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Animals associate cues with outcomes and update these associations as new information is presented. This requires the hippocampus, yet how hippocampal neurons track changes in cue-outcome associations remains unclear. Using two-photon calcium imaging, we tracked the same dCA1 and vCA1 neurons across days to determine how responses evolve across phases of odor-outcome learning. Initially, odors elicited robust responses in dCA1, whereas, in vCA1, odor responses primarily emerged after learning and embedded information about the paired outcome. Population activity in both regions rapidly reorganized with learning and then stabilized, storing learned odor representations for days, even after extinction or pairing with a different outcome. Additionally, we found stable, robust signals across CA1 when mice anticipated outcomes under behavioral control but not when mice anticipated an inescapable aversive outcome. These results show how the hippocampus encodes, stores and updates learned associations and illuminates the unique contributions of dorsal and ventral hippocampus. more...

IntroductionObstructive sleep apnea (OSA) is a common disorder with major neurocognitive and cardiovascular sequelae. The treatment of symptomatic patients with mild OSA remains controversial given that adherence to positive airway pressure (PAP) has historically been suboptimal. With this notion in mind, we assessed a daily transoral neuromuscular electrical stimulation (NMES) device for individuals with mild OSA.MethodsThe sample represents a subset of participants with a baseline AHI 5-14.9 events/hour, drawn from a parent study which also included participants with primary snoring. Outcome measures for the current study included changes in apnea-hypopnea index (AHI), Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI) and snoring levels before and after use of the NMES.  RESULTS: Among 65 participants (68% men) with median age of 49 years (range 24 to 79) and median BMI of 27.7 kg/m2 (range 20 to 34), the NMES device was used daily for 6 weeks. We observed a significant improvement in the AHI from 10.2 to 6.8 events/hour among all participants and from 10.4 to 5.0 events/h among responders. Statistically significant improvements in the ESS, PSQI, objectively measured snoring, and bed partner-reported snoring were observed. Adherence among all participants was 85%.DiscussionThis NMES device has the benefit of being a treatment modality of daytime therapy which confers a high level of tolerability and patient acceptance. It alleviates the need for an in situ device during sleep and leads to improvements in OSA severity, snoring, and subjective sleep metrics, potentially crucial in mild OSA. Further studies are needed to define which individuals may benefit most from the device across the wider spectrum of OSA severity and assess long-term therapeutic outcomes.Trial registrationClinicalTrials.gov Identifier: NCT03829956. more...

OBJECTIVE: People who experience marginalization, including Black, Indigenous, People of Color (BIPOC) and Lesbian, Gay, Bisexual, Transgender, Queer, Plus (ie, all other marginalized genders and sexual orientations) people (LGBTQ+) experience discrimination during healthcare interactions, which negatively impacts patient-provider communication and care. Yet, scarce research examines the lived experience of unfair treatment among patients from marginalized groups to guide patient-centered tools that improve healthcare equity. MATERIALS AND METHODS: We interviewed 25 BIPOC and/or LGBTQ+ people about their experiences of unfair treatment and discrimination when visiting healthcare providers. Through thematic analysis, we describe participants immediate reactions and longer-term consequences of those experiences. RESULTS: We identified 4 ways that participants reacted to discrimination in the moment: Fighting, Fleeing, Excusing, and Working Around Bias. Long-term consequences reflect 6 ways they coped: Delaying or Avoiding Care, Changing Healthcare Providers, Self-prescribing, Covering Behaviors, Experiencing Health Complications, and Mistrusting Healthcare Institutions. DISCUSSION: By describing how patients react to experiences of unfair treatment and discrimination, our findings enhance the understanding of health disparities as patients cope and struggle to speak out.To combat these problems, we identify 3 future directions for informatics interventions that improve provider behavior, support patient advocacy, and address power dynamics in healthcare. CONCLUSIONS: BIPOC and LGBTQ+ patients perspectives on navigating unfair treatment and discrimination in healthcare offers critical insight into their experiences and long-term consequences of those experiences. Understanding the circumstances and consequences of unfair treatment, discrimination, and the impact of bias through this patient-centered lens is crucial to inform informatics technologies that promote health equity. more...

BackgroundRegenerative therapies to mitigate Alzheimer's disease (AD) neuropathology have shown very limited success. In the recent era, extracellular vesicles (EVs) derived from multipotent and pluripotent stem cells have shown considerable promise for the treatment of dementia and many neurodegenerative conditions.MethodsUsing the 5xFAD accelerated transgenic mouse model of AD, we now show the regenerative potential of human neural stem cell (hNSC)-derived EVs on the neurocognitive and neuropathologic hallmarks in the AD brain. Two- or 6-month-old 5xFAD mice received single or two intra-venous (retro-orbital vein, RO) injections of hNSC-derived EVs, respectively.ResultsRO treatment using hNSC-derived EVs restored fear extinction memory consolidation and reduced anxiety-related behaviors 4-6 weeks post-injection. EV treatment also significantly reduced dense core amyloid-beta plaque accumulation and microglial activation in both age groups. These results correlated with partial restoration of homeostatic levels of circulating pro-inflammatory cytokines in the AD mice. Importantly, EV treatment protected against synaptic loss in the AD brain that paralleled improved cognition. MiRNA analysis of the EV cargo revealed promising candidates targeting neuroinflammation and synaptic function.ConclusionsCollectively, these data demonstrate the neuroprotective effects of systemic administration of stem cell-derived EVs for remediation of behavioral and molecular AD neuropathologies. more...

Bias toward historically marginalized patients affects patient-provider interactions and can lead to lower quality of care and poor health outcomes for patients who are Black, Indigenous, People of Color (BIPOC) and Lesbian, Gay, Bisexual, Transgender and Gender Diverse (LGBTQ+). We gathered experiences with biased healthcare interactions and suggested solutions from 25 BIPOC and LGBTQ+ people. Through qualitative thematic analysis of interviews, we identified ten themes. Eight themes reflect the experience of bias: Transactional Care, Power Inequity, Communication Casualties, Bias-Embedded Medicine, System-level problems, Bigotry in Disguise, Fight or Flight, and The Aftermath. The remaining two themes reflect strategies for improving those experiences: Solutions and Good Experiences. Characterizing these themes and their interconnections is crucial to design effective informatics solutions that can address biases operating in clinical interactions with BIPOC and LGBTQ+ patients, improve the quality of patient-provider interactions, and ultimately promote health equity. more...

BackgroundRegenerative therapies to mitigate Alzheimer's disease (AD) neuropathology have shown very limited success. In the recent era, extracellular vesicles (EVs) derived from multipotent and pluripotent stem cells have shown considerable promise for the treatment of dementia and many neurodegenerative conditions.MethodsUsing the 5xFAD accelerated transgenic mouse model of AD, we now show the regenerative potential of human neural stem cell (hNSC)-derived EVs on the neurocognitive and neuropathologic hallmarks in the AD brain. Two- or 6-month-old 5xFAD mice received single or two intra-venous (retro-orbital vein, RO) injections of hNSC-derived EVs, respectively.ResultsRO treatment using hNSC-derived EVs restored fear extinction memory consolidation and reduced anxiety-related behaviors 4-6 weeks post-injection. EV treatment also significantly reduced dense core amyloid-beta plaque accumulation and microglial activation in both age groups. These results correlated with partial restoration of homeostatic levels of circulating pro-inflammatory cytokines in the AD mice. Importantly, EV treatment protected against synaptic loss in the AD brain that paralleled improved cognition. MiRNA analysis of the EV cargo revealed promising candidates targeting neuroinflammation and synaptic function.ConclusionsCollectively, these data demonstrate the neuroprotective effects of systemic administration of stem cell-derived EVs for remediation of behavioral and molecular AD neuropathologies. more...

This study examines the link between peripheral immune changes in perpetuation of the Alzheimer's disease (AD) neuropathology and cognitive deficits. Our research design using human AD patients and rodent model is supported by past evidence from genomic studies. We observed an active immune response against Aβ as indicated by the increased Aβ specific IgG antibody in the serum of AD and patients with mild cognitive impairments as compared to healthy controls. A similar increase in IgG and decrease in IgM antibody against Aβ was also confirmed in the 5xFAD mouse model of AD. More importantly, we observed a negative correlation between reduced IgM levels and cognitive dysfunction that manifested as impaired memory consolidation. Strong peripheral immune activation was supported by increased activation of microglia in the brain and macrophages in the spleen of AD mice compared to wild type control littermates. Furthermore, inflammatory cytokine IL-21 that is involved in antibody class switching was elevated in the plasma of AD patients and correlated positively with the IgG antibody levels. Concurrently, an increase in IL-21 and IL-17 was observed in spleen cells from AD mice. Further investigation revealed that proportions of T follicular helper (Tfh) cells that secrete IL-21 are increased in the spleen of AD mice. In contrast to Tfh, the frequency of B1 cells that produce IgM antibodies was reduced in AD mice. Altogether, these data indicate that in AD the immune tolerance to Aβ is compromised leading to chronic immune/inflammatory responses against Aβ that are detrimental and cause neuropathology. Graphical Abstract Healthy subjects are tolerant to Aβ and usually react weakly to it resulting the in the production of IgM class of antibodies that are efficient at clearing up self-antigens such as Aβ without causing inflammation. In contrast, Alzheimer's disease patients mount a strong immune response against Aβ probably in an effort to clear up excessive Aβ. There is enhanced production of inflammatory cytokines such as IL-21 as well as an increase in Tfh cells that cause antibody class switching form IgM to IgG. The strong immune response is inefficient at clearing up Aβ and instead exacerbates inflammation that causes AD neuropathology and cognitive dysfunction. more...

This study examines the link between peripheral immune changes in perpetuation of the Alzheimer's disease (AD) neuropathology and cognitive deficits. Our research design using human AD patients and rodent model is supported by past evidence from genomic studies. We observed an active immune response against Aβ as indicated by the increased Aβ specific IgG antibody in the serum of AD and patients with mild cognitive impairments as compared to healthy controls. A similar increase in IgG and decrease in IgM antibody against Aβ was also confirmed in the 5xFAD mouse model of AD. More importantly, we observed a negative correlation between reduced IgM levels and cognitive dysfunction that manifested as impaired memory consolidation. Strong peripheral immune activation was supported by increased activation of microglia in the brain and macrophages in the spleen of AD mice compared to wild type control littermates. Furthermore, inflammatory cytokine IL-21 that is involved in antibody class switching was elevated in the plasma of AD patients and correlated positively with the IgG antibody levels. Concurrently, an increase in IL-21 and IL-17 was observed in spleen cells from AD mice. Further investigation revealed that proportions of T follicular helper (Tfh) cells that secrete IL-21 are increased in the spleen of AD mice. In contrast to Tfh, the frequency of B1 cells that produce IgM antibodies was reduced in AD mice. Altogether, these data indicate that in AD the immune tolerance to Aβ is compromised leading to chronic immune/inflammatory responses against Aβ that are detrimental and cause neuropathology. Graphical Abstract Healthy subjects are tolerant to Aβ and usually react weakly to it resulting the in the production of IgM class of antibodies that are efficient at clearing up self-antigens such as Aβ without causing inflammation. In contrast, Alzheimer's disease patients mount a strong immune response against Aβ probably in an effort to clear up excessive Aβ. There is enhanced production of inflammatory cytokines such as IL-21 as well as an increase in Tfh cells that cause antibody class switching form IgM to IgG. The strong immune response is inefficient at clearing up Aβ and instead exacerbates inflammation that causes AD neuropathology and cognitive dysfunction. more...

Abstract: Background: Regenerative therapies to mitigate Alzheimer’s disease (AD) neuropathology have shown very limited success. In the recent era, extracellular vesicles (EV) derived from multipotent and pluripotent stem cells have shown considerable promise for the treatment of dementia and many neurodegenerative conditions. Methods: Using the 5xFAD accelerated transgenic mouse model of AD, we now show the regenerative potential of human neural stem cell (hNSC)-derived EV on the neurocognitive and neuropathologic outcomes in the AD brain. Two or six-month-old 5xFAD mice received single or two intra-venous (retro-orbital vein, RO) injections of hNSC-derived EV, respectively.Results: RO treatment using hNSC-derived EV restored fear extinction memory consolidation and reduced anxiety-related behaviors 4-6 weeks post-injection. EV treatment also significantly reduced dense core amyloid-beta plaque accumulation and microglial activation in both age groups. These results correlated with partial restoration of homeostatic levels of circulating pro-inflammatory cytokines in the AD mice. Importantly, EV treatment protected against synaptic loss in the AD brain that paralleled improved cognition. MiRNA analysis of the EV cargo revealed promising candidates targeting neuroinflammation and synaptic function. Conclusions: Collectively, these data demonstrate the neuroprotective effects of systemic administration of stem cell-derived EV for remediation of behavioral and molecular AD neuropathologies. more...

This study examines the link between peripheral immune changes in perpetuation of the Alzheimer's disease (AD) neuropathology and cognitive deficits. Our research design using human AD patients and rodent model is supported by past evidence from genomic studies. We observed an active immune response against Aβ as indicated by the increased Aβ specific IgG antibody in the serum of AD and patients with mild cognitive impairments as compared to healthy controls. A similar increase in IgG and decrease in IgM antibody against Aβ was also confirmed in the 5xFAD mouse model of AD. More importantly, we observed a negative correlation between reduced IgM levels and cognitive dysfunction that manifested as impaired memory consolidation. Strong peripheral immune activation was supported by increased activation of microglia in the brain and macrophages in the spleen of AD mice compared to wild type control littermates. Furthermore, inflammatory cytokine IL-21 that is involved in antibody class switching was elevated in the plasma of AD patients and correlated positively with the IgG antibody levels. Concurrently, an increase in IL-21 and IL-17 was observed in spleen cells from AD mice. Further investigation revealed that proportions of T follicular helper (Tfh) cells that secrete IL-21 are increased in the spleen of AD mice. In contrast to Tfh, the frequency of B1 cells that produce IgM antibodies was reduced in AD mice. Altogether, these data indicate that in AD the immune tolerance to Aβ is compromised leading to chronic immune/inflammatory responses against Aβ that are detrimental and cause neuropathology. Graphical Abstract Healthy subjects are tolerant to Aβ and usually react weakly to it resulting the in the production of IgM class of antibodies that are efficient at clearing up self-antigens such as Aβ without causing inflammation. In contrast, Alzheimer's disease patients mount a strong immune response against Aβ probably in an effort to clear up excessive Aβ. There is enhanced production of inflammatory cytokines such as IL-21 as well as an increase in Tfh cells that cause antibody class switching form IgM to IgG. The strong immune response is inefficient at clearing up Aβ and instead exacerbates inflammation that causes AD neuropathology and cognitive dysfunction. more...

Animals must discern important stimuli and place them onto their cognitive map of their environment. The neocortex conveys general representations of sensory events to the hippocampus, and the hippocampus is thought to classify and sharpen the distinctions between these events. We recorded populations of dentate gyrus granule cells (DG GCs) and lateral entorhinal cortex (LEC) neurons across days to understand how sensory representations are modified by experience. We found representations of odors in DG GCs that required synaptic input from the LEC. Odor classification accuracy in DG GCs correlated with future behavioral discrimination. In associative learning, DG GCs, more so than LEC neurons, changed their responses to odor stimuli, increasing the distance in neural representations between stimuli, responding more to the conditioned and less to the unconditioned odorant. Thus, with learning, DG GCs amplify the decodability of cortical representations of important stimuli, which may facilitate information storage to guide behavior. more...

Evaluating the risk for central nervous system (CNS) effects after whole-body or partial-body irradiation presents challenges due in part to the varied exposure scenarios in the context of occupational, accidental or wartime releases. Risk estimations are further complicated by the fact that robust changes in brain function are unlikely to manifest until significantly late post exposure times. Collectively, the current data regarding CNS radiation risk are conflicting in humans and a survey of the animal model data shows that it is similarly inconsistent. Due to the sparseness of such data, the current study was conducted using male and female mice to evaluate the brain for the delayed effects of a 2 Gy whole-body exposure to c rays starting six months postirradiation. Behavioral testing indicated sex-specific differences in the induction of anxiety-like behaviors and in the ability to abolish fear memories. Molecular analyses showed alterations in post-synaptic protein levels that might affect synaptic plasticity and increased levels of global DNA methylation, suggesting a potential epigenetic mechanism that might contribute to radiation-induced cognitive dysfunction. These data add to the understanding of the CNS response to whole-body irradiation and may lead to improved risk assessment and provide guidance in the development of effective radiation countermeasures to protect military personnel and civilians alike. more...

Evaluating the risk for central nervous system (CNS) effects after whole-body or partial-body irradiation presents challenges due in part to the varied exposure scenarios in the context of occupational, accidental or wartime releases. Risk estimations are further complicated by the fact that robust changes in brain function are unlikely to manifest until significantly late post exposure times. Collectively, the current data regarding CNS radiation risk are conflicting in humans and a survey of the animal model data shows that it is similarly inconsistent. Due to the sparseness of such data, the current study was conducted using male and female mice to evaluate the brain for the delayed effects of a 2 Gy whole-body exposure to c rays starting six months postirradiation. Behavioral testing indicated sex-specific differences in the induction of anxiety-like behaviors and in the ability to abolish fear memories. Molecular analyses showed alterations in post-synaptic protein levels that might affect synaptic plasticity and increased levels of global DNA methylation, suggesting a potential epigenetic mechanism that might contribute to radiation-induced cognitive dysfunction. These data add to the understanding of the CNS response to whole-body irradiation and may lead to improved risk assessment and provide guidance in the development of effective radiation countermeasures to protect military personnel and civilians alike. more...

Numerous clinical studies have established the debilitating neurocognitive side effects of chemotherapy in the treatment of breast cancer, often referred as chemobrain. We hypothesize that cognitive impairments are associated with elevated microglial inflammation in the brain. Thus, either elimination of microglia or restoration of microglial function could ameliorate cognitive dysfunction. Using a rodent model of chronic Adriamycin (ADR) treatment, a commonly used breast cancer chemotherapy, we evaluated two strategies to ameliorate chemobrain: 1) microglia depletion using the colony stimulating factor-1 receptor (CSF1R) inhibitor PLX5622 and 2) human induced pluripotent stem cell-derived microglia (iMG)-derived extracellular vesicle (EV) treatment. In strategy 1 mice received ADR once weekly for 4 weeks and were then administered CSF1R inhibitor (PLX5622) starting 72 h post-ADR treatment. ADR-treated animals given a normal diet exhibited significant behavioral deficits and increased microglial activation 4-6 weeks later. PLX5622-treated mice exhibited no ADR-related cognitive deficits and near complete depletion of IBA-1 and CD68+ microglia in the brain. Cytokine and RNA sequencing analysis for inflammation pathways validated these findings. In strategy 2, 1 week after the last ADR treatment, mice received retro-orbital vein injections of iMG-EV (once weekly for 4 weeks) and 1 week later, mice underwent behavior testing. ADR-treated mice receiving EV showed nearly complete restoration of cognitive function and significant reductions in microglial activation as compared to untreated ADR mice. Our data demonstrate that ADR treatment elevates CNS inflammation that is linked to cognitive dysfunction and that attenuation of neuroinflammation reverses the adverse neurocognitive effects of chemotherapy. more...

Numerous clinical studies have established the debilitating neurocognitive side effects of chemotherapy in the treatment of breast cancer, often referred as chemobrain. We hypothesize that cognitive impairments are associated with elevated microglial inflammation in the brain. Thus, either elimination of microglia or restoration of microglial function could ameliorate cognitive dysfunction. Using a rodent model of chronic Adriamycin (ADR) treatment, a commonly used breast cancer chemotherapy, we evaluated two strategies to ameliorate chemobrain: 1) microglia depletion using the colony stimulating factor-1 receptor (CSF1R) inhibitor PLX5622 and 2) human induced pluripotent stem cell-derived microglia (iMG)-derived extracellular vesicle (EV) treatment. In strategy 1 mice received ADR once weekly for 4 weeks and were then administered CSF1R inhibitor (PLX5622) starting 72 h post-ADR treatment. ADR-treated animals given a normal diet exhibited significant behavioral deficits and increased microglial activation 4-6 weeks later. PLX5622-treated mice exhibited no ADR-related cognitive deficits and near complete depletion of IBA-1 and CD68+ microglia in the brain. Cytokine and RNA sequencing analysis for inflammation pathways validated these findings. In strategy 2, 1 week after the last ADR treatment, mice received retro-orbital vein injections of iMG-EV (once weekly for 4 weeks) and 1 week later, mice underwent behavior testing. ADR-treated mice receiving EV showed nearly complete restoration of cognitive function and significant reductions in microglial activation as compared to untreated ADR mice. Our data demonstrate that ADR treatment elevates CNS inflammation that is linked to cognitive dysfunction and that attenuation of neuroinflammation reverses the adverse neurocognitive effects of chemotherapy. more...

Numerous clinical studies have established the debilitating neurocognitive side effects of chemotherapy in the treatment of breast cancer, often referred as chemobrain. We hypothesize that cognitive impairments are associated with elevated microglial inflammation in the brain. Thus, either elimination of microglia or restoration of microglial function could ameliorate cognitive dysfunction. Using a rodent model of chronic Adriamycin (ADR) treatment, a commonly used breast cancer chemotherapy, we evaluated two strategies to ameliorate chemobrain: 1) microglia depletion using the colony stimulating factor-1 receptor (CSF1R) inhibitor PLX5622 and 2) human induced pluripotent stem cell-derived microglia (iMG)-derived extracellular vesicle (EV) treatment. In strategy 1 mice received ADR once weekly for 4 weeks and were then administered CSF1R inhibitor (PLX5622) starting 72 h post-ADR treatment. ADR-treated animals given a normal diet exhibited significant behavioral deficits and increased microglial activation 4-6 weeks later. PLX5622-treated mice exhibited no ADR-related cognitive deficits and near complete depletion of IBA-1 and CD68+ microglia in the brain. Cytokine and RNA sequencing analysis for inflammation pathways validated these findings. In strategy 2, 1 week after the last ADR treatment, mice received retro-orbital vein injections of iMG-EV (once weekly for 4 weeks) and 1 week later, mice underwent behavior testing. ADR-treated mice receiving EV showed nearly complete restoration of cognitive function and significant reductions in microglial activation as compared to untreated ADR mice. Our data demonstrate that ADR treatment elevates CNS inflammation that is linked to cognitive dysfunction and that attenuation of neuroinflammation reverses the adverse neurocognitive effects of chemotherapy. more...

Objective: This meta-analysis examines the predictive validity of client change language subtypes in motivational interviewing (MI) sessions addressing addictive behavior change. Method: A systematic review identified k = 13 primary studies, contributing 16 MI conditions (N = 1556). The pooled correlation coefficient was used to assess the significance, direction, and strength of seven language subtypes (i.e., reason, desire, need, ability, commitment, taking steps, and other) by three valences (i.e., frequency positive or change talk, frequency negative or sustain talk, and proportion change talk) and their relationship to subsequent engagement in addictive behavior. Results: For frequency measures, more sustain talk related to reason, desire, ability, and other were associated with more addictive behavior at follow up. Other change talk was associated with MI outcomes but in an unexpected direction (i.e., more addictive behavior). Proportion measures showed more proportion change talk-reason and -other statements were associated with less addictive behavior at follow up. Sensitivity analyses indicated some heterogeneity and instability of effect sizes, but no evidence of publication bias. Conclusions: This preliminary meta-analysis suggests that aggregate measures of change and sustain talk are comprised of statement subtypes that are not equally meaningful in predicting outcome following MI for addictive behavior change. more...

Objective: This meta-analysis examines the predictive validity of client change language subtypes in motivational interviewing (MI) sessions addressing addictive behavior change. Method: A systematic review identified k = 13 primary studies, contributing 16 MI conditions (N = 1556). The pooled correlation coefficient was used to assess the significance, direction, and strength of seven language subtypes (i.e., reason, desire, need, ability, commitment, taking steps, and other) by three valences (i.e., frequency positive or change talk, frequency negative or sustain talk, and proportion change talk) and their relationship to subsequent engagement in addictive behavior. Results: For frequency measures, more sustain talk related to reason, desire, ability, and other were associated with more addictive behavior at follow up. Other change talk was associated with MI outcomes but in an unexpected direction (i.e., more addictive behavior). Proportion measures showed more proportion change talk-reason and -other statements were associated with less addictive behavior at follow up. Sensitivity analyses indicated some heterogeneity and instability of effect sizes, but no evidence of publication bias. Conclusions: This preliminary meta-analysis suggests that aggregate measures of change and sustain talk are comprised of statement subtypes that are not equally meaningful in predicting outcome following MI for addictive behavior change. more...

Brief motivational interventions (BMIs) are widely used and efficacious interventions that address alcohol misuse in mandated college students. Consistent with motivational interviewing (MI; Miller & Rollnick, 2013) theory, within-therapist improvements in MI-consistent (MICO) skills over time-that is, as a therapist gains skill through repeated practice-may be associated with concurrent increases in client change language and subsequent changes in behavior. This study examined how therapist skill changed over time and whether within-therapist improvement in MICO skills impacted in-session client change language and subsequent alcohol-related outcomes. BMI sessions (N = 228) from 2 randomized clinical trials that had led to significant reductions in alcohol use and alcohol-related problems in mandated student drinkers were coded using the Motivational Interviewing Skills Code 2.0 (Miller, Moyers, Ernst, & Amrhein, 2003). In both studies, the BMI consisted of a single 45- to 60-min session. Analyses examined session-by-session changes in therapist MICO skills, client change language, and alcohol use outcomes. Therapist MICO skills improved over time, and there were significant increases in client change language and decreases in client discussion of topics other than personal alcohol use. Among relatively heavy-drinking clients, those treated by a more experienced therapist demonstrated greater reductions in alcohol use; however, this association was not mediated by client change language. Increased experience conducting BMIs improved therapist MICO skills over time, which in turn increased the focus on personal alcohol use during the session. However, it remains unclear how client language predicts behavior change following a BMI. (PsycINFO Database Record (c) 2019 APA, all rights reserved). more...

Brief motivational interventions (BMIs) are widely used and efficacious interventions that address alcohol misuse in mandated college students. Consistent with motivational interviewing (MI; Miller & Rollnick, 2013) theory, within-therapist improvements in MI-consistent (MICO) skills over time-that is, as a therapist gains skill through repeated practice-may be associated with concurrent increases in client change language and subsequent changes in behavior. This study examined how therapist skill changed over time and whether within-therapist improvement in MICO skills impacted in-session client change language and subsequent alcohol-related outcomes. BMI sessions (N = 228) from 2 randomized clinical trials that had led to significant reductions in alcohol use and alcohol-related problems in mandated student drinkers were coded using the Motivational Interviewing Skills Code 2.0 (Miller, Moyers, Ernst, & Amrhein, 2003). In both studies, the BMI consisted of a single 45- to 60-min session. Analyses examined session-by-session changes in therapist MICO skills, client change language, and alcohol use outcomes. Therapist MICO skills improved over time, and there were significant increases in client change language and decreases in client discussion of topics other than personal alcohol use. Among relatively heavy-drinking clients, those treated by a more experienced therapist demonstrated greater reductions in alcohol use; however, this association was not mediated by client change language. Increased experience conducting BMIs improved therapist MICO skills over time, which in turn increased the focus on personal alcohol use during the session. However, it remains unclear how client language predicts behavior change following a BMI. (PsycINFO Database Record (c) 2019 APA, all rights reserved). more...

As NASA prepares for a mission to Mars, concerns regarding the health risks associated with deep space radiation exposure have emerged. Until now, the impacts of such exposures have only been studied in animals after acute exposures, using dose rates ∼1.5×105 higher than those actually encountered in space. Using a new, low dose-rate neutron irradiation facility, we have uncovered that realistic, low dose-rate exposures produce serious neurocognitive complications associated with impaired neurotransmission. Chronic (6 month) low-dose (18 cGy) and dose rate (1 mGy/d) exposures of mice to a mixed field of neutrons and photons result in diminished hippocampal neuronal excitability and disrupted hippocampal and cortical long-term potentiation. Furthermore, mice displayed severe impairments in learning and memory, and the emergence of distress behaviors. Behavioral analyses showed an alarming increase in risk associated with these realistic simulations, revealing for the first time, some unexpected potential problems associated with deep space travel on all levels of neurological function. more...

As NASA prepares for a mission to Mars, concerns regarding the health risks associated with deep space radiation exposure have emerged. Until now, the impacts of such exposures have only been studied in animals after acute exposures, using dose rates ∼1.5×105 higher than those actually encountered in space. Using a new, low dose-rate neutron irradiation facility, we have uncovered that realistic, low dose-rate exposures produce serious neurocognitive complications associated with impaired neurotransmission. Chronic (6 month) low-dose (18 cGy) and dose rate (1 mGy/d) exposures of mice to a mixed field of neutrons and photons result in diminished hippocampal neuronal excitability and disrupted hippocampal and cortical long-term potentiation. Furthermore, mice displayed severe impairments in learning and memory, and the emergence of distress behaviors. Behavioral analyses showed an alarming increase in risk associated with these realistic simulations, revealing for the first time, some unexpected potential problems associated with deep space travel on all levels of neurological function. more...

Advancement of the scientific enterprise relies on individuals conducting research in an ethical and responsible manner. Educating emergent scholars in the principles of ethics/responsible conduct of research (E/RCR) is therefore critical to ensuring such advancement. The recent impetus to include authentic research opportunities as part of the undergraduate curriculum, via course-based undergraduate research experiences (CUREs), has been shown to increase cognitive and noncognitive student outcomes. Because of these important benefits, CUREs are becoming more common and often constitute the first research experience for many students. However, despite the importance of E/RCR in the research process, we know of few efforts to incorporate E/RCR education into CUREs. The Ethics Network for Course-based Opportunities in Undergraduate Research (ENCOUR) was created to address this concern and promote the integration of E/RCR within CUREs in the biological sciences and related disciplines. During the inaugural ENCOUR meeting, a four-pronged approach was used to develop guidelines for the effective integration of E/RCR in CUREs. This approach included: 1) defining appropriate student learning objectives; 2) identifying relevant curriculum; 3) identifying relevant assessments; and 4) defining key aspects of professional development for CURE facilitators. Meeting outcomes, including the aforementioned E/RCR guidelines, are described herein. more...

Advancement of the scientific enterprise relies on individuals conducting research in an ethical and responsible manner. Educating emergent scholars in the principles of ethics/responsible conduct of research (E/RCR) is therefore critical to ensuring such advancement. The recent impetus to include authentic research opportunities as part of the undergraduate curriculum, via course-based undergraduate research experiences (CUREs), has been shown to increase cognitive and noncognitive student outcomes. Because of these important benefits, CUREs are becoming more common and often constitute the first research experience for many students. However, despite the importance of E/RCR in the research process, we know of few efforts to incorporate E/RCR education into CUREs. The Ethics Network for Course-based Opportunities in Undergraduate Research (ENCOUR) was created to address this concern and promote the integration of E/RCR within CUREs in the biological sciences and related disciplines. During the inaugural ENCOUR meeting, a four-pronged approach was used to develop guidelines for the effective integration of E/RCR in CUREs. This approach included: 1) defining appropriate student learning objectives; 2) identifying relevant curriculum; 3) identifying relevant assessments; and 4) defining key aspects of professional development for CURE facilitators. Meeting outcomes, including the aforementioned E/RCR guidelines, are described herein. more...

This report presents an experiment in which four starch sampling methods are compared in order to identify the most successful and effective technique for starch extraction from large groundstone and milling features in the field. Testing archaeological specimens in situ is necessary when the artifact is too large or cumbersome to bring back to a laboratory. In addition, preliminary testing in the field allows researchers to obtain quick results thatprovides guidance for ongoing excavation and sampling methods. more...

High-energy charged particles are considered particularly hazardous components of the space radiation environment. Such particles include fully ionized energetic nuclei of helium, silicon, and oxygen, among others. Exposure to charged particles causes reactive oxygen species production, which has been shown to result in neuronal dysfunction and myelin degeneration. Here we demonstrate that mice exposed to high-energy charged particles exhibited alterations in dendritic spine density in the hippocampus, with a significant decrease of thin spines in mice exposed to helium, oxygen, and silicon, compared to sham-irradiated controls. Electron microscopy confirmed these findings and revealed a significant decrease in overall synapse density and in nonperforated synapse density, with helium and silicon exhibiting more detrimental effects than oxygen. Degeneration of myelin was also evident in exposed mice with significant changes in the percentage of myelinated axons and g-ratios. Our data demonstrate that exposure to all types of high-energy charged particles have a detrimental effect, with helium and silicon having more synaptotoxic effects than oxygen. These results have important implications for the integrity of the central nervous system and the cognitive health of astronauts after prolonged periods of space exploration. more...

High-energy charged particles are considered particularly hazardous components of the space radiation environment. Such particles include fully ionized energetic nuclei of helium, silicon, and oxygen, among others. Exposure to charged particles causes reactive oxygen species production, which has been shown to result in neuronal dysfunction and myelin degeneration. Here we demonstrate that mice exposed to high-energy charged particles exhibited alterations in dendritic spine density in the hippocampus, with a significant decrease of thin spines in mice exposed to helium, oxygen, and silicon, compared to sham-irradiated controls. Electron microscopy confirmed these findings and revealed a significant decrease in overall synapse density and in nonperforated synapse density, with helium and silicon exhibiting more detrimental effects than oxygen. Degeneration of myelin was also evident in exposed mice with significant changes in the percentage of myelinated axons and g-ratios. Our data demonstrate that exposure to all types of high-energy charged particles have a detrimental effect, with helium and silicon having more synaptotoxic effects than oxygen. These results have important implications for the integrity of the central nervous system and the cognitive health of astronauts after prolonged periods of space exploration. more...

ObjectiveIn the present meta-analysis, we test the technical and relational hypotheses of Motivational Interviewing (MI) efficacy. We also propose an a priori conditional process model where heterogeneity of technical path effect sizes should be explained by interpersonal/relational (i.e., empathy, MI Spirit) and intrapersonal (i.e., client treatment seeking status) moderators.MethodA systematic review identified k = 58 reports, describing 36 primary studies and 40 effect sizes (N = 3,025 participants). Statistical methods calculated the inverse variance-weighted pooled correlation coefficient for the therapist to client and the client to outcome paths across multiple target behaviors (i.e., alcohol use, other drug use, other behavior change).ResultsTherapist MI-consistent skills were correlated with more client change talk (r = .55, p < .001) as well as more sustain talk (r = .40, p < .001). MI-inconsistent skills were correlated with more sustain talk (r = .16, p < .001), but not change talk. When these indicators were combined into proportions, as recommended in the Motivational Interviewing Skill Code, the overall technical hypothesis was supported. Specifically, proportion MI consistency was related to higher proportion change talk (r = .11, p = .004) and higher proportion change talk was related to reductions in risk behavior at follow up (r = -.16, p < .001). When tested as two independent effects, client change talk was not significant, but sustain talk was positively associated with worse outcome (r = .19, p < .001). Finally, the relational hypothesis was not supported, but heterogeneity in technical hypothesis path effect sizes was partially explained by inter- and intrapersonal moderators.ConclusionsThis meta-analysis provides additional support for the technical hypothesis of MI efficacy; future research on the relational hypothesis should occur in the field rather than in the context of clinical trials. (PsycINFO Database Record more...

The mechanisms underlying detection and transmission of sensory signals arising from visceral organs, such as the urethra, are poorly understood. Recently, specialized ACh-expressing cells embedded in the urethral epithelium have been proposed as chemosensory sentinels for detection of bacterial infection. Here, we examined the morphology and potential role in sensory signalling of a different class of specialized cells that express serotonin (5-HT), termed paraneurones. Urethrae, dorsal root ganglia neurones and spinal cords were isolated from adult female mice and used for immunohistochemistry and calcium imaging. Visceromotor reflexes (VMRs) were recorded in vivo. We identified two morphologically distinct groups of 5-HT+ cells with distinct regional locations: bipolar-like cells predominant in the mid-urethra and multipolar-like cells predominant in the proximal and distal urethra. Sensory nerve fibres positive for calcitonin gene-related peptide, substance P, and TRPV1 were found in close proximity to 5-HT+ paraneurones. In vitro 5-HT (1 μm) stimulation of urethral primary afferent neurones, mimicking 5-HT release from paraneurones, elicited changes in the intracellular calcium concentration ([Ca2+ ]i ) mediated by 5-HT2 and 5-HT3 receptors. Approximately 50% of 5-HT responding cells also responded to capsaicin with changes in the [Ca2+ ]i . In vivo intra-urethral 5-HT application increased VMRs induced by urethral distention and activated pERK in lumbosacral spinal cord neurones. These morphological and functional findings provide insights into a putative paraneurone-neural network within the urethra that utilizes 5-HT signalling, presumably from paraneurones, to modulate primary sensory pathways carrying nociceptive and non-nociceptive (mechano-sensitive) information to the central nervous system. more...

ObjectiveBrief motivational interventions (BMIs) are currently the most efficacious individual intervention for mandated college students. However, little is known about how BMIs facilitate client language in relation to subsequent changes in alcohol use and problems in mandated student samples.MethodThe current study used the Motivational Interviewing Skills Code (MISC 2.0; Miller, Moyers, Ernst, & Amrhein, 2003) to code BMI sessions (N = 252) from 2 randomized clinical trials that led to significant reductions in alcohol use and alcohol-related problems in mandated student drinkers. A proportion of change language was calculated for each decile (1st to 10th) of the BMI sessions.ResultsLatent class analyses of in-session speech indicated that there were 3 distinct trajectories of change language over the course of the session: high (n = 59), increasing (n = 122), and low (n = 71). Members of the high trajectory group showed higher rates of alcohol-related problems prior to the BMI and members of the low trajectory group were more likely to be male. Six months following the BMI, members of the high and low trajectory groups demonstrated significant reductions in alcohol use and problems, and members of the increasing trajectory group only reduced alcohol-related problems.ConclusionsAssociations among the 3 trajectories of client change language and subsequent reductions in alcohol use and problems partially supported the technical hypothesis of MI efficacy. Client factors as well as the nature of the discussion of personalized feedback may determine the link between in-session client language and subsequent behavior change. (PsycINFO Database Record more...

ObjectiveIn the present meta-analysis, we test the technical and relational hypotheses of Motivational Interviewing (MI) efficacy. We also propose an a priori conditional process model where heterogeneity of technical path effect sizes should be explained by interpersonal/relational (i.e., empathy, MI Spirit) and intrapersonal (i.e., client treatment seeking status) moderators.MethodA systematic review identified k = 58 reports, describing 36 primary studies and 40 effect sizes (N = 3,025 participants). Statistical methods calculated the inverse variance-weighted pooled correlation coefficient for the therapist to client and the client to outcome paths across multiple target behaviors (i.e., alcohol use, other drug use, other behavior change).ResultsTherapist MI-consistent skills were correlated with more client change talk (r = .55, p < .001) as well as more sustain talk (r = .40, p < .001). MI-inconsistent skills were correlated with more sustain talk (r = .16, p < .001), but not change talk. When these indicators were combined into proportions, as recommended in the Motivational Interviewing Skill Code, the overall technical hypothesis was supported. Specifically, proportion MI consistency was related to higher proportion change talk (r = .11, p = .004) and higher proportion change talk was related to reductions in risk behavior at follow up (r = -.16, p < .001). When tested as two independent effects, client change talk was not significant, but sustain talk was positively associated with worse outcome (r = .19, p < .001). Finally, the relational hypothesis was not supported, but heterogeneity in technical hypothesis path effect sizes was partially explained by inter- and intrapersonal moderators.ConclusionsThis meta-analysis provides additional support for the technical hypothesis of MI efficacy; future research on the relational hypothesis should occur in the field rather than in the context of clinical trials. (PsycINFO Database Record more...

Native Californians collected and consumed wild plants and animals even as they encountered colonial programs.Persistent interaction with native plant and animal communities can usually be inferred from colonial documents orby their presence as archaeological remains collected at missions, ranchos, or other colonial sites. Growing interestin the archaeology of spaces beyond the walls of colonial sites encourages expanded perspectives on indigenousfoodways and the natural environments that may have supported resilient traditions, even as both transformed.In this article, we assess the persistence of indigenous foodways at CA-MRN-202, the site of a mid-nineteenth centurytrading post on Toms Point in western Marin County. Analysis of zooarchaeological and paleoethnobotanicalassemblages suggests native people continued to collect and consume wild foods. They also selectively incorporatednew foods and new technologies, we argue, to maintain connections to meaningful places. more...

[This corrects the article DOI: 10.3389/fnsys.2018.00013.].

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating chronic disease of unknown etiology. A naturally occurring disease termed feline interstitial cystitis (FIC) reproduces many features of IC/BPS patients. To gain insights into mechanisms underlying IC/BPS, we investigated pathological changes in the lamina propria (LP) of the bladder and proximal urethra in cats with FIC, using histological and molecular methods. Compared to control cat tissue, we found an increased number of de-granulated mast cells, accumulation of leukocytes, increased cyclooxygenase (COX)-1 expression in the bladder LP, and increased COX-2 expression in the urethra LP from cats with FIC. We also found increased suburothelial proliferation, evidenced by mucosal von Brunns nests, neovascularization and alterations in elastin content. Scanning electron microscopy revealed normal appearance of the superficial urethral epithelium, including the neuroendocrine cells (termed paraneurons), in FIC urethrae. Together, these histological findings suggest the presence of chronic inflammation of unknown origin leading to tissue remodeling. Since the mucosa functions as part of a sensory network and urothelial cells, nerves and other cells in the LP are influenced by the composition of the underlying tissues including the vasculature, the changes observed in the present study may alter the communication of sensory information between different cellular components. This type of mucosal signaling can also extend to the urethra, where recent evidence has revealed that the urethral epithelium is likely to be part of a signaling system involving paraneurons and sensory nerves. Taken together, our data suggest a more prominent role for chronic inflammation and tissue remodeling than previously thought, which may result in alterations in mucosal signaling within the urinary bladder and proximal urethra that may contribute to altered sensations and pain in cats and humans with this syndrome. more...

Motivational interviewing (MI) is often incorporated into screening, brief intervention, and referral to treatment (SBIRT) interventions in critical care settings to address alcohol and other drug use. However, cognitive status has been linked to differential response to MI sessions in emergency department (ED) settings. The current study examined one possible explanation for this differential response: whether higher versus lower mental status impacts patient response to clinician statements during MI sessions conducted in an ED. Participants were 126 patients receiving an MI-based single-session alcohol brief intervention, and 13 therapists who provided treatment. Participants completed a mental status exam (MSE) as part of the screening process. Intervention sessions were audio-taped, and transcribed and coded using the Motivational Interviewing Skills Code (MISC 2.0; Miller, Moyers, Ernst, & Amrhein, 2003). The MISC 2.0 coded therapist behaviors that are related to the use of motivational interviewing, and patient language reflecting movement toward (change talk) or away from (sustain talk) changing personal alcohol use. Overall, patients responded in a similar manner to therapist MI behaviors regardless of high versus low level of mental functioning at the time of the intervention. Group differences emerged on patient response to only three specific therapist skills: giving information, open questions, and complex reflection. Thus, the differential effects of SBIRT in critical care settings do not appear to be a result of differences in the therapist and patient communication process. more...

Motivational interviewing (MI) is often incorporated into screening, brief intervention, and referral to treatment (SBIRT) interventions in critical care settings to address alcohol and other drug use. However, cognitive status has been linked to differential response to MI sessions in emergency department (ED) settings. The current study examined one possible explanation for this differential response: whether higher versus lower mental status impacts patient response to clinician statements during MI sessions conducted in an ED. Participants were 126 patients receiving an MI-based single-session alcohol brief intervention, and 13 therapists who provided treatment. Participants completed a mental status exam (MSE) as part of the screening process. Intervention sessions were audio-taped, and transcribed and coded using the Motivational Interviewing Skills Code (MISC 2.0; Miller, Moyers, Ernst, & Amrhein, 2003). The MISC 2.0 coded therapist behaviors that are related to the use of motivational interviewing, and patient language reflecting movement toward (change talk) or away from (sustain talk) changing personal alcohol use. Overall, patients responded in a similar manner to therapist MI behaviors regardless of high versus low level of mental functioning at the time of the intervention. Group differences emerged on patient response to only three specific therapist skills: giving information, open questions, and complex reflection. Thus, the differential effects of SBIRT in critical care settings do not appear to be a result of differences in the therapist and patient communication process. more...

ObjectiveTo identify individual therapist behaviors which elicit client change talk or sustain talk in motivational interviewing sessions.MethodMotivational interviewing sessions from a single-session alcohol intervention delivered to college students were audio-taped, transcribed, and coded using the Motivational Interviewing Skill Code (MISC), a therapy process coding system. Participants included 92 college students and eight therapists who provided their treatment. The MISC was used to code 17 therapist behaviors related to the use of motivational interviewing, and client language reflecting movement toward behavior change (change talk), away from behavior change (sustain talk), or unrelated to the target behavior (follow/neutral).ResultsClient change talk was significantly more likely to immediately follow individual therapist behaviors [affirm (p=.013), open question (p more...

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Substance use among adolescents with one or more psychiatric disorders is a significant public health concern. In this study, 151 psychiatrically hospitalized adolescents, ages 13-17 with comorbid psychiatric and substance use disorders, were randomized to a two-session Motivational Interviewing intervention to reduce substance use plus treatment as usual (MI) vs. treatment as usual only (TAU). Results indicated that the MI group had a longer latency to first use of any substance following hospital discharge relative to TAU (36 days versus 11 days). Adolescents who received MI also reported less total use of substances and less use of marijuana during the first 6 months post-discharge, although this effect was not significant across 12 months. Finally, MI was associated with a significant reduction in rule-breaking behaviors at 6-month follow-up. Future directions are discussed, including means of extending effects beyond 6 months and dissemination of the intervention to community-based settings. more...

The bacteriophage population is large, dynamic, ancient, and genetically diverse. Limited genomic information shows that phage genomes are mosaic, and the genetic architecture of phage populations remains ill-defined. To understand the population structure of phages infecting a single host strain, we isolated, sequenced, and compared 627 phages of Mycobacterium smegmatis. Their genetic diversity is considerable, and there are 28 distinct genomic types (clusters) with related nucleotide sequences. However, amino acid sequence comparisons show pervasive genomic mosaicism, and quantification of inter-cluster and intra-cluster relatedness reveals a continuum of genetic diversity, albeit with uneven representation of different phages. Furthermore, rarefaction analysis shows that the mycobacteriophage population is not closed, and there is a constant influx of genes from other sources. Phage isolation and analysis was performed by a large consortium of academic institutions, illustrating the substantial benefits of a disseminated, structured program involving large numbers of freshman undergraduates in scientific discovery. more...

ObjectiveEach year, thousands of college students receive mandated intervention as a sanction for alcohol use or alcohol-related behavior. For these mandated students, brief motivational interventions (BMIs) are currently the most efficacious individual intervention. However, little is known about how the technical (therapist behaviors) and relational (e.g., global ratings of therapist empathy) components of BMIs influence client language as well as subsequent change in alcohol use and consequences.MethodThis study used the Motivational Interviewing Skills Code (MISC 2.0; Miller, Moyers, Ernst, & Amrhein, 2003) to code BMI sessions from 2 randomized clinical trials that facilitated significant reductions in alcohol use (Study 1, n = 91) and alcohol-related consequences (Study 2, n = 158) in mandated students.ResultsThere were significant relationships among therapist behaviors, global scores, and client language both for and against change, yet there were no links between in-session client language and subsequent changes in alcohol use or problems. In contrast, relational aspects of motivational interviewing (MI; global ratings of therapist MI Spirit and client self-exploration) were most predictive of postsession alcohol use. Mediation models incorporating both technical and relational components revealed that higher levels of client self-exploration mediated the relationship between higher therapist ratings of MI Spirit and reduced drinking at follow-up.ConclusionsFindings highlight the importance of considering how both technical and relational components of MI may influence alcohol use in mandated college students and also suggest more exact analyses to better understand this complex relationship. more...

ObjectiveThe technical hypothesis of motivational interviewing (MI) posits that therapist-implemented MI skills are related to client speech regarding behavior change and that client speech predicts client outcome. The current meta-analysis is the first aggregate test of this proposed causal model.MethodA systematic literature review, using stringent inclusion criteria, identified 16 reports describing 12 primary studies. We used review methods to calculate the inverse-variance-weighted pooled correlation coefficient for the therapist-to-client and the client-to-outcome paths across multiple targeted behaviors (i.e., alcohol or illicit drug use, other addictive behaviors).ResultsTherapist MI-consistent skills were correlated with more client language in favor of behavior change (i.e., change talk; r = .26, p < .0001), but not less client language against behavior change (i.e., sustain talk; r = .10, p = .09). MI-inconsistent skills were associated with less change talk (r = -.17, p = .001) as well as more sustain talk (r = .07, p = .009). Among these studies, client change talk was not associated with follow-up outcome (r = .06, p = .41), but sustain talk was associated with worse outcome (r = -.24, p = .001). In addition, studies examining composite client language (e.g., an average of negative and positive statements) showed an overall positive relationship with client behavior change (r = .12, p = .006; k = 6).ConclusionsThis meta-analysis provides an initial test and partial support for a key causal model of MI efficacy. Recommendations for MI practitioners, clinical supervisors, and process researchers are provided. more...