“If you can’t see a dilemma in this situation you should probably regard it as a warning”. A metasynthesis and theoretical modeling of general practitioners’ opioid prescription experiences in primary care.

Background: The prescribing of opioids has increased internationally in developed countries in recent decades within primary and secondary care.1 The majority of patients with chronic non-malignant pain (CNMP) are managed by their GP.2 Recent qualitative studies have examined the issue of opioid prescribing for chronic non-malignant pain (CNMP) from a GP viewpoint. Several factors have been reported to influence the prescribing of opioids for CNMP including aetiology of pain condition, co-morbidities, access to specialised care, history of drug abuse and professional scrutiny. We require a better understanding of problems GP’s face when making opioid prescribing decisions, interventions to provide better supports in the prescribing of opioids for CNMP. The aim of this study is to identify and synthesize the qualitative literature describing the factors influencing the nature and extent of opioid prescribing in CNMP in primary care. A theoretical model is then proposed which seeks to explain the relationship between factors influencing prescribing of opioids for CNMP by GPs. Methods: MEDLINE, Embase, PsychINFO, Cochrane Database, International Pharmaceutical Abstracts, Database of Abstracts of Reviews of Effects, CINAHL and Web of Science were systematically searched from January 1986- Feb 2018. Two reviewers independently screened titles and abstracts. Studies were excluded from the review if they were non-English language, theoretical or methodological articles, policy documents, conference abstracts or presentations, as where quotations were not clearly attributed to GPs participating in the study. The reviewers then independently assessed the full text of the articles using the Critical Appraisal Skills Programme (CASP) tool for qualitative research. The papers were coded by two researcher and these codes organised using Thematic Network Analysis. Basis themes were defined initially, organising themes were then developed followed by global themes which summarised the key theories emerging from the articles. Finally, a theoretical model was derived by the researchers using the global themes to explain the interplay between factors influencing opioid prescribing decisions. Results: From 7020 records, 18 full text papers were assessed, and 13 studies included in the synthesis; 9 were from USA, 3 from UK and 1 from Sweden. Seven organising themes were identified including trust and mistrust, the importance of aetiology, monitoring of prescription use, physical, psychological and societal harm, consultation variables, inadequate pain management, stigma and stereotypes and system barriers to effective and safe prescribing such as limited access to specialist care or support from allied healthcare professionals in primary care. Four global themes emerged;suspicion, risk, agreement and encompassing systems level factors. These global themes are inter-related and capture the complex decision-making processes underlying the opioid prescribing whereby the physician both consciously and subconsciously quantifies the risk-benefit relationship associated with initiating or continuing an opioid prescription. Conclusion: Prescribing of opioids for CNMP is influenced by a myriad of factors. Rather, than a simple risk-benefit view of the process, it is more useful to view this as a dynamic process in which unique considerations such as the morality of opioid use exert an effect. Recognising the inherent complexity of the process and the limitations of healthcare systems, guidelines directed at GPs should offer more nuanced recommendations on managing opioid prescribing consultations in primary care

Molecular diagnosis of SARS-CoV-2 in seminal fluid

Purpose Due to relevant repercussions on reproductive medicine, we aimed to evaluate feasibility of RT-PCR as a detection method of SARS-CoV-2 RNA in seminal fluid. Methods A qualitative determination of the RT-PCR assays in semen was performed through different approaches: (1) efficiency of RNA extraction from sperm and seminal plasma was determined using PRM1 and PRM2 mRNA and a heterologous system as control; (2) samples obtained by diluting viral preparation from a SARS-CoV-2 panel (virus cultured in Vero E6 cell lines) were tested; (3) viral presence in different fractions of seminal fluid (whole sample, seminal plasma and post-centrifugation pellet) was evaluated. Semen samples from mild and recovered COVID-19 subjects were collected by patients referring to the Infectious Disease Department of the Policlinico Umberto I Hospital - "Sapienza" University of Rome. Control subjects were recruited at the Laboratory of Seminology-Sperm Bank "Loredana Gandini'' of the same hospital. Results The control panel using viral preparations diluted in saline and seminal fluid showed the capability to detect viral RNA presence with C-t values depending on the initial viral concentration. All tested semen samples were negative for SARS-CoV-2, regardless of the nasopharyngeal swab result or seminal fluid fraction. Conclusion These preliminary data show that RT-PCR for SARS-CoV-2 RNA testing appears to be a feasible method for the molecular diagnosis of SARS-CoV-2 in seminal fluid, supported by results of the control panel. The ability to detect SARS-CoV-2 in semen is extremely important for reproductive medicine, especially in assisted reproductive technology and sperm cryopreservation

"You see yourself like in a mirror”: The effects of internet-mediated personal networks on body image and eating disorders

Body image issues associated with eating disorders involve attitudinal and perceptual components: individuals’ dissatisfaction with body shape or weight, and inability to assess body size correctly. While prior research has mainly explored social pressures produced by the media, fashion, and advertising industries, this paper focuses on the effects of personal networks on body image, particularly in the context of internet communities. We use data collected on a sample of participants to websites on eating disorders, and map their personal networks. We specify and estimate a model for the joint distribution of attitudinal and perceptual components of body image as a function of network-related characteristics and attributional factors. Supported by information gathered through in-depth interviews, the empirical estimates provide evidence that personal networks can be conducive to positive body image development, and that the influence of personal networks varies significantly by body size. We situate our discussion in current debates about the effects of computer-mediated and face-to-face communication networks on eating disorders and related behaviors

5-HTR3 and 5-HTR4 located on the mitochondrial membrane and functionally regulated mitochondrial functions

5-HT has been reported to possess significant effects on cardiac activities, but activation of 5-HTR on the cell membrane failed to illustrate the controversial cardiac reaction. Because 5-HT constantly comes across the cell membrane via 5-HT transporter (5-HTT) into the cytoplasm, whether 5-HTR is functional present on the cellular organelles is unknown. Here we show 5-HTR3 and 5-HTR4 were located in cardiac mitochondria, and regulated mitochondrial activities and cellular functions. Knock down 5-HTR3 and 5-HTR4 in neonatal cardiomyocytes resulted in significant increase of cell damage in response to hypoxia, and also led to alternation in heart beating. Activation of 5-HTR4 attenuated mitochondrial Ca2+ uptake under the both normoxic and hypoxic conditions, whereas 5-HTR3 augmented Ca2+ uptake only under hypoxia. 5-HTR3 and 5-HTR4 exerted the opposite effects on the mitochondrial respiration: 5-HTR3 increased RCR (respiration control ratio), but 5-HTR4 reduced RCR. Moreover, activation of 5-HTR3 and 5-HTR4 both significantly inhibited the opening of mPTP. Our results provided the first evidence that 5-HTR as a GPCR and an ion channel, functionally expressed in mitochondria and participated in the mitochondria function and regulation to maintain homeostasis of mitochondrial [Ca2+], ROS, and ATP generation efficiency in cardiomyocytes in response to stress and O2 tension

NQO1-Dependent Redox Cycling of Idebenone: Effects on Cellular Redox Potential and Energy Levels

Short-chain quinones are described as potent antioxidants and in the case of idebenone have already been under clinical investigation for the treatment of neuromuscular disorders. Due to their analogy to coenzyme Q10 (CoQ10), a long-chain quinone, they are widely regarded as a substitute for CoQ10. However, apart from their antioxidant function, this provides no clear rationale for their use in disorders with normal CoQ10 levels. Using recombinant NAD(P)H:quinone oxidoreductase (NQO) enzymes, we observed that contrary to CoQ10 short-chain quinones such as idebenone are good substrates for both NQO1 and NQO2. Furthermore, the reduction of short-chain quinones by NQOs enabled an antimycin A-sensitive transfer of electrons from cytosolic NAD(P)H to the mitochondrial respiratory chain in both human hepatoma cells (HepG2) and freshly isolated mouse hepatocytes. Consistent with the substrate selectivity of NQOs, both idebenone and CoQ1, but not CoQ10, partially restored cellular ATP levels under conditions of impaired complex I function. The observed cytosolic-mitochondrial shuttling of idebenone and CoQ1 was also associated with reduced lactate production by cybrid cells from mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) patients. Thus, the observed activities separate the effectiveness of short-chain quinones from the related long-chain CoQ10 and provide the rationale for the use of short-chain quinones such as idebenone for the treatment of mitochondrial disorders

Mitochondrial ATP synthase: architecture, function and pathology

Human mitochondrial (mt) ATP synthase, or complex V consists of two functional domains: F1, situated in the mitochondrial matrix, and Fo, located in the inner mitochondrial membrane. Complex V uses the energy created by the proton electrochemical gradient to phosphorylate ADP to ATP. This review covers the architecture, function and assembly of complex V. The role of complex V di-and oligomerization and its relation with mitochondrial morphology is discussed. Finally, pathology related to complex V deficiency and current therapeutic strategies are highlighted. Despite the huge progress in this research field over the past decades, questions remain to be answered regarding the structure of subunits, the function of the rotary nanomotor at a molecular level, and the human complex V assembly process. The elucidation of more nuclear genetic defects will guide physio(patho)logical studies, paving the way for future therapeutic interventions

Opportunistic infections in immunosuppressed patients with juvenile idiopathic arthritis: analysis by the Pharmachild Safety Adjudication Committee

Background To derive a list of opportunistic infections (OI) through the analysis of the juvenile idiopathic arthritis (JIA) patients in the Pharmachild registry by an independent Safety Adjudication Committee (SAC). Methods The SAC (3 pediatric rheumatologists and 2 pediatric infectious disease specialists) elaborated and approved by consensus a provisional list of OI for use in JIA. Through a 5 step-procedure, all the severe and serious infections, classified as per MedDRA dictionary and retrieved in the Pharmachild registry, were evaluated by the SAC by answering six questions and adjudicated with the agreement of 3/5 specialists. A final evidence-based list of OI resulted by matching the adjudicated infections with the provisional list of OI. Results A total of 772 infectious events in 572 eligible patients, of which 335 serious/severe/very severe non-OI and 437 OI (any intensity/severity), according to the provisional list, were retrieved. Six hundred eighty-two of 772 (88.3%) were adjudicated as infections, of them 603/682 (88.4%) as common and 119/682 (17.4%) as OI by the SAC. Matching these 119 opportunistic events with the provisional list, 106 were confirmed by the SAC as OI, and among them infections by herpes viruses were the most frequent (68%), followed by tuberculosis (27.4%). The remaining events were divided in the groups of non-OI and possible/patient and/or pathogen-related OI. Conclusions We found a significant number of OI in JIA patients on immunosuppressive therapy. The proposed list of OI, created by consensus and validated in the Pharmachild cohort, could facilitate comparison among future pharmacovigilance studies

Sarcopenia; Aging-related loss of muscle mass and function

Sarcopenia is a loss of muscle mass and function in the elderly that reduces mobility, diminishes quality of life, and can lead to fall-related injuries, which require costly hospitalization and extended rehabilitation. This review focuses on the aging-related structural changes and mechanisms at cellular and subcellular levels underlying changes in the individual motor unit: specifically, the perikaryon of -motoneuron, its neuromuscular junction(s), and the muscle fibers that it innervates. Loss of muscle mass with aging, which is largely due to the progressive loss of motoneurons, is associated with reduced muscle fiber number and size. Muscle function progressively declines because motoneuron loss is not adequately compensated by reinnervation of muscle fibers by the remaining motoneurons. At the intracellular level, key factors are qualitative changes in posttranslational modifications of muscle proteins and the loss of coordinated control between contractile, mitochondrial, and sarcoplasmic reticulum protein expression. Quantitative and qualitative changes in skeletal muscle during the process of aging also have been implicated in the pathogenesis of acquired and hereditary neuromuscular disorders. In experimental models, specific intervention strategies have shown encouraging results on limiting deterioration of motor unit structure and function under conditions of impaired innervation. Translated to the clinic, if these or similar interventions, by saving muscle and improving mobility, could help alleviate sarcopenia in the elderly, there would be both great humanitarian benefits and large cost savings for health care systems