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1.
The impact of metabolic control on cognition, neurophysiology, and well-being in PKU: A systematic review and meta-analysis of the within-participant literature.
Thomas, L, Olson, A, Romani, C
Molecular genetics and metabolism. 2023;(1):106969
Abstract
Phenylketonuria (PKU) is a metabolic disease where Phenylalanine (Phe) rises much above normal levels. Cross-sectional and correlational studies provide valuable information on the importance of maintaining low blood-Phe to achieve good outcomes, but they may be confounded, at least partially, by differences in participant demographics. Moreover, the effect of Phe at older ages is difficult to ascertain because of strong associations between Phe levels across ages. Within-participant studies avoid confounding issues. We have reviewed these studies. We followed PRISMA guidelines to search the literature for studies reporting the impact of Phe changes within participants. Phe was either increased or decreased through diet relaxation/resumption or through pharmacological interventions. Forty-six separate articles reported, singly or in combination, results on cognition (N = 37), well-being (N = 22) and neurophysiological health (N = 14). For all studies, we established, in a binary way, whether a benefit of lower Phe was or was not demonstrated and compared numbers showing benefit versus a null or negative outcome. We then analyzed whether critical parameters (e.g., length of the study/condition for the change, size of Phe change achieved) influenced presence or absence of benefit. For a subset of studies that reported quantitative cognitive outcomes, we carried out a meta-analysis to estimate the size of change in cognitive performance associated with a change in Phe and its significance. There were significantly more studies with benefits than no benefits, both for cognitive and well-being outcomes, and a trend in this direction for neurophysiological outcomes. The meta-analysis showed a highly significant effect size both overall (0.55) and when studies with adults/adolescents were considered separately (0.57). There was some indication that benefits were easier to demonstrate when differences in Phe were larger and achieved across a longer period, but these effects were not always consistent. These results reinforce results from the literature by demonstrating the importance of lower Phe in children as well as in adolescents and adults, even when confounding factors in group composition are eliminated. The field would benefit from further studies where Phe levels are contrasted within-participants to ascertain how much Phe needs to be changed and for how long to see a difference and which measures demonstrate a difference (e.g., which cognitive tasks).
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Cardiac reverse remodelling by imaging parameters with recent changes to guideline medical therapy in heart failure.
Kodsi, M, Makarious, D, Gan, GCH, Choudhary, P, Thomas, L
ESC heart failure. 2023;(6):3258-3275
Abstract
Recently established heart failure therapies, including sodium glucose co-transporter 2 inhibitors, angiotensin-neprilysin inhibitors, and cardiac resynchronization therapy, have led to both clinical and structural improvements. Reverse remodelling describes the structural and functional responses to therapy and has been shown to correlate with patients' clinical response, acting as a biomarker for treatment success. The introduction of these new therapeutic agents in addition to advances in non-invasive cardiac imaging has led to an expansion in the evaluation and the validation of cardiac reverse remodelling. Methods including volumetric changes as well as strain and myocardial work have all been shown to be non-invasive end-points of reverse remodelling, correlating with clinical outcomes. Our review summarizes the current available evidence on reverse remodelling in heart failure by the non-invasive cardiac imaging techniques, in particular transthoracic echocardiography.
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Evaluation of the Safety and Tolerability of Sodium-Glucose Co-transporter 2 Inhibitors in the Older Population: A Systematic Review.
Edwards, S, Lam, C, Thomas, L
The Senior care pharmacist. 2023;(7):276-287
Abstract
Objective The objective of this systematic review was to evaluate adverse effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors in older people. Data Sources Articles in PubMed and EBSCOhost-Medline databases between January 2011 and 2021 were analyzed. Search terms were SGLT2 inhibitor, SGLT2 inhibitors, geriatric/elderly/older people, and safety/ adverse drug reaction/tolerability. Meta-analyses, systematic reviews, review articles, journal clubs, articles that did not address the research question, excluded patients 65 years of age and older, had an updated article available, did not stratify by age group, or were a commentary on a cohort study were excluded. Data Synthesis The search resulted in 113 articles. There were 62 duplicates removed, and 30 excluded based on the abstract. Of the 32 articles remaining, 19 were removed for not meeting the research question or meeting exclusion criteria. A total of 13 studies, including randomized controlled trials, cohort studies, and case reports, were assessed. Conclusion Current evidence demonstrates that patients taking SGLT2 inhibitors and diuretics were more likely to experience volume depletion. Findings suggest that risk of UTI was highest when the patient's age is 75 years or older. Some studies indicated that risk of genital mycotic infection is prevalent in older people. Use of SGLT2 inhibitors in the older population was not associated with a higher risk of developing diabetic ketoacidosis. Use of SGLT2 inhibitors appears to be relatively safe in older people. The risk of side effects may be decreased by considering concomitant medications. Randomized controlled trials assessing safety of SGLT2 inhibitors in the older population is still warranted.
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Cell death of Acanthamoeba castellanii following exposure to antimicrobial agents commonly included in contact lens disinfecting solutions.
Thomas, L, Khan, NA, Siddiqui, R, Alawfi, BS, Lloyd, D
Parasitology research. 2023;(1):16
Abstract
Several antimicrobial agents are commonly included in contact lens disinfectant solutions including chlorhexidine diacetate (CHX), polyhexamethylene biguanide (PHMB) or myristamidopropyl dimethylamine (MAPD); however, their mode of action, i.e. necrosis versus apoptosis is incompletely understood. Here, we determined whether a mechanism of cell death resembling that of apoptosis was present in Acanthamoeba castellanii of the T4 genotype (NEFF) following exposure to the aforementioned antimicrobials using the anticoagulant annexin V that undergoes rapid high affinity binding to phosphatidylserine in the presence of calcium, making it a sensitive probe for phosphatidylserine exposure. The results revealed that under the conditions employed in this study, an apoptotic pathway of cell death in this organism at the tested conditions does not occur. Our findings suggest that necrosis is the likely mode of action; however, future mechanistic studies should be accomplished in additional experimental conditions to further comprehend the molecular mechanisms of cell death in Acanthamoeba.
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A comprehensive review on chromium (Cr) contamination and Cr(VI)-resistant extremophiles in diverse extreme environments.
Rahman, Z, Thomas, L, Chetri, SPK, Bodhankar, S, Kumar, V, Naidu, R
Environmental science and pollution research international. 2023;(21):59163-59193
Abstract
Chromium (Cr) compounds are usually toxins and exist abundantly in two different forms, Cr(VI) and Cr(III), in nature. Their contamination in any environment is a major problem. Many extreme environments including cold climate, warm climate, acidic environment, basic/alkaline environment, hypersaline environment, radiation, drought, high pressure, and anaerobic conditions have accumulated elevated Cr contamination. These harsh physicochemical conditions associated with Cr(VI) contamination damage biological systems in various ways. However, several unique microorganisms belonging to phylogenetically distant taxa (bacteria, fungi, and microalgae) owing to different and very distinct physiological characteristics can withstand extremities of Cr(VI) in different physicochemical environments. These challenging situations offer great potential and extended proficiencies in extremophiles for environmental and biotechnological applications. On these issues, the present review draws attention to Cr(VI) contamination from diverse extreme environmental regions. The study gives a detailed account on the ecology and biogeography of Cr(VI)-resistant microorganisms in inhospitable environments, and their use for detoxifying Cr(VI) and other applications. The study also focuses on physiological, multi-omics, and genetic engineering approaches of Cr(VI)-resistant extremophiles.
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Vitamin D receptor gene polymorphism and vitamin D supplementation on clinical/ treatment outcome in tuberculosis: current and future perspectives.
Sekhar Miraj, S, Vyas, N, Kurian, SJ, Baral, T, Thomas, L, Reddy, BS, Munisamy, M, Banerjee, M, Rao, M
Expert review of anti-infective therapy. 2022;(9):1179-1186
Abstract
INTRODUCTION Tuberculosis (TB) is a transnational public health concern, which requires more precise treatment strategies than the existing approaches. Vitamin D modulates the inflammatory and immune response to the disease. Robust evidence shows that vitamin D deficiency and its receptor gene polymorphism influence the susceptibility to TB and the outcome of the anti-tubercular treatment (ATT). However, in the different populations, these findings were inconsistent and even contradictory. AREAS COVERED The current review focuses on the association between vitamin D receptor (VDR) gene polymorphism with the risk of development of TB disease and response to the ATT. Additionally, it reviews various systematic reviews and meta-analyses on the impact of vitamin D supplements on both clinical and treatment outcomes in TB patients. EXPERT OPINION Although the majority of the findings rule out the benefits of the supplementation, sufficient evidence is available to warrant larger epidemiological research that should be aimed to generate possible interaction among the VDR polymorphism, vitamin D status, and the outcome in TB. We conclude that establishing such an association in different ethnic populations will help design nutrigenomics- or pharmacogenomics-based vitamin D supplementation to develop a personalized medicine approach to flatten the curve of TB disease.
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Apixaban or Warfarin and Aspirin or Placebo After Acute Coronary Syndrome or Percutaneous Coronary Intervention in Patients With Atrial Fibrillation and Prior Stroke: A Post Hoc Analysis From the AUGUSTUS Trial.
Bahit, MC, Vora, AN, Li, Z, Wojdyla, DM, Thomas, L, Goodman, SG, Aronson, R, Jordan, JD, Kolls, BJ, Dombrowski, KE, et al
JAMA cardiology. 2022;(7):682-689
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Abstract
IMPORTANCE Data are limited regarding the risk of cerebrovascular ischemic events and major bleeding in patients with atrial fibrillation (AF) and recent acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI). OBJECTIVE Determine the efficacy and safety of apixaban or vitamin K antagonists (VKA) and aspirin or placebo according to prior stroke, transient ischemic attack (TIA), or thromboembolism (TE). DESIGN, SETTING, AND PARTICIPANTS In this prospective, multicenter, 2-by-2 factorial, randomized clinical trial, post hoc parallel analyses were performed to compare randomized treatment regimens according to presence or absence of prior stroke/TIA/TE using Cox proportional hazards models. Patients with AF, recent ACS or PCI, and planned use of P2Y12 inhibitors for 6 months or longer were included; 33 patients with missing data about prior stroke/TIA/TE were excluded. INTERVENTIONS Apixaban (5 mg or 2.5 mg twice daily) or VKA and aspirin or placebo. MAIN OUTCOMES AND MEASURES Major or clinically relevant nonmajor (CRNM) bleeding. RESULTS Of 4581 patients included, 633 (13.8%) had prior stroke/TIA/TE. Patients with vs without prior stroke/TIA/TE were older; had higher CHA2DS2-VASC and HAS-BLED scores; and more frequently had prior bleeding, heart failure, diabetes, and prior oral anticoagulant use. Apixaban was associated with lower rates of major or CRNM bleeding and death or hospitalization than VKA in patients with (hazard ratio [HR], 0.69; 95% CI, 0.46-1.03) and without (HR, 0.68; 95% CI, 0.57-0.82) prior stroke/TIA/TE. Patients without prior stroke/TIA/TE receiving aspirin vs placebo had higher rates of bleeding; this difference appeared less substantial among patients with prior stroke/TIA/TE (P = .01 for interaction). Aspirin was associated with numerically lower rates of death or ischemic events than placebo in patients with (HR, 0.71; 95% CI, 0.42-1.20) and without (HR, 0.93; 95% CI, 0.72-1.21) prior stroke/TIA/TE (not statistically significant). CONCLUSIONS AND RELEVANCE The safety and efficacy of apixaban compared with VKA was consistent with the AUGUSTUS findings, irrespective of prior stroke/TIA/TE. Aspirin increased major or CRNM bleeding, particularly in patients without prior stroke/TIA/TE. Although aspirin may have some benefit in patients with prior stroke, our findings support the use of apixaban and a P2Y12 inhibitor without aspirin for the majority of patients with AF and ACS and/or PCI, regardless of prior stroke/TIA/TE status. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02415400.
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Effect of Vitamin D Supplementation in Type 2 Diabetes Patients with Tuberculosis: A Systematic Review.
Patel, DG, Kurian, SJ, Miraj, SS, Rashid, M, Thomas, L, Rodrigues, GS, Banerjee, M, Khandelwal, B, Saravu, K, Rao, M
Current diabetes reviews. 2022;(4):e020921196096
Abstract
BACKGROUND Diabetes mellitus (DM) and tuberculosis (TB) have been recognized as reemerging epidemics, especially in developing countries. Among all the risk factors, diabetes causes immunosuppression, increasing the risk of active TB three times. Vitamin D has been found as a link between DM-TB co-morbidity. OBJECTIVE Vitamin D affects the immune response, suppresses Mycobacterium tuberculosis (Mtb) growth, and affects insulin secretion. The present systematic review determines the effect of vitamin D supplementation on clinical and therapeutic outcomes of DM-TB patients. METHOD A comprehensive literature search was carried out in PubMed, Cochrane, Web of Science, and Scopus database to determine eligible studies from inception to January 2021. Out of the 639 articles retrieved, three randomized controlled trials (RCTs) were included in the systematic review. RESULT The effect of vitamin D3 or oral cholecalciferol supplementation was assessed on outcomes, such as duration to sputum smear conversion, TB scores improvement, change in glycemic parameters, including HbA1c, FBS, and PLBS, and laboratory parameters, such as Hb, ESR, and CRP. Duration of sputum smear conversion was decreased by two weeks in the vitamin D3 supplemented group in two studies. TB score improvement and changes in glycemic parameters were inclined towards supplemented group; however, they were not significant. CONCLUSION The overall effect of vitamin D3 supplementation on TB patients with DM was not significant. Further studies are required in the future examining the effect of supplementation on outcomes in this population.
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Clinical and biochemical profile of 786 sequential episodes of diabetic ketoacidosis in adults with type 1 and type 2 diabetes mellitus.
Ooi, E, Nash, K, Rengarajan, L, Melson, E, Thomas, L, Johnson, A, Zhou, D, Wallett, L, Ghosh, S, Narendran, P, et al
BMJ open diabetes research & care. 2021;(2)
Abstract
INTRODUCTION We explored the clinical and biochemical differences in demographics, presentation and management of diabetic ketoacidosis (DKA) in adults with type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS This observational study included all episodes of DKA from April 2014 to September 2020 in a UK tertiary care hospital. Data were collected on diabetes type, demographics, biochemical and clinical features at presentation, and DKA management. RESULTS From 786 consecutive DKA, 583 (75.9%) type 1 diabetes and 185 (24.1%) type 2 diabetes episodes were included in the final analysis. Those with type 2 diabetes were older and had more ethnic minority representation than those with type 1 diabetes. Intercurrent illness (39.8%) and suboptimal compliance (26.8%) were the two most common precipitating causes of DKA in both cohorts. Severity of DKA as assessed by pH, glucose and lactate at presentation was similar in both groups. Total insulin requirements and total DKA duration were the same (type 1 diabetes 13.9 units (9.1-21.9); type 2 diabetes 13.9 units (7.7-21.1); p=0.4638). However, people with type 2 diabetes had significantly longer hospital stay (type 1 diabetes: 3.0 days (1.7-6.1); type 2 diabetes: 11.0 days (5.0-23.1); p<0.0001). CONCLUSIONS In this population, a quarter of DKA episodes occurred in people with type 2 diabetes. DKA in type 2 diabetes presents at an older age and with greater representation from ethnic minorities. However, severity of presentation and DKA duration are similar in both type 1 and type 2 diabetes, suggesting that the same clinical management protocol is equally effective. People with type 2 diabetes have longer hospital admission.
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Association between sacubitril/valsartan initiation and real-world health status trajectories over 18 months in heart failure with reduced ejection fraction.
Thomas, M, Khariton, Y, Fonarow, GC, Arnold, SV, Hill, L, Nassif, ME, Chan, PS, Butler, J, Thomas, L, DeVore, AD, et al
ESC heart failure. 2021;(4):2670-2678
Abstract
AIMS: Improving the health status (symptoms, function, and quality of life) of patients with heart failure with reduced ejection fraction (HFrEF) is a primary treatment goal. Angiotensin receptor neprilysin inhibitors (ARNI) improve short-term health status in clinical practice, but the sustainability of these improvements is unknown. METHODS AND RESULTS In CHAMP-HF, a multicentre observational study of outpatients with HFrEF, patients initiated on ARNI were propensity score matched 1:2 to patients not using ARNI with Cox regression modelling time to ARNI initiation, adjusted for sociodemographic and clinical variables, medical history, medications, and baseline Kansas City Cardiomyopathy Questionnaire (KCCQ) scores. Repeated measures models for the overall KCCQ score and each domain compared the health status trajectories of patients initiated on ARNI vs. not. Among 3930 participants, 746 (19.0%) began ARNI, of whom 576 were matched to 1152 non-ARNI patients. Prior to matching, participants initiated on ARNI were younger, non-Hispanic, had lower EFs, more commonly had a history of ventricular arrhythmia, were less likely to be taking an ACEI/ARB, and more likely to be treated with beta-blockers and mineralocorticoid receptor antagonists. There were no differences after matching. In the matched cohort, participants initiated on ARNI experienced improved health status by 3 months that persisted through 12 months [KCCQ Overall Summary Score (OSS) = 73.4 vs. 70.8; P < 0.001], with the largest benefit observed in the KCCQ Quality of Life domain (68.7 vs. 64.7; P < 0.001). Similar health status benefits were noted through 18 months (KCCQ-OSS = 73.9 vs. 71.3; P < 0.001). A responder analysis showed that 12 patients would need to be initiated on ARNI for one to experience at least a large improvement (≥10 points) in health status benefit at 12 months. CONCLUSIONS In outpatient practice, ARNI therapy was associated with improved health status by 3 months and continued to 18 months after initiating therapy.