Changes in social, sexual, and hedonic behaviors in rats in response to stress and restoration by a negative allosteric modulator of α5-subunit containing GABA receptor.

Major depressive disorder (MDD) is a debilitating and costly human condition. Treatment for MDD relies heavily on the use of antidepressants that are slow to produce mood-related changes and are not effective in all patients, such as selective serotonin reuptake inhibitors (SSRIs). Several novel compounds, including negative allosteric modulators of GABA-A receptors containing the α5-subunit (GABA-NAMs), are under investigation for potential fast acting therapeutic use in MDD. Preclinical evidence that these compounds produce a rapid antidepressant-like response comes primarily from simple tests of escape behavior and preference for rewarding stimuli after chronic stress. To increase the ethological relevance of these compounds, we tested the hypothesis that the GABA-NAM, L-655,708, would produce an antidepressant-like response in more complex stress-sensitive social and sex behaviors, which are of relevance to the symptoms of human depression. In male rats subjected to chronic restraint stress, injection of L-655,708 increased reward in a sexual conditioned place preference task, increased male sexual activity with a receptive female, and re-established male social dominance hierarchies within 24 h. We also report increased sucrose preference in the social defeat stress (SDS) model of depression following GABA-NAM administration, demonstrating that its antidepressant-like actions are independent of the type of chronic stress administered. This work extends the impact of GABA-NAMs beyond traditional tests of anhedonia and further supports the development of alpha5 subunit-selective GABA-NAMs as a potential fast-acting therapeutic approach for treating human MDD.

Resistance to Pyrrolobenzodiazepine Dimers Is Associated with SLFN11 Downregulation and Can Be Reversed through Inhibition of ATR.

Resistance to antibody-drug conjugates (ADCs) has been observed in both preclinical models and clinical studies. However, mechanisms of resistance to pyrrolobenzodiazepine (PBD)-conjugated ADCs have not been well characterized and thus, this study was designed to investigate development of resistance to PBD dimer warheads and PBD-conjugated ADCs. We established a PBD-resistant cell line, 361-PBDr, by treating human breast cancer MDA-MB-361 cells with gradually increasing concentrations of SG3199, the PBD dimer released from the PBD drug-linker tesirine. 361-PBDr cells were over 20-fold less sensitive to SG3199 compared with parental cells and were cross-resistant to other PBD warhead and ADCs conjugated with PBDs. Proteomic profiling revealed that downregulation of Schlafen family member 11 (SLFN11), a putative DNA/RNA helicase, sensitizing cancer cells to DNA-damaging agents, was associated with PBD resistance. Confirmatory studies demonstrated that siRNA knockdown of SLFN11 in multiple tumor cell lines conferred reduced sensitivity to SG3199 and PBD-conjugated ADCs. Treatment with EPZ011989, an EZH2 inhibitor, derepressed SLFN11 expression in 361-PBDr and other SLFN11-deficient tumor cells, and increased sensitivity to PBD and PBD-conjugated ADCs, indicating that the suppression of SLFN11 expression is associated with histone methylation as reported. Moreover, we demonstrated that combining an ataxia telangiectasia and Rad3-related protein (ATR) inhibitor, AZD6738, with SG3199 or PBD-based ADCs led to synergistic cytotoxicity in either resistant 361-PBDr cells or cells that SLFN11 was knocked down via siRNA. Collectively, these data provide insights into potential development of resistance to PBDs and PBD-conjugated ADCs, and more importantly, inform strategy development to overcome such resistance.

Synthesis and evaluation of pyrrolobenzodiazepine dimer antibody-drug conjugates with dual ß-glucuronide and dipeptide triggers.

Antibody-drug conjugates (ADCs) containing pyrrolobenzodiazepine (PBD) dimers are currently being evaluated in human oncology clinical trials with encouraging results. To further improve the therapeutic window, next-generation PBD drug-linker design has focused on the inclusion of additional tumor-selective triggers and use of lower-potency PBDs. ß-Glucuronidase is a well-known target for discovery prodrugs due to increased presence in tumor cells and microenvironment. In this study, a ß-glucuronidase cleavable cap was investigated at the PBD N10-position and compared with corresponding free imine ADCs. SG3600 (glucuronide) ADCs showed in vitro and in vivo efficacy/tolerability comparable to SG3400 (imine) ADCs, and good 50% inhibitory concentration differentials were observed in vitro between control non-antigen-targeted ADCs and targeted ADCs. Dependence on ß-glucuronidase for SG3600 activity was demonstrated through CRISPRCas9 knockdown studies and addition of exogenous ß-glucuronidase. SG3600 showed better serum stability, improved conjugation efficiency and was able to reach high drug-to-antibody ratio without aggregation.

Improved Inhibition of Tumor Growth by Diabody-Drug Conjugates via Half-Life Extension.

Despite some clinical success with antibody-drug conjugates (ADCs) in patients with solid tumors and hematological malignancies, improvements in ADC design are still desirable due to the narrow therapeutic window of these compounds. Tumor-targeting antibody fragments have distinct advantages over monoclonal antibodies, including more rapid tumor accumulation and enhanced penetration, but are subject to rapid clearance. Half-life extension technologies such as PEGylation and albumin-binding domains (ABDs) have been widely used to improve the pharmacokinetics of many different types of biologics. PEGylation improves pharmacokinetics by increasing hydrodynamic size to reduce renal clearance, whereas ABDs extend half-life via FcRn-mediated recycling. In this study, we used an anti-oncofetal antigen 5T4 diabody conjugated with a highly potent cytotoxic pyrrolobenzodiazepine (PBD) warhead to assess and compare the effects of PEGylation and albumin binding on the in vivo efficacy of antibody fragment drug conjugates. Conjugation of 2× PEG20K to a diabody improved half-life from 40 min to 33 h, and an ABD-diabody fusion protein exhibited a half-life of 45 h in mice. In a xenograft model of breast cancer MDA-MB-436, the ABD-diabody-PBD showed greater tumor growth suppression and better tolerability than either PEG-diabody-PBD or diabody-PBD. These results suggest that the mechanism of half-life extension is an important consideration for designing cytotoxic antitumor agents.

Evaluation of Pharmacodynamic Responses to Cancer Therapeutic Agents Using DNA Damage Markers.

PURPOSE: We sought to examine the pharmacodynamic activation of the DNA damage response (DDR) pathway in tumors following anticancer treatment for confirmation of target engagement. EXPERIMENTAL DESIGN: We evaluated the time course and spatial activation of 3 protein biomarkers of DNA damage recognition and repair (γH2AX, pS343-Nbs1, and Rad51) simultaneously in a quantitative multiplex immunofluorescence assay (IFA) to assess DDR pathway activation in tumor tissues following exposure to DNA-damaging agents. RESULTS: Because of inherent biological variability, baseline DDR biomarker levels were evaluated in a colorectal cancer microarray to establish clinically relevant thresholds for pharmacodynamic activation. Xenograft-bearing mice and clinical colorectal tumor biopsies obtained from subjects exposed to DNA-damaging therapeutic regimens demonstrated marked intratumor heterogeneity in the timing and extent of DDR biomarker activation due, in part, to the cell-cycle dependency of DNA damage biomarker expression. CONCLUSIONS: We have demonstrated the clinical utility of this DDR multiplex IFA in preclinical models and clinical specimens following exposure to multiple classes of cytotoxic agents, DNA repair protein inhibitors, and molecularly targeted agents, in both homologous recombination-proficient and -deficient contexts. Levels exceeding 4% nuclear area positive (NAP) γH2AX, 4% NAP pS343-Nbs1, and 5% cells with ≥5 Rad51 nuclear foci indicate a DDR activation response to treatment in human colorectal cancer tissue. Determination of effect-level cutoffs allows for robust interpretation of biomarkers with significant interpatient and intratumor heterogeneity; simultaneous assessment of biomarkers induced at different phases of the DDR guards against the risk of false negatives due to an ill-timed biopsy.

Impact of recreational and medicinal marijuana on surgical patients: A review.

BACKGROUND: As medicinal and recreational marijuana use broadens across the United States, knowledge of its effects on the body will become increasingly important to all health care providers, including surgeons. DATA SOURCES: We performed a literature review of Pubmed for articles discussing the basic science related to cannabinoids, as well as articles regarding cannabinoid medications, and cannabis use in surgical patients. CONCLUSIONS: The primary components in the cannabis plant, tetrahydrocannabinol (THC) and cannabidiol (CBD), have been made available in numerous forms and formulations to treat multiple medical conditions, and recreational access to marijuana is increasing. Of particular importance to the surgeon may be their effects on prolonging intestinal motility, decreasing inflammation, increasing hunger, mitigating pain, and reducing nausea and vomiting. Perioperative use of medicinal or recreational marijuana will become increasingly prevalent, and the surgeon should be aware of the positive and negative effects of these cannabinoids.

Utilizing Geographic Information Systems to Identify Clusters of Severe Sepsis Patients Presenting in the Out-of-Hospital Environment.

UNLABELLED: Understanding the geographic distribution of critical illness within a community may provide public health stakeholders with information that can be used to expedite access to specialized care. We hypothesized that severe sepsis patients transported by emergency medical services (EMS) exhibit geospatial clustering and that prehospital providers would recognize sepsis more frequently in patients transported from sepsis clusters. Retrospective review of a prospective, observational study of patients with severe sepsis transported to the emergency department (ED) by EMS and treated with early goal-directed therapy (EGDT). INCLUSION CRITERIA: suspected infection, 2 or more criteria for systemic inflammation, and either systolic blood pressure <90 mmHg after a fluid bolus or lactate >4 mmol/liter. EXCLUSION CRITERIA: age <18 or need for immediate surgery. Patient location at the time of EMS activation was recorded. Analysis of the addresses identified clusters, defined as a location in which EMS transported more than one patient experiencing the above associated signs and symptoms of septic shock. Other data collected included self-reported patient location as private residence or chronic care facility. One hundred sixty severe sepsis patients transported by EMS were eligible for analysis, presenting from 125 locations. Ninety-one patients (57%) presented from a private residence and 69 (37%) from a chronic care facility. Fifty (31%) patients were transported from 15 locations, with 25 of those transported from just 4 locations. Cluster patients tended to be older, come from medical facilities, and were more likely to have sepsis recognized by prehospital providers. Results from this study demonstrate low pre-hospital recognition of sepsis, as well as geospatially clustered presentations, most notably from skilled nursing facilities. Community education, public health initiatives, and EMS interventions could be targeted in such clusters of cases in order to both improve sepsis recognition and potentially expedite time-sensitive interventions.

Single-stage revision from gastric band to gastric bypass or sleeve gastrectomy: 6- and 12-month outcomes.

BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) is increasingly requiring revisional surgery for complications and failures. Removal of the band and conversion to either laparoscopic Roux-en-y gastric bypass (LRYGB) or laparoscopic sleeve gastrectomy (LSG) is feasible as a single-stage procedure. The objective of this study is to compare the safety and efficacy of single-stage revision from LAGB to either LRYGB or LSG at 6 and 12 months postoperatively. METHODS: Retrospective analysis was performed on patients undergoing single-stage revision between 2009 and 2014 at a single academic medical center. Patients were reassessed for weight loss and complications at 6 and 12 months postoperatively. RESULTS: Thirty-two patients underwent single-stage revision to LRYGB, and 72 to LSG. Preoperative BMIs were similar between the two groups (p = 0.27). Median length of stay for LRYGB was 3 days versus 2 for LSG (p = 0.14). Four patients in the LRYGB group required reoperation within 30 days, and two patients in the LSG group required reoperation within 30 days (p = 0.15). There was no difference in ER visits (p = 0.24) or readmission rates (p = 0.80) within 30 days of operation. Six delayed complications were seen in the LSG group with three requiring intervention. At 6 months postoperatively, percent excess weight loss (%EWL) was 50.20 for LRYGB and 30.64 for LSG (p = 0.056). At 12 months, %EWL was 51.19 for LRYGB and 34.89 for LSG (p = 0.31). There was no difference in diabetes or hypertension medication reduction at 12 months between LRYGB and LSG (p > 0.07). CONCLUSION: Single-stage revision from LAGB to LRYGB or LSG is technically feasible, but not without complications. The complications in the bypass group were more severe. There was no difference in readmission or reoperation rates, weight loss or comorbidity reduction. Revision to LRYGB trended toward higher rate and greater severity of complications with equivalent weight loss and comorbidity reduction.

State Variation in the Delivery of Comprehensive Services for Medicaid Beneficiaries with Schizophrenia and Bipolar Disorder.

Medicaid beneficiaries with schizophrenia and bipolar disorder require a range of services and supports. This descriptive study used 2007 Medicaid claims data from 21 states and the District of Columbia to examine the extent to which this population received guideline-concordant medications, medication monitoring, outpatient mental health care, and preventive physical health care. More than 80 % of beneficiaries in each state filled at least one prescription for a guideline-concordant medication during the year but, on average, only 57 % of those with schizophrenia and 45 % of those with bipolar disorder maintained a continuous supply of medications. Roughly 25 % did not have an outpatient mental health visit during the year (excluding case management and some other services); in some states more than half did not have such a visit. Only 11 % of beneficiaries received a physical health examination or health behavior counseling when claims codes were used to identify these services rather than all primary care physician visits. Less than 5 % of beneficiaries maintained their supply of medications, received medication monitoring and had an outpatient mental health visit, physical health examination or received health behavior counseling during the year. Although these rates of service utilization are likely conservative and the data predate recent efforts to integrate care, the findings underscore the need for quality improvement efforts targeted to this population and may provide a baseline for monitoring progress.

Superior mesenteric artery syndrome following sleeve gastrectomy: case report, review of the literature, and video on technique for surgical correction.

Superior mesenteric artery (SMA) syndrome is a rare condition in which the duodenum is compressed between the SMA and aorta. This often occurs following extreme weight loss and has been reported in the bariatric population. We present the first reported case of SMA syndrome following sleeve gastrectomy. The patient underwent laparoscopic duodenojejunostomy and recovered uneventfully. The following is a review of the literature and detailed operative approach in the attached video.

Primary sleeve gastrectomy compared to sleeve gastrectomy as revisional surgery: weight loss and complications at intermediate follow-up.

INTRODUCTION: The laparoscopic adjustable gastric band (LAGB) can be revised to sleeve gastrectomy (LSG) for various reasons. Data are limited on the safety and efficacy of single-stage removal of LAGB and creation of LSG. METHODS: A retrospective review of cases was performed from 2010 to 2013. From the primary LSG group, a control group was matched in a 2:1 ratio. RESULTS: Thirty-two patients underwent single-stage revision from LAGB to LSG, with a control group of 64. The most common indication for revision was insufficient weight loss (62.5%). Operative time for revision and control groups was 134 and 92 min, respectively (p < 0.0001). Hospital stay was 3.22 and 2.59 days, respectively (p = 0.02). Overall, the 30-day complication rate for revision and control patients was 14.71 and 6.25%, respectively (p = 0.20). There were no leaks, one stricture (3.13%) in the revision group, and one reoperation for bleeding in the control group (1.56%). For patients with BMI >30 at surgery, change in BMI at 12 months for revision and control was 8.77 and 11.58, respectively (p = 0.02). CONCLUSION: Single-stage revision can be performed safely, with minimal increases in hospital stay and 30-day complications. Weight loss is greater in those who undergo primary LSG compared to those who undergo LSG as revision.

State and demographic variation in use of depot antipsychotics by Medicaid beneficiaries with schizophrenia.

OBJECTIVE: This study examined state and demographic variation in use of depot antipsychotics among Medicaid beneficiaries with schizophrenia. METHOD: Medicaid claims data (2007) from 21 states and the District of Columbia were analyzed for 102,884 beneficiaries age 18 to 64 with schizophrenia. Rates of receipt of depot antipsychotics were determined for all beneficiaries and for African Americans, Caucasians, and beneficiaries from "all other races." RESULTS: Across study states, a mean of 10% of beneficiaries with schizophrenia received depot antipsychotics. Rates ranged from 1.9% in the District of Columbia to 20.9% in Alabama. In 12 states, African Americans were disproportionately likely to receive these medications compared with beneficiaries of other races. CONCLUSIONS: Use of depot antipsychotics varied across state Medicaid programs. African Americans received a disproportionate share in many states. Further research is needed to understand the sources of such variation. These findings underscore the need to monitor the use of depot antipsychotics.

Medication continuity among Medicaid beneficiaries with schizophrenia and bipolar disorder.

OBJECTIVE: This study was conducted to examine whether medication continuity among Medicaid beneficiaries with schizophrenia and bipolar disorder was associated with medication utilization management practices (prior authorization, copayment amounts, and refill and pill quantity limits), managed care enrollment, and other state and beneficiary characteristics. METHODS: With 2007 Medicaid Analytic Extract claims data from 22 states, random-effects logistic regression modeled the odds of high medication continuity, defined as receiving medications for at least 80% of the days enrolled in Medicaid, among beneficiaries ages 18-64 with a diagnosis of schizophrenia (N=91,451) or bipolar disorder (N=33,234). RESULTS: Sixty-four percent of beneficiaries with schizophrenia and 54% of beneficiaries with bipolar disorder had high medication continuity. Medication continuity was worse among beneficiaries with schizophrenia in states that required prior authorization for antipsychotics, $2-$3 copayments for generic medications, or $1 copayments for branded medications (compared with no copayments). For beneficiaries with bipolar disorder, medication continuity was worse among those in states with more prior-authorization requirements for different classes of medications or $1 copayments for branded medications. Medication continuity was worse among beneficiaries who were African American, Hispanic, younger, or enrolled in a health maintenance organization health plan or who had a comorbid substance use disorder or cardiovascular disease. CONCLUSIONS: Prior-authorization requirements and copayments for medications may present barriers to refilling medications for Medicaid beneficiaries with schizophrenia or bipolar disorder. State Medicaid programs should consider the unintended consequences of medication utilization management practices for this population.

Medicaid beneficiaries using mental health or substance abuse services in fee-for-service plans in 13 states, 2003.

OBJECTIVE: This study identified Medicaid beneficiaries using mental health or substance abuse services in fee-for-service plans in 13 states in 2003 (N=1,380,190) and examined their use of medical services. METHODS: Administrative and fee-for-service claims data from Medicaid Analytic eXtract files were analyzed to identify mutually exclusive groups of beneficiaries who used either mental health or substance abuse services and to describe patterns of medical service use. RESULTS: Overall, 11.7% of Medicaid beneficiaries were identified as using mental health or substance abuse services (10.9% and .7% used each of these services, respectively), with substantial variation across age and eligibility groups. Among beneficiaries using mental health services, 47.4% had visited an emergency room for any reason, 7.8% were treated for their disorder in inpatient settings, 13.8% received inpatient treatment for problems other than their mental or substance use disorders, and 70.4% received prescriptions for psychotropic medications. Among beneficiaries using substance abuse services, 60.7% had visited an emergency room, 12.6% were treated for their disorder in inpatient settings, 24.7% received other inpatient treatment, and 46.1% received prescriptions for psychotropic medications. Among beneficiaries not using either mental health or substance use services, 29.0% had visited an emergency room, 12.7% received inpatient treatment, and 10.1% received prescriptions for psychotropic medications. CONCLUSIONS: Beneficiaries who used mental health or substance abuse services entered general inpatient settings and visited emergency rooms more frequently than other beneficiaries.

Mental disorders and service use among welfare and disability program participants in fee-for-service Medicaid.

OBJECTIVE: In recent years, welfare caseloads have declined dramatically, leaving on the rolls recipients with mental disorders or other challenges that may affect their ability to work. This study identified Temporary Assistance for Needy Families (TANF) recipients (that is, welfare recipients) who use mental health services, compared them with Supplemental Security Income (SSI) recipients, and estimated the number of TANF recipients who might qualify for SSI. METHODS: Based on data from the 2003 Medicaid Analytic eXtract (MAX) files from four states, this analysis included female Medicaid beneficiaries aged 19 to 64 in fee-for-service payment systems receiving SSI (N=65,303) or TANF (N=22,691). RESULTS: Thirteen percent of TANF beneficiaries and 32% of SSI beneficiaries with Medicaid claims had a mental disorder. Common disorders among TANF beneficiaries included neurotic and other depressive disorders and major depression and affective psychoses. Eleven percent of TANF recipients had levels of service use comparable with those of SSI recipients. CONCLUSIONS: The proportion of TANF recipients using mental health services was lower than the proportion of TANF recipients identified through surveys as having a mental disorder, most likely because some TANF recipients had mental disorders that were undiagnosed and untreated. Among those using services, some had patterns of use indicating potential eligibility for SSI, but most appeared to have more modest limitations.

How Medicaid agencies administer mental health services: results from a 50-state survey.

OBJECTIVE: This brief report describes some notable variations in how state Medicaid agencies administer and fund Medicaid mental health services. METHODS: Hour-long telephone interviews were conducted with all state and District of Columbia Medicaid directors or their designees. RESULTS: Responses indicated that Medicaid and mental health agencies were located within the same umbrella agency in 28 states, potentially facilitating collaboration. The mental health agency provided funding for some Medicaid mental health services in 32 states, and counties provided such funding in 22 states. Medicaid agencies generally delegated more authority to state mental health agencies in states where some Medicaid funding came from mental health sources and also in states where both agencies were in the same umbrella agency. CONCLUSIONS: The increasing role of Medicaid in funding state mental health services, combined with new federal limits on Medicaid financing of these services, underscores the importance of interagency collaboration and better alignment of Medicaid and mental health responsibilities.

Public reporting of quality information on Medicaid health plans.

Transparency through public reporting of quality data is key to achieving the Institute of Medicine's (IOM) vision for 21st century health care. This article reviews the status of States' voluntary public reporting of Medicaid managed care (MMC) quality data, and analyzes these data. Twenty-one States, including 17 of the 20 largest managed care States, have made plan-level data publicly available online, although the data are sometimes thin, with few measures reported, hard-to-access, and old. We conclude that CMS could better leverage the power of public reporting for quality improvement (QI) by increasing the visibility of health plan employer data and information set (HEDISV) data that States already collect.