SHIV susceptibility changes during the menstrual cycle of pigtail macaques.

BACKGROUND: Hormonal changes during menstrual cycling may affect susceptibility to HIV. METHODS: We determined the simian human immunodeficiency virus (SHIV) acquisition time point in 43 cycling pigtail macaques infected by repeated vaginal virus exposures initiated randomly in the cycle. RESULTS: SHIV infection was first detected in the follicular phase in 38 macaques (88%), and in the luteal phase in five macaques (12%), indicating a statistically significant timing difference. Assuming a 7-day eclipse phase, most infections occurred during or following a high-progesterone period associated with menstruation, vaginal epithelium thinning, and suppressed mucosal immunity. CONCLUSIONS: This raises questions whether other high-progesterone conditions (pregnancy, hormonal contraception) similarly affect HIV risk.

Evaluation of the lymphocyte trafficking drug FTY720 in vaginal tissues.

BACKGROUND: FTY720 is an immunomodulatory agent that reduces lymphocytes in peripheral tissues and circulation. Such agents may be effective as vaginal microbicides for HIV prevention. Systemic or vaginal application of FTY720 may reduce lymphocyte concentrations in genital tissues, reducing HIV target cell numbers. METHODS: Five female pigtail macaques received topical vaginal gel FTY720 (n = 2), intravenous (i.v.) FTY720 (n = 2), or placebo gel (n = 1) in this pilot study. Circulating and mucosal lymphocytes and genital mucosa, cytokines, and tissue histology were analyzed to document topical and i.v. FTY720 effects. RESULTS: Topical and i.v. FTY720 appeared to decrease the levels of cervicovaginal IL-8, IL-1ra, and genital inflammatory cells. Small sample size precluded statistical analysis. Topical administration had no overt adverse effects. CONCLUSIONS: This study introduces FTY720 as an immunomodulatory agent for the vaginal mucosa, compares topical effects to those of i.v. administration, and provides the basis for future studies involving FTY720 for HIV prevention.

FIT4Safety: recommendations in the diabetes care setting.

Sharps injuries pose a serious threat to health professionals, patients, and downstream workers. FIT4Safety is an initiative that seeks to promote safety and best practice in the diabetes setting. An Introduction to FIT4Safety and its Recommendations for the Safety of Sharps in the Diabetes Care Setting explains how and why the FIT4Safety initiative was formed, what it aims to achieve, and the importance of ensuring safety in the diabetes care setting. Outputs from FIT4Safety include Injection Safety in UK and Ireland: Safety of Sharps in Diabetes Recommendations. These recommendations were developed to provide a resource for all those directly involved in, or overseeing, diabetes care. The main topics and guidance detailed within the recommendations are discussed, as well as EU Directive 2010/32 on sharps injury prevention and the UK's Health and Safety (Sharp Instruments in Healthcare) Regulations 2013.

Reduced inflammation and CD4 loss in acute SHIV infection during oral pre-exposure prophylaxis.

BACKGROUND: The impact of pre-exposure prophylaxis (PrEP) with antiretrovirals on breakthrough HIV or SHIV infection is not fully documented. We addressed the hypothesis that SHIV(SF162P3) infection despite active PrEP results in altered early immune parameters, compared with untreated infection. METHODS: Eleven rhesus macaques were infected during repeated, rectal, low-dose SHIV(SF162P3) exposures while receiving concurrent oral PrEP (Truvada [n = 2] or GS7340 [n = 4]) or as untreated controls (n = 5). We measured SHIV RNA, inflammatory cytokines, CD4 cells, and SHIV-specific and memory T cells until 20 weeks after peak viremia. RESULTS: SHIV infection during PrEP resulted in 100-fold lower peak viremia and lower IL-15, IL-18, and IL-1Ra levels, compared with controls (P < .05; Wilcoxon rank-sum test). Unlike controls, PrEP-treated macaques showed no significant CD4 cell count reduction during acute infection and developed more SHIV-specific central memory T cells, relative to controls. After in vivo CD8 cell depletion, viral load increased to similar levels, indicating that CD8 cells were critical for viral control in both groups. CONCLUSIONS: PrEP with antiretrovirals has beneficial effects on early SHIV infection even when infection is not prevented. Although long-term immune control could not be examined in this SHIV infection model, our results suggest that PrEP results in improved early disease parameters in breakthrough infections.

Needlestick and sharps injuries: practice update.

Member states of the European Union have until May 112013 to implement the Council Directive 2010/32/EU Implementing the Framework Agreement on Prevention from Sharps Injuries in the Hospital and Healthcare Sector. The aim of this legislation is to achieve a safe working environment and prevent injuries to healthcare professionals caused by all medical sharps, including needlesticks. This article examines the issues surrounding needlestick and sharps injuries, including risk assessment and prevention, information provision, raising awareness, use of safety devices, training and reporting procedures.

Investigation and management of an A. Baumannii outbreak in ICU.

Acinetobacter baumannii infection is responsible for a wide range of infections, including pneumonia, bacteraemia, meningitis, wound infections, and urinary tract infections. During June 2010, two patients on an intensive care unit in an acute hospital in the UK had multi-resistant A. baumannii identified in samples obtained from a variety of specimens. A further case was identified 31 days following confirmation of the first outbreak. The investigation and management of this outbreak included the introduction of enhanced infection prevention and control precautions; the establishment of an Outbreak Control Team; epidemiological investigations; and the decontamination of equipment and the environment. Isolate typing by the Health Protection Agency Centre for Infections laboratory confirmed the three cases had identical A. baumannii strains: European clone II lineage encoded with an OXA-51-type carbapenemase. This suggests that there was a patient-to-patient spread of multi-resistant A. baumannii.

Durable protection against repeated penile exposures to simian-human immunodeficiency virus by broadly neutralizing antibodies.

Penile acquisition of HIV accounts for most infections among men globally. Nevertheless, candidate HIV interventions for men advance to clinical trials without preclinical efficacy data, due primarily to a paucity of relevant animal models of penile HIV infection. Using our recently developed macaque model, we show that a single subcutaneous administration of broadly neutralizing antibody (bNAb) 10-1074 conferred durable protection against repeated penile exposures to simian-human immunodeficiency virus (SHIVSF162P3). Macaques co-administered bNAbs 10-1074 and 3BNC117, or 3BNC117 alone, also exhibited significant protection against repeated vaginal SHIVAD8-EO exposures. Regression modeling estimated that individual plasma bNAb concentrations of 5 µg ml-1 correlated with ≥99.9% relative reduction in SHIV infection probability via penile (10-1074) or vaginal (10-1074 or 3BNC117) challenge routes. These results demonstrate that comparably large reductions in penile and vaginal SHIV infection risk among macaques were achieved at clinically relevant plasma bNAb concentrations and inform dose selection for the development of bNAbs as long-acting pre-exposure prophylaxis candidates for use by men and women.

Evaluation of the lymphocyte trafficking drug FTY720 in SHIVSF162P3-infected rhesus macaques.

OBJECTIVES: FTY720 causes retention of lymphocytes in lymphatic tissues. Previous studies revealed that FTY720 can decrease or eliminate chronic viral infections of mice. We address here whether therapeutic use of FTY720 in simian human immunodeficiency virus (SHIV)-infected rhesus macaques could also decrease viraemia. METHODS: FTY720 was administered intravenously to three SHIV(SF162P3)-infected macaques at 39, 7 or 6 weeks of infection; three control macaques (47, 48 or 6 weeks of infection) did not receive drug. FTY720 was given at 0.004 mg/kg on days 0, 1, 2, 14, 15 and 16, followed by 0.1 mg/kg on days 28, 29, 30, 42, 43 and 44. Blood was collected seven times throughout and four times during 47 days of follow-up. RESULTS: Only the 0.1 mg/kg dose resulted in a reduction in mean blood CD4+ T cells and B cells (to 33% and 27% of pre-drug levels, P=0.0024 and 0.003, respectively). FTY720 treatment did not lead to significant deviations from the natural pattern of viral control. Plasma viraemia progressed from a range of 10(4)-10(2) copies/mL before treatment to 10(4)-temporarily undetectable levels on the last day of treatment. SHIV(SF162P3) was not eliminated, however, as plasma viraemia and proviral DNA persisted during the follow-up. No significant alterations in T cell activity were noted throughout the drug course. CONCLUSIONS: FTY720 administration had no detectable therapeutic effect at the doses and schedules outlined here, although blood CD4+ T cells and B cells were effectively reduced. Future work might reveal whether FTY720 could be beneficial in more pathogenic SHIV, simian immunodeficiency virus or HIV infections.

Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir.

BACKGROUND: In the absence of an effective vaccine, HIV continues to spread globally, emphasizing the need for novel strategies to limit its transmission. Pre-exposure prophylaxis (PrEP) with antiretroviral drugs could prove to be an effective intervention strategy if highly efficacious and cost-effective PrEP modalities are identified. We evaluated daily and intermittent PrEP regimens of increasing antiviral activity in a macaque model that closely resembles human transmission. METHODS AND FINDINGS: We used a repeat-exposure macaque model with 14 weekly rectal virus challenges. Three drug treatments were given once daily, each to a different group of six rhesus macaques. Group 1 was treated subcutaneously with a human-equivalent dose of emtricitabine (FTC), group 2 received orally the human-equivalent dosing of both FTC and tenofovir-disoproxil fumarate (TDF), and group 3 received subcutaneously a similar dosing of FTC and a higher dose of tenofovir. A fourth group of six rhesus macaques (group 4) received intermittently a PrEP regimen similar to group 3 only 2 h before and 24 h after each weekly virus challenge. Results were compared to 18 control macaques that did not receive any drug treatment. The risk of infection in macaques treated in groups 1 and 2 was 3.8- and 7.8-fold lower than in untreated macaques (p = 0.02 and p = 0.008, respectively). All six macaques in group 3 were protected. Breakthrough infections had blunted acute viremias; drug resistance was seen in two of six animals. All six animals in group 4 that received intermittent PrEP were protected. CONCLUSIONS: This model suggests that single drugs for daily PrEP can be protective but a combination of antiretroviral drugs may be required to increase the level of protection. Short but potent intermittent PrEP can provide protection comparable to that of daily PrEP in this SHIV/macaque model. These findings support PrEP trials for HIV prevention in humans and identify promising PrEP modalities.

Quality improvement collaborative: A novel approach to improve infection prevention and control. Perceptions of lead infection prevention nurses who participated.

BACKGROUND: In response to the ongoing infection prevention (IP) challenges in England, a 90-day quality improvement (QI) collaborative programme was developed. The paper discusses the approach, benefits, challenges and evaluation of the programme. OBJECTIVE: The objective of the collaborative was to develop new approaches to enable sustainable and effective IP. METHODOLOGY: Six trusts in the region participated in the collaborative. Each defined their bespoke IP focus. There was no expectation that statistically significant measurable improvements would be identified during the short time frame. The experiences of the participants were sought both during the programme to facilitate its constant review and at the end of the programme to evaluate its effectiveness. The feedback focused on achievements, barriers to change and benefits of participating in a QI collaborative. To measure the potential success of the projects, participants completed the Model for Understanding Success in Quality framework. (MUSIQ; Kaplan et al., 2012). RESULTS: Since each trusts IP focus was bespoke commonalities of success were not evaluated. Participants identified a positive outcome from their QI interventions. The MUSIQ score identified the projects had the potential for success. DISCUSSION: The feedback from the participants demonstrated that it is worthy of further development.

Development of a repeat-exposure penile SHIV infection model in macaques to evaluate biomedical preventions against HIV.

Penile acquisition of HIV infection contributes substantially to the global epidemic. Our goal was to establish a preclinical macaque model of penile HIV infection for evaluating the efficacy of new HIV prevention modalities. Rhesus macaques were challenged once or twice weekly with consistent doses of SHIVsf162P3 (a chimeric simian-human immunodeficiency virus containing HIV env) ranging from 4-600 TCID50 (50% tissue culture infective dose), via two penile routes, until systemic SHIV infection was confirmed. One route exposed the inner foreskin, glans and urethral os to virus following deposition into the prepuce (foreskin) pouch. The second route introduced the virus non-traumatically into the distal urethra only. Single-route challenges resulted in dose-dependent rates of SHIV acquisition informing selection of optimal SHIV dosing. Concurrent SHIV challenges via the prepuce pouch (200 TCID50) and urethra (16 TCID50) resulted in infection of 100% (10/10) animals following a median of 2.5 virus exposures (range, 1-12). We describe the first rhesus macaque repeat-exposure SHIV challenge model of penile HIV acquisition. Utilization of the model should further our understanding of penile HIV infection and facilitate the development of new HIV prevention strategies for men.

Hypnosis for childbirth: a retrospective comparative analysis of outcomes in one obstetrician's practice.

This exploratory, descriptive study, done retrospectively from perinatal medical records, compared childbirth outcomes in one obstetrician's caseload between 50 women who elected antepartal hypnosis preparation (usually a 5-class series) and 51 who did not. The groups were demographically similar. To achieve similar numbers to the hypnosis group, the control group was randomly selected from the women in the caseload who opted not to take hypnosis preparation, based on characteristics of parity and delivery mode. Prenatal hypnosis preparation resulted in significantly less use of sedatives, analgesia, and regional anesthesia during labor and in higher 1-minute neonatal Apgar scores. Other physiologic and outcome measures did not reveal statistical significance, although some trends were of clinical interest. Well-controlled studies are warranted for clinicians to offer hypnosis more frequently as a pain relief option for childbirth. Additional information provided includes pragmatic, clinical, and cost information about incorporating hypnosis into a physician's practice.

Skin antiseptics used prior to intravascular catheter insertion.

The recent epic2 publication (Pratt et al, 2007) provides evidence-based guidelines for the prevention of healthcare-associated infections. One of the new recommendations related to the prevention of central venous catheter (CVC) associated infection states that 2% chlorhexidine gluconate (CHG) in 70% isopropyl alcohol (IPA) should be used for cutaneous antisepsis prior to device insertion. This article reviews cutaneous antisepsis prior to intravascular catheter placement.

Chronic HIV-2 infection protects against total CD4+ cell depletion and rapid disease progression induced by SHIV89.6p challenge.

OBJECTIVE: To better understand HIV-1 sexual transmission risk, we have studied the susceptibility of HIV-2-exposed, uninfected (EU) female pig-tailed macaques to intravaginal (IVAG) re-challenge with the homologous HIV-2 strain, followed by heterologous SHIV89.6p. METHODS: Nine female macaques, previously protected by a post-exposure prophylaxis (PEP) regimen, along with one mock-treated EU animal, were re-exposed to HIV-2 by the IVAG route approximately 1.5 years later. A single follow-up challenge was performed approximately 1 year later with SHIV89.6p to assess susceptibility of chronic HIV-2-infected animals to further re-infection and pathogenic effects with a heterologous virus, somewhat mimicking HIV-1. RESULTS: Eight of ten macaques (80%) became infected systemically with HIV-2, and plasma or cervicovaginal vRNA levels did not appreciably differ from prior historic non-PEP control macaques. Interestingly, all eight HIV-2-infected females were susceptible to SHIV89.6p infection by either intravenous (n = 4) or IVAG exposure (n = 4) after one inoculation. Plasma vRNA levels in these groups were controlled by week 8 and there were no decrease in CD4+ T cells > 50%. The remaining two HIV-2 EU macaques, inoculated intrarectally with SHIV89.6p, were unable to control virus replication and succumbed to disease by week 25 or week 61. CONCLUSIONS: Our findings demonstrate that successful PEP regimens to prevent an initial infection do not have any lasting protective effects. The observed lack of cross-protection against SHIV89.6p transmission among chronic HIV-2-infected macaques provides modeling support for limited epidemiologic data indicating that human HIV-2 infection does not protect against HIV-1 infection, but may serve to alter overt clinical outcome.

A comparative user evaluation of three needle-protective devices.

Needlestick injuries (NSI) can result in healthcare workers being exposed to blood-borne viruses. Between 1997 and 2002, three healthcare workers in the UK have seroconverted to hepatitis C and one to human immunodeficiency virus (Public Health Laboratory Service (PHLS), 2003). Experience both in the UK and the USA suggests that even robust educational strategies may be insufficient to reduce the number of occupationally acquired NSI (Jagger et al, 1988). Needle-protective devices have now become more widely available and several studies have demonstrated an associated reduced risk of NSK. It is, however, essential that the devices are appropriately evaluated before introduction to ensure that they meet user requirements, do not interfere with function and reduce NSI risk. This article describes an evaluation programme carried out at the University Hospital Birmingham, UK. The programme focused on three key areas: safety, usability and compatibility. Results demonstrated that nurses rapidly adapt their practices to use the new safety devices and the study highlighted key education requirements that would be required before implementation. In addition, without this evaluation, it would not have been identified that attachment of the safety needles to the syringes requires a push-and-twist method or the use of LuerLok syringes to prevent detachment on activation of the safety procedure

Healthcare workers' knowledge of inoculation injuries and glove use.

Healthcare workers' (HCWs') occupational risk of exposure to blood-borne pathogens has been well documented. Subsequent educational programmes, awareness campaigns and policy implementation made limited impact on HCWs' level of knowledge of these risks and compliance with universal precautions. Two hundred HCWs completed a questionnaire to evaluate their level of knowledge. Results demonstrated that despite a comprehensive educational programme for nurses and training for medical staff, knowledge of inoculation injuries and associated issues remained inadequate. Indeed, policies and procedures were not followed. Furthermore, gloves were not routinely worn in the clinical setting. Educational programmes ware essential to inform HCWs of occupational risk of exposure to blood-borne pathogens and guide practice following an inoculation injury. However, efficacy of such programmes must be reviewed, alternative strategies evaluated, and the cause of HCWs' limited knowledge determined.

Susceptibility to repeated, low-dose, rectal SHIVSF162P3 challenge is independent of TRIM5 genotype in rhesus macaques.

Infections following repeated, low-dose (RLD), mucal S(H)IV exposures of macaques are used to model sexual HIV exposures for biomedical prevention testing. Different susceptibilities among animals can complicate study designs. In rhesus macaques, TRIM5 alleles Q, CypA, and TFP are resistance factors for infection with some S(H)IV strains, but not for SIVmac239 due to its capsid properties. SIVmac239-derived SHIVSF162P3 has been demonstrated to reproducibly infect mucosally in vaginal and rectal RLD models. To further test the suitability of SHIVSF162P3 for RLD models, we studied the influence of the TRIM5 genotype on susceptibility to rectal RLD infection and on plasma viremia by analyzing 43 male Indian rhesus macaques from control arms of completed studies. The median number of exposures required for infection was three (Q/Q, n=4) (TRIM5 alleles, number of macaques, respectively), four (Q/CypA, n=7), three (TFP/Q, n=15), three (TFP/TFP, n=15), and two (TFP/CypA, n=2); TRIM5(CypA/CypA) was not represented in our study. Median peak viremia (log10 viral copies/ml) in infected animals was 7.4 (Q/Q, n=4), 7.2 (Q/CypA, n=6), 7.3 (TFP/Q, n=13), 7.1 (TFP/TFP, n=15), and 6.5 (TFP/CypA; n=2). Neither susceptibility nor peak viremia was significantly different (log rank test, Kruskal-Wallis test, respectively). Rhesus macaques' susceptibility to RLD SHIVSF162P3 is independent of the TRIM5 TFP, CypA, and Q alleles, with the limitation that the power to detect any impact of CypA/CypA and TFP/CypA genotypes was nonexistent or low, due to absence or infrequency, respectively. The finding that TRIM5 alleles do not restrict mucosal infection or ensuing replication rates suggests that SHIVSF162P3 is indeed suitable for RLD experimentation.

Needle stick and sharps injuries: practice update.

Member states of the European Union have until May 11 2013 to implement the Council Directive 2010/32/EU Implementing the Framework Agreement on Prevention from Sharps Injuries in the Hospital and Healthcare Sector. The aim of this legislation is to achieve a safe working environment and prevent injuries to healthcare professionals caused by all medical sharps, including needlesticks. This article examines the issues surrounding needlestick and sharps injuries, including risk assessment and prevention, information provision, raising awareness, use of safety devices, training and reporting procedures.