Zhx2 Is a Candidate Gene Underlying Oxymorphone Metabolite Brain Concentration Associated with State-Dependent Oxycodone Reward.

Understanding the pharmacogenomics of opioid metabolism and behavior is vital to therapeutic success, as mutations can dramatically alter therapeutic efficacy and addiction liability. We found robust, sex-dependent BALB/c substrain differences in oxycodone behaviors and whole brain concentration of oxycodone metabolites. BALB/cJ females showed robust state-dependent oxycodone reward learning as measured via conditioned place preference when compared with the closely related BALB/cByJ substrain. Accordingly, BALB/cJ females also showed a robust increase in brain concentration of the inactive metabolite noroxycodone and the active metabolite oxymorphone compared with BALB/cByJ mice. Oxymorphone is a highly potent, full agonist at the mu opioid receptor that could enhance drug-induced interoception and state-dependent oxycodone reward learning. Quantitative trait locus (QTL) mapping in a BALB/c F2 reduced complexity cross revealed one major QTL on chromosome 15 underlying brain oxymorphone concentration that explained 32% of the female variance. BALB/cJ and BALB/cByJ differ by fewer than 10,000 variants, which can greatly facilitate candidate gene/variant identification. Hippocampal and striatal cis-expression QTL (eQTL) and exon-level eQTL analysis identified Zhx2, a candidate gene coding for a transcriptional repressor with a private BALB/cJ retroviral insertion that reduces Zhx2 expression and sex-dependent dysregulation of cytochrome P450 enzymes. Whole brain proteomics corroborated the Zhx2 eQTL and identified upregulated CYP2D11 that could increase brain oxymorphone in BALB/cJ females. To summarize, Zhx2 is a highly promising candidate gene underlying brain oxycodone metabolite levels. Future studies will validate Zhx2 and its site of action using reciprocal gene editing and tissue-specific viral manipulations in BALB/c substrains. SIGNIFICANCE STATEMENT: Our findings show that genetic variation can result in sex-specific alterations in whole brain concentration of a bioactive opioid metabolite after oxycodone administration, reinforcing the need for sex as a biological factor in pharmacogenomic studies. The cooccurrence of female-specific increased oxymorphone and state-dependent reward learning suggests that this minor yet potent and efficacious metabolite of oxycodone could increase opioid interoception and drug-cue associative learning of opioid reward, which has implications for cue-induced relapse of drug-seeking behavior and for precision pharmacogenetics.

The Characteristics and Outcomes of Patients Who Make an Emergency Department Visit for Hypertension After Use of a Home or Pharmacy Blood Pressure Device.

STUDY OBJECTIVE: Emergency department (ED) visits for hypertension are rapidly increasing. Hypertension guidelines began recommending use of self-measurement blood pressure (BP) devices in the early 2000s, which could be contributing to the increase. We aim to examine the proportion of ED visits for hypertension that occurred after a BP measurement with a self-measuring device, and the associated outcomes. METHODS: This retrospective observational study included adults who made an ED visit and received a primary diagnosis of hypertension at 1 of 5 community and tertiary hospitals in Ontario, Canada, between April 2010 and March 2011. We categorized ED visits into 4 groups: those made after a home BP reading, a pharmacy reading, as a result of a physician referral, and all others (termed "not documented"). We examined rates of admission to the hospital, ED treatment (administration of antihypertensive medication and prescription provision), and post-ED clinical events (follow-up care, return ED visits, and long-term all-cause mortality) by group. RESULTS: Among 1,508 qualifying patients, median presenting ED BP was 182/97 mm Hg (interquartile range 164 to 200/85 to 109 mm Hg). The percentage of patients who presented to the ED after a reading at home, at a pharmacy, or by physician referral and the remaining patients not documented was 40.9%, 8.3%, 13.3%, and 37.5%, respectively. Overall, 109 patients (7.2%) were admitted to the hospital. The proportion of patients admitted after a home or pharmacy reading, after a physician referral, or who were not documented was 3.1%, 11.9%, and 11.0%, respectively. Two-year mortality rates were 5.4%, 0.0%, 6.5%, and 5.3% for the home, pharmacy, physician referral, and not documented groups, respectively. Among the 92.8% of patients who were discharged from the ED, 11% made another ED visit for hypertension within a year. CONCLUSION: In this study, half of patients with an ED visit that was primarily for hypertension presented after elevated readings on self-measurement devices. Only 3% of these patients were admitted to the hospital.

Development and validation of prediction models for endometrial cancer in postmenopausal bleeding.

OBJECTIVE: To develop and assess the accuracy of risk prediction models to diagnose endometrial cancer in women having postmenopausal bleeding (PMB). METHODS: A retrospective cohort study of 4383 women in a One-stop PMB clinic from a university teaching hospital in Hong Kong. Clinical risk factors, transvaginal ultrasonic measurement of endometrial thickness (ET) and endometrial histology were obtained from consecutive women between 2002 and 2013. Two models to predict risk of endometrial cancer were developed and assessed, one based on patient characteristics alone and a second incorporated ET with patient characteristics. Endometrial histology was used as the reference standard. The split-sample internal validation and bootstrapping technique were adopted. The optimal threshold for prediction of endometrial cancer by the final models was determined using a receiver-operating characteristics (ROC) curve and Youden Index. The diagnostic gain was compared to a reference strategy of measuring ET only by comparing the AUC using the Delong test. RESULTS: Out of 4383 women with PMB, 168 (3.8%) were diagnosed with endometrial cancer. ET alone had an area under curve (AUC) of 0.92 (95% confidence intervals [CIs] 0.89-0.94). In the patient characteristics only model, independent predictors of cancer were age at presentation, age at menopause, body mass index, nulliparity and recurrent vaginal bleeding. The AUC and Youdens Index of the patient characteristic only model were respectively 0.73 (95% CI 0.67-0.80) and 0.72 (Sensitivity=66.5%; Specificity=68.9%; +ve LR=2.14; -ve LR=0.49). ET, age at presentation, nulliparity and recurrent vaginal bleeding were independent predictors in the patient characteristics plus ET model. The AUC and Youdens Index of the patient characteristic plus ET model where respectively 0.92 (95% CI 0.88-0.96) and 0.71 (Sensitivity=82.7%; Specificity=88.3%; +ve LR=6.38; -ve LR=0.2). Comparison of AUC indicated that a history alone model was inferior to a model using ET alone (difference=0.19, 95% CI 0.15-0.24; p<0.0001) and History plus ET (difference=0.19, 95% CI 0.16-0.23, p<0.0001) and history plus ET was similar to that of using ET alone (difference=0.001 95% CI -0.015 to 0.0018, p=0.84). CONCLUSIONS: A risk model using only patient characteristics showed fair diagnostic accuracy. Addition of patient characteristics to ET did not improve the diagnostic accuracy as compared to ET alone in our cohort.

Transcervical intralesional vasopressin injection compared with placebo in hysteroscopic myomectomy: a randomized controlled trial.

OBJECTIVE: To evaluate the efficacy of transcervical intralesional vasopressin injection to submucous myoma in hysteroscopic myomectomy from 2011 to 2014. METHODS: This was a prospective, randomized, double-blind study in a single center. Forty premenopausal women with symptomatic submucous myoma requiring hysteroscopic myomectomy were randomized to transcervical intralesional vasopressin injection or placebo in a 4:4 ratio. The primary outcome was operative time. Secondary outcomes including fluid volumes, blood loss, and visual clarity were compared between the two groups. RESULTS: The median duration for myomectomy was 19.9 minutes (range 3.1-54.2 minutes) in the vasopressin group compared with 29.0 minutes (range 8.0-60.9 minutes) in the placebo group, a nonsignificant difference (P=.14). There were significant reductions in the median volume of fluid used (4,200 mL [range 1,300-21,000 mL] compared with 9,800 mL (range 1,500-23,000 mL; P=.004) and fluid intravasation (0 mL [range 0-3,100] compared with 300 mL [range -150-3,150 mL; P=.029) in the vasopressin group. The median intraoperative blood loss was reduced (5 mL [range 1-50 mL] compared with 20 mL [range 1-150 mL; P=.002). The operative surgeon rated that 95% of the vasopressin group had "minimal" bleeding compared with 36.8% in the placebo group. The surgical field (visual analog scale [VAS] 9 [range 2-10] compared with 6 [range 2-10; P<.001]; 0=worst visual clarity, 10=best visual clarity) and the effluent fluid (VAS 1 [range 0-7] compared with 4 [range 0-8; P<.001]; 0=clear, 10=unclear) were statistically significantly clearer in the vasopressin group. CONCLUSION: Transcervical intralesional vasopressin injection in hysteroscopic myomectomy did not reduce operative time but did reduce volume of inflow fluid, fluid intravasation, intraoperative blood loss, and improving visual clarity. CLINICAL TRIAL REGISTRATION: Centre for Clinical Research and Biostatistics, http://www.cct.cuhk.edu.hk/Registry/publictriallist.aspx, CUHK_CCT00291.

Safety and efficacy of sonographically guided high-intensity focused ultrasound for symptomatic uterine fibroids: preliminary study of a modified protocol.

OBJECTIVES: We aimed to assess the safety and efficacy of sonographically guided high-intensity focused ultrasound for treating patients with symptomatic uterine fibroids using a modified protocol. METHODS: This work was part of an ongoing prospective phase 1 study. Twenty patients with 22 symptomatic fibroids were treated with sonographically guided high-intensity focused ultrasound under no anesthesia. The modified protocol consisted of repeated and shortened (<25 minutes) treatment sessions of high-input acoustic intensity (1000-1500 W/cm(2)) and intensified sonication pulses (1500-2000) at each spot. The primary end points were periprocedural complications. The secondary end points were symptomatic improvement and radiologic evidence of treatment responses, including the degree of fibroid infarction and volume shrinkage 3 months after treatment. Symptomatic improvement was assessed by a pain score, a pictorial chart menstrual score, the Urogenital Distress Inventory short form, and the Incontinence Impact Questionnaire short form. The degree of fibroid infarction was assessed by the nonperfused ratio on contrast-enhanced magnetic resonance imaging, defined as the ratio of the nonperfused fibroid volume to the total fibroid volume. RESULTS: Nineteen patients tolerated the treatment well, with no major adverse events. One patient who received treatment for a fibroid located within 6 cm from the skin had third-degree skin burns at 2 sites of 1 cm in diameter. Fibroid-related abdominal pain, pictorial chart, Urogenital Distress Inventory, and Incontinence Impact Questionnaire scores were significantly improved (P < .05). The median nonperfused ratio at 3 months was 20% (95% confidence interval, 5%-32.5%). Median volume shrinkage at 3 months was 17.2% (95% confidence interval, 4.3%-26.6%). CONCLUSIONS: Sonographically guided high-intensity focused ultrasound using a modified protocol may be safe and effective for symptomatic uterine fibroids in selected patients to avoid skin burns.

Epidemiology and spectrum of positive bacteriological culture in intrauterine fluid collected from women with postmenopausal bleeding.

OBJECTIVE: This study aims to examine the prevalence and bacteriological findings of different types of intrauterine fluid collection in women presenting with postmenopausal bleeding and the risk factors for predicting positive microbiological culture, mixed growth, and anaerobic growth. METHODS: This is a retrospective cohort study. Data from all of the women who were assessed in our one-stop postmenopausal bleeding clinic between 2008 and 2011 and who were found to have intrauterine fluid collection were reviewed. Endometrial aspirates of all women were sent for bacterial culture and histological examination. The risk factors for positive culture were assessed by both univariate and multivariate analyses. RESULTS: A total of 228 cases of intrauterine fluid collection were included for analysis. There were 109 (47.8%) cases of pyometra, 98 (43.0%) cases of hydrometra, and 21 (9.2%) cases of hematometra. Escherichia coli, Bacteroides fragilis, and Enterococcus were the commonest microorganisms isolated from endometrial aspirates. Both endometrial malignancy and benign intrauterine pathologies are not risk factors for positive culture. Advanced age (>75 y) is an independent risk factor for positive culture (odds ratio, 2.89; 95% CI, 1.39-6.01) and mixed growth (odds ratio, 2.18; 95% CI, 1.02-4.67). Residency in nursing homes is an independent risk factor for mixed growth (odds ratio, 2.61; 95% CI, 1.21-5.63) and anaerobic growth (odds ratio, 2.55; 95% CI, 1.01-6.44). CONCLUSIONS: E. coli, B. fragilis, and Enterococcus are the commonest microorganisms isolated from intrauterine fluid. Apart from drainage of the intrauterine fluid collection, successful management also requires appropriate antibiotics and improvement in perineal hygiene.

Transcervical intralesional vasopressin injection in hysteroscopic myomectomy--description of a new technique.

An original technique of transcervical intralesional vasopressin injection that allowed direct infiltration to submucous myomas under hysteroscopic control is described. Five patients with a symptomatic submucous myoma 1.5-5 cm in size scheduled for hysteroscopic myomectomy were recruited. The time required for vasopressin injection was less than 3 minutes in all cases. The time required for myomectomy ranged from 3 to 32 minutes. Four cases had no fluid absorption, whereas 1 had absorption of 1000 mL. The patient with the longest operative time and fluid absorption had multiple submucous myomas, including a large G2 myoma of 5 cm. All cases had complete excision without complication. The surgeons rated the operations as having minimal bleeding and excellent clarity. Transcervical intralesional vasopressin injection is a potentially simple, quick, and feasible method to facilitate complete resection of submucous myomas in hysteroscopic myomectomy.