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ObjectivesThe Centers for Disease Control and Prevention considers carbapenem-resistant Enterobacteriaceae (CRE) an urgent public health threat; however, its economic burden is unknown.MethodsWe developed a CRE clinical and economics outcomes model to determine the cost of CRE infection from the hospital, third-party payer, and societal, perspectives and to evaluate the health and economic burden of CRE to the USA.ResultsDepending on the infection type, the median cost of a single CRE infection can range from $22 484 to $66 031 for hospitals, $10 440 to $31 621 for third-party payers, and $37 778 to $83 512 for society. An infection incidence of 2.93 per 100 000 population in the USA (9418 infections) would cost hospitals $275 million (95% CR $217-334 million), third-party payers $147 million (95% CR $129-172 million), and society $553 million (95% CR $303-1593 million) with a 25% attributable mortality, and would result in the loss of 8841 (95% CR 5805-12 420) quality-adjusted life years. An incidence of 15 per 100 000 (48 213 infections) would cost hospitals $1.4 billion (95% CR $1.1-1.7 billion), third-party payers $0.8 billion (95% CR $0.6-0.8 billion), and society $2.8 billion (95% CR $1.6-8.2 billion), and result in the loss of 45 261 quality-adjusted life years.ConclusionsThe cost of CRE is higher than the annual cost of many chronic diseases and of many acute diseases. Costs rise proportionally with the incidence of CRE, increasing by 2.0 times, 3.4 times, and 5.1 times for incidence rates of 6, 10, and 15 per 100 000 persons.

Maladaptive decision-making is a hallmark of substance use disorders (SUDs), though how drugs of abuse alter neural representations supporting adaptive behavior remains poorly understood. Past studies show that the orbitofrontal (OFC) and prelimbic (PL) cortices are important for decision-making, tracking both task-relevant and latent information. However, previous studies have focused on how drugs of abuse impact the firing rates of individual units. More work at the ensemble level is necessary to accurately characterize potential drug-induced changes. Using single-unit recordings in rats during a multidimensional decision-making task and then applying population- and ensemble-level analyses, we show that prior use of cocaine altered the strength and structure of task-relevant and latent representations in the OFC, changes relatable to suboptimal decision-making in this and perhaps other settings. These data expand our understanding of the neuropathological underpinnings of maladaptive decision-making in SUDs, potentially enabling enhanced future treatment strategies., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Rationale: Corticotropin-releasing factor (CRF), the apical stress-inducing hormone, exacerbates stress and addictive behaviors. TCAP-1 is a peptide that directly inhibits both CRF-mediated stress and addiction-related behaviors; however, the direct action of TCAP-1 on morphine withdrawal-associated behaviors has not previously been examined., Objective: To determine whether TCAP-1 administration attenuates behavioral and physiological consequences of morphine withdrawal in mice., Methods: Mice were administered via subcutaneous route TCAP-1 either before or after initial morphine exposure, after which jumping behavior was quantified to assess the effects of TCAP-1 on naloxone-precipitated morphine withdrawal. As a comparison, mice were treated with nonpeptide CRF 1 receptor antagonist CP-154,526. In one experiment, plasma corticosterone (CORT) was also measured as a physiological stress indicator., Results: Pretreatment with TCAP-1 (10-250 nmol/kg) before morphine treatment significantly inhibited the development of naloxone-precipitated withdrawal. TCAP-1 (250-500 nmol/kg) treatment administered after morphine treatment attenuated the behavioral expression of naloxone-precipitated withdrawal. TCAP-1 (250 nmol/kg) treatment during morphine treatment was more effective than the optimal dosing of CP-154,526 (20 mg/kg) at suppressing the behavioral expression of naloxone-precipitated withdrawal, despite similar reduction of withdrawal-induced plasma CORT level increases., Conclusions: These findings establish TCAP-1 as a potential therapeutic candidate for the prevention and treatment of morphine withdrawal., (© 2024. The Author(s).)

Background: Radiofrequency ablation (RFA) utilizes minimally invasive high-energy current to precisely ablate tumor cells. It has been utilized in many cancer types including thyroid, lung, and liver cancer. It has been shown to provide adequate ablative margins with minimal complications; however, incomplete RFA may lead to recurrence of tumor. The underlying cellular mechanism and behavior of ablated cancer tissue is poorly understood., Methods: A systematic review was performed, searching EMBASE, Web of Science, PubMed, and Scopus for studies published up to March 2022 and reported following PRISMA guidelines. Collection was performed by two groups of investigators to avoid risk of bias. The Cochrane Collaboration's tool was used for assessing risk of bias. We identified human, in vivo , and in vitro research studies utilizing RFA for tumor tissues. We required that the studies included at least one of the following: complications, recurrence, or survival, and took interest to studies identifying cellular signaling pathway patterns after RFA. Descriptive statistical analysis was performed in 'R' software including mean and confidence interval., Results: The most frequent cancers studied were liver and lung cancers accounting for 57.4% (N=995) and 15.4% (N=267), followed by esophageal (N=190) and breast cancer (N=134). The most common reported complications were bleeding (19%) and post-operative pain (14%). In our literature search, four independent studies showed upregulation and activation of the VEGF pathway following RFA, four showed upregulation and activation of the AKT pathway following RFA, three studies demonstrated involvement of matrix metalloproteinases, and four showed upregulation of c-Met protein following RFA., Conclusions: In our review and meta-analysis, we identify several proteins and pathways of interest of which are important in wound healing, angiogenesis, and cellular growth and survival. These proteins and pathways of interest may implicate areas of research towards RFA resistance and cancer recurrence., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-22-555/coif). The series “RFA and Recent Innovations in Endocrine Surgery” was commissioned by the editorial office without any funding or sponsorship. E.K. served as the unpaid Guest Editor of the series and serves as an Editor-in-Chief of Gland Surgery from May 2017 to April 2024. E.T. receives a research grant (THYROIDGRANT2021-0000000232) from the Bite Me Cancer and facilitated by the American Thyroid Association. The authors have no other conflicts of interest to declare., (2024 Gland Surgery. All rights reserved.)

Next generation on-skin electrodes will require soft, flexible, and gentle materials to provide both high-fidelity sensing and wearer comfort. However, many commercially available on-skin electrodes lack these key properties due to their use of rigid hardware, harsh adhesives, uncomfortable support structures, and poor breathability. To address these challenges, this work presents a new device paradigm by joining biocompatible electrospun spider silk with printable liquid metal to yield an incredibly soft and scalable on-skin electrode that is strain-tolerant, conformable, and gentle on-skin. These electrodes, termed silky liquid metal (SLiM) electrodes, are found to be over five times more breathable than commercial wet electrodes, while the silk's intrinsic adhesion mechanism allows SLiM electrodes to avoid the use of harsh artificial adhesives, potentially decreasing skin irritation and inflammation over long-term use. Finally, the SLiM electrodes provide comparable impedances to traditional wet and other liquid metal electrodes, offering a high-fidelity sensing alternative with increased wearer comfort. Human subject testing confirmed the SLiM electrodes ability to sense electrophysiological signals with high fidelity and minimal irritation to the skin. The unique properties of the reported SLiM electrodes offer a comfortable electrophysiological sensing solution especially for patients with pre-existing skin conditions or surface wounds., (© 2023 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)

Dopamine neuron activity is tied to the prediction error in temporal difference reinforcement learning models. These models make significant simplifying assumptions, particularly with regard to the structure of the predictions fed into the dopamine neurons, which consist of a single chain of timepoint states. Although this predictive structure can explain error signals observed in many studies, it cannot cope with settings where subjects might infer multiple independent events and outcomes. In the present study, we recorded dopamine neurons in the ventral tegmental area in such a setting to test the validity of the single-stream assumption. Rats were trained in an odor-based choice task, in which the timing and identity of one of several rewards delivered in each trial changed across trial blocks. This design revealed an error signaling pattern that requires the dopamine neurons to access and update multiple independent predictive streams reflecting the subject's belief about timing and potentially unique identities of expected rewards., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer. Due to its heterogeneity and lack of hormone receptor expression, this subtype is more likely to metastasize and resist treatment attempts than are other forms of breast cancer. Due to the absence of targetable receptors, chemotherapy and breast conserving surgery have been the predominant treatment options for patients. However, resistance to chemotherapy and local recurrence of the tumors is frequent. Emerging immunotherapies have begun to change treatment plans for patients diagnosed with TNBC. In this review, we discuss the various immune pathways identified in TNBC and the role they play as targets for new potential treatment choices. Various therapeutic options that inhibit key pathways in cellular growth cycles, DNA repair mechanisms, epithelial mesenchymal transition, and immunosuppression have been shown to improve survival in patients with this disease. With promising results thus far, continued studies of immunotherapy and neoadjuvant therapy options for TNBC are likely to alter the treatment course for these diagnoses in the future.

The orbitofrontal cortex (OFC) and hippocampus share striking cognitive and functional similarities. As a result, both structures have been proposed to encode "cognitive maps" that provide useful scaffolds for planning complex behaviors. However, while this function has been exemplified by spatial coding in neurons of hippocampal regions-particularly place and grid cells-spatial representations in the OFC have been investigated far less. Here we sought to address this by recording OFC neurons from male rats engaged in an open-field foraging task like that originally developed to characterize place fields in rodent hippocampal neurons. Single-unit activity was recorded as rats searched for food pellets scattered randomly throughout a large enclosure. In some sessions, particular flavors of food occurred more frequently in particular parts of the enclosure; in others, only a single flavor was used. OFC neurons showed spatially localized firing fields in both conditions, and representations changed between flavored and unflavored foraging periods in a manner reminiscent of remapping in the hippocampus. Compared with hippocampal recordings taken under similar behavioral conditions, OFC spatial representations were less temporally reliable, and there was no significant evidence of grid tuning in OFC neurons. These data confirm that OFC neurons show spatial firing fields in a large, two-dimensional environment in a manner similar to hippocampus. Consistent with the focus of the OFC on biological meaning and goals, spatial coding was weaker than in hippocampus and influenced by outcome identity. SIGNIFICANCE STATEMENT The orbitofrontal cortex (OFC) and hippocampus have both been proposed to encode "cognitive maps" that provide useful scaffolds for planning complex behaviors. This function is exemplified by place and grid cells identified in hippocampus, the activity of which maps spatial environments. The current study directly demonstrates very similar, though not identical, spatial representatives in OFC neurons, confirming that OFC-like hippocampus-can represent a spatial map under the appropriate experimental conditions., (Copyright © 2021 the authors.)

Importance: Multidrug-resistant organisms (MDROs) can spread across health care facilities in a region. Because of limited resources, certain interventions can be implemented in only some facilities; thus, decision-makers need to evaluate which interventions may be best to implement., Objective: To identify a group of target facilities and assess which MDRO intervention would be best to implement in the Shared Healthcare Intervention to Eliminate Life-threatening Dissemination of MDROs in Orange County, a large regional public health collaborative in Orange County, California., Design, Setting, and Participants: An agent-based model of health care facilities was developed in 2016 to simulate the spread of methicillin-resistant Staphylococcus aureus (MRSA) and carbapenem-resistant Enterobacteriaceae (CRE) for 10 years starting in 2010 and to simulate the use of various MDRO interventions for 3 years starting in 2017. All health care facilities (23 hospitals, 5 long-term acute care hospitals, and 74 nursing homes) serving adult inpatients in Orange County, California, were included, and 42 target facilities were identified via network analyses., Exposures: Increasing contact precaution effectiveness, increasing interfacility communication about patients' MDRO status, and performing decolonization using antiseptic bathing soap and a nasal product in a specific group of target facilities., Main Outcomes and Measures: MRSA and CRE prevalence and number of new carriers (ie, transmission events)., Results: Compared with continuing infection control measures used in Orange County as of 2017, increasing contact precaution effectiveness from 40% to 64% in 42 target facilities yielded relative reductions of 0.8% (range, 0.5%-1.1%) in MRSA prevalence and 2.4% (range, 0.8%-4.6%) in CRE prevalence in health care facilities countywide after 3 years, averting 761 new MRSA transmission events (95% CI, 756-765 events) and 166 new CRE transmission events (95% CI, 158-174 events). Increasing interfacility communication of patients' MDRO status to 80% in these target facilities produced no changes in the prevalence or transmission of MRDOs. Implementing decolonization procedures (clearance probability: 39% in hospitals, 27% in long-term acute care facilities, and 3% in nursing homes) yielded a relative reduction of 23.7% (range, 23.5%-23.9%) in MRSA prevalence, averting 3515 new transmission events (95% CI, 3509-3521 events). Increasing the effectiveness of antiseptic bathing soap to 48% yielded a relative reduction of 39.9% (range, 38.5%-41.5%) in CRE prevalence, averting 1435 new transmission events (95% CI, 1427-1442 events)., Conclusions and Relevance: The findings of this study highlight the ways in which modeling can inform design of regional interventions and suggested that decolonization would be the best strategy for the Shared Healthcare Intervention to Eliminate Life-threatening Dissemination of MDROs in Orange County.

Background: Although current human papillomavirus (HPV) genotype screening tests identify genotypes 16 and 18 and do not specifically identify other high-risk types, a new extended genotyping test identifies additional individual (31, 45, 51, and 52) and groups (33/58, 35/39/68, and 56/59/66) of high-risk genotypes., Methods: We developed a Markov model of the HPV disease course and evaluated the clinical and economic value of HPV primary screening with Onclarity (BD Diagnostics, Franklin Lakes, NJ) capable of extended genotyping in a cohort of women 30 years or older. Women with certain genotypes were later rescreened instead of undergoing immediate colposcopy and varied which genotypes were rescreened, disease progression rate, and test cost., Results: Assuming 100% compliance with screening, HPV primary screening using current tests resulted in 25,194 invasive procedures and 48 invasive cervical cancer (ICC) cases per 100,000 women. Screening with extended genotyping (100% compliance) and later rescreening women with certain genotypes averted 903 to 3163 invasive procedures and resulted in 0 to 3 more ICC cases compared with current HPV primary screening tests. Extended genotyping was cost-effective ($2298-$7236/quality-adjusted life year) when costing $75 and cost saving (median, $0.3-$1.0 million) when costing $43. When the probabilities of disease progression increased (2-4 times), extended genotyping was not cost-effective because it resulted in more ICC cases and accrued fewer quality-adjusted life years., Conclusions: Our study identified the conditions under which extended genotyping was cost-effective and even cost saving compared with current tests. A key driver of cost-effectiveness is the risk of disease progression, which emphasizes the need to better understand such risks in different populations., Competing Interests: Conflict of Interest and Sources of Funding: This work was supported by Becton, Dickinson and Company, the Agency for Healthcare Research and Quality via grant R01HS023317, and the National Institute of General Medical Sciences via MIDAS grant U24GM110707. The funders did not in any way restrict our ability or right to publish any analyses, results, or interpretation of results that emerged from this study. C.H., J.C.A., and C.A. are employees of Becton, Dickinson and Company, the sponsor of the study. The remaining authors report no conflicts of interest., (Copyright © 2020 American Sexually Transmitted Diseases Association. All rights reserved.)

Experimental research controls for past experience, yet prior experience influences how we learn. Here, we tested whether we could recruit a neural population that usually encodes rewards to encode aversive events. Specifically, we found that GABAergic neurons in the lateral hypothalamus (LH) were not involved in learning about fear in naïve rats. However, if these rats had prior experience with rewards, LH GABAergic neurons became important for learning about fear. Interestingly, inhibition of these neurons paradoxically enhanced learning about neutral sensory information, regardless of prior experience, suggesting that LH GABAergic neurons normally oppose learning about irrelevant information. These experiments suggest that prior experience shapes the neural circuits recruited for future learning in a highly specific manner, reopening the neural boundaries we have drawn for learning of particular types of information from work in naïve subjects.

Typically, long-term acute care hospitals (LTACHs) have less experience in and incentives to implementing aggressive infection control for drug-resistant organisms such as carbapenem-resistant Enterobacteriaceae (CRE) than acute care hospitals. Decision makers need to understand how implementing control measures in LTACHs can impact CRE spread regionwide. Using our Chicago metropolitan region agent-based model to simulate CRE spread and control, we estimated that a prevention bundle in only LTACHs decreased prevalence by a relative 4.6%-17.1%, averted 1,090-2,795 new carriers, 273-722 infections and 37-87 deaths over 3 years and saved $30.5-$69.1 million, compared with no CRE control measures. When LTACHs and intensive care units intervened, prevalence decreased by a relative 21.2%. Adding LTACHs averted an additional 1,995 carriers, 513 infections, and 62 deaths, and saved $47.6 million beyond implementation in intensive care units alone. Thus, LTACHs may be more important than other acute care settings for controlling CRE, and regional efforts to control drug-resistant organisms should start with LTACHs as a centerpiece., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: When trying to control regional spread of antibiotic-resistant pathogens such as carbapenem-resistant Enterobacteriaceae (CRE), decision makers must choose the highest-yield facilities to target for interventions. The question is, with limited resources, how best to choose these facilities., Methods: Using our Regional Healthcare Ecosystem Analyst-generated agent-based model of all Chicago metropolitan area inpatient facilities, we simulated the spread of CRE and different ways of choosing facilities to apply a prevention bundle (screening, chlorhexidine gluconate bathing, hand hygiene, geographic separation, and patient registry) to a resource-limited 1686 inpatient beds., Results: Randomly selecting facilities did not impact prevalence, but averted 620 new carriers and 175 infections, saving $6.3 million in total costs compared to no intervention. Selecting facilities by type (eg, long-term acute care hospitals) yielded a 16.1% relative prevalence decrease, preventing 1960 cases and 558 infections, saving $62.4 million more than random selection. Choosing the largest facilities was better than random selection, but not better than by type. Selecting by considering connections to other facilities (ie, highest volume of discharge patients) yielded a 9.5% relative prevalence decrease, preventing 1580 cases and 470 infections, and saving $51.6 million more than random selection. Selecting facilities using a combination of these metrics yielded the greatest reduction (19.0% relative prevalence decrease, preventing 1840 cases and 554 infections, saving $59.6 million compared with random selection)., Conclusions: While choosing target facilities based on single metrics (eg, most inpatient beds, most connections to other facilities) achieved better control than randomly choosing facilities, more effective targeting occurred when considering how these and other factors (eg, patient length of stay, care for higher-risk patients) interacted as a system., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Substance use disorders (SUDs) are characterized by maladaptive behavior. The ability to properly adjust behavior according to changes in environmental contingencies necessitates the interlacing of existing memories with updated information. This can be achieved by assigning learning in different contexts to compartmentalized "states." Though not often framed this way, the maladaptive behavior observed in individuals with SUDs may result from a failure to properly encode states because of drug-induced neural alterations. Previous studies found that the dorsomedial striatum (DMS) is important for behavioral flexibility and state encoding, suggesting the DMS may be an important substrate for these effects. Here, we recorded DMS neural activity in cocaine-experienced male rats during a decision-making task where blocks of trials represented distinct states to probe whether the encoding of state and state-related information is affected by prior drug exposure. We found that DMS medium spiny neurons (MSNs) and fast-spiking interneurons (FSIs) encoded such information and that prior cocaine experience disrupted the evolution of representations both within trials and across recording sessions. Specifically, DMS MSNs and FSIs from cocaine-experienced rats demonstrated higher classification accuracy of trial-specific rules, defined by response direction and value, compared with those drawn from sucrose-experienced rats, and these overly strengthened trial-type representations were related to slower switching behavior and reaction times. These data show that prior cocaine experience paradoxically increases the encoding of state-specific information and rules in the DMS and suggest a model in which abnormally specific and persistent representation of rules throughout trials in DMS slows value-based decision-making in well trained subjects. SIGNIFICANCE STATEMENT Substance use disorders (SUDs) may result from a failure to properly encode rules guiding situationally appropriate behavior. The dorsomedial striatum (DMS) is thought to be important for such behavioral flexibility and encoding that defines the situation or "state." This suggests that the DMS may be an important substrate for the maladaptive behavior observed in SUDs. In the current study, we show that prior cocaine experience results in over-encoding of state-specific information and rules in the DMS, which may impair normal adaptive decision-making in the task, akin to what is observed in SUDs., (Copyright © 2021 the authors.)

Background: Clinical testing detects a fraction of carbapenem-resistant Enterobacteriaceae (CRE) carriers. Detecting a greater proportion could lead to increased use of infection prevention and control measures but requires resources. Therefore, it is important to understand the impact of detecting increasing proportions of CRE carriers., Methods: We used our Regional Healthcare Ecosystem Analyst-generated agent-based model of adult inpatient healthcare facilities in Orange County, California, to explore the impact that detecting greater proportions of carriers has on the spread of CRE., Results: Detecting and placing 1 in 9 carriers on contact precautions increased the prevalence of CRE from 0% to 8.0% countywide over 10 years. Increasing the proportion of detected carriers from 1 in 9 up to 1 in 5 yielded linear reductions in transmission; at proportions >1 in 5, reductions were greater than linear. Transmission reductions did not occur for 1, 4, or 5 years, varying by facility type. With a contact precautions effectiveness of ≤70%, the detection level yielding nonlinear reductions remained unchanged; with an effectiveness of >80%, detecting only 1 in 5 carriers garnered large reductions in the number of new CRE carriers. Trends held when CRE was already present in the region., Conclusion: Although detection of all carriers provided the most benefits for preventing new CRE carriers, if this is not feasible, it may be worthwhile to aim for detecting >1 in 5 carriers., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Regions are considering the use of electronic registries to track patients who carry antibiotic-resistant bacteria, including carbapenem-resistant Enterobacteriaceae (CRE). Implementing such a registry can be challenging and requires time, effort, and resources; therefore, there is a need to better understand the potential impact., Methods: We developed an agent-based model of all inpatient healthcare facilities (90 acute care hospitals, 9 long-term acute care hospitals, 351 skilled nursing facilities, and 12 ventilator-capable skilled nursing facilities) in the Chicago metropolitan area, surrounding communities, and patient flow using our Regional Healthcare Ecosystem Analyst software platform. Scenarios explored the impact of a registry that tracked patients carrying CRE to help guide infection prevention and control., Results: When all Illinois facilities participated (n = 402), the registry reduced the number of new carriers by 11.7% and CRE prevalence by 7.6% over a 3-year period. When 75% of the largest Illinois facilities participated (n = 304), registry use resulted in a 11.6% relative reduction in new carriers (16.9% and 1.2% in participating and nonparticipating facilities, respectively) and 5.0% relative reduction in prevalence. When 50% participated (n = 201), there were 10.7% and 5.6% relative reductions in incident carriers and prevalence, respectively. When 25% participated (n = 101), there was a 9.1% relative reduction in incident carriers (20.4% and 1.6% in participating and nonparticipating facilities, respectively) and 2.8% relative reduction in prevalence., Conclusions: Implementing an extensively drug-resistant organism registry reduced CRE spread, even when only 25% of the largest Illinois facilities participated due to patient sharing. Nonparticipating facilities garnered benefits, with reductions in new carriers., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Dopamine neurons are proposed to signal the reward prediction error in model-free reinforcement learning algorithms. This term represents the unpredicted or 'excess' value of the rewarding event, value that is then added to the intrinsic value of any antecedent cues, contexts or events. To support this proposal, proponents cite evidence that artificially-induced dopamine transients cause lasting changes in behavior. Yet these studies do not generally assess learning under conditions where an endogenous prediction error would occur. Here, to address this, we conducted three experiments where we optogenetically activated dopamine neurons while rats were learning associative relationships, both with and without reward. In each experiment, the antecedent cues failed to acquire value and instead entered into associations with the later events, whether valueless cues or valued rewards. These results show that in learning situations appropriate for the appearance of a prediction error, dopamine transients support associative, rather than model-free, learning.

Background: Multidrug-resistant organisms (MDROs) spread between hospitals, nursing homes (NHs), and long-term acute care facilities (LTACs) via patient transfers. The Shared Healthcare Intervention to Eliminate Life-threatening Dissemination of MDROs in Orange County is a regional public health collaborative involving decolonization at 38 healthcare facilities selected based on their high degree of patient sharing. We report baseline MDRO prevalence in 21 NHs/LTACs., Methods: A random sample of 50 adults for 21 NHs/LTACs (18 NHs, 3 LTACs) were screened for methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus spp. (VRE), extended-spectrum β-lactamase-producing organisms (ESBL), and carbapenem-resistant Enterobacteriaceae (CRE) using nares, skin (axilla/groin), and peri-rectal swabs. Facility and resident characteristics associated with MDRO carriage were assessed using multivariable models clustering by person and facility., Results: Prevalence of MDROs was 65% in NHs and 80% in LTACs. The most common MDROs in NHs were MRSA (42%) and ESBL (34%); in LTACs they were VRE (55%) and ESBL (38%). CRE prevalence was higher in facilities that manage ventilated LTAC patients and NH residents (8% vs <1%, P < .001). MDRO status was known for 18% of NH residents and 49% of LTAC patients. MDRO-colonized adults commonly harbored additional MDROs (54% MDRO+ NH residents and 62% MDRO+ LTACs patients). History of MRSA (odds ratio [OR] = 1.7; confidence interval [CI]: 1.2, 2.4; P = .004), VRE (OR = 2.1; CI: 1.2, 3.8; P = .01), ESBL (OR = 1.6; CI: 1.1, 2.3; P = .03), and diabetes (OR = 1.3; CI: 1.0, 1.7; P = .03) were associated with any MDRO carriage., Conclusions: The majority of NH residents and LTAC patients harbor MDROs. MDRO status is frequently unknown to the facility. The high MDRO prevalence highlights the need for prevention efforts in NHs/LTACs as part of regional efforts to control MDRO spread., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Persistent transcriptional and morphological events in the nucleus accumbens (NAc) and other brain reward regions contribute to the long-lasting behavioral adaptations that characterize drug addiction. Opiate exposure reduces the density of dendritic spines on medium spiny neurons of the NAc; however, the underlying transcriptional and cellular events mediating this remain unknown. We show that heroin self-administration negatively regulates the actin-binding protein drebrin in the NAc. Using virus-mediated gene transfer, we show that drebrin overexpression in the NAc is sufficient to decrease drug seeking and increase dendritic spine density, whereas drebrin knockdown potentiates these effects. We demonstrate that drebrin is transcriptionally repressed by the histone modifier HDAC2, which is relieved by pharmacological inhibition of histone deacetylases. Importantly, we demonstrate that heroin-induced adaptations occur only in the D1 + subset of medium spiny neurons. These findings establish an essential role for drebrin, and upstream transcriptional regulator HDAC2, in opiate-induced plasticity in the NAc.

OBJECTIVEWhile previous work showed that the Centers for Disease Control and Prevention toolkit for carbapenem-resistant Enterobacteriaceae (CRE) can reduce spread regionally, these interventions are costly, and decisions makers want to know whether and when economic benefits occur.DESIGNEconomic analysisSETTINGOrange County, CaliforniaMETHODSUsing our Regional Healthcare Ecosystem Analyst (RHEA)-generated agent-based model of all inpatient healthcare facilities, we simulated the implementation of the CRE toolkit (active screening of interfacility transfers) in different ways and estimated their economic impacts under various circumstances.RESULTSCompared to routine control measures, screening generated cost savings by year 1 when hospitals implemented screening after identifying ≤20 CRE cases (saving $2,000-$9,000) and by year 7 if all hospitals implemented in a regional coordinated manner after 1 hospital identified a CRE case (hospital perspective). Cost savings was achieved only if hospitals independently screened after identifying 10 cases (year 1, third-party payer perspective). Cost savings was achieved by year 1 if hospitals independently screened after identifying 1 CRE case and by year 3 if all hospitals coordinated and screened after 1 hospital identified 1 case (societal perspective). After a few years, all strategies cost less and have positive health effects compared to routine control measures; most strategies generate a positive cost-benefit each year.CONCLUSIONSActive screening of interfacility transfers garnered cost savings in year 1 of implementation when hospitals acted independently and by year 3 if all hospitals collectively implemented the toolkit in a coordinated manner. Despite taking longer to manifest, coordinated regional control resulted in greater savings over time.Infect Control Hosp Epidemiol 2018;39:516-524.

Associative learning is driven by prediction errors. Dopamine transients correlate with these errors, which current interpretations limit to endowing cues with a scalar quantity reflecting the value of future rewards. We tested whether dopamine might act more broadly to support learning of an associative model of the environment. Using sensory preconditioning, we show that prediction errors underlying stimulus-stimulus learning can be blocked behaviorally and reinstated by optogenetically activating dopamine neurons. We further show that suppressing the firing of these neurons across the transition prevents normal stimulus-stimulus learning. These results establish that the acquisition of model-based information about transitions between nonrewarding events is also driven by prediction errors and that, contrary to existing canon, dopamine transients are both sufficient and necessary to support this type of learning. Our findings open new possibilities for how these biological signals might support associative learning in the mammalian brain in these and other contexts.

Vaccines reside in a complex multiscale system that includes biological, clinical, behavioral, social, operational, environmental, and economical relationships. Not accounting for these systems when making decisions about vaccines can result in changes that have little effect rather than solutions, lead to unsustainable solutions, miss indirect (e.g., secondary, tertiary, and beyond) effects, cause unintended consequences, and lead to wasted time, effort, and resources. Mathematical and computational modeling can help better understand and address complex systems by representing all or most of the components, relationships, and processes. Such models can serve as "virtual laboratories" to examine how a system operates and test the effects of different changes within the system. Here are ten lessons learned from using computational models to bring more of a systems approach to vaccine decision making: (i) traditional single measure approaches may overlook opportunities; (ii) there is complex interplay among many vaccine, population, and disease characteristics; (iii) accounting for perspective can identify synergies; (iv) the distribution system should not be overlooked; (v) target population choice can have secondary and tertiary effects; (vi) potentially overlooked characteristics can be important; (vii) characteristics of one vaccine can affect other vaccines; (viii) the broader impact of vaccines is complex; (ix) vaccine administration extends beyond the provider level; and (x) the value of vaccines is dynamic., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Delays often occur between CLSI and FDA revisions of antimicrobial interpretive criteria. Using our Regional Healthcare Ecosystem Analyst (RHEA) simulation model, we found that the 32-month delay in changing carbapenem-resistant Enterobacteriaceae (CRE) breakpoints might have resulted in 1,821 additional carriers in Orange County, CA, an outcome that could have been avoided by identifying CRE and initiating contact precautions. Policy makers should aim to minimize the delay in the adoption of new breakpoints for antimicrobials against emerging pathogens when containment of spread is paramount; delays of <1.5 years are ideal., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Background: Drug addiction is defined as a chronic disease characterized by compulsive drug seeking and episodes of relapse despite prolonged periods of drug abstinence. Neurobiological adaptations, including transcriptional and epigenetic alterations in the nucleus accumbens, are thought to contribute to this life-long disease state. We previously demonstrated that the transcription factor SMAD3 is increased after 7 days of withdrawal from cocaine self-administration. However, it is still unknown which additional factors participate in the process of chromatin remodeling and facilitate the binding of SMAD3 to promoter regions of target genes. Here, we examined the possible interaction of BRG1-also known as SMARCA4, an adenosine triphosphatase-containing chromatin remodeler-and SMAD3 in response to cocaine exposure., Methods: The expression of BRG1, as well as its binding to SMAD3 and target gene promoter regions, was evaluated in the nucleus accumbens and dorsal striatum of rats using western blotting, co-immunoprecipitation, and chromatin immunoprecipitation following abstinence from cocaine self-administration. Rats were assessed for cocaine-seeking behaviors after either intra-accumbal injections of the BRG1 inhibitor PFI3 or viral-mediated overexpression of BRG1., Results: After withdrawal from cocaine self-administration, BRG1 expression and complex formation with SMAD3 are increased in the nucleus accumbens, resulting in increased binding of BRG1 to the promoter regions of Ctnnb1, Mef2d, and Dbn1. Intra-accumbal infusion of PFI3 attenuated, whereas viral overexpression of Brg1 enhanced, cocaine-reinstatement behavior., Conclusions: BRG1 is a key mediator of the SMAD3-dependent regulation of cellular and behavioral plasticity that mediates cocaine seeking after a period of withdrawal., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the potential impact and value of applications (e.g. adjusting ordering levels, storage capacity, transportation capacity, distribution frequency) of data from demand forecasting systems implemented in a lower-income country's vaccine supply chain with different levels of population change to urban areas., Materials and Methods: Using our software, HERMES, we generated a detailed discrete event simulation model of Niger's entire vaccine supply chain, including every refrigerator, freezer, transport, personnel, vaccine, cost, and location. We represented the introduction of a demand forecasting system to adjust vaccine ordering that could be implemented with increasing delivery frequencies and/or additions of cold chain equipment (storage and/or transportation) across the supply chain during varying degrees of population movement., Results: Implementing demand forecasting system with increased storage and transport frequency increased the number of successfully administered vaccine doses and lowered the logistics cost per dose up to 34%. Implementing demand forecasting system without storage/transport increases actually decreased vaccine availability in certain circumstances., Discussion: The potential maximum gains of a demand forecasting system may only be realized if the system is implemented to both augment the supply chain cold storage and transportation. Implementation may have some impact but, in certain circumstances, may hurt delivery. Therefore, implementation of demand forecasting systems with additional storage and transport may be the better approach. Significant decreases in the logistics cost per dose with more administered vaccines support investment in these forecasting systems., Conclusion: Demand forecasting systems have the potential to greatly improve vaccine demand fulfilment, and decrease logistics cost/dose when implemented with storage and transportation increases. Simulation modeling can demonstrate the potential health and economic benefits of supply chain improvements., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Substance abuse and other psychiatric diseases may share molecular pathology. In order to test this hypothesis, we examined the role of Disrupted In Schizophrenia 1 (DISC1), a psychiatric risk factor, in cocaine self-administration (SA). Cocaine SA significantly increased expression of DISC1 in the nucleus accumbens (NAc); while knockdown of DISC1 in NAc significantly increased cocaine SA and decreased phosphorylation of GSK-3β at Ser9 compared to scrambled shRNA. Our study provides the first mechanistic evidence of a critical role of DISC1 in drug-induced behavioral neuroadaptations and sheds more light at the shared molecular pathology of drug abuse and other major psychiatric disorders., (Copyright © 2015 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.)

Background: Many of the world's vaccine supply chains do not adequately provide vaccines, prompting several questions: how are vaccine supply chains currently structured, are these structures closely tailored to individual countries, and should these supply chains be radically redesigned?, Methods: We segmented the 57 GAVI-eligible countries' vaccine supply chains based on their structure/morphology, analyzed whether these segments correlated with differences in country characteristics, and then utilized HERMES to develop a detailed simulation model of three sample countries' supply chains and explore the cost and impact of various alternative structures., Results: The majority of supply chains (34 of 57) consist of four levels, despite serving a wide diversity of geographical areas and population sizes. These four-level supply chains loosely fall into three clusters [(1) 18 countries relatively more bottom-heavy, i.e., many more storage locations lower in the supply chain, (2) seven with relatively more storage locations in both top and lower levels, and (3) nine comparatively more top-heavy] which do not correlate closely with any of the country characteristics considered. For all three cluster types, our HERMES modeling found that simplified systems (a central location shipping directly to immunization locations with a limited number of Hubs in between) resulted in lower operating costs., Conclusion: A standard four-tier design template may have been followed for most countries and raises the possibility that simpler and more tailored designs may be warranted., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Activin receptor signaling, including the transcription factor Smad3, was upregulated in the rat nucleus accumbens (NAc) shell following withdrawal from cocaine. Direct genetic and pharmacological manipulations of this pathway bidirectionally altered cocaine seeking while governing morphological plasticity in NAc neurons. Thus, Activin/Smad3 signaling is induced following withdrawal from cocaine, and such regulation may be a key molecular mechanism underlying behavioral and cellular plasticity in the brain following cocaine self-administration.

Although the peptide urotensin II (UII) has well studied direct actions on the cardiovascular system, the UII receptor (UIIR) is expressed by neurons of the hindbrain. Specifically, the UIIR is expressed by the cholinergic neurons of the laterodorsal tegmentum (LDTg) and the pedunculopontine tegmentum (PPTg). These neurons send axons to the ventral tegmental area (VTA), for which the PPTg and LDTg are the sole source of acetylcholine. Therefore, it was hypothesized that UIIR activation within the VTA would modulate reward-related behaviors, such as cocaine-induced drug seeking. Intra-VTA microinjections of UII at high concentrations (1 nmole) established conditioned place preference (CPP), but also blocked cocaine-mediated CPP (10 mg/kg). When rats received systemic sub-effectual doses of cocaine (7.5 mg/kg) with intra-VTA injections of 1 or 10 pmole of UII CPP was formed. Furthermore, the second endogenous ligand for the UIIR, urotensin II-related peptide, had the same effect at the 10 pmole dose. The effects of low doses of UII were blocked by pretreatment with the UIIR antagonist SB657510. Furthermore, it was found that intra-VTA UII (10 pmole) further increased cocaine-mediated (7.5 mg/kg) rises in electrically evoked dopamine in the nucleus accumbens. Our study has found that activation of VTA-resident UIIR produces observable behavioral changes in rats, and that UIIR is able to modulate the effects of cocaine. In addition, it was found that UIIR activation within the VTA can potentiate cocaine-mediated neurochemical effects. Therefore, the coincident activation of the UII-system and cocaine administration may increase the liability for drug taking behavior., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Although vaccine supply chains in many countries require additional stationary storage and transport capacity to meet current and future needs, international donors tend to donate stationary storage devices far more often than transport equipment. To investigate the impact of only adding stationary storage equipment on the capacity requirements of transport devices and vehicles, we used HERMES (Highly Extensible Resource for Modeling Supply Chains) to construct a discrete event simulation model of the Niger vaccine supply chain. We measured the transport capacity requirement for each mode of transport used in the Niger vaccine cold chain, both before and after adding cold rooms and refrigerators to relieve all stationary storage constraints in the system. With the addition of necessary stationary storage, the average transport capacity requirement increased from 88% to 144% for cold trucks, from 101% to 197% for pickup trucks, and from 366% to 420% for vaccine carriers. Therefore, adding stationary storage alone may worsen or create new transport bottlenecks as more vaccines flow through the system, preventing many vaccines from reaching their target populations. Dynamic modeling can reveal such relationships between stationary storage capacity and transport constraints.

Background: When addressing the urgent task of improving vaccine supply chains, especially to accommodate the introduction of new vaccines, there is often a heavy emphasis on stationary storage. Currently, donations to vaccine supply chains occur largely in the form of storage equipment., Methods: This study utilized a HERMES-generated detailed, dynamic, discrete event simulation model of the Niger vaccine supply chain to compare the impacts on vaccine availability of adding stationary cold storage versus transport capacity at different levels and to determine whether adding stationary storage capacity alone would be enough to relieve potential bottlenecks when pneumococcal and rotavirus vaccines are introduced by 2015., Results: Relieving regional level storage bottlenecks increased vaccine availability (by 4%) more than relieving storage bottlenecks at the district (1% increase), central (no change), and clinic (no change) levels alone. Increasing transport frequency (or capacity) yielded far greater gains (e.g., 15% increase in vaccine availability when doubling transport frequency to the district level and 18% when tripling). In fact, relieving all stationary storage constraints could only increase vaccine availability by 11%, whereas doubling the transport frequency throughout the system led to a 26% increase and tripling the frequency led to a 30% increase. Increasing transport frequency also reduced the amount of stationary storage space needed in the supply chain. The supply chain required an additional 61,269L of storage to relieve constraints with the current transport frequency, 55,255L with transport frequency doubled, and 51,791L with transport frequency tripled., Conclusions: When evaluating vaccine supply chains, it is important to understand the interplay between stationary storage and transport. The HERMES-generated dynamic simulation model showed how augmenting transport can result in greater gains than only augmenting stationary storage and can reduce stationary storage needs.

The mechanism of high-frequency stimulation used in deep brain stimulation (DBS) for Parkinson's disease (PD) has not been completely elucidated. Previously, high-frequency stimulation of the rat entopeduncular nucleus, a basal ganglia output nucleus, elicited an increase in [K(+)](e) to 18 mm, in vitro. In this study, we assessed whether elevated K(+) can elicit DBS-like therapeutic effects in hemiparkinsonian rats by employing the limb-use asymmetry test and the self-adjusting stepping test. We then identified how these effects were meditated with in-vivo and in-vitro electrophysiology. Forelimb akinesia improved in hemiparkinsonian rats undergoing both tests after 20 mm KCl injection into the substantia nigra pars reticulata (SNr) or the subthalamic nucleus. In the SNr, neuronal spiking activity decreased from 38.2 ± 1.2 to 14.6 ± 1.6 Hz and attenuated SNr beta-frequency (12-30 Hz) oscillations after K(+) treatment. These oscillations are commonly associated with akinesia/bradykinesia in patients with PD and animal models of PD. Pressure ejection of 20 mm KCl onto SNr neurons in vitro caused a depolarisation block and sustained quiescence of SNr activity. In conclusion, our data showed that elevated K(+) injection into the hemiparkinsonian rat SNr improved forelimb akinesia, which coincided with a decrease in SNr neuronal spiking activity and desynchronised activity in SNr beta frequency, and subsequently an overall increase in ventral medial thalamic neuronal activity. Moreover, these findings also suggest that elevated K(+) may provide an ionic mechanism that can contribute to the therapeutic effects of DBS for the motor treatment of advanced PD., (© 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)