Navigating Pre-exposure Prophylaxis Access: Qualitative Insights From Black Women at a Northeastern Historically Black College and University.

ABSTRACT: Black women are essential to ending the HIV epidemic in the United States; yet prevention, access, testing, and structural racism affect how HIV disproportionately affects them. Limited public health research focuses on Black women attending Historically Black Colleges and Universities (HBCUs) and the ability to address HIV prevention, such as pre-exposure prophylaxis (PrEP) uptake. PrEP is a once-daily oral pill used to prevent HIV transmission and has suboptimal uptake within the Black community. This generic qualitative descriptive analysis identifies the barriers and facilitators of PrEP uptake among Black women attending an HBCU using the health belief model. Overall, 22 Black college women participated in a 60-minute focus group. Emergent categories were as follows: (a) Barriers-stigma, cost, and side effects; (b) Facilitators-PrEP's effectiveness, exposure to HIV, and unprotected sex. Our findings can inform future efforts to increase PrEP uptake among Black women attending an HBCU.

Economics of Emergency Department Visits by Patients With Inflammatory Bowel Disease: A Real-World Analysis.

Background: Inflammatory bowel disease (IBD) is associated with significant psychosocial, economic, and physical burden on patients. IBD care in the United States results in significant healthcare expenditure with recurring emergency department (ED) care and hospital admissions. Despite advances in therapy and improved access to specialty care, there is still room for improvement in cost-efficient care. Specialty medical homes and interdisciplinary care models have emerged as ways to improve medical care, patient outcomes, and quality of life, as well as improve the impact of healthcare costs. There is limited real-world data on cost in the United States, with many articles citing cost estimates from models. Methods: We analyzed real-world data from our tertiary care center with a focus on recurrent ED visits by IBD patients. Descriptive statistics were used for a cost analysis of multiple ED visits by IBD patients. Patients with ≥4 visits to the ED in a 6-month period were described as SuperUsers and were included in a separate analysis. The cost of hospitalization was also included. Results: Total cost associated with all ED visits from SuperUsers were $72 999.57 with an average of $6636.32 per patient. When the patients were admitted, the total cost of ED visits and hospitalizations was $721 461.52, with an average of $65 587.41 per patient. Conclusions: ED utilization by IBD patients with or without hospitalization is expensive and is typically driven by a cohort of SuperUsers. More work needs to be done to improve cost-effectiveness in IBD care, including reducing the frequency of ED visits.

c.202_204del in NUP214 causes late onset form of febrile encephalopathy.

Nucleoporins (NUPs) are a group of transporter proteins that maintain homeostasis of nucleocytoplasmic transport of proteins and ribonucleic acids under physiological conditions. Biallelic pathogenic variants in NUP214 are known to cause susceptibility to acute infection-induced encephalopathy-9 (IIAE9, MIM#618426), which is characterized by severe and early-onset febrile encephalopathy causing neuroregression, developmental delay, microcephaly, epilepsy, ataxia, brain atrophy, and early death. NUP214-related IIAE9 has been reported in eight individuals from four distinct families till date. We identified a novel in-frame deletion, c.202_204del p.(Leu68del), in NUP214 by exome sequencing in a 20-year-old male with episodic ataxia, seizures, and encephalopathy, precipitated by febrile illness. Neuroimaging revealed progressive cerebellar atrophy. In silico predictions show a change in the protein conformation that may alter the downstream protein interactions with the NUP214 N-terminal region, probably impacting the mRNA export. We report this novel deletion in NUP214 as a cause for a late onset and less severe form of IIAE9.

De novo variants underlying monogenic syndromes with intellectual disability in a neurodevelopmental cohort from India.

The contribution of de novo variants as a cause of intellectual disability (ID) is well established in several cohorts reported from the developed world. However, the genetic landscape as well as the appropriate testing strategies for identification of de novo variants of these disorders remain largely unknown in low-and middle-income countries like India. In this study, we delineate the clinical and genotypic spectrum of 54 families (55 individuals) with syndromic ID harboring rare de novo variants. We also emphasize on the effectiveness of singleton exome sequencing as a valuable tool for diagnosing these disorders in resource limited settings. Overall, 46 distinct disorders were identified encompassing 46 genes with 51 single-nucleotide variants and/or indels and two copy-number variants. Pathogenic variants were identified in CREBBP, TSC2, KMT2D, MECP2, IDS, NIPBL, NSD1, RIT1, SOX10, BRWD3, FOXG1, BCL11A, KDM6B, KDM5C, SETD5, QRICH1, DCX, SMARCD1, ASXL1, ASXL3, AKT3, FBN2, TCF12, WASF1, BRAF, SMARCA4, SMARCA2, TUBG1, KMT2A, CTNNB1, DLG4, MEIS2, GATAD2B, FBXW7, ANKRD11, ARID1B, DYNC1H1, HIVEP2, NEXMIF, ZBTB18, SETD1B, DYRK1A, SRCAP, CASK, L1CAM, and KRAS. Twenty-four of these monogenic disorders have not been previously reported in the Indian population. Notably, 39 out of 53 (74%) disease-causing variants are novel. These variants were identified in the genes mainly encoding transcriptional and chromatin regulators, serine threonine kinases, lysosomal enzymes, molecular motors, synaptic proteins, neuronal migration machinery, adhesion molecules, structural proteins and signaling molecules.

Further delineation of KIF21B-related neurodevelopmental disorders.

Kinesin Family Member 21B (KIF21B) encoded by KIF21B (MIM*608322), belongs to the Kinesin superfamily proteins, which play a key role in microtubule organisation in neuronal dendrites and axons. Recently, heterozygous variants in KIF21B were implicated as the cause of intellectual disability and brain malformations in four unrelated individuals. We report a 9-year-old male with delayed speech, hyperactivity, poor social interaction, and autistic features. A parent-offspring trio exome sequencing identified a novel de novo rare heterozygous variant, NM_001252102.2: c.1513A>C, p.(Ser505Arg) in exon 11 of KIF21B. In vivo functional analysis using in utero electroporation in mouse embryonic cortex revealed that the expression of Ser505Arg KIF21B protein in the cerebral cortex impaired the radial migration of projection neurons, thus confirming the pathogenicity of the variant. Our report further validates pathogenic variants in KIF21B as a cause of neurodevelopmental disorder.

Variants in the zinc transporter TMEM163 cause a hypomyelinating leukodystrophy.

Hypomyelinating leukodystrophies comprise a subclass of genetic disorders with deficient myelination of the CNS white matter. Here we report four unrelated families with a hypomyelinating leukodystrophy phenotype harbouring variants in TMEM163 (NM_030923.5). The initial clinical presentation resembled Pelizaeus-Merzbacher disease with congenital nystagmus, hypotonia, delayed global development and neuroimaging findings suggestive of significant and diffuse hypomyelination. Genomic testing identified three distinct heterozygous missense variants in TMEM163 with two unrelated individuals sharing the same de novo variant. TMEM163 is highly expressed in the CNS particularly in newly myelinating oligodendrocytes and was recently revealed to function as a zinc efflux transporter. All the variants identified lie in highly conserved residues in the cytoplasmic domain of the protein, and functional in vitro analysis of the mutant protein demonstrated significant impairment in the ability to efflux zinc out of the cell. Expression of the mutant proteins in an oligodendroglial cell line resulted in substantially reduced mRNA expression of key myelin genes, reduced branching and increased cell death. Our findings indicate that variants in TMEM163 cause a hypomyelinating leukodystrophy and uncover a novel role for zinc homeostasis in oligodendrocyte development and myelin formation.

Further evidence of muscle involvement in neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy.

TRAPPC4-related neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy (MIM# 618741) is a recently described TRAPPopathy with clinical findings of developmental delay, seizures, postnatal microcephaly, spasticity, facial dysmorphism, and cerebral and cerebellar atrophy. Muscle involvement, a frequent finding in TRAPPopathies, was observed in one individual with TRAPPC4-related disorder previously. Only a single variant, an in-frame deletion in one family has been reported outside a recurrent disease-causing variant. We report three individuals from two Indian families harboring novel bi-allelic missense variants c.191T>C and c.278C>T (NM_016146.6) in TRAPPC4 with classic clinical presentation in one and milder and later onset in the other family. We provide further evidence for muscle involvement and review the detailed phenotypic findings in individuals reported with this disorder till date.

Multilocus disease-causing genomic variations for Mendelian disorders: role of systematic phenotyping and implications on genetic counselling.

Multilocus disease-causing genomic variations (MGVs) and multiple genetic diagnoses (MGDs) are increasingly being recognised in individuals and families with Mendelian disorders. This can be mainly attributed to the widespread use of genomic tests for the evaluation of these disorders. We conducted a retrospective study of families evaluated over the last 6 years at our centre to identify families with MGVs and MGDs. MGVs were observed in fourteen families. We observed five different consequences: (i) individuals with MGVs presenting as blended phenotypes (ii) individuals with MGVs presenting with distinct phenotypes (iii) individuals with MGVs with age-dependent penetrance (iv) individuals with MGVs with one phenotype obscured by another more predominant phenotype (v) two distinct phenotypes in different individuals in families with MGVs. Consanguinity was present in eight (8/14, 57.1%) of them. Thirteen families had two Mendelian disorders and one had three Mendelian disorders. The risk of recurrence of one or more conditions in these families ranged from 25% to 75%. Our findings underline the importance of the role of a clinical geneticist in systematic phenotyping, challenges in genetic counselling and risk estimation in families with MGVs and MGDs, especially in highly inbred populations.

Clinical and genetic spectrum of 104 Indian families with central nervous system white matter abnormalities.

Genetic disorders with predominant central nervous system white matter abnormalities (CNS WMAs), also called leukodystrophies, are heterogeneous entities. We ascertained 117 individuals with CNS WMAs from 104 unrelated families. Targeted genetic testing was carried out in 16 families and 13 of them received a diagnosis. Chromosomal microarray (CMA) was performed for three families and one received a diagnosis. Mendeliome sequencing was used for testing 11 families and all received a diagnosis. Whole exome sequencing (WES) was performed in 80 families and was diagnostic in 52 (65%). Singleton WES was diagnostic for 50/75 (66.67%) families. Overall, genetic diagnoses were obtained in 77 families (74.03%). Twenty-two of 47 distinct disorders observed in this cohort have not been reported in Indian individuals previously. Notably, disorders of nuclear mitochondrial pathology were most frequent (9 disorders in 20 families). Thirty-seven of 75 (49.33%) disease-causing variants are novel. To sum up, the present cohort describes the phenotypic and genotypic spectrum of genetic disorders with CNS WMAs in our population. It demonstrates WES, especially singleton WES, as an efficient tool in the diagnosis of these heterogeneous entities. It also highlights possible founder events and recurrent disease-causing variants in our population and their implications on the testing strategy.

Genetic disorders with central nervous system white matter abnormalities: An update.

Several genetic disorders have variable degree of central nervous system white matter abnormalities. We retrieved and reviewed 422 genetic conditions with prominent and consistent involvement of white matter from the literature. We herein describe the current definitions, classification systems, clinical spectrum, neuroimaging findings, genomics, and molecular mechanisms of these conditions. Though diagnosis for most of these disorders relies mainly on genomic tests, specifically exome sequencing, we collate several clinical and neuroimaging findings still relevant in diagnosis of clinically recognizable disorders. We also review the current understanding of pathophysiology and therapeutics of these disorders.

P069 The Unrelenting Ulcer.

CASE: Inflammatory Bowel Disease (IBD) is becoming more common in an increasingly diverse population. Exposure history is important, especially when prescribing immunosuppressive therapy. We present a case of suspected disseminated histoplasmosis in a gentleman with longstanding Ulcerative Colitis (UC) on anti-TNF with an atypical, large, non-healing duodenal ulcer. We aim to highlight risks, presentation, and management of histoplasmosis in IBD patients on immunosuppression with anti-TNFs. A 49-year-old-male with a 21-year history of left sided UC in remission on Infliximab (10 years) presented to our ED with orthostatic symptoms and melena. He reported two months of heartburn and epigastric pain refractory to acid suppression. In the ED, vitals were unremarkable. Labs showed BUN 38 mg/dL, hemoglobin 13.3 g/dL, and abnormal AST/ALT. Evaluation of mild chest discomfort revealed normal EKG and calcified nodule in the left lower lobe on chest X-ray. Tuberculosis testing was negative. EGD found a massive, 3-4cm, cratered, medial wall, hemi-circumferential ulcer from duodenal apex into the second duodenal segment (D2). Biopsies revealed acute inflammation, without CMV, dysplasia, malignancy or helicobacter pylori. CT identified a large mass 5x3.1x3.2cm in the pancreaticoduodenal groove from D2 without pancreatic duct dilation. There were prominent right axillary and sub-pectoral lymph nodes and the calcified granuloma seen on X-ray. He denied NSAID use. Symptomatic improvement occurred on aggressive acid suppression. EGD a month later showed persistent ulcer with unchanged pathology. EUS showed significant peri-duodenal thickening without malignant findings. IgG/IgG4 immunostains were negative. CEA and CA 19-9 were normal. Subsequent EGDs and imaging showed no changes. He developed duodenal stenosis requiring dilation. Hematology/Oncology evaluation was unrevealing and hyper-secretory disorder was ruled out. Lack of healing over seven months prompted referral to Infectious Disease. They identified bird dropping exposure with repeated deck pressure washing. Positive Histoplasma immunodiffusion M band indicated prior infection. Given exposure, lab, chest imaging and endoscopic findings, treatment for disseminated histoplasmosis (DH) with Itraconazole was initiated. Infliximab was held and mesalamines were restarted. Histoplasmosis is endemic to the Ohio/Mississippi River Valley and other countries. Disseminated histoplasmosis, typically found in the immunocompromised, presents in many ways with GI involvement in 70%. Diagnosis can be difficult as histoplasmosis mimics other diseases, including IBD. Prognosis is poor if left untreated. Endoscopically, ulcerations, mass-like lesions, or strictures are seen. Aside from identifying yeast, pathology is nonspecific. Severity guides treatment, classically involving Itraconazole. In IBD and diseases managed with immunosuppression (e.g. anti-TNFs), stopping therapy during infections is standard of care. Therapy may resume after treatment response. Treatment may be a year for DH. Prophylaxis for histoplasmosis, the most common fungal infection with anti-TNF use, is controversial. Literature exists where anti-TNF was continued during treatment of histoplasmosis with good outcomes. There were no recurrences with continuation or re-initiation of anti-TNF after treatment. However, many patients switched therapies. Though histoplasmosis rarely causes infection in IBD patients, outcomes can be poor. We must be aware of possible exposures, atypical or presentations mimicking IBD to identify infection early, stop immunosuppression and provide timely treatment.

P070 Next Generation Wearable Technology for IBD Patients: A Feasibility Study.

BACKGROUND: Inflammatory Bowel Disease (IBD) prevalence is rising. Quality of life (QOL) in chronic illness is affected by various physical and psychosocial factors. Recent studies in other chronic illnesses have used remote physiologic monitoring (RPM) to help predict changes in disease activity and provide opportunities for patient self-management. It has been proposed that bowel inflammation can lead to suboptimal sleep, circadian rhythm disruption and even additional immune system activation. Heart rate variability (HRV) is a validated metric that has been used to predict outcomes and help manage other disease states. To date, there is limited data on the benefit of RPM in IBD care. We wish to explore the potential benefit of the Whoop Strap (new wearable technology device) as a method of RPM for IBD patients. METHODS: We recruited patients with Ulcerative Colitis from our tertiary care IBD center 18 years and older willing to wear the Whoop Strap 3.0 for 12 months with support from the Penn State Hershey Medical Center, 2020 Department of Medicine House Staff Grant; Clinical Trial Identifier is NCT04333810. During this time, participants were encouraged to use the Whoop mobile application to record symptoms. Physiologic metrics of interest included sleep, resting heart rate (RHR), and HRV; each were correlated to IBD related symptoms. Additionally, we performed monthly "check-ins" to collect disease activity (SCCAI), mood (HADS) and stress (PSS4) questionnaire data. Descriptive statistics were utilized along with correlation coefficient testing to explore potential relationships between Whoop metrics, disease activity scores and patient reported outcomes. RESULTS: Enrollment is ongoing with 7 participants, one of which was lost to follow up. Of note, 2 patients proactively reached out to communicate concern for an underlying disease flare as they noticed significant change in their Whoop metrics in conjunction with worrying symptoms. Patient 1 subsequently had serologic testing after having increased HRV and elevated RHR several days prior to symptoms; results were consistent with active inflammation exhibiting a rise in C-reactive protein from 0.25 mg/dL in 2020 to 2.82 mg/dL. Fecal calprotectin was also elevated at 566 ug/g. Colonoscopy is scheduled for the near future. Patient 2 also had noticeable HRV and RHR changes alongside significant sleep disturbances, which has prompted additional testing. CONCLUSION: Remote physiologic monitoring is a feasible way to give patients ownership of their medical care and involve them in the diagnostic and treatment process of their underlying IBD. As exhibited with our preliminary results, the Whoop device appears easy to use and may empower patients to reach out to providers even before symptoms occur, leading to an expedited evaluation for increased disease activity. Our feasibility study will hopefully lead to larger prospective efforts utilizing wearable technology devices such as the Whoop in IBD patients.

Risk of Lymphoma Associated with Anti-TNF Therapy in Patients with Inflammatory Bowel Disease: Implications for Therapy.

Anti-tumor necrosis factor alpha (ATA) therapy plays a significant role in the treatment of moderate to severe inflammatory bowel disease (IBD). There are concerns regarding risks associated with their use, including malignancy and, specifically, lymphoma. Many previous studies have sought to determine whether there is a true link between ATA therapy in IBD and development of lymphoma. However they have been hindered by short follow-up times, few cases, and confounding factors such as previous thiopurine exposure. This review seeks to update the literature by evaluating more recent studies assessing the link between ATA monotherapy and lymphoma development. It also summarizes findings of those studies and provides additional clinical guidance pertaining to this class of biologic therapy.

Health Disparities Among American Indians/Alaska Natives - Arizona, 2017.

Compared with other racial/ethnic groups, American Indians/Alaska Natives (AI/AN) have a lower life expectancy, lower quality of life, and are disproportionately affected by many chronic conditions (1,2). Arizona has the third largest population of AI/AN in the United States (approximately 266,000 in 2017), and is home to 22 federally recognized American Indian tribal nations.* The small AI/AN sample size in previous Behavioral Risk Factor Surveillance System (BRFSS) surveys has presented analytic challenges in making statistical inferences about this population. To identify health disparities among AI/AN living in Arizona, the Arizona Department of Health Services (ADHS) and CDC analyzed data from the 2017 BRFSS survey, for which AI/AN were oversampled. Compared with whites, AI/AN had significantly higher prevalences of sugar-sweetened beverage consumption (33.0% versus 26.8%), being overweight or having obesity (76.7% versus 63.2%), diabetes (21.4% versus 8.0%), high blood pressure (32.9% versus 27.6%), report of fair or poor health status (28.7% versus 16.3%), and leisure-time physical inactivity during the past month (31.1% versus 23.0%). AI/AN also reported a lower prevalence of having a personal doctor or health care provider (63.1%) than did whites (72.8%). This report highlights the need to enhance surveillance measures at the local, state, and national levels and can inform interventions centered on confronting social inequities, developing culturally competent prevention strategies, and facilitating access to care to improve population health and work toward health equity.

Prevalence of Arthritis Among Adults with Prediabetes and Arthritis-Specific Barriers to Important Interventions for Prediabetes - United States, 2009-2016.

An estimated 54.4 million U.S. adults have doctor-diagnosed arthritis (arthritis), and this number is projected to rise to 78.4 million by 2040 (1,2). Physical inactivity and obesity are two factors associated with an increased risk for developing type 2 diabetes,* and arthritis has been determined to be a barrier to physical activity among adults with obesity (3). The prevalence of arthritis among the 33.9% (estimated 84 million)† of U.S. adults with prediabetes and how these conditions are related to physical inactivity and obesity are unknown. To examine the relationships among arthritis, prediabetes, physical inactivity, and obesity, CDC analyzed combined data from the 2009-2016 National Health and Nutrition Examination Surveys (NHANES). Overall, the unadjusted prevalence of arthritis among adults with prediabetes was 32.0% (26 million). Among adults with both arthritis and prediabetes, the unadjusted prevalences of leisure-time physical inactivity and obesity were 56.5% (95% confidence intervals [CIs] = 51.3-61.5) and 50.1% (CI = 46.5-53.6), respectively. Approximately half of adults with both prediabetes and arthritis are either physically inactive or have obesity, further increasing their risk for type 2 diabetes. Health care and public health professionals can address arthritis-specific barriers§ to physical activity by promoting evidence-based physical activity interventions.¶ Furthermore, weight loss and physical activity promoted though the National Diabetes Prevention Program can reduce the risk for type 2 diabetes and reduce pain from arthritis.