Search

Introduction: This study investigated the acceptability and feasibility of digital phenotyping in a military sample with a history of traumatic brain injury and co-occurring psychological and cognitive symptoms. The first aim was to evaluate the acceptability of digital phenotyping by (1a) quantifying the proportion of participants willing to download the app and rates of dropout and app discontinuation and (1b) reviewing the stated reasons for both refusing and discontinuing use of the app. The second aim was to investigate technical feasibility by (2a) characterizing the amount and frequency of transferred data and (2b) documenting technical challenges. Exploratory aim 3 sought to leverage data on phone and keyboard interactions to predict if a participant (a) is depressed and (b) has depression that improves over the course of the study., Materials and Methods: A passive digital phenotyping app (Mindstrong Discovery) functioned in the background of the participants' smartphones and passively collected phone usage and typing kinematics data., Results: Fifteen out of 16 participants (93.8%) consented to install the app on their personal smartphone devices. Four participants (26.7%) discontinued the use of the app partway through the study, primarily because of keyboard usability and technical issues. Fourteen out of 15 participants (93.3%) had at least one data transfer, and the median number of days with data was 40 out of a possible 57 days. The exploratory machine learning models predicting depression status and improvement in depression performed better than chance., Conclusions: The findings of this pilot study suggest that digital phenotyping is acceptable and feasible in a military sample and provides support for future larger investigations of this technology., (© The Association of Military Surgeons of the United States 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Feline infectious peritonitis (FIP) is a potentially fatal coronavirus-driven disease of cats. Treatment with nucleoside analogue GS-441524 and or prodrug remdesivir (RDV) have produced remission in both experimentally induced and naturally occurring FIP, yet information regarding metabolism of RDV into GS-441524 in cats is scarce. This study assessed possible phase I metabolism of RDV in cats, utilising an in vitro  feline microsome model with in vitro t 1/2 and  in vitro  Cl int  calculated using the substrate depletion method. A previously validated high-performance liquid chromatography (HPLC) fluorescence method was utilised for detection and analysis of RDV and GS-441524. Qualitative yield of RDV and intermediate metabolite GS-441524 were determined following microsome incubation, then compared to whole blood and plasma incubations. In vitro  microsome incubation resulted in rapid depletion of RDV, though it did not appear to resemble a conventional phase I-dependent reaction in cats, as it is in humans and dogs. Depletion of RDV into GS-441524 was demonstrated in whole blood in vitro , suggesting cats convert RDV to GS-441524, likely via blood esterases, as observed in mice and rats. RDV metabolism is unlikely to be impacted by impaired liver function in cats. Furthermore, as RDV depletes within minutes, whereas GS-441524 is very stable, whole blood or plasma GS-441524 concentrations, rather than plasma RDV concentrations, are more appropriate for therapeutic drug monitoring (TDM) in cats receiving RDV.

Purpose: Stressful life events are associated with problematic drinking, and alcohol misuse has been exacerbated during the coronavirus disease 2019 (COVID-19) pandemic. While coping motives may account for this association, positive life events (PLEs) and enhancement motives are understudied. To address these gaps, we examined the associations of history of alcohol use disorder (AUD), negative life events (NLEs), and PLEs with problematic alcohol use and tested coping and enhancement motives as mediators., Methods: The sample included baseline and follow-up data from 241 participants enrolled in the National Institute on Alcohol Abuse and Alcoholism COVID-19 Pandemic Impact on Alcohol Study. Endorsements of past year PLEs and NLEs and their associations with problematic alcohol use were examined. Among the 202 current drinkers, path analyses tested mediational pathways via coping and enhancement motives., Results: The top two PLEs were change in work conditions (21.6%) and taking a vacation (20.3%). The top two NLEs were change in social activities (36.5%) and major change in recreation (26.6%). Individuals with a history of AUD and those who experienced more NLEs reported higher coping and enhancement motives, which were associated with higher problematic alcohol use. Individuals who experienced more PLEs reported lower coping motives, which was associated with lower problematic alcohol use., Conclusions: Besides coping motives, enhancement motives were also associated with pandemic problematic alcohol use. Alcohol interventions targeting reward- and relief-driven drinking patterns may be beneficial to individuals with a history of AUD and those who experienced more NLEs. More research is needed to study PLEs which may help inform the development of strength-based alcohol interventions., (Published by Oxford University Press on behalf of Medical Council on Alcohol 2024.)

Objective: Individuals with a history of suicidality may be especially vulnerable to the adverse impact of COVID-related stressors, but this vulnerability has not been demonstrated. This study examined the longitudinal effects of suicidality history (ideation only or attempt vs. none) and interactions with COVID-related stressors (e.g., work interruptions, childcare challenges, and financial stress) on anxiety symptoms, depressive symptoms, and problematic drinking., Methods: Longitudinal data from 517 participants were drawn from the National Institute on Alcohol Abuse and Alcoholism Natural History Protocol and COVID-19 Pandemic Impact on Alcohol Study. Lifetime history of suicidality was assessed using the clinician administered Columbia-Suicide Severity Rating Scale. Multiple regressions tested the interaction between suicidality history and COVID-related stressors on clinical outcomes., Results: Compared to individuals without any history of suicidality (79.9%; n  = 413), individuals with a history of suicide ideation only (14.5%; n  = 75) and suicide attempt (5.6%; n  = 29) had higher anxiety symptoms, depressive symptoms, and problematic drinking during the pandemic. Significant interaction effects showed the associations between COVID-related stressors and mental disorder symptoms were stronger among individuals with suicide attempt history than individuals without suicidality history., Conclusions: History of suicide attempt in combination with high COVID-related stressors put individuals at the greatest risk for pandemic mental disorder symptoms. Individuals with suicide attempt history may have lower coping resources to handle COVID-related stressors. Suicide risk assessment and intervention to increase cognitive flexibility and emotional regulation skills may help these individuals manage emotional distress experienced during the COVID-19 pandemic and beyond., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Psychiatric Research and Clinical Practice published by Wiley Periodicals LLC on behalf of American Psychiatric Association.)

Background: Suicide ideation and attempt are linked to adverse mental health outcomes, but few studies have examined their associations with quality of life (QoL). This study examined the impact of lifetime history of suicidal ideation and attempt on four QoL domains via perceived stress and problematic drinking., Methods: Participants were drawn from the National Institute on Alcohol Abuse and Alcoholism Natural History Protocol (N = 1055), including those with no history of suicidality (78.6 %), suicidal ideation only (15.3 %), and a history of suicide attempt (6.2 %). Structural equation modeling (SEM) was utilized to test perceived stress and drinking as mediational pathways to multidimensional QoL., Results: Individuals with a history of suicide ideation and/or attempt reported higher perceived stress in the past month, more problematic drinking in the past year, and lower QoL domains in the past two weeks. SEM showed significant mediation effects through dimensions of perceived stress (helplessness, lack of self-efficacy) and alcohol problems. When these mediators were considered simultaneously, the mediation effects through alcohol problems were attenuated, while several direct effects of suicidality on physical, psychological, and social QoL were weakened but remained significant., Limitations: Cross-sectional data with retrospective report of suicidality history., Conclusions: A lifetime history of suicidality was associated with lower multidimensional QoL. These associations were partially explained by stress and alcohol-related coping mechanisms such as feeling helpless or inadequate when encountering stressors and problematic drinking. Perceived stress and drinking to cope may be important intervention targets to improve QoL among those with a history of suicidality., Competing Interests: Declaration of competing interest The authors have no conflict of interests to declare., (Published by Elsevier B.V.)

Objective: To describe the imaging findings in Australian cats and dogs with CNS cryptococcosis., Animals: 23 cases (10 cats; 13 dogs) with CNS cryptococcosis and brain MRI or CT studies available to review., Methods: Retrospective, multi-institutional case series. Brain MRI or CT studies were reviewed by a board-certified radiologist. Imaging findings were described and the differences between cats and dogs explored., Results: Morphologic features were consistent with extra-axial lesions in all (n = 13) dogs and either intra-axial (5/10) or extra-axial (4/10) lesions in cats, with 1 cat having no detectable lesions in low-field brain MRI scans. Meningeal abnormalities were most common, followed by forebrain and cerebellar lesions. Intracranial MRI lesions were typically T2 hyperintense and T1 hypo- to isointense. Four cases had T2 hypointense lesions affecting the brain, sinonasal cavity, or regional lymph nodes. Intracranial CT lesions were mostly soft tissue attenuating. Contrast enhancement was present in all cases with contrast series available, with ring enhancement shown only in cats. Osteolysis was more common in dogs than cats, particularly affecting the cribriform plate. All 13 dogs and many (6/10) cats had at least 1 lesion affecting sinonasal or contiguous tissues, and locoregional lymphadenomegaly was common (7/10 cats; 11/13 dogs)., Clinical Relevance: Imaging lesions in cryptococcal meningoencephalitis were extra-axial in dogs but could be intra-axial or extra-axial in cats. Careful examination for extracranial lesions (sinonasal, retrobulbar, facial soft tissue, tympanic bullae, or locoregional lymph nodes) is important to provide alternative safe biopsy sites. T2 hypointense lesions, while rare, should prompt consideration of cryptococcosis.

Background: Prior research has identified altered brain structure and function in individuals at risk for self-directed violence thoughts and behaviors. However, these studies have largely utilized healthy controls and findings have been inconsistent. Thus, this study examined differences in resting-state functional network connectivity among individuals with lifetime suicide attempt(s) v. lifetime self-directed violence thoughts alone., Methods: Using data from the UK Biobank, this study utilized a series of linear regressions to compare individuals with lifetime suicide attempt(s) ( n = 566) v. lifetime self-directed violence thoughts alone ( n = 3447) on within- and between- network resting-state functional connectivity subnetworks., Results: There were no significant between-group differences for between-network, within-network, or whole-brain functional connectivity after adjusting for age, sex, ethnicity, and body mass index and performing statistical corrections for multiple comparisons. Resting-state network measures may not differentiate between individuals with lifetime suicide attempt(s) and lifetime self-directed violence thoughts alone., Conclusions: Null findings diverge from results reported in smaller neuroimaging studies of suicide risk, but are consistent with null findings in other large-scale studies and meta-analyses. Strengths of the study include its large sample size and stringent control group. Future research on a wider array of imaging, genetic, and psychosocial risk factors can clarify relative contributions of individual and combined variables to suicide risk and inform scientific understanding of ideation-to-action framework.

The adenosine analogue GS-441524 has demonstrated efficacy in treatment of feline infectious peritonitis (FIP). With no commercially registered formulations of GS-441524 available, global focus shifted to its pro-drug remdesivir, as it became more accessible throughout the COVID-19 pandemic. This study developed and validated a simple liquid chromatography equipped with a fluorescence detector to quantify plasma concentrations of GS-441524 applicable for routine therapeutic monitoring of remdesivir or GS-441524 therapy for FIP infected cats. A Waters X-Bridge C18, 5 µm, 150 × 4.6 mm, column was used and mixtures of 20 mM ammonium acetate (pH 4.5) with acetonitrile of 5% and 70% were prepared for gradient mobile phase. With a simple protein precipitation using methanol to clean plasma sample, GS-441524 was monitored at excitation and emission wavelengths of 250 nm and 475 nm, respectively. Using an external standard, the lowest and highest limits of quantification were 19.5 ng/mL to 10,000 ng/mL, respectively. The intra- and inter day trueness of the quality controls (QCs) were within 10% of their nominal concentrations and intra- and inter day precision of the QCs (expressed as the coefficient of variation) ranged from 1.7 to 5.7%, This assay was able to quantify plasma trough levels of GS-441524 (23.7-190.1 ng/mL) after the administration of remdesivir (9.9-15.0 mg/kg BW, IV or SC) in FIP cats ( n  = 12). Accordingly, this study generated an alternative and cost-effective way to quantify GS-441524 in feline biological fluids at least up to 24 hr after administrations of remdesivir.

Introduction: Veteran suicide rates continue to be unacceptably high, with the most common risk factor being a past suicide attempt (SA). However, some characteristics of suicidal ideation (SI) and behavior among Veterans hospitalized for suicide risk remain under-reported., Materials and Methods: One hundred and eighty-three Veterans hospitalized for either an SA or SI with intent were screened for enrollment in a treatment study to prevent suicide. Veterans completed a demographic form, the Columbia-Suicide Severity Rating Scale, and the McLean borderline personality disorder screening measure shortly after inpatient psychiatric admission. Chi-squared and t-tests were used to compare suicide characteristics (e.g., intensity, duration, deterrents, and controllability) between Veterans with and without a lifetime history of SA. Thematic analyses of the reported method of SI were conducted., Results: Sixty-seven percent of participants were hospitalized for SI and 33% were hospitalized for SA. Twenty-one percent of Veterans hospitalized for SI also endorsed a recent SA in the weeks preceding hospitalization. Most participants reported at least one lifetime SA (71%). Veterans with a lifetime history of SA reported greater frequency and duration of ideation in the week before hospitalization (t[169] =  -2.56, P = .01; t[168] =  -2.04, P = .04) while also reporting that deterrents were less likely to prevent an SA (t[107.09] =  -3.58, P = .001) compared to those with no lifetime SA., Conclusion: Overall, Veterans hospitalized for SI/SA demonstrated markers of chronic suicide risk, as most participants endorsed a past attempt in their lifetime. Some Veterans admitted for SI also reported a past month's attempt, suggesting that in certain cases, hospitalization does not immediately follow an acute suicidal crisis. A past SA differentiated Veterans on average frequency and duration of SI as well as the perception of deterrents preventing suicidal behavior. Therefore, a thorough evaluation of suicide methods and intensity may be informative in treatment planning for Veterans at greatest risk of suicide., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2023. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: Nucleoside analog GS-441524 is effective in treating cats with feline infectious peritonitis (FIP). Investigation into the use of parent nucleotide analog remdesivir (GS-5734) is needed., Objectives: To assess efficacy and tolerability of remdesivir with or without transition to GS-441524 in cats with FIP and document clinical and clinicopathologic progression over 6 months., Animals: Twenty-eight client-owned cats with FIP., Methods: Cats were prospectively recruited between May 2021 and May 2022. An induction dosage of remdesivir 10 to 15 mg/kg intravenously or subcutaneously q24h was utilized for 4 doses, with a maintenance dosage of remdesivir (6-15 mg/kg SC) or GS-441524 (10-15 mg/kg per os) every 24 hours continued for at least 84 days. Laboratory testing, veterinary, and owner assessments were recorded., Results: Twenty-four cats survived to 6 months (86%). Three cats died within 48 hours. Excluding these, survival from 48 hours to 6 months was 96% (24/25). Remission was achieved by day 84 in 56% (14/25). Three cats required secondary treatment for re-emergent FIP. Remission was achieved in all 3 after higher dosing (15-20 mg/kg). Adverse reactions were occasional site discomfort and skin irritation with remdesivir injection. Markers of treatment success included resolution of pyrexia, effusions, and presenting signs of FIP in the first half of treatment and normalization of globulin concentration, and continued body weight gains in the latter half of the treatment period., Conclusions and Clinical Importance: Parenteral administration of remdesivir and oral administration of GS-441524 are effective and well-tolerated treatments for FIP. Early emphasis on clinical, and later emphasis on clinicopathologic response, appears prudent when monitoring treatment efficacy., (© 2023 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

While the neuroanatomical correlates of impulsivity in youths have been examined, there is little research on whether those correlates are consistent across childhood/adolescence. The current study uses data from the age 11/12 ( N = 7,083) visit of the Adolescent Brain Cognitive Development Study to investigate the replicability of previous work (Owens et al., 2020) the neuroanatomical correlates of impulsive personality traits identified at age 9/10. Neuroanatomy was measured using structural and diffusion magnetic resonance imaging, and impulsive personality was measured using the UPPS-P Impulsive Behavior Scale. Replicability was quantified using three Open Science Collaboration replication criteria, intraclass correlations, and elastic net regression modeling to make predictions across timepoints. Replicability was highly variable among traits: The neuroanatomical correlates of positive urgency showed substantial similarity between ages 9/10 and 11/12, negative urgency and sensation seeking showed moderate similarity across ages, and (lack of) premeditation and perseverance showed substantial dissimilarity across ages. In all cases, effect sizes between impulsive traits and brain variables were small. These findings suggest that, even for studies with large sample sizes and the same participant pool, the replicability of brain-behavior correlations across a 2-year period cannot be assumed. This may be due to developmental changes across the two timepoints or false-positive/false-negative results at one or both timepoints. These results also highlight an array of neuroanatomical structures that may be important to impulsive personality traits across development from childhood into adolescence. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Objective: To determine how engagement of the hospital and/or vendor with performance improvement strategies combined with an automated hand hygiene monitoring system (AHHMS) influence hand hygiene (HH) performance rates., Design: Prospective, before-and-after, controlled observational study., Setting: The study was conducted in 58 adult and pediatric inpatient units located in 10 hospitals., Methods: HH performance rates were estimated using an AHHMS. Rates were expressed as the number of soap and alcohol-based hand rub portions dispensed divided by the number of room entries and exits. Each hospital self-assigned to one of the following intervention groups: AHHMS alone (control group), AHHMS plus clinician-based vendor support (vendor-only group), AHHMS plus hospital-led unit-based initiatives (hospital-only group), or AHHMS plus clinician-based vendor support and hospital-led unit-based initiatives (vendor-plus-hospital group). Each hospital unit produced 1–2 months of baseline HH performance data immediately after AHHMS installation before implementing initiatives., Results: Hospital units in the vendor-plus-hospital group had a statistically significant increase of at least 46% in HH performance compared with units in the other 3 groups ( P ≤ .006). Units in the hospital only group achieved a 1.3% increase in HH performance compared with units that had AHHMS alone ( P = .950). Units with AHHMS plus other initiatives each had a larger change in HH performance rates over their baseline than those in the AHHMS-alone group ( P < 0.001)., Conclusions: AHHMS combined with clinician-based vendor support and hospital-led unit-based initiatives resulted in the greatest improvements in HH performance. These results illustrate the value of a collaborative partnership between the hospital and the AHHMS vendor.

Objective: To describe the clinical findings and outcomes of Australian cats and dogs with CNS cryptococcosis., Animals: 19 cats and 31 dogs with CNS cryptococcosis diagnosed between 2000 and 2020., Procedures: A case series and cohort study were performed using the same 50 animals. Both studies were multi-institutional and both retrospective and prospective. Disease features were compared between cats and dogs, and associations between putative risk factors and survival time (ST) were assessed., Results: Dogs were younger at initial presentation than cats and had lower latex cryptococcal antigen agglutination titers. Extraneurologic signs were common and frequently involved sinonasal and contiguous tissues. Neuroanatomic localization was predominantly forebrain, central vestibular (including cerebellum), multifocal, or diffuse. CSF analysis predominantly showed pleocytosis, with eosinophilic inflammation common in dogs. Seventy-eight percent (39/50) of patients received antifungal treatment. Median STs (from presentation) in treated patients were 1,678 days for cats and 679 days for dogs. Abnormal mentation at presentation (in dogs) and CSF collection (in cats) were associated with shorter STs. In treated dogs, those that received glucocorticoids prior to diagnosis, or single rather than multiple antifungal agents, had shorter STs., Clinical Relevance: The prognosis for feline and canine CNS cryptococcosis is guarded, yet long STs are possible with appropriate treatment. Presence of subtle upper respiratory tract signs may suggest cryptococcosis in patients with neurologic signs, while the absence of neurologic signs does not preclude CNS involvement.

Background: Limited knowledge exists regarding targets for suicide-focused care among high-risk United States (U.S.) civilian and military sexual minorities., Purpose: This study aimed to understand the demographic and clinical characteristics of a suicidal sexual minority sample, psychiatrically hospitalized in military treatment facilities, to advance future targeted care for this vulnerable subgroup., Methods: Secondary analysis of baseline data from a multisite psychotherapy randomized controlled trial was performed comparing those who self-identified as lesbian, gay, or bisexual (LGB; n = 39) to heterosexual participants (n = 170)., Results: LGB participants were more likely than heterosexual participants to be younger, female, never married, and enlisted rank. LGB participants reported significantly lower family support, higher perceived burdensomeness, lower acquired capability for suicide, and were twice as likely to report that they could not control their suicidal thoughts. LGB and heterosexual participants reported similar levels of other suicide risk indicators and similar lifetime suicidal ideation and attempt histories., Conclusions: Compared to heterosexual participants, LGB participants reported increased risk indicators for suicide yet similar lifetime suicidal ideation and attempt histories. Suicide prevention programs should address the unique needs of this vulnerable subgroup. Interventions targeting family support, perceived burdensomeness, and controllability of suicidal thoughts may be promising., (© 2021 The American Association of Suicidology.)

Background: To describe prevalence and identify clinical correlates of hazardous drinking among suicidal inpatients at military medical settings., Method: Data were drawn from the baseline assessment of a multisite randomized controlled trial of Post-Admission Cognitive Therapy (PACT). Participants were military Service members or adult beneficiaries (N = 218) who were admitted to inpatient care following a suicide-related crisis. Hazardous alcohol use in the past year was assessed using the Alcohol Use Disorder Identification Test (AUDIT)., Results: The average AUDIT score was 6.78 (SD = 7.87), with 28.9% reporting hazardous drinking (scored ≥8 on the AUDIT). Hazardous drinkers were more likely than nonhazardous drinkers to meet diagnosis of Substance Use Disorder (SUD; Odds Ratio [OR] = 5.96, 95% confidence intervals [CI] = 2.13, 16.71). Hazardous drinking was neither associated with measures of suicide ideation nor aborted or interrupted suicide attempt. However, hazardous drinkers had greater risk of having both single (RRR [Relative Risk Ratio] = 2.55, 95% CI = 1.18, 5.50) and multiple actual suicide attempts (RRR = 2.38, 95% CI = 1.06, 5.32) than nonhazardous drinkers. The association between hazardous drinking and single (but not multiple) actual suicide attempt remained significant after controlling for gender, depressive symptoms, hopelessness, Post-Traumatic Stress Disorder, and SUD (adjusted RRR = 2.48, 95% CI = 1.09, 5.65)., Conclusions: A history of actual suicide attempt is associated with hazardous alcohol use among suicidal psychiatric inpatients. Assessment of drinking and drug use may inform case conceptualization and treatment of suicide-related behaviors in psychiatric inpatient settings., (Published by Elsevier Ltd.)

Mentholated cigarettes capture a quarter of the US market, and are disproportionately smoked by adolescents. Menthol allosterically modulates nicotinic acetylcholine receptor function, but its effects on the brain and nicotine addiction are unclear. To determine if menthol is psychoactive, we assessed locomotor sensitization and brain functional connectivity. Adolescent male Sprague Dawley rats were administered nicotine (0.4 mg/kg) daily with or without menthol (0.05 mg/kg or 5.38 mg/kg) for nine days. Following each injection, distance traveled in an open field was recorded. One day after the sensitization experiment, functional connectivity was assessed in awake animals before and after drug administration using magnetic resonance imaging. Menthol (5.38 mg/kg) augmented nicotine-induced locomotor sensitization. Functional connectivity was compared in animals that had received nicotine with or without the 5.38 mg/kg dosage of menthol. Twenty-four hours into withdrawal after the last drug administration, increased functional connectivity was observed for ventral tegmental area and retrosplenial cortex with nicotine+menthol compared to nicotine-only exposure. Upon drug re-administration, the nicotine-only, but not the menthol groups, exhibited altered functional connectivity of the dorsal striatum with the amygdala. Menthol, when administered with nicotine, showed evidence of psychoactive properties by affecting brain activity and behavior compared to nicotine administration alone.

Interprofessional collaborative practice (IPC) is paramount to the future of oral health education. As such, it is critical that today's health care education continues to expand its curriculum to promote oral health as an essential component in the IPC approach to women's health. This article explores models that can be implemented using an IPC framework to foster better approaches in the delivery of care to female patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

A defining characteristic of type 1 diabetes mellitus (T1DM) pathophysiology is pancreatic β-cell death and dysfunction, resulting in insufficient insulin secretion to properly control blood glucose levels. Treatments that promote β-cell replication and survival, thus reversing the loss of β-cell mass, while also preserving β-cell function, could lead to a real cure for T1DM. The α-subunit of the heterotrimeric Gz protein, Gαz, is a tonic negative regulator of adenylate cyclase and downstream cAMP production. cAMP is one of a few identified signaling molecules that can simultaneously have a positive impact on pancreatic islet β-cell proliferation, survival, and function. The purpose of our study was to determine whether mice lacking Gαz might be protected, at least partially, from β-cell loss and dysfunction after streptozotocin treatment. We also aimed to determine whether Gαz might act in concert with an activator of the cAMP-stimulatory glucagon-like peptide 1 receptor, exendin-4 (Ex4). Without Ex4 treatment, Gαz-null mice still developed hyperglycemia, albeit delayed. The same finding held true for wild-type mice treated with Ex4. With Ex4 treatment, Gαz-null mice were protected from developing severe hyperglycemia. Immunohistological studies performed on pancreas sections and in vitro apoptosis, cytotoxicity, and survival assays demonstrated a clear effect of Gαz signaling on pancreatic β-cell replication and death; β-cell function was also improved in Gαz-null islets. These data support our hypothesis that a combination of therapies targeting both stimulatory and inhibitory pathways will be more effective than either alone at protecting, preserving, and possibly regenerating β-cell mass and function in T1DM.

Stimulation of digestive organs by enteric peptides is lost during total parental nutrition (PN). Here we examine the role of the enteric peptide bombesin (BBS) in stimulation of the exocrine and endocrine pancreas during PN. BBS protects against exocrine pancreas atrophy and dysfunction caused by PN. BBS also augments circulating insulin levels, suggesting an endocrine pancreas phenotype. While no significant changes in gross endocrine pancreas morphology were observed, pancreatic islets isolated from BBS-treated PN mice showed a significantly enhanced insulin secretion response to the glucagon-like peptide-1 (GLP-1) agonist exendin-4, correlating with enhanced GLP-1 receptor expression. BBS itself had no effect on islet function, as reflected in low expression of BBS receptors in islet samples. Intestinal BBS receptor expression was enhanced in PN with BBS, and circulating active GLP-1 levels were significantly enhanced in BBS-treated PN mice. We hypothesized that BBS preserved islet function indirectly, through the enteroendocrine cell-pancreas axis. We confirmed the ability of BBS to directly stimulate intestinal enteroid cells to express the GLP-1 precursor preproglucagon. In conclusion, BBS preserves the exocrine and endocrine pancreas functions during PN; however, the endocrine stimulation is likely indirect, through the enteroendocrine cell-pancreas axis.

The aggrecan degrading metalloprotease ADAMTS-4 has been identified as a novel therapeutic target for osteoarthritis. Here, we use DNA-encoded Library Technology (ELT) to identify novel ADAMTS-4 inhibitors from a DNA-encoded triazine library by affinity selection. Structure-activity relationship studies based on the selection information led to the identification of potent and highly selective inhibitors. For example, 4-(((4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-6-(((4-methylpiperazin-1-yl)methyl)amino)-1,3,5-triazin-2-yl)amino)methyl)-N-ethyl-N-(m-tolyl)benzamide has IC50 of 10 nM against ADAMTS-4, with >1000-fold selectivity over ADAMT-5, MMP-13, TACE, and ADAMTS-13. These inhibitors have no obvious zinc ligand functionality.

Objective: The NeoSphere trial demonstrated that the addition of pertuzumab to trastuzumab and docetaxel for the neoadjuvant treatment of HER2-positive locally advanced, inflammatory, or early breast cancer (eBC) resulted in a significant improvement in pathological complete response (pCR). Furthermore, the TRYPHAENA trial supported the benefit of neoadjuvant dual anti-HER2 therapy. Survival data from these trials is not yet available; however, other studies have demonstrated a correlation between pCR and improved event-free survival (EFS) and overall survival (OS) in this patient population. This study represents the first Canadian cost-effectiveness analysis of pertuzumab in the neoadjuvant treatment of HER2-positive eBC., Methods: A cost-utility analysis (CUA) was conducted using a three health state Markov model ('event-free', 'relapsed', and 'dead'). Two separate analyses were conducted; the first considering total pCR (ypT0/is ypN0) data from NeoSphere, and the second from TRYPHAENA. Published EFS and OS data partitioned for patients achieving/not achieving pCR were used in combination with the percentage achieving pCR in the pertuzumab trials to estimate survival. This CUA included published utility values and direct medical costs including drugs, treatment administration, management of adverse events, supportive care, and subsequent therapy. To address uncertainty, a probabilistic sensitivity analysis (PSA) and alternative scenarios were explored., Results: Both analyses suggested that the addition of pertuzumab resulted in increased life-years and quality-adjusted life-years (QALYs). The incremental cost per QALY ranged from $25,388 (CAD; NeoSphere analysis) to $46,196 (TRYPHAENA analysis). Sensitivity analyses further support the use of pertuzumab, with cost-effectiveness ratios ranging from $9230-$64,421. At a threshold of $100,000, the addition of pertuzumab was cost-effective in nearly all scenarios (93% NeoSphere; 79% TRYPHAENA)., Conclusion: Given the improvement in clinical efficacy and a favorable cost per QALY, the addition of pertuzumab in the neoadjuvant setting represents an attractive treatment option for HER2-positive eBC patients.

Purpose: Because of rising drug expenditures, cost considerations have become essential, necessitating the requirement for cost-effectiveness analyses for managed care organizations (MCOs). The study objective is to examine the impact of various drug-cost components, in addition to wholesale acquisition cost (WAC), on the cost-effectiveness of osteoporosis therapies., Design: A Markov model of osteoporosis was used to exemplify different drug cost scenarios., Methodology: We examined the effect of varying rebates for oral bisphosphonates--risedronate and ibandronate--as well as considering the impact of varying copayments and administration costs for intravenous zoledronate. The population modeled was 1,000 American women, > or = 50 years with osteoporosis. Patients were followed for 1 year to reflect an annual budget review of formularies by MCOs. The cost of therapy was based on an adjusted WAC, and is referred to as net drug cost. The total annual cost incurred by an MCO for each drug regimen was calculated using the net drug cost and fracture cost. We estimated cost on a quality adjusted life year (QALY) basis., Principal Findings: When considering different rebates, results for risedronate versus ibandronate vary from cost-savings (i.e., costs less and more effective) to approximately $70,000 per QALY. With no risedronate rebate, an ibandronate rebate of approximately 65% is required before cost per QALY surpasses $50,000. With rebates greater than 25% for risedronate, irrespective of ibandronate rebates, results become cost-saving. Results also showed the magnitude of cost savings to the MCO varied by as much as 65% when considering no administration cost and the highest coinsurance rate for zoledronate., Conclusion: Our study showed that cost-effectiveness varies considerably when factors in addition to the WAC are considered. This paper provides recommendations for pharmaceutical manufacturers and MCOs when developing and interpreting such analyses.

Establishment of asymptomatic bacteriuria is a novel alternative to antimicrobial therapy for management of recurrent bacterial urinary tract infection in humans and may also be useful for dogs if it can be shown that colonization of the canine bladder can be achieved. A three-dose protocol for Escherichia coli strain 83972 inoculation was developed to attempt induction of persistent bacteriuria in healthy dogs. A previous study using a single inoculation colonized dogs for no longer than 10 days and multi-dose protocols have been used to establish persistent bacteriuria in human patients. Three doses of approximately 10(9)E. coli 83972 bacteria were introduced into the bladder of eight healthy female dogs over 24h via an indwelling sterile urinary catheter. Three additional dogs were sham-inoculated. Duration of colonization ranged from 1 to 28 days (median 2 days) with no discernible reason for the prolonged colonization in one dog. Multi-dose inoculation of healthy dogs was not obviously superior to our previous use of single-dose inoculation apart from one dog remaining colonized for 28 days following the three-dose inoculation protocol., (Crown Copyright © 2012. Published by Elsevier B.V. All rights reserved.)

The prevalence of spotted fever group rickettsial infection in dogs from a remote indigenous community in the Northern Territory (NT) was determined using molecular tools. Blood samples collected from 130 dogs in the community of Maningrida were subjected to a spotted fever group (SFG)-specific PCR targeting the ompB gene followed by a Rickettsia felis-specific PCR targeting the gltA gene of R. felis. Rickettsia felis ompB and gltA genes were amplified from the blood of 3 dogs. This study is the first report of R. felis infection in indigenous community dogs in NT.

Uncomplicated bacterial urinary tract infections (UTIs) occur commonly in dogs. Persistent or recurrent infections are reported less frequently. They typically occur in dogs with an underlying disease and are sometimes asymptomatic, especially in dogs with predisposing chronic disease. Escherichia coli is the organism most frequently cultured in both simple and complicated UTIs. Organisms such as Enterococcus spp. and Pseudomonas spp. are less common in uncomplicated UTI, but become increasingly prominent in dogs with recurrent UTI. The ability of bacteria to acquire resistance to antimicrobials and/or to evade host immune defence mechanisms is vital for persistence in the urinary tract. Antimicrobial therapy limitations and bacterial strains with such abilities require novel control strategies. Sharing of resistant bacteria between humans and dogs has been recently documented and is of particular concern for E. coli O25b:H4-ST131 strains that are both virulent and multi-drug resistant. The epidemiology of complicated UTIs, pathogenic traits of uropathogens and new therapeutic concepts are outlined in this review., (Copyright © 2011. Published by Elsevier Ltd.)

Rickettsia felis causes flea-borne spotted fever in humans worldwide. The cat flea, Ctenocephalides felis, serves as vector and reservoir host for this disease agent. To determine the role of dogs as potential reservoir hosts for spotted fever group rickettsiae, we screened blood from 100 pound dogs in Southeast Queensland by using a highly sensitive genus-specific PCR. Nine of the pound dogs were positive for rickettsial DNA and subsequent molecular sequencing confirmed amplification of R. felis. A high prevalence of R. felis in dogs in our study suggests that dogs may act as an important reservoir host for R. felis and as a potential source of human rickettsial infection.

Objectives: Recent results of the U.S. Oncology Adjuvant Trial 9735 demonstrated significant disease-free survival and overall survival benefits for docetaxel and cyclophosphamide (tc) compared with doxorubicin and cyclophosphamide (ac) in the adjuvant treatment of operable invasive breast cancer. Based on clinical data from the 9735 study, we evaluated the lifetime cost-effectiveness of tc compared with ac from the perspective of the Canadian publicly funded health care system., Methods: A Markov model was developed to estimate the incremental cost per quality-adjusted life-year gained and per life-year gained. Monthly survival and risk of disease recurrence up to 7 years were obtained directly from the overall survival and disease-free survival curves in the 9735 study; life-years beyond 7 years were estimated using the average life expectancy of age-matched women in the general Canadian population. Canadian-specific resource utilization and unit costs (in 2008 Canadian dollars) were applied to estimate costs for chemotherapy administration, chemotherapy-related toxicities, recurrence, and adverse events. Health-utility scores and decrements used in the calculation of quality-adjusted life-years were derived from the literature., Results: The lifetime cost per quality-adjusted life-year gained was $8,251 for tc compared with ac, and the cost per life-year gained was $6,842. The results were robust across a range of sensitivity analyses., Conclusions: Cost-effectiveness, combined with efficacy and an acceptable safety profile, support the adoption of tc as an alternative to ac in Canadian clinical practice for the adjuvant treatment of operable early breast cancer.

Establishment of asymptomatic bacteriuria (ABU) with Escherichia coli 83972 is a viable prophylactic alternative to antibiotic therapy for the prevention of recurrent bacterial urinary tract infection in humans. Approximately 2 × 10(8) viable E. coli 83972 cells were introduced into the bladder of six healthy female dogs via a sterile urinary catheter. The presence of pyuria, depression, stranguria, pollakiuria and haematuria was documented for 6 weeks and urinalysis and aerobic bacterial cultures were performed every 24-72 h. Pyuria was present in all dogs on day 1 post-inoculation and 4/6 dogs (67%) had a positive urine culture on this day. Duration of colonization ranged from 0 to 10 days (median 4 days). Four dogs were re-inoculated on day 20. Duration of colonization following the second inoculation ranged from 1 to 3 days. No dog suffered pyrexia or appeared systemically unwell but all dogs initially exhibited mild pollakiuria and a small number displayed gross haematuria and/or stranguria. By day 3 of each trial all clinical signs had resolved. Persistent bacteriuria was not achieved in any dog but two dogs were colonized for 10 days following a single inoculation. Further research is required to determine whether establishment of ABU in dogs with recurrent urinary tract infection is a viable alternative to repeated doses of antimicrobial agents., (Crown Copyright © 2010. Published by Elsevier B.V. All rights reserved.)

Unlabelled: The RisedronatE and ALendronate (REAL) study provided a unique opportunity to conduct cost-effectiveness analyses based on effectiveness data from real-world clinical practice. Using a published osteoporosis model, the researchers found risedronate to be cost-effective compared to generic or brand alendronate for the treatment of Canadian postmenopausal osteoporosis in patients aged 65 years or older., Introduction: The REAL study provides robust data on the real-world performance of risedronate and alendronate. The study used these data to assess the cost-effectiveness of brand risedronate versus generic or brand alendronate for treatment of Canadian postmenopausal osteoporosis patients aged 65 years or older., Methods: A previously published osteoporosis model was populated with Canadian cost and epidemiological data, and the estimated fracture risk was validated. Effectiveness data were derived from REAL and utility data from published sources. The incremental cost per quality-adjusted life-year (QALY) gained was estimated from a Canadian public payer perspective, and comprehensive sensitivity analyses were conducted., Results: The base case analysis found fewer fractures and more QALYs in the risedronate cohort, providing an incremental cost per QALY gained of $3,877 for risedronate compared to generic alendronate. The results were most sensitive to treatment duration and effectiveness., Conclusions: The REAL study provided a unique opportunity to conduct cost-effectiveness analyses based on effectiveness data taken from real-world clinical practice. The analysis supports the cost-effectiveness of risedronate compared to generic or brand alendronate and the use of risedronate for the treatment of osteoporotic Canadian women aged 65 years or older with a BMD T-score < or =-2.5., Competing Interests: of interest Daniel Grima is a paid employee of and shareholder in Cornerstone Research Group, Inc. Cornerstone received funding to conduct the cost-effectiveness analysis and develop the manuscript. Cornerstone conducts other consulting activities for the Alliance for Better Bone Health and other pharmaceutical companies that market osteoporosis therapies. Alexandra Papaioannou is or has been a consultant to the following companies: Amgen, Eli Lilly, Merck Frosst, Procter & Gamble, Sanofi-Aventis. Dr Papaioannou has conducted clinical trials for: Eli Lilly, Merck Frosst, Procter & Gamble, and Sanofi-Aventis. Melissa Thompson is a paid employee of Cornerstone Research Group, Inc. Cornerstone received funding to conduct the cost-effectiveness analysis and develop the manuscript. Cornerstone conducts other consulting activities for the Alliance for Better Bone Health and other pharmaceutical companies that market osteoporosis therapies. Margaret Pasquale is a paid employee of P&G Pharmaceuticals Inc., which is a member of the Alliance for Better Bone Health. Jonathan D. Adachi is/has been a consultant/speaker for Amgen, Astra Zeneca, Eli Lilly, GSK, Merck, Novartis, Pfizer, Procter & Gamble, Roche, Sanofi-Aventis, and Servier. He has participated in clinical trials for Amgen, Eli Lilly, GSK, Merck, Novartis, Pfizer, Procter & Gamble, and Roche.

Background and Objective: Intensive insulin therapy improves glycosylated haemoglobin (Hb(A1C)) levels and delays the onset of long-term diabetes-related complications. Current treatment guidelines recommend maintaining a glycosylated haemoglobin (Hb(A1C)) of < or = 7% in patients with type 1 and 2 diabetes mellitus. However, the risk of hypoglycaemia increases with lower Hb(A1C) levels. As such, patients often choose to settle for suboptimal glucose control in order to prevent hypoglycaemic events. At a given Hb(A1C) level, treatment with insulin glargine results in a lower risk of hypoglycaemia in type 1 and 2 diabetes compared with NPH insulin. It has been proposed that the lower hypoglycaemic risk will allow more patients to achieve target Hb(A1C) levels with insulin glargine compared with NPH insulin. The objective of this study was to assess the cost effectiveness of insulin glargine compared with NPH insulin in patients with type 1 or 2 diabetes who had inadequate glycaemic control., Methods: A long-term, state-transition model was developed to simulate the natural history of type 1 and 2 diabetes. Risks of diabetes-related macro- and microvascular complications and mortality by Hb(A1C) levels were estimated based on the UKPDS (United Kingdom Prospective Diabetes Study). Outcome measures included complication rates and associated costs, insulin costs, life years (LYs) and QALYs. The baseline analysis was conducted for patients with type 1 and 2 diabetes (aged 27 and 53 years, respectively) with Hb(A1C) levels >7%, using a 36-year time horizon and a Canadian public payer perspective. Costs and effects were discounted at 5% per annum. Univariate sensitivity analyses were performed on key model inputs. All costs were reported in $Can (2005 values)., Results: The NPH insulin group had lower total costs than the insulin glargine group for patients with inadequately controlled diabetes (Hb(A1C) >7%; lifetime difference 1398 Can dollars and 1992 Can dollars, respectively, in type 1 and 2 diabetes). However, patients treated with insulin glargine had greater total and quality-adjusted life expectancy than those who received NPH insulin (incremental LY = 0.08 and QALYs = 0.07 in type 1 diabetes and incremental LY = 0.25 and QALYs = 0.23 in type 2 diabetes). The weighted incremental cost per LY gained and QALY gained were 18,661 Can dollars and 20,799 Can dollars, respectively, in type 1 diabetes and 8041 Can dollars and 8618 Can dollars, respectively, in type 2 diabetes (discounted results)., Conclusions: The cost-effectiveness ratios for insulin glargine use for type 1 and 2 diabetes provide evidence for its adoption from a Canadian healthcare payer perspective.

The movement to reform dying in America promotes hospice as a model for change. Yet terminally ill patients increasingly are closer to death when they enter some 3,300 hospices. Hospice leaders blame physicians for delaying referrals and charge that delays cause hardships for their organizations and patients. Based on symmetrical theory and the coorientation model, a survey of one Southern hospice and its referring physicians was conducted to measure agreement, perceived agreement, and accuracy between the two sides on the issue of timely referral. Results showed that hospice leaders inaccurately perceive a high degree of disagreement when they and physicians generally agree on the issue.

Thirteen dogs with primary immune-mediated hemolytic anemia received fresh-frozen plasma within 12 hours of admission, in addition to unfractionated heparin and other therapies, such as prednisone, azathioprine, and packed red blood cell transfusion. Antithrombin activity was quantified prior to transfusion and at 30 minutes and 48 hours after transfusion. Plasma antithrombin activity did not change significantly after a single plasma transfusion. There were no deaths in the first 48 hours of treatment. Thromboembolism was identified at necropsy in six of 10 dogs that died within 12 months of admission. There was no significant difference in the incidence of thromboembolism between the current treatment group and a historical control group.

An 11-year-old spayed female Labrador Retriever and a 9-year-old castrated male miniature Poodle were evaluated because of clinical signs of hyperadrenocorticism. Cortisol testing did not support a diagnosis of hypercortisolemia in either dog; however, imaging studies revealed unilateral adrenal tumors in both dogs. Serum concentrations of 17-hydroxyprogesterone, progesterone, and estradiol were high in both dogs, and androstenedione concentrations were also high in 1 dog. It is suspected that sex hormone secretion by the adrenal tumors in these dogs resulted in clinical signs of hyperadrenocorticism. Clinical signs and hormonal abnormalities resolved in the male dog after surgical resection of the tumor. There was no improvement in clinical signs after treatment with mitotane in the female dog, which died 2 months after diagnosis. Histologic evaluation confirmed the presence of adrenocortical carcinoma in both dogs.

The substrate kinetic properties of histamine methyltransferase from human skin were studied at limiting concentrations of both histamine and S-adenosylmethionine. Substrate inhibition by histamine was observed at concentrations above 10 microM. Primary plots showed evidence of a sequential reaction mechanism. The Michaelis constants were derived from secondary plots of slopes from the primary plots ([S]/v versus [S]) versus reciprocal of the second substrate concentration. The mean Km values for histamine and S-adenosylmethionine were 4.2 and 1.8 microM respectively. Histamine in concentrations of 25-100 microM inhibited enzyme activity uncompetitively with respect to S-adenosylmethionine. No substrate inhibition was observed with S-adenosylmethionine. To elucidate the reaction mechanism further, inhibition by the two products, S-adenosylhomocysteine and 1-methylhistamine, was studied. S-Adenosylhomocysteine inhibited non-competitively with respect to histamine and competitively with respect to S-adenosylmethionine. 1-Methylhistamine inhibited non-competitively with respect to histamine and to S-adenosylmethionine. These results are interpreted as providing evidence for an ordered sequential Bi Bi reaction mechanism, with the methyl-group donor S-adenosylmethionine as the first substrate that adds to the enzyme and histamine as the second substrate. 1-Methylhistamine is the first product to leave the enzyme and S-adenosylhomocysteine is the second. The results are discussed in terms of the possible role that this enzyme could play in the modulation of histamine-mediated reactions in skin.

Properties of the cerebral glycolytic enzyme, hexokinase, were studied in biopsy samples of human temporal lobe, obtained during lobectomy for drug-resistant epilepsy and compared "blind" with contol biopsy samples of human cerebral cortex. No significant changes in the total activity or subcellular distribution of the enzyme were observed but the Km value for glucose was altered. The 17 control samples gave a normal mean value for Km (glucose) of 0.05 mM and the 14 epileptic samples gave a significantly higher mean value of 0.09 mM. The drugs used in previous treatment of the epilepsies were "scored" with respect to type and dose; analysis of these in relation to the kinetic results eliminated the possibility that the increase in Km value was an artifact due to the drugs. The observed change in enzyme kinetic properties is discussed in terms of potential interactions of small molecules with the isoenzymes of cerebral hexokinase.

The kinetics of biotransformation of methoxyflurane by rat hepatic microsomes in vitro was studied. The rate of biotransformation as measured by analysis of metabolites continued to increase even at near-saturation concentrations of the anesthetic. Methoxyflurane biotransformation followed either an unbounded curve with empirical formula y = a ln(bx + 1) or an asymptotic curve with formula (see article) No substrate inhibition was observed. Total fluoride Vmax of 135.1 mmumol F-/mg protein/30' was increased to 931.9 by phenobarbital induction; free fluoride Vmax from 39.2 to 403.2. Thus, enzyme induction shifted biotransformation to the production of greater amounts of inorganic free fluoride metabolites than organic fluoride-containing metabolites. Phenobarbital induction caused qualitative as well as quantitative alteration in the biotransformation of methoxyflurane.

Symptomatic arm vein thrombosis secondary to permanent transvenous cardiac pacing electrodes is an uncommon occurrence with an incidence of 1 to 3 percent. Two patients with this problem are presented who were treated with streptokinase followed by conventional anticoagulation therapy with heparin and warfarin. Near total resolution of the thromboses was accomplished in both patients. In follow-up periods of nine and 20 months, the patients have remained asymptomatic. An aggressive approach to this problem may decrease the current high morbidity.

1. Clear kinetic differences between cytoplasmic and mitochondrial forms of type-I cerebral hexokinase were demonstrated from experiments performed under identical conditions on three (cytoplasmic, bound mitochondrial and solubilized mitochondrial) preparations of the enzyme. 2. Whereas the Michaelis constant for glucose (KmGlc) was consistent, that for MgATP2- (KmATP) was lower in the cytoplasmic than in the two mitochondrial preparations. The substrate dissociation constants (KsGlc and KsATP) were both higher in the cytoplasmic than in the mitochondrial preparations. A further difference in the substrate kinetic patterns was that KmATP=KmATP for the cytoplasmic enzyme, in contrast with the mitochondrial enzyme, where KmATP was clearly not equal to KsATP [Bachelard et al. (1971) Biochem. J. 123, 707-715]. 3. Dead-end inhibition produced by N-acetyl-glucosamine and by AMP also exhibited different quantitative kinetic patterns for the two enzyme sources. Both inhibitions gave Ki values similar or equal to those of Ki' for the cytoplasmic activity, whereas Ki was clearly not equal to Ki' for the mitochondrial activity. 4. All of these studies demonstrated the similarity of the two mitochondrial activities (particulate and solubilized), which were both clearly different from the cytoplasmic activity. 5. The analysis gives a practical example of our previous theoretical treatment on the derivation of true inhibition constants. 6. The results are discussed in terms of the function of cerebral hexokinases.