Psychosocial and pharmacologic interventions for methamphetamine addiction: protocol for a scoping review of the literature.

BACKGROUND: Methamphetamine use and harms are rising rapidly. Management of patients with methamphetamine use disorder (MUD) and problematic methamphetamine use (PMU) is challenging, with no clearly established best approach; both psychosocial and pharmacologic interventions have been described. Furthermore, given the diversity of individuals that use methamphetamines, there is a need to assess evidence for treatments for subgroups including youths; gay, bisexual, and other men who have sex with men; individuals with mental health comorbidities; and individuals in correction services. Establishing awareness of the messages regarding treatment from recent clinical practice guidelines (CPG) in the field is also of value. The first study objective will be to establish a greater understanding of the methods, populations, and findings of controlled studies for psychosocial and pharmacologic treatments for MUD and PMU. Investigation of this information can help establish the potential for advanced syntheses of the evidence (such as network meta-analysis) to compare therapies for this condition and to identify gaps related to key populations where more primary research is needed. Summarizing the recommendations regarding treatment of MUD/PMU from recent CPGs and systematic reviews will be an important secondary objective. METHODS: A scoping review will be performed. Using the OVID platform, MEDLINE, Embase, PsycINFO, and relevant Cochrane databases from EBM Reviews will be searched (from databases' inception onwards). Eligibility criteria will include individuals described as having MUD or PMU, with designs of interest including randomized trials, non-randomized trials, and controlled cohort studies with three or more months of follow-up; systematic reviews and CPGs will also be sought. Two reviewers (with support from automation tools) will independently screen all citations, full-text articles, and chart data. Different approaches to handling and summarizing the data will be implemented for each type of study design. Tables and graphics will be used to map evidence sources and identify evidence gaps. DISCUSSION: This research will enhance awareness of evidence addressing the effects of psychosocial and pharmacologic interventions for MUD/PMU overall and in sub-populations, both in terms of recent CPGs/reviews and primary studies; inspection of the latter will also help establish the feasibility of future syntheses to compare treatments, such as network meta-analysis. SYSTEMATIC REVIEW PROTOCOL REGISTRATION: Open Science Framework ( https://osf.io/9wy8p ).

Economic evaluation of vancomycin-resistant enterococci (VRE) control practices: a systematic review.

Preventing vancomycin-resistant enterococci (VRE) infection is a healthcare priority. However, the cost-effectiveness of VRE control interventions is unclear. The aim of this study was to synthesize evidence on economic evaluation of VRE control practices such as screening, contact precautions, patient cohorting, and others. The literature was searched from January 1985 to June 2018, and included economic evaluations of VRE control practices in hospital settings, published in English. A total of 4711 articles were screened; nine primary studies met our criteria. All studies evaluated some form of VRE screening and contact precautions, in populations ranging from single hospital wards (or select patient groups) to multiple healthcare facilities. There was significant variability in the interventions and comparisons used. Most studies (N = 7) conducted a cost-effectiveness analysis; two studies were cost-consequence studies. All economic evaluations were from the hospital perspective. Four studies found implementing enhanced VRE-specific control practices to be cost-effective/cost-saving and two studies found that discontinuing VRE-specific control practices was not cost-effective. Three studies found decreasing VRE-specific control practices to be cost-effective/cost-saving. The quality of the included studies was generally low according to the Joanna Briggs Institute (JBI) checklist for economic evaluations; major limitations included risks of bias in intervention effect estimates, and a lack of sensitivity analyses. Most studies show that some form of VRE screening and use of Contact Precautions is cost-effective. The low study quality and heterogeneity of interventions and comparators precludes definitive conclusions about the cost effectiveness of specific VRE control interventions. Additional high-quality economic evaluations are needed to strengthen the available evidence.

Application of the Theoretical Domains Framework to identify factors that influence hand hygiene compliance in long-term care.

BACKGROUND: Healthcare worker (HCW) hand hygiene compliance is key to patient safety; however, compliance is suboptimal. Nevertheless hand hygiene compliance is not well studied in the long-term care setting. AIM: To apply a behaviour change framework, the Theoretical Domains Framework (TDF), to identify modifiable facilitators and barriers for HCW hand hygiene compliance in long-term care settings. METHODS: HCW hand hygiene compliance facilitators and barriers were examined using a questionnaire for HCWs from long-term care homes in Ontario, Canada. The questionnaire was informed by the TDF, which is based on a synthesis of constructs from a number of relevant psychological theories of behaviour change. FINDINGS: Barriers identified from the questionnaire aligned with the TDF domain environmental context and resources (time pressure, workload, and environmental controls). Facilitators identified from questionnaire results aligned with the TDF domains social/professional role and identity (it is what is expected of HCWs), and beliefs about consequences (risk of transmission of micro-organisms to self or others). CONCLUSION: There are several barriers to hand hygiene compliance that persist in long-term care. A behaviour change theory-informed framework such as the TDF can be helpful to identify those barriers. This study identified several key behavioural constructs aligned with the TDF that can be targeted when developing novel hand hygiene interventions.

The second-hand effects of antibiotics: communicating the public health risks of drug resistance.

Antimicrobial resistance (AMR) poses a threat to modern medicine, but there are challenges in communicating its urgency and scope and potential solutions to this growing problem. It is recognized that AMR has a 'language problem' and the way in which healthcare professionals communicate about AMR may not always resonate with patients. Many patients are unaware that antibiotics can have detrimental effects to those beyond the recipient, due to transmission of drug-resistant organisms. The overestimation of benefits and underestimation of risks helps to fuel demand for antibiotic use in situations where they may be of little or no benefit. To better communicate risks, clinicians may borrow the term 'second-hand' from efforts to reduce smoking cessation. We present several examples where antibiotics themselves have second-hand effects beyond the individual recipient in hospitals, long-term care homes and the community. Incorporation of the concept of the second-hand effects of antibiotics into patient counselling, mass messaging and future research may help facilitate a more balanced discussion about the benefits and risks of antibiotic use in order to use these agents more appropriately.

Applying psychological frameworks of behaviour change to improve healthcare worker hand hygiene: a systematic review.

BACKGROUND: Despite the importance of hand hygiene in preventing transmission of healthcare-associated infections, compliance rates are suboptimal. Hand hygiene is a complex behaviour and psychological frameworks are promising tools to influence healthcare worker (HCW) behaviour. AIM: (i) To review the effectiveness of interventions based on psychological theories of behaviour change to improve HCW hand hygiene compliance; (ii) to determine which frameworks have been used to predict HCW hand hygiene compliance. METHODS: Multiple databases and reference lists of included studies were searched for studies that applied psychological theories to improve and/or predict HCW hand hygiene. All steps in selection, data extraction, and quality assessment were performed independently by two reviewers. FINDINGS: The search yielded 918 citations; seven met eligibility criteria. Four studies evaluated hand hygiene interventions based on psychological frameworks. Interventions were informed by goal setting, control theory, operant learning, positive reinforcement, change theory, the theory of planned behaviour, and the transtheoretical model. Three predictive studies employed the theory of planned behaviour, the transtheoretical model, and the theoretical domains framework. Interventions to improve hand hygiene adherence demonstrated efficacy but studies were at moderate to high risk of bias. For many studies, it was unclear how theories of behaviour change were used to inform the interventions. Predictive studies had mixed results. CONCLUSION: Behaviour change theory is a promising tool for improving hand hygiene; however, these theories have not been extensively examined. Our review reveals a significant gap in the literature and indicates possible avenues for novel research.

Barriers to hepatitis C virus treatment in a Canadian HIV-hepatitis C virus coinfection tertiary care clinic.

BACKGROUND: Despite demonstrated efficacy in HIV-hepatitis C virus (HCV) coinfection, not all patients initiate, complete or achieve success with HCV antiviral therapy. PATIENTS AND METHODS: All HIV-HCV coinfected patient consults received at The Ottawa Hospital Viral Hepatitis Clinic (Ottawa, Ontario) between June 2000 and September 2006 were identified using a clinical database. A descriptive analysis of primary and contributing factors accounting for why patients did not initiate HCV therapy, as well as the therapeutic outcomes of treated patients, was conducted. RESULTS: One hundred two consults were received. Sixty-seven per cent of patients did not initiate HCV therapy. The key primary reasons included: HIV therapy was more urgently needed (22%), loss to follow-up (12%), patients were deemed unlikely to progress to advanced liver disease (18%) and patient refusal (12%). Many patients had secondary factors contributing to the decision not to treat, including substance abuse (23%) and psychiatric illness (14%). Overall, 59% of untreated patients (40 of 68) were eventually lost to follow-up. Thirty-three per cent of referred patients started HCV therapy. Twenty-seven of 42 courses (64%) were interrupted prematurely for reasons such as virological nonresponse (48%), psychiatric complications (10%) and physical side effects (7%). Of all treatment recipients, 12 of 42 full courses of therapy were completed and three remained on HCV medication. Overall, eight of the 102 coinfected patients studied (8%) achieved a sustained virological response. DISCUSSION: Not all HIV-HCV coinfected patients who are deemed to be in need of HCV treatment are initiating therapy. Only a minority of patients who do receive treatment achieve success. Implementation of HIV treatment, patient retention, attention to substance abuse and mental health care should be the focus of efforts designed to increase HCV treatment uptake and success. This can be best achieved within a multidisciplinary model of health care delivery.

Development and psychometric validation of the HIV Treatment Knowledge Scale.

Accurate treatment knowledge is required for patients to successfully manage complex medical conditions. Existing HIV knowledge scales focus on disease transmission and risk factors. This is the first study to develop and validate a scale to measure HIV treatment knowledge about complex treatment issues such as adherence, side-effects and drug resistance. A total of 346 participants were recruited into this cross-sectional study. Participants included HIV-positive patients (n=130), HIV-hepatitis C co-infected patients (n=22), hepatitis C patients, (n=78), community healthcare providers (n=35) and college students (n=81). Participants completed the proposed HIV Treatment Knowledge Scale and a validated measure of general knowledge about HIV transmission and risk factors. Two-week test-retest data were collected. Results demonstrated that the HIV Treatment Knowledge Scale was significantly correlated with general HIV knowledge across all samples. Among HIV-positive patients, the HIV Treatment Knowledge Scale was positively associated with time since HIV diagnosis. HAART-experienced patients had significantly higher treatment knowledge than HAART-naïve patients. HIV-positive patients scored significantly higher than hepatitis C patients and college students on HIV treatment knowledge. Test-retest reliability (r=0.83) and internal consistency (reliability coefficient=0.90) were both satisfactory. The HIV Treatment Knowledge Scale is a novel, easy-to-administer measure demonstrating high levels of validity and reliability. It has important applications as a clinical teaching tool with patients and healthcare workers and it could be used as an outcome indicator in HIV educational intervention studies.

The effect of ABCB1 polymorphism on the pharmacokinetics of saquinavir alone and in combination with ritonavir.

This genotype panel study investigated the effect of ABCB1 polymorphism in exon 26 (C3435T), exon 21 (G2677T/A), and exon 12 (C1236T) on saquinavir pharmacokinetics and on the expression and activity of P-glycoprotein (P-gp) in peripheral blood monocytic cells (PBMCs). One hundred and fifty healthy volunteers were genotyped to identify 15 TT3435 and 15 CC3435 individuals. In these individuals, saquinavir pharmacokinetics were assessed after administration of a single oral dose of saquinavir 1,000 mg and saquinavir/ritonavir 1,000/100 mg. PBMC P-gp expression and activity were assessed in 15 and 19 subjects. The co-administration of ritonavir on study day 2 caused a significant increase in saquinavir exposure, in both TT3435 and CC3435 individuals. No correlation was observed between the ABCB1 C3435T, G2677T/A, and C1236T polymorphisms, separately and in haplotypes, with saquinavir pharmacokinetics, administered with or without ritonavir and with PBMC P-gp expression and activity. In conclusion, ABCB1 polymorphism has no pronounced effect on saquinavir exposure.

A randomized controlled psycho-education intervention trial: Improving psychological readiness for successful HIV medication adherence and reducing depression before initiating HAART.

The purpose of this study was to evaluate a novel psycho-educational intervention intended to increase patients' medication preparedness and treatment adherence skills before initiating highly active antiretroviral therapy (HAART). Sixty-three HIV-positive patients not currently on antiretroviral therapy participated in a randomized controlled trial of a standardized, four-session psycho-educational intervention (Supportive Therapy for Adherence to Antiretroviral Treatment; STAART). Session topics included learning techniques to increase medication adherence and learning effective strategies to cope with stress and depression. Patients completed psychological questionnaires assessing psychological readiness to initiate HAART and depressed mood. They completed both measures at study baseline and at four-weeks post-baseline. After controlling for baseline medication readiness scores, intervention patients (n = 30) reported significantly higher mean medication readiness following the STAART intervention (four-weeks post-baseline) (27.3+/-6.9) compared to controls (n = 33; 24.6+/-9.9; p < 0.05). Among depressed patients (n = 27), those receiving the intervention (n = 15) reported significantly lower mean depression scores at four-weeks post-baseline (22.5+/-12.9) compared to controls (n = 12; 27+/-9.9; p < 0.05). The STAART intervention enhanced HIV treatment readiness by better preparing patients prior to initiating HAART. It was also beneficial for reducing depressive symptoms in depressed, HIV-positive patients.

Clinical outcomes of first antiretroviral regimen in HIV/hepatitis C virus co-infection.

OBJECTIVES: Despite the benefits of HAART, initiation of antiretroviral therapy in HIV-HCV co-infected patients is often delayed as a consequence of patient and physician concern pertaining to liver toxicity. It is unclear whether this is justified. METHODS: We retrospectively evaluated treatment duration and outcome in 186 patients initiating a first HAART regimen. RESULTS: Despite frequent HIV RNA suppression and CD4 T-cell increase following initiation of HAART, the median duration of therapy was only 8 months. Therapy was discontinued primarily for gastrointestinal intolerance (26%), poor adherence (19%), neurocognitive side effects (13%), and substance abuse (6%). Regimes were changed to reduce pill burden and/or frequency of dosing as well (11%). Only six (4%) subjects interrupted therapy as a result of clinically apparent liver toxicity. None were on low dose ritonavir-containing therapy. In those subjects remaining on HAART for at least 12 months, the median ALT level increased marginally from a baseline of 44 IU/mL to 56 IU/mL. The median AST was 44 IU/mL at baseline and at month 12. CONCLUSIONS: These results support our contention that regimen potency, durability, and extrahepatic side effect profile should remain the paramount considerations related to the selection of HAART regimen in HIV-HCV co-infection.

Absence of circadian variation in the pharmacokinetics of lopinavir/ritonavir given as a once daily dosing regimen in HIV-1-infected patients.

AIMS: To compare the pharmacokinetics of lopinavir/ritonavir (LPV/r) 800/200 mg administered once daily in the morning compared with the evening. METHODS: This was a randomized, two-way, cross-over study in HIV+ subjects. In each subject the pharmacokinetics of each drug were characterized after 2 weeks of LPV/r 800/200 mg administered once daily at 08.00 h and 19.00 h. On study days, LPV/r was taken with a standardized meal (800 kCal, 25% from fat) after fasting for at least 5 h. LPV/r concentrations were measured by LC-MS/MS, and the data were analyzed by noncompartmental pharmacokinetic analysis. RESULTS: Fourteen subjects completed the study (all men, mean age/weight 44 year/81 kg). The median (interquartile range) LPV AUC(0,24 h), maximum plasma concentration (C(max)) and concentration at the end of the dosing interval (C(24 h)) after am and pm dosing was, respectively, 143 (116-214) mg l(-1) h, 12.8 (10.3-17.2) mg l(-1), 1.34 (0.58-3.25) mg l(-1), and 171 (120-232) mg l(-1) h, 12.9 (8.22-16.3) mg l(-1), 1.15 (0.59-1.98) mg l(-1). The geometric mean ratio (GMR, am : pm) and 95% CI of the LPV AUC(0,24 h), C(max), and C(24 h) was 0.91 (0.79, 1.06), 1.11 (0.94, 1.32), and 1.19 (0.72, 1.96), respectively. The median ritonavir C(max) after am and pm dosing was 1.05 and 0.90 mg l(-1), respectively. The GMR (95% CI) of the RTV AUC(0,24 h), C(max), and C(24 h) was 0.93 (0.80, 1.08), 1.27 (1.00, 1.63), and 1.04 (0.68, 1.60), respectively. Administration of LPV/r in a once-daily regimen was generally well tolerated. CONCLUSIONS: No differences were observed in the pharmacokinetics of LPV/r after am or pm dosing with food, which suggests that this once daily combination, can be taken in the morning or evening. Such flexibility in dosing may improve adherence.

Prophylactic antibiotics for abdominal hysterectomy: indication for low-risk Canadian women.

OBJECTIVE: To determine whether prophylactic antibiotics decrease the risk of infectious morbidity after total abdominal hysterectomy (TAH) in women at low risk for infection. METHODS: An analysis of data from 1570 women undergoing planned TAH at 15 secondary and tertiary hospitals in Nova Scotia, Ontario, and Quebec, who agreed to participate in a centrally randomized controlled trial of vaginal antisepsis with povidone-iodine gel compared to no gel after the standard preoperative vaginal preparation with povidone-iodine solution. RESULTS: Prophylactic antibiotics were used in 993 of 1570 women (63%). Appropriately timed prophylactic antibiotics decreased infectious morbidity (odds ratio [OR], 0.65; 95% confidence interval [CI], 0.50-0.85; P < .002). After controlling for risk factors for infection and study centre, the protective effect was even more pronounced (adjusted OR, 0.51; 95% CI, 0.36-0.73). Prophylactic antibiotics were associated with decreases in abdominal wound infection (OR, 0.45; 95% CI, 0.30-0.66) and pelvic infection (OR, 0.49; 95% CI, 0.26-0.92). CONCLUSION: Women who did not receive prophylactic antibiotics had a higher surgical infection rate. Prophylactic antibiotics should be recommended for all women undergoing TAH.

Monoclonal antibodies against a 62 kDa proteinase of Trichomonas vaginalis decrease parasite cytoadherence to epithelial cells and confer protection in mice.

Trichomonas vaginalis infects the epithelium of the genital tract. The mechanism by which it invades the tissue leading to the disease is not thoroughly understood. However, results of several studies seem to agree that parasite adhesion to epithelium cells is the initial step leading to infection in women. T. vaginalis is associated with high levels of proteolytic activity. The role of some of these proteinases in the development of infection has been demonstrated. The current study establishes the role of a 62 kDa excretion-secretion proteinase in parasite cytoadherence. Monoclonal antibodies (MAbs) against this enzyme were tested for their ability to inhibit this process. Three stable hybrid producers of IgG(1)class MAbs (4D8, 1A8, 3C11) against the 62 kDa proteinase were obtained. Two of them (4D8 and 1A8) showed parasite recognition by immunofluorescence. Parasite cytoadherence to a monolayer of HeLa cells was inhibited by the 4D8, 1A8 and 3C11 antibodies. MAb 4D8 administered 24 h before a challenge with T. vaginalis by the intraperitoneal route was able to protect the majority of mice. Nitric oxide levels in the serum of animals inoculated with MAb 4D8 and challenged with the parasite were significantly different from those recorded in mice treated with an unrelated MAb. These studies show that an appropriate antibody against 62 kDa proteinase can help the host resist a challenge by the intraperitoneal route with T. vaginalis.

Antisepsis for abdominal hysterectomy: a randomised controlled trial of povidone-iodine gel.

OBJECTIVE: To assess whether infectious morbidity after total abdominal hysterectomy is decreased by the addition of 20 cc povidone-iodine gel at the vaginal apex after the usual vaginal preparation with povidone-iodine solution. STUDY DESIGN: Randomised controlled trial. SETTING: Fifteen secondary and tertiary hospitals in Canada. SAMPLE: A total of 1570 women undergoing planned total abdominal hysterectomy. METHODS: Computer-generated randomisation using a centralised telephone service was stratified by study centre with variable block size. In the operating room, a swab for bacterial vaginosis was taken before vaginal antisepsis. Study group remained concealed until the standard surgical preparation in the operating room was complete. Then povidone-iodine gel 20 cc was placed at the vaginal apex in the intervention group only. Participants were followed for one month post-operative. MAIN OUTCOME MEASURES: The primary outcome was post-operative infectious morbidity during the 30 days after surgery, defined as: febrile morbidity with hospital stay greater than five days or antibiotic treatment, or infection requiring readmission to hospital or additional visit. Other outcomes included abdominal wound infection, pelvic abscess and other pelvic infections. RESULTS: Post-operative infectious morbidity within 30 days occurred in 128/780 (16%) women receiving povidone-iodine gel preparation and 142/790 (18%) women not receiving gel (RR 0.9, 95% CI 0.7 to 1.1). Pelvic abscess was diagnosed in 0 patients in the gel group and in seven patients in the control group (P < 0.01). No significant difference was found in pelvic cellulitis (eight in each group) or abdominal wound infection (51 in the gel group and 58 in the control group, P= 0.5). CONCLUSION: Povidone-iodine vaginal gel antisepsis led to a 9% relative decrease in overall infectious morbidity after abdominal hysterectomy, which was not statistically significant. Povidone-iodine vaginal gel decreased the risk of pelvic abscess after total abdominal hysterectomy.

Intravenous and oral itraconazole versus intravenous amphotericin B deoxycholate as empirical antifungal therapy for persistent fever in neutropenic patients with cancer who are receiving broad-spectrum antibacterial therapy. A randomized, controlled trial.

BACKGROUND: Amphotericin B deoxycholate is currently the standard empirical antifungal therapy in neutropenic patients with cancer who have persistent fever that does not respond to antibiotic therapy. However, this treatment often causes infusion-related and metabolic toxicities, which may be dose limiting. OBJECTIVE: To compare the efficacy and safety of itraconazole with those of amphotericin B as empirical antifungal therapy. DESIGN: An open randomized, controlled, multicenter trial, powered for equivalence. SETTING: 60 oncology centers in 10 countries. PATIENTS: 384 neutropenic patients with cancer who had persistent fever that did not respond to antibiotic therapy. INTERVENTION: Intravenous amphotericin B or intravenous itraconazole followed by oral itraconazole solution. MEASUREMENTS: Defervescence, breakthrough fungal infection, drug-related adverse events, and death. RESULTS: For itraconazole and amphotericin B, the median duration of therapy was 8.5 and 7 days and the median time to defervescence was 7 and 6 days, respectively. The intention-to-treat efficacy analysis of data from 360 patients showed response rates of 47% and 38% for itraconazole and amphotericin B, respectively (difference, 9.0 percentage points [95% CI, -0.8 to 19.5 percentage points]). Fewer drug-related adverse events occurred in the itraconazole group than the amphotericin B group (5% vs. 54% of patients; P = 0.001), and the rate of withdrawal because of toxicity was significantly lower with itraconazole (19% vs. 38%; P = 0.001). Significantly more amphotericin B recipients had nephrotoxicity (P < 0.001). Breakthrough fungal infections (5 patients in each group) and mortality rates (19 deaths in the itraconazole group and 25 deaths in the amphotericin B group) were similar. Sixty-five patients switched to oral itraconazole solution after receiving the intravenous formulation for a median of 9 days. CONCLUSIONS: Itraconazole and amphotericin B have at least equivalent efficacy as empirical antifungal therapy in neutropenic patients with cancer. However, itraconazole is associated with significantly less toxicity.

Effect of cessation of highly active antiretroviral therapy during a discordant response: implications for scheduled therapeutic interruptions.

Although treatment with combination antiretroviral therapy leads to a reduction in the level of plasma viremia and an improvement in CD4 T cell count for most patients, for a minority of patients, an improvement in CD4 T cell count occurs despite the failure of treatment to suppress viral replication. Recent reports suggest that these discordant improvements in CD4 T cell count may last for months to years and are associated with improved clinical outcomes. In a retrospective observational study, we evaluated the effect of therapy cessation on 8 patients with discordant immunologic responses to therapy and found that improved CD4 T cell responses are dependent upon ongoing drug pressure. If antiretroviral agents that are likely to resuppress the virus are not available, we suggest that patients continue the therapy associated with immunologic improvement to maximize the clinical benefit of the discordant response.

Efficacy and safety of recombinant human activated protein C for severe sepsis.

BACKGROUND: Drotrecogin alfa (activated), or recombinant human activated protein C, has antithrombotic, antiinflammatory, and profibrinolytic properties. In a previous study, drotrecogin alfa activated produced dose-dependent reductions in the levels of markers of coagulation and inflammation in patients with severe sepsis. In this phase 3 trial, we assessed whether treatment with drotrecogin alfa activated reduced the rate of death from any cause among patients with severe sepsis. METHODS: We conducted a randomized, double-blind, placebo-controlled, multicenter trial. Patients with systemic inflammation and organ failure due to acute infection were enrolled and assigned to receive an intravenous infusion of either placebo or drotrecogin alfa activated (24 microg per kilogram of body weight per hour) for a total duration of 96 hours. The prospectively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion. Patients were monitored for adverse events; changes in vital signs, laboratory variables, and the results of microbiologic cultures; and the development of neutralizing antibodies against activated protein C. RESULTS: A total of 1690 randomized patients were treated (840 in the placebo group and 850 in the drotrecogin alfa activated group). The mortality rate was 30.8 percent in the placebo group and 24.7 percent in the drotrecogin alfa activated group. On the basis of the prospectively defined primary analysis, treatment with drotrecogin alfa activated was associated with a reduction in the relative risk of death of 19.4 percent (95 percent confidence interval, 6.6 to 30.5) and an absolute reduction in the risk of death of 6.1 percent (P=0.005). The incidence of serious bleeding was higher in the drotrecogin alfa activated group than in the placebo group (3.5 percent vs. 2.0 percent, P=0.06). CONCLUSIONS: Treatment with drotrecogin alfa activated significantly reduces mortality in patients with severe sepsis and may be associated with an increased risk of bleeding.

An overview of fungal infections.

The incidence of fungal infections is increasing at an alarming rate, presenting an enormous challenge to healthcare professionals. This increase is directly related to the growing population of immunocompromised individuals, resulting from changes in medical practice such as the use of intensive chemotherapy and immunosuppressive drugs. HIV and other diseases which cause immunosuppression have also contributed to this problem. Superficial and subcutaneous fungal infections affect the skin, keratinous tissues and mucous membranes. Included in this class are some of the most frequently occurring skin diseases, affecting millions of people worldwide. Although rarely life threatening, they can have debilitating effects on a person's quality of life and may in some circumstances spread to other individuals or become invasive. Most superficial and subcutaneous fungal infections are easily diagnosed and readily amenable to treatment. Systemic fungal infections may be caused by either an opportunistic organism that infects an at-risk host, or may be associated with a more invasive organism that is endemic to a specific geographical area. Systemic infections can be life threatening and are associated with high morbidity and mortality. Because diagnosis is difficult and the causative agent is often confirmed only at autopsy, the exact incidence of systemic infections is difficult to determine. The most frequently encountered pathogens are Candida albicans and Aspergillus spp. but other fungi such as non-albicans Candida spp. are increasingly important.