Search

The recent discovery of Hepatitis D (HDV)-like viruses across a wide range of taxa led to the establishment of the Kolmioviridae family. Recent studies suggest that kolmiovirids can be satellites of viruses other than Hepatitis B virus (HBV), challenging the strict HBV/HDV-association dogma. Studying whether kolmiovirids are able to replicate in any animal cell they enter is essential to assess their zoonotic potential. Here, we compared replication of three kolmiovirids: HDV, rodent (RDeV) and snake (SDeV) deltavirus in vitro and in vivo. We show that SDeV has the narrowest and RDeV the broadest host cell range. High resolution imaging of cells persistently replicating these viruses revealed nuclear viral hubs with a peculiar RNA-protein organization. Finally, in vivo hydrodynamic delivery of viral replicons showed that both HDV and RDeV, but not SDeV, efficiently replicate in mouse liver, forming massive nuclear viral hubs. Our comparative analysis lays the foundation for the discovery of specific host factors controlling Kolmioviridae host-shifting., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Khalfi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Myxovirus resistance protein 1 (MX1) and MX2 are homologous, dynamin-like large GTPases, induced upon interferon exposure. Human MX1 (HsMX1) is known to inhibit many viruses, including influenza A virus, by likely acting at various steps of their life cycles. Despite decades of studies, the mechanism(s) of action with which MX1 proteins manage to inhibit target viruses is not fully understood. MX1 proteins are mechano-enzymes and share a similar organization to dynamin, with a GTPase domain and a carboxy-terminal stalk domain, connected by a bundle signaling element. These three elements are known to be essential for antiviral activity. HsMX1 has two unstructured regions, the L4 loop, also essential for antiviral activity, and a short amino (N)-terminal region, which greatly varies between MX1 proteins of different species. The role of this N-terminal domain in antiviral activity is not known. Herein, using mutagenesis, imaging, and biochemical approaches, we demonstrate that the N-terminal domain of HsMX1 is essential for antiviral activity against influenza A virus, Vesicular Stomatitis Virus, and La Crosse virus. Furthermore, we pinpoint a highly conserved leucine within this region, which is absolutely crucial for human, mouse, and bat MX1 protein antiviral activity. Importantly, mutation of this leucine does not compromise GTPase activity or oligomerization capabilities but does modify MX1 protein subcellular localization. The discovery of this essential and highly conserved residue defines this region as key for antiviral activity and may reveal insights as to the mechanism(s) of action of MX1 proteins., Competing Interests: Conflict of interests The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Genome-wide screens are powerful approaches to unravel regulators of viral infections. Here, a CRISPR screen identifies the RNA helicase DDX42 as an intrinsic antiviral inhibitor of HIV-1. Depletion of endogenous DDX42 increases HIV-1 DNA accumulation and infection in cell lines and primary cells. DDX42 overexpression inhibits HIV-1 infection, whereas expression of a dominant-negative mutant increases infection. Importantly, DDX42 also restricts LINE-1 retrotransposition and infection with other retroviruses and positive-strand RNA viruses, including CHIKV and SARS-CoV-2. However, DDX42 does not impact the replication of several negative-strand RNA viruses, arguing against an unspecific effect on target cells, which is confirmed by RNA-seq analysis. Proximity ligation assays show DDX42 in the vicinity of viral elements, and cross-linking RNA immunoprecipitation confirms a specific interaction of DDX42 with RNAs from sensitive viruses. Moreover, recombinant DDX42 inhibits HIV-1 reverse transcription in vitro. Together, our data strongly suggest a direct mode of action of DDX42 on viral ribonucleoprotein complexes. Our results identify DDX42 as an intrinsic viral inhibitor, opening new perspectives to target the life cycle of numerous RNA viruses., (© 2022 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)

CRISPR knockout (KO) screens have identified host factors regulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication. Here, we conducted a meta-analysis of these screens, which showed a high level of cell-type specificity of the identified hits, highlighting the necessity of additional models to uncover the full landscape of host factors. Thus, we performed genome-wide KO and activation screens in Calu-3 lung cells and KO screens in Caco-2 colorectal cells, followed by secondary screens in four human cell lines. This revealed host-dependency factors, including AP1G1 adaptin and ATP8B1 flippase, as well as inhibitors, including mucins. Interestingly, some of the identified genes also modulate Middle East respiratory syndrome coronavirus (MERS-CoV) and seasonal human coronavirus (HCoV) (HCoV-NL63 and HCoV-229E) replication. Moreover, most genes had an impact on viral entry, with AP1G1 likely regulating TMPRSS2 activity at the plasma membrane. These results demonstrate the value of multiple cell models and perturbational modalities for understanding SARS-CoV-2 replication and provide a list of potential targets for therapeutic interventions., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Staphylococcus aureus causes a broad spectrum of diseases in humans and animals. It is frequently associated with inflammatory skin disorders such as atopic dermatitis, where it aggravates symptoms. Treatment of S. aureus-associated skin infections with antibiotics is discouraged due to their broad-range deleterious effect on healthy skin microbiota and their ability to promote the development of resistance. Thus, novel S. aureus-specific antibacterial agents are desirable. We constructed two chimeric cell wall-lytic enzymes, Staphefekt SA.100 and XZ.700, which are composed of functional domains from the bacteriophage endolysin Ply2638 and the bacteriocin lysostaphin. Both enzymes specifically killed S. aureus and were inactive against commensal skin bacteria such as Staphylococcus epidermidis, with XZ.700 proving more active than SA.100 in multiple in vitro activity assays. When surface-attached mixed staphylococcal cultures were exposed to XZ.700 in a simplified microbiome model, the enzyme selectively removed S. aureus and retained S. epidermidis. Furthermore, XZ.700 did not induce resistance in S. aureus during repeated rounds of exposure to sublethal concentrations. Finally, we demonstrated that XZ.700 formulated as a cream is effective at killing S. aureus on reconstituted human epidermis and that an XZ.700-containing gel significantly reduces bacterial numbers compared to an untreated control in a mouse model of S. aureus-induced skin infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of coronavirus disease 19 (COVID-19), which ranges from mild respiratory symptoms to acute respiratory distress syndrome, and death in the most severe cases. Immune dysregulation with altered innate cytokine responses is thought to contribute to disease severity. Here, we characterized in depth host cell responses against SARS-CoV-2 in primary human airway epithelia (HAE) and immortalized cell lines. Our results demonstrate that primary HAE and model cells elicit a robust induction of type I and III interferons (IFNs). Importantly, we show for the first time that melanoma differentiation associated gene (MDA)-5 is the main sensor of SARS-CoV-2 in lung cells. IFN exposure strongly inhibited viral replication and de novo production of infectious virions. However, despite high levels of IFNs produced in response to SARS-CoV-2 infection, the IFN response was unable to control viral replication in lung cells, contrary to what was previously reported in intestinal epithelial cells. Altogether, these results highlight the complex and ambiguous interplay between viral replication and the timing of IFN responses. IMPORTANCE Mammalian cells express sensors able to detect specific features of pathogens and induce the interferon response, which is one of the first line of defenses against viruses and help controlling viral replication. The mechanisms and impact of SARS-CoV-2 sensing in lung epithelial cells remained to be deciphered. In this study, we report that despite a high production of type I and III interferons specifically induced by MDA-5-mediated sensing of SARS-CoV-2, primary and immortalized lung epithelial cells are unable to control viral replication. However, exogenous interferons potently inhibited replication, if provided early upon viral exposure. A better understanding of the ambiguous interplay between the interferon response and SARS-CoV-2 replication is essential to guide future therapeutical interventions., (Copyright © 2021 American Society for Microbiology.)

The threat of a new influenza pandemic is real. With past pandemics claiming millions of lives, finding new ways to combat this virus is essential. Host cells have developed a multi-modular system to detect incoming pathogens, a phenomenon called sensing. The signaling cascade triggered by sensing subsequently induces protection for themselves and their surrounding neighbors, termed interferon (IFN) response. This response induces the upregulation of hundreds of interferon-stimulated genes (ISGs), including antiviral effectors, establishing an antiviral state. As well as the antiviral proteins induced through the IFN system, cells also possess a so-called intrinsic immunity, constituted of antiviral proteins that are constitutively expressed, creating a first barrier preceding the induction of the interferon system. All these combined antiviral effectors inhibit the virus at various stages of the viral lifecycle, using a wide array of mechanisms. Here, we provide a review of mammalian and avian influenza A restriction factors, detailing their mechanism of action and in vivo relevance, when known. Understanding their mode of action might help pave the way for the development of new influenza treatments, which are absolutely required if we want to be prepared to face a new pandemic.

Influenza virus infections are major public health threats due to their high rates of morbidity and mortality. Upon influenza virus entry, host cells experience modifications of endomembranes, including those used for virus trafficking and replication. Here we report that influenza virus infection modifies mitochondrial morphodynamics by promoting mitochondria elongation and altering endoplasmic reticulum-mitochondria tethering in host cells. Expression of the viral RNA recapitulates these modifications inside cells. Virus induced mitochondria hyper-elongation was promoted by fission associated protein DRP1 relocalization to the cytosol, enhancing a pro-fusion status. We show that altering mitochondrial hyper-fusion with Mito-C, a novel pro-fission compound, not only restores mitochondrial morphodynamics and endoplasmic reticulum-mitochondria contact sites but also dramatically reduces influenza replication. Finally, we demonstrate that the observed Mito-C antiviral property is directly connected with the innate immunity signaling RIG-I complex at mitochondria. Our data highlight the importance of a functional interchange between mitochondrial morphodynamics and innate immunity machineries in the context of influenza viral infection., Competing Interests: The authors have declared that no competing interests exist.

Chikungunya virus (CHIKV) is a rapidly emerging mosquito-borne RNA virus that causes epidemics of debilitating disease in tropical and sub-tropical regions with autochtonous transmission in regions with temperate climate. Currently, there is no licensed vaccine or specific antiviral drug available against CHIKV infection. In this study, we examine the role, in the CHIKV viral cycle, of fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD1), two key lipogenic enzymes required for fatty acid production and early desaturation. We show that both enzymes and their upstream regulator PI3K are required for optimal CHIKV infection. We demonstrate that pharmacologic manipulation of FASN or SCD1 enzymatic activity by non-toxic concentrations of cerulenin or CAY10566 decreases CHIKV genome replication. Interestingly, a similar inhibitory effect was also obtained with Orlistat, an FDA-approved anti-obesity drug that targets FASN activity. These drugs were also effective against Mayaro virus (MAYV), an under-studied arthritogenic Old world Alphavirus endemic in South American countries with potential risk of emergence, urbanization and dispersion to other regions. Altogether, our results identify FASN and SCD1 as conserved druggable cofactors of Alphavirus genome replication and support the broad-spectrum activity of drugs targeting the host fatty acids metabolism., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: This paper assesses the effects of training in and implementation of Cognitive-Behavioral Therapy for Chronic Pain (CBT-CP) in the US Department of Veterans Affairs (VA) health care system on therapists' CBT-CP competencies and patients' pain-related outcomes., Methods: A total of 71 therapists participated in the VA CBT-CP Training Program. Patients included 148 Veterans treated by therapist training participants. Therapists completed a 3-day workshop followed by 6 months of weekly consultation. Therapy session tapes were rated by expert training consultants using a standardized competency rating form. Patient outcomes were assessed with measures of patient-reported pain intensity, pain-related cognitions, overall distress, depression, pain interference, and quality of life. The therapeutic alliance was also assessed., Results: Among the 71 therapists who participated in the training program, 60 (85%) completed all training requirements, including competency-based performance criteria. Of the 148 Veteran patients treated, 117 (79%) completed all CBT-CP protocol sessions. Intent-to-treat analyses indicated significant improvements in pain catastrophizing, interference, quality of life, and other domains, as well as on the therapeutic alliance., Discussion: Training in and implementation of CBT-CP in the VA health care system were associated with significant increases in therapist competencies to deliver CBT-CP and improvements in several domains for Veteran patients. Results support the feasibility and effectiveness of broad dissemination of CBT-CP in routine, nonpain specialty settings.

Objectives: This study evaluated the guided use of the Community Re-engagement Cue to Action Trigger Tool (CRCATT), a patient-mediated question prompt list, and its impact on self-reported re-engagement in activities post-stroke., Methods: A multi-site, single-blind randomized controlled study in which 77 persons with stroke participated from three rehab organizations in Toronto, Canada. Of the 77 participants, a total 57 within the two groups completed the study and Reintegration to Normal Living Index (mailed response questionnaire) and a sub-set of all participants participated in qualitative interviews. Data collection occurred 3-4 months after enrollment. Quantitative responses were analyzed in SPSS (Chicago, IL, USA) for descriptive frequencies and differences between groups. Qualitative responses were analyzed using an inductive approach with thematic analytic procedures., Results: No between group differences were observed due to small sample size. A multi-variable regression model including age, gender, level of education, treatment group, and language, suggests those with higher education are more likely to participate in activities. Interview analysis revealed participants' ability to recover and re-engage is influenced by an interplay of the CRCATT with external factors. These factors include social support, interactions with providers, and ability to access information., Conclusion: The CRCATT was perceived as a useful tool as it assisted persons with stroke to take a more self-directed role in their care by asking relevant questions and anticipating their needs. The tool complemented the external factors that persons with stroke draw on to support recovery and participate in activities post-stroke.

There is debate about whether dually diagnosed patients benefit from mutual-help groups (MHGs), partly because social anxiety may make participation problematic. We examined dually diagnosed patients' participation in MHGs and outcomes at 6, 12, and 24 months post-treatment, and the extent to which social anxiety was associated with participation. We also examined whether MHG participation and social anxiety were related to outcomes, and whether social anxiety moderated associations between participation and outcomes. We found high rates of MHG participation. Among patients who attended at least one meeting, outcomes were positive. Social anxiety was not associated with levels of MHG participation, but more participation was associated with better outcomes. When social anxiety moderated associations between MHG participation and outcomes, patients with more social anxiety benefited more from participation. Treated dually diagnosed patients participate in, and benefit from, MHGs, and participation and benefits are comparable, or even strengthened, among more socially-anxious patients., (Published by Elsevier Inc.)

Within the last 30 years, a substantial number of interventions for alcohol use disorders (AUDs) have received empirical support. Nevertheless, fewer than 25% of individuals with alcohol-related problems access these interventions. If several intensive psychosocial treatments are relatively effective, but most individuals in need do not access them, it seems logical to place a priority on developing more engaging interventions. Accordingly, after briefly describing findings about barriers to help-seeking, we focus on identifying an array of innovative and effective low-intensity intervention strategies, including telephone, computer-based, and Internet-based interventions, that surmount these barriers and are suitable for use within a stepped-care model. We conclude that these interventions attract individuals who would otherwise not seek help, that they can benefit individuals who misuse alcohol and those with more severe AUDs, and that they can facilitate subsequent help-seeking when needed. We note that these types of low-intensity interventions are flexible and can be tailored to address many of the perceived barriers that hinder individuals with alcohol misuse or AUDs from obtaining timely help. We also describe key areas of further research, such as identifying the mechanisms that underlie stepped-care interventions and finding out how to structure these interventions to best initiate a program of stepped care.

Hazardous drinking is a major barrier to antiviral treatment eligibility among hepatitis C (HCV) patients. We evaluated differences in substance-related coping, drinking-related consequences, and importance and confidence in ability to change alcohol use among hazardous drinkers with and without HCV (N = 554; 93.5% male). We examined group differences between HCV+ patients (n = 43) and their negative HCV counterparts (n = 511). Results indicate a higher percentage of HCV+ patients report using substances to cope with possible symptoms of PTSD (P < .05) and depression (P < .01), and endorse more lifetime drinking-related negative consequences than HCV patients (P < .01). Furthermore, HCV+ patients place greater importance on changing alcohol use (P < .01) but report less confidence in their ability to change (P < .01). Use of brief assessment and feedback with skills-based interventions to decrease alcohol use may be well-received by HCV+ patients.

Background: Many patients treated for substance use disorder (SUD) do not achieve lasting recovery from a single episode of treatment and require continuing care. The current randomized clinical trial investigated whether in-person continuing care as usual (CCAU) following intensive outpatient SUD treatment leads to better SUD outcomes when compared with telephone case monitoring (TCM)., Method: This study randomized 667 intensive SUD outpatients to telephone case monitoring versus face-to-face continuing care as usual at two sites. Patients completed data at baseline, 3 and 12months with telephone interviews. Data of interest include self-report of substance use, psychiatric symptoms, quality of life, and treatment satisfaction. We also evaluated potential interaction effects for distance to VA provider, SUD severity, and presence of co-morbid psychiatric disorder., Results: Participants randomized to the telephone case monitoring condition substantially engaged with face-to-face continuing care resulting in cross-over contamination. We addressed this issue by using randomization as an instrumental variable to evaluate the impact of telephone case monitoring (contamination adjusted, intent to treat analysis). Instrumental variable analyses indicated significant benefit of telephone case monitoring for drug and alcohol percent days abstinent and psychiatric symptom outcomes at 3-months follow-up, but not at 12-month follow-up. No interaction analyses were significant., Discussion: Participants receiving telephone case monitoring achieved better short term outcomes in terms of substance use and psychiatric symptoms. The "on treatment" effects suggests the need for future studies to investigate consumer (patient) perspectives on the optimal duration of telephone case monitoring and use of alternative monitoring methods such as text messaging., (Published by Elsevier Ltd.)

Purpose: This study evaluated the impact of an educational intervention that integrates concepts of a community re-engagement framework (CR) and interprofessional collaboration (IPC) on health care providers' (HCP) practice with persons living with stroke (PLS)., Method: A mixed-methods design was used in which HCPs (n = 67) and PLS (n = 29) participated from 9 organizations across the care continuum. Pre- and postintervention surveys and interviews were conducted with the HCPs. One-on-one interviews with stroke clients were also conducted pre and post intervention. Quantitative responses were analyzed in SPSS (Chicago, Illinois, USA) for descriptive frequencies and differences between pre- and postintervention groups. Qualitative open-ended responses were thematically coded using NVivo7., Results: Significant increases occurred in HCPs' knowledge of CR, confidence levels in working with PLS, enhanced understanding of the complex needs of PLS, and positive self-reported impacts on practice. PLS reported positive perceptions of care pre and post intervention., Conclusions: The intervention provided HCPs with a common language and framework to work collaboratively and holistically in delivering care consistent with stroke best practices.

We examined change in family support and depressive symptoms over the course of 23 years and included the potential moderators of gender and participation in treatment. A sample of 373 depressed individuals provided data in five waves, with baseline, 1-year, 4-year, 10-year, and 23-year follow-ups. Multilevel modeling was used to evaluate longitudinal relationships between variables. Higher family support was associated with less depression at baseline and predicted a steeper trajectory of recovery from depression over 23 years. This relationship was moderated by gender, such that women with supportive families reported the most rapid recovery from depression. Evaluating family context may be clinically relevant when beginning treatment with a depressed patient, particularly for female patients., (© 2011 Wiley Periodicals, Inc.)

The present study examined the role of ambivalence about change as (1) a predictor of subsequent heavy alcohol use and drinking problems and (2) a mediator of change between entering treatment and heavy alcohol use and drinking problems among individuals self-referring for treatment with an alcohol use disorder. A sample of 439 individuals (49.9% female) who initiated help-seeking was surveyed at baseline, and at 1 year and 3 year follow-ups on domains of alcohol-related and personal functioning. A series of regression analyses indicated that a measure reflecting ambivalence significantly predicted subsequent heavy alcohol use and related problems and mediated changes between entering treatment and heavy alcohol use and related problems. The findings highlight one mechanism associated with treatment seeking, initiation of and engagement in treatment, and reduction in heavy alcohol use and related problems., (2009 Elsevier Ltd. All rights reserved.)

Approximately 12,000 children in the United States are diagnosed with cancer each year, and roughly 75% of these patients become long-term survivors. The Passport for Care was developed to support these survivors and their health care providers.

Objective: This observational study examined the association between continuing outpatient care for a psychiatric disorder, a substance use disorder, or both and decreased risk of readmission to psychiatric care after an index episode of inpatient psychiatric treatment., Methods: Treatment records from all patients with co-occurring substance use and psychiatric disorders discharged from an inpatient psychiatric setting in the Department of Veterans Affairs (VA) between July 1, 2004, and June 30, 2005 (N=26,826), were used to determine the impact of psychiatric and substance use disorder continuing care on readmission to inpatient psychiatric treatment in the 90 days after discharge., Results: Over 23% (6,280 of 26,826) of patients with both a psychiatric disorder and a substance use disorder who received inpatient psychiatric treatment in the VA were readmitted for additional psychiatric care within 90 days of discharge. Survival analyses indicated that receiving continuing care for a substance use disorder (hazard ratio [HR]=.84, 95% confidence interval [CI]=.77-.92, p<.001) in the 30 days after discharge from the index episode was associated with a lower likelihood of rehospitalization. Psychiatric continuing care was not associated with risk of rehospitalization. A supplementary analysis indicated that substance use disorder continuing care was still associated with a reduced risk of rehospitalization over the 12 months after discharge, although the overall magnitude of the association was diminished (HR=.92, 95% CI=.86-.99, p=.02)., Conclusions: Readmission to inpatient psychiatric treatment was common for patients with co-occurring disorders, and these observational findings indicate that continuing care for a substance use disorder was associated with lower risk of early readmission.

Self-efficacy is a robust predictor of short- and long-term remission after treatment. This study examined the predictors of self-efficacy in the year after treatment and 15 years later. A sample of 420 individuals with alcohol use disorders was assessed five times over the course of 16 years. Predictors of self-efficacy at 1 year included improvement from baseline to 1 year in heavy drinking, alcohol-related problems, depression, impulsivity, avoidance coping, social support from friends, and longer duration of participation in Alcoholics Anonymous (AA). Female gender, more education, less change in substance use problems, and impulsivity during the first year predicted improvement in self-efficacy over 16 years. Clinicians should focus on keeping patients engaged in AA, addressing depressive symptoms, improving patient's coping, and enhancing social support during the first year and reduce the risk of relapse by monitoring individuals whose alcohol problems and impulsivity improve unusually quickly.

This study identified which aspects of substance abuse treatment in community residential facilities (CRFs) were correlated with patients' post-treatment coping. A total of 2376 patients supplied demographic information and completed measures at baseline (coping and abstinence self-efficacy) and one year after treatment (coping, level of drug and alcohol use, and substance-related problems). Staff provided information about treatment orientation and patients' participation in treatment (e.g., life skills training, vocational counseling). The data were used to predict coping 1 year after treatment. As expected, higher levels of general approach coping and alcohol-specific coping and lower levels of general avoidance coping were associated with less 1-year alcohol and drug use and fewer drinking problems. Patients' greater level of participation in life skills counseling predicted more approach coping at 1 year. In addition, positive social relationships and participation in 12-step self-help groups predicted less general avoidance coping and more alcohol-specific coping at 1 year post-treatment. Life skills training, 12-step self-help groups, and enhancement of supportive relationships during CRF treatment for substance abuse are related to healthy coping. Future research should examine the effect of these components in less intensive programs and with women.

In the wake of Hurricane Katrina's landfall on August 29, 2005, and the subsequent levee failures, operations of Tulane University School of Medicine became unsustainable. As New Orleans collapsed, faculty, students, residents, and staff were scattered nationwide. In response, four Texas medical schools created an alliance to assist Tulane in temporarily relocating operations to south Texas. Resuming operations in a three- to four-week time span required developing and implementing a coordinated communication plan in the face of widespread communication infrastructure disruptions. A keystone of the strategy involved rapidly creating a "recovery Web site" to provide essential information on immediate recovery plans, mechanisms for reestablishing communications with displaced persons, housing relocation options (over 200 students, faculty, and staff were relocated using Web site resources), classes and residency training, and other issues (e.g., financial services, counseling support) vitally important to affected individuals. The database-driven Web site was launched in four days on September 11, 2005, by modifying an existing system and completing new programming. Additional functions were added during the next week, and the site operated continuously until March 2006, providing about 890,000 pages of information in over 100,000 visitor sessions. The site proved essential in disseminating announcements, reestablishing communications among the Tulane family, and supporting relocation and recovery. This experience shows the importance of information technology in collaborative efforts of academic health centers in early disaster response and recovery, reinforcing recommendations published recently by the Association of Academic Health Centers and the National Academy of Sciences.

Objective: To understand better the relationship between substance-use disorder treatment and abstinence self-efficacy, more information is needed about what factors predict greater abstinence self-efficacy., Method: Participants (n = 2,350) from 88 community residential facilities were assessed at treatment entry and 1-year follow-up. Treatment providers reported on patients' engagement in specific components of treatment. After examining univariate associations with self-efficacy, a multiple regression analysis was used to test a model of patient- and treatment-related predictors of self-efficacy 1 year after treatment., Results: More years of education, lower baseline substance- related problems, and higher baseline confidence in abstinence were associated with higher posttreatment self-efficacy. After controlling for these patient factors, patients who were more engaged in skills-training activities and who inspired providers' confidence in their ability to remain abstinent had higher 1-year self-efficacy., Conclusions: The development of higher levels of posttreatment abstinence self-efficacy is driven not only by what a patient brings to treatment but by the activities a patient engages in during treatment. Because of the close relationship between self-efficacy and treatment outcomes, providers may want to target patients with low self- efficacy for interventions that focus on skills-training techniques.

Although motivational readiness to change predicts alcohol use disorder (AUD) treatment outcomes, little is known about treatment aspects that are helpful for patients with low motivation. We examined whether a positive therapeutic alliance is particularly beneficial for patients entering AUD treatment with low motivation. Among Project MATCH outpatients (n = 753), we tested the influence of motivation, therapeutic alliance, and their interaction on 6-month and 1-year alcohol use. The impact of motivation on alcohol use varied depending on therapists' perceptions of alliance. Interactions involving treatment compliance did not mediate the Motivation x Alliance interaction. Thus, a positive therapeutic relationship may be particularly important for patients with low motivation, but mechanisms underlying this possible patient-treatment "match" remain to be determined.

Objective: The aim of this study was to use pretreatment and treatment factors to predict dropout from residential substance use disorder program and to examine how the treatment environment modifies the risk for dropout., Method: This study assessed 3649 male patients at entry to residential substance use disorder treatment and obtained information about their perceptions of the treatment environment., Results: Baseline factors that predicted dropout included younger age, greater cognitive dysfunction, more drug use, and lower severity of alcohol dependence. Patients in treatment environments appraised as low in support or high in control also were more likely to drop out. Further, patients at high risk of dropout were especially likely to dropout when treated in a highly controlling treatment environment., Conclusion: Better screening of risk factors for dropout and efforts to create a less controlling treatment environment may result in increased retention in substance use disorder treatment.

To better understand the relationship between abstinence self-efficacy and treatment outcomes in substance use disorder patients, experts in the field need more information about the levels of abstinence self-efficacy most predictive of treatment outcomes. Participants (N = 2,967) from 15 residential substance use disorder treatment programs were assessed at treatment entry, discharge, and 1-year follow-up. A signal detection analysis compared the ability of different measures of self-efficacy to predict 1-year abstinence and identified the optimal cutoffs for significant predictors. The maximal level of abstinence self-efficacy (i.e., 100% confident) measured at discharge was the strongest predictor of 1-year abstinence. Treatment providers should focus on obtaining high levels of abstinence self-efficacy during treatment with the goal of achieving 100% confidence in abstinence.

Background: Comparing the dose-response of a new drug to that of a previously studied drug can aid in understanding their relative potencies. Two dose-finding studies addressed the effect of a new drug, rosuvastatin, on its ability to decrease low-density lipoprotein cholesterol (LDL-C) levels. One of these studies included 2 doses of atorvastatin, and substantial additional information is available in the literature about the effect of atorvastatin on LDL-C level lowering., Methods: The 2 dose-finding studies of rosuvastatin considered otherwise healthy patients who had hypercholesterolemia. Comparable studies of atorvastatin were identified via a MEDLINE search in December 1999. Multiple reviewer consensus identified 15 of 41 studies on atorvastatin published since 1996 that met these selection criteria: reporting of LDL-C level change from baseline at least 6 weeks after treatment initiation, doses administered, and treatment group sizes. Eligible populations had clinical evidence of hypercholesterolemia. We excluded studies with patients who had severe illness or a previous history of transplantation. Data extraction of the mean, sample sizes, and SDs (or CIs) by dose was carried out independently by multiple reviewers. We combined the results from the various studies with Bayesian hierarchical modeling and analyzed them with Markov chain Monte Carlo techniques., Results: Combining this study and literature results substantially increased the power to compare the dose-response relationships of rosuvastatin and atorvastatin. Rosuvastatin reduced LDL-C level by an estimated 10 to 17 percentage points more than atorvastatin when both were given at the same dose. Approximately one quarter of the dose of rosuvastatin achieved about the same magnitude of LDL-C level reduction as atorvastatin at dosages as high as 80 mg. This finding does not imply a 4-fold difference in efficacy overall and specifically does not describe the results at higher dosage levels., Conclusions: Bayesian meta-analysis of results from related studies allows the comparison of the dose-response relationships of 2 drugs, better estimates of a particular dose-response relationship within an individual study, and the expression of relative benefits (of dose and drug) in terms of probabilities. Explicitly comparing a study's results with historical data using Bayesian meta-analysis allows clinicians to view the study in the larger context of medical research.

A positive corelation between Alcoholics Anonymous (AA) involvement and better alcohol-related outcomes has been identified in research studies, but whether this correlation reflects a causal relationship remains a subject of meaningful debate. The present study evaluated the question of whether AA affiliation appears causally related to positive alcohol-related outcomes in a sample of 2,319 male alcohol-dependent patients. An initial structural equation model indicated that 1-year posttreatment levels of AA affiliation predicted lower alcohol-related problems at 2-year follow-up, whereas level of alcohol-related problems at 1-year did not predict AA affiliation at 2-year follow-up. Additional models found that these effects were not attributable to motivation or psychopathology. The findings are consistent with the hypothesis that AA participation has a positive effect on alcohol-related outcomes.

Rosuvastatin is a new, synthetic, orally active statin, with marked low-density lipoprotein (LDL) cholesterol-lowering activity. We conducted 2 dose-ranging studies. In the first study, after a 6-week dietary run-in, 142 moderately hypercholesterolemic patients were randomized equally to receive double-blind placebo or rosuvastatin 1, 2.5, 5, 10, 20, or 40 mg or open-label atorvastatin 10 or 80 mg once daily for 6 weeks; in the second study, conducted to extend the rosuvastatin dose range, 64 patients were randomized to double-blind, once-daily placebo or rosuvastatin 40 or 80 mg (1:1:2 ratio) for 6 weeks. Data from both studies were combined for analysis of lipid effects. No statistical comparison of atorvastatin arms with placebo or rosuvastatin was performed. Rosuvastatin was associated with highly significant dose-dependent reductions in LDL cholesterol compared with placebo (p <0.001); decreases ranged from 34% (1 mg) to 65% (80 mg). Linear regression analysis indicated an additional 4.5% LDL cholesterol reduction for each doubling of the rosuvastatin dose. Across the dose range, approximately 90% of LDL cholesterol reduction occurred within the first 2 weeks of treatment. Significant, dose-dependent reductions in total cholesterol and apolipoprotein B with rosuvastatin were also observed (p <0.001). High-density lipoprotein cholesterol increases and triglyceride reductions were consistently observed and statistically significant at some dose levels. All lipid ratios were significantly reduced at all rosuvastatin dose levels (p <0.001). Adverse events were similar across placebo and active treatments. No significant increases in alanine aminotransferase or creatine kinase were seen in any patient. Over 6 weeks, rosuvastatin produced large, rapid, dose-dependent LDL cholesterol reductions and was well tolerated in hypercholesterolemic patients.

The primary objective of the MYSTIC study is to monitor the performance of meropenem over a period of at least 3 years during which this carbapenem is prescribed in different hospital units thus allowing profiles to be established within individual hospitals. Monitoring is being carried out by assessing the antibiotic susceptibility of bacterial pathogens isolated from patients with a predominate problem of intraabdominal infections (IAI) and/or lower respiratory tract infections (LRTI), treated in specialist centres (haematology wards, the Intensive Care Unit [ICU], cystic fibrosis units) and non-specialised centres. Samples will be collected over each year and tested against meropenem and a set of comparators. The data obtained from the first year of the study (1997) come from 33 centres spread mainly throughout Europe but also in Israel and Mexico. The results shows that meropenem retains its broad spectrum and potency whilst there is evidence that the activity of comparator antibiotics is being eroded by a variety of resistance mechanisms. Data from subsequent years of the programme will determine whether these trends continue and will allow a series of individual centre profiles to be compiled and presented.

Satisfaction with, and subjective tolerability of, antipsychotic medication have emerged as important factors in determining treatment compliance and eventual outcome in the management of psychotic disorders. The acceptability of long-term treatment with quetiapine, an atypical antipsychotic agent with a lower incidence of extrapyramidal effects than standard therapy, was examined in this open-label, multicentre study of patient satisfaction. One hundred and twenty-nine patients with major psychiatric disorders, who had each been receiving quetiapine for at least 6 months in open-label extension studies, were asked to complete a 7-item questionnaire concerning subjective experience and satisfaction with treatment. Over 75% of respondents indicated that they were either "very" or "extremely" satisfied with their antipsychotic medication while 73.7% indicated that, over the last month, they regarded their antipsychotic medication to have been "very" or "extremely" helpful. Subjectively reported side-effects were uncommon, with 74.4% of patients reporting no side-effects, 23.3% mild side-effects and only 2.3% moderate side-effects. There were no unambiguous reports of extrapyramidal symptoms. An overwhelming majority of patients (114/118; 96.6%) reported that they preferred quetiapine to previous antipsychotic medications, the predominant reasons being their perceptions of better tolerability and greater efficacy. Patients also identified improvements in quality of life and their activities of daily living. These positive evaluations appeared to be reflected in the high proportion of respondents who indicated a readiness to continue quetiapine treatment. This study indicates that the combination of efficacy and a favourable tolerability profile shown by quetiapine may result in benefits that are evident to the patient and may be reflected in high levels of patient satisfaction and acceptance of treatment. By improving compliance with treatment, these benefits may also enhance clinical outcome.

Assessing the effect of novel pharmaceutical treatments on the quality of life (QoL) of a patient, or group of patients, has been approached in numerous ways over the last 20 years. Techniques as diverse as single questions to multidimensional scales requiring trained assessors to devote several hours to each assessment; from generic questions about how life might have changed to specific issues such as the ability to use a toothbrush. In the pharmaceutical industry, the emphasis is on the registration of a product with national licensing bodies. Each body has tended to see the issue from a different perspective, which has driven study designs to be different in different countries; even different over time within one country. This paper emphasises the basic statistical steps necessary to ensure that a measure of QoL is appropriately recorded, while retaining sufficient flexibility to support the registration in several countries. Aspects about possible study design are included to assist with developing some simple concepts about analysing and then interpreting the results. It is not the intention of the paper to provide the answer, merely to provide the tools to develop the answer robustly. Put briefly, with the right approach generic solutions are feasible and these solutions will have greater utility. The challenge is to recognise exactly what QoL is, and not to deviate from it.

The MS Contin tablet 200 mg (controlled release morphine sulphate) provides an equivalent rate and extent of absorption to two MS Contin tablets 100 mg. The characteristics of controlled release from this higher strength formulation are also consistent with those of the 100 mg tablet. The level of analgesia provided during the early post-dosing period, at the end of the dosing period and overall over the twelve hour interval were also equivalent between the preparations. The addition of the MS Contin tablet 200 mg to the existing range will facilitate oral dosing in patients requiring large doses of morphine. This extension to the range will increase the choice available to the clinician and provide a natural progression for those patients requiring a step-up in the dose titration procedure.

The management of a patient with an unusual combination of anaesthetic problems, namely phaeochromocytoma and difficult intubation is described. Angiotensin II is discussed in the management of hypotension after excision of the tumour.

The photochemistry of 3,5,3',4'-tetrachlorosalicylanilide has been studied in solution under carefully controlled conditions. When irradiated in a buffered solution of pH 7.4 (physiological pH), three atoms of chlorine are liberated from the molecule instead of one as suggested by earlier photochemical work. From this observation a mechanism is proposed to explain the long-term photobiological effect of this compound in skin i.e. that of the persistent light reactor.

Platelet free intracellular calcium levels were measured during a double-blind, placebo-controlled parallel study to investigate the antihypertensive activity of 50 micrograms, 125 micrograms, and 500 micrograms cyclopenthiazide, in mild essential hypertension. Cytosolic free calcium levels were significantly higher in established hypertensive patients (135 +/- 28 nmol/l, P less than 0.001) but not in borderline hypertensive patients (123 +/- 26 nmol/l) compared with normotensive controls (111 +/- 9 nmol/l). A positive correlation between platelet free calcium level and systolic and diastolic blood pressure was confirmed (n = 68; r = 0.309 P = 0.01; r = 0.405 P less than 0.001, respectively). The 125-micrograms and 500-microgram doses of cyclopenthiazide produced mean decrements in blood pressure of 18/10 mmHg and 23/8 mmHg, respectively, (P less than 0.05 for both), after 8 weeks of therapy. The 50-microgram dose displayed no useful antihypertensive activity. Platelet free calcium levels fell by a similar amount in the four groups. The fall in blood pressure produced by the 125 and 500-microgram doses of cyclopenthiazide did not correlate with changes in platelet [Ca2+]i (r = 0.166 systolic and r = 0.169 diastolic). These findings do not support the hypothesis that changes in platelet cytosolic calcium levels are determined by the same factors that control blood pressure.