Association of genetic ancestry with striatal dopamine D2/D3 receptor availability.

Despite ethnic differences in allele frequencies of variants in dopaminergic genes associated with dopamine D2/D3 receptor availability (D2R), no study to date has investigated the relationship between genetic ancestry and striatal D2R. Here, we show that ancestry-informative markers significantly predict dorsal striatal D2R in 117 healthy ethnically diverse residents of the New York metropolitan area using Positron Emission Tomography (PET) with [11C]raclopride (P<0.0001), while correcting for age, sex, BMI, education, smoking status, and estimated socioeconomic status (ZIP codes). Effects of ethnicity on D2R were not driven by variation in dopaminergic candidate genes. Instead, candidate gene associations with striatal D2R were diminished when correcting for ancestry. These findings imply that future studies investigating D2 receptor genes should covary for genetic ancestry or study homogeneous populations. Moreover, ancestry studies on human neurobiology should control for socioeconomic differences between ethnic groups.

Predictors of predominant Lupus Low Disease Activity State (LLDAS-50).

AIM: The Lupus Low Disease Activity State (LLDAS) is a potential treat to target goal in systemic lupus erythematosus (SLE). SLE patients in LLDAS for more than half of the observation time have about a 50% lower risk of new organ damage and have reduced mortality. We identified predictors of being in LLDAS ≥50% of the observation time. METHODS: A total of 2228 SLE patients who had at least three clinical visits were included. Percentage of time in LLDAS was calculated based on the proportion of days under observation. LLDAS-50 was defined as being in LLDAS for ≥50% of the observation time. We used the stepwise selection procedure in logistic regression to identify predictors of LLDAS-50. RESULTS: A total of 1169 (52.5%) SLE patients, but only 37.6% of African Americans, achieved LLDAS-50. In the multivariable model, African American ethnicity, hypocomplementemia, serositis, renal activity, arthritis, anti-RNP, anti-dsDNA, vasculitis, malar rash, discoid rash, thrombocytopenia, and immunosuppressive use were negative predictors of LLDAS-50. Older age at diagnosis, longer disease duration, higher education level, and greater percentage of time taking hydroxychloroquine remained positive predictors of LLDAS-50. CONCLUSION: In this large cohort, only 52.5% achieved LLDAS-50. This proportion was even less in African Americans. A higher percentage of time taking hydroxychloroquine was a modifiable positive predictor of LLDAS-50. Anti-RNP, anti-dsDNA, and low complement were negatively associated with LLDAS-50. Our findings further emphasize the importance of inclusion of African Americans in clinical trials and hydroxychloroquine adherence in both clinical practice and clinical trials.

The ESC/E(Z) complex, an effector of response to ovarian steroids, manifests an intrinsic difference in cells from women with premenstrual dysphoric disorder.

Clinical evidence suggests that mood and behavioral symptoms in premenstrual dysphoric disorder (PMDD), a common, recently recognized, psychiatric condition among women, reflect abnormal responsivity to ovarian steroids. This differential sensitivity could be due to an unrecognized aspect of hormonal signaling or a difference in cellular response. In this study, lymphoblastoid cell line cultures (LCLs) from women with PMDD and asymptomatic controls were compared via whole-transcriptome sequencing (RNA-seq) during untreated (ovarian steroid-free) conditions and following hormone treatment. The women with PMDD manifested ovarian steroid-triggered behavioral sensitivity during a hormone suppression and addback clinical trial, and controls did not, leading us to hypothesize that women with PMDD might differ in their cellular response to ovarian steroids. In untreated LCLs, our results overall suggest a divergence between mRNA (for example, gene transcription) and protein (for example, RNA translation in proteins) for the same genes. Pathway analysis of the LCL transcriptome revealed, among others, over-expression of ESC/E(Z) complex genes (an ovarian steroid-regulated gene silencing complex) in untreated LCLs from women with PMDD, with more than half of these genes over-expressed as compared with the controls, and with significant effects for MTF2, PHF19 and SIRT1 (P<0.05). RNA and protein expression of the 13 ESC/E(Z) complex genes were individually quantitated. This pattern of increased ESC/E(Z) mRNA expression was confirmed in a larger cohort by qRT-PCR. In contrast, protein expression of ESC/E(Z) genes was decreased in untreated PMDD LCLs with MTF2, PHF19 and SIRT1 all significantly decreased (P<0.05). Finally, mRNA expression of several ESC/E(Z) complex genes were increased by progesterone in controls only, and decreased by estradiol in PMDD LCLs. These findings demonstrate that LCLs from women with PMDD manifest a cellular difference in ESC/E(Z) complex function both in the untreated condition and in response to ovarian hormones. Dysregulation of ESC/E(Z) complex function could contribute to PMDD.

The contribution of rare and common variants in 30 genes to risk nicotine dependence.

Genetic and functional studies have revealed that both common and rare variants of several nicotinic acetylcholine receptor subunits are associated with nicotine dependence (ND). In this study, we identified variants in 30 candidate genes including nicotinic receptors in 200 sib pairs selected from the Mid-South Tobacco Family population with equal numbers of African Americans (AAs) and European Americans (EAs). We selected 135 of the rare and common variants and genotyped them in the Mid-South Tobacco Case-Control (MSTCC) population, which consists of 3088 AAs and 1430 EAs. None of the genotyped common variants showed significant association with smoking status (smokers vs non-smokers), Fagerström Test for ND scores or indexed cigarettes per day after Bonferroni correction. Rare variants in NRXN1, CHRNA9, CHRNA2, NTRK2, GABBR2, GRIN3A, DNM1, NRXN2, NRXN3 and ARRB2 were significantly associated with smoking status in the MSTCC AA sample, with weighted sum statistic (WSS) P-values ranging from 2.42 × 10(-3) to 1.31 × 10(-4) after 10(6) phenotype rearrangements. We also observed a significant excess of rare nonsynonymous variants exclusive to EA smokers in NRXN1, CHRNA9, TAS2R38, GRIN3A, DBH, ANKK1/DRD2, NRXN3 and CDH13 with WSS P-values between 3.5 × 10(-5) and 1 × 10(-6). Variants rs142807401 (A432T) and rs139982841 (A452V) in CHRNA9 and variants V132L, V389L, rs34755188 (R480H) and rs75981117 (N549S) in GRIN3A are of particular interest because they are found in both the AA and EA samples. A significant aggregate contribution of rare and common coding variants in CHRNA9 to the risk for ND (SKAT-C: P=0.0012) was detected by applying the combined sum test in MSTCC EAs. Together, our results indicate that rare variants alone or combined with common variants in a subset of 30 biological candidate genes contribute substantially to the risk of ND.

Genetic background of extreme violent behavior.

In developed countries, the majority of all violent crime is committed by a small group of antisocial recidivistic offenders, but no genes have been shown to contribute to recidivistic violent offending or severe violent behavior, such as homicide. Our results, from two independent cohorts of Finnish prisoners, revealed that a monoamine oxidase A (MAOA) low-activity genotype (contributing to low dopamine turnover rate) as well as the CDH13 gene (coding for neuronal membrane adhesion protein) are associated with extremely violent behavior (at least 10 committed homicides, attempted homicides or batteries). No substantial signal was observed for either MAOA or CDH13 among non-violent offenders, indicating that findings were specific for violent offending, and not largely attributable to substance abuse or antisocial personality disorder. These results indicate both low monoamine metabolism and neuronal membrane dysfunction as plausible factors in the etiology of extreme criminal violent behavior, and imply that at least about 5-10% of all severe violent crime in Finland is attributable to the aforementioned MAOA and CDH13 genotypes.

Updated prostate imaging reporting and data system (PIRADS v2) recommendations for the detection of clinically significant prostate cancer using multiparametric MRI: critical evaluation using whole-mount pathology as standard of reference.

OBJECTIVES: To evaluate the recommendations for multiparametric prostate MRI (mp-MRI) interpretation introduced in the recently updated Prostate Imaging Reporting and Data System version 2 (PI-RADSv2), and investigate the impact of pathologic tumour volume on prostate cancer (PCa) detectability on mpMRI. METHODS: This was an institutional review board (IRB)-approved, retrospective study of 150 PCa patients who underwent mp-MRI before prostatectomy; 169 tumours ≥0.5-mL (any Gleason Score [GS]) and 37 tumours <0.5-mL (GS ≥4+3) identified on whole-mount pathology maps were located on mp-MRI consisting of T2-weighted imaging (T2WI), diffusion-weighted (DW)-MRI, and dynamic contrast-enhanced (DCE)-MRI. Corresponding PI-RADSv2 scores were assigned on each sequence and combined as recommended by PI-RADSv2. We calculated the proportion of PCa foci on whole-mount pathology correctly identified with PI-RADSv2 (dichotomized scores 1-3 vs. 4-5), stratified by pathologic tumour volume. RESULTS: PI-RADSv2 allowed correct identification of 118/125 (94 %; 95 %CI: 90-99 %) peripheral zone (PZ) and 42/44 (95 %; 95 %CI: 89-100 %) transition zone (TZ) tumours ≥0.5 mL, but only 7/27 (26 %; 95 %CI: 10-42 %) PZ and 2/10 (20 %; 95 %CI: 0-52 %) TZ tumours with a GS ≥4+3, but <0.5 mL. DCE-MRI aided detection of 4/125 PZ tumours ≥0.5 mL and 0/27 PZ tumours <0.5 mL. CONCLUSIONS: PI-RADSv2 correctly identified 94-95 % of PCa foci ≥0.5 mL, but was limited for the assessment of GS ≥4+3 tumours ≤0.5 mL. DCE-MRI offered limited added value to T2WI+DW-MRI. KEY POINTS: • PI-RADSv2 correctly identified 95 % of PCa foci ≥0.5 mL • PI-RADSv2 was limited for the assessment of GS ≥4+3 tumours ≤0.5 mL • DCE-MRI offered limited added value to T2WI+DW-MRI.

FAAH selectively influences placebo effects.

Endogenous opioid and cannabinoid systems are thought to act synergistically regulating antinociceptive and reward mechanisms. To further understand the human implications of the interaction between these two systems, we investigated the role of the common, functional missense variant Pro129Thr of the gene coding fatty acid amide hydrolase (FAAH), the major degrading enzyme of endocannabinoids, on psychophysical and neurotransmitter (dopaminergic, opioid) responses to pain and placebo-induced analgesia in humans. FAAH Pro129/Pro129 homozygotes, who constitute nearly half of the population, reported higher placebo analgesia and more positive affective states immediately and 24 h after placebo administration; no effects on pain report in the absence of placebo were observed. Pro129/Pro129 homozygotes also showed greater placebo-induced µ-opioid, but not D(2/3) dopaminergic, enhancements in neurotransmission in regions known involved in placebo effects. These results show that a common genetic variation affecting the function of the cannabinoid system is serving as a probe to demonstrate the involvement of cannabinoid and opioid transmitters on the formation of placebo effects.

Functional genetic variants in the vesicular monoamine transporter 1 modulate emotion processing.

Emotional behavior is in part heritable and often disrupted in psychopathology. Identification of specific genetic variants that drive this heritability may provide important new insight into molecular and neurobiological mechanisms involved in emotionality. Our results demonstrate that the presynaptic vesicular monoamine transporter 1 (VMAT1) Thr136Ile (rs1390938) polymorphism is functional in vitro, with the Ile allele leading to increased monoamine transport into presynaptic vesicles. Moreover, we show that the Thr136Ile variant predicts differential responses in emotional brain circuits consistent with its effects in vitro. Lastly, deep sequencing of bipolar disorder (BPD) patients and controls identified several rare novel VMAT1 variants. The variant Phe84Ser was only present in individuals with BPD and leads to marked increase monoamine transport in vitro. Taken together, our data show that VMAT1 polymorphisms influence monoamine signaling, the functional response of emotional brain circuits and risk for psychopathology.

Volume-based quantitative FDG PET/CT metrics and their association with optimal debulking and progression-free survival in patients with recurrent ovarian cancer undergoing secondary cytoreductive surgery.

OBJECTIVE: Our aim was to evaluate the associations between quantitative (18)F-fluorodeoxyglucose positron-emission tomography (FDG-PET) uptake metrics, optimal debulking (OD) and progression-free survival (PFS) in patients with recurrent ovarian cancer undergoing secondary cytoreductive surgery. METHODS: Fifty-five patients with recurrent ovarian cancer underwent FDG-PET/CT within 90 days prior to surgery. Standardized uptake values (SUVmax), metabolically active tumour volumes (MTV), and total lesion glycolysis (TLG) were measured on PET. Exact logistic regression, Kaplan-Meier curves and the log-rank test were used to assess associations between imaging metrics, OD and PFS. RESULTS: MTV (p = 0.0025) and TLG (p = 0.0043) were associated with OD; however, there was no significant association between SUVmax and debulking status (p = 0.83). Patients with an MTV above 7.52 mL and/or a TLG above 35.94 g had significantly shorter PFS (p = 0.0191 for MTV and p = 0.0069 for TLG). SUVmax was not significantly related to PFS (p = 0.10). PFS estimates at 3.5 years after surgery were 0.42 for patients with an MTV ≤ 7.52 mL and 0.19 for patients with an MTV > 7.52 mL; 0.46 for patients with a TLG ≤ 35.94 g and 0.15 for patients with a TLG > 35.94 g. CONCLUSION: FDG-PET metrics that reflect metabolic tumour burden are associated with optimal secondary cytoreductive surgery and progression-free survival in patients with recurrent ovarian cancer. KEY POINTS: • Both TLG and MTV were associated with optimal tumour debulking. • There was no significant association between SUVmax and tumour debulking status. • Patients with higher MTV and/or TLG had significantly shorter PFS. • SUVmax was not significantly related to PFS.

Volume and landmark analysis: comparison of MRI measurements obtained with an endorectal coil and with a phased-array coil.

AIM: To compare prostate volumes and distances between anatomical landmarks on MRI images obtained with a phased-array coil (PAC) only and with a PAC and an endorectal coil (ERC). MATERIALS AND METHODS: Informed consent was waived for this Health Insurance Portability and Accountability Act-compliant study. Fifty-nine men underwent PAC-MRI and ERC-MRI at 1.5 (n = 3) or 3 T (n = 56). On MRI images, two radiologists independently measured prostate volume and distances between the anterior rectal wall (ARW) and symphysis pubis at the level of the verumontanum; ARW and symphysis pubis at the level of the mid-symphysis pubis; and bladder neck and mid-symphysis pubis. Differences between measurements from PAC-MRI and ERC-MRI were assessed with the Wilcoxon RANK SUM test. Inter-reader agreement was assessed using the concordance correlation coefficient (CCC). RESULTS: Differences in prostate volume between PAC-MRI and ERC-MRI [median: -0.75 mm(3) (p = 0.10) and median: -0.84 mm(3) (p = 0.06) for readers 1 and 2, respectively] were not significant. For readers 1 and 2, median differences between distances were as follows: -10.20 and -12.75 mm, respectively, ARW to symphysis pubis at the level of the verumontanum; -6.60 and -6.08 mm, respectively, ARW to symphysis pubis at the level of the mid-symphysis pubis; -3 and -3 mm respectively, bladder neck to mid-symphysis pubis. All differences in distance were significant for both readers (p ≤ 0.0005). Distances were larger on PAC-MRI (p ≤ 0.0005). Inter-reader agreement regarding prostate volume was almost perfect on PAC-MRI (CCC: 0.99; 95% CI: 0.98-1.00) and ERC-MRI (CCC: 0.99; 95% CI: 0.99-1.00); inter-reader agreement for distance measurements varied (CCCs: 0.54-0.86). CONCLUSION: Measurements of distances between anatomical landmarks differed significantly between ERC-MRI and PAC-MRI, although prostate volume measurements did not.

Making sense of deep sequencing.

This review, the first of an occasional series, tries to make sense of the concepts and uses of deep sequencing of polynucleic acids (DNA and RNA). Deep sequencing, synonymous with next-generation sequencing, high-throughput sequencing and massively parallel sequencing, includes whole genome sequencing but is more often and diversely applied to specific parts of the genome captured in different ways, for example the highly expressed portion of the genome known as the exome and portions of the genome that are epigenetically marked either by DNA methylation, the binding of proteins including histones, or that are in different configurations and thus more or less accessible to enzymes that cleave DNA. Deep sequencing of RNA (RNASeq) reverse-transcribed to complementary DNA is invaluable for measuring RNA expression and detecting changes in RNA structure. Important concepts in deep sequencing include the length and depth of sequence reads, mapping and assembly of reads, sequencing error, haplotypes, and the propensity of deep sequencing, as with other types of 'big data', to generate large numbers of errors, requiring monitoring for methodologic biases and strategies for replication and validation. Deep sequencing yields a unique genetic fingerprint that can be used to identify a person, and a trove of predictors of genetic medical diseases. Deep sequencing to identify epigenetic events including changes in DNA methylation and RNA expression can reveal the history and impact of environmental exposures. Because of the power of sequencing to identify and deliver biomedically significant information about a person and their blood relatives, it creates ethical dilemmas and practical challenges in research and clinical care, for example the decision and procedures to report incidental findings that will increasingly and frequently be discovered.

Pain in alcohol use disorder: Evaluating effects of childhood trauma, perceived stress, and psychological comorbidity.

The relationship between pain and alcohol use disorder (AUD) is complex and bidirectional. The current study examines risk factors for pain in a large comprehensively phenotyped sample including individuals from across the spectrum of alcohol use and misuse. Participants (n = 1101) were drawn from the National Institute on Alcohol Abuse and Alcoholism Natural History Protocol and included treatment-seeking AUD inpatients (AUD+Tx, n = 369), individuals with AUD not seeking treatment (AUD+, n = 161), and individuals without AUD (AUD-, n = 571). General linear models were utilized to test the effects of AUD status, history of childhood trauma exposure, perceived stress, and psychological comorbidity on daily percent time in pain, as well as change in daily percent time in pain across the inpatient stay in AUD+Tx individuals. Overall, 60.2% individuals reported any pain, with a significantly higher prevalence in the AUD+Tx group (82.1%) compared to the AUD+ (56.5%) and AUD- (47.1%) groups. Daily percent time in pain was also highest in the AUD+Tx group (30.2%) and was further increased in those with a history of childhood abuse and comorbid posttraumatic stress disorder (PTSD). Years of heavy drinking and craving were also associated with increased percent time in pain in the AUD+Tx group. Percent time in pain decreased following acute withdrawal in the AUD+Tx group but plateaued around 25% just prior to discharge. Individuals seeking inpatient treatment for AUD, especially those with a history of childhood trauma and/or comorbid PTSD, report greater percent time in pain compared to those not seeking treatment and those without AUD. The prolonged experience of pain in abstinent AUD inpatients after the resolution of acute withdrawal may signal the early stages of protracted withdrawal. Integrative treatments targeting pain and other symptoms of protracted withdrawal may be effective in improving overall function in people with severe AUD.

Ocular retardation mouse caused by Chx10 homeobox null allele: impaired retinal progenitor proliferation and bipolar cell differentiation.

Ocular retardation (or) is a murine eye mutation causing microphthalmia, a thin hypocellular retina and optic nerve aplasia. Here we show that mice carrying the OrJ allele have a premature stop codon in the homeobox of the Chx10 gene, a gene expressed at high levels in uncommitted retinal progenitor cells and mature bipolar cells. No CHX10 protein was detectable in the retinal neuroepithelium of orJ homozygotes. The loss of CHX10 leads both to reduced proliferation of retinal progenitors and to a specific absence of differentiated bipolar cells. Other major retinal cell types were present and correctly positioned in the mutant retina, although rod outer segments were short and retinal lamination was incomplete. These results indicate that Chx10 is an essential component in the network of genes required for the development of the mammalian eye, with profound effects on retinal progenitor proliferation and bipolar cell specification or differentiation. off

Clonal hematopoiesis related TET2 loss-of-function impedes IL1ß-mediated epigenetic reprogramming in hematopoietic stem and progenitor cells.

Clonal hematopoiesis (CH) is defined as a single hematopoietic stem/progenitor cell (HSPC) gaining selective advantage over a broader range of HSPCs. When linked to somatic mutations in myeloid malignancy-associated genes, such as TET2-mediated clonal hematopoiesis of indeterminate potential or CHIP, it represents increased risk for hematological malignancies and cardiovascular disease. IL1ß is elevated in patients with CHIP, however, its effect is not well understood. Here we show that IL1ß promotes expansion of pro-inflammatory monocytes/macrophages, coinciding with a failure in the demethylation of lymphoid and erythroid lineage associated enhancers and transcription factor binding sites, in a mouse model of CHIP with hematopoietic-cell-specific deletion of Tet2. DNA-methylation is significantly lost in wild type HSPCs upon IL1ß administration, which is resisted by Tet2-deficient HSPCs, and thus IL1ß enhances the self-renewing ability of Tet2-deficient HSPCs by upregulating genes associated with self-renewal and by resisting demethylation of transcription factor binding sites related to terminal differentiation. Using aged mouse models and human progenitors, we demonstrate that targeting IL1 signaling could represent an early intervention strategy in preleukemic disorders. In summary, our results show that Tet2 is an important mediator of an IL1ß-promoted epigenetic program to maintain the fine balance between self-renewal and lineage differentiation during hematopoiesis.

Increased chitinase expression and fungal-specific antibodies in the bronchoalveolar lavage fluid of asthmatic children.

BACKGROUND: Increasing evidence highlights the contribution of chitinases and fungal infection to the development of asthma. OBJECTIVE: The purpose of this study was to characterize chitinase expression and serological markers of fungal infection in children with severe asthma. METHODS: Bronchoalveolar lavage fluid (BALF) was collected from children undergoing clinically indicated flexible bronchoscopy. A diagnosis of asthma was confirmed by pulmonary function testing. BALF was tested for chitinase activity and YKL-40 (an enzymatically inactive chitinase) concentrations. Specimens were cultured for fungal organisms and tested for cryptococcal antigen by ELISA. IgG and IgA reactivity to whole extract fungal (Aspergillus fumigatus, Alternaria alternata, Cryptococcus neoformans and Candida albicans) proteins were determined by immunoblot assay. RESULTS: Among the 37 patients studied, 30 were asthmatic and 7 were non-asthmatic. Asthmatics exhibited elevated serum IgE levels (median: 748 IU/mL, IQR: 219-1765 IU/mL). Chitinase activity was greater in the BALF of asthmatics (mean, 0.85 ± 1.2 U/mL) compared with non-asthmatics (mean: 0.23 ± 0.21 U/mL, P = 0.012). Likewise YKL-40 concentrations were higher in the BALF of asthmatics and correlated with chitinase activity. There was a trend towards increased fungal-specific IgG in the BALF of asthmatics compared with non-asthmatics and for C. albicans this difference reached statistical significance. IgA reactivity to C. neoformans and A. fumigatus was greater in the BALF of asthmatics compared with non-asthmatics. CONCLUSIONS AND CLINICAL RELEVANCE: Compared with non-asthmatics, asthmatic children exhibited increased chitinase activity and increased YKL-40 levels in BALF. Increased IgG and IgA reactivity to fungal proteins in the BALF of asthmatics may reflect a local response to fungal infection. Our findings are consistent with and suggest a role for chitinases in asthma pathogenesis among Bronx children and provide serological evidence of an association between fungal infection and severe asthma.

Functional genetic variants that increase synaptic serotonin and 5-HT3 receptor sensitivity predict alcohol and drug dependence.

The 5-HT3 receptor is rapidly potentiated by ethanol and mediates fast excitatory serotonin (5-HT) transmission that modulates dopamine release in the reward circuitry. The 5-HT transporter regulates synaptic 5-HT availability. Functional polymorphisms in genes encoding the transporter and receptor may therefore influence addiction vulnerability. In this study, 360 treatment-seeking African American male patients with single and comorbid DSM-IV lifetime diagnoses of alcohol, cocaine and heroin dependence and 187 African American male controls were genotyped for the triallelic 5-HTTLPR functional polymorphism in the 5-HT transporter gene (SLC6A4) and 16 haplotype-tagging single-nucleotide polymorphisms (SNPs) across HTR3B (including the functional rs1176744 Tyr129Ser) and HTR3A, genes encoding 5-HT3 receptors. The HTR3B rs1176744 gain-of-function Ser129 allele predicted alcohol dependence (P=0.002) and low 5-HTTLPR activity predicted cocaine/heroin dependence (P=0.01). Both the HTR3B Ser129 allele (P=0.014, odds ratio (OR)=1.7 (1.1-2.6)) and low 5-HTTLPR activity (P=0.011, OR=2.5 (1.3-4.6)) were more common in men with alcohol+drug dependence compared with controls. Moreover, the HTR3B Ser129 allele and low 5-HTTLPR activity had an additive (but not an interactive) effect on alcohol+drug dependence (OR=6.0 (2.1-16.6)) that accounted for 13% of the variance. One possible explanation of our findings is that increased synaptic 5-HT coupled with increased 5-HT3 receptor responsiveness may result in enhanced dopamine transmission in the reward pathway, a predictor of increased risk for addiction. Our results may have pharmacogenetic implications for 5-HT3 therapeutic antagonists such as ondansetron.

The oral microbiome in alcohol use disorder: a longitudinal analysis during inpatient treatment.

BACKGROUND: Alcohol use disorder (AUD)-induced disruption of oral microbiota can lead to poor oral health; there have been no studies published examining the longitudinal effects of alcohol use cessation on the oral microbiome. AIM: To investigate the oral microbiome during alcohol cessation during inpatient treatment for AUD. METHODS: Up to 10 oral tongue brushings were collected from 22 AUD patients during inpatient treatment at the National Institutes of Health. Alcohol use history, smoking, and periodontal disease status were measured. Oral microbiome samples were sequenced using 16S rRNA gene sequencing. RESULTS: Alpha diversity decreased linearly during treatment across the entire cohort (P = 0.002). Alcohol preference was associated with changes in both alpha and beta diversity measures. Characteristic tongue dorsum genera from the Human Microbiome Project such as Streptococcus, Prevotella, Veillonella and Haemophilus were highly correlated in AUD. Oral health-associated genera that changed longitudinally during abstinence included Actinomyces, Capnocytophaga, Fusobacterium, Neisseria and Prevotella. CONCLUSION: The oral microbiome in AUD is affected by alcohol preference. Patients with AUD often have poor oral health but abstinence and attention to oral care improve dysbiosis, decreasing microbiome diversity and periodontal disease-associated genera while improving acute oral health.

MRI at the completion of chemoradiotherapy can accurately evaluate the extent of disease in women with advanced urethral carcinoma undergoing anterior pelvic exenteration.

AIM: To demonstrate the value of pelvic magnetic resonance imaging (MRI) in mapping tumour extension after chemoradiotherapy and before anterior pelvic exenteration in patients with primary carcinoma of the urethra. MATERIALS AND METHODS: The Institutional Review Board approved and issued a waiver of informed consent for this retrospective study, which was compliant with the Health Insurance Portability and Accountability Act. Six women (median age 51 years, range 39-63 years) with histopathology-proven urethral carcinoma who underwent neoadjuvant chemoradiotherapy before anterior pelvic exenteration were included in the study. All had MRI performed at first presentation and after completion of chemoradiotherapy. MRI images were analysed by an experienced reader, who was blinded to the clinical data. The tumour location, signal intensity, size, local extension, and presence of enlarged lymph nodes were recorded for each patient at baseline and after chemoradiotherapy. Surgical histopathology constituted the reference standard. RESULTS: All tumours were locally advanced (stage T3) at baseline MRI. The mean maximum diameter of the tumour at baseline MRI was 3.7 cm (range 2.4-5 cm). After chemoradiotherapy, the mean reduction in maximum tumour diameter on MRI was 44% (range 13-67%), but only three cases were down-staged. MRI was accurate in the evaluation of tumour extension after completion of chemoradiotherapy in all cases. Persistence of bladder neck and anterior vaginal wall invasion was correctly identified in three cases. CONCLUSION: In women with advanced primary urethral cancer, MRI is an excellent tool for monitoring neo-adjuvant chemoradiotherapy changes and evaluating the extent of disease before exenterative surgery.

Transradial Approach for Neuroendovascular Procedures: A Single-Center Review of Safety and Feasibility.

BACKGROUND AND PURPOSE: In recent years, the transradial approach has become more widely adopted for neuroendovascular procedures. The purpose of this study was to evaluate the safety and feasibility of a transradial approach and distal transradial access for neuroendovascular procedures in a single center. MATERIALS AND METHODS: Retrospective analysis was performed for all patients who underwent transradial approach or distal transradial access neuroendovascular procedures from January 2016 to August 2019 at a single center. Exclusion criteria included a Barbeau D waveform, a radial artery of <2 mm on sonographic evaluation, and known radial artery occlusion. Procedures were evaluated for technical success (defined as successful radial artery access and completion of the intended procedure without crossover to an auxiliary access site), complications, and adverse events during follow-up at 30 days. RESULTS: The transradial approach or distal transradial access was attempted in 279 consecutive patients (58.1% women; median age, 57.7 years) who underwent 328 standard or distal transradial approach procedures. Two-hundred seventy-nine transradial approach and 49 distal transradial approach procedures were performed (cerebral angiography [n = 213], intracranial intervention [n = 64], head and neck intervention [n = 30], and stroke intervention [n = 21]). Technical success was 92.1%. Immediate adverse events (2.1%) included radial access site hematoma (n = 5), radial artery occlusion (n = 1), and acute severe radial artery spasm (n = 1). Thirty-day adverse events (0.3%) included a radial artery pseudoaneurysm (n = 1). Twenty-six cases (7.9%) required crossover to transfemoral access. CONCLUSIONS: The transradial approach for neuroendovascular procedures is safe and feasible across a wide range of neuroendovascular interventions.