Rapamycin does not alter bone microarchitecture or material properties quality in young-adult and aged female C57BL/6 mice.

Advancing age is the strongest risk factor for osteoporosis and skeletal fragility. Rapamycin is an FDA-approved immunosuppressant that inhibits the mechanistic target of rapamycin (mTOR) complex, extends lifespan, and protects against aging-related diseases in multiple species; however, the impact of rapamycin on skeletal tissue is incompletely understood. We evaluated the effects of a short-term, low-dosage, interval rapamycin treatment on bone microarchitecture and strength in young-adult (3 mo old) and aged female (20 mo old) C57BL/6 mice. Rapamycin (2 mg/kg body mass) was administered via intraperitoneal injection 1×/5 d for a duration of 8 wk; this treatment regimen has been shown to induce geroprotective effects while minimizing the side effects associated with higher rapamycin dosages and/or more frequent or prolonged delivery schedules. Aged femurs exhibited lower cancellous bone mineral density, volume, trabecular connectivity density and number, higher trabecular thickness and spacing, and lower cortical thickness compared to young-adult mice. Rapamycin had no impact on assessed microCT parameters. Flexural testing of the femur revealed that both yield strength and ultimate strength were lower in aged mice compared to young-adult mice. There were no effects of rapamycin on these or other measures of bone biomechanics. Age, but not rapamycin, altered local and global measures of bone turnover. These data demonstrate that short-term, low-dosage interval rapamycin treatment does not negatively or positively impact the skeleton of young-adult and aged mice.

Atopic dermatitis (eczema) guidelines: 2023 American Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters GRADE- and Institute of Medicine-based recommendations.

BACKGROUND: Guidance addressing atopic dermatitis (AD) management, last issued in 2012 by the American Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force, requires updating as a result of new treatments and improved guideline and evidence synthesis methodology. OBJECTIVE: To produce evidence-based guidelines that support patients, clinicians, and other decision-makers in the optimal treatment of AD. METHODS: A multidisciplinary guideline panel consisting of patients and caregivers, AD experts (dermatology and allergy/immunology), primary care practitioners (family medicine, pediatrics, internal medicine), and allied health professionals (psychology, pharmacy, nursing) convened, prioritized equity, diversity, and inclusiveness, and implemented management strategies to minimize influence of conflicts of interest. The Evidence in Allergy Group supported guideline development by performing systematic evidence reviews, facilitating guideline processes, and holding focus groups with patient and family partners. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach informed rating the certainty of evidence and strength of recommendations. Evidence-to-decision frameworks, subjected to public comment, translated evidence to recommendations using trustworthy guideline principles. RESULTS: The panel agreed on 25 recommendations to gain and maintain control of AD for patients with mild, moderate, and severe AD. The eAppendix provides practical information and implementation considerations in 1-2 page patient-friendly handouts. CONCLUSION: These evidence-based recommendations address optimal use of (1) topical treatments (barrier moisturization devices, corticosteroids, calcineurin inhibitors, PDE4 inhibitors [crisaborole], topical JAK inhibitors, occlusive [wet wrap] therapy, adjunctive antimicrobials, application frequency, maintenance therapy), (2) dilute bleach baths, (3) dietary avoidance/elimination, (4) allergen immunotherapy, and (5) systemic treatments (biologics/monoclonal antibodies, small molecule immunosuppressants [cyclosporine, methotrexate, azathioprine, mycophenolate, JAK inhibitors], and systemic corticosteroids) and UV phototherapy (light therapy).

Evidence on Buprenorphine Dose Limits: A Review.

OBJECTIVES: As overdose deaths from fentanyl continue to increase, optimizing use of medications for opioid use disorder has become increasingly important. Buprenorphine is a highly effective medication for reducing the risk of overdose death, but only if a patient remains in treatment. Shared decision making between prescribers and patients is important to establish a dose that meets each patient's treatment needs. However, patients frequently face a dose limit of 16 or 24 mg/d based on dosing guidelines on the Food and Drug Administration's package label. METHODS: This review discusses patient-centered goals and clinical criteria for determining dose adequacy, reviews the history of buprenorphine dose regulation in the United States, examines pharmacological and clinical research results with buprenorphine doses up to 32 mg/d, and evaluates whether diversion concerns justify maintaining a low buprenorphine dose limit. RESULTS: Pharmacological and clinical research results consistently demonstrate buprenorphine's dose-dependent benefits up to at least 32 mg/d, including reductions in withdrawal symptoms, craving, opioid reward, and illicit use while improving retention in care. Diverted buprenorphine is most often used to treat withdrawal symptoms and reduce illicit opioid use when legal access to it is limited. CONCLUSIONS: In light of established research and profound harms from fentanyl, the Food and Drug Administration's current recommendations on target dose and dose limit are outdated and causing harm. An update to the buprenorphine package label with recommended dosing up to 32 mg/d and elimination of the 16 mg/d target dose would improve treatment effectiveness and save lives.

Topical treatments for atopic dermatitis (eczema): Systematic review and network meta-analysis of randomized trials.

BACKGROUND: Atopic dermatitis (AD) is a common skin condition with multiple topical treatment options, but uncertain comparative effects. OBJECTIVE: We sought to systematically synthesize the benefits and harms of AD prescription topical treatments. METHODS: For the 2023 American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters AD guidelines, we searched MEDLINE, EMBASE, CENTRAL, CINAHL, LILACS, ICTRP, and GREAT databases to September 5, 2022, for randomized trials addressing AD topical treatments. Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random-effects network meta-analyses addressed AD severity, itch, sleep, AD-related quality of life, flares, and harms. The Grading of Recommendations Assessment, Development and Evaluation approach informed certainty of evidence ratings. We classified topical corticosteroids (TCS) using 7 groups-group 1 being most potent. This review is registered in the Open Science Framework (https://osf.io/q5m6s). RESULTS: The 219 included trials (43,123 patients) evaluated 68 interventions. With high-certainty evidence, pimecrolimus improved 6 of 7 outcomes-among the best for 2; high-dose tacrolimus (0.1%) improved 5-among the best for 2; low-dose tacrolimus (0.03%) improved 5-among the best for 1. With moderate- to high-certainty evidence, group 5 TCS improved 6-among the best for 3; group 4 TCS and delgocitinib improved 4-among the best for 2; ruxolitinib improved 4-among the best for 1; group 1 TCS improved 3-among the best for 2. These interventions did not increase harm. Crisaborole and difamilast were intermediately effective, but with uncertain harm. Topical antibiotics alone or in combination may be among the least effective. To maintain AD control, group 5 TCS were among the most effective, followed by tacrolimus and pimecrolimus. CONCLUSIONS: For individuals with AD, pimecrolimus, tacrolimus, and moderate-potency TCS are among the most effective in improving and maintaining multiple AD outcomes. Topical antibiotics may be among the least effective.

Systemic treatments for atopic dermatitis (eczema): Systematic review and network meta-analysis of randomized trials.

BACKGROUND: Atopic dermatitis (AD) is an inflammatory skin condition with multiple systemic treatments and uncertainty regarding their comparative impact on AD outcomes. OBJECTIVE: We sought to systematically synthesize the benefits and harms of AD systemic treatments. METHODS: For the 2023 American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters AD guidelines, we searched MEDLINE, EMBASE, CENTRAL, Web of Science, and GREAT databases from inception to November 29, 2022, for randomized trials addressing systemic treatments and phototherapy for AD. Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random-effects network meta-analyses addressed AD severity, itch, sleep, AD-related quality of life, flares, and harms. The Grading of Recommendations Assessment, Development and Evaluation approach informed certainty of evidence ratings. This review is registered in the Open Science Framework (https://osf.io/e5sna). RESULTS: The 149 included trials (28,686 patients with moderate-to-severe AD) evaluated 75 interventions. With high-certainty evidence, high-dose upadacitinib was among the most effective for 5 of 6 patient-important outcomes; high-dose abrocitinib and low-dose upadacitinib were among the most effective for 2 outcomes. These Janus kinase inhibitors were among the most harmful in increasing adverse events. With high-certainty evidence, dupilumab, lebrikizumab, and tralokinumab were of intermediate effectiveness and among the safest, modestly increasing conjunctivitis. Low-dose baricitinib was among the least effective. Efficacy and safety of azathioprine, oral corticosteroids, cyclosporine, methotrexate, mycophenolate, phototherapy, and many novel agents are less certain. CONCLUSIONS: Among individuals with moderate-to-severe AD, high-certainty evidence demonstrates that high-dose upadacitinib is among the most effective in addressing multiple patient-important outcomes, but also is among the most harmful. High-dose abrocitinib and low-dose upadacitinib are effective, but also among the most harmful. Dupilumab, lebrikizumab, and tralokinumab are of intermediate effectiveness and have favorable safety.

Germ-Free C57BL/6 Mice Have Increased Bone Mass and Altered Matrix Properties but Not Decreased Bone Fracture Resistance.

The gut microbiome impacts bone mass, which implies a disruption to bone homeostasis. However, it is not yet clear how the gut microbiome affects the regulation of bone mass and bone quality. We hypothesized that germ-free (GF) mice have increased bone mass and decreased bone toughness compared with conventionally housed mice. We tested this hypothesis using adult (20- to 21-week-old) C57BL/6J GF and conventionally raised female and male mice (n = 6-10/group). Trabecular microarchitecture and cortical geometry were measured from micro-CT of the femur distal metaphysis and cortical midshaft. Whole-femur strength and estimated material properties were measured using three-point bending and notched fracture toughness. Bone matrix properties were measured for the cortical femur by quantitative back-scattered electron imaging and nanoindentation, and, for the humerus, by Raman spectroscopy and fluorescent advanced glycation end product (fAGE) assay. Shifts in cortical tissue metabolism were measured from the contralateral humerus. GF mice had reduced bone resorption, increased trabecular bone microarchitecture, increased tissue strength and decreased whole-bone strength that was not explained by differences in bone size, increased tissue mineralization and fAGEs, and altered collagen structure that did not decrease fracture toughness. We observed several sex differences in GF mice, most notably for bone tissue metabolism. Male GF mice had a greater signature of amino acid metabolism, and female GF mice had a greater signature of lipid metabolism, exceeding the metabolic sex differences of the conventional mice. Together, these data demonstrate that the GF state in C57BL/6J mice alters bone mass and matrix properties but does not decrease bone fracture resistance. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Sex-specific effects of calving season on joint health and biomarkers in Montana ranchers.

BACKGROUND: Agricultural workers have a higher incidence of osteoarthritis (OA), but the etiology behind this phenomenon is unclear. Calving season, which occurs in mid- to late-winter for ranchers, includes physical conditions that may elevate OA risk. Our primary aim was to determine whether OA biomarkers are elevated at the peak of calving season compared to pre-season, and to compare these data with joint health survey information from the subjects. Our secondary aim was to detect biomarker differences between male and female ranchers. METHODS: During collection periods before and during calving season, male (n = 28) and female (n = 10) ranchers completed joint health surveys and provided samples of blood, urine, and saliva for biomarker analysis. Statistical analyses examined associations between mean biomarker levels and survey predictors. Ensemble cluster analysis identified groups having unique biomarker profiles. RESULTS: The number of calvings performed by each rancher positively correlated with plasma IL-6, serum hyaluronic acid (HA) and urinary CTX-I. Thiobarbituric acid reactive substances (TBARS), a marker of oxidative stress, was significantly higher during calving season than pre-season and was also correlated with ranchers having more months per year of joint pain. We found evidence of sexual dimorphism in the biomarkers among the ranchers, with leptin being elevated and matrix metalloproteinase-3 diminished in female ranchers. The opposite was detected in males. WOMAC score was positively associated with multiple biomarkers: IL-6, IL-2, HA, leptin, C2C, asymmetric dimethylarginine, and CTX-I. These biomarkers represent enzymatic degradation, inflammation, products of joint destruction, and OA severity. CONCLUSIONS: The positive association between number of calvings performed by each rancher (workload) and both inflammatory and joint tissue catabolism biomarkers establishes that calving season is a risk factor for OA in Montana ranchers. Consistent with the literature, we found important sex differences in OA biomarkers, with female ranchers showing elevated leptin, whereas males showed elevated MMP-3.

Values and Preferences of Patients and Caregivers Regarding Treatment of Atopic Dermatitis (Eczema): A Systematic Review.

Importance: Patient values and preferences can inform atopic dermatitis (AD) care. Systematic summaries of evidence addressing patient values and preferences have not previously been available. Objective: To inform American Academy of Allergy, Asthma & Immunology (AAAAI)/American College of Allergy, Asthma and Immunology (ACAAI) Joint Task Force on Practice Parameters AD guideline development, patient and caregiver values and preferences in the management of AD were systematically synthesized. Evidence Review: Paired reviewers independently screened MEDLINE, Embase, PsycINFO, and CINAHL databases from inception until March 20, 2022, for studies of patients with AD or their caregivers, eliciting values and preferences about treatment, rated risk of bias, and extracted data. Thematic and inductive content analysis to qualitatively synthesize the findings was used. Patients, caregivers, and clinical experts provided triangulation. The GRADE-CERQual (Grading of Recommendations Assessment, Development and Evaluation-Confidence in the Evidence from Reviews of Qualitative Research) informed rating of the quality of evidence. Findings: A total of 7780 studies were identified, of which 62 proved eligible (n = 19 442; median age across studies [range], 15 years [3-44]; 59% female participants). High certainty evidence showed that patients and caregivers preferred to start with nonmedical treatments and to step up therapy with increasing AD severity. Moderate certainty evidence showed that adverse effects from treatment were a substantial concern. Low certainty evidence showed that patients and caregivers preferred odorless treatments that are not visible and have a minimal effect on daily life. Patients valued treatments capable of relieving itching and burning skin and preferred to apply topical corticosteroids sparingly. Patients valued a strong patient-clinician relationship. Some studies presented varied perspectives and 18 were at high risk for industry sponsorship bias. Conclusions and Relevance: In the first systematic review to address patient values and preferences in management of AD to our knowledge, 6 key themes that may inform optimal clinical care, practice guidelines, and future research have been identified.

Recruitment challenges for a prospective telehealth cohort study.

Background: The COVID-19 pandemic presents challenges in participant recruitment strategies for clinical research involving people with opioid use disorders recently engaged in treatment. We describe challenges to participant recruitment in a trial comparing virtual buprenorphine treatment platform to office-based buprenorphine treatment. Methods: The parent study was a cohort trial of telehealth delivered buprenorphine treatment compared to office-based buprenorphine treatment, however, due to the pandemic potential participant recruitment for both arms became virtual. Between 9/27/2021 and 7/11/2022, telephone, email, flyers, and word-of-mouth were used to recruit study participants from each treatment setting. Recruitment tracking documents recorded the primary outcomes: number of outreach attempts and most effective contact methods. Results: Treatment settings provided contact information for 1485 potential study participants. Information was incorrect or disconnected for 282 (19%) individuals, 695 (47%) did not respond to outreach, and 508 (34%) responded to outreach. Of these responders, 369 were interested in study participation, 259 completed the online informed consent and screening assessment, and 148 met eligibility criteria and enrolled in the study. A total of 3804 virtual outreach attempts across 1485 potential participants were made, resulting in an average of 2.7 attempts per contact and a mean of 25.7 attempts per enrolled participant (n = 148). Conclusion: Conducting research during the COVID-19 pandemic required shifting from in-person to virtual recruitment strategies to contact and engage potential study participants. Virtual recruitment for this population during a pandemic appears to be less efficient and hindered efforts to meet recruitment goals.

Enhancing Patient Choice: Using Self-administered Intranasal Naloxone for Novel Rapid Buprenorphine Initiation.

Buprenorphine-naloxone (BUP-NX) is a lifesaving treatment for opioid use disorder. The increasing use of illicitly manufactured fentanyl, however, has made initiating BUP-NX more likely to precipitate withdrawal-an experience that deters treatment and causes return to use. If BUP-NX cannot be successfully started, it cannot work. We describe the case of a patient who was able to transition to a therapeutic dose of BUP-NX less than 3 hours after his last illicitly manufactured fentanyl use by choosing to self-administer intranasal naloxone. After the naloxone, the transition took 31 minutes, including 14 minutes of expected moderately severe withdrawal. He remains in care with BUP-NX and would recommend this transition approach to others.

Allergen immunotherapy for atopic dermatitis: Systematic review and meta-analysis of benefits and harms.

BACKGROUND: Atopic dermatitis (AD, eczema) is driven by a combination of skin barrier defects, immune dysregulation, and extrinsic stimuli such as allergens, irritants, and microbes. The role of environmental allergens (aeroallergens) in triggering AD remains unclear. OBJECTIVE: We systematically synthesized evidence regarding the benefits and harms of allergen immunotherapy (AIT) for AD. METHODS: As part of the 2022 American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters AD Guideline update, we searched the MEDLINE, EMBASE, CENTRAL, CINAHL, LILACS, Global Resource for Eczema Trials, and Web of Science databases from inception to December 2021 for randomized controlled trials comparing subcutaneous immunotherapy (SCIT), sublingual immunotherapy (SLIT), and/or no AIT (placebo or standard care) for guideline panel-defined patient-important outcomes: AD severity, itch, AD-related quality of life (QoL), flares, and adverse events. Raters independently screened, extracted data, and assessed risk of bias in duplicate. We synthesized intervention effects using frequentist and Bayesian random-effects models. The GRADE approach determined the quality of evidence. RESULTS: Twenty-three randomized controlled trials including 1957 adult and pediatric patients sensitized primarily to house dust mite showed that add-on SCIT and SLIT have similar relative and absolute effects and likely result in important improvements in AD severity, defined as a 50% reduction in SCORing Atopic Dermatitis (risk ratio [95% confidence interval] 1.53 [1.31-1.78]; 26% vs 40%, absolute difference 14%) and QoL, defined as an improvement in Dermatology Life Quality Index by 4 points or more (risk ratio [95% confidence interval] 1.44 [1.03-2.01]; 39% vs 56%, absolute difference 17%; both outcomes moderate certainty). Both routes of AIT increased adverse events (risk ratio [95% confidence interval] 1.61 [1.44-1.79]; 66% with SCIT vs 41% with placebo; 13% with SLIT vs 8% with placebo; high certainty). AIT's effect on sleep disturbance and eczema flares was very uncertain. Subgroup and sensitivity analyses were consistent with the main findings. CONCLUSIONS: SCIT and SLIT to aeroallergens, particularly house dust mite, can similarly and importantly improve AD severity and QoL. SCIT increases adverse effects more than SLIT. These findings support a multidisciplinary and shared decision-making approach to optimally managing AD.

Integrated hepatitis C treatment is associated with improved retention and success in outpatient treatment for opioid use disorder at a private clinic.

Background: Direct acting antiretrovirals (DAA) are effective for individuals who are infected with chronic hepatitis C virus (HCV), yet many people go without access to these lifesaving treatments. Materials and methods: We conducted a non-randomized study evaluating treatment data for patients in outpatient treatment for opioid use disorder (OUD) at a private clinic. Patients who were HCV-positive, had been in OUD treatment for at least 4 weeks, and engaged in integrated HCV treatment with DAA (co-located within their treatment for OUD) were compared to patients with HCV who only received OUD treatment. We evaluated HCV cure; OUD medication adherence, treatment utilization and retention; and illicit substance use for those engaged in treatment between 9/2016 and 1/2018. Results: Seventy-four patients completed integrated HCV-OUD treatment with DAA, with 87.8% achieving cure. Of the 66 who completed treatment and were subsequently evaluated for sustained viral response 98.5% were cured. Patients who received integrated HCV and OUD treatment in our clinic, stayed in OUD treatment longer, demonstrated higher OUD medication adherence, and used less opioids or cocaine compared to HCV-infected patients (n = 572) being treated only for OUD. Discussion: We have reported on a reproducible intervention that lends itself to outpatient OUD treatment. Analyses demonstrate the potential positive impact HCV treatment has on OUD recovery, including reduction in opioid and cocaine use and increased retention in care. Conclusion: Co-locating HCV treatment with existing OUD treatment is feasible, effective, and demonstrates positive outcomes for the treatment of both conditions.

Patient evaluation of a smartphone application for telehealth care of opioid use disorder.

BACKGROUND: People with opioid use disorder (OUD) face barriers to entering and remaining in life-saving treatment (e.g., stigma, detrimental interactions with health care, and privacy concerns). Telehealth and related technology can reduce barriers to entering and staying in care. Patient feedback is critical to the development of these newer treatment approaches to ensure they are usable and do not inadvertently recreate treatment barriers. PURPOSE: Evaluate the perceived usability of existing and planned features of a mobile application (app) that facilitates delivery of OUD treatment via telehealth. METHODS: People with current or prior experience with OUD treatment were eligible for the study. Participants (n = 31; 55% women) provided feedback on an interactive prototype demonstration via individual qualitative interviews and completed a quantitative survey on the app's perceived usability. Descriptive statistics summarized the usability survey. We analyzed qualitative interview transcripts to elicit common themes. RESULTS: Participants were primarily white (77%) with a mean age of 42.2 years (range 22-69). Participants rated the six major features of the current app as helpful (median response 5 out of 5) and appreciated the flexibility of conducting a visit from a place of their choosing. Participants regarded the five proposed components of the app, such as daily affirmations and medication treatment-related reminders (e.g., pick up medication at pharmacy, medication schedule), as useful features with medians 5 out of 5, and reported they would recommend the app to others for OUD care. Participant qualitative interviews provided additional information on perceived usability of existing and proposed app features. CONCLUSION: Our study suggests that an appealing, easy-to-use app-with tools and features that effectively support care-could circumvent existing barriers and foster sustained recovery.

Dietary Elimination for the Treatment of Atopic Dermatitis: A Systematic Review and Meta-Analysis.

BACKGROUND: The influence of diet on atopic dermatitis (AD) is complex, and the use of dietary elimination as a treatment has conflicting views. OBJECTIVE: To systematically review the benefits and harms of dietary elimination for the treatment of AD. METHODS: We searched MEDLINE, Embase, AMED, PsycINFO, and the Cochrane Central Register of Controlled Trials from inception to January 18, 2022, without language restrictions, for randomized controlled trials (RCTs) and observational studies comparing dietary elimination and no dietary elimination for the treatment of AD. We conducted random-effects meta-analyses of eczema outcomes. We used the grading of recommendations, assessment, development, and evaluation approach to assess certainty of evidence (CRD42021237953). RESULTS: Ten RCT (n = 599; baseline median of study mean age, 1.5 years; median of study mean SCOring Atopic Dermatitis index, 20.7, range, 3.5-37.6) were included in the meta-analysis. Compared with no dietary elimination, low-certainty evidence showed that dietary elimination may slightly improve eczema severity (50% with vs 41% without dietary elimination improved the SCOring Atopic Dermatitis index by a minimally important difference of 8.7 points, risk difference of 9% [95% CI, 0-17]), pruritus (daytime itch score [range, 0-3] mean difference, -0.21 [95% CI, -0.57 to 0.15]), and sleeplessness (sleeplessness score [range, 0-3] mean difference, -0.47 [95% CI, -0.80 to -0.13]). There were no credible subgroup differences based on elimination strategy (empiric vs guided by testing) or food-specific sensitization. Insufficient data addressed harms of elimination diets among included RCTs, although indirect evidence suggests that elimination diets may increase the risk for developing IgE-mediated food allergy. CONCLUSIONS: Dietary elimination may lead to a slight, potentially unimportant improvement in eczema severity, pruritus, and sleeplessness in patients with mild to moderate AD. This must be balanced against potential risks for indiscriminate elimination diets including developing IgE-mediated food allergy and withholding more effective treatment options for AD.

Circumstances Around Cigarette Use after Enforced Abstinence From Smoking in an American Prison.

OBJECTIVES: Most adults return to smoking after enforced tobacco abstinence when incarcerated in US prisons. Little is known about the specific relapse triggers on reentry. This study examines situational, affective, and motivational antecedents of return to smoking immediately after release from a tobacco-free prison. METHODS: Assessments were administered before release and 1 and 7 days after release to 190 incarcerated adults who were smokers before incarceration. Those reporting smoking within 7 days after release were asked about circumstances surrounding their first cigarette. RESULTS: Two-thirds reported smoking in the 7 days after release (76% of those in the first day) with the first cigarette smoked 21 hours after release on average. Smoking occurred more quickly for women than men and for those who planned to smoke after release ( P values from 0.05 to 0.001). Forty-one percent of participants smoked while waiting for a ride or on the way home, 68% were given their first cigarette, 28% reported first smoking when reuniting with others, 42% first smoked with smokers, and 26% first smoked as celebration. The moods most reported before smoking were happy (60%) or excited (41.5%). Factors reported that could have prevented smoking were avoiding other smokers (27%), avoiding stress (16%), not drinking/using drugs (12%), and not having access to cigarettes (11%). CONCLUSIONS: High rates of return to smoking occurred rapidly when around other smokers, using other substances, and in a positive mood. Interventions that focus specifically on these factors and can be immediately accessed upon release are required to help sustain people's desired abstinence.

The Cortical Bone Metabolome of C57BL/6J Mice Is Sexually Dimorphic.

Cortical bone quality, which is sexually dimorphic, depends on bone turnover and therefore on the activities of remodeling bone cells. However, sex differences in cortical bone metabolism are not yet defined. Adding to the uncertainty about cortical bone metabolism, the metabolomes of whole bone, isolated cortical bone without marrow, and bone marrow have not been compared. We hypothesized that the metabolome of isolated cortical bone would be distinct from that of bone marrow and would reveal sex differences. Metabolite profiles from liquid chromatography-mass spectrometry (LC-MS) of whole bone, isolated cortical bone, and bone marrow were generated from humeri from 20-week-old female C57Bl/6J mice. The cortical bone metabolomes were then compared for 20-week-old female and male C57Bl/6J mice. Femurs from male and female mice were evaluated for flexural material properties and were then categorized into bone strength groups. The metabolome of isolated cortical bone was distinct from both whole bone and bone marrow. We also found sex differences in the isolated cortical bone metabolome. Based on metabolite pathway analysis, females had higher lipid metabolism, and males had higher amino acid metabolism. High-strength bones, regardless of sex, had greater tryptophan and purine metabolism. For males, high-strength bones had upregulated nucleotide metabolism, whereas lower-strength bones had greater pentose phosphate pathway metabolism. Because the higher-strength groups (females compared with males, high-strength males compared with lower-strength males) had higher serum type I collagen cross-linked C-telopeptide (CTX1)/procollagen type 1 N propeptide (P1NP), we estimate that the metabolomic signature of bone strength in our study at least partially reflects differences in bone turnover. These data provide novel insight into bone bioenergetics and the sexual dimorphic nature of bone material properties in C57Bl/6 mice. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Project ECHO and primary care buprenorphine treatment for opioid use disorder: Implementation and clinical outcomes.

Background: Our rural health system sought to (1) increase the number of primary care clinicians waivered to prescribe buprenorphine for treatment of opioid use disorder (OUD) and (2) consequently increase the number of our patients receiving this treatment. Methods: We used the Project for Extension for Community Health Outcomes (ECHO) tele-education model as an implementation strategy. We examined the number of clinicians newly waivered, the number of patients treated with buprenorphine, the relationship between clinician engagement with ECHO training and rates of buprenorphine prescribing, and treatment retention at 180 days. Results: The number of clinicians with a waiver and number of patients treated increased during and after ECHO training. There was a moderate correlation between the number of ECHO sessions attended by a clinician and number of their buprenorphine prescriptions (r = 0.50, p = 0.01). The 180-day retention rate was 80.7%. Conclusions: Project ECHO was highly effective for increasing access to this evidence-based treatment. The high retention rate in this rural context indicates that most patients are increasing their likelihood of favorable outcomes.

Rapamycin impairs bone accrual in young adult mice independent of Nrf2.

Advanced age is the strongest risk factor for osteoporosis. The immunomodulator drug rapamycin extends lifespan in numerous experimental model organisms and is being investigated as a potential therapeutic to slow human aging, but little is known about the effects of rapamycin on bone. We evaluated the impact of rapamycin treatment on bone mass, architecture, and indices of bone turnover in healthy adult (16-20 weeks old at treatment initiation) female wild-type (ICR) and Nrf2-/- mice, a mouse model of oxidative damage and aging-related disease vulnerability. Rapamycin (4 mg/kg bodyweight) was administered by intraperitoneal injection every other day for 12 weeks. Mice treated with rapamycin exhibited lower femur bone mineral content, bone mineral density, and bone volume compared to vehicle-treated mice. In midshaft femur diaphysis (cortical bone), rapamycin-treated mice had lower cortical volume and thickness, and in the distal femur metaphysis (cancellous bone), rapamycin-treated mice had higher trabecular spacing and lower connectivity density. Mice treated with rapamycin exhibited lower bone volume, bone volume fraction, and trabecular thickness in the 5th lumbar vertebra. Rapamycin-treated mice had lower levels of bone formation in the distal femur metaphysis compared to vehicle-treated mice which occurred co-incidentally with increased serum CTX-1, a marker of global bone resorption. Rapamycin had no impact on tibia inflammatory cytokine gene expression, and we found no independent effects of Nrf2 knockout on bone, nor did we find any interactions between genotype and treatment. These data show that rapamycin may have a negative impact on the skeleton of adult mice that should not be overlooked in the clinical context of its usage as a therapy to retard aging and reduce the incidence of age-related pathologies.

Rhesus monkeys as a translational model for late-onset Alzheimer's disease.

Age is a major risk factor for late-onset Alzheimer's disease (AD) but seldom features in laboratory models of the disease. Furthermore, heterogeneity in size and density of AD plaques observed in individuals are not recapitulated in transgenic mouse models, presenting an incomplete picture. We show that the amyloid plaque microenvironment is not equivalent between rodent and primate species, and that differences in the impact of AD pathology on local metabolism and inflammation might explain established differences in neurodegeneration and functional decline. Using brain tissue from transgenic APP/PSEN1 mice, rhesus monkeys with age-related amyloid plaques, and human subjects with confirmed AD, we report altered energetics in the plaque microenvironment. Metabolic features included changes in mitochondrial distribution and enzymatic activity, and changes in redox cofactors NAD(P)H that were shared among species. A greater burden of lipofuscin was detected in the brains from monkeys and humans of advanced age compared to transgenic mice. Local inflammatory signatures indexed by astrogliosis and microglial activation were detected in each species; however, the inflamed zone was considerably larger for monkeys and humans. These data demonstrate the advantage of nonhuman primates in modeling the plaque microenvironment, and provide a new framework to investigate how AD pathology might contribute to functional loss.