Endotaxis: A neuromorphic algorithm for mapping, goal-learning, navigation, and patrolling.

An animal entering a new environment typically faces three challenges: explore the space for resources, memorize their locations, and navigate towards those targets as needed. Here we propose a neural algorithm that can solve all these problems and operates reliably in diverse and complex environments. At its core, the mechanism makes use of a behavioral module common to all motile animals, namely the ability to follow an odor to its source. We show how the brain can learn to generate internal "virtual odors" that guide the animal to any location of interest. This endotaxis algorithm can be implemented with a simple 3-layer neural circuit using only biologically realistic structures and learning rules. Several neural components of this scheme are found in brains from insects to humans. Nature may have evolved a general mechanism for search and navigation on the ancient backbone of chemotaxis.

A Proposal for the Comprehensive Care of Men on Androgen Deprivation Therapy: Recommendations From the Multidisciplinary Prostate Cancer 360 Working Group.

INTRODUCTION: To promote comprehensive care of patients throughout the androgen deprivation therapy (ADT) prescribing process, the Prostate Cancer 360 (PC360) Working Group developed monitoring and management recommendations intended to mitigate or prevent ADT-associated adverse events. METHODS: The PC360 Working Group included 14 interdisciplinary experts with a dedicated clinical interest in prostate cancer and ADT management. The working group defined challenges associated with ADT adverse event management and then collaboratively developed comprehensive care recommendations intended to be practical for ADT prescribers. RESULTS: The PC360 Working Group developed both overarching recommendations for ADT adverse event management and specific recommendations across 5 domains (cardiometabolic, bone, sexual, psychological, and lifestyle). The working group recommends an interdisciplinary, team-based approach wherein the ADT prescriber retains an oversight role for ADT management while empowering patients and their primary and specialty care providers to manage risk factors. The PC360 recommendations also emphasize the importance of proactive patient education that involves partners or other support providers. Recommended monitoring and assessment tools, risk factor management, and patient counseling points are also included for the 5 identified domains, with an emphasis on lifestyle and behavioral interventions that can improve quality of life and reduce the risk for ADT-associated complications. CONCLUSIONS: Comprehensive care of patients receiving ADT requires early and ongoing coordinated management of a variety of health domains, including cardiometabolic, bone, sexual, psychological health. Patient education and primary care provider involvement should begin prior to ADT initiation and continue throughout treatment to improve patient and partner quality of life.

Updated Estimates of Annual U.S. Health System Spending from a Hypothetical National Naloxone Co-Prescribing Mandate.

Background: Naloxone-prescription opioid co-prescribing mandates have increasingly been proposed and adopted in the U.S., at both the national and state levels, as a public health intervention for mitigating the impacts of opioid overdoses. In this study, we assess whether a hypothetical national, naloxone co-prescribing mandate has become less costly for the U.S. health system since 2018. Methods: We expand and update an existing economic model of naloxone co-prescribing to estimate annual health system spending. We refresh the model inputs through 2021 to reflect changes to the opioid and naloxone landscapes, expand the model to account for more types of market responses, and develop additional scenarios around alternate implementation strategies such as bulk purchasing. Results: We estimate annual spending increases across all retail opioid patients of $1.4-$4.0 billion with naloxone nasal sprays and auto-injectors, and $0.6-$0.9 billion with traditional injectable naloxone formulations. We also find that bulk purchasing could lead to higher spending increases in some patient populations absent volume discounts. Conclusions: Our estimates are substantially lower than prior research. Key drivers include lower prices for naloxone, higher current naloxone distribution, a longer approved shelf life for naloxone, and lower estimated sizes for some patient populations. Additional research is needed to estimate the potential benefits of naloxone co-prescribing for mitigating opioid overdoses, and whether they could outweigh spending increases. Steps that could make this policy more beneficial or less costly include targeting higher risk patient populations and promoting large-scale purchasing agreements with volume discounts to help offset potential price increases.

6″-Modifed α-GalCer-peptide conjugate vaccine candidates protect against liver-stage malaria.

Self-adjuvanting vaccines consisting of peptide epitopes conjugated to immune adjuvants are a powerful way of generating antigen-specific immune responses. We previously showed that a Plasmodium-derived peptide conjugated to a rearranged form of α-galactosylceramide (α-GalCer) could stimulate liver-resident memory T (TRM) cells that were effective killers of liver-stage Plasmodium berghei ANKA (Pba)-infected cells. To investigate if similar or even superior TRM responses can be induced by modifying the α-GalCer adjuvant, we created new conjugate vaccine cadidates by attaching an immunogenic Plasmodium-derived peptide antigen to 6″-substituted α-GalCer analogues. Vaccine synthesis involved developing an efficient route to α-galactosylphytosphingosine (α-GalPhs), from which the prototypical iNKT cell agonist, α-GalCer, and its 6″-deoxy-6″-thio and -amino analogues were derived. Attaching a cathepsin B-cleavable linker to the 6″-modified α-GalCer created pro-adjuvants bearing a pendant ketone group available for peptide conjugation. Optimized reaction conditions were developed that allow for the efficient conjugation of peptide antigens to the pro-adjuvants via oxime ligation to create new glycolipid-peptide (GLP) conjugate vaccines. A single dose of the vaccine candidates induced acute NKT and Plasmodium-specific CD8+ T cell responses that generated potent hepatic TRM responses in mice. Our findings demonstrate that attaching antigenic peptides to 6″-modifed α-GalCer generates powerful self-adjuvanting conjugate vaccine candidates that could potentially control hepatotropic infections such as liver-stage malaria.

The activities and impacts of a community-based volunteer ambulance service in Cape Town, South Africa.

Introduction: Volunteering yields valuable benefits to communities, yet globally there is limited published data regarding emergency medical volunteering in communities. Hout Bay Volunteer Emergency Medical Service is thought to be the oldest volunteer ambulance service in Cape Town. The objective of this paper is to quantify the contribution of the community service to the Western Cape Government Health: Emergency Medical Service. This paper describes the inputs, key stakeholder relationships, and the impact of COVID-19 on volunteer input and community needs. Methods: Electronic Computer-Aided Dispatch records were used for analysis. Data extracted included detailed information about all recorded incidents between 1 January 2015 to 31 December 2020. Data were analysed in Google Sheets using Pivot Tables and summary statistics. Results: Between 2015 and 2020 HBVEMS responded to approximately 12% of all call-outs in the Hout Bay area, which equates to 2187.16 h of operational time spent on calls. This excludes standby time, i.e., time spent waiting to be dispatched. There was an expected noticeable difference between response times for ambulances based within Hout Bay, and those from outside Hout Bay. Despite a decline in average call-out rate during the 2020 Level 5 lockdown, the volunteers were able to do more shifts and thus more calls within the community. Call-outs during 2020 were visualised as a ratio of trauma to medical calls. In this period there were noticeably fewer trauma calls. Conclusions: There is a growing need for emergency medical care, and volunteer ambulance services can have a meaningful impact on the continent. The findings support the benefit of developing community-based ambulance services, especially in areas that are remote due to distance or topography. The model can be expanded to other communities across the continent. A key factor for success is actively managing stakeholder relationships which include community-based relationships as well as governmental or formal emergency medical services relationships.

Mice in a labyrinth show rapid learning, sudden insight, and efficient exploration.

Animals learn certain complex tasks remarkably fast, sometimes after a single experience. What behavioral algorithms support this efficiency? Many contemporary studies based on two-alternative-forced-choice (2AFC) tasks observe only slow or incomplete learning. As an alternative, we study the unconstrained behavior of mice in a complex labyrinth and measure the dynamics of learning and the behaviors that enable it. A mouse in the labyrinth makes ~2000 navigation decisions per hour. The animal explores the maze, quickly discovers the location of a reward, and executes correct 10-bit choices after only 10 reward experiences - a learning rate 1000-fold higher than in 2AFC experiments. Many mice improve discontinuously from one minute to the next, suggesting moments of sudden insight about the structure of the labyrinth. The underlying search algorithm does not require a global memory of places visited and is largely explained by purely local turning rules.

The Impact of COVID-19 on Telemedicine Utilization Across Multiple Service Lines in the United States.

The impact of COVID-19 on the U.S. healthcare industry cannot be overstated. Telemedicine utilization increased overnight as all healthcare providers rushed to implement this delivery model to ensure accessibility and continuity of patient care. Our research objective was to determine measures that were implemented to accommodate community and individual patient needs to afford access to critical services and to maintain safety standards. We analyzed literature since 2016 from two databases using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We compared observations, themes, service lines addressed, issues identified, and interventions requiring in-person care. From 44 articles published, we identified ten effectiveness themes overall and drew conclusions on service line successes. COVID-19 has caused rapid expansion in telemedicine. Necessary and required changes in access, risk mitigation, the need for social distancing, compliance, cost, and patient satisfaction are a few of the driving factors. This review showcased the healthcare industry's ability to rapidly acclimate and change despite the pervasive spread of COVID-19 throughout the U.S. Although imperfect, unique responses were developed within telemedicine platforms to mitigate disruptions broadly and effectively in care and treatment modalities.

FDA postmarketing safety labeling changes: What have we learned since 2010 about impacts on prescribing rates, drug utilization, and treatment outcomes.

PURPOSE: Prior literature reviews have identified gaps in understanding of how postmarketing safety labeling changes and related FDA communications impact key clinical and behavioral outcomes. We conducted a review of newly published studies on this topic to determine what new evidence exists and to identify which gaps may still remain. We believe that this information can support FDA as it develops and implements future risk communication approaches. METHODS: We searched PubMed and Embase for studies published between January 1, 2010, and August 7, 2017 that examined the impact of labeling changes or associated FDA safety-related communications. For each study, we extracted information on research design and findings for key clinical outcomes and behaviors. We also conducted a ROBINS-I review to identify potential for bias in the research design of each study. RESULTS: We found that the estimated impacts of FDA labeling changes on several key outcomes-including adverse events-varied. Labeling changes also yielded unintended consequences on drug prescribing in some cases, despite low provider adherence. Finally, some studies we reviewed exhibited potential for bias due to confounding, among other factors. CONCLUSIONS: The new studies we reviewed contain many of the same limitations identified in previously published reviews. While there are several challenges to conducting this research there is substantial room for improvement in the quality of the evidence base. More information, particularly with respect to the types of populations and medications affected by labeling changes, is needed to support the development of more effective and targeted safety communications.

Factors that have an Impact on Abbreviated New Drug Application (ANDA) Submissions.

BACKGROUND: Increasing generic drug price competition by facilitating abbreviated new drug applications (ANDA) submission may help patients have access to affordable care. This study examined factors associated with first ANDA submission for the brand drug to be copied [the "reference listed drug" (RLD)]. METHODS: This study used several data sources from 1/1/2011 to 12/31/2017, including FDA's Approved Drug Products With Therapeutic Equivalence Evaluations (the Orange Book), internal ANDA submission data, FDA's Product-Specific Guidances (PSGs), National Drug Code, and IQVIA National Sales Perspectives. Two Cox proportional hazard models were separately performed to determine factors associated with first ANDA submissions for groups of ANDAs for RLDs with "new chemical entity" (NCE) exclusivity that were submitted on the first lawfully permissible date NCE ANDAs, and non-NCE ANDA groups. RESULTS: For NCE group, annual market sales were the only factor associated with increased likelihood of first ANDA submission. Specifically, adjusted hazard ratio (HR) for RLDs with annual sales > $250 million was nearly 5 times higher than those with annual sales < $10 million (HR 4.74; Confidence Interval [CI] 1.85-12.13) suggesting RLDs with higher sales are more likely to have ANDA submissions. For the non-NCE group, annual market sales (HR 2.40; CI 1.09-5.25, sales > $100-250 million compared with sales < $10 million) and PSG availability were associated with increased likelihood of first ANDA submission. Being an ANDA for a complex drug product was associated with decreased likelihood of submission for both NCE (HR 0.51; CI 0.26-0.99) and non-NCE groups (HR 0.62; CI 0.39-0.98). CONCLUSION: Given the impact of regulatory-related factors, particularly PSG availability prior to ANDA submission, the findings provide opportunities to address high drug prices with specific FDA actions. Specifically, timely development of PSGs, including those for complex generics, and research prioritizing complex generics may facilitate ANDA submission; and thus, promote drug price competition.

The impact of the abuse-deterrent reformulation of extended-release OxyContin on prescription pain reliever misuse and heroin initiation.

The introduction of abuse-deterrent OxyContin in 2010 was intended to reduce its misuse by making it more tamper resistant. However, some studies have suggested that this reformulation might have had unintended consequences, such as increases in heroin-related deaths. We used the 2005-2014 cross-sectional U.S. National Survey on Drug Use and Health to explore the impact of this reformulation on intermediate outcomes that precede heroin-related deaths for individuals with a history of OxyContin misuse. Our study sample consisted of adults who misused any prescription pain reliever prior to the reformulation of OxyContin (n = 81,400). Those who misused OxyContin prior to the reformulation were considered the exposed group and those who misused other prescription pain relievers prior to the reformulation were considered the unexposed group. We employed multivariate logistic regression under a difference-in-differences framework to examine the effect of the reformulation on five dichotomous outcomes: prescription pain reliever misuse; prescription pain reliever use disorder; heroin use; heroin use disorder; and heroin initiation. We found a net reduction in the odds of prescription pain reliever misuse (OR:0.791, p < 0.001) and heroin initiation (OR:0.422, p = 0.011) after the reformulation for the exposed group relative to the unexposed group. We found no statistically significant effects of the reformulation on prescription pain reliever use disorder (OR: 0.934, p = 0.524), heroin use (OR: 1.014p = 0.941), and heroin use disorder (OR: 1.063, p = 0.804). Thus, the reformulation of OxyContin appears to have reduced prescription pain reliever misuse without contributing to relatively greater new heroin use among those who misused OxyContin prior to the reformulation.

Predictive Analysis of First Abbreviated New Drug Application Submission for New Chemical Entities Based on Machine Learning Methodology.

Generic drug products are approved by the US Food and Drug Administration (FDA) through Abbreviated New Drug Applications (ANDAs). The ANDA review and approval involves multiple offices across the FDA. Forecasting ANDA submissions can critically inform resource allocation and workload management. In this work, we used machine learning (ML) methodologies to predict the time to first ANDA submissions referencing new chemical entities following their earliest lawful ANDA submission dates. Drug product information, regulatory factors, and pharmacoeconomic factors were used as modeling inputs. The random survival forest ML method, as well as the conventional Cox model, was used for ANDA submission predictions. The ML method outperformed the conventional Cox regression model in predictive performance that was adequately assessed by both internal and external validations. In conclusion, it can potentially serve as an effective forecasting tool for strategic workload and research planning for generic applications.

The language of music: Common neural codes for structured sequences in music and natural language.

The ability to process structured sequences is a central feature of natural language but also characterizes many other domains of human cognition. In this fMRI study, we measured brain metabolic response in musicians as they generated structured and non-structured sequences in language and music. We employed a univariate and multivariate cross-classification approach to provide evidence that a common neural code underlies the production of structured sequences across the two domains. Crucially, the common substrate includes Broca's area, a region well known for processing structured sequences in language. These findings have several implications. First, they directly support the hypothesis that language and music share syntactic integration mechanisms. Second, they show that Broca's area is capable of operating supramodally across these two domains. Finally, these results dismiss the recent hypothesis that domain general processes of neighboring neural substrates explain the previously observed "overlap" between neuroimaging activations across the two domains.

Trends and economic drivers for United States naloxone pricing, January 2006 to February 2017.

Anecdotal evidence indicates that naloxone prices have risen in recent years, but limited research has examined the magnitude of these increases and potential causes. We contribute nationally representative evidence to help answer each of these questions, including wholesale pricing data from a proprietary drug sales database spanning January 2006 to February 2017. We find that all formulations of naloxone increased in price since 2006 except for Narcan Nasal Spray. These cumulative increases totaled 2281% for the 0.4 MG single-dose products, 244% for the 2 MG single-dose products, 3797% for the 4 MG multi-dose products, and 469% for the 0.4 MG Evzio auto-injector. We believe that increased demand for naloxone from the opioid epidemic may explain the more gradual price increases for the 0.4 MG single-dose and 4 MG multi-dose products prior to 2012. On the other hand, we believe that the sudden, sustained prices increases occurring for all of the products since 2012 may be the result of a drug shortage for the 0.4 MG single-dose products and the fact that each naloxone product has historically been sold by only a single competitor.

Laser-Induced Breakdown Spectroscopy for the Rapid Characterization of Lead-Free Gunshot Residues.

This study investigated the use of laser-induced breakdown spectroscopy (LIBS) and scanning electron microscopy energy dispersive X-ray spectroscopy (SEM-EDX) as means of characterizing gunshot residue (GSR) originating from commercially available lead-free rounds. Data from two experiments are presented in this work. One experiment focused on identifying prominent analytical markers present in lead-free GSR by LIBS while the other applied SEM-EDX to determine the degree of evidence preservation after LIBS analysis. Samples of GSR were collected via tape-lift method from the hands of volunteer shooters and instrumental analyses were conducted in triplicate. As a result, the lead-free ammunition analyzed in this work generated GSRs comprising primarily Ba, Al, Si, and/or K. Trace amounts of Ti, Fe, and S were also apparent in some compositions. Through SEM-EDX analysis, a spheroidal geometry consistent with traditional lead-containing GSR was observed. Additionally, it was determined that evidence is preserved after LIBS analysis which supports the implementation of LIBS as a rapid preliminary screening method followed by confirmatory testing via SEM-EDX on the preserved evidence.

Intra-articular dysplasia of the femoral head in developmental dysplasia of the hip.

Central to the current treatment of dysplasia of the hip (DDH) is the concept of congruent reduction of the hip. If the femoral head is aspherical in DDH, this concept needs reconsideration. MRI scans are used to examine the femoral head in children. Diameters of 14 DDH and 12 normal hips were measured in three planes by eight observers on two occasions. Femoral head sphericity was determined using the mathematical concept of eccentricity. In DDH, the femoral head was less spherical, most marked in the coronal plane, yielding a 'rugby ball'-shaped femoral head. Accordingly, concentric reduction of the femoral head in DDH is impossible.

Frontostriatal Circuit Dynamics Correlate with Cocaine Cue-Evoked Behavioral Arousal during Early Abstinence.

It is thought that frontostriatal circuits play an important role in mediating conditioned behavioral responses to environmental stimuli that were previously encountered during drug administration. However, the neural correlates of conditioned responses to drug-associated cues are not well understood at the level of large populations of simultaneously recorded neurons, or at the level of local field potential (LFP) synchrony in the frontostriatal network. Here we introduce a behavioral assay of conditioned arousal to cocaine cues involving pupillometry in awake head-restrained mice. After just 24 h of drug abstinence, brief exposures to olfactory stimuli previously paired with cocaine injections led to a transient dilation of the pupil, which was greater than the dilation effect to neutral cues. In contrast, there was no cue-selective change in locomotion, as measured by the rotation of a circular treadmill. The behavioral assay was combined with simultaneous recordings from dozens of electrophysiologically identified units in the medial prefrontal cortex (mPFC) and ventral striatum (VS). We found significant relationships between cocaine cue-evoked pupil dilation and the proportion of inhibited principal cells in the mPFC and VS. Additionally, LFP coherence analysis revealed a significant correlation between pupillary response and synchrony in the 25-45 Hz frequency band. Together, these results show that pupil dilation is sensitive to drug-associated cues during acute stages of abstinence, and that individual animal differences in this behavioral arousal response can be explained by two complementary measures of frontostriatal network activity.

Probing interactions of Vpu from HIV-1 with amiloride-based compounds.

Viral ion channels or viroporins are short membrane proteins that participate in wide-ranging functions including virus replication and entry, assembly, and virus release. One such viroporin is the 81 amino acid residue Vpu protein derived from HIV-1. This protein consists of one transmembrane (TM) and two cytoplasmic helical domains, the former of which oligomerises to form cation-selective ion channels. In this study, we investigate the binding properties of amiloride compounds to Vpu embedded into liposomes using surface plasmon resonance (SPR). We explore the Vpu ion channel inhibitor, hexamethylene amiloride (HMA), as a molecular tool to examine the potential interactive role of key TM residues, Trp23, Ser24, and Glu29, in terms of positioning of these residues on the channel pore and the orientation of its constituent helices. The study provides experimental support that a direct interaction between Ser24 and HMA occurs and that this residue is most likely located in the channel pore. Mutation of Trp23 does not impact HMA affinity suggesting no direct involvement in binding and that this residue is lipid facing. These findings indicate that small molecules such as amilorides are capable of specifically interacting with Vpu ion channels. Although a correlation between ion channel and functional activity cannot be dismissed, alternative mechanisms involving protein-protein interactions may play an important role in the efficacy of these compounds.

Optogenetic fMRI reveals distinct, frequency-dependent networks recruited by dorsal and intermediate hippocampus stimulations.

Although the connectivity of hippocampal circuits has been extensively studied, the way in which these connections give rise to large-scale dynamic network activity remains unknown. Here, we used optogenetic fMRI to visualize the brain network dynamics evoked by different frequencies of stimulation of two distinct neuronal populations within dorsal and intermediate hippocampus. Stimulation of excitatory cells in intermediate hippocampus caused widespread cortical and subcortical recruitment at high frequencies, whereas stimulation in dorsal hippocampus led to activity primarily restricted to hippocampus across all frequencies tested. Sustained hippocampal responses evoked during high-frequency stimulation of either location predicted seizure-like afterdischarges in video-EEG experiments, while the widespread activation evoked by high-frequency stimulation of intermediate hippocampus predicted behavioral seizures. A negative BOLD signal observed in dentate gyrus during dorsal, but not intermediate, hippocampus stimulation is proposed to underlie the mechanism for these differences. Collectively, our results provide insight into the dynamic function of hippocampal networks and their role in seizures.

Thalamo-frontal connectivity mediates top-down cognitive functions in disorders of consciousness.

OBJECTIVE: We employed functional MRI (fMRI) to assess whether (1) patients with disorders of consciousness (DOC) retain the ability to willfully engage in top-down processing and (2) what neurophysiologic factors distinguish patients who can demonstrate this ability from patients who cannot. METHODS: Sixteen volunteers, 8 patients in vegetative state (VS), 16 minimally conscious patients (MCS), and 4 exit from MCS (eMCS) patients were enrolled in a prospective cross-sectional fMRI study. Participants performed a target detection task in which they counted the number of times a (changing) target word was presented amidst a set of distractors. RESULTS: Three of 8 patients diagnosed as being in a VS exhibited significant activations in response to the task, thereby demonstrating a state of consciousness. Differential activations across tasks were also observed in 6 MCS patients and 1 eMCS patient. A psycho-physiologic interaction analysis revealed that the main factor distinguishing patients who responded to the task from those who did not was a greater connectivity between the anterior section of thalamus and prefrontal cortex. CONCLUSIONS: In our sample of patients, the dissociation between overt behavior observable in clinical assessments and residual cognitive faculties is prevalent among DOC patients (37%). A substantial number of patients, including some diagnosed with VS, can demonstrate willful engagement in top-down cognition. While neuroimaging data are not the same as observable behavior, this suggests that the mental status of some VS patients exceeds what can be appreciated clinically. Furthermore, thalamo-frontal circuits might be crucial to sustaining top-down functions.