The association between blood biological age at rehabilitation admission and physical activity during rehabilitation in geriatric inpatients: RESORT.

Geriatric rehabilitation inpatients have high levels of sedentary behaviour (SB) and low levels of physical activity (PA). Biological age predicted by blood biomarkers is indicative of adverse outcomes. The objective was to determine the association between blood biological age at rehabilitation admission and levels of SB and PA during rehabilitation in geriatric inpatients. Inpatients admitted to geriatric rehabilitation wards at the Royal Melbourne Hospital (Melbourne, Australia) from October 22, 2019, to March 29, 2020, in the REStORing health of acute unwell adulTs (RESORT) observational cohort were included. Blood biological age was predicted using SenoClock-BloodAge, a hematological ageing clock. Patients wore an inertial sensor to measure SB and PA. Logistic regression analyses were conducted. A total of 111 patients (57.7% female) with mean age 83.3 ± 7.5 years were included in the analysis. The mean blood biological age was 82.7 ± 8.4 years. Patients with 1-year higher blood biological age had higher odds of having high SB measured as non-upright time greater than 23 h/day (odds ratio (OR): 1.050, 95% confidence interval (CI): 1.000-1.102). Individuals having 1-year higher age deviation trended towards lower odds of having high levels of PA measured as stepping time greater than 7.4 min/day (OR: 0.916, CI: 0.836-1.005) and as greater than 19.5 sit-to-stand transitions/day (OR: 0.915, CI: 0.836-1.002). In conclusion, higher biological age was associated with higher levels of SB and trended towards lower PA. Incorporating blood biological age could facilitate resource allocation and the development of more tailored rehabilitation plans.

Association of Race and Ethnicity With High Longevity Deceased Donor Kidney Transplantation Under the US Kidney Allocation System.

RATIONALE & OBJECTIVE: The US Kidney Allocation System (KAS) prioritizes candidates with ≤20% Estimated Post-Transplant Survival (EPTS) for high longevity kidneys defined by a ≤20% Kidney Donor Profile Index (KDPI). Use of EPTS in the KAS deprioritizes candidates with older age, diabetes, and longer dialysis durations. We assessed whether this use also disadvantages racial-ethnic minority candidates, who are younger but more likely to have diabetes and longer durations of kidney failure requiring dialysis. STUDY DESIGN: Observational cohort study. SETTING: & Participants: Adult candidates for and recipients of kidney transplantation represented in the Scientific Registry of Transplant Recipients from January 2015 through December 2020. EXPOSURE: Race and ethnicity. OUTCOMES: Age-adjusted assignment to ≤20% EPTS, transplantation of a ≤20% KDPI kidney, and post-transplant survival in longevity matched recipients by racial-ethnicity. ANALYTIC APPROACH: Multivariable logistic regression, Fine-Gray competing risks survival analysis, and Kaplan-Meier and Cox Proportional Hazards methods. RESULTS: The cohort included 199,444 candidates (7% Asian, 29% Black, 19% Hispanic/Latino, 43% White) listed for deceased donor kidney transplantation. Non-White candidates had significantly higher rates of diabetes, longer dialysis duration, and were younger than White candidates. Adjusted for age, Asian, Black, and Hispanic/Latino candidates had significantly lower odds of having a ETPS score ≤20% (OR 0.86, [0.81, 0.91], 0.52 [0.50, 0.54], and 0.49, [0.47, 0.51]), and were less likely to receive a ≤20% KDPI kidney (subHR 0.70 [0.66, 0.75], 0.89 [0.87, 0.92], and 0.73 [0.71, 0.76]), compared to White candidates. Among recipients with ≤20% EPTS scores transplanted with a ≤20% KDPI deceased donor kidney, Asian and Hispanic recipients had lower post-transplant mortality (HR 0.45 [0.27, 0.77], and 0.63 [0.47, 0.86]) and Black recipients had higher but not statistically significant post-transplant mortality (HR 1.22 [0.99, 1.52]) compared to White recipients. LIMITATIONS: Provider reported race-ethnicity data and 5-year post transplant follow-up period. CONCLUSIONS: The US kidney allocation system is less likely to identify racial-ethnic minority candidates as having a ≤20% EPTS score which triggers allocation of high longevity deceased donor kidneys. These findings should inform the OPTN about how to remedy racial/ethnic disparities introduced through KAS's current approach of allocating allografts with longer predicted longevity to recipients with longer estimated post-transplant survival.

The role of G protein-coupled receptor kinases in GLP-1R ß-arrestin recruitment and internalisation.

The glucagon-like peptide 1 receptor (GLP-1R) is a validated clinical target for the treatment of type 2 diabetes and obesity. Unlike most G protein-coupled receptors (GPCRs), the GLP-1R undergoes an atypical mode of internalisation that does not require ß-arrestins. While differences in GLP-1R trafficking and ß-arrestin recruitment have been observed between clinically used GLP-1R agonists, the role of G protein-coupled receptor kinases (GRKs) in affecting these pathways has not been comprehensively assessed. In this study, we quantified the contribution of GRKs to agonist-mediated GLP-1R internalisation and ß-arrestin recruitment profiles using cells where endogenous ß-arrestins, or non-visual GRKs were knocked out using CRISPR/Cas9 genome editing. Our results confirm the previously established atypical ß-arrestin-independent mode of GLP-1R internalisation and revealed that GLP-1R internalisation is dependent on the expression of GRKs. Interestingly, agonist-mediated GLP-1R ß-arrestin 1 and ß-arrestin 2 recruitment were differentially affected by endogenous GRK knockout with ß-arrestin 1 recruitment more sensitive to GRK knockout than ß-arrestin 2 recruitment. Moreover, individual overexpression of GRK2, GRK3, GRK5 or GRK6 in a newly generated GRK2/3/4/5/6 HEK293 cells, rescued agonist-mediated ß-arrestin 1 recruitment and internalisation profiles to similar levels, suggesting that there is no specific GRK isoform that drives these pathways. This study advances mechanistic understanding of agonist-mediated GLP-1R internalisation and provides novel insights into how GRKs may fine-tune GLP-1R signalling.

Remote monitoring technologies for measuring cardiovascular functions in community-dwelling adults: a systematic review.

Remote monitoring technologies (RMTs) allow continuous, unobtrusive, and real-time monitoring of the cardiovascular system. An overview of existing RMTs measuring cardiovascular physiological variables is lacking. This systematic review aimed to describe RMTs measuring cardiovascular functions in community-dwelling adults. An electronic search was conducted via PubMed, EMBASE, and Cochrane Library from January 1, 2020, to April 7, 2022. Articles reporting on non-invasive RMTs used unsupervised in community-dwelling adults were included. Reviews and studies in institutionalized populations were excluded. Two reviewers independently assessed the studies and extracted the technologies used, cardiovascular variables measured, and wearing locations of RMTs. Validation of the RMTs was examined based on the COSMIN tool, and accuracy and precision were presented. This systematic review was registered with PROSPERO (CRD42022320082). A total of 272 articles were included representing 322,886 individuals with a mean or median age from 19.0 to 88.9 years (48.7% female). Of all 335 reported RMTs containing 216 distinct devices, photoplethysmography was used in 50.3% of RMTs. Heart rate was measured in 47.0% of measurements, and the RMT was worn on the wrist in 41.8% of devices. Nine devices were reported in more than three articles, of which all were sufficiently accurate, six were sufficiently precise, and four were commercially available in December 2022. The top four most reported technologies were AliveCor KardiaMobile®, Fitbit Charge 2, and Polar H7 and H10 Heart Rate Sensors. With over 200 distinct RMTs reported, this review provides healthcare professionals and researchers an overview of available RMTs for monitoring the cardiovascular system.

Stereoselective Metabolism of Bupropion to Active Metabolites in Cellular Fractions of Human Liver and Intestine.

Striking stereoselective disposition of the antidepressant and smoking cessation aid bupropion (BUP) and its active metabolites observed clinically influence patients' response to BUP therapy and its clinically important drug-drug interactions (DDI) with CYP2D6 substrates. However, understanding of the biochemical mechanisms responsible is incomplete. This study comprehensively examined hepatic and extrahepatic stereoselective metabolism of BUP in vitro Racemic-, R-, and S-BUP were incubated separately with pooled cellular fractions of human liver [microsomes (HLMs), S9 fractions (HLS9s), and cytosols (HLCs)] and intestinal [microsomes (HIMs), S9 fractions (HIS9s), and cytosols (HICs)] and cofactors. Formations of diastereomers of 4-hydroxyBUP (OHBUP), threohydroBUP (THBUP), and erythrohydroBUP (EHBUP) were quantified using a novel chiral ultra-high performance liquid chromatography/tandem mass spectrometry method. Racemic BUP (but not R- or S-BUP) was found suitable to determine stereoselective metabolism of BUP; both enantiomers showed complete racemization. Compared with that of RR-THBUP, the in vitro intrinsic clearance (Clint) for the formation of SS-THBUP was 42-, 19-, and 8.3-fold higher in HLMs, HLS9 fractions, and HLCs, respectively; Clint for the formation of SS-OHBUP and RS-EHBUP was also higher (2.7- to 3.9-fold) than their R-derived counterparts. In cellular fractions of human intestine, ≥ 95% of total reduction was accounted by the formation of RR-THBUP. Ours is the first to demonstrate marked stereoselective reduction of BUP in HLCs, HIMs, HIS9 fractions, and HICs, providing the first evidence for tissue- and cellular fraction-dependent stereoselective metabolism of BUP. These data may serve as the first critical step toward understanding factors dictating BUP's stereoselective disposition, effects, and DDI risks. SIGNIFICANCE STATEMENT: This work provides a deeper insight into bupropion (BUP) stereoselective oxidation and reduction to active metabolites in cellular fractions of human liver and intestine tissues. The results demonstrate tissue- and cellular fraction-dependent stereospecific metabolism of BUP. These data may improve prediction of BUP stereoselective disposition and understanding of BUP's effects and CYP2D6-dependent drug-drug interaction in vivo.

Understanding VPAC receptor family peptide binding and selectivity.

The vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) receptors are key regulators of neurological processes. Despite recent structural data, a comprehensive understanding of peptide binding and selectivity among different subfamily receptors is lacking. Here, we determine structures of active, Gs-coupled, VIP-VPAC1R, PACAP27-VPAC1R, and PACAP27-PAC1R complexes. Cryo-EM structural analyses and molecular dynamics simulations (MDSs) reveal fewer stable interactions between VPAC1R and VIP than for PACAP27, more extensive dynamics of VIP interaction with extracellular loop 3, and receptor-dependent differences in interactions of conserved N-terminal peptide residues with the receptor core. MD of VIP modelled into PAC1R predicts more transient VIP-PAC1R interactions in the receptor core, compared to VIP-VPAC1R, which may underlie the selectivity of VIP for VPAC1R over PAC1R. Collectively, our work improves molecular understanding of peptide engagement with the PAC1R and VPAC1R that may benefit the development of novel selective agonists.

Prevalence, parameters, and pathogenic mechanisms for splice-altering acceptor variants that disrupt the AG exclusion zone.

Predicting the pathogenicity of acceptor splice-site variants outside the essential AG is challenging, due to high sequence diversity of the extended splice-site region. Critical analysis of 24,445 intronic extended acceptor splice-site variants reported in ClinVar and the Leiden Open Variation Database (LOVD) demonstrates 41.9% of pathogenic variants create an AG dinucleotide between the predicted branchpoint and acceptor (AG-creating variants in the AG exclusion zone), 28.4% result in loss of a pyrimidine at the -3 position, and 15.1% result in loss of one or more pyrimidines in the polypyrimidine tract. Pathogenicity of AG-creating variants was highly influenced by their position. We define a high-risk zone for pathogenicity: > 6 nucleotides downstream of the predicted branchpoint and >5 nucleotides upstream from the acceptor, where 93.1% of pathogenic AG-creating variants arise and where naturally occurring AG dinucleotides are concordantly depleted (5.8% of natural AGs). SpliceAI effectively predicts pathogenicity of AG-creating variants, achieving 95% sensitivity and 69% specificity. We highlight clinical examples showing contrasting mechanisms for mis-splicing arising from AG variants: (1) cryptic acceptor created; (2) splicing silencer created: an introduced AG silences the acceptor, resulting in exon skipping, intron retention, and/or use of an alternative existing cryptic acceptor; and (3) splicing silencer disrupted: loss of a deep intronic AG activates inclusion of a pseudo-exon. In conclusion, we establish AG-creating variants as a common class of pathogenic extended acceptor variant and outline factors conferring critical risk for mis-splicing for AG-creating variants in the AG exclusion zone, between the branchpoint and acceptor.

Targeting VIP and PACAP Receptor Signaling: New Insights into Designing Drugs for the PACAP Subfamily of Receptors.

Pituitary Adenylate Cyclase-Activating Peptide (PACAP) and Vasoactive Intestinal Peptide (VIP) are neuropeptides involved in a diverse array of physiological and pathological processes through activating the PACAP subfamily of class B1 G protein-coupled receptors (GPCRs): VIP receptor 1 (VPAC1R), VIP receptor 2 (VPAC2R), and PACAP type I receptor (PAC1R). VIP and PACAP share nearly 70% amino acid sequence identity, while their receptors PAC1R, VPAC1R, and VPAC2R share 60% homology in the transmembrane regions of the receptor. PACAP binds with high affinity to all three receptors, while VIP binds with high affinity to VPAC1R and VPAC2R, and has a thousand-fold lower affinity for PAC1R compared to PACAP. Due to the wide distribution of VIP and PACAP receptors in the body, potential therapeutic applications of drugs targeting these receptors, as well as expected undesired side effects, are numerous. Designing selective therapeutics targeting these receptors remains challenging due to their structural similarities. This review discusses recent discoveries on the molecular mechanisms involved in the selectivity and signaling of the PACAP subfamily of receptors, and future considerations for therapeutic targeting.

Influence of CYP2B6 Pharmacogenetics on Stereoselective Inhibition and Induction of Bupropion Metabolism by Efavirenz in Healthy Volunteers.

We investigated the acute and chronic effects of efavirenz, a widely used antiretroviral drug, and CYP2B6 genotypes on the disposition of racemic and stereoisomers of bupropion (BUP) and its active metabolites, 4-hydroxyBUP, threohydroBUP and erythrohydroBUP. The primary objective of this study was to test how multiple processes unique to the efavirenz-CYP2B6 genotype interaction influence the extent of efavirenz-mediated drug-drug interaction (DDI) with the CYP2B6 probe substrate BUP. In a three-phase, sequential, open-label study, healthy volunteers (N=53) were administered a single 100 mg oral dose of BUP alone (control phase), with a single 600 mg oral efavirenz dose (inhibition phase), and after 17-days pretreatment with efavirenz (600 mg/day) (induction phase). Compared to the control phase, we show for the first time that efavirenz significantly decreases and chronically increases the exposure of hydroxyBUP and its diastereomers, respectively, and these interactions were CYP2B6 genotype dependent. Chronic efavirenz enhances the elimination of racemic BUP and its enantiomers as well as of threo- and erythro-hydroBUP and their diastereomers, suggesting additional novel mechanisms underlying efavirenz interaction with BUP. The effects of efavirenz and genotypes were nonstereospecific. In conclusion, acute and chronic administration of efavirenz inhibits and induces CYP2B6 activity. Efavirenz-BUP interaction is complex involving time- and CYP2B6 genotype-dependent inhibition and induction of primary and secondary metabolic pathways. Our findings highlight important implications to the safety and efficacy of BUP, study design considerations for future efavirenz interactions, and individualized drug therapy based on CYP2B6 genotypes. Significance Statement The effects of acute and chronic doses of efavirenz on the disposition of racemic and stereoisomers of BUP and its active metabolites were investigated in healthy volunteers. Efavirenz causes an acute inhibition, but chronic induction of CYP2B6 in a genotype dependent manner. Chronic efavirenz induces BUP reduction and the elimination of BUP active metabolites. Efavirenz's effects were non-stereospecific. These data reveal novel mechanisms underlying efavirenz DDI with BUP and provide important insights into time- and CYP2B6 genotype dependent DDIs.

No pelvic exam, no problem: patient satisfaction following the integration of comprehensive urogynecology telemedicine.

INTRODUCTION AND HYPOTHESIS: The COVID-19 pandemic revolutionized the practice of medicine, requiring rapid adoption of telemedicine. However, patient satisfaction has not been well characterized for telemedicine visits for a broad range of urogynecologic conditions. METHODS: We performed a cross-sectional survey study following a retrospective review of all urogynecologic telemedicine visits from March 1, 2020, to March 31, 2021, at a tertiary care center. The survey queried patient satisfaction using the Likert scale. Descriptive statistics and Fisher's exact analyses were performed. RESULTS: There were 256 telemedicine visits at our institution during the study period, and 88 patients (34% unadjusted response rate) completed the survey. The average age of study participants was 55 (SD 17; 24, 84) years old. The majority of patients were white (69%), lived within the five boroughs of NYC (81%), and had higher levels of education (72% with a bachelor's or professional degree). Most visits were for urinary complaints (68%), with those patients reporting greater fulfillment of urogynecologic needs compared to patients presenting with pelvic complaints (p = 0.02). There were no significant differences in satisfaction among other demographics (p > 0.05). Altogether, high satisfaction rates were noted for scheduling (99%), technology (90%), provider interaction (96%), fulfillment of personal needs (91%), and overall satisfaction (94%). CONCLUSIONS: We demonstrate high patient satisfaction for telemedicine visits in a tertiary urogynecology clinic for a variety of indications, with greater fulfillment of urogynecologic needs observed for those visits which may not necessitate an in-person exam (e.g., urinary complaint).

The societal economic value of COVID-19 vaccines in the United States.

AIMS: The COVID-19 pandemic has claimed the lives of more than 800,000 people in the United States (US) and has been estimated to carry a societal cost of $16 trillion over the next decade. The availability of COVID-19 vaccines has had a profound effect on the trajectory of the pandemic, with wide-ranging benefits. We aimed to estimate the total societal economic value generated in the US from COVID-19 vaccines. METHODS: We developed a population-based economic model informed by existing data and literature to estimate the total societal value generated from COVID-19 vaccines by avoiding COVID-19 infections as well as resuming social and economic activity more quickly. To do this, we separately estimated the value generated from life years saved, healthcare costs avoided, quality of life gained, and US gross domestic product (GDP) gained under a range of plausible assumptions. RESULTS: Findings from our base case analysis suggest that from their launch in December 2020, COVID-19 vaccines were projected to generate $5.0 trillion in societal economic value for the US from avoided COVID-19 infections and resuming unrestricted social and economic activity more quickly. Our scenario analyses suggest that the value could range between $1.8 and $9.9 trillion. Our model indicates that the most substantial sources of value are derived from reduction in prevalence of depression ($1.9 trillion), gains to US GDP ($1.4 trillion), and lives saved from fewer COVID-19 infections ($1.0 trillion). LIMITATIONS: Constructed as a projection from December 2020, our model does not account for the Delta or future variants, nor does it account for improvements in COVID-19 treatment. CONCLUSIONS: The magnitude of economic benefit from vaccination highlights the need for coordinated policy decisions to support continued widespread vaccine uptake in the US.

Do online decision aids reflect new prenatal screening and testing options? An environmental scan and content analysis.

Objective: Decision aids have been developed to help prospective parents make informed, shared decisions about medical tests, but these options are rapidly changing. This study aimed to identify and evaluate publicly available decision aids written in English for prospective parents seeking prenatal test information. Methods: A systematic review process was followed using 3 sources: known decision aid repositories, fetal medicine organisations and Google. The search, screening process, quality assessment, and data extraction was performed by two independent researchers. The quality assessment of the decision aids was based on the International Patient Decision Aids Standards (IPDAS v.4.0). Results: We identified 13 decision aids, which varied in the screening and diagnostic tests that they discussed. No decision aid met all the IPDAS v.4.0. criteria and no decision aid reported updated risk of miscarriage for amniocentesis and chorionic villus sampling (CVS). There was a lack of decision aids for some common decisions in the prenatal context. Conclusion: We identified outdated content in current prenatal decision aids. The findings will inform healthcare professionals of the quality of current prenatal decision aids, which may facilitate their patients' informed decision-making about prenatal tests. Innovation: Considerations for improving future decision aids are outlined.

Circulating miRNAs as Biomarkers for CYP2B6 Enzyme Activity.

The CYP2B6 gene is highly polymorphic and its activity shows wide interindividual variability. However, substantial variability in CYP2B6 activity remains unexplained by the known CYP2B6 genetic variations. Circulating, cell-free micro RNAs (miRNAs) may serve as biomarkers of hepatic enzyme activity. CYP2B6 activity in 72 healthy volunteers was determined using the disposition of efavirenz as a probe drug. Circulating miRNA expression was quantified from baseline plasma samples. A linear model consisting of the effects of miRNA expression, genotype-determined metabolizer status, and demographic information was developed to predict CYP2B6 activity. Expression of 2,510 miRNAs were quantified out of which 7 miRNAs, together with the CYP2B6-genotypic metabolizer status and demographics, was shown to be predictive markers for CYP2B6 activity. The reproducibility of the model was evaluated by cross-validation. The average Pearson's correlation (R) between the predicted and observed maximum plasma concentration (Cmax ) ratios of efavirenz and its metabolite-8-OH efavirenz using the linear model with all features (7 miRNA + metabolizer status + age + sex + race) was 0.6702. Similar results were also observed using area under the curve (AUC) ratios (Pearson correlation's R = 0.6035). Thus, at least 36% (R2 ) of the variability of in vivo CYP2B6 activity was explained using this model. This is a significant improvement over the models using only the genotype-based metabolizer status or the demographic information, which explained only 6% or less of the variability of in vivo CYP2B6 activity. Our results, therefore, demonstrate that circulating plasma miRNAs can be valuable biomarkers for in vivo CYP2B6 activity.

Pathogenic deep intronic MTM1 variant activates a pseudo-exon encoding a nonsense codon resulting in severe X-linked myotubular myopathy.

X-linked myotubular myopathy (XLMTM) is a severe congenital myopathy characterised by generalised weakness and respiratory insufficiency. XLMTM is associated with pathogenic variants in MTM1; a gene encoding the lipid phosphatase myotubularin. Whole genome sequencing (WGS) of an exome-negative male proband with severe hypotonia, respiratory insufficiency and centralised nuclei on muscle biopsy identified a deep intronic MTM1 variant NG_008199.1(NM_000252.2):c.1468-577A>G, which strengthened a cryptic 5' splice site (A>G substitution at the +5 position). Muscle RNA sequencing was non-diagnostic due to low read depth. Reverse transcription PCR (RT-PCR) of muscle RNA confirmed the c.1468-577A>G variant activates inclusion of a pseudo-exon encoding a premature stop codon into all detected MTM1 transcripts. Western blot analysis establishes deficiency of myotubularin protein, consistent with the severe XLMTM phenotype. We expand the genotypic spectrum of XLMTM and highlight benefits of screening non-coding regions of MTM1 in male probands with phenotypically concordant XLMTM who remain undiagnosed following exome sequencing.

A multicenter study evaluating the effectiveness and safety of single-dose low molecular weight iron dextran vs single-dose ferumoxytol for the treatment of iron deficiency.

There are multiple intravenous (IV) iron formulations available, of which several may be administered as single-dose infusions such as low-molecular weight iron dextran (LMWID), ferumoxytol, ferric carboxymaltose, and ferric derisomaltose. However, administration of ferumoxytol as a single-dose infusion is off-label as it is approved as a two-dose series. Previous studies of ferumoxytol alone support the effectiveness and safety of the single-dose regimen, but there is a paucity of data directly comparing single-dose ferumoxytol to other single-dose IV iron formulations. This multicenter cohort study sought to affirm the safety and effectiveness of single-dose ferumoxytol compared to single-dose LMWID. Overall, 906 patients who received single-dose LMWID (n = 439) or ferumoxytol (n = 467) were identified, of whom 351 met criteria for the primary effectiveness endpoint defined as median change in hemoglobin (Hb), hematocrit (Hct), and ferritin 8 to 12 weeks from baseline. All 906 patients were included for the secondary analysis evaluating the incidence of adverse events (AE) and requirement of additional IV iron infusions. Median change in Hb (LMWID 0.5 g/dL; ferumoxytol 0.8 g/dL; P = .24), Hct (LMWID 1.1%; ferumoxytol 1.25%; P = .89), and ferritin (LMWID 87 ng/dL; ferumoxytol 71 ng/dL; P = .47) was not significantly different between groups. Both groups experienced similar rates of AEs (LMWID 2.3%; ferumoxytol 2.8%; P = .63). The LMWID patients more frequently required additional IV iron infusions (LMWID 28.5%; ferumoxtyol 16.1%; P < .001). These findings support that single-dose ferumoxytol is effective and safe, and that patients may require fewer additional infusions compared to patients who received LMWID.

Epidemiology and Patient Distribution of Oral Cavity and Oropharyngeal SCC in Canada.

BACKGROUND: Oral cavity cancers (OCCs) and oropharyngeal cancers (OPCs) continue to be a major source of morbidity and mortality worldwide requiring the shared effort of numerous specialists. Tobacco and alcohol consumption have long been identified as risk factors for both OCC and OPC. In addition, human papilloma virus (HPV) is gaining its position as the main causal agent for OPC. OBJECTIVE: The objective of this study is to analyze the epidemiology of OCC and OPC in Canada. METHODS: Data pertaining to the year of diagnosis, the patient's sex, age at the time of diagnosis, province/territory, city and postal code of oral cavity, and oropharyngeal malignancies diagnosed during 1992-2010 were extracted from the Canadian Cancer Registry and Le Registre Québécois du Cancer. RESULTS: In total, 21 685 OCC cases and 15 965 OPC cases were identified from 1992 to 2010. Of those, 84.97% were oral cavity squamous cell carcinomas (SCCs), 88.10% were oropharyngeal SCCs, and both had a significant male predominance. While oral cavity SCC incidence stabilized over the study period, oropharyngeal SCC continued to increase. Oral cavity SCC incidence increased with age, while oropharyngeal SCC incidence peaked in the 50- to 59-year age group. Detailed geographic distribution analysis of patients at the provincial/territorial, city, and postal code levels identified several patient clusters. CONCLUSIONS: This work highlights important epidemiological differences in trends between oral and oropharyngeal cancers, identifies high-incidence postal codes for each malignancy, and correlates incidence/mortality with known risk factors including alcohol/tobacco use and HPV infections, therefore providing a comprehensive understanding of epidemiology for these cancers in Canada.

Influence of Uridine Diphosphate Glucuronosyltransferase Family 1 Member A1 and Solute Carrier Organic Anion Transporter Family 1 Member B1 Polymorphisms and Efavirenz on Bilirubin Disposition in Healthy Volunteers.

Chronic administration of efavirenz is associated with decreased serum bilirubin levels, probably through induction of UGT1A1 We assessed the impact of efavirenz monotherapy and UGT1A1 phenotypes on total, conjugated, and unconjugated serum bilirubin levels in healthy volunteers. Healthy volunteers were enrolled into a clinical study designed to address efavirenz pharmacokinetics, drug interactions, and pharmacogenetics. Volunteers received multiple oral doses (600 mg/day for 17 days) of efavirenz. Serum bilirubin levels were obtained at study entry and 1 week after completion of the study. DNA genotyping was performed for UGT1A1 [*80 (C>T), *6 (G>A), *28 (TA7), *36 (TA5), and *37 (TA8)] and for SLCO1B1 [*5 (521T>C) and *1b (388A>G] variants. Diplotype predicted phenotypes were classified as normal, intermediate, and slow metabolizers. Compared with bilirubin levels at screening, treatment with efavirenz significantly reduced total, conjugated, and unconjugated bilirubin. After stratification by UGT1A1 phenotypes, there was a significant decrease in total bilirubin among all phenotypes, conjugated bilirubin among intermediate metabolizers, and unconjugated bilirubin among normal and intermediate metabolizers. The data also show that UGT1A1 genotype predicts serum bilirubin levels at baseline, but this relationship is lost after efavirenz treatment. SLCO1B1 genotypes did not predict bilirubin levels at baseline or after efavirenz treatment. Our data suggest that efavirenz may alter bilirubin disposition mainly through induction of UGT1A1 metabolism and efflux through multidrug resistance-associated protein 2. SIGNIFICANCE STATEMENT: Efavirenz likely alters the pharmacokinetics of coadministered drugs, potentially causing lack of efficacy or increased adverse effects, as well as the disposition of endogenous compounds relevant in homeostasis through upregulation of UGT1A1 and multidrug resistance-associated protein 2. Measurement of unconjugated and conjugated bilirubin during new drug development may provide mechanistic understanding regarding enzyme and transporters modulated by the new drug.