Repression of SPI2 transcription by nitric oxide-producing, IFNγ-activated macrophages promotes maturation of Salmonella phagosomes

By remodeling the phagosomal membrane, the type III secretion system encoded within the Salmonella pathogenicity island-2 (SPI2) helps Salmonella thrive within professional phagocytes. We report here that nitric oxide (NO) generated by IFNγ-activated macrophages abrogates the intracellular survival advantage associated with a functional SPI2 type III secretion system. NO congeners inhibit overall expression of SPI2 effectors encoded both inside and outside the SPI2 gene cluster, reflecting a reduced transcript level of the sensor kinase SsrA that governs overall SPI2 transcription. Down-regulation of SPI2 expression in IFNγ-treated macrophages does not seem to be the result of global NO cytotoxicity, because transcription of the housekeeping rpoD sigma factor remains unchanged, whereas the expression of the hmpA-encoded, NO-metabolizing flavohemoprotein is stimulated. Because of the reduced SPI2 expression, Salmonella-containing vacuoles interact more efficiently with compartments of the late endosomal/lysosomal system in NO-producing, IFNγ-treated macrophages. These findings demonstrate that inhibition of intracellular SPI2 transcription by NO promotes the interaction of Salmonella phagosomes with the degradative compartments required for enhanced antimicrobial activity. Transcriptional repression of a type III secretion system that blocks phagolysosome biogenesis represents a novel mechanism by which NO mediates resistance of IFNγ-activated phagocytes to an intracellular pathogen

Harmonizing healthcare and other resource measures for evaluating economic costs in substance use disorder research

Background Standardization and harmonization of healthcare resource utilization data can improve evaluations of the economic impact of treating people with substance use disorder (SUD), including reductions in use of expensive hospital and emergency department (ED) services, and can ensure consistency with current cost-effectiveness and cost-benefit analysis guidelines. Methods We examined self-reported healthcare and other resource utilization data collected at baseline from three National Institute on Drug Abuse (NIDA)-funded Seek, Test, Treat, and Retain intervention studies of individuals living with/at risk for HIV with SUD. Costs were calculated by multiplying mean healthcare resource utilization measures by monetary conversion factors reflecting cost per unit of care. We normalized baseline recall timeframes to past 30 days and evaluated for missing data. Results We identified measures that are feasible and appropriate for estimating healthcare sector costs including ED visits, inpatient hospital and residential facility stays, and outpatient encounters. We also identified two self-reported measures to inform societal costs (days experiencing SUD problems, participant spending on substances). Missingness was 8% or less for all study measures and was lower for single questions measuring utilization in a recall period. Conclusions We recommend including measures representing units of service with specific recall periods (e.g., 6 months vs. lifetime), and collecting healthcare resource utilization data using single-question measures to reduce missingness

Constitutive Acid Sphingomyelinase Enhances Early and Late Macrophage Killing of Salmonella enterica Serovar Typhimurium▿

We have identified acid sphingomyelinase (ASM) as an important player in the early and late anti-Salmonella activity of macrophages. A functional ASM participated in the killing activity of macrophages against wild-type Salmonella enterica serovar Typhimurium. The role of ASM in early macrophage killing of Salmonella appears to be linked to an active NADPH phagocyte oxidase enzymatic complex, since the flavoprotein inhibitor diphenyleneiodonium not only blocked a productive respiratory burst but also abrogated the survival advantage of Salmonella in macrophages lacking ASM. Lack of ASM activity also increased the intracellular survival of an isogenic ΔspiC::FRT Salmonella strain deficient in a translocator and effector of the Salmonella pathogenicity island 2 (SPI2) type III secretion system, suggesting that the antimicrobial activity associated with ASM is manifested regardless of the SPI2 status of the bacteria. Constitutively expressed ASM is responsible for the role that this lipid-metabolizing hydrolase plays in the innate host defense of macrophages against Salmonella. Accordingly, the ASM activity and intracellular concentration and composition of ceramide, gangliosides, and neutral sphingolipids did not increase upon Salmonella infection. Salmonella triggered, nonetheless, a significant increase in the secreted fraction of ASM. Collectively, these findings have elucidated a novel role for constitutive ASM in the anti-Salmonella activity of murine macrophages

Economic benefits of substance use disorder treatment: A systematic literature review of economic evaluation studies from 2003 to 2021

The economic burden of substance use disorder (SUD) is significant, comprising costs of health care and social services, criminal justice resources, loss of productivity, and premature mortality. This study assembles and synthesizes two decades of evidence describing the benefits of SUD treatment across five main outcome domains; 1) health care utilization; 2) self-reported criminal activity by offense type; 3) criminal justice involvement collected from administrative records or self-reported; 4) productivity assessed through working hours or wages earned; and 5) social services (e.g., a day spent in transitional housing). This review included studies if they reported the monetary value of the intervention outcomes, most commonly through a cost-benefit or cost-effectiveness framework. The search included studies from 2003 to the present day as of this writing (up to October 15, 2021). Summary cost estimates were adjusted using the US Consumer Price Index (CPI) to reflect the 12-month benefits per client in USD 2021. We followed the PRISMA methodology for study selection and assessed quality using the Checklist for Health Economic Evaluation Reporting Standards (CHEERS). The databases yielded 729 studies after removing duplicates, and we ultimately selected 12 for review. Studies varied widely regarding analytical approaches, time horizons, outcome domains, and other methodological factors. Among the ten studies that found positive economic benefits, reductions in criminal activity or criminal justice costs represented the largest or second largest component of these benefits (range $621 to$193,440 per client). Consistent with previous findings, a reduction in criminal activity costs is driven by the relatively high societal cost per criminal offense, notably for violent crimes, such as aggravated assault and rape/sexual assault. Accepting the economic rationale for increased investment in SUD interventions will require recognizing that more benefits accrue to individuals by avoiding being victims of a crime than to governments through budget offsets resulting from savings in non-SUD program expenses. Future studies should explore individually tailored interventions to optimize care management, which may yield unexpected economic benefits to services utilization, and criminal activity data to estimate economic benefits across a broad range of interventions. •The greatest economic benefits over one year resulted from a reduction in criminal activity.•Alcohol use disorder interventions were associated with a decrease in healthcare utilization costs.•Reduced productivity following intervention was generally due to reduced labor force participation and lost earnings

Nitric Oxide Protects Bacteria from Aminoglycosides by Blocking the Energy-Dependent Phases of Drug Uptake▿

Our investigations have identified a mechanism by which exogenous production of nitric oxide (NO) induces resistance of Gram-positive and -negative bacteria to aminoglycosides. An NO donor was found to protect Salmonella spp. against structurally diverse classes of aminoglycosides of the 4,6-disubstituted 2-deoxystreptamine group. Likewise, NO generated enzymatically by inducible NO synthase of gamma interferon-primed macrophages protected intracellular Salmonella against the cytotoxicity of gentamicin. NO levels that elicited protection against aminoglycosides repressed Salmonella respiratory activity. NO nitrosylated terminal quinol cytochrome oxidases, without exerting long-lasting inhibition of NADH dehydrogenases of the electron transport chain. The NO-mediated repression of respiratory activity blocked both energy-dependent phases I and II of aminoglycoside uptake but not the initial electrostatic interaction of the drug with the bacterial cell envelope. As seen in Salmonella, the NO-dependent inhibition of the electron transport chain also afforded aminoglycoside resistance to the clinically important pathogens Pseudomonas aeruginosa and Staphylococcus aureus. Together, these findings provide evidence for a model in which repression of aerobic respiration by NO fluxes associated with host inflammatory responses can reduce drug uptake, thus promoting resistance to several members of the aminoglycoside family in phylogenetically diverse bacteria

Cost of pharmacotherapy for opioid use disorders following inpatient detoxification

To estimate the costs of providing extended-release injectable naltrexone (XR-NTX) and buprenorphine-naloxone (BUP-NX) following inpatient detoxification using data derived from a multisite randomized controlled trial at 8 US community-based treatment programs. Cost data were collected for 3 intervention phases: program start-up, inpatient detoxification, and up to 24 weeks of medication induction and management visits (post detoxification). Cost analyses were from the healthcare sector perspective (2015 US$); patient costs are also reported. We conducted site visits, administered a cost survey to treatment programs, and analyzed study data on medication and services utilization. Nationally representative sources were used to estimate unit costs. Uncertainty was evaluated in sensitivity analyses. Mean start-up costs were$1071 per program for XR-NTX and $828 per program for BUP-NX. Mean costs per participant were$5416 for XR-NTX (57% detoxification, 37% medication, 3% provider, 3% patient) and $4148 for BUP-NX (64$2979 to $8963 for XR-NTX and from$2521 to $6486 for BUP-NX. For treatment providers, offering XR-NTX and/or BUP-NX as part of existing detoxification treatment modalities generates modest costs in addition to the costs of detoxification, which vary substantially among the 8 sites. From the patient's perspective, the costs associated with medication management visits may be a barrier for some individuals considering these treatments

Influence of Gelatin-Thrombin Matrix Tissue Sealant on Bacterial Colony Formation and Risk of Pelvic Infection

Objective. Gelatin-thrombin matrix (GTM) tissue sealant use was previously identified as an independent predictor of pelvic infection following hysterectomies. We aim to elucidate contributing factors by assessing influence of GTM on bacterial colony formation and characterizing bacteria present at the vaginal cuff. Methods. Escherichia coli was incubated in phosphate-buffered saline (PBS) and pelvic washings with and without GTM to assess influence on colony formation. Pelvic washings of the vaginal cuff were collected from hysterectomies occurring from June through October 2015. In vitro techniques, 16S rRNA gene qPCR, and 16S amplicon sequencing were performed with washings to characterize bacteria at the vaginal cuff. Results. Mean bacterial colony formation in PBS was greater for E. coli incubated in the presence of GTM (1.48 × 107 CFU/mL) versus without (9.95 × 105 CFU/mL) following 20-hour incubation (p=0.001). Out of 61 pelvic washings samples, 3 were culture positive (≥5000 CFU/mL) with Enterococcus faecalis. Conclusion. In vitro experiments support a facilitating role of GTM on colony formation of E. coli in PBS. However, given the negative results of surgical site washings following adequate disinfection, the role of GTM in promoting posthysterectomy pelvic infections may be limited. Analysis of pelvic washings revealed presence of E. faecalis, but results were inconclusive. Further studies are recommended

Cost-Effectiveness of Buprenorphine-Naloxone Versus Extended-Release Naltrexone to Prevent Opioid Relapse

Not enough evidence exists to compare buprenorphine-naloxone with extended-release naltrexone for treating opioid use disorder. To evaluate the cost-effectiveness of buprenorphine-naloxone versus extended-release naltrexone. Cost-effectiveness analysis alongside a previously reported randomized clinical trial of 570 adults in 8 U.S. inpatient or residential treatment programs. Study instruments. Adults with opioid use disorder. 24-week intervention with an additional 12 weeks of observation. Health care sector and societal. Buprenorphine-naloxone and extended-release naltrexone. Incremental costs combined with incremental quality-adjusted life-years (QALYs) and incremental time abstinent from opioids. Use of the health care sector perspective and a willingness-to-pay threshold of $100 000 per QALY showed buprenorphine-naloxone to be preferable to extended-release naltrexone in 97% of bootstrap replications at 24 weeks and in 85% at 36 weeks. Similar results were obtained with incremental time abstinent from opioids as an outcome and with use of the societal perspective. The base-case results were sensitive to the cost of the 2 treatments and the success of randomized treatment initiation. Relatively short follow-up for a chronic condition, substantial missing data, no information on patient out-of-pocket and social service costs. Buprenorphine-naloxone is preferred to extended-release naltrexone as first-line treatment when both options are clinically appropriate and patients require detoxification before initiating extended-release naltrexone. National Institute on Drug Abuse, National Institutes of Health