JMIRx Med. 2022 May 3;3(2):e32902. doi: 10.2196/32902.

ABSTRACT

BACKGROUND: The availability of pharmacogenomic (PGx) methods to determine the right drug and dosage for individualized patient treatment has increased over the past decade. Adoption of the resulting PGx reports in a clinical setting and monitoring of clinical outcomes is a challenging and long-term commitment.

OBJECTIVE: This study summarizes an extended PGx deep sequencing panel intended for medication dosing and prescription guidance newly adopted in a pain management clinic. The primary outcome of this retrospective study reports the number of cases and types of drugs covered, for which PGx data appears to have assisted in optimal drug prescription and dosing.

METHODS: A PGx panel is described, encompassing 23 genes and 141 single-nucleotide polymorphisms or indels, combined with PGx dosing guidance and drug-gene interaction (DGI) and drug-drug interaction (DDI) reporting to prevent adverse drug reactions (ADRs). During a 2-year period, patients (N=171) were monitored in a pain management clinic. Urine toxicology, PGx reports, and progress notes were studied retrospectively for changes in prescription regimens before and after the PGx report was made available to the provider. An additional algorithm provided DGIs and DDIs to prevent ADRs.

RESULTS: Among patient PGx reports with medication lists provided (n=146), 57.5% (n=84) showed one or more moderate and 5.5% (n=8) at least one serious PGx interaction. A total of 96 (65.8%) patients showed at least one moderate and 15.1% (n=22) one or more serious DGIs or DDIs. A significant number of active changes in prescriptions based on the 102 PGx/DGI/DDI report results provided was observed for 85 (83.3%) patients for which a specific drug was either discontinued or switched within the defined drug classes of the report, or a new drug was added.

CONCLUSIONS: Preventative action was observed for all serious interactions, and only moderate interactions were tolerated for the lack of other alternatives. This study demonstrates the application of an extended PGx panel combined with a customized informational report to prevent ADRs and improve patient care.

PMID:37725552 | DOI:10.2196/32902

Pharmgenomics Pers Med. 2023 Sep 13;16:847-857. doi: 10.2147/PGPM.S422495. eCollection 2023.

ABSTRACT

BACKGROUND: N-acetyltransferase 2 (NAT2) enzyme is a Phase II drug-metabolizing enzyme that metabolizes different compounds. Genetic variations in NAT2 can influence the enzyme's activity and potentially lead to the development of certain diseases.

AIM: This study aimed to investigate the association of NAT2 variants with the risk of Type II diabetes mellitus (T2DM) and the lipid profile among Jordanian patients.

METHODS: We sequenced the whole protein-coding region in NAT2 using Sanger's method among a sample of 45 Jordanian T2DM patients and 50 control subjects. Moreover, we analyzed the lipid profiles of the patients and examined any potential associations with NAT2 variants.

RESULTS: This study revealed that the heterozygous NAT2*13 C/T genotype is significantly (P = 0.03) more common among T2DM (44%) than non-T2DM subjects (23.5%). Furthermore, the frequency of homozygous NAT2*13 T/T genotype was found to be significantly higher (P = 0.03) among T2DM patients (26.7%) compared to that of non-T2DM subjects (11%). The heterozygous NAT2*7 G/A genotype was exclusively observed in T2DM patients (11.1%) and absent in the control non-T2DM group. Moreover, among T2DM patients, those with a homozygous NAT2*11 T/T genotype exhibited significantly higher levels of triglycerides (381.50 ± 9.19 ng/dL) with a P value of 0.01 compared to those with heterozygous NAT2*11 C/T (136.23 ± 51.12 ng/dL) or wild-type NAT2*11 C/C (193.65 ± 109.89 ng/dL) genotypes. T2DM patients with homozygous NAT2*12 G/G genotype had a significantly (P = 0.04) higher triglyceride levels (275.67 ± 183.42 ng/dL) than the heterozygous NAT2*12 A/G (140.02 ± 49.53 ng/dL) and the wild NAT2*12 A/A (193.65 ± 109.89 ng/dL).

CONCLUSION: The finding in this study suggests that the NAT2 gene is a potential biomarker for the development of T2DM and changes in triglyceride levels among Jordanians. However, it is important to note that our sample size was limited; therefore, further clinical studies with a larger cohort are necessary to validate these findings.

PMID:37724295 | PMC:PMC10505377 | DOI:10.2147/PGPM.S422495

Cureus. 2023 Aug 18;15(8):e43697. doi: 10.7759/cureus.43697. eCollection 2023 Aug.

ABSTRACT

Diabetes mellitus poses a substantial global health challenge, necessitating innovative approaches to improve patient outcomes. Conventional one-size-fits-all treatment strategies have shown limitations in addressing the diverse nature of the disease. In recent years, personalized medicine has emerged as a transformative solution, tailoring treatment plans based on individual genetic makeup, lifestyle factors, and health characteristics. This review highlights the role of genetic screening in predicting diabetes susceptibility and response to treatment, as well as the potential of pharmacogenomics in optimizing medication choices. Moreover, it discusses the incorporation of lifestyle modifications and behavioral interventions to empower patients in their health journey. Telemedicine and remote patient monitoring are also examined for their role in enhancing accessibility and adherence. Ethical considerations and challenges in implementing personalized medicine are addressed. The review envisions a future where personalized medicine becomes a cornerstone in diabetes management, ensuring improved patient outcomes and fostering more effective and patient-centric care on a global scale.

PMID:37724233 | PMC:PMC10505357 | DOI:10.7759/cureus.43697

JCO Oncol Pract. 2023 Sep 18:OP2300034. doi: 10.1200/OP.23.00034. Online ahead of print.

ABSTRACT

PURPOSE: There is a paucity of real-world data on opioid screening and urine toxicology testing in outpatient oncology palliative medicine.

METHODS: This was a retrospective analysis of adult patients with cancer completing ≥ one outpatient palliative medicine visit and the Edmonton Symptom Assessment Scale (ESAS). Patient demographics, the Screener and Opioid Assessment for Patients with Pain-Short Form (SOAPP-SF), ESAS, medications, and urine toxicology screens (UTSs) were collected at baseline and follow-up visits. The primary end point was the frequency and type(s) of noncompliant UTSs (ie, presence of a nonprescribed substance or absence of a prescribed substance). Secondarily, risk factors for noncompliant UTSs were evaluated using univariate and multivariable logistic regression.

RESULTS: Of 189 evaluable patients (632 clinic visits), 113 underwent ≥one UTSs, 125 SOAPP-SF, and 75 had both. The median age was 56 (range, 26-80) years, 56% were female, 58% were White, 40% were Black, 48% had stage IV disease, the median baseline pain score was 7, and the median SOAPP-SF was 3. Oxycodone was the most prescribed drug (n = 125). Of 113 patients who underwent UTSs, 54% (n = 61) had ≥one noncompliant result. Thirty-nine percent (n = 44) had a total of 128 noncompliant results for the presence of a nonprescribed substance; 29% (n = 33) had a total of 53 noncompliant results for the absence of a prescribed substance. SOAPP-SF Q4 (use of illegal drugs) (odds ratio [OR], 3.61; 95% CI, 1.81 to 7.19; P < .001) and prescription with nonopioid adjuvant medications (OR, 2.83; 95% CI, 1.12 to 7.19; P = .029) were associated with increased odds of a noncompliant UTS.

CONCLUSION: More than half of the tested population had noncompliant UTS. Screening and evaluating risk factors for nonmedical opioid use is critical in oncology palliative medicine.

PMID:37722086 | DOI:10.1200/OP.23.00034

JAMA Netw Open. 2023 Sep 5;6(9):e2333533. doi: 10.1001/jamanetworkopen.2023.33533.

ABSTRACT

IMPORTANCE: The optimal maintenance strategy after induction chemotherapy with anti-epidermal growth factor receptor antibody for patients with RAS wild-type metastatic colorectal cancer (mCRC) remains to be debated.

OBJECTIVE: To evaluate the efficacy and safety of maintenance therapy with single-agent cetuximab after FOLFIRI (leucovorin [folinic acid], fluorouracil, and irinotecan) plus cetuximab induction therapy.

DESIGN, SETTING, AND PARTICIPANTS: The TIME (Treatment After Irinotecan-Based Frontline Therapy: Maintenance With Erbitux]) (PRODIGE 28 [Partenariat de Recherche en Oncologie Digestive]-UCGI 27 [UniCancer GastroIntestinal Group]) phase 2 noncomparative, multicenter randomized clinical trial was conducted from January 15, 2014, to November 23, 2018, among 139 patients with unresectable RAS wild-type mCRC. The cutoff date for analysis was July 21, 2022.

INTERVENTIONS: After first-line induction therapy with 8 cycles of FOLFIRI plus cetuximab, patients without disease progression were randomized (1:1) to biweekly maintenance with cetuximab or observation. On disease progression, the same induction regimen was recommended for 16 weeks followed by further maintenance with cetuximab or observation until disease progression under the full induction regimen.

MAIN OUTCOMES AND MEASURES: The primary end point was the 6-month progression-free rate from randomization. Analysis was performed on an intention-to-treat basis. An exploratory biomolecular analysis, using next-generation sequencing, investigated the putative prognostic value of the tumor mutation profile.

RESULTS: Of 214 patients enrolled (141 men [65.9%]; median age, 67 years [range, 23-85 years]), 139 were randomized to receive cetuximab (n = 67; 45 men [67.2%]; median age, 64 years [range, 34-85 years]) or to be observed (n = 72; 50 men [69.4%]; median age, 68 years [23-85 years]). The 6-month progression-free rate was 38.8% ([26 of 67] 95% CI, 27.1%-51.5%) in the cetuximab group and 5.6% ([4 of 72] 95% CI, 1.5%-13.6%) in the observation group. At a median follow-up of 40.5 months (95% CI, 33.6-47.5 months), median progression-free survival (PFS) from randomization was 5.3 months (95% CI, 3.7-7.4 months) in the cetuximab group and 2.0 months (95% CI, 1.8-2.7 months) in the observation group. Median overall survival (OS) was 24.8 months (95% CI, 18.7-30.4 months) in the cetuximab group and 19.7 months (95% CI, 13.3-24.4 months) in the observation group. In an exploratory multivariate analysis, any tumor-activating mutation in the mitogen-activated protein kinase (MAPK) pathway genes was associated with shorter PFS from randomization regardless of treatment group (hazard ratio, 1.63 [95% CI, 1.01-2.62]; P = .04). The most frequent grade 3 or 4 treatment-related toxic effect in the cetuximab group during maintenance therapy was rash (8 of 67 [11.9%]).

CONCLUSION AND RELEVANCE: The randomized clinical trial did not meet its primary end point but suggests clinically meaningful PFS and OS benefits associated with cetuximab maintenance therapy. However, maintenance cetuximab or treatment breaks after first-line combination FOLFIRI-cetuximab therapy seems inappropriate for patients with MAPK-mutated independently of the side of primary tumor. A more complete assessment of MAPK pathway mutations warrants further investigation to the refine treatment strategy for patients with RAS wild-type mCRC.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02404935.

PMID:37721754 | DOI:10.1001/jamanetworkopen.2023.33533

Clin Transl Sci. 2023 Sep 18. doi: 10.1111/cts.13637. Online ahead of print.

ABSTRACT

Pharmacogenomics (PGx) implementation into clinical care is rapidly increasing in China. However, the extent to which the public understands PGx testing and important knowledge domains requiring patient education or counseling remains unclear. To address this, we created and validated the Chinese version of the Minnesota Assessment of Pharmacogenomic Literacy (MAPL-C). The MAPL-C was developed by translating English MAPL to Chinese following cross-cultural translation guidelines. An online survey validated the MAPL-C and assessed Chinese individuals' PGx literacy. Validation analyses and associations with participants' characteristics were quantified. Of 959 high-quality responses, the majority of respondents were Han Chinese (96.3%), male (54.5%), aged 18-29 years (70.9%), residing in China (97.3%), and had received college or higher education (95.0%). Out of 15 starting items developed to query specific predefined knowledge domains, two uninformative items were excluded, resulting in a 13-item MAPL-C. Chinese participants' MAPL-C performance was best explained by a three-factor model, encompassing PGx concepts and function, testing limitations, and privacy. Higher MAPL-C performance was associated with younger age, higher education, and previous genetic testing experience. Correct response rates for questions related to testing limitations were lower than other domains. The creation and validation of the MAPL-C fills a gap in determining PGx knowledge among Chinese speakers, quantifying PGx literacy within a Chinese cohort and identifying response patterns and knowledge gaps. The MAPL-C can be useful in clinical practice to guide patient counseling, assess PGx education interventions, and quantify PGx knowledge in relation to outcomes in research studies involving Chinese participants.

PMID:37721333 | DOI:10.1111/cts.13637

Front Pharmacol. 2023 Aug 31;14:1274075. doi: 10.3389/fphar.2023.1274075. eCollection 2023.

ABSTRACT

[This corrects the article DOI: 10.3389/fphar.2023.1178421.].

PMID:37719864 | PMC:PMC10502220 | DOI:10.3389/fphar.2023.1274075

Asian Biomed (Res Rev News). 2023 Sep 17;17(2):84-92. doi: 10.2478/abm-2023-0048. eCollection 2023 Apr.

ABSTRACT

BACKGROUND: The cytochrome P450 (CYP450) family is well known as a major group of drug metabolizing enzymes. The polymorphism of CYP450 genes is the main factor having an impact on the interindividual difference in drug response, including drug efficacy and drug safety. The single nucleotide polymorphism (SNPs) of Vietnamese Kinh has been widely studied, but information about the copy number variations (CNVs) of other CYP450 genes is still unknown.

OBJECTIVE: To identify the CNV variability of CYP450 in 154 healthy unrelated Kinh Vietnamese, except eCYP2D6, which was previously reported.

METHODS: Multiplex Ligation-Dependent Probe Amplification (MLPA) was applied for determination of copy number of 10 CYP450 genes. Later, PCR or quantitative PCR (qPCR) was used to confirm the detected CNVs in randomly chosen subjects.

RESULTS: Of the 154 subjects, along with CYP2D6, 4 other CYP450 genes showed CNVs including duplications (CYP1B1), deletions (CYP2A6 and CYP2C9), and both duplications and deletions (CYP2E1). Among these, CYP2A6 exhibited the greatest frequency of CNVs compared with other CYP450, in which CYP2A6Del accounted for 11%. Meanwhile, allele CYP2E1Del showed the lowest frequency with only 0.3%.

CONCLUSIONS: The present study provides new insight into CYP450 CNVs in the Kinh Vietnamese cohort. Our data have contributed to genetic profiling of CYP450 CNVs in Vietnam, which would be helpful for facilitating implementation of pharmacogenetics in drug dosing adjustment in Vietnam.

PMID:37719322 | PMC:PMC10505059 | DOI:10.2478/abm-2023-0048

Br J Clin Pharmacol. 2023 Sep 15. doi: 10.1111/bcp.15909. Online ahead of print.

ABSTRACT

AIMS: This study aimed to provide up-to-date information on pediatric population pharmacokinetics (PopPK) models of tacrolimus and to identify factors influencing tacrolimus pharmacokinetic variability.

METHODS: Systematic searches in the Web of Science, PubMed, Scopus, Science Direct, Cochrane, EMBASE databases, and reference lists of articles were conducted from inception to March 2023. All PopPK studies of tacrolimus using nonlinear mixed-effect modeling in pediatric solid organ transplant patients were included.

RESULTS: Of the 21 studies reviewed, 62% developed from liver transplant recipients and 33% from kidney transplant recipients. Most studies used a one-compartment model to describe tacrolimus pharmacokinetics. Body weight was a significant predictor for tacrolimus volume of distribution (Vd/F). The estimated Vd/F for one-compartment models ranged from 20 to 1890 l, whereas the peripheral volume of distribution (Vp/F) for two-compartment models was between 290 and 1520 l. Body weight, days post-transplant, CYP3A5 genotype, or hematocrit were frequently reported as significant predictors of tacrolimus clearance. The estimated apparent clearance values range between 0.12 and 2.18 L/h/kg, with inter-individual variability from 13.5% to 110.0%. Only 29% of the studies assessed the generalizability of the models with external validation.

CONCLUSION: This review highlights the potential factors, modeling approaches, and validation methods that impact tacrolimus pharmacokinetics in a pediatric population. The clinician could predict tacrolimus clearance based on body weight, CYP3A5 genotype, days post-transplant, or hematocrit. Further research is required to determine the relationship between pharmacogenetics and tacrolimus pharmacodynamics in pediatric patients and confirm the applicability of nonlinear kinetics in this population.

PMID:37714740 | DOI:10.1111/bcp.15909

Am J Pharm Educ. 2023 Sep;87(9):100077. doi: 10.1016/j.ajpe.2023.100077. Epub 2023 May 10.

ABSTRACT

OBJECTIVE: Incorporating diversity, equity, inclusion, and anti-racism principles into clinical and didactic education is essential because each influence cognitive and affective attitudes in pharmacy practice. Educators must learn from the past to enlighten the future. For example, race is a social construct, not a biological construct. However, it persistently acts as a surrogate for determining medical diagnoses and treatment.

FINDINGS: Precision medicine and pharmacogenomics can serve as a basis for deconstructing social constructs surrounding race and other social determinants of health.

SUMMARY: In this review, the authors highlight why using race in health education will lead to less-than-optimal clinical decisions and discuss best practices for incorporating diversity, equity, inclusion, and anti-racism into health education from a pharmacogenomic-based perspective.

PMID:37714655 | DOI:10.1016/j.ajpe.2023.100077

ESMO Open. 2023 Sep 13;8(5):101628. doi: 10.1016/j.esmoop.2023.101628. Online ahead of print.

ABSTRACT

BACKGROUND: Testing for epidermal growth factor receptor (EGFR) mutations is an essential recommendation in guidelines for metastatic non-squamous non-small-cell lung cancer, and is considered mandatory in European countries. However, in practice, challenges are often faced when carrying out routine biomarker testing, including access to testing, inadequate tissue samples and long turnaround times (TATs).

MATERIALS AND METHODS: To evaluate the real-world EGFR testing practices of European pathology laboratories, an online survey was set up and validated by the Pulmonary Pathology Working Group of the European Society of Pathology and distributed to 64 expert testing laboratories. The retrospective survey focussed on laboratory organisation and daily EGFR testing practice of pathologists and molecular biologists between 2018 and 2021.

RESULTS: TATs varied greatly both between and within countries. These discrepancies may be partly due to reflex testing practices, as 20.8% of laboratories carried out EGFR testing only at the request of the clinician. Many laboratories across Europe still favour single-test sequencing as a primary method of EGFR mutation identification; 32.7% indicated that they only used targeted techniques and 45.1% used single-gene testing followed by next-generation sequencing (NGS), depending on the case. Reported testing rates were consistent over time with no significant decrease in the number of EGFR tests carried out in 2020, despite the increased pressure faced by testing facilities during the COVID-19 pandemic. ISO 15189 accreditation was reported by 42.0% of molecular biology laboratories for single-test sequencing, and by 42.3% for NGS. 92.5% of laboratories indicated they regularly participate in an external quality assessment scheme.

CONCLUSIONS: These results highlight the strong heterogeneity of EGFR testing that still occurs within thoracic pathology and molecular biology laboratories across Europe. Even among expert testing facilities there is variability in testing capabilities, TAT, reflex testing practice and laboratory accreditation, stressing the need to harmonise reimbursement technologies and decision-making algorithms in Europe.

PMID:37713929 | DOI:10.1016/j.esmoop.2023.101628

Anal Chem. 2023 Sep 15. doi: 10.1021/acs.analchem.3c01668. Online ahead of print.

ABSTRACT

The detection of single nucleotide polymorphisms (SNPs) is of increasing importance in many areas including clinical diagnostics, patient stratification for pharmacogenomics, and advanced forensic analysis. In the work reported, we apply a semiautomated system for solid-phase electrochemical melting curve analysis (éMCA) for the identification of the allele present at a specific SNP site associated with an increased risk of bone fracture and predisposition to osteoporosis. Asymmetric isothermal recombinase polymerase amplification using ferrocene labeled forward primers was employed to generate single stranded redox labeled amplicons. In a first approach to demonstrate the proof of concept of combining asymmetric RPA with solid-phase éMCA, a simplified system housing a multielectrode array within a polymeric microsystem, sandwiched between two aluminum plates of a heater device, was used. Sample manipulation through the microfluidic channel was controlled by a syringe pump, and an external Ag/AgCl reference electrode was employed. Individual electrodes of the array were functionalized with four different oligonucleotide probes, each probe equivalent in design with the exception of the middle nucleotide. The isothermally generated amplicons were allowed to hybridize to the surface-tethered probes and subsequently subjected to a controlled temperature ramp, and the melting of the duplex was monitored electrochemically. A clear difference between the fully complementary and a single mismatch was observed. Having demonstrated the proof-of-concept, a device for automated éMCA with increased flexibility to house diverse electrode arrays with internal quasi-gold reference electrodes, higher resolution, and broader melting temperature range was developed and exploited for the detection of SNP hetero/homozygosity. Using the optimized conditions, the system was applied to the identification of the allele present at an osteoporosis associated SNP site, rs2741856, in 10 real fingerprick/venous blood samples, with results validated using Sanger sequencing.

PMID:37713191 | DOI:10.1021/acs.analchem.3c01668

J Clin Invest. 2023 Sep 15;133(18):e173932. doi: 10.1172/JCI173932.

NO ABSTRACT

PMID:37712423 | DOI:10.1172/JCI173932

Am J Hypertens. 2023 Sep 15:hpad084. doi: 10.1093/ajh/hpad084. Online ahead of print.

ABSTRACT

BACKGROUND: Apparent treatment-resistant hypertension (aTRH) is defined as uncontrolled blood pressure (BP) despite using ≥3 antihypertensive classes or controlled BP while using ≥4 antihypertensive classes. Patients with aTRH have a higher risk for adverse cardiovascular outcomes compared to patients with controlled hypertension (HTN). Although there have been prior reports on the prevalence, characteristics, and predictors of aTRH, these have been broadly derived from smaller datasets, randomized controlled trials, or closed healthcare systems.

METHODS: We extracted patients with HTN defined by ICD 9 and 10 codes during 1/1/2015-12/31/2018, from two large electronic health record databases: the OneFlorida Data Trust (n=223,384) and Research Action for Health Network (REACHnet) (n=175,229). We applied our previously validated aTRH and stable controlled HTN computable phenotype algorithms and performed univariate and multivariate analyses to identify the prevalence, characteristics, and predictors of aTRH in these populations.

RESULTS: The prevalence of aTRH among patients with HTN in OneFlorida (16.7%) and REACHnet (11.3%) was similar to prior reports. Both populations had a significantly higher proportion of Black patients with aTRH compared to those with stable controlled HTN. aTRH in both populations shared similar significant predictors, including Black race, diabetes, heart failure, chronic kidney disease, cardiomegaly, and higher body mass index. In both populations, aTRH was significantly associated with similar comorbidities, when compared with stable controlled HTN.

CONCLUSIONS: In two large, diverse real-world populations, we observed similar comorbidities and predictors of aTRH as prior studies. In the future, these results may be used to improve healthcare professionals' understanding of aTRH predictors and associated comorbidities.

PMID:37712350 | DOI:10.1093/ajh/hpad084

Pharmacogenomics. 2023 Sep 15. doi: 10.2217/pgs-2023-0122. Online ahead of print.

ABSTRACT

A woman with ocular hypertension suffered from severe bradycardia, hypotension and syncope attacks in temporal relation with ophthalmic timolol application. Topically applied timolol is nasally absorbed and has been shown to reach potentially relevant systemic concentrations. Timolol is mainly metabolized by CYP2D6, which exhibits interindividual metabolic capacity due to genetic variations. A reactive pharmacogenetic panel test identified the patient as a CYP2D6 homozygous *4 allele carrier, which has been associated with a poor metabolizer phenotype and lacking enzyme activity. Thus, the adverse drug reactions possibly resulted from increased systemic timolol exposure. This case report highlights that pharmacogenetic panel testing can contribute to safe and effective pharmacotherapy, even for topically applied drugs.

PMID:37712172 | DOI:10.2217/pgs-2023-0122

Pharmacogenomics. 2023 Sep 15. doi: 10.2217/pgs-2023-0084. Online ahead of print.

ABSTRACT

Introduction: As the most distressing complication of sickle cell disease (SCD), pain is marked by considerable heterogenicity. In this study we explored the potential association of alcohol dehydrogenase 7 gene (ADH7) polymorphism rs971074 with sickle cell pain. Methods: We analyzed clinical phenotypes and the rs971074 single-nucleotide polymorphism in ADH7 by MassARRAY-iPlex analysis in a cohort of SCD patients. Results: The synonymous rs971074 was significantly associated with both acute and chronic pain in SCD. Patients with the minor T allele(s) recorded significantly more crisis episodes and severe chronic pain symptoms. Conclusion: Our study has identified the rs971074 minor T allele as a genetic biomarker potentially influencing acute and chronic pain. These findings may ultimately help inform strategies to develop precision pain therapies in SCD.

PMID:37712142 | DOI:10.2217/pgs-2023-0084

Front Pharmacol. 2023 Aug 29;14:1277561. doi: 10.3389/fphar.2023.1277561. eCollection 2023.

NO ABSTRACT

PMID:37711174 | PMC:PMC10497968 | DOI:10.3389/fphar.2023.1277561

Diabetes Ther. 2023 Sep 14. doi: 10.1007/s13300-023-01463-9. Online ahead of print.

ABSTRACT

BACKGROUND: Type 2 diabetes mellitus (T2D) is commonly associated with an increasing complexity of multimorbidity. While some progress has been made in identifying genetic and non-genetic risk factors for T2D, understanding the longitudinal clinical history of individuals before/after T2D diagnosis may provide additional insights.

METHODS: In this study, we utilised longitudinal data from the DARE (Diabetes Alliance for Research in England) study to examine the trajectory of clinical conditions in individuals with and without T2D. Data from 1932 individuals (T2D n = 1196 vs. matched non-T2D controls n = 736) were extracted and subjected to trajectory analysis over a period of up to 50 years (25 years pre-diagnosis/25 years post-diagnosis). We also analysed the cumulative proportion of people with diagnosed coronary artery disease (CAD) in their general practice (GP) record with an analysis of lower respiratory tract infection (RTI) as a comparator group.

RESULTS: The mean age of diagnosis of T2D was 52.6 (95% confidence interval 52.0-53.4) years. In the years leading up to T2D diagnosis, individuals who eventually received a T2D diagnosis consistently exhibited a considerable increase in several clinical phenotypes. Additionally, immediately prior to T2D diagnosis, a significantly greater prevalence of hypertension (35%)/RTI (34%)/heart conditions (17%)/eye, nose, throat infection (19%) and asthma (12%) were observed. The corresponding trajectory of each of these conditions was much less dramatic in the matched controls. Post-T2D diagnosis, proportions of T2D individuals exhibiting hypertension/chronic kidney disease/retinopathy/infections climbed rapidly before plateauing. At the last follow-up by quintile of disadvantage, the proportion (%) of people with diagnosed CAD was 6.4% for quintile 1 (least disadvantaged) and 11% for quintile 5 (F = 3.4, p = 0.01 for the difference between quintiles).

CONCLUSION: These findings provide novel insights into the onset/natural progression of T2D, suggesting an early phase of inflammation-related disease activity before any clinical diagnosis of T2D is made. Measures that reduce social inequality have the potential in the longer term to reduce the social gradient in health outcomes reported here.

PMID:37707702 | DOI:10.1007/s13300-023-01463-9

Histopathology. 2023 Sep 14. doi: 10.1111/his.15040. Online ahead of print.

ABSTRACT

AIMS: Malignant tumours of the lacrimal apparatus are rare and frequently show a poor prognosis, with no clear therapeutic standards. Characterisation of the genetic landscape of these rare tumours is sparse, and therefore therapeutics generally follow those of their common salivary gland counterparts. To further clarify the pathophysiology and discover potential therapeutic targets, we investigated the genetic landscape of eight tumours of the lacrimal apparatus.

METHODS AND RESULTS: DNA and RNA sequencing were performed to identify genetic mutations and gene fusions. Immunohistochemistry, fluorescence in-situ hybridisation and reverse transcription-polymerase chain reaction followed by Sanger sequencing were performed to confirm the identified molecular alterations. Genetic alterations were detected in six tumours. Among five adenoid cystic carcinomas (ACC), four had confirmed alterations of MYB or MYBL1 genes, including a MYB::NFIB fusion, a MYBL1::NFIB fusion, a MYB amplification and a novel NFIB::THSD7B fusion. Mutations in genes encoding epigenetic modifiers, as well as NOTCH1, FGFR2 and ATM mutations, were also identified in ACCs. A carcinoma ex pleomorphic adenoma showed TP53 and CIC mutations and an amplification of ERBB2. A transitional cell carcinoma was associated with HPV16 infection. No genetic alteration was found for one adenocarcinoma, not otherwise specified.

CONCLUSIONS: Our study highlights the variety of molecular alterations associated with lacrimal system tumours and emphasises the importance of molecular testing in these tumours, which can reveal potentially targetable mutations. Our results also reinforce the hypothesis of a common physiopathology of all ACCs, regardless of their primary location.

PMID:37706251 | DOI:10.1111/his.15040

Pharmacogenomics. 2023 Sep 14. doi: 10.2217/pgs-2023-0111. Online ahead of print.

ABSTRACT

Background: ALK rearrangements account for around 5% of non-small-cell lung cancers. Aim: This study surveys physicians on the potential efficacy of a mobile application in improving the management of ALK-rearranged non-small-cell lung cancer, through knowledge, treatment adherence and real-time adverse events reporting. Materials & methods: A total of 118 physicians from 11 countries in the Middle East participated. Results & conclusion: Results indicate 94% support for enhancing team communication via an application, and 93% believe real-time adverse events reporting improves the quality of care. Participants found an ALK-rearrangement patient-physicians forum valuable for communication improvement. Motivations for application use included treatment planning (73%), care enhancement (60%) and contributing to publications (40%).

PMID:37706248 | DOI:10.2217/pgs-2023-0111