Improving the Mental Health of Surgical Teams Through Operating Room Design.

OBJECTIVE: In this study, we aim to develop and propose an evaluation method for analyzing the design of operating rooms (ORs) from the perspective of surgical teams' reported experiences and stress levels. BACKGROUND: Stress and burnout of surgical team members can lead to diminished performance and medical errors, which endangers the safety of both the patients and team members. The design and layout of the OR play a critical role in managing such stress. METHODS: To understand surgical teams' spatial needs related to their experiences and stress, we administered a survey and in-depth focus group discussions to three surgical teams from the same organization. The identified spatial needs were translated into functional scenarios and spatial metrics, essentially viewing the OR through the perspective of users. RESULTS: Our analysis revealed four integral sections-patient flow, room organization, access to facilities/medical equipment/support staff/team members, and staff well-being-identified as critical design factors associated with the experiences and stress levels of the surgical teams in the ORs. CONCLUSIONS: We expect this method to serve as a tool for evaluating the effect of the design of OR layouts on stress, thereby supporting the well-being and resiliency of surgical teams.

Reducing burden and building goodwill for practice-embedded trials: Results of rapid qualitative methods in the preimplementation phase of a community paramedic trial to reduce hospitalizations.

Pragmatic trials aim to generate timely evidence while ensuring feasibility, minimizing practice burden, and maintaining real-world conditions. We conducted rapid-cycle qualitative research in the preimplementation period of a trial evaluating a community paramedic program to shorten and prevent hospitalizations. Between December 2021 and March 2022, interviews (n = 30) and presentations/discussions (n = 17) were conducted with clinical and administrative stakeholders. Two investigators analyzed interview and presentation data to identify potential trial challenges, and team reflections were used to develop responsive strategies. Solutions were implemented prior to the commencement of trial enrollment and were aimed at bolstering feasibility and building ongoing practice feedback loops.

Genome-wide DNA methylation patterns harbour signatures of hatchling sex and past incubation temperature in a species with environmental sex determination.

Conservation of thermally sensitive species depends on monitoring organismal and population-level responses to environmental change in real time. Epigenetic processes are increasingly recognized as key integrators of environmental conditions into developmentally plastic responses, and attendant epigenomic data sets hold potential for revealing cryptic phenotypes relevant to conservation efforts. Here, we demonstrate the utility of genome-wide DNA methylation (DNAm) patterns in the face of climate change for a group of especially vulnerable species, those with temperature-dependent sex determination (TSD). Due to their reliance on thermal cues during development to determine sexual fate, contemporary shifts in temperature are predicted to skew offspring sex ratios and ultimately destabilize sensitive populations. Using reduced-representation bisulphite sequencing, we profiled the DNA methylome in blood cells of hatchling American alligators (Alligator mississippiensis), a TSD species lacking reliable markers of sexual dimorphism in early life stages. We identified 120 sex-associated differentially methylated cytosines (DMCs; FDR < 0.1) in hatchlings incubated under a range of temperatures, as well as 707 unique temperature-associated DMCs. We further developed DNAm-based models capable of predicting hatchling sex with 100% accuracy (in 20 training samples and four test samples) and past incubation temperature with a mean absolute error of 1.2°C (in four test samples) based on the methylation status of 20 and 24 loci, respectively. Though largely independent of epigenomic patterning occurring in the embryonic gonad during TSD, DNAm patterns in blood cells may serve as nonlethal markers of hatchling sex and past incubation conditions in conservation applications. These findings also raise intriguing questions regarding tissue-specific epigenomic patterning in the context of developmental plasticity.

Comparative prevalence of anogenital injury following sexual assault in women who have had recent consensual sexual contact.

OBJECTIVE: The purpose of this study was to compare the frequency and types of anogenital trauma in rape victims as a function of the time interval between the assault and recent (72 h) consensual sexual intercourse. METHODS: This retrospective cohort trial evaluated consecutive female patients, age 13 years or older, presenting to a community-based nurse examiner clinic (NEC) during a 5-year study period. The NEC facility is staffed by forensic nurses trained to perform medical-legal examinations using colposcopy with nuclear staining and digital imaging. Eligible patients were classified into five different groups based on the time interval from the last consensual intercourse to the forensic examination (none, 0-24 h, 25-48 h, 49-72 h, 73-96 h). Patient demographics, assault characteristics, and injury patterns were recorded using a standardized classification system. RESULTS: A total of 947 cases of sexual assault met the inclusion criteria and were divided into five groups. The age range was 13 to 87 years (mean, 23.9 years); 78% were examined within 24 h following sexual assault. The five study groups were comparable in terms of demographics, assault history, and incidence of non-genital injuries. The overall frequency, type, or location of anogenital injury did not vary significantly between groups (p > 0.5). CONCLUSION: This is the first clinical study to systematically compare the prevalence and typology of anogenital injuries in sexual assault victims who have had consensual intercourse within four days before a forensic exam. The frequency, type or location of anogenital trauma did not vary significantly based on the time interval from last consensual intercourse to the forensic examination.

Treatment of Headache in the Emergency Department: Haloperidol in the Acute Setting (THE-HA Study): A Randomized Clinical Trial.

BACKGROUND: Headache is a common complaint of emergency department (ED) patients and current treatment varies with significant limitations. OBJECTIVE: Our aim was to evaluate the efficacy and safety of 2.5 mg i.v. haloperidol in the treatment of severe benign headache in the ED. METHODS: A randomized, double-blind, placebo-controlled trial was performed in the ED of a single high-volume teaching hospital. Convenience sampling identified 287 eligible patients 13 to 55 years old with benign headache. One hundred and eighteen patients were enrolled to receive either 2.5 mg of haloperidol i.v. or placebo. The primary outcome measure was pain reduction at 60 min. Patients were evaluated for adverse events and follow-up was conducted after discharge. QT measurement was performed at baseline and discharge. RESULTS: Fifty-eight patients received haloperidol and 60 patients received placebo. Patients in the haloperidol group reported an average 4.77-unit reduction in visual analogue scale score at 60 min compared to a 1.87-unit reduction in the control group. Thirty-four patients (58.6%) in the haloperidol group had complete resolution of their headache. Treatment with rescue ketorolac was required in 78.3% of the control group and 31% of the haloperidol group. Adverse events were uncommon, benign, and easily treated. No patients in the haloperidol group were found to have QT lengthening. CONCLUSIONS: This study suggests that 2.5 mg i.v. haloperidol is a rapid and effective treatment for acute, severe, benign headache in ED patients aged 18 to 55 years. Further study is warranted to confirm these results in adolescents. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02747511.

Assessing impacts of precocious steroid exposure on thyroid physiology and gene expression patterns in the American alligator (Alligator mississippiensis).

The thyroid gland is sensitive to steroid hormone signaling, and many thyroid disrupting contaminants also disrupt steroid hormone homeostasis, presenting the possibility that thyroid disruption may occur through altered steroid hormone signaling. To examine this possibility, we studied short-term and persistent impacts of embryonic sex steroid exposure on thyroid physiology in the American alligator. Alligators from a lake contaminated with endocrine disrupting contaminants (Lake Apopka, FL, USA) have been shown to display characteristics of thyroid and steroid hormone disruption. Previous studies suggest these alterations arise during development and raise the possibility that exposure to maternally deposited contaminants might underlie persistent organizational changes in both thyroidal and reproductive function. Thus, this population provides a system to investigate contaminant-mediated organizational thyroid disruption in an environmentally-relevant context. We assess the developmental expression of genetic pathways involved in thyroid hormone biosynthesis and find that expression of these genes increases prior to hatching. Further, we show that nuclear steroid hormone receptors are also expressed during this period, indicating the developing thyroid is potentially responsive to steroid hormone signaling. We then explore functional roles of steroid signaling during development on subsequent thyroid function in juvenile alligators. We exposed alligator eggs collected from both Lake Apopka and a reference site to 17ß-estradiol and a non-aromatizable androgen during embryonic development, and investigated effects of exposure on hatchling morphometrics and thyroidal gene expression profiles at 5 months of age. Steroid hormone treatment did not impact the timing of hatching or hatchling size. Furthermore, treatment with steroid hormones did not result in detectable impacts on thyroid transcriptional programs, suggesting that precocious or excess estrogen and androgen exposure does not influence immediate or long-term thyroidal physiology.

Embryonic estrogen exposure recapitulates persistent ovarian transcriptional programs in a model of environmental endocrine disruption.

Estrogens regulate key aspects of sexual determination and differentiation, and exposure to exogenous estrogens can alter ovarian development. Alligators inhabiting Lake Apopka, FL, are historically exposed to estrogenic endocrine disrupting contaminants and are characterized by a suite of reproductive abnormalities, including altered ovarian gene expression and abated transcriptional responses to follicle stimulating hormone. Here, we test the hypothesis that disrupting estrogen signaling during gonadal differentiation results in persistent alterations to ovarian gene expression that mirror alterations observed in alligators from Lake Apopka. Alligator embryos collected from a reference site lacking environmental contamination were exposed to estradiol-17 beta or a nonaromatizable androgen in ovo and raised to the juvenile stage. Changes in basal and gonadotropin-challenged ovarian gene expression were then compared to Apopka juveniles raised under identical conditions. Assessing basal transcription in untreated reference and Apopka animals revealed a consistent pattern of differential expression of key ovarian genes. For each gene where basal expression differed across sites, in ovo estradiol treatment in reference individuals recapitulated patterns observed in Apopka alligators. Among those genes affected by site and estradiol treatment were three aryl hydrocarbon receptor (AHR) isoforms, suggesting that developmental estrogen signaling might program sensitivity to AHR ligands later in life. Treatment with gonadotropins stimulated strong ovarian transcriptional responses; however, the magnitude of responses was not strongly affected by steroid hormone treatment. Collectively, these findings demonstrate that precocious estrogen signaling in the developing ovary likely underlies altered transcriptional profiles observed in a natural population exposed to endocrine disrupting contaminants.

Associations between perfluorinated alkyl acids in blood and ovarian follicular fluid and ovarian function in women undergoing assisted reproductive treatment.

Endocrine disrupting contaminants, in combination with other environmental variables, are associated with altered reproductive health. Assisted reproductive technology (ART) procedures offer valuable opportunities to explore the connections between environmental contaminants in the ovarian microenvironment and measures of fertility, including impaired responsiveness to gonadotropins. Here, we investigate an emerging class of environmental contaminants, the perfluorinated alkyl acids (PFAAs), to determine whether ovarian contaminant levels are associated with measures of ovarian responsiveness and fertility outcomes in a South Carolina population of women undergoing ART. Levels of PFAAs in plasma and follicular fluid samples collected from women undergoing ovarian stimulation were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Six PFAAs were detected in both plasma and follicular fluid. PFAA concentrations in plasma correlate strongly to those detected in ovary and, with the exception of one compound, remain stable throughout ovarian stimulation. The concentration of PFHxS in follicular fluid inversely relates to baseline follicle counts. While no significant relationships were detected between ovarian response measures and PFAA concentrations, we identified a negative relationship between follicular fluid PFDA and PFuNA and blastocyst conversion rates. Our assessments indicate that plasma levels of PFAAs serve as a sound proxy of those in the ovarian compartment and that follicular fluid levels of specific PFAA compounds are inversely related to important clinical measures of reproductive health including baseline follicle count and post-fertilization success.

Environmentally relevant concentrations of nitrate increase plasma testosterone concentrations in female American alligators (Alligator mississippiensis).

Anthropogenic nitrogen is a ubiquitous environmental contaminant that is contributing to the degradation of freshwater, estuarine, and coastal ecosystems worldwide. The effects of environmental nitrate, a principal form of nitrogen, on the health of aquatic life is of increasing concern. We exposed female American alligators to three concentrations of nitrate (0.7, 10 and 100mg/L NO3-N) for a duration of five weeks and five months from hatch. We assessed growth, plasma sex steroid and thyroid hormone concentrations, and transcription levels of key genes involved in steroidogenesis (StAR, 3ß-HSD, and P450scc) and hepatic clearance (Cyp1a, Cyp3a). Exposure to 100mg/L NO3-N for both five weeks and five months resulted in significantly increased plasma testosterone (T) concentrations compared with alligators in the reference treatment. No differences in 17ß-estradiol, progesterone, or thyroid hormones were observed, nor were there differences in alligator weight or the mRNA abundance of steroidogenic or hepatic genes. Plasma and urinary nitrate concentrations increased with increasing nitrate treatment levels, although relative plasma concentrations of nitrate were significantly lower in five month, versus five week old animals, possibly due to improved kidney function in older animals. These results indicate that environmentally relevant concentrations of nitrate can increase circulating concentrations of T in young female alligators.

The influence of thermal signals during embryonic development on intrasexual and sexually dimorphic gene expression and circulating steroid hormones in American alligator hatchlings (Alligator mississippiensis).

Incubation temperatures experienced by developing embryos exert powerful influences over gonadal sex determination and differentiation in many species. However, the molecular mechanisms controlling these impacts remain largely unknown. We utilize the American alligator to investigate the sensitivity of the reproductive system to thermal signals experienced during development and ask specifically whether individuals of the same sex, yet derived from different incubation temperatures display persistent variation in the expression patterns of sex biased transcripts and plasma sex hormones. Our analysis focuses on assessments of circulating sex steroids and transcript abundance in brain and gonad, two tissues that display sexually dimorphic gene expression and directly contribute to diverse sexually dimorphic phenotypes. Whereas our results identify sexually dimorphic patterns for several target gonadal genes in postnatal alligators, sex linked variation in circulating 17ß-estradiol, testosterone, and expression of two brain transcripts (aromatase and gonadotropin releasing hormone) was not observed. Regarding intrasexual variation, we found that AMH transcript abundance in hatchling testes is positively correlated with temperatures experienced during sexual differentiation. We also describe highly variable patterns of gene expression and circulating hormones within each sex that are not explained by the intensity of embryonic incubation temperatures. The magnitude of sexually dimorphic gene expression, however, is directly associated with temperature for SOX9 and AMH, two transcripts with upstream roles in Sertoli cell differentiation. Collectively, our findings regarding temperature linked variation provide new insights regarding the connections between embryonic environment and persistent impacts on sexual differentiation in a reptile species that displays temperature dependent sex determination.

Integrative and comparative reproductive biology: From alligators to xenobiotics.

Dr. Louis J. Guillette Jr. thought of himself as a reproductive biologist. However, his interest in reproductive biology transcended organ systems, life history stages, species, and environmental contexts. His integrative and collaborative nature led to diverse and fascinating research projects conducted all over the world. He doesn't leave us with a single legacy. Instead, he entrusts us with several. The purpose of this review is to highlight those legacies, in both breadth and diversity, and to illustrate Dr. Guillette's grand contributions to the field of reproductive biology. He has challenged the field to reconsider how we think about our data, championed development of novel and innovative techniques to measure endocrine function, helped define the field of endocrine disruption, and lead projects to characterize new endocrine disrupting chemicals. He significantly influenced our understanding of evolution, and took bold and important steps to translate all that he has learned into advances in human reproductive health. We hope that after reading this manuscript our audience will appreciate and continue Dr. Guillette's practice of open-minded and passionate collaboration to understand the basic mechanisms driving reproductive physiology and to ultimately apply those findings to protect and improve wildlife and human health.

Incubation history prior to the canonical thermosensitive period determines sex in the American alligator.

Despite the widespread occurrence of environmental sex determination (ESD) among vertebrates, our knowledge of the temporal dynamics by which environmental factors act on this process remains limited. In many reptiles, incubation temperature determines sex during a discrete developmental window just prior to and coincident with the differentiation of the gonads. Yet, there is substantial variation in sex ratios among different clutches of eggs incubated at identical temperatures during this period. Here, we test the hypothesis that temperatures experienced prior to the reported thermosensitive period for alligators (Alligator mississippiensis) can impact how the sex determination system responds to thermal cues later in development. Temperature shift experiments on eggs collected from the field within 24  h of oviposition were employed to decouple various maternal influences from thermal effects, and results demonstrate a previously undefined window of thermosensitivity occurring by stage 15 of embryonic development, six stages earlier than previously reported. We also examine the intrasexual expression of several male- and female-biased genes and show that while male-biased genes display no intrasexual differences, ovarian CYP19A1 (aromatase) transcript abundance differs by approximately twofold depending on thermal exposures experienced at early stages of embryonic development. These findings expand our understanding of the ESD in the alligator and provide the rationale for reevaluation of the temporal dynamics of sex determination in other crocodilians.

Influence of tissue, age, and environmental quality on DNA methylation in Alligator mississippiensis.

Epigenetic modifications are key mediators of the interactions between the environment and an organism's genome. DNA methylation represents the best-studied epigenetic modification to date and is known to play key roles in regulating transcriptional activity and promoting chromosome stability. Our laboratory has previously demonstrated the utility of the American alligator (Alligator mississippiensis) as a sentinel species to investigate the persistent effects of environmental contaminant exposure on reproductive health. Here, we incorporate a liquid chromatography-tandem mass spectrometry method to directly measure the total (global) proportion of 5-methyl-2'-deoxycytidine (5mdC) in ovarian and whole blood DNA from alligators. Global DNA methylation in ovaries was significantly elevated in comparison with that of whole blood. However, DNA methylation appeared similar in juvenile alligators reared under controlled laboratory conditions but originating from three sites with dissimilar environmental qualities, indicating an absence of detectable site-of-origin effects on persistent levels of global 5mdC content. Analyses of tissues across individuals revealed a surprising lack of correlation between global methylation levels in blood and ovary. In addition, global DNA methylation in blood samples from juvenile alligators was elevated compared with those from adults, suggesting that age, as observed in mammals, may negatively influence global DNA methylation levels in alligators. To our knowledge, this is the first study examining global levels of DNA methylation in the American alligator and provides a reference point for future studies examining the interplay of epigenetics and environmental factors in a long-lived sentinel species.

Differential incubation temperatures result in dimorphic DNA methylation patterning of the SOX9 and aromatase promoters in gonads of alligator (Alligator mississippiensis) embryos.

Environmental factors are known to influence sex determination in many nonmammalian vertebrates. In all crocodilians studied thus far, temperature is the only known determinant of sex. However, the molecular mechanisms mediating the effect of temperature on sex determination are not known. Aromatase (CYP19A1) and SOX9 play critical roles in vertebrate sex determination and gonadogenesis. Here, we used a variety of techniques to investigate the potential roles of DNA methylation patterning on CYP19A1 and SOX9 expression in the American alligator, an organism that relies on temperature-dependent sex determination. Our findings reveal that developing gonads derived from embryos incubated at a male-producing temperature (MPT) show elevated CYP19A1 promoter methylation and decreased levels of gene expression relative to incubation at a female-producing temperature (FPT). The converse was observed at the SOX9 locus, with increased promoter methylation and decreased expression occurring in embryonic gonads resulting from incubation at FPT relative to that of MPT. We also examined the gonadal expression of the three primary, catalytically active DNA methyltransferase enzymes and show that they are present during critical stages of gonadal development. Together, these data strongly suggest that DNA methylation patterning is a central component in coordinating the genetic cascade responsible for sexual differentiation. In addition, these data raise the possibility that DNA methylation could act as a key mediator integrating temperature into a molecular trigger that determines sex in the alligator.

Organizational changes to thyroid regulation in Alligator mississippiensis: evidence for predictive adaptive responses.

During embryonic development, organisms are sensitive to changes in thyroid hormone signaling which can reset the hypothalamic-pituitary-thyroid axis. It has been hypothesized that this developmental programming is a 'predictive adaptive response', a physiological adjustment in accordance with the embryonic environment that will best aid an individual's survival in a similar postnatal environment. When the embryonic environment is a poor predictor of the external environment, the developmental changes are no longer adaptive and can result in disease states. We predicted that endocrine disrupting chemicals (EDCs) and environmentally-based iodide imbalance could lead to developmental changes to the thyroid axis. To explore whether iodide or EDCs could alter developmental programming, we collected American alligator eggs from an estuarine environment with high iodide availability and elevated thyroid-specific EDCs, a freshwater environment contaminated with elevated agriculturally derived EDCs, and a reference freshwater environment. We then incubated them under identical conditions. We examined plasma thyroxine and triiodothyronine concentrations, thyroid gland histology, plasma inorganic iodide, and somatic growth at one week (before external nutrition) and ten months after hatching (on identical diets). Neonates from the estuarine environment were thyrotoxic, expressing follicular cell hyperplasia (p = 0.01) and elevated plasma triiodothyronine concentrations (p = 0.0006) closely tied to plasma iodide concentrations (p = 0.003). Neonates from the freshwater contaminated site were hypothyroid, expressing thyroid follicular cell hyperplasia (p = 0.01) and depressed plasma thyroxine concentrations (p = 0.008). Following a ten month growth period under identical conditions, thyroid histology (hyperplasia p = 0.04; colloid depletion p = 0.01) and somatic growth (body mass p<0.0001; length p = 0.02) remained altered among the contaminated sites. This work supports the hypothesis that embryonic EDC exposure or iodide imbalance could induce adult metabolic disease states, thereby stressing the need to consider the multiple environmental variables present during development.

Binge eating disorder in elderly individuals.

OBJECTIVE: To preliminarily describe the clinical features of elderly individuals with binge eating disorder (BED). METHOD: The psychological and general medical characteristics of 20 elderly individuals (65 years of age and older) who met DSM-IV-TR for BED were systematically evaluated. RESULTS: Elderly individuals with BED reported an average (SD) of 4.5 (2.9) binge eating episodes per week. Weight and shape concerns were of significant importance for participants' schema for self-evaluation. Mood disorders were the most frequent co-occurring psychiatric disorders. Despite having a mean (SD) body mass index of 36.4 (10.6), most participants presented in good general medical health. DISCUSSION: Regarding eating pathology, psychiatric comorbidity, and associated obesity, BED in this group of elderly individuals was similar to BED in younger adults. However, other than presenting with obesity, the participants reported good general medical health. BED might be a problem for a subset of physically healthy elderly individuals. Studies further examining psychiatric and medical presentation, including metabolic profile, of elderly individuals with BED may be warranted.

A randomized, placebo-controlled study of zonisamide to prevent olanzapine-associated weight gain.

Weight gain is commonly observed with olanzapine treatment. Zonisamide is an antiepileptic drug associated with weight loss. This study examined the effectiveness of zonisamide in preventing weight gain in 42 patients beginning olanzapine for bipolar disorder or schizophrenia. Each patient had a body mass index of 22 mg/kg or greater and was randomized to taking olanzapine with either zonisamide (n = 20) or placebo (n = 22) for 16 weeks. The primary outcome measure was change in body weight in kilograms from baseline. In the primary analysis using longitudinal regression, patients who received zonisamide had a significantly slower rate of weight gain and increase in body mass index than those who received placebo. The patients treated with zonisamide gained a mean (SD) of 0.9 (3.3) kg, whereas those treated with placebo gained a mean (SD) of 5.0 (5.5) kg; P = 0.01. None of the patients in the zonisamide group, compared with 7 patients (33%) in the placebo group, gained 7% of body weight or greater from baseline (Fisher exact test, P = 0.009). The zonisamide group, however, reported significantly more cognitive impairment as an adverse event than the placebo group (25% vs 0, respectively; P = 0.02). Zonisamide was effective for mitigating weight gain in patients with bipolar disorder or schizophrenia initiating treatment with olanzapine but was associated with cognitive impairment as an adverse event.

Duloxetine in the treatment of binge eating disorder with depressive disorders: a placebo-controlled trial.

OBJECTIVE: This study evaluated duloxetine in the treatment of binge eating disorder (BED) with comorbid current depressive disorders. METHOD: In this 12-week, double-blind, placebo-controlled trial, 40 patients with Diagnostic and Statistical Manual of Mental Disorders-IV-TR BED and a comorbid current depressive disorder received duloxetine (N = 20) or placebo (N = 20). The primary outcome measure was weekly binge eating day frequency. RESULTS: In the primary analysis, duloxetine (mean 78.7 mg/day) was superior to placebo in reducing weekly frequency of binge eating days (p = .04), binge eating episodes (p = .02), weight (p = .04), and Clinical Global Impression-Severity of Illness ratings for binge eating (p = .02) and depressive disorders (p = .01). Changes in body mass index and measures of eating pathology, depression, and anxiety did not differ between the two groups. DISCUSSION: Duloxetine may be effective for reducing binge eating, weight, and global severity of illness in BED with a comorbid current depressive disorder, but this finding needs confirmation in larger, placebo-controlled trials.

Acamprosate in the treatment of binge eating disorder: a placebo-controlled trial.

OBJECTIVE: To assess preliminarily the effectiveness of acamprosate in binge eating disorder (BED). METHOD: In this 10-week, randomized, placebo-controlled, flexible dose trial, 40 outpatients with BED received acamprosate (N = 20) or placebo (N = 20). The primary outcome measure was binge eating episode frequency. RESULTS: While acamprosate was not associated with a significantly greater rate of reduction in binge eating episode frequency or any other measure in the primary longitudinal analysis, in the endpoint analysis it was associated with statistically significant improvements in binge day frequency and measures of obsessive-compulsiveness of binge eating, food craving, and quality of life. Among completers, weight and BMI decreased slightly in the acamprosate group but increased in the placebo group. DISCUSSION: Although acamprosate did not separate from placebo on any outcome variable in the longitudinal analysis, results of the endpoint and completer analyses suggest the drug may have some utility in BED.

A randomized, placebo-controlled study of adjunctive ramelteon in ambulatory bipolar I disorder with manic symptoms and sleep disturbance.

This study evaluated the efficacy and tolerability of ramelteon in ambulatory bipolar I disorder with manic symptoms and insomnia. Twenty-one outpatients with bipolar I disorder by Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria with mild-to-moderate manic symptoms and sleep disturbance were randomized to receive either ramelteon (N=10) or placebo (N=11) in an 8-week, double-blind, fixed-dose (8 mg/day) study. Ramelteon and placebo had similar rates of reduction in ratings of symptoms of insomnia, mania, and global severity of illness. However, ramelteon was associated with improvement in a global rating of depressive symptoms. It was also well tolerated and associated with no serious adverse events. The small sample size may have limited the ability of the study to detect potentially clinically important drug-placebo differences. Further studies of ramelteon in subgroups of bipolar patients with sleep disturbance, including those with depression or euthymia, seem indicated.