Morphological profiling in human neural progenitor cells classifies hits in a pilot drug screen for Alzheimer's disease.

Alzheimer's disease accounts for 60-70% of dementia cases. Current treatments are inadequate and there is a need to develop new approaches to drug discovery. Recently, in cancer, morphological profiling has been used in combination with high-throughput screening of small-molecule libraries in human cells in vitro. To test feasibility of this approach for Alzheimer's disease, we developed a cell morphology-based drug screen centred on the risk gene, SORL1 (which encodes the protein SORLA). Increased Alzheimer's disease risk has been repeatedly linked to variants in SORL1, particularly those conferring loss or decreased expression of SORLA, and lower SORL1 levels are observed in post-mortem brain samples from individuals with Alzheimer's disease. Consistent with its role in the endolysosomal pathway, SORL1 deletion is associated with enlarged endosomes in neural progenitor cells and neurons. We, therefore, hypothesized that multi-parametric, image-based cell phenotyping would identify features characteristic of SORL1 deletion. An automated morphological profiling method (Cell Painting) was adapted to neural progenitor cells and used to determine the phenotypic response of SORL1-/- neural progenitor cells to treatment with compounds from a small internationally approved drug library (TargetMol, 330 compounds). We detected distinct phenotypic signatures for SORL1-/- neural progenitor cells compared to isogenic wild-type controls. Furthermore, we identified 16 compounds (representing 14 drugs) that reversed the mutant morphological signatures in neural progenitor cells derived from three SORL1-/- induced pluripotent stem cell sub-clones. Network pharmacology analysis revealed the 16 compounds belonged to five mechanistic groups: 20S proteasome, aldehyde dehydrogenase, topoisomerase I and II, and DNA synthesis inhibitors. Enrichment analysis identified DNA synthesis/damage/repair, proteases/proteasome and metabolism as key pathways/biological processes. Prediction of novel targets revealed enrichment in pathways associated with neural cell function and Alzheimer's disease. Overall, this work suggests that (i) a quantitative phenotypic metric can distinguish induced pluripotent stem cell-derived SORL1-/- neural progenitor cells from isogenic wild-type controls and (ii) phenotypic screening combined with multi-parametric high-content image analysis is a viable option for drug repurposing and discovery in this human neural cell model of Alzheimer's disease.

Loss of SORCS2 is Associated with Neuronal DNA Double-Strand Breaks.

SORCS2 is one of five proteins that constitute the Vps10p-domain receptor family. Members of this family play important roles in cellular processes linked to neuronal survival, differentiation and function. Genetic and functional studies implicate SORCS2 in cognitive function, as well as in neurodegenerative and psychiatric disorders. DNA damage and DNA repair deficits are linked to ageing and neurodegeneration, and transient neuronal DNA double-strand breaks (DSBs) also occur as a result of neuronal activity. Here, we report a novel role for SORCS2 in DSB formation. We show that SorCS2 loss is associated with elevated DSB levels in the mouse dentate gyrus and that knocking out SORCS2 in a human neuronal cell line increased Topoisomerase IIß-dependent DSB formation and reduced neuronal viability. Neuronal stimulation had no impact on levels of DNA breaks in vitro, suggesting that the observed differences may not be the result of aberrant neuronal activity in these cells. Our findings are consistent with studies linking the VPS10 receptors and DNA damage to neurodegenerative conditions.

The Impact of Kindness in Medical Student Education in Rural South Dakota.

All medical students at the University of South Dakota Sanford School of Medicine (SSOM) have rural healthcare rotations. Because SSOM has adopted kindness as a focal point in its new five year strategic plan, we designed a qualitative study to assess students' perception of kindness in the rural setting.

Large Solitary Fibrous Tumor of the Kidney.

Solitary fibrous tumors (SFT) are rare mesenchymal neoplasms that can affect any soft tissue in the body. Given their infrequency, no definitive risk factors have been identified. Typically, surgical extrication en bloc is the only known curative treatment option for SFTs; however, systemic therapy can be used for metastatic or unresectable disease. Only 10 perent to 15 perent of SFTs are aggressive in behavior and termed malignant, leading to a high survival rate for affected patients. Surveillance is required post-operatively to detect recurrence.

Skin Cancer Prevention and Screening Behaviors among Agricultural Workers: A Survey of the Attendees of the Sioux Falls Farm Show.

INTRODUCTION: Agricultural workers are at a higher risk for skin cancer due to excessive amounts of sun exposure, poor sun safety practices, and limited access to healthcare. This study aimed to assess skin cancer history, sun protection practices, and skin cancer surveillance measures among Midwestern agricultural workers. METHODS: Individuals that attended the 2020 Sioux Falls Farm Show were asked to complete a 12-question survey on sun exposure, sun protective practices, and skin cancer surveillance. Survey responses were aggregated and analyzed using Microsoft Excel. RESULTS: A total of 99 individuals participated in the study, of which 70 identified as agricultural workers. Most individuals reported working outdoors eight to 10 hours daily for 10-12 months of the year. Most participants reported poor sun protection habits, such as limited sunscreen and limited wide-brimmed hat use. A large number of participants reported they had previously received a professional skin check, although 33 percent reported never examining their own skin for suspicious lesions. CONCLUSIONS: Midwestern agricultural workers present a unique population that could benefit from improved skin cancer prevention. Opportunities for improvement include education of skin cancer preventative measures using platforms that are likely to reach rural agricultural workers and education regarding skin self-examinations. This study identified high risk factors of this population including substantial sun exposure, poor sun protection, and minimal self-skin examinations. Our findings may help guide future methods to increase skin cancer education, prevention, and surveillance in agricultural workers.

Skin Cancer Education in the Rural Salon.

INTRODUCTION: Due to an increase in the incidence of skin cancer and a shortage of primary care and specialty physicians in rural areas, creative public health strategies must be employed to address disparities in skin cancer education, prevention, and detection. METHODS: Hair salons in eastern South Dakota communities with populations less than 15,000 were visited in-person by medical student facilitators. Hair professionals at these locations completed pre-survey assessments for baseline self-assessed comfort with detecting suspicious skin lesions and with educating patrons on skin cancer prevention strategies. Their likelihood to both alert patrons of suspicious skin lesions and encourage them to have their lesion evaluated by a physician was also assessed. A 20-minute educational PowerPoint presentation was given. Final assessment was evaluated with a post-presentation survey. RESULTS: Self-assessed hair professional comfort with identifying suspicious skin lesions was higher in post-survey results, in addition, the educational presentation increased comfort with sharing skin cancer prevention information with patrons. Hair professionals also reported increased likelihood that they would alert patrons to suspect skin lesions. Also, hair professionals reported increased likelihood that they would encourage patrons to seek medical care for their concerning lesions. CONCLUSIONS: Hair professionals may act as lay skin cancer educators in rural salons. Educational programs for hair professionals can increase their comfort with detecting lesions suspicious for skin cancer, increase their comfort with sharing skin protection information with patrons, and increase their likelihood of both alerting their patrons about suspicious skin lesions and encouraging their patrons to have their suspicious lesions evaluated.

DISC1 regulates N-methyl-D-aspartate receptor dynamics: abnormalities induced by a Disc1 mutation modelling a translocation linked to major mental illness.

The neuromodulatory gene DISC1 is disrupted by a t(1;11) translocation that is highly penetrant for schizophrenia and affective disorders, but how this translocation affects DISC1 function is incompletely understood. N-methyl-D-aspartate receptors (NMDAR) play a central role in synaptic plasticity and cognition, and are implicated in the pathophysiology of schizophrenia through genetic and functional studies. We show that the NMDAR subunit GluN2B complexes with DISC1-associated trafficking factor TRAK1, while DISC1 interacts with the GluN1 subunit and regulates dendritic NMDAR motility in cultured mouse neurons. Moreover, in the first mutant mouse that models DISC1 disruption by the translocation, the pool of NMDAR transport vesicles and surface/synaptic NMDAR expression are increased. Since NMDAR cell surface/synaptic expression is tightly regulated to ensure correct function, these changes in the mutant mouse are likely to affect NMDAR signalling and synaptic plasticity. Consistent with these observations, RNASeq analysis of the translocation carrier-derived human neurons indicates abnormalities of excitatory synapses and vesicle dynamics. RNASeq analysis of the human neurons also identifies many differentially expressed genes previously highlighted as putative schizophrenia and/or depression risk factors through large-scale genome-wide association and copy number variant studies, indicating that the translocation triggers common disease pathways that are shared with unrelated psychiatric patients. Altogether, our findings suggest that translocation-induced disease mechanisms are likely to be relevant to mental illness in general, and that such disease mechanisms include altered NMDAR dynamics and excitatory synapse function. This could contribute to the cognitive disorders displayed by translocation carriers.

Altered DNA methylation associated with a translocation linked to major mental illness.

Recent work has highlighted a possible role for altered epigenetic modifications, including differential DNA methylation, in susceptibility to psychiatric illness. Here, we investigate blood-based DNA methylation in a large family where a balanced translocation between chromosomes 1 and 11 shows genome-wide significant linkage to psychiatric illness. Genome-wide DNA methylation was profiled in whole-blood-derived DNA from 41 individuals using the Infinium HumanMethylation450 BeadChip (Illumina Inc., San Diego, CA). We found significant differences in DNA methylation when translocation carriers (n = 17) were compared to related non-carriers (n = 24) at 13 loci. All but one of the 13 significant differentially methylated positions (DMPs) mapped to the regions surrounding the translocation breakpoints. Methylation levels of five DMPs were associated with genotype at SNPs in linkage disequilibrium with the translocation. Two of the five genes harbouring significant DMPs, DISC1 and DUSP10, have been previously shown to be differentially methylated in schizophrenia. Gene Ontology analysis revealed enrichment for terms relating to neuronal function and neurodevelopment among the genes harbouring the most significant DMPs. Differentially methylated region (DMR) analysis highlighted a number of genes from the MHC region, which has been implicated in psychiatric illness previously through genetic studies. We show that inheritance of a translocation linked to major mental illness is associated with differential DNA methylation at loci implicated in neuronal development/function and in psychiatric illness. As genomic rearrangements are over-represented in individuals with psychiatric illness, such analyses may be valuable more widely in the study of these conditions.

Epidemiologic Study of Bacteria Zoonotic Diseases in South Dakota: 2010-2014.

BACKGROUND: Although the burden of infectious diseases has decreased dramatically due to advances in health care, disease prevention and numerous public health efforts and innovations, zoonotic diseases continue to pose a problem in terms of both existing and emerging diseases. These risks are of particular concern in rural areas, in which there is more contact with animals for occupational and recreational purposes. As a rural and agricultural state, South Dakota has a large percentage of its population at risk of exposure to zoonotic diseases through their substantial contact time with animals. METHODS: De-identified data from the South Dakota Department of Health containing the variables and diseases of interest from the time period of 2010-2014 was obtained. From this data were calculated the incidence rates by county, and seasonal and demographic patterns of the diseases were plotted. RESULTS: The incidence of disease in South Dakota were higher than the national rates for campylobacteriosis (threefold), cryptosporidiosis (sixfold), enterohemorrhagic E. coli (fourfold), Q fever (tenfold), salmonellosis (1.2-fold), and tularemia (14-fold). Only listeriosis had a lower incidence than the national rate among zoonoses included in this study. Seasonality of campylobacteriosis in the state was earlier in the year than is reported for the disease nationally. CONCLUSION: Zoonotic infections are a substantial threat to health in South Dakota. There is a need to develop collaboration between healthcare providers, public health professionals, livestock producers, veterinarians, and sportsmen to develop a strategy to address this issue.

The Impact of a Rural Training Track on Medical Students Specialty Choice.

BACKGROUND: Compare the expectations and outcomes of students involved in rural medical training versus those of urban trainees. METHODS: Survey items relating to primary care interest were added to program evaluation surveys already being sent at the beginning and end of the primary clinical year. Students from the graduating class of 2016 and the class of 2017 responded to the surveys (N=115). Responses from students trained in rural sites were compared with students trained in medium or large communities. For the purposes of the survey, primary care was not specifically defined and was open to participants' interpretation. Primary care is commonly thought of as the medical care from the doctor who sees a patient first and provides treatment or decides the other specialist care that the patient may need. Primary care specialties can include family medicine, internal medicine, pediatrics and obstetrics and gynecology. RESULTS: Most students enter their primary clinical year undecided about specialty choice and preferred practice location. At the end of the primary clinical year, most students have decided on a specialty and most report wanting to practice in communities similar to where they trained during that year. Before the primary clinical year student attitudes toward primary care are not significantly different based on selected training site. However at the end of the primary clinical year, students who had been trained in small communities were significantly more likely to choose primary care compared with students trained in medium to large communities. CONCLUSIONS: For students who begin the primary clinical year undecided regarding specialty choice, and practice location, the community size of the training site plays a large role in the decisions they will make. A majority of students trained in small communities chose to go into primary care and practice in small communities.

Correlations between community size and student perceptions of value.

INTRODUCTION: The purpose of this study was to determine if medical students' feeling of being valued was correlated to community size. The study, conducted in several communities in South Dakota, examined students' feeling of value relating to attending physicians, healthcare teams and patients. METHODS: Student value items were added to student satisfaction surveys sent out to students at the end of their primary clinical year and data collected from two graduating classes of students (n=114). Student responses were grouped by clinical campus and mean responses by community size were calculated. Additionally, student encounter logs were reviewed for study participants to gauge participation levels during clinical encounters. RESULTS: The degree to which students felt valued by their physician attending, the healthcare team and the patients decreased consistently as community size increased. Differences were statistically significant between students in the smallest and largest communities. Additionally, students in the community of 15 000 felt significantly more valued than students in the community of 170 000. Furthermore, there also appears to be a relationship between the percentage of participation in patient care by students and community size. Students in the smaller, rural communities participated at a higher percentage rather than observing. CONCLUSIONS: There appears to be a relationship between community size and the extent to which students feel value. The degree to which students felt valued decreased consistently as community size increased. Differences were statistically significant between students in the smallest communities and the two largest communities. Students in the smaller, rural communities participated at a higher percentage. Additional studies are needed to address whether students participate more as a result of feeling valued, or whether participation leads to an enhanced perception of value by students.

Promoting Student Interest in Family Medicine Through National Conference Attendance.

INTRODUCTION: The University of South Dakota Sanford School of Medicine (USDSSOM) had success in preparing students to enter family medicine. A sharp decline in students choosing the specialty became noticeable in 2004. In 2005, only 10.2% of the graduating class entered family medicine residency programs. To reverse this trend, the Department of Family Medicine partnered with the South Dakota Academy of Family Physicians (SDAFP) chapter that year to send students to the American Academy of Family Physicians (AAFP) National Conference of Family Medicine Residents and Medical Students. This report examines the influence of national conference attendance on career choice. While many factors influence student choice, conference attendance served as an additive method for recruitment. METHODS: Internal departmental records on national conference attendance and subsequent National Resident Matching Program (NRMP) data were reviewed retrospectively, to determine if a correlation existed between conference attendance and choice of family medicine as a specialty. Chi-squared analysis was utilized to further examine this relationship. RESULTS: The association between conference attendance and number of times attending is significant (χ2 =6.78, P<.05). The recent data show that this intervention has resurrected student interest in family medicine, with USDSSOM now exceeding the NRMP average for family medicine. CONCLUSIONS: A positive correlation exists between national conference attendance and medical student choice to enter family medicine residency programs. This intervention may be used by more medical schools wishing to promote family medicine in order to help meet our nation's primary care workforce needs.

Medical Imaging of Oral and Oropharyngeal Cancer.

Oral cancer is associated with documented risk factors, yet no comprehensive screening program is in place in the United States for early detection of the disease. Oral cancer often is diagnosed in more advanced stages, resulting in a poor prognosis. Dental practitioners and radiographers play an important role in the management of the disease and in helping to improve the quality of life for people who have oral cancer. This article discusses types of oral and oropharyngeal cancer, their diagnosis, treatment options, and the role of dental imaging in patients with these cancers.

Student perceptions of their value to patient care.

PURPOSE: Engagement in meaningful activities is integral to professional identity formation, yet little has been reported in the medical education literature and no studies have focused on the medical student's perspective. This study sought to further define meaningful activities and value to patient care as perceived by third- and fourth-year medical students and to explore whether there was correlation with a sense of accomplishment. METHODS: The authors surveyed third- and fourth-year medical students of the University of South Dakota Sanford School of Medicine regarding their perceptions using the Engagement in Meaningful Activities Survey. Responses of the two groups were compared, and correlations between perceived outcomes and a sense of accomplishment were calculated. RESULTS: Both third- and fourth-year medical students perceived themselves to be of value to patients and attending physicians and of help to patients, attending physicians, and the patient care team, although in all cases the mean responses for fourth-year students trended higher. The correlation between these items and a sense of accomplishment was greater among fourth year students. CONCLUSION: Student perceptions of their value to the patient and patient care team begin to play a more prominent role as clinical experiences progress in parallel with their identify formation as physicians.

Aplasia cutis congenita--a case study of a family with two siblings with this disorder.

BACKGROUND: Aplasia cutis congenita (ACC) is a rare dermatologic disorder. The cause is unknown. It is a heterogeneous group of disorders whose common characteristic is focal absence of skin. It is a congenital absence of epidermis. In the majority of cases, this is limited to the scalp, although other areas may also be involved. The lesions are non-inflammatory and well demarcated. These lesions can be circular, linear, oval or stellate and range in size from 0.5 to 10 cm. Treatment has been controversial.

Extenuating circumstances. Student selection of case presentations for a required rural family medicine clerkship.

PURPOSE: The Fourth Year Rural Family Medicine Clerkship has been a required four-week clinical rotation at the Sanford School of Medicine of the University of South Dakota (SSOM) for more than 30 years. Among the clerkship requirements has been a graded, formal case presentation. The purpose of this study was to examine the case presentations selected by the medical students for this required component of the clerkship and to determine if this correlated with their overall clinical experiences. METHODS: Clinical diagnoses of patients selected by all students for their formal case presentations were recorded and compared with the overall clinical experiences as documented using the Student Patient Experience Log database. The frequency of multiple diagnosis cases was also determined. RESULTS: Although the large majority of clinical experiences occur in ambulatory settings during this clerkship, findings suggest students have a preference for presenting on patients who were hospitalized. This does not, however, indicate that students wish to necessarily present more complicated cases. In fact, the percentage of patients selected who had multiple diagnoses was much lower compared with their overall clinical experiences. CONCLUSIONS: The variety of clinical cases selected for presentation is different than the variety of overall clinical experiences. This suggests that some selection criteria are being used by students.

The DISC1 promoter: characterization and regulation by FOXP2.

Disrupted in schizophrenia 1 (DISC1) is a leading candidate susceptibility gene for schizophrenia, bipolar disorder and recurrent major depression, which has been implicated in other psychiatric illnesses of neurodevelopmental origin, including autism. DISC1 was initially identified at the breakpoint of a balanced chromosomal translocation, t(1;11) (q42.1;14.3), in a family with a high incidence of psychiatric illness. Carriers of the translocation show a 50% reduction in DISC1 protein levels, suggesting altered DISC1 expression as a pathogenic mechanism in psychiatric illness. Altered DISC1 expression in the post-mortem brains of individuals with psychiatric illness and the frequent implication of non-coding regions of the gene by association analysis further support this assertion. Here, we provide the first characterization of the DISC1 promoter region. Using dual luciferase assays, we demonstrate that a region -300 to -177 bp relative to the transcription start site (TSS) contributes positively to DISC1 promoter activity, while a region -982 to -301 bp relative to the TSS confers a repressive effect. We further demonstrate inhibition of DISC1 promoter activity and protein expression by forkhead-box P2 (FOXP2), a transcription factor implicated in speech and language function. This inhibition is diminished by two distinct FOXP2 point mutations, R553H and R328X, which were previously found in families affected by developmental verbal dyspraxia. Our work identifies an intriguing mechanistic link between neurodevelopmental disorders that have traditionally been viewed as diagnostically distinct but which do share varying degrees of phenotypic overlap.