Enantiomeric Agonists of the Type 2 Cannabinoid Receptor Reduce Retinal Damage during Proliferative Vitreoretinopathy and Inhibit Hyperactive Microglia In Vitro.

Microglia are resident immune cells of the central nervous system (CNS) and propagate inflammation following damage to the CNS, including the retina. Proliferative vitreoretinopathy (PVR) is a condition that can emerge following retinal detachment and is characterized by severe inflammation and microglial proliferation. The type 2 cannabinoid receptor (CB2) is an emerging pharmacological target to suppress microglial-mediated inflammation when the eyes or brain are damaged. CB2-knockout mice have exacerbated inflammation and retinal pathology during experimental PVR. We aimed to assess the anti-inflammatory effects of CB2 stimulation in the context of retinal damage and also explore the mechanistic roles of CB2 in microglia function. To target CB2, we used a highly selective agonist, HU-308, as well as its enantiomer, HU-433, which is a putative selective agonist. First, ß-arrestin2 and Gαi recruitment was measured to compare activation of human CB2 in an in vitro heterologous expression system. Both agonists were then utilized in a mouse model of PVR, and the effects on retinal damage, inflammation, and cell death were assessed. Finally, we used an in vitro model of microglia to determine the effects of HU-308 and HU-433 on phagocytosis, cytokine release, migration, and intracellular signaling. We observed that HU-308 more strongly recruited both ß-arrestin2 and Gαi compared to HU-433. Stimulation of CB2 with either drug effectively blunted LPS- and IFNγ-mediated signaling as well as NO and TNF release from microglia. Furthermore, both drugs reduced IL-6 accumulation, total caspase-3 cleavage, and retinal pathology following the induction of PVR. Ultimately, this work supports that CB2 is a valuable target for drugs to suppress inflammation and cell death associated with infection or sterile retinopathy, although the magnitude of effector recruitment may not be predictive of anti-inflammatory capacity.

Variation in benefit among patients with serious mental illness who receive integrated psychiatric and primary care.

PURPOSE: The population with serious mental illness has high risk for hospitalization or death due to unhealthy behaviors and inadequate medical care, though the level of risk varies substantially. Programs that integrate medical and psychiatric services improve outcomes but are challenging to implement and access is limited. It would be useful to know whether benefits are confined to patients with specific levels of risk. METHODS: In a population with serious mental illness and increased risk for hospitalization or death, a specialized medical home integrated services and improved treatment and outcomes. Treatment quality, chronic illness care, care experience, symptoms, and quality of life were assessed for a median of 385 days. Analyses examine whether improvements varied by baseline level of patient risk. RESULTS: Patients with greater risk were more likely to be older, more cognitively impaired, and have worse mental health. Integrated services increased appropriate screening for body mass index, lipids, and glucose, but increases did not differ significantly by level of risk. Integrated services also improved chronic illness care, care experience, mental health-related quality of life, and psychotic symptoms. There were also no significant differences by risk level. CONCLUSIONS: There were benefits from integration of primary care and psychiatric care at all levels of increased risk, including those with extremely high risk above the 95th percentile. When developing integrated care programs, patients should be considered at all levels of risk, not only those who are the healthiest.

Informing implementation and dissemination of a specialized primary care medical home for patients with serious mental illness: Clinician and administrator perspectives.

People with serious mental illness (SMI) have lower rates of use of preventative medical services and higher rates of mortality compared to the general population. Research shows that specialized primary care medical homes improve the health care of patients with SMI and are feasible to implement, safe, and more effective than usual care. However, specialized medical homes remain uncommon and model dissemination limited. As part of a controlled trial assessing an SMI-specialized medical home, we examined clinician and administrator perspectives regarding specialized versus mainstream primary care and identified ways to enhance the scale-up of a specialized primary care model for future dissemination. We conducted semistructured interviews with clinicians and administrators at three sites prior to the implementation of an SMI-specialized primary care medical home (n = 26) and at 1-year follow-up (n = 24); one site implemented the intervention, and two sites served as controls. Interviews captured service design features that affected the quality of care provided; contextual factors that supported or impeded medical home implementation; and knowledge, attitudes, and behaviors regarding the care of patients with SMI. Interviews were transcribed and coded. Clinicians and administrators described SMI-specialized primary care medical homes as advancing care coordination and outcomes for patients with SMI. Stakeholders identified elements of a specialized medical home that they viewed as superior to usual care, including having a holistic picture of patients' needs and greater care coordination. However, to enable scale-up, efforts are needed to increase staffing on care teams, develop robust clinician onboarding or training, and ensure close coordination with mental health care providers. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The Characteristics of People with Serious Mental Illness Who are at High Risk for Hospitalization or Death.

Many individuals with serious mental illness are at high risk for hospitalization or death due to inadequate treatment of medical conditions or unhealthy behaviors. The authors describe demographic and clinical characteristics associated with increased risk in this population. Electronic data were obtained for individuals in treatment at a large Veterans' healthcare system who were at high risk according to a validated model. A random sample of these individuals was assessed in person. Multivariable regressions estimated the effect of numerous demographic, health, and clinical characteristics on risk. Emergency visits and hospitalizations were common. Greater risk was associated with being male, not married, and having more diagnoses. While risk varied by race, this effect was no longer significant after controlling for other factors. Health-related quality of life worsened with increasing risk. Routine data identify a large population of high-risk individuals who may benefit from outreach to provide healthcare services.

JAK1/2 Regulates Synergy Between Interferon Gamma and Lipopolysaccharides in Microglia.

Microglia, the resident immune cells of the brain, regulate neuroinflammation which can lead to secondary neuronal damage and cognitive impairment under pathological conditions. Two of the many molecules that can elicit an inflammatory response from microglia are lipopolysaccharide (LPS), a component of gram-negative bacteria, and interferon gamma (IFNγ), an endogenous pro-inflammatory cytokine. We thoroughly examined the concentration-dependent relationship between LPS from multiple bacterial species and IFNγ in cultured microglia and macrophages. We measured the effects that these immunostimulatory molecules have on pro-inflammatory activity of microglia and used a battery of signaling inhibitors to identify the pathways that contribute to the microglial response. We found that LPS and IFNγ interacted synergistically to induce a pro-inflammatory phenotype in microglia, and that inhibition of JAK1/2 completely blunted the response. We determined that this synergistic action of LPS and IFNγ was likely dependent on JNK and Akt signaling rather than typical pro-inflammatory mediators such as NF-κB. Finally, we demonstrated that LPS derived from Escherichia coli, Klebsiella pneumoniae, and Akkermansia muciniphila can elicit different inflammatory responses from microglia and macrophages, but these responses could be consistently prevented using ruxolitinib, a JAK1/2 inhibitor. Collectively, this work reveals a mechanism by which microglia may become hyperactivated in response to the combination of LPS and IFNγ. Given that elevations in circulating LPS and IFNγ occur in a wide variety of pathological conditions, it is critical to understand the pharmacological interactions between these molecules to develop safe and effective treatments to suppress this process.

Genome-wide association studies have problems due to confounding: Are family-based designs the answer?

Genome-wide association studies (GWASs) can be affected by confounding. Family-based GWAS uses random, within-family genetic variation to avoid this. A study in PLOS Biology details how different sources of confounding affect GWAS and whether family-based designs offer a solution.

Testing an implementation package in a housing skills training pilot for homeless-experienced persons with serious mental illness.

Background: Evidence-based practices (EBPs) improve housing and health for persons who have experienced homelessness with serious mental illness (PEH-SMI) but are challenging to implement. We tested a strategy to support pilot implementation of a 12-session housing skills training intervention for PEH-SMI, tailored from effective social skills training interventions. We aimed to optimize the implementation strategy and intervention prior to an implementation trial. Method: We provided training and technical assistance to nine providers to support pilot implementation of this intervention to six groups of PEH-SMI (n = 35) engaged in VA Greater Los Angeles' homeless services. We used scales and semi-structured interviews with 14 PEH-SMI and all interventionists to inform implementation strategy adaptations, identify factors that impacted implementation, and assess perceptions of the intervention. Attendance was tracked and we observed a random sample of each interventionist's groups to assess treatment fidelity. Results: Interventionists perceived the implementation strategy and the intervention favorably. However, interventionists often lacked physical space, staff, and resources (e.g., computers) to conduct the intervention. Interventionists found the content valuable for participants and a few suggested that group engagement should be a prerequisite for obtaining housing services. PEH-SMI were interested in the intervention's content and receptive to the group-based format. Participants attended a mean of 4 ± 3/12 groups; all groups observed had acceptable fidelity. Problems with intervention retention were described, suggesting challenges maintaining group participation when participants transitioned between VA homeless services. Conclusions: To support the implementation of an EBP for PEH-SMI in homeless programs, these data suggest the value of training/technical assistance and strategies that enhance program-level buy-in to address resource concerns. Intervention adaptations, e.g., using a drop-in, open group format, in community-based settings that are easily accessible to PEH-SMI, may also increase adoption. This project was registered as "Improving Housing Outcomes for Homeless Veterans" Trial registration NCT03646149, registered 8/24/2018.

There are effective social skills programs for people with serious psychiatric disorders; we adapted these programs into a 12-session housing skills program for people who had experienced homelessness. We then tested a training and technical assistance package to support the program's delivery by nine providers (e.g., social workers) to six groups of homeless people with serious psychiatric disorders (n = 35). We used surveys and interviews with some participants (n = 14) and all involved providers (n = 9) to understand their perspectives on our training and technical assistance, as well as the program itself; and to assess their views on factors that affected the program's use in real-world settings. We tracked participants' attendance at the groups and observed a random selection of groups to see if providers adhered to key program elements. We found that participants attended an average of one-third of the program's groups (4/12) but that providers were able to deliver the program to include all key elements. Some providers lacked important resources (e.g., classroom space or computers) to deliver the program as it was intended; they liked the training and technical assistance offered. Participants liked the program's content and format. Difficulties with participant retention may relate to drop-out from homeless services in which the program was delivered. This pilot project suggests that getting buy-in from leaders across levels and structuring the program as a drop-in group, in the community, or in places where attendance is easy for participants may increase its likelihood of being used as part of routine homeless services.

Pannexin 1 Channels Control Cardiomyocyte Metabolism and Neutrophil Recruitment During Non-Ischemic Heart Failure.

Pannexin 1 (PANX1), a ubiquitously expressed ATP release membrane channel, has been shown to play a role in inflammation, blood pressure regulation, and myocardial infarction. However, a possible role of PANX1 in cardiomyocytes in the progression of heart failure has not yet been investigated. We generated a novel mouse line with constitutive deletion of PANX1 in cardiomyocytes (Panx1 MyHC6 ). PANX1 deletion in cardiomyocytes had no effect on unstressed heart function but increased the glycolytic metabolism both in vivo and in vitro . In vitro , treatment of H9c2 cardiomyocytes with isoproterenol led to PANX1-dependent release of ATP and Yo-Pro-1 uptake, as assessed by pharmacological blockade with spironolactone and siRNA-mediated knock-down of PANX1. To investigate non-ischemic heart failure and the preceding cardiac hypertrophy we administered isoproterenol, and we demonstrate that Panx1 MyHC6 mice were protected from systolic and diastolic left ventricle volume increases and cardiomyocyte hypertrophy. Moreover, we found that Panx1 MyHC6 mice showed decreased isoproterenol-induced recruitment of immune cells (CD45 + ), particularly neutrophils (CD11b + , Ly6g + ), to the myocardium. Together these data demonstrate that PANX1 deficiency in cardiomyocytes impacts glycolytic metabolism and protects against cardiac hypertrophy in non-ischemic heart failure at least in part by reducing immune cell recruitment. Our study implies PANX1 channel inhibition as a therapeutic approach to ameliorate cardiac dysfunction in heart failure patients.

Inpatient peritoneal dialysis catheters placed across the United States during a 3-year period: Lessons learned from 15,000 patients.

BACKGROUND: Peritoneal dialysis is a popular option for patients with end-stage renal disease. A recent presidential executive order has incentivized in-home end-stage renal disease treatments, leading to an increase in peritoneal dialysis use. Guidelines exist for creating and maintaining peritoneal dialysis access without addressing the optimal technique. This study evaluates nationwide peritoneal dialysis catheter placement practices and their long-term outcomes. METHODS: Retrospective cohort analysis of Nationwide Readmission Database from 2017 to 2019. Patients with end-stage renal disease undergoing inpatient peritoneal dialysis catheter placement were included. Six-month readmissions, mortality, and peritoneal dialysis catheter-specific outcome measures were assessed among survivors of admission, including catheter leakage, mechanical breakdown, displacement, revision or replacement, removal, exit site infections, intra-abdominal abscess, and sepsis. Binary logistic regression analyses were performed. RESULTS: In the study, 14,863 patients with inpatient peritoneal dialysis catheter insertions were identified, of which 7,096 were analyzed (4,150 [59%] laparoscopic, 1,781 [25%] fluoroscopic, 1,165 [16%] open), 847 (12%) had major complications, 931 (13%) were readmitted, and 102 (1.4%) died within 6 months. Univariate analyses demonstrated that laparoscopy had higher mechanical complications, exit-site infections, catheter revision, and removal within 6 months, and fluoroscopy had higher sepsis and mortality. Multivariate analyses showed fluoroscopy was associated with intraabdominal abscess (adjusted odds ratio, 2.36; P = .025), laparoscopy with exit-site infections (adjusted odds ratio, 0.49; P = .005), and open surgery with catheter displacement (adjust odds ratio, 2.95; P = .021). CONCLUSION: This is the first large-scale study on inpatient peritoneal dialysis catheter placement outcomes in the United States. Fluoroscopic and open surgical placements are routinely performed, but laparoscopy remains the mainstay with fewer exit-site infections. Overall, peritoneal dialysis is a safe option, with 1 in 9 patients having an infectious or mechanical complication within 6 months. Furthermore, large-scale prospective studies are warranted to identify the optimal placement technique.

Patient experiences with a primary care medical home tailored for people with serious mental illness.

INTRODUCTION: People with serious mental illness (SMI) have low rates of primary care (PC) use and die years prematurely, mostly because of medical illnesses such as cardiovascular disease or cancer. To meet the needs of these individuals, a novel, specialized patient-centered medical home with care coordination ("SMI PACT") was developed and implemented in PC. This study qualitatively examined patients' experiences with this innovative care model. METHOD: After implementation of the medical home in 2018, one-on-one semistructured interviews were conducted with 28 patients (32% women, 43% Black, and 25% Hispanic). Interviews were professionally transcribed and coded prior to thematic analysis. RESULTS: Patients overwhelmingly described positive experiences with SMI PACT because of the qualities of interpersonal communication displayed by SMI PACT staff (e.g., nonjudgment, good listening, patience), structural features of the SMI PACT collaborative care model (e.g., frequent follow-up communication), and other unique aspects of the SMI PACT model tailored for SMI, such as easy-to-understand language. For these reasons, most patients expressed a desire to continue care in SMI PACT. Patients also self-reported improved engagement with their healthcare and self-management of diet, exercise, blood pressure, and diabetes control as a result of SMI PACT participation. DISCUSSION: Patients enrolled in a specialized PC medical home identified clinician characteristics and behaviors that informed an overwhelmingly positive impression of the program model. Their experiences can guide dissemination of specialized PC models and integrated services for people with SMI. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Clinician and Patient Perspectives on the Use of Passive Mobile Monitoring and Self-Tracking for Patients With Serious Mental Illness: User-Centered Approach.

BACKGROUND: Early intervention in mental health crises can prevent negative outcomes. A promising new direction is remote mental health monitoring using smartphone technology to passively collect data from individuals to rapidly detect the worsening of serious mental illness (SMI). This technology may benefit patients with SMI, but little is known about health IT acceptability among this population or their mental health clinicians. OBJECTIVE: We used the Health Information Technology Acceptability Model to analyze the acceptability and usability of passive mobile monitoring and self-tracking among patients with serious mental illness and their mental health clinicians. METHODS: Data collection took place between December 2020 and June 2021 in 1 Veterans Administration health care system. Interviews with mental health clinicians (n=16) assessed the acceptability of mobile sensing, its usefulness as a tool to improve clinical assessment and care, and recommendations for program refinements. Focus groups with patients with SMI (n=3 groups) and individual usability tests (n=8) elucidated patient attitudes about engaging in health IT and perceptions of its usefulness as a tool for self-tracking and improving mental health assessments. RESULTS: Clinicians discussed the utility of web-based data dashboards to monitor patients with SMI health behaviors and receiving alerts about their worsening health. Potential benefits included improving clinical care, capturing behaviors patients do not self-report, watching trends, and receiving alerts. Clinicians' concerns included increased workloads tied to dashboard data review, lack of experience using health IT in clinical care, and how SMI patients' associated paranoia and financial instability would impact patient uptake. Despite concerns, all mental health clinicians stated that they would recommend it. Almost all patients with SMI were receptive to using smartphone dashboards for self-monitoring and having behavioral change alerts sent to their mental health clinicians. They found the mobile app easy to navigate and dashboards easy to find and understand. Patient concerns centered on privacy and "government tracking," and their phone's battery life and data plans. Despite concerns, most reported that they would use it. CONCLUSIONS: Many people with SMI would like to have mobile informatics tools that can support their illness and recovery. Similar to other populations (eg, older adults, people experiencing homelessness) this population presents challenges to adoption and implementation. Health care organizations will need to provide resources to address these and support successful illness management. Clinicians are supportive of technological approaches, with adapting informatics data into their workflow as the primary challenge. Despite clear challenges, technological developments are increasingly designed to be acceptable to patients. The research development-clinical deployment gap must be addressed by health care systems, similar to computerized cognitive training. It will ensure clinicians operate at the top of their skill set and are not overwhelmed by administrative tasks, data summarization, or reviewing data that do not indicate a need for intervention. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/39010.

Tractable limitations of current polygenic scores do not excuse genetically confounded social science.

Burt's critique of using polygenic scores in social science conflates the "scientific costs" of sociogenomics with "sociopolitical and ethical" concerns. Furthermore, she paradoxically enlists recent advances in controlling for environmental confounding to argue such confounding is scientifically "intractable." Disinterested social scientists should support ongoing efforts to improve this technology rather than obstructing progress and excusing genetically confounded research.

Discovering genes that affect cognitive ability.

Twin and genomic studies indicate that genes play an important role in the development of cognitive ability. However, data limitations have made it difficult to pinpoint specific genes with a large impact. By examining the full gene sequences of >300 000 individuals, Chen et al. find eight such genes.

Estimation of indirect genetic effects and heritability under assortative mating.

Both direct genetic effects (effects of alleles in an individual on that individual) and indirect genetic effects - effects of alleles in an individual (e.g. parents) on another individual (e.g. offspring) - can contribute to phenotypic variation and genotype-phenotype associations. Here, we consider a phenotype affected by direct and parental indirect genetic effects under assortative mating at equilibrium. We generalize classical theory to derive a decomposition of the equilibrium phenotypic variance in terms of direct and indirect genetic effect components. We extend this theory to show that popular methods for estimating indirect genetic effects or 'genetic nurture' through analysis of parental and offspring polygenic predictors (called polygenic indices or scores - PGIs or PGSs) are substantially biased by assortative mating. We propose an improved method for estimating indirect genetic effects while accounting for assortative mating that can also correct heritability estimates for bias due to assortative mating. We validate our method in simulations and apply it to PGIs for height and educational attainment (EA), estimating that the equilibrium heritability of height is 0.699 (S.E. = 0.075 ) and finding no evidence for indirect genetic effects on height. We estimate a very high correlation between parents' underlying genetic components for EA, 0.755 (S.E. = 0.035), which is inconsistent with twin based estimates of the heritability of EA, possibly due to confounding in the EA PGI and/or in twin studies. We implement our method in the software package snipar, enabling researchers to apply the method to data including observed and/or imputed parental genotypes. We provide a theoretical framework for understanding the results of PGI analyses and a practical methodology for estimating heritability and indirect genetic effects while accounting for assortative mating.

Retention of older veterans with serious mental illness in a clinical exercise program.

Older adults with serious mental illness (SMI) have compromised physical function that could be improved with exercise; however, retention in exercise programs is a challenge. This study was a retrospective analysis of retention for the 150 older veterans with SMI that enrolled in Gerofit, a clinical exercise program offered in the Veterans Health Administration. Chi-square and t-tests were conducted to evaluate baseline differences between those that were and were not retained at six and 12 months. Retention was 33% and better health-related quality of life and endurance were related to retention. Future work is needed to improve exercise program retention in this population.

Primary care provider perspectives on virtual and in-person depression management during the COVID-19 pandemic.

INTRODUCTION: During the COVID-19 pandemic, primary care providers (PCPs), nurses, and integrated mental health specialists continued to collaboratively manage depression among patients using both in-person and virtual (i.e., hybrid) modalities. Few studies have characterized how hybrid services are currently delivered within interdisciplinary primary care teams. This study aimed to understand frontline PCPs' perspectives on providing hybrid virtual and in-person depression care during the pandemic. METHOD: From September to November 2020, 12 semistructured individual interviews focused on depression management were conducted with PCPs in two Veterans Health Administration (VA) clinics in Los Angeles, which resumed in-person services while balancing rising COVID-19 cases. Interviews were audio-recorded, transcribed, and coded for depression management patterns. Themes were derived using a team-based constant comparative analytic approach. RESULTS: The pandemic and subsequent expanded use of virtual care necessitated clinic adaptations to depression assessments and procedures. PCPs perceived increased depression and anxiety among patients with existing psychiatric conditions, attributed to social distancing and isolation restrictions. They expressed acceptance of virtual care modalities for patients' depression management. PCPs did not perceive a delay in mental health care delivery in the shift to virtual care but noted the possibility of patients being lost to follow-up. CONCLUSIONS: During the pandemic, there has been heightened PCP concern for patients' emotional well-being and adaptations of clinic processes to meet needs for depression care. While PCPs were optimistic about new virtual care options for depression management, virtual care transfers remained poorly defined and the extent to which patient care experiences and health outcomes have been disrupted remains unknown. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

De novo priming: driver of immunotherapy responses or epiphenomenon?

The introduction of immunotherapy, in particular immune checkpoint inhibition, has revolutionised the treatment of a range of tumours; however, only a minority of patients respond to these therapies. Understanding the mechanisms by which different immune checkpoint inhibitors work will be critical for both predicting patients who will respond and to developing rational combination therapies to extend these benefits further. The initiation and maintenance of anti-tumour T cell responses is a complicated process split between both the tumour microenvironment and the tumour draining lymph node. As understanding of this process has increased, it has become apparent that immune checkpoint inhibitors can act both within the tumour and in the draining lymph node and that they can target both already activated T cells as well as stimulating the priming of novel T cell clones. Currently, it seems likely that immune checkpoint inhibition acts both within the tumour and in the tumour draining lymph node both reinvigorating existing clones and driving further de novo priming of novel clones. The relative contributions of these sites and targets may depend on the type of model being used and the timeline of the response. Shorter models emphasise the effect of reinvigoration in the absence of recruitment of new clones but studies spanning longer time periods examining T cell clones in patients demonstrate clonal replacement. Ultimately, further work is needed to determine which of the diverse effects of immune checkpoint inhibitors are the fundamental drivers of anti-tumour responses in patients.

Mutual information: Measuring nonlinear dependence in longitudinal epidemiological data.

Given a large clinical database of longitudinal patient information including many covariates, it is computationally prohibitive to consider all types of interdependence between patient variables of interest. This challenge motivates the use of mutual information (MI), a statistical summary of data interdependence with appealing properties that make it a suitable alternative or addition to correlation for identifying relationships in data. MI: (i) captures all types of dependence, both linear and nonlinear, (ii) is zero only when random variables are independent, (iii) serves as a measure of relationship strength (similar to but more general than R2), and (iv) is interpreted the same way for numerical and categorical data. Unfortunately, MI typically receives little to no attention in introductory statistics courses and is more difficult than correlation to estimate from data. In this article, we motivate the use of MI in the analyses of epidemiologic data, while providing a general introduction to estimation and interpretation. We illustrate its utility through a retrospective study relating intraoperative heart rate (HR) and mean arterial pressure (MAP). We: (i) show postoperative mortality is associated with decreased MI between HR and MAP and (ii) improve existing postoperative mortality risk assessment by including MI and additional hemodynamic statistics.

Patterns of physical, chemical, and metabolic characteristics of sugar maple leaves with depth in the crown and in response to nitrogen and phosphorus addition.

Few previous studies have described the patterns of leaf characteristics in response to nutrient availability and depth in the crown. Sugar maple has been studied for both sensitivity to light, as a shade-tolerant species, and sensitivity to soil nutrient availability, as a species in decline due to acid rain. To explore leaf characteristics from the top to bottom of the canopy, we collected leaves along a vertical gradient within mature sugar maple crowns in a full-factorial nitrogen (N) by phosphorus (P) addition experiment in three forest stands in central New Hampshire, USA. Thirty-two of the 44 leaf characteristics had significant relationships with depth in the crown, with the effect of depth in the crown strongest for leaf area, photosynthetic pigments and polyamines. Nitrogen addition had a strong impact on the concentration of foliar N, chlorophyll, carotenoids, alanine and glutamate. For several other elements and amino acids, N addition changed patterns with depth in the crown. Phosphorus addition increased foliar P and boron (B); it also caused a steeper increase of P and B with depth in the crown. Since most of these leaf characteristics play a direct or indirect role in photosynthesis, metabolic regulation or cell division, studies that ignore the vertical gradient may not accurately represent whole-canopy performance.

It's not what you said, it's how you said it: An analysis of therapist vocal features during psychotherapy.

Psychotherapy is a conversation, whereby, at its foundation, many interventions are derived from the therapist talking. Research suggests that the voice can convey a variety of emotional and social information, and individuals may change their voice based on the context and content of the conversation (e.g., talking to a baby or delivering difficult news to patients with cancer). As such, therapists may adjust aspects of their voice throughout a therapy session depending on if they are beginning a therapy session and checking in with a client, conducting more therapeutic "work," or ending the session. In this study, we modeled three vocal features-pitch, energy, and rate-with linear and quadratic multilevel models to understand how therapists' vocal features change throughout a therapy session. We hypothesized that all three vocal features would be best fit with a quadratic function - starting high and more congruent with a conversational voice, decreasing during the middle portions of therapy where more therapeutic interventions were being administered, and increasing again at the end of the session. Results indicated a quadratic model for all three vocal features was superior in fitting the data, as compared to a linear model, suggesting that therapists begin and end therapy using a different style of voice than in the middle of a session.