report on the first Asian all-comers experience and outcomes who underwent thoracic endovascular aortic repair with the use of this new stent graft system. Methods Between May 2019 and October 2020, 21 patients with different aortic pathologies were prospectively recruited and retrospectively analyzed. Important clinical and device-related outcomes were evaluated. The endpoints included short-term survival, technical success, access failures, major vascular and clinical complications, endoleaks, and hospital stay. Results The commonest indication of stenting was penetrating aortic ulcers (28.6%) and 6 (28.6%) patients had emergency stenting performed for aortic transection or rupture. 30 days of survival post-procedure was recorded and complete. There were no major vascular complications. Deployment accuracy was 100%, and the technical success rate was 94.7% (18/19) with 1 patient having a type 2 endoleak on follow-up imaging. No neurological complications were noted. The mean operative time was 95 +/- 73.6 mins and the mean fluoroscopy time was 16.2 +/- 10.8 mins. Mean hospital stay for elective zone 2, 3 and 4 stenting was 5.3 +/- 3.8 days, and only 1 patient post zone 1 TEVAR required a brief (0.5 days) ICU stay. All procedures were performed via the percutaneous transfemoral route with 100% success in percutaneous closure. Conclusion This first reported Asian case series demonstrated versatility, safety, and efficacy of the Valiant NavionTM stent in Asian patients with different aortic pathologies
Emicizumab is a recombinant, humanized, and bispecific monoclonal antibody that bridges activated factor (F) IX and FX in place of FVIII to restore hemostasis in persons with hemophilia A (PHA). Data on the efficacy and safety of emicizumab in young children is limited. Immunologic naivety, physiologically decreased production of vitamin K dependent proteins, specifically FIX, and enhanced clearance of emicizumab in infants may support decreased emicizumab effectiveness. We report on the facilitation of care rendered by using emicizumab in young PHA with inhibitors and extend data on the efficacy and safety in PHA < 3 years.
Seed recruitment is a major driver of mangrove restoration globally. It is hypothesized that soil condition and channel hydrology can accelerate seedling recruitment and regeneration after a major disturbance. Species abundance, diversity indices, microbial and chemical concentrations in sand-filled mangrove forest was studied. Eight plots (area = 3902.16 m2) were established with ten transects in each plot in a random block design to investigate the effect of soil conditions on seedling growth. A total of 1, 886 seedlings were physically counted. Seedling abundance was significantly different between red (Rizophora racemosa), white (Laguncularia racemosa) and black (Avicennia germinans) mangroves and nypa palm (nypa fruticans). The most dominant species was black mangroves and the least dominant species was nypa palm. Muddy soils had the most abundant species while sandy soils had the least abundant species. Furthermore, semi-muddy soils had the highest species diversity (H = 0.948) whereas muddy soils had the least species diversity (H = 0.022). The soil metal concentration has no correlation with seed abundance and occur in the order Iron>Nitrate>Copper>Cadmium. Soil with high species diversity had high soil microbial population; however, seedling abundance was correlated with soil nutrients and not heavy metals. Small seeds are easily recruited while good soil condition plus existing hydrological connection facilitated natural seedling regeneration in the disturbed mangrove forest.
In the context of non-relativistic quantum mechanics, we use information theory to study Shannon’s entropy of a non-Hermitian system and understand how the information is modified with the cyclotron frequency. Subsequently, we turn our attention to the construction of an ensemble of these spinless particles in the presence of a uniform magnetic field. Then, we study the thermodynamic properties of the model. Finally, we show how information and thermodynamic properties are modified with the action of the magnetic field. KEYWORDS: Non-relativistic Quantum Mechanics; Quantum Information; Shannon Entropy.
Abstract Background: Ataxia-telangiectasia (A-T) is a rare genetic disorder characterized by a distinct range of clinical manifestations, including progressive ataxia, immunodeficiency, and radiosensitivity. Methods: Clinical data, laboratory results, and genetic data were collected from forty-three A-T patients. Whole exome sequencing and Sanger sequencing were done for the patients clinically diagnosed as suffering from A-T. Based on the phenotype severity of the disease, patients were divided into severe and mild sub-groups. Results: The median (IQR) age of diagnosis in this cohort was 5 (3-7) years and various types of clinical manifestations, including fever (p= 0.005), lower respiratory tract infection (p= 0.033), diarrhea (p= 0.014), and hepatosplenomegaly (p= 0.032) were significantly higher amongst patients diagnosed with the severe phenotype. Our results showed a strong correlation between phenotype severity and mutation type. The chance of having severe phenotype in patients who have severe mutations, including frameshift and nonsense, was 7.3 times higher compared to patients who were categorized in the mild genotype group (odds ratio= 7.3, p= 0.006). Thirty-four types of mutations including 9 novel mutations, were observed in our study. Conclusion: Molecular analysis provides the opportunity for accurate diagnosis and timely management in A-T patients with chronic progressive disease, especially infections and the risk of malignancies. This study characterizes for the first time, the broad spectrum of mutations and phenotypes in Iranian A-T patients which are required for carrier detection and reducing the burden of disease in future using the patients’ families and for the public health care system. Keywords: Ataxia-telangiectasia (A-T), ATM, Whole-exome sequencing, Class switching recombination (CSR), phenotype severity.
Infants born before 32 weeks post-menstrual age (PMA) and receiving respiratory support at 36 weeks PMA are diagnosed with bronchopulmonary dysplasia. This label suggests that their need for supplemental oxygen is primarily due to acquired dysplasia of airways and airspaces, and that the supplemental oxygen (O2) is treating residual parenchymal lung disease. However, current approaches to ventilatory support in the first days of life, including artificial surfactant use and lower ventilating pressures have changed the pathology of chronic lung disease, and emerging evidence suggests that immature ventilatory control may also contribute to the need for supplemental oxygen at 36 weeks PMA. In all newborns, maturation of ventilatory control continues ex utero and is a plastic process. Supplemental O2 mitigates the hypoxemic effects of delayed maturation of ventilatory control, as well as reduces the duration and frequency of periodic breathing events. Prematurity is associated with altered and occasionally aberrant maturation of ventilatory control. Infants born prematurely, with or without a diagnosis of BPD, are more prone to long-lasting effects of dysfunctional ventilatory control. Awareness of the interaction between parenchymal lung disease and delayed maturation of ventilatory control is essential to understanding why a given premature infant requires and is benefitting from supplemental O2 at 36 weeks PMA.
With the increasing deployment of smart buildings and infrastructure, Supervisory Control and Data Acquisition (SCADA) devices and the underlying IT network have become essential elements for the proper operations of these highly complex systems. Of course, with the increase in automation and the proliferation of SCADA devices, a corresponding increase in surface area of attack on critical infrastructure has increased. Understanding device behaviors in terms of known and understood or potentially qualified activities versus unknown and potentially nefarious activities in near-real time is a key component of any security solution. In this paper, we investigate the challenges with building robust machine learning models to identify unknowns purely from network traffic both inside and outside firewalls, starting with missing or inconsistent labels across sites, feature engineering and learning, temporal dependencies and analysis, and training data quality (including small sample sizes) for both shallow and deep learning methods. To demonstrate these challenges and the capabilities we have developed, we focus on Building Automation and Control networks (BACnet) from a private commercial building system. Our results show that ”Model Zoo” built from binary classifiers based on each device or behavior combined with an ensemble classifier integrating information from all classifiers provides a reliable methodology to identify unknown devices as well as determining specific known devices when the device type is in the training set. The capability of the Model Zoo framework is shown to be directly linked to feature engineering and learning, and the dependency of the feature selection varies depending on both the binary and ensemble classifiers as well.
The patient was a 40-year-old man with penetrating chest trauma two days before being referred to our hospital.during first repair LAD artery was sutured.because of ongoing CP, he was candidate for bypass surgery and revascularization .The surgeon had reported ligation of LADA by some sutures during previous cardiac repair.
Chronic rhinosinusitis with nasal polyps is a type 2-mediated inflammatory disease associated with significant burden due to symptoms and high recurrence rate after surgery. Dupilumab, a monoclonal antibody against the interleukin-4 receptor subunit α, has demonstrated good clinical efficacy and acceptable safety in phase II and phase III trials.
Muscle protein catabolism in patients with diabetic nephropathy (DN) results in striking losses of muscle proteins, which increases morbidity and mortality risks. Emerging evidence shows that short-chain fatty acids (SCFAs) play an important role in the maintenance of health and disease development. Recently, the connection between butyrate (a SCFA) and DN has been revealed, although the relationship between butyrate and muscle atrophy is still not clear. In our study, we found a significant decrease in butyrate in DN using metabolomics analyses. The addition of butyrate remarkably intestinal barrier function. Concurrently, butyrate could alleviate muscle atrophy and promote PI3K/AKT/mTOR signals, and suppress oxidative stress and autophagy in the skeletal muscle of db/db mice as well as high glucose/lipopolysaccharide (HG/LPS)-induced C2C12 cells. To further explore the mechanism, we found that GPR43, the key SCFAs signaling molecule, was significantly decreased in the skeletal muscle of db/db mice and HG/LPS-induced C2C12 cells. Overexpression of GPR43 could activate PI3K/AKT/mTOR signals and inhibit oxidative stress and autophagy in HG/LPS-induced C2C12 cells. Silencing of GPR43 blocked PI3K/AKT/mTOR signals improved by butyrate, as well as suppression of oxidative stress and reduction of autophagy. Ultimately, butyrate alleviated muscle atrophy in DN via GPR43-mediated PI3K/AKT/mTOR pathway
Background and Purpose: Liver fibrosis is one of the leading causes of morbidity and mortality worldwide of which no acceptable therapy exists. Accumulating evidence supports that glioma-associated oncogene homologue 1(GLI1) is a potentially important therapeutic target for liver fibrosis. This study investigates the antifibrotic activities and potential mechanisms of Physalin B (PB), a natural Solanaceae compound. Experimental Approach: Mice subjected to CCl4 challenge and bile duct ligation were used to study the antifibrotic effects of PB in vivo. Mouse primary hepatic stellate cells (pHSCs) and human HSC line LX‐2 also served as an in vitro liver fibrosis model. Liver fibrogenic genes, GLI1 downstream genes were examined using western blot and real-time PCR analyses. GLI1 acetylation and LAP2α-HDAC1 interaction were analyzed by coimmunoprecipitation. Key Results: In animal models, PB administration attenuated hepatic histopathological injury, collagen accumulation, and reduced the expression of fibrogenic genes. PB dose‐dependently suppressed fibrotic marker expression in LX‐2 cells and mouse pHSCs. Mechanistic studies showed PB inhibited GLI activity in a non-canonical Hedgehog signaling. PB blocked lamina-associated polypeptide 2 α (LAP2α)/ histone deacetylase 1 (HDAC1) complex formation thereby inhibited HDAC1mediated GLI1 deacetylation. PB downregulated the acetylation and expression of GLI1, and subsequently inhibiting HSC activation. Conclusions and Implications: PB exerted potent antifibrotic effects in vitro and in vivo by disrupting the LAP2α/HDAC1 complex, increasing GLI1 acetylation and inactivating GLI1. This indicates that PB may be a potential therapeutic candidate for the treatment of liver fibrosis.
Background: To investigate the relationship between ureteral wall thickness (UWT) and other variables of patients who underwent extracorporeal shock wave lithotripsy (SWL) in the primary treatment of the ureteral stone above the iliac crest level. Material and methods: A total of 147 patients aged 18 years and older, who underwent SWL in our clinic between December 2016 and December 2019 for the treatment of ureteral stones above the iliac crest level and had a non-contrast-enhanced abdominal computed tomography (NCCT) scans before the procedure were included in the clinical study. The results were evaluated at three months after SWL. The absence of residual fragments was considered as stone-free status, and the existence of any size residual fragment was considered as treatment failure. Results: In our study, the mean age of the patients was 42.4 ± 12.8 years, and the stone-free rate was 92.5%. The median transverse stone size was 7.5 mm (min 2.8 - max 15), and the median UWT was 4.2 mm (1 - 8.7). In the multivariate analysis, UWT (p = 0.002) and multiple stone presence (p = 0.027) were found to be independent factors affecting stone-free status. In the receiver operating characteristic (ROC) curve analysis, the optimal threshold value for UWT was determined as 5.25 mm. Conclusions: We found that UWT was the most important independent variable associated with increased failure in SWL treatment. The presence of multiple stones was another independent factor that increased failure rates. Using SWL technology through experience accumulated with the mechanical hardware of the machine, we can select patients who are more suitable for this treatment and improve treatment outcomes.
Background: Early-life exposures to geohelminths may protect against the development of wheeze/asthma and atopy. Objective: Study effect of maternal geohelminths and infections in children during the first 5 years of life on atopy, wheeze/asthma, and airways reactivity/inflammation at 8 years. Methods: Birth cohort of 2,404 neonates followed to 8 years in rural Ecuador. Data on wheeze/asthma were collected by questionnaire and atopy by skin prick test (SPT) reactivity to 9 allergens. We measured airways reactivity to bronchodilator, fractional exhaled nitric oxide (FeNO), and nasal eosinophilia. Stool samples were examined for geohelminths by microscopy. Results: 1,933 (80.4%) children were evaluated at 8 years. Geohelminths were detected in 45.8% of mothers and in 45.5% of children to 5 years. Frequencies of outcomes at 8 years were: wheeze (6.6%), asthma between 5 and 8 years (7.9%), SPT (14.7%), airways reactivity (10%), and elevated FeNO (10.3%) and nasal eosinophilia (9.2%). Any maternal geohelminth was associated with reduced prevalence of SPT (OR 0.72). Childhood T. trichiura infections were associated with reduced wheeze (OR 0.57) but greater parasite burdens with A. lumbricoides were associated with increased wheeze (OR 2.83) and asthma (OR 2.60). Associations between maternal geohelminths and wheeze/asthma were modified by atopy. Parasite-specific effects on wheeze/asthma and airways reactivity and inflammation were observed in non-atopic children. Conclusions: Our data provide novel evidence for persistent effects of in utero geohelminth exposures on childhood atopy but highlight the complex nature of the relationship between geohelminths and the airways. Registered as an observational study (ISRCTN41239086).