Leveraging clinical decision support to reduce the risk of discordant pharmacogenomics results.

Pharmacogenomics (PGx) testing is commonly utilized to predict a patient's response to medications based on the presence of genetic variants. However, certain conditions have been associated with potentially inaccurate PGx results. The majority of medications are predominantly metabolized in the liver; therefore, in the case of liver transplantation, PGx results may be misinterpreted in the context of drug-metabolizing enzymes. Other instances of ambiguous PGx results have been reported in the literature in conditions such as allogeneic stem cell or bone marrow transplant, chronic lymphocytic leukemia, acute or chronic myeloid leukemia and blood transfusion. In order to prevent potential inaccuracies in PGx testing, Sanford Imagenetics developed an active, interruptive alert to inform providers of the potential for inaccurate PGx results.

The Generational Impact Of Racism On Health: Voices From American Indian Communities.

Structural racism toward American Indians and Alaska Natives is found in nearly every policy regarding and action taken toward that population since non-Natives made first contact with the Indigenous peoples of the United States. Generations of American Indians and Alaska Natives have suffered from policies that called for their genocide as well as policies intended to acculturate and dominate them-such as the sentiment from Richard Henry Pratt to "kill the Indian…, save the man." The intergenerational effect is one that has left American Indians and Alaska Natives at the margins of health and the health care system. The effect is devastating psychologically, eroding a value system that is based on community and the sanctity of all creation. Using stories we collected from American Indian people who have experienced the results of racist policies, we describe historical trauma and its links to the health of American Indians and Alaska Natives. We develop two case studies around these stories, including one from a member of the Navajo Nation's experiences during the COVID-19 pandemic, to illustrate biases in institutionalized structures. Finally, we describe how the American Indian and Alaska Native Cultural Wisdom Declaration can help policy makers eliminate the effect of systemic racism on the health of American Indians and Alaska Natives-for instance, by lifting constraints on federal funding for American Indian and Alaska Native initiatives and allowing payment to traditional healers for their health services.

Use of Middleware Data to Dissect and Optimize Hematology Autoverification.

BACKGROUND: Hematology analysis comprises some of the highest volume tests run in clinical laboratories. Autoverification of hematology results using computer-based rules reduces turnaround time for many specimens, while strategically targeting specimen review by technologist or pathologist. METHODS: Autoverification rules had been developed over a decade at an 800-bed tertiary/quarternary care academic medical central laboratory serving both adult and pediatric populations. In the process of migrating to newer hematology instruments, we analyzed the rates of the autoverification rules/flags most commonly associated with triggering manual review. We were particularly interested in rules that on their own often led to manual review in the absence of other flags. Prior to the study, autoverification rates were 87.8% (out of 16,073 orders) for complete blood count (CBC) if ordered as a panel and 85.8% (out of 1,940 orders) for CBC components ordered individually (not as the panel). RESULTS: Detailed analysis of rules/flags that frequently triggered indicated that the immature granulocyte (IG) flag (an instrument parameter) and rules that reflexed platelet by impedance method (PLT-I) to platelet by fluorescent method (PLT-F) represented the two biggest opportunities to increase autoverification. The IG flag threshold had previously been validated at 2%, a setting that resulted in this flag alone preventing autoverification in 6.0% of all samples. The IG flag threshold was raised to 5% after detailed chart review; this was also the instrument vendor's default recommendation for the newer hematology analyzers. Analysis also supported switching to PLT-F for all platelet analysis. Autoverification rates increased to 93.5% (out of 91,692 orders) for CBC as a panel and 89.8% (out of 11,982 orders) for individual components after changes in rules and laboratory practice. CONCLUSIONS: Detailed analysis of autoverification of hematology testing at an academic medical center clinical laboratory that had been using a set of autoverification rules for over a decade revealed opportunities to optimize the parameters. The data analysis was challenging and time-consuming, highlighting opportunities for improvement in software tools that allow for more rapid and routine evaluation of autoverification parameters.

Interstitial duplication of 20q11.22q13.11: A case report and review of literature.

BACKGROUND: Reports of interstitial duplication of chromosome 20q11 are rare with only nine published patients to date. METHODS: We performed karyotype and chromosomal microarray analysis on a peripheral blood sample for our patient and reviewed the genes in the region to provide genotype-phenotype correlation. RESULTS: Clinical features of the patient include minor dysmorphic facial features, shorthands and feet, bilateral conductive hearing loss, global developmental delay, and behavioral issues with attention deficit hyperactivity disorder. Together with previously published cases of 20q11 duplication, we show that patients with overlapping duplications share a similar clinical phenotype of dysmorphic craniofacial features and developmental delay. CONCLUSION: We report an 8-year-old girl with a 9.1 Mb interstitial duplication of chromosome 20q11.22q13.11. Our observations suggest that a novel duplication syndrome and documentation of similar cases will further help clarify the phenotype.

IgG4-Related Disease of the Craniovertebral Junction.

BACKGROUND: The majority of the abnormalities and diseases that affect the craniovertebral junction (CVJ) have already been reported, and therefore it is exceedingly rare to identify new pathology that affects the CVJ. Immunoglobulin G4-related disease (IgG4-RD) is an immune mediated process treated with immunosuppressive medications. To our knowledge, this is the first reported case of IgG4-RD affecting the CVJ. CASE DESCRIPTION: The authors report the case of a woman aged 71 years with IgG4-RD of the CVJ. She presented with intractable left occipital pain and limited flexion, extension, and rotation of the neck. Computed tomography and magnetic resonance imaging revealed a lytic enhancing lesion of the left occipital condyle, left C1 lateral mass, and left C1 anterior arch resulting in cranial settling, basilar invagination, and CVJ instability. An open biopsy, subtotal resection, and occiput to C2 fusion was performed. Pathology revealed IgG4-RD. The patient was subsequently placed on rituximab immunotherapy with complete resolution of enhancement on magnetic resonance imaging and bone growth at the previous site of the lytic IgG4-RD lesion. CONCLUSIONS: To our knowledge, this case describes the first case of IgG4-RD affecting the CVJ, which mimicked a tumor-like process. When IgG4-RD affects the CVJ, stability must be accounted for, especially in the cases of osteolytic destruction. The combination of medical therapy to target the underlying inflammatory process and surgery to provide structural stability was successful.

Snyder-Robinson syndrome.

Snyder-Robinson syndrome, also known as spermine synthase deficiency, is an X-linked intellectual disability syndrome (OMIM #390583). First described by Drs. Snyder and Robinson in 1969, this syndrome is characterized by an asthenic body habitus, facial dysmorphism, broad-based gait, and osteoporosis with frequent fractures. We report here a pediatric autopsy of a 4 year old male with a history of intellectual disability, gait abnormalities, multiple fractures, and seizures previously diagnosed with Snyder-Robinson syndrome with an SMS gene mutation (c.831G>T:p.L277F). The cause of death was hypoxic-ischemic encephalopathy secondary to prolonged seizure activity. Although Snyder-Robinson syndrome is rare, the need to recognize clinical findings in order to trigger genetic testing has likely resulted in under diagnosis.

Snyder-Robinson syndrome

Snyder-Robinson syndrome, also known as spermine synthase deficiency, is an X-linked intellectual disability syndrome (OMIM #390583). First described by Drs. Snyder and Robinson in 1969, this syndrome is characterized by an asthenic body habitus, facial dysmorphism, broad-based gait, and osteoporosis with frequent fractures. We report here a pediatric autopsy of a 4 year old male with a history of intellectual disability, gait abnormalities, multiple fractures, and seizures previously diagnosed with Snyder-Robinson syndrome with an SMS gene mutation (c.831G>T:p.L277F). The cause of death was hypoxic-ischemic encephalopathy secondary to prolonged seizure activity. Although Snyder-Robinson syndrome is rare, the need to recognize clinical findings in order to trigger genetic testing has likely resulted in under diagnosis.

Regulation of Insulin Receptor Trafficking by Bardet Biedl Syndrome Proteins.

Insulin and its receptor are critical for the regulation of metabolic functions, but the mechanisms underlying insulin receptor (IR) trafficking to the plasma membrane are not well understood. Here, we show that Bardet Biedl Syndrome (BBS) proteins are necessary for IR localization to the cell surface. We demonstrate that the IR interacts physically with BBS proteins, and reducing the expression of BBS proteins perturbs IR expression in the cell surface. We show the consequence of disrupting BBS proteins for whole body insulin action and glucose metabolism using mice lacking different BBS genes. These findings demonstrate the importance of BBS proteins in underlying IR cell surface expression. Our data identify defects in trafficking and localization of the IR as a novel mechanism accounting for the insulin resistance commonly associated with human BBS. This is supported by the reduced surface expression of the IR in fibroblasts derived from patients bearing the M390R mutation in the BBS1 gene.