Anna K. Barker

PDCD2 is essential for inner cell mass development and embryonic stem cell maintenance

PDCD2 is a conserved eukaryotic protein implicated in cell cycle regulation by virtue of its interactions with HCFC1 and the NCOR1/SIN3A corepressor complex. Pdcd2 transcripts are enriched in ES cells and other somatic stem cells, and its ortholog is essential for hematopoietic stem cell maintenance in Drosophila. To characterize the physiological role(s) of mammalian PDCD2, we created a disruption allele in mice. Pdcd2(-/-) embryos underwent implantation but did not undergo further development. Inner cell masses (ICMs) from Pdcd2(-/-) blastocysts failed to outgrow in vitro. Furthermore, embryonic stem cells (ESCs) require PDCD2 as demonstrated by the inability to generate Pdcd2(-/-) ESCs in the absence of an ectopic transgene. Upon differentiation of ESCs by retinoic acid treatment or LIF deprivation, PDCD2 levels declined. In conjunction with prior studies, these results indicate that in vivo, PDCD2 is critical for blastomere and ESC maintenance by contributing to the regulation of genes in a manner essential to the undifferentiated state of these cells.

High resolution mapping and positional cloning of ENU-induced mutations in the Rw region of mouse chromosome 5

BackgroundForward genetic screens in mice provide an unbiased means to identify genes and other functional genetic elements in the genome. Previously, a large scale ENU mutagenesis screen was conducted to query the functional content of a ~50 Mb region of the mouse genome on proximal Chr 5. The majority of phenotypic mutants recovered were embryonic lethals.ResultsWe report the high resolution genetic mapping, complementation analyses, and positional cloning of mutations in the target region. The collection of identified alleles include several with known or presumed functions for which no mutant models have been reported (Tbc1d14, Nol14, Tyms, Cad, Fbxl5, Haus3), and mutations in genes we or others previously reported (Tapt1, Rest, Ugdh, Paxip1, Hmx1, Otoe, Nsun7). We also confirmed the causative nature of a homeotic mutation with a targeted allele, mapped a lethal mutation to a large gene desert, and localized a spermiogenesis mutation to a region in which no annotated genes have coding mutations. The mutation in Tbc1d14 provides the first implication of a critical developmental role for RAB-GAP-mediated protein transport in early embryogenesis.ConclusionThis collection of alleles contributes to the goal of assigning biological functions to all known genes, as well as identifying novel functional elements that would be missed by reverse genetic approaches.

Patients' Hand Hygiene at Home Predicts Their Hand Hygiene Practices in the Hospital

We examine factors associated with hand hygiene practices of hospital patients. Hygiene in the hospital decreased compared to that at home, and home practices were strongly associated with hospital practices. Understanding and leveraging the intrinsic value some patients associate with hand hygiene may be important for improving overall hospital hygiene and decreasing healthcare-associated infections.

Impact of Probiotics for Reducing Infections in Veterans (IMPROVE): Study protocol for a double-blind, randomized controlled trial to reduce carriage of Staphylococcus aureus

BACKGROUND Staphylococcus aureus (S. aureus) is an organism of great public health importance, causing 20,000 deaths annually. Decolonization of patients with S. aureus may prevent infections, yet current options are limited to antimicrobials that promote antibiotic resistance and can cause adverse side effects. Probiotics have potential to reduce colonization of pathogenic bacteria, representing a promising alternative for S. aureus decolonization, but thus far lack rigorous evaluation. METHODS Potential subjects were recruited from inpatient and outpatient settings within a VA medical center and screened for S. aureus gastrointestinal (GI) or extra-GI colonization using swabs at multiple body sites. Positive, eligible, consenting participants were stratified by colonization site and randomized in a 1:1 ratio to 4-weeks of daily placebo or Lactobacillus rhamnosus (L. rhamnosus) HN001 probiotic treatment. Blood and stool samples, and treatment adherence reports were collected from each subject throughout the study, along with a final set of swabs at study completion to detect S. aureus carriage. The outcomes of this study are GI or extra-GI carriage by S. aureus at the end of 4weeks of therapy, change in phagocytic activity of polymorphonuclear cells from pre-intervention to post-intervention, and symptomatic S. aureus infection at any site during the study period. CONCLUSION 114 participants have been recruited for this study. Analysis of outcomes is underway. This is the first clinical trial to examine the efficacy of L. rhamnosus HN001 for decolonization of S. aureus, and investigates the mechanism by which L. rhamnosus HN001 mediates its effect on S. aureus colonization. ClinicalTrials.govIdentifier NCT01321606.

Barriers and facilitators to infection control at a hospital in northern India: a qualitative study

BackgroundHospital acquired infections occur at higher rates in low- and middle-income countries, like India, than in high-income countries. Effective implementation of infection control practices is crucial to reducing the transmission of hospital acquired infections at hospitals worldwide. Yet, no comprehensive assessments of the barriers to sustained, successful implementation of hospital interventions have been performed in Indian healthcare settings to date. The Systems Engineering Initiative for Patient Safety (SEIPS) model examines problems through the lens of interactions between people and systems. It is a natural fit for investigating the behavioral and systematic components of infection control practices.MethodsWe conducted a qualitative study to assess the facilitators and barriers to infection control practices at a 1250 bed tertiary care hospital in Haryana, northern India. Twenty semi-structured interviews of nurses and physicians, selected by convenience sampling, were conducted in English using an interview guide based on the SEIPS model. All interview data was subsequently transcribed and coded for themes.ResultsPerson, task, and organizational level factors were the primary barriers and facilitators to infection control at this hospital. Major barriers included a high rate of nursing staff turnover, time spent training new staff, limitations in language competency, and heavy clinical workloads. A well developed infection control team and an institutional climate that prioritizes infection control were major facilitators.ConclusionsInstitutional support is critical to the effective implementation of infection control practices. Prioritizing resources to recruit and retain trained, experienced nursing staff is also essential.

Probiotics for Clostridium difficile infection in adults (PICO): Study protocol for a double-blind, randomized controlled trial.

BACKGROUND Clostridium difficile is a pathogen of rapidly increasing public health importance. An estimated quarter of a million Clostridium difficile infections (CDI) occur in the United States annually, at a resultant cost of 14,000 deaths and 1 billion dollars. Clostridium difficile related deaths have risen 400% over the last decade, and current standard antibiotic treatments are only 75 to 85% successful. Besides increasing the risk of antibiotic resistance and side effects, these treatments are very expensive. The most vulnerable population for Clostridium difficile is older adults, who make up approximately half of the cases, but account for 90% of the related deaths. Probiotics may have potential as adjunctive therapeutic agents for CDIs, however, current data is limited. METHODS This pilot study is a single-site, randomized, placebo-controlled, double-blind, phase two clinical trial. The trial primarily evaluates the effect of four weeks of probiotic therapy in addition to standard of care on Clostridium difficile diarrhea duration and recurrence. Secondary outcomes include effect on fecal cytokines, fecal lactoferrin, and Clostridium difficile toxin density in stool, as well as patient functional status. DISCUSSION This pilot study will determine the feasibility and effect size to conduct larger randomized controlled trials of probiotic interventions in patients with CDI, to determine the impact of probiotics on the symptoms of CDI. ClinicalTrials.gov Identifier: NCT01680874.

A randomized controlled trial of probiotics for Clostridium difficile infection in adults (PICO)

Background Clostridium difficile is the most common cause of hospital-acquired infections, responsible for >450000 infections annually in the USA. Probiotics provide a promising, well-tolerated adjunct therapy to standard C. difficile infection (CDI) treatment regimens, but there is a paucity of data regarding their effectiveness for the treatment of an initial CDI. Objectives We conducted a pilot randomized controlled trial of 33 participants from February 2013 to February 2015 to determine the feasibility and health outcomes of adjunct probiotic use in patients with an initial mild to moderate CDI. Methods The intervention was a 28 day, once-daily course of a four-strain oral probiotic capsule containing Lactobacillus acidophilus NCFM, Lactobacillus paracasei Lpc-37, Bifidobacterium lactis Bi-07 and B. lactis Bl-04. The control placebo was identical in taste and appearance. Registered at clinicaltrials.gov: trial registration number = NCT01680874. Results Probiotic adjunct therapy was associated with a significant improvement in diarrhoea outcomes. The primary duration of diarrhoea outcome (0.0 versus 1.0 days; P = 0.039) and two exploratory outcomes, total diarrhoea days (3.5 versus 12.0 days; P = 0.005) and rate of diarrhoea (0.1 versus 0.3 days of diarrhoea/stool diary days submitted; P = 0.009), all decreased in participants with probiotic use compared with placebo. There was no significant difference in the rate of CDI recurrence or functional improvement over time between treatment groups. Conclusions Probiotics are a promising adjunct therapy for treatment of an initial CDI and should be further explored in a larger randomized controlled trial.

Social determinants of antibiotic misuse: a qualitative study of community members in Haryana, India

BackgroundAntibiotic resistance is a global public health crisis. In India alone, multi-drug resistant organisms are responsible for over 58,000 infant deaths each year. A major driver of drug resistance is antibiotic misuse, which is a pervasive phenomenon worldwide. Due to a shortage of trained doctors, access to licensed allopathic doctors is limited in India’s villages. Pharmacists and unlicensed medical providers are commonly the primary sources of healthcare. Patients themselves are also key participants in the decision to treat an illness with antibiotics. Thus, better understanding of the patient-provider interactions that may contribute to patients’ inappropriate use of antibiotics is critical to reducing these practices in urban and rural Indian villages.MethodsWe conducted a qualitative study of the social determinants of antibiotic use among twenty community members in Haryana, India. Semi-structured interview questions focused on two domains: typical antibiotic use and the motivation behind these practices. A cross-sectional pilot survey investigated the same twenty participants’ understanding and usage of antibiotics. Interview and open-ended survey responses were translated, transcribed, and coded for themes.ResultsAntibiotics and the implications of their misuse were poorly understood by study participants. No participant was able to correctly define the term antibiotics. Participants with limited access to an allopathic doctor, either for logistic or economic reasons, were more likely to purchase medications directly from a pharmacy without a prescription. Low income participants were also more likely to prematurely stop antibiotics after symptoms subsided. Regardless of income, participants were more likely to seek an allopathic doctor for their children than for themselves.ConclusionsThe prevalent misuse of antibiotics among these community members reinforces the importance of conducting research to develop effective strategies for stemming the tide of antibiotic resistance in India’s villages.

Assessment of Fidelity in Interventions to Improve Hand Hygiene of Healthcare Workers: A Systematic Review

OBJECTIVE Compliance with hand hygiene in healthcare workers is fundamental to infection prevention yet remains a challenge to sustain. We examined fidelity reporting in interventions to improve hand hygiene compliance, and we assessed 5 measures of intervention fidelity: (1) adherence, (2) exposure or dose, (3) quality of intervention delivery, (4) participant responsiveness, and (5) program differentiation. DESIGN Systematic review METHODS A librarian performed searches of the literature in PubMed, Cumulative Index to Nursing and Allied Health (CINAHL), Cochrane Library, and Web of Science of material published prior to June 19, 2015. The review protocol was registered in PROSPERO International Prospective Register of Systematic Reviews, and assessment of study quality was conducted for each study reviewed. RESULTS A total of 100 studies met the inclusion criteria. Only 8 of these 100 studies reported all 5 measures of intervention fidelity. In addition, 39 of 100 (39%) failed to include at least 3 fidelity measures; 20 of 100 (20%) failed to include 4 measures; 17 of 100 (17%) failed to include 2 measures, while 16 of 100 (16%) of the studies failed to include at least 1 measure of fidelity. Participant responsiveness and adherence to the intervention were the most frequently unreported fidelity measures, while quality of the delivery was the most frequently reported measure. CONCLUSIONS Almost all hand hygiene intervention studies failed to report at least 1 fidelity measurement. To facilitate replication and effective implementation, reporting fidelity should be standard practice when describing results of complex behavioral interventions such as hand hygiene.

Risk of Clostridium difficile Infection in Hematology-Oncology Patients Colonized With Toxigenic C. difficile

The prevalence of colonization with toxigenic Clostridium difficile among patients with hematological malignancies and/or bone marrow transplant at admission to a 566-bed academic medical care center was 9.3%, and 13.3% of colonized patients developed symptomatic disease during hospitalization. This population may benefit from targeted C. difficile infection control interventions. Infect Control Hosp Epidemiol 2017;38:718-720.