Considerations for Designing and Implementing a Multi-institution Undergraduate Medical Education Experience.

Cancer Care Experience (CCE) is a unique elective educational program to further explore the subspecialty of oncology beyond the scope of the traditional undergraduate medical education curriculum. During the COVID-19 pandemic, CCE moved from an in-person to a virtual learning platform. This transition allowed program leaders to offer CCE as a multi-institutional program, with students participating from both Duke University School of Medicine and Penn State College of Medicine. Our study aimed to investigate the effectiveness of virtual learning, student perspectives on multi-institutional collaboration, and the program's impact on the student's understanding of oncology care and clerkship preparedness. Overall, students indicated CCE was an impactful program for them to learn more about oncology and that virtual learning was an effective learning platform. Furthermore, our results suggest students found the multi-institutional aspect valuable and that a multi-institution, hybrid (in-person and virtual) platform was preferred. Our study highlights the success of CCE as a multi-institution program and an effective elective program to expose students to the field of oncology further.

Cervical Collar Clearance in Obtunded Children Presenting Without a Known Traumatic Mechanism: Is Imaging Necessary?

BACKGROUND: Obtunded pediatric patients are often placed in cervical collars (c-collars) to protect their cervical spine (c-spine) while injury is being ruled out, even without a known traumatic injury. The goal of this study was to determine the necessity of c-collars in this population by determining the rate of c-spine injury among patients with suspected non-traumatic mechanisms of loss of consciousness. METHODS: A single institution, ten-year retrospective chart review was conducted including all obtunded patients admitted to the Pediatric Intensive Care Unit without a known traumatic event. Patients were categorized into five groups based on etiology of obtundation: respiratory, cardiac, medical/metabolic, neurologic, and other. Comparisons were made between those placed in a c-collar and a control group who were not, using Wilcoxon rank sum test for continuous measures, and Chi-square or Fisher's exact test for categorical measures. RESULTS: 464 patients were included, of which 39 (8.41%) were placed in a c-collar. There was a significant difference in whether a patient was placed in a c-collar based on diagnosis category (p < 0.001). Those placed in a-c-collar were more likely to undergo imaging studies than the control group (p < 0.001). The overall incidence of c-spine injury in this patient population in our study was zero. CONCLUSION: Cervical collar placement and radiographic evaluation is not necessary in obtunded pediatric patients who present without a known traumatic mechanism as the overall risk of injury is low. Consideration for collar placement should be given in cases when trauma cannot be definitively ruled out at initial evaluation. LEVELS OF EVIDENCE: III.

Prevalence, predictors, and prognosis of mortality among elderly stroke patients with convulsive status epilepticus in the United States.

BACKGROUND: Stroke is the most common cause of epilepsy in the elderly. However, despite the high mortality typically associated with convulsive status epilepticus (CSE), there is a dearth of nationwide data on the magnitude and association of CSE with mortality among hospitalized elderly with stroke in the United States. METHODS: We analyzed the 2006-2014 National Inpatient Sample (NIS) to identify elderly patients (65+ years) with a primary discharge diagnosis of stroke using the International Classification of Diseases, Ninth Revision-Clinical Modification (ICD-9-CM) codes 433.X1, 434.X1, 436, 430, 431, 432.0, 432.1, and 432.9. We examined a subgroup with a secondary discharge diagnosis of convulsive status epilepticus (ICD-9-CM: 345.3). We estimated the hospital mortality rate by CSE status and then evaluated the independent association of CSE and other key factors with mortality among hospitalized elderly with stroke. RESULTS: A total of 1220 elderly patients (0.14%) had a secondary discharge diagnosis of CSE. Inpatient mortality rate was 25.8% among those with CSE vs. 7.7% for non-CSE patients. CSE was independently associated with a 4-fold increased odds of in-hospital death. Increased age, medical comorbidities, weekend admissions, being a Medicare beneficiary, and hospitalization in large urban teaching hospitals were also independently associated with a greater likelihood of in-hospital death. The small number of events did not allow analysis by stroke subtypes. CONCLUSION: While CSE occurs in just 14 of 10,000 hospitalized elderly stroke patients in the United States, it is associated with a 4-fold higher odds of in-hospital death.

Clinical care of neonates undergoing opioid withdrawal in the immediate postpartum period.

As the opioid epidemic escalates in westernized countries around the world, chronic opioid use during pregnancy has become a growing public health issue. There are increasing concerns that chronic maternal opioid use might adversely affect the developing fetal brain. Furthermore, the sudden discontinuation of the trans-placental opioid supply at birth puts newborns at acute risk for neonatal opioid withdrawal syndrome (NOWS). NOWS is a multi-system disorder that has been identified in approximately 50-80% of neonates exposed to opioids due to chronic maternal use. Clinically, NOWS affects the central and autonomic nervous systems as well as the gastrointestinal and respiratory tracts. The clinical features of NOWS include hyperirritability, high-pitched crying, restlessness, tremors, poor sleep, agitation, seizures, sweating, fever, poor feeding, regurgitation, diarrhea, and tachypnea. NOWS is currently diagnosed using a clinical scoring tool followed by toxicological confirmation of the presence of opioids in meconium or tissue specimens. The first-line treatments for NOWS are non-pharmacologic comfort measures. If these measures fail, neonates may be treated with opioids and/or sedatives. Since the severity of NOWS can be highly variable, it is quite difficult to predict which opioid-exposed neonates will require pharmacotherapy and prolonged hospitalization. Factors associated with maternal polysubstance use, including the use of illicit substances and tobacco, have been associated with the increased severity and duration of NOWS. Since neonates with NOWS are at increased risk for long-term adverse neurodevelopmental outcomes, ongoing monitoring beyond the neonatal period is essential.

NPC1-mTORC1 Signaling Couples Cholesterol Sensing to Organelle Homeostasis and Is a Targetable Pathway in Niemann-Pick Type C.

Lysosomes promote cellular homeostasis through macromolecular hydrolysis within their lumen and metabolic signaling by the mTORC1 kinase on their limiting membranes. Both hydrolytic and signaling functions require precise regulation of lysosomal cholesterol content. In Niemann-Pick type C (NPC), loss of the cholesterol exporter, NPC1, causes cholesterol accumulation within lysosomes, leading to mTORC1 hyperactivation, disrupted mitochondrial function, and neurodegeneration. The compositional and functional alterations in NPC lysosomes and nature of aberrant cholesterol-mTORC1 signaling contribution to organelle pathogenesis are not understood. Through proteomic profiling of NPC lysosomes, we find pronounced proteolytic impairment compounded with hydrolase depletion, enhanced membrane damage, and defective mitophagy. Genetic and pharmacologic mTORC1 inhibition restores lysosomal proteolysis without correcting cholesterol storage, implicating aberrant mTORC1 as a pathogenic driver downstream of cholesterol accumulation. Consistently, mTORC1 inhibition ameliorates mitochondrial dysfunction in a neuronal model of NPC. Thus, cholesterol-mTORC1 signaling controls organelle homeostasis and is a targetable pathway in NPC.

Antidepressant actions of histone deacetylase inhibitors.

Persistent symptoms of depression suggest the involvement of stable molecular adaptations in brain, which may be reflected at the level of chromatin remodeling. We find that chronic social defeat stress in mice causes a transient decrease, followed by a persistent increase, in levels of acetylated histone H3 in the nucleus accumbens, an important limbic brain region. This persistent increase in H3 acetylation is associated with decreased levels of histone deacetylase 2 (HDAC2) in the nucleus accumbens. Similar effects were observed in the nucleus accumbens of depressed humans studied postmortem. These changes in H3 acetylation and HDAC2 expression mediate long-lasting positive neuronal adaptations, since infusion of HDAC inhibitors into the nucleus accumbens, which increases histone acetylation, exerts robust antidepressant-like effects in the social defeat paradigm and other behavioral assays. HDAC inhibitor [N-(2-aminophenyl)-4-[N-(pyridine-3-ylmethoxy-carbonyl)aminomethyl]benzamide (MS-275)] infusion also reverses the effects of chronic defeat stress on global patterns of gene expression in the nucleus accumbens, as determined by microarray analysis, with striking similarities to the effects of the standard antidepressant fluoxetine. Stress-regulated genes whose expression is normalized selectively by MS-275 may provide promising targets for the future development of novel antidepressant treatments. Together, these findings provide new insight into the underlying molecular mechanisms of depression and antidepressant action, and support the antidepressant potential of HDAC inhibitors and perhaps other agents that act at the level of chromatin structure.

Storage and binding of object features in visual working memory.

An influential conception of visual working memory is of a small number of discrete memory "slots", each storing an integrated representation of a single visual object, including all its component features. When a scene contains more objects than there are slots, visual attention controls which objects gain access to memory. A key prediction of such a model is that the absolute error in recalling multiple features of the same object will be correlated, because features belonging to an attended object are all stored, bound together. Here, we tested participants' ability to reproduce from memory both the color and orientation of an object indicated by a location cue. We observed strong independence of errors between feature dimensions even for large memory arrays (6 items), inconsistent with an upper limit on the number of objects held in memory. Examining the pattern of responses in each dimension revealed a gaussian distribution of error centered on the target value that increased in width under higher memory loads. For large arrays, a subset of responses were not centered on the target but instead predominantly corresponded to mistakenly reproducing one of the other features held in memory. These misreporting responses again occurred independently in each feature dimension, consistent with 'misbinding' due to errors in maintaining the binding information that assigns features to objects. The results support a shared-resource model of working memory, in which increasing memory load incrementally degrades storage of visual information, reducing the fidelity with which both object features and feature bindings are maintained.

A role for repressive histone methylation in cocaine-induced vulnerability to stress.

Substance abuse increases an individual's vulnerability to stress-related illnesses, which is presumably mediated by drug-induced neural adaptations that alter subsequent responses to stress. Here, we identify repressive histone methylation in nucleus accumbens (NAc), an important brain reward region, as a key mechanism linking cocaine exposure to increased stress vulnerability. Repeated cocaine administration prior to subchronic social defeat stress potentiated depressive-like behaviors in mice through decreased levels of histone H3 lysine 9 dimethylation in NAc. Cre-mediated reduction of the histone methyltransferase, G9a, in NAc promoted increased susceptibility to social stress, similar to that observed with repeated cocaine. Conversely, G9a overexpression in NAc after repeated cocaine protected mice from the consequences of subsequent stress. This resilience was mediated, in part, through repression of BDNF-TrkB-CREB signaling, which was induced after repeated cocaine or stress. Identifying such common regulatory mechanisms may aid in the development of new therapies for addiction and depression.