DrugnomeAI is an ensemble machine-learning framework for predicting druggability of candidate drug targets.

The druggability of targets is a crucial consideration in drug target selection. Here, we adopt a stochastic semi-supervised ML framework to develop DrugnomeAI, which estimates the druggability likelihood for every protein-coding gene in the human exome. DrugnomeAI integrates gene-level properties from 15 sources resulting in 324 features. The tool generates exome-wide predictions based on labelled sets of known drug targets (median AUC: 0.97), highlighting features from protein-protein interaction networks as top predictors. DrugnomeAI provides generic as well as specialised models stratified by disease type or drug therapeutic modality. The top-ranking DrugnomeAI genes were significantly enriched for genes previously selected for clinical development programs (p value < 1 × 10-308) and for genes achieving genome-wide significance in phenome-wide association studies of 450 K UK Biobank exomes for binary (p value = 1.7 × 10-5) and quantitative traits (p value = 1.6 × 10-7). We accompany our method with a web application ( http://drugnomeai.public.cgr.astrazeneca.com ) to visualise the druggability predictions and the key features that define gene druggability, per disease type and modality.

Pilot Randomized Controlled Trial of Diabetes Group Prenatal Care.

OBJECTIVE: This study aimed to determine the feasibility and effectiveness of Diabetes Group Prenatal Care to increase patient engagement in diabetes self-care activities. STUDY DESIGN: A pilot randomized controlled trial was conducted at two sites. Inclusion criteria were English or Spanish speaking, type 2 or gestational diabetes, 22 to 34 weeks of gestational age at first study visit, ability to attend group care at specified times, and willingness to be randomized. Exclusion criteria included type 1 diabetes, multiple gestation, major fetal anomaly, serious medical comorbidity, and serious psychiatric illness. Women were randomized to Diabetes Group Prenatal Care or individual prenatal care. The primary outcome was completion of diabetes self-care activities, including diet, exercise, blood sugar testing, and medication adherence. Secondary outcomes included antenatal care characteristics, and maternal, neonatal, and diabetes management outcomes. Analysis followed the intention-to-treat principle. RESULTS: Of 159 eligible women, 84 (53%) consented to participate in the study and were randomized to group (n = 42) or individual (n = 42) prenatal care. Demographic characteristics were similar between study arms. Completion of diabetes self-care activities was similar overall, but women in group care ate the recommended amount of fruits and vegetables on more days per week (5.1 days/week ± 2.0 standard deviation [SD] in group care vs. 3.4 days ± 2.6 SD in individual care; p < 0.01) and gained less weight per week during the study period (0.2 lbs/week [interquartile range: 0-0.7] vs. 0.5 lbs/week [interquartile range: 0.2-0.9]; p = 0.03) than women in individual care. Women with gestational diabetes randomized to group care were 3.5 times more likely to have postpartum glucose tolerance testing than those in individual care (70 vs. 21%; relative risk: 3.5; 95% confidence interval: 1.4-8.8). Other maternal, neonatal, and pregnancy outcomes were similar between study arms. CONCLUSION: Diabetes group care is feasible and shows promise for decreasing gestational weight gain, improving diet, and increasing postpartum diabetes testing among women with pregnancies complicated by diabetes. KEY POINTS: · Women with gestational diabetes in group care were 3.5 times more likely to return for postpartum glucose tolerance testing.. · Women with gestational diabetes in group care had less gestational weight gain during the study period.. · Diabetes Group Prenatal Care is a promising intervention to improve outcomes for women with diabetes in pregnancy..

The effect of group prenatal care for women with diabetes on social support and depressive symptoms: a pilot randomized trial.

Objective: To measure the impact of group prenatal care (GPC) on diabetes-specific peer support and depressive symptoms in women with pregnancies complicated by diabetes.Materials and methods: This is a planned secondary analysis of a two-center pilot randomized controlled trial conducted at Denver health (DH) and Washington University in St. Louis (WU) including Spanish (DH) or English (WU) speaking women with type 2 or gestational diabetes. Women were randomized to diabetes GPC or individual prenatal care (IPC) in the resident diabetes clinic. Participants completed an Edinburgh Postnatal Depression Scale (EPDS) at randomization, at 38-week gestation and at 6-12 weeks postpartum. The diabetes support scale (DSS), which includes 12 questions answered on a Likert scale, was administered at 38 weeks. Analysis was by intention to treat (clincaltrials.gov#NCT02444325).Results: A total of 84 women were consented and randomized. Six withdrew consent (two from each cohort) or were lost to follow-up (two from IPC), and three did not complete the 38-week assessment (two from GPC and one from IPC), resulting in primary outcome data available for 75 women: 38 in GPC and 37 in IPC. More women randomized to GPC reported composite positive peer support on the DSS (52.5 versus 26.3%; p < .02). There were no differences in EPDS scores, depression (EPDS >10), or rates of improved EPDS score from baseline to 38 weeks.Conclusion: GPC for women with diabetes is associated with improved diabetes-specific peer social support with no significant impact on depressive symptoms.Clinical trial registration: Clincaltrials.gov NCT02444.

Implementation of Trauma-Informed Care and Brief Solution-Focused Therapy: A Quality Improvement Project Aimed at Increasing Engagement on an Inpatient Psychiatric Unit.

Addressing tense and escalating situations with noncoercive measures is an important element of inpatient psychiatric treatment. Although restraint rates are frequently monitored, the use of pro re nata (PRN) intramuscular (IM) injections to address agitation is also an important indicator. In 2015, at the current study site, a significant increase was noted in PRN IM medication use despite unit leadership's efforts to build a culture of trauma-informed care (TIC). The purpose of the current quality improvement project was to educate staff on methods to incorporate TIC into daily practice and the use of brief solution-focused therapy techniques in escalating situations. Measurement of attitudes toward patient aggression and engagement with patients followed two waves of staff education. Upon completion of the project, a decrease in PRN IM medications, improvement in staff attitudes toward patient aggression, and improved sense of staff competency in handling tense situations were noted. [Journal of Psychosocial Nursing and Mental Health Services, 56(8), 16-22.].

Intuition in Clinical Decision Making: Differences Among Practicing Nurses.

PURPOSE: To examine the relationships and differences in the use of intuition among three categories of practicing nurses from various clinical units at a medical center in the Midwest. DESIGN: Descriptive, correlational, cross-sectional, prospective design. METHOD: Three categories of nurses were based on the clinical unit: medical/surgical nurses ( n = 42), step-down/progressive care nurses ( n = 32), and critical care nurses ( n = 24). Participants were e-mailed the Rew Intuitive Judgment Scale (RIJS) via their employee e-mail to measure intuition in clinical practice. Participants were also asked to rate themselves according to Benner's (novice to expert) proficiency levels. FINDINGS: Nurses practicing at higher self-reported proficiency levels, as defined by Benner, scored higher on the RIJS. More years of clinical experience were associated with higher self-reported levels of nursing proficiency and higher scores on the RIJS. There were no differences in intuition scores among the three categories of nurses. CONCLUSION: Nurses have many options, such as the nursing process, evidence-based clinical decision-making pathways, protocols, and intuition to aid them in the clinical decision-making process. Nurse educators and development professionals have a responsibility to recognize and embrace the multiple thought processes used by the nurse to better the nursing profession and positively affect patient outcomes.

Group prenatal care for women with gestational diabetes (.).

OBJECTIVE: We aimed to determine if group prenatal care affects the progression to A2 gestational diabetes mellitus (GDM) when compared with conventional care for women with GDM. METHODS: Prospective observational cohort of women diagnosed with GDM who attended group visits compared with a historical control group of women who received conventional obstetrical care in the year prior but would have met inclusion criteria for group care. The primary outcome was progression to A2 GDM. Secondary outcomes included antepartum, intrapartum and postpartum maternal outcomes and neonatal outcomes. RESULTS: A total of 165 subjects were included: 62 in group care and 103 in conventional care. Compared with patients with conventional care, group subjects were more likely to attend a postpartum visit (92% versus 66%; p = 0.002) and were almost 4 times more likely to receive recommended diabetes screening postpartum (OR 3.9, CI 1.8-8.6). Group subjects were much less likely to progress to A2 GDM (OR 0.15, CI 0.07-0.30). There were no differences in neonatal outcomes. CONCLUSIONS: Group prenatal care for women with diabetes is associated with decreased progression to A2 GDM and improved postpartum follow-up for appropriate diabetes screening without significantly affecting obstetrical or neonatal outcomes.

Characterization of novel respiratory syncytial virus inhibitors identified by high throughput screen.

Respiratory Syncytial Virus (RSV) is a major cause of lower respiratory tract infections with no effective treatment available. Finding novel inhibitors of RSV is an important first step towards developing an efficacious RSV therapy. Here we report the characterization of three novel classes of RSV replication inhibitors identified through a high throughput RSV replicon screen of ∼1million compounds in the AstraZeneca compound collection. These inhibitors, cpd 1, 2, and 3, specifically targeted RSV and were not active against other viruses tested. Resistance selection in RSV A2 with cpd 1 identified escape viruses with mutations mapped to the RSV L protein, an RNA-dependent RNA polymerase (Y1631C and I1413T). Recombinant RSV containing the L Y1631C substitution conferred resistance towards cpd 1, suggesting that the RSV polymerase is the target of this inhibitor. Interestingly, cpd 3, a nucleoside analog, induced a single resistant mutation in the P protein (D231V), indicating a novel mode of action not previously reported. cpd 2 affected host cell cycle and no frequent mutation was isolated following resistance selection, suggesting its possible involvement of a host-targeted mechanism. Taken together, we have identified three novel RSV inhibitors with different modes of action, providing new chemistry starting points for the discovery and development of future RSV therapeutic treatment.

Overexpression of Pseudomonas aeruginosa LpxC with its inhibitors in an acrB-deficient Escherichia coli strain.

In Gram-negative bacteria, the cell wall is surrounded by an outer membrane, the outer leaflet of which is comprised of charged lipopolysaccharide (LPS) molecules. Lipid A, a component of LPS, anchors this molecule to the outer membrane. UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a zinc-dependent metalloamidase that catalyzes the first committed step of biosynthesis of Lipid A, making it a promising target for antibiotic therapy. Formation of soluble aggregates of Pseudomonas aeruginosa LpxC protein when overexpressed in Escherichia coli has limited the availability of high quality protein for X-ray crystallography. Expression of LpxC in the presence of an inhibitor dramatically increased protein solubility, shortened crystallization time and led to a high-resolution crystal structure of LpxC bound to the inhibitor. However, this approach required large amounts of compound, restricting its use. To reduce the amount of compound needed, an overexpression strain of E. coli was created lacking acrB, a critical component of the major efflux pump. By overexpressing LpxC in the efflux deficient strain in the presence of LpxC inhibitors, several structures of P. aeruginosa LpxC in complex with different compounds were solved to accelerate structure-based drug design.

Optimization of pyrrolamide topoisomerase II inhibitors toward identification of an antibacterial clinical candidate (AZD5099).

AZD5099 (compound 63) is an antibacterial agent that entered phase 1 clinical trials targeting infections caused by Gram-positive and fastidious Gram-negative bacteria. It was derived from previously reported pyrrolamide antibacterials and a fragment-based approach targeting the ATP binding site of bacterial type II topoisomerases. The program described herein varied a 3-piperidine substituent and incorporated 4-thiazole substituents that form a seven-membered ring intramolecular hydrogen bond with a 5-position carboxylic acid. Improved antibacterial activity and lower in vivo clearances were achieved. The lower clearances were attributed, in part, to reduced recognition by the multidrug resistant transporter Mrp2. Compound 63 showed notable efficacy in a mouse neutropenic Staphylococcus aureus infection model. Resistance frequency versus the drug was low, and reports of clinical resistance due to alteration of the target are few. Hence, 63 could offer a novel treatment for serious issues of resistance to currently used antibacterials.

Selective inhibitors of bacterial t-RNA-(N(1)G37) methyltransferase (TrmD) that demonstrate novel ordering of the lid domain.

The tRNA-(N(1)G37) methyltransferase (TrmD) is essential for growth and highly conserved in both Gram-positive and Gram-negative bacterial pathogens. Additionally, TrmD is very distinct from its human orthologue TRM5 and thus is a suitable target for the design of novel antibacterials. Screening of a collection of compound fragments using Haemophilus influenzae TrmD identified inhibitory, fused thieno-pyrimidones that were competitive with S-adenosylmethionine (SAM), the physiological methyl donor substrate. Guided by X-ray cocrystal structures, fragment 1 was elaborated into a nanomolar inhibitor of a broad range of Gram-negative TrmD isozymes. These compounds demonstrated no activity against representative human SAM utilizing enzymes, PRMT1 and SET7/9. This is the first report of selective, nanomolar inhibitors of TrmD with demonstrated ability to order the TrmD lid in the absence of tRNA.

Exploring the UDP pocket of LpxC through amino acid analogs.

Lipopolysaccharide (LPS) biosynthesis is an attractive antibacterial target as it is both conserved and essential for the survival of key pathogenic bacteria. Lipid A is the hydrophobic anchor for LPS and a key structural component of the outer membrane of Gram-negative bacteria. Lipid A biosynthesis is performed in part by a unique zinc dependent metalloamidase, LpxC (UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase), which catalyzes the first non-reversible step in lipid A biosynthesis. The UDP portion of the LpxC substrate-binding pocket has been relatively unexplored. We have designed and evaluated a series of hydroxamate based inhibitors which explore the SAR of substitutions directed into the UDP pocket with a range of substituted α-amino acid based linkers. We also provide the first wild type structure of Pseudomonas aeruginosa LpxC which was utilized in the design of many of these analogs.

Women's perceptions of childbirth experience at a hospital in rural Tanzania.

Tanzania's health care provider shortage, especially in rural areas, makes it challenging to meet women's support needs in hospitals. We describe women's perceptions of childbirth support at a hospital in rural Tanzania. We interviewed 25 women within 24 hours after delivery using semistructured interviews. Most women sought life-saving technological support in case of complications. They also valued having family present to provide care and affection. Women's needs, however, were difficult to fulfill at this busy facility. Increasing women-centered childbirth support and recognizing family as important contributors may provide a strategy to meet the needs of both women and providers.

What level of knowledge do elementary school teachers possess concerning the care of children with asthma? A pilot study.

A self-report questionnaire was used to assess the level of knowledge among a convenience sample of 34 elementary school teachers in a rural school district in Illinois. The questionnaire addressed general asthma knowledge and management, including signs and symptoms, triggers, and treatment. The results suggest a knowledge deficit among this sample of elementary school teachers; the average score was 75%. Teachers with an increased exposure/experience with asthma scored significantly higher than did those with limited exposure. Implications of these findings for schools in rural areas are discussed.

Design of inhibitors of Helicobacter pylori glutamate racemase as selective antibacterial agents: incorporation of imidazoles onto a core pyrazolopyrimidinedione scaffold to improve bioavailabilty.

Structure-activity relationships are presented around a series of pyrazolopyrimidinediones that inhibit the growth of Helicobacter pylori by targeting glutamate racemase, an enzyme that provides d-glutamate for the construction of N-acetylglucosamine-N-acetylmuramic acid peptidoglycan subunits assimilated into the bacterial cell wall. Substituents on the inhibitor scaffold were varied to optimize target potency, antibacterial activity and in vivo pharmacokinetic stability. By incorporating an imidazole ring at the 7-position of scaffold, high target potency was achieved due to a hydrogen bonding network that occurs between the 3-position nitrogen atom, a bridging water molecule and the side chains Ser152 and Trp244 of the enzyme. The lipophilicity of the scaffold series proved important for expression of antibacterial activity. Clearances in vitro and in vivo were monitored to identify compounds with improved plasma stability. The basicity of the imidazole may contribute to increased aqueous solubility at lower pH allowing for improved oral bioavailability.

Comparison of pulse oximetry measures in a healthy population.

In this study finger and ear oximetry readings of 89 healthy persons were compared. The findings do not support the common nursing practice of using a finger sensor to obtain a pulse oximetry reading from an individual's ear if the finger is not usable.

Rapid response team in a rural hospital.

PURPOSE/OBJECTIVES: The objective of this study was to explore the nurses' knowledge and perceptions of the Rapid Response Team (RRT). DESIGN: This study was of a prospective, quantitative, descriptive design. SETTING: The setting was a 175-bed rural community nonteaching regional hospital. SAMPLE: Fifty-seven nurses participated, resulting in a 90.4% response. METHODS: Data were collected through distribution of an adapted survey termed Rapid Response Team Survey; the tool consisted of 3 parts. FINDINGS: The mean knowledge score was average. A "physician positive" response to the calling of an RRT was not particularly important; a "physician negative" response to calling the RRT was even less important. Knowledge of the RRT criteria and the understanding of the call criteria were important. Knowledge of the process for calling the RRT and how to call were less important to this group. CONCLUSIONS: Although the nurses were able to identify that changes in the patient's condition had occurred, weakness existed in recognition that those changes required rapid intervention through the calling of the RRT. The nurses positively perceived the RRT and the hospital's commitment to it. The nurses generally did not allow physician response to impact their willingness to call the RRT. IMPLICATIONS: The results of this study suggest that education is needed on early identification of the unstable patient and the early insidious signs seen in diseases such as sepsis.

Risk of breastfeeding cessation among low-income women, infants, and children: a discrete time survival analysis.

BACKGROUND: Women who receive services from the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) often stop breastfeeding earlier than recommended. Little is known about maternal background and intrapersonal variables that predict the timing of breastfeeding cessation over the 12-month postpartum period. OBJECTIVES: The aim of this study was to identify the maternal background and intrapersonal predictors associated with the timing of breastfeeding cessation in WIC participants over the course of the 12-month postpartum period. METHOD: Existing longitudinal survey and administrative data from low-income breastfeeding WIC recipients (n = 309) were analyzed using discrete time survival analysis. Risk of breastfeeding cessation was the outcome, and self-reported items were used to derive predictor variables that corresponded to the background and intrapersonal variables of the Interaction Model of Client Health Behavior. RESULTS: Rates of breastfeeding were low (31% at 6 months and 6% at 12 months). In the best fitting discrete time survival analysis model, women who were older and of Mexican ethnicity, who had previous breastfeeding experience, and who had breastfeeding support from family or friends were at lowest risk for breastfeeding cessation at each monthly interval. DISCUSSION: Breastfeeding duration rates were lower than Healthy People 2020 benchmarks of 61% at 6 months and 34% at 12 months. Clinicians and researchers can use the findings from this study to develop interventions that are targeted to periods of greatest risk of premature breastfeeding cessation to prolong breastfeeding duration in this vulnerable population.

Evaluation of the Tiredness Management Guide: a pilot study.

The Tiredness Management Guide (TMG), developed by N. W. Troy and P. Dialgas-Pelish (1995), consists of 59 interventions that may be helpful in decreasing maternal fatigue in the postpartum period. The purpose of this pilot study was to evaluate which interventions mothers perceived as most helpful and thus reduce the length of the TMG and update its relevance. A convenience sample of 30 Women, Infants, and Children Program (WIC) participants between the ages of 18 and 35 years completed a demographic tool and the TMG. The 25 most helpful interventions can be placed into the following broad categories: rest and relaxation, time management, rearranging usual activities, relief/prevention of hemorrhoids/constipation, signs of infection, and emotional support.