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Background: ASP8062 is a novel orally active GABAB receptor positive allosteric modulator in clinical development for the treatment of alcohol use disorder (AUD) and opioid use disorder (OUD). Aims: This study assessed the potential pharmacokinetic/pharmacodynamic interaction between ASP8062 and alcohol under single-dose conditions in healthy adults. Methods: A double-blind, placebo-controlled, crossover phase 1 study was conducted in which 20 subjects were randomly assigned to four treatment sequences (ASP8062 + alcohol; ASP8062 + placebo alcohol; placebo + alcohol; placebo + placebo alcohol) each consisting of four treatment periods, separated by washout periods of at least 14 days. An analysis of variance was used to assess pharmacokinetic interaction and a mixed-effects analysis of covariance was used to assess pharmacodynamic interaction. Results/outcomes: After administration of alcohol, a mild to minimal increase in plasma exposure (AUCinf and Cmax) of ASP8062 was observed, but tmax and t½ for ASP8062 remained unchanged after administration of alcohol. In contrast, ASP8062 did not affect the AUClast and Cmax of ethanol. No clinically relevant differences in cognition measurements were observed with ASP8062 compared with placebo, but there were expected impairments in psychomotor and executive function with alcohol alone. ASP8062 in combination with alcohol resulted in worse scores in cognition measurements than alcohol alone, but this potentiation was not consistent. ASP8062 administered alone was safe and well-tolerated and safety findings in subjects administered alcohol alone were not augmented when ASP8062 was administered in combination with alcohol. Conclusion/interpretation: The data support further clinical studies investigating ASP8062 in patients with AUD.

Rationale Previous research suggests that sleep polysomnography and EEG endpoints can be used to assess GABAergic activity; however, the impact of GABAB receptor positive allosteric modulators on sleep endpoints remains unclear. Objectives This phase 1 study compared a single dose of ASP8062 (35 mg or 70 mg), a GABAB receptor positive allosteric modulator, with placebo and paroxetine (40 mg). Methods Healthy adult volunteers were randomized to four treatments (35 mg ASP8062, 70 mg ASP8062, paroxetine 40 mg, or matching placebo), each separated by a 14-day washout. Primary endpoints obtained by polysomnography were time in stage N3 or SWS and time in rapid eye movement (REM) sleep. Secondary endpoints included impact on sleep stages and electroencephalography parameters, pharmacokinetics, nighttime growth hormone (GH), and safety/tolerability. Results In 20 randomized volunteers, ASP8062 led to a significant and seemingly dose-dependent increase in SWS over the entire night; this increase was mainly observed during the first third of the night. ASP8062 did not impact time in REM sleep. Paroxetine had no effect on SWS but produced a significant reduction in time spent in REM sleep. A dose-dependent trend in increased GH release was also observed with ASP8062. Headache and nausea were the most commonly reported treatment-emergent adverse events (TEAEs) for ASP8062; most TEAEs were mild in severity. Conclusions Single-dose ASP8062 (35 and 70 mg) appeared to result in CNS penetration and enhanced GABAergic activity as measured by increases in slow-wave sleep and growth hormone release.

ASP8062 is an orally active γ-amino-butyric acid type B (GABAB ) receptor positive allosteric modulator currently in phase 2 development. Safety and pharmacokinetic (PK) profiles of ASP8062 were evaluated in 2 studies in healthy subjects. The first study (a first-in-human study) evaluated single ascending doses (SAD) of ASP8062. The second study was composed of 2 parts: part 1 evaluated multiple ascending doses (MAD) of ASP8062 for 14 days, and part 2 was a single-dose arm to assess the PK of ASP8062 in cerebrospinal fluid (CSF). Fifty-six men (SAD) and 56 subjects (24 women and 32 men; MAD) were enrolled. Across the SAD dosing range, area under the concentration-time curve was dose proportional; increases in maximum plasma concentration appeared linear but were slightly less than dose proportional. Time to maximal concentration and half-life were 1-4 hours and ∼40-50 hours, respectively; no food effect was observed. ASP8062 PK properties at steady state were similar to those following a single dose. Steady state was achieved by ∼day 9 with ∼2-fold accumulation, and ASP8062 was detected in CSF. ASP8062 was well tolerated; no clear evidence of ASP8062's effects on safety, cognition, drug withdrawal, or suicidal ideation/behavior was observed. These data support the development of ASP8062 in indications where the GABAB receptor is a target.

Psychopathology among liver and kidney transplant patients is prevalent. Although pre-surgical psychological evaluations are routinely conducted, understanding which specific psychological test to use is under-developed. The purpose of this review is to examine the psychometric properties of broadband and narrowband psychological measures in pre-surgical liver and kidney transplant evaluations. Overall, there is a paucity of research in this domain that hamper abilities to make clear recommendations on what to use alongside a clinical interview. This review highlights the need for additional research examining instruments that may predict patients' successful recovery from transplant surgery. Despite the scarcity of research, instruments that appear to be useful in this population include the Minnesota Multiphasic Personality Inventory-2 (MMPI-2), the Personality Assessment Inventory (PAI), the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT), and the Transplant Evaluation and Rating Scale (TERS).

ASP0367, or bocidelpar sulfate, is an orally administered small molecule that potently and selectively modulates peroxisome proliferator-activated receptor δ (PPARδ) to address mitochondrial dysfunction occurring in diseases including primary mitochondrial myopathy and Duchenne muscular dystrophy. The objectives of this first-in-human trial were to evaluate the safety/tolerability, pharmacokinetics, and pharmacodynamics of ASP0367 in healthy participants.In this double-blind phase 1 study, adult participants were randomized to single or multiple ascending oral doses of ASP0367 or placebo. The study duration was 1 and 14 days, respectively. Pharmacokinetic parameters under fed conditions were also evaluated.A total of 64 (single-dose cohort) and 37 (multiple-dose cohort) participants were included in the study. After single doses of 1 to 120 mg, ASP0367 was rapidly absorbed, with median time to maximum plasma concentration (tASP0367, or bocidelpar sulfate, was well tolerated; rapid absorption, roughly dose-proportional bioavailability, and effects on PPARδ target genes were demonstrated in healthy adult participants.

Inhibition of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) represents a potential mechanism for improving pain conditions. ASP3662 is a potent and selective inhibitor of 11β-HSD1. Two phase I clinical studies were conducted to assess the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of single and multiple ascending doses of ASP3662 in healthy young and elderly non-Japanese and young Japanese subjects. Nonlinear, more than dose-proportional PKs were observed for ASP3662 after single-dose administration, particularly at lower doses (≤ 6 mg); the PKs at steady state were dose proportional, although the time to ASP3662 steady state was dose dependent at lower doses (≤ 2 mg). Similar PKs were observed among young Japanese, young non-Japanese, and elderly non-Japanese subjects. Specific inhibition of 11β-HSD1 occurred after both single and multiple doses of ASP3662. A marked dissociation between PKs and PDs was observed after single but not multiple doses of ASP3662. ASP3662 was generally safe and well tolerated.

Background Bariatric surgery usually results in substantial weight loss and a reduction in medical comorbidities. Many patients, as a consequence of the weight loss, subsequently evidence loose, redundant skin. Objectives This investigation seeks to examine the prevalence of body contouring surgery (BCS) by patients approximately 4 to 5 years after Roux-en-Y gastric bypass surgery. Demographics, change in BMI, and psychosocial variables were also used to predict body dissatisfaction, desire for BCS, and patients who reported obtaining BCS. Setting The clinical sites involved in the Longitudinal Assessment of Bariatric Surgery project, which included 10 hospitals across the United States. Methods The sample comprised 1159 patients who underwent Roux-en-Y gastric bypass and were enrolled in the Longitudinal Assessment of Bariatric Surgery-2 study. Participants were surveyed using the Excessive Skin Survey and other psychosocial measures at their 4- or 5-year postoperative outcome. The participants were predominately women (80.5%), Caucasian (88.3%), and middle-aged (mean = 46.1 yr, standard deviation = 11.11 yr). Results Participants reported modest degrees of being bothered by excessive skin, primarily in their waist/abdomen, thighs, and chest/breasts body areas. Only 11.2% of the sample had undergone any BCS procedure, and a majority of those participants paid "out of pocket" for BCS. Desire for BCS and body dissatisfaction 4 to 5 years postsurgery was associated with higher depression scores and poorer quality of life scores. Conclusions Excessive skin is associated with poorer psychosocial functioning. Despite reporting modest levels of being bothered by excessive skin and body dissatisfaction, only a small fraction of participants underwent BCS. Cost of BCS was reported to be a primary barrier for not obtaining BCS. All rights reserved.

Psychopathology has been associated with patient reports of poor outcome and an algorithm has been useful in predicting short-term outcomes. The objective of this study is to investigate whether a pre-surgical psychological algorithm could predict 1-year spine surgery outcome reports, including pain, functional disability, and emotional functioning. A total of 1,099 patients consented to participate. All patients underwent spine surgery (e.g., spinal fusion, discectomy, etc.). Pre-operatively, patients completed self-report measures prior to surgery. An algorithm predicting patient prognosis based on data from the pre-surgical psychological evaluation was filled out by the provider for each patient prior to surgery. Post-operatively, patients completed self-report measures at 3- and 12-months after surgery. Longitudinal latent class growth analysis (LCGA) was used to derive patient outcome groups. These outcome groups were then compared to pre-surgical predictions made. LCGA analyses derived three groups of patients from the reported outcome data (entropy = .84): excellent outcomes, good outcomes, and poor outcomes. The excellent and good groups demonstrated improvements over time, but the poor outcome groups, on some measures, reported worsening of pain, functional disability, and emotional functioning over time. The pre-surgical algorithm yielded good concordance with the statistically derived outcome groups (Kendall's W = .81). Using a pre-surgical psychological evaluation algorithm for predicting long-term spine surgery outcomes can identify patients who are unlikely to report good outcomes, and point to areas for psychological intervention that can either improve surgery results or to be utilized as alternatives to elective spine surgery. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Background Cognitive impairment is a core feature of schizophrenia. While first- and second-generation antipsychotic drugs treat psychotic exacerbations, no treatment is approved for the cognitive dysfunction. We have identified ASP4345, a positive allosteric modulator of the dopamine type 1 (D1) receptor that selectively binds to, and enhances the activity of, D1 receptors. ASP4345 has the potential to be an effective and well-tolerated treatment option for cognitive impairment associated with schizophrenia. Objective The objective of this study was to determine the pharmacokinetics of ASP4345 in two phase I single ascending-dose and multiple ascending-dose studies. Methods Both phase I studies were randomized, double blind, and placebo controlled. The single dose-ascending study assessed pharmacokinetics of single oral doses of 3–900 mg of ASP4345 or placebo in the fasted state in healthy adult volunteers. This study also assessed cerebrospinal fluid pharmacokinetics, as well as the effects of food on pharmacokinetic parameters. The multiple ascending-dose study (NCT02720263) assessed the pharmacokinetics of multiple oral doses of 3–150 mg of ASP4345 in patients with schizophrenia or schizoaffective disorder receiving stable antipsychotic drug treatment. The pharmacokinetic data from both studies were summarized using descriptive statistics. Results The plasma concentration–time profile in both studies showed a rapid increase in concentrations of ASP4345. The median time to maximum concentration range was 1.00–2.26 h in the single ascending-dose study in the fasted state and 1.25–3.02 h in the multiple ascending-dose study at steady state. There were less than dose-proportional increases in maximum concentration and area under the curve in the single ascending-dose study, where doses had a range from 3 to 900 mg, and in the multiple ascending-dose study in patients with stabilized schizophrenia or schizoaffective disorder, where doses had a range from 3 to 150 mg. The mean terminal elimination half-life was dose independent and had a range from 9.12 to 14.3 h in the single ascending-dose study and from 11.1 to 26.8 h in the multiple ascending-dose study. Additionally, in the single ascending-dose study, absorption of 300 mg of ASP4345 was slightly delayed when administered in the fed state compared with the fasted state; median time to maximum concentration was 1.5 h under the fasting state and 4.0 h under fed states. All other pharmacokinetic parameters were comparable for both conditions. ASP4345 appeared in the cerebrospinal fluid with some delay; time to maximum concentration range was from 2.48 to 7.98 h in cerebrospinal fluid compared with 0.75 to 1.03 h in plasma (median cerebrospinal fluid/plasma = 0.188). The ratio of cerebrospinal fluid to total plasma for area under the curve from 0 to 24 h (0.157–0.573%) and maximum concentration (0.0899–0.311%) and the ratio of cerebrospinal fluid to unbound plasma for maximum concentration (25.0–86.4%) confirm the distribution of ASP4345 into the brain. Conclusions The pharmacokinetics of ASP4345 suggest that single daily dosing is appropriate for ASP4345. Furthermore, the concentration of ASP4345 in cerebrospinal fluid compared to free drug concentrations in plasma provides evidence of penetration of ASP4345 into the brain.

The aim of this study was to evaluate the use of a mobile application (app) in patients already using total body photography (TBP) to increase skin self-examination (SSE) rates and pilot the effectiveness of examination reminders and accountability partners. Randomized controlled trial with computer generated randomization table to allocate interventions. University of Pennsylvania pigmented lesion clinic. 69 patients aged 18 years or older with an iPhone/iPad, who were already in possession of TBP photographs. A mobile app loaded with digital TBP photos for all participants, and either (1) the mobile app only, (2) skin examination reminders, (3) an accountability partner, or (4) reminders and an accountability partner. Change in SSE rates as assessed by enrollment and end-of-study surveys 6 months later. Eighty one patients completed informed consent, however 12 patients did not complete trial enrollment procedures due to device incompatibility, leaving 69 patients who were randomized and analyzed [mean age 54.3 years, standard deviation 13.9). SSE rates increased significantly from 58% at baseline to 83% at 6 months (odds ratio 2.64, 95% confidence interval 1.20–4.09), with no difference among the intervention groups. The group with examination reminders alone had the highest (94%) overall satisfaction, and the group with accountability partners alone accounted for the lowest (71%). A mobile app alone, or with reminders and/or accountability partners, was found to be an effective tool that can help to increase SSE rates. Skin examination reminders may help provide a better overall experience for a subset of patients. ClinicalTrials.gov Identifier: NCT02520622.

The present study investigated the comparability of laptop computer- and tablet-based administration modes for the Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF). Employing a counterbalanced within-subjects design, the MMPI-2-RF was administered via both modes to a sample of college undergraduates ( N = 133). Administration modes were compared in terms of mean scale scores, internal consistency, test-retest consistency, external validity, and administration time. Mean scores were generally similar, and scores produced via both methods appeared approximately equal in terms of internal consistency and test-retest consistency. Scores from the two modalities also evidenced highly similar patterns of associations with external criteria. Notably, tablet administration of the MMPI-2-RF was substantially longer than laptop administration in the present study (mean difference 7.2 minutes, Cohen's d = .95). Overall, results suggest that varying administration mode between laptop and tablet has a negligible influence on MMPI-2-RF scores, providing evidence that these modes of administration can be considered psychometrically equivalent.

Prospective data are needed to ascertain the impact of iron chelation therapy in patients with myelodysplastic syndromes. The present 5-year prospective registry analysis was conducted to compare clinical outcomes between chelated and nonchelated patients with lower-risk myelodysplastic syndromes and transfusional iron overload. In an interim analysis at 24 months, we previously reported that chelation therapy was associated with longer median overall survival and a tendency toward longer leukemia-free survival and fewer cardiac events. In the present report, we detail findings from the final analysis at 5 years. We confirm, at the conclusion of this 5-year, prospective, non-interventional study, that overall survival was significantly longer in patients who received iron chelation therapy vs those who did not. Causes of death in the overall population were predominantly myelodysplastic syndromes/acute myeloid leukemia followed by cardiac disease. Time to progression to acute myeloid leukemia was also significantly longer in patients receiving chelation therapy, and significantly fewer patients progressed to leukemia vs those not receiving chelation therapy. Limitations of the study include a potential for clinical bias, as patients with longer predicted survival may have been chosen for chelation therapy, the differences present in concomitant conditions at baseline, and the possibility that some high-risk patients were not identified due to limited cytogenetic classification.

Research using a categorical-polythetic classification system for mental illness has raised concern regarding the validity of categorical classification systems. Recent efforts suggest psychopathology is better understood from a dimensional framework, though there has been varying evidence of a somatization factor. The current investigation seeks to produce and validate a dimensional model of psychopathology, with a particular emphasis on the placement of somatization, across three nonoverlapping medical samples. Using a bariatric surgery seeking sample (n = 1,268), a spine surgery/spinal cord stimulator seeking sample (n = 1,711), and a chronic pain treatment seeking sample (n = 1,388), a dimensional model of psychopathology was replicated across all three samples using a dimensional measure of psychopathology (the Minnesota Multiphasic Personality Inventory-2-Restructured Form [MMPI-2-RF]). Clear evidence of a separate somatization factor was found in addition to broad internalizing, externalizing, and social detachment factors. Constructs assessable with the model yielded good convergent and discriminant validity coefficients with external criteria, and further supported the presence of a higher-order somatization construct. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Aims The EURO-ENDO registry aimed to study the management and outcomes of patients with infective endocarditis (IE). Methods and results Prospective cohort of 3116 adult patients (2470 from Europe, 646 from non-ESC countries), admitted to 156 hospitals in 40 countries between January 2016 and March 2018 with a diagnosis of IE based on ESC 2015 diagnostic criteria. Clinical, biological, microbiological, and imaging [echocardiography, computed tomography (CT) scan, 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT)] data were collected. Infective endocarditis was native (NVE) in 1764 (56.6%) patients, prosthetic (PVIE) in 939 (30.1%), and device-related (CDRIE) in 308 (9.9%). Infective endocarditis was community-acquired in 2046 (65.66%) patients. Microorganisms involved were staphylococci in 1085 (44.1%) patients, oral streptococci in 304 (12.3%), enterococci in 390 (15.8%), and Streptococcus gallolyticus in 162 (6.6%). 18F-fluorodeoxyglucose positron emission tomography/computed tomography was performed in 518 (16.6%) patients and presented with cardiac uptake (major criterion) in 222 (42.9%) patients, with a better sensitivity in PVIE (66.8%) than in NVE (28.0%) and CDRIE (16.3%). Embolic events occurred in 20.6% of patients, and were significantly associated with tricuspid or pulmonary IE, presence of a vegetation and Staphylococcus aureus IE. According to ESC guidelines, cardiac surgery was indicated in 2160 (69.3%) patients, but finally performed in only 1596 (73.9%) of them. In-hospital death occurred in 532 (17.1%) patients and was more frequent in PVIE. Independent predictors of mortality were Charlson index, creatinine > 2 mg/dL, congestive heart failure, vegetation length > 10 mm, cerebral complications, abscess, and failure to undertake surgery when indicated. Conclusion Infective endocarditis is still a life-threatening disease with frequent lethal outcome despite profound changes in its clinical, microbiological, imaging, and therapeutic profiles.

It is not uncommon for patients to report diminished outcomes as a result of spine surgery or a spinal cord stimulator implant. Presurgical psychological evaluations are increasingly used to identify patients at increased risk for such outcomes and use of personality assessment instruments in these evaluations provides incremental information beyond a clinical interview and medical chart review. This investigation explores the psychometric properties of the Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF) in a sample of spine surgery patients (

The 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme converts cortisone to cortisol and participates in the regulation of glucocorticoid levels in tissues. 11β-HSD1 is expressed in the liver, kidney, adipose tissue, placenta, and brain. 11β-HSD1 is a target for treatment of depression, anxiety, posttraumatic stress disorder, and also against age-related cognitive function and memory loss. In this study, we evaluated the radiotracer

Background The Binge Eating Scale (BES) is a widely-used self-report measure of binge eating severity. Hood et al. [1] reported a 2-factor structure for the BES in a sample of bariatric surgery candidates, with factors labeled feelings/cognitions and behavioral manifestations. The present study aims to replicate and extend the factor structure obtained by Hood et al. [1] by testing the utility of a bifactor model that removes binge eating severity variance, which the total BES score purports to assess, in another sample of bariatric surgery candidates. Methods Bariatric surgery candidates (n = 517; 71.2% women; mean body mass index=49.50 kg/m 2 ; SD=10.17) were sampled. Twenty-four percent met DSM-IV-TR diagnostic criteria for binge eating disorder. Results Consistent with previous research, a 2-factor structure for the BES was supported; however, the 2 factors were substantially correlated ( r = .89). A bifactor model significantly improved model fit, supporting the presence of a higher-order severity factor accounting for a significant amount of variance. This factor was primarily marked by binge eating severity as demonstrated by associations with number of objective binge eating episodes and DSM-IV-TR diagnosis. In the bifactor model, the feelings/cognitions factor was modestly associated with self-reported mood psychopathology. However, contrary to expectations, the behavioral manifestation factor was not associated with empirically derived behavioral problems. Conclusions The current findings partially converge with those of Hood et al. [1] However, the use of the BES as a 2-factor measure is not recommended at this point because of lack of incremental validity demonstrated by the behavioral manifestation factor. Continued use of the BES as a unidimensional measure of binge eating severity, in conjunction with a comprehensive clinical interview, can provide useful guidance for presurgical treatment recommendations.

Background Presurgical psychological screening is used to identify factors that may impact postoperative adherence and surgical outcomes in bariatric surgery candidates. Minnesota Multiphasic Personality Inventory – 2 Restructured Form (MMPI-2-RF) findings have demonstrated utility for this task. Objectives To explore whether there are clinically meaningful gender, ethnicity, or age differences in presurgical MMPI-2-RF scores and the validity of these scores in bariatric surgery candidates. Methods The sample was composed of 872 men and 2337 women. Ethnicity/race groups included 2,204 Caucasian, 744 African American, and 96 Hispanic individuals. A sample of 165 were not included in the ethnicity/race analyses because they were of another descent. Ages groups included 18–35 year olds (n = 454), 36–49 year olds (n = 1154), 50–64 year olds, (n = 1246), and 65 years old or older (n = 355). Validity data, obtained via a retrospective chart review, were available for a subset patients (n = 1,268) who were similarly distributed. Step-down hierarchical regression analyses were conducted to assess for differential validity. Results Bariatric surgery candidates produced comparable MMPI-2-RF scores in all subsamples, indicating that the test norms generalize across demographic groups. Validity findings were also generally comparable, indicating that MMPI-2-RF scores have the same interpretive implications in demographically diverse subgroups of bariatric surgery candidates. Conclusions The MMPI-2-RF can assist in presurgical psychological screening of demographically diverse bariatric surgery candidates.

A substantial proportion of individuals who undergo surgical procedures to relieve spine pain continue to report significant pain and dysfunction after recovery. Psychopathology and patient expectations have been linked to poor results, leading to an increasing reliance on presurgical psychological screening (PPS) as part of the surgical diagnostic process. The original Minnesota Multiphasic Personality Inventory (MMPI; Hathaway & McKinley, 1943) and the MMPI-2 (Butcher, Graham, Ben-Porath, Tellegen, & Dahlstrom, 2001) were among the measures most commonly used in PPS evaluations and research. This study focuses on the newest version of the test, the MMPI-2-Restructured Form (MMPI-2-RF; Ben-Porath & Tellegen, 2008/2011; Tellegen & Ben-Porath, 2008/2011) as a predictor of outcomes for spine surgery candidates. Using a sample of 172 men and 210 women who underwent a PPS, we examined the ability of MMPI-2-RF scale scores to predict early surgical outcomes independent of other presurgical risk factors identified by other means, as well as patients' presurgical expectations. MMPI-2-RF results accounted for up to 11% of additional variance in measures of early postoperative functioning. MMPI-2-RF scales that assess for emotional/internalizing problems, specifically Demoralization, measures of somatoform dysfunction, and interpersonal problems contributed most to the prediction of diminished outcome.

ObjectiveTo evaluate the efficacy and safety of coadministered lanreotide Autogel (LA; 120 mg/month) and pegvisomant (40–120 mg/week) in acromegaly.DesignThis is a 28-week, multicenter, open-label, single-arm sequential study.MethodsPatients (n=92) biochemically uncontrolled, on somatostatin analogs (SSAs) or using pegvisomant monotherapy entered a 4-month run-in taking LA (120 mg/month). Patients uncontrolled after the run-in period (n=57) entered a 28-week coadministration period, receiving LA 120 mg/month plus pegvisomant (60 mg once weekly, adapted every 8 weeks based on IGF1 levels to 40–80 mg once weekly or 40 or 60 mg twice weekly).ResultsIn total, 33 (57.9%) patients had normalized IGF1 following coadministration (PP5×upper limit of normal with normalization after withdrawal).ConclusionsIn patients partially controlled by SSAs, LA (120 mg/month) plus pegvisomant normalized IGF1 in 57.9% of patients after 7 months, at a median effective pegvisomant dose of 60 mg/week, and 78.9% at any time. In these patients, results suggest a pegvisomant-sparing effect versus daily pegvisomant monotherapy.

The current investigation aims to predict 3-year postoperative percent total weight loss among a sample of bariatric surgery patients with super-super obesity.Previous research implies that persons with presurgical super-super obesity (body mass index [BMI] ≥60 kg/mCleveland Clinic, BariatricMetabolic Institute, Cleveland, OH.Bariatric surgery candidates (N = 1231; 71.9% female; 65.8% Caucasian) completed a presurgical psychological evaluation and the Minnesota Multiphasic Personality Inventory-2-Restructured Form. Participants with a baseline BMI ≥60 (n = 164) were compared with BMI60 (n = 1067) on psychosocial and demographic factors, the Minnesota Multiphasic Personality Inventory-2-Restructured Form, and in the subset that had surgery (n = 870), percent total weight loss extending to the 3-year follow-up.Patients with a BMI ≥60 were younger, less educated, and more likely to be male compared with lower BMI patients. Patients with a BMI ≥60 had greater psychosocial sequelae as evidenced by being more likely to have a history of sexual abuse, history of psychiatric hospitalization, more binge eating episodes, and higher prevalence of major depression disorder and binge eating disorder. On the Minnesota Multiphasic Personality Inventory-2-Restructured Form, those with BMI ≥60 reported greater demoralization, low positive emotions, ideas of persecution, and dysfunctional negative emotions. After controlling for surgery type, weight loss for individuals with BMI ≥60 did not greatly differ from weight loss in patients with BMI60. Variables predictive of less weight loss at 3 years regardless of presurgical BMI, included being older, having a sexual abuse history, and higher ideas of persecution scores.Although patients with BMI ≥60 evidenced more psychopathology before surgery, findings suggest that the relationship between higher BMI and poorer outcome may better be explained by other co-morbid factors.

Objective Binge eating disorder (BED) was recently included in the DSM-5. The prevalence rate for BED using the DSM-IV-TR research criteria tends to be higher in bariatric surgery candidates than the normative population; however, no studies have examined how many more bariatric surgery candidates will meet the new, less conservative criteria of DSM-5. We explore the current BED prevalence rate change in a sample of bariatric surgery candidates. Method Data were obtained for 1,283 bariatric surgery candidates. 84 men and 213 women were diagnosed with current BED using DSM-IV-TR research criteria. A semi-structured interview, the binge eating scale (BES), and a Minnesota Multiphasic Personality Inventory—2 Restructured Form (MMPI-2-RF) were given to every patient as part of standard procedures mandated by the facility. Results and Discussion An additional 3.43% (p

This 5-year, prospective registry enrolled 600 lower-risk MDS patients (pts) with transfusional iron overload. Clinical outcomes were compared between chelated and nonchelated pts. At baseline, cardiovascular comorbidities were more common in non-chelated pts, and MDS therapy was more common in chelated pts. At 24 months, chelation was associated with longer median overall survival (52.2 months vs. 104.4 months; p

Presurgical psychological screening of bariatric surgery candidates includes some form of standardized psychological assessment. However, associations between presurgical psychological screening and postoperative outcome have not been extensively studied. Here, we explore associations between presurgical Minnesota Multiphasic Personality Inventory-2 Restructured Form (MMPI-2-RF) scores and early postoperative Somatic Concerns, Psychological Distress, and Maladaptive Eating Behaviors.The sample consisted of male (n = 238) and female (n = 621) patients who were administered the MMPI-2-RF at their presurgical psychological evaluation and received bariatric surgery. Patients were evaluated at their 1- and 3-month postoperative appointments.Confirmatory factor analysis indicated that three latent constructs-somatic concerns, psychological distress, and maladaptive eating behaviors-were represented by responses to a postoperative assessment and that these constructs could be measured consistently over time. Presurgical scores on MMPI-2-RF scales measuring internalizing dysfunction were associated with more psychological distress at postoperative follow-ups, scores on scales measuring somatization were associated with more postoperative somatic concerns, and scores on scales assessing emotional/internalizing, behavioral/externalizing, cognitive complaints, and thought dysfunction prior to surgery were associated with maladaptive eating behaviors after surgery.In conjunction with a presurgical psychological interview, the MMPI-2-RF provides information that can assist in anticipating postoperative outcomes and inform efforts to prevent them.

Background Psychosocial factors contribute to poorer weight loss outcomes following bariatric surgery; however, findings on associations between preoperative psychiatric diagnoses, psychological testing, and weight loss are inconsistent. Objectives Examine associations between presurgical psychiatric diagnoses derived from a semi-structured clinical interview and test scores from the Minnesota Multiphasic Personality-Inventory−2 – Restructured Form (MMPI-2-RF) and 5-year Body Mass Index (BMI) outcomes. Setting Cleveland Clinic Bariatric and Metabolic Institute Methods 446 consecutively consented patients who underwent a Roux-en-Y gastric bypass (RYGB) at least 5 years prior were included in the study. A majority were women (74.2%) and Caucasian (66.2%). Patients' mean presurgical BMI was 49.14 kg/m 2 [SD = 9.50 kg/m 2 ]. Psychiatric diagnoses were obtained from a presurgical, semi-structured clinical interview and all participants were administered the MMPI-2-RF at their presurgical evaluations. BMIs were collected at 4 postoperative time points across a 5-year trajectory. This prospective design utilized latent growth curve modeling. Results Older patients evidenced a slower rate of BMI reduction over time. A presurgical diagnosis of Binge Eating Disorder predicted higher BMIs at the 5-year outcome. Scores on MMPI-2-RF measures of emotional and behavioral dysfunction domains incrementally predicted poorer weight loss outcomes. Conclusion Preoperative indicators of psychopathology, notably indicators that are dimensional in nature, are important in predicting postoperative outcomes. Closer follow-up with patients who evidence presurgical psychological factors, both before and after surgery, may help improve outcomes.

The neurokinin-1 (NK-1) antagonist LY686017 showed activity in preclinical anxiety models. The clinical development of LY686017 included a PET study and a proof-of-concept in social anxiety disorder (SAD). [ 11 C]GR205171 was used healthy volunteers receiving 1–100 mg/d LY686017 for 28 days to determine brain receptor occupancy (RO). The mean NK-1 RO increased ranged from 25% with 1 mg to 93% with 100 mg. Subsequently, a 12-week randomized clinical trial tested LY686017 vs. paroxetine, or placebo in SAD. Pharmacokinetic (PK)/RO modeling based on the PET results predicted that once daily dosing of > 30 mg LY686017 led to sustained trough RO of over 80%. 189 outpatients 1 suffering from SAD were randomly assigned to 12-weeks treatment with 50 mg/d LY686017 ( N = 77), placebo ( N = 74), or 20 mg/d paroxetine ( N = 38). There was no significant difference between LY686017 and placebo as measured with the Liebowitz Social Anxiety scale (LSAS). The active comparator paroxetine showed positive trends on primary and secondary measures. The plasma concentrations were above the level expected to produce maximal brain NK-1 RO based on the PK/RO relationship obtained in the human PET investigation. Thus, further evaluation of LY686017 for the treatment of SAD does not seem warranted.

Using the 133Xe tissue clearance method, the blood flow in the greater trochanter of the femur was studied in 30 patients with acromegaly. Both the washout rate constant (k2) and blood flow (P2) values are significantly decreased in acromegaly (p less than 0.01). There is a significant negative correlation (r = -0.42, p less than 0.05) between the flow values and mean daily concentrations of growth hormone in serum of acromegalic patients. The observations is presented as a preliminary evidence of a possible influence of growth hormone on the blood flow in bone.

We present the first reported treatment failure of a reconstructed scapula body that proceeded to nonunion. This is a unique case report of an otherwise healthy patient who underwent open reduction and internal fixation of a scapula fracture nonunion, which is very rare. Failure of internal fixation in this application has not been reported, and, to our knowledge, this is only the fifth case report of a scapula body nonunion that was reconstructed. Of 159 reported cases of open reduction and internal fixation for treatment of scapula neck and body fractures (with or without intraarticular glenoid fractures), there is not one reported case of a nonunion. Our case is described in detail, including the method of surgical reconstruction, and a review of the literature regarding surgical treatment of scapula nonunions after nonoperative treatment also is presented.

The incidence of distal femur fractures is approximately 37 per 100,000 person-years. Typically, distal femur fractures are caused by a high-energy injury mechanism in young men or a low-energy mechanism in elderly women. Managing these fractures can be a challenging task. Most surgeons agree that distal femur fractures need to be treated operatively to achieve optimal patient outcomes. The articular fracture component is usually treated with open reduction and internal lag screw fixation or external tension wire fixation (Illizarov). However, there is no consensus on the type of implant for the fixation of the metaphyseal-diaphyseal fracture component.The aim of this study is to systematically summarize and compare the results of different fixation techniques (traditional compression plating, antegrade nailing, retrograde nailing, submuscular locked internal fixation, and external fixation) in the operative management of acute nonperiprosthetic distal femur fractures (AO/OTA type 33A and C) and the characteristics of the fractures for each treatment (articular/nonarticular and open/closed). Additionally an attempt was made to evaluate the impact of surgical experience on nonunion rate, fixation failure rate, deep infection rate, and secondary surgical procedure rate. In the context of this article compression plating relates to techniques/implants that require compression of the implant to the femoral shaft-it does not relate to interfragmentary compression.

Cushing's syndrome is associated with typical central redistribution of adipose tissue. The aim of the study was to assess lipolysis and catecholamines and their metabolites in subcutaneous abdominal adipose tissue using an in-vivo microdialysis technique. Nine patients with Cushing's syndrome and nine age-, gender- and body mass index (BMI)-matched control subjects were included in the study. Local glycerol concentrations were significantly increased in subcutaneous adipose tissue of patients with Cushing's syndrome (p

Background Some research suggests that higher levels of depression and anxiety-related symptoms at intake are associated with premature termination from psychotherapy, but findings are mixed. However, theoretical and measurement considerations – introduced by a common mood factor – might complicate literature synthesis. Tellegen (1985) demonstrated that demoralization causes multicollinearity between measures of depression and anxiety, and other lines of research have converged to indicate that this construct is an important non-specific factor to consider when assessing mood pathology. Methods We utilized a sample of 557 community mental health center outpatients (188 males, 265 females; 80% Caucasian) with an average age of 32.2 years (SD=10.2). We used self-report indicators to model latent low positive emotionality and negative emotionality constructs, which are temperament markers of core depressive and anxiety symptoms. We further specified a latent demoralization bifactor from these indicators. Results As hypothesized, the bifactor model yielded significantly better fit than competing one-factor and two-factor models. Furthermore, the bifactor was substantially correlated with a demoralization measure (r=.96). As expected, low positive emotionality and negative emotionality were significant predictors of therapist ratings of premature termination. Though demoralization was a non-significant predictor, the structural paths from the other two internalizing constructs markedly increased in the bifactor model relative to the two-factor model. Limitations Replications with other, more diverse clinical populations using multi-method indicators of premature termination are needed. Conclusions This research indicates that after accounting for demoralization patients presenting with core mood disorder symptoms are at substantially increased risk for premature termination.

In patients with histopathologically proven or suspected endometriosis with possible involvement of the rectum, endorectal ultrasound was performed to determine the sensitivity and specificity of this method with regard to rectal wall involvement and the impact on the following operation. METHODS: In an historical cohort analysis, 85 females with histopathologically proven or suspected endometriosis with possible involvement of the rectum were treated between 1992 and 2001. Endorectal ultrasound was performed with a 7.5 MHz real-time unit, and results of endorectal ultrasound were compared with intraoperative findings and histopathologic diagnosis of 65 patients undergoing operation. A questionnaire was used to evaluate postoperative signs and symptoms. RESULTS: Of 65 patients undergoing surgery, 37 underwent laparotomy with 25 resections of the bowel and 28 laparoscopy. In 31 of 32 patients with suspected rectal wall infiltration, preoperative endorectal ultrasound diagnosis was confirmed. In patients in whom endorectal ultrasound showed no rectal wall involvement, histopathology revealed infiltration in one patient, leading to sensitivity of 97 percent and specificity of 97 percent with regard to rectal wall involvement. In terms of the deepness of rectal wall infiltration, endorectal ultrasound had a sensitivity of 76 percent with regard to infiltration of the muscularis propria and 66 percent for infiltration of the submucosa. Operations led to a significant (P< 0.05) reduction of preoperative symptoms by approximately 60 percent. CONCLUSIONS: Endorectal ultrasound is a useful, noninvasive technique for preoperative evaluation of possible rectal wall involvement in endometriosis. Based on the high sensitivity and specificity, recommendation for laparotomy and bowel resection in cases with suspected rectal involvement can be facilitated.

PURPOSE: Because of the potential risk of malignancy and technical difficulties in achieving complete removal, large colorectal polyps represent a special problem for the endoscopist. The aim of this study was to evaluate the capabilities and risks of endoscopy in complete removal of large colorectal polyps. METHODS: Endoscopic polypectomy of 186 colorectal polyps larger than 3 cm in diameter (range, 3–13 cm) was performed; 141 were sessile and 45 pedunculated. Most of the polyps were located in the rectum (n = 88), sigmoid (n = 63), and cecum (n = 9). The remaining adenomas were situated in other parts of the colon. Sessile polyps were removed using the piecemeal technique. RESULTS: Histology results showed an adenoma in 167 cases, and invasive carcinoma was present in the adenoma in 19 patients. Of the adenomas, 29 were tubulous, 118 tubulovillous, and 20 villous; adenoma with severe dysplasia was found in 49 cases. Complete endoscopic removal was achieved in all sessile and pedunculated polyps. None of the patients with invasive carcinoma who underwent surgical resection (n = 10) had any evidence of tumor in the resected specimen. Bleeding occurred in 4 patients after polypectomy (2 percent). Perforation occurred in 1 patient (0.5 percent), who had an invasive carcinoma of the cecum. There was no procedure-related mortality. During a mean follow-up period of 40 (range, 3–87) months, 6 patients presented with recurrence of a benign adenoma (3 percent), which was treated endoscopically, and 1 patient presented with a recurrent invasive carcinoma, which was treated surgically. CONCLUSIONS: Endoscopic polypectomy is a safe and effective method of treating large colorectal polyps.

Previous studies suggest that presurgical psychopathology accounts for some of the variance in suboptimal weight loss outcomes among Roux-en-Y gastric bypass (RYGB) patients, but research has been equivocal.The present study seeks to extend the past literature by examining associations between presurgical scale scores on the broadband Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF) and suboptimal weight loss and poor adherence to follow-up 1 year postoperatively after accounting for several methodologic considerations.Cleveland Clinic Bariatric and Metabolic Institute, Cleveland, Ohio, USA.The sample consisted of 498 RYGB patients, who produced a valid presurgical MMPI-2-RF protocol at program intake. The sample was primarily female (72.9%), Caucasian (64.9%), and middle-aged (mean = 46.4 years old; standard deviation [SD] = 11.6). The mean presurgical body mass index (BMI) was 47.4 kg/m(2) (SD = 8.2) and mean percent weight loss (%WL) at 1 year postoperatively was 31.18 %WL (SD = 8.44).As expected, scales from the Behavioral/Externalizing Dysfunction (BXD) domain of the MMPI-2-RF were associated with worse weight loss outcomes and poor adherence to follow-up, particularly after accounting for range restriction due to underreporting. Individuals producing elevated scores on these scales were at greater risk for achieving suboptimal weight loss (50% excess weight loss) and not following up with their appointment compared with those who scored below cut-offs.Patients who are more likely to engage in undercontrolled behavior (e.g., poor impulse control), as indicated by presurgical MMPI-2-RF findings, are at greater risk for suboptimal weight loss and poor adherence to follow-up following RYGB. Objective psychological assessments should also be conducted postoperatively to ensure that intervention is administered in a timely manner. Future research in the area of presurgical psychological screening should consider the impact of underreporting and other discussed methodologic issues in predictive analyses.

ABT-384 is a potent and selective inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (HSD-1). The pharmacokinetics of ABT-384 was evaluated in healthy volunteers in single-dose (1, 8, 20, 50, 120 and 240 mg) and multiple-dose studies (1, 2, 4, 8, 20, 30 and 100 mg once daily). Less than dose-proportional pharmacokinetics of ABT-384 was observed when ABT-384 was administered at single doses lower than 8 mg. This nonlinear phenomenon disappeared after repeated doses. The dose-normalized plasma concentration-time curves superposed across all dose groups on day 7, but not on day 1. This phenomenon cannot be explained by the half-life of ABT-384. Based on available data, the nonlinearity is likely due to binding of ABT-384 to a high-affinity-low-capacity site, such that this interaction was reflected in ABT-384 pharmacokinetics. To characterize the pharmacokinetics of ABT-384, a population pharmacokinetic model for ABT-384 was constructed. The model provided reasonable fitting for both single- and multiple-dose data. Further investigation is warranted to evaluate the disposition of ABT-384 at low doses using a larger number of subjects. The constructed model would be useful in predicting ABT-384 concentrations at different doses and guiding the selection of dosing regimens in further clinical trials.

Cushing's syndrome is a rare disorder with variable aetiology which is connected with significantly increased morbidity and mortality. Therefore, early determination of correct aetiology and early treatment are essential for a decrease of morbidity and mortality of patients. Present article introduces review and current recommendation of Czech Society of Endocrinology for the treatment of Cushings syndrome.

Odland, Berthelson, Sharma, Martin, and Mittenberg ( 2013 ) caution that clinically elevated scale scores produced by members of the Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF; Ben-Porath & Tellegen, 2008 /2011) normative sample raise concerns about the potential for false positive findings of psychopathology. However, the MMPI-2-RF normative sample is intended to represent the general population of the United States, 26.2% of which met criteria for a Diagnostic and Statistical Manual-IV (APA, 1994 ) disorder in a 12-month period (Kessler, Chiu, Demler, & Walters, 2005 ). In the current study we compare scale elevation rates in the MMPI-2-RF normative sample to prevalence rates of mental disorders primarily drawn from the National Comorbidity Study Replication (Kessler et al., 2005 ). Our objective was to evaluate MMPI-2-RF elevation rates in an epidemiological context. Results indicate that MMPI-2-RF scale elevation rates were generally consistent with epidemiological data when examined in the context of standard interpretation guidelines for the inventory. We also reiterate Ben-Porath and Tellegen's (2008/2011) caution that MMPI-2-RF scale elevations alone are not sufficient to indicate the presence of psychiatric disorder. Rather they are best viewed as indications of the need to evaluate the individual for possible disorder(s). Implications of these results, limitations of this study, and future directions in research are discussed.

In pregnancy, the volume of pituitary increases by multiplication of lactotopic and gonadotropic cells and developing placenta is the source of numerous hormones and enzymes that significantly affect and alter the function of the endocrine system. This naturally has an impact on the course of pituitary disorders and their treatment. The most common disorders of pituitary gland, which we can meet in pregnancy, are adenomas, particularly prolactinomas, and functionless adenomas. During pregnancy we avoid the treatment of microprolactinomas, but in macroprolactinomas where there is the risk of their enlargement by stimulation of placental estrogens, we administer preventively the dopaminergic agonists. Patients with acromegaly usually do not need the treatment during pregnancy, unless there is a danger to damage the visual pathway or heavy headaches occur. ACTH secreting adenomas (Cushings disease) in pregnancy are rare, they are difficult to diagnose but existing hypercortisolism is very dangerous to fetus and may damage even mother. Large functionless adenomas, unless treated before pregnancy, may damage the visual pathway. The volume of the enlarged pituitary gland in pregnancy and sometimes even of the functionless adenoma adenoma, may be reduced by cabergoline, so that the urgent neurosurgery in pregnancy is very rare. A typical disease that occurs primarily in pregnant women is autoimmune lymphocytic hypophysitis. Diagnosis is established on the basis of headaches and symptoms and signs of the deficits of adrenocorticotropic and thyreotropic function usually in the last third of pregnancy or in the first six months after birth, using a specific image in magnetic resonance. Treatment is limited to hormone replacement. It is also possible to meet pregnant women with deficient pituitary functions. In hypocortical women with exception of strains like as pregnancy vomiting, doses of hydrocortisone replacement usually do not change until birth. Childbirth, however, must be secured by increasing the doses of corticosteroids. Careful replacement of thyroid hormones in hypothyroid women is very important for the development of fetus. In women treated with growth hormone its administration during pregnancy may be omitted because the placental growth hormone takes over its function. Desmopressin dose for diabetes insipidus in pregnancy is unchanged - desmopressin is resistant to placental vasopressinases. However, their effects may cause manifestation of partial diabetes insipidus, which was compensated so far.

Studies have demonstrated that negative affect increases prior to food intake in individuals diagnosed with an eating disorder. Mindfulness has been supported empirically to treat experiential avoidance stemming from anxiety. Thus, the current objective in this study is to empirically compare mindfulness vs. thought suppression invention during a food exposure in both clinical and nonclinical samples.In a 2 (Group: clinical vs. nonclinical) × 2 (INTERVENTION: mindfulness vs. distraction) counterbalanced within treatment design, the current investigation sought to determine the differential effectiveness of a brief mindfulness intervention vs. a brief distraction intervention in women diagnosed with AN and BN in a clinical and nonclinical sample during a food exposure.Results indicated that the eating disorder group reported a significant increase in negative affect after the mindfulness intervention as compared to the distraction intervention, whereas the nonclinical group reported a significant decrease in negative affect after the mindfulness intervention as compared to the distraction intervention.Preliminary findings suggest that clinicians may want to proceed cautiously when using mindful eating in those with severe eating disorders during the early stages of food exposure. Limitations and future directions are discussed.

γ-Glutamyltranspeptidase (GGT, syn. γ-Glutamyltransferase) and dipeptidylpeptidase-IV (DPP-IV) activity participates in metabolic and growth control of normal and tumor cells by processing biologically active peptides. Here, we report on up-regulation of these enzymes in human brain gliomas determined by catalytic enzyme histochemistry and immunocytochemistry. Higher activity of GGT was found in 50%, 68% and 81% of WHO grade II, III and IV tumors, respectively. The process started at/near the microvasculature, from where it spread to the parenchyma. On average, the enzyme activity in grade II, III and IV gliomas exceeded controls 2.0, 3.0 and 3.5-fold, respectively. Up-regulation of DPP-IV-like activity also started at the microvasculature, but mainly in pericytes and mononuclear-like cells around the vessels and dispersed in the parenchyma. Marked elevation of this enzyme activity, comprising also tumor parenchyma, occurred only in grade IV glioblastomas (65% patients; 3.6 times above controls) which can, therefore, help in their differentiation from grade III gliomas. The increase of total DPP-IV-like activity also included its two enzymatic homologs, the canonical DPP-IV/CD26 and FAP-1α. The increase in GGT is supposed to be a tumor grade dependent response of microvasculature and tumor astrocytes to stress induced by tissue hypoxia and/or the metabolic aberrancies. The increase in DPP-IV-like activity in high-grade tumors can be attributed to inflammatory/scavenging processes performed by the mononuclear-like cells and, in glioblastomas, also to regressive changes in the structure and function of the microvasculature and tumor parenchyma, including astrocyte stress response. The inverse relationship between DPP-IV-like activity and Ki67 in most glioblastomas and shorter survival time of patients with low activity of this enzyme also suggest its anti-oncogenic effects.

Epidermolysis bullosa simplex (EBS) is an inherited skin disorder caused by mutations in the keratin 5 (KRT5) and keratin 14 (KRT14) genes, with fragility of basal keratinocytes leading to epidermal cytolysis and blistering.In this study, we characterized mutations in KRT5 and KRT14 genes in patients with EBS and investigated their possible structure-function correlations.Mutations were characterized using polymerase chain reaction (PCR) and DNA sequencing. Further, to explore possible correlations with function, the structural effects of the mutations in segment 2B of KRT5 and KRT14 and associated with EBS in our patients, as well as those reported previously, were modelled by molecular dynamics with the aid of the known crystal structure of the analogous segment of human vimentin.We have identified mutations in the KRT5 and KRT14 genes in 16 of 23 families affected by EBS in the Czech Republic. Eleven different sequence variants were found, of which four have not been reported previously. Novel mutations were found in two patients with the EBS-Dowling-Meara variant (EBS-DM) [KRT14-p.Ser128Pro and KRT14-p.Gln374_Leu387dup(14)] and in three patients with localized EBS (KRT14-p.Leu136Pro and KRT5-p.Val143Ala). Molecular dynamics studies show that the mutations p.Glu411del and p.Ile467Thr perturb the secondary alpha-helical structure of the mutated polypeptide chain, the deletion p.Glu411del in KRT14 has a strong but only local influence on the secondary structure of KRT14, and the structural impact of the mutation p.Ile467Thr in KRT5 is spread along the helix to the C-terminus. In all the other point mutations studied, the direct structural impact was significantly weaker and did not destroy the alpha-helical pattern of the secondary protein structure. The changes of 3-D structure of the KRT5/KRT14 dimer induced by the steric structural impact of the single point mutations, and the resulting altered inter- and intramolecular contacts, are spread along the protein helices to the protein C-terminus, but the overall alpha-helical character of the secondary structure is not destroyed and the atomic displacements induced by mutations cause only limited-scale changes of the quaternary structure of the dimer.The results of molecular modelling show relationships between patients' phenotypes and the structural effects of individual mutations.

Background: Fractures of the scapula involve a unique and challenging set of considerations, which must be understood to provide optimal treatment. The primary goal of this study was to create a frequency map of a series of surgically treated scapular fractures that specifically involved the scapular body and/or neck. Methods: A prospective database was used in the collection of consecutive radiographic imaging studies of patients undergoing operative treatment of scapular fractures. Scanned three-dimensional computed tomography images were superimposed and oriented to fit a model scapular template. Size dimensions were normalized by aligning specific scapular landmarks. Fracture lines were identified and traced over the combined three-dimensional computed tomography model to create a scapular fracture map. Results: Of ninety fractures that met the criteria for inclusion, 68% involved the inferior aspect of the glenoid neck and 71% involved the superior vertebral border. Seventeen percent of the patterns included articular extension, and 22% of the fractures entered the spinoglenoid notch. Of fractures involving the inferior aspect of the glenoid neck at the lateral scapular border, 84% traversed medially to exit just inferior to the medial extent of the scapular spine, and 59% of these inferior neck fractures also had propagation to the inferior third of the vertebral border. Among the fractures involving the spinoglenoid notch, the most common pattern was demonstrated by coexisting fracture lines; 60% of the fractures of the spinoglenoid notch exited just inferior to the glenoid, 65% extended to the superior-medial vertebral border, and 45% extended to the inferior-medial vertebral border. In contrast, articular fractures did not follow predictable patterns; they demonstrated the greatest variability in trajectory, which was almost random, and there was a wide distribution of exit points along the vertebral border. Conclusions: Surgically treated scapular fractures display very common patterns. The most common pattern is the lateral border fracture immediately inferior to the glenoid, which extends to the superior vertebral border in more than two-thirds of cases. A smaller proportion of scapular fractures enter the spinoglenoid notch or the articular surface. There is great variation in the patterns of fractures involving the articular surface. Clinical Relevance: These study results can yield insight relevant to surgical approaches and reduction and fixation strategies, and they elucidate the most common fracture patterns encountered during surgery.

Increased activity level after total hip arthroplasty (THA) is considered a risk factor for early prosthetic failure in young patients. Forty-one primary total hip arthroplasties in 34 patients were evaluated. Walking activity was measured using a pedometer to record gait cycles. Patients completed a University of California, Los Angeles (UCLA) activity questionnaire. Linear wear rates were measured. Mean ages at surgery and final follow-up were 42 and 50.3 years, respectively (mean gait cycles per year, 1.2 million; mean UCLA score, 6; mean linear wear, 0.16 mm/y). Increased body mass index and age correlated with decreased gait cycles per year. Patients with systemic disease were less active than patients with localized hip conditions. Femoral head diameter was a predictor of linear wear. The average gait cycles per year and wear rate for this population do not appear accelerated relative to average values reported in older populations.

Management of an open wound is a problem frequently encountered in the treatment of fractures. Skin grafting, rotational flaps, free flaps, and healing by secondary intention add a considerable amount of morbidity and cost to the patient. Therefore, it is ideal to obtain primary closure when possible. This communication describes a technique that uses spinal needles, using towel clips and the natural stretching ability of the skin to enable primary closure of wounds. The technique described uses dermatotraction to stretch the skin is a cost-effective way to achieve primary closure of large wounds with supplies that are readily available in every operating room.

There is a lack of studies evaluating the prevalence of smoking habit among Polish priests. Due to difficulties in receiving permission from catholic authorities to perform questionnaire study we attempted to assess the prevalence of cigarette smoking among priests from one religious congregation. The aim of the study was also to analyze factors influencing smoking habits in this group. The anonymous questionnaire was sent to all Polish Pallotins and students of Pallotin Seminary in Ołtarzew. Only one fourth of them--138 subjects in the age from 20 to 92 yrs (mean age 37.7 yrs)--answered the questionnaire. Among them were 72 priests aged 27-92 yrs. (mean age 50.7 yrs) and 66 students in the age 20-41 yrs (mean age 23.7 yrs.). The rate of current smokers among priests was 13.9%, including 11.1% of daily smokers and 2.8% occasional smokers. The rates of daily and occasional smokers among Seminary students were 4.5% and 6.1%, respectively. Cigarette smoking in the past was reported by 26,4% of priests--8.3% of them had smoked daily, remaining subjects had smoked occasionally. Most of responders considered the fifth commandment of the Decalogue as sufficient reason for abstaining from cigarette smoking. The majority of current smokers attempted to stop smoking, mainly because of wholesome reasons. Near a half of smoking priests and over three fourth of smoking students felt embarrassed to smoke in company of laymen. Every tenth priest and every third student hide his smoking habit from other priests. The study showed low prevalence of cigarette smoking in priests, what resulted mainly from religious reasons.

A case of congenital absence of both aortic and pulmonary valves with severe heart failure detected prenatally by cross-sectional and pulsed and colour Doppler echocardiography is reported in small for gestational age male fetus in 17th week of gestation. Additional double outlet right ventricle, hypoplastic left ventricle, and ventricular septal defect, as well as multiple extracardiac anomalies, were found by prenatal echocardiographic investigation and confirmed by necropsy examination. Retrograde diastolic Doppler waveforms retrieved from pulmonary artery, aorta, and umbilical arteries revealed massive insufficiency throughout both the great arteries, which eliminated diastolic placental perfusion, documented by absent anterograde diastolic flow in the umbilical vein. These prenatal echocardiographic findings may contribute to an understanding of the mechanism of rapid and progressive heart failure and growth retardation in the fetus. Severe cardiac failure may explain why congenital aplasia of both the aortic and the pulmonary valves has not been described postnatally, and only two fetal cases revealed by necropsy have been published.

Objective: To examine nurses' attitudes toward pregnancy termination in the labor and delivery setting and the frequency of nurse refusal to care for patients undergoing pregnancy termination. Design: Nonexperimental, descriptive study. Setting: Six central and northern California hospitals, including Level 1, 2, and 3 facilities. Participants: Seventy‐five labor and delivery registered nurses. Method: Anonymous survey with visual analog scales. Results: Ninety‐five percent of the nurses indicated they would agree to care for patients terminating a pregnancy because of fetal demise, 77% would care for patients terminating a fetus with anomalies that were incompatible with life, and 37% would care for patients terminating for serious but nonlethal anomalies, with a significant drop in agreement as gestation advanced. Few nurses would agree to care for patients undergoing termination for sex selection, selective reduction, or personal reasons. Nurses both accepting and refusing patient care assignments were criticized by coworkers. Conclusion: Clear guidelines should be established on how to handle nurse refusal to care for patients terminating pregnancy in advance. Open discussions should be encouraged between staff and management to minimize criticism.

Pregnancy and its outcome in a woman with systemic lupus erythematosus.Case report.Obstetrics and Gynecology Department, Charles University, 2nd Medical Faculty and Faculty Hospital Motol, Prague, Cardiocentrum, University Hospital Motol, Prague.Patient with systemic lupus erythematosus (SLE) was admitted to our department at 31 weeks of gestation with diagnosed fetal bradycardia. Detailed prenatal echocardiography revealed complete atrioventricular block (AVB III) with atrial rate of 140 b.p.m. and ventricular rate of 70 b.p.m., fetoplacental failure was not present at initial examination. Patient was hospitalised for the remainder of the pregnancy, which continued to full-term without complications. During delivery, fetal pulse oxymetry was utilized to monitor fetal state saturation levels. Labour proceeded without complications with an Apgar score of 9-9-9. The newborn was observed at the ICU and the Cardiac center and deemed to be in stable condition with AVB III without any signs of heart failure and without the necessity for pacemaker implantation.In cases of diagnosed fetal bradycardia, it is beneficial to expand the methods of fetal monitoring during labour. Pre-, peri-, and postnatal observation of pregnant women diagnosed with SLE and fetal bradycardia should be done in specialised facilities that are able to provide the appropriate level of care for mother and infant.