Effect of Paroxetine or Quetiapine Combined With Oxycodone vs Oxycodone Alone on Ventilation During Hypercapnia: A Randomized Clinical Trial.

Importance: Opioids can cause severe respiratory depression by suppressing feedback mechanisms that increase ventilation in response to hypercapnia. Following the addition of boxed warnings to benzodiazepine and opioid products about increased respiratory depression risk with simultaneous use, the US Food and Drug Administration evaluated whether other drugs that might be used in place of benzodiazepines may cause similar effects. Objective: To study whether combining paroxetine or quetiapine with oxycodone, compared with oxycodone alone, decreases the ventilatory response to hypercapnia. Design, Setting, and Participants: Randomized, double-blind, crossover clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) with 25 healthy participants from January 2021 through May 25, 2021. Interventions: Oxycodone 10 mg on days 1 and 5 and the following in a randomized order for 5 days: paroxetine 40 mg daily, quetiapine twice daily (increasing daily doses from 100 mg to 400 mg), or placebo. Main Outcomes and Measures: Ventilation at end-tidal carbon dioxide of 55 mm Hg (hypercapnic ventilation) using rebreathing methodology assessed for paroxetine or quetiapine with oxycodone, compared with placebo and oxycodone, on days 1 and 5 (primary) and for paroxetine or quetiapine alone compared with placebo on day 4 (secondary). Results: Among 25 participants (median age, 35 years [IQR, 30-40 years]; 11 female [44%]), 19 (76%) completed the trial. The mean hypercapnic ventilation was significantly decreased with paroxetine plus oxycodone vs placebo plus oxycodone on day 1 (29.2 vs 34.1 L/min; mean difference [MD], -4.9 L/min [1-sided 97.5% CI, -∞ to -0.6]; P = .01) and day 5 (25.1 vs 35.3 L/min; MD, -10.2 L/min [1-sided 97.5% CI, -∞ to -6.3]; P < .001) but was not significantly decreased with quetiapine plus oxycodone vs placebo plus oxycodone on day 1 (33.0 vs 34.1 L/min; MD, -1.2 L/min [1-sided 97.5% CI, -∞ to 2.8]; P = .28) or on day 5 (34.7 vs 35.3 L/min; MD, -0.6 L/min [1-sided 97.5% CI, -∞ to 3.2]; P = .37). As a secondary outcome, mean hypercapnic ventilation was significantly decreased on day 4 with paroxetine alone vs placebo (32.4 vs 41.7 L/min; MD, -9.3 L/min [1-sided 97.5% CI, -∞ to -3.9]; P < .001), but not with quetiapine alone vs placebo (42.8 vs 41.7 L/min; MD, 1.1 L/min [1-sided 97.5% CI, -∞ to 6.4]; P = .67). No drug-related serious adverse events were reported. Conclusions and Relevance: In this preliminary study involving healthy participants, paroxetine combined with oxycodone, compared with oxycodone alone, significantly decreased the ventilatory response to hypercapnia on days 1 and 5, whereas quetiapine combined with oxycodone did not cause such an effect. Additional investigation is needed to characterize the effects after longer-term treatment and to determine the clinical relevance of these findings. Trial Registration: ClinicalTrials.gov Identifier: NCT04310579.

Two-dimensional NMR measurement and point dipole model prediction of paramagnetic shift tensors in solids.

A new two-dimensional Nuclear Magnetic Resonance (NMR) experiment to separate and correlate the first-order quadrupolar and chemical/paramagnetic shift interactions is described. This experiment, which we call the shifting-d echo experiment, allows a more precise determination of tensor principal components values and their relative orientation. It is designed using the recently introduced symmetry pathway concept. A comparison of the shifting-d experiment with earlier proposed methods is presented and experimentally illustrated in the case of (2)H (I = 1) paramagnetic shift and quadrupolar tensors of CuCl2⋅2D2O. The benefits of the shifting-d echo experiment over other methods are a factor of two improvement in sensitivity and the suppression of major artifacts. From the 2D lineshape analysis of the shifting-d spectrum, the (2)H quadrupolar coupling parameters are 〈Cq〉 = 118.1 kHz and 〈ηq〉 = 0.88, and the (2)H paramagnetic shift tensor anisotropy parameters are 〈ζP〉 = - 152.5 ppm and 〈ηP〉 = 0.91. The orientation of the quadrupolar coupling principal axis system (PAS) relative to the paramagnetic shift anisotropy principal axis system is given by (α,ß,γ)=(π2,π2,0). Using a simple ligand hopping model, the tensor parameters in the absence of exchange are estimated. On the basis of this analysis, the instantaneous principal components and orientation of the quadrupolar coupling are found to be in excellent agreement with previous measurements. A new point dipole model for predicting the paramagnetic shift tensor is proposed yielding significantly better agreement than previously used models. In the new model, the dipoles are displaced from nuclei at positions associated with high electron density in the singly occupied molecular orbital predicted from ligand field theory.

Anti-N-methyl-D-aspartate receptor encephalitis: a targeted review of clinical presentation, diagnosis, and approaches to psychopharmacologic management.

BACKGROUND: Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis was formally described in 2007 and includes a range of psychiatric and neurologic symptoms. Most patients with anti-NMDAR encephalitis initially present to psychiatrists for diagnosis and treatment. However, there is limited literature summarizing treatment strategies for psychiatric symptoms. In an effort to improve identification and treatment, this review article provides an overview of anti-NMDAR encephalitis, with a focus on psychopharmacologic treatment strategies. Two case reports provide a clinical context for the literature review. METHODS: The authors conducted a PubMed search. RESULTS: Prominent psychiatric symptoms of anti-NMDAR encephalitis include psychosis, agitation, insomnia, and catatonia. Neuroleptics may be helpful for managing psychosis and agitation, but may exacerbate movement abnormalities. Diphenhydramine and benzodiazepines are helpful for agitation and insomnia. In addition, the anticholinergic affinity of diphenhydramine can improve dystonia or rigidity attributable to anti-NMDAR encephalitis, while benzodiazepines and electroconvulsive therapy have been used for catatonia associated with this condition. CONCLUSIONS: Psychiatrists play an important role in the diagnosis and treatment of anti-NMDAR encephalitis. Recognizing the typical clinical progression and closely monitoring for accompanying neurologic symptoms will facilitate diagnosis and timely treatment. Careful selection of psychopharmacological interventions may reduce suffering.

Innovative Technologies in CNS Trials: Promises and Pitfalls for Recruitment, Retention, and Representativeness.

Objective: Recruitment of a sufficiently large and representative patient sample and its retention during central nervous system (CNS) trials presents major challenges for study sponsors. Technological advances are reshaping clinical trial operations to meet these challenges, and the COVID-19 pandemic further accelerated this development. Method of Research: The International Society for CNS Clinical Trials and Methodology (ISCTM; www.isctm.org) Innovative Technologies for CNS Trials Working Group surveyed the state of technological innovations for improved recruitment and retention and assessed their promises and pitfalls. Results: Online advertisement and electronic patient registries can enhance recruitment, but challenges with sample representativeness, conversion rates from eligible prescreening to enrolled patients, data privacy and security, and patient identification remain hurdles for optimal use of these technologies. Electronic medical records (EMR) mining with artificial intelligence (AI)/machine learning (ML) methods is promising but awaits translation into trials. During the study treatment phase, technological innovations increasingly support participant retention, including adherence with the investigational treatment. Digital tools for adherence and retention support take many forms, including patient-centric communication channels between researchers and participants, real-time study reminders, and digital behavioral interventions to increase study compliance. However, such tools add technical complexities to trials, and their impact on the generalizability of results are largely unknown. Conclusion: Overall, the group found a scarcity of systematic data directly assessing the impact of technological innovations on study recruitment and retention in CNS trials, even for strategies with already high adoption, such as online recruitment. Given the added complexity and costs associated with most technological innovations, such data is needed to fully harness technologies for CNS trials and drive further adoption.

Y-STR variation in the Basque diaspora in the Western USA: evolutionary and forensic perspectives.

Individuals of Basque origin migrated in large numbers to the Western USA in the second half of the nineteenth century, and the flow continued with less intensity during the last century. The European source population, that of the Basque Country, has long been a cultural and geographical isolate. Previous studies have demonstrated that Y-STR frequencies of Basques are different from those of other Spanish and European populations [1]. The Basque diaspora in the Western USA is a recent migration, but the founder effect and the incorporation of new American Y chromosomes into the paternal genetic pool of the Basque diaspora could have influenced its genetic structure and could thus have practical implications for forensic genetics. To check for genetic substructure among the European source and Basque diaspora populations and determine the most suitable population database for the Basque diaspora in the Western USA, we have analysed the haplotype distribution of 17 Y-STRs in both populations. We have found that the Basque diaspora in the Western USA largely conserve the Y chromosome lineage characteristic of the autochthonous European Basque population with no statistically significant differences. This implies that a common 17 Y-STR Basque population database could be used to calculate identification or kinship parameters regardless of whether the Basque individuals are from the European Basque Country or from the Basque diaspora in the Western USA.

Bcl-2 differentially regulates Ca2+ signals according to the strength of T cell receptor activation.

To investigate the effect of Bcl-2 on Ca2+ signaling in T cells, we continuously monitored Ca2+ concentration in Bcl-2-positive and -negative clones of the WEHI7.2 T cell line after T cell receptor (TCR) activation by anti-CD3 antibody. In Bcl-2-negative cells, high concentrations of anti-CD3 antibody induced a transient Ca2+ elevation, triggering apoptosis. In contrast, low concentrations of anti-CD3 antibody induced Ca2+ oscillations, activating the nuclear factor of activated T cells (NFAT), a prosurvival transcription factor. Bcl-2 blocked the transient Ca2+ elevation induced by high anti-CD3, thereby inhibiting apoptosis, but did not inhibit Ca2+ oscillations and NFAT activation induced by low anti-CD3. Reduction in the level of all three inositol 1,4,5-trisphosphate (InsP(3)) receptor subtypes by small interfering RNA inhibited the Ca2+ elevation induced by high but not low anti-CD3, suggesting that Ca2+ responses to high and low anti-CD3 may have different requirements for the InsP(3) receptor. Therefore, Bcl-2 selectively inhibits proapoptotic Ca2+ elevation induced by strong TCR activation without hindering prosurvival Ca2+ signals induced by weak TCR activation.

Morphology, morphometrics, and molecular characterization of Bryophrya gemmea n. sp. (Ciliophora, Colpodea): implications for the phylogeny and evolutionary scenario for the formation of oral ciliature in the order Colpodida.

We studied the morphology, morphometry, resting, and reproductive cysts, as well as the molecular phylogeny of Bryophrya gemmea n. sp., a colpodid ciliate that was discovered in ephemeral puddles in Idaho, northwest United States. This new species is distinguished from congeners by the irregularly pentagonal adoral organelles, four to five vestibular kineties, the single micronucleus, and one to three rows of brightly refractive protuberant interkinetal cortical granules to the right of the preoral suture. Resting cysts have two distinct membranes and an outer mucous coat. As typical for most colpodids, reproduction occurs in division cysts but details of ontogenesis are unknown. The 18S rRNA gene sequence shows only weak support for the phylogenetic relationship between Bryophrya and the bryophryid genus Notoxoma previously inferred from morphologic characters. Further, our molecular phylogenies classify bryophryids rather basal within the order Colpodida, not supporting ordinal status suggested by morphologists. Based on molecular data and morphologic characters, the colpodid genus Ilsiella is removed from the family Marynidae and placed in a new family, Ilsiellidae. Considering the molecular data, an evolutionary scenario for the formation of colpodid oral structures from a cyrtolophosidid ancestor through a bryophryid intermediate is proposed.

The Y-STR genetic diversity of an Idaho Basque population, with comparison to European Basques and US Caucasians.

Fifty unrelated Basque males from southwest Idaho were typed for the 17 Y-STR loci in the Yfiler multiplex kit (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635, YGATA H4.1 and DYS385a/b). In total, 42 haplotypes were identified, with no more than two individuals sharing a single haplotype. The haplotype diversity (HD) was 0.9935, and gene diversity (D) over loci was 0.457 ± 0.137. The Idaho Basque population was compared to the source population from the Basque autonomous region of Northern Spain and Southern France, as well as a United States Caucasian population. The haplotype diversity for the immigrant Basque sample is within 0.4% of the haplotype diversity of the European Basques (0.9903); thus the power of discrimination is similar for each population. The Idaho Basque population has less diversity in 9 out of 16 loci (considering DYS385a/b together) and 3% less diversity across all loci, compared to the European Basque population. A multidimensional scaling analysis (MDS) was created using pairwise R(ST) values to compare the Idaho Basques to other populations. Based upon R(ST) and F(ST) measures, no significant differentiation was found between the Idaho and source European Basque population.

Mitochondrial DNA analysis of an immigrant Basque population: loss of diversity due to founder effects.

The Basques have a well-documented history of migration and settlement in the Americas, and they often retain cultural identity across generations. Numerous genetic studies have been carried out on European Basques; thus, immigrant Basques are an ideal population for investigating the genetic consequences of a recent human migration event. We have sampled 53 unrelated individuals with Basque ancestry in Boise, Idaho and determined the mitochondrial DNA (mtDNA) sequence variation of the first and second hypervariable regions. Thirty-six mtDNA haplotypes were detected in our sample. We found evidence of genetic changes consistent with founder effects, which is compatible with the known history of migration. Compared with the European Basque population, the immigrant Basques are significantly different in terms of haplogroup frequency distribution and diversity. They have a lower measure of weighted intralineage mean pairwise diversity (WIMP) and greater genetic distance from other European populations. These data indicate that this immigrant Basque population has experienced a reduction in genetic diversity compared with the putative source population. However, this loss of diversity is not detectable using indices of demographic history such as Tajima's D and Fu's F. This study represents the first description of mtDNA diversity in an immigrant Basque population, and our findings indicate that founder effects accompanying this relatively recent migration event have shaped the genetic diversity of this population.

Effects of sedative psychotropic drugs combined with oxycodone on respiratory depression in the rat.

Following a decision to require label warnings for concurrent use of opioids and benzodiazepines and increased risk of respiratory depression and death, the US Food and Drug Administratioin (FDA) recognized that other sedative psychotropic drugs may be substituted for benzodiazepines and be used concurrently with opioids. In some cases, data on the ability of these alternatives to depress respiration alone or in conjunction with an opioid are lacking. A nonclinical in vivo model was developed that could detect worsening respiratory depression when a benzodiazepine (diazepam) was used in combination with an opioid (oxycodone) compared to the opioid alone based on an increased arterial partial pressure of carbon dioxide (pCO2 ). The current study used that model to assess the impact on respiration of non-benzodiazepine sedative psychotropic drugs representative of different drug classes (clozapine, quetiapine, risperidone, zolpidem, trazodone, carisoprodol, cyclobenzaprine, mirtazapine, topiramate, paroxetine, duloxetine, ramelteon, and suvorexant) administered alone and with oxycodone. At clinically relevant exposures, paroxetine, trazodone, and quetiapine given with oxycodone significantly increased pCO2 above the oxycodone effect. Analyses indicated that most pCO2 interaction effects were due to pharmacokinetic interactions resulting in increased oxycodone exposure. Increased pCO2 recorded with oxycodone-paroxetine co-administration exceeded expected effects from only drug exposure suggesting another mechanism for the increased pharmacodynamic response. This study identified drug-drug interaction effects depressing respiration in an animal model when quetiapine or paroxetine were co-administered with oxycodone. Clinical pharmacodynamic drug interaction studies are being conducted with these drugs to assess translatability of these findings.

Disorders of orgasm in women: a literature review of etiology and current treatments.

INTRODUCTION: Disorders of orgasm in women, defined as the persistent or recurrent delay in or absence of orgasm, affect up to a quarter of the female population. AIM: To review existing research findings on the etiology and treatments of disorders of orgasm in women to provide a useful reference tool for clinicians who evaluate and treat patients with these conditions. METHODS: PubMed and PsycINFO search for articles published between 1980 and 2009 using the keywords "orgasm*,""anorgasmia," and "female*,""woman," or "women," in addition to "female orgasmic disorder" and "disorders of orgasm in women." MAIN OUTCOME MEASURES: Findings on the etiological factors and effects of a variety of treatment interventions on improving disorders of orgasm in women. Results. Literature on prevalence and causes of disorders of orgasm in women is abundant, yet more reports of successful treatments are needed. Nevertheless, many promising approaches have been suggested, and data support several potential treatments such as bupropion, sildenafil, estrogen, and testosterone among others. CONCLUSIONS: Although more research is needed to better understand and manage disorders of orgasm in women, significant progress is being made.

Q(n) species distribution in K2O.2SiO2 glass by 29Si magic angle flipping NMR.

Two-dimensional magic angle flipping (MAF) was employed to measure the Q((n)) distribution in a (29)Si-enriched potassium disilicate glass (K(2)O.2SiO(2)). Relative concentrations of [Q((4))] = 7.2 +/- 0.3%, [Q((3))] = 82.9 +/- 0.1%, and [Q((2))] = 9.8 +/- 0.6% were obtained. Using the thermodynamic model for Q((n)) species disproportionation, these relative concentrations yield an equilibrium constant k(3) = 0.0103 +/- 0.0008, indicating, as expected, that the Q((n)) species distribution is close to binary in the potassium disilicate glass. A Gaussian distribution of isotropic chemical shifts was observed for each Q((n)) species with mean values of -82.74 +/- 0.03, -91.32 +/- 0.01, and -101.67 +/- 0.02 ppm and standard deviations of 3.27 +/- 0.03, 4.19 +/- 0.01, and 5.09 +/- 0.03 ppm for Q((2)), Q((3)), and Q((4)), respectively. Additionally, nuclear shielding anisotropy values of zeta =-85.0 +/- 1.3 ppm, eta = 0.48 +/- 0.02 for Q((2)) and zeta = -74.9 +/- 0.2 ppm, eta = 0.03 +/- 0.01 for Q((3)) were observed in the potassium disilicate glass.

Developing an animal model to detect drug-drug interactions impacting drug-induced respiratory depression.

Opioids and benzodiazepines were frequently co-prescribed to patients with pain and psychiatric or neurological disorders; however, co-prescription of these drugs increased the risk for severe respiratory depression and death. Consequently, the U.S. Food and Drug Administration added boxed label warnings describing this risk for all opioids and benzodiazepines. Sedating psychotropic drugs with differing mechanisms of action (e.g., antipsychotics, antidepressants, non-benzodiazepine sedative-hypnotics, etc.) may be increasingly prescribed in place of benzodiazepines. Despite being marketed for years, many sedating psychotropic drugs have neither human nor animal data that quantify or qualify the potential for causing respiratory depression, either alone or in combination with an opioid. In this study, diazepam was selected as the benzodiazepine to detect any additive or synergistic effects on respiratory depression caused by the opioid, oxycodone. Pharmacokinetic studies were conducted at three doses with oxycodone (6.75, 60, 150 mg/kg) and with diazepam (2, 20, 200 mg/kg). Dose dependent decrease in arterial partial pressure of oxygen and increase in arterial partial pressure of carbon dioxide were observed with oxycodone. Diazepam caused similar partial pressure changes only at the highest dose. Further decreases in arterial partial pressure of oxygen and increases in arterial partial pressure of carbon dioxide consistent with exacerbated respiratory depression were observed in rats co-administered oxycodone 150 mg/kg and diazepam 20 mg/kg. These findings confirm previous literature reports of exacerbated opioid-induced respiratory depression with benzodiazepine and opioid co-administration and support the utility of this animal model for assessing opioid-induced respiratory depression and its potential exacerbation by co-administered drugs.

Serum IL-18 level, clinical symptoms and IL-18-607A/C polymorphism among chronic patients with schizophrenia in a Chinese Han population.

Literature suggests that alterations in the inflammatory and immune systems are involved in the pathogenesis of schizophrenia. Specifically, patients diagnosed with schizophrenia exhibit increased IL-18, a pleiotropic proinflammatory cytokine in type 1 T-helper (Th1) responses. The functional 607A/C promoter polymorphism of the IL-18 gene is also associated with the psychopathology of this disorder. However, no current study has explored its role in the clinical symptoms of schizophrenia as mediated through IL-18 levels. We recruited 772 inpatients with schizophrenia and 775 healthy controls in a Han Chinese population and genotyped the IL-18-607A/C polymorphism. Patient psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). Serum IL-18 levels were measured in 80 patients and 93 healthy controls. Our results showed that there were no significant differences in the distribution of the allele and genotype frequencies between the patients and controls. Both increased IL-18 serum level and the IL-18-607A/C polymorphism were positively associated with the PANSS general psychopathology subscore and the PANSS total score. Moreover, interaction of increased IL-18 serum level and the IL-18-607A/C polymorphism influenced the clinical psychopathological symptoms, indicating that association of IL-18 level with the PANSS general psychopathology subscale or the total scores was present only among patients carrying the C allele. We demonstrate an association between the IL-18-607A/C variant and clinical psychopathological symptoms in schizophrenia. Findings suggest that the association between higher IL-18 levels and clinical symptoms in schizophrenia is dependent on the IL-18-607A/C polymorphism.

NPITxt, a 21st-Century Reporting System: Engaging Residents in a Lean-Inspired Process.

Operational waste, or workflow processes that do not add value, is a frustrating but nonetheless largely tolerated barrier to efficiency and morale for medical trainees. In this article, the authors tested a novel reporting system using several submission formats (text messaging, e-mail, Web form, mobile application) to allow residents to report various types of operational waste in real time. This system informally promoted "lean" principles of waste identification and continuous improvement. In all, 154 issues were submitted between March 30, 2011, and June 30, 2012, and categorized as closely as possible into lean categories of operational waste; 131 issues were completely addressed with the requested outcome partially or fully implemented or with successful clarification of existing policies. A real-time, voluntary reporting system can effectively capture trainee observations of waste in health care and training processes, give trainees a voice in a hierarchical system, and lead to meaningful operations improvement.

Psychopharmacology of the negative symptoms: current status and prospects for progress.

The past decade has witnessed a resurgence of interest in the development of novel pharmacological agents to treat the negative symptoms of schizophrenia. This review provides an overview of pharmacological approaches that have been evaluated as potential treatments and describes the emergence of several promising new approaches. First, we briefly describe recent methodological developments, including consensus-based clinical trial guidelines for patient selection criteria, symptom assessment, and trial duration. Next, we overview mono- and adjunctive-therapies that have been evaluated, including first- and second-generation antipsychotics, antidepressants, psychostimulants, molecules targeting cholinergic and glutamatergic systems, and hormones. We highlight the most promising pharmacological agents on the horizon, including glycine transporter-1 inhibitors, α7-nicotinic receptor positive allosteric modulators, and oxytocin, as well as non-pharmacological electromagnetic stimulation approaches. Further investigations, using optimal clinical trial design, hold considerable promise for discovering effective treatments for these functionally disabling symptoms in the near future.

Associations between oxytocin receptor genotypes and social cognitive performance in individuals with schizophrenia.

Individuals with schizophrenia often show substantial deficits in social cognitive abilities, which are strongly associated with social functioning. To advance our understanding of the genetic variation that is associated with social cognitive deficits in schizophrenia, we genotyped 74 schizophrenia outpatients who completed social cognitive performance measures assessing mentalizing, social perception, and emotional intelligence, as well as clinical symptoms. We assessed seven single nucleotide polymorphisms (SNPs) of the oxytocin receptor (OXTR) previously found to show replicable associations with socio-emotional processes. For one of the seven SNPs, rs2268493, the 'T' allele was significantly associated with poorer performance on a composite social cognition index, as well as specific tests of mentalizing and social perception. None of the SNPs were associated with clinical symptoms. Though the sample size is small, these findings provide initial support for the involvement of genetic variants of the OXTR in social cognitive impairments in schizophrenia.