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.