A telemedicine bridge clinic improves access and reduces cost for opioid use disorder care.

Objective: We evaluated the impact of a telemedicine bridge clinic on treatment outcomes and cost for patients with opioid use disorder. Telemedicine bridge clinics deliver low-barrier rapid assessment of patients with opioid use disorder via audio-only and audiovisual telemedicine to facilitate induction on medication therapy and connection to ongoing care. Methods: A pre-post analysis of UPMC Health Plan member claims was performed to evaluate the impact of this intervention on the trajectory of care for patients with continuous coverage before and after bridge clinic visit(s). Results: Analysis included 150 UPMC Health Plan members evaluated at the bridge clinic between April 2020 and October 2021. At least one buprenorphine prescription was filled within 30 days by 91% of patients; median proportion of days covered by buprenorphine was 73.3%, 54.4%, and 50.6% at 30, 90, and 180 days after an initial visit compared to median of no buprenorphine claims 30 days prior among the same patients. Patients had an 18% decline in unplanned care utilization 30 days after initial Bridge Clinic visit, with a 62% reduction in unplanned care cost per member per month (PMPM), 38% reduction in medical cost PMPM, and 10% reduction in total PMPM (medical + pharmacy cost) at 180 days. Primary care, outpatient behavioral health, and laboratory costs increased while emergency department, urgent care, and inpatient costs declined. Conclusion: Utilization of a telemedicine bridge clinic was associated with buprenorphine initiation, linkage to ongoing care with retention including medication treatment, reduced unplanned care cost, and overall savings.

Both Las17-binding sites on Arp2/3 complex are important for branching nucleation and assembly of functional endocytic actin networks in S. cerevisiae.

Arp2/3 complex nucleates branched actin filaments that drive membrane invagination during endocytosis and leading-edge protrusion in lamellipodia. Arp2/3 complex is maximally activated in vitro by binding of a WASP family protein to two sites-one on the Arp3 subunit and one spanning Arp2 and ARPC1-but the importance of each site in the regulation of force-producing actin networks is unclear. Here, we identify mutations in budding yeast Arp2/3 complex that decrease or block engagement of Las17, the budding yeast WASP, at each site. As in the mammalian system, both sites are required for maximal activation in vitro. Dimerization of Las17 partially restores activity of mutations at both CA-binding sites. Arp2/3 complexes defective at either site assemble force-producing actin networks in a bead motility assay, but their reduced activity hinders motility by decreasing actin assembly near the bead surface and by failing to suppress actin filament bundling within the networks. While even the most defective Las17-binding site mutants assembled actin filaments at endocytic sites, they showed significant internalization defects, potentially because they lack the proper architecture to drive plasma membrane remodeling. Together, our data indicate that both Las17-binding sites are important to assemble functional endocytic actin networks in budding yeast, but Arp2/3 complex retains some activity in vitro and in vivo even with a severe defect at either Las17-binding site.

The use of buprenorphine to-go packs in the emergency department.

OBJECTIVE: Buprenorphine is an effective treatment for opioid use disorder (OUD). Patients in the emergency department (ED) can be initiated or continued on buprenorphine as a bridge to follow-up in the outpatient setting, but gaps in care may arise. The objective was to evaluate the impact of buprenorphine to-go packs as a continuing treatment option for patients presenting to the ED with OUD across a health system. METHODS: Adult patients discharged with a buprenorphine to-go pack from one of ten EDs within a major health system were included. The primary outcomes assessed within 30 days of ED discharge were: (1) return to a health system ED, and (2) fill history of buprenorphine in the state prescription drug monitoring program database. Data was analyzed using descriptive statistics in Microsoft Excel (Redmond, WA). RESULTS: A total of 124 patients received buprenorphine to-go packs. The sample was primarily male (79; 63.7%), white (89; 71.8%), on Medicaid (79; 63.7%), and had a mean age of 40.9 years. A total of 43 patients (34.7%) were initiated on buprenorphine for the first time, while 81 (65.3%) had received buprenorphine (prescription or to-go) previously. At 30 days post-visit, 76 (61.3%) had filled buprenorphine prescriptions, and 40 (32.3%) returned to an ED within the health system for opioid withdrawal (17; 42.5%), non-OUD-related reasons (22; 55%), or overdose (1; 2.5%). CONCLUSION: The implementation of a system-wide buprenorphine to-go supply at ED discharge is a feasible option to provide continuity of care to patients with OUD.

Lysinoalanine cross-linking is a conserved post-translational modification in the spirochete flagellar hook.

Spirochetes cause Lyme disease, leptospirosis, syphilis, and several other human illnesses. Unlike other bacteria, spirochete flagella are enclosed within the periplasmic space where the filaments distort and push the cell body by the action of the flagellar motors. We previously demonstrated that the oral pathogen Treponema denticola (Td) and Lyme disease pathogen Borreliella burgdorferi (Bb) form covalent lysinoalanine (Lal) cross-links between conserved cysteine and lysine residues of the FlgE protein that composes the flagellar hook. In Td, Lal is unnecessary for hook assembly but is required for motility, presumably due to the stabilizing effect of the cross-link. Herein, we extend these findings to other, representative spirochete species across the phylum. We confirm the presence of Lal cross-linked peptides in recombinant and in vivo-derived samples from Treponema spp., Borreliella spp., Brachyspira spp., and Leptospira spp. As was observed with Td, a mutant strain of Bb unable to form the cross-link has greatly impaired motility. FlgE from Leptospira spp. does not conserve the Lal-forming cysteine residue which is instead substituted by serine. Nevertheless, Leptospira interrogans FlgE also forms Lal, with several different Lal isoforms being detected between Ser-179 and Lys-145, Lys-148, and Lys-166, thereby highlighting species or order-specific differences within the phylum. Our data reveal that the Lal cross-link is a conserved and necessary posttranslational modification across the spirochete phylum and may thus represent an effective target for the development of spirochete-specific antimicrobials.

A chemosensory-like histidine kinase is dispensable for chemotaxis in vitro but regulates the virulence of Borrelia burgdorferi through modulating the stability of RpoS.

As an enzootic pathogen, the Lyme disease bacterium Borrelia burgdorferi possesses multiple copies of chemotaxis proteins, including two chemotaxis histidine kinases (CHK), CheA1 and CheA2. Our previous study showed that CheA2 is a genuine CHK that is required for chemotaxis; however, the role of CheA1 remains mysterious. This report first compares the structural features that differentiate CheA1 and CheA2 and then provides evidence to show that CheA1 is an atypical CHK that controls the virulence of B. burgdorferi through modulating the stability of RpoS, a key transcriptional regulator of the spirochete. First, microscopic analyses using green-fluorescence-protein (GFP) tags reveal that CheA1 has a unique and dynamic cellular localization. Second, loss-of-function studies indicate that CheA1 is not required for chemotaxis in vitro despite sharing a high sequence and structural similarity to its counterparts from other bacteria. Third, mouse infection studies using needle inoculations show that a deletion mutant of CheA1 (cheA1mut) is able to establish systemic infection in immune-deficient mice but fails to do so in immune-competent mice albeit the mutant can survive at the inoculation site for up to 28 days. Tick and mouse infection studies further demonstrate that CheA1 is dispensable for tick colonization and acquisition but essential for tick transmission. Lastly, mechanistic studies combining immunoblotting, protein turnover, mutagenesis, and RNA-seq analyses reveal that depletion of CheA1 affects RpoS stability, leading to reduced expression of several RpoS-regulated virulence factors (i.e., OspC, BBK32, and DbpA), likely due to dysregulated clpX and lon protease expression. Bulk RNA-seq analysis of infected mouse skin tissues further show that cheA1mut fails to elicit mouse tnf-α, il-10, il-1ß, and ccl2 expression, four important cytokines for Lyme disease development and B. burgdorferi transmigration. Collectively, these results reveal a unique role and regulatory mechanism of CheA1 in modulating virulence factor expression and add new insights into understanding the regulatory network of B. burgdorferi.

Indirect Modulation by FLP-1 Peptides on Chemotaxis and Dispersal Behavior in C. elegans.

Parasitic nematodes infect and cause morbidity in over one billion people worldwide, with current anthelmintic drugs decreasing in efficacy. To date, nematodes produce more types of neuropeptides than any other animal. We are interested in the role of neuropeptide signaling systems as a possible target for new anthelmintic drugs. Although FMRFamide-related peptides are found throughout the animal kingdom, the number of these peptides in nematodes greatly exceeds that of any other phylum. We are using Caenorhabditis elegans as a model for examining FMRFamide-like peptides, all of which share a C-terminal Arg-Phe-amide and which are known as FLPs in nematodes. Our previous work indicated interactions between the daf-10 , tax-4 , and flp-1 signaling pathways. In this paper, we further explore these interactions with chemotaxis and dispersal assays.

Safe administration of Crotalidae equine immune F(ab')2 antivenom in a patient who suffered anaphylaxis from Crotalidae polyvalent immune Fab antivenom.

Allergic reactions to Crotalidae polyvalent immune Fab and Crotalidae immune F(ab')2 are uncommon but potentially life-threatening. It is unknown whether cross-reactivity reactions exist between these two antivenoms. We report a case of a patient who suffered anaphylaxis from Crotalidae polyvalent immune Fab but subsequently was safely administered Crotalidae immune F(ab')2 after a presumed Agkistrodon contortix (copperhead) envenomation. This single case supports the safety of Crotalidae immune F(ab')2 administration in patients with a history of anaphylaxis to Crotalidae polyvalent immune Fab treatment.

Lysinoalanine crosslinking is a conserved post-translational modification in the spirochete flagellar hook.

Spirochete bacteria cause Lyme disease, leptospirosis, syphilis and several other human illnesses. Unlike other bacteria, spirochete flagella are enclosed within the periplasmic space where the filaments distort and push the cell body by action of the flagellar motors. We previously demonstrated that the oral pathogen Treponema denticola (Td) catalyzes the formation of covalent lysinoalanine (Lal) crosslinks between conserved cysteine and lysine residues of the FlgE protein that composes the flagellar hook. Although not necessary for hook assembly, Lal is required for motility of Td, presumably due to the stabilizing effect of the crosslink. Herein, we extend these findings to other, representative spirochete species across the phylum. We confirm the presence of Lal crosslinked peptides in recombinant and in vivo -derived samples from Treponema spp., Borreliella spp., Brachyspira spp., and Leptospira spp.. Like with Td, a mutant strain of the Lyme disease pathogen Borreliella burgdorferi unable to form the crosslink has impaired motility. FlgE from Leptospira spp. does not conserve the Lal-forming cysteine residue which is instead substituted by serine. Nevertheless, Leptospira interrogans also forms Lal, with several different Lal isoforms being detected between Ser-179 and Lys-145, Lys-148, and Lys-166, thereby highlighting species or order-specific differences within the phylum. Our data reveals that the Lal crosslink is a conserved and necessary post-translational modification across the spirochete phylum and may thus represent an effective target for spirochete-specific antimicrobials. Significance Statement: The phylum Spirochaetota contains bacterial pathogens responsible for a variety of diseases, including Lyme disease, syphilis, periodontal disease, and leptospirosis. Motility of these pathogens is a major virulence factor that contributes to infectivity and host colonization. The oral pathogen Treponema denticola produces a post-translational modification (PTM) in the form of a lysinoalanine (Lal) crosslink between neighboring subunits of the flagellar hook protein FlgE. Herein, we demonstrate that representative spirochetes species across the phylum all form Lal in their flagellar hooks. T. denticola and B. burgdorferi cells incapable of forming the crosslink are non-motile, thereby establishing the general role of the Lal PTM in the unusual type of flagellar motility evolved by spirochetes.

Use of a Telemedicine Bridge Clinic to Engage Patients in Opioid Use Disorder Treatment.

OBJECTIVES: We aimed to assess the feasibility of using a telemedicine bridge clinic model as a low-barrier mechanism to initiate patients on medication treatment for opioid use disorder (MOUD) while facilitating engagement in long-term treatment. METHODS: We established a telemedicine bridge clinic after the U.S. Drug Enforcement Administration temporarily suspended regulations limiting initial treatment of patients with buprenorphine via both audiovisual and audio-only technology during the COVID-19 public health emergency. The rate of engagement in medication treatment for opioid use disorder MOUD based upon review of the Prescription Drug Monitoring Program is described. Referral sources, technology utilization, and payer mix are also presented. RESULTS: The Bridge Clinic scheduled 208 new patient visits and physicians evaluated 200, a show rate of 96% from April 2020 to July 2021. Of the 200 patients who were treated, 192 (96%) were diagnosed with opioid use disorder. Most patients (159/200, 79%) scheduled audio-only visits. At least 1 prescription for buprenorphine was filled by 185/192 (96%) of opioid use disorder patients within 30 days of the telemedicine visit and 147/192 (77%) of patients filled 2 or more prescriptions. Most patients were covered by Medicaid (62%) or were uninsured (19%). There was no significant difference in outcomes for patients evaluated by audio-only vs. audiovisual techniques. CONCLUSION: A Bridge Clinic using audiovisual and audio-only telemedicine served a high-risk, vulnerable population and facilitated engagement in evidence-based MOUD.

The Climate Change-Temperature-Crime Hypothesis: Evidence from a Sample of 15 Large US Cities, 2002 to 2015.

Drawing on prior studies, green criminologists have hypothesized that climate change will both raise the mean temperature and the level of crime. We call this the "climate change-temperature-crime hypothesis" ("CC-T-C"). This hypothesis is an extension of research performed on temperature and crime at the individual level. Other research explores this relationship by testing for the relationship between seasonality and crime within a given period of time (i.e., within years). Climate change, however, produces small changes in temperature over long periods of time, and in this view, the effect of climate change on crime should be assessed across and not within years. In addition, prior CC-T-C studies sometimes employ large geographic aggregations (e.g., the entire whole United States), which masks the CC-T-C association that appears at lower levels of aggregation. Moreover, globally, crime has declined across nations since the early 1990s, during a period of rising mean global temperatures, suggesting that the CC-T-C hypothesis does not fit the general trends in temperature and crime over time. Addressing these issues, the present study assesses the CC-T-C relationship for a sample of 15 large (N = 15) US cities over a 14-year period. Given the CC-T-C hypothesis parameters, we assessed this relationship using correlations between individual crime and temperature trends for each city. Crime trends were measured by both the number and rate of eight Uniform Crime Report (UCR) Part I crimes, so that for each city, there are 16 crime-temperature correlations. Using a liberal p value (p = .10), the temperature-crime correlations were rejected as insignificant in 220 of the 234 tests (94%). We discuss the Implications of this finding and suggest that rather than focusing on the temperature-crime relationship, green criminologists interested in the deleterious effects of climate change draw attention to its larger social, economic, environmental and ecological justice implications.

Linking Physical Activity to Breast Cancer via Sex Hormones, Part 1: The Effect of Physical Activity on Sex Steroid Hormones.

The effect of physical activity on breast cancer risk may be partly mediated by sex steroid hormones. This review synthesized and appraised the evidence for an effect of physical activity on sex steroid hormones. Systematic searches were performed using MEDLINE (Ovid), EMBASE (Ovid), and SPORTDiscus to identify experimental studies and prospective cohort studies that examined physical activity and estrogens, progestins, and/or androgens, as well as sex hormone binding globulin (SHBG) and glucocorticoids in pre- and postmenopausal women. Meta-analyses were performed to generate effect estimates. Risk of bias was assessed, and the GRADE system was used to appraise quality of the evidence. Twenty-eight randomized controlled trials (RCT), 81 nonrandomized interventions, and six observational studies were included. Estrogens, progesterone, and androgens mostly decreased, and SHBG increased, in response to physical activity. Effect sizes were small, and evidence quality was graded moderate or high for each outcome. Reductions in select sex steroid hormones following exercise supports the biological plausibility of the first part of the physical activity-sex hormone-breast cancer pathway. The confirmed effect of physical activity on decreasing circulating sex steroid hormones supports its causal role in preventing breast cancer.See related reviews by Lynch et al., p. 11 and Drummond et al., p. 28.

Intrathecal bupivacaine and morphine toxicity leading to transient hypotension and delayed status epilepticus.

BACKGROUND: Local anesthetic systemic toxicity characteristically occurs after inadvertent intravascular injection of local anesthetics; however, it is unclear if similar symptoms arise after intrathecal adminstration. Intrathecal use of local anesthetics for chronic pain is increasing and carries a potential risk of toxicity. Experience with the presenting symptoms and appropriate treatment for intrathecal local anesthetic toxicity is limited. CASE STUDY: A 74-year-old woman with an intrathecal bupivacaine/morphine pump developed lower extremity sensory neuropathy followed by obtundation, hypotension, and lower extremity flaccidity after an intrathecal pump refill. Her condition evolved to status epilepticus (SE) refractory to standard treatment. Intravenous fat emulsion (IFE) was administered, but was not immediately effective thus necessitating phenobarbital loading and propofol infusion. Despite significant bupivacaine neurotoxicity, no cardiotoxicity developed. DISCUSSION: The patient developed intrathecal local anesthetic and opioid toxicity after a malfunction of her intrathecal pump during a refill. We hypothesize that no cardiotoxicity developed secondary to sequestration of bupivacaine within the central nervous system. Likewise, poor CNS penetration of intravenous lipid emulsion may have negated or delayed any antidotal effect. CONCLUSION: We present a case of intrathecal toxicity leading to prolonged spinal anesthesia, progressive encephalopathy, and SE refractory to intravenous lipid emulsion. Management of SE with benzodiazepines and barbiturates may be more effective than lipids in cases of toxicity from intrathecal administration of bupivacaine.

Pulmonary Complications of Opioid Overdose Treated With Naloxone.

STUDY OBJECTIVE: We aim to determine whether administration of higher doses of naloxone for the treatment of opioid overdose is associated with increased pulmonary complications. METHODS: This was a retrospective, observational, cross-sectional study of 1,831 patients treated with naloxone by the City of Pittsburgh Bureau of Emergency Medical Services. Emergency medical services and hospital records were abstracted for data in regard to naloxone dosing, route of administration, and clinical outcomes, including the development of complications such as pulmonary edema, aspiration pneumonia, and aspiration pneumonitis. For the purposes of this investigation, we defined high-dose naloxone as total administration exceeding 4.4 mg. Multivariable analysis was used to attempt to account for confounders such as route of administration and pretreatment morbidity. RESULTS: Patients receiving out-of-hospital naloxone in doses exceeding 4.4 mg were 62% more likely to have a pulmonary complication after opioid overdose (42% versus 26% absolute risk; odds ratio 2.14; 95% confidence interval 1.44 to 3.18). This association remained statistically significant after multivariable analysis with logistic regression (odds ratio 1.85; 95% confidence interval 1.12 to 3.04). A secondary analysis showed an increased risk of 27% versus 13% (odds ratio 2.57; 95% confidence interval 1.45 to 4.54) when initial naloxone dosing exceeded 0.4 mg. Pulmonary edema occurred in 1.1% of patients. CONCLUSION: Higher doses of naloxone in the out-of-hospital treatment of opioid overdose are associated with a higher rate of pulmonary complications. Furthermore, prospective study is needed to determine the causality of this relationship.

Newly Emerging Drugs of Abuse.

Drug use and the associated overdose deaths have been a serious public health threat in the United States and the world. While traditional drugs of abuse such as cocaine remain popular, recreational use of newer synthetic drugs has continued to increase, but the prevalence of use is likely underestimated. In this review, epidemiology, chemistry, pharmacophysiology, clinical effects, laboratory detection, and clinical treatment are discussed for newly emerging drugs of abuse in the following classes: (1) opioids (e.g., fentanyl, fentanyl analogues, and mitragynine), (2) cannabinoids [THC and its analogues, alkylindole (e.g., JWH-018, JWH-073), cyclohexylphenol (e.g., CP-47,497), and indazole carboxamide (e.g., FUB-AMB, ADB-FUBINACA)], (3) stimulants and hallucinogens [ß-keto amphetamines (e.g., methcathinone, methylone), pyrrolidinophenones (e.g., α-PVP, MDPV), and dimethoxyphenethylamine ("2C" and "NBOMe")], (4) dissociative agents (e.g., 3-MeO-PCP, methoxetamine, 2-oxo-PCE), and (5) sedative-hypnotics (e.g., gabapentin, baclofen, clonazolam, etizolam). It is critically important to coordinate hospital, medical examiner, and law enforcement personnel with laboratory services to respond to these emerging threats.