A Novel Case-Based Learning Activity With a Focus on Food Insecurity.

OBJECTIVE: Food insecurity is a social determinant of health (SDOH) affecting 1 in 10 households per year in the United States and has major impacts on the course of chronic health conditions. It is beneficial to introduce screening and appropriate treatment plans to medical students. This study utilized a novel case-based learning exercise (CBLE) to assess confidence, attitudes and improvements in knowledge on recognizing and addressing food insecurity. METHODS: A CBLE focused on food insecurity was developed to be implemented in a 2-h session as part of the curriculum for all first-year medical students at the Medical University of South Carolina. The CBLE included a case for discussion, followed by an interview with a standardized patient. Students received invitations to complete pre- and post-CBLE assessment surveys. RESULTS: Completion of both pre- and post-surveys was achieved by 29% of students (48 out of 166). Knowledge around the formal definition of "food insecurity," how to recognize food insecurity versus hunger, and how to screen for food insecurity all increased significantly (P < .05). Responses relating to the association between certain chronic diseases and food insecurity did not change pre and post-CBLE. CONCLUSION: This novel CBLE was successfully implemented within a 2-h teaching session and improved knowledge on recognizing food insecurity in practice. However, additional learning exercises are likely needed to improve knowledge of the relationship between food insecurity and chronic disease states. Nonetheless, the CBLE structure provided students with multiple formats of learning and integration of skills, which shows promise and may be applicable to improve knowledge of other SDOHs.

Valosin-containing protein (VCP/p97) is prognostically unfavorable in pediatric AML, and negatively correlates with unfolded protein response proteins IRE1 and GRP78: A report from the Children's Oncology Group.

PURPOSE: The endoplasmic reticulum (ER) is the major site of protein synthesis and folding in the cell. ER-associated degradation (ERAD) and unfolded protein response (UPR) are the main mechanisms of ER-mediated cell stress adaptation. Targeting the cell stress response is a promising therapeutic approach in acute myeloid leukemia (AML). EXPERIMENTAL DESIGN: Protein expression levels of valosin-containing protein (VCP), a chief element of ERAD, were measured in peripheral blood samples from in 483 pediatric AML patients using reverse phase protein array methodology. Patients participated in the Children's Oncology Group AAML1031 phase 3 clinical trial that randomized patients to standard chemotherapy (cytarabine (Ara-C), daunorubicin, and etoposide [ADE]) versus ADE plus bortezomib (ADE+BTZ). RESULTS: Low-VCP expression was significantly associated with favorable 5-year overall survival (OS) rate compared to middle-high-VCP expression (81% versus 63%, p < 0.001), independent of additional bortezomib treatment. Multivariable Cox regression analysis identified VCP as independent predictor of clinical outcome. UPR proteins IRE1 and GRP78 had significant negative correlation with VCP. Five-year OS in patients characterized by low-VCP, moderately high-IRE1 and high-GRP78 improved after treatment with ADE+BTZ versus ADE (66% versus 88%, p = 0.026). CONCLUSION AND CLINICAL RELEVANCE: Our findings suggest the potential of the protein VCP as biomarker in prognostication prediction in pediatric AML.

Reverse Phase Protein Array Profiling Identifies Recurrent Protein Expression Patterns of DNA Damage-Related Proteins across Acute and Chronic Leukemia: Samples from Adults and the Children's Oncology Group.

DNA damage response (DNADR) recognition and repair (DDR) pathways affect carcinogenesis and therapy responsiveness in cancers, including leukemia. We measured protein expression levels of 16 DNADR and DDR proteins using the Reverse Phase Protein Array methodology in acute myeloid (AML) (n = 1310), T-cell acute lymphoblastic leukemia (T-ALL) (n = 361) and chronic lymphocytic leukemia (CLL) (n = 795) cases. Clustering analysis identified five protein expression clusters; three were unique compared to normal CD34+ cells. Individual protein expression differed by disease for 14/16 proteins, with five highest in CLL and nine in T-ALL, and by age in T-ALL and AML (six and eleven proteins, respectively), but not CLL (n = 0). Most (96%) of the CLL cases clustered in one cluster; the other 4% were characterized by higher frequencies of deletion 13q and 17p, and fared poorly (p < 0.001). T-ALL predominated in C1 and AML in C5, but both occurred in all four acute-dominated clusters. Protein clusters showed similar implications for survival and remission duration in pediatric and adult T-ALL and AML populations, with C5 doing best in all. In summary, DNADR and DDR protein expression was abnormal in leukemia and formed recurrent clusters that were shared across the leukemias with shared prognostic implications across diseases, and individual proteins showed age- and disease-related differences.

DNA Damage Response-Related Proteins Are Prognostic for Outcome in Both Adult and Pediatric Acute Myelogenous Leukemia Patients: Samples from Adults and from Children Enrolled in a Children's Oncology Group Study.

The survival of malignant leukemic cells is dependent on DNA damage repair (DDR) signaling. Reverse Phase Protein Array (RPPA) data sets were assembled using diagnostic samples from 810 adult and 500 pediatric acute myelogenous leukemia (AML) patients and were probed with 412 and 296 strictly validated antibodies, respectively, including those detecting the expression of proteins directly involved in DDR. Unbiased hierarchical clustering identified strong recurrent DDR protein expression patterns in both adult and pediatric AML. Globally, DDR expression was associated with gene mutational statuses and was prognostic for outcomes including overall survival (OS), relapse rate, and remission duration (RD). In adult patients, seven DDR proteins were individually prognostic for either RD or OS. When DDR proteins were analyzed together with DDR-related proteins operating in diverse cellular signaling pathways, these expanded groupings were also highly prognostic for OS. Analysis of patients treated with either conventional chemotherapy or venetoclax combined with a hypomethylating agent revealed protein clusters that differentially predicted favorable from unfavorable prognoses within each therapy cohort. Collectively, this investigation provides insight into variable DDR pathway activation in AML and may help direct future individualized DDR-targeted therapies in AML patients.

Extracorporeal membrane oxygenation in children receiving haematopoietic cell transplantation and immune effector cell therapy: an international and multidisciplinary consensus statement.

Use of extracorporeal membrane oxygenation (ECMO) in children receiving haematopoietic cell transplantation (HCT) and immune effector cell therapy is controversial and evidence-based guidelines have not been established. Remarkable advancements in HCT and immune effector cell therapies have changed expectations around reversibility of organ dysfunction and survival for affected patients. Herein, members of the Extracorporeal Life Support Organization (ELSO), Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network (HCT and cancer immunotherapy subgroup), the Pediatric Diseases Working Party of the European Society for Blood and Marrow Transplantation (EBMT), the supportive care committee of the Pediatric Transplantation and Cellular Therapy Consortium (PTCTC), and the Pediatric Intensive Care Oncology Kids in Europe Research (POKER) group of the European Society of Pediatric and Neonatal Intensive Care (ESPNIC) provide consensus recommendations on the use of ECMO in children receiving HCT and immune effector cell therapy. These are the first international, multidisciplinary consensus-based recommendations on the use of ECMO in this patient population. This Review provides a clinical decision support tool for paediatric haematologists, oncologists, and critical care physicians during the difficult decision-making process of ECMO candidacy and management. These recommendations can represent a base for future research studies focused on ECMO selection criteria and bedside management.

Retrospective Review of Flexible Bronchoscopy in Pediatric Cancer Patients.

The use of flexible bronchoscopy (FB) with bronchoalveolar lavage (BAL) to diagnose and manage pulmonary complications has been shown to be safe in adult cancer patients, but whether its use is safe in pediatric cancer patients remains unclear. Thus, to describe the landscape of FB outcomes in pediatric cancer patients and to help define the populations most likely to benefit from the procedure, we undertook a retrospective review of FBs performed in patients younger than 21 years treated at our institution from 2002 to 2017. We found that a greater volume of total fluid instilled during BAL was significantly associated with increased probabilities of positive BAL culture (p=0.042), positive bacterial BAL culture (p=0.037), and positive viral BAL culture (p=0.0496). In more than half of the FB cases, findings resulted in alterations in antimicrobial treatment. Our study suggests that for pediatric cancer patients, FB is safe, likely provides diagnostic and/or therapeutic benefits, and has implications for treatment decisions.

Orientation selectivity of synaptic input to neurons in mouse and cat primary visual cortex.

Primary visual cortex (V1) is the site at which orientation selectivity emerges in mammals: visual thalamus afferents to V1 respond equally to all stimulus orientations, whereas their target V1 neurons respond selectively to stimulus orientation. The emergence of orientation selectivity in V1 has long served as a model for investigating cortical computation. Recent evidence for orientation selectivity in mouse V1 opens cortical computation to dissection by genetic and imaging tools, but also raises two essential questions: (1) How does orientation selectivity in mouse V1 neurons compare with that in previously described species? (2) What is the synaptic basis for orientation selectivity in mouse V1? A comparison of orientation selectivity in mouse and in cat, where such measures have traditionally been made, reveals that orientation selectivity in mouse V1 is weaker than in cat V1, but that spike threshold plays a similar role in narrowing selectivity between membrane potential and spike rate. To uncover the synaptic basis for orientation selectivity, we made whole-cell recordings in vivo from mouse V1 neurons, comparing neuronal input selectivity-based on membrane potential, synaptic excitation, and synaptic inhibition-to output selectivity based on spiking. We found that a neuron's excitatory and inhibitory inputs are selective for the same stimulus orientations as is its membrane potential response, and that inhibitory selectivity is not broader than excitatory selectivity. Inhibition has different dynamics than excitation, adapting more rapidly. In neurons with temporally modulated responses, the timing of excitation and inhibition was different in mice and cats.

Pemoline (2-amino-5-phenyl-1,3-oxazol-4-one)-induced self-injurious behavior: a rodent model of pharmacotherapeutic efficacy.

Self-injury is a devastating, maladaptive behavior disorder that is common in developmental disabilities and is comorbid with numerous psychiatric disorders. Examples of self-injurious behavior (SIB) include head-banging, self-biting, and self-punching. The neurochemical basis of SIB is unknown; however, many different classes of drugs are prescribed (e.g., neuroleptics, atypical neuroleptics, anti-epileptics, opioid antagonists) to reduce these behaviors. These drugs have all shown clinically significant but limited efficacy in patient populations, and no class of drug is effective for all patients. The development and characterization of a valid animal model could provide important information regarding the neurochemical basis of SIB and could be used to screen potential new pharmacotherapies. In one model of SIB, high doses of pemoline (2-amino-5-phenyl-1,3-oxazol-4-one) are administered to rats. Using this model, we evaluated the effectiveness of three drugs (risperidone, valproate, and topiramate) that reduce SIB in humans. We also screened the potential effectiveness of tramadol, a drug that decreases stereotyped and compulsive behaviors but has not been assessed in human self-injurers. We found that risperidone, valproate, and topiramate each significantly attenuate pemoline-induced SIB, whereas tramadol does not. These findings suggest that the pemoline model of SIB has predictive validity across a range of drug classes and implicate important potential neurochemical mechanisms that may contribute to the behavior disorder. The findings also indicate that tramadol may not be an effective pharmacotherapy for SIB.

Roles of the bed nucleus of stria terminalis and of the amygdala in N/OFQ-mediated anxiety and HPA axis activation.

Nociceptin/orphanin FQ (N/OFQ) is an opioid-related neuropeptide that is widely distributed in limbic regions of the brain. After intracerebroventricular (icv) injections in rodents, N/OFQ produces elevations in hypothalamic-pituitary-adrenal (HPA) axis activity, and has been reported to produce both anxiogenic and anxiolytic actions. We examined the neuroanatomical basis of these effects with injections of N/OFQ (0.01-1.0nmol) into the lateral ventricle, the amygdala, and the bed nucleus of stria terminalis (BNST) in independent groups of well-handled rats under low stress conditions. Anxiety-related behaviors were evaluated in a neophobic test of anxiety. The latency to enter, total time spent in, and number of entries into an unfamiliar open field and its central zone were measured. After the open field testing, plasma samples were obtained for analysis of HPA axis activity. The N/OFQ-treated rats displayed more anxiety-related behaviors than vehicle-treated rats did with all three of the injection types. However, these effects were greater and more consistent after the icv injections (0.01-1.0nmol) than they were after the amygdala (0.10-1.0nmol) or BNST (1.0nmol) injections. The icv and BNST injections also produced elevations in circulating corticosterone, indicating that the HPA axis was activated in these rats. Intra-amygdaloid injections did not affect corticosterone levels during the open field testing. These results indicate that the amygdala and BNST participate in the anxiogenic behavioral effects of N/OFQ. However, since the most potent effects were seen after icv N/OFQ injections, the anxiogenic and HPA axis-activating effects of N/OFQ appear to occur through additive actions in multiple limbic (and perhaps cortical and brainstem) sites.

Influence of resident and attending surgeon seniority on operative performance in laparoscopic cholecystectomy.

BACKGROUND: Resident participation in laparoscopic cholecystectomy (LC) is important for education but increases the time of operation. This time cost in training programs is not well-defined, and available data show no decrease in operative time as residents progress in training. We undertook this study to determine the effect of the resident and attending surgeon seniority on the operative performance of LC. PATIENTS AND METHODS: We undertook a retrospective review of LCs performed for all indications over two academic years in our training program. Operations were performed by junior (PGY 1-3) or senior (PGY 4-5) residents, assisted by junior (trained after 1994) or senior attending surgeons, none of whom had fellowship training in advanced laparoscopy. Demographics, surgeon, assistant, operative time, and operative complications were recorded. Operative diagnoses were defined as noninflammatory (biliary colic, dyskinesia, or polyps) or inflammatory (cholecystitis, pancreatitis). The primary outcome was time in minutes from skin incision to closure; secondary outcomes were complications and conversions to laparotomy. ANOVA, Student's t-test, and chi2 tests were used as appropriate with statistical significance attributed to P < 0.05. RESULTS: Three hundred fifteen LCs were performed. Two hundred seventy were without conversion to laparotomy or intraoperative cholangiography and were included in time and complication analysis. Junior attendings averaged 4 and senior attendings averaged 21 postresidency years. No differences were found on univariate analysis between groups in demographics or diagnosis category. Operative times were longer for junior residents irrespective of attending seniority: Jr Res/Jr Staff (n = 65): 86 +/- 32 min; Jr/Sr (n = 78): 88 +/- 38 min; Sr/Jr (n = 52): 73 +/- 27 min; Sr/Sr (n = 75): 67 +/- 24 min (P < 0.05). The overall rate of operative complications was higher in junior than senior resident cases (5.6% versus 0.78%, P < 0.05). The most common complication was cystic duct leak, of which 4/5 occurred in junior resident cases. Senior attendings had a trend toward increased conversions (8.4% versus 3.7%, P = 0.09). CONCLUSION: Resident, but not attending surgeon, seniority influences operative time and complication rate in LC. This information may help surgical educators maximize both resident learning and operative efficiency and safety.

Laparoscopic cholecystectomy in the elderly: increased operative complications and conversions to laparotomy.

BACKGROUND: The incidence of gallstones increases with age and as the proportion of the population 65 years of age and older continues to grow, increased demand for laparoscopic cholecystectomy (LC) in the geriatric population is likely. LC has advantages over open cholecystectomy, but comparative evaluation of the procedure in elderly patients is lacking. METHODS: We performed a two-year review of patients undergoing LC at our institution. Demographic information, diagnosis, operation performed, and operative complications were recorded. Patients were placed into two groups by age: 65 years and older, and those younger than 65 years of age. Primary outcome measures were complication rate and conversions to laparotomy. RESULTS: A total of 315 patients underwent LC during the study period, of whom 59 (19%) were 65 years of age or older. The older age group experienced higher rates of conversion to an open procedure (22% vs. 2.7%, P<0.05), and operative complications (17% vs. 3.1%, P<0.05). Elderly patients also had longer operative times (108+/-55 minutes vs. 83<34 minutes, P<0.05). Acute (31% vs. 16%) and chronic (14% vs. 7.4%) cholecystitis were the operative diagnoses in a greater proportion of patients in the older age group, and elderly patients were more likely to have had prior upper abdominal surgery (8.5% vs. 1.6%, P<0.05). CONCLUSION: LC in the geriatric population carries increased risk for conversion to laparotomy and operative complications compared to LC in younger patients. This is likely due to increased acuity and chronic right upper quadrant inflammation in this population. Surgeons should bear these issues in mind in the counseling and care of these patients.