Effect of deuteration on the single dose pharmacokinetic properties and postoperative analgesic activity of methadone

Although methadone is effective in the management of acute pain, the complexity of its absorption-distribution-metabolism-excretion profile limits its use as an opioid of choice for perioperative analgesia. Because deuteration is known to improve the pharmacokinetic, pharmacodynamic and toxicological properties of some drugs, here we characterized the single dose pharmacokinetic properties and post-operative analgesic efficacy of d₉-methadone.The pharmacokinetic profiles of d₉-methadone and methadone administered intravenously to CD-1 male mice revealed that deuteration leads to a 5.7- and 4.4-fold increase in the area under the time-concentration curve and maximum concentration in plasma, respectively, as well as reduction in clearance (0.9 ± 0.3 L/h/kg vs 4.7 ± 0.8 L/h/kg). The lower brain-to-plasma ratio of d₉-methadone compared to that of methadone (0.35 ± 0.12 vs 2.05 ± 0.62) suggested that deuteration decreases the transfer of the drug across the blood-brain barrier. The estimated LD₅₀ value for a single intravenous dose of d₉-methadone was 2.1-fold higher than that for methadone. Moreover, d₉-methadone outperformed methadone in the efficacy against postoperative pain by primarily activating peripheral opioid receptors. Collectively, these data suggest that the replacement of three hydrogen atoms in three methyl groups of methadone altered its pharmacokinetic properties, improved safety, and enhanced its analgesic efficacy.     

Coming Soon: Ability to Orgasm After Gender Affirming Vaginoplasty

BackgroundMany patients have goals related to sexual health when seeking gender-affirming vaginoplasty, and previous investigations have only studied the ability to orgasm at cross-sectional timepoints.AimOur aim is to quantify the time to orgasm postoperative gender-affirming vaginoplasty and describe potential correlative factors, including preoperative orgasm, to improve preoperative counseling.MethodsA retrospective chart review was utilized to extract factors thought to influence pre and postoperative orgasm in patients undergoing robotic peritoneal flap vaginoplasty. Mean days to orgasm plus one standard deviation above that mean was used to define the time at which patients would be considered anorgasmic.OutcomesOrgasm was documented as a categorical variable on the basis of surgeon interviews during pre and postoperative appointments while time to orgasm was measured as days from surgery to first date documented as orgasmic in the medical record.ResultsA total of 199 patients underwent surgery from September 2017 to August 2020. The median time to orgasm was 180 days. 178 patients had completed 1 year or greater of follow-up, and of these patients, 153 (86%) were orgasmic and 25 patients (14%) were not. Difficulty in preoperative orgasm was correlated only with older age (median age 45.9 years vs 31.7, P = .03). Postoperative orgasm was not significantly correlated with preoperative orgasm. The only factor related to postoperative orgasm was smoking history: 12 of 55 patients (21.8%) who had a positive smoking history and sufficient follow-up reported anorgasmia (P-value .046). Interventions for anorgasmic patients include testosterone replacement, pelvic floor physical therapy, and psychotherapy.Clinical ImplicationsPreoperative difficulty with orgasm improves with gender-affirming robotic peritoneal flap vaginoplasty, while smoking had a negative impact on postoperative orgasm recovery despite negative cotinine test prior to surgery.Strengths & LimitationsThis investigation is the first effort to determine a timeline for the return of orgasmic function after gender-affirming vaginoplasty. It is limited by retrospective review methodology and lack of long-term follow-up. The association of smoking with postoperative orgasm despite universal nicotine cessation prior to surgery may indicate prolonged smoking cessation improves orgasmic outcomes or that underlying, unmeasured exposures correlated with smoking may be the factor inhibiting recovery of orgasm.ConclusionThe majority of patients were orgasmic at their 6-month follow-up appointments, however, patients continued to become newly orgasmic in appreciable numbers more than 1 year after surgery.Blasdel G, Kloer C, Parker A, et al. Coming Soon: Ability to Orgasm After Gender Affirming Vaginoplasty. J Sex Med 2022;19:781–788.     

Polyvictimization and Psychiatric Sequelae Associated with Female Genital Mutilation/Cutting (FGM/C)

Female Genital mutilation/cutting (FGM/C) is associated with enduring psychiatric complications. In this study, we investigate the rates of co-morbid abuses and polyvictimization experienced by survivors of FGM/C. This is a sub-analysis of a cohort study examining the patient population at the EMPOWER Center for Survivors of Sex Trafficking and Sexual Violence in New York City. A retrospective chart-review of electronic medical records was conducted for all consenting adult patients who had FGM/C and had an intake visit between January 16, 2014 and March 6, 2020. Of the 80 participants, ages ranged from 20 to 62 years with a mean of 37.4 (SD?=?9.1) years. In addition to FGM/C, participants were victims of physical abuse (43; 53.8%), emotional abuse (35; 43.8%), sexual abuse (35; 43.8%), forced marriage (20; 25%), child marriage (13; 16.3%), and sex trafficking (1; 1.4%). There was a high degree of polyvictimization, with 41 (51.2%) experiencing 3 or more of the aforementioned abuses. Having FGM/C on or after age 13 or having a higher total abuse score was also found to be strong predictors of depression and PTSD. The high rates of polyvictimization among survivors of FGM/C are associated with development of depression and PTSD. Despite co-morbid abuses, patients still attribute substantial psychiatric symptoms to their FGM/C. Health care providers should understand the high risk of polyvictimization when caring for this patient population.

     

Socioeconomic Deprivation and Premature Cardiovascular Mortality in the United States

ObjectiveTo determine the variability in county cardiovascular (CV) premature mortality explained by integrated metrics of socioeconomic deprivation and to explore temporal trends in CV mortality by county socioeconomic deprivation.MethodsThis is a cross-sectional analysis of US county-level death certificate data from 1999 to 2018 of age-adjusted premature (25 to 64 years) CV mortality. Integrated metrics of socioeconomic deprivation (Social Deprivation Index [SDI] and county Area Deprivation Index [ADI]) were associated with mortality using linear regression analysis. Relative change in county CV mortality from 1999 to 2018 was associated with indices using linear regression analysis.ResultsCounties with higher quartile SDI and ADI had significantly higher total, non-Hispanic Black/African American, and female premature CV mortality (P<.001). Both SDI and ADI were significantly associated with CV mortality by linear regression (P<.001) explaining 40% and 44% of county variability in CV mortality, respectively. Counties with lower deprivation indices experienced a larger decreased in premature CV mortality (P<.001).ConclusionThis study demonstrates an association between multiple integrated metrics of socioeconomic deprivation and premature cardiovascular mortality and shows potentially worsening disparities.     

Addressing bias and disparities in periviable counseling and care

Addressing bias and disparities in counseling and care requires that we contend with dehumanizing attitudes, stereotypes, and beliefs that our society and profession holds towards people of color, broadly, and Black birthing people in particular. It also necessitates an accounting of the historically informed, racist ideologies that shape present-day implicit biases. These biases operate in a distinctly complex and damaging manner in the context of end-of-life care, which centers around questions related to human pain, suffering, and value. Therefore, this paper aims to trace biases and disparities that operate in periviable care, where end-of-life decisions are made at the very beginning of life. We start from a historical context to situate racist ideologies into present day stereotypes and tropes that dehumanize and disadvantage Black birthing people and Black neonates in perinatal care. Here, we review the literature, address historical incidents and consider their impact on our ability to deliver patient-centered periviable care.