Reducing Psychiatric Inpatient Readmissions Using an Organizational Change Model.

INTRODUCTION: Thirty-day hospital readmission rates have become a quality indicator for many regulators and payers, but published accounts of reducing these rates across a patient population are lacking. OBJECTIVE: This article describes and evaluates the Wisconsin Mental Health Readmissions Project, which aimed to reduce psychiatric inpatient 30-day readmission rates in Wisconsin. METHODS: Nineteen county human services boards representing 23 of Wisconsin's 72 counties and 61% of the state's residential admissions participated in a statewide quality improvement collaborative from January 1, 2010 to December 31, 2013. Participants applied a standardized organizational change model, called NIATx, in the context of a multicounty quality improvement collaborative to reduce 30-day readmission rates. Readmission rates were tracked through national and state databases, using 2009 as a baseline, and analyzed using a chi-square analysis to test the proportion of means. The study team compared readmission rates of Wisconsin counties that participated in the statewide collaborative with those that did not. RESULTS: Between 2009 and 2013, the 30-day readmission rates in Wisconsin declined significantly for counties that participated in the project when compared to those that did not (2009-2013) [Χ2(4) = 54.503, P < .001], based on a 2.5% decline for participants vs a 0.7% decline for nonparticipants. CONCLUSIONS: Reductions to behavioral health inpatient readmission rates beyond individual case examples have been difficult to document. This analysis evaluates a method that Wisconsin behavioral health providers applied as part of a multicounty program addressing readmission rates. The findings highlight quality improvement program design elements and interventions to consider in reducing inpatient behavioral health readmissions, as well as the need for further research on this complex systems issue.

The Impact of Conventional Stroke Risk Factors on Early and Late Onset Ischemic Stroke: a Mendelian Randomization Study.

Objective: Although stroke incidence is decreasing in older ages, it is increasing in young adults. While these divergent trends in stroke incidence are at least partially attributable to diverging prevalence trends in stoke risk factors, age-dependent differences in the impact of stroke risk factors on stroke may also contribute. To address this issue, we utilized Mendelian Randomization (MR) to assess differences in the association of stroke risk factors between early onset ischemic stroke (EOS) and late onset ischemic stroke (LOS). Methods: We employed a two-sample MR design with inverse variance weighting as the primary method of analysis. Using large publicly available genome-wide association summary results, we calculated MR estimates for conventional stroke risk factors (body mass index, total, HDL-and LDL-cholesterol, triglycerides, type 2 diabetes, systolic and diastolic blood pressure, and smoking) in EOS cases (onset 18-59 years, n = 6,728) and controls from the Early Onset Stroke Consortium and in LOS cases (onset ≥ 60 years, n = 9,272) and controls from the Stroke Genetics Network. We then compared odds ratios between EOS and LOS, stratified by TOAST subtypes, to determine if any differences observed between effect sizes could be attributed to differences in the distribution of stroke subtypes. Results: EOS was significantly associated with all risk factors except for total cholesterol levels, and LOS was associated with all risk factors except for triglyceride and total cholesterol levels. The associations of BMI, DBP, SBP, and HDL-cholesterol were significantly stronger in EOS than LOS (all p < 0.004). The differential distribution of stroke subtypes could not explain the difference in effect size observed between EOS and LOS. Conclusion: These results suggest that interventions targeted at lowering body mass index and blood pressure may be particularly important for reducing stroke risk in young adults.

A randomized phase 2 trial of azacitidine with or without durvalumab as first-line therapy for higher-risk myelodysplastic syndromes.

Azacitidine-mediated hypomethylation promotes tumor cell immune recognition but may increase the expression of inhibitory immune checkpoint molecules. We conducted the first randomized phase 2 study of azacitidine plus the immune checkpoint inhibitor durvalumab vs azacitidine monotherapy as first-line treatment for higher-risk myelodysplastic syndromes (HR-MDS). In all, 84 patients received 75 mg/m2 subcutaneous azacitidine (days 1-7 every 4 weeks) combined with 1500 mg intravenous durvalumab on day 1 every 4 weeks (Arm A) for at least 6 cycles or 75 mg/m² subcutaneous azacitidine alone (days 1-7 every 4 weeks) for at least 6 cycles (Arm B). After a median follow-up of 15.25 months, 8 patients in Arm A and 6 in Arm B remained on treatment. Patients in Arm A received a median of 7.9 treatment cycles and those in Arm B received a median of 7.0 treatment cycles with 73.7% and 65.9%, respectively, completing ≥4 cycles. The overall response rate (primary end point) was 61.9% in Arm A (26 of 42) and 47.6% in Arm B (20 of 42; P = .18), and median overall survival was 11.6 months (95% confidence interval, 9.5 months to not evaluable) vs 16.7 months (95% confidence interval, 9.8-23.5 months; P = .74). Durvalumab-related adverse events (AEs) were reported by 71.1% of patients; azacitidine-related AEs were reported by 82% (Arm A) and 81% (Arm B). Grade 3 or 4 hematologic AEs were reported in 89.5% (Arm A) vs 68.3% (Arm B) of patients. Patients with TP53 mutations tended to have a worse response than patients without these mutations. Azacitidine increased programmed cell death ligand 1 (PD-L1 [CD274]) surface expression on bone marrow granulocytes and monocytes, but not blasts, in both arms. In summary, combining azacitidine with durvalumab in patients with HR-MDS was feasible but with more toxicities and without significant improvement in clinical outcomes over azacitidine alone. This trial was registered at www.clinicaltrials.gov as #NCT02775903.

A randomized phase 2 trial of azacitidine with or without durvalumab as first-line therapy for older patients with AML.

Evidence suggests that combining immunotherapy with hypomethylating agents may enhance antitumor activity. This phase 2 study investigated the activity and safety of durvalumab, a programmed death-ligand 1 (PD-L1) inhibitor, combined with azacitidine for patients aged ≥65 years with acute myeloid leukemia (AML), including analyses to identify biomarkers of treatment response. Patients were randomized to first-line therapy with azacitidine 75 mg/m2 on days 1 through 7 with (Arm A, n = 64) or without (Arm B, n = 65) durvalumab 1500 mg on day 1 every 4 weeks. Overall response rate (complete response [CR] + CR with incomplete blood recovery) was similar in both arms (Arm A, 31.3%; Arm B, 35.4%), as were overall survival (Arm A, 13.0 months; Arm B, 14.4 months) and duration of response (Arm A, 24.6 weeks; Arm B, 51.7 weeks; P = .0765). No new safety signals emerged with combination treatment. The most frequently reported treatment-emergent adverse events were constipation (Arm A, 57.8%; Arm B, 53.2%) and thrombocytopenia (Arm A, 42.2%; Arm B, 45.2%). DNA methylation, mutational status, and PD-L1 expression were not associated with response to treatment. In this study, first-line combination therapy with durvalumab and azacitidine in older patients with AML was feasible but did not improve clinical efficacy compared with azacitidine alone. ClinicalTrials.gov: NCT02775903.

A gene expression signature for insulin resistance.

Insulin resistance is a heterogeneous disorder caused by a range of genetic and environmental factors, and we hypothesize that its etiology varies considerably between individuals. This heterogeneity provides significant challenges to the development of effective therapeutic regimes for long-term management of type 2 diabetes. We describe a novel strategy, using large-scale gene expression profiling, to develop a gene expression signature (GES) that reflects the overall state of insulin resistance in cells and patients. The GES was developed from 3T3-L1 adipocytes that were made "insulin resistant" by treatment with tumor necrosis factor-α (TNF-α) and then reversed with aspirin and troglitazone ("resensitized"). The GES consisted of five genes whose expression levels best discriminated between the insulin-resistant and insulin-resensitized states. We then used this GES to screen a compound library for agents that affected the GES genes in 3T3-L1 adipocytes in a way that most closely resembled the changes seen when insulin resistance was successfully reversed with aspirin and troglitazone. This screen identified both known and new insulin-sensitizing compounds including nonsteroidal anti-inflammatory agents, ß-adrenergic antagonists, ß-lactams, and sodium channel blockers. We tested the biological relevance of this GES in participants in the San Antonio Family Heart Study (n = 1,240) and showed that patients with the lowest GES scores were more insulin resistant (according to HOMA_IR and fasting plasma insulin levels; P < 0.001). These findings show that GES technology can be used for both the discovery of insulin-sensitizing compounds and the characterization of patients into subtypes of insulin resistance according to GES scores, opening the possibility of developing a personalized medicine approach to type 2 diabetes.

Utilization, Utility, and Variability in Usage of Adjunctive Hyperbaric Oxygen Therapy in Spinal Management: A Review of the Literature.

The objective of this review was to understand the clinical utilization, utility, and variability in the usage of adjunctive hyperbaric oxygen therapy (HBOT). Surgical site infection is associated with high morbidity and mortality, increased health care expenditure, and decreased quality of life. With the increasing prevalence of adult spinal deformity and spinal fusion surgery, it is imperative to understand the potential benefits of adjunctive treatments. HBOT is a safe and common procedure indicated to treat various medical conditions. We conducted a literature search across 3 databases for English articles published between December 1, 2019 and December 1, 2000. Thirteen studies were included. HBOT may lessen the duration of antimicrobial therapy and mitigate instrument removal and revision surgery. The current usage indications for HBOT are supported by level III evidence for chronic osteomyelitis and level IV evidence for osteoradionecrosis. However, the same level of evidence exists to support the beneficial use of adjunctive HBOT for noncomplicated spinal infections within 2 months after surgery. When cultured, the most common organisms were Staphylococcus aureus and other low-virulence organisms. The most common treatment protocol consists of 90-minute sessions of 100% Fio2 at 2-3 atmosphere absolute with a mean of 35.3 ± 11.6 sessions for 5.2 ± 1.4 weeks. Adjunctive HBOT should be considered in select high-risk patients. Further improvements in diagnosis and categorization of spinal infections are necessary and will indelibly aid the decision making for the initiation of HBOT.

Accentuated cortico-cortical evoked potentials in neocortical epilepsy in areas of ictal onset.

OBJECTIVE: To determine whether patients with neocortical epilepsy show evidence for increased excitability measured by cortico-cortical evoked potentials (CCEPs) in ictal-onset regions. METHODS: In patients undergoing intracranial recordings with subdural electrodes for epilepsy surgery, we measured amplitudes, latencies, and stimulus thresholds of CCEPs near ictal onset zones (iCCEPs), and compared with adjacent neocortex not associated with ictal EEG (nCCEP). CCEP amplitude and latency measurements were made with each stimulation site, using graded stimulation intensities. RESULTS: Ten patients were included in this study. CCEPs were recorded in eight of 10 patients. The first negative (N1) iCCEP amplitude was higher than that of nCCEP in seven of the eight patients. In the group analysis, this difference was statistically significant. In three of these patients, the difference was individually significant. In one patient, the amplitude was higher in nCCEP than iCCEP and the area selected as nCCEP was within primary eloquent cortex. There was no significant difference seen in latency changes or stimulus threshold. CONCLUSIONS: Accentuated CCEP amplitudes near ictal onset zones could reflect an increased excitability of the cortex associated with the epileptogenic zone in some patients with neocortical epilepsy. The response of the neocortex to low-frequency stimulation may vary depending on the presence or absence of intrinsic epileptogenicity.

Inhibition of inosine monophosphate dehydrogenase reduces adipogenesis and diet-induced obesity.

We previously described a putative role for inosine monophosphate dehydrogenase (IMPDH), a rate-limiting enzyme in de novo guanine nucleotide biosynthesis, in lipid accumulation. Here we present data which demonstrate that IMPDH activity is required for differentiation of preadipocytes into mature, lipid-laden adipocytes and maintenance of adipose tissue mass. In 3T3-L1 preadipocytes inhibition of IMPDH with mycophenolic acid (MPA) reduced intracellular GTP levels by 60% (p<0.05) and blocked adipogenesis (p<0.05). Co-treatment with guanosine, a substrate in the salvage pathway of nucleotide biosynthesis, restored GTP levels and adipogenesis demonstrating the specificity of these effects. Treatment of diet-induced obese mice with mycophenolate mofetil (MMF), the prodrug of MPA, for 28 days did not affect food intake or lean body mass but reduced body fat content (by 36%, p=0.002) and adipocyte size (p=0.03) and number. These data suggest that inhibition of IMPDH may represent a novel strategy to reduce adipose tissue mass.

Quantifying rehabilitation risks for surface-strip coal mines using a soil compaction Bayesian network in South Africa and Australia: To demonstrate the R2 AIN Framework.

Environmental information is acquired and assessed during the environmental impact assessment process for surface-strip coal mine approval. However, integrating these data and quantifying rehabilitation risk using a holistic multidisciplinary approach is seldom undertaken. We present a rehabilitation risk assessment integrated network (R2 AIN™) framework that can be applied using Bayesian networks (BNs) to integrate and quantify such rehabilitation risks. Our framework has 7 steps, including key integration of rehabilitation risk sources and the quantification of undesired rehabilitation risk events to the final application of mitigation. We demonstrate the framework using a soil compaction BN case study in the Witbank Coalfield, South Africa and the Bowen Basin, Australia. Our approach allows for a probabilistic assessment of rehabilitation risk associated with multidisciplines to be integrated and quantified. Using this method, a site's rehabilitation risk profile can be determined before mining activities commence and the effects of manipulating management actions during later mine phases to reduce risk can be gauged, to aid decision making. Integr Environ Assess Manag 2019;15:190-208. © 2019 SETAC.

Outcomes of a randomized trial of continuum of care services for children in a child welfare system.

The Connecticut Department of Children and Families Title IV-E waiver demonstration evaluated whether the well-being of children approved for residential mental health services could be improved, and lengths of stay in restrictive placements reduced, by providing case rate payments to community agencies to provide continuum of care services. Children between ages 7 and 15 were randomly assigned to either the demonstration group (n = 78) or to usual state-supported services (n = 79). One-year outcome results indicated that in a situation that is less costly, improvement in outcomes occurred in less restrictive settings. Continuum of care services were more effective in 1) returning children to in-home placements, 2) reducing the length of stay in restrictive placements, and (3) utilizing higher levels of case management through coordination among agencies and family support services.

Geometric subspace methods and time-delay embedding for EEG artifact removal and classification.

Generalized singular-value decomposition is used to separate multichannel electroencephalogram (EEG) into components found by optimizing a signal-to-noise quotient. These components are used to filter out artifacts. Short-time principal components analysis of time-delay embedded EEG is used to represent windowed EEG data to classify EEG according to which mental task is being performed. Examples are presented of the filtering of various artifacts and results are shown of classification of EEG from five mental tasks using committees of decision trees.

Public costs of better mental health services for children and adolescents.

OBJECTIVE: This study evaluated how improved community mental health services for youths affect public expenditures in other sectors, including inpatient hospitalization, the juvenile justice system, the child welfare system, and the special education system. METHODS: Participants were youths aged six to 17 years who received services through a mental health agency in one of a matched pair of communities. One community delivered mental health services according to the principles of systems of care (N=220). The comparison community delivered mental health services but did not provide for the interagency integration of services (N=211). The analyses are based on administrative and interview data. RESULTS: Preliminary analyses revealed that mental health services delivered as part of a system-of-care approach are more expensive. However, incorporating expenditures in other sectors reduced the between-site gap in expenditures from 81 to 18 percent. This estimate is robust to changes in analytical methods as well as adjustments for differences between the two sites in the baseline characteristics of participants. CONCLUSIONS: These findings suggest that reduced expenditures in other sectors that serve youths substantially, but only partially, offset the costs of improved mental health services. The full fiscal impact of improved mental health services can be assessed only in the context of their impact on other sectors.

Zinc finger nuclease mediated knockout of ADP-dependent glucokinase in cancer cell lines: effects on cell survival and mitochondrial oxidative metabolism.

Zinc finger nucleases (ZFN) are powerful tools for editing genes in cells. Here we use ZFNs to interrogate the biological function of ADPGK, which encodes an ADP-dependent glucokinase (ADPGK), in human tumour cell lines. The hypothesis we tested is that ADPGK utilises ADP to phosphorylate glucose under conditions where ATP becomes limiting, such as hypoxia. We characterised two ZFN knockout clones in each of two lines (H460 and HCT116). All four clones had frameshift mutations in all alleles at the target site in exon 1 of ADPGK, and were ADPGK-null by immunoblotting. ADPGK knockout had little or no effect on cell proliferation, but compromised the ability of H460 cells to survive siRNA silencing of hexokinase-2 under oxic conditions, with clonogenic survival falling from 21±3% for the parental line to 6.4±0.8% (p = 0.002) and 4.3±0.8% (p = 0.001) for the two knockouts. A similar increased sensitivity to clonogenic cell killing was observed under anoxia. No such changes were found when ADPGK was knocked out in HCT116 cells, for which the parental line was less sensitive than H460 to anoxia and to hexokinase-2 silencing. While knockout of ADPGK in HCT116 cells caused few changes in global gene expression, knockout of ADPGK in H460 cells caused notable up-regulation of mRNAs encoding cell adhesion proteins. Surprisingly, we could discern no consistent effect on glycolysis as measured by glucose consumption or lactate formation under anoxia, or extracellular acidification rate (Seahorse XF analyser) under oxic conditions in a variety of media. However, oxygen consumption rates were generally lower in the ADPGK knockouts, in some cases markedly so. Collectively, the results demonstrate that ADPGK can contribute to tumour cell survival under conditions of high glycolytic dependence, but the phenotype resulting from knockout of ADPGK is cell line dependent and appears to be unrelated to priming of glycolysis in these lines.

Methazolamide is a new hepatic insulin sensitizer that lowers blood glucose in vivo.

We previously used Gene Expression Signature technology to identify methazolamide (MTZ) and related compounds with insulin sensitizing activity in vitro. The effects of these compounds were investigated in diabetic db/db mice, insulin-resistant diet-induced obese (DIO) mice, and rats with streptozotocin (STZ)-induced diabetes. MTZ reduced fasting blood glucose and HbA(1c) levels in db/db mice, improved glucose tolerance in DIO mice, and enhanced the glucose-lowering effects of exogenous insulin administration in rats with STZ-induced diabetes. Hyperinsulinemic-euglycemic clamps in DIO mice revealed that MTZ increased glucose infusion rate and suppressed endogenous glucose production. Whole-body or cellular oxygen consumption rate was not altered, suggesting MTZ may inhibit glucose production by different mechanism(s) to metformin. In support of this, MTZ enhanced the glucose-lowering effects of metformin in db/db mice. MTZ is known to be a carbonic anhydrase inhibitor (CAI); however, CAIs acetazolamide, ethoxyzolamide, dichlorphenamide, chlorthalidone, and furosemide were not effective in vivo. Our results demonstrate that MTZ acts as an insulin sensitizer that suppresses hepatic glucose production in vivo. The antidiabetic effect of MTZ does not appear to be a function of its known activity as a CAI. The additive glucose-lowering effect of MTZ together with metformin highlights the potential utility for the management of type 2 diabetes.

Can better mental health services reduce the risk of juvenile justice system involvement?

OBJECTIVES: We evaluated how improved mental health services affect justice involvement among juveniles treated in the public mental health system. METHODS: Our analyses were based on administrative and interview data collected in 2 communities participating in the evaluation of a national initiative designed to improve mental health services for children and youths. RESULTS: Results derived from Cox proportional hazard models suggested that better mental health services reduced the risks of initial and subsequent juvenile justice involvement by 31% and 28%, respectively. Effects were somewhat more pronounced for serious offenses. CONCLUSIONS: Our findings suggest that improved mental health services reduce the risk of juvenile justice involvement.

Overexpression and rapid purification of Escherichia coli formamidopyrimidine-DNA glycosylase.

Formamidopyrimidine DNA glycosylase (Fpg) is a DNA glycosylase with an associated AP lyase activity. As a DNA repair enzyme, Fpg excises several modified bases from DNA associated with exposure to oxidizing agents such as free radicals. Experiments in many laboratories have been limited by the availability of the enzyme, and its production required at least a week of work to complete its purification. We have devised a new method that decreases the time and expense of purification of Fpg that should render this protein accessible to any laboratory. Fpg was subcloned into a gamma P(L) promoter-containing vector (pRE) and overproduced in the appropriate Escherichia coli host cells to about 25% of the total cellular protein. Fpg was purified to homogeneity in a simple two-step procedure with a 50% saving in time when compared to the previously known procedure. Comparative studies showed that the excision of 8-hydroxyguanine, 2,6-diamino-4-hydroxy-5-formamidopyrimidine, and 4,6-diamino-5-formamidopyrimidine, and to a lesser extent, 8-hydroxyadenine was virtually identical for the Fpg purified using this method and for the Fpg purified by the original method. Therefore, this method should prove useful for a large number of laboratories and further research on oxidative DNA damage.