Lenacapavir Exhibits Atropisomerism - Mechanistic Pharmacokinetics and Disposition Studies of Lenacapavir Reveal Intestinal Excretion as a Major Clearance Pathway.

Lenacapavir (LEN), a long-acting injectable, is the first approved human immunodeficiency virus type 1 capsid inhibitor and one of a few FDA-approved drugs that exhibit atropisomerism. LEN exists as a mixture of two class 2 atropisomers that interconvert at a fast rate (t1/2 <2 hours) with a ratio that is stable over time and unaffected by enzymes or binding to proteins in plasma. LEN exhibits low systemic clearance (CL) in nonclinical species and humans; however, in all species the observed CL was higher than the in vitro predicted CL. The volume of distribution was moderate in nonclinical species and consistent with the tissue distribution observed by whole body autoradiography in rats. LEN does not distribute to brain, consistent with being a P-glycoprotein (P-gp) substrate. Mechanistic drug disposition studies with [14C]LEN in IV-dosed BDC rats and dogs showed a substantial amount of unchanged LEN (31 - 60% of dose) excreted in feces, indicating that intestinal excretion (IE) was a major clearance pathway for LEN in both species. Coadministration of oral elacridar, a P-gp inhibitor, in rats decreased CL and IE of LEN. Renal excretion was <1% of dose in both species. In plasma, almost all radioactivity was unchanged LEN. Low levels of metabolites in excreta included LEN-conjugates with glutathione, pentose, and glucuronic acid, which were consistent with metabolites formed in vitro in Hµrel® hepatocyte co­cultures and those observed in human. Our studies highlight the importance of IE for efflux substrates that are highly metabolically stable compounds with slow elimination rates. Significance Statement LEN is a long-acting injectable that exists as conformationally stable atropisomers. Due to an atropisomeric interconversion rate that significantly exceeds the in vivo elimination rate, the atropisomer ratio of LEN remains constant in circulation. The disposition of LEN highlights that intestinal excretion has a substantial part in the elimination of compounds that are metabolically highly stable and efflux transporter substrates.

Skin α-Synuclein Seeding Activity in Patients with Type 1 Gaucher Disease.

BACKGROUND: Patients with type 1 Gaucher disease (GD1) have a significantly increased risk of developing Parkinson's disease (PD). OBJECTIVE: The objective of this study was to evaluate skin α-synuclein (αSyn) seeding activity as a biomarker for GD1-related PD (GD1-PD). METHODS: This single-center study administered motor and cognitive examinations and questionnaires of nonmotor symptoms to adult patients with GD1. Optional skin biopsy was performed for skin αSyn seed amplification assay (αSyn SAA) using real-time quaking-induced conversion assay. RESULTS: Forty-nine patients were enrolled, and 36 underwent skin biopsy. Two study participants had PD. Ten participants were αSyn SAA positive (27.8%), 7 (19.4%) were intermediate, and 19 (52.8%) were negative. Positive αSyn seeding activity was observed in the single GD1-PD case who consented to biopsy. αSyn SAA positivity was associated with older age (p = 0.043), although αSyn SAA positivity was more prevalent in patients with GD1 than historic controls. CONCLUSIONS: Longitudinal follow-up is required to determine whether skin αSyn seeding activity can be an early biomarker for GD1-PD. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Adjusting models to better predict obstetric anal sphincter injury (OASIS) in forceps-assisted vaginal deliveries: A retrospective cross-sectional trial.

OBJECTIVE: Obesity and maternal age are increasing among pregnant patients. The understood effect of body mass index (BMI), advanced maternal age (AMA), and second stage of labor on obstetric anal sphincter injury (OASIS) at delivery is varied. The objective of this study was to assess whether incorporating BMI, second stage of labor length, and AMA into a model for predicting OASIS among forceps-assisted vaginal deliveries (FAVD) had a higher predictivity value compared to models without these additions. METHOD: This was an IRB-approved retrospective cohort study of singleton gestations who underwent a FAVD between 2017 and 2021. The primary outcome was prediction of OASIS via established models versus models including the addition of new predictive factors. RESULTS: A total of 979 patients met inclusionary criteria and were included in the final analysis. 20.4% of patients had an OASIS laceration, 11.3% of neonates had NICU admissions, 23.7% had a composite all neonatal outcome, and 8% had a composite subgaleal/cephalohematoma outcome. Comparisons of known factors that predict OASIS (nulliparity, race, episiotomy status) to known factors with additional predictors (BMI, AMA, and length of second stage in labor) were explored. After comparing each model's AUC to one another (a total of 3 comparisons made), there was no statistically significant difference between the models (all P > 0.62). CONCLUSION: Including BMI, AMA, and second stage of labor length does not improve the predictivity of OASIS in patients with successful FAVD. These factors should not impact a provider's decision to perform a FAVD when solely considering increased odds of OASIS.

Neonatal Birth Weight With Daily Compared With Every-Other-Day Glucose Monitoring in Gestational Diabetes Mellitus: A Randomized Controlled Trial.

OBJECTIVE: To assess whether universal use of every-other-day glucose monitoring in patients with gestational diabetes mellitus (GDM) resulted in similar birth weights and medication use and was preferred by the patient compared with traditional daily glucose monitoring. METHODS: This was a noninferiority randomized controlled trial conducted at a single New York City hospital between April 2021 and May 2022. Patients with singleton pregnancies who were diagnosed with GDM after 20 weeks of gestation and had a minimum of 7 days of previous daily blood glucose testing were randomly assigned to test blood glucose values daily or every other day. The primary outcome was neonatal birth weight. We calculated a total sample size of 196 participants needed for noninferiority to be tested, assuming the mean birth weight in the every-other-day group, compared with the daily group, was no higher than the predefined noninferiority margin of 200 g (80% power and one-sided alpha of 0.05). Postrandomization characteristics, including blood glucose values and medication initiation and timing, were recorded. Satisfaction with treatment group was assessed using the validated Oxford Maternity Diabetes Treatment Satisfaction Questionnaire. RESULTS: A total of 197 patients were randomized: 98 in the daily group and 99 in the every-other-day group. Baseline characteristics were similar between groups. The mean neonatal birth weight was similar between groups (mean±SD 3,090±418 g among newborns in the daily group compared with 3,181±482 g among newborns in the every-other-day group). For the primary outcome, the every-other-day group was found to be noninferior to the daily group with an upper confidence limit for the mean difference in mean birth weight of 197 g, which was below the noninferiority margin of 200 g (P=.046). Postrandomization, there were no significant differences in the number of patients who required medication, the gestational age at which medication was started, or the type of medication used. Average fasting and postprandial glucose values were similar between groups. There was an increase in adherence to treatment group in those randomized to every-other-day blood sugars, but no difference in patient satisfaction. CONCLUSION: In patients with GDM, testing blood glucose values every other day was as effective as testing daily, without apparent effects on birth weight, medication initiation, or glucose control. Reduced frequency of blood glucose monitoring might help decrease the emotional, physical, and financial burden experienced by patients with GDM. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04857073.

Visual Abstract of "Six Tips for Giving Good Health Care to Anyone With a Cervix".

This visual abstract is based on an article from the February 2020 issue of the journal.

Epigenetic priming targets tumor heterogeneity to shift transcriptomic phenotype of pancreatic ductal adenocarcinoma towards a Vitamin D susceptible state.

As a highly heterogeneous tumor, pancreatic ductal adenocarcinoma (PDAC) exhibits non-uniform responses to therapies across subtypes. Overcoming therapeutic resistance stemming from this heterogeneity remains a significant challenge. Here, we report that Vitamin D-resistant PDAC cells hijacked Vitamin D signaling to promote tumor progression, whereas epigenetic priming with glyceryl triacetate (GTA) and 5-Aza-2'-deoxycytidine (5-Aza) overcame Vitamin D resistance and shifted the transcriptomic phenotype of PDAC toward a Vitamin D-susceptible state. Increasing overall H3K27 acetylation with GTA and reducing overall DNA methylation with 5-Aza not only elevated the Vitamin D receptor (VDR) expression but also reprogrammed the Vitamin D-responsive genes. Consequently, Vitamin D inhibited cell viability and migration in the epigenetically primed PDAC cells by activating genes involved in apoptosis as well as genes involved in negative regulation of cell proliferation and migration, while the opposite effect of Vitamin D was observed in unprimed cells. Studies in genetically engineered mouse PDAC cells further validated the effects of epigenetic priming for enhancing the anti-tumor activity of Vitamin D. Using gain- and loss-of-function experiments, we further demonstrated that VDR expression was necessary but not sufficient for activating the favorable transcriptomic phenotype in respond to Vitamin D treatment in PDAC, highlighting that both the VDR and Vitamin D-responsive genes were prerequisites for Vitamin D response. These data reveal a previously undefined mechanism in which epigenetic state orchestrates the expression of both VDR and Vitamin D-responsive genes and determines the therapeutic response to Vitamin D in PDAC.

Abortion restrictions and medical residency applications.

Residency selection is a challenging process for medical students, one further complicated in the USA by the recent Dobbs v Jackson Women's Health Organization (Dobbs) decision over-ruling the federal right to abortion. We surveyed medical students to examine how Dobbs is influencing the ideological, personal and professional factors they must reconcile when choosing where and how to complete residency.Between 6 August and 22 October 2022, third-year and fourth-year US medical students applying to US residency programmes were surveyed through social media and direct outreach to medical schools. Analysis of quantitative and qualitative data from 494 responses was performed to assess downstream effects of Dobbs on residency applicants' family, health and career choices.Most respondents said changes in abortion access would likely or very likely influence their decision regarding location of considered residency programme (76.9%), where to start a family (72.2%) and contraceptive planning for them or their partner (57.9%). Cis-gender females were more influenced by Dobbs regarding where (5 (4, 5) p<0.001) and when (3 (3, 5) p<0.001) to start a family. In qualitative responses, medical trainees highlighted the importance of abortion access for their patients, themselves and their loved ones.Medical trainees are incorporating state abortion access into their residency programme choices. Future physicians care about both the quality of care they will be able to provide and their own health. For personal and professional reasons, reproductive healthcare access is now a key factor in residency match decisions.

Lenacapavir: A Novel, Potent, and Selective First-in-Class Inhibitor of HIV-1 Capsid Function Exhibits Optimal Pharmacokinetic Properties for a Long-Acting Injectable Antiretroviral Agent.

Lenacapavir (LEN) is a picomolar first-in-class capsid inhibitor of human immunodeficiency virus type 1 (HIV-1) with a multistage mechanism of action and no known cross resistance to other existing antiretroviral (ARV) drug classes. LEN exhibits a low aqueous solubility and exceptionally low systemic clearance following intravenous (IV) administration in nonclinical species and humans. LEN formulated in an aqueous suspension or a PEG/water solution formulation showed sustained plasma exposure levels with no unintended rapid drug release following subcutaneous (SC) administration to rats and dogs. A high total fraction dose release was observed with both formulations. The long-acting pharmacokinetics (PK) were recapitulated in humans following SC administration of both formulations. The SC PK profiles displayed two-phase absorption kinetics in both animals and humans with an initial fast-release absorption phase, followed by a slow-release absorption phase. Noncompartmental and compartmental analyses informed the LEN systemic input rate from the SC depot and exit rate from the body. Modeling-enabled deconvolution of the input rates from two processes: absorption of the soluble fraction (minor) from a direct fast-release process leading to the early PK phase and absorption of the precipitated fraction (major) from an indirect slow-release process leading to the later PK phase. LEN SC PK showed flip-flop kinetics due to the input rate being substantially slower than the systemic exit rate. LEN input rates via the slow-release process in humans were slower than those in both rats and dogs. Overall, the combination of high potency, exceptional stability, and optimal release rate from the injection depot make LEN well suited for a parenteral long-acting formulation that can be administered once up to every 6 months in humans for the prevention and treatment of HIV-1.

How to Teach Cross-Cultural Communication: A Workshop Using the Experiential Learning Model.

Introduction: The United States population is diversifying, leading to higher rates of cultural, ethnic, and racial discordance between medical teams and patients. Studies show that pediatric residents lack training in cross-cultural communication (CCC). Methods: We based learning objectives on the AAMC's Tool for Assessing Cultural Competency Training. The workshop design was based on Kolb's experiential learning model. In 2020-2021, we delivered this 2-hour workshop to trainees at two large, urban sites. We administered two surveys to evaluate our workshop: a retrospective pre-post survey following the workshop and a 3-month follow-up survey. Using 5-point Likert scales, participants rated their awareness of the effect of their own cultural identity on CCC and familiarity with and confidence using CCC models. We analyzed responses using Wilcoxon signed rank tests. Results: Sixty-two trainees participated in the workshop; 44 completed the retrospective pre-post survey (71%). After the workshop, 36% were extremely aware of the effect of their own cultural identity on CCC compared to 4% before the workshop (p < .001). Confidence managing cross-cultural misunderstandings when conveying a diagnosis and explaining disease management increased after the workshop (70% vs. 25%, p < .001; 70% vs. 20%, p < .001, respectively). Twelve participants completed a 3-month follow-up survey (27%). Discussion: A workshop using the experiential learning model to teach CCC increased participants' awareness of how their cultural identity impacted CCC and familiarity with and confidence in using two CCC models. This workshop offers pediatric program directors a tool to enhance their CCC curricula and meet ACGME requirements.

Long-acting lenacapavir protects macaques against intravenous challenge with simian-tropic HIV.

BACKGROUND: Long-acting subcutaneous lenacapavir (LEN), a first-in-class HIV capsid inhibitor approved by the US FDA for the treatment of multidrug-resistant HIV-1 with twice yearly dosing, is under investigation for HIV-1 pre-exposure prophylaxis (PrEP). We previously derived a simian-tropic HIV-1 clone (stHIV-A19) that encodes an HIV-1 capsid and replicates to high titres in pigtail macaques (PTM), resulting in a nonhuman primate model well-suited for evaluating LEN PrEP in vivo. METHODS: Lenacapavir potency against stHIV-A19 in PTM peripheral blood mononuclear cells in vitro was determined and subcutaneous LEN pharmacokinetics were evaluated in naïve PTMs in vivo. To evaluate the protective efficacy of LEN PrEP, naïve PTMs received either a single subcutaneous injection of LEN (25 mg/kg, N = 3) or vehicle (N = 4) 30 days before a high-dose intravenous challenge with stHIV-A19, or 7 daily subcutaneous injections of a 3-drug control PrEP regimen starting 3 days before stHIV-A19 challenge (N = 3). FINDINGS: In vitro, LEN showed potent antiviral activity against stHIV-A19, comparable to its potency against HIV-1. In vivo, subcutaneous LEN displayed sustained plasma drug exposures in PTMs. Following stHIV-A19 challenge, while all vehicle control animals became productively infected, all LEN and 3-drug control PrEP animals were protected from infection. INTERPRETATION: These findings highlight the utility of the stHIV-A19/PTM model and support the clinical development of long-acting LEN for PrEP in humans. FUNDING: Gilead Sciences as part of a Cooperative Research and Development Agreement between Gilead Sciences and Frederick National Lab; federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024/HHSN261201500003I; NIH grant R01AI078788.

Letters of recommendation for gynecologic oncology fellowship differ by gender and race.

INTRODUCTION: Letters of recommendation (LOR) play a significant role in applicant selection for gynecologic oncology (GO) fellowship. LORs can be agentic, associated with competence, independence and strength, or communal, associated with being accommodating, cooperative and empathetic. Agentic LORs have been shown to reflect favorably on applicants, making them more likely to be selected for interview. The primary goal of this study was to determine linguistic differences in LORs for applicants applying to GO fellowship based on applicant gender and race. METHODS: All applications to a single academic institution from the years 2018-2020 were analyzed. LORs were extracted from all applicants who self-reported their gender and race/ethnicity. Analysis was performed using Linguistic Inquiry Word Count (LIWC) in terms of agentic and communal language. All analysis was done using SAS version 9.4. RESULTS: From 2018 to 2020, there were 239 GO fellowship applications to a single academic institution. There were 186 (78.1%) applicants who identified as female and 52 (21.8%) who identified as male. Female applicants were more likely to have more research (p = 0.047) and volunteer activities (p = 0.02) than male applicants. There were no differences between female and male applicants in terms of age, geographic location of residency, USMLE scores, AOA status, number of publications or attending a Doximitiy-rated top 20 residency program. There were 139 (60.7%) applicants who identified as White, 46 (20.1%) as Asian, 16 (7.0%) as Black, 19 (8.3%) as Latinx and 9 (3.9%) as other. On multivariable analysis, LORs written for male applicants had higher agentic scores compared to females (p < 0.05), and LORs of female applicants received higher communal scores (p < 0.05). LORs for applicants who identified as Black or Latinx were found to have lower agentic scores compared to individuals who identified as White(p < 0.05 for both). CONCLUSION: There were demonstrated linguistic differences in LOR for GO fellowship based on applicant gender and race/ethnicity. LORs written for white, male applicants were more likely to have higher agentic scores compared to minority, female applicants. LORs written for female applicants were more likely to have higher communal scores. As LORs have been shown to be instrumental in GO fellowship interview selection and linguistic differences exist based on applicant gender and race/ethnicity, this study highlights the need for a more objective GO fellowship application process. DISCLOSURES: Portion of this paper was presented at the Society for Gynecologic Oncology as part of a focus plenary.

Long-acting lenacapavir acts as an effective preexposure prophylaxis in a rectal SHIV challenge macaque model.

Long-acting antiretroviral agents for preexposure prophylaxis (PrEP) represent a promising new alternative to daily oral regimens for HIV prevention. Lenacapavir (LEN) is a first-in-class long-acting capsid inhibitor approved for the treatment of HIV-1 infection. Here, we assessed the efficacy of LEN for PrEP using a single high-dose simian-human immunodeficiency virus (SHIV) rectal challenge macaque model. In vitro, LEN showed potent antiviral activity against SHIV, as it did for HIV-1. In macaques, a single subcutaneous administration of LEN demonstrated dose proportional increases in and durability of drug plasma levels. A high-dose SHIV inoculum for the PrEP efficacy evaluation was identified via virus titration in untreated macaques. LEN-treated macaques were challenged with high-dose SHIV 7 weeks after drug administration, and the majority remained protected from infection, as confirmed by plasma PCR, cell-associated proviral DNA, and serology testing. Complete protection and superiority to the untreated group was observed among animals whose LEN plasma exposure exceeded its model-adjusted clinical efficacy target at the time of challenge. All infected animals had subprotective LEN concentrations and showed no emergent resistance. These data demonstrate effective SHIV prophylaxis in a stringent macaque model at clinically relevant LEN exposures and support the clinical evaluation of LEN for HIV PrEP in humans.

Is Increasing Parity Associated with Adverse Perinatal Outcomes in Dichorionic Twin Gestations?

OBJECTIVE: Dichorionic twins have increased risk of preterm birth and hypertensive disorders of pregnancy. Grand multiparity may be associated with adverse perinatal outcomes in singleton pregnancies, although the effect of increasing parity in twins is unclear. This study aimed to elucidate whether grand multiparity leads to adverse outcomes in dichorionic twins compared with multiparity and nulliparity. STUDY DESIGN: This was a retrospective review of dichorionic twins at a single institution between January 2008 and December 2019 comparing pregnancy outcomes among grand multiparity, multiparity, and nulliparity. Primary outcome was preterm birth less than 37 weeks. Multivariable regression controlled for differing demographics, prior preterm birth, use of reproductive technologies, and hypertensive disorders of pregnancy. Chi square and Fisher's exact were used for categorical variables and Kruskal-Wallis was used for continuous variables. RESULTS: A total of 843 (60.3%) pregnancies were nulliparous, 499 (35.7%) multiparous, and 57(4.1%) grand multiparous. Univariate analysis indicated that multiparous women had lower incidence of preterm birth less than 37, 34, and 32 weeks (57 vs. 51%, p = 0.04; 19.2 vs. 14.0%, p = 0.02; 9.6 vs. 5.6%, p = 0.01) and that grand multiparous women had lower incidence of preterm birth less than 34 weeks (19.2 vs. 5.3%, p = 0.008) compared with nulliparous women. Multivariable regression confirmed multiparous women had lower odds of preterm birth less than 34 and 32 weeks compared with nulliparous women (<34 wk: odds ratio [OR] = 0.69, 95% confidence interval [CI] = 0.49-0.97, p = 0.03; <32 wk: OR = 0.48, 95% CI = 0.29-0.79, p = 0.004) and that multiparous women (OR = 0.57, 95% CI = 0.42-0.77, p = 0.0002) and grand multiparous women (OR = 0.23, 95% CI = 0.08-0.68, p = 0.0074) had lower incidence of hypertensive disorders of pregnancy when compared with nulliparous women. CONCLUSION: Grand multiparity is not associated with adverse perinatal outcomes compared with nulliparity or multiparity in dichorionic twins. Increasing parity may protect against incidence of preterm birth and hypertensive disorders of pregnancy even among grand multiparous women. KEY POINTS: · Incidence of preterm birth may decrease with increasing parity in twins.. · Hypertensive disorders of pregnancy may decrease with increasing parity in twins.. · Grand multiparity is not associated with adverse perinatal outcomes in twins..

Ledipasvir/Sofosbuvir Is Effective as Sole Treatment of Porphyria Cutanea Tarda with Chronic Hepatitis C.

BACKGROUND AND AIMS: Chronic hepatitis C [CHC] is a risk factor for porphyria cutanea tarda [PCT]. To assess whether ledipasvir/sofosbuvir is effective for treating both PCT and CHC, we treated patients with CHC + PCT solely with ledipasvir/sofosbuvir and followed them for at least 1 year to assess cure of CHC and remission of PCT. METHODS: Between September 2017 and May 2020, 15 of 23 screened PCT + CHC patients were eligible and enrolled. All were treated with ledipasvir/sofosbuvir at recommended doses and durations, according to their stage of liver disease. We measured plasma and urinary porphyrins at baseline and monthly for the first 12 months and at 16, 20, and 24 mos. We measured serum HCV RNA at baseline, 8-12, and 20-24 mos. Cure of HCV was defined as no detectable serum HCV RNA ≥ 12 weeks after the end of treatment (EOT). Remission of PCT was defined clinically as no new blisters or bullae and biochemically as urinary uro- plus hepta-carboxyl porphyrins ≤ 100 mcg/g creatinine. RESULTS: All 15 patients, 13 of whom were men, were infected with HCV genotype 1. 2/15 withdrew or were lost to follow-up. Of the remaining 13, 12 achieved cure of CHC; 1 had complete virological response, followed by relapse of HCV after ledipasvir/sofosbuvir but was subsequently cured by treatment with sofosbuvir/velpatasvir. Of the 12 cured of CHC, all achieved sustained clinical remission of PCT. CONCLUSIONS: Ledipasvir/sofosbuvir [and likely other direct-acting antivirals] is an effective treatment for HCV in the presence of PCT and leads to clinical remission of PCT without additional phlebotomy or low-dose hydroxychloroquine treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT03118674.

Lexical inferencing as a generation effect for foreign language vocabulary learning.

Prior research suggests that second language (L2) vocabulary learning often occurs through lexical inferencing (translations based on context), but there has been less emphasis on how lexical inferencing compares with other methods of L2 word learning. The present study compared lexical inferencing to simply studying word lists for L2 learning. A secondary goal was to determine whether any effect of inferencing is mediated by the generation effect of memory, a phenomenon wherein generated information (inferencing) is remembered better than obtained information (reading). Across four experiments, participants read English sentences with embedded Swahili words and were asked either to infer the word meaning using context or were provided with translations before reading the sentence (reading condition). In contrast to our initial hypotheses, the inference condition resulted in lower rates of retention compared with the reading condition. In addition, the data suggest a number of differences between lexical inferencing and the generation effect, that argue against the proposal that lexical inferencing operates as a type of generation effect.

Resting-State Brain Temperature: Dynamic Fluctuations in Brain Temperature and the Brain-Body Temperature Gradient.

BACKGROUND: While fluctuations in healthy brain temperature have been investigated over time periods of weeks to months, dynamics over shorter time periods are less clear. PURPOSE: To identify physiological fluctuations in brain temperature in healthy volunteers over time scales of approximately 1 hour. STUDY TYPE: Prospective. SUBJECTS: A total of 30 healthy volunteers (15 female; 26 ± 4 years old). SEQUENCE AND FIELD STRENGTH: 3 T; T1-weighted magnetization-prepared rapid gradient-echo (MPRAGE) and semi-localized by adiabatic selective refocusing (sLASER) single-voxel spectroscopy. ASSESSMENTS: Brain temperature was calculated from the chemical shift difference between N-acetylaspartate and water. To evaluate within-scan repeatability of brain temperature and the brain-body temperature difference, 128 spectral transients were divided into two sets of 64-spectra. Between-scan repeatability was evaluated using two time periods, ~1-1.5 hours apart. STATISTICAL TESTS: A hierarchical linear mixed model was used to calculate within-scan and between-scan correlations (Rw and Rb , respectively). Significance was determined at P ≤ .05. Values are reported as the mean ± standard deviation. RESULTS: A significant difference in brain temperature was observed between scans (-0.4 °C) but body temperature was stable (P = .59). Brain temperature (37.9 ± 0.7 °C) was higher than body temperature (36.5 ± 0.5 °C) for all but one subject. Within-scan correlation was high for brain temperature (Rw  = 0.95) and brain-body temperature differences (Rw  = 0.96). Between scans, variability was high for both brain temperature (Rb  = 0.30) and brain-body temperature differences (Rb  = 0.41). DATA CONCLUSION: Significant changes in brain temperature over time scales of ~1 hour were observed. High short-term repeatability suggests temperature changes appear to be due to physiology rather than measurement error. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

Effects of orientation-dependent susceptibility on MR chemical shift brain thermometry.

PURPOSE: The presence of orientation-dependent susceptibility artifacts in magnetic resonance chemical shift thermometry (CST) can confound accurate temperature calculations. Here, we quantify the effect of white matter (WM) tract orientation on CST due to tissue-specific susceptibility. METHODS: Twenty-nine healthy volunteers (27 ± 4 years old) were scanned on a 3 T MR scanner with a 32-channel head coil. Diffusion tensor imaging (DTI), T1-weighted imaging, and single voxel spectroscopy (SVS) for CST were acquired. Participants were then asked to rotate their head ∼3-5° (yaw or roll) to alter the orientation of WM tracts relative to the external magnetic field. After head rotation, a second SVS scan and T1-weighted imaging were acquired. The WM-fraction-normalized DTI principal eigenvector (V1) images were used to calculate the length of the x-y component of V1, which was used as a surrogate for WM tracts perpendicular to B0. A linear regression model was used to determine the relationship between the perpendicular WM tracts and brain temperature. RESULTS: Significant temperature differences between post- and pre-head rotation scans were observed for brain (-0.72 °C ± 1.36 °C, p = 0.01) but not body (0.012 °C ± 0.07 °C, p = 0.37) temperatures. The difference in brain temperature was positively associated with the corresponding change in perpendicular WM tracts after head rotation (R2 = 0.26, p = 0.005). CONCLUSION: Our results indicate WM tract orientation affects temperature calculations, suggesting artifacts from orientation-dependent susceptibility may be present in CST.

Human and nonclinical disposition of [14C]bictegravir, a potent integrase strand-transfer inhibitor for the treatment of HIV-1 infection.

Bictegravir (BIC) is a potent small-molecule integrase strand-transfer inhibitor (INSTI) and a component of Biktarvy®, a single-tablet combination regimen that is currently approved for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. The absorption, metabolism, distribution, and elimination (ADME) characteristics of BIC were determined through in vivo nonclinical and clinical studies (IND 121318).[14C]BIC was rapidly absorbed orally in mice, rats, monkeys and human. The cumulative dose recovery was high in nonclinical species (>80%) and humans (95.3%), with most of the excreted dose recovered in faeces. Quantifiable radioactivity with declining concentration was observed in rat tissues suggesting reversible binding. Unchanged BIC was the most abundant circulating component in all species along with two notable metabolites M20 (a sulphate conjugate of hydroxylated BIC) and M15 (a glucuronide conjugate of BIC). BIC was primarily eliminated by hepatic metabolism followed by excretion of the biotransformed products into faeces. In vitro drug-drug interaction (DDI) studies with M15 and M20 demonstrated that no clinically relevant interactions were expected.Overall, BIC is a novel and potent INSTI with a favourable resistance, PK, and ADME profile that provides important improvements over other currently available INSTIs for the treatment of HIV-1.

Identification and characterization of pleiotropic and epistatic QDRL conferring partial resistance to Pythium irregulare and P. sylvaticum in soybean.

KEY MESSAGE: Pleiotropic and epistatic quantitative disease resistance loci (QDRL) were identified for soybean partial resistance to different isolates of Pythium irregulare and Pythium sylvaticum. Pythium root rot is an important seedling disease of soybean [Glycine max (L.) Merr.], a crop grown worldwide for protein and oil content. Pythium irregulare and P. sylvaticum are two of the most prevalent and aggressive Pythium species in soybean producing regions in the North Central U.S. Few studies have been conducted to identify soybean resistance for management against these two pathogens. In this study, a mapping population (derived from E13390 x E13901) with 228 F4:5 recombinant inbred lines were screened against P. irregulare isolate MISO 11-6 and P. sylvaticum isolate C-MISO2-2-30 for QDRL mapping. Correlation analysis indicated significant positive correlations between soybean responses to the two pathogens, and a pleiotropic QDRL (qPirr16.1) was identified. Further investigation found that the qPirr16.1 imparts dominant resistance against P. irregulare, but recessive resistance against P. sylvaticum. In addition, two QDRL, qPsyl15.1, and qPsyl18.1 were identified for partial resistance to P. sylvaticum. Further analysis revealed epistatic interactions between qPirr16.1 and qPsyl15.1 for RRW and DRX, whereas qPsyl18.1 contributed resistance to RSE. Marker-assisted resistance spectrum analysis using F6:7 progeny lines verified the resistance of qPirr16.1 against four additional P. irregulare isolates. Intriguingly, although the epistatic interaction of qPirr16.1 and qPsyl15.1 can be confirmed using two additional isolates of P. sylvaticum, the interaction appears to be suppressed for the other two P. sylvaticum isolates. An 'epistatic gene-for-gene' model was proposed to explain the isolate-specific epistatic interactions. The integration of the QDRL into elite soybean lines containing all the desirable alleles has been initiated.

Novel Endoscopic Polypectomy Surveillance Technique for Fundic Gland Polyps in Familial Adenomatous Polyposis Can Improve Early Detection of Dysplasia and Gastric Cancer.

INTRODUCTION: Fundic gland polyps (FGPs) are commonly found in patients with familial adenomatous polyposis (FAP) and are considered benign. Biopsies are not routinely performed, and conventional forceps may be time-consuming and/or yield nonrepresentative histology. The purpose of this study was to evaluate the role of a novel endoscopic polypectomy surveillance (EPS), a large volume cold-snare polypectomy technique of random FGPs, in the incidence of dysplasia and gastric cancer (GC) in FAP. METHODS: This is a retrospective longitudinal cohort of patients with FAP referred to a tertiary care center for duodenal adenoma surveillance and who underwent EPS of FGPs between 2001 and 2019. Demographic, endoscopic, and clinicopathologic information was reviewed. RESULTS: Thirty-five patients with FAP were identified at initial endoscopy by the mean age of 43.4 years (±12.8). One hundred thirteen surveillance endoscopies were performed in total using EPS. Dysplasia of FGPs was present on initial esophagogastroduodenoscopy in 7 patients (20%), and 13 additional patients (46.4%) progressed to low-grade dysplasia. Three patients (15%) who subsequently had progression to GC were found to have signet ring cell cancer within the foci of FGPs through EPS. One patient presented as metastatic GC. Progression from nondysplastic FGP to low-grade dysplasia occurred over 63 months (±46.3) with further progression to GC over 34 months (±8.5). Endoscopic risk factors for cancer were polyps >10 mm in size ( P < 0.001) and carpeting of polyps ( P < 0.001). The 5-year cumulative incidence of developing dysplasia was 35.7%. DISCUSSION: We identified that the incidence of dysplasia and GC is higher than previously reported in patients with FAP. Our study used a novel EPS technique and was able to identify GC within the foci of FGPs. Upper endoscopic guidelines should include a more rigorous sampling method for FGPs, such as EPS, to optimize early detection of dysplasia and GC.