Managing Hepatotoxicity Caused by Anti-tuberculosis Drugs: A Comparative Study of Approaches.

BACKGROUND: Tuberculosis (TB) is one of the oldest and most well-known diseases that has been associated with humans for many years and remains a global health challenge today. Timely diagnosis and proper treatment are crucial for controlling and preventing the spread of the disease. While anti-TB drugs offer many benefits, inadequate monitoring can lead to a range of side effects, including hepatotoxicity, which is a major concern and can cause treatment discontinuation. The aim of this study was to determine the approach to the hepatotoxicity of anti-TB drugs and to investigate potential relationships between demographic factors, underlying medical conditions, and successful retreatment outcomes for hepatotoxicity induced by anti-TB drugs. METHODS: For this study, we reviewed the medical records of patients who experienced hepatotoxicity due to anti-TB treatment and were admitted to the infectious ward of Imam Khomeini Hospital between April 2015 and February 2019. The data were collected using a questionnaire. RESULTS: The findings indicated that the female gender, weight loss at the beginning of hospitalization, hepatitis C virus, hepatitis B virus (HBV), heart disease, and high levels of aspartate aminotransferase (AST) and alanine transaminase (ALT) at the beginning of hepatotoxicity are risk factors for failure to the retreatment of hepatotoxicity. There were two different approaches to the anti-TB retreatment regimen. The first approach involved gradually starting the drugs in full dose, while the second approach encompassed starting the drugs in the minimum dose and then increasing to the maximum dose. The results demonstrated no significant difference between the two approaches to managing hepatotoxicity induced by anti-TB drugs. CONCLUSION: Drug-induced hepatotoxicity is a common occurrence that often results in treatment discontinuation. Understanding the prevalence of this complication and identifying appropriate methods of rechallenge treatment is crucial to reducing complications and mortality rates.

Evolving global responses to the pandemic: sustaining interprofessional education and collaborative practice.

The COVID-19 pandemic created global disruption in health professions education and healthcare practice, necessitating an abrupt move to digital delivery. A longitudinal survey was conducted to track the evolution of global responses to the pandemic. During the initial stages, educational and health institutions were forced to adapt quickly without careful consideration of optimal pedagogy, practices, and effectiveness of implemented approaches. In this paper, we report the results of Phase 3 of the global survey that was distributed between November 2021 and February 2022 through InterprofessionalResearch.Global (IPR.Global). The Phase 3 qualitative survey received 27 responses, representing 25 institutions from 13 countries in 6 regions. Using inductive thematic analysis, the data analysis resulted in three emerging themes: Impact of the pandemic on the delivery of interprofessional education and collaborative practice (IPECP); Impact of the pandemic on the healthcare system (team, population/client health, clients); and Sustainability and innovation. This study highlights the evolving nature of health education and collaborative practices in response to the COVID-19 pandemic. IPECP educators need to be resilient and deal with the complexities of face-to-face and digital learning delivery. Preparing for emerging forms of teamwork is essential for new work contexts and optimal health services.

The status of interprofessional education (IPE) at regional and global levels - update from 2022 global IPE situational analysis.

This short report is based on the 2022 Global IPE Situational Analysis Results e-Book that is available at https://interprofessionalresearch.global/. As an up-to-date global environmental scan of interprofessional education (IPE), this cross-sectional study investigated institutional, administrative, and system-level processes that support IPE program development and implementation globally. Conducted by InterprofessionalResearch.Global (IPR.Global), the survey included 17 quantitative questions that were analyzed at global and regional levels. Three open-text questions were thematically analyzed. In total, 152 institutions from six regions worldwide contributed to this study. Results revealed that only 51.97% of all responding institutions have an established IPE program, with Canada and the USA having the highest (84%) and Africa (26%) having the lowest numbers. Globally, 37.33% of respondents reported no formal leadership positions and 41.33% reported the absence of a designated IPE Director or Coordinator. In addition, IPE funding varies considerably across the world, with 32.65% of institutions reporting no financial support. Over 48.22% of respondents indicated their institutions are rarely or not involved in IPE-related scholarly work or research. The open-text analysis revealed that supportive senior leadership, a culture of collaboration, and recognition of IPE as a strategic direction and/or priority at the institutional level, could foster the successful implementation of IPE. On the other hand, inadequate administrative support, lack of funding, poor attitudes regarding IPE, and limited dedicated time for research, seemed to impair successful implementation of scholarly activities in the field.

Machine learning-based models to predict the need for neurosurgical intervention after moderate traumatic brain injury.

Background and Aims: Traumatic brain injury (TBI) is a widespread global health issue with significant economic consequences. However, no existing model exists to predict the need for neurosurgical intervention in moderate TBI patients with positive initial computed tomography scans. This study determines the efficacy of machine learning (ML)-based models in predicting the need for neurosurgical intervention. Methods: This is a retrospective study of patients admitted to the neuro-intensive care unit of Emtiaz Hospital, Shiraz, Iran, between January 2018 and December 2020. The most clinically important variables from patients that met our inclusion and exclusion criteria were collected and used as predictors. We developed models using multilayer perceptron, random forest, support vector machines (SVM), and logistic regression. To evaluate the models, their F1-score, sensitivity, specificity, and accuracy were assessed using a fourfold cross-validation method. Results: Based on predictive models, SVM showed the highest performance in predicting the need for neurosurgical intervention, with an F1-score of 0.83, an area under curve of 0.93, sensitivity of 0.82, specificity of 0.84, a positive predictive value of 0.83, and a negative predictive value of 0.83. Conclusion: The use of ML-based models as decision-making tools can be effective in predicting with high accuracy whether neurosurgery will be necessary after moderate TBIs. These models may ultimately be used as decision-support tools to evaluate early intervention in TBI patients.

Brucella myocarditis with unusual clinical features & abnormal cardiac MRI: A case report.

Brucellosis is a zoonotic disease that remains an important public health problem in developing countries. It can affect almost all organs, including the heart. While cardiac complications of brucellosis are not common, they usually manifest as endocarditis. Brucella myocarditis, on the other hand, is a highly rare complication of brucellosis. In this case report, we present the case of a 35-year-old woman who was admitted to the hospital with severe palpitations, fever, and fatigue. Due to the patient's long history of brucellosis and clinical symptoms, she underwent cardiac evaluation, including cardiac magnetic resonance imaging, which was a promising method to diagnose Brucella myocarditis. Hopefully our patient responded well to Rifampin and Doxycycline with gentamicin. It is important to raise awareness of this rare but potentially serious complication of brucellosis and to emphasize the value of early diagnosis and treatment.

Tenofovir alafenamide plus dolutegravir as a switch strategy in HIV-infected patients: a pilot randomized controlled trial.

BACKGROUND: Currently, two-drug antiretroviral regimens are emerging fields in life-long treatment in people living with HIV. OBJECTIVES: This randomized non-inferiority open-label controlled trial was designed to compare the 48-week efficacy and safety of tenofovir alafenamide plus dolutegravir versus the standard triple therapy in virologically suppressed people living with HIV. To the best of our knowledge this combination has not been studied before. METHODS: This open-label randomized controlled trial was conducted in treatment-experienced people with HIV who had HIV-RNA < 47 copies/mL for at least two years. Patients received either tenofovir alafenamide plus dolutegravir combination (26 patients) or a standard three-drug regimen (29 patients). The primary outcome was the proportion of patients maintaining HIV-RNA < 47 copies/mL during 48 weeks, and the secondary outcomes were CD4 cell count changes, the adherence rate, and adverse drug reactions, all over 48 weeks of study. RESULTS: HIV viral load remained undetectable (HIV-RNA < 47 copies/mL) during the 48 weeks of the study in both arms. The absolute CD4 cell count change was not significant between the two groups. The overall proportion of adverse effects in each group was comparable. The rate of adherence to treatment was acceptable in both groups, and no significant difference was observed. CONCLUSIONS: Treatment simplification with tenofovir alafenamide plus dolutegravir regimen as maintenance therapy was non-inferior in terms of efficacy and safety compared to the standard triple therapy. Comparing efficacy of antiretroviral therapy.

The perceived impact of the COVID-19 pandemic on interprofessional education and collaborative practice: preliminary results from phase I of a global survey.

The COVID-19 pandemic has had a sizable effect on interprofessional education and collaborative practice (IPECP) globally, yet much of the available literature on the topic remains anecdotal and locally bounded. This body of literature reflects celebratory and aspirational reports, with many case studies of successful response and perseverance under conditions of extreme pressure. There is, however, a more worrisome narrative emerging that pointed to differences in pandemic response with concerns raised about the sustainability of IPECP during and after the pandemic. The COVID-19 task force of InterprofessionalResearch.Global (IPRGlobal) set out to capture the successes and challenges of the interprofessional community over the pandemic through a longitudinal survey, with a view to inform global attempts at recovery and resilience. In this article, we report preliminary findings from Phase 1 of the survey. Phase 1 of the survey was sent to institutions/organizations in IPRGlobal (representing over 50 countries from Europe, North and South America, Australia, and Africa). The country-level response rate was over 50%. Key opportunities and challenges include the abrupt digitalization of collaborative learning and practice; de-prioritization of interprofessional education (IPE); and rise in interprofessional collaborative spirit. Implications for IPECP pedagogy, research, and policy post-pandemic are considered.

Safety of megadose meropenem in the empirical treatment of nosocomial sepsis: a pilot randomized clinical trial.

Objective: To evaluate the safety of megadose meropenem as empirical treatment of nosocomial sepsis. Materials & methods: Critically ill patients diagnosed with sepsis received either high-dose (2 g every 8 h) or megadose (4 g every 8 h) meropenem as an intravenous infusion over 3 h. Results: A total of 23 patients with nosocomial sepsis were eligible and included in the megadose (n = 11) or high-dose (n = 12) group. No treatment-related adverse events were observed during a 14-day follow-up. Clinical response was also comparable between the groups. Conclusion: Megadose meropenem may be considered for empirical treatment of nosocomial sepsis without serious concern regarding its safety.

As resistance to antibiotics is increasing among microbes, rational use of these drugs is important both in the community and in hospitals. Many infections with resistant microorganisms may be fatal. For a long time, carbapenems have been the last resort for treatment of resistant microorganisms. Unfortunately, resistance to these drugs is increasing. It appears that use of higher doses of antibiotics may help in some cases. However, the potential harm caused by higher doses is a problem. In this primary study, higher doses of meropenem, a common carbapenem, were found to be safe.

Treatment options for infections caused by multidrug-resistant Gram-negative bacteria: a guide to good clinical practice.

The rapid emergence of multidrug-resistant Gram-negative bacterial infections necessitates the development of new treatments or the repurposing of available antibiotics. Here, treatment options for treatment of these infections, recent guidelines and evidence are reviewed. Studies that included treatment options for infections caused by multidrug-resistant Gram-negative bacteria (Enterobacterales and nonfermenters), as well as extended-spectrum ß-lactamase-producing and carbapenem-resistant bacteria, were considered. Potential agents for the treatment of these infections, considering type of microorganism, mechanism of resistant, source and severity of infection as well as pharmacotherapy considerations, are summarized.

Gram-negative bacteria (GNB) are one of the most important causes of infection in humans. GNB can evolve to neutralize the effects of antibiotics by producing proteins called enzymes that break down the antibiotics or through mechanisms that discharge antibiotics from bacteria. The antibiotic can therefore no longer kill the bacteria, so they are considered antibiotic-resistant. For the treatment of resistant GNB infections, smart consideration and selection of potential combinations of available antibiotics or the development of new drugs are needed. In this review, we summarized and collected the recent guidelines and literature reports and present the pharmacological considerations for treatment of resistant GNB infections.

Adherence to recommendations for the evaluation and management of fungal infections in a referral teaching hospital in Iran: A retrospective cross-sectional study.

INTRODUCTION: Early diagnosis and appropriate management of fungal infections are critical for reducing complications and mortality in hospitalized patients. Due to the lack of appropriate local management protocols as well as the unavailability and cost of advanced tests for diagnosis of fungal infections, the irrational use of antifungals is a concern in developing countries. OBJECTIVES: This study was designed to evaluate diagnosis and management of fungal infections in hospitalized patients. METHODS: In a retrospective cross-sectional study, the use of parenteral antifungal medications among hospitalized patients was evaluated according to the prepared protocols adapted from the international guidelines. RESULTS: Among 151 patients, diagnostic approaches were appropriate and inappropriate in 90 and 61 patients respectively. Indications for antifungal drug administration were empiric therapy (80.1%) followed by targeted therapy (19.2%) and prophylaxis (0.7%). The indications were appropriate and inappropriate in 123 and 28 patients respectively. Selection of antifungals was appropriate in 117 patients, inappropriate in 16 patients, and was not assessable in other cases. The doses of antifungal medications were appropriate and inappropriate in 111 and 14 patients respectively. Among 151 patients, the duration of treatment was appropriate just in 33 cases. The techniques for antifungal administration were appropriate in 133 patients and inappropriate in 18 cases. CONCLUSIONS: Due to limited access to diagnostic tests, most parenteral antifungal medications were administered as empiric therapy. The diagnostic workups, treatment monitoring, and follow-up were inadequate in most patients. Development of local diagnostic and management protocols for invasive fungal infections and considering a stewardship program for antifungal medications are essential for each medical center.

Comparing efficacy and safety of high-dose and standard-dose rifampicin in the treatment of brucellosis: a randomized clinical trial.

BACKGROUND: In a few studies, higher doses of rifampicin improved the outcome of patients with TB. There is no information regarding efficacy and safety of higher doses of rifampicin in patients with brucellosis. OBJECTIVES: To compare efficacy and safety of higher and standard doses of rifampicin, each with doxycycline, in the treatment of patients with brucellosis. METHODS: Within a randomized clinical trial, clinical response and adverse events of high-dose rifampicin (900-1200 mg/day) plus doxycycline 100 mg twice daily were compared with standard-dose rifampicin (600 mg/day) plus doxycycline 100 mg twice daily in 120 patients with brucellosis. RESULTS: Clinical response occurred in 57 (95%) of patients in the high-dose group and 49 (81.66%) of patients in the standard-dose group (P = 0.04). The most common adverse events of the treatment were nausea (37.5%), skin rash (13.33%), vomiting (10%) and transaminitis (7.22%). Incidence of these events was comparable between the groups. CONCLUSIONS: The rate of clinical response in patients with brucellosis who were treated with high-dose rifampicin plus standard-dose doxycycline was significantly higher than in the patients who received the standard doses of rifampicin and doxycycline, without further adverse events. The high-dose rifampicin therefore improved clinical response in patients with brucellosis with a similar safety profile to the standard dose. If these findings are confirmed in future studies, higher doses of rifampicin may be recommended for treatment of patients with brucellosis.

Atorvastatin versus Placebo in ICU Patients with COVID-19: Ninety-day Results of the INSPIRATION-S Trial.

BACKGROUND: In the INSPIRATION-S trial, atorvastatin versus placebo was associated with a nonsignificant 16% reduction in 30-day composite of venous/arterial thrombosis or death in intensive care unit (ICU) patients with COVID-19. Thrombo-inflammatory response in coronavirus disease 2019 (COVID-19) may last beyond the first 30 days. METHODS: This article reports the effects of atorvastatin 20 mg daily versus placebo on 90-day clinical and functional outcomes from INSPIRATION-S, a double-blind multicenter randomized trial of adult ICU patients with COVID-19. The main outcome for this prespecified study was a composite of adjudicated venous/arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause mortality. Functional status was assessed with the Post-COVID-19 Functional Scale. RESULTS: In the primary analysis, 587 patients were included (age: 57 [Q1-Q3: 45-68] years; 44% women). By 90-day follow-up, the main outcome occurred in 96 (33.1%) patients assigned to atorvastatin and 113 (38.0%) assigned to placebo (hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.60-1.05, p = 0.11). Atorvastatin in patients who presented within 7 days of symptom onset was associated with reduced 90-day hazard for the main outcome (HR: 0.60, 95% CI: 0.42-0.86, p interaction = 0.02). Atorvastatin use was associated with improved 90-day functional status, although the upper bound CI crossed 1.0 (ORordinal: 0.64, 95% CI: 0.41-1.01, p = 0.05). CONCLUSION: Atorvastatin 20 mg compared with placebo did not significantly reduce the 90-day composite of death, treatment with ECMO, or venous/arterial thrombosis. However, the point estimates do not exclude a potential clinically meaningful treatment effect, especially among patients who presented within 7 days of symptom onset (NCT04486508).

Linezolid pharmacokinetics: a systematic review for the best clinical practice.

OBJECTIVES: To summarize the pharmacokinetics of linezolid to optimize the dosing regimen in special populations. METHODS: A literature search was performed in three largest medical databases, including Embase, Scopus, and PubMed. The main applied keywords were linezolid and pharmacokinetics. Of 3663 retrieved publications in the English language, 35 original research articles, clinical studies, and case reports about linezolid pharmacokinetics in different populations such as pregnant women, pediatrics, elderly subjects, obese people, individuals with organ dysfunction, and critically ill patients were included. RESULTS AND CONCLUSION: Dose adjustment is not currently recommended for linezolid in patients with mild to moderate renal or hepatic impairment, older adults, and pregnant women. Although dose adjustment is not recommended in patients with severe renal or hepatic impairment, it should be considered that these patients are more vulnerable to linezolid adverse effects and drug interactions. In pediatrics, reducing the linezolid dosing interval to 8 h is suggested. Despite the lack of sufficient information in obese individuals, dosing based on body weight or use of higher dose seems to be justifiable to prevent sub-therapeutic concentrations. Although dose adjustment of linezolid is not recommended in critically ill patients, administration of linezolid as continuous intravenous infusion is suggested in this population. Blood level monitoring should be considered in populations that are vulnerable to linezolid underexposure (such as critically ill patients with augmented renal clearance, pediatrics, overweight, and obese patients) or overexposure (such as elderly, patients with hepatic and renal impairment). To assess the efficacy and safety of linezolid, the area under the concentration-time curve over 24 h to minimum inhibitory concentration (AUC0-24 h/MIC) equal to 80-120, percentage of time above the MIC ≥ 85%, and serum trough concentration between 2 and 7 mg/L are suggested.

A hybrid model for robust design of sustainable closed-loop supply chain in lead-acid battery industry.

Considering supply chain efficiency during the network design process significantly affect chain performance improvement. In this paper, the design process of a sustainable lead-acid battery supply chain network was addressed. Because the design of such networks always involves great computational complexity, in the present study, a two-stage model was proposed to overcome this issue. In the first stage, candidate sites of recycling centers were identified using data envelopment analysis (DEA) and based on their efficiency scores. Unlike the previous studies, not only economic criteria but also technical and geographical criteria were employed to select these locations. In the second stage, a bi-objective programming model was developed to simultaneously determine the tactical and strategic decisions of the chain. Since some data was subject to uncertainty, a robust possibilistic approach was presented. The model ensures that the resulting structure for the chain will be robust to noise and disturbance in parameters. A life cycle assessment model based on the ReCiPe 2008 method was developed in SimaPro software. To evaluate the applicability of the presented method, a case study in the automotive industry was used. The results of implementing the DEA method showed that from among 23 available locations, 11 potential places were selected for construct recycling centers. The final results showed that the inappropriate potential locations of recycling centers were eliminated, and the complexity of the mathematical model proposed in the second stage was reduced. The obtained results of environmental protection costs revealed that this criterion changed from 0 to 8,333,874,332. Moreover, the first objective function resulted in a centralized network to minimize costs, and in contrast, the second objective function tended to decentralize the network to minimize environmental impacts.

A Multiobjective Optimization Model for a Dynamic and Sustainable Cellular Manufacturing System under Uncertainty.

For many years, cellular manufacturing has been implemented by owners of manufacturing units. Furthermore, the increasing importance of sustainable development has led manufacturers and managers to consider the concepts of sustainable manufacturing. Sustainable manufacturing includes three components: economic, environmental, and social responsibility. Many research and studies have been conducted in the field of cellular manufacturing, and also in most studies, only the economic component or at most two components of sustainable manufacturing have been taken into account. With increasing concerns about global warming, environmental issues have become particularly important in the production of products and goods. On the other hand, customer satisfaction as one of the aspects of social responsibility is of significant importance. In this research, we put the sustainable manufacturing system in the dynamic cellular manufacturing system under uncertainty (fuzzy parameters). A multiobjective sustainable mathematical model with objective functions of minimizing costs minimizing CO2 emissions and minimizing product shortages (customer satisfaction) was proposed. In order to confirm the validity and accuracy of the proposed model, a small example was solved in GAMS software with CPLEX solver and epsilon constraint method, and its basic variables were investigated. Then, due to the high complexity of the proposed cellular manufacturing model, two meta-heuristic algorithms NSGA-II and MOGWO were used to solve larger problems in MATLAB software. To compare the performance of the two proposed algorithms, ten problems with different dimensions were designed and then the two algorithms were compared with each other based on several performance evaluation indicators. Also, in order to investigate the significance of the difference between the two algorithms based on each index, a statistical analysis was carried out by Minitab software. Taguchi method was also used to adjust the parameters of both algorithms. Based on the analytic results and statistical analysis, the MOGWO algorithm performed better than NSGA-II algorithm and the exact solution method, GAMS software.

Antibiotic use during the first 6 months of COVID-19 pandemic in Iran: A large-scale multi-centre study.

WHAT IS KNOWN AND OBJECTIVE: Although antibiotics are ineffective against viral infections, epidemiological studies have revealed that the COVID-19 pandemic resulted in the overuse of antibiotics and disruption of antimicrobial stewardship programmes. We investigated the pattern of antibiotic use during the first 6 months of the COVID-19 pandemic in Iran. METHODS: A multi-centre retrospective study was designed to investigate the use of 16 broad-spectrum antibiotics in 12 medical centres. The rate of antibiotic use was calculated and reported based on the Defined Daily Dose (DDD) per 100 hospital bed-days. The bacterial co-infection rate was also reported. RESULTS AND DISCUSSION: Totally, 43,791 hospitalized COVID-19 patients were recruited in this study. It was found that 121.6 DDD of antibiotics were used per 100 hospital bed-days, which estimated that each patient received approximately 1.21 DDDs of antibiotics every day. However, the bacterial co-infections were detected only in 14.4% of the cases. A direct correlation was observed between the rate of antibiotic use and mortality (r[142] = 0.237, p = 0.004). The rate of antibiotic consumption was not significantly different between the ICU and non-ICU settings (p = 0.15). WHAT IS NEW AND CONCLUSION: In this study, widespread antibiotic use was detected in the absence of the confirmed bacterial coinfection in COVID-19 patients. This over-consumption of broad-spectrum antibiotics may be associated with increased mortality in hospitalized COVID-19 patients, which can be an alarming finding.

Direct oral anticoagulants toxicity in children: an overview and practical guide.

INTRODUCTION: By increasing use of direct oral anticoagulants (DOACs) in adults and children, gradual increase in the number of intentional or unintentional DOAC poisonings among children is suspected in the near future. Hence, clinicians and pharmacists need to be familiar with the clinical features and management of DOAC-toxicity among pediatric population. AREAS COVERED: This article provides an overview and practical guide to DOAC-toxicity in pediatrics according to the available clinical evidence. EXPERT OPINION: Based on limited available data, accidental pediatric ingestion of DOACs can be managed by supportive care in most cases. However, serious toxicity may occur following massive overdose, in presence of underlying disorders (renal or hepatic dysfunction) and concurrent anticoagulant therapy. Activated charcoal is recommended for known recent ingestion of DOACs (within 2-4 hours) to reduce the gastrointestinal absorption. Supportive interventions including local hemostatic measures and volume resuscitation are the cornerstone of management of bleeding. Vitamin K and fresh frozen plasma are ineffective for DOAC reversal and thus are not recommended. Currently, safety and efficacy data regarding the use of specific reversal agents (including idarucizumab and andexanet alfa) and 3-factor or 4-factor prothrombin complex concentrate (PCC) or activated PCC (aPCC) among children with DOAC-associated bleeding are lacking.

Bleeding Complication in a Patient with Concomitant Use of Rivaroxaban and Saffron Supplement: a Case Report.

BACKGROUND: Direct oral anticoagulants (DOACs) carry a lower potential risk of food/herb and drug interactions compared with oral vitamin K antagonists. However, as a new class of medications, drug interactions of DOACs have not been fully known. CASE PRESENTATION: We herein present the case of a 64-year old male with the complaint of acute onset epistaxis and bleeding gums following the concomitant use of rivaroxaban and saffron supplement. It seems that coadministration of DOACs and saffron supplements should be avoided due to the potential drug-herbal interactions and possible risk of subsequent bleeding complications. CONCLUSION: However, further larger scale surveillance studies are needed to confirm the findings and assess the clinical significance.

Designing an optimization model for green closed-loop supply chain network of heavy tire by considering economic pricing under uncertainty.

The conditions of global competition and environmental sensitivities have made organizations and factories to collect returned products, in such a way that these organizations have tried to rehabilitate, recycle, or destroy these products in order to protect the environment. This paper propose a mathematical model for the green closed-loop supply chain network of heavy tire by considering the economic pricing of its products under conditions of uncertainty, which economically determines the price and leads to more profitability. In addition, the relevant model is a two-objective fuzzy model, the first objective of which is to minimize costs and maximize profits, and the second objective is to minimize environmental issues. The proposed model can also determine the optimal location of each center based on potential locations, the optimal amount of production, distribution, collection, recycling, as well as the reproduction of products. The ε-constraint method is used to solve the model with two objective functions; this method ensures strong Pareto optimal answers and prevents weak Pareto answers. Independent two-sample t-test is used to verify the results of certain and uncertain models in the studied model. In order to evaluate the effectiveness and profitability of the proposed method, a case study in the field of heavy tires is finally used, through which very useful results are obtained.

Comparing efficacy and safety of tocilizumab and methylprednisolone in the treatment of patients with severe COVID-19.

OBJECTIVES: This study was designed to compare the efficacy and safety of methylprednisolone and tocilizumab in the treatment of patients with severe COVID-19. METHODS: During a prospective cohort study, hospitalized patients with severe COVID-19 received intravenous methylprednisolone (250-500 mg daily up to three doses), weight-based tocilizumab (maximum 800 mg, one or two doses as daily interval) or dexamethasone (8 mg daily). The primary outcome was time to onset of clinical response. Secondary outcomes were improvement rate of oxygen saturation and CRP, need for ICU admission, duration of hospitalization and 28-day mortality. During study, adverse events of the treatments were recorded. RESULTS: Although the difference was not statistically significant (p = 0.090), clinical response occurred faster in the tocilizumab group than other groups (10 vs. 16 days). Clinical response was detected in 74.19%, 81.25%, and 60% of patients in the methylprednisolone, tocilizumab, and dexamethasone groups respectively (p = 0.238). Based on the Cox regression analysis and considering dexamethasone as the reference group, HR (95% CI) of clinical response was 1.08 (0.65-1.79) and 1.46 (0.89-2.39) in the methylprednisolone and tocilizumab groups respectively. Improvement rate of oxygen saturation and CRP was not significantly different between the groups (p = 0.791 and p = 0.372 respectively). Also need for ICU admission and 28-day mortality was comparable between the groups (p = 0.176 and p = 0.143 respectively). Compared with methylprednisolone, tocilizumab caused more sleep disturbances (p = 0.019). Other adverse events were comparable among patients in the groups. CONCLUSION: When or where access to tocilizumab is a problem, methylprednisolone may be considered as an alternative for the treatment of patients with severe COVID-19.