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Electrolyte imbalances as poor prognostic markers in COVID-19: a systemic review and meta-analysis.
Song, HJJMD, Chia, AZQ, Tan, BKJ, Teo, CB, Lim, V, Chua, HR, Samuel, M, Kee, A
Journal of endocrinological investigation. 2023;46(2):235-259
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Plain language summary
Salt imbalances in individuals with Covid-19 are highly prevalent, however it is not fully understood if they determine whether a patient has a good or bad prognosis. This systematic review and meta-analysis of 28 observational studies aimed to determine the associations and prognostic value of different salt imbalances in individuals with Covid-19. The results showed that out of several salt imbalances analysed, high and low sodium levels and low calcium levels could predict poor outcomes in those with Covid-19. High sodium levels were particularly indicative, but this was not due to the relationship between high sodium and inflammation in the body and causal reasons remained undiscovered. It was concluded that sodium imbalances and low calcium levels were associated with poor clinical outcomes in individuals with Covid-19. This study could be used by healthcare professionals to understand that correcting these imbalances may be of benefit to individuals with Covid-19.
Abstract
PURPOSE Serum electrolyte imbalances are highly prevalent in COVID-19 patients. However, their associations with COVID-19 outcomes are inconsistent, and of unknown prognostic value. We aim to systematically clarify the associations and prognostic accuracy of electrolyte imbalances (sodium, calcium, potassium, magnesium, chloride and phosphate) in predicting poor COVID-19 clinical outcome. METHODS PubMed, Embase and Cochrane Library were searched. Odds of poor clinical outcome (a composite of mortality, intensive-care unit (ICU) admission, need for respiratory support and acute respiratory distress syndrome) were pooled using mixed-effects models. The associated prognostic sensitivity, positive and negative likelihood ratios (LR + , LR-) and predictive values (PPV, NPV; assuming 25% pre-test probability), and area under the curve (AUC) were computed. RESULTS We included 28 observational studies from 953 records with low to moderate risk-of-bias. Hyponatremia (OR = 2.08, 95% CI = 1.48-2.94, I2 = 93%, N = 8), hypernatremia (OR = 4.32, 95% CI = 3.17-5.88, I2 = 45%, N = 7) and hypocalcemia (OR = 3.31, 95% CI = 2.24-4.88, I2 = 25%, N = 6) were associated with poor COVID-19 outcome. These associations remained significant on adjustment for covariates such as demographics and comorbidities. Hypernatremia was 97% specific in predicting poor outcome (LR + 4.0, PPV = 55%, AUC = 0.80) despite no differences in CRP and IL-6 levels between hypernatremic and normonatremic patients. Hypocalcemia was 76% sensitive in predicting poor outcome (LR- 0.44, NPV = 87%, AUC = 0.71). Overall quality of evidence ranged from very low to moderate. CONCLUSION Hyponatremia, hypernatremia and hypocalcemia are associated with poor COVID-19 clinical outcome. Hypernatremia is 97% specific for a poor outcome, and the association is independent of inflammatory marker levels. Further studies should evaluate if correcting these imbalances help improve clinical outcome.
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The efficacy and safety of cinacalcet in primary hyperparathyroidism: a systematic review and meta-analysis of randomized controlled trials and cohort studies.
Chandran, M, Bilezikian, JP, Lau, J, Rajeev, R, Yang, SP, Samuel, M, Parameswaran, R
Reviews in endocrine & metabolic disorders. 2022;(3):485-501
Abstract
Cinacalcet, a positive allosteric modulator of the calcium sensing receptor (CaSR) reduces parathyroid hormone (PTH) secretion by increasing the sensitivity of the CaSR on parathyroid cells. We conducted a systematic review and meta-analysis on the safety and efficacy of cinacalcet in Primary Hyperparathyroidism (PHPT). MEDLINE, Embase, BIOSIS, and the Cochrane Library were searched for published articles (from database inception to Sept 2020). All double-blind RCTs and cohort studies that reported data on the efficacy and safety of cinacalcet therapy in individuals ≥ 18 with PHPT were included. Random effect meta-analysis was performed to estimate the efficacy of cinacalcet in lowering serum calcium and PTH levels compared with placebo. 4 RCTs (177 participants) and 17 cohort studies (763 participants) were eligible for final analysis. Pooled results from the RCTs suggest that, when compared to placebo and administered for up to 28 weeks, cinacalcet normalizes serum calcium (≤ 10.3 mg/dl) in patients with PHPT [RR 20 (95% CI 6.04 - 68.52, I2 = 0%, pheterogeneity < 0·00001)]. Serum PTH levels decreased significantly after 2 weeks and up to 28 weeks after treatment with cinacalcet. In the pooled analysis of the 17 cohort studies, serum calcium levels normalized in 76% (95% CI 66% to 86%; I2 = 92%, pheterogeneity < 0·00001) of patients regardless of the duration of treatment. In most studies, PTH levels decreased by 13% to 55%. No RCT reported on BMD as a primary or secondary outcome, and no improvement in BMD was noted in the 2 non-randomized studies that reported densitometric findings. No significant difference in urinary calcium was noted with cinacalcet therapy in either the RCTs or non-randomized studies. There was no significant difference in overall adverse events (AE) (RD 0.01, 95% CI -0.07 to 0.26) compared to placebo noted in the RCTs. In the non-randomized studies, pooled weighted AE rate was 45% (95% CI 32 to 59%). Risk of bias was low in 2/4 RCTs and 6/17cohort studies; risk was intermediate in 2/4 RCTs and 8/17 cohort studies, and risk was high in 3/17 cohort studies. In PHPT, cinacalcet lowers serum calcium and PTH with greater effects on calcium than on PTH in the short term. In the doses reported, the drug is safe with tolerable side effects. These findings can help inform targeted medical therapy of PHPT in those for whom lowering the serum calcium is indicated and for whom parathyroidectomy is not an option.
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Synthesis, characterization, ADMET, in vitro and in vivo studies of mixed ligand metal complexes from a curcumin Schiff base and lawsone.
Jeyaraman, P, Samuel, M, Johnson, A, Raman, N
Nucleosides, nucleotides & nucleic acids. 2021;(3):242-263
Abstract
Complexes are currently synthesized from plant origin because of their therapeutic effect against certain diseases with toxicity. Hence, in this work, four new transition metal(II) mixed ligand complexes have been synthesized using a curcumin Schiff base (primary ligand) and lawsone (as co-ligand). The geometry of these complexes was explored by elemental analyses, molar conductance, thermal analysis, magnetic moment values, IR, NMR, Mass, electronic and EPR spectral studies. Electronic absorption titrations, viscosity measurements and molecular docking studies reveal that all the metal complexes interact with the CT DNA by groove binding. Among all the complexes, the copper(II) complex (complex 1) exhibits a higher Kb value (3.5 × 10-4 M) which reveals that it has a strong binding efficiency toward the CT DNA. The complexes also possess strong DNA cleavage efficiency. Cytotoxicity investigations on Artemia salina show that all the complexes possess higher cytotoxic effect than the ligand. Moreover, all the metal complexes have better antimicrobial efficacy than the ligand. Swiss ADME, PASS and pkCSM online softwares are helpful to predict the pharmacokinetic and biological actions of the curcumin Schiff base. Theoretical results obtained from the in silico study are experimentally corroborated by in vivo anti-inflammatory screening study. All the above studies demonstrate that the copper complex possesses biological activity similar to that of the drug like molecules. Research Highlights Synthesis and characterization of four novel transition mixed ligand complexes using plant moieties Promising in vivo anti-inflammatory agents and in vitro DNA metallonucleases Cytotoxicity investigation on Artemia salina Higher cytotoxic effect for the complexes than the ligand Identification of copper(II) complex as lead like molecule among all.
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Parathyroid allotransplantation to treat post-thyroidectomy hypoparathyroidism: A review of case studies.
Parameswaran, R, Samuel, M, Satish, RL, Kripesh, A, Moorthy, V, Vajjhala, R, Ng, XL, Yip, GW, Voon, FCT, Chandran, M
The surgeon : journal of the Royal Colleges of Surgeons of Edinburgh and Ireland. 2021;(3):183-192
Abstract
OBJECTIVE Symptomatic long-term hypoparathyroidism following thyroid surgery requires an alternative and permanent therapy that would effectively restore parathyroid function and eliminate the need for substitution drug therapy. The aim of this study was to systematically review the literature on the efficacy and safety of parathyroid allotransplantation to treat post-operative hypoparathyroidism. METHODS MEDLINE, Embase, BIOSIS and the Cochrane Library were searched for published articles (from inception of each database to September 30, 2018). A total of 9 studies comprising 146 patients (177 allotransplantations) with post thyroidectomy hypoparathyroidism were identified. RESULTS Parathyroid tissues used for allotransplant were cultured parathyroid cells, cryopreserved parathyroid cells and encapsulated microspheres. Post-transplant immunosuppression was only reported in three studies, mainly with oral prednisolone for 2 weeks to 6 months. Mean graft survival following allotransplantation was 47% (95% CI 24%-71%) when patients were followed-up to 6 months and 41% (95% CI 2.3%-80%) at 12 months. There was significant unexplained heterogeneity observed between studies in both these groups (I2 > 50%). Parathyroid hormone (PTH) levels, and serum calcium levels post intervention was not reported in all studies, but available evidence suggests the levels remains higher (PTH level around 12 pg/ml; Ca level around 8 mg/dl) post-allotransplantation for up to 24 months. CONCLUSIONS Long-term benefit and harms of allotransplantation is still unclear due to the clinical and statistical heterogeneity observed among the studies. Therefore, conduct of a well-designed controlled clinical trial in the immediate future on allotransplantation is of paramount importance.
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Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci.
Erzurumluoglu, AM, Liu, M, Jackson, VE, Barnes, DR, Datta, G, Melbourne, CA, Young, R, Batini, C, Surendran, P, Jiang, T, et al
Molecular psychiatry. 2020;(10):2392-2409
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Abstract
Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.
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Assessment and Management of the Left Atrial Appendage Thrombus in Patients With Nonvalvular Atrial Fibrillation.
Zhan, Y, Joza, J, Al Rawahi, M, Barbosa, RS, Samuel, M, Bernier, M, Huynh, T, Thanassoulis, G, Essebag, V
The Canadian journal of cardiology. 2018;(3):252-261
Abstract
BACKGROUND Intracardiac thrombi arising in the left atrial appendage (LAA) are the principal cause of stroke in nonvalvular atrial fibrillation (AF). Predicting the presence of LAA thrombi is of vital importance in stratifying patients that would need further LAA imaging prior to cardioversion or AF ablation. METHODS We comprehensively searched PubMed from its inception to November 2017 for randomized controlled trials, cohort and case control studies, as well as for case series on LAA thrombi risk factors, imaging, prevention, and anticoagulation management in atrial fibrillation. RESULTS A systematic review of the literature identified 106 articles that investigated the presence of LAA thrombi in AF patients. We classified the articles according to topic and reported on: (1) risk factors; (2) diagnostic imaging modalities; (3) prevention strategies before cardioversion; (4) prevention strategies before AF ablation; and (5) management of detected LAA thrombi. CONCLUSIONS Integration of clinical, biomarker, and imaging risk factors can improve overall prediction for the presence of LAA thrombi, translating into improved patient selection for imaging. The gold standard for the diagnosis of LAA thrombi remains transesophageal echocardiography, although intracardiac ultrasound, cardiac computed tomography, and cardiovascular magnetic imaging are promising alternative modalities. When LAA thrombi are discovered, the treatment regimen remains variable, although direct oral anticoagulants might have efficacy similar to vitamin K antagonists. Future trials will help further elucidate direct oral anticoagulant use for the treatment of LAA thrombi.
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Unmet need in the hyperlipidaemia population with high risk of cardiovascular disease: a targeted literature review of observational studies.
Mitchell, S, Roso, S, Samuel, M, Pladevall-Vila, M
BMC cardiovascular disorders. 2016;:74
Abstract
BACKGROUND The aim of this study was to examine recommended target levels of low-density lipoprotein cholesterol (LDL-C) for hyperlipidaemia patients at high risk (i.e., with two or more risk factors or coronary heart disease or its risk equivalents) for cardiovascular disease (CVD); to determine LDL-C targets recommended by guidelines, and to examine the proportions of patients who do not achieve targeted LDL-C levels in real-world studies. METHODS Electronic databases were searched: Medline, Medline In-Process, Embase, BIOSIS, and the Cochrane Library (1 January 2005 to 31 December 2013). Guideline searches were limited to publications in the last 5 years. There were no geographical or language restrictions. RESULTS Seventeen guidelines and 42 observational studies that reported on high-risk hyperlipidaemia patients were identified. The National Cholesterol Education Program-Adult Treatment Panel III's LDL-C target levels were the most common guidelines used for patients with very high hyperlipidaemia. However, between 68 and 96 % of patients in the studies did not achieve an LDL-C goal <70 mg/dL, except in one study conducted in China (16.9 %). In high-risk patients, 61.8 to 93.8 % did not achieve a target of <100 mg/dL. Regarding common comorbidities, patients with concomitant CVD or diabetes were least likely to reach their target LDL-C goals. CONCLUSION In patients with high risk for CVD, the majority of patients do not attain recommended LDL-C goals, highlighting worldwide suboptimal hyperlipidaemia management and missed opportunities for reduction of the patients CVD risk. Lipid-modifying management strategies need to be intensified.
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Significantly greater triglyceridemia in Black African compared to White European men following high added fructose and glucose feeding: a randomized crossover trial.
Goff, LM, Whyte, MB, Samuel, M, Harding, SV
Lipids in health and disease. 2016;(1):145
Abstract
BACKGROUND Black African (BA) populations are losing the cardio-protective lipid profile they historically exhibited, which may be linked with increasing fructose intakes. The metabolic effects of high fructose diets and how they relate to blood lipids are documented for Caucasians, but have not been described in BA individuals. OBJECTIVE The principle objective of this pilot study was to assess the independent impacts of high glucose and fructose feeding in men of BA ancestry compared to men of White European (WE) ancestry on circulating triglyceride (TG) concentrations. METHODS Healthy males, aged 25-60 years, of BA (n = 9) and WE (n = 11) ethnicity were randomly assigned to 2 feeding days in a crossover design, providing mixed nutrient meals with 20 % total daily caloric requirements from either added glucose or fructose. Circulating TG, non-esterified fatty acids (NEFA), glucose, insulin and C-peptide were measured over two 24-h periods. RESULTS Fasting TGs were lower in BAs than WEs on the fructose feeding day (p < 0.05). There was a trend for fasting TG concentrations 24 h following fructose feeding to increase in both BA (baseline median fasting: 0.80, IQR 0.6-1.1 vs 24-h median post-fructose: 1.09, 0.8-1.4 mmol/L; p = 0.06) and WE (baseline median fasting 1.10, IQR 0.9-1.5 vs 24-h median post-fructose: 1.16, IQR 0.96-1.73 mmol/L; p = 0.06). Analysis within ethnic group demonstrated that in TG iAUC was significantly higher in BA compared to WE on both glucose (35, IQR 11-56 vs -4, IQR -10-1 mmol/L/min; p = 0.004) and fructose (48, IQR 15-68 vs 13, IQR -7-38 mmol/L/min; p = 0.04). Greater suppression of postprandial NEFA was evident in WE than BA after glucose feeding (-73, IQR -81- -52 vs -26, IQR -48- -3 nmol/L/min; p = 0.001) but there was no ethnic difference following fructose feeding. CONCLUSIONS Understanding the metabolic effects of dietary acculturation and Westernisation that occurs in Black communities is important for developing prevention strategies for chronic disease development. These data show postprandial hypertriglyceridemia following acute feeding of high added fructose and glucose in BA men, compared to WE men, may contribute to metabolic changes observed during dietary acculturation and Westernisation. TRIAL REGISTRATION The study was retrospectively registered on clinicaltrials.gov: NCT02533817 .
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A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease.
Nikpay, M, Goel, A, Won, HH, Hall, LM, Willenborg, C, Kanoni, S, Saleheen, D, Kyriakou, T, Nelson, CP, Hopewell, JC, et al
Nature genetics. 2015;(10):1121-1130
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Abstract
Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.
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Major bleeding in patients with atrial fibrillation receiving vitamin K antagonists: a systematic review of randomized and observational studies.
Roskell, NS, Samuel, M, Noack, H, Monz, BU
Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2013;(6):787-97
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Abstract
AIMS: Clinical trials have shown that anticoagulation with vitamin K antagonists (VKAs), e.g. warfarin, decreases the risk of stroke in patients with atrial fibrillation (AF); however, increased bleeding risk is one of the safety concerns. The primary objective was to conduct a systematic review of the published literature, assessing the risk of major bleeding and mortality in patients with AF treated with VKAs. METHODS AND RESULTS Online searches of MEDLINE, EMBASE, BIOSIS, and the Cochrane Library were performed to a pre-specified protocol from 1960 to March 2012 for randomized controlled trials (RCTs) and from January 1990 to March 2012 for observational studies. A total of 47 studies (16 RCTs and 31 observational studies) were included. Cumulative follow-up was 61,563 patient-years for RCTs and 484 241 patient-years for observational studies. The overall median incidence of major bleeding was 2.1 per 100 patient-years (range, 0.9-3.4 per 100 patient-years) for RCTs and 2.0 per 100 patient-years (range, 0.2-7.6 per 100 patient-years) for observational studies. With study year as a proxy for changing management patterns, some evidence of bleeding rates and/or their reporting increasing over time was noted. Mortality rates from observational studies were inadequately reported to allow comparison with those from RCT data. CONCLUSION The median rate of major bleeding in observational studies and RCTs is similar. The larger heterogeneity in bleeding rates observed in a real-life setting could reflect a high variability in standard of care of patients on VKAs and/or methodological differences between observational studies and/or variability in data sources.