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Compassionate behavior, or the ability to help others in need, is a cornerstone of prosocial interactions. To benefit others, it is necessary for individuals not only to perceive the internal states or emotions of others but also to take appropriate actions. Yet, how mammalian neurons precisely link social-specific information with adaptive behavior has been a major challenge to understand. Here, we developed a place-preference assay that allowed mice to directly control in real-time the experience of a nearby conspecific partner while also allowing the animal’s own actions to be dissociated from the other’s identity. Behaviorally, we found that wild-type male mice consistently chose to reduce aversive experiences of familiar but not unfamiliar partners, actions not observed when visual and olfactory cues were blocked. By recording from anterior insular (AI) neurons, we identified cells that encoded task relevant information, including the social identity of the animal’s partners and their specific experiences. Dorsal anterior cingulate (dACC) neurons, by contrast, preferentially encoded information about the act of helping their partners, displaying changes in activity prior to making their decisions. Further, whereas information about the experience of others could be predominantly decoded from AI activity, information about the animal’s prosocial actions could be predominantly decoded from dACC activity; demonstrating a partitioning of information within the insular-prefrontal circuit. Finally, chemogenetic excitation of AI-to-dACC projectors but not dACC-to-AI projections increased compassionate behavior while inhibitions of both dACC to AI as well as AI to dACC projectors, on the other hand, decreased this behavior with familiar partners. Taken together, these findings identify a putative insular-prefrontal circuit for driving compassionate behavior and a mechanism that could allow insular neurons to instruct social-specific actions through prefrontal control.

AMA Research Challenge 2022

Insular-prefrontal circuit driving compassionate social behavior

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The 44th Annual Meeting of the Cognitive Science Society highlighted research on the theme Cognitive Diversity in addition to the full breadth and diversity of research topics offered by the society’s membership. 





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Welcome to the largest national, multi-specialty research event featuring research from 750 medical students, residents and fellows, and international medical graduates.


Background: Pneumocystis jirovecii pneumonia (PJP) remains a cause of mortality in HIV-negative patients. The clinical benefit of adjuvant corticosteroids in these patients is uncertain. This study aimed to determine if corticosteroids reduced mortality in a cohort of HIV-negative PJP patients and to propose a novel mechanism explaining corticosteroid benefits in patients regardless of HIV status. 
Methods: We examined a retrospective case series of patients diagnosed with PJP at the University of Colorado Hospital between 1995-2019. Data were collected from 71 PJP-infected patients. Twenty-eight patients were HIV-negative, and 43 were infected with HIV. We performed bivariate and forward, stepwise multivariable logistic regressions to identify predictors of mortality. 
Results: Common underlying conditions in HIV-negative patients were hematologic malignancies (28.6%), autoimmune disorders (25.9%), or solid organ transplantation (10.7%). HIV-negative patients had higher rates and duration of mechanical ventilation and ICU stay. Survival was significantly increased in HIV-negative patients receiving adjunct corticosteroids, with 100% mortality in patients not receiving corticosteroids vs 60% mortality in patients receiving corticosteroids (p=0.034). In an adjusted multivariable model, corticosteroids were associated with lower mortality (OR 13.5, 95% CI: 1.1-158.5, p= 0.039) regardless of HIV status. We propose corticosteroids reduce immune-mediated lysis of Pneumocystis organisms that curtails the surfactant-disabling effect of PJP internal contents. 
Conclusions: We found substantial mortality among HIV-negative patients with PJP, and adjuvant corticosteroid use was associated with decreased mortality. Decreased PJP lysis reduces surfactant disruption resulting from pneumocystis internal substances. Suppressing pneumocystis lysis best explains the adjuvant corticosteroid mortality-lowering effect.


Lower mortality associated with adjuvant corticosteroid therapy in non-HIV infected patients with pneumocystis jirovecii pneumonia

Background: Total knee arthroplasty (TKA) was removed from the “Inpatient Only List”(IOL) in 2018, enabling access to outpatient TKA for a broader cohort of beneficiaries. The effect of this reimbursement policy across the U.S. has yet to be fully explored. Therefore, we aimed to: 1) quantify the annual volume of inpatient/outpatient primary TKAs; 2) compare patient characteristics before/after 2018; and 3) compare annual trends in 30-day-readmissions, 30-day- complications, and healthcare utilization parameters for inpatient/outpatient TKAs.

Methods: The American College of Surgeons-National Surgical Quality Improvement Program was reviewed (January 2010 - December 2020) for patients who underwent primary TKA (n=470,456). The primary outcome was annual volumes of inpatient/outpatient TKA. Secondary outcomes included 30-day-readmissions, 30-day-reoperations, and 30-day-major/minor complications. Demographic characteristics and healthcare utilization parameters were compared between cohorts via Chi-square goodness of fit tests. All analyses were performed using R version 4.2.1.

Results: Overall, 89% had inpatient TKA (n=416,972) and 11% had outpatient TKA (n=53,854). Between 2017 and 2020, the volume of outpatient TKA grew by 2,025% (1,019 to 20,633), while inpatient TKA decreased by 47% (61,874 to 29,280). Patients who had outpatient TKA after 2018 were older (p<0.001), predominantly male (p<0.001), more commonly White (p<0.001), and had a greater proportion of ASA class III (p<0.001). Overall, patients who had inpatient TKA had higher rates of 30-day readmissions, reoperations, and complications. Average LOS and non-home discharges decreased for both cohorts.

Conclusion: Outpatient TKA increased exponentially since its removal from the IOL. The observed changes in comorbidity profiles and the increase in volumes of outpatient TKA were not associated with a rise in cumulative 30-day readmissions and complications, supporting the continued implementation of outpatient TKA. Further research and policy endeavors should focus on enhancing outpatient care pathways and building tools to identify patients who would benefit from inpatient TKA.

Major National Shifts to Outpatient Total Knee Arthroplasties in The United States: A 10-year Trends Analysis Of Procedure Volumes, Complications, and Healthcare Utilizations (2010 to 2020)

Characterization of Salivary Extracellular Vesicles in Preterm Infants

Mosaic Chromosomal Alterations Increase Risk of MGUS and Multiple Myeloma

The aim of this study was to create an accurate risk stratification tool for Covid-19 admissions. We looked at data from 1093 patients admitted to a regional hospital in Michigan with the primary diagnosis of Covid-19. Through various statistical approaches we analyzed factors that lead to worse outcomes. We then combined our analysis to determine which predictive factor had a stronger influence on Covid-19 mortality. Our end goal is to use this data to drive clinical decision making by identifying patients at greater risk of worse outcomes.

Multifaceted, Data-Driven Approach for Characterization and Prediction of Covid-19 Morbidity and Mortality in Rural Health Care Facilities

Background: The purpose of this study was to define the prevalence of orthopaedic knee scooter (OKS)-related injuries, describe the patient perceptions of OKS safety and identify potential risk factors.
Methods: This single-surgeon prospective study enrolled 134 patients at a community-based orthopaedic clinic from 6/2020 to 4/2021. Our primary outcome informed an a priori power analysis. The prevalence of OKS-related injury, patient perceptions, and riskfactors were analyzed.
Results: The prevalence of patient falls was 37% (44/118, 95CI 29-46%), and the prevalence of patient injury was 15% (18/118, 95CI 10-23%). Sedentary lifestyle increased odds (OR = 4.67, 1.52-14.35 95CI) of OKS-related injury.
Conclusion: Despite a high prevalence of patient falls (37%), there is a low prevalence of injury (15%) and a favorable perception of OKS safety. Sedentary lifestyles may be a risk factor for OKS-related injury.

Orthopaedic Knee Scooter-Related Injury: Prevalence and Patient Safety Perception in a Prospective Cohort with Exploratory Risk Factor Analysis

Orthopaedic surgery, the NFL's biggest gateway drug: a case study

Background
Colorectal adenomas are precursors of colorectal cancer (CRC). Pro-inflammatory states associated with colorectal adenomas significantly predispose for colorectal tumorigenesis via upregulation of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) synthesis. The PGE2/COX-2 axis allows cancer cells to progress and evade attack from immune cells via increasing immunosuppressive cell activity, disrupting antigen-presenting and T-cell functions, and interrupting innate leukocyte responses. The purpose of this study was to demonstrate that PGE2 can upregulate expression of PD-1, an immunosuppressive signaling receptor, on THP-1-derived macrophages and CD8+ T-cells. 

Methods
THP-1 cells were differentiated into macrophages via phorbol 12-myristate-13-acetate (PMA) administration. Following serum starvation and incubation with three different concentrations of PGE2 (0.1μM, 0.3μM, and 1μM), the cells were analyzed with western blot and qRT-PCR. CD8+ T-cells were isolated from mice spleens using biotin-antibody cocktail and anti-biotin microbeads and then stimulated with rIL-2 and CD3/CD28 Dynabeads. The cells were serum starved, incubated with two different concentrations of PGE2 (0.1μM and 0.3μM), and analyzed utilizing flow cytometry and qRT-PCR.

Results
Western blot analysis of THP-1-derived macrophages incubated in 0.1μM, 0.3μM, and 1.0μM PGE2 demonstrated increased PD-1 expression. qRT-PCR analysis of THP-1-derived macrophages incubated in 0.1μM, 0.3μM, and 1.0μM PGE2 demonstrated 3.030-fold, 5.712-fold, and 2.683-fold increased PD-1 mRNA expression, respectively. qRT-PCR of mouse CD8+ T-cells incubated in 0.1μM and 0.3μM PGE2 demonstrated 1.874-fold and 9.594-fold increased PD-1 mRNA expression, respectively. Flow cytometry demonstrated that 9.14% and 9.35% of mouse CD8+ T-cells incubated in 0.1μM and 0.3μM PGE2 expressed PD-1, respectively, while 4.65% of control cells expressed PD-1. 

Conclusion
Our in vitro data shows PGE2 inducing PD-1 expression in THP-1-derived macrophages and mouse CD8+ T-cells. Greater PD-1 expression would allow cancer cells to progress safe from the host immune system. These data demonstrate that PGE2 produced in the colorectal tumor microenvironment promotes immune evasion by suppressing tumor-infiltrating CD8+ T-cell cytotoxicity and macrophage phagocytosis via induction of PD-1. Because of PGE2’s immunosuppressive effects, NSAIDs and COXIBs are effective at preventing and treating CRC by inhibiting PGE2 synthesis via COX-2 blockade.

PGE2 Promotes Colorectal Tumorigenesis via Increased PD-1 Expression on Macrophages and CD8+ T-Cells

Background: Pulmonary Artery Pulsatility index (PAPi) is calculated by pulmonary artery pulse pressure divided by central venous pressure and is directly proportional to right ventricular contractility and stroke volume, and inversely related to pulmonary artery afterload and filling pressures. While PAPi as a prognostic hemodynamic measure has been studied in various adult populations, including to predict right ventricular (RV) failure following left ventricular assist device (LVAD) implantation and to predict renal outcomes following heart transplant (HTx), it has not been evaluated in children post HTx. We hypothesize that PAPi will correlate with known hemodynamic parameters and predict acute kidney injury (AKI) following pediatric HTx.

Methods: Medical records and hemodynamic data were retrospectively reviewed for patients ≤18 years old undergoing HTx at a single center between 1/2007-9/2021. Subgroups by HTx indication were myopathy or congenital heart disease (CHD). PAPi was calculated at routine cardiac catheterizations initially following HTx, and at 6 months, 1 year, and 5 years post HTx, with normal being PAPi ≥2.0. Correlations between PAPi and established hemodynamic measures collected at post HTx catheterizations including right ventricular end diastolic pressure (RVEDp), thermodilution cardiac index (TDCI), and central venous pressure to pulmonary capillary wedge pressure ratio (CVP-to-PCWP ratio) were analyzed using linear regressions. Correlation between PAPi and AKI was analyzed using a Fischer’s Exact test. 

Results: Fifty-three children underwent HTx in myopathy (n=27) or CHD (n=26) subgroups. PAPi correlated with RVEDp (p<0.001), TDCI (p=0.004), and CVP-to-PCWP ratio (p<0.001). At 6 months post HTx, PAPi <2.0 was associated with increased incidence of AKI (n=12/53, p=0.047). In analyzing 5-year trends, the myopathy subgroup had a normal early PAPi with no significant change at any time point. However, the CHD subgroup had a normal early (2.12 ± 0.18) and 6 month (2.45 ± 0.25) PAPi, but had a decline to an abnormal PAPi at 1 year (1.98 ± 0.13) and 5 years post HTx (1.67 ± 0.16). This decline between the 6 month and 5-year catheterizations was statistically significant (p=0.048).

Conclusions: PAPi in children post HTx correlates with established hemodynamic parameters routinely collected post HTx and may serve as a marker predicting renal dysfunction 6 months post HTx. Following HTx, PAPi declined significantly for the CHD subgroup. These findings suggest that incorporating PAPi into existing risk models may substantially improve earlier implementation for advanced therapies, thus improving clinical outcomes. PAPi as a comprehensive prognostic hemodynamic measure post pediatric HTx should be investigated in a larger multi-center study.


Pulmonary Artery Pulsatility Index After Pediatric Heart Transplant

Background
Rett Syndrome (RTT) is a pervasive neurodevelopmental disorder affecting females. RTT results from loss of function mutations in the X-linked gene Methyl CpG Binding Protein 2 (MeCP2*). MeCP2 encodes for the eponymously named protein, a ubiquitously expressed transcription factor critical for neuronal development and mature synapse maintenance. However, this pathogenesis is complicated by unequal mutation distribution; heterozygous mosaicism, one X-chromosome in each cell in lionized, results in a patchwork pattern of protein expression. Differences in the number, type, and location of MeCP2-deficient cells likely underlies the phenotype spectrum among the RTT patients. Whether some cells are more dependent on MeCP2, and therefore contribute more to clinical symptomatology or severity, is unknown. Here we explore that hypothesis in the context of impaired perceptive communication. 

Methods
We used Cre-lox genetic mouse lines to examine the consequences of cell-type restricted Mecp2 mutation to perception of naturally produced ultrasonic vocalizations (USVs). We employed infant pup retrieval behavior as a learned and ecologically relevant readout of auditory perception. Adult rodents naturally learn this behavior in response to pup USVs. We collected electrophysiology recordings and conducted calcium imaging to identify single neuron firing and neuronal population activity patterns in the auditory cortex during retrieval behavior and during passive playback of USVs. 

Results
Cortical cell type identity dictated MeCP2 dependence for supporting auditory processing. Mecp2 mutation restricted to parvalbumin positive (PV) inhibitory interneurons (IN) impaired pup retrieval behavior. However, mutation restricted to somatostatin- or vasoactive-intestinal-peptide- positive IN had no such effect. The inability of PV-Mecp2 mutants to response behaviorally to USVs resulted from degraded stimulus-driven neuronal activity in the auditory cortex, both at the single unit and population levels. That is, PV-restricted Mecp2 mutation impaired inhibitory cortical plasticity.

Conclusion
Our findings demonstrate a disproportionate dependence among cortical cell populations on MeCP2. This argues for cell-type specific pharmacological or genetic therapies, and a personalized medicine approach to the treatment of mosaic genetic disorders, including RTT. Moreover, these findings expand our understanding of neurotypical processes of audition and the contributions of various cortical subtype populations to those processes.

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