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BackgroundTreating Chronic Non-Cancer Pain (CNCP) with long-term, high dose and more potent opioids puts patients at increased risk of harm, whilst providing limited pain relief. Socially deprived areas mapped from Index of Multiple Deprivation (IMD) scores show higher rates of high dose, strong opioid prescribing compared to more affluent areas.ObjectiveTo explore if opioid prescribing is higher in more deprived areas of Liverpool (UK) and assess the incidence of high dose prescribing to improve clinical pathways for opioid weaning.Design and settingThis retrospective observational study used primary care practice and patient level opioid prescribing data for N = 30,474 CNCP patients across Liverpool Clinical Commissioning Group (LCCG) between August 2016 and August 2018.MethodA Defined Daily Dose (DDD) was calculated for each patient prescribed opioids. DDD was converted into a Morphine Equivalent Dose (MED) and patients stratified according to high (≥120mg) MED cut off. The association between prescribing and deprivation was analysed by linking GP practice codes and IMD scores across LCCG.Results3.5% of patients were prescribed an average dose above 120mg MED/day. Patients prescribed long-term, high dose, strong opioids were more likely to be female, aged 60+, prescribed three opioids and reside in the North of Liverpool where there is a higher density of areas in the IMD most deprived deciles.ConclusionA small but significant proportion of CNCP patients across Liverpool are currently prescribed opioids above the recommended dose threshold of 120mg MED. Identification of fentanyl as a contributor to high dose prescribing resulted in changes to prescribing practice, and reports from NHS pain clinics that fewer patients require tapering from fentanyl. In conclusion, higher rates of high dose opioid prescribing continue to be evident in more socially deprived areas further increasing health inequalities.

Clinicians' perspectives of the reasons for performing caesarean section (CS) are fundamental to deepening knowledge and understanding of factors influencing decision-making for CS. The aim of this study was to explore midwives' and obstetricians' views of factors influencing decision-making for CS for first-time mothers. A qualitative descriptive study with semi-structured one-to-one audio-recorded interviews was used to gather data from clinicians (15 midwives and 20 senior obstetricians). Following research ethics committee approval, clinicians, who were directly involved in the decision-making process for CS during the period of data collection, were purposively selected from three maternity units in the Republic of Ireland between June 2016 to July 2017. The interviews were transcribed verbatim and analysed thematically. Three interrelated themes with several subthemes reflective of clinicians' views and experiences emerged following data analysis. These were: 'A fear factor' describing clinicians' fear of adverse outcomes and subsequent litigation, 'Personal preferences versus a threshold-clinician driven factors emphasising the influence of clinicians' personal beliefs, and 'Standardised versus individualised care-a system perspective' explaining the effects of, or lack of, organisational policy and its direct and indirect impact on the decision-making process. Findings show that decisions to perform a CS are, on occasion, based on clinicians' personal beliefs and interpretation, similar to findings from other published literature. Consideration of broader issues related to organisational, socio-cultural and political context is essential when seeking solutions to the rising CS rates. The findings will enable clinicians to reflect on their day-to-day practice, in order to look for modifiable factors that influence their decision-making, and help women understand the multitude of factors that can lead to a decision to perform a CS. Findings will also contribute to the development of the 'next step action' and assist in devising future intervention studies to reduce any unnecessary CSs.

This study aimed to describe how video laryngoscopy is used outside the operating room within the hospital setting. Specifically, we aimed to summarise the evidence for the use of video laryngoscopy outside the operating room, and detail how it appears in current clinical practice guidelines. A literature search was conducted across two databases (MEDLINE and Embase), and all articles underwent screening for relevance to our aims and pre-determined exclusion criteria. Our results include 14 clinical practice guidelines, 12 interventional studies, 38 observational studies. Our results show that video laryngoscopy is likely to improve glottic view and decrease the incidence of oesophageal intubations; however, it remains unclear as to how this contributes to first-pass success, overall intubation success and clinical outcomes such as mortality outside the operating room. Furthermore, our results indicate that the appearance of video laryngoscopy in clinical practice guidelines has increased in recent years, and particularly through the COVID-19 pandemic. Current COVID-19 airway management guidelines unanimously introduce video laryngoscopy as a first-line (rather than rescue) device.

BackgroundCaesarean section rates continue to rise in most parts of the world. While CS is a lifesaving procedure there is evidence that, beyond a certain threshold, CS rates may contribute to increased maternal and perinatal morbidity. This study aimed to elicit the views of pregnant women's and clinicians' on how CS rates might be reduced.MethodsPregnant women and their partners, and clinicians working with pregnant women in a maternity hospital in the Republic of Ireland of Ireland, were invited to participate in focus groups. Eligibility criteria included all women attending antenatal classes and clinicians working with pregnant women. A convenience sample was used and interviews were audio recorded, transcribed, and analysed using thematic analysis.ResultsFour focus group interviews were conducted with 30 clinicians and 15 pregnant women and two partners participated in three focus groups. A further two women were interviewed individually. Participants expressed a view that rising CS rates were impacted by a societal perception that CS had become a 'normal mode of birth'. Suggestions for reducing CS rates were offered by clinicians and pregnant women and their partners.ConclusionsClinicians and pregnant women consider that CS rates can be reduced if a shared philosophy supporting normal birth is prioritised alongside adequate resourcing. Women and their partners also believe that enhanced communication with clinicians is central to reducing CS rates.

AIM:To estimate the economic burden of common health problems associated with pregnancy and childbirth, such as incontinence, mental health problems, or gestational diabetes, excluding acute complications of labour or birth, or severe acute adverse maternal outcomes. METHODS:Searches for relevant studies were carried out to November 2019 in Medline, Embase, CINAHL, PsycINFO and EconLit databases. After initial screening, all results were reviewed for inclusion by two authors. An adapted version of a previously developed checklist for cost-of-illness studies was used for quality appraisal. All costs were converted to 2018 Euro using national consumer price indices and purchasing power parity conversion factors. RESULTS:Thirty-eight relevant studies were identified, some of which reported incremental costs for more than one health problem (16 gestational diabetes, 13 overweight/obesity, 8 mental health, 4 hypertensive disorders, 2 nausea and vomiting, 2 epilepsy, 1 intimate partner violence). A high level of heterogeneity was observed in both the methods used, and the incremental cost estimates obtained for each morbidity. Average incremental costs tended to be higher in studies that modelled a hypothetical cohort of women using data from a range of sources (compared to analyses of primary data), and in studies set in the United States. No studies that examined the economic burden of some common pregnancy-related morbidities, such as incontinence, pelvic girdle pain, or sexual health problems, were identified. CONCLUSION:Our findings indicate that maternal morbidity is associated with significant costs to health systems and society, but large gaps remain in the evidence base for the economic burden of some common health problems associated with pregnancy and childbirth. More research is needed to examine the economic burden of a range of common maternal health problems, and future research should adopt consistent methodological approaches to ensure comparability of results.

Caesarean section (CS) rates throughout Europe have risen significantly over the last two decades. As well as being an important clinical issue, these changes in mode of birth may have substantial resource implications. Policy initiatives to curb this rise have had to contend with the multiplier effect of women who had a CS for their first birth having a greater likelihood of requiring one during subsequent births, thus making it difficult to decrease CS rates in the short term. Our study examines the long-term resource implications of reducing CS rates among first-time mothers, as well as improving rates of vaginal birth after caesarean section (VBAC), among an annual cohort of women over the course of their most active childbearing years (18 to 44 years) in two public health systems in Europe. We found that the economic benefit of improvements in these two outcomes is considerable, with the net present value of the savings associated with a five-percentage-point change in nulliparous CS rates and VBAC rates being €1.1million and £9.8million per annual cohort of 18-year-olds in Ireland and England/Wales, respectively. Reductions in CS rates among first-time mothers are associated with a greater payoff than comparable increases in VBAC rates. The net present value of achieving CS rates comparable to those currently observed in the best performing Scandinavian countries was €3.5M and £23.0M per annual cohort in Ireland and England/Wales, respectively.

One hundred human-derived coagulase negative staphylococci (CoNS) were screened for antimicrobial activity using agar-based deferred antagonism assays with a range of indicator bacteria. Based on the findings of the screen and subsequent well assays with cell free supernatants and whole cell extracts, one strain, designated CIT060, was selected for further investigation. It was identified as Staphylococcus capitis and herein we describe the purification and characterisation of the novel bacteriocin that the strain produces. This bacteriocin which we have named capidermicin was extracted from the cell-free supernatant of S. capitis CIT060 and purified to homogeneity using reversed-phase high performance liquid chromatography (RP-HPLC). Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometric (MS) analysis revealed that the capidermicin peptide has a mass of 5,464 Da. Minimal inhibitory concentration (MIC) experiments showed that capidermicin was active in the micro-molar range against all the Gram-positive bacteria that were tested. Antimicrobial activity was retained over a range of pHs (2-11) and temperatures (10-121°C x 15 mins). The draft genome sequence of S. capitis CIT060 was determined and the genes predicted to be involved in the biosynthesis of capidermicin were identified. These genes included the predicted capidermicin precursor gene, and genes that are predicted to encode a membrane transporter, an immunity protein and a transcriptional regulator. Homology searches suggest that capidermicin is a novel member of the family of class II leaderless bacteriocins.

Concern has been expressed globally over rising caesarean birth rates. Recently, the International Federation of Gynaecology and Obstetrics (FIGO) called for help from governmental bodies, professional organisations, women's groups, and other stakeholders to reduce unnecessary caesareans. As part of a wider research initiative, we conducted an overview of systematic reviews of antenatal and intrapartum interventions, and reports of evidence based recommendations, to identify and highlight those that have been shown to be effective for reducing caesarean birth, promoting vaginal birth and reducing fear of childbirth. Following registration of the review protocol, (PROSPERO 2018 CRD42018090681), we searched The Cochrane Database of Systematic Reviews, PubMed, CINAHL and EMBASE (Jan 2000-Jan 2018) and searched for grey literature in PROSPERO, and on websites of health professional and other relevant bodies. Screening and selection of reviews, quality appraisal using AMSTAR-2, and data extraction were performed independently by pairs of at least two reviewers. Excluding reviews assessed as 'critically low' on AMSTAR-2 (n = 54), 101 systematic reviews, and 10 reports of evidence based recommendations were included in the overview. Narrative synthesis was performed, due to heterogeneity of review methodology and topics. The results highlight twenty-five interventions, across 17 reviews, that reduced the risk of caesarean, nine interventions across eight reviews that increased the risk of caesarean, eight interventions that reduced instrumental vaginal birth, four interventions that increased spontaneous vaginal birth, and two interventions that reduced fear of childbirth. This overview of reviews identifies and highlights interventions that have been shown to be effective for reducing caesarean birth, promoting vaginal births and reducing fear of childbirth. In recognising that clinical practices change over time, this overview includes reviews published from 2000 onwards only, thus providing contemporary evidence, and a valuable resource for clinicians when making decisions on practices that should be implemented for reducing unnecessary caesarean births safely. Protocol Registration: PROSPERO 2018 CRD42018090681. Available from: http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42018090681.

[This corrects the article DOI: 10.1371/journal.pone.0200941.].

Although cancer patients (CPs) are increasingly likely to visit emergency department (ED), no population-based study has compared the characteristics of CPs and non-cancer patients (NCPs) who visit the ED and examined factors associated with hospitalization via the ED. In this study, we (1) compared characteristics and diagnoses between CPs and NCPs who visited the ED in a cancer center or general hospital; (2) compared characteristics and diagnoses between CPs and NCPs who were hospitalized via the ED in a cancer center or general hospital; and (3) investigated important factors associated with such hospitalization.We analyzed patient characteristic and diagnosis [based on International Classification of Diseases-9 (ICD-9) codes] data from the ED of a comprehensive cancer center (MDACC), 24 general EDs in Harris County, Texas (HCED), and the National Hospital Ambulatory Medical Care Survey (NHAMCS) from 1/1/2007-12/31/2009. Approximately 3.4 million ED visits were analyzed: 47,245, 3,248,973, and 104,566 visits for MDACC, HCED, and NHAMCS, respectively, of which 44,143 (93.4%), 44,583 (1.4%), and 632 (0.6%) were CP visits. CPs were older than NCPs and stayed longer in EDs. Lung, gastrointestinal (excluding colorectal), and genitourinary (excluding prostate) cancers were the three most common diagnoses related to ED visits at general EDs. CPs visiting MDACC were more likely than CPs visiting HCED to be privately insured. CPs were more likely than NCPs to be hospitalized. Pneumonia and influenza, fluid and electrolyte disorders, and fever were important predictive factors for CP hospitalization; coronary artery disease, cerebrovascular disease, and heart failure were important factors for NCP hospitalization.CPs consumed more ED resources than NCPs and had a higher hospitalization rate. Given the differences in characteristics and diagnoses between CPs and NCPs, ED physicians must pay special attention to CPs and be familiar with their unique set of oncologic emergencies.

BACKGROUND:Caesarean section rates are increasing worldwide and are a growing concern with limited explanation of the factors that influence the rising trend. Understanding obstetricians' and midwives' views can give insight to the problem. This systematic review aimed to offer insight and understanding, through aggregation, summary, synthesis and interpretation of findings from studies that report obstetricians' and midwives' views on the factors that influence the decision to perform caesarean section. METHODS:The electronic databases of PubMed (1958-2016), CINAHL (1988-2016), Maternity and Infant Care (1971-2016), PsycINFO (1980-2016) and Web of Science (1991-2016) were searched in September 2016. All quantitative, qualitative and mixed methods studies, published in English, whose aim was to explore obstetricians' and/or midwives' views of factors influencing decision-making for caesarean section were included. Papers were independently reviewed by two authors for selection by title, abstract and full text. Thomas et al's 12 assessment criteria checklist (2003) was used to assess methodological quality of the included studies. RESULT:The review included 34 studies: 19 quantitative, 14 qualitative, and one using mixed methods, involving 7785 obstetricians and 1197 midwives from 20 countries. Three main themes, each with several subthemes, emerged. Theme 1: "clinicians' personal beliefs"-('Professional philosophies'; 'beliefs in relation to women's request for CS'; 'ambiguous versus clear clinical reasons'); Theme 2: "health care systems"-('litigation'; 'resources'; 'private versus public/insurance/payments'; 'guidelines and management policy'). Theme 3: "clinicians' characteristics" ('personal convenience'; 'clinicians' demographics'; 'confidence and skills'). CONCLUSION:This systematic review and metasynthesis identified clinicians' personal beliefs as a major factor that influenced the decision to perform caesarean section, further contributed by the influence of factors related to the health care system and clinicians' characteristics. Obstetricians and midwives are directly involved in the decision to perform a caesarean section, hence their perspectives are vital in understanding various factors that have influence on decision-making for caesarean section. These results can help clinicians identify and acknowledge their role as crucial members in the decision-making process for caesarean section within their organisation, and to develop intervention studies to reduce caesarean section rates in future.

Environmental and metabolic sources of reactive oxygen species (ROS) can damage DNA, proteins and lipids to promote disease. Regulation of gene expression can prevent this damage and can include increased transcription, translation and post translational modification. Cellular responses to ROS play important roles in disease prevention, with deficiencies linked to cancer, neurodegeneration and ageing. Here we detail basal and damage-induced translational regulation of a group of oxidative-stress response enzymes by the tRNA methyltransferase Alkbh8. Using a new gene targeted knockout mouse cell system, we show that Alkbh8-/- embryonic fibroblasts (MEFs) display elevated ROS levels, increased DNA and lipid damage and hallmarks of cellular stress. We demonstrate that Alkbh8 is induced in response to ROS and is required for the efficient expression of selenocysteine-containing ROS detoxification enzymes belonging to the glutathione peroxidase (Gpx1, Gpx3, Gpx6 and likely Gpx4) and thioredoxin reductase (TrxR1) families. We also show that, in response to oxidative stress, the tRNA modification 5-methoxycarbonylmethyl-2'-O-methyluridine (mcm5Um) increases in normal MEFs to drive the expression of ROS detoxification enzymes, with this damage-induced reprogramming of tRNA and stop-codon recoding corrupted in Alkbh8-/- MEFS. These studies define Alkbh8 and tRNA modifications as central regulators of cellular oxidative stress responses in mammalian systems. In addition they highlight a new animal model for use in environmental and cancer studies and link translational regulation to the prevention of DNA and lipid damage.

Several clinical trials in oncology have reported increased mortality or disease progression associated with erythropoiesis-stimulating agents. One hypothesis proposes that erythropoiesis-stimulating agents directly stimulate tumor proliferation and/or survival through cell-surface receptors. To test this hypothesis and examine if human tumors utilize the erythropoietin receptor pathway, the response of tumor cells to human recombinant erythropoietin was investigated in disaggregated tumor cells obtained from 186 patients with colorectal, breast, lung, ovarian, head and neck, and other tumors. A cocktail of well characterized tumor growth factors (EGF, HGF, and IGF-1) were analyzed in parallel as a positive control to determine whether freshly-isolated tumor cells were able to respond to growth factor activation ex vivo. Exposing tumor cells to the growth factor cocktail resulted in stimulation of survival and proliferation pathways as measured by an increase in phosphorylation of the downstream signaling proteins AKT and ERK. In contrast, no activation by human recombinant erythropoietin was observed in isolated tumor cells. Though tumor samples exhibited a broad range of cell-surface expression of EGFR, c-Met, and IGF-1R, no cell-surface erythropoietin receptor was detected in tumor cells from the 186 tumors examined (by flow cytometry or Western blot). Erythropoiesis-stimulating agents did not act directly upon isolated tumor cells to stimulate pathways known to promote proliferation or survival of human tumor cells isolated from primary and metastatic tumor tissues.

BACKGROUND:The genus Burkholderia includes pathogenic gram-negative bacteria that cause melioidosis, glanders, and pulmonary infections of patients with cancer and cystic fibrosis. Drug resistance has made development of new antimicrobials critical. Many approaches to discovering new antimicrobials, such as structure-based drug design and whole cell phenotypic screens followed by lead refinement, require high-resolution structures of proteins essential to the parasite. METHODOLOGY/PRINCIPAL FINDINGS:We experimentally identified 406 putative essential genes in B. thailandensis, a low-virulence species phylogenetically similar to B. pseudomallei, the causative agent of melioidosis, using saturation-level transposon mutagenesis and next-generation sequencing (Tn-seq). We selected 315 protein products of these genes based on structure-determination criteria, such as excluding very large and/or integral membrane proteins, and entered them into the Seattle Structural Genomics Center for Infection Disease (SSGCID) structure determination pipeline. To maximize structural coverage of these targets, we applied an "ortholog rescue" strategy for those producing insoluble or difficult to crystallize proteins, resulting in the addition of 387 orthologs (or paralogs) from seven other Burkholderia species into the SSGCID pipeline. This structural genomics approach yielded structures from 31 putative essential targets from B. thailandensis, and 25 orthologs from other Burkholderia species, yielding an overall structural coverage for 49 of the 406 essential gene families, with a total of 88 depositions into the Protein Data Bank. Of these, 25 proteins have properties of a potential antimicrobial drug target i.e., no close human homolog, part of an essential metabolic pathway, and a deep binding pocket. We describe the structures of several potential drug targets in detail. CONCLUSIONS/SIGNIFICANCE:This collection of structures, solubility and experimental essentiality data provides a resource for development of drugs against infections and diseases caused by Burkholderia. All expression clones and proteins created in this study are freely available by request.

Iron is an essential micronutrient for Pseudomonas syringae pv. syringae strain B728a and many other microorganisms; therefore, B728a has evolved methods of iron acquirement including the use of iron-chelating siderophores. In this study an extracytoplasmic function (ECF) sigma factor, AcsS, encoded within the achromobactin gene cluster is shown to be a major regulator of genes involved in the biosynthesis and secretion of this siderophore. However, production of achromobactin was not completely abrogated in the deletion mutant, implying that other regulators may be involved such as PvdS, the sigma factor that regulates pyoverdine biosynthesis. RNA-seq analysis identified 287 genes that are differentially expressed between the AcsS deletion mutant and the wild type strain. These genes are involved in iron response, secretion, extracellular polysaccharide production, and cell motility. Thus, the transcriptome analysis supports a role for AcsS in the regulation of achromobactin production and the potential activity of both AcsS and achromobactin in the plant-associated lifestyle of strain B728a.

Nisin is a bacteriocin widely utilized in more than 50 countries as a safe and natural antibacterial food preservative. It is the most extensively studied bacteriocin, having undergone decades of bioengineering with a view to improving function and physicochemical properties. The discovery of novel nisin variants with enhanced activity against clinical and foodborne pathogens has recently been described. We screened a randomized bank of nisin A producers and identified a variant with a serine to glycine change at position 29 (S29G), with enhanced efficacy against S. aureus SA113. Using a site-saturation mutagenesis approach we generated three more derivatives (S29A, S29D and S29E) with enhanced activity against a range of Gram positive drug resistant clinical, veterinary and food pathogens. In addition, a number of the nisin S29 derivatives displayed superior antimicrobial activity to nisin A when assessed against a range of Gram negative food-associated pathogens, including E. coli, Salmonella enterica serovar Typhimurium and Cronobacter sakazakii. This is the first report of derivatives of nisin, or indeed any lantibiotic, with enhanced antimicrobial activity against both Gram positive and Gram negative bacteria.

Vitamin B1 is in its active form thiamine pyrophosphate (TPP), an essential cofactor for several key enzymes in the carbohydrate metabolism. Mammals must salvage this crucial nutrient from their diet in order to complement the deficiency of de novo synthesis. In the human pathogenic bacterium Staphylococcus aureus, two operons were identified which are involved in vitamin B1 metabolism. The first operon encodes for the thiaminase type II (TenA), 4-amino-5-hydroxymethyl-2-methylpyrimidine kinase (ThiD), 5-(2-hydroxyethyl)-4-methylthiazole kinase (ThiM) and thiamine phosphate synthase (ThiE). The second operon encodes a phosphatase, an epimerase and the thiamine pyrophosphokinase (TPK). The open reading frames of the individual operons were cloned, their corresponding proteins were recombinantly expressed and biochemically analysed. The kinetic properties of the enzymes as well as the binding of TPP to the in vitro transcribed RNA of the proposed operons suggest that the vitamin B1 homeostasis in S. aureus is strongly regulated at transcriptional as well as enzymatic levels.

BACKGROUND: Circumcision reduces HIV acquisition among heterosexual men in Africa, but it is unclear if circumcision may reduce HIV acquisition among men who have sex with men (MSM) in the United States, or whether MSM would be willing to be circumcised if recommended. METHODS: We interviewed presumed-HIV negative MSM at gay pride events in 2006. We asked uncircumcised respondents about willingness to be circumcised if it were proven to reduce risk of HIV among MSM and perceived barriers to circumcision. Multivariate logistic regression was used to identify covariates associated with willingness to be circumcised. RESULTS: Of 780 MSM, 133 (17%) were uncircumcised. Of these, 71 (53%) were willing to be circumcised. Willingness was associated with black race (exact odds ratio [OR]: 3.4, 95% confidence interval [CI]: 1.3-9.8), non-injection drug use (OR: 6.1, 95% CI: 1.8-23.7) and perceived reduced risk of penile cancer (OR: 4.7, 95% CI: 2.0-11.9). The most commonly endorsed concerns about circumcision were post-surgical pain and wound infection. CONCLUSIONS: Over half of uncircumcised MSM, especially black MSM, expressed willingness to be circumcised. Perceived risks and benefits of circumcision should be a part of educational materials if circumcision is recommended for MSM in the United States.

Yeast strains lacking Anc1, a member of the YEATS protein family, are sensitive to several DNA damaging agents. The YEATS family includes two human genes that are common fusion partners with MLL in human acute leukemias. Anc1 is a member of seven multi-protein complexes involved in transcription, and the damage sensitivity observed in anc1Delta cells is mirrored in strains deleted for some other non-essential members of several of these complexes. Here we show that ANC1 is in the same epistasis group as SRS2 and RAD5, members of the postreplication repair (PRR) pathway, but has additive or synergistic interactions with several other members of this pathway. Although PRR is traditionally divided into an "error-prone" and an "error-free" branch, ANC1 is not epistatic with all members of either established branch, and instead defines a new error-free branch of the PRR pathway. Like several genes involved in PRR, an intact ANC1 gene significantly suppresses spontaneous mutation rates, including the expansion of (CAG)(25) repeats. Anc1's role in the PRR pathway, as well as its role in suppressing triplet repeats, point to a possible mechanism for a protein of potential medical interest.

Upon exposure to DNA damaging agents, Saccharomyces cerevisiae respond by activating a massive transcriptional program that reflects the fact that "DNA damaging" agents also damage other cellular macromolecules. To identify the transcriptional response that is specific to DNA damage, we have modulated the first two enzymes in the base excision repair (BER) pathway generating yeast strains with varied levels of the repair intermediates, abasic sites or strand breaks. We show that the number of abasic sites is significantly increased when the 3-methyladenine DNA glycosylase (Mag): AP endonuclease (Apn1) ratio is increased and that spontaneous frame shift mutation is considerably elevated when either Mag, or Mag plus Apn1, expression is elevated. Expression profiling identified 633 ORFs with differential expression associated with BER modulation. Analysis of transcriptional networks associated with the accumulation of DNA repair intermediates identifies an enrichment for numerous biological processes. Moreover, most of the BER-activated transcriptional response was independent of the classical yeast environmental stress response (ESR). This study highlights that DNA damage in the form of abasic sites or strand breaks resulting from BER modulation is a trigger for substantial genome-wide change and that this response is largely ESR-independent. Taken together, these results suggest that a branch point exists in the current model for DNA damage-signaled transcription in S. cerevisiae.

BACKGROUND: Nonadherence to antiretroviral therapy (ARVT) is an important behavioral determinant of the success of ARVT. Nonadherence may lead to virological failure, and increases the risk of development of drug resistance. Understanding the prevalence of nonadherence and associated factors is important to inform secondary HIV prevention efforts. METHODOLOGY/PRINCIPAL FINDINGS: We used data from a cross-sectional interview study of persons with HIV conducted in 18 U.S. states from 2000-2004. We calculated the proportion of nonadherent respondents (took or=4 medications; living in a shelter or on the street; and feeling "blue" >or=14 of the past 30 days. We found weaker associations with having both male-male sex and injection drug use risks for HIV acquisition; being prescribed ARVT for >or=21 months; and being prescribed a protease inhibitor (PI)-based regimen not boosted with ritonavir. The median proportion of doses missed was 50%. The most common reasons for missing doses were forgetting and side effects. CONCLUSIONS/SIGNIFICANCE: Self-reported recent nonadherence was high in our study. Our data support increased emphasis on adherence in clinical settings, and additional research on how providers and patients can overcome barriers to adherence.