Deployment of a Digital Advance Care Planning Platform at an Accountable Care Organization.

BACKGROUND: Advance care planning (ACP), a process of sharing one's values and preferences for future medical treatments, can improve quality of life, reduce loved ones' anxiety, and decrease unwanted medical utilization and costs. Despite benefits to patients and health care systems, ACP uptake often remains low, due partially to lack of knowledge and difficulty initiating discussions. Digital tools may help reduce these barriers to entry. METHODS: We retrospectively examined data from pilot deployment of Koda Health patient-facing ACP among Houston Methodist Coordinated Care patients, for quality improvement (QI) purposes. Patients referred by nurse navigators could access Koda's digital platform, complete ACP, and share the legal documentation generated. Analyzed measures include usage rates and ACP-related decisions within the platform. RESULTS: Of eligible patients (n = 203), 52.7% voluntarily completed their plan. Engagement and completion rates were similar across demographics. Patients indicated majority preference (66.4%) toward spending the last days of life at home. Most patients indicated wanting no life-support intervention if quality of life became unacceptable (51 to 71% across 4 treatments). Life-support decisions were similar between demographic categories, excepting CPR and dialysis, wherein a greater portion of Black patients than White patients preferred at least trial intervention, rather than none. CONCLUSIONS: As an observational QI analysis, limitations include bounded geographical reach and lack of data on ACP impacts to subsequent health care utilization, which future studies will address. Findings suggest that digital health tools like Koda can effectively facilitate equitable ACP access and may help support health systems and providers in offering comprehensive ACP.

Extracellular vesicles from mouse trophoblast cells: Effects on neural progenitor cells and potential participants in the placenta-brain axis†.

The fetal brain of the mouse is thought to be dependent upon the placenta as a source of serotonin (5-hydroxytryptamine; 5-HT) and other factors. How factors reach the developing brain remains uncertain but are postulated here to be part of the cargo carried by placental extracellular vesicles (EV). We have analyzed the protein, catecholamine, and small RNA content of EV from mouse trophoblast stem cells (TSC) and TSC differentiated into parietal trophoblast giant cells (pTGC), potential primary purveyors of 5-HT. Current studies examined how exposure of mouse neural progenitor cells (NPC) to EV from either TSC or pTGC affect their transcriptome profiles. The EV from trophoblast cells contained relatively high amounts of 5-HT, as well as dopamine and norepinephrine, but there were no significant differences between EV derived from pTGC and from TSC. Content of miRNA and small nucleolar (sno)RNA, however, did differ according to EV source, and snoRNA were upregulated in EV from pTGC. The primary inferred targets of the microRNA (miRNA) from both pTGC and TSC were mRNA enriched in the fetal brain. NPC readily internalized EV, leading to changes in their transcriptome profiles. Transcripts regulated were mainly ones enriched in neural tissues. The transcripts in EV-treated NPC that demonstrated a likely complementarity with miRNA in EV were mainly up- rather than downregulated, with functions linked to neuronal processes. Our results are consistent with placenta-derived EV providing direct support for fetal brain development and being an integral part of the placenta-brain axis.

Successful Formulation Window for the design of pharmaceutical tablets with required mechanical properties.

Pharmaceutical tablet formulations combine the active ingredient with processing aids and functional components. This paper evaluates compressibility based predictive models for binary and ternary formulations to establish an acceptable range of tablet compression parameters that satisfy prescribed quality target criteria for tablets including minimum tablet strength and processing constraints such as maximum ejection stress and maximum compaction pressure. The concept of Successful Formulation Window (SFW) is introduced. A methodology is proposed to determine the SFW for a given formulation based on compaction simulator data collected for individual formulation components. The methodology is validated for binary and ternary mixtures and lubricated formulations. The SFW analysis was developed to support tablet formulation design to meet mechanical requirements.

The Mindful Reappraisal of Pain Scale (MRPS): Validation of a New Measure of Psychological Mechanisms of Mindfulness-Based Analgesia.

Objectives: Mindfulness is theorized to decrease the affective amplification of chronic pain by facilitating a shift from emotionally-laden, catastrophic pain appraisals of nociceptive input to reappraising chronic pain as an innocuous sensory signal that does not signify harm. Understanding of these hypothetical psychological mechanisms of mindfulness-based analgesia has been limited by a lack of direct measures. We conducted a series of psychometric and experimental studies to develop and validate the Mindful Reappraisal of Pain Sensations Scale (MPRS). Methods: After item generation, we conducted exploratory and confirmatory factor analyses of the MRPS in samples of opioid-treated chronic pain patients both before (n=450; n=90) and after (n=222) participating in Mindfulness-Oriented Recovery Enhancement (MORE). We then examined the convergent and divergent validity of the MRPS. Finally, in data from a randomized clinical trial (n=250), the MRPS was tested as a mediator of the effects of MORE on reducing chronic pain severity. Results: Exploratory and confirmatory factor analyses demonstrated the single-factor structure of the MRPS. The MRPS also evidenced convergent and divergent validity. Mindfulness training through MORE significantly increased MRPS scores relative to supportive psychotherapy (F4,425.03 = 16.15, p < .001). Changes in MRPS scores statistically mediated the effect of MORE on reducing chronic pain severity through 9-month follow-up. Conclusions: Taken together, these studies demonstrate that the MRPS is a psychometrically sound and valid measure of novel analgesic mechanisms of mindfulness including attentional disengagement from affective pain appraisals and interoceptive exposure to pain sensations.

Development of properly-polarized trophoblast stem cell-derived organoids to model early human pregnancy.

The development of human trophoblast stem cells (hTSC) and stem cell-derived trophoblast organoids has enabled investigation of placental physiology and disease and early maternal-fetal interactions during a stage of human pregnancy that previously had been severely restricted. A key shortcoming in existing trophoblast organoid methodologies is the non-physiologic position of the syncytiotrophoblast (STB) within the inner portion of the organoid, which neither recapitulates placental villous morphology in vivo nor allows for facile modeling of STB exposure to the endometrium or the contents of the intervillous space. Here we have successfully established properly-polarized human trophoblast stem cell (hTSC)-sourced organoids with STB forming on the surface of the organoid. These organoids can also be induced to give rise to the extravillous trophoblast (EVT) lineage with HLA-G + migratory cells that invade into an extracellular matrix-based hydrogel. Compared to previous hTSC organoid methods, organoids created by this method more closely mimic the architecture of the developing human placenta and provide a novel platform to study normal and abnormal human placental development and to model exposures to pharmaceuticals, pathogens and environmental insults. Motivation: Human placental organoids have been generated to mimic physiological cell-cell interactions. However, those published models derived from human trophoblast stem cells (hTSCs) or placental villi display a non-physiologic "inside-out" morphology. In vivo , the placental villi have an outer layer of syncytialized cells that are in direct contact with maternal blood, acting as a conduit for gas and nutrient exchange, and an inner layer of progenitor, single cytotrophoblast cells that fuse to create the syncytiotrophoblast layer. Existing "inside-out" models put the cytotrophoblast cells in contact with culture media and substrate, making physiologic interactions between syncytiotrophoblast and other cells/tissues and normal and pathogenic exposures coming from maternal blood difficult to model. The goal of this study was to develop an hTSC-derived 3-D human trophoblast organoid model that positions the syncytiotrophoblast layer on the outside of the multicellular organoid.

FGF2, LIF, and IGF1 (FLI) supplementation during human in vitro maturation enhances markers of gamete competence.

STUDY QUESTION: Does a chemically defined maturation medium supplemented with FGF2, LIF, and IGF1 (FLI) improve in vitro maturation (IVM) of cumulus-oocyte complexes (COCs) obtained from children, adolescents, and young adults undergoing ovarian tissue cryopreservation (OTC)? SUMMARY ANSWER: Although FLI supplementation did not increase the incidence of oocyte meiotic maturation during human IVM, it significantly improved quality outcomes, including increased cumulus cell expansion and mitogen-activated protein kinase (MAPK) expression as well as enhanced transzonal projection retraction. WHAT IS KNOWN ALREADY: During OTC, COCs, and denuded oocytes from small antral follicles are released into the processing media. Recovery and IVM of these COCs is emerging as a complementary technique to maximize the fertility preservation potential of the tissue. However, the success of IVM is low, especially in the pediatric population. Supplementation of IVM medium with FLI quadruples the efficiency of pig production through improved oocyte maturation, but whether a similar benefit occurs in humans has not been investigated. STUDY DESIGN, SIZE, DURATION: This study enrolled 75 participants between January 2018 and December 2021 undergoing clinical fertility preservation through the Fertility & Hormone Preservation & Restoration Program at the Ann & Robert H. Lurie Children's Hospital of Chicago. Participants donated OTC media, accumulated during tissue processing, for research. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants who underwent OTC and include a pediatric population that encompassed children, adolescents, and young adults ≤22 years old. All participant COCs and denuded oocytes were recovered from media following ovarian tissue processing. IVM was then performed in either a standard medium (oocyte maturation medium) or one supplemented with FLI (FGF2; 40 ng/ml, LIF; 20 ng/ml, and IGF1; 20 ng/ml). IVM outcomes included meiotic progression, cumulus cell expansion, transzonal projection retraction, and detection of MAPK protein expression. MAIN RESULTS AND THE ROLE OF CHANCE: The median age of participants was 6.3 years, with 65% of them classified as prepubertal by Tanner staging. Approximately 60% of participants had been exposed to chemotherapy and/or radiation prior to OTC. On average 4.7 ± 1 COCs and/or denuded oocytes per participant were recovered from the OTC media. COCs (N = 41) and denuded oocytes (N = 29) were used for IVM (42 h) in a standard or FLI-supplemented maturation medium. The incidence of meiotic maturation was similar between cohorts (COCs: 25.0% vs 28.6% metaphase II arrested eggs in Control vs FLI; denuded oocytes: 0% vs 5.3% in Control vs FLI). However, cumulus cell expansion was 1.9-fold greater in COCs matured in FLI-containing medium relative to Controls and transzonal projection retraction was more pronounced (2.45 ± 0.50 vs 1.16 ± 0.78 projections in Control vs FLIat 16 h). Additionally, MAPK expression was significantly higher in cumulus cells obtained from COCs matured in FLI medium for 16-18 h (chemiluminescence corrected area 621,678 vs 2,019,575 a.u., P = 0.03). LIMITATIONS, REASONS FOR CAUTION: Our samples are from human participants who exhibited heterogeneity with respect to age, diagnosis, and previous treatment history. Future studies with larger sample sizes, including adult participants, are warranted to determine the mechanism by which FLI induces MAPK expression and activation. Moreover, studies that evaluate the developmental competence of eggs derived from FLI treatment, including assessment of embryos as outcome measures, will be required prior to clinical translation. WIDER IMPLICATIONS OF THE FINDINGS: FLI supplementation may have a conserved beneficial effect on IVM for children, adolescents, and young adults spanning the agricultural setting to clinical fertility preservation. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Department of Obstetrics and Gynecology startup funds (F.E.D.), Department of Surgery Faculty Practice Plan Grant and the Fertility & Hormone Preservation & Restoration Program at the Ann & Robert H. Lurie Children's Hospital of Chicago (M.M.L. and E.E.R.). M.M.L. is a Gesualdo Foundation Research Scholar. Y.Y.'s research is supported by the internal research funds provided by Colorado Center of Reproductive Medicine. Y.Y., L.D.S., R.M.R., and R.S.P. have a patent pending for FLI. The remaining authors have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Tight junction protein occludin is an internalization factor for SARS-CoV-2 infection and mediates virus cell-to-cell transmission.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreads efficiently by spike-mediated, direct cell-to-cell transmission. However, the underlying mechanism is poorly understood. Herein, we demonstrate that the tight junction protein occludin (OCLN) is critical to this process. SARS-CoV-2 infection alters OCLN distribution and expression and causes syncytium formation that leads to viral spread. OCLN knockdown fails to alter SARS-CoV-2 binding but significantly lowers internalization, syncytium formation, and transmission. OCLN overexpression also has no effect on virus binding but enhances virus internalization, cell-to-cell transmission, and replication. OCLN directly interacts with the SARS-CoV-2 spike, and the endosomal entry pathway is involved in OCLN-mediated cell-to-cell fusion rather than in the cell surface entry pathway. All SARS-CoV-2 strains tested (prototypic, alpha, beta, gamma, delta, kappa, and omicron) are dependent on OCLN for cell-to-cell transmission, although the extent of syncytium formation differs between strains. We conclude that SARS-CoV-2 utilizes OCLN as an internalization factor for cell-to-cell transmission.

Diastereoselective synthesis of cyclic tetrapeptide pseudoxylallemycin A illuminates the impact of base during macrolactamization.

Therapeutic agents with unique molecular structures and new mechanisms of action are needed to confront the phenomenon of multidrug resistance among bacteria. Pseudoxylallemycins, cyclic tetrapeptide (CTP) natural products, have exhibited modest antibiotic activity, but their synthesis has proven challenging. Inherent ring strain in CTPs decreases the rate of cyclization in lieu of polymerization and racemization pathways, which has resulted in previous syntheses describing mixtures of diastereomers containing predominantly an undesired epimer. We have optimized the cyclization step of pseudoxylallemycin A to favor production of the natural diastereomer; notably, variation of the base, temperature, and solvent with peptide coupling reagent propylphosphonic anhydride (T3P) afforded exquisite selectivity for the natural product in as high as 97 : 3 DR, and our conditions can provide the natural product in up to 32% overall yield through 8 steps. Employing weaker bases than those typically used in peptide coupling reactions led to the greatest improvement in diastereoselectivity, and these studies demonstrated that the identity of the amine base has enormous impact on the rate of C-terminal epimerization when T3P is used, a variable usually considered of lesser consequence when combined with typical amide coupling reagents. Toward fully characterizing pseudoxylallemycin stereoisomers, variable temperature NMR was described as a tool to more clearly analyze CTPs that exhibit multiple conformational states. These synthetic and spectroscopic insights were applied toward synthesizing several natural product analogues, and their antibacterial activity was examined using microdilution assays.

Effects of Integrated Vector Management in the Control of Malaria Infection: An Intervention Study in a Malaria Endemic Community in Nigeria.

BACKGROUND/AIM: Malaria is a vector borne disease with high morbidity and mortality in endemic regions. In view to eliminating the disease, integrated vector and environmental hygiene practices have been advocated. There is paucity of studies on the effect of vector control measures on asymptomatic malaria infection which has been observed to be a reflection of malaria transmission. METHODS: Longitudinal community-based intervention study carried out from October to December 2017. Study participants were 477 individuals living in 100 households selected by snow-balling sampling methods. Pre-intervention period included training of all heads of households on vector control methods. During the intervention period, each household received waste bins, two long lasting insecticide bed nets and had wire screen on their doors and windows; every household member was screened for malaria (antigen) using the pf rapid diagnostic test kits. Each household were monitored to ensure they comply with the environmental hygiene practices they were taught. Post-intervention malaria infection was obtained at 8 week being end of the intervention period. RESULTS: Of the 100 households selected, 54.0% were from the lower social class, 45.0% middle class and only 1.0% upper class. Mean age [±] of the heads of the households was 37.1 ± 11.0 (range 16-68) years. There were 477 individuals recruited in the study from the 100 households; 234 (49.0%) females and 243 (51.0%) males; median age was 20.0 (range 1-100) years. Prevalence of malaria infection using mRDT during pre-intervention was 16.8% and an incidence of 1.3% post-intervention. There was 92.0% reduction in asymptomatic malaria infection showing marked reduction in malaria transmission in the study locale. CONCLUSION: Some integrated vector control measures such as use of insecticide-treated net and sanitation were found effective methods for reducing malaria infection and transmission in endemic region.

CONTEXTE/OBJECTIF: Le paludisme est une maladie à transmission vectorielle avec une morbidité et une mortalité élevées dans les régions endémiques. En vue d'éliminer la maladie, des pratiques d'hygiène intégrée des vecteurs et de l'environnement ont été préconisées. Il existe peu d'études sur l'effet des mesures de lutte antivectorielle sur l'infection palustre asymptomatique, qui s'est avérée être le reflet de la transmission du paludisme. MÉTHODES: Étude longitudinale d'intervention communautaire réalisée d'octobre à décembre 2017. Les participants à l'étude étaient 477 personnes vivant dans 100 ménages sélectionnés par des méthodes d'échantillonnage en boule de neige. La période de pré-intervention comprenait la formation de tous les chefs de ménage sur les méthodes de lutte antivectorielle. Au cours de la période d'intervention, chaque ménage a reçu des poubelles, deux moustiquaires à insecticide longue durée et avait des grillages sur leurs portes et fenêtres ; chaque membre du ménage a été dépisté pour le paludisme (antigène) à l'aide des kits de test de diagnostic rapide pf. Chaque ménage a été suivi pour s'assurer qu'il respecte les pratiques d'hygiène environnementale qui lui ont été enseignées. L'infection antipaludique post-intervention a été obtenue à 8 semaines, fin de la période d'intervention. RÉSULTATS: Sur les 100 ménages sélectionnés, 54,0% appartenaient à la classe sociale inférieure, 45,0% à la classe moyenne et seulement 1,0% à la classe supérieure. L'âge moyen [±] des chefs de ménage était de 37,1 ± 11,0 (fourchette de 16 à 68) ans. Il y avait 477 personnes recrutées dans l'étude à partir des 100 ménages ; 234 (49,0 %) femmes et 243 (51,0 %) hommes ; l'âge médian était de 20,0 (intervalle de 1 à 100) ans. La prévalence de l'infection du paludisme à l'aide de mRDT pendant la pré-intervention était de 16,8 % et l'incidence de 1,3 % après l'intervention. Il y avait une réduction de 92,0 % de l'infection asymptomatique du paludisme, montrant une réduction marquée de la transmission du paludisme dans le lieu de l'étude. CONCLUSION: Certaines mesures intégrées de lutte antivectorielle telles que l'utilisation de moustiquaires imprégnées d'insecticide et l'assainissement se sont révélées être des méthodes efficaces pour réduire l'infection et la transmission du paludisme dans les régions endémiques. Mots clés: Endémique, Hygiène Environnementale, Ménages, Intervention, Paludisme, Transmission, Vecteur.

Early Childhood Exposures to Fluorides and Child Behavioral Development and Executive Function: A Population-Based Longitudinal Study.

It is important to both protect the healthy development and maintain the oral health of the child population. The study examined the effect of early childhood exposures to water fluoridation on measures of school-age executive functioning and emotional and behavioral development in a population-based sample. This longitudinal follow-up study used information from Australia's National Child Oral Health Study 2012-14. Children aged 5 to 10 y at baseline were contacted again after 7 to 8 y, before they had turned 18 y of age. Percent lifetime exposed to fluoridated water (%LEFW) from birth to the age 5 y was estimated from residential history and postcode-level fluoride levels in public tap water. Measures of children's emotional and behavioral development were assessed by the Strength and Difficulties Questionnaire (SDQ), and executive functioning was measured by the Behavior Rating Inventory of Executive Function (BRIEF). Multivariable regression models were generated to compare the associations between the exposure and the primary outcomes and controlled for covariates. An equivalence test was also conducted to compare the primary outcomes of those who had 100% LEFW against those with 0% LEFW. Sensitivity analysis was also conducted. A total of 2,682 children completed the SDQ and BRIEF, with mean scores of 7.0 (95% confidence interval, 6.6-7.4) and 45.3 (44.7-45.8), respectively. Those with lower %LEFW tended to have poorer scores of the SDQ and BRIEF. Multivariable regression models reported no association between exposure to fluoridated water and the SDQ and BRIEF scores. Low household income, identifying as Indigenous, and having a neurodevelopmental diagnosis were associated with poorer SDQ/BRIEF scores. An equivalence test confirmed that the SDQ/BRIEF scores among those with 100% LEFW were equivalent to that of those who had 0% LEFW. Exposure to fluoridated water during the first 5 y of life was not associated with altered measures of child emotional and behavioral development and executive functioning.

High real-world effectiveness of 12-week elbasvir/grazoprevir without resistance testing in the treatment of patients with HCV genotype 1a infection in Norway.

BACKGROUND AND AIMS: The recommended treatment duration of hepatitis C virus (HCV) genotype 1a (GT1a) infection with elbasvir/grazoprevir (EBR/GZR) in the presence of a high baseline viral load and resistance associated substitutions (RAS) is 16 weeks with ribavirin added. The objective of this study was to evaluate the real-world effectiveness of 12 weeks of EBR/GZR without ribavirin and regardless of baseline viral load and RAS testing. METHOD: This retrospective, observational cohort study was performed at five Norwegian hospitals that did not systematically utilize RAS testing. All adult patients with chronic HCV GT1a and compensated liver disease who had received 12 weeks of EBR/GZR without ribavirin and baseline RAS testing, were included. The primary endpoint was sustained virologic response at week 12 (SVR12), or if not available, at week 4 (SVR4). RESULTS: We included 433 patients and attained SVR data on 388. The mean age was 45.7 years (22-73 years). 67.2% were male. HIV co-infection was present in 3.8% (16/424) and cirrhosis in 4% (17/424). The viral load was >800 000 IU/mL in 55.0% (235/427) of patients. Overall SVR was achieved in 97.2% (377/388). SVR was achieved in 98.3% (169/172) of those with viral load ≤800 000 IU/mL and in 96.2% (202/210) of those with viral load >800 000 IU/mL. CONCLUSION: We observed high SVR rates among patients with HCV GT1a infection treated with EBR/GZR for 12 weeks without ribavirin, with no regard to baseline viral load and no RAS testing.

High-resolution ribosome profiling reveals translational selectivity for transcripts in bovine preimplantation embryo development.

High-resolution ribosome fractionation and low-input ribosome profiling of bovine oocytes and preimplantation embryos has enabled us to define the translational landscapes of early embryo development at an unprecedented level. We analyzed the transcriptome and the polysome- and non-polysome-bound RNA profiles of bovine oocytes (germinal vesicle and metaphase II stages) and early embryos at the two-cell, eight-cell, morula and blastocyst stages, and revealed four modes of translational selectivity: (1) selective translation of non-abundant mRNAs; (2) active, but modest translation of a selection of highly expressed mRNAs; (3) translationally suppressed abundant to moderately abundant mRNAs; and (4) mRNAs associated specifically with monosomes. A strong translational selection of low-abundance transcripts involved in metabolic pathways and lysosomes was found throughout bovine embryonic development. Notably, genes involved in mitochondrial function were prioritized for translation. We found that translation largely reflected transcription in oocytes and two-cell embryos, but observed a marked shift in the translational control in eight-cell embryos that was associated with the main phase of embryonic genome activation. Subsequently, transcription and translation become more synchronized in morulae and blastocysts. Taken together, these data reveal a unique spatiotemporal translational regulation that accompanies bovine preimplantation development.

The effectiveness of an Australian community suicide prevention networks program in preventing suicide: a controlled longitudinal study.

BACKGROUND: Suicide is a major issue affecting communities around the world. Community-based suicide prevention approaches can tailor activities at a local level and are recognised as a key component of national suicide prevention strategies. Despite this, research exploring their effects on completed suicides is rare. This study examined the effect of a national program of community suicide prevention networks on suicide rates in catchment areas across Australia. METHODS: Australian suicide data from the National Coronial Information System for 2001-2017 were mapped to geographic catchment areas of community suicide prevention networks and matched control areas with similar characteristics. The effect of network establishment on suicide rates was evaluated using longitudinal models including fixed effects for site type (network or control), time, season, and intervention (network establishment), with site included as a random intercept. RESULTS: Sixty suicide prevention networks were included, servicing areas with a population of 3.5 million. Networks varied in when they were established, ranging from 2007 to 2016. Across the time-period, suicide rates per 100,000 per quarter averaged 3.73 (SD = 5.35). A significant reduction in the suicide rate of 7.0% was found after establishment of networks (IRR = 0.93, 95% CI 0.87 to 0.99, p = .025). CONCLUSION: This study found evidence of an average reduction in suicide rates following the establishment of suicide prevention networks in Australian communities. These findings support the effectiveness of empowering local communities to take action to prevent suicide.

Association between opioid use disorder and blunted heart rate variability among opioid-treated chronic pain patients.

Given the severity of the ongoing opioid epidemic, it is essential to understand the mechanisms of risk for development and maintenance of opioid use disorder (OUD). The aim of the current large-scale psychophysiological investigation was to test whether patients with OUD had lower resting-state high-frequency heart rate variability (HF-HRV) than those without OUD, controlling for sociodemographic and clinical confounds. Additionally, we tested whether HF-HRV was associated with opioid craving in this population. Participants in this cross-sectional study were 490 chronic pain patients (50.4% female) treated with long-term opioid therapy. OUD diagnosis was determined by psychiatric interview. HF-HRV was measured at resting baseline. We computed the association between OUD and resting-state HF-HRV, controlling for age, gender, race, pain severity, emotional distress and opioid dose. Opioid craving was measured with visual analogue scales to assess whether HF-HRV was associated with craving. Results showed that resting HF-HRV was significantly lower for patients with OUD than for those without OUD (p < 0.001, d = 0.36), indicating deficits in autonomic flexibility. OUD diagnosis (p = 0.002) and OUD severity (p = 0.03) were associated with lower HF-HRV in regression models accounting for a range of confounders. Additionally, lower HF-HRV was significantly (but weakly) correlated with heightened opioid craving (r = -0.166, p < 0.001). Overall, findings suggest that resting-state HF-HRV may serve as a valid biomarker of addiction among people on long-term opioid therapy.

Mindfulness-Oriented Recovery Enhancement for Addictive Behavior, Psychiatric Distress, and Chronic Pain: A Multilevel Meta-Analysis of Randomized Controlled Trials.

Objectives: Mindfulness-Oriented Recovery Enhancement (MORE) is an integrative intervention designed to ameliorate addiction, chronic pain, and psychiatric symptoms. Although multiple randomized controlled trials (RCTs) have examined the clinical efficacy of MORE, no study has quantitatively synthesized this body of research. Thus, we conducted a meta-analysis of RCTs examining the effects of MORE on addictive behaviors, craving, opioid dose, pain, and psychiatric symptoms. Methods: Relevant manuscripts were identified through comprehensive searches of four bibliographic databases. Two- and three-level random-effects models were used to generate synthesized effect size estimates, and meta-regressions were performed to examine whether study and sample characteristics influenced the magnitude of aggregate effect sizes. Results: Our search identified 16 manuscripts reporting data from eight RCTs (N = 816). Moderate to small effects in favor of MORE were observed for addictive behaviors (SMC = - .54, p = .007), craving (SMC = - .42, p = .010), opioid dose (MC = - 17.95, p < .001), chronic pain (SMC = - .60, p < .001), and psychiatric symptoms (SMC = - .34, p < .001). MORE's effects on psychiatric symptoms and craving were not moderated by participant race, gender, age, or income. Conclusions: Study findings provide empirical evidence of MORE's efficacy for a wide diversity of individuals, and as such, MORE should now be disseminated broadly throughout the healthcare system. Supplementary Information: The online version contains supplementary material available at 10.1007/s12671-022-01964-x.

Mindful Lawyering: a Pilot Study on Mindfulness Training for Law Students.

Objectives: Many US law schools are now offering elective courses in mindfulness training to alleviate disproportionately high levels of anxiety, depression, stress, and disordered alcohol use among law students. To date, empirical evidence on the effectiveness of these courses has been lacking. The aim of this pilot study was to explore the feasibility and impact of a 13-week mindfulness course, "Mindful Lawyering," specifically tailored to law students. The primary hypothesis was that mindfulness training would be significantly correlated with improvements in well-being and mindfulness. Methods: The design was a non-randomized, quasi-experimental study involving 64 law students. The mindfulness group was 31 students taking Mindful Lawyering; the comparison group was 33 students taking other law school courses. Outcome measures were the Depression, Anxiety, and Stress Scale; the Positive and Negative Affect Scale; the Alcohol Use Disorders Identification Test; and the Five Facet Mindfulness Questionnaire. Results: Results provide promising evidence to support the hypothesis. The mindfulness group showed significantly greater improvement on measures of stress (p < .001, d = 1.15), anxiety (p < .001, d = . 90), depression (p = .012, d = .66), negative affect (p = .002, d = .81), disordered alcohol use (p = .011, d = .67), and mindfulness (p < .001, d = 1.32) from pre to post relative to the comparison group. The course was well accepted and feasible for law students. Conclusions: Findings from the current study suggest that mindfulness training may occasion improvements in the well-being of law students. More research is needed to replicate these findings in larger, randomized samples of law students. Supplementary Information: The online version contains supplementary material available at 10.1007/s12671-022-01965-w.

Estrogen-related receptor gamma regulates mitochondrial and synaptic genes and modulates vulnerability to synucleinopathy.

Many studies implicate mitochondrial dysfunction as a key contributor to cell loss in Parkinson disease (PD). Previous analyses of dopaminergic (DAergic) neurons from patients with Lewy-body pathology revealed a deficiency in nuclear-encoded genes for mitochondrial respiration, many of which are targets for the transcription factor estrogen-related receptor gamma (Esrrg/ERRγ). We demonstrate that deletion of ERRγ from DAergic neurons in adult mice was sufficient to cause a levodopa-responsive PD-like phenotype with reductions in mitochondrial gene expression and number, that partial deficiency of ERRγ hastens synuclein-mediated toxicity, and that ERRγ overexpression reduces inclusion load and delays synuclein-mediated cell loss. While ERRγ deletion did not fully recapitulate the transcriptional alterations observed in postmortem tissue, it caused reductions in genes involved in synaptic and mitochondrial function and autophagy. Altogether, these experiments suggest that ERRγ-deficient mice could provide a model for understanding the regulation of transcription in DAergic neurons and that amplifying ERRγ-mediated transcriptional programs should be considered as a strategy to promote DAergic maintenance in PD.