A controlled trial of adaptive disclosure-enhanced to improve functioning and treat posttraumatic stress disorder.

OBJECTIVE: This is a randomized controlled trial (NCT03056157) of an enhanced adaptive disclosure (AD) psychotherapy compared to present-centered therapy (PCT; each 12 sessions) in 174 veterans with posttraumatic stress disorder (PTSD) related to traumatic loss (TL) and moral injury (MI). AD employs different strategies for different trauma types. AD-Enhanced (AD-E) uses letter writing (e.g., to the deceased), loving-kindness meditation, and bolstered homework to facilitate improved functioning to repair TL and MI-related trauma. METHOD: The primary outcomes were the Sheehan Disability Scale (SDS), evaluated at baseline, throughout treatment, and at 3- and 6-month follow-ups (Brief Inventory of Psychosocial Functioning was also administered), the Clinician-Administered PTSD Scale (CAPS-5), the Dimensions of Anger Reactions, the Revised Conflict Tactics Scale, and the Quick Drinking Screen. RESULTS: There were statistically significant between-group differences on two outcomes: The intent-to-treat (ITT) mixed-model analysis of SDS scores indicated greater improvement from baseline to posttreatment in the AD-E group (d = 2.97) compared to the PCT group, d = 1.86; -2.36, 95% CI [-3.92, -0.77], t(1,510) = -2.92, p < .001, d = 0.15. Twenty-one percent more AD-E cases made clinically significant changes on the SDS than PCT cases. From baseline to posttreatment, AD-E was also more efficacious on the CAPS-5 (d = 0.39). These differential effects did not persist at follow-up intervals. CONCLUSION: This was the first psychotherapy of veterans with TL/MI-related PTSD to show superiority relative to PCT with respect to functioning and PTSD, although the differential effect sizes were small to medium and not maintained at follow-up. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Predictors of certification in infection prevention and control among infection preventionists: APIC MegaSurvey findings.

BACKGROUND: The 2015 APIC MegaSurvey was completed by 4,078 members to assess infection prevention practices. This study's purpose was to examine MegaSurvey results to relate infection preventionist (IP) certification status with demographic characteristics, organizational structure, compensation benefits, and practice and competency factors. METHODS: Descriptive statistics were used to examine population characteristics and certification status. Bivariate logistic regression was performed to evaluate relationships between independent variables and certification status. Variables demonstrating statistical significance (P <.05) were included in multivariable logistic regression analyses. RESULTS: Forty-seven percent of survey respondents had their CIC. IPs were less likely certified if their educational attainment was less than a bachelor's degree, they were aged 18-45 years, they worked in rural facilities, they had <16 years' experience in health care before becoming an IP, and the percentage of job dedicated to infection prevention was <75%. However, certification was associated with CIC benefit paid fully by employer, self-rating as proficient and expert-advanced, and surveillance and epidemiologic investigation competency obtained via professional development and training. CONCLUSIONS: CIC attainment was associated with IP characteristics. Additional research should focus on identifying strategies to increase certification among noncertified IPs because CIC is a measure of proficiency that should be a goal for all IPs.

Success of a Colorectal Surgical Site Infection Prevention Bundle in a Multihospital System.

Surgical site infections, readmissions, and extended hospital stays are risks for patients undergoing colon surgeries. These procedures are often urgent, and patients may have multiple comorbidities. Preoperative and postoperative steps to reduce the number of complications provide substantial benefits clinically, economically, and psychologically. We used a multidisciplinary, collaborative approach to identify best practices when developing and implementing a standardized approach to the management of patients undergoing elective colon surgery. Interventions included nutrition supplements and preoperative and postoperative protocols. Our management project showed a 74.6% reduction in readmissions, a 22.73% reduction in length of stay, an 85% reduction in colon surgical site infections measured by incidence (84.5% reduction) and standard infection ratio (54.55% reduction), and 95% compliance with the use of both order sets during an 18-month period. Applying standardized order sets for assessing and addressing patient comorbidities before colorectal surgery can result in a substantial and sustainable reduction in complications.

A journey to zero: reduction of post-operative cesarean surgical site infections over a five-year period.

BACKGROUND: Surgical site infections (SSI) are a substantial concern for cesarean deliveries in which a surgical site complication is most unwelcome for a mother with a new infant. Steps taken pre- and post-operatively to reduce the number of complications may be of substantial benefit clinically, economically, and psychologically. METHODS: A risk-based approach to incision management was developed and implemented for all cesarean deliveries at our institution. A number of incremental interventions for low-risk and high-risk patients including pre-operative skin preparations, standardized pre- and post-operative protocols, post-operative nanocrystalline silver anti-microbial barrier dressings, and incisional negative pressure wound therapy (NPWT) were implemented sequentially over a 5-y period. A systematic clinical chart review of 4,942 patients spanning all cesarean deliveries between 2007-2012 was performed to determine what effects the interventions had on the rate of SSI for cesarean deliveries. RESULTS: The percentage of SSI was reduced from 2.13% (2007) to 0.10% (2012) (p<0.0001). There were no substantial changes in the patient population risk factors over this time. As a result of the changes in incision management practice, a total of 92 cesarean post-operative SSIs were avoided: A total cost saving of nearly $5,000,000. CONCLUSION: Applying a clinical algorithm for assessing the risk of surgical site complication and making recommendations on pre-operative and post-operative incision management can result in a substantial and sustainable reduction in cesarean SSI.

Characterization of resistance to the protease inhibitor GS-9451 in hepatitis C virus-infected patients.

GS-9451, a novel hepatitis C virus (HCV) nonstructural 3/4a (NS3/4a) protease inhibitor, is highly active in patients infected with HCV genotype 1 (GT 1). The aim of this study is to characterize the clinical resistance profile of GS-9451 in GT 1 HCV-infected patients in a phase 1, 3-day monotherapy study. The full-length NS3/4A gene was population sequenced at baseline, on the final treatment day, and at follow-up time points. NS3 protease domains from patient isolates with emerging mutations were cloned into an NS3 shuttle vector, and their susceptibilities to GS-9451 and other HCV inhibitors were determined using a transient replication assay. No resistance mutations at NS3 position 155, 156, or 168 were detected in any of the baseline samples or in viruses from patients treated with 60 mg of GS-9451 once daily. Among patients who received 200 mg and 400 mg of GS-9451, viruses with mutations at position D168 (D168E/G/V) and R155 (R155K), which confer high-level resistance to GS-9451, were detected in those with GT 1b and GT 1a virus, respectively. Viruses with D168 mutations were no longer detected in any GT 1b patient at day 14 and subsequent time points. In GT 1a patients, R155K mutants were replaced by the wild type in 57% of patients at week 24. These NS3 clinical mutants were sensitive to NS5B and NS5A inhibitors, as well as alpha interferon (IFN-α) and ribavirin. The lack of cross-resistance between GS-9451 and other classes of HCV inhibitors supports the utility of combination therapy.

Reduced emergence of the M184V/I resistance mutation when antiretroviral-naïve subjects use emtricitabine versus lamivudine in regimens composed of two NRTIs plus the NNRTI efavirenz.

PURPOSE: To compare the development of the M184V/I substitution among antiretroviral treatment-naïve patients taking the nucleoside reverse transcriptase inhibitors (NRTIs) emtricitabine (FTC) or lamivudine (3TC) from three phase 3 clinical trials of dual NRTIs (including either FTC or 3TC) plus the non-nucleoside reverse transcriptase inhibitor efavirenz (EFV). METHODS: Study subjects from three phase 3 clinical trials (FTC 301A, GS-99-903, and GS-01-934) were classified as virologic failures (VF) if they had confirmed ≥400 copies/mL of HIV-1 RNA at week 48 or early study drug discontinuation. Subjects with VF were genotyped by population sequencing. The prevalence of the M184V/I substitution in the FTC or 3TC groups was analyzed using Fisher exact test and in multivariate logistic regression analyses. RESULTS: Among the 3 trials, 522 subjects were treated with FTC dosed once daily and 841 subjects were treated with 3TC dosed twice daily. Among VF subjects at week 48, 5/26 (19.2%) FTC-treated subjects and 27/77 (35.5%) 3TC-treated subjects developed the M184V/I mutation (P = .145). Using the denominator of all subjects treated, 5/522 (1.0%) FTC-treated subjects versus 27/841 (3.2%) 3TC-treated subjects developed the M184V/I substitution (P = .009). Multivariate analyses adjusting for baseline viral load, baseline CD4 cell counts, and baseline NRTI resistance showed that treatment with FTC had a significantly lower rate of M184V/I development than treatment with 3TC (odds ratio 0.32; P = .02). CONCLUSIONS: The results of this pooled analysis of 3 clinical trials indicate a lower frequency of development of the M184V/I mutation in subjects treated with FTC versus 3TC when combined in regimens containing dual NRTIs and EFV.

Susceptibility of treatment-naive hepatitis C virus (HCV) clinical isolates to HCV protease inhibitors.

In order to assess the natural variation in susceptibility to hepatitis C virus (HCV) NS3 protease inhibitors (PIs) among untreated HCV patient samples, the susceptibilities of 39 baseline clinical isolates were determined using a transient-replication assay on a panel of HCV PIs, including two α-ketoamides (VX-950 and SCH-503034) and three macrocyclic inhibitors (MK-7009, ITMN-191, and TMC-435350). Some natural variation in susceptibility to all HCV PIs tested was observed among the baseline clinical isolates. The susceptibility to VX-950 correlated strongly with the susceptibility to SCH-503034. A moderate correlation was observed between the susceptibilities to ITMN-191 and MK-7009. In contrast, the phenotypic correlations between the α-ketoamides and macrocyclic inhibitors were significantly lower. This difference is partly attributable to reduced susceptibility of the HCV variants containing the NS3 polymorphism Q80K (existing in 47% of genotype 1a isolates) to the macrocyclic compounds but no change in the sensitivity of the same variants to the α-ketoamides tested. Our results suggest that the natural variation in baseline susceptibility may contribute to different degrees of antiviral response among patients in vivo, particularly at lower doses.

Mutations in the thumb-connection and RNase H domain of HIV type-1 reverse transcriptase of antiretroviral treatment-experienced patients.

BACKGROUND: Antiretroviral therapy that targets HIV type-1 (HIV-1) reverse transcriptase (RT) can be linked to mutations in the thumb-connection (amino acids [AA] 241-426) and RNase H (AA 427-560) domains, which could affect drug resistance. METHODS: Genotypical and statistical analyses were performed on HIV-1 RT from 100 antiretroviral treatment-naive and 248 antiretroviral treatment-experienced patients, the majority of whom were infected with HIV-1 subtype B. The RT region was analysed in three parts: the polymerase (AA 1-240), thumb-connection (AA 241-426) and RNase H (AA 427-560) domains. RESULTS: The polymerase domain had statistically significant changes between the two groups at 24 AA positions that are known resistance sites. Within the thumb-connection domain, R284 and N348 had statistically significant changes between the groups (P=0.007 and P< or =0.001, respectively). In treatment-experienced patients, 17.3% had R284K, whereas 24.5% had N348I substitutions. Both R284 and N348 were 100% conserved in treatment-naive patients. Within the RNase H domain, only K451 showed a statistically significant change (P

Development of a replicon-based phenotypic assay for assessing the drug susceptibilities of HCV NS3 protease genes from clinical isolates.

Hepatitis C virus (HCV) protease inhibitors targeting HCV NS3 can efficiently suppress HCV replication. However, the selection of resistance has been observed both in vitro and in vivo. Here, we describe a new method for efficient analysis of the drug susceptibility of the NS3 protease genes from patient isolates. Luciferase-reporter 1b replicon shuttle vectors that allow cloning of either the HCV full-length NS3/4A gene or the NS3 protease domain gene only were created. Initially, chimeric replicons carrying patient-derived full-length NS3/4A failed to replicate in cell culture. However, the poor replication efficiency of the NS3/4A shuttle vector was enhanced by approximately 100-fold when the NS3 helicase domains of clinical isolates were substituted for that of the 1b Con1 lab strain. Chimeric replicons carrying only the patient-derived NS3 protease domains replicated at levels sufficient for phenotypic analysis in 20/20 clinical isolates. EC(50) values for the NS3 inhibitor BILN-2061 ranged from 0.2 to 1.1nM for 20 genotype 1 patient isolates. Significantly reduced susceptibility to BILN-2061 was observed with mutant/wild type mixtures of 5%/95% for the D168V or 50%/50% for A156T resistance mutations in the NS3. These shuttle vectors can be used to evaluate candidate drugs and assist in the development of new drugs targeting the NS3 protease.

Long-term safety and efficacy results of once-daily emtricitabine-based highly active antiretroviral therapy regimens in human immunodeficiency virus-infected pediatric subjects.

OBJECTIVES: The purpose of this work was to obtain long-term safety and efficacy data for antiretroviral regimens containing emtricitabine in HIV-infected pediatric subjects and confirm that a pediatric dose of 6 mg/kg once daily would provide steady-state emtricitabine concentrations comparable to those observed in adults given 200 mg of emtricitabine once daily. PATIENTS AND METHODS: HIV-infected subjects between 3 months and 16 years of age were enrolled, including 71 antiretroviral-naïve subjects and 45 antiretroviral-experienced subjects. Naive subjects received emtricitabine plus stavudine plus lopinavir or ritonavir. Experienced subjects replaced the lamivudine in their existing regimens with emtricitabine. Tolerance, safety, disease progression, and virologic and immunologic responses were evaluated. RESULTS: The Kaplan-Meier probability of persistent virologic response in the intent-to-treat population through week 164 at < or = 400 copies per mL and < or = 50 copies per mL was 74% and 62%, respectively. Three subjects (3%) discontinued the study for adverse events, 8 (7%) for virologic failure, and 1 died through a median follow-up of 164 weeks. The annualized incidence rate of grade 3 to 4 adverse events and grade 3 to 4 laboratory abnormalities was 6% and 3%, respectively. The annualized incidence rate of serious adverse events was 9%, with 1% attributed as related to emtricitabine. Genotypic analysis showed the emergence of the M184V mutation in 4 of the 15 subjects who experienced virologic failure through week 164. Pharmacokinetic evaluation demonstrated plasma drug exposures in these children comparable to adults receiving the approved dose of 200 mg once daily. CONCLUSIONS: These results demonstrate the safety and efficacy of emtricitabine in pediatric patients. They also support that the safety and efficacy profile of emtricitabine in children is similar to that demonstrated in adults.

Baseline genotype as a predictor of virological failure to emtricitabine or stavudine in combination with didanosine and efavirenz.

The presence of drug-associated mutations among ART-naive, HIV-1(+) patients may compromise the response to antiviral therapy. We evaluated the effect of preexisting drug-associated resistance mutations to the response in treatment-naive patients to therapy with emtricitabine (FTC) or stavudine (d4T) in combination with didanosine (ddI) and efavirenz (EFV). Study FTC-301A compared emtricitabine once daily (QD) with stavudine twice daily in combination with didanosine and efavirenz in ART-naive patients. Genotypic analysis was performed on baseline plasma HIV-1 RNA for all available samples and at time of virologic failure (VF). Drug resistance mutations present at baseline were evaluated as predictors of VF using logistic regression. VF rates were compared between subgroups using a two-sided exact test. Baseline drug resistance mutations were observed in 90/546 (16.5%) patients: 56/90 (62.2%) with nonnucleoside analogue (NNRTI) mutations and 42/90 (46.6%) with nucleoside analogue mutations. In a stepwise, multiple regression analysis, the presence of the K103N mutation at initiation of therapy was associated with VF in both arms (p = 0.001), however, there was a higher incidence of VF in the stavudine arm compared to the emtricitabine arm regardless of the presence or absence of mutations at baseline (p = 0.001). In this study, the presence of drug-associated resistance mutations in ART-naive patients was significantly correlated with subsequent development of virologic failure underscoring the utility of testing for resistance in addition to the use of potent and well-tolerated first line regimens in treatment-naive patients.

Short-term safety and pharmacodynamics of amdoxovir in HIV-infected patients.

OBJECTIVES: To evaluate the pharmacodynamics and safety of escalating doses of amdoxovir (DAPD) monotherapy administered to treatment-naive and experienced HIV-1-infected patients over 15 days. DESIGN: Ninety patients with plasma HIV-1 RNA levels between 5000 and 250,000 copies/ml were randomized to DAPD 25, 100, 200, 300 or 500 mg twice daily or 600 mg once daily monotherapy [antiretroviral therapy (ART)-naive and ART-experienced] or to add DAPD 300 or 500 mg twice daily to existing ART. After 15 days of dosing, patients were followed for an additional 7 days. METHODS: Antiviral activity was compared between treatment arms using log10 HIV-1 RNA based on average area under the curve minus baseline to day 15. Safety and tolerability was analyzed by incidence of grade 1 to 4 clinical and laboratory adverse events. RESULTS: In ART-naive patients receiving short-term DAPD monotherapy, a median reduction in plasma HIV-1 RNA of 1.5 log10 copies/ml at the highest doses was observed. In ART-experienced patients, the reduction in viral load observed at each dose was less than that observed in treatment-naive patients (reduction of 0.7 log10 at 500 mg twice daily). The incidence of adverse events was similar across groups with the majority of adverse events reported as mild or moderate in severity. Steady-state plasma concentrations of DAPD and dioxolane guanosine followed linear kinetics. CONCLUSIONS: DAPD was well tolerated and produced antiviral activity in treatment-naive and in some treatment-experienced patients. In ART-experienced patients, the antiviral activity was significant in those with no thymidine-analogue mutations and higher baseline CD4+ cell counts.

Pharmacokinetic and pharmacodynamic characteristics of emtricitabine support its once daily dosing for the treatment of HIV infection.

Emtricitabine (FTC) is a potent deoxycytidine nucleoside analogue that was recently approved for the treatment of HIV infection. Emtricitabine is activated by intracellular phosphorylation to its 5'-triphosphate (FTC5'-TP), a competitive inhibitor of the HIV reverse transcriptase (RT). Early clinical studies incorporating pharmacokinetic-pharmacodynamic (PK-PD) analyses provided a sound rationale for developing FTC as a once daily drug. A short-term open-label monotherapy trial in therapy naive HIV-infected subjects evaluated various dosage regimens of FTC, i.e., 25, 100, and 200 mg qd and/or bid, with serial measurements of plasma HIV RNA, plasma FTC, and intracellular (PBMC) FTC-5'-TP levels over the 14 days of treatment. PK data were augmented by other steady-state studies, one in healthy volunteers and the other in HIV-infected patients receiving 200 mg FTC qd, with measurements of plasma FTC and/or intracellular FTC-5'-TP levels. Correlation between anti-HIV activity and FTC-5'-TP levels was examined with dose- and concentration-response relationships determined. The once daily dosing schedule is supported by the relatively long half-lives of plasma FTC (8-10 hr) and PBMC FTC-TP (39 hr) and the high plasma FTC and PBMC FTC-5'-TP concentrations. HIV RNA suppression (PD) correlates well with PBMC FTC-5'-TP levels (PK), both reaching a plateau at doses > or = 200 mg/day. The PK and PD characteristics of FTC demonstrate that it is a once daily nucleoside RT inhibitor.

Prospective randomized trial of emtricitabine versus lamivudine short-term monotherapy in human immunodeficiency virus-infected patients.

We conducted a randomized, open-label, 10-day study that compared the antiretroviral activity of emtricitabine (FTC) 25, 100, and 200 mg once daily and lamivudine (3TC) 150 mg 2 times/day in 82 human immunodeficiency virus (HIV)-infected patients with virus loads >5000 and <100,000 copies/mL who were naive for 3TC and abacavir. All FTC doses demonstrated potent antiretroviral activity. Significantly greater virus suppression was seen at the 200 mg/day dose of FTC than with the lower FTC doses and/or 3TC (P=.02, P=.04, and P=.04, respectively). At the 200 mg/day dose, FTC produced a 1.7-log10 mean reduction in virus load. Trough FTC levels at the 200 mg/day dose exceeded the in vitro 90% inhibitory concentration dose for FTC by 5-fold. The long plasma half-life and the superior antiviral activity versus 3TC of the 200 mg/day FTC dose confirmed the results of other studies and led to the selection of this dose for subsequent therapeutic trials.

Environmental, policy, and cultural factors related to physical activity in well-educated urban African American women.

The purpose of this qualitative study was to identify environmental, policy, and cultural predictors of physical activity in urban African American women living in Baltimore, MD. Thirty-nine mostly well-educated women participated in eight focus group discussions, five for women aged 36 to 50 years and three for women 20 to 35 years of age. Transcripts were analyzed using QSR NUD*IST qualitative software, and themes were identified. The discussions identified numerous opportunities and barriers for physical activity. The women reported being aware of physical activity resources and facilities available to them, but they lacked time and motivation to participate. Family responsibilities and duties unique to African American women were cited often. The results suggest that providing more environmental facilities may not be sufficient to increase physical activity in well-educated urban African American women. Intervention strategies that place value on family and cultural responsibilities should be considered.

Dioxolane guanosine, the active form of the prodrug diaminopurine dioxolane, is a potent inhibitor of drug-resistant HIV-1 isolates from patients for whom standard nucleoside therapy fails.

Amdoxovir ([-]-beta-D-2,6-diaminopurine dioxolane [DAPD]) is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against HIV-1. DAPD is deaminated in vivo by adenosine deaminase to (-)-beta-D-dioxolane guanosine (DXG), a highly active anti-HIV compound. The median 50% effective concentrations (EC 50 ) +/- SD (representing antiviral activity against a laboratory-derived HIV-1 isolate) for DAPD and DXG in peripheral blood mononuclear cells were 4.0 +/- 2.2 micromol/L and 0.25 +/- 0.17 micromol/L, respectively. The 50% cytotoxic dose (CC 50 ) of both DAPD and DXG was >500 micromol/L. Recombinant viruses and clinical isolates of HIV-1 from patients for whom NRTI therapy and/or nonnucleoside reverse transcriptase inhibitor (NNRTI) combination therapies failed remained susceptible to inhibition by DXG (less than fourfold change in EC 50). Similar analysis showed that recombinant viruses harboring mutations known to confer resistance to NRTIs (zidovudine, lamivudine, and abacavir) and NNRTIs (efavirenz and nevirapine) as well as the multidrug resistance-associated mutation Q151M and double codon insertions (SS and SG) were also susceptible to inhibition by DXG. Resistance to DXG was observed only in recombinant isolates containing the 65R and 151M double mutations. Phenotypic analysis of a site-directed mutant containing only the 151M mutation demonstrated moderate resistance to DXG (<10-fold change in EC 50). We also examined site-directed mutants containing only L74V or K65R, the characteristic resistance mutations for DXG. The L74V mutant remained susceptible to inhibition by DXG, and the K65R mutant demonstrated moderate resistance to DXG.