Corrigendum to "Analytical validation of protein biomarkers for risk of spontaneous preterm birth" [Clin. Mass Spectrom. 3 (2017) 25-38].

[This corrects the article DOI: 10.1016/j.clinms.2017.06.002.].

Measuring the Impact of Medication-Related Interventions on 30-Day Readmission Rates in a Skilled Nursing Facility.

BACKGROUND: There is a lack of published literature that measures the impact of transitional care pharmacist (TCP) medication-related interventions within the skilled nursing facility (SNF) setting. OBJECTIVES: To evaluate the impact of TCP medication-related interventions on 30-day hospital readmissions among SNF patients compared to current standard of care. METHODS: This was a retrospective pilot study. All patients included in the study were discharged from an inpatient facility to a SNF. The control group received transitional services from a care team with no pharmacist. The intervention group received transitional services from a care team plus a pharmacist. RESULTS: The 30-day readmission rates in the intervention group were 14 (12%)/116 compared to the control group, 19 (16%)/116; however, the difference was not statistically significant (P = .35). The median time to readmission was statistically significantly longer in the intervention group, 17.5 days, compared to the control group, 10 days (P = .02). One hundred seventy-four medication-related interventions were performed in the intervention group during the study period. CONCLUSION: This study demonstrates that TCP interventions in an SNF are associated with a significant delay in readmission. A continuation of the pilot program may show a role in reducing all-cause 30-day readmission and ED visit rates.

Patient and clinical characteristics that heighten risk for heart failure readmission.

BACKGROUND: Within 30 days of hospital discharge, heart failure (HF) readmission rates nationally accumulate to more than 20%. Due to this high rate of unplanned re-hospitalization, predictive models are needed to identify patients who pose the highest readmission risk. OBJECTIVE: To evaluate the diagnosis and timing and to identify patient and clinical characteristics associated with 30 day readmissions among HF patients. METHODS: A retrospective analysis of electronic health records was conducted to study HF admissions during the period October 2008 to November 2014. Patients with a primary discharge diagnosis consistent with HF were included. Descriptive statistics were used to compare the readmitted and non-readmitted cohorts. Logistic regression was used to develop a predictive model to determine patient and clinical variables associated with 30 day readmission. RESULTS: Characteristics of the study cohort (n = 2420) are: a mean age of 72, predominantly male (55%), white (55%), currently not employed (91%), and utilizing Medicare as a payer (68%). Overall, 42% were married. Over the study time period there were 394 (16.3%) 30 day readmissions after 2420 hospitalizations. The 3 most common reasons for readmission were HF (36.0%), renal disorders (8.4%), and other cardiac diseases (6.9%). Analysis showed that 11.9% of patients readmitted during days 0-3, 15.2% during days 4-7, 31.5% during days 8-15, and 41.4% during days 16-30. The final multivariate predictive model included 5 variables that were associated with an increased risk for 30-day readmission: employment status as retired or disabled, > 1 emergency department visit in the past 90 days, length of stay >5 days during index visit, and a BUN value > 45 mg/dL. CONCLUSION: This study provides a deeper understanding of patient and clinical characteristics that are associated with readmission in HF. Evaluation of these characteristics will provide additional information to guide strategies meant to reduce HF readmission rates.

Medication regimen complexity and readmissions after hospitalization for heart failure, acute myocardial infarction, pneumonia, and chronic obstructive pulmonary disease.

OBJECTIVES: Readmission rate is increasingly being viewed as a key indicator of health system performance. Medication regimen complexity index scores may be predictive of readmissions; however, few studies have examined this potential association. The primary objective of this study was to determine whether medication regimen complexity index is associated with all-cause 30-day readmission after admission for heart failure, acute myocardial infarction, pneumonia, or chronic obstructive pulmonary disease. METHODS: This study was an institutional review board-approved, multi-center, case-control study. Patients admitted with a primary diagnosis of heart failure, acute myocardial infarction, pneumonia, or chronic obstructive pulmonary disease were randomly selected for inclusion. Patients were excluded if they discharged against medical advice or expired during their index visit. Block randomization was utilized for equal representation of index diagnosis and site. Discharge medication regimen complexity index scores were compared between subjects with readmission versus those without. Medication regimen complexity index score was then used as a predictor in logistic regression modeling for readmission. RESULTS: Seven hundred and fifty-six patients were randomly selected for inclusion, and 101 (13.4%) readmitted within 30 days. The readmission group had higher medication regimen complexity index scores than the no-readmission group (p < 0.01). However, after controlling for demographics, disease state, length of stay, site, and medication count, medication regimen complexity index was no longer a significant predictor of readmission (odds ratio 0.99, 95% confidence interval 0.97-1.01) or revisit (odds ratio 0.99, 95% confidence interval 0.98-1.02). CONCLUSION: There is little evidence to support the use of medication regimen complexity index in readmission prediction when other measures are available. Medication regimen complexity index may lack sufficient sensitivity to capture an effect of medication regimen complexity on all-cause readmission.

Development and validation of a spontaneous preterm delivery predictor in asymptomatic women.

BACKGROUND: Preterm delivery remains the leading cause of perinatal mortality. Risk factors and biomarkers have traditionally failed to identify the majority of preterm deliveries. OBJECTIVE: To develop and validate a mass spectrometry-based serum test to predict spontaneous preterm delivery in asymptomatic pregnant women. STUDY DESIGN: A total of 5501 pregnant women were enrolled between 17(0/7) and 28(6/7) weeks gestational age in the prospective Proteomic Assessment of Preterm Risk study at 11 sites in the United States between 2011 and 2013. Maternal blood was collected at enrollment and outcomes collected following delivery. Maternal serum was processed by a proteomic workflow, and proteins were quantified by multiple reaction monitoring mass spectrometry. The discovery and verification process identified 2 serum proteins, insulin-like growth factor-binding protein 4 (IBP4) and sex hormone-binding globulin (SHBG), as predictors of spontaneous preterm delivery. We evaluated a predictor using the log ratio of the measures of IBP4 and SHBG (IBP4/SHBG) in a clinical validation study to classify spontaneous preterm delivery cases (<37(0/7) weeks gestational age) in a nested case-control cohort different from subjects used in discovery and verification. Strict blinding and independent statistical analyses were employed. RESULTS: The predictor had an area under the receiver operating characteristic curve value of 0.75 and sensitivity and specificity of 0.75 and 0.74, respectively. The IBP4/SHBG predictor at this sensitivity and specificity had an odds ratio of 5.04 for spontaneous preterm delivery. Accuracy of the IBP4/SHBG predictor increased using earlier case-vs-control gestational age cutoffs (eg, <35(0/7) vs ≥35(0/7) weeks gestational age). Importantly, higher-risk subjects defined by the IBP4/SHBG predictor score generally gave birth earlier than lower-risk subjects. CONCLUSION: A serum-based molecular predictor identifies asymptomatic pregnant women at risk of spontaneous preterm delivery, which may provide utility in identifying women at risk at an early stage of pregnancy to allow for clinical intervention. This early detection would guide enhanced levels of care and accelerate development of clinical strategies to prevent preterm delivery.

Discovery of an L-alanine ester prodrug of the Hsp90 inhibitor, MPC-3100.

Various types of Hsp90 inhibitors have been and continue to undergo clinical investigation. One development candidate is the purine-based, synthetic Hsp90 inhibitor 1 (MPC-3100), which successfully completed a phase I clinical study. However, further clinical development of 1 was hindered by poor solubility and consequent formulation issues and promoted development of a more water soluble prodrug. Towards this end, numerous pro-moieties were explored in vitro and in vivo. These studies resulted in identification of L-alanine ester mesylate, 2i (MPC-0767), which exhibited improved aqueous solubility, adequate chemical stability, and rapid bioconversion without the need for solubilizing excipients. Based on improved physical characteristics and favorable PK and PD profiles, 2i mesylate was selected for further development. A convergent, scalable, chromatography-free synthesis for 2i mesylate was developed to support further clinical evaluation.

Safety of Prothombin Complex Concentrate to Control Excess Bleeding During Continuous Flow LVAD Insertion.

In cardiovascular surgery, hemostatic complexities require the provision of blood products to control bleeding as well as the use of a number of hemostatic agents, some of which cause significant morbidity. Among these agents is prothrombin complex concentrates (PCC), however there is no clear consensus on PCC use in cardiovascular surgery. To investigate the safety of PCC in patients undergoing left ventricular assist device (LVAD) placement, we reviewed our single institution experience to examine the incidence of thromboembolic events and a variety of hospital markers including morbidity and mortality. A retrospective review was conducted of patients who underwent LVAD placement between January 2010 and October 2012. Patients who received intraoperative PCC constituted the PCC group (n = 41) and those who did not constituted the non-PCC group (n = 27). The overall incidence of thromboembolic events at 3 months postoperative was 12 (29.3%) in the PCC group compared with six (22.2%) in the non-PCC group, respectively (p > 0.05). Morbidity did not differ between groups and one patient in the PCC group died. The intraoperative use of PCC in LVAD insertion does not appear to be associated with a significant increase in thromboembolic events; however, larger randomized trials are needed to confirm these findings.

Small molecule suppressors of Drosophila kinesin deficiency rescue motor axon development in a zebrafish model of spinal muscular atrophy.

Proximal spinal muscular atrophy (SMA) is the most common inherited motor neuropathy and the leading hereditary cause of infant mortality. Currently there is no effective treatment for the disease, reflecting a need for pharmacologic interventions that restore performance of dysfunctional motor neurons or suppress the consequences of their dysfunction. In a series of assays relevant to motor neuron biology, we explored the activities of a collection of tetrahydroindoles that were reported to alter the metabolism of amyloid precursor protein (APP). In Drosophila larvae the compounds suppressed aberrant larval locomotion due to mutations in the Khc and Klc genes, which respectively encode the heavy and light chains of kinesin-1. A representative compound of this class also suppressed the appearance of axonal swellings (alternatively termed axonal spheroids or neuritic beads) in the segmental nerves of the kinesin-deficient Drosophila larvae. Given the importance of kinesin-dependent transport for extension and maintenance of axons and their growth cones, three members of the class were tested for neurotrophic effects on isolated rat spinal motor neurons. Each compound stimulated neurite outgrowth. In addition, consistent with SMA being an axonopathy of motor neurons, the three axonotrophic compounds rescued motor axon development in a zebrafish model of SMA. The results introduce a collection of small molecules as pharmacologic suppressors of SMA-associated phenotypes and nominate specific members of the collection for development as candidate SMA therapeutics. More generally, the results reinforce the perception of SMA as an axonopathy and suggest novel approaches to treating the disease.

Lead optimization of purine based orally bioavailable Mps1 (TTK) inhibitors.

Efforts to optimize biological activity, novelty, selectivity and oral bioavailability of Mps1 inhibitors, from a purine based lead MPI-0479605, are described in this Letter. Mps1 biochemical activity and cytotoxicity in HCT-116 cell line were improved. On-target activity confirmation via mechanism based G2/M escape assay was demonstrated. Physico-chemical and ADME properties were optimized to improve oral bioavailability in mouse.