Effect of chlorpyrifos on cypermethrin-induced dopaminergic neurotoxicity in rats.

The study aimed to investigate the combined effects of chlorpyrifos and cypermethrin combined on dopaminergic neurotoxicity, motor behaviours and level of selected inflammatory proteins in rats compared to either alone for delineating an interaction between these two pesticides. The rotarod and grip strength tests were employed to assess neurobehavioural changes. The striatal dopamine content and expression of tyrosine hydroxylase (TH), α-synuclein, cyclooxygenase-2 (COX-2), and tumour necrosis factor-α (TNF-α) proteins in the nigrostriatal tissue were measured. Chlorpyrifos impaired the neurobehavioural indexes, reduced the striatal dopamine level, augmented the level of α-synuclein, COX-2, and TNF-α and attenuated the expression of TH similar to but a little less than cypermethrin. Half the dose of both pesticides together produced additional neurotoxicity compared with the usual (highest employed) dose of either alone. The results showed that chlorpyrifos induced moderately less dopaminergic neurotoxicity than cypermethrin. In the combination, they produced a little higher toxicity than either pesticide alone.

The impact of electronic cigarette use on periodontitis and periodontal outcomes: a systematic review and meta-analysis.

BACKGROUND: Periodontitis, a prevalent inflammatory disease affecting tooth-supporting structures, leads to significant oral health and systemic complications if untreated. While traditional smoking is a well-known risk factor for periodontitis, the impact of electronic cigarettes (e-cigarettes) on periodontal health remains unclear. This systematic review and meta-analysis aim to synthesize existing evidence on the effects of e-cigarette use on periodontitis and other periodontal outcomes. METHODS: A literature search was conducted across PubMed, EMBASE, and Web of Science from their inception up to June 15 2024. Eligible studies included those assessing the impact of e-cigarette use on periodontal outcomes such as bleeding on probing (BOP), plaque index, probing depth, clinical attachment loss, and marginal bone loss. Data were extracted and analyzed using random-effect models to calculate pooled mean differences. R statistical software was used to perform meta-analyses. RESULTS: Twelve studies were included in the meta-analysis. E-cigarette users showed a significantly lower mean BOP score compared to non-users (pooled mean difference: -14.233; 95% CI: -20.424 to -8.043; I² = 99%). For other periodontal outcomes, the findings were as follows: Plaque Index (MD: -0.160; 95% CI: -0.680 to 0.360; I² = 95%), Clinical Attachment Loss (MD: 0.120; 95% CI: -0.045 to 0.285; I² = 90%), Probing Depth (MD: 0.056; 95% CI: -0.070 to 0.182; I² = 85%), and Marginal Bone Loss (MD: -0.052; 95% CI: -0.168 to 0.064; I² = 88%). CONCLUSION: Present studies have not identified a significant link between e-cigarette use and adverse effects on periodontal health, but the available research is limited. Further longitudinal research is necessary to evaluate the long-term effects of e-cigarette use on periodontal health and to clarify any associated risks.

Lymphocytic emperipolesis in breast carcinoma on cytology smears-A curious finding!

In this article, we discuss an intimidating finding of lymphocytic emperipolesis which was observed in breast carcinoma cells on cytology smears.

Hypertension in men - An emerging public health challenge for India: Evidence from national family health survey-4.

Background: Men in the 25-54 year age group form the major workforce in developing countries like India. The rising trend of hypertension in this age group is a growing matter of concern. Objectives: This study analyzed secondary data analysis from the National Family Health Survey-4. Methods: Men in the 25-54 age group (n = 76,410) from 640 districts of the country were included in the study. State and district-wise trends in hypertension in men along with selected individual lifestyle characteristics were displayed using a geographic information system. Results: The prevalence of hypertension among men in the age group of 25-54 was found to be 35.6% for the entire country. In urban India, the prevalence of hypertension was 38.4% (uncorrected - 40.2%) compared with 33.8% (uncorrected - 34.9%) in rural India. Among the 27,973 hypertensives, 6984 (25%) were the known hypertensives prior to the survey. Out of these only 2403 (34.4%) were taking medicines. The prevalence of tobacco use in any form among the men in this age group was 45.7% (uncorrected - 49%). Conclusion: In conclusion, the study highlights the burden of hypertension in men in the prime age group along with the alarming burden of tobacco consumption and recommends public health and policy interventions targeting both hypertension and tobacco control. It requires urgent attention and specialized strategies in tiding over this epidemic brewing in the workforce of the country.

Is Gut Dysbiosis an Epicenter of Parkinson's Disease?

Once recognized as one of the most esoteric diseases of the central nervous system, Parkinson's disease (PD) is now deemed to be a chronic illness contributed by the central, autonomic and enteric nervous systems. Most likely, an accumulation of α-synuclein in the central and enteric nervous systems is the key that supports this viewpoint. Constipation, one of the non-motor hallmarks in roughly two-third of PD patients, is regulated by the composition of gut bacteria, which is assumed to set off the enteric α-synuclein accrual. Vagus nerve is suggested to direct the signal for α-synuclein over-expression and accumulation to the brain. While trillions of microorganisms reside in the intestinal tract, only one third of the proportion inhabits evenly in all individuals. Existence of an impaired gut-microbe-brain axis consonant with dysbiosis could be an epicenter of this inexplicable disorder. Any alteration in the structure and function of the gastrointestinal tract owing to exposure of endogenous or exogenous chemicals or toxicants could lead to dysbiosis. However, inconsistency in the symptoms even after exposure to same chemical or toxicant in PD patients emphatically creates a conundrum. While the level of a few specific neurotransmitters and metabolites is influenced by microbes, implication of dysbiosis is still debatable. Nevertheless, the scientific literature is overflowing with the remarkable observations supporting the role of dysbiosis in PD. Lack of specificity to differentially diagnose PD with non-PD or PD-plus syndrome, to identify highly precise drug targets and to develop therapeutic stratagems to encounter the disease on the basis of this approach, causes us to be open-minded about the dysbiosis theory. The article reviews the facts supporting gut dysbiosis as the foremost trigger for PD onset along with disagreements.

Managing Attribute-Based Access Control Policies in a Unified Framework using Data Warehousing and In-Memory Database.

Over the last few years, various types of access control models have been proposed for expressing the growing needs of organizations. Out of these, there is an increasing interest towards specification and enforcement of flexible and dynamic decision making security policies using Attribute Based Access Control (ABAC). However, it is not easy to migrate an existing security policy specified in a different model into ABAC. Furthermore, there exists no comprehensive approach that can specify, enforce and manage ABAC policies along with other policies potentially already existing in the organization as a unified security policy. In this article, we present a unique and flexible solution that enables concurrent specification and enforcement of such security policies through storing and querying data in a multi-dimensional and multi-granular data model. Specifically, we present a unified database schema, similar to that traditionally used in data warehouse design, that can represent different types of access control policies and store relevant policies as in-memory data, thereby significantly reducing the execution time of access request evaluation. We also present a novel approach for combining multiple access control policies through meta-policies. For ease of management, an administrative schema is presented that can specify different types of administrative policies. Extensive experiments on a wide range of data sets demonstrate the viability of the proposed approach.

Methionine sulfoxide reductase A deficiency exacerbates acute liver injury induced by acetaminophen.

Acetaminophen (APAP) overdose induces acute liver injury via enhanced oxidative stress and glutathione (GSH) depletion. Methionine sulfoxide reductase A (MsrA) acts as a reactive oxygen species scavenger by catalyzing the cyclic reduction of methionine-S-sulfoxide. Herein, we investigated the protective role of MsrA against APAP-induced liver damage using MsrA gene-deleted mice (MsrA-/-). We found that MsrA-/- mice were more susceptible to APAP-induced acute liver injury than wild-type mice (MsrA+/+). The central lobule area of the MsrA-/- liver was more impaired with necrotic lesions. Serum alanine transaminase, aspartate transaminase, and lactate dehydrogenase levels were significantly higher in MsrA-/- than in MsrA+/+ mice after APAP challenge. Deletion of MsrA enhanced APAP-induced hepatic GSH depletion and oxidative stress, leading to increased susceptibility to APAP-induced liver injury in MsrA-deficient mice. APAP challenge increased Nrf2 activation more profoundly in MsrA-/- than in MsrA+/+ livers. Expression and nuclear accumulation of Nrf2 and its target gene expression were significantly elevated in MsrA-/- than in MsrA+/+ livers after APAP challenge. Taken together, our results demonstrate that MsrA protects the liver from APAP-induced toxicity. The data provided herein constitute the first in vivo evidence of the involvement of MsrA in hepatic function under APAP challenge.

Methionine sulfoxide reductase A protects hepatocytes against acetaminophen-induced toxicity via regulation of thioredoxin reductase 1 expression.

Thioredoxin reductase 1 (TXNRD1) is associated with susceptibility to acetaminophen (APAP)-induced liver damage. Methionine sulfoxide reductase A (MsrA) is an antioxidant and protein repair enzyme that specifically catalyzes the reduction of methionine S-sulfoxide residues. We have previously shown that MsrA deficiency exacerbates acute liver injury induced by APAP. In this study, we used primary hepatocytes to investigate the underlying mechanism of the protective effect of MsrA against APAP-induced hepatotoxicity. MsrA gene-deleted (MsrA-/-) hepatocytes showed higher susceptibility to APAP-induced cytotoxicity than wild-type (MsrA+/+) cells, consistent with our previous in vivo results. MsrA deficiency increased APAP-induced glutathione depletion and reactive oxygen species production. APAP treatment increased Nrf2 activation more profoundly in MsrA-/- than in MsrA+/+ hepatocytes. Basal TXNRD1 levels were significantly higher in MsrA-/- than in MsrA+/+ hepatocytes, while TXNRD1 depletion in both MsrA-/- and MsrA+/+ cells resulted in increased resistance to APAP-induced cytotoxicity. In addition, APAP treatment significantly increased TXNRD1 expression in MsrA-/- hepatocytes, while no significant change was observed in MsrA+/+ cells. Overexpression of MsrA reduced APAP-induced cytotoxicity and TXNRD1 expression levels in APAP-treated MsrA-/- hepatocytes. Collectively, our results suggest that MsrA protects hepatocytes from APAP-induced cytotoxicity through the modulation of TXNRD1 expression.

Methionine sulfoxide reductase A protects against lipopolysaccharide-induced septic shock via negative regulation of the proinflammatory responses.

Methionine sulfoxide reductase A (MsrA) is a major antioxidant enzyme that specifically catalyzes the reduction of methionine S-sulfoxide. In this study, we used MsrA gene-knockout (MsrA-/-) mice and bone marrow-derived macrophages (BMDMs) to investigate the role of MsrA in the regulation of inflammatory responses induced by lipopolysaccharide (LPS). MsrA-/- mice were more susceptible to LPS-induced lethal shock than wild-type (MsrA+/+) mice. Serum levels of the proinflammatory cytokines IL-6 and TNF-α induced by LPS were higher in MsrA-/- than in MsrA+/+ mice. MsrA deficiency in the BMDMs also increased the LPS-induced cytotoxicity as well as TNF-α level. Basal and LPS-induced reactive oxygen species (ROS) levels were higher in MsrA-/- than in MsrA+/+ BMDMs. Phosphorylation levels of p38, JNK, and ERK were higher in MsrA-/- than in MsrA+/+ BMDMs in response to LPS, suggesting that MsrA deficiency increases MAPK activation. Furthermore, MsrA deficiency increased the expression and nuclear translocation of NF-κB and the expression of inducible nitric oxide synthase, a target gene of NF-κB, in response to LPS. Taken together, our results suggest that MsrA protects against LPS-induced septic shock, and negatively regulates proinflammatory responses via inhibition of the ROS-MAPK-NF-κB signaling pathways.

Selenoprotein MsrB1 deficiency exacerbates acetaminophen-induced hepatotoxicity via increased oxidative damage.

Acetaminophen (APAP) overdose induces acute liver damage and failure via reactive oxygen species production and glutathione (GSH) depletion. Methionine sulfoxide reductase B1 (MsrB1) is an antioxidant selenoenzyme that specifically catalyzes the reduction of methionine R-sulfoxide residues. In this study, we used MsrB1 gene-knockout mice and primary hepatocytes to investigate the effect of MsrB1 on APAP-induced hepatotoxicity. Analyses of histological alterations and serum indicators of liver damage showed that MsrB1-/- mice were more susceptible to APAP-induced acute liver injury than wild-type (MsrB1+/+) mice. Consistent with the in vivo results, primary MsrB1-/- hepatocytes displayed higher susceptibility to APAP-induced cytotoxicity than MsrB1+/+ cells. MsrB1 deficiency increased hepatic oxidative stress after APAP challenge such as hydrogen peroxide production, lipid peroxidation, and protein oxidation levels. Additionally, basal and APAP-induced ratios of reduced-to-oxidized GSH (GSH/GSSG) were significantly lower in MsrB1-/- than in MsrB1+/+ livers. Nrf2 nuclear accumulation and heme oxygenase-1 expression levels after APAP challenge were lower in MsrB1-/- than in MsrB1+/+ livers, suggesting that MsrB1 deficiency attenuates the APAP-induced activation of Nrf2. Collectively, the results of this study suggest that selenoprotein MsrB1 plays a protective role against APAP-induced hepatotoxicity via its antioxidative function.

Cytochrome P450 2D6 and Parkinson's Disease: Polymorphism, Metabolic Role, Risk and Protection.

Cytochrome P450 (CYP) 2D6 is one of the most highly active, oxidative and polymorphic enzymes known to metabolize Parkinsonian toxins and clinically established anti-Parkinson's disease (PD) drugs. Albeit CYP2D6 gene is not present in rodents, its orthologs perform almost the similar function with imprecise substrate and inhibitor specificity. CYP2D6 expression and catalytic activity are found to be regulated at every stage of the central dogma except replication as well as at the epigenetic level. CYP2D6 gene codes for a set of alternate splice variants that give rise to a range of enzymes possessing variable catalytic activity. Case-control studies, meta-analysis and systemic reviews covering CYP2D6 polymorphism and PD risk have demonstrated that poor metabolizer phenotype possesses a considerable genetic susceptibility. Besides, ultra-rapid metabolizer offers protection against the risk in some populations while lack of positive or inverse association is also reported in other inhabitants. CYP2D6 polymorphisms resulting into deviant protein products with differing catalytic activity could lead to inter-individual variations, which could be explained to certain extent on the basis of sample size, life style factors, food habits, ethnicity and tools used for statistical analysis across various studies. Current article describes the role played by polymorphic CYP2D6 in the metabolism of anti-PD drugs/Parkinsonian toxins and how polymorphisms determine PD risk or protection. Moreover, CYP2D6 orthologs and their roles in rodent models of Parkinsonism have also been mentioned. Finally, a perspective on inconsistency in the findings and futuristic relevance of CYP2D6 polymorphisms in disease diagnosis and treatment has also been highlighted.

Minocycline, levodopa and MnTMPyP induced changes in the mitochondrial proteome profile of MPTP and maneb and paraquat mice models of Parkinson's disease.

Mitochondrial dysfunction is the foremost perpetrator of the nigrostriatal dopaminergic neurodegeneration leading to Parkinson's disease (PD). However, the roles played by majority of the mitochondrial proteins in PD pathogenesis have not yet been deciphered. The present study investigated the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and combined maneb and paraquat on the mitochondrial proteome of the nigrostriatal tissues in the presence or absence of minocycline, levodopa and manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin (MnTMPyP). The differentially expressed proteins were identified and proteome profiles were correlated with the pathological and biochemical anomalies induced by MPTP and maneb and paraquat. MPTP altered the expression of twelve while combined maneb and paraquat altered the expression of fourteen proteins. Minocycline, levodopa and MnTMPyP, respectively, restored the expression of three, seven and eight proteins in MPTP and seven, eight and eight proteins in maneb- and paraquat-treated groups. Although levodopa and MnTMPyP rescued from MPTP- and maneb- and paraquat-mediated increase in the microglial activation and decrease in manganese-superoxide dismutase expression and complex I activity, dopamine content and number of dopaminergic neurons, minocycline defended mainly against maneb- and paraquat-mediated alterations. The results demonstrate that MPTP and combined maneb and paraquat induce mitochondrial dysfunction and microglial activation and alter the expression of a bunch of mitochondrial proteins leading to the nigrostriatal dopaminergic neurodegeneration and minocycline, levodopa or MnTMPyP variably offset scores of such changes.

Single shot interferogram analysis for optical metrology.

We report a novel constrained optimization method for single shot interferogram analysis. The unknown test wavefront is estimated as a minimum L2-norm squared solution whose phase is constrained to the space spanned by a finite number of Zernike polynomials. Using a single frame from standard phase shifting datasets, we demonstrate that our approach provides a phase map that matches with that generated using phase shifting algorithms to within λ/100 rms error. Our simulations and experimental results suggest the possibility of a simplified low-cost high quality optical metrology system for performing routine metrology tests involving smooth surface profiles.

A Complex Interplay of DJ-1, LRRK2, and Nrf2 in the Regulation of Mitochondrial Function in Cypermethrin-Induced Parkinsonism.

Cypermethrin impairs mitochondrial function, induces redox imbalance, and leads to Parkinsonism in experimental animals. Knockdown of deglycase-1 (DJ-1) gene, which encodes a redox-sensitive antioxidant protein, aggravates cypermethrin-mediated α-synuclein overexpression and oxidative alteration of proteins. DJ-1 is also reported to be essential for maintaining stability of nuclear factor erythroid 2-related factor 2 (Nrf2), shielding cells against oxidative insult. Leucine-rich repeat kinase 2 (LRRK2), another protein associated with Parkinson's disease, is also involved in regulating mitochondrial function. However, underlying molecular mechanisms remain elusive. The study intended to explore an interaction of DJ-1, LRRK2, and Nrf2 in the regulation of mitochondrial function in cypermethrin-induced Parkinsonism. Small interfering RNA-mediated knockdown of DJ-1 and LRRK2 gene and pharmacological activation of Nrf2 were performed in rats and/or human neuroblastoma cells with or without cypermethrin. Indexes of oxidative stress, mitochondrial impairment, and Parkinsonism along with α-synuclein expression, post-translational modification, and aggregation were measured. DJ-1 gene knockdown exacerbated cypermethrin-induced increase in oxidative stress and intrinsic apoptosis and reduction in expression of mitochondrial antioxidant proteins via inhibiting nuclear translocation of Nrf2. Additionally, cypermethrin-induced oxidative stress, mitochondrial impairment, and α-synuclein expression and aggregation were found to be suppressed by LRRK2 gene knockdown, by promoting Nrf2 nuclear translocation and expression of mitochondrial antioxidant proteins. Furthermore, Nrf2 activator, sulforaphane, ameliorated cypermethrin-induced mitochondrial impairment and oxidative stress and provided protection against dopaminergic neuronal death. The findings indicate that DJ-1 and LRRK2 independently alter Nrf2-mediated changes and a complex interplay among DJ-1, LRRK2, and Nrf2 exists in the regulation of mitochondrial function in cypermethrin-induced Parkinsonism.

Early-onset familial hypercholesterolemia: A case of extensive xanthomas and premature coronary artery disease.

Key Clinical Message: Early recognition and management of familial hypercholesterolemia (FH) are crucial, especially in patients with extensive xanthomas and premature coronary artery disease. Prompt diagnosis and aggressive lipid-lowering therapy can significantly reduce morbidity and mortality rates. Careful clinical assessment in resource-limited settings is essential for optimal outcomes. Abstract: Familial hypercholesterolemia (FH) is an autosomal dominant inherited disorder that causes chronically elevated levels of low-density lipoprotein (LDL) cholesterol. Based on LDL levels, FH can be heterozygous or homozygous, further established through clinical features, laboratory findings, and genetic analysis. Elevated cholesterol levels cause atherosclerosis, coronary artery disease, myocardial infarction, and sudden death. Xanthomas are a clinical manifestation of FH that reveal the underlying systemic genetic disease. We present the case of a 47-year-old male with triple vessel coronary artery disease and widespread xanthomas, diagnosed with homozygous FH based on "The Dutch Lipid Clinic Network Diagnostic Criteria for Familial Hypercholesterolemia." Lifelong therapy with lipid-lowering medications and lifestyle changes is necessary in such cases.

A decade of pyridine-containing heterocycles in US FDA approved drugs: a medicinal chemistry-based analysis.

Heterocyclic scaffolds, particularly, pyridine-containing azaheterocycles, constitute a major part of the drugs approved in the past decade. In the present review, we explored the pyridine ring part of US FDA-approved small molecules (2014-2023). The analysis of the approved drugs bearing a pyridine ring revealed that a total of 54 drugs were approved. Among them, the significant number comprised the anticancer category (18 drugs, 33%), followed by drugs affecting the CNS system (11 drugs, 20%), which include drugs to treat migraines, Parkinsonism disorders, chemotherapeutic-induced nausea, insomnia, and ADHD or as CNS-acting analgesics or sedatives. Next, six drugs (11%) were also approved to treat rare conditions, followed by five drugs that affect the hematopoietic system. The analysis also revealed that drug approval was granted for antibiotics, antivirals, and antifungals, including drugs for the treatment of tropical and sub-tropical diseases. Primary drug targets explored were kinases, and the major metabolizing enzyme was CYP3A4. Further analysis of formulation types revealed that 50% of the approved drugs were tablets, followed by 17% capsules and 15% injections. Elemental analysis showed that most approved drugs contained sulfur, while fluorine was noted in 32 compounds. Therefore, the present review is a concerted effort to cover drugs bearing pyridine rings approved in the last decade and provide thorough discussion and commentary on their pharmacokinetics and pharmacodynamics aspects. Furthermore, in-depth structural and elemental analyses were explored, thus providing comprehensive guidance for medicinal chemists and scientists working in allied science domains.

Exploring the Artificial Intelligence and Its Impact in Pharmaceutical Sciences: Insights Toward the Horizons Where Technology Meets Tradition.

The technological revolutions in computers and the advancement of high-throughput screening technologies have driven the application of artificial intelligence (AI) for faster discovery of drug molecules with more efficiency, and cost-friendly finding of hit or lead molecules. The ability of software and network frameworks to interpret molecular structures' representations and establish relationships/correlations has enabled various research teams to develop numerous AI platforms for identifying new lead molecules or discovering new targets for already established drug molecules. The prediction of biological activity, ADME properties, and toxicity parameters in early stages have reduced the chances of failure and associated costs in later clinical stages, which was observed at a high rate in the tedious, expensive, and laborious drug discovery process. This review focuses on the different AI and machine learning (ML) techniques with their applications mainly focused on the pharmaceutical industry. The applications of AI frameworks in the identification of molecular target, hit identification/hit-to-lead optimization, analyzing drug-receptor interactions, drug repurposing, polypharmacology, synthetic accessibility, clinical trial design, and pharmaceutical developments are discussed in detail. We have also compiled the details of various startups in AI in this field. This review will provide a comprehensive analysis and outline various state-of-the-art AI/ML techniques to the readers with their framework applications. This review also highlights the challenges in this field, which need to be addressed for further success in pharmaceutical applications.

Effect of GLP-1 receptor agonists on prostate cancer risk reduction: a systematic review and meta-analysis.

BACKGROUND: Prostate cancer is one of the most prevalent malignancies among men globally. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs), primarily used for type 2 diabetes mellitus (T2DM) management, have been investigated for their potential effects on cancer risks. This systematic review and meta-analysis aimed to assess the association between GLP-1 RA use and risk reduction of prostate cancer. METHODS: A comprehensive literature search was conducted across PubMed, Embase, and Web of Science up to July 30, 2024. Studies that met the inclusion criteria randomized controlled trials, cohort studies, case-control studies, and observational studies assessing the incidence of prostate cancer in GLP-1 RA-treated patients were included. The quality of studies was evaluated using the Newcastle-Ottawa Scale and the Cochrane Risk of Bias tool. Meta-analysis was performed using a random effects model. RESULTS: A total of five studies were included, analyzing data from diverse international contexts. The included studies showed a reduced risk of prostate cancer with both adjusted and unadjusted effect estimates with GLP-1 RAs. The meta-analysis revealed an RR of 0.72 (95% CI: 0.610 to 0.832), indicating a statistically significant 28% reduction in prostate cancer risk associated with GLP-1 RA use compared to placebo or other antidiabetic drugs. Moderate heterogeneity was observed (I2 = 51%). Sensitivity analysis confirmed the results. CONCLUSION: The findings suggest a significant protective association between GLP-1 RA use and reduced prostate cancer risk in men, particularly those with T2DM. This supports the potential of GLP-1 RAs not only in diabetes management but also as a strategy to mitigate cancer risk. Further research is required to confirm these findings and explore the underlying mechanisms, considering different dosages, durations of therapy, and patient subgroups based on demographic and metabolic characteristics.