Development of a new observer-rated measure to assess the real relationship in psychotherapy sessions.

OBJECTIVES: Real relationship (RR) refers to a genuine human relationship between client and therapist, that has been found to be positively related to treatment outcome, and to predict unique variance in outcome over and above the working alliance. However, thus far, the measurement of RR has been limited to self-report. We aimed to develop an observer-rated version of the RR measure (RR-O) to assess RR in therapy sessions. METHODS: We adapted items from the self-report measures to an observer rated measure, which was reviewed by RR experts. The final 24-item RR-O was rated in 540 session transcripts from 27 psychoanalytic treatments that already had existing process and outcome scores. RESULTS: The RR-O showed good internal consistency and good interrater reliability. In hierarchical EFA, items clustered into a general RR factor, and client realism, client genuineness, therapist genuineness, and therapist realism group factors. In addition, the RR-O was positively related to another RR measure and to the therapeutic alliance. CONCLUSION: The RR-O shows initial reliability and validity as an observer-rated measure of the RR to be used in post-hoc psychotherapy research. Future research should clarify the relation between RR-O and treatment outcome.

Development and implementation of a case-based collaborative learning flipped classroom preclinical neurology course.

This paper describes the development, content, structure, and implementation of a case-based collaborative learning, flipped classroom, integrated preclinical neurology, neuroanatomy, and neuroscience course for first year medical students at Harvard Medical School. We report the methods for pre-class preparation, in-class instruction, and evaluation; student feedback with respect to content, teaching method, and learning environment; and several lessons learned regarding how to optimize preparatory and in-class learning in a case-based flipped classroom course.

Short- and medium-chain chlorinated paraffins in surface sediment from Lake Ontario.

Concentrations of short- and medium-chain chlorinated paraffins (SCCPs and MCCPs) were analyzed and investigated in surficial sediment collected in 2018 from ten different nearshore sites in Lake Ontario and the St. Lawrence River influenced by inputs from varying urban and historical land uses. Sites were grouped into two categories of tributary and lake according to their location. Results show that tributary sites had higher concentrations of total chlorinated paraffin (CP) than lake sites. Humber Bay, a lake site, had the highest total CP concentration (55,000 ng/gTOC) followed by Humber River, a tributary site (50,000 ng/gTOC). The lowest concentrations were found in eastern Lake Ontario and Lake St. Francis in the St. Lawrence River (540 ng/gTOC). Higher concentrations of chlorinated paraffins (CPs) were found where runoff and wastewater inputs from urban areas, current industrial activities, and population were the greatest. Levels of MCCPs were higher than SCCPs at all sites but one, Lake St. Francis. Among the SCCPs, C13 and among the MCCPs C14 were the dominant chain length alkanes, with C14 being the highest among both groups. The SCCPs and MCCPs profiles suggest that they can be used to distinguish between sites impacted by local sources vs. sites impacted by short-/long-range transport of these chemicals.

Payment Innovation in Emergency Care: A Case for Global Clinician Budgets.

The fee-for-service funding model for US emergency department (ED) clinician groups is increasingly fragile. Traditional fee-for-service payment systems offer no financial incentives to improve quality, address population health, or make value-based clinical decisions. Fee-for-service also does not support maintaining ED capacity to handle peak demand periods. In fee-for-service, clinicians rely heavily on cross-subsidization, where high reimbursement from commercial payors offsets low reimbursement from government payors and the uninsured. Although fee-for-service survived decades of steady cuts in government reimbursement rates, it is increasingly strained because of visit volatility and the effects of the No Surprises Act, which is driving down commercial reimbursement. Financial pressures on ED clinician groups and higher hospital boarding and clinical workloads are increasing workforce attrition. Here, we propose an alternative model to address some of these fundamental issues: an all-payer-funded, voluntary global budget for ED clinician services. If designed and implemented effectively, the model could support robust clinician staffing over the long term, ensure stability in clinical workload, and potentially improve equity in payments. The model could also be combined with population health programs (eg, pre-ED and post-ED telehealth, frequent ED use programs, and other innovations), offering significant payer returns and addressing quality and value. A linked program could also change hospital incentives that contribute to boarding. Strategies exist to test and refine ED clinician global budgets through existing government programs in Maryland and potentially through state-level legislation as a precursor to broader adoption.

Examining the Associations Between Substance Misuse and Suicide Bereavement.

Focusing on the understudied question of substance misuse among suicide bereaved adults we investigated patterns of binge drinking and non-prescribed drug use among a recently bereaved sample (n = 1,132). Comparing our respondents to the non-bereaved, those in the 2022 National Survey of Drug Use and Health (n = 71,369), we did not find heightened problematical substance misuses among our respondents. With t-tests and multiple regression analyses we examined whether binge drinkers and non-prescribed drug users had heightened levels of grief difficulties, PTSD, self-blaming and depression compared to others not bingeing or using non-prescribed drugs. Results showed binge drinkers had more of all these grieving problems when important confounding variables were also considered. Analysis of the demographic correlates of bingeing showed them dimly aware of their own additional grieving and substance misusing problems. Since 75% indicated being under the care of counseling professionals, this represents an important opportunity for psycho-educational helping.

Radiation-induced alteration of apatite on the surface of Mars: first in situ observations with SuperCam Raman onboard Perseverance.

Planetary exploration relies considerably on mineral characterization to advance our understanding of the solar system, the planets and their evolution. Thus, we must understand past and present processes that can alter materials exposed on the surface, affecting space mission data. Here, we analyze the first dataset monitoring the evolution of a known mineral target in situ on the Martian surface, brought there as a SuperCam calibration target onboard the Perseverance rover. We used Raman spectroscopy to monitor the crystalline state of a synthetic apatite sample over the first 950 Martian days (sols) of the Mars2020 mission. We note significant variations in the Raman spectra acquired on this target, specifically a decrease in the relative contribution of the Raman signal to the total signal. These observations are consistent with the results of a UV-irradiation test performed in the laboratory under conditions mimicking ambient Martian conditions. We conclude that the observed evolution reflects an alteration of the material, specifically the creation of electronic defects, due to its exposure to the Martian environment and, in particular, UV irradiation. This ongoing process of alteration of the Martian surface needs to be taken into account for mineralogical space mission data analysis.

Defining Incidental Versus Non-incidental COVID-19 Hospitalizations.

Background Rates of COVID-19 hospitalization are an important measure of the health system burden of severe COVID-19 disease and have been closely followed throughout the pandemic. The highly transmittable, but often less severe, Omicron COVID-19 variant has led to an increase in hospitalizations with incidental COVID-19 diagnoses where COVID-19 is not the primary reason for admission. There is a strong public health need for a measure that is implementable at low cost with standard electronic health record (EHR) datasets that can separate these incidental hospitalizations from non-incidental hospitalizations where COVID-19 is the primary cause or an important contributor. Two crude metrics are in common use. The first uses in-hospital administration of dexamethasone as a marker of non-incidental COVID-19 hospitalizations. The second, used by the United States (US) CDC, relies on a limited set of COVID-19-related diagnoses (i.e., respiratory failure, pneumonia). Both measures likely undercount non-incidental COVID-19 hospitalizations. We therefore developed an improved EHR-based measure that is better able to capture the full range of COVID-19 hospitalizations. Methods We conducted a retrospective study of ED visit data from a national emergency medicine group from April 2020 to August 2023. We assessed the CDC approach, the dexamethasone-based measure, and alternative approaches that rely on co-diagnoses likely to be related to COVID-19, to determine the proportion of non-incidental COVID-19 hospitalizations. Results Of the 153,325 patients diagnosed with COVID-19 at 112 general EDs in 17 US states, and admitted or transferred, our preferred measure classified 108,243 (70.6%) as non-incidental, compared to 71,066 (46.3%) using the dexamethasone measure and 77,399 (50.5%) using the CDC measure. Conclusions Identifying non-incidental COVID-19 hospitalizations using ED administration of dexamethasone or the CDC measure provides substantially lower estimates than our preferred measure.

Implicit relational aspects of the therapeutic relationship in psychoanalytic treatments: an examination of linguistic style entrainment over time.

OBJECTIVE: In an attempt to operationalize an implicit aspect of the therapeutic relationship, this study assesses reciprocal linguistic style entrainment (rLSM) between the patient and therapist. rLSM is defined as the dynamic adjustment of function word usage to synchronize or to be in rhythm with another person as they change over time. METHOD: In this exploratory study, levels of rLSM per talk turn were analyzed for 540 sessions of 27 long-term psychoanalytic treatments in relation to treatment outcomes. RESULTS: Within sessions, rLSM appeared to decrease by the end of sessions and followed a negative linear trajectory, ßlinear = -0.0002, SE < .001, t = -13.04, p < .001. Between sessions, rLSM showed significant variability such that neither a linear, nor a quadratic, nor a cubic trend line fit the session-by-session change over treatment. On average, therapist talk turns had significantly lower rLSM than patient talk turns, while accounting for the nested nature of the data using multilevel models ßSpeakerT = -0.033, SE = 0.009, t = -3.65, p < .001. Levels of rLSM did not relate to treatment outcome. CONCLUSION: Most of the rLSM variance was at the within-patient and within-session level. rLSM was no indicator of psychoanalytic treatment outcomes.

Cardiac allograft vasculopathy in heart transplant recipients from hepatitis C viremic donors.

BACKGROUND: Recent studies suggest the transplantation of Hepatitis C (HCV) hearts from viremic donors is associated with comparable 1 year survival to nonviremic donors. Though HCV viremia is a known risk factor for accelerated atherosclerosis, data on cardiac allograft vasculopathy (CAV) outcomes are limited. We compared the incidence of CAV in heart transplant recipients from HCV viremic donors (nucleic acid amplification test positive; NAT+) compared to non-HCV infected donors (NAT-). METHODS: We retrospectively reviewed annual coronary angiograms with intravascular ultrasound from April 2017 to August 2020 at two large cardiac transplant centers. CAV was graded according to ISHLT guidelines. Maximal intimal thickness (MIT) ≥ 0.5 mm was considered significant for subclinical disease. RESULTS: Among 270 heart transplant recipients (mean age 54; 77% male), 62 patients were transplanted from NAT+ donors. CAV ≥ grade 1 was present in 8.8% of the NAT+ versus 16.8% of the NAT- group at 1 year, 20% versus 28.8% at 2 years, and 33.3% versus 41.5% at 3 years. After adjusting for donor age, donor smoking history, recipient BMI, recipient, hypertension, and recipient diabetes, NAT+ status did not confer increased risk of CAV (HR.80; 95% CI.45-1.40, p = 0.43) or subclinical IVUS disease (HR.87; 95% CI.58-1.30, p = 0.49). Additionally, there was no difference in the presence of rapidly progressive lesions on IVUS. CONCLUSION: Our data show that NAT+ donors conferred no increased risk for early CAV or subclinical IVUS disease following transplantation in a cohort of heart transplant patients who were treated for HCV, suggesting the short-term safety of this strategy to maximize the pool of available donor hearts.

Role of phosphatidic acid lipids on plasma membrane association of the Ebola virus matrix protein VP40.

The Ebola virus matrix protein VP40 is responsible for the formation of the viral matrix by localizing at the inner leaflet of the human plasma membrane (PM). Various lipid types, including PI(4,5)P2 (i.e. PIP2) and phosphatidylserine (PS), play active roles in this process. Specifically, the negatively charged headgroups of both PIP2 and PS interact with the basic residues of VP40 and stabilize it at the membrane surface, allowing for eventual egress. Phosphatidic acid (PA), resulting from the enzyme phospholipase D (PLD), is also known to play an active role in viral development. In this work, we performed a biophysical and computational analysis to investigate the effects of the presence of PA on the membrane localization and association of VP40. We used coarse-grained molecular dynamics simulations to quantify VP40 hexamer interactions with the inner leaflet of the PM. Analysis of the local distribution of lipids shows enhanced lipid clustering when PA is abundant in the membrane. We observed that PA lipids have a similar role to that of PS lipids in VP40 association due to the geometry and charge. Complementary experiments performed in cell culture demonstrate competition between VP40 and a canonical PA-binding protein for the PM. Also, inhibition of PA synthesis reduced the detectable budding of virus-like particles. These computational and experimental results provide new insights into the early stages of Ebola virus budding and the role that PA lipids have on the VP40-PM association.

Pharmacokinetics, pharmacodynamics, and toxicity of a PD-1-targeted IL-15 in cynomolgus monkeys.

PF-07209960 is a novel bispecific fusion protein composed of an anti-PD-1 antibody and engineered IL-15 cytokine mutein with reduced binding affinity to its receptors. The pharmacokinetics (PK), pharmacodynamics (PD), and toxicity of PF-07209960 were evaluated following once every other week subcutaneous (SC) or intravenous (IV) administration to cynomolgus monkeys in a repeat-dose PKPD (0.01-0.3 mg/kg/dose) and GLP toxicity study (0.1-3 mg/kg/dose). PF-07209960 showed dose dependent pharmacokinetics with a terminal T1/2 of 8 and 13 hours following IV administration at 0.03 and 0.1 mg/kg, respectively. The clearance is faster than a typical IgG1 antibody. Slightly faster clearance was also observed following the second dose, likely due to increased target pool and formation of anti-drug antibodies (ADA). Despite a high incidence rate of ADA (92%) observed in GLP toxicity study, PD-1 receptor occupancy, IL-15 signaling (STAT5 phosphorylation) and T cell expansion were comparable following the first and second doses. Activation and proliferation of T cells were observed with largest increase in cell numbers found in gamma delta T cells, followed by CD4+ and CD8+ T cells, and then NK cells. Release of cytokines IL-6, IFNγ, and IL-10 were detected, which peaked at 72 hours postdose. There was PF-07209960-related mortality at ≥1 mg/kg. At scheduled necropsy, microscopic findings were generalized mononuclear infiltration in various tissues. Both the no observed adverse effect level (NOAEL) and the highest non severely toxic dose (HNSTD) were determined to be 0.3 mg/kg/dose, which corresponded to mean Cmax and AUC48 values of 1.15 µg/mL and 37.9 µg*h/mL, respectively.

Red blood cell-derived arginase release in hemolytic uremic syndrome.

BACKGROUND: Hemolysis is a cardinal feature of hemolytic uremic syndrome (HUS) and during hemolysis excess arginase 1 is released from red blood cells. Increased arginase activity leads to reduced L-arginine, as it is converted to urea and L-ornithine, and thereby reduced nitric oxide bioavailability, with secondary vascular injury. The objective of this study was to investigate arginase release in HUS patients and laboratory models and correlate arginase levels to hemolysis and kidney injury. METHODS: Two separate cohorts of patients (n = 47 in total) with HUS associated with Shiga toxin-producing enterohemorrhagic E. coli (EHEC) and pediatric controls (n = 35) were investigated. Two mouse models were used, in which mice were either challenged intragastrically with E. coli O157:H7 or injected intraperitoneally with Shiga toxin 2. An in vitro model of thrombotic microangiopathy was developed in which Shiga toxin 2- and E. coli O157 lipopolysaccharide-stimulated human blood cells combined with ADAMTS13-deficient plasma were perfused over glomerular endothelial cells. Two group statistical comparisons were performed using the Mann-Whitney test, multiple groups were compared using the Kruskal-Wallis test followed by Dunn's procedure, the Wilcoxon signed rank test was used for paired data, or linear regression for continuous variables. RESULTS: HUS patients had excessively high plasma arginase 1 levels and activity (conversion of L-arginine to urea and L-ornithine) during the acute phase, compared to remission and controls. Arginase 1 levels correlated with lactate dehydrogenase activity, indicating hemolysis, as well as the need for dialysis treatment. Patients also exhibited high levels of plasma alpha-1-microglobulin, a heme scavenger. Both mouse models exhibited significantly elevated plasma arginase 1 levels and activity. Plasma arginase 1 levels correlated with lactate dehydrogenase activity, alpha-1-microglobulin and urea levels, the latter indicative of kidney dysfunction. In the in vitro model of thrombotic microangiopathy, bioactive arginase 1 was released and levels correlated to the degree of hemolysis. CONCLUSIONS: Elevated red blood cell-derived arginase was demonstrated in HUS patients and in relevant in vivo and in vitro models. The excessively high arginase levels correlated to the degree of hemolysis and kidney dysfunction. Thus, arginase inhibition should be investigated in HUS.

PI(4,5)P2 binding sites in the Ebola virus matrix protein VP40 modulate assembly and budding.

Ebola virus (EBOV) causes severe hemorrhagic fever in humans and is lethal in a large percentage of those infected. The EBOV matrix protein viral protein 40 kDa (VP40) is a peripheral binding protein that forms a shell beneath the lipid bilayer in virions and virus-like particles (VLPs). VP40 is required for virus assembly and budding from the host cell plasma membrane. VP40 is a dimer that can rearrange into oligomers at the plasma membrane interface, but it is unclear how these structures form and how they are stabilized. We therefore investigated the ability of VP40 to form stable oligomers using in vitro and cellular assays. We characterized two lysine-rich regions in the VP40 C-terminal domain (CTD) that bind phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) and play distinct roles in lipid binding and the assembly of the EBOV matrix layer. The extensive analysis of VP40 with and without lipids by hydrogen deuterium exchange mass spectrometry revealed that VP40 oligomers become extremely stable when VP40 binds PI(4,5)P2. The PI(4,5)P2-induced stability of VP40 dimers and oligomers is a critical factor in VP40 oligomerization and release of VLPs from the plasma membrane. The two lysine-rich regions of the VP40 CTD have different roles with respect to interactions with plasma membrane phosphatidylserine (PS) and PI(4,5)P2. CTD region 1 (Lys221, Lys224, and Lys225) interacts with PI(4,5)P2 more favorably than PS and is important for VP40 extent of oligomerization. In contrast, region 2 (Lys270, Lys274, Lys275, and Lys279) mediates VP40 oligomer stability via lipid interactions and has a more prominent role in release of VLPs.

Pre-hospital ECPR in an Australian metropolitan setting: a single-arm feasibility assessment-The CPR, pre-hospital ECPR and early reperfusion (CHEER3) study.

INTRODUCTION: Survival from refractory out of hospital cardiac arrest (OHCA) without timely return of spontaneous circulation (ROSC) utilising conventional advanced cardiac life support (ACLS) therapies is dismal. CHEER3 was a safety and feasibility study of pre-hospital deployed extracorporeal membrane oxygenation (ECMO) during cardiopulmonary resuscitation (ECPR) for refractory OHCA in metropolitan Australia. METHODS: This was a single jurisdiction, single-arm feasibility study. Physicians, with pre-existing ECMO expertise, responded to witnessed OHCA, age < 65 yrs, within 30 min driving-time, using an ECMO equipped rapid response vehicle. If pre-hospital ECPR was undertaken, patients were transported to hospital for investigations and therapies including emergent coronary catheterisation, and standard intensive care (ICU) therapy until either cardiac and neurological recovery or palliation occurred. Analyses were descriptive. RESULTS: From February 2020 to May 2023, over 117 days, the team responded to 709 "potential cardiac arrest" emergency calls. 358 were confirmed OHCA. Time from emergency call to scene arrival was 27 min (15-37 min). 10 patients fulfilled the pre-defined inclusion criteria and all were successfully cannulated on scene. Time from emergency call to ECMO initiation was 50 min (35-62 min). Time from decision to ECMO support was 16 min (11-26 min). CPR duration was 46 min (32-62 min). All 10 patients were transferred to hospital for investigations and therapy. 4 patients (40%) survived to hospital discharge neurologically intact (CPC 1/2). CONCLUSION: Pre-hospital ECPR was feasible, using an experienced ECMO team from a single-centre. Overall survival was promising in this highly selected group. Further prospective studies are now warranted.

Divergent neuroimmune signatures in the cerebrospinal fluid predict differential gender-specific survival among patients with HIV-associated cryptococcal meningitis.

Introduction: Survival among people with HIV-associated cryptococcal meningitis (CM) remains low, particularly among women, despite the currently optimal use of antifungal drugs. Cryptococcus dissemination into the central nervous system [brain, spinal cord, and cerebrospinal fluid (CSF)] elicits the local production of cytokines, chemokines, and other biomarkers. However, no consistent diagnostic or prognostic neuroimmune signature is reported to underpin the risk of death or to identify mechanisms to improve treatment and survival. We hypothesized that distinct neuroimmune signatures in the CSF would distinguish survivors from people who died on antifungal treatment and who may benefit from tailored therapy. Methods: We considered baseline clinical features, CSF cryptococcal fungal burden, and CSF neuroimmune signatures with survival at 18 weeks among 419 consenting adults by "gender" (168 women and 251 men by biological sex defined at birth). Results: Survival at 18 weeks was significantly lower among women than among men {47% vs. 59%, respectively; hazard ratio (HR) = 1.4 [95% confidence interval (CI), 1.0 to 1.9; p = 0.023]}. Unsupervised principal component analysis (PCA) demonstrated divergent neuroimmune signatures by gender, survival, and intragender-specific survival. Overall, women had lower levels of programmed death ligand 1, Interleukin (IL) (IL-11RA/IL-1F30, and IL-15 (IL-15) than men (all p < 0.028). Female survivors compared with those who died expressed significant elevations in levels of CCL11 and CXCL10 chemokines (both p = 0.001), as well as increased T helper 1, regulatory, and T helper 17 cytokines (all p < 0.041). In contrast, male survivors expressed lower levels of IL-15 and IL-8 compared with men who died (p < 0.044). Conclusions: Survivors of both genders demonstrated a significant increase in the levels of immune regulatory IL-10. In conclusion, the lower survival among women with CM was accompanied by distinct differential gender-specific neuroimmune signatures. These female and male intragender-specific survival-associated neuroimmune signatures provide potential targets for interventions to advance therapy to improve the low survival among people with HIV-associated CM.

Transformation of Undergraduate Medical Education in 2023.

This Viewpoint discusses potential shifts in teaching and learning for undergraduate medical education with the advent of artificial intelligence tools.

Emergency Department Volume, Severity, and Crowding Since the Onset of the Coronavirus Disease 2019 Pandemic.

STUDY OBJECTIVE: We describe emergency department (ED) visit volume, illness severity, and crowding metrics from the onset of the coronavirus disease 2019 (COVID-19) pandemic through mid-2022. METHODS: We tabulated monthly data from 14 million ED visits on ED volumes and measures of illness severity and crowding from March 2020 through August 2022 compared with the same months in 2019 in 111 EDs staffed by a national ED practice group in 18 states. RESULTS: Average monthly ED volumes fell in the early pandemic, partially recovered in 2022, but remained below 2019 levels (915 per ED in 2019 to 826.6 in 2022 for admitted patients; 3,026.9 to 2,478.5 for discharged patients). The proportion of visits assessed as critical care increased from 7.9% in 2019 to 11.0% in 2022, whereas the number of visits decreased (318,802 to 264,350). Visits billed as 99285 (the highest-acuity Evaluation and Management code for noncritical care visits) increased from 35.4% of visits in 2019 to 40.0% in 2022, whereas the number of visits decreased (1,434,454 to 952,422). Median and median of 90th percentile length of stay for admitted patients rose 32% (5.2 to 6.9 hours) and 47% (11.7 to 17.4 hours) in 2022 versus 2019. Patients leaving without treatment rose 86% (2.9% to 5.4%). For admitted psychiatric patients, the 90th percentile length of stay increased from 20 hours to more than 1 day. CONCLUSION: ED visit volumes fell early in the pandemic and have only partly recovered. Despite lower volumes, ED crowding has increased. This issue is magnified in psychiatric patients.