Colchicine anti-inflammatory therapy for non-intensive care unit hospitalized COVID-19 patients: results from a pilot open-label, randomized controlled clinical trial.

Systemic inflammation is a hallmark of severe coronavirus disease-19 (COVID-19). Anti-inflammatory therapy is considered crucial to modulate the hyperinflammatory response (cytokine storm) in hospitalized COVID-19 patients. There is currently no specific, conclusively proven, cost-efficient, and worldwide available anti-inflammatory therapy available to treat COVID-19 patients with cytokine storm. The present study aimed to investigate the treatment benefit of oral colchicine for hospitalized COVID-19 patients with suspected cytokine storm. Colchicine is an approved drug and possesses multiple anti-inflammatory mechanisms. This was a pilot, open-label randomized controlled clinical trial comparing standard of care (SOC) plus oral colchicine (colchicine arm) vs. SOC alone (control arm) in non-ICU hospitalized COVID-19 patients with suspected cytokine storm. Colchicine treatment was initiated within first 48 hours of admission delivered at 1.5 mg loading dose, followed by 0.5 mg b.i.d. for next 6 days and 0.5 mg q.d. for the second week. A total of 96 patients were randomly allocated to the colchicine (n=48) and control groups (n=48). Both colchicine and control group patients experienced similar clinical outcomes by day 14 of hospitalization. Treatment outcome by day 14 in colchicine vs control arm: recovered and discharged alive: 36 (75.0%) vs. 37 (77.1%), remain admitted after 14-days: 4 (8.3%) vs. 5 (10.4%), ICU transferred: 4 (8.3%) vs. 3 (6.3%), and mortality: 4 (8.3%) vs. 3 (6.3%). The speed of improvement of COVID-19 acute symptoms including shortness of breath, fever, cough, the need of supplementary oxygen, and oxygen saturation level, was almost identical in the two groups. Length of hospitalization was on average 1.5 day shorter in the colchicine group. There was no evidence for a difference between the two groups in the follow-up serum levels of inflammatory biomarkers including C-reactive protein (CRP), D-dimer, lactate dehydrogenase (LDH), ferritin, interleukin-6 (IL-6), high-sensitivity troponin T (hs-TnT) and N-terminal pro b-type natriuretic peptide (NT pro-BNP). According to the results of our study, oral colchicine does not appear to show clinical benefits in non-ICU hospitalized COVID-19 patients with suspected cytokine storm. It is possible that the anti-inflammatory pathways of colchicine are not crucially involved in the pathogenesis of COVID-19.

Tocilizumab therapy for severely-ill COVID-19 pneumonia patients: a single-centre retrospective study.

Systemic hyperinflammation is a hallmark of severe coronavirus disease-2019 (COVID-19). Tocilizumab (TCZ) (an interleukin-6 receptor blocker) therapy is currently used as an anti-inflammatory intervention alongside corticosteroids to modulate the hyperinflammatory response (cytokine storm) in hospitalized patients with severe COVID-19 to prevent mortality. There is, however, a wide uncertainty about its pros and cons in patients with COVID-19, particularly, its possible immunosuppressive effect is of serious concern for the clinicians. The present study aimed to report response of a cohort of severely-ill hospitalized COVID-19 pneumonia patients who were treated with tocilizumab after the initial corticosteroids therapy failed to improve the patients' clinical condition. This was a single-arm retrospective study of 100 severely-ill COVID-19 pneumonia patients who were admitted to the specialized COVID-19 units of Mayo Hospital, Lahore, Pakistan from March 12, 2020, to May 25, 2021. These COVID-19 patients had progressed to cytokine storm with persistent hypoxia, associated with pneumonia, and markedly elevated serum levels of inflammatory biomarkers including C-reactive protein (CRP), D-dimer, and ferritin. All the patients had received two separate doses of intravenous 400 mg (4 mg/kg) tocilizumab with an 8-hour interval alongside standard COVID-19 care which includes corticosteroid, antibiotics, and anticoagulants. Following tocilizumab intervention, 75 (75.0%) patients showed clinical improvement, continued to recover, and were safely discharged from the hospital, while in 25 (25.0%) patients, TCZ failed to prevent clinical deterioration, and patients eventually died in the hospital. Amongst the 25 (25.0%) deaths, 8 (32.0%) patients had a single comorbidity, while 9 (36.0%) had two or more comorbidities. The median IQR age for survivors was 57.0 (50.0, 60.0) years, and non-survivors was 60.0 (55.0, 70.0) years; and the period of hospitalization was 25 (20, 40) days and 20 (14, 34) days, respectively. Tocilizumab treatment improved serum inflammatory biomarker levels including CRP, D-dimer, and ferritin, by almost a similar magnitude in both survivors and non-survivors. Development of secondary infections were reported in 25 (25.0%) patients, including 21% patients with bacterial (Pseudomonas, Klebsiella, Acinetobacter) and 4% with fungal (Aspergillus) infection. The emergence of secondary infection was higher in patients who died (72.0%) as compared to those who survived (28.0%). In conclusion: in low- and middle-income countries in the presence of limited therapeutic options, a timely intervention of TCZ alongside corticosteroids may be a suitable anti-inflammatory therapy for severely-ill hospitalized COVID-19 pneumonia patients to prevent mortality. However, patients must be closely monitored for secondary bacterial/fungal infections. Early diagnosis and management of secondary infection can reduce morbidity and mortality.

Mathematical Modelling of HIV-HCV Coinfection Dynamics in Absence of Therapy.

Globally, it is estimated that of the 36.7 million people infected with human immunodeficiency virus (HIV), 6.3% are coinfected with hepatitis C virus (HCV). Coinfection with HIV reduces the chance of HCV spontaneous clearance. In this work, we formulated and analysed a deterministic model to study the HIV and HCV coinfection dynamics in absence of therapy. Due to chronic stage of HCV infection being long, asymptomatic, and infectious, our model formulation was based on the splitting of the chronic stage into the following: before onset of cirrhosis and its complications and after onset of cirrhosis. We computed the basic reproduction numbers using the next generation matrix method. We performed numerical simulations to support the analytical results. We carried out sensitivity analysis to determine the relative importance of the different parameters influencing the HIV-HCV coinfection dynamics. The findings reveal that, in the long run, there is a substantial number of individuals coinfected with HIV and latent HCV. Therefore, HIV and latently HCV-infected individuals need to seek early treatment so as to slow down the progression of HIV to AIDS and latent HCV to advanced HCV.

Modeling the Impact of Seasonal Weather Variations on the Infectiology of Brucellosis.

A deterministic mathematical model for brucellosis that incorporates seasonality on direct and indirect transmission parameters for domestic ruminants, wild animals, humans, and the environment was formulated and analyzed in this paper. Both analytical and numerical simulations are presented. From this study, the findings show that variations in seasonal weather have the great impact on the transmission dynamics of brucellosis in humans, livestock, and wild animals. Thus, in order for the disease to be controlled or eliminated, measures should be timely implemented upon the fluctuation in the transmission of the disease.

Distribution and dynamics of Greenland subglacial lakes.

Few subglacial lakes have been identified beneath the Greenland Ice Sheet (GrIS) despite extensive documentation in Antarctica, where periodic release of water can impact ice flow. Here we present an ice-sheet-wide survey of Greenland subglacial lakes, identifying 54 candidates from airborne radio-echo sounding, and 2 lakes from ice-surface elevation changes. These range from 0.2-5.9 km in length, and are mostly distributed away from ice divides, beneath relatively slow-moving ice. Based on our results and previous observations, we suggest three zones of formation: stable lakes in northern and eastern regions above the Equilibrium Line Altitude (ELA) but away from the interior; hydrologically-active lakes near the ELA recharged by surface meltwater and; small, seasonally-active lakes below the ELA, which form over winter and drain during the melt season. These observations provide important constraints on the GrIS's basal thermal regime and help refine our understanding of the subglacial hydrological system.

Modelling Optimal Control of In-Host HIV Dynamics Using Different Control Strategies.

HIV is one of the major causes of deaths, especially in Sub-Saharan Africa. In this paper, an in vivo deterministic model of differential equations is presented and analyzed for HIV dynamics. Optimal control theory is applied to investigate the key roles played by the various HIV treatment strategies. In particular, we establish the optimal strategies for controlling the infection using three treatment regimes as the system control variables. We have applied Pontryagin's Maximum Principle in characterizing the optimality control, which then has been solved numerically by applying the Runge-Kutta forth-order scheme. The numerical results indicate that an optimal controlled treatment strategy would ensure significant reduction in viral load and also in HIV transmission. It is also evident from the results that protease inhibitor plays a key role in virus suppression; this is not to underscore the benefits accrued when all the three drug regimes are used in combination.

Plague disease model with weather seasonality.

The plague disease model that include the effect of seasonal weather variation in its transmission is investigated in this paper. The disease is caused by an extremely virulent bacteria Yersinia pestis named after a French bacteriologist Alexandre Yersin. The analysis shows that, when the periodic reproduction number (RT) is greater than one there exist a globally asymptotically stable disease free equilibrium solution (DFS). Using fundamental existence-uniqueness theorem we were able to prove the existence of positive periodic solutions. The analysis further shows that when RT > 1 then there is at least one positive periodic solution. We additionally establish the conditions for global stability of periodic solutions of the model and finally using numerical simulation we depict the behavioral dynamics of plague disease and justify the theoretical solutions.

Modelling hepatotoxicity and antiretroviral therapeutic effect in HIV/HBV coinfection.

Enzyme alanine aminotransferase (ALT) elevation which reflects hepatocellular injury is a current challenge in people infected with human immunodeficiency virus (HIV) on antiretroviral therapy (ART). One of the factors that enhance the risk of hepatotoxicity is underlying diseases such as hepatitis caused by hepatitis B virus (HBV). HIV/HBV coinfected patients stand a greater risk of hepatotoxicity because all ART are toxic and liver cells (hepatocytes) that are responsible for metabolising the toxic ART, support all stages of HIV and HBV viral production. Mathematical models coupled with numerical simulations are used in this study with the aim of investigating the optimal combination of ART in HIV/HBV coinfection. Emtricitabine, tenofovir and efavirenz is the optimal combination that maximises the therapeutic effect of therapy and minimises the toxic response to medication in HIV/HBV coinfection.

The In Vivo Dynamics of HIV Infection with the Influence of Cytotoxic T Lymphocyte Cells.

The in vivo dynamics of HIV infection, the infection mechanism, the cell types infected, and the role played by the cytotoxic cells are poorly understood. This paper uses mathematical modelling as a tool to investigate and analyze the immune system dynamics in the presence of HIV infection. We formulate a six-dimensional model of nonlinear ordinary differential equations derived from known biological interaction mechanisms between the immune cells and the HIV virions. The existence and uniqueness as well as positivity and boundedness of the solutions to the differential equations are proved. Furthermore, the disease-free reproduction number is derived and the local asymptotic stability of the model investigated. In addition, numerical analysis is carried out to illustrate the importance of having R0 < 1. Lastly, the biological dynamics of HIV in vivo infection are graphically represented. The results indicate that, at acute infection, the cytotoxic T-cells play a paramount role in reducing HIV viral replication. In addition, the results emphasize the importance of developing controls, interventions, and management policies that when implemented would lead to viral suppression during acute infection.

Preliminary Single-Center Canadian Experience of Human Normothermic Ex Vivo Liver Perfusion: Results of a Clinical Trial.

After extensive experimentation, outcomes of a first clinical normothermic machine perfusion (NMP) liver trial in the United Kingdom demonstrated feasibility and clear safety, with improved liver function compared with standard static cold storage (SCS). We present a preliminary single-center North American experience using identical NMP technology. Ten donor liver grafts were procured, four (40%) from donation after circulatory death (DCD), of which nine were transplanted. One liver did not proceed because of a technical failure with portal cannulation and was discarded. Transplanted NMP grafts were matched 1:3 with transplanted SCS livers. Median NMP was 11.5 h (range 3.3-22.5 h) with one DCD liver perfused for 22.5 h. All transplanted livers functioned, and serum transaminases, bilirubin, international normalized ratio, and lactate levels corrected in NMP recipients similarly to controls. Graft survival at 30 days (primary outcome) was not statistically different between groups on an intent-to-treat basis (p = 0.25). Intensive care and hospital stays were significantly more prolonged in the NMP group. This preliminary experience demonstrates feasibility as well as potential technical risks of NMP in a North American setting and highlights a need for larger, randomized studies.

End-stage renal disease and survival in people with diabetes: a national database linkage study.

BACKGROUND: Increasing prevalence of diabetes worldwide is projected to lead to an increase in patients with end-stage renal disease (ESRD) requiring renal replacement therapy (RRT). AIM: To provide contemporary estimates of the prevalence of ESRD and requirement for RRT among people with diabetes in a nationwide study and to report associated survival. METHODS: Data were extracted and linked from three national databases: Scottish Renal Registry, Scottish Care Initiative-Diabetes Collaboration and National Records of Scotland death data. Survival analyses were modelled with Cox regression. RESULTS: Point prevalence of chronic kidney disease (CKD)5 in 2008 was 1.63% of 19 414 people with type 1 diabetes (T1DM) compared with 0.58% of 167 871 people with type 2 diabetes (T2DM) (odds ratio for DM type 0.97, P = 0.77, on adjustment for duration. Although 83% of those with T1DM and CKD5 and 61% of those with T2DM and CKD5 were receiving RRT, there was no difference when adjusted for age, sex and DM duration (odds ratio for DM type 0.83, P = 0.432). Diabetic nephropathy was the primary renal diagnosis in 91% of people with T1DM and 58% of people with T2DM on RRT. Median survival time from initiation of RRT was 3.84 years (95% CI 2.77, 4.62) in T1DM and 2.16 years (95% CI: 1.92, 2.38) in T2DM. CONCLUSION: Considerable numbers of patients with diabetes continue to progress to CKD5 and RRT. Almost half of all RRT cases in T2DM are considered to be due to conditions other than diabetic nephropathy. Median survival time for people with diabetes from initiation of RRT remains poor. These prevalence data are important for future resource planning.

Characterizing plasma albumin concentration changes in TB/HIV patients on anti retroviral and anti -tuberculosis therapy.

PURPOSE: Plasma albumin, a biomarker for hepatic function, is reported to correspondingly decrease in concentration as disease severity increases in chronic infections including HIV and TB. Our objective was to develop a semi-mechanistic disease progression model to quantify plasma albumin concentration changes during TB and HIV therapy and identify the associated covariate factors. METHODS: Plasma albumin concentration data was collected at specified times for 3 months from 262 HIV participants receiving efavirenz based anti retroviral therapy. Of these, 158 were TB co-infected and on Rifampicin based anti -tuberculosis co-treatment. An indirect response model with zero order albumin production and first order elimination was developed in NONMEM version 7.2 to describe our data. Genotype (CYP2B6*6 and 11, CYP3A5, ABCB1c.3435C>T and ABCB1rs), TB disease status, baseline age, body weight, plasma creatinine, alanine transaminase enzyme and CD4(+) count were the potential model covariates tested. RESULTS: The proposed model successfully described plasma albumin concentration changes in the study population. There was a 10.9% and 48.6% increase in albumin production rates in HIV only and TB co-infected participants respectively. Participants co-infected with TB showed a 44.2% lower baseline albumin secretion rate than those without TB while ABCB1c.3435C>T mutation was associated with a 16% higher steady state albumin secretion rate following treatment. CONCLUSION: A semi-mechanistic model describes plasma albumin concentration changes in HIV patients on ART. Further work is required to establish the utility of the model in monitoring disease progression and predicting prognosis in HIV and TB co-infected patients in absence of or during treatment.

Modeling the impact of climate change on the dynamics of Rift Valley Fever.

A deterministic SEIR model of rift valley fever (RVF) with climate change parameters was considered to compute the basic reproduction number ℛ 0 and investigate the impact of temperature and precipitation on ℛ 0. To study the effect of model parameters to ℛ 0, sensitivity and elasticity analysis of ℛ 0 were performed. When temperature and precipitation effects are not considered, ℛ 0 is more sensitive to the expected number of infected Aedes spp. due to one infected livestock and more elastic to the expected number of infected livestock due to one infected Aedes spp. When climatic data are used, ℛ 0 is found to be more sensitive and elastic to the expected number of infected eggs laid by Aedes spp. via transovarial transmission, followed by the expected number of infected livestock due to one infected Aedes spp. and the expected number of infected Aedes spp. due to one infected livestock for both regions Arusha and Dodoma. These results call for attention to parameters regarding incubation period, the adequate contact rate of Aedes spp. and livestock, the infective periods of livestock and Aedes spp., and the vertical transmission in Aedes species.

A case series exploring possible predictors and mechanisms of change in hearing voices groups.

OBJECTIVES: Hearing voices groups (HVGs) are increasingly common in National Health Services and are often preferred to individual therapy by both service users and providers. Whilst a range of approaches exist, mixed results have been found and only cognitive behaviour therapy (CBT) was supported by well-controlled trials. This study aimed to explore possible predictors and mechanisms of change in a seven-session CBT group for voice hearers. DESIGN: An exploratory case series design was used. Method. Fifteen outpatients with a diagnosis of schizophrenia or schizoaffective disorder completed a HVG and carried out weekly measures of distress, negative beliefs about voices, self-esteem, effective coping strategies, and activity levels. Visual inspection and quantitative rules were used to group participants with similar results and cross-correlations and t tests were used to verify key findings. RESULTS: Several pathways emerged across therapy. Despite measurement frequency, changes on different outcomes tended to occur simultaneously, making conclusions about mechanisms difficult. However, changes in beliefs about voice malevolence and omnipotence correlated most frequently with changes in distress. Visual analysis indicated 53% of participants improved on a measured outcome but satisfaction scores were higher, with 93% feeling the group helped them deal with their problems more effectively. Clients especially valued the chance to meet similar others. CONCLUSIONS: The results suggest HVGs are valued by clients, regardless of their background or symptoms. HVGs should emphasize testing negative beliefs about voices and allow space for supportive discussions between clients. Recommendations for future research are discussed, including consideration of benefits not detected by outcome measures.

Mathematical modeling of liver enzyme elevation in HIV mono-infection.

HIV-infected individuals are increasingly becoming susceptible to liver disease and, hence, liver-related mortality is on a rise. The presence of CD4+ in the liver and the presence of C-X-C chemokine receptor type 4 (CXCR4) on human hepatocytes provide a conducive environment for HIV invasion. In this study, a mathematical model is used to analyse the dynamics of HIV in the liver with the aim of investigating the existence of liver enzyme elevation in HIV mono-infected individuals. In the presence of HIV-specific cytotoxic T-lymphocytes, the model depicts a unique endemic equilibrium with a transcritical bifurcation when the basic reproductive number is unity. Results of the study show that the level of liver enzyme alanine aminotransferase (ALT) increases with increase in the rate of hepatocytes production. Numerical simulations reveal significant elevation of alanine aminotransferase with increase in viral load. The findings presuppose that while liver damage in HIV infection has mostly been associated with HIV/HBV coinfection and use of antiretroviral therapy (ART), it is possible to have liver damage solely with HIV infection.

Hospitalised hip fracture risk with rosiglitazone and pioglitazone use compared with other glucose-lowering drugs.

AIMS/HYPOTHESIS: Current drug labels for thiazolidinediones (TZDs) warn of increased fractures, predominantly for distal fractures in women. We examined whether exposure to TZDs affects hip fracture in women and men and compared the risk to that found with other drugs used in diabetes. METHODS: Using a nationwide database of prescriptions, hospital admissions and deaths in those with type 2 diabetes in Scotland we calculated TZD exposure among 206,672 individuals. Discrete-time failure analysis was used to model the effect of cumulative drug exposure on hip fracture during 1999-2008. RESULTS: There were 176 hip fractures among 37,479 exposed individuals. Hip fracture risk increased with cumulative exposure to TZD: OR per year of exposure 1.18 (95% CI 1.09, 1.28; p = 3 × 10(-5)), adjusted for age, sex and calendar month. Hip fracture increased with cumulative exposure in both men (OR 1.20; 95% CI 1.03, 1.41) and women (OR 1.18; 95% CI 1.07, 1.29) and risks were similar for pioglitazone (OR 1.18) and rosiglitazone (OR 1.16). The association was similar when adjusted for exposure to other drugs for diabetes and for other potential confounders. There was no association of hip fracture with cumulative exposure to sulfonylureas, metformin or insulin in this analysis. The 90-day mortality associated with hip fractures was similar in ever-users of TZD (15%) and in never-users (13%). CONCLUSIONS/INTERPRETATION: Hip fracture is a severe adverse effect with TZDs, affecting both sexes; labels should be changed to warn of this. The excess mortality is at least as much as expected from the reported association of pioglitazone with bladder cancer.

The dynamics, causes and possible prevention of Hepatitis E outbreaks.

Rapidly spreading infectious diseases are a serious risk to public health. The dynamics and the factors causing outbreaks of these diseases can be better understood using mathematical models, which are fit to data. Here we investigate the dynamics of a Hepatitis E outbreak in the Kitgum region of northern Uganda during 2007 to 2009. First, we use the data to determine that R0 is approximately 2.25 for the outbreak. Secondly, we use a model to estimate that the critical level of latrine and bore hole coverages needed to eradicate the epidemic is at least 16% and 17% respectively. Lastly, we further investigate the relationship between the co-infection factor for malaria and Hepatitis E on the value of R0 for Hepatitis E. Taken together, these results provide us with a better understanding of the dynamics and possible causes of Hepatitis E outbreaks.

A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts.

AIMS/HYPOTHESIS: In this study we aimed to replicate the previously reported association between the glycaemic response to metformin and the SNP rs11212617 at a locus that includes the ataxia telangiectasia mutated (ATM) gene in multiple additional populations. METHODS: Incident users of metformin selected from the Diabetes Care System West-Friesland (DCS, n = 929) and the Rotterdam Study (n = 182) from the Netherlands, and the CARDS Trial (n = 254) from the UK were genotyped for rs11212617 and tested for an association with both HbA(1c) reduction and treatment success, defined as the ability to reach the treatment target of an HbA(1c) ≤ 7 % (53 mmol/mol). Finally, a meta-analysis including data from literature was performed. RESULTS: In the DCS cohort, we observed an association between rs11212617 genotype and treatment success on metformin (OR 1.27, 95% CI 1.03, 1.58, p = 0.028); in the smaller Rotterdam Study cohort, a numerically similar but non-significant trend was observed (OR 1.45, 95% CI 0.87, 2.39, p = 0.15); while in the CARDS cohort there was no significant association. In meta-analyses of these three cohorts separately or combined with the previously published cohorts, rs11212617 genotype is associated with metformin treatment success (OR 1.24, 95% CI 1.04, 1.49, p = 0.016 and OR 1.25, 95% CI 1.33, 1.38, p = 7.8 × 10(-6), respectively). CONCLUSIONS/INTERPRETATION: A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetic patients from the Netherlands and the UK. This is the first robustly replicated common susceptibility locus found to be associated with metformin treatment response.