Aims: Opioid misuse and overuse has contributed to a widespread overdose crisis and many patients and physicians are considering medical cannabis to support opioid tapering and chronic pain control. Using a five-step modified Delphi process, we aimed to develop consensus-based recommendations on: 1) when and how to safely initiate and titrate cannabinoids in the presence of opioids, 2) when and how to safely taper opioids in the presence of cannabinoids, and 3) how to monitor patients and evaluate outcomes when treating with opioids and cannabinoids. Results: In patients with chronic pain taking opioids not reaching treatment goals, there was consensus that cannabinoids may be considered for patients experiencing or displaying opioid-related complications, despite psychological or physical interventions. There was consensus observed to initiate with a CBD-predominant oral extract in the daytime and consider adding THC. When adding THC, start with 0.5–3 mg, and increase by 1–2 mg once or twice weekly up to 30–40 mg/day. Initiate opioid tapering when the patient reports a minor/major improvement in function, seeks less as-needed medication to control pain, and/or the cannabis dose has been optimized. The opioid tapering schedule may be 5%–10% of the morphine equivalent dose (MED) every 1 to 4 weeks. Clinical success could be defined by an improvement in function/quality of life, a ≥ 30% reduction in pain intensity, a ≥ 25% reduction in opioid dose, a reduction in opioid dose to < 90 mg MED, and/or reduction in opioid-related adverse events. Conclusions: This five-stage modified Delphi process led to the development of consensus-based recommendations surrounding the safe introduction and titration of cannabinoids in concert with tapering opioids.
i. Rationale, aims and objectives Antimicrobial Stewardship programs are critical for promoting and monitoring judicious use of antimicrobials, however, there are many well-established barriers to their effective implementation the rural setting. Pharmacist involvement in such programs is recommended as part of a multidisciplinary approach to improve appropriate antimicrobial prescribing. The aim of this study was to describe the impact of implementing a clinical pharmacy service on antimicrobial prescribing in a rural GP led hospital; explore areas of suboptimal antimicrobial prescribing; and review the change in total antimicrobial cost per patient day. ii. Methods: A retrospective case series audit of pre- and post-implementation of a new clinical pharmacy service was undertaken. All adult patients who had presented with sepsis, cellulitis, urinary tract infections and pneumonia between May and August 2015 and repeated for months in 2018 were included. Appropriateness of therapy was assessed using the National Antimicrobial Prescribing Survey guidelines. iii. Results: A total of 115 antibiotic orders from 2015 and 158 orders from 2018 were included. During admission, 86% of patients (55/64) in the post-intervention group were reviewed by a clinical pharmacist. Appropriate prescribing increased from 57% (66/115) in 2015 to 82% (129/158) in 2018 (P=0.001). Ceftriaxone was the most inappropriately prescribed antimicrobial. The cost of antimicrobial therapy was halved from $10.00 to $5.33 per patient day, pre- and post-implementation of a clinical pharmacy service respectively. iv. Conclusions: The implementation of a clinical pharmacy service in a small rural GP led hospital can significantly improve antimicrobial prescribing practices and provide considerable cost savings. Keywords Antimicrobial stewardship; antibiotics; pharmacists; hospitals, Rural; Inappropriate Prescribing
Rationale, aims and objectives: The diversity of safety signals (e.g., case reports, animal studies and observational studies) makes the assessment of the (un-)safety of a drug a formidable challenge. While frequentist viewpoints to uncertain inference struggle in aggregating these signals, the more flexible Bayesian approaches seem better suited for this quest. Artificial Intelligence (AI) offers great promise to these approaches for information retrieval, decision support and leaning probabilities from data. E-Synthesis is a Bayesian framework for drug safety assessments build on philosophical principles and considerations. It aims to aggregate all the available information, in order to provide a Bayesian probability of a drug causing an adverse reaction. We delineate and assess ways in which AI can support E-Synthesis. Results: We find that AI can help with information retrieval, usability (graphical decision making aids), learning Bayes factors from historical data, assessing quality of information and determining conditional probabilities for the so-called “indicators” of causation for E-Synthesis. Conclusions: Properly applied, AI can help the transition of philosophical principles and considerations concerning evidence aggregation for drug safety to a tool that can be used in practise.
Viral vectors have a great potential for gene delivery, but manufacturing at pharmaceutical scale is a big challenge for the industry. The baculovirus-insect cells system is one of the most scalable platforms to produce clinical grade recombinant Adeno-Associated Virus (rAAV) vectors, however, the standard procedure to generate recombinant baculovirus based on Tn7 transposition is time consuming and still suffers technical constraints. Indeed, we recently shown that baculoviral sequences adjacent to the AAV ITRs are preferentially encapsidated into the rAAV vector particles. This observation raised concern about safety for clinical applications due to the presence of bacterial and antibiotic resistance coding sequences with Tn7-mediated system for the construction of recombinant baculoviruses. Here, we investigated a faster and safer method to generate baculovirus reagents based on homologous recombination (HR) for its use in rAAV manufacturing compared to the Tn7-based system. First, we confirmed the functionality of inserted cassette and the absence of undesirable genes into HR-derived baculoviral genomes. Strikingly, we found that the exogenous cassette shown an increased stability over passages when using HR system. Finally, we tested these materials to produce rAAV vectors. The baculoviruses originated from either system lead to high rAAV vector genome yields, with the advantage for the HR method being that the rAAV lots are exempted of undesirable gentamycin and kanamycin genes derived sequences which provides an additional level of safety for the manufacturing of rAAV vectors. Overall, this study highlights the importance of the upstream process and starting biologic materials to generate safer rAAV biotherapeutic products.
BACKGROUND AND PURPOSE: Pharmacological treatments are unavailable to patients with cocaine use disorders. Efforts to develop pharmacotherapies have led to the study of cannabidiol, a constituent of the C. sativa plant. However, the specific effects and mechanisms of action of cannabidiol in a rodent model of extinction-based abstinence and drug seeking relapse remain unclear. EXPERIMENTAL APPROACH: In this study, cannabidiol was provided during extinction training to male CD-1 mice trained to self-administer cocaine. We evaluated the reinstatement of cocaine seeking induced by cues, stress, and drug priming. To ascertain the participation of CB1 receptors in these behavioural changes, we administered the neutral CB1 antagonist AM4113 before each reinstatement session. KEY RESULTS The results document that cannabidiol did not modulate extinction learning. After cannabidiol treatment, increased levels of CB1 receptor protein were found in the prelimbic and orbitofrontal parts of the prefrontal cortex, as well as in the ventral striatum; an effect paralleled by a reduction of ∆FosB accumulation and increased GluR2 AMPA receptor subunits. Furthermore, cue-induced reinstatement of cocaine seeking was prevented in cannabidiol-treated mice. Unexpectedly, cannabidiol facilitated stress-induced reinstatement of cocaine-maintained responding. Cocaine-primed reinstatement remained unaltered by cannabidiol. Both, the blockade of cue-induced reinstatement and the facilitation of stress-induced reinstatement were abolished by AM4113 in cannabidiol-treated mice. CONCLUSION AND IMPLICATIONS: Our results reveal a series of complex CB1-related changes induced by cannabidiol with opposite implications for the reinstatement of cocaine seeking behaviour that may limit therapeutic opportunities.
Aim: CQ and HCQ are currently being investigated worldwide for their clinical efficacy against COVID-19, however a major concern regarding these drugs remains their safety profile. The aim of the present study was to identify potential safety signals of CQ and HCQ use, in the period prior to their repurpose as COVID-19 treatment options analyzing safety data retrieved from the FDA Adverse Event Reporting System (FAERS) pharmacovigilance database. Methods: We performed a disproportionality analysis of all available FAERS data between the first quarter of 2004 and December 2019 using the OpenVigil2.1-MedDRA software. Disproportionality was quantified using the reporting odds ratio (ROR) and its 95% confidence interval (CIs). The reporting mortality of CQ and HCQ was also investigated Results: The dataset contained 6,635,356 reports. Based on the comparison of the RORs, significant differences were observed between CQ and HCQ for most of the adverse events: cardiomyopathy, cardiac arrhythmias, retinal disorders, corneal disorders, hearing disorders, headache, hepatic disorders, severe cutaneous reactions, musculoskeletal disorders and cytopenia. Only CQ was significantly associated with psychotic disorders, suicide and self-injury, convulsions, peripheral neuropathy and decreased appetite. In multivariable logistic regression, outcome death was more frequently associated with CQ users, generally older females, with co-reported suicide and self-injury, cardiomyopathy, cardiac arrhythmias and decreased appetite. Discussion: Our results suggest that HCQ has a safer clinical profile compared to CQ, especially regarding cardiotoxicity and thus could serve as a safer therapeutic approach in COVID-19. However, until more real-world and RCTs’ data are available, close supervision is strongly recommended.
The FastDesign protocol in the molecular modeling program Rosetta iterates between sequence optimization and structure refinement to stabilize de novo designed protein structures and complexes. FastDesign has been used previously to design novel protein folds and assemblies with important applications in research and medicine. To promote sampling of alternative conformations and sequences, FastDesign includes stages where the energy landscape is smoothened by reducing repulsive forces. Here, we discover that this process disfavors larger amino acids in the protein core because the protein compresses in the early stages of refinement. By testing alternative ramping strategies for the repulsive weight, we arrive at a scheme that produces lower energy designs with more native-like sequence composition in the protein core. We further validate the protocol by designing and experimentally characterizing over 4000 proteins and show that the new protocol produces higher stability proteins.
Background: Recent reports have revealed better clinical outcomes with extracorporeal cardiopulmonary resuscitation (ECPR) than with conventional cardiopulmonary resuscitation (CPR) for patients with refractory cardiac arrest. This study attempted to investigate favorable predictors of pre-, intra-, and post-ECPR for successful weaning off extracorporeal membrane oxygenation (ECMO) support. Methods: We enrolled 30 ECPR patients aged over 18 years old between August 2016 and January 2019. All clinical data were retrospectively collected. The primary endpoint was that the patient was weaned off ECMO support after ECPR. Patients were divided into two groups based on successful weaning off ECMO support (Weaned vs. Failed). Results: Fourteen patients were in the weaned group. These patients were significantly younger and have shorter CPR duration than those in the failed group (p = 0.03, < 0.01). Age, CPR duration, ECMO complications and loss of pulsatility were significantly confirmed as predictive factors for successful weaning off ECMO support through univariate logistic regression analysis. However, loss of pulsatility and CPR duration remained predictors of the favorable outcome of weaning off ECMO support after ECPR by two models of multivariate logistic regression analysis. Conclusion: We conclude that CPR duration and loss of pulsatility are predictive factors of successful weaning off from ECMO support after ECPR. Loss of pulsatility relates to management during post-ECPR, unlike CPR duration. In patients with decreased pulsatility after ECPR, careful management is warranted because the loss of pulsatility is closely associated with weaning off ECMO support after ECPR.
Roots promote the formation of slow-cycling soil carbon (C), yet we have limited understanding of the magnitude and controls on this flux. We hypothesized that root-derived inputs from ectomycorrhizal (ECM)-associated trees would be greater than those from arbuscular mycorrhizal (AM)-associated trees, and that soils receiving the greatest inputs would promote greater root-derived C accumulation in mineral-associated pools. We installed δ13C-enriched ingrowth cores across mycorrhizal gradients in six Eastern U.S. forests (n = 54 plots). Counter to our hypothesis, root-derived C was 54% greater in AM versus ECM-dominated plots, resulting in 175% more root-derived C in mineral-associated, slow-cycling pools in AM compared to ECM plots. Notably, root-derived soil C was comparable in magnitude to leaf litter inputs and aboveground net primary production. Our results suggest that variation in root-derived C inputs due to tree mycorrhizal dominance may be a key control of soil C dynamics in forests.
Spike development of wheat is closely associated with the ability of response to cold stress and inhibited under cold stress in spring. Morphological investigation showed that the ftin gene in 3558M is associated with multiple phenotypic characteristics, including fewer tillers, delayed floral transition, and the death of shoot apical meristem. In this study, we systematically researched the genetic nature of spike development using ITRAQ, transcriptome sequencing, western blot and RNAi technologies. The results showed that the ftin mutant is cold sensitive and activates the cold acclimation pathway. Multiple defence responses, including the ROS-mediated hypersensitive response, SA-mediated systemic acquired resistance and FLS2-induced pathogen-associated defence response, were activated to respond to normal cold stress and led to the apex death. Meanwhile, the continuous cold acclimation pathway inhibited the SVP-SCO1-LFY flowering pathway and leads to inhibition of spike development. Two TaPIN proteins were significantly downregulated, and multiple auxin signalling genes were also differentially expressed after cold stress. We used RNAi technology to knock down the two TaPIN genes and the tiller number was significantly reduced in TaPINa-RNAi and TaPINb-RNAi wheat. Taken together, the results revealed that the ftin gene might directly or indirectly regulate multiple biological pathways to affect multiple phenotypic characteristics.
Coffee flowering requires a period of water deficit followed by rainfall to break flower bud dormancy and promote anthesis. Since drought followed by re-watering can increase shoot ethylene production, we investigated changes in root, leaf and flower bud ethylene production and expression of genes within the ethylene biosynthesis and signalling pathways and their relationship to coffee flowering. Drought decreased foliar and flower bud ethylene production without changing root ethylene production, even though all tissues likely accumulated the ethylene precursor ACC (1-aminocyclopropane-1-carboxylic acid), since ACS gene expression was maintained while ACO gene expression decreased. The ethylene receptor CaETR4-like was not differentially expressed in leaves under water deficit, but it was downregulated in roots. Re-watering restored shoot ethylene production, which seems important in promoting anthesis. 1-MCP, an ethylene action inhibitor, triggered coffee anthesis without re-watering the plants, which hitherto was considered essential to allow flowering. 1-MCP positively regulated ethylene biosynthesis genes (CaACS1-like and CaACO1-like), similar to re-watering, and downregulated CaETR4-like, suggesting that changes in ethylene levels and sensitivity are required to promote coffee anthesis. Thus, drought and re-watering-induced changes in ethylene levels and sensitivity allow coffee flowering, while the growth regulator 1-MCP can potentially regulate anthesis time and intensity.
A research study on morphometrics of Kalophrynus palmatissimus (known as Lowland Grainy Frog) at Ayer Hitam Forest Reserve (AHFR), Selangor and Pasoh Forest Reserve (PFR), Negeri Sembilan was carried out from 12 November 2016 to 13 September 2017. The study was conducted to examine data on the morphometric traits of K. palmatissimus at the two forest reserves. 15 morphometric traits of K. palmatissimus were taken by using vernier calipers. Frog surveys were done by using 15 and 18 nocturnal 400 m transect lines at AHFR and PFR, respectively. In addition, five climatic data were recorded. The results showed that most of the morphometric traits in AHFR (n = 34) and PFR (n = 31) were positively correlated within each other. General Linear Model (GLM) analysis, showed that snout-vent length (SVL) influenced most morphometric traits, except for hand length. Later, it was found that the snout-vent length of K. palmatissimus in AHFR were slightly larger than PFR. From PCA analysis, morphometric traits were grouped into two components for AHFR and PFR, respectively. In AHFR, head length, eye diameter, head width, internarial distance, interorbital distance, forearm length, tibia length, foot length, and thigh length were strongly correlated while snout length and eye-nostril distance were strongly correlated. In PFR, eye diameter, head width, internarial distance, interorbital distance, foot length and thigh length were strongly correlated, while snout length and eye-nostril distance were strongly correlated; hence, suggesting that all morphometric traits grow simultaneously in K. palmatissimus with eye-nostril distance (EN), and snout length (SL) were closely growing simultaneously at AHFR and PFR. To conclude, the data collections showed the 15 different morphometric traits of K. palmatisssimus between AHFR and PFR with K. palmatissimus at AHFR were slightly larger than at PFR. Key words: Kalophrynus palmatissimus, forest reserve, morphometrics, climatic factors, transect lines
We established three simulated erosion severities with topsoil depths of 10, 20 and 30 cm in a Mollisol farmland under a maize-soybean rotation system with no-tillage. After three consecutive years of field experiment, the decrease in topsoil thickness from 30 to 10 cm resulted in 9−22% of decrease in maize yield but not soybean. Compared to the 30 and 20-cm topsoil thickness, the 10-cm topsoil significantly lowered root and shoot biomass of maize at the jointing (V7) and milk stages (R3) and of soybean at the mid-seed filling stage (R6). Compared to the 30-cm topsoil, the 10-cm topsoil decreased available nitrogen and phosphorus in soil by 42% and 36% under maize, and by 25% and 19% under soybean, respectively, while the shallow topsoil also decreased N, P and K uptake per unit root length with the decreases being less for maize than soybean. Compared to the 30-cm topsoil, the 10-cm and 20-cm topsoil significantly increased the activities of urease, phosphatase and invertase in maize-grown soil, but not in soybean-grown soil except for the activity of urease in 10-cm topsoil. Maize was more sensitive to soil erosion than soybean due to the greater decreases in soil nutrient availability and its capability of nutrient uptake. The greater stimulation of nutrient mineralization processes in soil did not alleviate the nutrient constraint to maize yield under severe erosion conditions.
Objective: To investigate whether vitamin A are associated with a lower fracture incidence in infants’ respiratory system diseases. Method: A systematic literature search of articles update to April 2020 was conducted via PubMed, Web of Science, and the Chinese National Knowledge Infrastructure (CNKI), Chinese biomedical literature database (CBM), and the references of the retrieved articles. Fixed- or random-effect models were used to summarize the estimates of OR with 95% CIs for the vitamin A are associated with a lower fracture incidence in infants’ respiratory system diseases. Result: This study includes 18 articles. Compared with control group, the experimental group’s infant babies are less likely to get poor health outcomes. Especially ，suffering from respiratory related disease, such as，neonatal respiratory distress syndrome (NRDS) (OR = 0.79), neonatal pneumonia (OR = 0.51), neonatal ALRI to acute lower respiratory infection (OR = 0.66), neonatal bronchial pulmonary hypoplasia bronchopulmonary dysplasia of premature infants （BPD）(OR = 0.49). All test of the difference had ensured statistical significance (P < 0.05). Conclusion: This meta-analysis indicated that Vitamin A intake was associated with a decreased risk of infants’ respiratory system related diseases. Further researches should be conducted to confirm the findings in our study and better clarify the potential biological mechanisms.
Abstract Introduction Acute kidney injury in pregnancy, while is now a rare entity in the developed countries, it is still a common issue in developing countries representing a major cause of maternal and fetal morbidity and mortality. Scarce data are published regarding PRAKI in Middle-east and African countries. Here, we present our experience in Mansoura University Hospital; an Egyptian tertiary care hospital. Methods This is a prospective observational study that included all patients with pregnancy related Acute Kidney Injury admitted to Mansoura Nephrology and Dialysis Unit over two years. All patients were prospectively followed for three months. All patients were evaluated regarding their maternal, fetal and renal outcomes. Results Preeclampsia and peri-partum hemorrhage constituted the most common causes of PRAKI. Maternal mortality occurred in 22.5% of patients. Regarding patients’ renal outcomes, the major portion of patients (62.5%) fully recovered while the remaining (37.5%) didn’t recover and became dialysis dependent. Fetal unfavorable events occurred in 31 pregnancies (77.5%), where 10 babies (25%) were delivered prematurely and 21 fetuses (52.5%) died intra-uterine. Fetal mortality was 45%, of those 70% occurred in patients with AKI on top of preeclampsia. Conclusion Pregnancy related acute kidney injury represents a continuous burden in low-income countries. A global strategy should be implemented to reduce its incidence and its related adverse consequences on both mother and fetus. The paucity of data in this field reflects the importance of implementing further research studies to deeply understand the precipitating and key pathophysiologic mechanisms involved in this disease.
The effect of a directional electric-field on the bonding of the undoped and sulphur doped diarylethene (DTE) switch molecule is investigated using next generation QTAIM (NG-QTAIM). We introduce chemical bonding concepts in the form of the least and most preferred directions of charge density accumulation relative to the associated bond-path, namely the precessions K and Kʹ that are demonstrated to be much more responsive to the electric-field than the Laplacian ∇2ρ(rb). A concept of bond fatigue is presented in terms of the tendency for a bond-path to rupture that provides directional versions of familiar bonding QTAIM concepts. Examples are included where the applied directional electric-field reduces the tendency towards bond-path rupture and also the converse. A brief discussion is undertaken of applications of the precessions K and Kʹ including switches, ring opening reactions and molecular rotary motors in the presence of fields that cause a redistribution of ρ(r).
Medical male circumcisions have been scaled-up for HIV prevention. Three 16-year-old clients were diagnosed with Haemophilia post-VMMC services. Greater emphasis on advocacy, training and placement of qualified health care workers for peri-operative screening and a high index of suspicion for pre-operative diagnosis and appropriate referral for bleeding disorders is essential.
Rupture of pulmonary artery pseudoaneurysm (PAP) can result in life-threatening hemoptysis. A 65-year-old male was diagnosed with PAP based on chest contrasted computer tomography (CT). He coughed up massive amounts of blood and could not be resuscitated. In the autopsy, macroscopic and microscopic findings supported the clinical course.